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Biomedical subjects

Gerald Schulman

Publications and source records attributed to Gerald Schulman.

17 recordsLinked to original sources
PubMed2006

A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study of AST-120 (Kremezin) in patients with moderate to severe CKD.

BACKGROUND: AST-120 (Kremezin; Kureha Chemical Industry Co Ltd, Tokyo, Japan) is an orally administered adsorbent showing adsorption ability superior to activated charcoal for certain organic compounds known to be precursors of substances that accumulate in patients with chronic kidney disease (CKD) and that are believed to accelerate the decline in kidney function. AST-120 is approved in Japan for prolonging time to hemodialysis therapy and improving uremic symptoms in patients with CKD. METHODS: A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study was designed to examine the nephroprotective effects of 3 doses of AST-120 versus placebo in adult patients with moderate to severe CKD and elevated serum indoxyl sulfate levels while following an adequate protein-intake diet. Eligible patients were randomly assigned to 1 of 3 doses of AST-120 (0.9, 2.1, or 3.0 g) or placebo 3 times daily for 12 weeks. RESULTS: AST-120 decreased serum indoxyl sulfate levels in a dose-dependent fashion. During the 12-week treatment period, AST-120 did not affect serum creatinine levels or 24-hour urine creatinine appearance. Significant improvements in malaise were observed in a dose-dependent fashion. All doses of AST-120 were well tolerated and did not adversely affect the general health status of patients. CONCLUSION: Results suggest that the dose of 3 g 3 times daily is an optimal dose for the US population, and it may be useful in the treatment of patients with CKD. Because AST-120 did not directly affect serum creatinine levels or 24-hour urine creatinine appearance, the composite end point of doubling of serum creatinine level, transplantation, and dialysis therapy would be appropriate for a confirmatory phase III therapeutic outcome study.

Adult↗
PubMed2006

A nexus of progression of chronic kidney disease: charcoal, tryptophan and profibrotic cytokines.

Fibrosis plays a role in the pathogenesis of progressive chronic kidney disease (CKD). The inhibition of the renin-angiotensin system, which promotes fibrosis, has become the standard of care in the treatment of patients with CKD. A novel charcoal compound, AST-120, has been used for over a decade in Japan to prevent progression of CKD. It is thought that the oral administration of AST-120 blocks the intestinal absorption of tryptophan-derived indole. This prevents the hepatic conversion of indole to indoxyl sulfate (IS). IS has been shown to stimulate the production of profibrotic cytokines such as transforming growth factor-beta. AST-120 lowers IS in a dose dependent fashion and does not change the creatinine appearance rate in the urine. Enteric capsules containing Bifidobacterium longum have been shown to prevent progression of CKD in a preliminary study. These findings suggest that prospective clinical trials be undertaken to determine if these other potential methods of inhibiting fibrosis are useful in slowing progressive CKD.

Administration, Oral↗
PubMed2005

Serum beta-2 microglobulin levels predict mortality in dialysis patients: results of the HEMO study.

In the randomized Hemodialysis (HEMO) Study, chronic high-flux dialysis, as defined by higher beta-2 microglobulin (beta(2)M) clearance, compared with low-flux dialysis did not significantly alter all-cause mortality in the entire cohort but was associated with lower mortality in long-term dialysis patients. This analysis examined the determinants of serum beta(2)M levels and the associations of serum beta(2)M levels or dialyzer beta(2)M clearance with mortality. In a multivariable regression model that examined 1704 patients, baseline residual kidney urea clearance and dialyzer beta(2)M clearance were strong predictors of predialysis serum beta(2)M levels at 1 mo of follow-up, with regression coefficients of -7.21 (+/-0.69 SE) mg/L per ml/min per 35 L urea volume (P < 0.0001) and -1.94 (+/-0.30) mg/L per ml/min (P < 0.0001),respectively. In addition, black race and baseline years on dialysis correlated positively whereas age, diabetes, serum albumin, and body mass index correlated negatively with serum beta(2)M levels (P < 0.05). In time-dependent Cox regression models, mean cumulative predialysis serum beta(2)M levels but not dialyzer beta(2)M clearance were associated with all-cause mortality (relative risk = 1.11 per 10-mg/L increase in beta(2)M level; 95% confidence interval 1.05 to 1.19; P = 0.001), after adjustment for residual kidney urea clearance and number of prestudy years on dialysis. This association is supportive of the potential value of beta(2)M as a marker to guide chronic hemodialysis therapy.

Adult↗
PubMed2005

Association of achieved dialysis dose with mortality in the hemodialysis study: an example of "dose-targeting bias".

In the intention-to-treat analysis of the Hemodialysis Study, all-cause mortality did not differ significantly between the high versus standard hemodialysis dose groups. The association of mortality with delivered dose within each of the two randomized treatment groups was examined, and implications for observational studies were considered. Time-dependent Cox regression was used to relate the relative risk (RR) for mortality to the running mean of the achieved equilibrated Kt/V (eKt/V) over the preceding 4 mo. eKt/V was categorized by quintiles within each dose group. Analyses were controlled for case-mix factors and baseline anthropometric volume. Within each randomized dose group, mortality was elevated markedly when achieved eKt/V was in the lowest quintile (RR, 1.93; 95% confidence interval [CI], 1.40 to 2.66; P < 0.0001 in the standard-dose group; RR, 2.04; 95% CI, 1.50 to 2.76; P < 0.0001 in the high-dose group; RR relative to the middle quintiles). The mortality rate in the lowest eKt/V quintile of the high-dose group was higher than in the full standard-dose group (RR, 1.59; 95% CI, 1.29 to 1.96; P < 0.0001). Each 0.1 eKt/V unit below the group median was associated with a 58% higher mortality in the standard-dose group (P < 0.001) and a 37% higher mortality in the high-dose group (P < 0.001). The magnitude of these dose-mortality effects was seven- to 12-fold higher than the upper limit of the 95% CI from the intention-to-treat analysis. The effects were attenuated in lagged analyses but did not disappear. When dialysis dose is targeted closely, as under the controlled conditions of the Hemodialysis Study, patients with the lowest achieved dose relative to their target dose experience markedly increased mortality, to a degree that is not compatible with a biologic effect of dose. The possibility of similar (albeit smaller) biases should be considered when analyzing observational data sets relating mortality to achieved dose of dialysis.

Black People↗
PubMed2004

Factors that affect postdialysis rebound in serum urea concentration, including the rate of dialysis: results from the HEMO Study.

Previous studies have suggested that postdialysis urea rebound is related to K/V, the rate of dialysis, but a systematic analysis of factors that affect rebound has not been reported. With the use of 30-min and, in a subset, 60-min postdialysis samples, postdialysis urea rebound was measured to (1) determine how well previously proposed equations based on the rate of dialysis (K/V) predict rebound in a large sample of patients with varying characteristics, (2) determine whether other factors besides K/V affect rebound, and (3) estimate more precise values for coefficients in prediction equations for rebound. Rebound was calculated relative to both immediate and 20-s postdialysis samples to study early components of rebound unrelated to access recirculation. The equilibrated Kt/V (eKt/V) computed by fitting the two-pool variable volume model to the 30-min postdialysis sample agreed well with eKt/V based on the 60-min postdialysis sample. Using the pre-, post-, and 30-min postdialysis samples for 1245 patients with arteriovenous (AV) accesses, the median intercompartmental mass transfer coefficient (Kc) was 797 ml/min for rebound computed relative to the 20-s postdialysis samples and 592 ml/min relative to the immediate postdialysis samples. K/V was the strongest predictor of rebound among 22 factors considered. Other factors associated with greater rebound for 1331 patients using AV accesses or venous catheters included access type, black race, male gender, absence of congestive heart failure, greater age, ultrafiltration rate, and low predialysis or intradialysis systolic BP. Equations of the form eKt/V = single-pool Kt/V - B x (K/V) were fit to the data. With AV access, the optimum values for the slope term (B) were 0.39 and 0.46 (in h(-1)) for single-pool Kt/V calculated based on 20-s postdialysis or immediate postdialysis samples, respectively. For patients using venous catheters, the respective values for B were 0.22 and 0.29. Postdialysis urea rebound can be predicted with acceptable accuracy from a postdialysis sample using a zero-intercept, K/V-based rate equation. Several patient or treatment-specific factors predict enhanced or reduced rebound. Rate equation slope coefficients for K/V of 0.39 (AV access) and 0.22 (venous access) are proposed when a 15- to 20-s slow-flow method is used to draw the postdialysis blood. Slightly higher K/V slope coefficients (0.46 and 0.29, respectively) should be used if a shorter (e.g., 10 s) slow-flow period is used.

Female↗
PubMed2003

The effects of sevelamer and calcium acetate on proxies of atherosclerotic and arteriosclerotic vascular disease in hemodialysis patients.

BACKGROUND: We recently determined that in hemodialysis patients, the use of calcium salts to correct hyperphosphatemia led to progressive coronary artery and aortic calcification as determined by sequential electron beam tomography (EBT) while the use of the non-calcium-containing binder sevelamer did not. Whether the specific calcium preparation (acetate vs. carbonate) might influence the likelihood of progressive calcification was debated. METHODS: To determine whether treatment with calcium acetate was specifically associated with hypercalcemia and progressive vascular calcification, we conducted an analysis restricted to 108 hemodialysis patients randomized to calcium acetate or sevelamer and followed for one year. RESULTS: The reduction in serum phosphorus was roughly equivalent with both agents (calcium acetate -2.5 +/- 1.8 mg/dl vs. sevelamer -2.8 +/- 2.0 mg/dl, p = 0.53). Subjects given calcium acetate were more likely to develop hypercalcemia (defined as an albumin-corrected serum calcium > or =10.5 mg/dl) (36 vs. 13%, p = 0.015). Treatment with calcium acetate (mean 4.6 +/- 2.1 g/day - equivalent to 1.2 +/- 0.5 g of elemental calcium) led to a significant increase in EBT-determined calcification of the coronary arteries (mean change 182 +/- 350, median change +20, p = 0.002) and aorta (mean change 181 +/- 855, median change +73, p < 0.0001). These changes were similar in magnitude to those seen with calcium carbonate. There were no significant changes in calcification among sevelamer-treated subjects. CONCLUSION: Despite purported differences in safety and efficacy relative to calcium carbonate, calcium acetate led to hypercalcemia and progressive vascular calcification in hemodialysis patients.

Acetates↗
PubMed2003

Hand-assisted laparoscopic radical nephrectomy-associated rhabdomyolysis with ARF.

Intraoperative rhabdomyolysis with resultant acute renal failure is a rare complication seen, most commonly, with urologic surgical procedures. Since the early 1990s, the refinement of laparoscopic techniques has permitted their application more broadly. Among the procedures to benefit from these less invasive surgical methods has been radical nephrectomy. In general, this has resulted in less postoperative pain and shorter convalescence. Nonetheless, laparoscopic radical nephrectomy still represents major surgery and is not free from operative risks. To highlight one of these risks, we present a case of a young, obese man with renal cell carcinoma who underwent a hand-assisted laparoscopic radical nephrectomy that was complicated by rhabdomyolsis resulting in acute renal failure (ARF). We discuss the clinical insults that contributed to the development of azotemia with particular attention paid to our current understanding of the pathogenesis of myoglobinuric ARF. In addition, we review the literature concerning surgery-associated, rhabdomyolytic ARF with the aim of providing clinicians guidance for the avoidance and early recognition of this rare, but very serious, surgical complication.

Acute Kidney Injury↗
PubMed2003

Nutrition in daily hemodialysis.

BACKGROUND: Reports of improved patient outcomes using very long hemodialysis sessions have rekindled interest in alternatives to the standard thrice weekly hemodialysis regimen. METHODS: A review of the current literature was undertaken to determine the effect of daily hemodialysis on nutritional indices. Several regimens that deliver longer treatments were considered, including thrice weekly dialysis for 6 to 8 hours, short daily hemodialysis (5 to 7 times per week) for 1.5 to 2.5 hours, and nocturnal hemodialysis for 6 to 8 hours. An increasing number of centers are experimenting with the latter 2 treatment schedules the results of which are reported herein. RESULTS: Nutritional status is an important predictor of outcome in end-stage renal disease (ESRD) patients. Nutritional status of patients can be improved by increasing the dose of conventional hemodialysis or by using biocompatible membranes. Therefore, it should not be surprising that daily hemodialysis treatments may affect nutrition. Beyond the effect that the enhanced clearance of small-molecular-weight substances may have on nutrition, the daily modalities open another dimension of depuration because of the ability to remove larger-molecular-weight substances to an extent that has never been approached by conventional hemodialysis. CONCLUSION: The preliminary data from the studies evaluating the influence of daily and nocturnal hemodialysis on nutrition status suggest a beneficial effect. In particular, a striking lowering of phosphorus level occurs with nocturnal hemodialysis. However, there is little prospective and randomized information on the effects of the modalities on incident patients. The number of patients enrolled in daily hemodialysis is only in the hundreds. Prospective clinical trials are required to delineate the full potential of these therapies as well the differences between them. Both daily and nocturnal regimens should be explored in future studies.

Appointments and Schedules↗
PubMed2003

Effects of high-flux hemodialysis on clinical outcomes: results of the HEMO study.

Among the 1846 patients in the HEMO Study, chronic high-flux dialysis did not significantly affect the primary outcome of the all-cause mortality (ACM) rate or the main secondary composite outcomes, including the rates of first cardiac hospitalization or ACM, first infectious hospitalization or ACM, first 15% decrease in serum albumin levels or ACM, or all non-vascular access-related hospitalizations. The high-flux intervention, however, seemed to be associated with reduced risks of specific cardiac-related events. The relative risks (RR) for the high-flux arm, compared with the low-flux arm, were 0.80 [95% confidence interval (CI), 0.65 to 0.99] for cardiac death and 0.87 (95% CI, 0.76 to 1.00) for the composite of first cardiac hospitalization or cardiac death. Also, the effect of high-flux dialysis on ACM seemed to vary, depending on the duration of prior dialysis. This report presents secondary analyses to further explore the relationship between the flux intervention and the duration of dialysis with respect to various outcomes. The patients were stratified into a short-duration group and a long-duration group, on the basis of the mean duration of dialysis of 3.7 yr before randomization. In the subgroup that had been on dialysis for >3.7 yr, randomization to high-flux dialysis was associated with lower risks of ACM (RR, 0.68; 95% CI, 0.53 to 0.86; P = 0.001), the composite of first albumin level decrease or ACM (RR, 0.74; 95% CI, 0.60 to 0.91; P = 0.005), and cardiac deaths (RR, 0.63; 95% CI, 0.43 to 0.92; P = 0.016), compared with low-flux dialysis. No significant differences were observed in outcomes related to infection for either duration subgroup, however, and the trends for beneficial effects of high-flux dialysis on ACM rates were considerably weakened when the years of dialysis during the follow-up phase were combined with the prestudy years of dialysis in the analysis. For the subgroup of patients with <3.7 yr of dialysis before the study, assignment to high-flux dialysis had no significant effect on any of the examined clinical outcomes. These data suggest that high-flux dialysis might have a beneficial effect on cardiac outcomes. Because these results are derived from multiple statistical comparisons, however, they must be interpreted with caution. The subgroup results that demonstrate that patients with different durations of dialysis are affected differently by high-flux dialysis are interesting and require further study for confirmation.

Female↗
PubMed2002

Effect of dialysis dose and membrane flux in maintenance hemodialysis.

BACKGROUND: The effects of the dose of dialysis and the level of flux of the dialyzer membrane on mortality and morbidity among patients undergoing maintenance hemodialysis are uncertain. METHODS: We undertook a randomized clinical trial in 1846 patients undergoing thrice-weekly dialysis, using a two-by-two factorial design to assign patients randomly to a standard or high dose of dialysis and to a low-flux or high-flux dialyzer. RESULTS: In the standard-dose group, the mean (+/-SD) urea-reduction ratio was 66.3+/-2.5 percent, the single-pool Kt/V was 1.32+/-0.09, and the equilibrated Kt/V was 1.16+/-0.08; in the high-dose group, the values were 75.2+/-2.5 percent, 1.71+/-0.11, and 1.53+/-0.09, respectively. Flux, estimated on the basis of beta2-microglobulin clearance, was 3+/-7 ml per minute in the low-flux group and 34+/-11 ml per minute in the high-flux group. The primary outcome, death from any cause, was not significantly influenced by the dose or flux assignment: the relative risk of death in the high-dose group as compared with the standard-dose group was 0.96 (95 percent confidence interval, 0.84 to 1.10; P=0.53), and the relative risk of death in the high-flux group as compared with the low-flux group was 0.92 (95 percent confidence interval, 0.81 to 1.05; P=0.23). The main secondary outcomes (first hospitalization for cardiac causes or death from any cause, first hospitalization for infection or death from any cause, first 15 percent decrease in the serum albumin level or death from any cause, and all hospitalizations not related to vascular access) also did not differ significantly between either the dose groups or the flux groups. Possible benefits of the dose or flux interventions were suggested in two of seven prespecified subgroups of patients. CONCLUSIONS: Patients undergoing hemodialysis thrice weekly appear to have no major benefit from a higher dialysis dose than that recommended by current U.S. guidelines or from the use of a high-flux membrane.

Adult↗
PubMed2002

Seasonal variations in clinical and laboratory variables among chronic hemodialysis patients.

Seasonal variations in BP among chronic hemodialysis patients have been reported. It was hypothesized that other characteristics of these patients might also vary with the seasons. Twenty-one clinical and laboratory variables were examined for seasonal variations among 1445 patients enrolled in the Hemodialysis Study, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases. Mixed-effects models were applied to longitudinal changes (up to 45 mo) for individual patients for 19 of the 21 variables, which were measured at least twice each year, to determine the seasonal component of each variable. Seasonal variations in the other two variables, i.e., protein and energy intakes determined from annual dietary records, were assessed in cross-sectional comparisons of intakes of patients entering the study at different time points. Thirteen of the 21 variables examined demonstrated statistically significant (P < 0.01) seasonal components in their longitudinal variations. Predialysis blood urea nitrogen concentrations peaked in March, which coincided approximately with the peak protein catabolic rates, as well as protein and energy intakes (determined by dietary recall). Predialysis systolic and diastolic BP values were highest in winter and lowest in summer, corroborating previous reports. In addition, the lower predialysis BP values in summer were associated with higher outdoor temperatures and less interdialytic fluid gain. The mean predialysis hematocrit values were highest in July, which could not be attributed solely to the estimated changes in plasma volume. Seasonal variations in clinical and laboratory variables occur commonly among chronic hemodialysis patients. The reasons for most of these variations are not apparent and require further investigation. Nonetheless, failure to consider these variations might lead to biases in the interpretation of clinical studies. In addition, awareness of these variations might facilitate the interpretation of laboratory results and the clinical treatment of these patients.

Adult↗
PubMedDate not supplied

The dose of dialysis in hemodialysis patients: impact on nutrition.

Multiple lines of evidence have indicated that the dose of hemodialysis impacts upon patient outcome. Among these outcome measures, nutrition is inextricably linked to the adequacy of the treatment. All of the methods of determining dialysis adequacy are based on assessing the removal of toxic substances retained in renal failure, the majority of which are derivatives of protein metabolism. Urea kinetics, employing urea as a surrogate for quantifying the elimination of small molecular weight nitrogenous substances, is the method that has been most thoroughly validated to date as defining a dose range for thrice-weekly hemodialysis: Both inadequate and optimal levels of hemodialysis dose have been identified by prospective, randomized clinic trials utilizing Kt/V(urea) as the index of adequacy. The impact of urea kinetics on nutritional status during thrice-weekly hemodialysis is discussed. Recently, in an attempt to improve outcome beyond that achievable with thrice-weekly hemodialysis, alternative regimens, consisting of daily treatments, have received increasing interest. In order to compare the dose of hemodialysis associated with these regimens with conventional thrice-weekly regimens in terms of removal of small molecular weight substances, standard Kt/V(urea), a parameter that combines treatment dose with treatment frequency, and thus allows for various intermittent therapies to be compared to continuous therapy, must be used. In addition, membrane flux and middle molecule removal, factors that have not yet been well defined as parameters of adequacy during thrice-weekly regimens, may be shown to be important indices with longer hemodialysis treatments, particularly daily nocturnal hemodialysis. The impact that these alternative regimens have had on nutritional status in hemodialysis patients and how they compare to conventional therapy are important considerations.

Blood Urea Nitrogen↗