William R. Clark

Serum β-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.

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.

Impact of the Nutritional Regimen on Protein Catabolism and Nitrogen Balance in Patients With Acute Renal Failure

BACKGROUND Patients with acute renal failure are in substantial negative nitrogen balance as a result of their extremely high protein catabolic rates. We prospectively evaluated a series of patients with acute renal failure managed with continuous venovenous hemofiltration to determine which nutritional and nonnutritional variables might influence protein catabolism and nitrogen balance. METHODS Forty consecutive patients (aged 52 +/- 20 years; mean +/- SD) were monitored for 357 treatment days (average treatment duration 8.9 +/- 8.6 days). All data (including nutritional regimen, laboratory values, APACHE II score, administered blood products, hemofiltration parameters, and medications) were collected daily. RESULTS For all patients, the mean normalized protein catabolic rate was 1.4 +/- 0.5 g/kg per day. The rate did not differ between those who received nutrition support and those who did not. The net nitrogen deficit was less in those patients receiving nutrition support (-6.0 +/- 5.2 vs -14.0 +/- 5.6 g N/d; p = .02). Using regression techniques (adjusted for the within-person correlation and the previous days normalized protein catabolic rate), the level of protein and energy provision and the interaction between protein and energy provision were predictive of the normalized protein catabolic rate. Predicted values, using this equation, suggest that at low protein administration rates (< 1 g/kg per day), increasing energy provision may reduce the protein catabolism. However, at this level of protein provision, patients remain in negative nitrogen balance. At protein administration rates necessary to achieve nitrogen balance (approximately 1.5 to 1.8 g/kg per day), protein catabolism may increase. Providing relatively low levels of energy may diminish the magnitude of this increase. CONCLUSION These results suggest that the optimal nutritional regimen for patients with acute renal failure may require a high-protein (approximately 1.5 to 1.8 g/kg per day) and a relatively low-energy (approximately 25 to 35 kcal/kg per day) content.

Urea kinetics during continuous hemofiltration.

Urea kinetic analysis allows for the calculation of the urea distribution volume and urea generation rate. This method was employed in patients with acute renal failure managed by continuous venovenous hemofiltration (CVVH). Based on serial serum urea nitrogen concentration measurements, each patients treatment course consisted of both steady state and non-steady state periods. Thirteen data sets were obtained from 11 critically ill patients treated with CVVH. The duration of therapy was 9.5 +/- 7.5 days (mean +/- SD). Serum urea nitrogen concentration fell from 114 +/- 32 mg/dl to a steady state value of 79 +/- 17 mg/dl (p < 0.0005). The urea distribution volume was 0.55 +/- 0.11 L/kg (range 0.29-0.73), and the urea generation rate 11.7 +/- 3.1 mg urea N/min (range 7.1-17.3). The steady state serum urea nitrogen concentration had a linear relationship to the rate of urea generation (r = 0.92). Urea kinetic analysis permitted the simultaneous determination of the urea generation rate and distribution volume, on an individualized basis, in patients with acute renal failure treated with CVVH.

Innovation in the Treatment of Uremia: Proceedings from the Cleveland Clinic Workshop: Blood–Membrane Interactions During Dialysis

In extracorporeal renal replacement therapies, the dialyzer is not only the site at which solute removal occurs but also the extracorporeal circuit component having the largest surface area exposed to blood. Therefore, it is not surprising that interactions between blood components and the dialyzer membrane influence the dialysis procedure in several ways. Based on engineering principles, fluid flow along a surface such as membrane results in the development of a boundary layer which can influence solute removal. Furthermore, the exposure of blood to any extracorporeal artificial surface results in the activation of several pathways within the body, including those involving coagulation and complement activation. One of the byproducts of this generalized activation process is protein adsorption to the membrane surface, another phenomenon which can have a significant impact on solute removal. In this article, a detailed review of the ways in which blood–membrane interactions influence solute removal during hemodialysis and related therapies is provided. The influences of secondary membrane formation and boundary layer/concentration polarization effects on solute removal are specifically discussed. Furthermore, the importance of adsorption as a specific removal mechanism for low‐molecular weight proteins by highly permeable synthetic membranes is highlighted.

Dialyzer-dependent changes in solute and water permeability with bleach reprocessing

The effects of bleach reprocessing on the performance of high-flux dialyzers have not been comprehensively characterized. We compared the effects of automated bleach/formaldehyde reprocessing on solute and hydraulic permeability for cellulose triacetate (CT190) and polysulfone (F80B) dialyzers using an in vitro model. Dialyzers were studied after initial blood exposure (R0) and after 1 (R1), 5 (R5), 10 (R10), and 15 (R15) reuse cycles. Ultrafiltration coefficient (K(uf)), serial clearances, and/or sieving coefficients (SCs) of urea, creatinine, vancomycin, inulin, myoglobin, and albumin were determined. Urea, creatinine, and vancomycin clearances and SCs did not significantly differ from R0 to R15 with either dialyzer. Inulin clearances and SC also did not significantly change from R0 to R15 for the CT190. However, these same values for the F80B significantly increased (P < 0.05). The inulin clearance and SC values for the CT190 dialyzer were significantly higher than those for the F80B at all stages except R15. Myoglobin clearances significantly increased over 15 reuses for both dialyzers (P < 0.01). However, CT190 myoglobin clearances were significantly higher at all stages (R0 = 37.7 +/- 9.7; R15 = 52.5 +/- 8.8 mL/min) than the F80B (R0 = negligible; R15 = 41.3 +/- 16.5 mL/min; P < 0.01). Albumin pre- and postdialysis SCs significantly increased for both dialyzers (P < 0.01). K(uf) for R0 and R15 were 52.3 +/- 3.3 and 52.6 +/- 7.6 mL/h/mm Hg for CT190 (P = not significant) and 48.8 +/- 4.4 and 87.3 +/- 7.0 mL/h/mm Hg for F80B (P < 0.0001). We conclude that bleach reprocessing significantly increases larger solute and hydraulic permeability of high-flux cellulosic and polysulfone dialyzers. This effect is more pronounced for the polysulfone membrane. Until 10 reuses or greater, the removal of solutes greater than 1,500 d is significantly compromised with the polysulfone dialyzer used in this study.

Efficacy of convective removal of plasma mediators of endotoxic shock by continuous veno-venous hemofiltration.

Continuous veno-venous hemofiltration (CWH) has been reported to provide beneficial effects during endotoxic shock. This experiment was designed to determine if selective removal of plasma mediators occurs during CWH and if plasma concentrations of these mediators are reduced. A swine endotoxic-shock model with three groups was used [lipopolysaccharide (LPS) only (n = 6); LPS followed by CWH (n = 6); and LPS followed by sham CWH (n = 4)]. Plasma and filtrate samples were collected at frequent intervals for 5 h. Lactic acid (LA), eicosanoids [prostacyclin (6-keto PGF-1α), thromboxane (TxB2), and prostaglandin E2 (PGE2)] and tumor necrosis factor (TNF) were measured in plasma and filtrate. Plasma concentrations of 6-keto PGF1α, TxB2, TNF, and LA were not significantly different in any group. LA, PGE2, 6-keto PGF1α, and TxB2 concentrations were similar in filtrate and plasma. TNF did not move across the membrane into the filtrate. CVVH, as used in this experiment, did not significantly reduce plasma concentrations of any of these mediators.

Recent Clinical Advances in the Management of Critically Ill Patients with Acute Renal Failure

Background: Significant progress has been made in the field of renal replacement therapy for critically ill patients with acute renal failure (ARF) over the past few years. This review highlights these developments. Methods: Recent studies assessing the clinical utility of the RIFLE classification system for the diagnosis of ARF were reviewed. Clinical outcome studies evaluating the effect of continuous renal replacement therapy (CRRT) dose and timing of initiation were assessed. The final review topic was the effect of dialysis modality on the recovery of renal function in ARF patients. Conclusions: Based on recent clinical studies, the increasing use of the RIFLE criteria is justified, as this approach appears to be a robust method for both the diagnosis of and prognostication in ARF. A large randomized trial involving convective CRRT supports the commonly used prescription of 35 ml/ kg/h in clinical practice. Moreover, numerous recent outcome studies, also largely involving convective CRRT, provide a clinical rationale for the increasingly common clinical practice of earlier initiation. Finally, several recent studies suggest CRRT, relative to conventional hemodialysis, results in a greater rate of renal recovery in ARF patients.

APPROACHES TO QUOTIDIAN DIALYSIS: The NxStage System One

Given the results of recent randomized controlled trials as well as staffing and budget challenges that today face many institutions across North America, a novel therapeutic approach is likely necessary to enable improvements in clinical outcomes for renal failure patients. The NxStage System One was developed to address these challenges. The system is an innovative, flexible device that delivers hemodialysis, hemofiltration, and/or ultrafiltration therapies to patients with renal failure or fluid overload. The unique characteristics of this system include a highly automated system design with a drop‐in cartridge to facilitate training and simple operation; portable size and independence from dedicated infrastructure to minimize practical barriers to where therapy may be administered; use of high‐quality premixed treatment fluids to enable capture of the potential clinical benefits of fluid purity without the hassles of local water treatment; and wide operating ranges to allow clinician flexibility in patient therapy prescriptions. In both the chronic and acute care environments, the System One presents clinicians with a new platform for delivering patient therapy improvements within real‐world constraints.

Effect of Flow Baffles on the Dialysate Flow Distribution of Hollow-Fiber Hemodialyzers: A Nonintrusive Experimental Study Using MRI

We used an innovative, nonintrusive MRI technique called the two-dimensional (2D) Phase-Contrast (2DPC) velocity-imaging technique to investigate the effect of flow baffles on the dialysate-side flow distribution in two different hollow-fiber hemodialyzers (A and B); each with flow rates between 200 and 1000 mL/min (3.33 x 10(-6) and 1.67 x 10(-5) m3/s). Our experimental results show that (1) the dialysate-side flow distribution was nonuniform with channeling flow occurred at the peripheral cross section of these hollow-fiber hemodialyzers, and (2) the existing designs of flow baffles failed to promote uniform dialysate-side flow distribution for all flow rates studies.