Michal Herman

The effects of weight loss on renal function in patients with severe obesity.

Severe obesity is associated with increased renal plasma flow (RPF) and glomerular filtration rate (GFR). The aim of the present study was to examine whether weight loss may reverse glomerular dysfunction in obese subjects without overt renal disease. Renal glomerular function was studied in eight subjects with severe obesity (body mass index [BMI] 48.0 +/- 2.4) before and after weight loss. Nine healthy subjects served as controls. GFR and RPF were determined by measuring inulin and PAH clearance. In the obese group, GFR (145 +/- 14 ml/min) and RPF (803 +/- 39 ml/min) exceeded the control value by 61% (90 +/- 5 ml/min, P = 0.001) and 32% (610 +/- 41 ml/min, P < 0.005), respectively. Consequently, filtration fraction was increased. Mean arterial pressure, although normal, was higher than in the control group (101 +/- 4 versus 86 +/- 2 mmHg, P < 0.01). After weight loss, BMI decreased by 32 +/- 4%, to 32.1 +/- 1.5 (P = 0.001). GFR and RPF decreased to 110 +/- 7 ml/min (P = 0.01) and 698 +/- 42 ml/min (P < 0.02), respectively. Albumin excretion rate decreased from 16 microg/min (range, 4 to 152 microg/min) to 5 microg/min (range, 3 to 37 microg/min) (P < 0.01). Fractional clearance of albumin decreased from 3.2 x 10(-6) (range, 1.1 to 23 x 10(-6)) to 1.2 x 10(-6) (range, 0.5 to 6.8 x 10(-6)) (P < 0.02). This study shows that obesity-related glomerular hyperfiltration ameliorates after weight loss. The improvement in hyperfiltration may prevent the development of overt obesity-related glomerulopathy.

Obesity-induced glomerular hyperfiltration: its involvement in the pathogenesis of tubular sodium reabsorption

BACKGROUND Obesity is associated with hypertension and glomerular hyperfiltration. A major mechanism responsible for the obesity-associated hypertension is renal salt retention. An increased glomerular filtration fraction (FF) is expected to raise postglomerular oncotic pressure and to increase proximal tubular sodium reabsorption. The aim of the present study was to verify whether obesity-associated hyperfiltration leads to increased postglomerular oncotic pressure and increased proximal sodium reabsorption. METHODS Twelve obese subjects (BMI >36) and 19 lean subjects participated in the study. They underwent measurement of glomerular filtration rate (GFR), renal plasma flow (RPF) and fractional excretion of lithium (FE Li). RESULTS GFR, RPF and FF were 61%, 28% and 29% higher, respectively, in the obese than in the control group (P < 0.00001 for GFR, P < 0.005 for RPF and P < 0.00005 for FF). Half of the obese group had increased FF with increased GFR, while the other half had normal FF with high-normal or increased GFR. Postglomerular oncotic pressure was 13% higher (P < 0.03) and FE Li was 33% lower (P < 0.005) in the obese group with high FF than in the lean group. Postglomerular oncotic pressure and FE Li were normal in the obese group with normal FF. CONCLUSIONS These results suggest that glomerular hyperfiltration may lead to increased proximal tubular sodium reabsorption in the obese.

Non-Occlusive Mesenteric Ischemia in Chronically Dialyzed Patients: A Disease with Multiple Risk Factors

Background: Non-occlusive mesenteric ischemia (NOMI) can be a fatal complication in dialysis patients. Intradialytic hypotension is usually the precipitating factor. The occurrence of 16 cases in 5 years (1998–2002), compared with only 4 in previous years, led us to investigate other risk factors contributing to NOMI. A control group of stable hemodialysis patients was used for comparison. Results: 20 patients were studied: 17 diagnosed surgically, and 3 clinically. The mean age was 70.8 ± 1.8 years, and the male:female ratio 7:13. Nineteen patients were on hemodialysis. Clinically overt atherosclerosis was present in 17 patients. Preceding dialysis-associated hypotension was identified in all patients studied and access thrombosis in 6 patients. In all patients, abdominal pain was the presenting symptom. Initial abdominal examination was unimpressive in 16 patients. The hemoconcentration, leukocytosis and metabolic acidosis were the most prominent laboratory findings. 5/11 abdominal sonograms showed intestinal pathology. 2/3 angiographies were diagnostic. Three patients responded to early fluid challenge and did not require surgery. Pathology was related to the area of the superior mesenteric artery in all 15 patients operated. Twelve (60%) patients died from the event. The 1-year mortality rate was 17/20 patients (85%). Possible contributing factors, other than dialysis-associated hypotension, included: high-dose recombinant human erythropoietin (rhEPO) therapy (179 ± 35 vs. 116 ± 10 U/kg/week in the control group, p < 0.05); metastatic calcifications (abdominal aorta 14/14, aortic valve 11/18; medial calcification of mesenteric arteries in 2/11 pathology specimens); digoxin, and hypoalbuminemia. Conclusions: The increased incidence of NOMI in dialysis patients may be related to overly aggressive rhEPO therapy and the unsuspected presence of mesenteric arterial medial calcifications. Identification of patients at risk, prevention of intradialytic hypotension and a controlled increase in dry weight may help to reduce the incidence of NOMI in chronically dialyzed patients.

Improved Immunogenicity of a Novel Third-Generation Recombinant Hepatitis B Vaccine in Patients with End-Stage Renal Disease

Hepatitis B (HBV) infection remains a significant epidemiological problem in the end-stage renal disease (ESRD) population. Vaccination programs using second-generation vaccines lead to effective seroprotection in only 50–60% of these patients. The purpose of this case series was to describe our experience with a novel third-generation vaccine, Bio-Hep-B®, in ESRD patients who had not developed protective anti-HBs titers following a second-generation HBV vaccination protocol. Twenty-nine ESRD patients who had not responded in the past to a standard second-generation HBV vaccination protocol were included in this series. Each patient received 10 µg of Bio-Hep-B® intramuscularly at 0, 1 and 6 months. A month after completion of the vaccination protocol, anti-HBs antibody levels were measured. Following immunization, 25 of 29 patients (86%) developed seroprotective anti-HBs levels ≧10 mIU/ml. There was a significant difference in the titers of anti-HBs antibodies prior to and following vaccination (p < 0.0001). Statistical analysis of the variables age, gender, diagnosis, dialysis mode, weight, hemoglobin, albumin, and KT/V failed to detect predictors of antibody response. A retrospective analysis of the results of a second-generation vaccination program for the years 1999–2001 in our department showed that 19 of 36 (56.4%) ESRD patients developed seroprotection. In conclusion, the results of this study show that the third-generation HBV vaccine Bio-Hep-B® is highly immunogenic in the population of ESRD patients who did not respond in the past to a second-generation vaccine. This enhanced seroprotection offers hope that the new vaccine will reduce the rate of non-responders and help to eliminate HBV infection from dialysis centers.

Fatalities and Severe Metabolic Disorders Associated With the Use of Sodium Phosphate Enemas: A Single Center's Experience

We report our experience with severe complications of sodium phosphate enemas. Eleven elderly patients received Fleet enemas for constipation. Three patients received 500 to 798 mL, and 8 received a standard 250-mL dose. Most presented within 24 hours with hypotension and volume depletion, extreme hyperphosphatemia (phosphorus level, 5.3-45.0 mg/dL), and severe hypocalcemia (calcium level, 2.0-8.7 mg/dL). Hypernatremia and hypokalemia were seen in most patients. Acute renal failure was present in all patients. Two patients required urgent hemodialysis. Five patients died (45%). One patient was autopsied. Calcium-phosphate deposition within the renal tubular lumens was found. Following an educational campaign, the use of Fleet enemas was reduced in our hospital by 96%. Sodium phosphate enemas, even in standard doses, may lead to severe metabolic disorders associated with a high mortality and morbidity. Their use should be limited to low-risk patients only.

Effects of histone deacetylase inhibitors on rat mesangial cells

Glomerular mesangial cells (MCs) proliferate and produce extracellular matrix proteins in many progressive renal diseases. Recently, histone deacetylase inhibitors (HDIs) were shown to have antiproliferative and antifibrogenic effects in some in vitro and in vivo models. Using the [(3)H]-thymidine incorporation test, we have found that the HDI trichostatin A (TSA) effectively inhibits MC growth at nontoxic nanomolar concentrations. Similarly, the HDI valproic acid also inhibited MCs proliferation. Cell-cycle analysis indicated an arrest in G(0)/G(1) phase in response to TSA, which was accompanied by elevation in synthesis of the cyclin-dependent kinase inhibitors (CDKIs) p21/Waf1 and p27/Kip1. TSA treatment suppressed alpha-smooth muscle actin, transforming growth factor-beta1, and collagen protein synthesis by MCs and induced myofibroblast-like appearance of proliferating MCs. In the in vivo model of the anti-Thy1.1-induced glomerulonephritis, TSA and valproic acid treatments significantly suppressed proteinuria. Collectively, these data suggest a therapeutic potential for HDIs in the treatment of mesangial proliferative diseases and glomerulosclerosis.

Acute Phosphate Nephropathy—An Emerging Threat

Background:Acute phosphate nephropathy (APN) is a clinicopathological entity causing renal failure, after ingestion of oral sodium phosphate solution (OSPS). Approximately 25 cases have been described, but OSPS is still widely used. This study reports a further 5 cases and discusses the ever-growing significance of APN. Methods:Five cases of APN were included, 3 retrospectively whereas 2 were diagnosed prospectively. In all, use of OSPS was established, and other causes of nephrocalcinosis were excluded. Results:Average age was 67.4 ± 7.0 years, with a female preponderance (4:1). All patients had hypertension. Baseline serum creatinine: 0.7 to 1.2 mg/dL (creatinine clearance: 52 to 77 mL/min). Time from colonoscopy to presentation was 56 ± 36 days. Serum creatinine levels at presentation: 1.4 to 3.6 mg/dL. Time from colonoscopy to renal biopsy was 123 ± 88 days. Urinalysis showed minimal proteinuria, leucocyturia, and hematuria. One patient had renal glucosuria. All patients were anemic (hemoglobin 8.8–11.4 gr/dL). Serum calcium and phosphate were normal. One required hemodialysis. Mean follow-up was 36 ± 17 months. Serum creatinine levels at end of follow-up were 1.3 to 3.1 mg/dL. Renal function did not recover completely in any patient. Four required long-term erythropoietin treatment. The prominent histopathological findings were calcium–phosphate tubular depositions (100%), interstitial fibrosis (80%), hypertensive changes (80%), and acute tubular degenerative and regenerative changes (60%). Conclusions:APN is a serious, irreversible renal complication of OSPS. It is probably under-recognized. Risk factors include female gender, older age, hypertension, and renal failure, although it may occur with preexisting normal renal function.

Haptoglobin phenotype as a predictive factor of mortality in diabetic haemodialysis patients

Introduction: The mortality rate in diabetic dialysis patients (DDPs) is over 15% per year, with the cause of death most often attributed to cardiovascular disease (CVD) or bacterial infection (sepsis). Identification of genetic markers predictive of early mortality would be useful in the evaluation of therapies for the reduction of mortality rate in this population. Haptoglobin (Hp) is a polymorphic protein which appears to confer differential susceptibility to bacterial infection and CVD. We therefore proposed that Hp phenotype can predict mortality in DDPs. Methods: We tested this hypothesis prospectively in a longitudinal study of 392 dialysis patients from eight medical centres in Israel. Hp was determined by polyacrylamide gel electrophoresis. Patients were followed for all-cause mortality over a 3-year period. Results: We found that Hp phenotype was a significant predictor of mortality in DDPs stratified by age. In diabetic individuals over 60 years of age there was a decrease in mortality associated with the Hp 1-1 phenotype (P = 0.03). However, in younger DDPs the Hp 2-2 phenotype was associated with a decreased mortality rate (P = 0.003). Conclusion: Hp phenotype may be useful in the risk stratification algorithm and management of DDPs.

Spontaneous DNA Repair Increases during Hemodialysis

Background: Hemodialysis (HD) patients are subjected to increased oxidative stress. Oxidative stress causes DNA damage, which may be repaired by a DNA repair system. ‘Spontaneous DNA repair’ expresses DNA repair of in vitro unstimulated cells. The aim of the study was to evaluate the effect of one HD session on spontaneous DNA repair in peripheral blood mononuclear cells (PBMC). Methods: PBMC were separated from blood samples for the determination of spontaneous DNA repair, measured by 3H-thymidine incorporation, before and immediately after one HD session. Percent double-stranded DNA (ds-DNA) was measured by the fluorometric assay of DNA unwinding (FADU). Results: DNA repair increased significantly following HD. To examine if this increase was caused by newly produced DNA damage, we studied the effect of HD on percent ds-DNA in PBMC. HD significantly reduced percent ds-DNA, indicating increased DNA breakage. By repeating FADU in the presence of formamidopyrimidine-DNA glycosylase (Fpg), which nicks DNA at oxidized purine sites, we could show that the increased DNA damage was caused by oxidation. Conclusion: Spontaneous DNA repair increases during HD in response to an increase in DNA damage induced by oxidative stress.

Residual Renal Function in Peritoneal Dialysis After Renal Transplant Failure

out of the question to perform any randomized studies to evaluate the effect of declining RRF on endothelial function. In conclusion, this study showed that the decline in RRF in incident CAPD patients is associated with worsened endothelial dysfunction, while a stable RRF seems not to affect endothelial function significantly. This study not only provided new understanding of the association between RRF and cardiovascular disease in dialysis patients, but also highlighted the justification of protecting RRF in this population.