Abstract: A G-->C polymorphism has been identified in the human cyclooxygenase-2 (COX-2) gene promoter at position -765 with C allele leading to a decreased promoter activity with low prostaglandin E2 (PGE2) production. PGE2 has strong immunomodulatory properties that could influence graft survival. We studied the association between this polymorphism and allograft failure in two independent cohorts of renal transplant recipients (RTRs) including a total of 603 patients. The functional effect of COX-2 gene promoter polymorphism was analyzed by measuring serum levels of PGE2. Median follow-up was 8.7 and 7.9 years for the first and second cohort, respectively. Analysis of 603 patients identified 20 CC (3.3%), 179 GC (29.7%) and 404 GG (67%) carriers. Patients with the GG genotype had significantly higher serum PGE2 concentrations than patients with the C allele. Carriers with a C allele have an independent increased risk of graft loss (hazard ratio (HR) 2.43 [95% CI 1.19-4.97], p = 0.015 for cohort 1; HR 1.72 [95% CI 0.99-3.77], p = 0.051 for cohort 2) compared to GG patients. COX-2 gene promoter polymorphism at position -765 (G-->C) is associated with a higher rate of graft loss in RTRs. Such findings may be used to influence immunosuppressive strategies and optimize patient management.
Abstract: INTRODUCTION: The incidence of genitourinary tumors (GUT) in renal transplant recipients (RTR) is higher than in the general population. We previously reported that CD4 lymphocytopenia is associated with a high incidence of skin cancer in RTR. Here, we investigate whether persistent CD4 T cell lymphopenia is associated with GUT occurrence. PATIENTS AND METHODS: A total of 433 patients were included in this study. All patients underwent annually systematic lymphocyte subset (CD3, CD4, CD8, CD19) determination by flow cytometry. RESULTS AND CONCLUSION: During the follow-up period, 13 patients developed GUT: 6 patients a prostate adenocarcinoma (incidence 0.06%/year) and 7 patients a renal cell carcinoma (incidence 0.07%/year). The patients with GUT were older than those without. Both groups did not differ in posttransplant duration, dialysis mode and duration, induction regimen, or acute rejection history. No persistent CD4 lymphopenia was observed in the patients with GUT. Although CD4 T cell lymphopenia is associated with skin cancer in long-term RTR, it did not appear to be a risk factor for GUT. This suggests that other factors encountered in the setting of kidney transplantation (e.g., immunosuppressive drugs, end-stage renal failure, etc.) favor the development of GUT in RTR.
Abstract: While the use of nonspecific immunosuppressive drugs has significantly reduced the incidence of acute graft rejection, the benefits of such therapies on chronic rejection and overall long-term graft survival are uncertain. Persistent excessive immunosuppression after immunosuppressive drug treatment is associated with long-term toxicity including increased incidence of cancers, severe infectious complications and metabolic diseases (for example, diabetes, atherosclerosis). One of our team's aims is to identify immunological factors that can predict such toxicities. We have previously demonstrated that CD4T cell cytopenia was correlated with high risk of cancers and infections as well as atherosclerosis in renal transplant recipients. Now, we are investigating the mechanisms involved in CD4T cell cytopenia. We are also exploring how inflammation and cells from the innate immunity influence the complications associated with kidney transplantation. This was performed through the analysis of gene polymorphism on TLR-4, NOD2/CARD15 receptors and IL-6 promoter and correlation with transplantation outcome. We already correlated IL-6 promoter gene polymorphism at position -174 with new-onset diabetes after transplantation in overweight patients. Identification of gene polymorphisms or factors associated with complications after transplantation may help physicians to determine high-risk recipient profiles and optimize pre- and post-transplantation treatment strategies.
Abstract: BACKGROUND: Serum levels of 25-OH-D3 inversely correlate with the incidence of various types of cancers in the general population. Because risk factors and incidence of cancer in renal transplant recipients (RTRs) are different from the general population, this study was designed to determine whether pretransplant 25-OH-D3 levels could be predictive of cancer risk in RTRs. METHODS: Pretransplant 25-OH-D3 levels were reviewed in 363 consecutive RTRs. The impact of 25-OH-D3 levels on the development of cancer was then analyzed with respect to other known risk factors. RESULTS: One hundred twenty-four patients (34.2%) showed vitamin D deficiency, 185 (51%) vitamin D insufficiency, and 54 (14.8%) with normal vitamin D levels. Thirty-two cancers (8.8%) occurred in 32 patients. A higher incidence of cancer was observed in patients with vitamin D deficiency (13.7% vs. 7% for patients with vitamin D insufficiency [P=0.068] and 3.7% for those with normal vitamin D levels [P=0.007]). 25-OH-D3 levels were lower in patients who developed cancer after transplantation (13.7+/-6 vs. 18.3+/-17.8 ng/mL, P=0.022). Age (hazard ratio, 1.06; 95% confidence interval, 1.02-1.11, for each 1 year increase; P=0.009) and low 25-OH-D3 levels (hazard ratio, 1.12; 95% confidence interval, 1.04-1.23, for every 1 ng/mL decrease; P=0.021) were independent risk factors for development of cancer. CONCLUSION: Pretransplant level of 25-OH-D3 is an important determinant for subsequent development of cancer after transplantation. Future studies should examine whether 25-OH-D3 supplementation can effectively decrease the incidence of cancer in RTRs.
Abstract: BACKGROUND: In the multicenter, open-label Myriade study, renal transplant patients were randomized to early cyclosporine microemulsion (CsA-ME, day 0) or delayed CsA-ME (day 6) with enteric-coated mycophenolate sodium (EC-MPS), steroids and interleukin-2 receptor induction. One-yr results have been published previously. We now report the results of an extension study in which patients were followed up for a period of three yr post-transplant. METHODS: All patients completing the one-yr core study on-treatment were eligible to enter the extension study. RESULTS: Of the 203 patients, 153 completed the core trial on-treatment; 144 (94%) entered the extension study with a minimum follow-up of one yr (73 early CsA-ME, 71 delayed CsA-ME). In 75% of patients receiving EC-MPS during the extension, the recommended dose was administered (1440 mg/d). Median creatinine clearance remained constant (57 mL/min) at 12, 24 and 30 months post-transplant and was similar in the early and delayed CsA-ME groups as well as in subpopulations with or without delayed graft function. One patient in the early CsA-ME group died. No grafts were lost. The incidence of BPAR from time of transplant to the end of the extension study was 17% (24/139). Seven patients (5%) discontinued the extension study prematurely because of adverse events. CONCLUSION: These results suggest that a regimen of CsA-ME, EC-MPS and steroids results in excellent survival rates with stable renal function over a mean follow-up of 30 months. Immediate introduction of CsA-ME has no deleterious effect on long-term renal function, even among patients with delayed graft function.
Abstract: BACKGROUND: Metabolic syndrome (MS) is a known cardiovascular risk factor in the general population. We explored the influence of MS on the occurrence of atherosclerotic events (AEs) after renal transplantation. METHODS: Three hundred thirty-seven renal transplant recipients were included in the study. Various parameters (e.g., anthropometric and biological) were measured 1 year after transplant. RESULTS: One year after transplant, 32% of the study population met criteria for MS. Older age, male gender, pretransplant high body mass index, and an increase in body mass index>or=5% in the first year after transplant were predictive factors for development of MS at 1 year after transplant. Forty-two patients (12.4%) experienced AEs during the 8 years of follow-up. The cumulated incidence of AEs was greater in patients with MS compared with others without MS (25% vs. 7%; P<0.001). In multivariate analysis, patients with MS at 1 year after transplant had an increased risk of AE (hazard ratio 3.40, 95% confidence interval 1.58-7.32, P=0.002). Older age, low creatinine clearance, high C-reactive protein level, and a past history of cardiovascular disease were other independent risk factors for AE. CONCLUSIONS: Similar to the general population, MS is an independent risk factor for AE after renal transplantation. Relevant preventive measures targeting different aspects of MS would then have a potential impact on prevalence of AE in this population.
Abstract: Patients with impaired glucometabolic status or renal function have a higher mortality after acute myocardial infarction. It is unclear whether this higher risk is independent or related to the quality of care. In a prospective registry, stress hyperglycaemia (SH) was defined as glucose level>140 mg/dl. Renal function was assessed by the glomerular filtration rate (GFR): normal (>/=60), mild (30-60) and severe dysfunction (<30 ml/min/1.72 m(2)). The level of risk was assessed by the TIMI risk index and the quality of care by the rate of use of five guidelines-recommended treatments. Among the 1388 patients included, 23% had diabetes, 16% had SH, renal function was normal in 55%, mildly impaired in 35% and severely impaired in 9.5%. At one month, the mortality rate was higher in patients with SH (18%) as compared with diabetics (9%) or those with normal glucometabolic status (5%). Similarly, the mortality rate was higher in those with impaired renal function. Multivariable analysis identified SH, GFR group, TIMI risk index, ST segment elevation MI and quality of care as independent predictors of one-month mortality. In patients with acute MI, SH and GFR<30 ml/min/m(2) are independent predictors of mortality after adjustment for the level of risk and acute care.
Abstract: Apolipoprotein Cs (apoC-1, apoC-II, and apoC-III) are lipoprotein components that have regulatory effects on enzymes involved in lipoprotein metabolism. Owing to their low molecular weights, apoCs can adsorb onto and/or pass through dialysis membranes. Our study determines the consequence of hemodialysis (HD) on plasma concentrations of apoCs and on the activities of enzymes modulated by apoCs. Plasma samples were collected from 28 patients with chronic renal failure before and after HD. Plasma apoC-II levels were unchanged, whereas apoC-III levels were slightly decreased in post-dialysis plasmas. The apoC-I content was markedly reduced during HD. This was due to a significant decrease in the apoC-I content of very low-density lipoprotein (VLDL), whereas the apoC-I content of high-density lipoprotein (HDL) was unchanged. Although HDL bound apoC-I is thought to inhibit cholesterol ester transfer protein, no change in the ability of pre- and post-dialysis VLDL to interact with the transfer protein were observed. Complementary experiments confirmed that VLDL-bound apoC-I has no transfer protein inhibitory potential. In contrast, an increase in the ability of post-dialysis apoC-I-poor VLDL to act as substrate for lipoprotein lipase (LPL) was found compared to pre-dialysis VLDL. Our study shows that apoC-I losses during HD might be beneficial by improving the ability of VLDL to be a substrate for LPL thus improving plasma triglyceride metabolism.
Abstract: Stable renal transplant recipients (RTR) display high rates of atherosclerotic events (AE). Innate immunity and especially vascular inflammation play a role in the pathogenesis of atherosclerosis. It is illustrated both by an increased occurrence of postrenal transplant cardiovascular events in patients with elevated levels of C-reactive protein and by a correlation between posttransplant AE and Toll-like receptor-4 Asp299Gly polymorphism. Here, we analyze the influence NOD2/CARD15 gene polymorphism since NOD2 can modulate macrophage pro-inflammatory activity and macrophage is present in early atherosclerotic lesions. The incidence of single nucleotide polymorphism (SNP) in the three major polymorphic region of NOD2 gene (SNP8, SNP12 and SNP13) was assessed in 182 RTR and the correlation between such polymorphism and the development of AE was analyzed. No correlation was observed between NOD2 gene polymorphism and the occurrence of AE after renal transplantation. NOD2 gene polymorphism thus does not appear to influence cardiovascular complications in RTR.
Abstract: Whether high total serum homocysteine levels (tHcy) contribute to increase mortality or offer a survival advantage in chronic hemodialysis patients remains controversial. We conducted a prospective study to determine the impact of tHcy on survival in this population with special respect to chronic inflammation-malnutrition state (CIMS). In this prospective study, 459 hemodialysis patients from 10 dialysis centers located in two regions of France were included. A number of baseline parameters were measured including tHcy and markers of CIMS. Over a mean follow-up period of 54 months, 219 deaths (47.7%) occurred, of which 114 (52%) were of cardiovascular (CV) origin. tHcy of equal to or greater than 30 micromol/l was associated with a higher risk of all-cause mortality in patients without CIMS (hazard ratio (HR): 1.55 (confidence interval (CI): 1.12-4.72)), but not in overall dialysis population or those with CIMS. When only CV mortality was considered, tHcy of equal to or greater than 30 micromol/l was associated with a higher risk in patients without (CIMS HR: 1.91 (CI: 1.23-3.23)), but not in those with CIMS. Hyperhomocysteinemia is a strong risk factor for all-cause and CV mortality in hemodialysis patients who do not present CIMS. This association might be masked in patients with CIMS.
Abstract: BACKGROUND: Survival after acute myocardial infarction (MI) is linked to multiple factors, including mild or severe chronic kidney dysfunction. The aim of this study was to determine to what extent a reduction in glomerular filtration rate (GFR) influences 1-year mortality when risk level at admission and quality of care are taken into account. METHODS: A prospective registry was carried out in a geographically delimited area, including all patients admitted with a diagnosis of acute MI over a 6-month period. The GFR was calculated from serum creatinine levels, and patients were stratified into 3 groups: GFR1 >59 mL/min per 1.73 m2, GFR2 >29 and <60 mL/min per 1.73 m2, and GFR3 <30 mL/min per 1.73 m2. A risk index based on initial presentation was calculated. Inhospital and discharge treatments were recorded, taking into account possible contraindications. Patients were followed up for 1 year to assess all-cause mortality rate. RESULTS: A total of 754 patients were included, 333 ST-elevation MI and 421 non-ST-elevation MI. Overall 1-year mortality was 11.5%. Patients with impaired GFR were older, with more comorbidities, and received fewer effective therapies (less reperfusion, glycoprotein IIb/IIIa receptor inhibitors, early angiography, beta-blockers, and statins). One-year mortality increased as GFR decreased: GFR1 2.3% (5/215), GFR2 9.4% (31/328), and GFR3 24.2% (51/211) (P < .001 for trend). By multivariable logistic regression, a significant association was found between 1-year mortality and risk index (odds ratio [OR] 1.41, 95% CI 1.16-1.71 per 10% increase in risk index), GFR (OR 0.97, 95% CI 0.95-0.98 per additional GFR unit), use of beta-blockers (OR 0.15, 95% CI 0.05-0.50 for users), and early coronary angiography (OR 0.26, 95% CI 0.32-0.66 for patients submitted to angiography). CONCLUSIONS: In patients with acute MI, decreased GFR is associated with higher mortality, and this relation remains strong after adjustment for the level of risk at admission and the effective treatments used.
Abstract: New-onset diabetes after transplantation (NODAT) is a serious complication of transplantation. This study tested whether IL-6 production capacity may influence the development of NODAT in two different groups of patients. The occurrence of NODAT was analyzed with respect to IL-6 gene promoter polymorphism at position -174 (G-->C) and other relevant risk factors retrospectively in 217 renal transplant recipients and prospectively in 132. A linear increase in both circulating IL-6 (P = 0.09) and C-reactive protein (an indicator of basal IL-6 secretion; P = 0.03) concentrations from the CC genotype to the GG genotype was observed. In the multivariate model, the CC genotype was associated with a decreased risk for NODAT compared with the GG genotype in the two cohorts. Homeostasis Model Assessment for Insulin Resistance also revealed lesser insulin sensitivity in the GG carriers than in the CC carriers (2.15 +/- 2 versus 1.32 +/- 1.03; P = 0.03). Subgroup analysis showed that the influence of IL-6 gene promoter polymorphism on the development of NODAT was restricted mostly to overweight patients. These results highly suggest that IL-6 production capacity influences the development of NODAT and that diabetes-inducing drug administration should be limited in overweight patients who carry the GG genotype.
Abstract: Perforin (P), Granzyme B (GB) and Fas-Ligand (FAS-L) are cytotoxic molecules involved in acute rejection (AR) after renal transplantation. A noninvasive diagnostic test to monitor AR and other complications could improve clinical management. We investigated the predictive and diagnostic interest of target mRNA measurements, with a quantitative PCR assay, in AR, as well as in other clinical complications recurrent in kidney transplantation. One hundred and sixty-two urine specimens from 37 allograft recipients were investigated. Clinical settings were AR, urinary tract infection (UTI), cytomegalovirus infection (CMVi) or disease (CMVd), chronic allograft nephropathy (CAN), delayed graft function (DGF) and stable graft course (controls). In the case of AR, mRNA levels of all three molecules were significantly higher than in recipients not showing any clinically evident signs of complication. Indeed, it was observed that expression levels of P, GB and Fas-L mRNA also increase in other clinical situations such as UTI, CMV and DGF. Finally, kinetic studies in three patients with AR revealed that increased P, GB and Fas-L mRNA levels could precede or were concomitant with increased serum creatinin levels. P, GB and Fas-L gene expression in urine specimens were upregulated in AR episodes but also in UTI, CMV infection and DGF. Therefore, this technique would appear to be of limited clinical value as a noninvasive method of diagnosing AR.
Abstract: Enteric-coated mycophenolate sodium (EC-MPS) is therapeutically equivalent to mycophenolate mofetil, but delays release of mycophenolic acid until it reaches the small intestine. De novo renal transplant patients taking part in a 12-month, multicenter, randomized study received cyclosporine microemulsion (CsA-ME, early or delayed to day 6), EC-MPS, steroids, and interleukin-2 antagonist induction. Tolerability data relating to EC-MPS are reported. Ninety-seven patients were randomized to early CsA-ME and 100 patients to delayed CsA-ME. Median daily dose of EC-MPS was 1440 mg at all time points throughout the 12-month period. The most frequently reported adverse events were constipation, anemia, urinary tract infection, abdominal pain, leukopenia, and cytomegalovirus infection; there were four malignancies. Fifty patients (24.6%) discontinued EC-MPS prematurely by 12 months, including 42 patients (84%) who discontinued owing to adverse events. No patient discontinued treatment because of gastrointestinal adverse events. Two-thirds of patients (137 [67.5%]) maintained full EC-MPS dose throughout the 12-month study and did not require any dose reduction or dose interruption. EC-MPS is well tolerated in de novo renal transplant recipients when administered in combination with CsA-ME and steroids, with low rates of dose reductions or interruptions. Gastrointestinal adverse events were responsible for dose reduction or interruption in only 5% of patients.
Abstract: Long-term use of calcineurine inhibitors (CNIs) may contribute to the development of chronic allograft dysfunction (CAD). We investigate the impact of the introduction of MMF combined with cyclosporine (CsA) 50% dose reduction. An open, randomized, controlled, multicenter, prospective study was conducted in 103 patients, receiving a CsA-based therapy with a serum creatinine between 1.7-3.4 mg/dL, more than 1 year after transplantation. They were randomized to receive MMF with half dose of CsA (MMF group) or to continue their maintenance CsA dose (control group). A total of 96 weeks after randomization, the evolution of renal function assessed by regression line analysis of 1/SeCr improved in the MMF group (positive slope) vs. the control group (negative slope), 4.2 x 10(-4) vs. -3.0 x 10(-4), respectively (p < 0.001). Concurrently, the absolute renal function improved significantly in the MMF group. No episode of biopsy-proven acute rejection occurred. One patient in each group lost his graft because of biopsy-proven chronic allograft nephropathy. There was a significant decrease of triglycerides level in the MMF group. Anemia and diarrhea were statistically more frequent in the MMF group. In CAD, the reduction of CsA in the presence of MMF results in significant improvement in renal function during a 2-year follow-up.
Abstract: We investigated the frequencies and predictive factors of prolonged renal failure (PRF) in a retrospective study of 181 consecutive patients undergoing allogeneic hematopoietic stem cell transplantation. Twenty-six patients (23% of long-term survivors) developed PRF. We identified 4 independent prognostic factors; cytomegalovirus infection and chronic graft-versus-host disease appeared as major risk factors for PRF.
Abstract: BACKGROUND: Polymorphisms in Toll-like receptor-4 (TLR4) have been reported to be associated with a blunted immune response to microbial pathogens, as well as a decreased risk of atherosclerosis in the general population. We assessed the impact of the two TLR4 variants on the risk of severe infection, the incidence of acute rejection, and the occurrence of atherosclerotic complications in renal transplant recipients (RTR). METHODS: TLR-4 polymorphisms were assessed in a cohort of 238 RTR. Post-transplant atherosclerotic events, acute rejection, severe bacterial infection, cytomegalovirus (CMV) disease, and opportunistic infections were evaluated as outcomes. RESULTS: The patients were followed for a mean duration of 95 +/- 29 months after transplant. TLR4 polymorphism was observed in 27 (11.3%) RTR. Subjects with TLR4 polymorphisms were less likely to experience post-transplant atherosclerotic events (RR 0.44; 95% CI 0.21 to 0.93; P= 0.02) and acute rejection (RR 0.41; 95% CI 0.30 to 0.83; P= 0.01), but presented severe bacterial infections (RR 1.33; 95% CI 1.12 to 1.67; P= 0.01) and opportunistic infections (RR 3.03; 95% CI 1.72 to 8.29; P= 0.008) more frequently. TLR4 polymorphism was marginally associated with CMV disease (RR 1.47; 95% CI 0.95 to 2.64; P= 0.08). CONCLUSION: RTR with TLR4 polymorphism present a lower risk of post-transplant atherosclerotic events and acute allograft rejection, but experience severe infectious episodes more frequently. This subset of RTR may benefit from a less potent immunosuppression regimen, along with increased preventive measures against infectious agents.
Abstract: BACKGROUND: Posttransplant diabetes mellitus (PTDM) is a frequent complication in renal-transplant recipients (RTRs). We conducted a prospective study to assess the potential role of PTDM in the development of atherosclerotic events (AE) in RTRs. METHODS: Three hundred fifty-seven consecutive RTRs were enrolled in this study. The incidence of various AE were assessed with respect to the presence of PTDM and a number of cardiovascular (CV) risk factors. RESULTS: The patients were followed for a mean duration of 60+/-14 months. Thirty-nine (11%) patients had PTDM. Fifty AE occurred in 48 (13.4%) patients. Although AE were more frequent in RTRs with PTDM compared with nondiabetic patients (33% vs. 8.8%; P=0.007), PTDM was only modestly associated with AE in the multivariate Cox regression analysis (relative risk [RR] 1.34; 95% confidence interval [CI], 1.04-2.18), mostly caused by significant interactions between PTDM and three confounding variables that were independently associated with AE: age, serum C-reactive protein (CRP) level, and serum high-density lipoprotein cholesterol concentration. Patients with high levels of homocysteine showed a significantly increased risk of AE (RR 4.67; 95% CI 1.82-15.87), as did those with high serum levels of CRP (RR 2.57; 95% CI 1.57-6.23). CONCLUSIONS: Our study shows a significant association between PTDM and AE. Nevertheless, a large amount of the excess risk of posttransplant diabetic RTR is explained by the coexistence of other CV risk factors. Moreover, high serum levels of CRP and hyperhomocystinemia were found to be among the nontraditional factors contributing to AE in our patients.
Abstract: Metabolic syndrome (MS) and obesity participate in the pathogenesis of kidney disease. We explored the impact of MS and post-transplant weight gain on graft survival. Two hundred ninety-two renal transplant recipients (RTRs) were included in the study. Various parameters (e.g. anthropometric, biological) were measured at the time of transplantation as well as 1 year post-transplant. The proportion of patients with overweight or obesity significantly increased during the first year post-transplant (p = 0.04). Mean weight gain was 2.7 +/- 5.8 kg. Thirty patients (10.3%) lost their graft during follow-up. In multivariate analysis, patients with an increase in body mass index (BMI) of more than 5% at 1 year post-transplant had an increased risk of graft loss with (HR: 2.82 [95% CI: 1.11-7.44], p = 0.015) or without death censoring (HR: 2.31 [95% CI: 1.06-5.04], p = 0.035). Low creatinine clearance (HR: 4.72 [95% CI: 1.63-13.69], p = 0.004), high urinary protein excretion (HR: 3.21 [95% CI: 1.27-8.18], p = 0.014) and delayed graft function (DGF) (HR: 2.621 [95% CI: 1.07-6.39], p = 0.036) were also independent risk factors for graft loss. MS did not independently predict graft loss, partly due to significant interactions with low-grade inflammation. We conclude that post-transplant weight gain significantly reduces graft survival.
Abstract: BACKGROUND: Antithymocyte globulin (ATG) preparations are frequently used as induction treatment in renal transplantation, but little is known about the clinical equivalence of these different agents. We performed a retrospective, single-center study to compare the long-term clinical effects of ATG Fresenius (ATGF) and Thymoglobulin (SangStat, Fremont, CA) in renal transplant recipients. PATIENTS AND METHODS: A total of 194 consecutive renal transplant recipients were included who had undergone transplantation in our center between June 1993 and April 2001 and had received ATGF or Thymoglobulin as induction treatment. RESULTS: A total of 129 patients received ATGF and 65 patients received Thymoglobulin. Thirty patients (23%) in the ATGF group demonstrated cytomegalovirus (CMV) disease, whereas 24 patients (37%) in the Thymoglobulin group demonstrated CMV (P =0.02). Five patients (3.9%) in the ATGF group and eight patients (12.3%) in the Thymoglobulin group developed posttransplant malignancy (P =0.01). Five patients (3.9%) in the ATGF group and nine patients (13.8%) in the Thymoglobulin group died during follow-up (P =0.005). Cox regression analysis revealed that Thymoglobulin was an independent predictor of CMV disease (relative risk [RR] 2.16, confidence interval [CI] 95% [1.04-4.48]), malignancy (RR 2.16, CI 95% [1.04-4.48]), and death (RR 4.14, CI 95% [1.36-12.6]). CONCLUSION: In renal transplant recipients, induction therapy with Thymoglobulin seems to be associated with a significantly greater incidence of CMV disease, malignancy, and death compared with ATGF.
Abstract: Renal-transplant recipients have a higher prevalence of thromboembolic events compared with the general population. This elevated risk has been attributed to immunosuppressive drugs as well as metabolic and immunologic factors. Cytomegalovirus (CMV) infection, a frequent complication of transplantation, is known to modify endothelial phenotype from anticoagulant into procoagulant. There are few reports addressing the association of venous thromboembolism with CMV infection in immunocompetent patients. Some authors have also reported cases of arterial thrombosis in transplant recipients presenting CMV infection. However, the association of venous thromboembolic events with CMV infection has not yet been discussed in these patients. We present seven cases of simultaneous acute CMV infection and venous thromboembolism in renal-transplant recipients and suggest a potential causative effect.
Abstract: Stable renal transplant recipients manifest a chronic hypercoagulable state with an increased risk of thromboembolic complications, which appears to be multifactorial. While this group of patients could present the known risk factors for thromboembolism in the general population (e.g. diabetes, cancer, pregnancy), they may also suffer from other situations which are mostly related to transplantation and are consequently specific to them. Here, we review briefly the clinical aspects and controversies of the most important of these factors including immunosuppressive agents, antiphospholipid antibodies, hyper-homocysteinemia, pre-transplant dialysis modality, and post-transplant erythrocytosis. In addition, other more recent topics including hypercysteinemia, recurrent proteinuria, and acute CMV infection are discussed.
Abstract: Loss of autonomic cardiovascular homoeostasis is often suspected in hypertension that has developed after organ transplantation. We serially assessed autonomic cardiovascular control in eight patients in generally good condition who needed cyclosporine (CyA) treatment because of high risk of rejection in corneal transplantation. To this aim, we investigated the patients, before and while they were receiving CyA, for 1 week and at 1, 3 and 6 months. For each period, spontaneous baroreflex, blood pressure, heart rate and variability were assessed, as well as neuro-hormonal indicators, while the patients were in both supine and 60 degrees upright positions. After 1 week of treatment, patients showed increases in systolic, diastolic and pulse blood pressures (P<0.05) that were concomitant with a transient decrease in plasma noradrenaline (P<0.05), which, thereafter, resumed the range of baseline values for 6 months. After patients had received CyA treatment for 1 month, the total power of systolic blood pressure variability and its low-frequency component remained higher than before treatment (P<0.05). At 3 and 6 months, heart rate was decreased (P<0.001) when high-frequency power of RR variability and plasma atrial natriuretic peptide were increased (P<0.05). As plasma noradrenaline never exceeded the baseline range, the hypertensive effect of CyA was not likely to have resulted from sympathetic activation. Rather, the increase in systolic blood pressure variability, its low-frequency component and the pattern of pulse pressure changes, pointed to a direct vascular effect of CyA. The maintenance of a normal cardiac baroreflex function during 6 months of CyA treatment might be pivotal to the adaptive responses towards direct CyA effects.
Abstract: Cytomegalovirus (CMV) infection is reported to be capable of modifying endothelial surface with subsequent increased risk of thromboembolic complications. Nevertheless, there are only sparse reports on its role in the development of bleeding diathesis. Here we report two renal transplant recipients who manifested severe coagulation disorders associated with acute CMV infection. Antiviral therapy was followed by consistent correction of coagulation abnormalities.
Abstract: We report two cases of cutaneous alternariosis in renal transplant recipients. The diagnosis was made by mycologic and histologic examination. The patients were treated with itraconazole. In one patient who had undergone surgical resection of the cutaneous lesion along with antifungal treatment, the follow-up period was uneventful with no signs of recurrence. In the other patient, surgical excision of the lesion was not performed prior to antifungal therapy. The lesion disappeared following treatment but local recurrence was observed 1.5 years later with an unfavorable evolution despite administration of the second course of therapy. Resection of the lesion and prolongation of the treatment resulted in a satisfactory course with no signs of local recurrence over a follow-up period of 4.5 years. Interestingly, both of the patients had a previous history of a mild traumatic event with a stretcher in our outpatient clinic where the follow-up visits were made. A vast mycologic survey was then made in our department, which disclosed that some of the stretchers were contaminated by the fungi and could have potentially served as the reservoirs and vectors for the transmission of the fungus.
Abstract: BACKGROUND: Current cardiovascular risk calculators, widely used in the general population, have not yet been validated in renal transplant recipients. We conducted a prospective study to determine the incidence and risk factors for ischemic heart disease in renal transplant recipients and to assess the relevance of the Framingham Heart Study risk calculator in this population. METHODS: Three hundred and forty four consecutive renal transplant recipients free of vascular disease were enrolled. Coronary events were registered and analyzed with respect to traditional and nontraditional cardiovascular risk factors. The risk of coronary events was assessed through the Framingham Heart Study formula and the relevance of this equation was then analyzed. RESULTS: The patients were followed for a mean duration of 72 +/- 14 months. Twenty seven coronary events occurred in 27 patients (7.8%). In addition to risk factors included in the Framingham Heart Study score, C-reactive protein (CRP) level (P= 0.009), and hyperhomocysteinemia (P= 0.01) were found to be independent risk factors for ischemic heart disease events in renal transplant recipients. The Framingham Heart Study model did not predict absolute ischemic heart disease risk in the transplant population as a whole. CONCLUSION: Nontraditional cardiovascular risk factors greatly contribute to increased incidence of ischemic heart disease events in renal transplant recipients. They should therefore be considered in preventive care of these patients which relies on reduction of overall absolute risk. Although the Framingham Heart Study score has an excellent predictive value in low-risk renal transplant recipients, it tends to underestimate the real cardiovascular risk in high-risk patients.
Abstract: Several animal studies suggest that T cell-mediated immunodeficiency may play a role in the progression of atherosclerosis. This study examined the association between lymphocyte subsets and atherosclerotic events in renal transplant recipients. A total of 302 consecutive renal transplant recipients were enrolled in this prospective study. Peripheral blood lymphocyte subsets were quantified and analyzed with respect to other known cardiovascular risk factors. The patients were followed for a mean duration of 23.5 +/- 4.5 mo. Mean CD4, CD8, and CD19 cell levels were 511 +/- 290/mm(3), 553 +/- 596/mm(3), and 66 +/- 62/mm(3), respectively. CD4 levels were positively related to transplant duration (r = 0.32; P = 0.02) and inversely related to age (r = 0.35; P = 0.01). Twenty-five atherosclerotic events (AE) occurred in 25 patients (8.3%). CD4 levels were lower in patients who experienced CVE (288 +/- 170/mm(3) versus 531 +/- 290/mm(3); P < 0.0001). Cox regression analysis showed that patients in the three upper quartiles of CD4 cell count had a decreased risk of CVE compared with those in the lowest quartile. There was a linear increase in risk of CVE with decreasing CD4 cell count (P < 0.0001). A CD4 cell count in the highest quartile (>663/mm(3)) divided the risk of CVE by 10 as compared with the lowest quartile. In conclusion, CD4 lymphocytopenia is an independent risk factor for the development of cardiovascular complications in renal transplant recipients, suggesting that impaired immune response promotes accelerated atherogenesis in this population.
Abstract: Chronic allograft nephropathy (CAN), the leading cause of graft loss, is due to both immunologic and non-immunologic factors. Cyclosporine (CsA) nephrotoxicity is supposed to significantly contribute to CAN. It has been suggested recently that new commercially available immunosuppressive drugs, such as Mycophenolate Mofetil (MMF) and Sirolimus (SRL), may have properties that may prevent and possibly partly reverse chronic rejection, the alloantigen-dependent immune process of CAN. Thus, our group and others have studied the efficiency of a 2-step therapeutic approach including CsA withdrawal and use of non-nephrotoxic immunosuppressive drugs with properties against chronic rejection, such as MMF or SRL. In this review, we will successively analyze how mechanisms of CsA-related nephrotoxicity, histopathologic findings in CAN, animal models and clinical studies justify this therapeutic approach.
Abstract: BACKGROUND: Epidemiologic studies reported that antiphospholipid antibodies (APAs) were independent predictors of atherosclerotic events. We recently reported a high prevalence of APAs in renal transplant recipients. Nevertheless, the role of APAs on atherosclerotic events has not been prospectively studied in this high-risk population. METHODS: Participants in the study were 324 consecutive renal transplant recipients. Patients were enrolled between January 1996 and May 1998 and followed up until June 2002. RESULTS: The patients were followed for a mean duration of 62 +/- 26 months. Eighty seven (26.8%) patients exhibited APAs. We found a slight, but significant, correlation between total plasma homocysteine (tHcy) concentration and anticardiolipin (ACA) titers (r = 0.26; P = 0.036). Fifty six athersclerotic events (17.2%) occurred in 54 patients. Atherosclerotic events occurred more frequently in patients with APAs (33% vs. 9%; P = 0.0003) and ACAs levels were higher in patients who experienced atherosclerotic events (23.7 +/- 13.1 IU vs. 13.9 +/- 9.4 IU; P = 0.003). APAs were associated with an increased risk of atherosclerotic events (RR, 2.82; 95% CI, 1.17 to 5.31). Cox regression analysis also revealed that age above the median (RR, 5.21; 95% CI, 1.67 to 17.13), a previous history of cardiovascular disease (RR, 3.54; 95% CI, 1.57 to 10.43), hyperhomocysteinemia (RR, 4.01; 95% CI, 1.22 to 14.61), and current smoking (RR, 2.17; 95% CI, 1.01 to 6.72) were risk factors for atherosclerotic events. CONCLUSION: The presence of APAs is an independent cardiovascular risk factor in renal transplant recipients. Prevention trials are necessary to assess the efficacy and safety of anticoagulation therapy in transplant patients with APAs.
Abstract: Although many articles have been published on polyomavirus-induced pathologies in transplant recipients, our knowledge regarding their clinical aspects remains relatively limited. In fact, the number of questions and controversies on the subject seems even to be increasing as new publications continue to appear. This article presents some of these controversies through a brief review of recent clinical facts about the three polyomaviruses that infect humans--JC virus, simian virus 40, and BK virus--as they relate to renal transplantation.
Abstract: BACKGROUND: In a recent uncontrolled retrospective report we suggested that the long-term supplementation of high-dose, i.v. folinic acid combined with high-dose i.v. pyridoxine was highly effective in correcting plasma total homocysteine (tHcy) concentrations in haemodialysis patients. To confirm these findings, we conducted a randomized, controlled trial aimed at evaluating whether i.v. or oral folinic acid provided improved tHcy-lowering efficacy in haemodialysis patients compared with oral folic acid. METHODS: In a 6-month prospective, randomized, controlled trial, 60 chronic haemodialysis patients, matched for age, gender, dialysis duration, and average screening pre-treatment-fasting tHcy levels, were given either 50 mg/week of i.v. calcium folinate (group 1), 50 mg/week of oral calcium folinate (group 2), or 45 mg/week oral folic acid (group 3). All 60 patients also received 750 mg/week of i.v. vitamin B6 and 3 mg/week of oral vitamin B12. RESULTS: Fasting tHcy decreased significantly and to a similar extent in the three groups after 2 months of treatment and remained stable at 4 and 6 months (16.6+/-3.5, 18.3+/-4, and 19.1+/-3.1, in groups 1, 2, and 3, respectively, P=NS). Mean percentage reduction at 6 months was also similar in the three treatment groups (46, 43, and 42% in groups 1, 2, and 3, respectively, P=NS). CONCLUSIONS: These findings show that the tHcy-lowering effects of high-dose i.v. folinic acid, oral folinic acid, or oral folic acid were comparable, suggesting that the hyperhomocysteinaemia observed in haemodialysis patients is not due to abnormal folate metabolism. Furthermore, they are compatible with the view that other abnormalities are also involved in the impaired clearance of homocysteine in uraemic patients.
Abstract: BACKGROUND: We conducted a prospective, uncontrolled, open study to assess the relationship between homocysteine (tHcy) and oxidative stress in chronic, stable, renal transplant recipients (RTR). METHODS: Included in the study were 17 chronic, stable RTR. All the patients received folic acid (5 mg/day). tHcy and total antioxidant capacity (TAOC) were measured before and at the end of the study period. RESULTS: Mean tHcy concentration was 26+/-10 micromol/L. tHcy significantly decreased during the study period (26+/-10 vs. 18+/-7 micromol/L; P<0.001). There was a significant inverse relationship between TAOC and tHcy (r= -0.33; P=0.01). TAOC significantly increased during the study period (1.49+/-0.23-1.78+/-0.6; P<0.001). There was an inverse relationship between the variation in tHcy and the variation in TAOC (r= -0.44; P=0.01). CONCLUSION: Our results demonstrate that hyperhomocysteinemia contributed to increased oxidative stress in RTR. tHcy-lowering treatment with folic acid may lower oxidative stress.
Abstract: AIMS: To determine the respective roles of donor and recipient factors in the subsequent development of hypertension after renal transplantation. PATIENTS AND METHODS: All the patients transplanted between January 1990 and December 1999 who still had a functioning graft 1 year post-transplant (n = 321) were retrospectively studied. Blood pressure was assessed at 1 year post-transplant. Hypertension was defined as a systolic BP > or equal 140 mmHg or diastolic BP > or equal 90 mmHg, or use of antihypertensive medication. Relevant donor and recipient characteristics were recorded. RESULTS: Two-hundred-and-sixty-three patients (82%) were hypertensive. In multivariate analysis, pretransplant hypertension (RR, 1.74, 95% CI, 1.07 to 2.87), anticalcineurin use (RR, 2.59, 95% CI, 1.13 to 5.92), urinary protein excretion (RR, 1.84, 95% CI, 1.06 to 3.18), BMI (RR, 1.08, 95% CI, 1.01 to 1.16), donor age (RR, 1.28,95% CI, 1.05 to 1.59, for each 10-year increase in donor age) and donor aortorenal atheroma (OR, 2.34; 95% CI, 1.24 to 4.46) were associated with hypertension. Among patients under calcineurin inhibitors, those receiving cyclosporine were more prone to have hypertension than those receiving tacrolimus (88.7% vs 78%; p = 0.04). CONCLUSION: Both recipient and donor factors contribute to hypertension in RTR.
Abstract: Because recent large studies have demonstrated that mycophenolate mofetil (MMF) is superior to azathioprine (AZA) as a post-transplant immunosuppressant, it has been speculated that MMF could have a cyclosporin (CsA)-sparing effect in renal transplant recipients with chronic allograft dysfunction. Between April 1996 and October 1998, 31 patients with chronic allograft dysfunction were assigned to have conversion from AZA to MMF with concomitant CsA withdrawal. Patient and graft outcomes were analysed. Mean follow-up time after MMF conversion was 27+/-11 months. Serum creatinine concentration (sCt) significantly decreased after conversion and remained stable at the end of follow-up (227+/-31 micro mol/l vs. 185+/-50 micro mol/l; P<0.0005). Mean variation in sCt was -24% after conversion, whereas it was +20% in the year before conversion ( P<0.001). There was a significant inverse relationship between proteinuria at baseline and improvement in renal function (r=-0.35; P=0.01). Proteinuria increased during follow-up (0.79+/-0.6 vs. 1.79+/-1.08 g/day; P=0.04). Isolated CsA nephropathy was associated with the best outcome. Renal function significantly improved in patients with grade 1 chronic rejection and remained stable in patients with grade 2 chronic rejection. Two patients (6.5%) experienced late acute rejection, respectively 13 and 24 months after CsA withdrawal. Eight patients (29%) experienced systemic infections requiring hospitalization. Blood pressure control and lipid profile improved after conversion. CsA withdrawal with a concomitant switch from AZA to MMF allows a substantial and durable improvement in renal function. Both allograft histology and proteinuria at baseline are predictive of the evolution of renal function after conversion. Physicians should consider the risk of over-immunosuppression possibly associated with this therapeutic strategy.
Abstract: Renal transplant recipients have a well-recognized increased risk of de novo neoplasia. In this study, we investigated whether lymphocyte subset count could predict the risk of developing noncutaneous neoplasia (NCSC) in renal transplant recipients (RTR). Between January 1995 and December 1995, lymphocyte subsets (CD4, CD8, CD19) were measured in 281 RTR. This population was studied until November 1999 for the development of NCSC. The mean follow-up was 42+/-9 months. Neoplasm was diagnosed in 22 patients (7.9%). Patients who developed a cancer were significantly older (53.8+/-6 years vs 38+/-16 years, P<0.0001), had lower CD4 (234+/-126/mm(3) vs 543+/-214/mm(3), P<0.005) and CD19 (19+/-9/mm(3) vs 51+/-22/mm(3), P<0.0001) levels, and more frequently had past histories of skin cancer (24% vs 4%, P<0.01). Cox regression revealed that high CD4 levels (RR 0.73, 95% CI 0.62-0.89 for each 100/mm(3) increase in CD4 cell count) were associated with decreased risk of NCSC, whereas age (RR 2.49, 95% CI 1.12-5.92 for each 10-year increase in age) was predictive of the subsequent development of NCSC. To conclude, CD4 cell depletion is associated with the development of solid cancers and lymphoma in RTR.
Abstract: BACKGROUND: Hyperhomocysteinemia is an independent risk factor for the development of cardiovascular conditions in chronic stable renal-transplant recipients (RTR). Major determinants of plasma total homocysteine (tHcy) in RTR are renal function and folate levels. The data dealing with the possible regulation of the tHcy metabolism by insulin and nutritional status is conflicting in non-transplant populations. METHODS: We examined the relationship between tHcy, insulin and nutritional status in 103 chronic, stable RTR. Demographic, clinical, and biochemical parameters were assessed for each patient. RESULTS: Mean tHcy was 19.7+/-9.2 micro mol/l (range 8.6-53). The tHcy was strongly related to creatinine clearance (r=0.55, P<0.0001). Fasting tHcy levels were negatively related to folate concentrations (r=-0.32, P=0.01). There was a positive relationship between tHcy and LDL-cholesterol (r=0.34, P=0.03) and a significant negative correlation between tHcy and insulin (r=-0.38, P=0.01). Fasting tHcy concentrations were significantly higher in the lower quartile of insulin concentration than in the upper quartile (27.7+/-12.7 vs 15.9+/-9.5, P=0.01). In multivariate analysis, tHcy was associated with serum creatinine (P=0.001), insulin (P=0.02) and folate concentration (P=0.03). Patients with the highest IGF-1 concentration had lower tHcy than patients with the lowest IGF-1 concentration (16.8+/-5.7 vs 23.3+/-11 micro mol/l, P=0.01). CONCLUSION: We observed an inverse relationship between insulin and tHcy in chronic, stable RTR.
Abstract: BACKGROUND: Elevated plasma concentrations of C-reactive protein (CRP) is a risk factor for cardiovascular disease (CVD) in the general population and in hemodialysis patients. The prognostic value of CRP is less well known in peritoneal dialysis (PD) patients. We examined the association between CRP and cardiovascular event (CVE) in a large population of PD patients. METHODS: Two hundred and forty patients starting PD were enrolled in this prospective study. The role of CRP was analyzed with respect to other known cardiovascular risk factors. RESULTS: The patients were followed for a mean duration of 41 +/- 21 months; the median value of CRP was 7 mg/L. Eighty-nine cardiovascular events (CVE; 37.1%) occurred in 84 patients and the CRP levels were higher in patients who experienced CVE (27 +/- 14 vs. 6 +/- 8 mg/L; P < 0.0001). In the Cox model, patients in the three lower quartiles of the CRP levels had a decreased risk of CVE compared with those in the highest quartile. Cox regression analysis also revealed that age, a previous history of cardiovascular disease, hyperhomocysteinemia and hypoalbuminemia were risk factors for CVE. CRP levels were higher in patients who died during the study period (25 +/- 12 vs. 5 +/- 8 mg/L; P = 0.003). In the Cox model, patients with CRP levels above the median had an increased risk of death compared with those in the lowest quartile. CONCLUSIONS: Chronic inflammation, as reflected by elevated CRP levels, is frequent in patients starting PD and independently contributes to an increased incidence of CVE in this population.
Abstract: Hypertension is highly prevalent in the dialysis population, and has been implicated in the pathogenesis of the observed excess of cardiovascular morbidity and mortality in these patients. Nevertheless, there are no reports on the clinical and biochemical determinants of both pulse pressure (PP) and mean arterial pressure (MAP) in dialysis populations. A total of 541 haemodialysed patients from 11 dialysis centres were included in the study. The demographic, clinical, and biological characteristics were recorded. Both pre- and post- dialytic blood pressures (systolic and diastolic) were measured. PP and MAP were calculated. Mean predialytic PP was 67 +/- 17 mm Hg and significantly decreased after dialysis (60 +/- 18 mm Hg; P < 0.0001). In multivariate analysis, a 10 mm Hg increase in PP was positively associated with age (RR, 2.01; 95% CI, 1.35-5.01, for a 10-year increase in age), diabetes mellitus (RR, 1.08; 95% CI, 1.04-1.14), interdialytic weight gain (IWG) (RR, 1.84; 95% CI, 1.07-3.18, for 1% increase in IWG), and current smoking (RR, 2.59; 95% CI, 1.13-5.92) and negatively with Hb concentration (RR, 0.92; 95% CI, 0.84-0.99, for a 1 g/100 ml in Hb). Mean predialytic MAP was 98 +/- 15 mm Hg and significantly decreased after dialysis (91 +/- 16 mm Hg; P < 0.0001). In multivariate analysis, a 10 mm Hg increase in MAP was positively associated with parathyroid hormone (PTH) (RR, 1.32; 95% CI, 1.15-1.6, for 50 ng/ml in PTH), erythropoietin (EPO) treatment (RR, 1.09; 95% CI, 1.03-1.16), and current smoking (RR, 1.87; 95% CI, 1.39-2.41). PP and MAP are associated with different clinical parameters. Most of these factors are potentially reversible. Smoking cessation, correction of anaemia and limitation of IWG should be important challenges for physicians in care of dialysis patients.
Abstract: Urinary TNF-alpha excretion correlates with proteinuria in patients with membranous nephropathy (MGN). Pentoxifylline suppresses or reduces the production of TNF-alpha. Between April, 1999 and August, 2000, we did a single-centre, prospective, pilot study to assess the effects of pentoxifylline (1200 mg/day) on proteinuria in patients with idiopathic MGN. Ten patients were included and treated for 6 months. Pentoxifylline significantly decreased proteinuria from 11 g/day [range 4.6-27] to 1.8 (0-10.9); p=0.001). Pentoxifylline may be a safe and effective adjunct to steroids and immunosuppressants in patients with MGN.
Abstract: Cardiovascular disease (CVD) is one of the leading cause of mortality in renal transplant recipients. Authors review accepted CVD risk factors. The role of additional factors like increased homocysteine level is discussed.
Abstract: BACKGROUND: Cyclosporine A (CsA) nephrotoxicity is a nonimmunologic factor of chronic allograft dysfunction (CAD) in kidney transplant recipients. Mycophenolate mofetil (MMF) may allow CsA dosage reduction or even complete withdrawal in selected populations with CsA nephrotoxicity or CAD. The aim of the present study was to evaluate the efficacy and safety of CsA withdrawal after azathioprine (AZA)-MMF conversion in a population of stable renal transplant recipients. METHODS: Twenty-eight first cadaver kidney recipients were included. AZA was then discontinued, MMF was introduced and after 4 months CsA was completely withdrawn. All patients underwent inuline clearance measurement and renal biopsy at inclusion and at the end of the follow-up (40 wk). RESULTS: CsA was completely discontinued in 20 patients. No patient lost his graft during the study period, but 1 patient experienced a reversible acute rejection episode. Inuline clearance improved significantly in the whole series. At the end of follow-up, histological worsening was observed in 50% of patients without any specific risk factor. In these patients, inuline clearance did not improve. Systolic blood pressure, the need for anti-hypertensive drugs and HDL cholesterol improved. CONCLUSION: In stable kidney transplant recipients, CsA withdrawal after AZA replacement by MMF switch was safe with regard to acute rejection. It improved blood pressure and the lipid profile, but, in 50% of patients was associated with histologic deterioration.
Abstract: Renal transplant recipients have disproportionately high rates of arteriosclerotic outcomes, and recent studies provided controlled evidence that clinically stable renal transplant recipients have an excess prevalence of hyperhomocysteinemia. Few studies suggest that hyperhomocysteinemia may be a cardiovascular risk factor in renal transplant recipients. In the study presented here, the association between atherosclerotic events and homocysteine concentrations was examined in 207 stable renal transplant recipients. The role of hyperhomocysteinemia was analyzed with respect to other known cardiovascular risk factors. The mean follow-up was 21.2 +/- 1.9 mo (range, 14 to 26). Mean total homocysteine (tHcy) was 21.1 +/-9.5 micromol/L and median concentration was 19 micromol/L. Seventy percent of patients (n = 153) were hyperhomocysteinemic (values >15 micromol/L). tHcy correlated negatively with folate concentration (r = -0.3; P < 0.01). tHcy was closely related to creatinine concentration (r = 0.54; P < 0.001). Cardiovascular disease events (CVE) including death were observed in 30 patients (14.5 %; 7.34 events per 1000 person-months of follow-up). Fasting tHcy values were higher in patients who experienced CVE (31.5 +/- 10.3 versus 17.8 +/- 7.5; P < 0.001). Cox regression analysis showed that tHcy was a risk factor for cardiovascular complications (relative risk [RR] 1.06; 95% confidence interval (95% CI), 1.04 to 1.09; P < 0.0001). This corresponds to an increase in RR for CVE of 6% per micromol/L increase in tHcy concentration. Age (RR 1.55; 95% CI, 1.09 to 2.19; P < 0.01) and creatinine concentration (RR 1.34; 95% CI, 1.08 to 1.66; P < 0.01) were also independent predictors for CVE. This study demonstrates that elevated fasting tHcy is an independent risk factor for the development of CVE in chronic stable renal transplant recipients. Randomized, placebo-controlled homocysteine studies of the effect of tHcy lowering on CVE rates are urgently required in this patient population.
Abstract: The aim of this study was to determine the prevalence of secondary hypertension in a population of refractory hypertension without initial clinical or biological findings suggesting identifiable causes of hypertension. METHODS: A survey included 200 consecutive hypertensive patients referred to hypertension specialists for refractory hypertension (BP > 140/90 mmHg on at least two antihypertensive drugs). Prior inclusion, the permanent elevation of blood pressure was confirmed by ambulatory monitoring. In each subject an extensive work-up was performed to detect a secondary cause for hypertension. RESULTS: An essential hypertension was confirmed in 61% of this cohort. A secondary hypertension was detected in 20% of the patients; 8.5% with a primary hyperaldosteronism, 8% with a reno-vascular hypertension and 3% with a nephropathy. Moreover, 18.5% had a low renin hypertension. Thus, 27% of these patients had an abnormality of the renin-aldosterone axis. CONCLUSION: Patients with refractory hypertension should be explored to detect secondary hypertension even without findings suggesting such causes. This additional diagnostic procedure must include at least renovascular investigations and plasma renin/aldosterone level determinations in appropriate conditions.
Abstract: BACKGROUND: The prevalence and clinical significance of antiphospholipid antibodies (APAs) have not been extensively studied in non-systemic lupus erythematosus (non-SLE) renal transplant recipients. METHODS: To further define the prevalence and clinical significance of APAs in non-SLE renal transplant recipients and the appearance of dialysis-related APAs after renal transplantation, we conducted a retrospective study on 178 renal transplant recipients. Documentation of anticardiolipin antibodies (ACAs) and lupus anticoagulant in non-SLE renal transplant recipients, retrospective documentation of ACAs on pretransplant frozen plasma and standardized collection of demographic characteristics and posttransplant history of thrombosis were assessed. RESULTS: Fifty of 178 patients (28.1%) had APAs. Transplant duration was shorter and hemodialysis duration was longer in patients with APAs. A posttransplant history of both venous and arterial thrombosis was more frequent in patients with posttransplant APAs (respectively, 18% vs. 6.2% [P<0.001] and 8% vs. 2.3% [P<0.001]). Pretransplant sera were available from 55 patients. Most of patients with posttransplant ACAs had ACAs in the pretransplant period (85%). Pretransplant ACAs were associated with a posttransplant history of venous thrombosis (P<0.001). CONCLUSIONS: Our study demonstrates a high prevalence of APAs in non-SLE renal transplant recipients. Most of them have been acquired in the pretransplant period. Both pretransplant ACAs and posttransplant APAs are associated with posttransplant episodes of thrombosis. Further studies are required to determine the interest of prophylactic measures.
Abstract: INTRODUCTION: Determinants of hyperhomocysteinaemia in peritoneal dialysis patients have been recently reported but there is still conflicting data on the influence of dialysis adequacy on homocysteine (Hcy). METHODS: We studied 46 consecutive new continuous ambulatory peritoneal dialysis (CAPD) patients to determine the variation of Hcy before and 1 and 6 months after dialysis. The variation in Hcy was analysed with respect to dialysis adequacy, factors known to influence its metabolism, and Hcy peritoneal clearance. RESULTS: Hcy was 31.9+/-9 micromol/l before dialysis. It was significantly higher before dialysis than 1 month after the onset of PD (31.9+/-9 micromol/l vs 23.2+/-6.9 micromol/l, P < 0.0005). Weekly PD Hcy clearance was 14.3+/-5.4 1. There was no relationship between pre-dialysis Hcy and 1 month post-dialysis Hcy (r=0.176, P=0.15). There was a strong relationship between PD Hcy clearance and both PD creatinine clearance (r=0.502, P<0.005) and Kt/V (r=0.42, P<0.005). There was no relationship between Hcy and PD creatinine clearance (r= -0.221, P=0.11). In contrast, the decrease in tHcy at 1 month was related to PD Hcy clearance (r=0.487, P<0.01), to PD creatinine clearance (r= 0.349, P<0.02) and to Kt/V (r=0.32, P<0.02). Multivariate analysis confirmed the relationship between the decrease in Hcy and dialysis adequacy. Eleven patients (24%) experienced arteriosclerotic complications. Fasting Hcy concentrations in this population were significantly higher before and 1 month-post-dialysis than in patients without cardiovascular complications. CONCLUSIONS: We observed a significant and prolonged reduction in Hcy concentrations by peritoneal dialysis in end-stage renal disease patients. The decrease in Hcy concentration was positively related to dialysis adequacy. This study suggests the possibility that dialysis adequacy may influence arteriosclerotic outcomes through an Hcy-lowering effect.
Abstract: BACKGROUND: Insulin resistance with compensatory hyperinsulinaemia has been reported in adult polycystic kidney disease (APKD) patients. Diabetes mellitus is a common complication following transplantation and previous studies have demonstrated that inadequate insulin secretion was a prerequisite for the development of post-transplant diabetes mellitus (PTDM). We conducted a retrospective study to determine whether APKD is a risk factor for PTDM. METHODS: Twenty-six consecutive patients transplanted because of end-stage renal disease due to APKD were studied. A control patient matched for age, gender, immunosuppressive therapy and transplant year was selected for each APKD patient. PTDM was defined by fasting glycaemia exceeding 7.8 mmol/l and the need for insulin or oral antidiabetic therapy. RESULTS: Age, renal function, immunosuppressive regimen, number of acute rejection, cumulative dose of steroids and haemodialysis duration before transplantation were similar in both groups. PTDM occured in 10 APKD patients and four controls (34.6% vs 15.3%; P < 0.005). Among diabetic patients, six APKD patients and two controls required insulin therapy (60% vs 50%; P = n.s.). Diabetic patients were significantly older (55.8 +/- 7 years vs 50.2 +/- 11 years; P < 0.05). CONCLUSION: Although retrospective, this study suggests that APKD confers an increased risk of PTDM.
Abstract: Monoclonal immunoglobulins (molg) have repeatedly been described in organ and bone marrow transplantation. Although their exact significance is not known, their occurrence is often associated with intensive immunosuppression. We investigated whether molg reflect T-cell immune defect and B-cell activation in renal transplant recipients. Immunofixations and lymphocyte subset analysis (CD4, CD8, CD19) were performed in 182 renal transplant recipients. Soluble CD23 concentrations were measured in patients with molg and in control transplant patients without molg. Monoclonal immunoglobulins were identified in 54 patients (29.6 %). Transplant endurance was shorter (62 +/- 53 months vs 81 +/- 47 months; P < 0.02) and age was older (53 +/- 13 years vs 46 +/- 13 years; P < 0.005) in patients with molg. Maintenance immunosuppression did not differ between patients with and without molg. Mean CD4-cell count was significantly lower in patients with molg (387 +/- 286/mm(3) vs 538 +/- 341/mm(3); P < 0.005). Both CD8- and CD19-cell counts were similar for the 2 groups. Soluble CD23 concentrations were higher in patients with abnormal immunoglobulin values than in patients with normal immunofixation (12.8 +/- 8 vs 1.9 +/- 1.8 microg/l; P < 0. 005). Our study provides new evidence that molg reflect T-cell immune defect in renal transplant recipients. Further studies are required to determine whether CD4-cell count and sCD23 may help to predict the risk of lymphoma in transplant patients with molg.
Abstract: BACKGROUND: Recurrence of hemolytic-uremic syndrome (HUS) in the allograft is associated with a very poor renal prognosis. Meta-analysis of previous trials may allow us to better estimate its real frequency, to identify risk factors for recurrence, and to predict the outcome of patients with definite recurrence. METHODS: An exhaustive search was conducted of HUS recurrence in renal transplantation from January 1977 to June 1997 using MEDLINE. RESULTS: Ten studies comprising 159 grafts in 127 patients were identified. The rate of recurrence was 27.8%. One-year graft survival was 76.6% in patients without recurrence and 33.3% in patients with recurrence (P<0.001). Older age at onset of HUS (16.96+/-7.6 years vs. 9.95+/-6.55 years; P<0.02), shorter mean interval between HUS and transplantation (2.51+/-2.7 years vs. 6.03+/-6.4 years; P<0.01), shorter mean interval between HUS and end-stage renal disease (0.79+/-0.39 years vs. 2.78+/-2.47 years; P<0.01), living-related donors, and the use of calcineurin inhibitors were associated with recurrence. CONCLUSION: Risk factors for HUS recurrence in renal transplantation could be identified through this meta-analysis.
Abstract: Studies have demonstrated that hyperhomocyst(e)inemia is present in renal transplant recipients and is correlated with cardiovascular disease. It is still unclear whether hyperhomocyst(e)inemia observed in renal transplant recipients solely depends on the moderate reduction of renal function in these patients or if additional mechanisms are operative in this patient category. A recent study suggested that cyclosporine (CsA) increased plasma homocyst(e)ine concentration in interfering with folate-assisted remethylation of homocysteine. To confirm this hypothesis, we studied plasma homocyst(e)ine folic acid and cobalamin concentrations in 122 renal transplant recipients (104 on CsA and 18 not receiving CsA). After adjusting for age, gender, transplant duration and serum creatinine concentration, patients with and without CsA had similar plasma homocyst(e)ine concentrations (17.9 +/- 6.1 mumol/l in CsA(+)patients vs 17.1 +/- 5.6 mumol/l in CsA(-)patients; p = 0.3). Moreover, we found a significant inverse relationship between plasma homocyst(e)ine and folic acid concentrations in both CsA(+) (r = 0.218; p < 0.01) and CsA(-) (r = -0.678; p < 0.05) patients. Patients with a past history of cardiovascular incidents had higher plasma homocyst(e)ine concentrations than those without cardiovascular antecedent (20.5 +/- 7.8 mumol/l vs. 18.01 +/- 9.9 mumol/l; p < 0.05. To conclude: 1, We did not find any influence of CsA on plasma homocyst(e)ine concentrations. 2. We demonstrated that as in other patient category, plasma folic acid and homocyst(e)ine concentrations are significantly correlated in CsA(+) patients. 3. Homocyst(e)ine-lowering therapy would be prescribed in CsA(+) patients to allow correction of hyperhomocyst(e)inemia.
Abstract: Post-transplant erythrosis (PTE) develops in 9%-22% of all renal transplant recipients. Defined as a persistently elevated hematocrit (> 0.51), it occurs most commonly during the first 2 years post-transplantation in hypertensive males with excellent allograft function. Several studies have focused on a major role for angiotensin II in PTE pathogenesis, and some case reports have suggested that losartan is an effective treatment for PTE. Nevertheless, its long-term safety and efficiency have not been reported in renal transplant recipients suffering from PTE. We describe four patients successfully treated with losartan for PTE. Hematocrit remained normal for 21, 18, 15, and 15 months, respectively, after the beginning of losartan therapy. Mean erythropoietin concentration was not modified by treatment (17 +/- 3.7 mU/ml vs 17 +/- 3.8 mU/ml) and serum creatinine concentration remained stable. We conclude that losartan is a safe and effective long-term treatment for PTE.
Abstract: BACKGROUND: Renal transplant recipients are at increased risk of developing skin cancer. It remains difficult to establish the actual influence of overimmunosuppression in the development of skin cancers. We investigated whether lymphocyte subset count may predict the risk of developing skin cancer in long-term renal transplant recipients. METHODS: One hundred fifty long-term renal transplant recipients were followed for a mean period of 26 months. Each patient was examined at least annually by a dermatologist. Lymphocyte subsets were measured annually. RESULTS: Fifteen patients exhibited skin cancers. Patients with and without skin cancer did not differ in age, gender, transplant duration, hemodialysis duration before transplantation, immunosuppressive regimen, and serum creatinine concentration. CD4 cell counts were significantly lower in patients with skin cancers (330+/-179/mm3 vs. 503+/-338/mm3; P<0.01), whereas total lymphocyte and CD8 and CD19 cell counts were similar between the two groups. CONCLUSIONS: CD4 cell depletion is associated with skin cancer in long-term renal transplant recipients.
Abstract: BACKGROUND: There is a great concern over cyclosporine (CsA) nephrotoxicity in renal transplant recipients, and the effects of conversion from CsA to azathioprine (AZA) remain controversial. Large studies have demonstrated that mycophenolate mofetil (MMF), the morpholinoethyl ester of mycophenolic acid, is superior to AZA as a posttransplant immunosuppressant. METHODS: Six patients with isolated biopsy-proven CsA nephrotoxicity were converted from CsA-AZA to MMF. RESULTS: Mean follow-up was 12+/-2 months. No patient experienced acute rejection. The mean serum creatinine concentration decreased from 225+/-58 to 159+/-66 micromol/L (P<0.0005). Hyperlipidemia and blood pressure improved after CsA withdrawal. CONCLUSION: In a selected transplant population with biopsy-proven CsA nephrotoxicity, CsA withdrawal with a concomitant switch from AZA to MMF seems to be safe and allows a significant improvement of renal function.
Abstract: BACKGROUND: Previous studies have demonstrated that hyperhomocyst(e)inaemia is present in patients with impaired renal function and is correlated with cardiovascular disease. Because conflicting data are available on the prevalence, determinants, and clinical significance of hyperhomocyst(e)inaemia in renal-transplant recipients, we conducted the largest cross-sectional study on homocysteine determinants and clinical correlates in renal transplant recipients. METHODS: Plasma homocyst(e)ine concentrations and factors known to influence homocysteine metabolism were analysed in 224 renal transplant recipients. Atherosclerotic complications were evaluated with respect to plasma homocysteine concentrations. RESULTS: Mean plasma homocyst(e)ine was 21.3+/-9.7 micromol/l. After adjusting for age, gender, transplant duration, and creatinine clearance, patients with and without cyclosporin A (CsA) had similar plasma homocyst(e)ine concentrations (16.9+/-5.9 micromol/l in CsA(+) patients vs 16.3+/-5.2 micromol/l in CsA(-) patients; P=0.3). We found a significant inverse relationship between plasma homocyst(e)ine and folate concentrations in both CsA(+) (r=-0.243; P<0.005) and CsA(-) (r=-0.396; P<0.05) patients. Patients with a past history of cardiovascular events had higher plasma homocyst(e)ine concentrations (25.2+/-11.7 mmol/l vs 20.5+/-8.9 mmol/l; P<0.005). CONCLUSION: Homocyst(e)inaemia is closely related to renal function and folate concentration in renal-transplant recipients. CsA does not seem to have direct effects on homocysteine metabolism. Hyperhomocyst(e)inaemia is associated with cardiovascular disease in renal-transplant recipients. Prospective placebo-controlled homocysteine-lowering therapy studies are required in this patient category.
Abstract: Mycophenolate mofetil (MMF) is a new immunosuppressant developed for the prevention and treatment of acute renal rejection after transplantation. Diarrhea is the most frequent side effect observed during treatment with MMF. Its pathogenic mechanisms remain unknown. We describe a case of severe diarrhea due to villous atrophy in a renal transplant recipient during treatment with MMF. The patient was free of symptoms before MMF. Villous atrophy disappeared a few months after MMF withdrawal.
Abstract: Cytomegalovirus (CMV) is regarded as a predominant infectious agent in solid organ transplants. CMV disease has highly protean clinical manifestations. Nevertheless, urinary tract involvement seems to be very rare during CMV infection. We report two cases of renal transplant recipients in whom ureteral stricture developed in the course of CMV disease. Histologic data were available for them and were consistent with CMV infection. We discuss previous case reports and propose physiopathologic mechanisms.
Abstract: The sudden onset of pulmonary edema in patients with renal artery stenosis is an increasingly recognized entity. Some data also support an association between renal artery stenosis and chronic cardiac failure. We report a 60-year-old man with chronic renal failure who had most normal arterial blood pressure despite highly severe chronic congestive heart failure. Renovascular disease was suspected and an arteriography revealed very tight bilateral artery stenosis. Removal of stenosis led to both renal and cardiac functions improvement.
Abstract: PURPOSE OF STUDY: To evaluate the effect of the angiotensin II type 1 receptor antagonist, losartan, on post-transplant erythrocytosis. METHODS: We retrospectively analyzed the influence of losartan therapy on haemoglobin levels of renal transplant recipients. Twenty-eight patients who received losartan therapy to control hypertension were divided into two groups. In 10 patients, losartan therapy was initiated after treatment with ACE inhibitors which was discontinued due to adverse reactions (Group A). Group B consisted of 18 patients treated with losartan who had never received ACE inhibitors. RESULTS: There was no difference in mean haemoglobin concentration and haematocrit between the two groups before the onset of losartan therapy. In Group B, mean haemoglobin concentration and haematocrit decreased from 137 +/- 20 g/l and 0.4 at the start of losartan therapy to 120 +/- 16 g/l (P < 0.0005) and 0.35 (P < 0.0005), respectively 3 months later. In Group A, neither haemoglobin nor haematocrit differed between the onset of losartan therapy and the end of the study. Serum creatinine increased from 158 mumol/l +/- 78 to 172 mumol/l +/- 80 in Group B (P < 0.005), but remained stable in Group A. Plasma protein concentrations remained stable in each group and there was no change in diuretic therapy during the study. CONCLUSION: Our study suggests that losartan therapy decreases haemoglobin in renal transplant recipients.
Abstract: Few data are available about the muscle status in renal transplant recipients. Moreover, the list of myotoxic drugs is growing longer and some of them are likely to be prescribed in renal transplant patients. These conditions may act as confounding factors in case reports of both cyclosporin and colchicine myopathies. Moreover no study has evaluated the frequency of myopathy in patients on both colchicine and cyclosporin. We conducted a retrospective study including all renal transplant recipients followed in our unit in whom colchicine was prescribed since January 1994. Clinical and biological data of patients on both colchicine and cyclosporin were analysed. Secondly case subjects were compared with matched controls not receiving colchicine but cyclosporin. Ten patients received colchicine in association with cyclosporin. Five patients (50%) experienced muscular symptoms and when performed, muscular histology showed vacuolar myopathy. All five patients improved after colchicine withdrawal. Cases with and without muscular symptoms did not differ in age, transplant duration, and serum creatinine level. Mean duration of colchicine therapy was 12.2 +/- 4.4 months in cases with muscular symptoms and 6.8 +/- 4.6 months in cases without muscular symptoms (P < 0.05). No control complained of either muscular pain nor weakness (P < 0.0005). Only one patient (3.3%) had elevated serum creatine phosphokinase concentration (P < 0.0005). We conclude that myopathy is very frequent in patient on both colchicine and cyclosporin. Muscular symptoms improve in all patients after colchicine withdrawal.
Abstract: High dose oral acyclovir has been reported to be effective in preventing both cytomegalovirus (CMV) infection and disease in renal transplant recipients. We conducted a case-controlled study in which 42 cadaveric kidney transplant recipients were prophylactically treated with high dose oral acyclovir for 3 months and compared to historical controls matched for donor/recipient CMV serological status, age, sex, and immunosuppressive therapy. Before transplantation, study group patients received acyclovir intravenously (500 mg/m2 over 1 hour) which was subsequently given orally (basal dose--800 mg four times daily) from day 2 post-transplantation according to renal function. All patients received 14-day induction immunosuppressive therapy with either a polyclonal or a monoclonal antibody together with low dose steroids and azathioprine, cyclosporin being introduced at day 10 post-transplantation. Blood viral cultures as well as CMV antibody titers were performed in study group and control patients in the same laboratory, before transplantation, weekly until 3 months and then monthly until 6 months. CMV infection was defined as a positive blood or bronchoalveolar lavage viral culture or presence of CMV IgM or CMV IgG in a previously seronegative patient. Diagnosis of CMV disease also required the presence of at least one concomitant febrile illness, with or without other clinical symptoms, not attributable to another pathogen. All patients were followed for 3 months. Incidence of both CMV infection and disease was compared in the two groups using the log-rank test. With regard to CMV infection, we found significantly less CMV infection in CMV seropositive patients (regardless of donor CMV serological status) in the study group compared to historical controls (P = 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)
