Abstract: Background: Although it is a known predictor of mortality, there is a relative lack of recent information about anaemia in kidney transplant recipients. Thus, we now report data about the prevalence and management of post-transplant anaemia (PTA) in Europe 5 years after the TRansplant European Survey on Anemia Management (TRESAM) study. Methods: In a cross-sectional study enrolling the largest number of patients to date, data were obtained from 5,834 patients followed at 10 outpatient transplant clinics in four European countries using the American Society of Transplantation anaemia guideline. Results: More than one third (42%) of the patients were anaemic. The haemoglobin (Hb) concentration was significantly correlated with the estimated glomerular filtration rate (eGFR) (r = 0.4, p < 0.001). In multivariate analysis, eGFR, serum ferritin, age, gender, time since transplantation and centres were independently and significantly associated with Hb. Only 24% of the patients who had a Hb concentration <110 g/l were treated with an erythropoiesis-stimulating agent. The prevalence of anaemia and also the use of erythropoiesis-stimulating agents were significantly different across the different centres, suggesting substantial practice variations. Conclusions: PTA is still common and under-treated. The prevalence and management of PTA have not changed substantially since the TRESAM survey.
Abstract: INTRODUCTION: The prevalence of chronic kidney disease (CKD) stages 3 to 5, defined as eGFR <60 ml/min/1.73 m(2) for more than three months, in the United Kingdom (UK) is 8%. We investigated the incidence of low eGFR and proteinuria in patients attending our large tertiary referral lipid clinic in 2008. METHODS: In 2008, 1,283 patients were seen, of which 1,029 had complete serum lipid and renal profiles. Estimated glomerular filtration rate (eGFR) was calculated for these patients using the 4-variable MDRD formula. The prevalence of low eGFR (eGFR < 60 ml/min/1.73 m(2)) and proteinuria (albumin/creatinine ratio >2.4 mg/mmol or urinary protein excretion >0.06 g/l) was calculated. RESULTS: The prevalence of low eGFR and proteinuria was 11.2 and 19.4%, respectively. The percentage of patients with serum lipid levels within the target range suggested by international guidelines was lower among those with low eGFR and proteinuria than in the entire study population, despite similar proportions being treated with statins across all groups. CONCLUSIONS: The prevalences of low eGFR and proteinuria in a group of 1,029 dyslipidaemic patients attending a large tertiary referral lipid clinic were 11.18 and 19.42%, respectively. These levels are much higher than in the general UK population.
Abstract: Cardiovascular disease including sudden death, myocardial infarction, cardiac arrest, malignant arrhythmias and other cardiac causes is the major cause of death accounting for 43% of all-cause mortality among hemodialysis patients. In addition to increased traditional risk factors, hemodialysis patients also have a number of nontraditional cardiovascular risk factors, which may play a prominent role in the development of sudden death such as left ventricular hypertrophy, coronary artery disease, rapid electrolyte shifts, QT dispersion, sympathetic overactivity, calcium-phosphate deposition. The purpose of the present review was to critically review the current literature to summarize the following aspects: (1) the pathophysiological mechanism responsible for sudden death in hemodialysis patients, and (2) the prevention and management of sudden death in hemodialysis patients.
Abstract: Cardiovascular disease is a major cause of death among patients with chronic kidney disease and vitamin D deficiency is a common problem also among these patients. Abnormalities in left ventricular size and function are frequent, as they are encountered in 70-80% of incident dialysis patients. These alterations develop early in the course of renal disease and their prevalence progresses in parallel with the decline in renal function. This process of left ventricular dilatation with compensatory hypertrophy continues after the institution of dialysis therapy, especially in the first year. The main factors responsible for the progression of left ventricular hypertrophy (LVH) are considered to be blood pressure and anemia, and in patients receiving hemodialysis, the arteriovenous fistula, volume overload and abnormalities in mineral metabolism. This additional potential set of factors related to LVH - mineral and bone metabolism - is intriguing and begs an immediate question: by what possible mechanism can these factors be linked to cardiac morphology? Recent observational studies have indeed indicated that vitamin D treatment was associated with a significant reduction of cardiovascular death among dialysis patients, and a reduction in LVH; in contrast, other studies suggested that excess vitamin D contributes to risk of hypercalcemia and vascular calcification, which is associated with reduced survival and morbidity. This review examines the evidence linking vitamin D with cardiac structure and function.
Abstract: Calciphylaxis/calcific uremic arteriolopathy is rare but an important cause of morbidity and mortality in patients with chronic and end-stage kidney disease with increasing prevalence. Intravenous sodium thiosulfate (STS) has rapidly emerged from a seldom used therapy for the treatment of calciphylaxis/calcific uremic arteriolopathy to a treatment that is being increasingly utilized globally due to multiple positive outcomes shared in the form of case reports and reviews during the past 6 years. Its role as a rather potent antioxidant has uniquely been associated with a prompt decrease in pain and its slower chelating properties are associated with regression of subcutaneous calcifications. Excessive reactive oxygen species (ROS) activate nuclear transcription factor, NF(kappa)B and downstream cytokines resulting in inflammation, which may result in dysregulated hepatic protein synthesis. Indeed, inflammation activates acute-phase reactant synthesis, while concurrently inhibiting synthesis of fetuin-A (an inhibitor of extraosseous calcification) and the antioxidant albumin. Additionally, ROS may decrease locally synthesized matrix GLA proteins and this combination may contribute to increased vascular and subcutaneous calcification. STS used alone or in combination with other novel emerging therapies may result in the improved clinical outcomes in this challenging clinical condition.
Abstract: VC (vascular calcification) is highly prevalent in patients with CKD (chronic kidney disease), but its mechanism is multifactorial and incompletely understood. In addition to increased traditional risk factors, CKD patients also have a number of non-traditional cardiovascular risk factors, which may play a prominent role in the pathogenesis of arterial calcification, such as duration of dialysis and disorders of mineral metabolism. The transformation of vascular smooth muscle cells into chondrocytes or osteoblast-like cells seems to be a key element in VC pathogenesis, in the context of passive calcium and phosphate deposition due to abnormal bone metabolism and impaired renal excretion. The process may be favoured by the low levels of circulating and locally produced VC inhibitors. VC determines increased arterial stiffness, left ventricular hypertrophy, a decrease in coronary artery perfusion, myocardial ischaemia and increased cardiovascular morbidity and mortality. Although current therapeutic strategies focus on the correction of phosphate, calcium, parathyroid hormone or vitamin D, a better understanding of the mechanisms of abnormal tissue calcification may lead to development of new therapeutic agents, which could reduce VC and improve cardiovascular outcome in CKD patients. The present review summarizes the following aspects: (i) the pathophysiological mechanism responsible for VC and its promoters and inhibitors, (ii) the methods for detection of VC in patients with CKD, including evaluation of arterial stiffness, and (iii) the management of VC in CKD patients.
Abstract: Under the auspices of the European Renal Best Practice, a group of European nephrologists, not serving on the Kidney Disease Improving Global Outcomes (KDIGO) working group, but with significant clinical and research interests and expertise in these areas, was invited to examine and critique the Chronic Kidney Disease-Mineral and Bone Disorder KDIGO document published in August 2009. The final form of this paper in Nephrology Dialysis Transplantation, as a commentary, not as a position statement, reflects the fact that we have had no more evidence to review, discuss and debate available to us than was available to the KDIGO working group. However, we have felt that we were able to comment on specific areas where we feel that further clinical guidance would be helpful, thereby going beyond the KDIGO position as reflected in their document. This present paper, we hope, will be of most use to the practising kidney specialist and those allied to the clinical team.
Abstract: Recent trials, and meta-analyses, have cast further doubt on the clinically desirable and safe range for increasing haemoglobin in chronic kidney disease using erythropoiesis-stimulating agents. In this article, I review the current dilemmas we face, suggest key clinical and biological research priorities, and conclude that we need to be brave enough to admit our present shortcomings, and then perhaps adopt a more patient-focused, individualized approach to anaemia management.
Abstract: Cardiovascular disease is the leading cause of mortality and morbidity in patients with chronic kidney disease, which is partly explained by the fact that 40-70% of patients receiving dialysis have significant coronary artery disease. Recent clinical studies have shown that lower serum magnesium (Mg) levels are associated with vascular calcification and cardiovascular mortality among patients with end-stage renal disease (ESRD). On the other hand, hypermagnesemia inhibits parathyroid hormone secretion, which is considered an important independent risk factor for vascular calcification, left ventricular hypertrophy and mortality in ESRD patients. Finally, increasing evidence points towards a link between Mg and cardiovascular disease, even in subjects without chronic kidney disease. The purpose of this review was to critically review the current literature examining the effects of plasma Mg levels on cardiovascular disease and parathyroid hormone homeostasis in ESRD, and renal transplant patients.
Abstract: The recombinant human erythropoietins and allied proteins (epoetin alfa, attempted copies and biosimilar variants of epoetin alfa, epoetin beta, epoetin delta, epoetin zeta, epoetin theta, epoetin omega, darbepoetin alfa, and methoxy-polyethylene glycol-epoetin beta) are among the most successful and earliest examples of biotechnologically manufactured products to be used in clinical medicine. This article charts a brief history of their use in clinical medicine, mainly dealing with chronic kidney disease, paying special attention to how these agents were introduced into clinical medicine and what has happened subsequently; in 2009, there were several developments that could be regarded as a "perfect storm" in terms of the long-term use of these compounds in chronic kidney disease and oncology and, likely, elsewhere. We are now very much at a "crossroads," where mature reflection is required, because with the latest trials and meta-analyses, these therapies seem not only expensive but also very much a clinical tradeoff (increased risk of adverse effects versus a small gain in fatigue scores). How we arrived at this crossroads is a useful illustration of how easy it is, without properly designed randomized, controlled trials, to assume that clinical benefit must follow therapeutic interventions.
Abstract: BACKGROUND: Sirolimus (SRL) has been implicated in the causation of post-transplantation anaemia (PTA). It also induces profound red blood cell (RBC) microcytosis, which is poorly understood. METHODS: We conducted a retrospective study of SRL-induced anaemia and microcytosis [mean corpuscular volume (MCV) <80 fl] with specific reference to iron homeostasis in 93 renal transplant patients treated with SRL for at least 3 months. RESULTS: While mean haemoglobin (Hb) and use of erythropoiesis-stimulating agents increased on SRL, RBC MCV underwent a significant decline throughout the whole study period of 24 months (P < 0.001) with the percentage of microcytosis rising from 2.2% at the start of SRL therapy to 40.7% after 24 months of therapy. An association between dMCV (MCV change on SRL) and SRL levels was shown at 3, 6, 12 and 24 months post-SRL (P = 0.015, P = 0.037, P = 0.002 and P = 0.001, respectively). Intravenous (IV) iron administration was an independent predictor of dMCV at 12 and 24 months on SRL (P = 0.031 and P = 0.048, respectively). All patients who, after starting SRL and seeing a fall in MCV, then went on to receive IV iron therapy, showed a marked increase in MCV; this did not happen to patients given oral iron therapy. CONCLUSIONS: SRL is associated with mild anaemia, but marked RBC microcytosis-these phenomena are correlated with SRL levels and the use of IV iron. Functional iron deficiency and impaired gastrointestinal absorption of iron seem likely explanations.
Abstract: We investigated the association between fibroblast growth factor-23 (FGF-23) and (1) the biochemical parameters implicated in chronic kidney disorder (CKD)-bone and mineral disorder (CKD-MBD) and (2) bone mineral density (BMD) in patients with CKD 1-4. C-reactive protein (CRP) and serum phosphate correlated with FGF-23. A significant association was seen between FGF-23 and BMD at the hip. INTRODUCTION: Circulating FGF-23 is elevated in CKD, although the primary stimulus remains unclear. Moreover, it is still unknown whether increase in FGF-23 has a biological effect on bone metabolism. The aim of the study was to investigate the association of FGF-23 with (1) the biochemical parameters linked with CKD-bone and mineral disorder (CKD-MBD) and (2) bone mineral density in CKD. METHODS: We studied 145 patients (74 M, 71 F) aged (mean [SD]) 53 [14] years with CKD 1-4. Serum calcium, phosphate, parathyroid hormone, FGF-23, 25 (OH) vitamin D, 1, 25 (OH)(2) vitamin D, bone turnover markers, CRP were determined. BMD was measured at the lumbar spine, femoral neck (FN), forearm, and total hip (TH). Multivariate analysis was undertaken to explore the association between (1) the biochemical variables and FGF-23 and (2) FGF-23 and BMD. RESULTS: Elevations in FGF-23 occurred in CKD stage 3 compared to CKD stage 1/2, although no significant differences in serum phosphate were observed. Serum phosphate (p<0.001), CRP (p<0.001) and diabetes mellitus (p<0.05) were associated with FGF-23. BMD Z-score was significantly lower at the TH and FN in CKD 4 (p<0.05). A significant association was seen between BMI, FGF-23, bone specific alkaline phosphatase and BMD at the TH (p<0.05). CONCLUSIONS: The data suggest that FGF-23 may be associated with parameters implicated in the complications of CKD. Longitudinal studies are required for further clinical evaluation.
Abstract: Diabetic nephropathy (diabetic kidney disease) is defined as a rise in urinary albumin excretion rate, often associated with an increase in blood pressure, and typically with concomitant retinopathy but without evidence of other causes of renal disease. It is characterized first by albuminuria and then by a progressive decline in glomerular filtration rate, eventually resulting in end-stage renal disease (ESRD). Diabetic nephropathy occurs in approximately 30-35% of type 1 and type 2 patients and tends to cluster in families. Diabetic kidney disease is associated with a very marked increase in cardiovascular disease and, even from the earliest stages, with microalbuminuria. A diabetic milieu is required for the diabetic glomerular lesion to develop, and the renin angiotensin aldosterone system (RAAS) has been implicated in the development and progression of diabetic nephropathy. Most patients with diabetes and renal impairment die from a cardiovascular disease event before they progress to ESRD. From the studies described in this review, we think that clear evidence of RAAS inhibition in the prevention of diabetic nephropathy is lacking and more studies are warranted. Nevertheless, tight blood pressure control with inhibitor of RAAS and multifactorial intervention (glycaemic, lipid control and so on) are warranted for secondary prevention and treatment of chronic kidney disease in diabetes.
Abstract: Background. Post-transplant anaemia (PTA) is common and is associated with adverse consequences. The protein-energy wasting (PEW) syndrome is associated with erythropoietin resistance in patients on maintenance dialysis. We assessed the association between PEW and PTA in a large prevalent cohort of stable kidney-transplanted patients. Methods. Data from 942 prevalent kidney-transplanted patients were analysed. Socio-demographic parameters, laboratory results, transplantation-related data and medication were obtained from the charts. Biomarkers reflecting nutritional status and inflammation [serum leptin, albumin, interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) and C-reactive protein] were measured. Anthropometric measures and the malnutrition-inflammation score (MIS) were also tabulated. Anaemia was defined according to the guidelines of the American Society of Transplantation. Results. Mean age was 51 ± 13 years, 57% were males and 22% had diabetes. The prevalence of PTA was 33%. The haemoglobin (Hb) level significantly and negatively correlated with the MIS (rho = - 0.316), marginally with serum TNF-α (rho = - 0.079) and serum IL-6 (rho = - 0.075) and positively with serum transferrin (r = 0.298), serum albumin (r = 0.274), abdominal circumference (r = 0.254) and serum leptin (rho = - 0.152), P < 0.05 for all. In a multivariable linear regression model, MIS was independently associated with Hb (beta = - 0.118, P = 0.004) in patients with estimated glomerular filtration rate (eGFR) lower than or equal to 60 mL/min/1.73 m(2), but not in patients with higher eGFR. Conclusions. The MIS is independently associated with PTA in the kidney-transplanted population with eGFR lower than or equal to 60 mL/min/1.73 m(2).
Abstract: BACKGROUND: Chronic volume overload is very frequent in hemodialysis (HD) patients and is directly associated with hypertension, increased arterial stiffness, left ventricular hypertrophy (LVH), heart failure and ultimately with higher mortality and morbidity. One major issue is that presently there are very few comparative studies of the various methods (clinical, bioimpedance, inferior cava vein diameter (ICV) and Brain Natriuretic Peptide (NT-proBNP)) for volume status evaluation and their correlation with cardiovascular disease. METHODS: In 160 patients treated by chronic HD in our center, euvolemic according to clinical assessment, we performed evaluation of volume status through bioimpedance spectroscopy (BIS), ICV and NT-proBNP, as well as echocardiography, to estimate the left ventricle structure and function. RESULTS: Despite appearing clinically euvolemic, severe fluid overload, as defined by a relative tissue hydration (RTH)--i.e. fluid overload over extracellular water ratio (FO/ECW)--above 15% was found in 25.6% of patients. Four categories of patients were considered according to pre-HD BP and BIS values. Forty-five percent of patients (group A) had a reasonable control of BP and volume (SBP < 150 mmHg and RTH < 15%), 29.3% (group B) were classified as hypertensive (SBP > 150 mmHg and RTH < 15%), 16.7% (group C) had high blood pressure and marked volume expansion, (SBP > 150 mmHg and RTH > 15%), while 9% (group D) had SBP < 150 mmHg despite RTH > 15%. Assuming that BIS is the most accurate and validated method to assess hydration status, we calculated the positive predictive value for ICV-based evaluation--18%, with a sensitivity of 67% and an important proportion of false negative cases (45%). NT-proBNP was even less accurate: PPV of only 26%, with a sensitivity of 60% and a specificity of only 45% and an extremely high proportion of false positive cases (73%). Group A patients had the best cardio-vascular profile: lowest LV mass and NT-proBNP levels. CONCLUSION: Using multi-frequency body impedance spectroscopy, we found a large group of hypertensive and/or fluid-overloaded patients despite apparently being at "dry weight" on clinical evaluation and a marked discrepancy between clinical appearance and fluid status. Of the 4 different methods, assuming BCM "gold standard", there were major disagreements and discrepancies between the other three methodologies. BCM is a valuable and simple bed-side tool for the correct management of BP and risk stratification in HD patients as it allows for excellent discriminators of more abnormal cardiac and vascular profiles.
Abstract: The metabolic syndrome is a constellation of defined cardiovascular risk factors occurring simultaneously in a single individual. The result of dysregulated glucose and vascular metabolism, the syndrome has been identified as a significant risk factor for cardiovascular morbidity in the general population. More recently, a relatively high prevalence of the metabolic syndrome has been recognized among kidney transplant recipients. The prevalence, risk factors, pathophysiology, and potential consequences of the metabolic syndrome in the general population and in kidney transplant recipients are reviewed. The definitions and clinical utility of the metabolic syndrome as a medical condition continue to be debated. Nevertheless, the burden of risk increases with the presence of multiple components, including insulin resistance, abdominal obesity, and dysregulated lipid metabolism. Risk factors specific to transplant recipients include the duration of pretransplant dialysis and posttransplant immunosuppression and weight gain. The metabolic syndrome is emerging as a significant surveillance target following kidney transplantation. Control of body mass index, blood glucose and lipid levels, as well as blood pressure, is required to prevent the consequences of the metabolic syndrome, including cardiovascular events and cardiovascular death. Immunosuppressive regimens should be designed to limit exacerbation of components of the metabolic syndrome.
Abstract: BACKGROUND: Chronic kidney disease (CKD) is associated with such complications as fractures and the need for parathyroidectomy. Mineral metabolism control in patients with CKD has been poor. Studies have assessed fractures and parathyroidectomy risk with mineral disturbances, but with considerable diversity in methods. Thus, a systematic review was conducted to assess method or clinical heterogeneity by comparing the design, analytical techniques, and results of studies. STUDY DESIGN: Systematic review of the MEDLINE, EMBASE, and Cochrane databases between 1980 and December 2007. SETTING & POPULATION: Patients with CKD or dialysis patients. SELECTION CRITERIA FOR STUDIES: Observational and clinical trials investigating the risk of fractures or parathyroidectomy with mineral disturbances. PREDICTOR: Mineral metabolism variables (phosphorus, calcium, and parathyroid hormone [PTH] levels). OUTCOMES: Fractures, need for parathyroidectomy. RESULTS: 9 studies were identified that assessed fractures (n = 6) or need for parathyroidectomy (n = 3). Data for fractures or parathyroidectomy risk in predialysis patients are absent. Diversity across studies was observed in populations, methods of exposure assessment, adjusted covariates, and reference mineral levels used in risk estimation. A significant fracture risk was observed with increasing PTH levels. However, additional data are required to understand fracture risk with changes in phosphorus or calcium levels. Data supported greater parathyroidectomy risk with increasing PTH, phosphorus, or calcium levels. LIMITATIONS: Clinical and method heterogeneity across studies precluding the quantitative synthesis of data. CONCLUSIONS: Serious limitations were observed in the number, quality, and method rigor of studies. Despite heterogeneity across studies, data suggest a significant parathyroidectomy risk with mineral disturbances and a fracture risk with increasing PTH levels in dialysis patients. Additional high-quality data for risk of fractures or parathyroidectomy with changes in phosphorus, calcium, or PTH levels is required to highlight the importance of managing such common, but subclinical, conditions as mineral metabolism disturbances.
Abstract: Transplantation remains the cornerstone of proper kidney disease treatments. Prevention of development or progression of chronic kidney disease, in native, or allografted, kidneys is hugely important. We review the issues around cholesterol, lipids and diabetes and therapeutic advances.
Abstract: BACKGROUND AND AIM: Due to increasing evidence suggesting a link between hyperphosphatemia and cardiovascular disease (CVD), mediated through vascular calcification in patients on dialysis, the following question arises: At what stage of chronic kidney disease (CKD) does the relationship between elevated phosphate levels, vascular calcification and increased cardiovascular mortality begin? Therefore, the purpose of the current study was to critically review the current literature regarding this issue. METHODS: We performed a systematic search of the National Library of Medicine and the Cochrane Library databases from January 1985 to February 2008 to identify clinical studies examining the effects of plasma phosphate on cardiovascular outcome, mortality and progression of kidney disease in subjects with and without CKD who have not yet received dialysis. The primary outcome measure was the development of CVD, mortality and progression of kidney disease. RESULTS: Twelve clinical trials investigated the role of serum phosphate levels and adverse outcome (9 studies examining CVD outcome and 3 examining progression of kidney disease). After adjustment for risk factors for mortality, adverse cardiovascular outcome and progression of kidney disease, all studies found a graded independent significant association between phosphate levels and mortality, development of CVD and progression of kidney disease. There was no such association with plasma calcium levels. CONCLUSIONS: There is a graded independent association between serum phosphate levels and mortality, mainly cardiovascular events, and the progression of renal disease in subjects with and without definable (loss of glomerular filtration rate) CKD.
Abstract: Patients with chronic kidney disease (CKD) have significantly increased risks of cardiovascular (CV) morbidity and mortality. Dyslipidemia is a common disorder in CKD patients. CKD patients have a different lipid profile with increased atherogenic lipid fractions, and serum low-density lipoprotein cholesterol (LDL-C) levels may underestimate the atherogenic effect of LDL-C in these patients. Dyslipidemia may contribute to the increased CV morbidity and mortality, and to the progression of kidney disease in CKD patients. Currently, statins are the pharmacologic intervention of first choice, if lifestyle changes fail adequately to lower LDL-C levels in the setting of normal or moderately elevated triglycerides. Statins have been extensively studied in a large variety of patient populations and have proven efficacy in the treatment of dyslipidemia, and in reducing CV mortality. Although much evidence supports the CV benefits of statins in patients with normal renal function, there are contradictory results for the beneficial effect of statin therapy on CV morbidity and mortality in CKD patients. While post hoc subgroup analyses of multiple randomized trials support statin use in early CKD patients, the only randomized trial conducted in diabetic dialysis patients found no evidence of benefit in overall mortality. Post transplant there is some definite CV benefit, albeit in a patient cohort selected to be at reduced CV risk by virtue of being eligible for organ transplant. The results from the AURORA and SHARP studies are awaited anxiously.
Abstract: Direct renin inhibitors are the first new class of antihypertensive to emerge since angiotensin II receptor blockers. We discuss their reno- and cardioprotective potential, based on extrapolation from animal models and phase three trials that are currently ongoing. This paper reviews the potential benefits of direct renin inhibitors (DRIs), the only new anti-hypertensive class developed in the last decade, as compared to pre-existing classes of drug inhibiting more downstream, such as Angiotensin Converting Enzyme inhibitors (ACEI), Angiotensin 2 Receptor Blockers (ARBS).
Abstract: We report a case of post-transplantation lymphoproliferative disorder presenting as a symptomatic lymphocele 12 years after cadaveric renal transplantation for IgA nephropathy. The presentation, imaging, and management are discussed. We review current literature concerning PTLD, posttransplantation lymphoceles, and state-of-the-art imaging techniques.
Abstract: Calciphylaxis-calcific uremic arteriolopathy, is a serious disorder of arteriolar calcification of the arteriole media and is associated with endovascular fibrosis and thrombosis in subcutaneous adipose tissue. It frequently results in severe ischemia, intense pain, and tissue necrosis with nonhealing skin ulcerations. It usually occurs in chronic kidney disease and especially in patients requiring renal replacement therapy. It is associated with a very high mortality rate, and the number of reports and reviews seemed to have increased over the past 5 years. Advances in therapy and salvaging patients from this high mortality risk have recently been reported with the use of sodium thiosulfate. The new application for this old drug used to treat cyanide poisoning and recently preventing neurotoxic effects resulting in hearing loss in those patients with head and neck cancer receiving cisplatin and carboplatin therapy are discussed. Recently, multiple case reports have demonstrated that sodium thiosulfate therapy has resulted in rapid pain relief, healing of skin ulcerations, and prevention of high mortality risk. This emerging treatment and its success are relatively unknown to many physicians. The purpose of this report is to share with others the emerging role of sodium thiosulfate and its new application as a treatment option to be used in combination with other treatment modalities for calciphylaxis-calcific uremic arteriolopathy. Indeed, as with any new treatment this emerging therapy should be studied in greater detail, but this old drug seems to have a new life in the hands of treating physicians.
Abstract: BACKGROUND: Biosimilars or follow-on biologics (FoB) are biopharmaceuticals that, unlike small molecule generic products, are copies of larger, much more complex proteins. As such, data generated from one biopharmaceutical cannot be extrapolated to another. Unlike small molecule generics, FoB require a full developmental programme, albeit smaller than for an originator product. This has been recognized by European regulatory authorities and it is becoming clear that accelerated processes for FoB marketing approval are not feasible. OBJECTIVE: To determine the balance between costs surrounding FoB (including relatively extensive developmental programmes and subsequent price to the market) and the necessity to ensure efficacy and safety. PRINCIPAL FINDINGS: It is important that FoB are sufficiently tested to ensure patient safety is not compromised. Conducting such a development programme followed by sound pharmacovigilance is very challenging and costly. CONCLUSIONS: Cost-savings associated with FoB may be limited.
Abstract: A 36-year-old Nigerian woman on thrice-weekly dialysis presented with symptoms and signs of hypercalcaemia. Laboratory findings were consistent with tertiary hyperparathyroidism. Parathyroid hormone levels remained elevated and she underwent elective parathyroidectomy. Intra-operatively all 4 parathyroid glands and local lymph nodes showed necrotising granulomas with occasional acid-fast bacilli, pathognomonic of tuberculosis (TB). Post-operatively she completed a full course of anti-TB therapy and at 9 months she experienced complete resolution in her plasma biochemistry and was essentially symptom-free. This is a rare yet fascinating cause of hypercalcaemia in a dialysis patient and is the first recorded case of tubercular involvement of parathyroid tissue in a case of tertiary hyperparathyroidism. This report demonstrates the coexistence of 2 diseases that simultaneously worsened hypercalcaemia and thus emphasises the importance of the differential diagnosis and of careful histological examination post-operation.
Abstract: The introduction of recombinant human erythropoietin (rHuEpo) nearly 20 years ago has revolutionised the management of patients with CKD, providing the opportunity for safe long-term anaemia correction without the attendant risks identified with blood products. Based on our expanding knowledge in this area, there are many exciting and innovative new approaches to anaemia correction that stand on, or are close to, the threshold of yielding products ready for clinical use. Recently, an Epo-related molecule called continuous Epo receptor activator has been licensed in Europe, and other molecules are in various processes of development, including Epo mimetic peptide. The search goes on for orally active antianaemic therapies, and several strategies are being investigated. Furthermore, it is now clear that in addition to the anaemia-correction properties of erythropoiesis-stimulating agents, there is the potential for cytoprotection by prevention of cellular apoptosis. This effect could be used in the prevention of ischaemia-reperfusion injury as well as other conditions associated with acute kidney injury and other disease processes. The aim of this article is to discuss these possible future strategies, focusing in particular on those with a reasonable likelihood of a pharmaceutical product that is likely to be used clinically.
Abstract: BACKGROUND: Chronic kidney disease (CKD) is a powerful risk factor for all-cause mortality and its most common aetiology, cardiovascular (CV) mortality. Mineral metabolism disturbances occur very early during the course of CKD but their control has been poor. A number of studies have assessed the relationship between all-cause mortality, CV mortality and events with mineral disturbances in CKD patients, but with considerable discrepancy and heterogeneity in results. Thus, a systematic review was conducted to assess methodological and clinical heterogeneity by comparing designs, analytical approaches and results of studies. METHODS: Medline, EMBASE and Cochrane databases were systematically searched for articles published between January 1980 and December 2007. RESULTS: Thirty-five studies were included in the review. All-cause mortality was the most commonly assessed outcome (n = 29). Data on CV mortality risk (n = 11) and CV events (congestive heart failure, stroke, myocardial infarction) (n = 4) are limited. The studies varied in populations scrutinized, exposure assessments, covariates adjusted and reference mineral levels used in risk estimation. A significant risk of mortality (all-cause, CV) and of CV events was observed with mineral disturbances. The data supported a greater mortality risk with phosphorus, followed by calcium and parathyroid hormone (PTH). The threshold associated with a significant all-cause mortality risk varied from 3.5-3.9 mg/dL (reference: 2.5-2.9) to 6.6-7.8 mg/dL (reference: 4.4-5.5) for high phosphorus, <3 mg/dL (reference: 5-7) to <5 mg/dL (reference: 5-6) for low phosphorus, 9.7-10.2 mg/dL (reference: </=8.7) to >10.5 mg/dL (reference: 9-9.5) for high calcium, </=8.8 mg/dL (reference: >8.8) to <9 mg/dL (reference: 9-9.5) for low calcium and >300 pg/mL (reference: 200-300) to >480 pg/mL (reference: </=37) for PTH. Thresholds at which the CV mortality risk significantly increased were >5.5 (reference: 3.5-5.5) and >6.5 mg/dL (reference: <6.5) for phosphorus and >476.1 pg/mL (reference: <476.1) for PTH. CONCLUSIONS: Serious limitations were observed in the quality and methodology across studies. In spite of enormous heterogeneity across studies, a significant mortality risk was observed with mineral disturbances in dialysis patients. Data on risk in pre-dialysis patients were less conclusive due to even more limited (numerically) evidence.
Abstract: STUDY AIMS: To survey bone mineral disturbances in the hemodialysis (HD) population in Europe and current clinical practice in Europe for the prevention, diagnosis and treatment of secondary hyperparathyroidism (SHPT) in HD patients. PRIMARY OBJECTIVES: First, to estimate the prevalence of Kidney Disease Outcomes Quality Initiative (K/DOQI) guideline achievement in a representative sample of European hemodialysis subjects. As part of this objective, we will investigate the prevalence of achievement by type of dialysis, type of center and time on dialysis (less than or greater than 1 year). Among new dialysis subjects (less than 1 year), we will evaluate prevalence of K/DOQI target achievement until the end of the study. The study will run for 3 years. Second, to estimate the association of bone mineral markers (parathyroid hormone [PTH], calcium [Ca], serum phosphorus [P] and calcium phosphate product [CaxP]) classified by achievement of K/DOQI targets with mortality and overall cardiovascular hospitalization. Third, to characterize the longitudinal changes in bone mineral markers. As part of this objective, we will describe the patterns and predictors of bone mineral markers and achievement, with K/DOQI targets, using repeated measurements on individuals over time. SECONDARY OBJECTIVES: First, To estimate the association of bone mineral markers (PTH, Ca, P and CaxP) classified by achievement of K/DOQI targets with specific cardiovascular outcomes, parathyroidectomy, manifest bone disease (including incidence of symptomatic bone fractures), hospitalizations and vascular access. Second, to evaluate the additional value of albumin and hemoglobin levels in conjunction with bone mineral markers in the prediction of mortality and clinical events.
Abstract: OBJECTIVE: The overall objective of this study was to estimate the costs and outcomes associated with treatment with sevelamer for hyperphosphataemia compared with calcium-based binders. METHODS: Using published data on mortality and hospitalisation rates, a Markov model was developed to predict health outcomes and associated costs for the treatment of hyperphosphataemia using either sevelamer or calcium binders in chronic kidney disease patients who had recently started haemodialysis. Patient outcomes were modelled for 5 years, and incremental cost-effective ratios (ICERs) were calculated for sevelamer relative to calcium carbonate and calcium acetate binders. The perspective adopted was that of the UK National Health Service. RESULTS: The total 5-year discounted treatment cost for patients treated with sevelamer is pound 24,216, while for the calcium carbonate group total cost was pound 17,695. This is an incremental cost of pound 6521 per sevelamer-treated patient over 5 years. Patients receiving sevelamer can be expected to experience 2.70 quality-adjusted life years (QALYs) compared to 2.46 for those treated with calcium carbonate (i.e. an incremental gain of 0.24 QALYs). This results in an incremental cost per QALY of pound 27,120 and an incremental cost per life year gained of pound 15,508. Results were similar with calcium acetate. CONCLUSION: Together with the unique morbidity and mortality benefits, this study suggests that treatment with sevelamer confers clinical benefits with a modest investment of additional economic resources.
Abstract: This editorial review takes an in-depth look to the effect of hemoglobin (Hb) normalization with erythropoietin on quality of life (QoL) in chronic kidney disease (CKD). The analysis of the current available data shows major inhomogeneities in the tools used for assessment of QoL and in data reporting. Furthermore, the major trials on Hb normalization were generally not primarily designed to analyze QoL as a specific end-point. However, current data suggest that only partial correction of anemia with EPO may improve QoL, whereas correction of Hb to above 12 g/dL does not exert any positive effect. Finally, the authors provide recommendations on a more rigorous assessment of QoL in future trials in CKD patients.
Abstract: The mortality rates which we have seen now over several decades of routine provision of renal replacement therapy are truly remarkable - even if, with time, we have become familiar, if not comfortable, with them. The remarkable nature of this mortality issue is its severity, and persistence, despite numerous efforts to combat it with 'active interventions'. These have included, in no particular order, correction of anaemia, better provision of dialysis adequacy, use of more permeable dialysis membranes, better control of dyslipidaemia, better control of mineral and bone metabolic parameters, correction of hyperhomocysteinaemia, and use of ACE inhibitors. One can now in 2008 be forgiven for some pessimism, nihilism (sometimes known as 'renalism') about the prospects for useful prolongation of life on dialysis except of course by transplantation. In this article (a fuller version of which appears also in Nephrology Dialysis and Transplantation, I discuss the reasons for the failure of the trials to date, the likely obstacles to future trials succeeding, and some suggestions for alternative strategies to try to grapple with this immense burden of vascular and all-cause morbidity and mortality.
Abstract: Sevelamer (Renagel), an orally administered metal-free cationic hydrogel polymer/resin that binds dietary phosphate in the gastrointestinal (GI) tract, is approved for use in the US, Europe and several other countries for the treatment of hyperphosphataemia in adult patients with end-stage renal disease (ESRD) on haemodialysis or peritoneal dialysis.Clinical evidence shows that sevelamer was at least as effective as calcium acetate and calcium carbonate at controlling serum phosphorus, calcium-phosphorus product (Ca x P) and intact parathyroid hormone (iPTH) levels, but generally reduced serum calcium levels to a greater extent and was associated with a lower risk of hypercalcaemic episodes than calcium-based phosphate binders. Sevelamer appeared to slow the progression of cardiovascular calcification in patients with ESRD and also had a beneficial effect on serum low-density lipoprotein-cholesterol (LDL-C) levels. In patients receiving chronic haemodialysis, there was no between-group difference in all-cause mortality between sevelamer and calcium-based phosphate binder therapy in the primary efficacy analysis in the large (n >2100), 3-year DCOR trial; in the smaller (n = 109) nonblind RIND trial in patients new to dialysis, data suggest there is an overall survival benefit with sevelamer versus calcium-based phosphate binder treatment. The relative survival benefits and cost effectiveness of these phosphate binder therapies remains to be fully determined. Sevelamer treatment was generally as well tolerated as calcium acetate or calcium carbonate treatment. Overall, sevelamer is a valuable option for the management of hyperphosphataemia in patients with ESRD on haemodialysis.
Abstract: Chronic kidney disease-mineral bone disorder is a common clinical picture encountered in patients with end-stage renal disease and is the result of additive pathophysiological processes. Renal transplantation remains the treatment of choice for these patients, especially as advances in this field have allowed for enhanced allograft survival. However, with increasing success of renal transplantation has come a greater appreciation of some of its subsequent complications, such as posttransplantation bone disease. Recently, persistent hyperparathyroidism and osteopenia-osteoporosis have been given specific attention. Traditionally, persistent hyperparathyroidism has been treated with parathyroidectomy, although the role that calcimimetics may play in the future is promising. Newer aspects to medical management of osteopenia-osteoporosis, such as the efficacy of bisphosphonate therapy and early steroid withdrawal, are becoming apparent and some of the newer drugs for the treatment of osteoporosis are yet to be investigated in this subgroup of patients.
Abstract: CASE REPORT: Septic arthritis due to Klebsiella species is a rare but serious infection that may destroy a joint and cause serious immobility. This is a report of two immunocompromised adult patients presenting with acute septic arthritis due to extended spectrum beta lactamase producing Klebsiella pneumoniae. The infection was treated successfully with a course of meropenem and amikacin in combination with early arthroscopic washout of the joint. Little information has been published on the management of this infection. We are therefore presenting a systematic literature review summarizing risk factors, clinical presentation, laboratory diagnosis, treatment regimens and outcome of this condition. DISCUSSION: On the basis of our study, we recommend an early diagnostic arthrocentesis of the joint for Gram stain microscopy, culture and antibiotic sensitivity testing to guide the appropriate use of antibiotics. In cases of hospital acquired infections where drug resistant Gram negative bacteria are suspected or prevalent, broad-spectrum antibiotics such as meropenem plus or minus amikacin may be given as the empirical treatment until the sensitivities are confirmed. In addition, adequate surgical joint lavage should be considered as the mainstay of treatment.
Abstract: For a long time, the inhibition of the renin-angiotensin-aldosterone (RAA) axis has been considered a must in almost all patients with progressive chronic kidney disease (CKD), with the aim of reducing the rate of progression to end-stage renal disease (ESRD). However, recent data from a meta-analysis, including the ALLHAT study, and a study in Canadian diabetic patients questioned the usefulness of angiotensin converting enzyme (ACE) inhibition in delaying the onset of dialysis. Publication of these data led to an intensive recent debate among reputed nephrologists, with numerous pros and cons regarding the pharmacological influence of CKD progression. The authors of the present review critically discuss the arguments and counterarguments of this challenging debate. Finally, a cautious view for the practicing nephrologist is expressed, highlighting the difference between study patients and real-life patients, and the possible overlooked aspects of recent renal protection studies (the importance of central blood pressure, of ambulatory blood pressure monitoring and possible, the impact of angiotensin converting inhibitors on stroke), are presented.
Abstract: Both chronic kidney disease (CKD) and type II diabetes mellitus (DM) are increasing in frequency among Western populations and both are potent risk factors for the development of anaemia. The presence of CKD and diabetes together represent the most important aetiopathogenic combination for the development of anaemia. New evidence has highlighted some of the underlying mechanisms which make diabetic patients more susceptible to dyserythropoiesis, particularly once they have developed concomitant CKD. In addition, recent publications from large-scale epidemiological studies have highlighted the impact of anaemia on diabetic patients. The purpose of this review was to focus on the pathophysiology and impact of anaemia in DM.
Abstract: Biopharmaceuticals have revolutionized the treatment and management of many diseases. The advent of recombinant erythropoietins has greatly benefited patients with anemia related to chronic kidney disease and cancer, virtually eliminating the need for blood transfusions. Currently, the patents for many biopharmaceutical molecules have expired or are approaching expiration and a number of biosimilars manufacturers are aiming to claim part of the market share. Unlike the situation for synthetic "small molecule" drugs, identical copies of far more complex biopharmaceuticals cannot be produced. A biopharmaceutical can be 100 to 1000 times larger than a synthetic chemical drug, with extremely complex three-dimensional structure and biological functions which are often not completely understood. Due to their nature and complexity, these fascinating therapeutic molecules are products of highly controlled biological processes. This review takes a look at how biosimilars are fundamentally different from their originator products by examining the biopharmaceutical production process and how it can influence the structure and function of the final drug product.
Abstract: Renal dysfunction is uncommon in patients with leukemic infiltration of the kidney due to Chronic Lymphocytic Leukanemia (CLL). Granulomatous interstitial nephritis (GIN) is also rare, but a characteristic hallmark of certain diseases such as sarcoidosis and tuberculosis. GIN has been associated with medications, infections, inflammation, Wegener's granulomatosis, and jejuno-ileal bypass. GIN combined with leukemic infiltration by CLL is very uncommon. We present a 72-year-old male with Binet stage A CLL who developed progressive renal failure over a period of four years requiring maintenance dialysis. During the course of his illness, he underwent renal biopsies at different time intervals, revealing varying degrees of involvement by GIN together with leukemic infiltration.
Abstract: We recently identified an erythrocyte nucleotide accumulating in end-stage renal disease as 4-pyridone-3-carboxamide ribonucleotide triphosphate (4PYTP), a nucleotide never described previously. Plasma tryptophan concentration has been previously reported to be reduced in patients in chronic renal failure that is in turn associated with elevated precursors of tryptophan metabolism, including L -kynurenine and quinolinic acid, both of which have been implicated in the neurotoxic manifestations of chronic renal failure. Here we compare mean erythrocyte 4PYTP, and plasma tryptophan concentrations, in controls and four patient groups with renal impairment (10 per group) and confirmed a reduction in plasma tryptophan in patients on dialysis that corrected with renal transplantation. We found: An inverse correlation between plasma tryptophan and red cell 4PYTP concentrations (R(2)=0.44, P<0.001) when all patients were grouped together. Restoration of both tryptophan and 4PYTP concentrations to control values was only achieved following renal transplantation. 4PYTP was absent from erythrocytes in Molybdenum cofactor (MoCF) deficiency implicating aldehyde oxidase/dehydrogenase, a Molybdenum requiring enzyme. High 4PYTP erythrocyte concentrations in adenine or hypoxanthine-phosphoribosyltransferase deficient patients in severe uremia (113 microM and 103 microM), confirmed the lack of involvement of either enzyme in 4PYTP formation. We propose that 4PYTP is formed by a novel route involving the oxidation of the intermediates of NAD turnover from quinolinic acid by aldehyde oxidase.
Abstract: BACKGROUND: Measures of aortic stiffness--aortic pulse wave velocity (PWV) and augmentation index (AIx)--have been shown to be powerful predictors of survival in adult haemodialysis (HD) patients. Very few data have been reported regarding arterial stiffness in paediatric renal populations. METHODS: PWV and aortic AIx were determined from contour analysis of arterial waveforms recorded by applanation tonometry using a SphygmoCor device in 14 children on HD (age = 14.1 years) and in 15 age, height matched children controls. RESULTS: Pre-HD AIx (29.7 +/- 15.4%) and PWV (6.6 +/- 1.0 m/s) were significantly higher compared with children controls (8.3 +/- 8.0% and 5.4 +/- 0.6 m/s, respectively, P < 0.0001). The only significant difference between normal and HD children was BP level: 103/61 vs 114/72 mmHg, P < 0.05. In children of HD patients, a multiple linear regression model including BP, age, height, weight, Ca and P levels as independent variables accounted for 57% of the variability in AIx. Dialysis had no impact on AIx (post-HD: 28.5 +/- 12.7%) or on PWV (post-HD: 6.7 +/- 0.8 m/s). CONCLUSIONS: We show, in this first-ever report of increased arterial stiffness in children on dialysis, that end-stage renal disease is associated with abnormalities in arterial wall elastic properties, comparable with adult levels, even in childhood. Most importantly, the absence of a discernible amelioration with dialysis implies that purely structural and not functional alterations lie behind the increased arterial stiffness.
Abstract: BACKGROUND: Chronic kidney disease (CKD) patients have a 3-30-fold increased risk of death compared with the general population. This mortality difference is even more pronounced in younger subjects. Two markers of aortic stiffness--aortic pulse wave velocity (PWV) and augmentation index (AIx)--have been prospectively related to all-cause and cardiovascular (CV) mortality in end-stage renal disease (ESRD) populations. The aims of our study were first, to confirm the important deleterious effect of arterial stiffness in uraemia and second, to assess the impact on survival of increased AIx in a relatively young non-diabetic dialysis population, with minimal CV disease. METHODS: Ninety-two patients (mean age 42.6 +/- 11.2 years) were included in the study and followed for a period of 61 +/- 25 months. None of the patients had diabetes mellitus, and only 3.3% had prior history of CV disease. AIx was determined by applantation tonometry using a SphygmoCor device (AtCor, PWV Inc., Westmead, Sydney, Australia). RESULTS: Mean AIx in our study population was 19.9 +/- 13.7%; other significant haemodynamic parameters were: systolic blood pressure (SBP) 129 +/- 24 mmHg, pulse pressure 35.3 +/- 17.5 mmHg with 27.2% of the study population receiving angiotensin-converting enzyme inhibitors (ACE-I). On univariate analysis, in our group AIx correlated with: body weight (P < 0.001), radial SBP (P < 0.001) and haemoglobin levels (P < 0.05). There was no correlation between AIx and any of the echocardiographic parameters. In the stepwise multiple regression analysis, the only independent predictors for AIx were weight (P < 0.001), SBP (P < 0.001) and haemoglobin (P < 0.05) with the model explaining 33% of the AIx variability (adjusted R(2) = 0.33). During the follow-up period, 15 deaths were recorded. In the Cox analysis (P = 0.014; chi square 20.7 for the model) the only independent predictors for all-cause mortality were age (P = 0.001), left ventricular mass index (P = 0.032) and ACE-I therapy (P = 0.039) while AIx did not reach statistical significance. There was no difference in patients' survival when divided by AIx tertiles, assessed by the log rank test (P = 0.78). CONCLUSION: Our results fail to support the notion that an increased effect of wave reflections on central arteries is a strong and independent predictor of mortality in all ESRD patients on haemodialysis. The effect of arterial wave reflections might be in fact dependent on patient age and concurrent comorbidity status.
Abstract: There is increasing evidence that even mild renal dysfunction is a novel potent cardiovascular risk factor in the general elderly population. With more severe renal impairment, cardiovascular risk increases proportionately. This issue deserves attention, as chronic kidney disease (CKD) is predominantly a disease of the elderly, and the mean age of end-stage renal disease patients entering dialysis is growing constantly. In the dialysis population, when clinically significant cardiovascular disease (CVD) (particularly congestive heart failure) is present, survival is worse. Thus, every effort should be made to identify and treat cardiovascular risk factor in the early stages of CKD. However, elderly renal patients receive less proper cardiovascular therapy compared to non-renal subjects of the same age. This review deals briefly with the most significant data published in the last decade on CVD in elderly with CKD.
Abstract: Two organ recipients developed serologic evidence of syphilis infection after renal transplantation from a common deceased donor with a history of treated syphilis. Testing of donor serum for syphilis, which occurred after transplantation, gave results interpreted as consistent with past infection. However, subsequent serologic results in the recipients suggested transmission of infection at transplantation due to active infection of the donor. This may be explained by recent donor re-infection in view of the current syphilis epidemic in the United Kingdom. An initial error in the treatment of recipients further served to highlight unfamiliarity in managing this resurgent infection in the context of organ transplantation.
Abstract: Improvements in patient care and longevity on dialysis programmes together with the increased numbers of patients referred for renal replacement therapy will inevitably result in enlarging numbers of subjects with functioning renal transplants. While this translates to a boon for the patients in terms of survival and quality of life, a very real problem has begun to emerge, that of post-transplantation anaemia (PTA). The prevalence of this condition has been estimated by several studies as varying somewhere between one third and two thirds of all patients, with the same attendant problems as anaemia in the context of chronic kidney disease. PTA is multifactorial in origin and involves interplay between a number of risk factors, not least of all the immunosuppressive protocol. It is the purpose of this article to briefly review the contribution from transplant immunosuppression to PTA and to assess its likely effects on and treatment options for patients.
Abstract: In renal transplantation the calcineurin inhibitors (CNIs) have played a crucial role in the reduction in acute rejection rates. Unfortunately this has not been matched by an improvement in long-term graft survival rate. The development of chronic allograft nephropathy (CAN) is the second most common cause of graft loss, after death from cardiovascular causes. CAN has a multifactorial aetiology that includes immunological and nonimmunological factors relating to both donor and recipient. The use of CNIs has been strongly implicated as a risk factor for the development of CAN. With the ongoing development of new immunosuppressant agents the possibility of avoiding the CNIs now exists. Many studies have been designed to investigate strategies to minimise or avoid CNI exposure and to prolong graft survival. To achieve CNI withdrawal whilst avoiding rejection, additional immunosuppressants need to be substituted into the drug regimen. Long-term side effects of the immunosuppressant used need to be taken into account when drug changes are being considered. In light of current evidence, CNI reduction with optimal use of mycophenolate mofetil appears to be the most effective strategy in managing the patient with CAN.
Abstract: The availability of biopharmaceuticals has been increasing over the past decade and as their patents expire, the emergence of biosimilar agents approaches. The primary issue of concern for the safety of these agents is the potential for immunogenicity. Both product- and host-related factors have documented impact on the immune response, but many factors are still unknown. Although in many cases the presence of antibodies may have little clinical consequence, the upsurge of pure red cell aplasia cases further increased concerns about potential clinical consequences of extensive use of biopharmaceuticals and biosimilars. Available laboratory measurement methods are insufficient to predict biological and clinical properties of biopharmaceuticals, or even to compare their bioequivalence. Comparison of results from different studies is complicated by the variability of assay measurements, presentation of data and lack of standardization.
Abstract: BACKGROUND: Few studies have addressed the description of serial changes in left ventricular mass (LVM) and relevant risk factors. All these studies were initiated before the implementation of EBPG or K/DOQI guidelines. The aims of our study were to prospectively describe trends in left ventricular (LV) structure and function, evaluate risk factors for progression of LVM derived from serial echocardiographic measurements starting January 2003, 6 months after full implementation of EBPG in our unit. METHODS: One hundred seventy-six patients were enrolled at baseline, between 1 January 2003 and 1 October 2004; 33 patients were excluded from analysis due to poor echocardiographic window, 14 patients died and 26 were transplanted or transferred during the follow-up period of minimum 12 months. One hundred and three patients were included in the final analysis (mean age 51 years, mean follow-up 24.1 +/- 14.4 months). Echocardiography was performed at inclusion and at the end of study. Biochemical, blood pressure (BP) and medication data were collected and the means of monthly values were used. RESULTS: At baseline, 86.4% of the patients had left ventricular hypertrophy (LVH) (56.3% concentric hypertrophy, 30.1% eccentric hypertrophy, 6.8% concentric remodeling and only 6.8% normal LV geometry), 25.6% had systolic dy-sfunction and 50.5% had abnormal LV volume index (LVVI). Similar data were recorded at follow-up (82.5%, 44.7%, 37.9%, 7.7%, 9.7%, and 19.5%, respectively). Baseline left ventricular mass index (LVMI) significantly correlated with hemoglobin (Hb) and total protein level. LVMI at follow-up correlated to Hb, SBP, PP, mean level of serum phosphate, calcium x phosphate product and cholesterol. Independent predictors for LVMI (multiple regressions) were anemia and mineral metabolism markers. In our population, 62.1% of the patients had a regression of LVMI, with a mean decrease in LVMI of 12 g/m 2 (1.7 +/- 11.7 g/m 2 /month) over more than 12 months of guideline implementation. Regressors had a significant improvement of anemia, serum phosphate level and calcium x phosphate product (p<0.05). CONCLUSION: Our study suggests that a holistic interventional approach, targeting various pathogenic mechanisms, as per guidelines, can elicit at least a partial regression in LV structural and functional abnormalities in hemodialysis patients.
Abstract: Renal disease is rare today in classic adult gout, and gout is rare in renal disease--especially in the young. Here we summarise studies in 158 patients from 31 kindreds diagnosed with familial juvenile hyperuricaemic nephropathy FJHN from a total of 230 kindred members studied in Great Britain. Some patients have been followed for up to 30 years, and allopurinol has ameliorated the progression of the renal disease in all 113 surviving members provided: They have been diagnosed and treated sufficiently early.Compliance with allopurinol treatment and diet has been as important as early recognition.Hypertension has been rigorously controlled.The use of oral contraceptives has been avoided, as has pregnancy in any female with a Glomelar Filtration Rate GFR <70 ml/min.The question arising is: Why is FJHN the most prevalent genetic purine disorder diagnosed in Britain? Is it a lack of awareness which needs to be improved Europe-wide?
Abstract: BACKGROUND: Clopidogrel, in addition to aspirin, has become a common treatment of acute coronary syndrome and for stent thrombosis prevention, when given before percutaneous transluminal coronary angioplasty. However, some patients turn out to have surgical coronary artery disease and are sent for coronary artery bypass grafting (CABG) where the irreversible effect of aspirin and clopidogrel on platelet function becomes a concern. This study was conducted to evaluate the role of preoperative use of clopidogrel in bleeding complications after CABG. MATERIAL AND METHODS: A total of 462 patients who underwent CABG between 2001 and 2003 were studied as a retrospective cohort. Comparison was made between patients who had taken clopidogrel within 7 days of surgery (n=162), and those who were not exposed to clopidogrel (n=300). Chest tube output and bleeding index (a modified TIMI criteria), were the primary outcomes measured. RESULTS: Our data showed that patients taking clopidogrel within 7 days of surgery have a higher bleeding index than those who were not exposed to the drug (p = 0.024). Similarly, chest tube output was significantly higher in those who were exposed to clopidogrel within 7 days compared to those not taking clopidogrel (p = 0.01). To further dissect this relationship, we divided our population into three categories. We found that patients taking clopidogrel within 3 days prior to CABG (immediate exposure) have a higher bleeding index and TIMI major bleeding than either patients taking the drug between 3 and 7 days (recent exposure) or patients not exposed to clopidogrel at all (p = 0.009 and 0.03 respectively for inter-groups comparison). The same was true for chest tube output (p = 0.05 and 0.01 respectively). CONCLUSION: Clopidogrel increased the risk of post-CABG bleeding if taken within three days prior to surgery but not if taken before that.
Abstract: Anemia in the setting of chronic kidney disease is a well-recognized phenomenon that is associated with decreasing renal function and deficiency of or resistance to erythropoietin. However, anemia in the post-renal transplantation setting has received comparatively less attention in the literature. In this review, we aim critically to appraise the available literature regarding posttransplantation anemia, concentrating in particular on the prevalence of posttransplantation anemia, its etiopathogenesis, potential effects on morbidity and mortality, and the rationale for intervention and treatment. Despite deficiencies in the literature, we conclude that posttransplantation anemia is a common phenomenon that can occur either early or late posttransplantation, and its causation is usually multifactorial and includes contributions notably from poor or decreasing renal function, immunosuppression, and iron deficiency. Conversely, there is a shortage of well-conducted prospective studies looking at the morbidity attributable to posttransplantation anemia and a lack of trial evidence to determine whether intervention improves patient morbidity and outcome.
Abstract: AIMS/HYPOTHESIS: We investigated the relationship between haemoglobin (Hb) and diabetes in patients with renal disease. SUBJECTS, MATERIALS AND METHODS: All adult patients with stable chronic kidney disease attending renal or diabetic outpatient clinics in a six-month period were identified. Patients' notes and electronic patient records were used to build a comprehensive biochemical and clinical database. Results were analysed for the predictors of Hb, the severity of anaemia in both groups and the relative impact of diabetes on haemoglobin and anaemia. RESULTS: The study group consisted of 468 patients, of whom 204 had diabetes and 264 did not. At every level of renal function haemoglobin levels were lower by an average of 10 g/l in subjects with diabetes than in those without. Likewise, anaemia was found to occur at an earlier stage of chronic kidney disease (and to be of greater severity) in diabetic patients. Independent predictors of haemoglobin included female sex, diabetes, renal function and serum albumin, with diabetes and renal function being the greatest predictors. Multiple logistic regression showed that patients with diabetes had an odds ratio of 4 for being anaemic. Had we used an estimated GFR of less than 60 ml/min to trigger investigation of anaemia, we would have detected 85% of anaemic patients. CONCLUSIONS/INTERPRETATION: Anaemia is frequently found in diabetic patients with renal disease, occurs earlier and is more severe than in similar but non-diabetic subjects. In contrast to previous publications, our findings suggest that anaemia is prevalent at the earliest stages of chronic kidney disease. We advocate an estimated GFR threshold of <60 ml/min to trigger investigation for anaemia in diabetic subjects.
Abstract: BACKGROUND: The commonest cause of renal transplant loss is death with a functioning graft, usually from an excess of cardiovascular disease (CVD). Anaemia is becoming increasingly recognized as a reversible risk factor for the development of CVD. The purpose of this study was to estimate the prevalence of post-transplantation anaemia (PTA) in a large population of stable adult and paediatric renal transplants in one centre and to correlate the estimated glomerular filtration rate (eGFR), iron indices and the use of immunosuppressants with the prevalence of anaemia. METHODS: Every adult and paediatric patient with a functioning renal transplant and more than 3 months post-engraftment at Guy's hospital, London, as of 31 December 2004 and who had a valid creatinine and haemoglobin, in the period 1 September-31 December 2004 inclusive, was identified. A large database of clinical and biochemical indices was built up on the basis of medical notes and electronic patient records. Results were analysed for the prevalence of anaemia and risk factors for its development. Anaemia was defined according to the WHO criteria. All patients on treatment with an erythropoiesis stimulating agent were classified as anaemic, irrespective of haemoglobin. RESULTS: A total of 878 adults and 73 children were identified. Mean haemoglobin in adults was 12.9 +/- 1.6 g/dl and 11.8 +/- 1.4 g/dl in the children. Mean eGFR was 49.3 +/- 20.1 ml/min in adults and 65.7 +/- 18.8 ml/min in the paediatric cohort. Haemoglobin correlated positively with the eGFR in both cohorts (R = 0.33 and 0.29 in adults and children, respectively (P < 0.0001 for both)). We identified anaemia in 45.3% of adults and 22% in children. Ferritin levels were lower in children than in adults (79 +/- 93 vs 204 +/- 353 mg/l), but were higher in both cohorts among the non-anaemic populations than in those with anaemia. 58% of adults taking mycophenolate mofetil (MMF) were anaemic compared with 22% of children. One child, and 68 adults, were on recombinant erythropoietin. Multiple regression analyses identified age, female gender, eGFR and serum ferritin levels as independent predictors of haemoglobin in adult subjects. CONCLUSIONS: The prevalence of PTA was high in both adult and paediatric cohorts while comparatively few patients were being treated with erythropoiesis stimulating agents. The strongest predictors of haemoglobin in this cohort of patients were age, female sex and graft function. Immunosuppression including MMF or sirolimus was associated with a higher prevalence of anaemia, but this was likely to be the result of poorer graft function in these subjects. Iron deficiency did not seem to be a causative factor for anaemia in this population.
Abstract: OBJECTIVE: To report the largest single series of renal transplant patients (adults and children) with urolithiasis, assess the risk factors associated with urolithiasis in renal transplant recipients, and report the outcome of the multimodal management by endourological and open procedures. PATIENTS AND METHODS: The records of all patients undergoing renal transplantation between 1977 and 2003 were reviewed. In all, 2085 patients had a renal transplant at our centre and 21 (17 adults and four children) developed urinary tract calculi. Their mode of presentation, investigations, treatments, complications and outcomes were recorded. Investigations included one or more of the following; ultrasonography (US), plain abdominal X-ray, intravenous urography, nephrostogram and computed tomography. Management of these calculi involved extracorporeal shock wave lithotripsy (ESWL), flexible ureteroscopy and in situ lithotripsy, percutaneous nephrolithotomy (PCNL), open pyelolithotomy and open cystolitholapaxy. RESULTS: Thirteen patients had renal calculi, seven had ureteric calculi and one had bladder calculi. The incidence of urolithiasis was 21/2085 (1.01%) in the series. Urolithiasis was incidentally discovered on routine US in six patients, six presented with oliguria or anuria, including one with acute renal failure, four with a painful graft, three with haematuria, one with sepsis secondary to obstruction and infection and in one, urolithiasis was found after failure to remove a stent. Ten patients (63%) had an identifiable metabolic cause for urolithiasis, two by obstruction, two stent-related, one secondary to infection and in six no cause was identifiable. Thirteen required more than one treatment method; 13 (69%) were treated by ESWL, eight of whom required multiple sessions; eight required ureteric stent insertion before a second procedure and four required a nephrostomy tube to relieve obstruction. Two patients had flexible ureteroscopy and stone extraction, three had a PCNL and one had open cystolithotomy. PCNL failed in one patient who subsequently had successful open pyelolithotomy. All patients were rendered stone-free when different treatments were combined. CONCLUSIONS: The incidence of urolithiasis in renal transplant patients is low. There is a high incidence of metabolic causes and therefore renal transplant patients with urolithiasis should undergo comprehensive metabolic screening. Management of these patients requires a multidisciplinary approach by renal physicians, transplant surgeons and urologists.
Abstract: According to recent data, arterial stiffness is a major independent risk factor for cardiovascular morbidity and mortality in both the general and renal populations. Because of several factors (vascular calcifications among them), large arteries are stiffer in patients with chronic kidney disease compared with the nonrenal population, contributing to the enormous cardiovascular mortality in renal patients. This review briefly analyzes methods for determination of arterial stiffness, focusing on 2 parameters, pulse wave velocity and the augmentation index, particularly useful in assessing arterial compliance in renal patients. Effects of different methods of renal replacement therapy on arterial wall properties also are discussed. Finally, the most promising novel and/or potential therapies regarding reduction of arterial stiffness in renal patients are reviewed.
Abstract: BACKGROUND: Chronic allograft nephropathy (CAN) is the most common cause of long-term renal-allograft dysfunction and the second most common cause of transplant loss. There are concerns that prolonged patient exposure to calcineurin inhibitors (CNIs) exacerbates or promotes the process of CAN. METHODS: In our unit, we carried out an observational study over the period 2000 to 2003 using low-dose mycophenolate mofetil (MMF) to facilitate a phased reduction in the dose of CNI in a group of patients with CAN. Low doses of MMF were chosen to minimize adverse effects and to reduce levels of CNIs without the attendant risks of under-immunosuppression. RESULTS: A step-wise reduction in mean reciprocalised creatinine was evident over the run-in period (mean 1/creatinine before MMF=0.005739-0.000083*month; R=0.77) with a step-wise monthly improvement postintroduction of MMF and dose reduction of CNI (mean 1/creatinine after MMF=0.004609+0.000049*month; R=0.74) (P<0.0001). The mean Cockroft-Gault estimated creatinine clearances were 47.1+/-24.2, 37.2+/-16.3, and 41.6+/-21.1 mL/min at time [t]=-12, t=0 and t=+12 months, respectively. Low-dose MMF therapy was well tolerated (only 7/89 patients stopped MMF because of side-effects in the first 12 months), and acute rejection was noted in only one patient. At latest follow-up, only 17 transplant losses had occurred, of which 6 patients had died with a functioning graft. CONCLUSIONS: Low-dose MMF was well tolerated and resulted in prolonged graft survival.
Abstract: Increased aortic stiffness-measured as aortic augmentation index (AIx), a global stiffness marker-has emerged as a powerful predictor of survival in hemodialysis (HD). A single HD session is known to produce considerable improvement in aortic stiffness. We set out, for the first time, to examine the relative contributions to the post-HD drastic improvement in aortic stiffness of ultrafiltration rate and volume, or blood pressure (BP) changes. Aortic AIx (difference between the first and the second systolic peak of the aortic pressure waveform divided by pulse wave height) was determined hourly and recorded by applanation tonometry using a SphygmoCor device in 20 chronic HD patients (9 males, age 55.1 years). The other parameters recorded were: weight pre- and post-HD, ultrafiltration volume (UFV), hemoglobin, albumin, creatinine, urea reduction rate (URR), calcium and PTH, and BP. The dialysis significantly decreased AIx from 24.2+/-11.27% to 15.57+/-12.58% (p<0.05). In a univariate analysis, the intradialytic decrease in AIx (AIx 0-4) did not correlate with UFV, URR or with any of the biochemical markers. Significant correlations for AIx 0-4 were age (p=0.018), systolic blood pressure (SBP) at the beginning of HD (p=0.049), the intradialytic decrease in the SBP (p=0.001), and in pulse pressure (PP) (p=0.009). Multivariate stepwise regression showed that the decrease in SBP, PP, and intradialytic percentage reduction in weight explained 64.9% of the total variation in AIx 0-4. The decrease in SBP was the most important factor influencing the AIx variation (b=1.54, p=0.007). The most significant reduction in AIx was from the beginning of HD to the third hour (p=0.039), and correlated with the reduction in SBP (p=0.006) and PP (p=0.025) between the same moments. A single HD session produces a drastic improvement in aortic stiffness. The effect is not explained by the UFV depletion but is highly correlated with the decrease in SBP and PP. Further work is now needed to explore a potential role for endothelin and nitric oxide metabolism.
Abstract: Development of microalbuminuria increases the risk for cardiovascular disease (CVD) in type 2 diabetes. The nature of this relationship is unclear but may involve arterial stiffness, an independent risk marker for CVD mortality. Aortic pulse wave velocity (Ao-PWV) and albumin creatinine ratio (ACR) were measured in 134 consecutive patients with type 2 diabetes without overt renal impairment (serum creatinine <150 micromol/L). ACR ranged from 0.2 to 153 mg/mmol. Patients with raised ACR (>/=3 mg/mmol) had higher Ao-PWV, poorer diabetic control, and higher pulse pressure (PP) and systolic BP (SBP) (all P < 0.05) than those with normal ACR. The closest univariate associations of Ao-PWV were positively with age, duration of diabetes, SBP, PP, ACR, and insulin treatment and negatively with GFR and weight (all P < 0.01). In a multiple linear step-down regression analysis, the significant predictors of Ao-PWV were age, SBP or PP, duration of diabetes, gender, number of antihypertensive medications, and use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, which together explained 55% of the variance of Ao-PWV. When ACR was offered in place of arterial pressure to a separate model, ACR emerged as a significant predictor of Ao-PWV. After age adjustment, patients with lower, below median GFR had higher Ao-PWV than those with GFR above the median (P = 0.043). In patients with type 2 diabetes without overt renal impairment, raised ACR is associated with higher Ao-PWV, a relationship most likely mediated by raised BP. The association of Ao-PWV with reduced GFR suggests that even modest renal dysfunction may affect the viscoelastic properties of large arteries.
Abstract: BACKGROUND: Increased aortic stiffness markers - aortic pulse wave velocity (PWV) and augmentation index (AIx) - are powerful predictors of survival in ESRD patients - well-recognized for the high prevalence of coronary artery disease (CAD) and unusually high PWV and AIx. Recently, decreased aortic compliance has been shown to be predictive of primary coronary events in hypertensive patients with normal renal function. We aimed to explore relationships between arterial stiffness and CAD in cohorts of patients with chronic kidney disease (CKD). METHODS AND RESULTS: 46 patients with chronic kidney disease (33 males, aged 55.7+/- 13.2 years, 20 on dialysis, 18 post renal transplantation, and 8 with glomerular filtration rate (GFR) between 10 and 25 ml/min) underwent coronary angiography for the assessment of CAD. PWV and aortic AIx were determined from pulse waveform analysis of arterial waveforms recorded by applanation tonometry using a SphygmoCortm device. The atherosclerosis burden score was calculated by adding the percentage luminal reduction of the most severe lesion in each artery. Patients with normal angiograms had significantly less arterial stiffness (as reflected by both a lower PWV=8.42+/-1.53 m/s and a lower AIx=17.9+/-5.55 %) compared with the 35 subjects with evidence of obstructive coronary disease at angiography (PWV=9.21+/-1.15 m/s and AIx=23.4+/-5.4 %, P<0.05 for both). Moreover, as more coronary vessels were affected, PWV and AIx increased proportionally. Based on receiver operating characteristics (ROC) curve analysis mean PWV levels showed an optimal cut-off point at 8.35 m/s (sensitivity=0.77; specificity=0.60), while mean AIx levels showed an optimal cut-off point at 17% (sensitivity=0.87; specificity=0.70). There was a statistically significant linear relationship between the atherosclerosis burden and both measures of arterial stiffness: PWV (r=0.31, p=0.007) and AIx (r=0.46, p=0.003). Independent predictors for the arterial stiffness parameters in this CKD population (multiple stepwise regression analysis) were age (r=0.69 for PWV and r=0.62 for AIx), and mean arterial pressure (MAP) (for AIx, p<0.0001). CONCLUSION: This study provides the first direct evidence in a cross-sectional investigation that PWV and AIx are related to the extent of coronary obstruction in CKD patients.
Abstract: Given the potency of modern immunosuppressive agents, kidney transplantation across alloantingen barriers is a routine phenomenon with excellent 1-year graft survival in most centers. However, the improvement in 1-year graft survival has not been matched by improvements in long-term graft function and chronic allograft nephropathy (CAN) remains the second commonest cause of graft attrition over time. Calcineurin inhibitors, namely cyclosporine A (CyA) and tacrolimus, have been implicated as causal agents in the development of the fibrotic processes that are the hallmarks of CAN. Many studies have, therefore, concentrated on the improvement of long term graft function through the modulation of immunosuppressive therapy. It is the purpose of this review to describe and appraise the available evidence for the prevention and management of CAN through modulation of immunosuppressive agents.
Abstract: BACKGROUND: Abnormalities of diurnal blood pressure (BP) rhythm ("nondipping") are well-described in dialysis patients, and have prognostic importance. It is controversial whether successful renal transplantation (RTx) improves diurnal BP rhythm. To date, no study has attempted to define and model the evolution of diurnal BP rhythm profiles from dialysis to engraftment, focusing on the immediate (4-6 weeks) and medium-term (>1 year) postengraftment periods. METHODS: To test if kidney transplantation normalizes the BP profile, ambulatory blood pressure monitoring (ABPM) was performed in 20 living related transplants (age, 30.3+/-5.1 years; 11 males, on dialysis for 25.6 months) 1 month preRTx and repeated 1 month and >1 year (ABPM3) after successful RTx. Dipping was defined as a sleep-to-awake ratio>0.92 (for systolic BP) and >0.90 (for diastolic BP). RESULTS: PreRTx only 15% patients were dippers. At 1 month postRTx (creatinine clearance, 65.8 ml/min), all patients were complete nondippers. However, after >1 year postRTx (creatinine clearance, 70.4 ml/min), 40% were now dippers. Most importantly, overall, 30% of the patients improved significantly their circadian rhythm (35.3% of the initial preRTx nondippers). Despite successful renal transplantation, 55% patients maintained unchanged their nondipping profile throughout all three ABPM recordings. The only determinants of "long-term" postRTx circadian rhythm are the contemporary level of the renal function and the baseline, dialysis dipping profile: SBP3 sleep-to-awake ratio is related with serum creatinine3 (r=0.58, P=0.001), creatinine clearance (r=-0.41, P=0.036) and SBP1 sleep-to-awake ratio (r=0.48, P=0.034); similarly DBP3 sleep-to-awake ratio is related with serum creatinine3 (r=0.63, P=0.001), creatinine clearance (r=-0.471, P=0.036) and SBP1 sleep-to-awake ratio (r=0.53, P=0.016). In all, 57% of the variance in dipping status can be attributed and explained by the contribution of renal function and initial circadian variability. CONCLUSIONS: Half of the nondipper dialysis patients maintain a permanently abnormal circadian rhythm, despite successful RTx. In the short term, RTx is associated with a highly abnormal diurnal profile, exclusively related to ciclosporin dose and levels. However, in the longer term, renal transplantation leads to a significant improvement of the circadian blood pressure profile, influenced by the renal function level and by the pretransplantation dipping profile.
Abstract: BACKGROUND: CyA A (CyA) may induce intrarenal vasoconstriction, endothelial dysfunction, and hypertension. There are only two contradictory reports describing the acute effect of CyA on renal resistances measured by color Doppler flowmetry. Therefore, we studied the acute influence of oral CyA on arterial haemodynamics by assessing simultaneous changes in blood pressure, applanation tonometry-derived pulse wave analysis and duplex ultrasound-derived intrarenal resistance indices. METHODS: Augmentation index (AIx) (difference between the first and second systolic peak on the aortic pressure waveform divided by the pulse pressure = AIx) was determined from contour analysis of arterial waveforms recorded by applanation tonometry using the AtCor device in 18 live-related renal transplants (11 females/7 males, age = 32.0 +/- 8.1 years, transplantation duration = 17.5 +/- 16.1 months, and mean serum creatinine = 133 +/- 70 micromol/L). All studies were performed just before (C0), and 2 hours after (C2) the oral administration of CyA. At the same C0 and C2 moments the resistive index (RI) = (peak systolic frequency shift - minimum diastolic frequency shift)/peak systolic frequency shift, and pulsatility index (PI) = (peak systolic frequency shift - minimum diastolic frequency shift)/mean frequency shift were calculated from Doppler recorded waveforms. RESULTS: Blood pressure and heart rate did not differ significantly at C0 and at C2 serum levels: 134.3/82.9 vs. 128.1/80.0 mm Hg and 72.0 vs. 71.0 beats/min, respectively, despite a marked increase in whole blood concentration (CyA(C0)= 90.8 +/- 45.9 vs. CyA(C2)= 547.4 +/- 251.3 ng/mL) (P= 0.05). Mean AIx fell significantly from 17.2 +/- 13.8 to 12.9 +/- 14.2 (P < 0.0001). There was no correlation between the extent (expressed as absolute or relative change) of the measured alteration in AIx and total administered CyA dose, or increment in blood level between C0 and C2. In support, the intake of CyA did not induce a significant increase in Doppler resistance (RI(C0)= 0.68 +/- 0.08 vs. RI(C2)= 0.70 +/- 0.09) and pulsatility indices (PI(C0)= 1.32 +/- 0.31 vs. PI(C2)= 1.33 +/- 0.28). Finally, three patients were studied twice (>1 week): one under two levels of creatinine, one with no antihypertensives, and a third receiving verapamil initially. All these maintained a significant decrease in AIx at C2 from C0 supporting the reproducibility of the phenomenon. CONCLUSION: We demonstrate that Neoral CyA acutely improves large arterial compliance function and does not induce an acute rise in intrarenal resistance in stable renal transplant subjects with normal renal function. We speculate that there may be an effect of vitamin E, the diluent vehicle in which CyA is carried (1000 IU/100 mg CyA), shown to improve endothelial function.
Abstract: Cardiovascular disease (CVD) is one of the major causes of mortality in patients with renal diseases, with increased odds ratio of mortality with risk factors as diverse as cholesterol, vascular stiffness, chronic inflammation and hyperhomocysteinemia. Several factors have been incriminated to explain the increase in coronary vascular calcification (CVC) in this particular population. Increased duration of dialysis, dyslipidemia, altered calcium-phosphorus metabolism, and chronic inflammation have all been associated with increased CVC. We present here four case reports illustrating the differences in the pathophysiology, therapy and prognosis of calcific coronary heart disease seen in uremic patients.
Abstract: Rifampicin re-administration may cause immunologically mediated acute tubulo-interstitial injury. Retrospectively, 170 consecutive cases with acute renal failure (ARF) following re-treatment with rifampicin (71% males, 29% females, age 21 to 68 years) were analysed, which accounted for 12% of all ARF patients treated by two large dialysis referral centres in Romania, Timisoara and Iasi, between 1974-2001 and 1988-2001, respectively. The most frequent clinical features of rifampicin-induced ARF were: Anuria, gastro-intestinal (abdominal pain, nausea, vomiting and diarrhoea) and "flu-like" symptoms. Urine analysis revealed sterile leucocyturia in 54%, proteinuria in 31%, haematuria in 26% and haemoglobinuria in 7% of cases. Haemolytic anaemia was frequent, found in 66% of the patients; half of these had Hct values of < 30%, thrombocytopenia and also more severe renal damage (a longer anuric phase and a slower recovery of the renal function), thus suggesting a severe multi-target autoimmune aggression. The association of hepatic injury--not explained by prior hepatic disease, B or C hepatitis virus infection or history of alcohol abuse--was encountered in 17% of the cases, without a significant influence on the renal and the general outcome. The outcome of rifampicin-induced ARF is generally favourable, with complete recovery of the renal function within 30 days in 52% of the cases and within 90 days in 92% of the cases. The mortality rate was 3.5%, compared to 21% for the overall ARF population treated during the same period (p < 0.05).
Abstract: BACKGROUND: Coronary artery calcification (CAC) measured by electron beam computed tomography (EBCT) correlates with plaque burden, vessel stenosis and is predictive of future cardiac events in the general population. Extensive CAC has been described recently in dialysis cohorts. For the first time we studied the relationship between CAC and coronary angiographic findings in patients with chronic renal failure, on dialysis and after renal transplantation. METHODS: We studied 46 patients who all had an EBCT-derived Agatston coronary calcium score and a diagnostic coronary angiogram within a 12-month period. The mean age was 55.7+/-13.2 (SD) years (range 29-80). The mean duration of dialysis was 54.4 months (range 1-372). RESULTS: The mean CAC was 2370+/-352.8. The mean CAC in patients with an abnormal coronary angiogram (n = 35) was 2869.6+/-417.9, while that in patients with a normal coronary angiogram (n = 11) was 559.4+/-255.1 (P = 0.001 for the inter-mean comparison). Total CAC correlated with the number of diseased vessels (P = 0.0001) and with severity of atherosclerosis in all the vessels (P = 0.0001). The individual coronary artery calcification score correlated well with the severity of atherosclerotic coronary disease (P<0.0001 for all) in the left anterior descending, right coronary and circumflex arteries. Running a multivariate regression analysis for atherosclerosis burden, we found that the only predictor was CAC (r = 0.34, P = 0.0001). CONCLUSION: CAC is common and more severe in patients with chronic kidney disease. Although in chronic kidney disease patients CAC can occur in the absence of occlusive coronary atherosclerosis, our data suggest that, as in the general population, CAC in chronic kidney disease patients is associated with obstructive atherosclerosis and may therefore be associated with a worse outcome.
Abstract: BACKGROUND: Patients with end-stage renal disease (ESRD) are at increased risk of cardiovascular mortality and morbidity. Many complications arise in ESRD patients as a result of the twin arterial pathologies of atherosclerosis and arteriosclerosis. Part of this latter process is calcification of the arterial media, which is thought significantly to increase vascular stiffness. The aim of our study was to explore the relationship between measures of arterial stiffness-pulse wave velocity (PWV)-and the extent of calcification in the coronary arteries (CAC). METHODS: Over a period of 2 years 82 patients from our renal unit were invited to participate in our study. Sixty-two patients agreed to undergo electron beam computerized tomography (EBCT), and in 55 (38 males and 17 females), PWV measurements were made. EBCT and PWV measurements were done according to previously described protocols. RESULTS: The mean age of the 55 patients was 56.4 years. The mean duration of dialysis was 65.4 months, and the mean CAC score was 2551. The mean PWV was 9.13 m/s. PWV strongly correlated with total CAC even after correction for age, dialysis duration, and time averaged C-reactive protein (CRP) (P= 0.0001). CAC scores were significantly different when compared according to PWV tertiles (P= 0.0001). CONCLUSION: We have demonstrated that PWV is strongly related to the degree of EBCT-derived coronary artery calcium score in chronic kidney disease patients.
Abstract: BACKGROUND: Cardiovascular disease (CVD) is more common in patients with renal failure, even after renal transplantation. We wished to examine the relationship between markers of inflammation and CVD in stable renal transplant patients. METHODS: Ninety stable renal transplant outpatients with no recent illnesses or rejection were invited for study. Blood was drawn for a variety of inflammatory markers including total plasma sialic acid (SA) levels. RESULTS: Patients with CVD were significantly older than patients without (54 +/- 12 vs. 42 +/- 14 yr, p < 0.01) and had significantly lower total cholesterol (4.5 +/- 1.6 vs. 5.1 +/- 1.0 mmol/L, p < 0.01). Time from transplantation, present creatinine and blood pressure, smoking history were similar in both groups. Patients with CVD had significantly higher levels of SA (89.2 +/- 22.3 vs. 77.4 +/- 13.9 mg/dL, p = 0.01); fibrinogen [4.6 (2.2-6.7) vs. 3.6(1.9-5.7) g/L; p = 0.05); and C-reactive protein (CRP) [2.2 (1.5-8.0) vs 1.5 (0.7-3.0) microg/dL] than those without CVD. A logistic multiple linear regression analysis of the data with CVD as the dependent variable, and all the other parameters as independent variables, showed significant associations (F = 16.9; p < 0.001) with diastolic blood pressure (beta = 5.6; p = 0.02) and CRP (beta = 4.4; p = 0.04). CONCLUSIONS: This study suggests that inflammation is associated with a higher prevalence of cardiovascular disease in patients with renal allografts. The measurement of sialic acid as a risk factor may be superior to that of CRP in this group as its concentration is independent of renal function.
Abstract: BACKGROUND: Increased aortic stiffness markers--aortic pulse wave velocity (PWV) and augmentation index (AIx)--have emerged as powerful predictors of survival in haemodialysis (HD). Various and often contradictory abnormalities of endothelium-dependent (ED) and endothelium-independent (EID) vasomotor function, have been described in dialysis subjects, pre- and post-dialysis, using methods that are difficult to export to the clinical setting or to large prospective trials assessing their relevance. Therefore, we determined the influence of a HD session on PWV and the ED and EID vascular reactivity, employing pulse wave analysis (PWA) of the aortic waveforms, combined with provocative pharmacological stimuli known to reduce wave reflection. METHODS: PWV and aortic AIx (difference between the first and second systolic peak on the aortic pressure waveform divided by the pulse wave height) were determined from PWA of arterial waveforms recorded by applanation tonometry using a SphygmoCor device in 41 HD (20 males, age 41.8 years) and in 20 controls with essential hypertension (10 males, age 43.6 years). ED and EID vascular reactivity were assessed by changes in AIx following inhaled salbutamol and sublingual nitroglycerin (GTN), respectively, pre- and post-dialysis session. Echocardiography was performed in all patients, pre-HD and before the PWV recordings. RESULTS: Pre-HD AIx (27.9+/-11.9%) was significantly higher compared with hypertensive patients with normal renal function (16.5+/-17%, P<0.05). Dialysis significantly reduced AIx to 18.2+/-18.3% (P<0.05 compared with pre-HD AIx), a level comparable with non-renal subjects (P = NS). Overall, PWV increased following HD to 7.89+/-2.09 m/s (P = 0.004 vs pre-HD, 6.34+/-1.32 m/s in essential hypertensive patients, P<0.05); however, a 19.1% increase was seen in 29 subjects and a 9.1% decrease in the remaining 12 subjects, both P<0.05. In HD patients, either pre- or post-HD, the EID vascular reactivity is significantly greater than the ED vasodilatation elicited by a beta 2-agonist. Moreover, when compared with hypertensive patients with normal renal function, the dialysis session only improved the EID abnormality (post-HD GTN AIx(HD) = -20.8+/-22.9% vs post-GTN AIx(hypertensive) = -14.2+/-5.7%, P = NS), while it had a non-additive effect on the ED response. A smaller response to a GTN challenge was associated with a greater left ventricular mass: r =-0.42, P = 0.007. In contrast, a diminished response to a beta 2-agonist did not represent a marker for cardiac abnormalities. CONCLUSIONS: The HD session acutely restores EID but not ED vasomotor function comparable with essential hypertensive patients. Pulse-wave analysis methodology, combined with provocative pharmacological testing may be used to unveil subsets of patients with more severe cardiac structural abnormalities.
Abstract: BACKGROUND: Coronary artery calcification measured by electron-beam computerized tomography (EBCT) correlates with plaque burden and vessel stenosis and is predictive of future cardiac events in the general population. Uremic vascular calcification is common and widespread, tends to be medial as well as intimal, and may not relate solely to atherosclerotic lesions. Despite this difference and in the absence of any direct evidence in uremic patients, it is generally implied that coronary artery calcification equates to occlusive atherosclerosis. METHODS: We set out to compare the predictive value of coronary artery calcification assessed by EBCT with contemporaneous coronary angiography. We studied 18 patients with end-stage renal disease undergoing maintenance dialysis. Seventy-two coronary vessels were analyzed for angiographic evidence of stenotic disease and correlated with individual vessel calcification score. RESULTS: There was no significant correlation between degree of vessel stenosis and calcification score for individual vessels in patients with a positive calcium scan. Specificity was 48% and the positive predictive value was 53%. However, a calcification score <20 strongly correlated with the absence of significant luminal narrowing, and a 0 calcification score had a negative predictive value of 87.5%. CONCLUSION: Coronary artery calcification measured by EBCT is not an accurate marker of the degree of vessel stenosis in coronary artery disease in uremic patients and should not be used as a single screening test for atherosclerotic coronary disease.
Abstract: Elevated blood pressure and diurnal blood pressure variation detected by ambulatory blood pressure monitoring has been shown to be predictive of worse outcome in end-stage renal disease patients in small studies. What has been lacking is a large study to determine whether these ambulatory blood pressure monitoring (ABPM)-derived variables are predictors of worse outcome in renal transplant recipients. All the patients that underwent renal transplantation and follow up at this institution from January 1998 till October 2002 were involved in this study (n=177). All patients were followed up for at least 48 weeks. Last creatinine correlated positively with duration of dialysis (p=0.035, r=0.158), kidney-donor age (p<0.0001, r=0.377), early kidney function (p<0.0001, r=0.610, r=0.683), 24-h systolic blood pressure (SBP) load (p=0.002, r=0.228), and ABPM-derived pulse pressure (p<0.0001, r=0.269). However neither office blood pressure nor SBP diurnal variation were predictors of kidney outcome. Regression analysis showed that early kidney function was the only independent predictor of transplant outcome (p<0.0001). Systolic blood pressure diurnal variation, though an important predictor of target organ damage in chronic kidney disease patients, was not a predictor of renal transplant function in renal transplant recipients. Only early kidney function was an independent predictor of later serum creatinine.
Abstract: A patient with isolated severe epistaxis and non-specific history or examination findings was shown to have anaemia, raised erythrocyte sedimentation rate (ESR), renal impairment and raised total protein with hypercoagulable blood. Waldenstrom's macroglobulinaemia was diagnosed after serum electrophoresis and bone marrow studies. Urgent plasma exchange and chemotherapy were undertaken to good effect. This case was a diagnostic dilemma, as the presentation of this common complaint did not initially suggest the rare underlying cause.
Abstract: BACKGROUND: Accurate diagnosis of hypertension is essential in chronic kidney disease patients, as it is linked to increased left ventricular mass, stroke, cardiovascular mortality and morbidity, and progression to end-stage renal disease. Elevated blood pressure (BP) detected by ambulatory BP monitoring (ABPM) has been shown to be predictive of worse outcome in chronic kidney disease patients. Another predictor of worse outcome is diurnal BP variation, measured also by ABPM. In this study, the authors examined the relationship (concordance or discordance) between blood pressure measured by ABPM compared with daytime office BP, and also explored the predictors of diurnal variation in renal transplant recipients. METHODS: All the patients who underwent renal transplantation and follow-up at the authors' institution from January 1998 to January 2003 were involved in this study (n=177) in addition to another randomly selected 64 patients that underwent transplantation before 1998. All patients had their ABPM performed according to previously described protocols at least 2 weeks after discharge from the hospital, dialysis-independent and with a functioning renal allograft. RESULTS: The authors found a positive correlation between systolic BP (SBP) diurnal variation and age (r =0.263, P <0.0001), glomerular filtration rate (GFR) (r =-0.229, P <0.0001), cyclosporine trough (r =0.171, P =0.047), and ABPM-to-transplant interval (r =-0.133, P =0.039). After fitting a regression model, the authors found that only GFR (P <0.0001) and age (P =0.001) were independent predictors of SBP diurnal variation (r =0.357). Concordance rate between casual BP and ABPM was 80%, and by using casual BP, only 15% of hypertensive renal transplant patients would be erroneously diagnosed as normotensive. CONCLUSIONS: The authors found that SBP diurnal variation is predicted independently by age and GFR, although it does correlate with cyclosporine trough and ABPM-to-transplant interval. In addition, the authors showed that ABPM is a more sensitive method for diagnosing hypertension than is sole reliance on office BP in renal transplant recipients.
Abstract: Ambulatory blood pressure (ABP) monitoring has been in use for nearly four decades. In that time, the advantages of using a more reproducible and accurate method to assess the true contribution of blood pressure to the cardiovascular risk profile of patients have steadily become more clearly established, balanced by the additional expense and expertise involved. In nephrology, and in particular in dialysis patients, there are significant difficulties in accurately registering truly representative blood pressure values and understanding the relationship between blood pressure, end-organ damage, and patient mortality. This arises because of the way in which hemodialysis acutely changes blood pressure values as well as the widespread abnormality of diurnal blood pressure rhythm seen in dialysis patients. Use of ABP monitoring can go some way to overcoming these obstacles. In this review we critically examine the use of ABP monitoring in the understanding of blood pressure control in dialysis patients.
Abstract: The case of a man with progressive breathlessness and pulmonary infiltration caused by AL amyloidosis associated with multiple myeloma is presented. There was a marked peripheral eosinophilia, which has not previously been described with amyloidosis.
Abstract: We show that GTP concentrations rise in the erythrocytes of renal transplant recipients receiving the immunosuppressant MMF, and demonstrate that this effect is not caused by poor renal function after engraftment. We propose a model that is consistent with our observations.
Abstract: Ambulatory blood pressure monitoring (ABPM) has been developed to overcome recognized deficiencies and inaccuracies of classic (office) BP measurements in the diagnosis and management of hypertension (HTN). Although in adults it has become a valuable tool for the diagnosis and ongoing management of HTN, and its use has been documented in over 50 studies in children, few pediatric nephrologists systematically use this approach for HTN assessment. Some of the reluctance to completely embrace the technique comes from the fact that none of the major hypertension trials has been based on ambulatory BP readings. The prognostic information from ABPM studies is slowly accumulating, but there is still relatively little information on the long-term prognostic value of ABPM-derived readings. For children there are particular problems in measuring representative BP values. It would be very helpful to know to what extent ABPM can help. However, there have been few comprehensive reviews in this particular population, which leaves the practicing nephrologist rather confused. The purpose of this review is to assess the present state of knowledge of ABPM usage in children, high-lighting important studies that help to delineate the place of ABPM in their medical management. We discuss: advantages and limitations of ABPM, the variability of blood pressure in children, clinical uses of ABPM in pre-dialysis renal failure, dialysis, renal transplantation, primary renal diseases, and diabetes, comparison with adult data. The relationship between casual BP (CBP) and ABPM is presented, specifically the prevalence and relevance of either white-coat hypertension or relative 'office' hypertension. We conclude that in 2004, the sole reliance on casual BP to diagnose and to treat hypertension in children brings with it many difficulties. ABPM offers some clear solutions to these problems and thus should be routinely used in appropriately defined clinical settings, but is not a panacea.
Abstract: Extensive evidence supports a pathogenic role for both local and systemic inflammation in acute coronary syndrome (ACS). The determination of inflammatory markers levels in combination with the new imaging modalities can be used to identify patients at high risk of future cardiovascular events. Interestingly, this inflammatory component is a novel therapeutic target in ACS.
Abstract: We have investigated an unusual nucleotide that accumulates, with precursors, in the erythrocytes of patients in uraemia. This nucleotide is related chemically to the NAD breakdown product, N1-methyl-2-pyridone-5-carboxamide (Me2Py), found in high concentrations in the plasma of uraemic patients. Both Me2Py and the nucleotide accumulate to high concentrations in the blood during uraemia: our investigations of samples from renal out-patients have provided information on a plausible link between the two compounds.
Abstract: Cytomegalovirus (CMV) is usually a complication of renal/solid organ or bone marrow transplantation. We describe three cases of severe CMV in the context of vasculitis immunosuppression.
Abstract: Urinary tract obstruction is a common problem associated with many complications. Decompression of an enlarged bladder has been associated with several complications, mainly vesicular bleeding. We report a case of a 42-year-old male patient who developed bilateral renal subcapsular hematomas secondary to relief of an extremely enlarged bladder.
Abstract: BACKGROUND: Measurements of aortic stiffness [aortic pulse wave velocity (PWV) and augmentation index (Alx)] have been established as powerful predictors of survival on hemodialysis (HD). Abnormal endothelial-dependent and endothelial-independent vascular reactivity and increased arterial stiffness are commonly described in HD patients. There is, however, a lack of information on the comparative impact of different renal replacement therapies (RRTs) on PWV and Alx, and how these different methods might influence endothelial-dependent abnormal vasodilatation. OBJECTIVE: To describe in a cross-sectional design arterial compliance and distensibility in continuous ambulatory peritoneal dialysis (CAPD) versus HD versus renal transplant (RTx) patients, compared with age- and blood pressure-matched essential hypertensive controls. The PWV and aortic Alx were determined from contour analysis of arterial waveforms recorded by applanation tonometry in 40 CAPD, 41 HD, 20 RTx patients (with normal serum creatinine), and 20 controls with essential hypertension (all normotensive under treatment). Endothelial-dependent and endothelial-independent vascular reactivities were assessed by changes in Alx following challenges with inhaled salbutamol and sublingual nitroglycerin respectively. RESULTS: CAPD patients had significantly stiffer arteries than all other categories. The PWV was 8.29 +/- 1.09 m/ second in CAPD patients, significantly higher (p < 0.05) compared to HD subjects (7.19 +/- 1.87 m/s). Both dialysis subgroups had significantly higher PWV values compared to RTx patients (6.59 +/- 1.62 m/s) and essential hypertensive controls (6.34 +/- 1.32 m/s), p < 0.05. The Alx had a profile similar to PWV in different RRTs. All groups with the exception of CAPD subjects had a significant decrease in Alx following salbutamol. Moreover, the vasodilatation induced by either nitroglycerin or salbutamol was significantly blunted compared to HD. Overall, both dialysis categories had more abnormal responses compared to RTx patients and essential hypertensive controls. CONCLUSION: CAPD is associated with stiffer arteries and more profoundly abnormal endothelial-dependent vasomotor function, compared to matched HD subjects. These differences in arterial physical properties might explain differences seen in cardiac structure and function between the RRTs.
Abstract: Anemia is a common feature of chronic renal dysfunction and is associated with significant morbidity and mortality. Although acquired insufficiency of erythropoietin is virtually universal, iron deficiency is also a common contributor to the development of anemia. Iron replacement, in particular via the intravenous route, has become commonplace and results in improved hematocrits either on its own or in association with an erythropoiesis stimulating agent. However, intravenous iron is not without its potential complications. These include acute allergic reactions, iron overload, potentially accelerated cardiovascular disease and risk of infection. It is the purpose of this review to critically evaluate the available clinical and experimental evidence linking iron supplementation therapy with these complications.
Abstract: There has been an explosion of interest in vascular calcification in the last 5 years. Four key "germinal" findings have fallen onto very fertile soil. First, on the background of an increasing cardiovascular disease burden it has been found that at least cross-sectionally, and in a limited fashion prospectively, achieved dialysis plasma phosphate levels are linked to all-cause and cardiovascular mortality. Second, there are increasing reports of calcific uremic arteriolopathy in Australia and the United States. Third, we know know that the mechanical properties of the carotid artery, and the aorta, have a profound influence on survival for dialysis patients. Vascular calcification itself (as assessed by x-ray films and ultrasound) has been linked to aortic stiffness. Fourth, increasing numbers of studies are showing extremely extensive coronary artery calcification (CAC) in dialysis patients, even at a young age. From these apparently unlinked observations the following assertion has been posited-that in the widespread (over) use of calcium-containing oral phosphate binders (OPB) to prevent uremic osteodystrophy in our dialysis population we have unwittingly accelerated widespread uremic vasculopathy and thereby contributed to premature cardiovascular mortality. It is the purpose of this article to discuss vascular calcification (and particularly CAC) in dialysis patients as we understand it today. We will review the published series, with special reference to the Sevelamer Treat to Goal trial and also discuss the new Kidney Disease Outcome Quality Initiative (K-DOQI) guidelines on the use of phosphate binders in chronic kidney disease.
Abstract: MMF (mycophenolate mofetil) has been proven to provide an effective immunosuppression by non-competitive selective reversible inhibition of IMPDH (inosine monophosphate dehydrogenase), the enzyme playing a crucial role in GTP biosynthesis. However, the exact metabolic changes induced by inhibition of IMPDH in target cells of the immune system have been the subject of recent debate. The aim of the present study was to evaluate whether MMF treatment produced sustained changes in the guanosine nucleotide pool of MNLs (mononuclear leucocytes) in vivo. Sixty-two renal failure patients were divided into three groups: chronic renal failure patients undergoing haemodialysis (CRF-HD; n=20) and two groups of patients after renal transplantation, the first on AZA (azathioprine; TN-AZA; n=23) and the second treated with MMF (TN-MMF; n=19). In addition, MNLs from 25 healthy subjects were analysed as controls. Anion-exchange HPLC was used to quantify purine and pyrimidine nucleotides in MNLs. We report a significant decrease in GTP and the total MNL guanine nucleotide pool in the TN-MMF group (P<0.05) compared with control, CRF-HD and TN-AZA groups, although no significant differences were found between any of the other groups. Adenine nucleotide concentrations in MNLs were decreased in the TN-AZA group, but not in the TN-MMF group compared with the CRF-HD group and controls. There were no differences in CTP concentrations, but UTP concentrations were decreased in the CRF-HD, TN-AZA and TN-MMF groups compared with controls. MMF caused a significant and sustained decrease in the guanine nucleotide pool in MNLs from renal transplant recipients. This decrease contrasts with the elevation in GTP reported in erythrocytes of MMF-treated patients.
Abstract: The immunosuppressant MMF (mycophenolate mofetil) has increasingly replaced AZA (azathioprine) in renal transplantation. MMF is a prodrug of MPA (mycophenolic acid), which inhibits lymphocyte IMPDH (inosine monophosphate dehydrogenase), thereby drastically decreasing GTP concentrations essential to lymphocyte proliferation in vitro and in vivo. Erythrocyte GTP concentrations are commonly elevated in severe renal disease, but normalize following successful engraftment. Consequently, elevated GTP in renal transplant recipients might signal impending loss of immunosuppression and graft failure. In the present study, we compared erythrocyte nucleotides and plasma metabolites in two groups of 25 patients after renal transplantation, both receiving prednisolone and cyclosporin A, but one group receiving MMF and the other AZA. No patients had recent allograft biopsy evidence of rejection. Erythrocyte GTP concentrations at MMF commencement were 50.4+/-23.4 micromol/l. An increase occurred during the first 3 months after transplant when MMF was used de novo, stabilizing at 146.7+/-62.9 micromol/l after 4 months. This was significantly higher (P=2.5 x 10(-6)) than erythrocyte GTP (40.4+/-15.9 micromol/l) in the AZA group, which was essentially unchanged from values immediately after successful transplantation. The effect of MMF on erythrocyte GTP levels was reversible, since GTP levels fell when MMF therapy was terminated. The results demonstrate paradoxically high GTP concentrations in erythrocytes of renal transplant patients receiving MMF. MPA may stabilize reticulocyte IMPDH, allowing the protein to persist during erythropoiesis. This behaviour is in marked contrast with the decrease in GTP levels seen in white blood cells of patients on chronic MMF therapy.
Abstract: Interstitial pneumonitis is a rare disease that is seen in the context of some infections (e.g. PCP and CMV pneumonia), as side-effects of drugs (e.g. beta-blockers, amiodarone) and rarely in the context of renal transplantation. It manifests itself usually as a pneumonic illness; with symptoms of dyspnea, cough, fatigue and sometimes fever. Characteristic radiological changes are bilateral lower zone haziness. Interstitial pneumonitis is now emerging in solid organ transplant patients secondary to sirolimus). We describe three cases of sirolimus-induced pneumonitis in two patients who started sirolimus to permit cyclosporin withdrawal and in one patient initially started on sirolimus. The presentations in these cases ranged from insidious to fulminant; there was a rapid response to sirolimus withdrawal. This is an important syndrome, with an unknown frequency.
Abstract: Page kidney was first described in animal experiments in 1939. In the 1950s and 1960s the human counterpart became evident. In this review we examine the modest literature on this rare but important renal/urological complication, summarize the clinical features, and discuss the best approach to diagnosis and management.
Abstract: Acute muscle infarction in diabetic patients on dialysis has rarely been reported. We present a small case series of 4 patients with unusally "inflammatory" presentations that caused diagnostic challenges. Diabetic muscle infarction should be in the differential diagnosis of acutely swollen lower limbs in dialysis patients.
Abstract: Cushing's syndrome is characterised by circulating steroid excess; the mainstay of treatment of systemic sarcoidosis is steroid therapy. We describe a case of sarcoidosis emerging after treatment for Cushing's syndrome.
Abstract: BACKGROUND: Renal involvement [as acute renal failure (ARF)] is a prominent feature of both mild and severe leptospirosis-a re-emerging infectious disease. Few large series describe in detail clinical and laboratory features of cases with ARF and their outcome. METHODS: We performed a retrospective analysis (1997-2001) of all consecutive, serological confirmed leptospirosis cases with ARF (n=58, 53 male, age 44+/-13 years, rural residents=31%, animal contact=88%. RESULTS: Clinical manifestations (>50% prevalence): oliguria 95%, fever and jaundice 93%, nausea and vomiting 83%, haemorrhagic diathesis 80%, headache, hepatomegaly 76%, myalgias, abdominal pain 70%, hypotension 62%, disturbed consciousness 50%. A pattern of multiple organ failure (MOF) was frequent: ARF together with hepatic failure in 72%, respiratory failure in 38%, circulatory failure in 33%, pancreatitis in 25% and rhabdomyolysis in 5% of cases. Renal dysfunction: 35% of cases had a renal K(+)-wasting defect and 43% a FE(Na)(+)>1% and low-osmolarity urine despite volume depletion. Haematuria was encountered in 12 and mild proteinuria in 10 subjects. Outcome: 26% deaths, 64% normal hepatic and renal function at 90 days from presentation (however 29% maintained the initial tubular defect), 10% persistent mild renal failure. All deceased patients had, beside ARF, at least two other organ failures, affected consciousness, and haemorrhagic diathesis vs a prevalence for the above features of only 34, 33, and 72%, respectively, in the survivors group (P<0.05). CONCLUSIONS: Leptospirosis presenting with ARF is a severe disease, frequently leading to MOF and to death in one-third of the patients. In particular, the haemorrhagic diathesis and cerebral involvement are markers for unfavourable patient and renal outcomes.
Abstract: BACKGROUND: Since the 1960s chronic hemodialysis (HD) has been recognized as a risk factor for the development of infective endocarditis (IE). Historically, it has been particularly associated with vascular access via dual lumen catheters. We wished to examine the risk factors for, and consequences of, IE in the modern dialysis era. METHODS: Cases of IE (using the Duke criteria) at St. Thomas' Hospital (1980 to 1995), Guy's (1995 to 2002), and King's College Hospitals (1996 to 2002) were reviewed. RESULTS: Twenty-eight patients were identified as having developed IE (30 episodes of IE). Twenty-seven patients were on long-term HD and one patient was on peritoneal dialysis (PD). Mean age was 54.1 years, and mean duration of HD prior to IE was 46.3 months. Eight patients were diabetic. Primary HD hemoaccess was an arteriovenous fistula (AVF) in 41.3%, a dual-lumen tunneled catheter (DLTC) in 37.9%, a polytetrafluoroethylene (PTFE) graft in 10.3%, and a dual- lumen non-tunneled catheter (DLNTC) in 4%. The presumed source of sepsis was directly related to hemoaccess in 25 HD patients: DLTC in 48%; AVF in 32%; PTFE in 12%; and DLNTC in 4%. Staphylococcus aureus[including methicillin resistant Staphylococcus aureus (MRSA)] was present in 63.3%. The mitral valve was affected in 41.4% of patients, aortic valve in 37.9% of patients, and both valves were affected in 17.2% of patients. Of note, 51.7% of patients had an abnormal valve before the episode of IE. In 15 cases surgery was undertaken. Fourteen patients survived to discharge, and 12 survived for 30 days. In 15 cases antibiotic treatment alone was employed; in this case, eight patients died and seven survived to discharge. CONCLUSION: This is the largest reported confirmed IE series in dialysis patients. Infective endocarditis in HD patients remains a challenging problem-although hemoaccess via dual-lumen catheters remains a significant risk, many cases developed in patients with AVFs and this group suffered the greatest mortality. An abnormal valve (frequently calcified) was another risk factor; because valve calcification is now common after 5 years on dialysis, more effort in preventing this avoidable form of ectopic calcification may reduce the risk of developing IE.
Abstract: BACKGROUND: Acute liver failure (ALF) as a result of mushroom poisoning is associated with a high mortality (particularly in children), despite optimal medical therapy (OMT), including charcoal haemoperfusion and haemodiafiltration. MARS is a new, cell-free, extracorporeal liver assistance method utilizing an albumin dialysate for the removal of albumin-bound toxins. METHODS: We describe the first series in the literature (also first MARS treatments in Romania) with ALF because of mushroom poisoning in children (M/F=2/4, age=7-16 years). Liver function was evaluated pre-MARS and 15-min post-MARS, 24 h following each treatment and 30 days post-MARS. FINDINGS: All patients had severe hepatic dysfunction: hepatic encephalopathy (HE; four grade II, one grade III, one grade IV), ALT=4082 (3400-5600) IU/L, bilirubin=6.3 (2-10) mg/dL, prothrombin time (PT)=52.5 (23-141) s. MARS was uneventful and well-tolerated. Two 6-h sessions per patient were performed with a similar immediate impact on liver tests: mean drop in ALT of -33 and -35%, respectively, and in bilirubin of -39 and -36%, respectively. ALT levels 24 h following MARS-1, remained unchanged but continued to drop by a further -28% following MARS-2. By contrast, all patients had a significant rebound in bilirubin (+39%) 24 h following MARS-1; however, following MARS-2 a rebound was seen only in two cases (+220%). PT improved by 37% after MARS-1 and normalized in four patients after MARS-2. OUTCOME: Four patients survived and completely recovered the hepatic function. Negative prognostic markers: lack of complete correction of PT, continuous rebound and increase in bilirubin, and lack of improvement in HE post-MARS-1. Survival in six well-matched cases, treated by OMT=0/6 (P<0.05). CONCLUSIONS: MARS is a safe and highly effective depurative therapy in children with ALF. Survival is predicted only by the impact/results of the initial MARS sessions and not by any of the baseline parameters.
Abstract: A man born in 1944 presented with an episode of macroscopic haematuria during a urinary tract infection in 1988. He was unusually tall at 2 metres. An intravenous pyelogram and an abdominal ultrasound disclosed the presence of bilaterally enlarged polycystic kidneys and a polycystic liver. There was a family history of renal disease. Plasma creatinine (180 micro mol/l) and blood pressure (150/100 mm Hg) were both raised. Despite good blood pressure control his renal function declined progressively and he started renal dialysis treatment in 1995. He received a renal allograft in 1996. In 1994 he had noticed a painful swelling behind his left knee. Computed tomography with contrast showed a large popliteal aneurysm. This was replaced with a vein graft. The right popliteal artery showed milder changes, and this was repaired in 1999. Popliteal aneurysms develop most often in older vasculopaths with multiple risk factors; connective tissue disorders have rarely been associated with their presence in younger patients. Polycystic kidney disease has been associated with several aneurysms, most notably cerebral, but not popliteal. The patient's marfanoid habitus also may have played a part. This case emphasises the mixed aetiology of popliteal aneurysms.
Abstract: INTRODUCTION: The aim of the present study is to understand the nature of acid-base disorders in critically ill patients with acute renal failure (ARF) using the biophysical principles described by Stewart and Figge. A retrospective controlled study was carried out in the intensive care unit of a tertiary hospital. MATERIALS AND METHODS: Forty patients with ARF, 40 patients matched for Acute Physiology and Chronic Health Evaluation II score (matched control group), and 60 consecutive critically ill patients without ARF (intensive care unit control group) participated. The study involved the retrieval of biochemical data from computerized records, quantitative biophysical analysis using the Stewart-Figge methodology, and statistical comparison between the three groups. We measured serum sodium, potassium, magnesium, chloride, bicarbonate, phosphate, ionized calcium, albumin, lactate and arterial blood gases. RESULTS: Intensive care unit patients with ARF had a mild acidemia (mean pH 7.30 +/- 0.13) secondary to metabolic acidosis with a mean base excess of -7.5 +/- 7.2 mEq/l. However, one-half of these patients had a normal anion gap. Quantitative acid-base assessment (Stewart-Figge methodology) revealed unique multiple metabolic acid-base processes compared with controls, which contributed to the overall acidosis. The processes included the acidifying effect of high levels of unmeasured anions (13.4 +/- 5.5 mEq/l) and hyperphosphatemia (2.08 +/- 0.92 mEq/l), and the alkalinizing effect of hypoalbuminemia (22.6 +/- 6.3 g/l). CONCLUSIONS: The typical acid-base picture of ARF of critical illness is metabolic acidosis. This acidosis is the result of the balance between the acidifying effect of increased unmeasured anions and hyperphosphatemia and the lesser alkalinizing effect of hypoalbuminemia.
Abstract: Posterior Leukoencephalopathy Syndrome (PLES) is a rare but serious neurological condition with many aetiologies. In the era of organ transplantation there have been sporadic reports of calcineurin-inhibitor associated PLES. We describe a case, with subsequent uneventful retransplantation using sirolimus.
Abstract: Thrombotic microangiopathy is a rare but important finding in the context of organ transplantation. Acute renal insufficiency in the setting of hemolysis and thrombocytopenia, a triad that constitutes 'hemolytic uremic syndrome', can be associated with, or triggered by, conditions such as verocytotoxin-producing Escherichia coli, viral infections, malignant hypertension, scleroderma, allograft rejection, lupus erythematosus, pregnancy, and medications including mitomycin C, calcineurin inhibitors, and oral contraceptives. After renal transplantation, it can occur, as either a de novo episode, or recurrent disease. Calcineurin inhibitors have long been associated with post-transplantation thrombotic microangiopathy. Sirolimus has been used as a primary immunosuppressant in patients transplanted with a history of earlier hemolytic-uremic syndrome, and also as rescue therapy in patients with calcineurin-inhibitor-associated thrombotic microangiopathy. We describe four cases where there was significant thrombotic microangiopathy in the context of contemporaneous or contiguous calcineurin inhibitor and sirolimus usage. As the intrarenal cyclosporin concentration is thought to be significantly elevated when cyclosporin and sirolimus are used together, this may explain these findings, and mandates caution in their co-administration.
Abstract: BACKGROUND: Patients with end-stage renal disease on dialysis have among the highest cardiovascular event rates documented. Abnormal nitric oxide (NO)-dependent endothelial reactivity and increased arterial stiffness are commonly described in hemodialysis (HD) patients. Measures of aortic stiffness--aortic pulse wave velocity (PWV) and augmentation index (AGI)--have been shown to be powerful predictors of survival on hemodialysis. It is not known how these parameters interfere with successful renal transplantation. METHODS: PWV and aortic AGI (difference between the first and second systolic peak on the aortic pressure waveform divided by the pulse wave height) were determined from contour analysis of arterial waveforms recorded by applanation tonometry using a SphygmoCor device in 41 HD patients (20 men; age, 41.8 years) and in a control group of 20 patients with essential hypertension (HTA) (10 men; age, 43.6 years). Twenty of the HD patients (10 men; age, 39.7 years) received live-related renal transplants (RTx) and were restudied (3 months after RTx, normal serum creatinine). NO-dependent and NO-independent vascular reactivity were assessed by changes in AGI after challenges with inhaled salbutamol (SAL) and sublingual nitroglycerin (NTG), respectively. RESULTS: AGI values were significantly lower in RTx patients compared with subjects on hemodialysis (15.9 +/- 13.9% vs. 27.9 +/- 11.9%, P<0.05), but similar to essential HTA controls (16.5 +/- 17%). Serial AGI measurements showed that successful renal transplantation is associated with a decrease in AGI in all cases, from a mean of 25.1 +/- 7.8% while on dialysis to 15.9 +/- 7.0% 3 months after transplantation (P<0.0001). The responsiveness to both endothelium-dependent stimuli (inhaled SAL) and endothelium-independent stimuli (sublingual NTG) was greater in transplant patients than in hemodialysis patients (SAL-induced decrease in AGI -82.3 +/- 65.7% vs. 45 +/- 72.3%, P<0.01; and NTG-induced decrease in AGI 197 +/- 108 vs. -129.0 +/- 215.5%, P<0.01). PWV values in dialysis patients (7.19 +/- 1.88 m/sec) were significantly higher than those measured in essential HTA patients (6.34 +/- 1.32 m/sec, P<0.05) with normal renal function (despite similar blood pressure levels). PWV after RTx was 6.59 +/- 1.62 m/sec, significantly different from pretransplantation (dialysis) values (P<0.05 for comparison) but similar to the control group of essential HTA patients. CONCLUSIONS: Renal transplantation is associated with marked improvements in vascular structure and function to a profile comparable to essential HTA patients.
Abstract: Cardiovascular disease (CVD) rates in dialysis patients are very high. One of the many associated risk factors is chronic inflammation. The relationship of baseline markers of chronic inflammation with the presence of CVD was assessed in a large cohort of stable dialysis patients. Median time (IQR) on dialysis treatment was 20(9-52) months. Forty-one patients had CVD (as defined by the history / clinical presence of ischemic heart disease, peripheral vascular disease, or cerebrovascular disease). Patients with CVD were significantly older than patients without (67 + /- 11 vs. 54 + /- 10 yrs, p < 0.03). Time from dialysis, urea reduction ratio (hemodialysis only) and smoking history were similar between the two groups. Patients with CVD had significantly higher levels of sialic acid (SA) (91.2 +/- 24.2 vs. 82.0 + /- 18.2 mg/dL, p = 0.03). Body weight, plasma fibrinogen, C-reactive protein (CRP), homocysteine, creatinine, total-, LDL (low density lipoprotein)-, or HDL (high density lipoprotein)-cholesterol, systolic, diastolic and pulse pressures did not differ between the CVD and CVD(-) groups. Patients on chronic ambulatory peritoneal dialysis (CAPD) had more elevated lipid fractions, inflammatory markers, and SA levels than did patients on hemodialysis (HD). The presence of diabetes, the use of lipid-lowering therapy, and smoking history was not associated with any difference in SA levels. In contrast to C-reactive protein (CRP) concentrations, SA levels were unaffected by the hemodialysis session. SA was strongly correlated with CRP (r = 0.59, p < 0.0001), but not with patient age, any measure of blood pressure (BP), urea reduction ratio, plasma creatinine, lipid fractions or homocysteine. Levels of the chronic inflammation marker sialic acid correlate strongly with CRP and are increased in patients with cardiovascular disease, but show no relationship to hemodialysis session. Thus sialic acid may be a superior marker to CRP for assessment of chronic inflammation in patients undergoing dialysis.
Abstract: Hyperparathyroidism is an important sequela of chronic renal failure, remains a considerable challenge to nephrologists, and can be seen as inevitable in patients undergoing long-term renal replacement therapy. As time with renal disease increases then so does the cumulative risk of hyperparathyroidism, and the eventual need for surgical parathyroidectomy when hyperparathyroidism becomes refractory to medical intervention. Parathyroidectomy before dialysis treatment has started, or after successful renal transplantation, is much less commonly performed than when the patient is receiving dialysis. Increasingly the propensity for residual parathyroid tissue left behind (by design or accident) at an initial parathyroidectomy to undergo progressive hyperplasia under the constant stimulus of uremia, and by so doing result in the need for a second, more complex, neck exploration, has increased support for initial total parathyroidectomy for patients on dialysis. The optimal operative procedure for autonomous hyperparathyroidism after successful renal engraftment is however less clearly established. We discuss two very unusual but instructive cases of post renal transplantation autonomous hyperparathyroidism requiring surgical parathyroidectomy. Using these cases as examples we discuss the various surgical options, and discuss the contentious issue of the place for autografting parathyroid tissue.
Abstract: OBJECTIVE: To evaluate BP control, white coat hypertension (WCH) and abnormal circadian variability in a significant outpatient sample of renal transplant (RTx) subjects, normotensive at the last regular visit. METHODS: ABPM (Spacelab 90217) was performed every 15 min between 07:00-23:00 h and every 30 min between 23:01-06.59 h. in all patients (N = 68, 39M, S-Cr. = 153 +/- 49 mumol/l) normotensive at their last regular office BP (O-BP) measurement and with available BP records for the 12 months preceding RTx and 6 months preceding ABPM. RESULTS: BP values were frequently abnormal in this RTx cohort considered to have a satisfactory BP control. O-BP (measured with a Hawksley random-0 sphygmomanometer on the day of ABPM) was 135.5/80.6 mmHg, 47.1% of the patients with abnormal BP values. By comparison, ABPM showed a lower prevalence of uncontrolled BP: 44.1% for 24 h.-BP and only 35.3% for the daytime awake period, with values of 134.5/80.4 and 135.3/81 mmHg respectively (P = NS from O-BP). The prevalence of WCH was 12%. 24-h SBP is related to O-SBP (r = 0.71, P < 0.01) and Bland-Altman analysis demonstrates that > 95.6% of all differences between systolic ABPM and O-BP values are within +/- 2SD of the identity line. However, although 24-h DBP is equally related to O-DBP (r = 0.64, P < 0.01), on Bland-Altman analysis, 8.8% of the differences between diastolic ABPM and O-BP values are outside +/- 2SD of the identity line. Thus, systolic but not diastolic O-BP correlates with, and can be substituted to ABPM derived values. Non-dipping was frequent, regardless of the definition of normal nocturnal BP fall (10 mmHg or 10% of the daytime SBP): 82.4%, 89.7%. Even if normality was strictly defined as a night/day ratio < 0.90 for SBP and < 0.92 for DBP, non-dipping prevalence was high 73.5%, with more than one-third of the RTx patients having nocturnal hypertension (ratio > 1). CONCLUSIONS: BP control is not optimal in one-third of a typical RTx population. Furthermore, nocturnal hypertension is a frequent and underestimated phenomenon in this population. There is a good agreement between ABPM derived and casual systolic values. Office measurements, due to WCH, are under-evaluating the quality and efficacy of the antihypertensive regimens.
Abstract: In renal transplant recipients, hypertension is common and associated with increased cardiovascular and allograft rejection risks. Ambulatory blood pressure monitoring is required for its accurate diagnosis and adequate treatment, as it clearly offers several advantages over office or casual blood pressure measurements. First, it correlates better with target-organ damage and with cardiovascular mortality. Second, ambulatory blood pressure monitoring can eliminate "white coat" hypertension. Most important is the identification of nocturnal hypertension, an independent cardiovascular risk factor. A circadian nondipping pattern is often found in renal transplant recipients, most probably resulting from cyclosporine A and persistent fluid overload in the early posttransplant phase (approximately 70% prevalence), but reflecting an underlying renal (parenchymal or vascular) allograft disease when persistent (approximately 25% prevalence) beyond the first year posttransplant.
Abstract: Due to the impressive cardiovascular (CV) morbidity and mortality in uremic patients, assessment of CV risk factors in the dialysis population is a crucial challenge in nephrology. Cardiovascular risk factors in dialysis patients may have a different significance in ESRD patients compared to the general population. The Framingham risk equation seems not to be valid in chronic uremia. Furthermore, new powerful outcome predictors have emerged in recent years: pulse pressure, dipping status, pulse wave velocity, augmentation index. The concept of "U"-shaped association between blood pressure (as well as cholesterolemia) and mortality are extensively discussed. The authors are focusing on the value of office and ambulatory blood pressure measurements in the uremic population. An extensive evaluation of blood pressure and vascular compliance in dialysis patients is proposed. Efficient dialysis, ACE-inhibitors and beta-blockers, statins, antiplatelet treatment and adequate control of calcium-phosphorus metabolism should be the mainstay of therapy in the ESRD patients with several CV risk factors.
Abstract: PURPOSE OF REVIEW: To identify and evaluate recent (2000-2003) published studies employing ambulatory blood pressure monitoring in patients with chronic renal failure, on dialysis, and after renal transplantation. RECENT FINDINGS: We discuss several studies that have employed ambulatory blood pressure monitoring to refine the analysis of the link between blood pressure levels, and diurnal alterations, and end-organ damage or patient survival. There is now some evidence that an abnormal diurnal blood pressure profile, although intrinsically not a very reproducible label, has predictive value for patient survival, and that the non-dipping phenomenon is linked to a high incidence of cardiovascular disease and autonomic dysfunction. SUMMARY: Ambulatory blood pressure monitoring remains an important adjunct to the comprehensive cardiovascular evaluation of patients with chronic, end-stage renal failure or after renal transplantation.
Abstract: Blood glucose monitoring is important in optimizing long-term outcomes in diabetic patients. Reliance on near-patient testing and the use of longer term measures of glycation are the current cornerstones. However, as this review details, there are significant problems using blood tests as measures of metabolic control in uremic diabetic patients.
Abstract: An overweight 56-year-old type II diabetic on peritoneal dialysis (body mass index 35 kg/m(2)) was taking Orlistat for some months up until live-unrelated renal transplantation. Despite oral cyclosporin A (CyA) for 48 hours pretransplantation, it was very difficult to achieve adequate CyA blood levels for the first week postengraftment despite the use of much larger oral CyA doses. After opening his bowels on day 7, and the use of 3 days intravenous CyA, good CyA blood levels were achieved then maintained with conventional oral doses. The authors believe that this case shows important interactions between CyA and Orlistat.
Abstract: Statins are now widely prescribed and without doubt save many lives. However there are rare potentially serious side-effects, including acute renal failure. Patient education and physician vigilence are vital.
Abstract: Endogenous Aspergillus endophthalmitis (AE) is a rare complication of invasive aspergillosis (IA) in transplant patients. In this report, we describe two patients with polycystic kidney disease, who developed AE with cerebral involvement after renal transplantation. Both patients received intense immunosuppression with methyl prednisolone and mycophenolate mofitil (MMF) because of persistent rejection, which rendered them diabetic and vulnerable to opportunistic infections. Endophthalmitis developed within six months of transplantation and was confirmed by microscopy and culture of the vitreous fluid. Patients were treated with combinations of different anti-fungal agents including liposomal amphotericin B, 5-flucytosine, itraconazole, voriconazole and terbinafine.In an electronic MEDLINE review, we found eight further cases of AE in renal transplant patients between 1959 and September 2002. Based on this review, we identified possible risk factors including CMV infection, diabetes mellitus and treatment for rejection with agents such as methyl prednisolone and MMF. In 70% of cases the histology, microscopy or culture of vitreous fluid confirmed the diagnosis. The outcome of AE in renal transplant patients was poor with 70-100% mortality. The review of reported cases and current practice guidelines suggests that vitrectomy and intravitreal amphoterecin B is the treatment of choice. In addition, new antifungal agents with good CSF and ocular penetration such as voriconalzole should be considered for the treatment of invasive cerebral/ocular aspergillosis.
Abstract: Renal stones rarely complicate renal transplants. Their causation is diverse. We describe 2 patients with significant staghorn calculi caused by metabolic factors.
Abstract: BACKGROUND: The efficacy of allopurinol in autosomal dominant familial juvenile hyperuricaemic nephropathy (FJHN) has been disputed. AIM: To address this question, in the absence of controlled trials. DESIGN:Retrospective long-term follow-up study. METHODS: All kindreds were biochemically screened. Measurements included uric acid clearance, creatinine clearance, serum creatinine, and glomerular filtration rate (GFR). We used five siblings who had died or progressed to transplantation, ten other deceased relatives, and two index cases (one untreated, one non-compliant) as controls to assess the effects of allopurinol. RESULTS: Of eight families with FJHN, six had a strong history of renal disease and early parental death (mean age 41 years, n=10). Of 27 patients started immediately on allopurinol and treated uninterruptedly, 21 responded well, including three children born subsequently. Eight siblings (mean age 19 years) with a normal plasma creatinine at start (<120 micromol/l, mean GFR 80 ml/min/1.73 m(2)) retained stable renal function (mean 14.5 years, mean age 34 years, GFR 85 ml/min/1.73 m(2)). Of the 13 other responders, treated for up to 34 years, 10 with a creatinine <200 micromol/l at diagnosis (mean age 28 years, mean creatinine 137 micromol/l at start) now have a mean creatinine of 210 micromol/l. In contrast, five patients (mean age 26 years) with a creatinine >200 micromol/l (GFR <35 ml/min/1.73 m(2)) when allopurinol commenced, plus one untreated index case, all progressed rapidly (mean 6 years) to end-stage renal failure. In two others (one non-compliant, one initially untreated), GFR fell by >50% in 7 years. Introduction of allopurinol in the latter has stabilized GFR. DISCUSSION: Allopurinol reduced the morbidity and mortality from renal failure seen in untreated siblings and previous generations of these families. Early diagnosis of FJHN is important, so that treatment can begin before irreversible renal damage has developed.
Abstract: Coronary artery disease is very frequent in dialysis patients, and influences their survival while on dialysis and even after renal transplantation. There are problems with screening tools in that they have reduced sensitivity and specificity in the uraemic individual. There is a real need for additional and complementary markers of coronary disease in these patients. We discuss some novel ideas for screening and for intervention in this most challenging clinical setting.
Abstract: BACKGROUND: Diurnal BP rhythm is known to be abnormal (reduced BP fall with sleep) in chronic renal failure, dialysis and renal transplantation patients. In subjects with primary hypertension and with reduced diurnal BP fall with sleep there is consistent evidence of increased target-organ damage. However, the few studies that have addressed the reproducibility of diurnal rhythm in normal or hypertensive subjects have concluded that the BP fall with sleep is poorly reproducible. It is not known whether the same is true for patients with renal disease. METHODS: In 30 subjects with autosomal polycystic kidney disease (ADPKD), mild chronic renal failure and normal office BP levels on standardised anti-hypertensive treatment, ambulatory blood pressure monitoring (ABPM) was done three times over a twelve month period to assess the reproducibility of blood pressure fall with sleep. RESULTS: When comparing ABPM 2 with the ABPM 1 recording (3 months difference between measurements) only 43.3% of the patients maintained the initial dipping category (defined by quartiles of the ABPM 1 diurnal BP distribution). The same proportion of subjects had a similar dipping category, when ABPM 3 was compared to ABPM 1 (9 months difference between measurements), but a large (24%) subset of patients had dramatic shifts in their amplitude in nocturnal BP fall, significantly greater than those recorded after a shorter inter-measurement interval. Equally important, our study reveals the fact that, with time, there is no tendency to decrease circadian variation: a similar proportion (a quarter to one third) of patients increased or decreased their amplitude in nocturnal BP fall, at 3 and 9 months. When several ABPM measurements are repeated for the same patients, the repeatability is even worse, since only 36.6% of our study population maintained the initial dipping category across all three ABPM determinations (ABPM 1 and ABPM 2 and ABPM 3). CONCLUSIONS: There is a widespread abnormality in diurnal BP rhythm in ADPKD patients with renal impairment, but the extent of this abnormality varies considerably over time. It is too simplistic to assume that, having arbitrarily categorised subjects into "dippers" or "non-dippers", these labels will always be valid. Thus, it would be unwise to extrapolate the impact of a single baseline circadian BP profile on organ target end points.
Abstract: BACKGROUND: HD has been reported to determine an increase in QTc interval and QTc dispersion (QT(max)-QT(min))-risk factors that predispose to severe ventricular arrhythmias and sudden death. However, most studies have included end-stage renal disease (ESRD) patients with significant heart pathology. We therefore aimed to study the impact of a single HD session in subjects without manifest cardiac disease. METHODS: Sixty-eight stable, non-diabetic HD patients (47.1% males, age 40.2+/-12.7 years, HD duration 57+/-36 months and 37% hypertensive), with normal maximal ECG stress test and sub-endocardiac viability index and without ECG left ventricular hypertrophy were included. QT interval was calculated 10 min pre- and post-HD, as an average of three consecutive complexes, and corrected for heart rate using Bazett's formula (QTc=QT/(R-R)(1/2)). Na(+), K(+), Ca(2+), PO(4), pH and BP levels were also determined pre- and post-HD. RESULTS: The QTc interval increased significantly post-HD to 434+/-29 from 421+/-26 ms pre-HD (P=0.005); an abnormally prolonged QTc (>440 ms) was recorded in 34% cases pre-HD and in 46% post-HD, i.e. 1.5-2.3 times higher than in the high risk EURODIAB IDDM population. However, this effect was not homogeneous. Only 47 subjects had an increase in QTc duration after a dialysis session, while in 21 a decrease in QTc duration was recorded. The increase in QTc post-HD correlated with Ca(2+) homeostasis. Patients with greater increases in QTc after dialysis had higher baseline plasma calcium levels (r=0.47, P<0.001); also, a larger decrease in Ca(2+) post-HD correlated with higher increases in QTc interval (r=0.33, P<0.05). In contrast with QTc behaviour and with data from the literature, in this young HD population without manifest cardiac disease and with a low prevalence of HTA, post-HD QTc dispersion was similar to pre-HD values, increasing in only 39 patients. Furthermore, changes in QTc dispersion were not related to changes in electrolytes and BP following dialysis. However, changes in QTc dispersion and in QTc interval were directly correlated (r=0.37, P=0.42). There were no relationships between pre-HD measured echocardiographic variables, including: LV ejection fraction, internal diameters, wall thickness, mass and mass index and baseline or changes in QTc or QTc-d. CONCLUSIONS: Haemodialysis increases the QTc interval in ESRD patients, mainly related to rapid changes in electrolyte plasma concentrations. However, the impact on QTc dispersion is less important in the absence of significant coexisting cardiac disease.
Abstract: BACKGROUND: Icodextrin is a new peritoneal dialysis fluid, with maltose polymers providing the osmotic drive, that may extend time on peritoneal dialysis in situations in which use of conventional glucose-based peritoneal dialysis fluid (Dianeal) has led to loss of ultrafiltration. Although cutaneous reactions have been reported, we report a new phenomenon of aseptic peritonitis that has arisen in our unit associated with icodextrin use. METHODS: Icodextrin was first introduced in our unit in 1997 and was used extensively beginning in late 1999. From a combination of an observational study of 141 patients in our unit in whom icodextrin was used over 3.5 years and our unit 2000 and 2001 peritonitis audits, we identified an increase in the incidence of culture-negative peritonitis (CNP). RESULTS: The rate in 2000 of 12.3% rose to 17% in 2001, but this increase was seen only in patients on icodextrin (Percentage changes 2000 audit > 2001 audit: icodextrin patients, 14%--31% increase; Dianeal alone, 12%--10% increase; P < 0.05). Six patients were affected in the period 2000 to 2001 out of a total of 141 patients exposed to icodextrin (4.3%). Two index cases of relapsing CNP responded after withdrawal of the icodextrin. We then adopted a protocol of cessation and rechallenge with icodextrin when dealing with CNP, which successfully confirmed the phenomenon and led to resolution of relapsing CNP after icodextrin withdrawal. All these patients had been on icodextrin for some time, and none had had an immediate reaction or any skin reaction. Eosinophils were reported in the peritoneal effluent from two patients. All patients continued Dianeal without further CNP episodes. CONCLUSION: Icodextrin use carries the risk of CNP, and we suggest a cessation and rechallenge protocol in all patients on icodextrin who have CNP.
Abstract: Oedema is the commonest presenting symptom and sign in nephrotic syndrome. Hypercholesterolaemia, thromboembolic events, and infectious complications may also be features. Three patients are described, each of whose nephrotic syndrome presented with a less common symptom or sign--recurrent pleural effusion, hypercholesterolaemia and oedema, pulmonary embolism--and, as a result, experienced some diagnostic delay. By forgetting to consider nephrotic syndrome, and its underlying causes, there may be inappropriate investigations and treatment for the patient.
Abstract: Ambulatory blood pressure monitoring has been steadily growing in popularity as equipment becomes more accurate, affordable, and patient-friendly. In addition, software packages are more powerful and physician-customizable, and more physicians are accepting of ambulatory blood pressure monitoring's advantages. Summarizing the studies that deal mainly with hemodialysis patients, there are clear advantages to using more than isolated pre- and posthemodialysis blood pressure readings. If enough predialysis blood pressure readings are taken and averaged, this is a reasonable guide to end-organ damage (ie, left ventricular hypertrophy). Home and ambulatory blood pressure-derived values are complementary, and only this approach can discern any further contribution from diurnal blood pressure elevation. The cross-sectional association between blood pressure and end-organ damage is very weak in end-stage renal disease patients if the blood pressure values are "casual," but the relationship is much stronger when ambulatory blood pressure monitoring-derived measurements are used. One prospective study clearly linked the sustained loss of diurnal blood pressure fall with sleep with progressive left ventricular dilatation. Loss of circadian variation in blood pressure is associated with an increased mortality rate for dialysis patients and for diabetic patients, regardless of diabetes type. The combination of nondipping in renal impairment leads to a high mortality rate. Much more work is needed to dissect out the causes for abnormal diurnal blood pressure rhythm and attempt to modulate this parameter. Obstructive sleep apnea may be a promising target for intervention.
Abstract: Amyloidosis frequently affects the kidney leading to proteinuria and loss of function. In cases of AA (reactive/inflammatory) amyloidosis, it is sometimes possible to quench the stimulus to chronic inflammation and by so doing stop further elaboration and deposition of amyloid fibrils. We describe the case of a man with a long-standing empyema who developed nephrotic syndrome and renal impairment. The empyema was resected and shortly afterwards proteinuria disappeared and renal function improved. Strenuous efforts are mandatory to locate and definitively treat underlying inflammatory foci in AA amyloidosis.
Abstract: Microscopic polyangiitis (MPA), or microscopic polyarteritis, is an idiopathic small vessel vasculitis that frequently causes glomerular damage and renal failure and skin and lung damage in many cases. The renal lesions include focal necrotizing glomerulonephritis, extracapillary proliferative (crescentic) glomerulonephritis, and tubulointerstitial infiltration with polymorphonuclear leukocytes and lymphocytes. MPA often is associated with the presence of antineutrophil cytoplasmic autoantibody (ANCA) (myeloperoxidase positive) as a diagnostic marker. MPA commonly is regarded as a serious condition that places the survival of the kidneys and the patient at risk. Typically, there is a prodrome of some weeks to months, with rapid decline in renal function and dialysis as a potential outcome if intensive immunosuppressive treatment is not given or is delayed. We describe an otherwise typical case of MPA occurring in a 52-year-old woman presenting with multisystem disease, antimyeloperoxidase ANCA antibodies, renal impairment, and necrotizing crescentic glomerulonephritis in whom this usual sequence of events was not followed because the patient refused steadfastly to have any treatment for nearly a decade. Renal function remained stable for nearly 10 years, although there were persistent proteinuria, microscopic hematuria, and antimyeloperoxidase ANCA antibodies. A late renal-pulmonary relapse occurred, and immunosuppression was permitted only briefly. Prolonged renal and patient survival in the absence of immunosuppressive treatment has been reported rarely in this context.
Abstract: Hyperparathyroidism is a common problem for patients on renal replacement therapy programs. Many long-term dialysis patients require parathyroidectomy while on dialysis. Some patients, however, despite severe renal osteodystrophy, are transplanted, and in these a large proportion show a slow resolution of bony problems, in the context of the removal of the uremic stimulus to abnormal bone metabolism. A proportion of these patients become hypercalcaemic after renal transplantation, sometimes with symptoms. There is not a consensus on how these patients should be managed, with opinions varying from early parathyroidectomy to later parathyroidectomy and to conservative treatment. We present the case of a lady who underwent 23 years of conservative management of her post-transplant hyperparathyroidism. She was hypercalcaemic for almost all of that period, despite excellent renal transplant function. Finally, after 23 years she underwent surgical parathyroidectomy with autografting with prompt sustained resolution of her symptomatic hypercalcaemia.
Abstract: AIM: Diabetes is now the commonest cause of end-stage renal failure, so there are many diabetic patients receiving dialysis therapy. There are several important ways in which dialysis practice can impinge unfavourably on glucose control. This study focuses on the interaction between maltose-derived metabolites in a new peritoneal dialysis fluid and blood glucose measurements using reagent sticks that depend on the glucose dehydrogenase method. CASE REPORT: We report the cases of three patients, with insulin-treated diabetes and end-stage renal disease treated with peritoneal dialysis, who experienced symptomatic hypoglycaemia with inaccurate glucose readings on reagent strips when converted to icodextrin. CONCLUSION: Careful teamwork between diabetes and renal physicians and specialist nurses is highly desirable to achieve good glucose control in a group of patients at particular risk of microvascular and macrovascular complications.
Abstract: Cardiovascular disease is prevalent in patients with advanced renal failure or on dialysis treatment, and after renal transplantation. The risk factors for the cardiovascular problems are a mixture of conventional and novel ones. Inflammation and oxidation may be especially important in the acceleration of atherosclerosis in chronic renal failure. This article discusses these factors and gathers together the evidence for cardiovascular intervention and treatment in a group of patients whose overall mortality is high.
Abstract: Malignant mesothelioma can present insidiously with progressive breathlessness and chest pain. Paraneoplastic, or non-chest related, presentations are very rare. The case of an elderly man with occupational exposure to asbestos who presented with nephrotic syndrome due to minimal change nephropathy in the context of advanced pleural mesothelial malignancy is reported.
Abstract: Both rheumatoid vasculitis and amyloidosis in rheumatoid arthritis (RA) are uncommon. We describe a patient in whom they occurred together and were associated with fatal intra-abdominal hemorrhage. A 56-year-old Caucasian woman was referred because of increasing lethargy, edema, and proteinuria. She had suffered from seropositive, erosive, nodular RA for 14 years. Previously, she had undergone numerous joint replacements, a thyroidectomy for amyloid-associated (AA) amyloidosis of the thyroid that caused a large goiter and a renal biopsy that showed renal AA-amyloidosis in the context of nephrotic syndrome. As her condition deteriorated, this patient became increasingly reluctant to go to the hospital and to take drugs beyond analgesics. Thus, her RA was chronically under treated. While in the hospital for evaluation, this patient suddenly developed hypotension, tachycardia, and a severe colicky left-sided abdominal pain radiating from the left upper quadrant/epigastric region to the left iliac fossa. Computed tomography (CT) showed a large amount of echogenic free fluid within the abdomen and marked thickening of the omentum. At laparotomy, 2 liters of free blood was found adjacent to a hematoma of the greater omentum, and it was evacuated without identification of a discrete bleeding point. All solid and hollow organs were normal. The omentum was noted to be very friable. She developed a more disseminated bleeding diathesis and persistent peritoneal hemorrhage via her abdominal drains. She succumbed shortly afterward. Histology revealed extensive omental hemorrhage and one large vessel within the area of hemorrhage showed a severe necrotizing vasculitis. Extensive amyloid deposition was also found within the walls of the smaller omental arterioles. Vasculitis in the context of RA is relatively rare and is associated with under treated, seropositive disease. Skin and nerve involvement are most common, but bowel involvement has been reported, with a highly significant morbidity (partly due to late presentation/recognition). Similarly, AA-amyloidosis is a rare but feared long-term concomitant of under treated RA. Early recognition can permit successful anti-inflammatory therapy to affect a clinical and pathological remission; continued inflammatory stimulation is associated with rapid progression and demise. Chronically under treated patients with RA are more prone to rare but potentially devastating complications. Gastrointestinal catastrophes are a feature of both rheumatoid vasculitis and of amyloidosis, here uniquely co-localized.
Abstract: Cardiovascular disease is a major challenge to nephrologists, whether we deal with patients with pre-end-stage renal failure, on dialysis or after successful renal transplantation. It is the most common cause for death in patients with a functional allograft, and prevents many dialysis patients from being engrafted. Coronary artery disease is a diagnostic and therapeutic challenge, as it differs in some respects from that seen in non-uremic cohorts, and lacks much of the evidence-base on which therapeutic intervention rests. This review examines the experimental and clinical literature on cardiovascular disease in uremia, focusing on coronary artery disease. We focus on the incidence, presenting syndromes, screening tools, and interventions in the context of acute and chronic coronary syndromes. Recent evidence comparing coronary angioplasty, coronary artery stenting, and bypass surgery in subjects with renal failure is also reviewed. Coronary artery disease is more prevalent in uremia, more difficult to diagnose and less rewarding to treat compared to non-uremic subjects. Many more randomized trials are needed. In the absence of information from such trials, we advocate aggressive control of conventional and novel cardiovascular risk factors, and early intervention for symptomatic coronary disease.
Abstract: Cardiovascular mortality places a considerable burden on chronic renal replacement therapy programs. Left ventricular hypertrophy (LVH) increases the risk for cardiovascular mortality. Risk factors for LVH in the dialysis population are numerous and include arterial distensibility, hypertension, anemia, arteriovenous fistula, and hyperparathyroidism. An important factor to consider in the diagnosis and evaluation of hypertension in this clinical setting is blood pressure (BP) level variation, only accessible using ambulatory BP monitoring (ABPM). In uremic patients, a relative elevation of BP during sleep periods leading to an increased 24-hour BP load is frequently described. Whether this additional BP burden is pathophysiologically significant has not been resolved. This study is designed to examine the effect on echocardiographically derived measurements of the left ventricle in 60 stable chronic hemodialysis patients of abnormal (reduced) diurnal BP variability, measuring ambulatory BP on three occasions and performing echocardiography twice over a 12-month period. First, we found that most dialysis patients (76%) had consistent diurnal BP rhythms over a 12-month period, and second, those patients with persistently reduced diurnal BP rhythm tended to develop a dilated left ventricle and left atrium in the absence of other known and/or relevant risk factors (persistently increased sleep BP group; n = 36; LV end-diastolic diameter, 38.2 +/- 2.5 mm/m(2) versus persistently normal sleep BP group; n = 10; LV end-diastolic diameter, 30.6 +/- 3. 3 mm/m(2); P < 0.05). These results suggest that persistent abnormal BP variability is a risk factor for a dilated heart on dialysis, independent of the BP level.
Abstract: A 75-year-old woman who had been receiving dialysis for 3 years and had a long history of chronic renal failure attributable to reflux nephropathy was investigated for progressive hypercalcemia in the context of very high intact parathormone (iPTH) levels. Imaging showed two functional parathyroid glands in the neck. At parathyroidectomy, four variously enlarged parathyroid glands were found and completely resected, without autotransplantation. The histology of one of the glands showed invasive parathyroid carcinoma. Parathyroid carcinoma is a very rare condition, with only 16 previous cases involving dialysis patients described in the literature. We review the literature to draw together presentational and therapeutic information on the management of this problem in the setting of renal replacement therapy.
Abstract: BACKGROUND: Arterial stiffening is very pronounced in renal patients. Carotid artery stiffening is a powerful predictor of future cardiovascular mortality, and measures of arterial compliance correlate much better with left ventricular mass (LVM) in dialysis patients than does brachial artery blood pressure (BP). The aim of our study was to describe the influence of a hemodialysis (HD) session on arterial cushioning function and to correlate the potential different types of behavior with echocardiographic derived parameters. METHODS: Radial artery pressure waveforms were measured and recorded noninvasively by applanation tonometry in 51 healthy patients on regular three times weekly HD. The data were then converted into aortic pressure waveforms using a regression equation (SphymoCortrade mark apparatus). Measurements were done pre- and post-HD in order to ascertain the effect of a single HD session on arterial hemodynamics. The augmentation index (AGI; the difference between early and late pressure peaks divided by the pulse pressure amplitude) was used as an index for vascular compliance. Reproducibility was assessed in 20 young healthy subjects by determining the aortic pulse wave augmentation index twice from radial artery BP measurements one minute apart. Intraobserver error was 2.4%. For 10 dialysis patients similarly studied, the intraobserver error was 1.6%. RESULTS: AGI was correlated with subjects' height (r = -0.37, P = 0.009), weight (r = -0.41, P = 0.002), and BP levels: radial systolic BP (r = 0.33, P = 0.018), radial diastolic BP (r = 0.29, P = 0.036), and central systolic BP (r = 0.51, P < 0.001). Comparing the pre- with the post-HD AGI values, four patterns of evolution became apparent: (1) The AGI was negative before the HD session and became even more negative afterward (N = 3 out of 51). (2) The AGI was positive before the HD session but became negative after dialysis (N = 19 out of 51). (3) The AGI was positive before the HD session and, although diminished afterward, remained positive (N = 23 out of 51). (4) The AGI was positive before the HD session and increased afterward (N = 6 out of 51). We also found that in some patients, AGI remained at lower than predialysis levels for at least 24 hours. Significant relationships between echocardiographic parameters and pulse wave contour (PWC) variables included pre-HD AGI and LVM (r = 0.47, P < 0. 001). There was better correlation between LVM and derived predialysis aortic systolic BP (r = 0.56, P < 0.001) than measured brachial (peripheral) systolic BP (r = 0.35, P = 0.04). Patients whose waveform remained abnormal (AGI remained positive) after HD had a more dilated LV (LV-EDD = 52.07 +/- 3.48 mm) than did those patients for whom HD restored "normal" arterial hemodynamics (LV-EDD 46.86 +/- 4.06 mm, P < 0.05). CONCLUSIONS: A standard HD session profoundly affected aortic BP waveform characteristics, with a reduction in wave reflection in 88% of patients. However, restoration by HD of a normal aortic waveform was unusual. Patients whose waveform remained abnormal after HD had larger more dilated LV chambers than did those patients for whom HD restored "normal" arterial hemodynamics.
Abstract: Atherosclerotic renal arterial disease (ARAD) is becoming a more important cause of end-stage renal failure. Diagnosis is more easily achieved because of greater clinical suspicion and more refined screening tools. However, the medical and interventional management of patients with ARAD is not well defined in the literature because there have been few randomized trials. Because the use of angiotensin-converting enzymes (ACE) inhibitors, and more recently angiotensin-antagonists, has become much more widespread, it is inevitable that we should, knowingly or not, give these drugs to patients with ARAD. We describe 2 case studies in which the angiotensin-antagonist irbesartan was given to 2 patients with effectively single-functional kidneys after successful renal arterial radiologic intervention. The rationale for the use of irbesartan was to control BP, which had not responded to the initial arterial intervention, and took place in patients both refractory to, and intolerant of, many other anti-hypertensive drugs. Irbesartan successfully and safely reduced systemic BP, measured by use of ambulatory BP, without prejudicing renal function (measured by use of individual kidney function GFR).
Abstract: Spinal osteomyelitis is a recognized complication in dialysis patients related to hematogenous spread of infection during bacteremia-septicemia. These episodes are often associated with sepsis due to temporary dialysis access. We describe the case of an unfortunate man whose osteomyelitis was located in the posterior facet joints. Such infection is rare and in the reviewed literature is usually associated with a more favorable outcome than described here.
Abstract: Emphysematous pyelonephritis most often presents as an acute medical emergency, typically in a septic diabetic patient with acute renal failure. The management of this condition has traditionally been surgical, with nephrectomy. However, some recent reports have described successful medical interventions. We describe a case of acute bilateral emphysematous pyelonephritis in a frail patient not suitable for bilateral nephrectomy and long-term dialysis. This condition was managed medically, not surgically, with intensive antibiotic and circulatory support. The outcome was complete recovery after months of hospital-based treatment. We discuss the management of this rare but important condition in detail.
Abstract: A new glucoee polymer, icodextrin, related to maltose, is in increasing use as a peritoneal dialysis fluid. We report on adverse events seen in our unit during a 12-month period after the introduction of this reagent.
Abstract: Two hundred and eighty-six patients (190 males and 96 females) with end-stage renal failure (ESRD) started haemodialysis (HD) at Withington Hospital between 1 January 1968 and 31 December 1986. Of these, 152 (53.1%) were successfully transplanted, while 134 had only HD or one transplant lasting < 3 months (i.e. total HD interruption < 3 months). For the whole group, the probabilities of being alive on long-hours home HD at 10 and 20 years were 58.7% and 33.2%, respectively. Mean gross mortality 1968-1986 was 6.5 +/- 3.2% per year. The main causes of death were cardiovascular (36.6%), infection-related (19.2%) and malignancy (9.6%). Males and younger cohorts had a significantly (p < 0.05) higher probability of being alive on long-hours home HD than did females and older cohorts. Eighty-two patients (29% of the total group) survived more than 10 years, of whom 54 were still alive at 1 January 1996: 44 continuing on HD while the other ten had been successfully transplanted. In these 54 patients, mean 24-h ambulatory blood pressure recorded at the date of the study was 117.6/68.9 mmHg; mean BP for the last 5 years on HD was 136.4/81.2 mmHg. Only four (7.4%) were regularly taking antihypertensive medication. Left ventricular hypertrophy (LVH) (by ECG) was present in 64.8% of the 54 patients; its prevalence by echocardiography (LVM index > 130 g/m2 for men and > 110 g/m2 for women) was 77.5%. Only 10 (18.5%) had symptoms or clinical signs of ischaemic heart disease and/or peripheral vascular disease. None had cardiac failure symptoms NYHA class 3-4. Our data show a low incidence of all-cause and cardiovascular mortality, confirming those from the Tassin unit in France, and make a medical case for extended haemodialysis treatment hours.
Abstract: Abnormalities (reduction in/absence of) in diurnal bp rhythm are much more commonly seen in patients with chronic uremia than in patients with primary hypertension or in normal subjects. Target-organ damage is greater in these patients. However, the extent to which these diurnal bp rhythm changes are consistent or variable is untested. We retrospectively examined 223 ambulatory blood pressure monitoring (ABPM) traces in 92 patients with chronic uremia who had undergone ABPM at least twice (mean 2.3 ABPM traces/patient) over the period 1991-1997. ABPM technique and analysis were constant over this period. We found that for patients with chronic declining renal function but not yet on dialysis therapy, 67% retained the same diurnal rhythm from one ABPM recording to the next; if the known tendency for declining renal function to accompanied by a greater prevalence of "non-dipping" is taken into account, 82% of all patients had a "predictable" diurnal pattern. 79% of transplant patients, 87% of haemodialysis patients and 100% of CAPD patients retained the diurnal rhythmicity from one ABPM session to the next. Non-dipping was much more frequent than dipping (67% vs 33%). We conclude that abnormalities of diurnal BP rhythm are reasonably consistent in patients with renal hypertension, especially as renal function declines and patients enter the renal replacement therapy programme.
Abstract: As accurate assessment of hypertension in renal patients must be the cornerstone of better prevention of its deleterious effects, ambulatory blood pressure monitoring (ABPM) has become an essential clinical and research procedure in day to day nephrological practice. However, despite numerous studies in the renal literature, a consensus is needed for normal (desirable?!) ambulatory daytime and nighttime BP levels and for defining normal sleep BP dipping. Nevertheless, blunted sleep BP fall appears to be a ubiquitous finding in renal disease (primary renal conditions, chronic renal failure pre-dialysis, peritoneal and hemodialysis, and renal transplantation). Abnormal diurnal variability should be considered as an important contributor to cardiac and general morbidity as it is clearly associated with a faster decline in renal function and also with more cardiac structural and functional abnormalities - especially left ventricular dilatation. Several mechanisms have been proposed to explain the reduced BP circadian rhythm, but the majority of the supporting evidence is still contradictory. A novel, unifying hypothesis to be tested in future studies, is linking the common diurnal rhythm abnormalities with functional disturbances in aortic and carotid baroreflexes caused by uraemia-related large arterial structural changes (arterial intima and media thickening, arterial calcifications and increased arterial stiffness).
Abstract: Bullous dermatoses (BD) are well recognized in patients with end-stage renal disease (ESRD). It is important to distinguish pseudoporphyria (porphyrin accumulation due to decreased clearance) from true porphyrias, particularly those in which acute neurological attacks may occur. Investigation of the dialysis patient poses practical diagnostic difficulties because urinary porphyrin profiles are not available. We describe a patient on continuous ambulatory peritoneal dialysis (CAPD) with several recognized causative factors for porphyria cutanea tarda (PCT). The patient presented with a blistering photosensitive rash. We highlight the importance of investigating anuric patients with fractionation of both fecal and plasma porphyrins. Plasma porphyrins were grossly elevated (345 nmol/L; reference range, <13), whereas plasma porphyrins in a control group of CAPD patients without blistering rashes were only minimally elevated (mean, 23.9 nmol/L; SD, 11.0; n = 9). Fractionation of fecal porphyrins by high-performance liquid chromatography (HPLC) yielded a pattern typical of PCT. In addition to the contributory factors for PCT that were present, it is possible that porphyrin accumulation secondary to renal failure played a role in the expression of her disease. Patients with ESRD presenting with BD require careful evaluation, including fractionation of fecal porphyrins.
Abstract: Three out of four patients with primary (light chain) amyloid nephrotic syndrome treated with vincristine, doxorubicin and dexamethasone (VAD) induction obtained a partial response and are alive in continuing remission at 4.1, 6.5 and 9.3 years. These preliminary results are of considerable interest and suggest that prospective evaluation of this regimen is warranted in patients with this condition.
Abstract: BACKGROUND: Longevity on dialysis is determined by many factors. One of these has increasingly been seen to be 'dialysis dose'. There are several methods for calculating dialysis dose. We wanted prospectively to test 'gold-standard' UKM-Kt/V with various shortcut bedside formulae, to see whether reliance on the latter approach was likely to lead to errors in over- or underprescribing dialysis regimens. METHODS: Ten bedside formulae for the calculation of Kt/V (urea) were compared with UKM Kt/V values, in a month-long study involving 507 dialysis sessions in 50 patients in a single-centre in-patient haemodialysis unit. RESULTS: For patients with UKM Kt/V<0.8 (median 0.69, n=140), simplified formulae had a difference (delta) of 0.094-0.396 from the calculated UKM resulting in an inter-method variability ranging from 13 to 57%. The least difference was seen with the Calzavara formula (P=NS), maximum difference with the Barth formulae (P<0.05). No statistically significant differences were seen when comparing Daugirdas 1 and 2 and Keshaviah formulae with UKM, for patients with UKM Kt/V<0.8. For patients with UKM Kt/V in the range 0.8-1.4 (median 1.06, n=285) the extreme recorded values from simplified formulae were 0.012 (least different) and 0.245 (most different) from the UKM mean, with an inter-method variability ranging between 1.1% (Basile method) to 23.1% (Calzavara). No statistically significant difference were seen when comparing Daugirdas 1 and 2, Keshaviah, and Lowrie formulae with UKM, for patients with UKM Kt/V 0.8-1.4. For patients with the highest UKM Kt/V values (>1.4; median 1.58, n=72), all simplified formulae gave Kt/V values lower than UKM Kt/V: the minimum difference was 0.070 using Jindal (P=NS, intermethod variability of 4.4%), while the maximum was seen when using Calzavara (P<0.05; difference = 0.69; intermethod variability of 43.7%). There was also no statistically significant difference for Basile and Kerr methods. For the group as a whole the biggest difference from UKM mean values was obtained using Barth's and Calzavara's formulae (delta of 0.171 and 0.140 respectively (P<0.05)). CONCLUSIONS: The best correlations were seen with the Daugirdas 2 formula (r2=0.953). Also, comparing grouped formulae containing ln(Co/Ct) terms with those incorporating the (Co-Ct)/Co ratio (i.e. the urea reduction) there was a better correlation for all formulae employing the logarithmic transformation (r2=0.951-0.953 cf. r2=0.939-0.940). Nevertheless no bedside formula had the accuracy of UKM-Kt/V.
Abstract: BACKGROUND: Since 1971, 55 case-reports of rifampicin-induced ARF have been published, but systematic data on this condition are not available, in view of the disparate nature of the observations. METHODS: We retrospectively assessed prevalence, clinical and biochemical features, and prognostic factors of 60 consecutive cases (41 males/19 females, age 22-68 years), who were admitted to the Iasi Dialysis Centre from 1987 to 1995 for acute renal failure (ARF) following re-treatment with rifampicin. RESULTS: The clinical appearance consisted mainly of gastrointestinal and 'flu-like' symptoms and clinical signs of intravascular haemolysis (the latter in 17% of cases). Frequent laboratory findings were anaemia (96% of cases), leukocytosis (63%), and thrombocytopenia (50%). Severe anaemia was associated with marked haemolysis (25% cases), thrombocytopenia, longer anuria, and slower rate of renal function recovery. Signs of hepatic injury were found in 25% of patients, but it did not seem to affect the outcome of renal function. Prognostic factors in post-rifampicin ARF proved to be the following: the duration of the anuric phase (correlated with the number of dialysis sessions and with the rate of decrease of azotaemia) and the severity of the immunological abnormalities and inflammatory syndrome (haemolysis, leukocytosis, hypergammaglobulinaemia). Post-rifampicin ARF accounted for 16.6% of all ARF cases hospitalized in our Centre during the studied period. Its clinical course was favourable; the mortality rate was only 1.6% (1 case), compared to a 20% general mortality rate among all ARF patients. Full recovery of renal function was achieved in 40% and 96% of patients, 30 and 90 days respectively from onset. CONCLUSIONS: ARF after treatment with rifampicin is not an uncommon condition, especially when tuberculosis prevalence is high, but renal prognosis is usually favourable. Thrombocytopenia, immune haemolytic anaemia, and intravascular haemolysis are frequent complications which are associated with a more severe renal injury.
Abstract: OBJECTIVE: Turner's syndrome (TS) is a disorder associated with characteristic defects in the X chromosome. Autoimmune conditions such as thyroiditis, inflammatory bowel diseases and diabetes have been described in association with TS. METHODS: We have studied the association between TS and juvenile arthritis (JA) by using a survey in which 28 pediatric rheumatology centers (15 in the USA, 10 in Europe, and 3 in Canada) participated. RESULTS: Eighteen cases of TS in a population of approximately 15,000 JRA patients have been found. Two different patterns of arthritis were present: polyarticular (7) and oligoarticular (11). Children with polyarticular disease had early onset, seronegative, progressively deforming arthritis and growth retardation. Those with oligoarticular arthritis had a benign course and were ANA+ (8/11). The oligoarticular children had varying karyotypes whereas almost all of the polyarthritic patients shared the same 45X0 karyotype (6/7). The light and electron microscopic studies of synovium performed in two patients showed chronic inflammation and hyperplasia of the synovial lining cells, vascular proliferation and infiltration with lymphocytes, plasma cells and mononuclear phagocytes. CONCLUSION: Juvenile arthritis is a new autoimmune condition association with Turner's syndrome. The prevalence seems to be at least six times greater than would be expected if the two conditions were only randomly associated. This is the first description of the synovium in Turner's syndrome; no differences from other forms of juvenile rheumatoid arthritis were found.
Abstract: A case report of a 50-year-old woman who has been treated with peritoneal dialysis for 9 years, with a short period off dialysis following transplantation. The patient had long-standing secondary hyperparathyroidism and had declined parathyroidectomy, she had had two episodes of peritonitis in the preceding eight years. She presented with blood-stained dialysate effluent and intermittent abdominal pain. Investigation revealed widespread peritoneal calcification with large plaques of calcium on the visceral peritoneum. She was treated with tidal automated peritoneal dialysis; adequate creatinine clearances have been maintained and the patient has had little further abdominal pain and bleeding. In this report we have illustrated an unusual complication of peritoneal dialysis, peritoneal calcification, and suggest that tidal peritoneal dialysis is a useful therapeutic tool in such cases.
Abstract: BACKGROUND: Hypertensive non-diabetic patients who lack the normal nocturnal decline in blood pressure ('non-dippers') have an increased incidence of cardiovascular complications. Poor blood pressure control is known to exacerbate the decline in glomerular filtration rate in patients with diabetic nephropathy. METHODS: The aim of this study was to assess the contribution of abnormal blood pressure diurnal rhythm to the progression of diabetic nephropathy. We retrospectively studied 26 diabetic patients with hypertension, proteinuria and relentless progressive impairment of renal function due to diabetic nephropathy between 1990 and 1996. Patients underwent ambulatory blood pressure monitoring and were classified as either 'dippers' or 'non-dippers' according to their blood pressure diurnal rhythm. Dippers were patients whose mean sleeping blood pressure (both systolic and diastolic) was 10% less than blood pressure whilst awake. Weight, glycated haemoglobin, serum creatinine (micromol/l) and blood pressure (mmHg) were recorded on a 3-monthly basis. Twenty four hour urine protein excretion and creatinine clearance were recorded annually. The rate of decline of creatinine clearance was derived from serum creatinine estimation. RESULTS: In the 'dipper' group, the rate of decline of creatinine clearance was -2.9 ml/min/year and in those with abnormal blood pressure diurnal rhythm it was -7.9 ml/min/year (P<0.05). There was no significant difference in day-time mean blood pressures, glycated haemoglobin, age and numbers with insulin-dependent diabetes mellitus. CONCLUSION: We found that there was a profound effect of non-dipping upon the rate of decline of renal function in patients with diabetic nephropathy.
Abstract: Blood pressure (BP) elevation and left ventricular hypertrophy are important factors in the high cardiovascular mortality rate in patients on the renal replacement program. Ambulatory BP monitoring is widely regarded as superior to random BP monitoring in predicting end-organ damage from elevated BP. One hundred seventeen patients (60 on hemodialysis [35 with long sessions and 25 with short sessions], 29 on continuous ambulatory peritoneal dialysis, and 28 transplant recipients) underwent ambulatory BP monitoring, with target organ assessment by electrocardiography. Mean 24-hour BP for the patients with the long hemodialysis sessions (LHD) was 115.5/66.6 mm Hg, without the regular use of antihypertensive drugs. The parathormone (PTH) level was the major determinant of BP on ambulatory BP monitoring analysis, with interdialytic weight gain and age each having weaker associations. The BPs of the other three patient cohorts were much higher (short hemodialysis session [SHD], 143.2/82.1 mm Hg; continuous ambulatory peritoneal dialysis, 137.1/76.8 mm Hg; transplant recipients, 135.9/79.2 mm Hg). Overall, two thirds of the patients had reduced diurnal BP variability. Electrocardiogram voltage criteria for left ventricular hypertrophy were exceeded in approximately one third to one half of the patients. Our findings show that good control of BP is possible without recourse to antihypertensive drugs in the context of dialysis with slow ultrafiltration.
Abstract: A 56-year-old man who received a live-related renal transplant in 1988 was started in 1995 on the selective angiotensin II antagonist losartan (Dupont-Merke) to treat worsening hypertension. Two months later because of pulmonary oedema, loop diuretics were started. Within two weeks, serum creatinine had increased from 245 to 571 mumol/l, and the patient became oliguric. A systolic bruit was noted over the graft. Renal angiography showed a 90% stenosis of the transplant renal artery. Losartan was withdrawn, with prompt improvement in renal function. A successful percutaneous transluminal angioplasty performed a few days later resulted in further improvement in renal function accompanied by a significant diuresis.
Abstract: Vascular calcification (VC), which is described in the elderly and in diabetics, is frequently seen in uraemia. It is usually regarded as having little significance. We studied the roentgenological appearance of VC in a homogeneous group of 38 long-hours haemodialysis patients whose longevity on dialysis allowed sustained (10-25 years) follow-up, including annual skeletal surveys and thrice-yearly clinical examinations and biochemical profiles. We compiled a dossier of clinical and laboratory parameters from the start of dialysis to the present day. We were able to analyze the natural history of VC and to determine which clinical parameters were linked with progression. We found that VC became steadily more prevalent-at dialysis onset present in 39% of the patients, but in 92% after an average dialysis duration of 16 years, with a mean onset 9.7 years after starting dialysis. As well as becoming more prevalent, the calcification became progressively more severe in most patients. There were two patterns of VC: axial (aorta and iliac and femoral arteries), seen alone in 32% of the patients, and peripheral (digital arteries), seen alone in 3% of patients. Most patients (65%) had evidence of both types. Calcification was scored for site and severity. Patient age (r = 0.57, p < 0.001), systolic blood pressure (r = 0.54, p < 0.001), hyperparathyroidism (reduced progression after parathyroidectomy), plasma phosphate (r = 0.34, p = 0.042), and vitamin D concentrations (r = 0.53, p < 0.001) were the principal determinants of severity and rate of progression of VC in this population. There was a weak negative association between progression and serum ferritin (r = -0.33, p = 0.046). The reduced vessel compliance that results from VC is likely to be cardiovascularly deleterious. In severe cases, tissue perfusion or vascular access for haemodialysis can be compromised. VC and accelerated cardiovascular mortality are common to uraemia, diabetes, and systolic hypertension in the elderly. Better understanding of these pathological processes may permit intervention and possibly lead to a reduction in cardiovascular mortality.
Abstract: OBJECTIVE: To determine the prevalence and outcome of chronic uveitis in patients with juvenile rheumatoid arthritis (JRA). METHODS: A retrospective analysis of 760 patients with JRA followed in 4 pediatric rheumatology centers. Patients with chronic uveitis were identified and their medical and ophthalmologic records were reviewed. RESULTS: Seventy-four patients with uveitis were identified. The prevalence of uveitis was 9.3%. The mean interval from the onset of JRA to the onset of uveitis was 21 months, and 90% of the patients who developed uveitis did so within the first 4 years of their disease. Visual complications (synechiae, band keratopathy, cataract, or glaucoma) developed in 31% of the patients with uveitis. Complications were more common in patients who presented with uveitis early in the course of their JRA. Complications were also more common in antinuclear antibody (ANA) negative than in ANA positive patients. Visual loss to 20/50 or worse occurred in only 11% of patients with uveitis, and no patient became blind. CONCLUSION: In a very large cohort of patients with JRA, uveitis was uncommon and poor visual outcome was rare. Visual complications did not necessarily result in a poor outcome.
Abstract: 1. The correction of metabolic acidosis with sodium bicarbonate remains controversial. Experiments in vitro have suggested possible deleterious effects after alkalinization of the extracellular fluid. Disequilibrium of carbon dioxide and bicarbonate across cell membranes after alkali administration, leading to the phenomenon of 'paradoxical' intracellular acidosis, has been held responsible for some of these adverse effects. 2. Changes in intracellular pH in suspensions of leucocytes from healthy volunteers were monitored using a fluorescent intracellular dye. The effect in vitro of increasing extracellular pH with sodium bicarbonate was studied at different sodium bicarbonate concentrations. Lactic acid and propionic acid were added to the extracellular buffer to mimic conditions of metabolic acidosis. 3. The addition of a large bolus of sodium bicarbonate caused intracellular acidification as has been observed previously. The extent of the intracellular acidosis was dependent on several factors, being most evident at higher starting intracellular pH. When sodium bicarbonate was added as a series of small boluses the reduction in intracellular pH was small. Under conditions of initial acidosis this was rapidly followed by intracellular alkalinization. 4. Although intracellular acidification occurs after addition of sodium bicarbonate to a suspension of human leucocytes in vitro, the effect is minimal when the conditions approximate those seen in clinical practice. We suggest that the observed small and transient lowering of intracellular pH is insufficient grounds in itself to abandon the use of sodium bicarbonate in human acidosis.
Abstract: BACKGROUND: Ambulatory blood pressure recordings have been shown to correlate better with target organ damage than have isolated clinic blood pressure readings. There have been some small studies demonstrating that abnormal blood pressure diurnal rhythm is common in uraemia and in patients on renal replacement therapy. Abnormal blood pressure diurnal rhythm itself may be a risk factor for accelerated target organ damage. METHODS: We retrospectively studied 480 ambulatory blood pressure recordings in 380 patients with essential hypertension, secondary hypertension, and on renal replacement therapy. We examined diurnal blood pressure rhythm in each group. RESULTS: Abnormal blood pressure diurnal rhythm (non-dipping) is significantly more prevalent in patients with underlying renal disease, even with normal excretory renal function (53%) than in age-, sex-, and race-matched controls with essential hypertension ((30%), P < 0.01). In patients with renal disease the prevalence of non-dipping rose with worsening renal function, reaching statistical significance once plasma creatinine was greater than 400 mumol/l. There was a direct correlation between plasma creatinine and percent decline in blood pressure at night for both systolic (r = 0.23) and diastolic (r = 0.24) blood pressure in patients with underlying renal disease and impaired excretory renal function. High prevalences of abnormal diurnal BP rhythm are seen in patients on haemodialysis (82%), peritoneal dialysis (78%), patients with plasma creatinine > 600 mumol/l (75%), and in renal transplant recipients (74%). CONCLUSIONS: Abnormal blood pressure diurnal rhythm ('non-dipping') is significantly more common in secondary than in primary hypertension, even with normal renal function. Abnormal blood pressure diurnal rhythm becomes increasingly common with advancing uraemia. Once the plasma creatinine is greater than 600 mumol/l the prevalence of non-dipping is the same as that seen with renal replacement therapy. This phenomenon is not modulated by successful renal transplantation.
Abstract: AL-amyloidosis has a poor prognosis, typically with cardiac or renal failure ensuing some months after diagnosis. However, sporadically there have been reports of long-term survivors, either with unusual manifestations of amyloidosis, or after concerted chemotherapy to suppress the overt or occult pathological monoclonal plasma cell population responsible for the elaboration of immunoglobulin light chains. We report the case of a 46-year-old man who has survived 21 years after the histological diagnosis of renal amyloidosis was made, after he had presented with severe nephrotic syndrome. This patient was given intensive chemotherapy but came to end-stage renal failure some 10 years later, was dialysed for 1 year, and then was the successful recipient of a cadaveric renal transplant, which is working excellently some 10 years later, with little evidence of recurrent renal or systemic amyloidosis. There is renewed interest in therapy for systemic amyloidosis, and this case demonstrates that with this approach the prognosis can be more favorable than is commonly assumed.
Abstract: After serious paracetamol overdose, charcoal haemoperfusion was used to remove paracetamol from the circulation, aiming to reduce the severity of subsequent hepatic damage. Daily long-hours high-flux dialysis was given to patients with grade III-IV hepatic encephalopathy, and also to those at risk of developing encephalopathy. We reviewed patients treated in this manner who had not received N-acetylcysteine within the first 15 h after overdose. From January 1983 to January 1993, 73 patients with serious paracetamol overdose were seen, of whom 51 received charcoal haemoperfusion and/or high-flux dialysis. Patients who were admitted within the first 42 h after overdose and who received haemoperfusion and/or dialysis had significantly lower peak levels of prothrombin time, bilirubin and creatinine than those who were admitted after 42 h. Mortality was also lower amongst patients admitted before 42 h, at 2/18 (11%) vs. 15/33 (45%), p < 0.05.
Abstract: Systemic amyloidosis normally has a dismal prognosis. However, there are several case reports of protracted survival, usually as a response to measures designed to retard the further deposition of amyloid fibrils. In AA amyloid, most commonly associated with inflammatory rheumatological, bowel, and chest diseases, such interventions have had some success, but the dramatic response of complete resolution of nephrotic syndrome as a result of the regular institution of postural chest drainage and antibiotic therapy, in the clinical context of bronchiectasis, has been previously reported only once. In both of our cases, after protracted remission, such therapy was abandoned by the patients, leading both to recurrence of nephrotic syndrome and also eventually to end-stage renal failure requiring dialysis.
Abstract: The proportion of patients with vasculitis and rapidly progressive nephritis aged 70 years or over has risen from about 10% in the 1980s to over 30% in series reported in the 1990s. This study was undertaken to examine the presentation and outcome of such older patients. Seventeen of 56 patients (30%) who presented at two renal units were aged 70 years or over. Mean creatinine level at presentation was 530 mumol/l, and five patients received dialysis at presentation. Outcome was dependent on three factors, namely comorbid pathology, response to immunosuppressive therapy, and the occurrence in three cases of temporary spontaneous partial remission. Overall patient survival at one and two years was 62.5% and 50%, respectively, and 90% and 100% of surviving patients were independent of dialysis at one and two years, respectively. Response to chemotherapy was excellent, with full rehabilitation in many cases and no deaths directly attributable to adverse effects of immunosuppressive therapy. We conclude that diagnosis of vasculitis and rapidly progressive glomerulonephritis by renal biopsy and the subsequent administration of chemotherapy (including cyclophosphamide in many cases) resulted in a worthwhile benefit in these elderly patients.
Abstract: This study was performed to evaluate prognostic factors in ADPKD progression to ERSF. Previously reported negative factors (male gender, age, hypertension, palpable kidneys and UTI) as well as the extra-renal presence of cysts and proteinuria, were analysed in a group of 45 ADPKD patients (Male/Female, 25/20; Age = 40.1 +/- 19.7 yrs, range 21-69). Palpable kidneys were associated with higher serum creatinine values (955 +/- 689 vs 743 +/- 504 umol/l, p < 0.001) but not with a greater prevalence of renal failure. Renal failure (100% vs 60%), higher creatinine values (981 +/- 495 vs 778 +/- 654 umol/l) and hypertension (50% vs 18%) were related to a higher prevalence of extra-renal cysts (p < 0.05). Older patients (> 40 years) had a greater prevalence of renal failure (96% vs 32%, p < 0.001). Also, subjects with palpable kidneys, and those with extra-renal cysts, were significantly older (52.8 +/- 10.3 vs 30.5 +/- 20.6 yrs, p < 0.025; and 42.1 +/- 21.9 vs 38.1 +/- 18.2 yrs, p < 0.025). Patients with renal failure and those with extra-renal cysts had a greater prevalence of proteinuria (65% vs 0%, p < 0.001; and 100% vs 24%, p < 0.001). No correlation was seen for male gender, hypertension or UTI with any known complications of ADPKD. The extrarenal presence of cysts, older age, proteinuria and palpable kidneys were associated with a worse renal outcome, but for this Romanian population we can't confirm previous reports suggesting a role for male gender and early onset of disease.
Abstract: A link between plasma calcium, dietary cations, and blood pressure has been suspected for some time, with human, experimental animal, and epidemiological data adduced to support this hypothesis. We identified 21 patients receiving regular maintenance hemodialysis, but not receiving any regular antihypertensive treatment, who had undergone 22 surgical removals of the parathyroid glands in the period 1978 to 1992. These patients' records were then scrutinized. The group preparathyroidectomy mean systolic blood pressure (BP) was 142.6 +/- 19.4 mm Hg. After the operation, the mean systolic BP was 133.6 +/- 21.9 mm Hg (P = 0.004). Plasma calcium decreased from 2.72 +/- 0.18 mmol/L to 2.52 +/- 0.19 mmol/L (P < 0.001). There was a correlation between the decreases in systolic blood pressure (SBP) (9.4%) and plasma calcium (7.3%); r = 0.60, P = 0.012. The decrease in SBP was not immediate, but delayed some months and complete by approximately 9 months after the operation. Furthermore, using ambulatory BP monitoring in a group of long-term hemodialysis patients, we found that parathyroidectomized patients had lower BP and pulse rates than those with intact parathyroid glands (SBP, 122.9 +/- 16.3 mm Hg v 102.9 +/- 9.9 mm Hg; pulse rates, 87.5 +/- 12.7 v 72.0 +/- 7.5 beats/min, P < .001, nonparathyroidectomy v postparathyroidectomy, both comparisons). These data support a link between plasma calcium and BP in patients receiving maintenance hemodialysis.
Abstract: This article describes the echocardiographic structural and functional findings in a cohort of 30 patients on ten or more years of uninterrupted long-hour (24 hours per week dialysis schedule) hemodialysis (mean duration 187.7 months, range 120 to 299 months). Cardiac structural analysis was remarkable for the prevalence of LVH (76%), very rarely asymmetric (3%). Hemoglobin and (log) plasma renin activity were determinants of the LV wall thickness ratio (r = -0.57 and 0.54, p = 0.003 and 0.044 respectively). Markers of systolic contractile function were frequently normal (100% MVCFS; 85% FSI). Diastolic ventricular compliance was abnormal in 59% of patients. Blood pressure history appeared important in determining LVH, but office/ABPM measures of BP were not. Patients after parathyroidectomy (PTx) had a smaller LVPWTN (8.68 mm/m2 without PTx cf 7.01 mm/m2 after PTx, p = 0.036). Left ventricular cavity size was rarely enlarged (10%), with hemoglobin (r = -0.47, p = 0.012) and PTH (r = -0.65, p < 0.001) the major determinants of EDDN. Left atrial diameter was increased in 77% of patients. Cardiac valvular calcification was seen in 50% of patients. Our findings show that despite good BP control without recourse to antihypertensive drugs, LVH with good LV systolic function is very common in these long-survivors.
Abstract: Based on correlation analysis with 24-h dialysis collections the peritoneal equilibration test (PET) has been promoted as an aid to prescribe and monitor dialysis dose. However correlation is an incorrect statistical technique to demonstrate the similarity of one measure to another. The closeness (or limits) of agreement should be measured using the technique of Bland and Altman. One hundred and nineteen patients underwent a 24-h dialysate collection and a PET. D/P ratios for urea and creatinine, dialysate volume, urea and creatinine clearance and KT/V (urea) were calculated using both methods and compared using correlation analysis. In addition the limits of agreement, reflecting the potential margins of difference between the two methods, were determined. When used to calculate a daily dialysate volume required to achieve adequacy targets, the PET was found to result in a prescription error range of -0.6 to +1.51/day for creatinine clearance and -0.9 to +0.61/day for urea clearance. The tendency of the PET to exaggerate clearance resulted in 14% of patients incorrectly achieving a target creatinine clearance of 50 1/week and 17% incorrectly reaching a target KT/V of 1.7. The PET cannot be used in place of 24-h dialysis collections to prescribe or monitor dialysis therapy.
Abstract: Theophylline poisoning with a blood level of 183 mg/l in a 38-year-old man was treated with activated charcoal by mouth, but despite this the blood level of theophylline rose and there was circulatory collapse with rhabdomyolysis, acute renal failure and hyperthermia. Treatment with charcoal haemoperfusion and simultaneous haemodialysis was given, followed by continuous arteriovenous haemodialysis (CAVHD). Mean extraction rates of theophylline were 26% during CAVHD, and 86% during combined dialysis and charcoal haemoperfusion. During combined treatment, the mean extraction rate of haemodialysis was 62%, compared with 48% for charcoal haemoperfusion. In summary, activated charcoal given by mouth may be unable to prevent a rise in blood levels and the development of complications after substantial theophylline overdose. If theophylline is to be removed from the blood, a combination of charcoal haemoperfusion and haemodialysis will give the best clearance, but haemodialysis alone may be effective.
Abstract: A 30 year old man with a 20 year history of chronic renal failure who presented with a testicular lesion is described. The lesional pathology, secondary oxalosis, and associated sperm granuloma of the epididymis was clinically considered to be an intrascrotal tumour. The oxalate crystal deposition was present within the rete testis, the ductuli efferents, and the epididymis along with sperm granulomata. This seems to be a rare complication of secondary oxalosis associated with chronic renal failure and having both clinical and pathological implications.
Abstract: The cellular basis for essential hypertension remains obscure. Abnormal ion transport has been demonstrated in both experimental and essential hypertension, raised levels of sodium-lithium (Na(+)-Li+) and sodium-proton (Na(+)-H+) exchange in blood cells being a consistent feature. However, Na(+)-H+ exchange is not the main regulator of intracellular pH at resting pH, while the importance of the contribution of bicarbonate to cellular pH regulation is now increasingly appreciated. Serum and serum-derived growth factors are known to affect intracellular pH and the activity of the Na(+)-H+ antiporter. This study was designed to investigate the activity of Na(+)-H+ exchange in the leucocytes of patients with essential hypertension in the presence of bicarbonate in vitro and to measure the effect of autologous serum on intracellular pH and Na(+)-H+ exchange. Paired serum samples from essential hypertensives and their controls were used on leucocytes from other (unrelated, normotensive) donors to investigate the same parameters. In a study of 30 patients with untreated essential hypertension and 30 controls matched for age, sex, race and body habitus we found no difference in resting pH or buffering capacity (pH 7.28 +/- 0.01 and 32.0 +/- 1.6 mmol/l per pH, hypertensives, versus 7.27 +/- 0.02 and 34.5 +/- 1.8 mmol/l per pH, controls) but a marked difference in the maximal rate of Na(+)-H+ exchange in response to intracellular acidification (57.8 +/- 3.2 mmol/l per min versus 47.2 +/- 1.4 mmol/l per min, P = 0.004).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: 1. Leucocyte Na+/H+ exchange and intracellular pH were investigated in physiological buffer containing bicarbonate. 2. The amiloride analogue 5-(N,N-hexamethylene) amiloride (1 x 10(-5) mol/l), an inhibitor of Na+/H+ exchange, had no significant effect on resting leucocyte pH, Na+ influx or Na+ content. 3. Ammonium chloride washout induced a profound intracellular acidosis, stimulating Na+/H+ exchange. This led to a 236% increase in Na+ influx. Eighty-eight per cent of this increase was inhibited by 5-(N,N-hexamethylene) amiloride. This demonstrates that 5-(N,N-hexamethylene) amiloride is an effective inhibitor of Na+/H+ exchange in human leucocytes. 4. The recovery from intracellular acidosis was shown to be dependent entirely on the presence of extracellular Na+. The Ki for inhibition by 5-(N,N-hexamethylene) amiloride of the recovery was 0.5 mumol/l. 5. Incubation with serum increased Na+ influx and Na+ content: the maximal effect was reached at 20% dilution. Serum (10%, v/v) increased influx by 40%, and 20% (v/v) serum by 102%, over resting levels. Only 43% of the serum-induced increase in Na+ influx was inhibited by 5-(N,N-hexamethylene) amiloride. This represented one-fifth of total Na+ influx. 6. Leucocyte intracellular pH increased on incubation with serum. This alkalinization was inhibited using 5-(N,N-hexamethylene) amiloride. 7. Studies of Na+/H+ exchange in leucocytes in physiological and pathological states are more likely to reflect the state in vivo if carried out in the presence of autologous serum.
Abstract: The role of Na-H exchange in endothelin-induced contraction of human peripheral resistance vessels was investigated. Endothelin produced a dose-dependent contraction which was greatly attenuated in the presence of a low extracellular sodium concentration. Inhibition of Na-H exchange by the amiloride analogue 5-(N,N-hexamethylene) amiloride (5-NNHA) resulted in a greater than 65% relaxation of a maximal endothelin-induced contraction in the presence of normal extracellular sodium. However, in the presence of a low extracellular sodium concentration, inhibition of Na-H exchange only resulted in a 25% relaxation. These data suggest that endothelin-induced vasoconstriction of human peripheral resistance vessels is mediated in part by stimulation of Na-H exchange.
