Yaacov Ori

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.

Severe Hyponatremia After Water Intoxication: A Potential Cause of Rhabdomyolysis

A 28-year-old woman, treated for schizophrenia, developed severe hypotonic hyponatremia (serum Na: 109 mEq/L) after several days of compulsive water drinking. The patient was admitted in a coma and required intensive supportive therapy. Rhabdomyolysis quickly followed with high serum creatine phosphokinase levels and myoglobinuria. A high volume alkaline diuresis was initiated. Renal failure or compartment syndrome did not complicate the clinical picture. The mechanisms causing water intoxication and hyponatremia are discussed as are the possible pathogenetic explanations behind acute hyponatremia and rhabdomyolysis.

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.

Subclavian Vein Stenosis, Permanent Cardiac Pacemakers and the Haemodialysed Patient

Two cases of subclavian vein stenosis secondary to permanent cardiac pacemakers are presented. Both stenoses were asymptomatic until arteriovenous fistulae/grafts were constructed in order to initiate haemodialysis. One patient experienced severe oedema of the arm which necessitated surgical closure of the graft. A literature review into major venous stenosis and cardiac pacemakers reveals an asymptomatic, but evidently underestimated, problem. As more elderly patients will be accepted onto haemodialysis programmes, this above-mentioned problem may become more common. Therapeutic answers as to haemodialysis access are discussed in these patients with permanent pacemakers who need haemodialysis.

Effect of Increased Dialysate Volume on Peritoneal Surface Area among Peritoneal Dialysis Patients

Large dialysate volumes are often required to increase solute clearance for peritoneal dialysis patients. The resulting increase in solute clearance might be attributable to an increased plasma-to-dialysate concentration gradient and/or to an increased effective peritoneal surface area. One of the factors affecting the latter is the peritoneal surface area in contact with dialysate (PSA-CD). The aim of this study was to estimate the change in PSA-CD after a 50% increase in the instilled dialysate volume for patients undergoing peritoneal dialysis. PSA-CD was estimated by using a method applying stereologic techniques to computed tomographic (CT) scans of the peritoneal space. The peritoneal cavity of 10 peritoneal dialysis patients was filled with a solution containing dialysate, half-isotonic saline solution, and contrast medium. Peritoneal function tests and CT scanning of the abdomen were performed twice for each patient (with an interval of 1 wk), after instillation of a 2- or 3-L solution. Scanning of thin helical CT sections was performed, and 36 random sections of the abdomen were obtained after reconstruction. A grid was superimposed on the sections. The surface area was estimated by using stereologic methods. After instillation of the 2-L solution, the volume of the peritoneal solution at the time of CT scanning was 2.32 +/- 0.05 L. The PSA-CD was 0.57 +/- 0.03 m(2), ranging from 0.41 to 0.76 m(2). The use of the 3-L solution increased the peritoneal volume by 46 +/- 2%. PSA-CD increased by 18 +/- 2.3% to 0.67 +/- 0.04 m(2) (range, 0.49 to 0.84 m(2); P < 0.01). Creatinine mass transfer increased from 112 +/- 10 mg to 142 +/- 11 mg (P < 0.0001). The slope of the change of the plasma-to-dialysate creatinine concentration gradient with time decreased from -2.26 +/- 0.23 x 10(-2) to -1.97 +/- 0.16 x 10(-2) (P = 0.01). K(BD-0) (permeability-surface area product or mass area transfer coefficient at time 0 of the dwell) increased from 10.6 +/- 0.7 to 13.6 +/- 1.2 ml/min (P < 0.02). These data demonstrate that increasing the instilled dialysate volume by 50% for peritoneal dialysis patients results in significant increases in the PSA-CD and K(BD).

Proximal Tubular Hypertrophy and Enlarged Glomerular and Proximal Tubular Urinary Space in Obese Subjects with Proteinuria

Background Obesity is associated with glomerular hyperfiltration, increased proximal tubular sodium reabsorption, glomerular enlargement and renal hypertrophy. A single experimental study reported an increased glomerular urinary space in obese dogs. Whether proximal tubular volume is increased in obese subjects and whether their glomerular and tubular urinary spaces are enlarged is unknown. Objective To determine whether proximal tubules and glomerular and tubular urinary space are enlarged in obese subjects with proteinuria and glomerular hyperfiltration. Methods Kidney biopsies from 11 non-diabetic obese with proteinuria and 14 non-diabetic lean patients with a creatinine clearance above 50 ml/min and with mild or no interstitial fibrosis were retrospectively analyzed using morphometric methods. The cross-sectional area of the proximal tubular epithelium and lumen, the volume of the glomerular tuft and of Bowman’s space and the nuclei number per tubular profile were estimated. Results Creatinine clearance was higher in the obese than in the lean group (P=0.03). Proteinuria was similarly increased in both groups. Compared to the lean group, the obese group displayed a 104% higher glomerular tuft volume (P=0.001), a 94% higher Bowman’s space volume (P=0.003), a 33% higher cross-sectional area of the proximal tubular epithelium (P=0.02) and a 54% higher cross-sectional area of the proximal tubular lumen (P=0.01). The nuclei number per proximal tubular profile was similar in both groups, suggesting that the increase in tubular volume is due to hypertrophy and not to hyperplasia. Conclusions Obesity-related glomerular hyperfiltration is associated with proximal tubular epithelial hypertrophy and increased glomerular and tubular urinary space volume in subjects with proteinuria. The expanded glomerular and urinary space is probably a direct consequence of glomerular hyperfiltration. These effects may be involved in the pathogenesis of obesity-related renal disease.

Regression of left ventricular hypertrophy in patients with primary aldosteronism/low-renin hypertension on low-dose spironolactone

BACKGROUND The incidence of left ventricular hypertrophy (LVH) in primary aldosteronism (PA) is higher than in essential hypertension. LVH is an independent cardiovascular risk factor. Treatment of PA with mineralocorticoid receptor blockers (MRBs) improves LVH. Previous studies included relatively small groups, low incidence of LVH and used high MRB dose. We tested the hypothesis that long-term regression of LVH in PA/low-renin hypertension may be achieved with low-dose MRB. METHODS Forty-eight patients (male/female 28/20, age 61.4 years, range 47-84) had PA (low renin, high aldosterone and high aldosterone/renin ratio, n=24) or low-renin hypertension (low renin, normal aldosterone and high aldosterone/renin ratio, n=24). All had either LVH or concentric remodelling. All had an echocardiogram both at baseline and at 1 year after the initiation of spironolactone. A subgroup of 29 patients had an echocardiogram at baseline, 1 year (range 0.5-1.5) and 3 years (range 1.8-7). RESULTS At baseline, spironolactone was commenced in all patients. The dose was 33.3±13.7 and 29.0±11.7 mg/day at 1 year and 3 years, respectively. A total of 73% of the patients received ≤37.5 mg/day. Introduction of spironolactone enabled the reduction of other antihypertensive medications (from 2.6±1.2 to 1.5±1.0 at 1 year). At 1 year, systolic and diastolic blood pressure decreased (149.3±14.1 to 126.2±12.0 mmHg, P<0.001, and 88.2±9.8 to 78.3±7.1 mmHg, P<0.001, respectively). At baseline, LVH was present in 39 of the 48 (81%) patients, and concentric remodelling, i.e. increased relative wall thickness (RWT) with a normal left ventricular mass index (LVMI), in 36 (75%). At 1 year, LVMI decreased in 44 of the 48 (92%) patients (142.9±25.4 versus 117.7±20.4 g/m2, P<0.001). LVH normalized in 16 of the 39 (41%) patients. RWT normalized in 36% of the patients. The changes in blood pressure and LVMI did not correlate. At 3 years, LVH decreased further and normalized in 57% of the patients. CONCLUSIONS In patients with PA/low-renin hypertension, long-term regression of LVH may be achieved with low-dose MRB.

H2 O2 induces DNA repair in mononuclear cells: Evidence for association with cytosolic Ca2+ fluxes

Cellular DNA repair systems are induced whenever DNA is damaged. Reactive oxygen species (ROS) are generated, in vivo, in the tissues as a result of regular cellular metabolism or after exposure to oxidizing agents, such as ultraviolet (UV) irradiation. It has been suggested that ROS mediate DNA damage. The objectives of the study were as follows: (1) to investigate whether hydrogen peroxide (H2O2), the commonly occurring cellular ROS, induces DNA repair as a response to the damage it probably causes; (2) to evaluate whether H2O2-induced DNA repair, if present, is signaled through a Ca2(+)-dependent pathway via the tyrosine kinase signal transduction. H2O2 was found to induce DNA repair in human peripheral blood mononuclear cells (PBMCs) in a dose-dependent manner. The recovery of RNA synthesis, which occurred after DNA repair, confirmed that transcribable DNA was repaired. The inhibition of tyrosine kinase activity by genistein reduced the DNA repair significantly. Furthermore, H2O2 caused a dose-dependent significant rise in cytosolic calcium ((Ca2+)i). H2O2 also induced a small rise in (Ca2+)i of cytosolic Ca2(+)-depleted cells, probably reflecting the release of Ca2+ from internal stores. Genistein inhibited both Ca2+ influx and Ca2+ release from internal stores. In summary, H2O2 induced a DNA repair synthesis that was in part Ca2+ dependent and signaled via tyrosine kinase. The changes in DNA repair paralleled changes in (Ca2+)i. The H2O2-induced (Ca2+)i rise was mostly the result of influx, but to some degree it was also due to the translocation of Ca2+ from internal stores.

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.