Uzi Gafter

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.

Antimicrobial Lock Solutions for the Prevention of Infections Associated with Intravascular Catheters in Patients Undergoing Hemodialysis: Systematic Review and Meta-analysis of Randomized, Controlled Trials

BACKGROUND Prevention of catheter-related bloodstream infections in patients undergoing hemodialysis by use of antimicrobial catheter lock solutions has been examined in several trials, but no consensus is available for clinical practice. METHODS A systematic review and meta-analysis were performed of randomized controlled trials that compared single or combination antimicrobial catheter lock solutions with heparin or another antimicrobial for the prevention of infections in patients undergoing hemodialysis. The primary outcomes assessed were bloodstream infections, catheter-related bloodstream infections, and the need for catheter removal. Relative risks with 95% confidence intervals (CIs) for individual trials were pooled. RESULTS Eleven trials (924 patients) that assessed antibiotic catheter lock solutions and 5 trials (661 patients)that assessed non antibiotic antimicrobial catheter lock solutions met inclusion criteria. None of the trials assessed all bloodstream infections. Antibiotic catheter lock solutions significantly reduced catheter-related bloodstream infections (relative risk, 0.44; 95% CI, 0.38-0.50). Significant heterogeneity for this outcome could be explained by smaller effect estimates in larger trials that reported adequate randomization methods (relative risk, 0.60; 95%CI, 0.54-0.67). Efficacy was higher when additional preventive measures were used and to prevent the first episode of catheter-related bloodstream infection. Catheter removal rates were significantly reduced (relative risk, 0.35;95% CI, 0.23-0.55). Resistance development was documented in a single patient. Data concerning nonantibiotic antimicrobial lock solutions were limited and heterogeneous. High-quality trials that used additional preventive measures showed a significant reduction in catheter-related bloodstream infections (relative risk, 0.25; 95% CI,0.13-0.50). CONCLUSIONS Antibiotic catheter lock solutions reduce catheter-related bloodstream infections, with a number needed to treat of 4 patients (95% CI, 4-5), and catheter removal rates in patients undergoing hemodialysis. The use of antibiotic catheter lock solutions should be considered in routine clinical practice in conjunction with other prevention modalities.

A Questionnaire for the Assessment of Pruritus: Validation in Uremic Patients

A questionnaire was constructed for the evaluation and measurement of pruritus. The questionnaire, based on the short form of the McGill Pain Questionnaire, was tested in 145 patients suffering from uremic pruritus and currently undergoing hemodialysis treatment in 3 centers. The newly developed questionnaire proved to be reliable and provided valid data on the sensory, affective and overall intensity of uremic pruritus. The data suggest that uremic pruritus tends to be prolonged, frequently intense and a major source of distress to the patient. Dialysis was not found to influence the pruritus. The questionnaire may also be useful in pruritus secondary to other causes.

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.

Anti-IL-10 Therapeutic Strategy Using the Immunomodulator AS101 in Protecting Mice from Sepsis-Induced Death: Dependence on Timing of Immunomodulating Intervention

The role of IL-10 in experimental sepsis is controversial. The nontoxic immunomodulator, ammonium trichloro(dioxoethylene-o,o′)tellurate (AS101) has been previously shown to inhibit IL-10 expression at the transcriptional level. In this study, we show that in mice subjected to cecal ligation and puncture (CLP), treatment with AS101 12 h after, but not before, CLP significantly increased survival of septic mice. This was associated with a significant decrease in serum IL-10 and in IL-10 secretion by peritoneal macrophages 24–48 h after CLP. At that time, the ability of these cells to secrete TNF-α and IL-1β was restored in AS101-treated mice. The increased survival of AS101-treated mice was due to the inhibition of IL-10, since cotreatment with murine rIL-10 abolished the protective activity of AS101. AS101 increased class II Ag expression on peritoneal macrophages, severely depressed in control mice, while it did not affect the expression of class I Ags. This was accompanied by a significant elevation in the level of IFN-γ secreted by splenocytes. Moreover, AS101 ameliorated bacterial clearance in the peritoneum and blood and decreased severe multiple organ damage, as indicated by clinical chemistry. Furthermore, myeloperoxidase levels in the liver and lung of AS101-treated mice, an indirect means of determining the recruitment of neutrophils, were significantly decreased. We suggest that nontoxic agents such as AS101, with the capacity to inhibit IL-10 and stimulate macrophage functions, may have clinical potential in the treatment of sepsis, provided they are administered during the phase of sepsis characterized by immune suppression.

Altered Renal Lipid Metabolism and Renal Lipid Accumulation in Human Diabetic Nephropathy

Animal models link ectopic lipid accumulation to renal dysfunction, but whether this process occurs in the human kidney is uncertain. To this end, we investigated whether altered renal TG and cholesterol metabolism results in lipid accumulation in human diabetic nephropathy (DN). Lipid staining and the expression of lipid metabolism genes were studied in kidney biopsies of patients with diagnosed DN (n = 34), and compared with normal kidneys (n = 12). We observed heavy lipid deposition and increased intracellular lipid droplets. Lipid deposition was associated with dysregulation of lipid metabolism genes. Fatty acid β-oxidation pathways including PPAR-α, carnitine palmitoyltransferase 1, acyl-CoA oxidase, and L-FABP were downregulated. Downregulation of renal lipoprotein lipase, which hydrolyzes circulating TGs, was associated with increased expression of angiopoietin-like protein 4. Cholesterol uptake receptor expression, including LDL receptors, oxidized LDL receptors, and acetylated LDL receptors, was significantly increased, while there was downregulation of genes effecting cholesterol efflux, including ABCA1, ABCG1, and apoE. There was a highly significant correlation between glomerular filtration rate, inflammation, and lipid metabolism genes, supporting a possible role of abnormal lipid metabolism in the pathogenesis of DN. These data suggest that renal lipid metabolism may serve as a target for specific therapies aimed at slowing the progression of glomerulosclerosis.

Growth Hormone Treatment during Hemodialysis in a Randomized Trial Improves Nutrition, Quality of Life, and Cardiovascular Risk

Nutritional markers, such as lean body mass (LBM) and serum albumin, predict outcome in dialysis patients, in whom protein-energy malnutrition is associated with increased morbidity and mortality. The metabolic effects of human growth hormone (hGH) may improve the nutritional and cardiovascular health of these patients and consequently reduce morbidity and mortality. The aim of this study was to establish clinical proof of concept of hGH treatment for the improvement of the nutritional status in adult patients who are on maintenance hemodialysis. A total of 139 adult patients who were on maintenance hemodialysis and had serum albumin levels < or =40 g/L were randomly assigned to 6 mo of treatment with placebo or 20, 35, or 50 microg/kg per d hGH. Change in LBM and serum albumin (primary outcomes), health-related quality of life, and secondary efficacy and safety parameters were monitored. The study showed that hGH treatment increased LBM significantly at all dosage levels (2.5 kg [95% confidence interval 1.8 to 3.1] versus -0.4 kg [95% confidence interval -1.4 to 0.6]; P < 0.001 for pooled hGH groups versus placebo). Serum albumin tended to increase (P = 0.076), serum transferrin (P = 0.001) and serum HDL (P < 0.038) increased, and plasma homocysteine was reduced (P = 0.029). TNF-alpha also tended to decrease with treatment (P = 0.134). An improvement in the Role Physical SF-36 quality-of-life subscale was observed (P = 0.042). There were no differences in clinically relevant adverse events between groups. In conclusion, hGH therapy safely improves LBM, other markers of mortality and morbidity, and health-related quality of life in adult patients who are on maintenance hemodialysis. A long-term study is warranted to investigate whether these treatment benefits result in reduced mortality and morbidity.

The protective role of the immunomodulator AS101 against chemotherapy‐induced alopecia studies on human and animal models

The immunomodulator AS101 has been demonstrated to exhibit radioprotective and chemoprotective effects in mice. Following phase‐I studies, preliminary results from phase‐II clinical trials on non‐small‐cell‐lung‐cancer patients showed a reduction in the severity of alopecia in patients treated with AS101 in combination with chemotherapy. To further substantiate these findings, the present study was extended to include 58 patients treated either with the optimal dose of 3 mg/m2 AS101 combined with carboplatin and VP‐16, or with chemotherapy alone. As compared with patients treated with chemotherapy alone, there was a significant decrease in the level of alopecia in patients receiving the combined therapy. The newly developed rat model was used to elucidate the protective mechanism involved in this effect. We show that significant prevention of chemotherapy‐induced alopecia is obtained in rats treated with Ara‐C combined with AS101, administered i.p. or s.c. or applied topically to the dorsal skin. We show that this protection by AS101 is mediated by macrophage‐derived factors induced by AS101. Protection by AS101 can be ascribed, at least in part, to IL‐1, since treatment of rats with IL‐1RA largely abrogated the protective effect of AS101. Moreover, we demonstrate that in humans there is an inverse correlation between the grade of alopecia and the increase in IL‐1α. In addition, protection by AS101 could be related to PGE2 secretion, since injection of indomethacin before treatment with AS101 and Ara‐C partly abrogated the protective effect of AS101. To assess the ability of AS101 to protect against chemotherapy‐induced alopecia, phase‐II clinical trials have been initiated with cancer patients suffering from various malignancies.

Vasopressin Receptor Antagonists for the Treatment of Hyponatremia: Systematic Review and Meta-analysis

BACKGROUND In patients with euvolemic and hypervolemic hyponatremia, the effect of vasopressin antagonists is yet undefined. STUDY DESIGN Systematic review and meta-analysis of randomized controlled trials (RCTs). SETTING & POPULATION In- and outpatients with euvolemic or hypervolemic hyponatremia. SELECTION CRITERIA FOR STUDIES We included all RCTs regardless of publication status or language. INTERVENTION Vasopressin antagonists with or without fluid restriction versus placebo or no treatment with or without fluid restriction. OUTCOMES Response rate defined as normalization of serum sodium level or significant increase in serum sodium level at 3-7 days (primary) and later, change from baseline serum sodium level at 3-7 days and later, adverse events, rate of rapid sodium level correction, and rate of hypernatremia. RESULTS 15 RCTs were identified. Vasopressin antagonist treatment significantly increased response rate both early (RR, 3.15; 95% CI, 2.27-4.37; 11 trials) and late (RR, 2.27; 95% CI, 1.79-2.89; 4 trials). Response rates were high in trials assessing mostly euvolemic patients and those assessing mostly hypervolemic patients, with greater effect estimate in the former. Change from baseline serum sodium level was significantly increased both early (weighted mean difference, 5.27 mEq/L; 95% CI, 4.27-6.26, 13 trials) and late (weighted mean difference, 3.49 mEq/L; 95% CI, 2.56-4.41, 8 trials). Although there was an increased rate of rapid sodium correction (RR, 2.52; 95% CI, 1.26-5.08, 8 trials) with vasopressin antagonists, hypernatremia rates were not significantly higher (RR, 2.21; 95% CI, 0.61-7.96; 5 trials), adverse events were not increased, and there were no reports of osmotic demyelination syndrome. LIMITATIONS Significant heterogeneity in the primary outcome. CONCLUSIONS Vasopressin antagonists are effective for the treatment of hypervolemic and euvolemic hyponatremia.

An antibody profile of systemic lupus erythematosus detected by antigen microarray

Patients with systemic lupus erythematosus (SLE) produce antibodies to many different self‐antigens. Here, we investigated antibodies in SLE sera using an antigen microarray containing many hundreds of antigens, mostly self‐antigens. The aim was to detect sets of antibody reactivities characteristic of SLE patients in each of various clinical states – SLE patients with acute lupus nephritis, SLE patients in renal remission, and SLE patients who had never had renal involvement. The analysis produced two novel findings: (i) an SLE antibody profile persists independently of disease activity and despite long‐term clinical remission, and (ii) this SLE antibody profile includes increases in four specific immunoglobulin G (IgG) reactivities to double‐stranded DNA (dsDNA), single‐stranded DNA (ssDNA), Epstein–Barr virus (EBV) and hyaluronic acid; the profile also includes decreases in specific IgM reactivities to myeloperoxidase (MPO), CD99, collagen III, insulin‐like growth factor binding protein 1 (IGFBP1) and cardiolipin. The reactivities together showed high sensitivity (> 93%) and high specificity for SLE (> 88%). A healthy control subject who had the SLE antibody profile was later found to develop clinical SLE. The present study did not detect antibody reactivities that differentiated among the various subgroups of SLE subjects with statistical significance. Thus, SLE is characterized by an enduring antibody profile irrespective of clinical state. The association of SLE with decreased IgM natural autoantibodies suggests that these autoantibodies might enhance resistance to SLE.