hosted by

Anthony Sebastian

Journal articles

Olga Schmidlin, Masae Tanaka, Anthony Sebastian, R Curtis Morris (2010)  Selective chloride loading is pressor in the stroke-prone spontaneously hypertensive rat despite hydrochlorothiazide-induced natriuresis.   J Hypertens 28: 1. 87-94 Jan  
Abstract: OBJECTIVE: To test the hypothesis that in the stroke-prone spontaneously hypertensive rat (SHRSP), the pressor effect of selective dietary chloride loading depends on a positive external sodium balance. METHODS: In 43 male SHRSP fed a Japanese style diet containing a low normal amount of NaCl (0.4%), we compared the effects on telemetrically measured SBP of hydrochlorothiazide, 25 mg/kg per day, alone ('TZ', n = 11); hydrochlorothiazide combined with either KCl ('KCLTZ', 2%K, n = 10) or KHCO3 ('KBCTZ', 2%K, n = 11) and no hydrochlorothiazide ('CTL', n = 11) over a 10-week period starting at 10 weeks of age. RESULTS: With either TZ or KBCTZ, SBP did not increase above baseline values. However, KCLTZ induced a sustained increase in SBP of 17 mmHg (P < 0.0001), an increase almost half of that occurring without hydrochlorothiazide (CTL), 38 mmHg (P < 0.0001). Such divergence of blood pressures with KCLTZ and KBCTZ began over the first 3 days of their administration, even while they induced similarly negative external sodium balances, a positive one occurring only in CTL. Body weight increased more without, than with, hydrochlorothiazide, but did not differ between KCLTZ and KBCTZ. Changes in SBP occurring on day 2 after treatment assignment predicted final changes. CONCLUSION: These results demonstrate that in the SHRSP, dietary KCl loading can induce a pressor effect despite concomitant hydrochlorothiazide-induced natriuresis that elicits a negative external sodium balance. The results provide evidence that in the SHRSP the pressor effect of selective chloride loading does not depend on a positive external sodium balance, but rather on a mechanism actuated by chloride per se.
Alexander Ströhle, Andreas Hahn, Anthony Sebastian (2010)  Estimation of the diet-dependent net acid load in 229 worldwide historically studied hunter-gatherer societies.   Am J Clin Nutr 91: 2. 406-412 Feb  
Abstract: BACKGROUND: Nutrition scientists are showing growing interest in the diet patterns of preagricultural (hunter-gatherer) humans. Retrojected preagricultural diets are reportedly predominantly net base producing in contrast to the net acid-producing modern Western diets. OBJECTIVE: We examined the dietary net acid load [net endogenous acid production (NEAP)] for 229 worldwide historically studied hunter-gatherer societies to determine how differences in plant-to-animal (P:A) dietary subsistence patterns and differences in the percentage of body fat in prey animals affect the NEAP. DESIGN: With the use of 1) ethnographic data of dietary P:A ratios of hunter-gatherer populations, 2) established computational methods, and 3) knowledge that fat densities of animal foods consumed by hunter-gatherers varied between 3% and 20%, we computed the NEAP for the diets of 229 populations in 4 different models of animal fat densities (model A, 3%; model B, 10%; model C, 15%; model D, 20%). RESULTS: As P:A ratios decreased from 85:15 to 5:95, the NEAP increased from -178 to +181 mEq/d (model A) and from -185 to +120 mEq/d (models B and C). Approximately 50% of the diets consumed by the 229 worldwide hunter-gatherer populations were net acid producing (models B and C). In model D, 40% of the diets were net acid producing. CONCLUSIONS: Our data confirm that the NEAP of hunter-gatherer diets becomes progressively more positive as P:A ratios decline. The high reliance on animal-based foods of a worldwide sample of historically studied hunter-gatherer populations renders their diets net acid producing in approximately 40-60% of subgroups of P:A ratios. Only further investigations can show the implications of these findings in determining the NEAP of human ancestral diets.
L A Frassetto, M Schloetter, M Mietus-Synder, R C Morris, A Sebastian (2009)  Metabolic and physiologic improvements from consuming a paleolithic, hunter-gatherer type diet.   Eur J Clin Nutr 63: 8. 947-955 Aug  
Abstract: BACKGROUND: The contemporary American diet figures centrally in the pathogenesis of numerous chronic diseases-'diseases of civilization'. We investigated in humans whether a diet similar to that consumed by our preagricultural hunter-gatherer ancestors (that is, a paleolithic type diet) confers health benefits. METHODS: We performed an outpatient, metabolically controlled study, in nine nonobese sedentary healthy volunteers, ensuring no weight loss by daily weight. We compared the findings when the participants consumed their usual diet with those when they consumed a paleolithic type diet. The participants consumed their usual diet for 3 days, three ramp-up diets of increasing potassium and fiber for 7 days, then a paleolithic type diet comprising lean meat, fruits, vegetables and nuts, and excluding nonpaleolithic type foods, such as cereal grains, dairy or legumes, for 10 days. Outcomes included arterial blood pressure (BP); 24-h urine sodium and potassium excretion; plasma glucose and insulin areas under the curve (AUC) during a 2 h oral glucose tolerance test (OGTT); insulin sensitivity; plasma lipid concentrations; and brachial artery reactivity in response to ischemia. RESULTS: Compared with the baseline (usual) diet, we observed (a) significant reductions in BP associated with improved arterial distensibility (-3.1+/-2.9, P=0.01 and +0.19+/-0.23, P=0.05);(b) significant reduction in plasma insulin vs time AUC, during the OGTT (P=0.006); and (c) large significant reductions in total cholesterol, low-density lipoproteins (LDL) and triglycerides (-0.8+/-0.6 (P=0.007), -0.7+/-0.5 (P=0.003) and -0.3+/-0.3 (P=0.01) mmol/l respectively). In all these measured variables, either eight or all nine participants had identical directional responses when switched to paleolithic type diet, that is, near consistently improved status of circulatory, carbohydrate and lipid metabolism/physiology. CONCLUSIONS: Even short-term consumption of a paleolithic type diet improves BP and glucose tolerance, decreases insulin secretion, increases insulin sensitivity and improves lipid profiles without weight loss in healthy sedentary humans.
Lynda A Frassetto, R Curtis Morris, Deborah E Sellmeyer, Anthony Sebastian (2008)  Adverse effects of sodium chloride on bone in the aging human population resulting from habitual consumption of typical American diets.   J Nutr 138: 2. 419S-422S Feb  
Abstract: A typical American diet contains amounts of sodium chloride far above evolutionary norms and potassium far below those norms. It also contains larger amounts of foods that are metabolized to noncarbonic acids than to organic bases. At baseline, in a steady state, diets that contain substantial sodium chloride and diets that are net acid producing each independently induce and sustain increased acidity of body fluid. With increasing age, the kidney's ability to excrete daily net acid loads declines, invoking homeostatically increased utilization of base stores (bone, skeletal muscle) on a daily basis to mitigate the otherwise increasing baseline metabolic acidosis, which results in increased calciuria and net losses of body calcium. Those effects of net acid production and its attendant increased body fluid acidity may contribute to development of osteoporosis and renal stones, loss of muscle mass, and age-related renal insufficiency. The inverted ratio of potassium to sodium in the diet compared with preagricultural diets affects cardiovascular function adversely and contributes to hypertension and stroke. The diet can return to its evolutionary norms of net base production inducing low-grade metabolic alkalosis and a high potassium-to-sodium ratio by 1) greatly reducing content of energy-dense nutrient-poor foods and potassium-poor acid-producing cereal grains, which would entail increasing consumption of potassium-rich net base-producing fruits and vegetables for maintenance of energy balance, and 2) greatly reducing sodium chloride consumption. Increasingly, evidence supports the health benefits of reestablishing evolutionary norms of dietary net base loads and high potassium and low sodium chloride loads. We focus here on the American diet's potential effects on bone through its superphysiologic content of sodium chloride.
Olga Schmidlin, Alex Forman Anthony Sebastian, R Curtis Morris (2007)  What initiates the pressor effect of salt in salt-sensitive humans? Observations in normotensive blacks.   Hypertension 49: 5. 1032-1039 May  
Abstract: We tested the traditional hypothesis that an abnormally enhanced renal reclamation of dietary NaCl alone initiates its pressor effect ("salt sensitivity"). Under metabolically controlled conditions, we grouped 23 normotensive blacks as either salt-sensitive (SS) or salt-resistant (SR), depending on whether or not dietary NaCl loading did or did not increase mean arterial blood pressure (MAP) by >or=5 mm Hg. We determined whether dietary NaCl loading induces greater increases in external Na(+) balance, plasma volume, and cardiac output in SS, compared with any in SR subjects, and differential changes in systemic vascular resistance (SVR) that could account for the pressor differences between SS and SR subjects. Using impedance cardiography, we measured cardiac output and SVR daily at 4-hour intervals throughout the last 3 days of a 7-day period of low NaCl intake (30 mmol per day) and throughout a subsequent 7-day period of NaCl loading (250 mmol per day). In the 11 SS subjects, compared with the 12 SR subjects, NaCl loading induced no greater increases in Na(+) balance, body weight, plasma volume, and cardiac output. Yet, from days 2 to 7 of NaCl loading, changes of MAP in SS diverged progressively from those in SR. From days 2 to 4, progressive increases of MAP in SS subjects reflected importantly impaired decreases of SVR, as judged from "normal" decreases of SVR in SR subjects. In SS and SR subjects combined, changes in both MAP and SVR on day 2 strongly predicted changes in MAP on day 7. In many normotensive blacks, vascular dysfunction is critical to the initiation of a pressor response to dietary NaCl.
Olga Schmidlin, Alex Forman, Anthony Sebastian, R Curtis Morris (2007)  Sodium-selective salt sensitivity: its occurrence in blacks.   Hypertension 50: 6. 1085-1092 Dec  
Abstract: We tested the hypothesis that the Na(+) component of dietary NaCl can have a pressor effect apart from its capacity to complement the extracellular osmotic activity of Cl(-) and, thus, expand plasma volume. We studied 35 mostly normotensive blacks who ingested a low-NaCl diet, 30 mmol/d, for 3 weeks, in the first and third of which Na(+) was loaded orally with either NaHCO(3) or NaCl, in random order (250 mmol/d). In subjects adjudged to be salt sensitive (n=18; Delta mean arterial pressure: >or=5 mm Hg with NaCl load), but not in salt-resistant subjects (n=17), loading with NaHCO(3) was also pressor. The pressor effect of NaHCO(3) was half that of NaCl: mean arterial pressure (millimeters of mercury) increased significantly from 90 on low NaCl to 95 with NaHCO(3) and to 101 with NaCl. The pressor effect of NaCl strongly predicted that of NaHCO(3.) As judged by hematocrit decrease, plasma volume expansion with NaCl was the same in salt-resistant and salt-sensitive subjects and twice that with NaHCO(3), irrespective of the pressor effect. In salt-sensitive subjects, mean arterial pressure varied directly with plasma Na(+) concentration attained with all Na(+) loading. In salt-sensitive but not salt-resistant subjects, NaHCO(3) and NaCl induced decreases in renal blood flow and increases in renal vascular resistance; changes in renal blood flow were not different with the 2 salts. Responses of renal blood flow and renal vascular resistance to NaHCO(3) were strongly predicted by those to NaCl. In establishing the fact of "sodium-selective" salt sensitivity, the current observations demonstrate that the Na(+) component of NaCl can have pressor and renal vasoconstrictive properties apart from its capacity to complement Cl(-) in plasma volume expansion.
Lynda A Frassetto, R Curtis Morris, Anthony Sebastian (2007)  Dietary sodium chloride intake independently predicts the degree of hyperchloremic metabolic acidosis in healthy humans consuming a net acid-producing diet.   Am J Physiol Renal Physiol 293: 2. F521-F525 Aug  
Abstract: We previously demonstrated that typical American net acid-producing diets predict a low-grade metabolic acidosis of severity proportional to the diet net acid load as indexed by the steady-state renal net acid excretion rate (NAE). We now investigate whether a sodium (Na) chloride (Cl) containing diet likewise associates with a low-grade metabolic acidosis of severity proportional to the sodium chloride content of the diet as indexed by the steady-state Na and Cl excretion rates. In the steady-state preintervention periods of our previously reported studies comprising 77 healthy subjects, we averaged in each subject three to six values of blood hydrogen ion concentration ([H]b), plasma bicarbonate concentration ([HCO(3)(-)]p), the partial pressure of carbon dioxide (Pco(2)), the urinary excretion rates of Na, Cl, NAE, and renal function as measured by creatinine clearance (CrCl), and performed multivariate analyses. Dietary Cl strongly correlated positively with dietary Na (P < 0.001) and was an independent negative predictor of [HCO(3)(-)]p after adjustment for diet net acid load, Pco(2) and CrCl, and positive and negative predictors, respectively, of [H]b and [HCO(3)(-)]p after adjustment for diet acid load and Pco(2). These data provide the first evidence that, in healthy humans, the diet loads of NaCl and net acid independently predict systemic acid-base status, with increasing degrees of low-grade hyperchloremic metabolic acidosis as the loads increase. Assuming a causal relationship, over their respective ranges of variation, NaCl has approximately 50-100% of the acidosis-producing effect of the diet net acid load.
R Curtis Morris, Olga Schmidlin, Lynda A Frassetto, Anthony Sebastian (2006)  Relationship and interaction between sodium and potassium.   J Am Coll Nutr 25: 3 Suppl. 262S-270S Jun  
Abstract: Compared with the Stone Age diet, the modern human diet is both excessive in NaCl and deficient in fruits and vegetables which are rich in K+ and HCO3- -yielding organates like citrate. With the modern diet, the K+/Na+ ratio and the HCO3-/Cl- ratio have both become reversed. Yet, the biologic machinery that evolved to process these dietary electrolytes remains largely unchanged, genetically fixed in Paleolithic time. Thus, the electrolytic mix of the modern diet is profoundly mismatched to its processing machinery. Dietary potassium modulates both the pressor and hypercalciuric effects of the modern dietary excess of NaCl. A marginally deficient dietary intake of potassium amplifies both of these effects, and both effects are dose-dependently attenuated and may be abolished either with dietary potassium or supplemental KHCO3. The pathogenic effects of a dietary deficiency of potassium amplify, and are amplified by, those of a dietary excess of NaCl and in some instances a dietary deficiency of bicarbonate precursors. Thus, in those ingesting the modern diet, it may not be possible to discern which of these dietary electrolytic dislocations is most determining of salt-sensitive blood pressure and hypercalciuria, and the hypertension, kidney stones, and osteoporosis they may engender. Obviously abnormal plasma electrolyte concentrations rarely characterize these dietary electrolytic dislocations, and when either dietary potassium or supplemental KHCO3 corrects the pressor and hypercalciuric effects of these dislocations, the plasma concentrations of sodium, potassium, bicarbonate and chloride change little and remain well within the normal range.
L A Frassetto, R C Morris, A Sebastian (2006)  A practical approach to the balance between acid production and renal acid excretion in humans.   J Nephrol 19 Suppl 9: S33-S40 Mar/Apr  
Abstract: Precise measurements of net endogenous acid production (NEAP) to determine net acid balance require labor and laboratory intensive steady-state measurements of dietary nutrient intakes and urine and stool composition. In an effort to simplify the task, investigators have devised several alternative methodologies, especially computational predictive models based on diet composition. This paper describes the so-called gold standard, and the details of each alternative methodology, discussing their strengths and potential pitfalls. We also briefly discuss what we believe the optimal NEAP for adult humans, and how to achieve that through diet.
Anthony Sebastian, Lynda A Frassetto, Deborah E Sellmeyer, R Curtis Morris (2006)  The evolution-informed optimal dietary potassium intake of human beings greatly exceeds current and recommended intakes.   Semin Nephrol 26: 6. 447-453 Nov  
Abstract: An organism best fits the environment described by its genes, an environment that prevailed during the time period (millions of years) when evolution naturally selected the genes of its ancestors-those who survived to pass on their genes. When an organism's current environment differs from its ancestral one, the environment's mismatch with the organism's genome may result in functional disadvantages for the organism. The genetically conditioned nutritional requirements of human beings established themselves over millions of years in which ancestral hominins, living as hunter-gatherers, ate a diet markedly different from that of agriculturally dependent contemporary human beings. In that context, we sought to quantify the ancestral-contemporary dietary difference with respect to the supply of one of the body's major mineral nutrients: potassium. In 159 retrojected Stone Age diets, human potassium intake averaged 400 +/- 125 mEq/d, which exceeds current and recommended intakes by more than a factor of 4. We accounted for the transition to the relatively potassium-poor modern diet by the fact that the modern diet has substantially replaced Stone Age amounts of potassium-rich plant foods (especially fruits, leafy greens, vegetable fruits, roots, and tubers), with energy-dense nutrient-poor foods (separated fats, oils, refined sugars, and refined grains), and with potassium-poor energy-rich plant foods (especially cereal grains) introduced by agriculture (circa 10,000 years ago). Given the fundamental physiologic importance of potassium, such a large magnitude of change in potassium intake invites the consideration in human beings of whether the quantitative values of potassium-influenced physiologic phenomena (eg, blood pressure, insulin and aldosterone secretion rates, and intracellular pH) currently viewed as normal, in fact disaccord with genetically conditioned norms. We discuss the potential implications of our findings in respect to human health and disease.
Lynda Frassetto, R Curtis Morris, Anthony Sebastian (2005)  Long-term persistence of the urine calcium-lowering effect of potassium bicarbonate in postmenopausal women.   J Clin Endocrinol Metab 90: 2. 831-834 Feb  
Abstract: Potassium bicarbonate (KBC) potently reduces urine calcium excretion in adult humans, including patients with hypertension or calcium urolithiasis, and postmenopausal women. In the latter, who have substantial risk of calcium deficiency, it remains unknown whether the observed short-term urine calcium-lowering effect of KBC persists over years. We studied 170 postmenopausal women randomized to KBC 30, 60, or 90 mmol/d (KBC treatment), or placebo, for up to 36 months. Each received a multivitamin with 400 IU vitamin D, and calcium carbonate as needed to produce a total dietary calcium intake of at least 30 mmol daily. Daily urine calcium excretion (UCaV) did not differ among groups at baseline (all-groups mean +/- SD, 155 +/- 83 mg/d). From 1-36 months of KBC treatment, adjusting UCaV for creatinine (Cr) excretion, each dose of KBC reduced UCaV (P < 0.01) with a dose-dependent trend (P = 0.05). The reduced UCaV/Cr persisted throughout the KBC treatment period (up to 36 months) in all KBC, and the greatest reductions occurred in the subjects with greatest baseline UCaV/Cr (Delta UCaV/Cr vs. baseline UCaV/Cr; P < 0.001). Twenty-eight percent of the subjects had high baseline calciuria (UCaV/Cr > 200 mg Ca/1000 mg Cr). With baseline UCaV/Cr of 250 mg/1000 mg Cr, KBC 60 mmol decreased UCaV/Cr by 55.8 mg/1000 mg Cr, a potential daily calcium retention that over a 36-month period would accumulate up to 55,845 mg of calcium, nearly 5% of bone calcium content. KBC treatment induced a dose-dependent decrease in UCaV/Cr that persisted up to 36 months, with the greatest decreases occurring in those women with the greatest baseline UCaV, nearly a third of whom had high baseline calciuria. Thus, one can preselect postmenopausal women most likely to have the urine calcium-lowering effect of KBC and predict their potential bone calcium increase.
Loren Cordain, S Boyd Eaton, Anthony Sebastian, Neil Mann, Staffan Lindeberg, Bruce A Watkins, James H O'Keefe, Janette Brand-Miller (2005)  Origins and evolution of the Western diet: health implications for the 21st century.   Am J Clin Nutr 81: 2. 341-354 Feb  
Abstract: There is growing awareness that the profound changes in the environment (eg, in diet and other lifestyle conditions) that began with the introduction of agriculture and animal husbandry approximately 10000 y ago occurred too recently on an evolutionary time scale for the human genome to adjust. In conjunction with this discordance between our ancient, genetically determined biology and the nutritional, cultural, and activity patterns of contemporary Western populations, many of the so-called diseases of civilization have emerged. In particular, food staples and food-processing procedures introduced during the Neolithic and Industrial Periods have fundamentally altered 7 crucial nutritional characteristics of ancestral hominin diets: 1) glycemic load, 2) fatty acid composition, 3) macronutrient composition, 4) micronutrient density, 5) acid-base balance, 6) sodium-potassium ratio, and 7) fiber content. The evolutionary collision of our ancient genome with the nutritional qualities of recently introduced foods may underlie many of the chronic diseases of Western civilization.
Charlotte Hwa, Anthony Sebastian, William C Aird (2005)  Endothelial biomedicine: its status as an interdisciplinary field, its progress as a basic science, and its translational bench-to-bedside gap.   Endothelium 12: 3. 139-151 May/Jun  
Abstract: The endothelium, a layer of endothelial cells lining the luminal surface of all blood vessels, functions as a highly metabolically active organ spatially distributed throughout the body. Despite enormous advances in our understanding of endothelial cell biology, little awareness of this organ reaches clinical practice. The present study aims to document the extent and scope of the bench-to-bedside gap in endothelial biomedicine, and to offer hypotheses to explain the gaping chasm. A PubMed search using keywords "endothelial cells" and "endothelium" yielded over 90,000 publications, increasing exponentially over the past decade. A Scirus search without date restriction returned journal results for the endothelium not greatly fewer than for the epithelium. A survey of representative vascular biology meetings revealed a high percentage of talks related to the endothelium. The number of grants awarded by the National Institutes of Health for studies in endothelial cell biology continues to steadily increase. At the bedside, however, few clinicians give consideration to the health of the endothelium. A survey of the major medical textbooks revealed a paucity of index entries for "endothelial cells" or "endothelium." The endothelium does not offer itself for inspection, palpation, percussion, and/or auscultation. No convenient blood tests measure endothelial function. The authors propose to explain the bench-to-bedside gap in endothelial biomedicine as a function of (1) historical constraints, (2) the unseen and diffuse nature of the cell layer, (3) the complexity of the system, and (4) its adaptability. Until the bench-to-bedside gap closes, the enormous potential of the endothelium as a diagnostic, preventive, and therapeutic target will remain largely untapped.
Deborah E Sellmeyer, Monique Schloetter, Anthony Sebastian (2002)  Potassium citrate prevents increased urine calcium excretion and bone resorption induced by a high sodium chloride diet.   J Clin Endocrinol Metab 87: 5. 2008-2012 May  
Abstract: The amount of sodium chloride in the diet of industrialized nations far exceeds physiological requirements. The impact of abundant dietary salt on skeletal health has yet to be established, but is potentially detrimental through increased urinary calcium losses. We examined the effect of increased dietary sodium chloride on urine calcium excretion and bone turnover markers in postmenopausal women and, further, whether potassium citrate attenuates the effects of increased dietary salt. Postmenopausal women (n = 60) were adapted to a low-salt (87 mmol/d sodium) diet for 3 wk, then randomized to a high-salt (225 mmol/d sodium) diet plus potassium citrate (90 mmol/d) or a high-salt diet plus placebo for 4 wk. Urine calcium, urine N-telopeptide, urine cAMP, serum osteocalcin, and fasting serum PTH were measured at the end of the low- and high-salt diets. On the high salt plus placebo diet, urine calcium increased 42 +/- 12 mg/d (mean +/- SEM), but decreased 8 +/- 14 mg/d in the high salt plus potassium citrate group (P = 0.008, potassium citrate vs. placebo, unpaired t test). N-telopeptide increased 6.4 +/- 1.4 nanomoles bone collagen equivalents per millimole creatinine in the high salt plus placebo group and 2.0 +/- 1.7 nanomoles bone collagen equivalents per millimole creatinine in the high salt plus potassium citrate group (P < 0.05, potassium citrate vs. placebo, unpaired t test). Osteocalcin, PTH, and cAMP were not significantly altered. The addition of oral potassium citrate to a high-salt diet prevented the increased excretion of urine calcium and the bone resorption marker caused by a high salt intake. Increased intake of dietary sources of potassium alkaline salts, namely fruit and vegetables, may be beneficial for postmenopausal women at risk for osteoporosis, particularly those consuming a diet generous in sodium chloride.
Anthony Sebastian, Lynda A Frassetto, Deborah E Sellmeyer, Renée L Merriam, R Curtis Morris (2002)  Estimation of the net acid load of the diet of ancestral preagricultural Homo sapiens and their hominid ancestors.   Am J Clin Nutr 76: 6. 1308-1316 Dec  
Abstract: BACKGROUND: Natural selection has had < 1% of hominid evolutionary time to eliminate the inevitable maladaptations consequent to the profound transformation of the human diet resulting from the inventions of agriculture and animal husbandry. OBJECTIVE: The objective was to estimate the net systemic load of acid (net endogenous acid production; NEAP) from retrojected ancestral preagricultural diets and to compare it with that of contemporary diets, which are characterized by an imbalance of nutrient precursors of hydrogen and bicarbonate ions that induces a lifelong, low-grade, pathogenically significant systemic metabolic acidosis. DESIGN: Using established computational methods, we computed NEAP for a large number of retrojected ancestral preagricultural diets and compared them with computed and measured values for typical American diets. RESULTS: The mean (+/- SD) NEAP for 159 retrojected preagricultural diets was -88 +/- 82 mEq/d; 87% were net base-producing. The computational model predicted NEAP for the average American diet (as recorded in the third National Health and Nutrition Examination Survey) as 48 mEq/d, within a few percentage points of published measured values for free-living Americans; the model, therefore, was not biased toward generating negative NEAP values. The historical shift from negative to positive NEAP was accounted for by the displacement of high-bicarbonate-yielding plant foods in the ancestral diet by cereal grains and energy-dense, nutrient-poor foods in the contemporary diet-neither of which are net base-producing. CONCLUSIONS: The findings suggest that diet-induced metabolic acidosis and its sequelae in humans eating contemporary diets reflect a mismatch between the nutrient composition of the diet and genetically determined nutritional requirements for optimal systemic acid-base status.
D E Sellmeyer, K L Stone, A Sebastian, S R Cummings (2001)  A high ratio of dietary animal to vegetable protein increases the rate of bone loss and the risk of fracture in postmenopausal women. Study of Osteoporotic Fractures Research Group.   Am J Clin Nutr 73: 1. 118-122 Jan  
Abstract: BACKGROUND: Different sources of dietary protein may have different effects on bone metabolism. Animal foods provide predominantly acid precursors, whereas protein in vegetable foods is accompanied by base precursors not found in animal foods. Imbalance between dietary acid and base precursors leads to a chronic net dietary acid load that may have adverse consequences on bone. OBJECTIVE: We wanted to test the hypothesis that a high dietary ratio of animal to vegetable foods, quantified by protein content, increases bone loss and the risk of fracture. DESIGN: This was a prospective cohort study with a mean (+/-SD) of 7.0+/-1.5 y of follow-up of 1035 community-dwelling white women aged >65 y. Protein intake was measured by using a food-frequency questionnaire and bone mineral density was measured by dual-energy X-ray absorptiometry. RESULTS: Bone mineral density was not significantly associated with the ratio of animal to vegetable protein intake. Women with a high ratio had a higher rate of bone loss at the femoral neck than did those with a low ratio (P = 0.02) and a greater risk of hip fracture (relative risk = 3.7, P = 0.04). These associations were unaffected by adjustment for age, weight, estrogen use, tobacco use, exercise, total calcium intake, and total protein intake. CONCLUSIONS: Elderly women with a high dietary ratio of animal to vegetable protein intake have more rapid femoral neck bone loss and a greater risk of hip fracture than do those with a low ratio. This suggests that an increase in vegetable protein intake and a decrease in animal protein intake may decrease bone loss and the risk of hip fracture. This possibility should be confirmed in other prospective studies and tested in a randomized trial.
L Frassetto, R C Morris, D E Sellmeyer, K Todd, A Sebastian (2001)  Diet, evolution and aging--the pathophysiologic effects of the post-agricultural inversion of the potassium-to-sodium and base-to-chloride ratios in the human diet.   Eur J Nutr 40: 5. 200-213 Oct  
Abstract: Theoretically, we humans should be better adapted physiologically to the diet our ancestors were exposed to during millions of years of hominid evolution than to the diet we have been eating since the agricultural revolution a mere 10,000 years ago, and since industrialization only 200 years ago. Among the many health problems resulting from this mismatch between our genetically determined nutritional requirements and our current diet, some might be a consequence in part of the deficiency of potassium alkali salts (K-base), which are amply present in the plant foods that our ancestors ate in abundance, and the exchange of those salts for sodium chloride (NaCl), which has been incorporated copiously into the contemporary diet, which at the same time is meager in K-base-rich plant foods. Deficiency of K-base in the diet increases the net systemic acid load imposed by the diet. We know that clinically-recognized chronic metabolic acidosis has deleterious effects on the body, including growth retardation in children, decreased muscle and bone mass in adults, and kidney stone formation, and that correction of acidosis can ameliorate those conditions. Is it possible that a lifetime of eating diets that deliver evolutionarily superphysiologic loads of acid to the body contribute to the decrease in bone and muscle mass, and growth hormone secretion, which occur normally with age? That is, are contemporary humans suffering from the consequences of chronic, diet-induced low-grade systemic metabolic acidosis? Our group has shown that contemporary net acid-producing diets do indeed characteristically produce a low-grade systemic metabolic acidosis in otherwise healthy adult subjects, and that the degree of acidosis increases with age, in relation to the normally occurring age-related decline in renal functional capacity. We also found that neutralization of the diet net acid load with dietary supplements of potassium bicarbonate (KHCO3) improved calcium and phosphorus balances, reduced bone resorption rates, improved nitrogen balance, and mitigated the normally occurring age-related decline in growth hormone secretion--all without restricting dietary NaCl. Moreover, we found that co-administration of an alkalinizing salt of potassium (potassium citrate) with NaCl prevented NaCl from increasing urinary calcium excretion and bone resorption, as occurred with NaCl administration alone. Earlier studies estimated dietary acid load from the amount of animal protein in the diet, inasmuch as protein metabolism yields sulfuric acid as an end-product. In cross-cultural epidemiologic studies, Abelow found that hip fracture incidence in older women correlated with animal protein intake, and they suggested a causal relation to the acid load from protein. Those studies did not consider the effect of potential sources of base in the diet. We considered that estimating the net acid load of the diet (i. e., acid minus base) would require considering also the intake of plant foods, many of which are rich sources of K-base, or more precisely base precursors, substances like organic anions that the body metabolizes to bicarbonate. In following up the findings of Abelow et al., we found that plant food intake tended to be protective against hip fracture, and that hip fracture incidence among countries correlated inversely with the ratio of plant-to-animal food intake. These findings were confirmed in a more homogeneous population of white elderly women residents of the U.S. These findings support affirmative answers to the questions we asked above. Can we provide dietary guidelines for controlling dietary net acid loads to minimize or eliminate diet-induced and age-amplified chronic low-grade metabolic acidosis and its pathophysiological sequelae. We discuss the use of algorithms to predict the diet net acid and provide nutritionists and clinicians with relatively simple and reliable methods for determining and controlling the net acid load of the diet. A more difficult question is what level of acidosis is acceptable. We argue that any level of acidosis may be unacceptable from an evolutionarily perspective, and indeed, that a low-grade metabolic alkalosis may be the optimal acid-base state for humans.
L A Frassetto, E Nash, R C Morris, A Sebastian (2000)  Comparative effects of potassium chloride and bicarbonate on thiazide-induced reduction in urinary calcium excretion.   Kidney Int 58: 2. 748-752 Aug  
Abstract: BACKGROUND: The chronic low-grade metabolic acidosis that occurs in various renal disorders and in normal people, and that is related both to dietary net acid load and age-related renal functional decline, may contribute to osteoporosis by increasing urine calcium excretion. Administration of potassium (K) alkali salts neutralizes acid and lowers urine calcium excretion. Urine calcium excretion also can be reduced by the administration of thiazide diuretics, which are often given with supplemental K to avoid hypokalemia. We determined whether the K alkali salt potassium bicarbonate (KHCO3) and the thiazide diuretic hydrochlorothiazide (HCTZ) combined is more effective in reducing urinary calcium than KHCO3 alone or HCTZ combined with the conventionally coadministered nonalkalinizing K salt potassium chloride (KCl). METHODS: Thirty-one healthy men and women aged 50 or greater were recruited for a four-week, double-blind, randomized study. After a baseline period of 10 days with three 24-hour urine and arterialized blood collections, subjects were randomized to receive either HCTZ (50 mg) plus potassium (60 mmol daily) as either the chloride or bicarbonate salt. Another 19 women received potassium bicarbonate (60 mmol) alone. After two weeks, triplicate collections of 24-hour urines and arterialized bloods were repeated. RESULTS: Urinary calcium excretion decreased significantly in all groups. KHCO3 alone and HCTZ + KCl induced similar decreases (-0.70 +/- 0.60 vs. -0.80 +/- 1. 0 mmol/day, respectively). Compared with those treatments, the combination of HCTZ + KHCO3 induced more than a twofold greater decrease in urinary calcium excretion (-1.8 +/- 1.2 mmol/day, P < 0. 05). Both HCTZ + KHCO3 and KHCO3 alone reduced net acid excretion significantly (P < 0.05) to values of less than zero. CONCLUSIONS: KHCO3 was superior to KCl as an adjunct to HCTZ, inducing a twofold greater reduction in urine calcium excretion, and completely neutralizing endogenous acid production so as to correct the pre-existing mild metabolic acidosis that an acid-producing diet usually induces in older people. Accordingly, for reducing urine calcium excretion in stone disease and osteoporosis, the combination of HCTZ + KHCO3 may be preferable to that of HCTZ + KCl.
L A Frassetto, K M Todd, R C Morris, A Sebastian (2000)  Worldwide incidence of hip fracture in elderly women: relation to consumption of animal and vegetable foods.   J Gerontol A Biol Sci Med Sci 55A: 10. M585-M592 Oct  
Abstract: BACKGROUND: Hip fracture, a major health problem in elderly persons, varies in incidence among the populations of different countries and is directly related to animal protein intake, a finding that suggests that bone integrity is compromised by endogenous acid production consequent to the metabolism of animal proteins. If that is so, vegetable foods might provide a countervailing effect, because they are a rich source of base (bicarbonate) in the form of metabolizable organic anions, which can neutralize protein-derived acid and supply substrate (carbonate) for bone formation. METHODS: We analyzed reported hip fracture incidence (HFI) data among countries (N = 33) in women aged 50 years and older, in relation to corresponding country-specific data on per capita consumption of vegetable and animal foods as reported by the United Nations Food and Agriculture Organization. RESULTS: HFI varied directly with total (r = +.67, p < .001) and animal (r = +.82, p < .001) protein intake and inversely with vegetable protein intake (r = .37, p < .04). The countries in the lowest tertile of HFI (n = 11) had the lowest animal protein consumption, and invariably, vegetable protein (VP) consumption exceeded the country's corresponding intake of animal protein (AP): VP/AP > 1.0. By contrast, among the countries in the highest tertile of HFI, animal protein intake exceeded vegetable protein intake in nearly every case (10 of 11 countries). Among all countries, HFI correlated inversely and exponentially with the ratio of vegetable/animal protein intake (r = -.84, p < .001) and accounted for 70% of the total variation in HFI. Adjusted for total protein intake, vegetable food consumption was an independent negative predictor of HFI. All findings were similar for the subset of 23 countries whose populations are predominantly Caucasian. CONCLUSION: The findings suggest that the critical determinant of hip fracture risk in relation to the acid-base effects of diet is the net load of acid in the diet, when the intake of both acid and base precursors is considered. Moderation of animal food consumption and an increased ratio of vegetable/animal food consumption may confer a protective effect.
R C Morris, A Sebastian, A Forman, M Tanaka, O Schmidlin (1999)  Normotensive salt sensitivity: effects of race and dietary potassium.   Hypertension 33: 1. 18-23 Jan  
Abstract: -Normotensive salt sensitivity, a putative precursor of hypertension, might be quite frequent in African Americans (blacks) and less frequent in Caucasian Americans (whites), but only when dietary potassium is deficient and not when maintained well within the normal range. We tested this hypothesis in 41 metabolically controlled studies of 38 healthy normotensive men (24 blacks, 14 whites) who ate a basal diet low in sodium (15 mmol/d) and marginally deficient in potassium (30 mmol/d) for 6 weeks. Throughout the last 4 weeks, NaCl was loaded (250 mmol/d); throughout the last 3, potassium was supplemented (as potassium bicarbonate) to either mid- or high-normal levels, 70 and 120 mmol/d. Salt sensitivity, defined as an increase in mean arterial blood pressure >/=3 mm Hg with salt loading, was deemed "moderate" if increasing </=10 mm Hg and "severe" if increasing more. When dietary potassium was 30 mmol/d, salt loading induced a mean increase in blood pressure only in blacks (P<0.001), and salt sensitivity occurred in most blacks but not whites (79% vs 36% (P<0.02). Supplementing potassium only to 70 mmol/d attenuated moderate salt sensitivity similarly in blacks and whites; 120 mmol/d abolished it, attenuated severe salt sensitivity, which occurred in a quarter of affected blacks, and suppressed the frequency and severity of salt sensitivity in blacks to levels similar to those observed in whites. These observations demonstrate that in most normotensive black men but not white men, salt sensitivity occurs when dietary potassium is even marginally deficient but is dose-dependently suppressed when dietary potassium is increased within its normal range. Such suppression might prevent or delay the occurrence of hypertension, particularly in the many blacks, in whom dietary potassium is deficient.
R C Morris, O Schmidlin, M Tanaka, A Forman, L Frassetto, A Sebastian (1999)  Differing effects of supplemental KCl and KHCO3: pathophysiological and clinical implications.   Semin Nephrol 19: 5. 487-493 Sep  
Abstract: Compared to the prehistoric diet, the modern human diet contains not only excessive NaCl and deficient K+, but also deficient precursors of HCO3- and sometimes excessive precursors of nonvolatile acid. The mismatch between the modern diet and the still ancient biological machinery of humans subtly but chronically disorders their internal milieu, giving rise to a prolonged state of low-grade potassium deficiency and low-grade metabolic acidosis whose severity increases with age. Supplemental KCI cannot redress this mismatch and correct this state. However, the mismatch is redressed and the state corrected by restoring intakes of K+ and HCO3- to levels approaching those in the diet of our prehistoric forebearers, with either fruits and vegetables or with supplemental KHCO3. So restored, KHCO3 can: 1) attenuate hypertension and possibly prevent its occurrence by suppressing the phenomenon of normotensive NaCl-sensitivity, in part by its natriuretic effect; (2) prevent kidney stones by reducing urinary excretion of calcium and increasing urinary excretion of citrate; (3) ameliorate and protect against the occurrence of osteoporosis by increasing the renal retention of calcium and phosphorus, and by suppressing bone resorption and enhancing bone formation; and (4) likely prevent stroke.
O Schmidlin, A Forman, M Tanaka, A Sebastian, R C Morris (1999)  NaCl-induced renal vasoconstriction in salt-sensitive African Americans: antipressor and hemodynamic effects of potassium bicarbonate.   Hypertension 33: 2. 633-639 Feb  
Abstract: In 16 African Americans (blacks, 14 men, 2 women) with average admission mean arterial pressure (MAP, mm Hg) 99.9+/-3.5 (mean+/-SEM), we investigated whether NaCl-induced renal vasoconstriction attends salt sensitivity and, if so, whether supplemental KHCO3 ameliorates both conditions. Throughout a 3-week period under controlled metabolic conditions, all subjects ate diets containing 15 mmol NaCl and 30 mmol potassium (K+) (per 70 kg body wt [BW] per day). Throughout weeks 2 and 3, NaCl was loaded to 250 mmol/d; throughout week 3, dietary K+ was supplemented to 170 mmol/d (KHCO3). On the last day of each study week, we measured renal blood flow (RBF) and glomerular filtration rate (GFR) using renal clearances of PAH and inulin. Ten subjects were salt sensitive (SS) (DeltaMAP >+5%) and 6 salt resistant (SR). In NaCl-loaded SS but not SR subjects, RBF (mL/min/1.73 m2) decreased from 920+/-75 to 828+/-46 (P<0.05); filtration fraction (FF, %) increased from 19. 4+/- to 21.4 (P<0.001); and renal vascular resistance (RVR) (10(3)xmm Hg/[mL/min]) increased from 101+/-8 to 131+/-10 (P<0.001). In all subjects combined, DeltaMAP varied inversely with DeltaRBF (r =-0.57, P=0.02) and directly with DeltaRVR (r = 0.65, P=0.006) and DeltaFF (r = 0.59, P=0.03), but not with MAP before NaCl loading. When supplemental KHCO3 abolished the pressor effect of NaCl in SS subjects, RBF was unaffected but GFR and FF decreased. The results show that in marginally K+-deficient blacks (1) NaCl-induced renal vasoconstrictive dysfunction attends salt sensitivity; (2) the dysfunction varies in extent directly with the NaCl-induced increase in blood pressure (BP); and (3) is complexly affected by supplemented KHCO3, GFR and FF decreasing but RBF not changing. In blacks, NaCl-induced renal vasoconstriction may be a pathogenetic event in salt sensitivity.
L A Frassetto, K M Todd, R C Morris, A Sebastian (1998)  Estimation of net endogenous noncarbonic acid production in humans from diet potassium and protein contents.   Am J Clin Nutr 68: 3. 576-583 Sep  
Abstract: Normal adult humans eating Western diets have chronic, low-grade metabolic acidosis, the severity of which is determined in part by the net rate of endogenous noncarbonic acid production (NEAP), which varies with diet. To prevent or reverse age-related sequelae of such diet-dependent acidosis (eg, bone and muscle loss), methods are needed for estimating and regulating NEAP. Because NEAP is difficult to measure directly, we sought a simple method to estimate it from diet-composition data. We focused on protein and potassium contents because the production of sulfuric acid from protein metabolism and bicarbonate from dietary potassium salts of organic acids are the major variable components of NEAP. Using steady state renal net acid excretion (RNAE) as an index of NEAP in 141 normal subjects eating 20 different diets, we found by multiple linear regression analysis that RNAE [mEq/d x 10460 kJ diet (mEq/d 2500 kcal)] was predictable (R2 = 0.62) from protein [g/d x 10460 kJ diet (g/d 2500 kcal); positive regression coefficient, P < 0.001] and potassium [mEq/d x 10460 kJ diet (mEq/d x 2500 kcal): negative regression coefficient, P = 0.001] contents, which were not themselves correlated. Among diets, 71% of the variation in RNAE could be accounted for by the ratio of protein (Pro) to potassium (K) content: RNAE = 62Pro/K - 17.9 (r = 0.84, R2 = 0.71, P < 0.001). Thus, by considering both the acidifying effect of protein and the alkalinizing effect of potassium (organic anions), NEAP can be predicted with confidence from the readily available contents of only 2 nutrients in foods. Provisionally, these findings allow estimation and regulation of NEAP through diet modification.
L Frassetto, R C Morris, A Sebastian (1997)  Potassium bicarbonate reduces urinary nitrogen excretion in postmenopausal women.   J Clin Endocrinol Metab 82: 1. 254-259 Jan  
Abstract: Previously we demonstrated that low grade chronic metabolic acidosis exists normally in humans eating ordinary diets that yield normal net rates of endogenous acid production (EAP), and that the degree of acidosis increases with age. We hypothesize that such diet-dependent and age-amplifying low grade metabolic acidosis contributes to the decline in skeletal muscle mass that occurs normally with aging. This hypothesis is based on the reported finding that chronic metabolic acidosis induces muscle protein breakdown, and that correction of acidosis reverses the effect. Accordingly, in 14 healthy postmenopausal women residing in a General Clinical Research Center and eating a constant diet yielding a normal EAP rate, we tested whether correcting their "physiological" acidosis with orally administered potassium bicarbonate (KHCO3; 60-120 mmol/day for 18 days) reduces their urinary nitrogen loss. KHCO3 reduced EAP to nearly zero, significantly reduced the blood hydrogen ion concentration (P < 0.001), and increased the plasma bicarbonate concentration (P < 0.001), indicating that pre-KHCO3, diet-dependent EAP was significantly perturbing systemic acid-base equilibrium, causing a low grade metabolic acidosis. Urinary ammonia nitrogen, urea nitrogen, and total nitrogen levels significantly decreased. The cumulative reduction in nitrogen excretion was 14.1 +/- 12.3 g (P < 0.001). Renal creatinine clearance and urine volume remained unchanged. We conclude that in postmenopausal women, neutralization of diet-induced EAP with KHCO3 corrects their preexisting diet-dependent low grade metabolic acidosis and significantly reduces their urinary nitrogen wasting. The magnitude of the KHCO3-induced nitrogen-sparing effect is potentially sufficient to both prevent continuing age-related loss of muscle mass and restore previously accrued deficits.
K Sudhir, A Forman, S L Yi, J Sorof, O Schmidlin, A Sebastian, R C Morris (1997)  Reduced dietary potassium reversibly enhances vasopressor response to stress in African Americans.   Hypertension 29: 5. 1083-1090 May  
Abstract: Acute vasopressor responses to stress are adrenergically mediated and hence potentially subject to differential modulation by dietary potassium and sodium. The greater vasopressor responsiveness in blacks compared with whites might then be consequent not only to a high dietary salt intake but also to a marginally reduced dietary potassium intake. Under controlled metabolic conditions, we compared acute vasopressor responses to cold and mental stress in black and white normotensive men during three successive dietary periods: (1) while dietary potassium was reduced (30 mmol K+/70 kg per day) and salt was restricted (10 to 14 days); (2) while salt was loaded (15 to 250 mmol Na+/70 kg per day) (7 days); and (3) while salt loading was continued and potassium was either supplemented (70 mmol K+/70 kg per day) (7 to 21 days) in 9 blacks and 6 whites or continued reduced (30 mmol K+/70 kg per day) (28 days) in 4 blacks (time controls). At the lower potassium intake, cold-induced increase in forearm vascular resistance in blacks was twice that in whites during both salt restriction and salt loading. Normalization of dietary potassium attenuated cold-induced increases in both forearm vascular resistance and systolic and diastolic blood pressures in blacks but only in systolic pressure in whites. In blacks but not in whites, normalization of dietary potassium attenuated mental stress-induced increases in systolic and diastolic pressures. In normotensive blacks but not whites, a marginally reduced dietary intake of potassium reversibly enhances adrenergically mediated vasopressor responsiveness to stress. That responsiveness so enhanced over time might contribute to the pathogenesis of hypertension in blacks.
L Frassetto, A Sebastian (1996)  Age and systemic acid-base equilibrium: analysis of published data.   J Gerontol A Biol Sci Med Sci 51: 1. B91-B99 Jan  
Abstract: To investigate whether systemic acid-base equilibrium changes with aging in normal adult humans, we reviewed published articles reporting the acid-base composition of arterial, arterialized venous, or capillary blood in age-identified healthy subjects. We extracted or calculated blood hydrogen ion concentration ([H+]), plasma bicarbonate concentration ([HCO3(-)]), blood PCO2, and age, and computed a total of 61 age-group means, distributed among eight 10-year intervals from age 20 to 100 years. Using linear regression analysis, we found that with increasing age, there is a significant increase in the steady-state blood [H+] (p < .001), and reduction in steady-state plasma [HCO3(-)] (p < .001), indicative of a progressively worsening low-level metabolic acidosis. Blood PCO2 decreased with age (p < .05), in keeping with the expected respiratory adaptation to metabolic acidosis. Such age-related increasing metabolic acidosis may reflect in part the normal decline of renal function with increasing age. The role of age-related metabolic acidosis in the pathogenesis of the degenerative diseases of aging warrants consideration.
L A Frassetto, R C Morris, A Sebastian (1996)  Effect of age on blood acid-base composition in adult humans: role of age-related renal functional decline.   Am J Physiol 271: 6 Pt 2. F1114-F1122 Dec  
Abstract: In 64 apparently healthy adult humans (ages 17-74 yr) ingesting controlled diets, we investigated the separate and combined effects of age, glomerular filtration rate (GFR, index of age-related renal functional decline), renal net acid excretion [NAE, index of endogenous acid production (EAP)], and blood PCO2 (PbCO2, index of respiratory set point) on steady-state blood hydrogen ion ([H+]b) and plasma bicarbonate concentration ([HCO3-]p). Independent predictors of [H+]b and [HCO3-]p were PbCO2, NAE, and either age or GFR, but not both, because the two were highly correlated (inversely). [H+]b increased with increasing PbCO2, NAE, and age and with decreasing GFR. [HCO3-]p decreased with increasing NAE and age but increased with increasing PbCO2 and GFR. Age (or GFR) at constant NAE had greater effect on both [H+]b and [HCO3-]p than did NAE at constant age (or GFR). Neither PbCO2 nor NAE correlated with age or GFR. Thus two metabolic factors, diet-dependent EAP and age (or GFR), operate independently to determine blood acid-base composition in adult humans. Otherwise healthy adults manifest a low-grade diet-dependent metabolic acidosis, the severity of which increases with age at constant EAP, apparently due in part to the normal age-related decline of renal function.
F Kusumoto, T Venet, N B Schiller, A Sebastian, E Foster (1995)  Measurement of aortic blood flow by Doppler echocardiography: temporal, technician, and reader variability in normal subjects and the application of generalizability theory in clinical research.   J Am Soc Echocardiogr 8: 5 Pt 1. 647-653 Sep/Oct  
Abstract: Although Doppler echocardiographic measurements of aortic flow have been found to correlate with stroke volume, the reliability of this technique is unknown. The purpose of this study was to measure the reliability of Doppler estimates of cardiac output by identifying and estimating the magnitude of different sources of error. We measured the reliability of Doppler estimates of cardiac output by identifying the magnitude of sources of error in 11 subjects with studies performed by two technicians and read by two readers. Analysis with generalizability theory demonstrated that the largest portion of the total variance was from differences among patients, with a smaller contribution due to day-to-day variability. Variability due to technician was low for continuous wave Doppler (2.0%), but high for pulsed wave (23.2%). Thus continuous wave, but not pulsed wave Doppler measurements, can be used to detect serial changes in cardiac output due to an intervention.
A Sebastian, S T Harris, J H Ottaway, K M Todd, R C Morris (1994)  Improved mineral balance and skeletal metabolism in postmenopausal women treated with potassium bicarbonate.   N Engl J Med 330: 25. 1776-1781 Jun  
Abstract: BACKGROUND: In normal subjects, a low level of metabolic acidosis and positive acid balance (the production of more acid than is excreted) are typically present and correlate in degree with the amount of endogenous acid produced by the metabolism of foods in ordinary diets abundant in protein. Over a lifetime, the counteraction of retained endogenous acid by base mobilized from the skeleton may contribute to the decrease in bone mass that occurs normally with aging. METHODS: To test that possibility, we administered potassium bicarbonate to 18 postmenopausal women who were given a constant diet (652 mg [16 mmol] of calcium and 96 g of protein per 60 kg of body weight). The potassium bicarbonate was given orally for 18 days in doses (60 to 120 mmol per day) that nearly completely neutralized the endogenous acid. RESULTS: During the administration of potassium bicarbonate, the calcium and phosphorus balance became less negative or more positive--that is, less was excreted in comparison with the amount ingested (mean [+/- SD] change in calcium balance, +56 +/- 76 mg [1.4 +/- 1.9 mmol] per day per 60 kg; P = 0.009; change in phosphorus balance, +47 +/- 64 mg [1.5 +/- 2.1 mmol] per day per 60 kg; P = 0.007) because of reductions in urinary calcium and phosphorus excretion. The changes in calcium and phosphorus balance were positively correlated (P < 0.001). Serum osteocalcin concentrations increased from 5.5 +/- 2.8 to 6.1 +/- 2.8 ng per milliliter (P < 0.001), and urinary hydroxyproline excretion decreased from 28.9 +/- 12.3 to 26.7 +/- 10.8 mg per day (220 +/- 94 to 204 +/- 82 mumol per day; P = 0.05). Net renal acid excretion decreased from 70.9 +/- 10.1 to 12.8 +/- 21.8 mmol per day, indicating nearly complete neutralization of endogenous acid. CONCLUSIONS: In postmenopausal women, the oral administration of potassium bicarbonate at a dose sufficient to neutralize endogenous acid improves calcium and phosphorus balance, reduces bone resorption, and increases the rate of bone formation.
S Hagiwara, N Lane, K Engelke, A Sebastian, D B Kimmel, H K Genant (1993)  Precision and accuracy for rat whole body and femur bone mineral determination with dual X-ray absorptiometry.   Bone Miner 22: 1. 57-68 Jul  
Abstract: Precision and accuracy for rat whole body and excised femur bone mineral density (BMD) measurements were evaluated with two dual X-ray absorptiometry (DXA) systems. The 'small subject' mode on the Norland XR-26 (XR), and the 'ultra high resolution mode' on the Hologic QDR-1000/W(QDR) were used for the analysis. The whole body mode was only available on the XR. The lowest precision error for the whole body was found using a scan resolution of 1.0 x 1.0 mm and a scan speed of 15 mm/s. The scan spatial resolution of the femur measurement was approximately eight times higher on the QDR than on the XR. However, the XR allowed analysis of an arbitrary region of interest within the femur, which was not easily done with the QDR. Precision for the total femur measurement on the QDR (0.5-0.9%) was approximately two to four times superior to that of the XR (1.5-4.3%). The difference may be due to the superior scan resolution of the QDR. Bone mineral content and BMD on the QDR significantly declined with an increase of water depth (P < 0.001). No significant change was observed on the XR. Both DXA systems demonstrated an excellent correlation (r > or = 0.98) with ash weight under the scan conditions examined. The optimal scan condition for the excised femur measurement on the XR was obtained with 1.5-2.5 cm of perspex or water and a scan speed of 10 mm/s. For the QDR, we recommend scanning the rat femur with approximately 2.5 cm of perspex or water in terms of precision and accuracy.
D Siegel, S B Hulley, D M Black, M D Cheitlin, A Sebastian, D G Seeley, N Hearst, R Fine (1992)  Diuretics, serum and intracellular electrolyte levels, and ventricular arrhythmias in hypertensive men.   JAMA 267: 8. 1083-1089 Feb  
Abstract: OBJECTIVE: To investigate the patterns of electrolyte abnormalities resulting from thiazide administration and whether they cause ventricular arrhythmias, and to help resolve the controversy over whether clinicians should routinely prescribe potassium-conserving therapy to all patients treated with thiazides. DESIGN: Double-blind, randomized controlled trial. PARTICIPANTS: A total of 233 hypertensive men aged 35 to 70 years. INTERVENTIONS: Participants were withdrawn from prior diuretic treatment and were replenished with oral potassium chloride and magnesium oxide. They were then randomized to 2 months of treatment with (1) hydrochlorothiazide; (2) hydrochlorothiazide with oral potassium; (3) hydrochlorothiazide with oral potassium and magnesium; (4) hydrochlorothiazide and triamterene; (5) chlorthalidone; or (6) placebo. MAIN OUTCOME MEASURES: Ventricular arrhythmias on 24-hour Holter monitoring and serum and intracellular potassium and magnesium levels. RESULTS: Of the 233 participants, 212 (91%) completed the study. Serum potassium levels were 0.4 mmol/L lower in the hydrochlorothiazide group than in the placebo group (P less than 0.01), and this mean difference was not affected by supplementation with potassium, with potassium and magnesium, or with triamterene. However, the supplements did prevent the occasional occurrence of marked hypokalemia; all 12 of the men who developed serum potassium levels of 3.0 mmol/L or less were among the 90 who received diuretics without supplementation (P less than 0.01). Similarly, the overall proportion of men with ventricular arrhythmias was not affected by randomized treatment, but there was a twofold increase in the proportion with arrhythmias among the 12 men with serum potassium levels of 3.0 mmol/L or less (P = .02). Serum magnesium and intracellular potassium and magnesium levels were not reduced by hydrochlorothiazide, nor were they related to ventricular arrhythmias. CONCLUSIONS: In the majority of hypertensive patients, treatment with 50 mg/d of hydrochlorothiazide does not cause marked hypokalemia or ventricular arrhythmias. However, because some individuals will develop hypokalemia after starting diuretic therapy, serum potassium levels should be monitored and potassium-sparing strategies should be used when indicated.
L Moulinier, T Venet, N B Schiller, T W Kurtz, R C Morris, A Sebastian (1991)  Measurement of aortic blood flow by Doppler echocardiography: day to day variability in normal subjects and applicability in clinical research.   J Am Coll Cardiol 17: 6. 1326-1333 May  
Abstract: To assess the reliability of Doppler ultrasound for detecting serial changes in cardiac output in response to experimental interventions, the day to day variability of the minute distance of aortic flow was determined in seven normal subjects maintained in a tightly controlled environment with regard to diet and activities. Measurements were made at the same time on 5 to 6 sequential days from an apical window with use of both continuous wave and pulsed wave Doppler techniques. Two statistical measures of reliability were calculated, the intraclass coefficient of correlation (R), which varies between 0 (null reliability) and +1 (perfect reliability), and the 95% confidence interval for the error-free value of a single measurement. For sequential measurements of arterial pressure, 24 h urinary volume and sodium excretion and body weight, the intraclass coefficients of correlation ranged from 0.85 to 0.99, indicating low day to day variability consistent with tight environmental control. Continuous and pulsed wave modes were proved equally and highly reliable for measuring minute distance of aortic flow. However, continuous wave Doppler ultrasound provided acceptable signals more frequently than did the pulsed wave technique. For continuous wave Doppler ultrasound, R was 0.87 (p less than 0.00001); the 95% confidence interval was +/- 1.81 m/min (or 11% of the mean of all measurements), which indicates that this method can be used in a single individual to detect a greater than 11% change in minute distance measured once before and after an intervention.(ABSTRACT TRUNCATED AT 250 WORDS)
M G Cogan, A V Carneiro, J Tatsuno, J Colman, R Krapf, R C Morris, A Sebastian (1990)  Normal diet NaCl variation can affect the renal set-point for plasma pH-(HCO3-) maintenance.   J Am Soc Nephrol 1: 2. 193-199 Aug  
Abstract: In humans who are ingesting abundant NaCl, blood pH (pHb) and plasma bicarbonate concentration [HCO3-)p) change little or imperceptibly in response to the ingestion of alkali salts. We tested the hypothesis that such tight homeostatic regulation is an artifact of eating a culturally imposed NaCl-enriched diet, not a fundamental physiological trait of humans. In five normal men ingesting a constant acid-producing diet with a low intrinsic NaCl content (0.15 mEq/kg of body weight per day), we measured plasma and urine acid-base composition during four 7-day periods in which the diet was supplemented as follows: no supplements----NaHCO3 only----NaHCO3 plus NaCl----NaCl only. Each sodium supplement was 2.0 mmol/kg body weight per day. With no supplements, pHb was 7.43 +/- 0.005 and (HCO3-)p was 25.0 +/- 0.4 mEq/L. When NaHCO3 only was added, pHb rose 0.02 (to 7.45 +/- 0.004; P less than 0.01) and (HCO3-)p rose nearly 4 mEq/L (to 28.9 +/- 0.6 mEq/L, P less than 0.001). The rise in (HCO3-)p was sustained predominantly by an increased rate of renal bicarbonate reabsorption. When NaCl was added, (HCO3-)p returned to the earlier level, despite continued NaHCO3 supplementation (24.9 +/- 0.6 mEq/L), and remained there when NaHCO3 supplementation was subsequently stopped (24.1 +/- 0.5 mEq/L). Thus, tight homeostatic regulation of plasma acid-base composition in response to a change in dietary base occurred only when dietary NaCl was abundant. To our knowledge, this is the first study in normal humans that demonstrates that diet NaCl variations within the normal range significantly influence plasma acid-base composition.(ABSTRACT TRUNCATED AT 250 WORDS)
A Sebastian, R E Hernandez, A A Portale, J Colman, J Tatsuno, R C Morris (1990)  Dietary potassium influences kidney maintenance of serum phosphorus concentration.   Kidney Int 37: 5. 1341-1349 May  
Abstract: In studying the metabolic effects of diet potassium (K+) variation in normal humans, we noted that varying diet K+ within its normal range influenced inorganic phosphorus (Pi) homeostasis and serum calcitriol (1,25-dihydroxyvitamin D) levels. In six men who ingested a constant whole-foods diet containing (per 70 kg body wt) 27 mmol/day Pi and 52 mEq/day K+, we increased diet K+ to 156 mmol/day with supplements first of potassium bicarbonate (KHCO3) alone and then of potassium chloride (KCL) alone, each for eight days interrupted by an eight-day recovery period of no K+ supplement. Urine Pi decreased promptly with either K(+)-salt, each inducing a persisting retention of 7 to 10 mmoles Pi, which was dumped during recovery. Fasting serum [Pi] increased with either K+ supplement (P = 0.022, repeated measures analysis of variance); the composite mean serum [Pi] for the two K(+)-supplement periods exceeded that for the two periods without supplements (P less than 0.01, paired t-test). Conversely, the concentrations of serum calcitriol decreased with either K+ supplement (P = 0.020). Among subjects, the diet K(+)-induced increases in serum [Pi] correlated with those in plasma [K+] (r = 0.64, P = 0.027); the decreases in serum calcitriol concentration correlated with the increases in serum [Pi] (r = -0.69, P = 0.014). There were no significant differences among periods in serum parathyroid hormone, ionized calcium, urine cyclic AMP excretion, plasma renin activity, body weight, serum albumin, or creatinine clearance; plasma volume decreased slightly during KCL but not during KHCO3 periods.(ABSTRACT TRUNCATED AT 250 WORDS)
M Petri, L Bockenstedt, J Colman, Q Whiting-O'Keefe, G Fitz, A Sebastian, D Hellmann (1988)  Serial assessment of glomerular filtration rate in lupus nephropathy.   Kidney Int 34: 6. 832-839 Dec  
Abstract: In patients with lupus nephropathy (LN), previous studies have shown that creatinine clearance (CCr) overestimates true glomerular filtration rate as measured by inulin clearance (CIn), and that among patients the degree of overestimation is highly variable. We sought to determine whether the discrepancy between CCr and CIn remains constant over time (months, years) in each individual patient, and therefore whether serial measurements of CCr reliably reflect the direction and magnitude of change in CIn. Twenty-five patients with LN underwent simultaneous determinations of CCr and CIn performed two to four (mean 3.3) times over three years. In a given patient, it was found that the ratio of CCr/CIn changed substantially over time (mean SD 0.16 with 95% confidence interval of 0.12 to 0.20). Thus, in about 32% of cases the ratio of CCr/CIn will vary more than +/- 16% from a previously measured value of CCr/CIn. Patients with both high and low values of CIn showed similar variability in CCR/CIn over time. Variability in CCr/CIn was found regardless of whether CIn was increasing, decreasing, or constant over time. In nearly one-half of all measurements of CCr, the corresponding change in CIn was directionally discordant. Iothalamate and technetium-DTPA renal clearances correlated highly with CIn (R2 = 0.99). We conclude that the discrepancy between CCr and CIn can vary greatly over time in an individual patient. Consequently, serial CCr does not accurately measure the direction or magnitude of change in glomerular filtration rate in lupus nephropathy.
A Vaz Carneiro, A Sebastian, M G Cogan (1987)  Reduced glomerular filtration rate can maintain a rise in plasma bicarbonate concentration in humans.   Am J Nephrol 7: 6. 450-454  
Abstract: In humans, deficiency of chloride and potassium were found to perpetuate the hyperbicarbonatemia that attends metabolic alkalosis induced by gastric aspiration partly by increasing renal bicarbonate reabsorption, commensurate with the attendant increase in filtered bicarbonate load, and partly by decreasing glomerular filtration rate (GFR), which minimizes the degree of which the filtered bicarbonate load increases and thereby minimizes the requisite increase in bicarbonate reabsorption. The relative contribution of stimulated renal bicarbonate reabsorption might increase, however, if the supply of extrarenal bicarbonate is increased, in which case a greater degree of hyperbicarbonatemia would be sustained. To investigate that possibility, we reexamined the mechanism of perpetuation of gastric alkalosis in normal subjects eating a low NaCl diet supplemented with bicarbonate salts. Prior to gastric aspiration, plasma bicarbonate concentration ([HCO3]p) and pH were higher than in similarly studied subjects not receiving bicarbonate: 29.9 +/- 0.6 vs. 25.3 +/- 0.1 and 7.43 +/- 0.008 vs. 7.41 +/- 0.002 mEq/l, respectively. With continued bicarbonate supplementation, gastric aspiration induced a further significant increase (p less than 0.05) in [HCO3]p of 10.8%, to values not significantly different from those in nonbicarbonate-loaded subjects with gastric alkalosis: 33.2 +/- 1.2 mEq/l. GFR decreased significantly by 8.4% (from 98 +/- 4 to 90 +/- 3 ml/min, p less than 0.025), offsetting nearly commensurately the increase in [HCO3]p so that total bicarbonate reabsorption was not significantly increased (2.90 +/- 0.12 vs. 2.97 +/- 0.19 mEq/min, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)
M Schambelan, A Sebastian, B A Katuna, E Arteaga (1987)  Adrenocortical hormone secretory response to chronic NH4Cl-induced metabolic acidosis.   Am J Physiol 252: 4 Pt 1. E454-E460 Apr  
Abstract: We examined the effect of chronic metabolic acidosis on adrenocortical hormone production by administering NH4Cl for 5 days to four normal subjects. Plasma aldosterone concentration, aldosterone secretion, and urinary excretion of aldosterone-18-glucuronide increased significantly, whereas there were no significant changes in the plasma concentrations of cortisol, corticosterone, or deoxycorticosterone, or in the urinary excretion of 17-hydroxycorticoids. By day 2, plasma renin activity (PRA) and concentration (PRC) were not significantly different from control, and the slope of the regression line relating plasma aldosterone concentration to PRA was significantly greater than the slope in the control period, i.e., the sensitivity of aldosterone secretion to renin stimulation was increased. By day 5, however, PRA and PRC were increased above control. Plasma potassium concentration did not change significantly. Thus chronic NH4Cl-induced acidosis induces a sustained stimulation of aldosterone secretion in the absence of a change in adrenocorticotropin-dependent adrenocortical hormone secretion. Factors other than an increase in renin secretion and plasma potassium concentration may be involved in at least the early phase of aldosterone stimulation, suggesting that plasma hydrogen ion concentration might be a separate regulator of aldosterone secretion.
R E Hernandez, M Schambelan, M G Cogan, J Colman, R C Morris, A Sebastian (1987)  Dietary NaCl determines severity of potassium depletion-induced metabolic alkalosis.   Kidney Int 31: 6. 1356-1367 Jun  
Abstract: It is uncertain whether, in humans, potassium depletion can cause or sustain metabolic alkalosis of clinically important degree in the absence of coexisting known alkalosis-producing conditions. Previously we found, in normal humans ingesting abundant NaCl, that dietary K+ depletion alone can induce and sustain a small decrease in blood acidity and increase in plasma bicarbonate concentration; we hypothesized that more severe alkalosis was prevented by mitigating mechanisms initiated by renal retention of dietary NaCl that was induced by K+ depletion. To ascertain the acid-base response to dietary K+ depletion under conditions in which the availability of NaCl for retention is greatly limited, in the present study of six normal men we restricted dietary K+ as in the previous study except that intake of NaCl was maintained low (2 to 7 mEq/day, Low NaCl Group) instead of high (126 mEq/day, High NaCl Group). Plasma acid-base composition and renal net-acid excretion (NAE) did not differ significantly between groups during the control period. In the steady state of K+ depletion (days 11 to 15 of K+ restriction), neither plasma K+ concentration (2.9 +/- 0.9 mEq/liter vs. 3.0 +/- 0.1 mEq/liter) nor cumulative K+ deficit (399 +/- 59 mEq vs. 466 +/- 48 mEq) differed significantly between groups. During K+ restriction, persisting metabolic alkalosis developed in both groups, which was more severe in the Low NaCl Group: increment in [HCO3-]p, 7.5 +/- 1.0 mEq/liter versus 2.0 +/- 0.3 mEq/liter, P less than 0.001; decrement in [H+]p, 5.5 +/- 0.6 nEq/liter versus 2.9 +/- 0.4 nEq/liter, P less than 0.003. A significantly more severe alkalosis in the Low NaCl Group was evident at all degrees of K+ deficiency achieved during the course of the 15 days of K+ restriction, and the severity of alkalosis in the Low NaCl Group correlated with the degree of K+ deficiency. During the generation of alkalosis (days 1 to 7 of K+ restriction), NAE increased in the Low NaCl Group whereas it decreased in the High NaCl Group. During the maintenance of alkalosis (days 11 to 15), NAE stabilized in both groups after it returned to values approximating the control values. In both groups, urine Cl- excretion decreased during K+ restriction even though Cl- intake had not been changed, with the result that body Cl- content increased negligibly in the Low NaCl Group (28 +/- 6 mEq) and substantially in the High NaCl Group (355 +/- 64 mEq).(ABSTRACT TRUNCATED AT 400 WORDS)
M Schambelan, A Sebastian (1985)  Type IV renal tubular acidosis: pathogenetic role of aldosterone deficiency and hyperkalemia   Nephrologie 6: 3. 135-137  
Abstract: Type IV renal tubular acidosis (RTA) is a syndrome of tubular dysfunction manifested clinically by persisting hyperkalemia and metabolic acidosis that occurs usually in patients with mild to moderate chronic glomerular insufficiency. The pathophysiologic characteristics include: reduced renal clearance of potassium; a reduced rate of renal bicarbonate reabsorption at normal plasma bicarbonate concentrations (the magnitude of which is insufficiently great to implicate the proximal tubule); an unimpaired ability to maintain a steep hydrogen ion concentration gradient between blood and urine during acidosis; and a reduced rate of renal net acid excretion despite highly acidic urine, due in part to reduced urinary excretion of ammonium, which in turn appears to be due in part to suppression of renal ammoniagenesis by hyperkalemia. Many patients with type IV RTA, but not all, have hyporeninemic hypoaldosteronism. The roles of mineralocorticoid deficiency and hyperkalemia in the pathogenesis of type IV RTA will be considered and the ameliorative effects of treatment with fludrocortisone, furosemide, and dietary potassium restriction reviewed.
H N Hulter, J H Licht, A Sebastian (1985)  Effects of dietary potassium depletion and mineralocorticoid excess on renal Cl-conservation in the dog.   Am J Physiol 248: 1 Pt 2. F104-F112 Jan  
Abstract: Preexisting dietary K+ depletion (KD) in dogs exaggerates the renal acid excretory response to mineralocorticoid hormone (MCH) and attenuates the renal Cl- reabsorptive response without altering the Na+ reabsorptive response. The exaggerated acid excretory response has been postulated to be an electrophysiological consequence of a defect in renal Cl- reabsorption caused by KD. To investigate the specific effects of KD on renal Cl- transport in dogs, we assessed renal Cl- conservation during dietary Cl- restriction in KD adrenalectomized dogs maintained on physiological replacement doses of MCH. After a 16-day period of dietary K+ restriction and physiological MCH replacement, reduction of dietary NaCl from 5.0 to 0.25 mmol X kg-1 X 24 h-1 was attended by reduction in urinary Cl- excretion to values less than intake and to significantly lower values than in K+ -replete controls. In a subsequent experimental period of continued Cl- restriction and administration of DOC (15 mg/24 h, i.m.), urinary Cl- excretion decreased further in both groups to stable values, but the values were significantly greater in KD (2.7 +/- 0.4 vs. 1.1 +/- 0.1 meq/24 h, P less than 0.05) and the cumulative retention of urinary Cl- was significantly less (10.3 +/- 1.4 vs. 29.5 +/- 6.7 meq, P less than 0.05). These findings demonstrate that preexisting dietary KD accelerates chronic renal Cl- conservation in response to dietary Cl- restriction under conditions in which MCH supply is normal and fixed but that it impairs maximal renal Cl- -conserving ability in response to MCH excess.
A Sebastian, M Schambelan, J M Sutton (1984)  Amelioration of hyperchloremic acidosis with furosemide therapy in patients with chronic renal insufficiency and type 4 renal tubular acidosis.   Am J Nephrol 4: 5. 287-300  
Abstract: In hypoaldosteronemic patients with chronic renal insufficiency, administration of a mineralocorticoid steroid such as fludrocortisone can ameliorate hyperkalemia and metabolic acidosis, but this therapy is not always safe owing to the deleterious consequences of extracellular fluid volume expansion resulting from mineralocorticoid-induced sodium chloride retention. In the present study of 8 patients with renal hyperchloremic acidosis, mild hyperkalemia and chronic glomerular insufficiency, we evaluated the therapeutic effect of chronic administration of a natriuretic/chloruretic agent, furosemide, a renoactive drug that is known to increase renal acid excretion in experimental animals without increasing body content of sodium chloride. 4 patients had hyporeninemic hypoaldosteronism. During 8 days of treatment in 6 patients who received furosemide alone, metabolic acidosis was significantly ameliorated. Urinary net acid excretion increased, except in the 2 patients who had the most severe hypoaldosteronism. For the group as a whole, the cumulative change in net acid excretion correlated positively with the rate of aldosterone excretion (r = 0.94, p less than 0.01). Thus, the aciduric response to furosemide is attenuated by aldosterone deficiency. When furosemide was administered in combination with fludrocortisone (4 subjects), an amelioration of metabolic acidosis occurred that was greater than that observed in the group treated with furosemide alone. Combined therapy ameliorated acidosis in the patient with the most severe degree of hypoaldosteronism, the same patient in whom administration of furosemide without fludrocortisone was ineffective even after 6 months of treatment. The findings in this study indicate that chronic furosemide therapy, alone or in combination with fludrocortisone, is a safe and effective means of ameliorating metabolic acidosis in patients with chronic renal insufficiency, including those with hypoaldosteronism.
R D Toto, H N Hulter, S Mackie, A Sebastian (1984)  Renal tubular acidosis induced by dietary chloride.   Kidney Int 25: 1. 26-32 Jan  
Abstract: Previous studies have demonstrated that dietary intake of anions with high renal reabsorbability (Cl- greater than SO4=) can result in either exacerbation of chronic metabolic acidosis or correction of chronic metabolic alkalosis. These results, however, fail to predict the renal acid-base response to Cl- administration when systemic acid-base composition is initially normal, but accompanied by an extracellular fluid (ECF) volume-mediated renal avidity for Cl- reabsorption; that is, the renal options include HCl retention, KCl retention, and phosphaturia. Accordingly, the present metabolic balance studies evaluated the response to substitution of dietary Cl- (2.5 mEq/kg/day) for Pi in five dogs previously ECF-depleted with diuretics and maintained on a dietary K+ supplement, 5.0 mEq/kg daily as neutral Pi (electrolyte-free diet) during a steady-state control period. Dietary Cl- resulted in a decrease in arterial plasma [HCO3-] from 21.2 +/- 0.7 to 17.8 +/- 0.8 mEq/liter, (P less than 0.01) and increase in [H+] from 38.5 +/- 0.7 to 43.3 +/- 0.8 nEq/liter (P less than 0.001). Urine pH increased (P less than 0.01), the cumulative change in net acid excretion decreased (-79 mEq, P less than 0.05), and Cl- retention (39 mEq, P less than 0.05) occurred. No change in Na+, K+, or Pi excretion occurred. The renal acidosis was fully corrected when SO4= was substituted for dietary Cl- and redeveloped when Cl- was resubstituted . Superimposition of a large oral buffer load (creatinine) did not ameliorate Cl- -induced renal acidosis. The results indicate that dietary reabsorbable anions can result in renal acidosis when Cl- reabsorption is stimulated and suggest that anion reabsorbability characteristics and not anion buffer properties are responsible.
H N Hulter, R D Toto, A Sebastian, S Mackie, C R Cooke, T E Wilson, J C Melby (1984)  Effect of extracellular fluid volume depletion on renal regulation of acid-base and potassium equilibrium during prolonged mineral acid administration.   J Lab Clin Med 103: 6. 854-868 Jun  
Abstract: Previous studies of the renal and systemic acid-base response to prolonged administration of mineral acids in dogs have suggested that during the steady state of acidosis, the level at which plasma bicarbonate concentration is regulated by the kidney is dependent on the degree of augmentation of "distal delivery" of sodium imposed by the increased filtered load of administered mineral acid anion with filtered sodium, and on the degree of augmentation of "distal avidity" for sodium reabsorption imposed by ECF volume ( ECFV ) contraction secondary to renal sodium losses accompanying the administered mineral acid anion. This formulation, however, fails to predict the level at which plasma bicarbonate concentration would be regulated under conditions of preexisting ECFV depletion, which would simultaneously limit distal delivery of sodium salts and yet increase distal avidity for sodium reabsorption. Our studies assessed the renal and systemic acid-base responses to prolonged daily administration of 5.0 mEq/kg of H+ as HCl (groups 1 and 2) or H2SO4 (groups 3 and 4) in dogs with normal ECFV (groups 1 and 3) vs. preexisting ECFV depletion (groups 2 and 4) induced by administration of ethacrynic acid. In response to HCl administration, dogs with depleted ECFV developed more severe acidosis than ECFV -replete dogs (delta[HCO-3,]p, -5.0 +/- 0.6 mEq/L, group 2 vs. -2.7 +/- 0.5 mEq/L, group 1, p less than 0.02). The exacerbated metabolic acidosis in group 2 persisted in the steady state, even though the steady-state net systemic acid load was not greater than in group 1. No exacerbation of acidosis was observed in H2SO4-fed dogs with depleted ECFV . In response to either HCl or H2SO4, persistent hypokalemia caused by increased renal potassium clearance occurred in ECFV -replete dogs but not in ECFV -depleted dogs. Our results indicate that preexisting ECFV depletion results in impaired renal hydrogen ion secretion during prolonged HCl feeding, but not during H2SO4 feeding. These results suggest that during prolonged HCl loading under conditions of preexisting ECFV depletion, hypovolemia-mediated restriction of the normal augmentation of distal delivery of sodium salts overrides the effects of enhanced distal cation secretory capacity that attends hypovolemia-mediated augmentation of distal avidity for sodium reabsorption.
T Maher, M Schambelan, I Kurtz, H N Hulter, J W Jones, A Sebastian (1984)  Amelioration of metabolic acidosis by dietary potassium restriction in hyperkalemic patients with chronic renal insufficiency.   J Lab Clin Med 103: 3. 432-445 Mar  
Abstract: Hyperkalemia has been implicated in the pathogenesis of metabolic acidosis in chronic renal insufficiency because acidosis is ameliorated after administration of medications that correct hyperkalemia: mineralocorticoids, diuretics, intestinal K+-binding agents. However, the acidosis-ameliorating effect of these medications may be a consequence not of their ability to correct hyperkalemia, but of their ability to directly stimulate renal or intestinal excretion of acid. To investigate the specific effect of correcting hyperkalemia, balance studies were performed wherein hyperkalemia was corrected solely by restriction of dietary K+ in three patients with moderate chronic renal insufficiency (Ccreat 36, 44, and 58 ml/min/1.73 m2, respectively). Reduction of K+ intake was effected by substitution of Na+ for K+ in the electrolyte supplement to a whole-food diet of low K+ content. This maneuver resulted in correction of hyperkalemia and sustained amelioration of metabolic acidosis in each patient. Net acid excretion increased only transiently, and not enough to fully account for the magnitude of the increment in plasma [HCO3-], suggesting that an extrarenal mechanism of HCO3- input to the systemic circulation was the major factor that ameliorated the systemic acidosis. Evidence of an extrarenal mechanism was obtained only during the phase of decreasing plasma [K+]. Subsequently, during sustained normokalemia, the increased plasma [HCO3-] was maintained as a consequence of a sustained increase in total renal H+ secretion, evidenced by complete reabsorption of the increased filtered load of HCO3- and no reduction in net acid excretion from control values. These results indicate that in some patients with moderate chronic renal insufficiency, metabolic acidosis is ameliorated when hyperkalemia is corrected by restriction of dietary K+ (Na+ substitution) without otherwise changing diet composition and without administration of medication. Amelioration of the acidosis is predominantly effected by extrarenal mechanisms, and is sustained by an increase in the set point at which plasma [HCO3-] is regulated by the kidney.
B E Berger, M G Cogan, A Sebastian (1984)  Reduced glomerular filtration and enhanced bicarbonate reabsorption maintain metabolic alkalosis in humans.   Kidney Int 26: 2. 205-208 Aug  
Abstract: The mechanism that sustains chloride-depletion metabolic alkalosis is presumed to be a stimulation of renal acidification, so that the elevated filtered bicarbonate load that attends hyperbicarbonatemia is completely reabsorbed. However, such enhancement of renal bicarbonate reabsorption is not necessary to maintain hyperbicarbonatemia if the filtered bicarbonate load is not increased owing to a concomitant reduction in glomerular filtration rate (GFR). To assess the relative contributions of enhanced renal bicarbonate reabsorption and reduced GFR in the maintenance of chloride-depletion alkalosis in humans, selective hydrochloric acid depletion was induced in five normal subjects. Plasma bicarbonate concentration increased by 27% (25.3 +/- 0.1 to 32.1 +/- 0.3 mEq/liter, P less than 0.005), whereas the rate of renal bicarbonate reabsorption increased by only 17% (2.7 +/- 0.1 to 3.2 +/- 0.2 mEq/min, P less than 0.05) owing to a 10% reduction in GFR (93.2 +/- 4.4 to 84.3 +/- 4.1 ml/min, P less than 0.01). Thus, in chloride-depletion metabolic alkalosis in humans, the increase in plasma bicarbonate concentration is not attended by a commensurate increase in filtered bicarbonate and rate of renal bicarbonate reabsorption. Both a reduction in GFR and an enhancement of renal bicarbonate reabsorption contribute to maintenance of the alkalotic state.
I Kurtz, T Maher, H N Hulter, M Schambelan, A Sebastian (1983)  Effect of diet on plasma acid-base composition in normal humans.   Kidney Int 24: 5. 670-680 Nov  
Abstract: Steady-state plasma and urine acid-base composition was assessed in 19 studies of 16 normal subjects who ingested constant amounts of one of three diets that resulted in different rates of endogenous noncarbonic acid production (EAP) within the normal range. Renal net acid excretion (NAE) was used to quantify EAP since the two variables are positively correlated in normal subjects. A significant positive correlation was observed between plasma [H+] and plasma PCO2, and between plasma [HCO3-] and plasma PCO2, among the subjects. Multiple correlation analysis revealed a significant interrelationship among plasma [H+], plasma PCO2, and NAE (r = 0.71, P less than 0.001), and among plasma [HCO3-], plasma PCO2, and NAE (r = 0.77, P less than 0.001). The partial correlation coefficients indicated a significant positive correlation between plasma [H+] and NAE, and a significant negative correlation between plasma [HCO3-] and NAE, when plasma PCO2 was held constant. These findings indicate that two factors influence the level at which plasma [H+] is maintained in normal subjects: (1) the steady-state rate of endogenous noncarbonic acid production, and (2) the setpoint at which plasma PCO2 is regulated by the respiratory system. Plasma [HCO3-] is also co-determined by these two factors. In disease states, therefore, both factors must be known before a disturbance in acid-base homeostasis can be excluded.
H N Hulter, R D Toto, L P Ilnicki, B Halloran, A Sebastian (1983)  Metabolic alkalosis in models of primary and secondary hyperparathyroid states.   Am J Physiol 245: 4. F450-F461 Oct  
Abstract: Hyperchloremic metabolic acidosis has been reported in clinical states of primary and secondary hyperparathyroidism (HPT). Acute administration of parathyroid hormone (PTH) decreases renal acidification in humans and dogs, but the renal and systemic acid-base effects of chronic HPT have not been extensively investigated. In chronically thyroparathyroidectomized (TPTX) dogs (group I), bPTH 1-5 U/kg twice daily resulted in sustained hypophosphatemia, hypercalcemia, and Cl- -resistant metabolic alkalosis that was of renal origin at least in part: delta [HCO3-]p + 4.1 +/- 0.8 meq/liter, P less than 0.01; delta [H+]p -4 +/- 1 neq/liter, P less than 0.001, days 10-12. The cumulative change (sigma delta) in net acid excretion (NAE) was +44 meq (day 9, P less than 0.05). Similarly, metabolic alkalosis of renal origin, at least in part, occurred when PTH was administered by chronic continuous intravenous infusion (group II). Since chronic administration of calcitriol in dogs results in metabolic alkalosis, plasma calcitriol concentration was measured and found not to be increased by chronic intravenous PTH administration. In intact dogs (group III), a continuous chronic intravenous infusion of the Ca2+ chelator, Na4EGTA (3.0 mmol/kg daily), substituted for an equimolar amount of prechelated EGTA (CaNa2EGTA), resulted in a model of hypocalcemic HPT and severe Cl- -resistant metabolic alkalosis: delta [HCO3-]p +9.1 +/- 1.9 meq/liter, P less than 0.05; delta [H+]p -5 +/- 1 neq/liter, P less than 0.01, days 6-8. NAE decreased significantly. Thus, whereas metabolic alkalosis induced by PTH administration could be accounted for by increased NAE (group I), EGTA-induced metabolic alkalosis was accounted for by an extrarenal mechanism of base input to extracellular fluid (group III). Neutralization of the extrarenal base input by chronic administration of HCl during the period of EGTA-induced HPT did not preclude the development of metabolic alkalosis (group V), suggesting that a renal component was present in EGTA-induced metabolic alkalosis as well as in models of primary HPT (groups I and II). During the steady state, in this group as in the groups administered PTH, the net endogenous load of acid to the systemic circulation requiring renal excretion was unchanged from control, as indicated by stable values of NAE not significantly different from control. Yet metabolic alkalosis persisted in the steady state.(ABSTRACT TRUNCATED AT 400 WORDS)
A Sebastian, H N Hulter, I Kurtz, T Maher, M Schambelan (1982)  Disorders of distal nephron function.   Am J Med 72: 2. 289-307 Feb  
Abstract: In this review, the distal nephron is considered to be that portion of the renal tubule commencing with the thick ascending limb of the loop of Henle and ending with the papillary collecting duct. The collecting duct, including its subdivisions in the cortex and medulla, originates from a different embryologic anlage than more proximal nephron segments, which may explain its morphologic and functional dissimilarities from the thick ascending limb and the distal convoluted tubule. This review summarizes selected aspects of the physiology of the distal nephron, with particular emphasis on the physiology of distal nephron transport of sodium, potassium, chloride and hydrogen ion. The pathophysiologic features of the following disorders of distal nephron function are reviewed: (1) pseudohypoaldosteronism, a heterogenous group of disorders in which the signs and symptoms are suggestive of aldosterone deficiency, but in which aldosterone levels are supernormal and administration of exogenous mineralocorticoid is not ameliorative; (2) pseudohyperaldosteronism (Liddle syndrome), a familial disorder in which the clinical manifestations closely resemble those resulting from an aldosterone-producing adenoma of the adrenal gland (primary aldosteronism), but in which the measured rate of aldosterone secretion and excretion is greatly subnormal; (3) Bartter syndrome and related syndromes of renal potassium wasting; (4) type 1 renal tubular acidosis (classic, distal); (5) type 4 renal tubular acidosis (hyperkalemic). Reference citations are generally to articles reporting recent advances in these areas and to review articles that contain comprehensive bibliographies.
R J Brenner, D B Spring, A Sebastian, E M McSherry, H K Genant, A J Palubinskas, R C Morris (1982)  Incidence of radiographically evident bone disease, nephrocalcinosis, and nephrolithiasis in various types of renal tubular acidosis.   N Engl J Med 307: 4. 217-221 Jul  
Abstract: The syndrome of renal tubular acidosis has been categorized into three physiologic types that have different clinical findings and prognostic and therapeutic implications. We reviewed radiographs of the skeleton and kidneys in 92 patients (56 children and 36 adults) with renal tubular acidosis in order to determine whether the radiologic findings could be related to the type of syndrome. Forty-four patients had Type 1 renal tubular acidosis, 18 had Type 2, and 30 had Type 4. Evidence of skeletal abnormalities was uncommon (17 per cent) and was confined to patients who had the Type 2 disorder or azotemia. The children with Type 2 and skeletal abnormalities had rickets; the adults had osteopenia without pseudofractures. Nephrocalcinosis was evident in approximately one fourth of the group (29 per cent) and was restricted to patients with the Type 1 syndrome. In patients with Type 4, osteopenia was evident in 12 per cent, all of whom were azotemic. Our observations indicate that the radiographic manifestations of renal tubular acidosis are influenced by the physiologic type of renal tubular acidosis.
M Schambelan, A Sebastian, F C Rector (1981)  Mineralocorticoid-resistant renal hyperkalemia without salt wasting (type II pseudohypoaldosteronism): role of increased renal chloride reabsorption.   Kidney Int 19: 5. 716-727 May  
Abstract: A rare syndrome has been described in which mineralocorticoid-resistant hyperkalemia of renal origin occurs in the absence of glomerular insufficiency and renal sodium wasting and in which hyperchloremic acidosis, hypertension, and hyporeninemia coexist. The primary abnormality has been postulated to be a defect of the potassium secretory mechanism of the distal nephron. The present studies were carried out to investigate the mechanism of impaired renal potassium secretion in a patient with this syndrome. When dietary intake of sodium chloride was normal, renal clearance of potassium was subnormal (CK/GFR = 3.6 +/- 0.2%; normal subjects, 9.0 +/- 0.9%, N = 4) despite high normal or supernormal levels of plasma and urinary aldosterone. The fractional clearance of potassium remained subnormal (CK/GFR = 5.1 +/- 0.2%) during superimposed chronic administration of superphysiologic doses of mineralocorticoid hormone. Little increase in renal potassium clearance occurred when the delivery of sodium to distal nephron segments was increased further by the i.v. infusion of sodium chloride, despite experimentally sustained hypermineralocorticoidism. But potassium clearance increased greatly when delivery of sodium to the distal nephron was increased by infusion of nonchloride anions: sulfate (sodium sulfate infusion, low sodium chloride diet; CK/GFR = 63.7 +/- 0.4%) or bicarbonate (sodium bicarbonate plus acetazolamide infusion; CK/GFR = 81.7 +/- 1.7%). These findings indicate that mineralocorticoid-resistant renal hyperkalemia in this patient cannot be attributed to the absence of a renal potassium secretory capability or to diminished delivery of sodium to distal nephron segments; instead it may be dependent on chloride delivery to the distal nephron. We suggest that the primary abnormality in this syndrome increases the reabsorptive avidity of the distal nephron for chloride, which (1) limits the sodium and mineralocorticoid-dependent voltage driving force for potassium and hydrogen ion secretion, resulting in hyperkalemia and acidosis and (2) augments distal sodium chloride reabsorption resulting in hyperchloremia, volume expansion, hyporeninemia, and hypertension.
H N Hulter, E L Bonner, R D Glynn, A Sebastian (1981)  Renal and systemic acid-base effects of chronic spironolactone administration.   Am J Physiol 240: 5. F381-F387 May  
Abstract: Studies in dogs were carried out to investigate the effects of chronic administration of the mineralcorticoid antagonist spironolactone (15 mg/kg orally) on renal and systemic acid-base metabolism. In adrenalectomized dogs administered fixed mineralocorticoid and glucocorticoid replacement, spironolactone resulted in a definite renal antimineralocorticoid effect, as evidenced by natriuresis and chloruresis, and sustained metabolic acidosis and hyperkalemia due in part to impaired renal secretion of hydrogen and potassium. In adrenalectomized dogs receiving physiological glucocorticoid without mineralocorticoid, metabolic acidosis also occurred, but a marked stimulatory effect of spironolactone on net acid excretion occurred in association with increased urinary SO4-2 and total nitrogen excretion. Accordingly, spironolactone results in sustained renal tubular acidosis when administered in the presence of constant physiological levels of mineralocorticoid and glucocorticoid steroids. When administered under conditions of complete lack of mineralocorticoid activity, spironolactone exerts systemic and renal acid-base effects similar to those of a glucocorticoid steroid, namely, increased protein catabolism and sulfuric acid production with resultant extrarenal metabolic acidosis associated with increased net acid excretion.
H N Hulter, R D Toto, E L Bonner, L P Ilnicki, A Sebastian (1981)  Renal and systemic acid-base effects of chronic hypoparathyroidism in dogs.   Am J Physiol 241: 5. F495-F501 Nov  
Abstract: MEtabolic alkalosis has been reported in patients with chronic hypoparathyroidism under conditions of uncontrolled diet and medication intake. Hypoparathyroidism has also been reported to result in increased renal bicarbonate reabsorptive capacity in acutely bicarbonate-loaded dogs. However, the acid-base effects of experimentally induced chronic hypoparathyroidism have not been investigated in any species. Accordingly, we investigated the chronic effects of hypoparathyroidism by thyroparathyroidectomy (TPTX) plus thyroxine replacement on renal regulation of plasma acid-base composition under metabolic balance conditions of normal dietary acid load (group I) and alkali load (group II, 9.0 meq/kg HCO3(-) daily) in dogs ingesting a normal Cl-, high Ca2+ diet throughout study. For groups I and II pre-TPTX: [HCO3(-)]p, 19.7 +/- 1.0, 20.1 +/- 0.9 meq/liter. Plasma acid-base composition (days 5-10) was unchanged by TPTX: delta [HCO3(-)]p, -0.7 +/- 0.4, 0.0 +/- 0.2 meq/liter; delta [H+]p, 0 +/- 1, -1 +/- 0 neq/liter, NS from control. A reduction in plasma total calcium concentration ([CaT]p) occurred and persisted (group I: [CaT]p, -1.6 +/- 0.2 mg/100 ml, P less than 0.01, day 1 and -1.2 +/- 0.9, days 5-10; group II: -1.4 +/- 0.3 mg/100 ml, P less than 0.01, day 1 and -2.3 +/- 0.4, days 5-10). No significant change in net acid or Cl- excretion occurred following TPTX. Thus, chronic hypoparathyroidism characterized by a chronic reduction in [CaT]p does not result in significant alterations in renal regulation of plasma acid-base composition in the dog.
A Sebastian, J M Sutton, H N Hulter, M Schambelan, S M Poler (1980)  Effect of mineralocorticoid replacement therapy on renal acid-base homeostasis in adrenalectomized patients.   Kidney Int 18: 6. 762-773 Dec  
Abstract: Chronic balance studies were performed in six adrenalectomized patients to investigate the renal and systemic acid-base consequences of mineralocorticoid deficiency in the absence of either glucocorticoid deficiency or parenchymal renal disease. Constant glucocorticoid replacement was provided with dexamethasone, 750 to 875 micrograms/day, administered orally. Creatinine clearance averaged 98 +/- 8 ml/min/1.73 m2. Following a control period, mineralocorticoid replacement with fludrocortisone (100 to 200 micrograms/day) was either discontinued (N = 3) or initiated (N = 2). In an additional patient, mineralocorticoid replacement was initiated and sustained (5 days) by continuous i.v. infusion of aldosterone, at a dose approximating the normal secretion rate (120 micrograms/day). Net acid excretion (NAE) and plasma total carbon dioxide decreased in each patient in whom mineralocorticoid was discontinued and increased in each patient in whom mineralocorticoid was initiated. The cumulative change in NAE (sigma delta NAE) independent of direction averaged 66 +/- 20 mEq (P less than 0.05) by the fifth experimental day in the six patients, and the corresponding change in plasma total CO2 averaged 1.2 +/- 0.3 mmoles/liter (P less than 0.02). The magnitude of sigma delta NAE correlated with the basal rate of NAE (r = 0.87, P less than 0.05), which averaged 0.9 +/- 0.1 mEq/kg body wt per day. The change in plasma total CO2 correlated with sigma delta NAE (r = 0.83, P less than 0.05). The changes in NAE correlated positively with the corresponding changes in sodium balance and negatively with the corresponding changes in potassium balance. These findings provide the first evidence that renal acidification is under tonic stimulation by mineralocorticoid at levels not exceeding those in normal subjects ingesting acid-producing diets of normal sodium and potassium content. The extent to which the tonic stimulation of renal acidification is mediated by a direct effect of mineralocorticoid on renal hydrogen ion transport or by an indirect effect dependent on altered renal sodium and/or potassium transport requires further investigation. The findings implicate mineralocorticoid deficiency as a significant renal acidosis-producing condition not dependent on the presence of renal disease or glucocorticoid deficiency, and potentially amplified when endogenous acid production is increased by diet or disease.
H N Hulter, J H Licht, E L Bonner, R D Glynn, A Sebastian (1980)  Effects of glucocorticoid steroids on renal and systemic acid-base metabolism.   Am J Physiol 239: 1. F30-F43 Jul  
Abstract: Clinical states of hyperglucocorticoidism are associated with renal metabolic alkalosis, yet the systemic and renal acid-base response to chronic administration of glucocorticoid steroids (dexamethasone, triamcinolone) possessing little or no mineralocorticoid activity has not been investigated. In balance studies studies in dogs administration of triamcinolone (Tcn), 1.0 mg . kg-1 . day-1 for 6-9 days (group I, n = 5), resulted in a persistent reduction in urine pH and increase in net acid excretion (NAE), and in the excretion of urinary unmeasured anions (C+NH4,Na;K minus A-Cl,HCO3,Pi), which were identified as organic anions and sulfate. A significant degree of metabolic acidosis occurred initially (delta [HCO3-]p, -3.4 meq/liter, P less than 0.05, day 1). As Tcn administration was continued, the cumulative increment in net acid excreted exceeded the cumulative increment in urinary unmeasured anion excreted and [HCO-3]p returned to pre-Tcn control values and remained stable thereafter. In the steady state of Tcn administration plasma potassium concentration and renal potassium clearance were not significantly different from pre-Tcn control, in contrast to the findings of hypokalemia and increased renal potassium clearance during chronic administration of deoxycorticosterone (DOC). Triamcinolone did not result in antinatriuresis or antichloruresis. Chronic administration of a 10-fold smaller dose of Tcn (0.1 mg . kg-1 . day-1) in an additional group (group III) also resulted in a persisting reduction in urine pH and an increase in net acid excretion that exceeded unmeasured anion excretion and resulted in a small increase in steady-state plasma bicarbonate concentration. These results suggest that chronic administration of potent glucocorticoid steroids results in 1) a persisting increase in endogenous acid production, and 2) stimulation of renal hydrogen ion secretion that was of greater degree than accounted for by the increment in endogenous acid production and that was not accompanied by renal mineralocorticoid effects on sodium and potassium transport.
H N Hulter, R D Glynn, A Sebastian (1980)  Renal and systemic acid-base effects of chronic dichloroacetate administration in dogs.   Metabolism 29: 10. 997-1002 Oct  
Abstract: Dichloroacetate (DCA) increases metabolic disposal of lactic acid secondary to activation of pyruvate dehydrogenase and consequent acceleration of pyruvate oxidation. DCA has thus been proposed as a therapeutic agent for clinical states of lactic acidosis. Yet, DCA has a potential metabolic acidosis-producing effect by virtue of reported effects of (A) increasing blood ketoacid concentration, (B) decreasing tubular reabsorption of filtered ketoacid anions, and (C) decreasing renal NH3 production. In the present study chronic administration of DCA, 50 mg/kg p.o. daily for 6-8 days, resulted in a cumulative increase in renal net acid excretion (NAE) (sigma delta NAE, +61 meq, p < 0.05). The increase in NAE was accounted for entirely by increased NH4+ excretion. Production of ammonia by the kidney appeared to be increased since the increased excretion of NH4+ was accompanied by an increase in urine pH (delta UpH, +0.18 +/- 0.07, p < 0.05). The increase in NAE was accompanied by a nearly identical increase in urinary anion gap (UAG) (UAG = [NH4+ + Na+ + K+] - [Cl- + HCO3- + HPO4(2-) + H2PO4-]). The increase in UAG was caused by increased urinary total organic anions, accounted for at least in part by a significant increase in urinary acetoacetate. No significant increase in urinary potassium or sodium excretion occurred. A change in plasma acid-base composition occurred that was consistent with a mild respiratory acidosis without associated primary metabolic acidosis or alkalosis. These findings indicate that chronic DCA administration results in (1) increased steady state endogenous noncarbonic organic acid production, and (2) retention of carbonic acid. Further investigation of the potential metabolic and respiratory acidosis-producing effects of DCA is required to determine its clinical efficacy in the treatment of clinical lactic acidosis.
H N Hulter, A Sebastian, J F Sigala, J H Licht, R D Glynn, M Schambelan, E G Biglieri (1980)  Pathogenesis of renal hyperchloremic acidosis resulting from dietary potassium restriction in the dog: role of aldosterone.   Am J Physiol 238: 2. F79-F91 Feb  
Abstract: In dogs dietary K+ restriction (16 days) results in diminished urinary net acid excretion (NAE) and systemic hyperchloremic metabolic acidosis (sigma delta NAE, -200 meq; delta[HCO3-]p, -2.9 +/- 0.3 meq/liter, P less than 0.05). Urinary aldosterone (aldo) excretion decreased by 34 +/- 3% (P less than 0.001) and metabolic clearance rate of aldo increased by 80 +/- 17% (P less than 0.02) during K+ restriction. Daily subcutaneous injection of a small amount of exogenous aldo (20 micrograms) during K+ restriction significantly attenuated the reduction in NAE (sigma delta NAE -51 vs. -200 meq, P less than 0.05) without raising plasma aldo concentrations to levels greater than control. These findings suggest that hypoaldosteronism induced by potassium depletion is at least in part the cause of the observed renal tubular acidosis. In adrenalectomized (ADX) dogs maintained on fixed mineralocorticoid and glucocorticoid replacement (aldo dose 60 micrograms/day), K+ restriction resulted in a significant degree of renal metabolic acidosis (delta[HCO3-]p, -1.4 +/- 0.3 meq/liter, P less than 0.01). In these ADX dogs, the exogenous supply of aldo was fixed but hypoaldosteronism may have developed owing to increased metabolic clearance rate of aldo caused by dietary K+ depletion. When mineralocorticoid replacement was withheld in ADX dogs, the steady-state degree of renal metabolic acidosis was no more severe in animals with preexisting dietary K+ depletion (16 days) than in the same animals when mineralocorticoid was withheld without preexisting K+ depletion. Thus, when neither endogenous nor exogenous aldo is present, K+ depletion does not result in a renal acidosis-producing effect that exacerbates that of aldo deficiency. The results of these studies suggest that the reduction in NAE and consequent metabolic acidosis induced by dietary K+ depletion is at least in part a consequence of aldo deficiency, and provide no evidence of an additional defect in acidification not caused by aldo deficiency.
M Schambelan, A Sebastian, E G Biglieri (1980)  Prevalence, pathogenesis, and functional significance of aldosterone deficiency in hyperkalemic patients with chronic renal insufficiency.   Kidney Int 17: 1. 89-101 Jan  
Abstract: Our findings indicate that hypoaldosteronism occurs commonly (23/31 patients) in hyperkalemic patients with chronic renal insufficiency and that the deficiency of aldosterone contributes to the pathogenesis of the hyperkalemia. In most patients (83%), hypoaldosteronism could be accounted for by deficient renal secretion of renin, but in some patients (17%) overt renin deficiency did not appear to be present, and therefore other (unidentified) causes of aldosterone deficiency must be invoked. The results also indicate that the urinary excretion rate of aldosterone secretion rate in this group of patients.
H N Hulter, J H Licht, R D Glynn, A Sebastian, L P Ilnicki (1980)  Pathophysiology of chronic renal tubular acidosis induced by administration of amiloride.   J Lab Clin Med 95: 5. 637-653 May  
Abstract: Amiloride is a "potassium-sparing" diuretic agent of moderate natriuretic potency with site of action in postmacula densa segments of the distal nephron. In isolated segments of mammalian cortical distal nephron, amiloride diminishes sodium reabsorption and transtubular electrical PD and inhibits potassium secretion. We investigated the effects of long-term administration of a demonstrably maximal dose of amiloride (1.0 mg/kg b.i.d.) on plasma and urine acid-base and electrolyte composition in fixed steroid-replaced ADX dogs. Amiloride administration resulted in potassium retention and hyperkalemia and reduced net acid excretion and caused chronic hyperchloremic metabolic acidosis. The cumulative reduction in net acid excretion and severity of systemic acidosis were not significantly different in additional groups in which potassium retention was prevented by restriction of dietary potassium during amiloride administration or in which amiloride was administered to animals with pre-existing dietary potassium depletion. The response of urine pH and ammonium excretion, however, differed among groups. In the steady state of chronic acidosis, urine pH and ammonium concentration were lowest in the hyperkalemic group and highest in the hypokalemic group, and among the three groups pH and ammonium were positively correlated (r = 0.67, p less than 0.001). Ammonium concentration varied inversely with plasma potassium concentration. Net acid excretion rates returned to control levels during the steady state of chronic amiloride-induced acidosis in the three groups. During continued amiloride administration, sustained correction of acidosis by long-term oral administration of sodium bicarbonate did not result in negative values of net acid excretion; that is, amiloride did not cause net wasting of base at normal plasma bicarbonate concentration. The results of these studies suggest that chronic amiloride administration results in a sustained impairment of renal hydrogen ion secretion restricted to the distal nephron and not dependent on alterations in potassium balance. Differences in potassium balance (positive or negative) appeared to influence only the availability of ammonia for diffusion into urine and steady-state urine pH, but not the steady-state net rate of renal hydrogen ion secretion during amiloride. These studies identify an experimental model of chronic distal renal tubular acidosis in which external hydrogen ion balance is re-established during chronic acidosis even when the availability of ammonia for excretion is decreased.
H N Hulter, L P Ilnicki, J A Harbottle, A Sebastian (1978)  Correction of metabolic acidosis by the kidney during isometric expansion of extracellular fluid volume.   J Lab Clin Med 92: 4. 602-612 Oct  
Abstract: In dogs with chronic hypochloremic metabolic alkalosis associated with ECFV contraction, plasma [HCO-3] ([HCO-3]p) normalizes during expansion of ECFV with a solution containing Cl- and HCO-3 in concentrations duplicating those in the plasma before expansion (isometric expansion). The kidney selectively rejects administered HCO-3 and retains Cl-. If this preferential Cl- less than HCO-3 reabsorptive selectivity were a characteristic renal response to ECFV expansion, isometric expansion during hyperchloremic acidosis would exacerbate the acid-base disturbance rather than correct it as it does in alkalosis. We examined the effect of isometric expansion in dogs with chronic hyperchloremic metabolic acidosis induced by HCl feeding or mineralocorticoid hormone deficiency. During expansion, as the expected decrease occurred in the fractional reabsorption of Na+, a lesser decrease occurred in fractional reabsorption of HCO-3, whereas a greater decrease occurred in fractional reabsorption of Cl-. The kidney selectively retained administered HCO3 and rejected Cl-. [HCO-3]p normalized. The shift to bicarbonate-selective from chloride-selective anion reabsorption during ECFV expansion in metabolic acidosis vs. metabolic alkalosis indicates that in response to ECFV expansion- the kidney selectively alters the ratio of bicarbonate to chloride concentration in the tubular reabsorbate in the direction that tends to normalize plasma acid-base composition, irrespective of the direction of deviation of the initial plasma bicarbonate concentration. The signal that initiates the shift in anion reabsorptive selectivity remains to be identified.
H N Hulter, L P Ilnicki, J A Harbottle, A Sebastian (1977)  Impaired renal H+ secretion and NH3 production in mineralocorticoid-deficient glucocorticoid-replete dogs.   Am J Physiol 232: 2. F136-F146 Feb  
Abstract: When the administration of exogenous mineralocorticoid hormones was discontinued in adrenalectomized dogs maintained on glucocorticoid, net acid excretion decreased due largely to a reduction in urinary ammonium excretion (UNH4+V), and hyperchloremic hyperkalemic metabolic acidosis occurred and persisted. The reduction in UNH4+V was not associated with an increase in urine pH (UpH) or a decrease in urine flow, but correlated with the severity of hyperkalemia and was mitigated by dietary potassium restriction. UpH decreased to values as low as 5.3. During acidosis, UpH varied directly with UNH4+V, but in relation to UNH4+V, UpH exceeded that in acid-fed mineralocorticoid-replete dogs. Extrapolated to UNH4+V=0, however, UpH was not significantly different in the two groups (5.27 vs. 5.44). When distal delivery of sodium was increased by infusion of sodium phosphate, titratable acid excretion increased in both groups but pateaued at lower rates in the mineralocorticoid-deficient dogs. These results suggest that in mineralocorticoid-deficient dogs, renal ammonia production is diminished, in part due to potassium retention and hyperkalemia; renal hydrogen ion secretory capacity is reduced even when sodium and buffer delivery to the distal nephron is not reduced; and the ability of the kidney to generate normally steep urine-to-blood hydrogen ion concentration gradients is unimpaired.
A Sebastian, M Schambelan, S Lindenfeld, R C Morris (1977)  Amelioration of metabolic acidosis with fludrocortisone therapy in hyporeninemic hypoaldosteronism.   N Engl J Med 297: 11. 576-583 Sep  
Abstract: In four patients with renal hyperchloremic acidosis and hyperkalemia, hyporeninemic hypoaldosteronism and chronic renal insufficiency (glomerular filtration rates of 13, 31, 35 and 44 ml per minute per 1.73 m2), prolonged administration of fludrocortisone increased urinary potassium and net acid excretion, corrected hyperkalemia and substantially ameliorated acidosis. Except in the patient with the lowest glomerular filtration rate, the increased net acid excretion was due mostly to increased ammonium excretion. Urine pH decreased initially in each patient, but in the three patients with the highest filtration rates, it increased subsequently as ammonium excretion increased, indicating that renal ammonia production increased. Urinary ammonium excretion correlated inversely with serum potassium concentration and did not decrease on discontinuation of therapy if hyperkalemia was prevented from recurring. In patients with renal acidosis and hyporeninemic hypoaldosteronism, administration of mineralocorticoid hormone can augment both renal hydrogen-ion secretion and, by correction of hyperkalemia, renal ammonia production, and thereby ameliorate metabolic acidosis.
E Short, R C Morris, A Sebastian, M Spencer (1976)  Exaggerated phosphaturic response to circulating parathyroid hormone in patients with familial X-linked hypophosphatemic rickets.   J Clin Invest 58: 1. 152-163 Jul  
Abstract: To determine whether the phosphaturic response to circulating parathyroid hormone (PTH) is exaggerated in patients with familial x-linked hypophosphatemic vitamin D-resistant rickets (FHR), we examined the phosphaturic response to parathyroid extract (PTE) (administered intravenously in the posthypercalcemic state) in two unrelated adult hemizygotes with FHR. In these two patients whose plasma concentration of PTH was normal (determined by radioimmunoassay). neither vitamin D nor phosphate therapy had been given during the past 10 yr. Two normal men and a hypophosphatemic man with intestinal malabsorption, hypocalcemia, and osteomalacia served as control subjects. In all subjects, calcium gluconate was adminstered intravenously from 6 p.m. to 12 midnight at a rate that maintained the concentration of serum calcium at 13-15 mg/100 ml during the administration of calcium. When normocalcemia had recurred the next morning, and the plasma PTH concentration and urinary excretion of cyclic 3', 5'-AMP were reduced. PTE was administered intravenously at successively increasing rates of 0.1, 0.4, and 0.8 U/kg per h, each rate lasting 90 min. Minutes after the initiation of PTE in the affected hemizygotes, fractional excretion of filtered phosphate increased from negligible values to values strikingly greater than those of similarly studied control subjects and plateaued at strikingly greater values throughout further administration of PTE. This phenomenon of exaggerated phosphaturia could not be attributed to volume expansion, decreases in serum concentration of calcium during the study, differences in percent of administered calcium retained, or hemodynamic changes. Only the phosphaturic response to PTE appeared to be exaggerated. At any cumulative dose of PTE, urinary excretion of cyclic 3', 5'-AMP in the hemizogytes was indistinguishable from that of control subjects. The findings in this study suggest that in patients with FHR, circulating PTH is required for the genetically transmitted abnormality to be physiologically expressed as a reduction in net renal reabsorption of phosphate, and that this physiological expression of the genetic abnormality is expressed fully at normal or nearly normal circulating levels of PTH.
A Sebastian, E McSherry, R C Morris (1976)  Impaired renal conservation of sodium and chloride during sustained correction of systemic acidosis in patients with type 1, classic renal tubular acidosis.   J Clin Invest 58: 2. 454-469 Aug  
Abstract: In 10 patients with classic renal tubular acidosis in whom correction of acidosis was sustained with orally administered potassium bicarbonate, renal conservation of sodium was evaluated when dietary intake of sodium was restricted to 9--13 meq/day. In five patients, renal conservation of sodium was impaired by at least one criterion of impairment. In the remaining patients, renal conservation of sodium appeared to be relatively well-maintained, but an impairment could not be excluded. In each of six patients studied during induced water diuresis, including two in whom renal conservation of sodium was not unequivocally impaired, the minimal urinary concentrations of sodium were inappropriately high and the urinary excretion rates of sodium were flow-dependent. These results provide direct evidence that an abnormality in renal transport of sodium can occur in classic renal tubular acidosis, and compel a reconsideration of the pathophysiology of disordered renal transport of sodium in this disorder. The results indicate that in at least some patients with classic renal tubular acidosis impaired renal conservation of sodium is not exclusively a reversible consequence of the renal acidification defect. These findings raise the question whether renal transport of sodium is unimpaired in any patients with classic renal tubular acidosis. In the presently studied patients, the impairment in renal conservation of sodium appeared to be in part the consequence of an impaired ability of the vasopressin-responsive segments of the distal nephron to generate and maintain appropriately steep transepithelial sodium concentration gradients.
E McSherry, A Sebastian, R C Morris (1972)  Renal tubular acidosis in infants: the several kinds, including bicarbonate-wasting, classic renal tubular acidosis.   J Clin Invest 51: 3. 499-514 Mar  
Abstract: In four infants with renal tubular acidosis (RTA), including three with apparently classic RTA and one with Fanconi syndrome (FS), the physiologic character of the renal acidification defect was investigated. In two of the infants with apparently classic RTA, the acidification defect was physiologically separable from that described in both adult patients and children with classic RTA (type 1 RTA) in the following ways. (a) The fractional excretion of filtered bicarbonate (C(HCO3)/C(ln)) was not trivial but substantial (6-9%), as well as relatively fixed, over a broad range of plasma bicarbonate concentrations (15-26 mmoles/liter). (b) This value of C(HCO3)/C(ln), combined with a normal or near normal glomerular filtration rate, translated to renal bicarbonate wasting (RBW). (c) RBW at normal plasma bicarbonate concentrations was the major cause of acidosis, and its magnitude was the major determinant of corrective alkali therapy (5-9 mEq/kg per day), just as in the patient with FS, who was found to have type 2 ("proximal") RTA. (d) Persistence of RBW at substantially reduced plasma bicarbonate concentrations, which did not occur in FS, accounted for the spontaneous occurrence of severe acidosis and its rapid recurrence after reduction in alkali therapy. (e) During severe acidosis the urinary pH was >7, a finding reported frequently in infants with apparently classic RTA and "alkali-resistant" acidosis but rarely in adult patients with classic RTA. Continued supplements of potassium were required to maintain normokalemia during sustained correction of acidosis with alkali therapy. Yet, in at least two of the three infants with apparently classic RTA, but in distinction from the patient with FS and other patients with type 2 RTA, fractional excretion of filtered potassium decreased when plasma bicarbonate was experimentally increased to normal values. In one of the two infants with apparently classic RTA and RBW, C(HCO3)/C(ln) and the therapeutic alkali requirement decreased concomitantly and progressively over 2 yr, but RBW continued. Renal tubular acidosis has persisted in all four patients for at least 3 yr, and in three for 4 years.
A Sebastian, E McSherry, R C Morris (1971)  On the mechanism of renal potassium wasting in renal tubular acidosis associated with the Fanconi syndrome (type 2 RTA).   J Clin Invest 50: 1. 231-243 Jan  
Abstract: The mechanism of renal potassium wasting in renal tubular acidosis associated with the Fanconi syndrome (type 2 RTA) was investigated in 10 patients, each of whom had impaired proximal renal tubular reabsorption of bicarbonate as judged from a greater than 15-20% reduction of renal tubular bicarbonate reabsorption (THCO(3) (-)) at normal plasma bicarbonate concentrations. When the plasma bicarbonate concentration ([HCO(3) (-)]p) was experimentally increased to normal levels in three patients with a fractional potassium excretion (C(K)/C(in)) of less than 1.0 during acidosis, C(K)/C(in) and urinary potassium excretion (U(K)V/C(in)) increased strikingly and concurrently with a striking increase in urinary sodium (U(Na)V/C(in)) and bicarbonate (U(HCO3-)V/C(in)) excretion. When [HCO(3) (-)]p was increased to normal levels in two patients with a C(K)/C(in) of greater than 1.0 during acidosis and in whom U(Na)V/C(in) and U(HCO3-)V/C(in) were already markedly increased, C(K)/C(in) did not increase further. When [HCO(3) (-)]p was decreased to subnormal levels in a patient given ammonium chloride, U(K)V/C(in), C(K)/C(in), and U(HCO3-)V/C(in) decreased concurrently. In the six patients in whom [HCO(3) (-)]p was maintained at normal levels (oral alkali therapy) for 2 months or longer, C(K)/C(in) was directly related to the urinary excretion rates of sodium and bicarbonate, hence was directly related to the magnitude of reduction of THCO(3) (-) at normal [HCO(3) (-)]p; C(K)/C(in) was greater than 0.55 in all six patients and greater than 1.0 in four. In eight patients with classic RTA (type 1 RTA), proximal renal tubular reabsorption of bicarbonate was largely intact as judged from a trivial reduction of THCO(3) (-) at normal [HCO(3) (-)]p. When [HCO(3) (-)]p was either increased from subnormal to normal levels, or decreased from normal to subnormal levels, U(HCO3-)V/C(in) remained essentially constant, and U(K)V/C(in) did not change significantly. When correction of acidosis was sustained, U(HCO3-)V/C(in) remained a trivial fraction of that filtered, and C(K)/C(in) was consistently less than 0.55. These results provide evidence that renal potassium wasting in type 2 RTA is physiologically separable from that in type 1 RTA and in part the result of a reduction in the rate at which the proximal tubule reabsorbs bicarbonate and the distal delivery of supernormal amounts of sodium bicarbonate. With an increased stimulus to distal sodium reabsorption, indicated by the finding of hyperaldosteronism, delivery to the distal nephron of supernormal amounts of sodium with the relatively impermeant bicarbonate anion would be expected to increase intraluminal negativity in the distal nephron, and as a consequence, increase potassium secretion and promote renal potassium wasting.
A Sebastian, E McSherry, R C Morris (1971)  Renal potassium wasting in renal tubular acidosis (RTA): its occurrence in types 1 and 2 RTA despite sustained correction of systemic acidosis.   J Clin Invest 50: 3. 667-678 Mar  
Abstract: IN TWO PATIENTS WITH CLASSIC RENAL TUBULAR ACIDOSIS (RTA) AND IN TWO PATIENTS WITH RTA ASSOCIATED WITH THE FANCONI SYNDROME, RENAL POTASSIUM WASTING PERSISTED DESPITE SUSTAINED CORRECTION OF ACIDOSIS: (a) during moderate degrees of hypokalemia, daily urinary excretion of potassium exceeded 80 mEq in each patient; (b) during more severe degrees of hypokalemia, daily urinary excretion of potassium exceeded 40 mEq in two patients and 100 mEq in another. These urinary excretion rates of potassium are more than twice those observed in potassium-depleted normal subjects with even minimal degrees of hypokalemia. The persistence of renal potassium wasting may have resulted in part from hyperaldosteronism, since urinary aldosterone was frankly increased in two patients and was probably abnormally high in the others relative to the degree of their potassium depletion. The hyperaldosteronism persisted despite sustained correction of acidosis, a normal sodium intake, and no reduction in measured plasma volume, and was not associated with hypertension; its cause was not defined. In the two patients with classic RTA, neither renal potassium wasting nor hyperaldosteronism could be explained as a consequence of a gradient restriction on renal H(+) - Na(+) exchange because the urinary pH remained greater than, or approximately equal to, the normal arterial pH or considerably greater than the minimal urinary pH attained during acidosis. The findings provide no support for the traditional view that renal potassium wasting in either classic RTA or RTA associated with the Fanconi syndrome is predictably corrected solely by sustained correction of acidosis with alkali therapy.
R C Morris, E McSherry, A Sebastian (1971)  Modulation of experimental renal dysfunction of hereditary fructose intolerance by circulating parathyroid hormone.   Proc Natl Acad Sci U S A 68: 1. 132-135 Jan  
Abstract: In a woman with hereditary fructose intolerance and intact parathyroid function, the experimental administration of fructose at different dosage schedules invariably induced the dose-dependent, complex dysfunction of the proximal renal tubule now recognized as characteristic. But in a woman with hereditary fructose intolerance and hypoparathyroidism given similar amounts of fructose, the experimental dysfunction was strikingly attenuated or nondemonstrable unless or until fructose and parathyroid hormone were administered in sustained combination. Thereupon, a renal dysfunction of characteristic type and severity occurred invariably and almost immediately. Thus, the concentration of circulating parathyroid hormone can modulate the functional expression of the experimental renal disorder. This effect of parathyroid hormone, which appears to involve more than simple physiologic summation, may have important clinical implications.
Powered by