Shmuel Smetana

Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial

BACKGROUND Excess cardiovascular mortality has been documented in chronic haemodialysis patients. Oxidative stress is greater in haemodialysis patients with prevalent cardiovascular disease than in those without, suggesting a role for oxidative stress in excess cardiovascular disease in haemodialysis. We investigated the effect of high-dose vitamin E supplementation on cardiovascular disease outcomes in haemodialysis patients with pre-existing cardiovascular disease. METHODS Haemodialysis patients with pre-existing cardiovascular disease (n=196) aged 40-75 years at baseline from six dialysis centres were enrolled and randomised to receive 800 IU/day vitamin E or matching placebo. Patients were followed for a median 519 days. The primary endpoint was a composite variable consisting of: myocardial infarction (fatal and non-fatal), ischaemic stroke, peripheral vascular disease (excluding the arteriovenous fistula), and unstable angina. Secondary outcomes included each of the component outcomes, total mortality, and cardiovascular-disease mortality. FINDINGS A total of 15 (16%) of the 97 patients assigned to vitamin E and 33 (33%) of the 99 patients assigned to placebo had a primary endpoint (relative risk 0.46 [95% CI 0.27-0.78], p=0.014). Five (5.1%) patients assigned to vitamin E and 17 (17.2%) patients assigned to placebo had myocardial infarction (0.3 [0.11-0.78], p=0.016). No significant differences in other secondary endpoints, cardiovascular disease, or total mortality were detected. INTERPRETATION In haemodialysis patients with prevalent cardiovascular disease, supplementation with 800 IU/day vitamin E reduces composite cardiovascular disease endpoints and myocardial infarction.

Regression Equation Predicts Dietary Phosphorus Intake from Estimate of Dietary Protein Intake

OBJECTIVE To develop a predictive equation for dietary phosphorus intake. DESIGN In this clinic-based, cross-sectional study, a dietitian-administered food frequency questionnaire provided dietary intake estimates for a population of patients with chronic renal failure. A prediction equation for dietary phosphorus intake was developed and was validated on another sample of patients with CRF from the same clinic. SUBJECTS Outpatients treated for chronic renal failure at the E. Wolfson Medical Center Institute of Nephrology in Holon, Israel, participated in the study (N = 104, 73 men and 31 women, mean age = 65.6 years). The validation sample consisted of 53 outpatients with chronic renal failure (38 men and 15 women, mean age = 64.2 years) from the same clinic. MAIN OUTCOME MEASURES Dietary variables (ie, energy, protein, carbohydrate, fat, phosphorus) were examined in terms of crude intake, as percentage of total energy intake, and per kilogram of body weight. STATISTICAL ANALYSES PERFORMED Stepwise linear regression analysis and Students t tests were used to examine relationships between dietary phosphorus and other variables. RESULTS Dietary phosphorus (milligrams) = 128 + 14 (protein intake [grams]) was the best-fitting equation and explained 84% of the variance in dietary phosphorus intake. APPLICATIONS The prediction equation for dietary phosphorus intake is especially useful for renal dietitians who calculate patient diets by hand.

Comparison of hemostatic factors and serum malondialdehyde as predictive factors for cardiovascular disease in hemodialysis patients

Hemodialysis (HD) patients have accelerated cardiovascular morbidity and mortality rates compared with the general population. Identifying the factors that predict major coronary events in this population can direct the focus on prevention. This cross-sectional study compares known and suspected cardiovascular risk factors in HD patients with and without prevalent cardiovascular disease (CVD). In 76 HD patients (prevalent CVD, 44 of 76 patients), serum lipid, lipoprotein, apolipoprotein (Apo), plasma fibrinogen, tissue plasminogen activator (TPA), plasminogen activator inhibitor (PAI-1), and factor VII levels were measured using standard kits. Serum malondialdehyde (MDA; a marker of oxidative stress) was measured using spectrophotometry. Predictor variables were compared using analysis of variance and chi-squared tests, as appropriate. CVD prevalence was modeled using multiple logistic regression analysis, and odds ratios (OR) were calculated. Serum lipid, lipoprotein, Apo, plasma TPA, PAI-1, and factor VII values did not differ significantly from laboratory norms or discriminate for prevalent CVD in HD patients. Plasma fibrinogen levels were significantly elevated in HD patients compared with laboratory norms (369.4 +/- 130.02 v 276.7 +/- 77.7 mg/dL; P < 0.0001) but were not significantly different in HD patients with and without prevalent CVD. Serum MDA levels, both before and after the midweek HD treatment, were significantly elevated in all HD patients compared with laboratory norms (pretreatment, 2.6 +/- 0.8 nmol/mL; posttreatment, 2.1 +/- 0.3 v 0.91 +/- 0.09 nmol/mL; P < 0.01) and were significantly elevated in HD patients with prevalent CVD versus those without (pretreatment, 2.8 +/- 0.6 v 2.4 +/- 0.4 nmol/mL; P < 0.01; posttreatment, 2.3 +/- 0.4 v 1.94 +/- 0.2 nmol/mL; P < 0.01). Only serum MDA levels, both before and after the midweek treatment, contributed to the explanation of variation in CVD prevalence. OR for CVD in the highest versus lowest tertile of pretreatment MDA level was 2.71 (95% confidence interval [CI], 1.42 to 5.19). ORs for CVD in the highest versus lowest tertile of posttreatment MDA level was 3.65 (95% CI, 1.6 to 8.32).

Pamidronate-induced nephrotoxic tubular necrosis--a case report.

Few cases of pamidronate (bisphosphonate class of drugs) nephrotoxicity in humans have been previously reported in the literature. In 7 patients, the pamidronate-related nephrotoxicity was attributed to focal collapsing glomerulosclerosis [Markowitz et al. 2001], and in 1 patient was related to tubulo-interstitial inflammatory nephritis [Van Doom et al. 2001]. We report herein on a 65-year-old Caucasian female patient who presented with acute chronic renal failure due to pamidronate-induced toxic proximal tubular necrosis without immunologic or inflammatory tubulo-interstitial involvement. The acute pattern of renal failure resolved following cessation of pamidronate administration in this patient for osteoporosis; the patient also had a monoclonal gammopathy of unspecific origin (MGUS).

Peripheral vascular disease and serum phosphorus in hemodialysis: a nested case-control study.

BACKGROUND Serum phosphorus (P) and the product of serum calcium x serum P (Ca x P), are frequently elevated in end-stage renal disease patients on maintenance hemodialysis (HD). Elevated P and Ca x P have been associated with vascular calcification in dialysis patients. OBJECTIVE [corrected] To examine the role of P and Ca x P as risk factors for incident peripheral vascular disease (PVD) in HD patients with pre-existing CVD. METHODS This nested case-control study is drawn from the 11 incident PVD events reported in the cohort of the Secondary prevention with antioxidants of cardiovascular disease in end-stage renal disease (SPACE): a randomized placebo-controlled trial. PVD was defined clinically and confirmed ultrasonographically. Each individual with a PVD event was matched for SPACE treatment group (vitamin E or placebo), age (in 4-year categories) and gender with two individuals who had no CVD end point during the follow-up period. RESULTS Serum P and Ca x P levels were significantly higher in PVD patients than in controls. In univariate logistic regression analysis, only serum P predicted PVD in this population (OR 2.02, 95% CI 1.07 - 3.81, p = 0.03). In multivariate analysis, adjustment was made for variables dissimilar by PVD status including underlying renal disease, diabetes, smoking, history of angina pectoris, prescription for vitamin D3, erythropoietin, calcium channel blockers and aspirin. In this model, serum P remained the only significant predictor of incident PVD (OR 2.4, 95% CI 1.01 - 5.74, p = 0.04). CONCLUSIONS Findings of the present study are consistent with a role for serum P and Ca x P in the pathogenesis of PVD in HD patients.

Baseline Oxysterols and Other Markers of Oxidative Stress, Inflammation and Malnutrition in the Vitamin E and Intima Media Thickness Progression in End-Stage Renal Disease (VIPER) Cohort

Background and Objectives: Oxysterols are markers of oxidative stress, levels of which have not yet been reported in hemodialysis (HD) patients. This study was designed to compare levels of the oxysterols 7-ketocholesterol (7KC) and 7β-hydroxycholesterol (7βOH) between a cohort of HD patients and healthy controls. Methods: This nested cross-sectional study reflects baseline (pre-intervention) values for markers of oxidative stress, inflammation and nutrition status in the 160-member vitamin E and carotid intima media thickness progression in end-stage renal disease (VIPER) cohort (age 64.1 ± 8.8, 33.5% female). Age- and sex-matched healthy volunteers served as controls. Plasma oxysterols 7KC and 7βOH were determined by isotope dilution gas chromatography/mass spectrometry. Results: Despite higher plasma α-tocopherol levels in HD patients than controls (36.0 ± 9.3 vs. 31.8 ± 8.4 µmol/l, p = 0.007), 7KC levels (9.8 ± 6.9 vs. 5.9 ± 2.8 nmol/mmol cholesterol, p < 0.0001) and 7βOH levels (8.7 ± 4.3 vs. 2.7 ± 1.6 nmol/mmol cholesterol, p < 0.0001) were higher in HD patients. The oxysterol 7βOH was significantly, inversely associated with prealbumin (r = –0.18, p = 0.03), though neither oxysterol was significantly associated with any other marker of oxidative stress, inflammation or nutrition status and did not discriminate for CVD in HD patients. Conclusions: Elevated levels of the oxysterols 7KC and 7βOH indicate that HD patients are in a state of oxidative stress compared to healthy controls. However, oxysterols 7KC and 7βOH did not appear to contribute additional information about oxidative stress among HD patients.

Varicella-Zoster Virus Immune Status in CAPD and Chronic Hemodialysis Patients

Patients on chronic dialysis who are supposed to disclose an impairment of the immune potential, seldom show clinical viral illnesses. Since severe varicella-zoster virus (VZV) infection develops in immunocompromised patients, we have examined the proliferative activity to VZV in the blood lymphocytes of 16 patients on continuous ambulatory peritoneal dialysis (CAPD) and compared it to healthy matched controls. The cellular in vitro response of these patients to specific VZV antigens was essentially normal. The mean stimulation index for CAPD patients was 7.06, and for matched controls 3.68 (p greater than 0.05). The mean percentage of lymphocytes in CAPD patients as determined by CD3 monoclonal antibodies was 57%, the CD4 helper and CD8 suppressor cells were 41 and 21%, respectively. When those 16 CAPD patients were followed up for the presence of anti-VZV IgA, IgM and IgG immunofluorescent antibody to membrane antigen antibodies during a period of 6 months, the recrudescence of VZV was documented by the appearance of IgA and IgM antibodies and/or fourfold increase in IgG titer in some patients, but no clinical illness was observed. The frequent reactivation of the virus without clinical symptoms in patients undergoing long-term intermittent chronic hemodialysis (HD) or CAPD was strengthened by the presence of increased anti-VZV geometric mean titers (52.68 and 53.00, respectively) in these patients as compared to control subjects (11.75).

Pregnancy in membranous glomerulonephritis: course, treatment and outcome

BACKGROUND The effect and outcome of pregnancy in women with preexisting glomerulonephritis is a controversial issue. CASE We report the clinical course and treatment of a 23-year-old pregnant woman with biopsy-proven membranous glomerulonephritis. When she conceived, the patient had been in stable remission for 1 year. In the 14th week of pregnancy, the patient developed uncontrolled hypertension and nephrotic syndrome. Daily 1 g methylprednisolone intravenous pulses were administered for 3 days, followed by a 4-week course of oral prednisone, 50 mg/day. Clinical improvement and normalization of arterial blood pressure were achieved. Oral prednisone 60 mg was administered on alternate days for another 4 weeks following 3 days of pulse therapy. At the end of treatment (26th gestational week), we observed a decrease of proteinuria (from 10.6-4.8 g/24 h) and rise in serum albumin (from 2.1-2.9 g/100 ml). At this time, blood pressure was 130/85. In the 34th week, a normal healthy male newborn was delivered by cesarean section. One year later she felt well, her blood pressure was 140/90, serum albumin was 3.4 g/100 ml, urine protein was 1.65 g/24 h and renal function was normal. The patients child was healthy and well developed. CONCLUSION Judicious use of a specific therapy to the underlying renal disease during pregnancy, together with a continuous supervision, can improve outcomes of these particular high-risk conditions.

Patterns of Dietary Intake and Serum Lipids Interact with Proteinuria as Risk Factors for Progression of Chronic Renal Failure

UNLABELLED This prospective study assessed the interactions between patterns of nutrient intake and serum lipids with other risk factors for progression of chronic renal failure. The study cohort consisted of 52 individuals with documented chronic renal failure, 18 women and 34 men, with a mean age of 65 +/- 11 years at the time of recruitment. The dependent variable was the rate of progression of chronic renal failure, which was determined by the slope of the curve generated from five or more values of the reciprocal of serum creatinine (SCr-1) and divided by time (in months of follow-up) for each patient, and recorded in dung/month. The independent variables included dietary factors (phosphorus, protein); serum lipids (total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides); proteinuria; serum phosphorus; serum albumin; serum glucose; and blood pressure. Serum creatinine was drawn in a fasting state and determined using the picric acid technique on five or more occasions for each patient. The mean monthly rate of decline in dL/mg/month was calculated for each patient. The cohort was followed for 1.5 years. Descriptive statistics were determined for all variables. Analysis of principal components was used to generate variables representing patterns of nutrient intake and serum lipids. The outcome variable was modeled using stepwise linear regression which included principal components representing dietary and serum lipid patterns. The Students t test and the F test were used for hypothesis testing. All tests were significant at p < 0.05. RESULTS AND CONCLUSIONS Multicolinearity prevented the inclusion of more than one individual dietary or serum lipid variable into the multiple linear regression model of rate of decline in kidney function. Principal components representing patterns of dietary intake and serum lipids, contributed to the prediction of rate of decline in renal function together with proteinuria.