Joshua Weissgarten

Homozygous SLC2A9 Mutations Cause Severe Renal Hypouricemia

Hereditary hypouricemia may result from mutations in the renal tubular uric acid transporter URAT1. Whether mutation of other uric acid transporters produces a similar phenotype is unknown. We studied two families who had severe hereditary hypouricemia and did not have a URAT1 defect. We performed a genome-wide homozygosity screen and linkage analysis and identified the candidate gene SLC2A9, which encodes the glucose transporter 9 (GLUT9). Both families had homozygous SLC2A9 mutations: A missense mutation (L75R) in six affected members of one family and a 36-kb deletion, resulting in a truncated protein, in the other. In vitro, the L75R mutation dramatically impaired transport of uric acid. The mean concentration of serum uric acid of seven homozygous individuals was 0.17 +/- 0.2 mg/dl, and all had a fractional excretion of uric acid >150%. Three individuals had nephrolithiasis, and three had a history of exercise-induced acute renal failure. In conclusion, homozygous loss-of-function mutations of GLUT9 cause a total defect of uric acid absorption, leading to severe renal hypouricemia complicated by nephrolithiasis and exercise-induced acute renal failure. In addition to clarifying renal handling of uric acid, our findings may provide a better understanding of the pathophysiology of acute renal failure, nephrolithiasis, hyperuricemia, and gout.

Effects of captopril and enalapril on zinc metabolism in hypertensive patients.

OBJECTIVE To investigate the effect of chronic captopril and enalapril treatment on zinc metabolism in hypertensive patients by assessing zinc levels in serum, urine and monocytes. METHODS Patients with newly diagnosed essential hypertension were randomly divided into two treatment groups: those treated with captopril only (n = 16) and those treated with enalapril only (n = 18). Ten healthy subjects served as controls. Prior to the start of treatment and again 6 months later, zinc was assessed in the serum, in urine collected over 24 hours, and in peripheral blood monocytes. RESULTS Significant enhancement of 24-hour urinary zinc excretion (micrograms/24 hour) after 6 months of treatment was observed only in the captopril-treated group (p < 0.01). However, intramonocytic zinc levels decreased significantly in both of the treated groups over the same period (p < 0.01 and P < 0.04 in the captopril- and enalapril-treated groups, respectively). CONCLUSION Treatment of hypertensive patients with captopril or enalapril may result in zinc deficiency.

Type II diabetes mellitus, congestive heart failure, and zinc metabolism

Zinc status was assessed in patients with type II diabetes mellitus and congestive heart failure (CHF). Three groups of patients were enrolled into the study: Group 1: 15 patients with type II diabetes mellitus and CHF; Group 2: 20 patients with isolated type II diabetes mellitus; and Group 3: nine patients with isolated CHF. Twenty-four-hour urine was measured for creatinine, protein, and zinc, and blood was drawn for creatinine, proteins, liver enzymes, hemoglobin A1c, and zinc. Insulin treatment and hemoglobin A1c were comparable in the diabetic patients of groups 1 and 2, but group 1 was also treated with captopril and diuretics like the CHF patients of group 3. Plasma zinc levels were statistically similar in all three groups, but urinary zinc excretion (μmol/24 h) and urinary zinc: creatinine (μmol/mmol) ratio were significantly higher in the type II diabetics and CHF group (27.2±1.5; 1.69±0.6, respectively) compared to the diabetic patients alone (19.4±0.76; 0.97±0.3, respectively) and the CHF patients (9.7±0.3; 0.62±0.3, respectively). Patients with type II diabetes mellitus and CHF were treated with higher doses of captopril than the CHF patients (56.25±24 mg vs 18.8±11 mgP<0.05). Thus, patients with type II diabetes mellitus and CHF excrete larger amounts of zinc, which may eventually lead to zinc deficiency.

Elevated Serum 1,25-Dihydroxyvitamin D Concentrations in Siblings with Primary Fanconi's Syndrome

THE de Toni–Debre–Fanconi syndrome,1 2 3 or Fanconis syndrome, is characterized by multiple abnormalities in renal tubular function. Defective handling of phosphate, glucose, and amino acids is th...

Effect of captopril treatment on recuperation from ischemia/reperfusion-induced acute renal injury

BACKGROUND Ischemia/reperfusion triggers acute kidney injury (AKI), mainly via aggravating hypoxia, oxidative stress, inflammation and renin-angiotensin system (RAS) activation. We investigated the role of angiotensin-converting enzyme (ACE) inhibition on the progression of AKI in a rat model of ischemia/reperfusion. METHODS Ninety-nine Sprague-Dawley rats were subjected to 1 h ischemia/reperfusion and/or left unilateral nephrectomy, with concurrent intraperitoneal implantation of Alzet pump. Via this pump, they were continuously infused with captopril 0.5 mg/kg/day, captopril 2 mg/kg/day or saline. The rats were sacrificed following 24, 48 or 168 h. Blood samples, 24-h urine collections and kidneys were allocated, to evaluate renal function, angiotensin-II, nitric oxide (NO), apoptosis, hypoxia, oxidative stress and inflammation. RESULTS Serum creatinine and cystatin-C significantly increased in ischemic rats, coinciding with histopathologic intrarenal damage, decreased NO, augmented angiotensin-II, interleukin (IL)-6, IL-10, transforming growth factor-beta. At the acute reperfusion stage, captopril prevented excessive angiotensin-II synthesis, ameliorated renal dysfunction, inhibited intrarenal inflammation and improved histopathologic findings. Most of the renoprotective effects of captopril were limited predominantly to acute reperfusion stage. Concurrently, captopril significantly decreased NO availability, exacerbated intrarenal hypoxia and augmented oxidative stress. CONCLUSIONS At the acute stage of renal ischemia/reperfusion-induced AKI, ACE inhibition substantially contributed to the amelioration of acute injury by improving renal function, inhibiting systemic and intrarenal angiotensin-II, attenuating intrarenal inflammation and preserving renal tissue structure. Later on, at the post-reperfusion stage, most of the beneficial effects of captopril administration on the recuperating post-ischemic kidney were no longer evident. Concurrently, ACE inhibition exacerbated intrarenal hypoxia and accelerated oxidative stress, indicating that renal adaptation to some consequences of ischemia does require bioavailability of RAS components.

Pulse oximetry in the evaluation of the painful hand after arteriovenous fistula creation

Five patients with a side-to-side arteriovenous fistula complaining of pain, numbness, and cold sensation were evaluated by pulse oximetry. Low SaO2 was noticed in all five. Closure of a major proximal venous collateral vessel eliminated the steal and resulted in SaO2 correction and was followed by clinical amelioration. Pulse oximetry proved to be a helpful adjunct in the evaluation of the painful hand after creation of an arteriovenous fistula. By applying the pulse oximeter to the patients affected limb, we were able to determine whether the pain was a result of ischemia and if the correction of the steal improved oxygenation.

Contrast media augmented apoptosis of cultured renal mesangial, tubular, epithelial, endothelial, and hepatic cells.

Peer A, Averbukh Z, Berman S, et al. Contrast Media Augmented Apoptosis of Cultured Renal Mesangial, Tubular, Epithelial, Endothelial, and Hepatic Cells. Invest Radiol 2003;38:177–182. Rationale and Objective. Nephrotoxicity of contrast media, resulting in apoptosis and acute necrosis of tubular cells, is well documented. No studies concerning mesangial cells apoptosis have been published yet. Aim Apoptosis of cultured mesangial, tubular, and hepatic cell lines was investigated following exposure to different contrast media. Methods. Apoptosis was assessed by TUNEL assay and verified by Mayer Hematoxylin staining. Results. Iopromide, Ioxaglate, and Ioxatalamate induced apoptosis in all cell cultures at final concentrations ranged from 0.1% to 10.0%. However, only 1% to 10% Iomeprol elicited a significant apoptosis. Moreover, at 10% concentration, Iomeprol induced significantly less apoptosis than Iopromide, Ioxaglate, or Ioxatalamate. Conclusions. First, Iomeprol, which has a different physico-chemical properties, proved to be less proapoptotic compared with other contrast compounds. Second, all types of cells similarly respond by apoptosis to contrast media induced injury. However, apoptosis of mesangial cells might generate additional deleterious effects in vivo.

IL-6 Levels, Nutritional Status, and Mortality in Prevalent Hemodialysis Patients

BACKGROUND AND OBJECTIVES The influence of serum IL-6 levels on nutritional status in chronic hemodialysis (HD) patients remains to be elucidated. The present report describes a prospective longitudinal study of IL-6 levels and nutritional parameters to determine whether high IL-6 levels are independently associated with nutritional status over time in a cohort of prevalent hemodialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS 85 clinically stable hemodialysis patients (37.6% women), with a mean age of 66.5 ± 10.6 years, were studied after exclusion of patients with BMI < 20 kg/m(2) and/or serum albumin <35 g/L. IL-6, dietary energy and protein intake, and biochemical markers of nutrition and body composition (anthropometry and bioimpedance analysis) were measured at baseline and at 6, 12, 18, and 24 months following enrollment. Observation of this cohort was continued over 2 additional years. RESULTS IL-6 levels increased with time in both unadjusted (linear estimate: 2.57 ± 0.44 pg/ml per 2 yrs; P = 0.001) and adjusted models (linear estimate: 2.35 ± 0.57 pg/ml per 2 yrs; P = 0.049). Significant reductions of daily energy intake, laboratory markers (albumin, transferrin, cholesterol, creatinine), and body composition (fat mass) with higher IL-6 levels were observed over the duration of the longitudinal observation period. However, none of the studied parameters were associated with changes in IL-6 levels over time (IL-6-by-time interactions were NS). Furthermore, cumulative incidences of survival were correlated with the baseline serum IL-6 levels (P = 0.004 by log-rank test). Finally, for each pg/ml increase in IL-6 level, the hazard ratio for death from all causes was 1.06 (95% CI 1.01 to 1.10) after adjustment for demographic and clinical parameters. CONCLUSIONS Our results suggest that higher serum IL-6 levels are associated with all-cause mortality without additional changes in clinical and laboratory markers of nutritional status in clinically stable HD patients.

Longitudinal study of leptin levels in chronic hemodialysis patients

BackgroundThe influence of serum leptin levels on nutritional status and survival in chronic hemodialysis patients remained to be elucidated. We conducted a prospective longitudinal study of leptin levels and nutritional parameters to determine whether changes of serum leptin levels modify nutritional status and survival in a cohort of prevalent hemodialysis patients.MethodsLeptin, dietary energy and protein intake, biochemical markers of nutrition and body composition (anthropometry and bioimpedance analysis) were measured at baseline and at 6, 12, 18 and 24 months following enrollment, in 101 prevalent hemodialysis patients (37% women) with a mean age of 64.6 ± 11.5 years. Observation of this cohort was continued over 2 additional years. Changes in repeated measures were evaluated, with adjustment for baseline differences in demographic and clinical parameters.ResultsSignificant reduction of leptin levels with time were observed (linear estimate: -2.5010 ± 0.57 ng/ml/2y; p < 0.001) with a more rapid decline in leptin levels in the highest leptin tertile in both unadjusted (p = 0.007) and fully adjusted (p = 0.047) models. A significant reduction in body composition parameters over time was observed, but was not influenced by leptin (leptin-by-time interactions were not significant). No significant associations were noted between leptin levels and changes in dietary protein or energy intake, or laboratory nutritional markers. Finally, cumulative incidences of survival were unaffected by the baseline serum leptin levels.ConclusionsThus leptin levels reflect fat mass depots, rather than independently contributing to uremic anorexia or modifying nutritional status and/or survival in chronic hemodialysis patients. The importance of such information is high if leptin is contemplated as a potential therapeutic target in hemodialysis patients.

PPAR-γ Activation Inhibits Angiotensin II Synthesis, Apoptosis, and Proliferation of Mesangial Cells from Spontaneously Hypertensive Rats

Background/Aim: The angiotensin II level is elevated in subjects genetically prone to develop hypertension, triggering renal hypercellularity, cytokine production, and matrix deposition. Angiotensin-converting enzyme inhibition and/or angiotensin II type 1 receptor blockade attenuate renal damage. Rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist possessing antihypertensive and anti-inflammatory properties, was demonstrated to provide better renal protection than angiotensin-converting enzyme inhibitors. We studied the effects of in vivo peroxisome proliferator-activated receptor gamma activation by rosiglitazone on angiotensin II synthesis, proliferation, and apoptosis of mesangial cells of spontaneously hypertensive rats versus normotensive Sprague-Dawley rats. Methods: The animals consumed either a high-sodium diet (8% Na) or a normal-sodium diet (0.5% Na). Half of each group received rosiglitazone at 5 mg/kg/day. After 3 weeks, all rats were sacrificed and the mesangial cells isolated and cultured. Angiotensin II was assessed by radioimmunoassay, apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, and cell proliferation by [3H]thymidine incorporation. Results: Only the spontaneously hypertensive rats which consumed the high-sodium diet developed hypertension (185 ± 6 mm Hg vs. basal 128 ± 5 mm Hg; p = 0.0007) which was attenuated by rosiglitazone (to 126 ± 4 mm Hg; p = 0.34). Angiotensin II synthesis, proliferation, and apoptosis were exaggerated in mesangial cell cultures from Sprague-Dawley rats and, more so, spontaneously hypertensive rats fed the high-sodium diet, but were inhibited in cultures from rosiglitazone-treated animals. Conclusions: Peroxisome proliferator-activated receptor gamma activation, in addition to lowering blood pressure, suppresses angiotensin II synthesis and downregulates angiotensin-II-mediated proliferation and apoptosis of mesangial cells. In the context of hypertension-induced renal damage, this would mean that the renoprotective role of rosiglitazone extends beyond glycemic and lipidemic control.