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Most patients with end-stage renal disease depend on intermittent hemodialysis to maintain levels of serum potassium and other electrolytes within a normal range. However, one of the challenges has been the safety of using a low-potassium dialysate to achieve that goal, given the concern about the effects that rapid and/or large changes in serum potassium concentrations may have on cardiac electrophysiology and arrhythmia. Additionally, in this patient population, there is a high prevalence of structural cardiac changes and ischemic heart disease, making them even more susceptible to acute arrhythmogenic triggers. This concern is highlighted by the knowledge that about two-thirds of all cardiac deaths in dialysis are due to sudden cardiac death and that sudden cardiac death accounts for 25% of the overall death for end-stage renal disease. Developing new approaches and practice standards for potassium removal during dialysis, as well as understanding other modifiable triggers of sudden cardiac death, such as other electrolyte components of the dialysate (magnesium and calcium), rapid ultrafiltration rates, and safety of a number of medications (ie, drugs that prolong the QT interval or use of digoxin), are critical in order to decrease the unacceptably high cardiac mortality experienced by hemodialysis-dependent patients., (Published by Elsevier Inc.)

Background: Insufficient clinical data exist to determine whether provision of oral nutritional supplements during dialysis can improve survival in hypoalbuminemic maintenance hemodialysis patients., Study Design: Retrospective matched-cohort study., Setting & Participants: All oral nutritional supplement program-eligible in-center maintenance hemodialysis patients with albumin level ≤3.5 g/dL in quarter 4 of 2009 without oral nutritional supplements in the prior 90 days at Fresenius Medical Care, North America facilities., Quality Improvement Plan: Monitored intradialytic oral nutritional supplements were provided to eligible maintenance hemodialysis patients upon physician order, to continue for a year or until serum albumin level was ≥4.0 g/dL., Outcome: Mortality (including deaths and withdrawals), followed up until December 31, 2010., Measurements: Both an intention-to-treat (ITT) and an as-treated analysis was performed using a 1:1 geographic region and propensity score-matched study population (using case-mix, laboratory test, access type, 30-day prior hospitalization, and incident patient status) comparing patients treated with intradialytic oral nutritional supplements with usual-care patients. Cox models were constructed, unadjusted and adjusted for facility standardized mortality ratio and case-mix and laboratory variables., Results: The ITT and as-treated analyses both showed lower mortality in the oral nutritional supplement group. The conservative ITT models with 5,227 matched pairs had 40% of controls subsequently receiving oral nutritional supplements after January 1, 2010 (because many physicians delayed participation), with comparative death rates of 30.1% versus 30.4%. The corresponding as-treated (excluding crossovers) death rates for 4,289 matched pairs were 30.9% versus 37.3%. The unadjusted ITT mortality HR for oral nutritional supplement use was 0.95 (95% CI, 0.88-1.01), and the adjusted HR was 0.91 (95% CI, 0.85-0.98); the corresponding as-treated HRs were 0.71 (95% CI, 0.66-0.76) and 0.66 (95% CI, 0.61-0.71) before and after adjustment, respectively., Limitations: Limited capture of oral nutritional supplement intake outside the facility and potential residual confounding from unmeasured variables, such as dietary intake., Conclusions: Maintenance hemodialysis patients with albumin levels ≤3.5 g/dL who received monitored intradialytic oral nutritional supplements showed survival significantly better than similar matched patient controls, with the as-treated analysis highlighting the potentially large effect of this strategy in clinical practice., (Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Patients' education about transplant, hemodialysis (HD), peritoneal dialysis (PD), and conservative care often is provided by nephrologists as needed and occurs as time allows., Study Design: Quality improvement report., Setting & Participants: Attendees of a national treatment options program (TOPs) who initiated long-term dialysis therapy (median, 3.4 months) at Fresenius Medical Care, North America facilities throughout 2008 were compared with period-prevalent incident patients receiving usual care., Quality Improvement Plan: Standardized predialysis treatment options education., Outcomes: Rates of opting for PD modality, arteriovenous HD access at initiation, and early (90-day) mortality risk., Measurements: Logistic regression (for choice of PD and HD access type) and Cox models (for early mortality) were constructed, including a 1:1 matched cohort. A post hoc sensitivity analysis also compared a propensity score-matched cohort., Results: 3,165 TOPs attendees (10.5% of 30,217 incident patients admitted between January 1 and December 31, 2008), were younger, more likely to be white, and had slightly larger body surface area. The unadjusted OR for TOPs attendees for selecting PD therapy was 8.45 (95% CI, 7.63-9.37) with a case-mix plus laboratory-adjusted OR of 5.13 (95% CI, 3.58-7.35). For patients who opted for in-center HD therapy, the OR was 2.14 (95% CI, 1.96-2.33) and adjusted OR was 2.06 (95% CI, 1.88-2.26) for starting with a fistula or graft. The unadjusted early mortality HR was 0.51 (95% CI, 0.43-0.60) and case-mix plus laboratory-adjusted adjusted HR was 0.61 (95% CI, 0.50-0.74) for TOPs attendees (all outcomes, P < 0.001). These results were consistent in the 1:1 matched analysis and propensity score-matched analysis., Limitations: It is possible that physicians who referred to these programs were more likely to prescribe PD therapy or place arteriovenous accesses. Motivated, treatment-adherent patients (who would have better outcomes) may have self-selected to attend education sessions., Conclusion: Attending an options class predialysis was associated with more frequent selection of home dialysis, fewer tunneled HD catheters, and lower mortality risk during the first 90 days of dialysis therapy., (Copyright © 2011 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: We hypothesized that a change from central venous catheters to a fistula or graft would improve short-term mortality risk in maintenance hemodialysis patients., Design: Prospective observational study., Setting & Participants: All maintenance in-center hemodialysis patients treated in Fresenius Medical Care, North America legacy facilities alive on January 1, 2007 with baseline laboratory data from December 2006., Predictor: Access type (fistula, catheter, or graft), determined on December 31, 2006, and monthly thereafter. Conversion from a catheter to a fistula or graft during the 4-month period from January 1 to April 30, 2007., Outcome: Mortality was tracked from May 1, 2007, to December 31, 2007. Standard and time-dependent Cox models were used to determine hazard risks (HRs) of death with and without adjustment for case-mix and laboratory values., Results: At baseline, 79,545 patients had 43% fistulas, 29% catheters, and 27% grafts. Mean age was 62 +/- 15 years, 54% were men, 51% were white, and 53% had diabetes. Compared with fistulas, unadjusted HRs of death were higher for grafts (1.22) and catheters (1.76; P < 0.001). In adjusted models, overall risk for grafts was decreased to 1.05 (95% limits, 1.003-1.100; P < 0.05) and approached that for fistulas consistently across multiple strata. Compared with patients who continued using a catheter, those who converted to either a graft or fistula had an HR of 0.69, whereas those who converted from a graft or fistula to a catheter had increased HRs to 2.12 (both P < 0.001). Similar trends were observed in the subset of incident patients (vintage < 90 days at study onset)., Limitations: Observational design with residual confounding from unmeasured patient, facility, and treatment-related factors., Conclusions: Catheters have the worst associated mortality risk. Changing from a catheter to a fistula or graft is associated with significantly improved survival. The risk for grafts approached that of fistulas, providing an alternative to prolonged catheter exposure and potentially less hazardous "bridge" toward a fistula.

Background: We evaluated whether incremental achievement of up to 8 facility quality goals was associated with improvement in facility-specific mortality and hospitalization rates., Study Design: Prospective observational study., Setting & Participants: 1,085 Fresenius Medical Care, North America facilities providing hemodialysis (HD) for 25 or more patients during January 2006., Measurements: The facility average for the period up to December 31, 2006, was used to determine achievement of each goal for equilibrated Kt/V, missed HD treatments, hemoglobin level, bicarbonate level, albumin level, phosphorus level, fistulae, and HD catheters. Linear regression models were used to relate facility-wide achievement of goals with facility-specific hospital days and standardized mortality ratios., Results: Most facilities (64%) achieved 2 to 4 of 8 goals, with only 8% meeting more than 5 quality goals. Achieving more than 5 goals averaged 3.5 fewer hospital days/patient-year and 20% lower standardized mortality ratios (all P < 0.001). The incremental number of goals met also was associated with improvement in facility mortality (P < 0.001) and hospital days (P < 0.001). Catheter and albumin level goals were achieved least (6% and 9% of facilities, respectively), but they had the best outcomes. Facilities achieving more than 5 goals had older patients (64.0 versus 61.5 years; P < 0.001), fewer African American patients (16% versus 38%; P < 0.001), and fewer women (44% versus 46%; P = 0.003) compared with the average., Limitations: Observational design with residual confounding from unmeasured patient-, facility-, and treatment-related factors., Conclusions: Achieving more facility quality goals was significantly associated with better facility-based measurements of patient outcomes. Although these results do not establish a causal relationship, findings agree with the present practice of monitoring facility performance for continuous quality improvement.

Background: To determine the most significant potentially actionable clinical variables associated with mortality and hospitalization risk in hemodialysis (HD) patients., Study Design: Cohort study., Setting & Participants: Adult maintenance HD patients in the Fresenius Medical Care, North America database as of January 1, 2004, with baseline information from October 1, 2003, to December 31, 2003, comprising approximately 26% of the US HD population., Predictors: Case-mix (age, sex, race, diabetes, vintage, and body surface area), vascular access, and laboratory (albumin, equilibrated Kt/V, hemoglobin, calcium, phosphorus, creatinine, bicarbonate, biointact parathyroid hormone, transferrin saturation, and white blood cell count) variables., Outcomes: 1-year mortality and hospitalization risk from January 1 to December 31, 2004., Measurements: Cox proportional hazards models for death and hospitalization., Results: The cohort (N = 78,420) had a mean age of 61.4 +/- 15.0 years, 47% were women, 49% were white, 41% were black race (10% defined as "other"), and 52% had diabetes. The top 5 actionable variables were the same for mortality and hospitalization. Final case-mix plus laboratory-adjusted hazard ratios for these top 5 actionable variables indicate 177% increased risk of death and 67% increased risk of hospitalization per 1-g/dL decrease in albumin level, 39% and 45% greater risk with catheters compared with fistulas, 18% and 9% greater risk per 1-mg/dL greater phosphorus level, 11% and 9% lower risk per 1-g/dL greater hemoglobin level, and 5% and 2% greater risk per 0.1-unit decrease in equilibrated Kt/V, respectively (all P < 0.0001)., Limitations: Observational cross-sectional study with limited comorbidity adjustment (for diabetes)., Conclusion: The same variables are associated with both mortality and hospitalization in HD patients. The top 5 potentially actionable variables are readily identifiable, with albumin level and catheter use the most prominent, and all 5 are appropriate targets for improvement.

Background: Medicare data indicate that black hemodialysis patients receive greater doses of erythropoietin (EPO) than white patients when achieving similar hemoglobin levels. We confirmed and evaluated this observed association between race and EPO dose., Study Design: Cross-sectional cohort study., Setting & Participants: Primary Medicare-insured white (57%) and black (43%) adult long-term hemodialysis patients treated by Fresenius Medical Care who received EPO from January 1 to 31, 2004 (N = 44,721)., Predictor: White/black race., Outcomes: Average weekly EPO dose., Measurements: Associations between race and baseline demographic and laboratory variables were evaluated by using logistic and linear regression models. Correlates of log-transformed weekly EPO dose were determined using linear regression models., Results: Black patients received 12.6% more EPO than white patients (95% limits, 10.9% to 14.3%; P < 0.001). This racial difference in EPO dose was observed across similar hemoglobin levels despite fewer catheters (P < 0.001) and fewer prior hospitalization events in black patients (P = 0.002). Black patients were younger and had larger body size and greater albumin and biointact parathyroid hormone levels, but lower equilibrated Kt/V and white blood cell counts (all P < 0.001). In the 95th percentile of EPO dose (those receiving > 60,000 U/wk), there was a greater proportion of black patients (6% of total black population compared with only 4% in all white patients; P < 0.001). The difference in EPO dose between black and white patients was modified by age and was significant at ages younger than 45 and 65 years or older., Limitations: Observational study limited to white and black adult Medicare patients only, correlating with EPO doses from a single month, without adjustment for comorbid conditions., Conclusions: Black patients were administered approximately 12% greater EPO doses than white patients while achieving similar hemoglobin levels. We identified variables that differed across race that may explain this difference, but they were either not actionable or presented limited opportunity for intervention. Additional studies are needed to define a physiological (or pathological) basis for these observations.

The success of Fistula First nationwide has been accompanied by an unplanned increase in hemodialysis catheters. Complications related to prolonged hemodialysis catheter use include increased morbidity, mortality, and cost. We hypothesize that the national focus on increasing fistulas may have inadvertently diverted attention away from initiatives to decrease dependence on hemodialysis catheters. Based on a synthesis of guidelines, reviews, published evidence, and the authors' opinions, we propose that the national vascular access initiative be revised to have a dual goal of Fistula First and "Catheters Last." These goals are not mutually exclusive, but rather complementary. We recommend a systematic refocus on interventions that not only increase fistulas, but help avoid extended catheter use. Clearly, the ideal practice for hemodialysis vascular access remains early placement of fistulas with enough maturation time such that they can be used for initiating long-term hemodialysis therapy when the need arises. To effect this change, a reimbursement policy covering the costs associated with permanent access placement before the need for dialysis is essential. Individualized patient management strategies may consider such innovative approaches as initiating patients on peritoneal dialysis therapy or using nonautogenous grafts as bridge accesses in lieu of catheters. For patients who are dialyzing using catheters, immediate active planning for permanent access placement and removal of the catheter is necessary. In the same vein as Fistula First, the renal community should once again be galvanized in working together toward controlling the catheter epidemic in our dialysis population.

Background: Protein-calorie malnutrition is highly prevalent in patients with chronic renal failure and on chronic dialysis therapy. Longitudinal studies evaluating nutritional outcomes after the initiation of chronic dialysis therapy in incident dialysis patients are limited., Methods: This prospective cohort study evaluated time-dependent changes in several well-defined markers of nutritional status before and after initiation of chronic hemodialysis therapy. Fifty incident hemodialysis (HD) patients (60% men, 38% white, 32% with insulin-dependent diabetes mellitus) were studied. Multiple nutritional markers, including biochemical parameters and analysis of body composition, were assessed before the initial outpatient CHD treatment and every 3 months thereafter for 12 months., Results: At baseline, nutritional markers correlated well with each other. After the initiation of HD therapy, there were marked improvements in most nutritional parameters, including serum albumin, serum prealbumin, normalized protein catabolic rate, fat mass, reactance, and phase angle (P < 0.05 for all). Improvements in nutritional parameters were influenced by baseline nutritional status; ie, baseline nutritional parameters were predictors of their end-of-study value., Conclusion: Initiation of CHD therapy is associated with improvements in most nutritional markers. Nutritional benefits of increased solute clearance provided by the initiation of chronic dialysis therapy prevail over its potential catabolic effects. However, the extent of improvement was dependent on nutritional status at the time of initiation of dialysis therapy, which remained an important determinant of subsequent nutritional improvements during the first year of treatment., (Copyright 2002 by the National Kidney Foundation, Inc.)

New revised policies relating to intradialytic parenteral nutrition (IDPN) reimbursement by Medicare have made it difficult, if not impossible, to qualify malnourished hemodialysis patients for this potentially useful therapy. These policies were adopted by Medicare because of a lack of studies that provide clear documentation of the medical benefits of IDPN or their cost-effectiveness. We propose a limited study of the role of IDPN with and without anabolic growth factors to improve predefined nutritional parameters and document its cost-effectiveness by monitoring hospitalization and mortality. The proposed study will be multicenter, prospective, limited to severely malnourished patients, and will include a control group that would receive standard of care.

A number of studies have suggested that type of dialysis membrane is associated with differences in long-term outcome of patients undergoing hemodialysis, both in terms of morbidity and mortality. The purpose of this study was to determine the relationship of membrane type and specific causes of death. Data from the United States Renal Data System Case Mix Adequacy Study, a national random sample of hemodialysis patients who were alive on December 31, 1990, were used. Our study was limited to patients in this data set who were undergoing dialysis for at least 1 year (n = 4,055). For the main analytic models, membrane type was classified into two categories: unmodified cellulose or MC/SYN (which combines modified cellulose [MC] and synthetic membranes [SYN]). The relationships of membrane type and major causes of mortality were analyzed using Cox proportional hazards models, which adjusted for multiple (21) covariates, including demographics, comorbidity, Kt/V, and other parameters. Patients were censored at transplantation or 60 days after a switch to peritoneal dialysis. Compared with patients dialyzed with unmodified cellulose membranes, the adjusted relative mortality risk (RR) from infection was 31% lower (RR = 0.69; P = 0.03) and from coronary artery disease was 26% lower (RR = 0.74; P = 0.07) for patients dialyzed with MC/SYN membranes. No statistically significant difference (all P > 0.1) was found in mortality risk from cerebrovascular disease (RR = 1.08), other cardiac causes (RR = 0.86), malignancy (RR = 0.90), or other known causes (RR = 0.82) between patients dialyzed with MC/SYN compared with unmodified cellulose membranes. These results offer support to reported experimental and observational clinical studies that have found that unmodified cellulose membranes may increase the risk for both infection and atherogenesis. Further studies are necessary to evaluate the possibility of confounding factors, compare more specific membrane types, and determine the pathophysiology linking membrane type to cause-specific mortality.

Data from the US Renal Data System (USRDS) document a substantial reduction in the use of cellulosic membranes, from approximately 70% in 1990 to less than 20% in 1996. These changes have been accompanied by a reduction in the adjusted mortality of patients with end-stage renal disease (ESRD) in the United States. The possibility that this association between the changes in the nature of the membrane and clinical outcome represents a cause-and-effect relationship is discussed in terms of the known biochemical actions of complement activation, consequent neutrophil and monocyte activation, and clinical studies that have been published comparing membranes with different biocompatibilities. Together, these studies support a role for the changes in the biocompatibility of dialysis membranes in the improvement of ESRD patient mortality in the United States.

The current study was designed first to determine separately the prescribed and delivered dose of dialysis and, second, to determine what factors lead to failure to deliver the prescribed dose of dialysis in patients with acute renal failure (ARF). Forty patients, who collectively underwent 136 dialysis treatments, were studied prospectively at two institutions. The results showed that almost half the prescriptions (49%) were for a Kt/V less than 1.2 and, more importantly, nearly 70% of the treatments delivered a Kt/V less than 1.2, the minimally acceptable dose defined in the Dialysis Outcomes Quality Initiative (DOQI) guidelines for chronic hemodialysis (CHD) patients. Patient predialysis weight was the most important variable associated with a low prescribed and delivered dose of dialysis, as well as lack of delivery of the prescribed dose of dialysis. From the statistical model, it is estimated that for every 10-kg increase in predialysis weight, the chance of prescribing or delivering a Kt/V less than 1.2 increased 4.6- and 1.95-fold, respectively. The lower than prescribed blood flow achieved by the temporary catheters and patients not receiving anticoagulation were variables also associated with not receiving the prescribed Kt/V. It is concluded that patients with ARF are prescribed and receive a dose of dialysis that would be considered inadequate for CHD patients. Until the association between dose of dialysis and outcome is better defined, it would be prudent that both the dialysis prescription and the delivery of dialysis to patients with ARF should be performed with the same care and goals as that currently received by patients with end-stage renal disease (ESRD).

Despite several decades of clinical experience, the mortality rate for patients with acute renal failure (ARF) requiring dialysis remains high, and the evaluation of the patients prognosis has been difficult. To date, the Acute Physiology and Chronic Health Evaluation II (APACHE II) scoring system has been used more frequently for prediction in studies of ARF than any other scoring system, but has not been prospectively validated in controlled multicenter studies of this entity. In a multicenter, prospective, controlled trial evaluating the use of biocompatible hemodialysis membranes (BCMs) in patients with ARF, we evaluated the extent to which the APACHE II scoring system, based on the physiological variables in the 24 hours before the onset of dialysis and the presence or absence of oliguria, is predictive of outcome. Analysis of survival and recovery of renal function for the 153 patients treated in this study show that APACHE II scores are predictive both of survival and recovery of renal function, whether analyzed separately by type of dialysis membrane used (BCM or bioincompatible [BICM]) or for both groups combined (all P < 0.01). There was no evidence of a significant center effect or interaction of APACHE II score with dialysis membrane in our study. After adjusting for the APACHE II score, there was a positive effect of the BCM on both probability of survival (P < 0.05) and recovery of renal function (P < 0.01). In patients dialyzed with BCMs, oliguria at onset of dialysis had an adverse effect on both survival and recovery of renal function (both P < 0.01). Receiver operator curves (ROCs) using APACHE II score and the use of BCMs in nonoliguric patients yielded a statistically significant improvement versus the use of APACHE II score alone in the area under the curve (AUC) for survival (0.747 to 0.801; P < 0.05) and recovery of renal function (0.712 to 0.775; P < 0.05). We conclude that the use of the APACHE II score determined at the time of initiation of dialysis for patients with ARF is a statistically significant predictor of patient survival and recovery of renal function. The use of the APACHE II score measured at the time of dialysis initiation, especially when modified by the presence or absence of oliguria, should help in predicting outcome when evaluating interventions for patients with ARF.

Bleeding and platelet dysfunction are prominent features of uremia. Sh ear-induced platelet aggregation (SIPA) involves the interaction of von Willebrand factor (vWF) with platelet membrane glycoproteins (GP) Ib and IIb-IIIa, the same receptor-ligand pair involved in in vivo adhesion and aggregation of platelets in the arterial circulation. We have used a modified rotational cone-plate viscometer to measure SIPA and calcium flux in platelets. Flow cytometric analysis of the surface expression of GP Ib and IIb-IIIa was performed using flourescein isothiocyanate-conjugated monoclonal antibodies CD42b and CD41a, respectively. Uremic patients showed decreased SIPA (controls, 43% +/- 2% [mean +/- SEM]; chronic renal failure patients, 36% +/- 3%; chronic hemodialysis patients, 26% +/- 2%; P < 0.001) along with a decrease in GP IIb-IIIa (controls, chronic renal failure patients, and chronic hemodialysis patients, 840 +/- 25, 649 +/- 42, 661 +/- 38 mean flourescence intensity, respectively; P < 0.0001). Glycoprotein Ib in uremic patients was not significantly different from normal. Chronic hemodialysis patients also demonstrated increased platelet-bound fibrinogen (P < 0.001) and platelet-bound vWF (p < 0.01). Calcium flux and thromboxane B(2) generation during SIPA of uremic platelets was normal. However, uremic plasma showed twice the normal concentration of vWF (P < 0.001) and sodium dodecyl sulfate agarose gel electrophoresis revealed the presence of fibrinogen fragments. Mixing experiments demonstrated an inhibitory effect of uremic plasma on SIPA of normal platelets (decreased from 39% +/- 3% at baseline to 31% +/- 3% after incubation in uremic plasma) along with an activation-independent increase in platelet-bound fibrinogen and platelet-bound vWF. When uremic platelets were incubated in normal plasma, their SIPA increased from 12% +/- 5% at baseline to 18% +/- 4% after incubation in normal plasma; (P = 0.002), although it did not return to normal. These results suggest that the uremic platelet dysfunction results from decreased GP IIb-IIa availability due to receptor occupancy by fibrinogen fragments (and possibly vWF fragments).

Protein and calorie malnutrition often starts before initiation of dialysis, and reflects the anorexia and the catabolic state of chronic renal failure. In the face of inadequate dialysis, which perpetuates the uremic state, malnutrition often worsens. Several studies, though not all, suggest that optimal dialysis improves nutritional status of dialysis patients. Such optimal dialysis now must include the use of biocompatible membranes to deliver Kt/V > 1.4 (urea reduction ratio > 65%). Additional interventions can include the use of enteral or intravenous hyperalimentation, and recombinant growth factors such as growth hormone or insulin-like growth factor-1. Importantly, studies to document the improvement in the morbidity and mortality of patients with these interventions are still needed and require large multicenter trials.

Bleeding is a prominent feature of uremia and remains a significant cause of morbidity in hemodialysis (HD)-dependent patients. To measure the impact of the HD procedure, we performed a prospective cross-over study in eight patients placed consecutively for 2-week periods each on low-flux biocompatible polymethylmethacrylate, low-flux complement-activating cuprophane, and high-flux biocompatible polysulfone membranes. The primary measure of platelet function studied was shear-induced platelet aggregation (SIPA), which has been shown to be a physiologically relevant marker of platelet function and involves the interaction of von Willebrand factor (vWf) with platelet membrane glycoproteins (GP) Ib and IIb-IIIa. Flow-cytometric analysis of the surface expression of platelet membrane GP Ib and GP IIb-IIIa was performed using fluorescein isothiocyanate (FITC)-conjugated monoclonal antibodies CD42b and CD41a, respectively. Multivariate analysis did not demonstrate a statistically significant effect of the type of dialysis membrane on platelet aggregation, calcium flux, or thromboxane B2 production. There was a marked decrease of SIPA in HD patients (pre-HD, mean +/- SEM, 19% +/- 3%) compared with normal controls (43% +/- 3%, P < 0.001), with a further decrease after the HD procedure (post-HD, 12% +/- 2%, P = 0.015 compared with pre-HD). This intradialytic decrease in SIPA correlated with a decrease in GP Ib (pre-HD, 385 +/- 21 mean fluorescence intensity [MFI]; post-HD, 285 +/- 21 MFI, P = 0.0001). GP IIb-IIIa was also significantly decreased post-HD (pre-HD, 1,022 +/- 70 MFI; post-HD, 881 +/- 64 MFI, P = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Iron supplementation is required by most dialysis patients receiving recombinant human erythropoietin. The efficacy of oral iron is variable in these patients, and many require the use of intravenous iron dextran to maintain adequate iron levels, defined as transferrin saturation greater than 20%, serum ferritin greater than 100 ng/mL, and serum iron greater than 80 micrograms/dL. To determine the efficacy of different oral iron preparations in maintenance of iron status, we prospectively studied 46 recombinant human erythropoietin-treated patients and randomized them to receive different oral iron preparations. These four preparations included Chromagen (ferrous fumarate; Savage Laboratories, Melville, NY), Feosol (ferrous sulfate; SmithKline Beecham, Inc, Pittsburgh, PA), Niferex (polysaccharide; Central Pharmaceuticals, Inc, Seymour, IN), or Tabron (ferrous fumarate; Parke-Davis, Morris Plains, NJ). All patients were prescribed approximately 200 mg of elemental iron daily of their assigned iron preparation with at least 100 mg ascorbic acid daily for 6 months. At baseline and bimonthly during the study, serum iron, transferrin saturation, ferritin, hematocrit, and recombinant human erythropoietin dose were monitored; in addition, compliance and side effects were recorded by patient interview. All patients were able to maintain target hematocrit during the 6 months of study. However, there were differences in the trends of serum iron, percent transferrin saturation, and ferritin when considered singly or in combination between the four groups of iron medications. The percent of laboratory values measured over the study period in each group that met the criteria of transferrin saturation more than 20% was greatest in the Tabron group (58%), followed by the Feosol (47%), Chromagen (33%), and Niferex (31%) groups.(ABSTRACT TRUNCATED AT 250 WORDS)

The annual mortality rate of patients on hemodialysis in the United States is 24.3%, substantially higher than the mortality of age-matched patients in Europe and Japan. Differences in the dose of dialysis received by US patients has been proposed as an important factor contributing to this high mortality rate. We undertook a prospective effort to increase the dose of dialysis delivered to 130 patients treated at an urban dialysis center affiliated with Vanderbilt University. From 1988 to 1991 the dose of dialysis, represented by the urea kinetic modelling parameter Kt/V (K = dialyzer clearance, t = dialysis time, V = volume of distribution of urea), has been gradually increased from a dose of 0.82 +/- 0.32 to 1.33 +/- 0.23. Concurrent with this increase, there was a reduction of the gross annual mortality rate from 22.8% in 1988 to 9.1% in 1991. To account for potential differences in patient characteristics during those years, we also calculated the number of expected deaths, based on data from the United States Renal Data System. The ratio of observed to expected deaths, termed the "standardized mortality rate," decreased from a value of 1.03 in 1988 to a value of 0.611 in 1991. In addition, the number of hospital days per patient per year decreased from 15.2 d/patient/yr to 10.3 d/patient/yr. We conclude that increasing the dose of delivered dialysis decreases the hospitalization and mortality rates of hemodialysis-dependent patients.

The United States end-stage renal disease (ESRD) population is growing progressively older. As a percentage of the overall ESRD population, the number of patients 65 years of age and older approached 40% by 1989. However, the percentage of ESRD patients with a functioning transplant was only 2.7% in this age group. Success of transplantation in geriatric ESRD patients over the last decade is due to improved patient selection as well as the use of cyclosporine A and lower doses of corticosteroids, with the achievement of 1-year patient and graft survival rates of 85% and 75%, respectively. For patients older than 60 or 65 years, the 5-year "functional" graft survival is 55% to 60%. Although overall results are excellent, the management of transplantation in the elderly requires an understanding of pharmacology, immunology, and physiology peculiar to this age group. Since the elderly have a degree of immune incompetence, they require less aggressive immunotherapy. Elderly patients have decreased hepatic enzyme activity, especially the P450 system, and therefore require a lower cyclosporine dose. Although elderly patients experience less rejection episodes than younger patients, graft loss in the elderly transplant recipient is due mainly to patient death. Most common causes of death in the elderly transplant recipient are cardiovascular disease and infection related to peaks of immunosuppression. Shortage of cadaver kidneys and limited life expectancy of the geriatric ESRD patient make allocation of cadaver kidneys to patients over 70 years (and even 65 years) a controversial issue and an ethical dilemma. Use of elderly cadaver donors (over 55 to 60 years) is associated with inferior success rates and is not an optimal solution to shortage of cadaver kidneys.

Recent demographic data from the United States and Europe demonstrate that the dialysis population is growing progressively older. In the United States the median age at onset of end-stage renal disease (ESRD) had reached 61 years in 1990, and the fraction of ESRD patients older than 65 years will approach 60% by the year 2000. The primary treatment of geriatric ESRD is center hemodialysis (82% of elderly patients). Chronic peritoneal dialysis in this age group is limited in the United States to less than 10%. Only 2.7% of elderly patients have a functioning transplant. Despite their complex medical and psychosocial conditions, survival and rehabilitation are acceptable in the elderly dialysis patient and these patients tend to be more complaint. Five-year dialysis patient survival rates in the United States are 19% and 10%, respectively, for the 65 to 74 and 75 to 84 age groups compared with 32% and 19%, respectively, for the same age groups in Europe. Five-year survival, particularly in the elderly, is even higher in Japan. Several factors favor the delivery of low doses of hemodialysis in the elderly and discontinuing dialysis is more common in the elderly. Continuous ambulatory peritoneal dialysis is a satisfactory alternative treatment modality for geriatric ESRD. Most studies confirm that survival of elderly patients on continuous ambulatory peritoneal dialysis and hemodialysis is similar. The 1991 United States Renal Data System report showing higher mortality among diabetic continuous ambulatory peritoneal dialysis patients than among hemodialysis patients may reflect selection of such patients, who may have more co-morbid conditions. In special cases, continuous cyclic peritoneal dialysis can be an alternative treatment for elderly ESRD patients.

Malnutrition in hemodialysis patients is associated with increased morbidity and mortality. The use of intradialytic parenteral nutrition (IDPN) to improve nutritional parameters has been shown to be of limited benefit in most studies. We studied the use of recombinant human growth hormone (rHuGH) in potentiating the effects of IDPN in seven hemodialysis patients dialyzed with a Kt/V of 1.03 +/- 0.11 (mean +/- SEM), but with evidence of malnutrition: albumin, 3.2 +/- 0.18 g/dL; transferrin, 215 +/- 30 mg/dL; insulin-like growth factor-1 (IGF-1), 115 +/- 19 ng/mL, protein catabolic rate (PCR), 0.70 +/- 0.05 g/kg/d; and weight, 12.3% +/- 4.0% below ideal body weight. During 6 weeks of IDPN, resulting in an additional 18 +/- 4 kcal and 0.69 +/- 0.03 g of protein/kg body weight per dialysis session, albumin concentration increased to 3.5 +/- 0.14 g/dL (compared with baseline, P = NS), transferrin increased to 279 +/- 36 mg/dL (P < 0.002), IGF-1 increased to 152 +/- 32 ng/mL (P = NS), and PCR increased to 0.81 +/- 0.04 g/kg/d (P = NS). During the next 6 weeks, IDPN administration was continued and rHuGH, at a dose of 5 mg subcutaneously during each dialysis, was added to the regimen. This resulted in an increase in albumin concentration to 3.8 +/- 0.08 g/dL (P < or = 0.04 compared with end of IDPN phase), an increase in transferrin to 298 +/- 41 mg/dL (P = NS compared with end of IDPN phase), and an increase in IGF-1 to 212 +/- 45 ng/mL (P = 0.05 compared with end of IDPN phase).(ABSTRACT TRUNCATED AT 250 WORDS)

Increasing attention has been paid recently to the problem of protein and energy malnutrition and its effects on mortality and morbidity in hemodialysis (HD) patients. Protein deficiency has received more attention than other nutritional problems, largely because its consequences are more easily measured and large population studies have demonstrated the adverse effects of even small decreases in serum albumin on patient's survival. This review discusses these findings and presents other indicators of early malnutrition, which range from static measurements of plasma constituents such as transferrin and insulin-like growth factor 1 (IGF-1), kinetic measurements of protein catabolic rate (PCR) derived from urea kinetic modeling, and noninvasive measurements of body composition. In addition, the predialytic and dialytic factors that influence nutritional status, including the adverse effects of uremia, inadequate dialysis, membrane bioincompatibility, and intercurrent illness requiring hospitalization, as well as socioeconomic factors, are discussed. While some of these are difficult to deal with, the review emphasizes simple interventions that are likely to benefit the patient, including the delivery of optimal dialysis, appropriate choice of medications, and dietary interventions. Once malnutrition is established, parenteral nutrition may reverse the objective evidence of malnutrition, but its effects on survival have not yet been documented. Finally, the review addresses the effects of therapeutic substances such as growth hormone (GH) and erythropoietin (EPO) in combination with nutrients that at present appear to be favorable but are still being evaluated.

Despite technical advances in the delivery of hemodialysis over the past decade, the mortality rate of hemodialysis-dependent, end-stage renal disease (ESRD) patients in the United States remains high. The increase in the number and severity of comorbid conditions of patients entering ESRD is a factor contributing to this high mortality. Nevertheless, there is increasing evidence that the dose of dialysis received by US patients is inadequate and that this plays a major role in the observed high mortality. In this review, we examine some of the parameters used to judge the adequacy of dialysis, as well as factors that can result in differences between prescribed and delivered dose of hemodialysis. Based on available evidence, we propose that for most patients the optimum dose of dialysis, above which further improvement of morbidity and mortality is doubtful, is represented by a delivered dose of dialysis equivalent to a Kt/V of 1.4 or greater, using biocompatible membranes. The prescription of this optimal dose of dialysis must be coupled with an ongoing effort to monitor delivery of the appropriate dose.

Plasma exchange (PE) is considered the most effective nonsurgical treatment modality for the reduction of low-density lipoprotein (LDL) in patients with familial hypercholesterolemia (FH). However, the concomitant reduction of high-density lipoprotein (HDL) and the necessity and cost of using blood products are major drawbacks of PE. We studied the effects of selective LDL reduction using monoclonal anti-LDL antibodies in an investigational immunoadsorption (IA) system. Results were compared with the effects of PE. During the study period, two homozygous FH patients with baseline cholesterol levels greater than 10.34 mmol/L (400 mg/dL) were treated sequentially for a combined total of 37 IA treatments and the results were compared with a total of 19 sequential PE treatments. The IA system consisted of on-line plasma processing over two columns of monoclonal anti-LDL antibodies in alternating cycles of column adsorption and regeneration. No replacement solution was needed. PE was performed with a centrifugal plasma separator using 5% albumin as replacement solution. Results showed that the reduction of lipids with IA was 43% +/- 0.9% for cholesterol, 51% +/- 1.0% for LDL, and 19% +/- 1.3% for HDL, resulting in a reduction in the LDL to HDL ratio of 41% +/- 1.7%. Compared with IA, percent reduction by PE was significantly greater (P less than 0.001) for all lipids, but was nonselective (cholesterol, 74% +/- 1.0%; LDL, 77% +/- 1.2%; HDL, 73% +/- 2.7%), and therefore the reduction of the LDL to HDL ratio was only 6% +/- 3.6%, which was significantly less than for IA (P less than 0.001). Pretreatment HDL concentration appeared to increase with repetitive IA treatment, but decreased back to prestudy levels with repetitive PE.(ABSTRACT TRUNCATED AT 250 WORDS)

We report on the results of a clinical trial in which 14 transplant candidates were treated with an extracorporeal immunoadsorption system using Protein A that selectively removes immunoglobulin from plasma; we also assessed the dynamics of anti-HLA antibody as a model of IgG removal and re-equilibration, as well as the clinical safety of the procedure. At the end of a treatment course, plasma IgG levels were reduced by 90% +/- 8% of control values (P less than 0.01). In contrast, albumin levels were reduced by only 15% (P less than 0.05). Specific cytotoxic anti-HLA antibody titers were reduced by approximately 18-fold. Panel reactivity was measured as the proportion of a 40-member cell donor panel killed by patients' serum in the presence of complement; in nine of the 14 patients, there was a significant reduction in this parameter (range, 23% to 87%). During the 4-week follow-up period, anti-HLA antibody titers returned to baseline levels. There were no remarkable changes observed in blood chemistries, nor were there any unanticipated adverse reactions seen in the patients treated. We conclude that selective extracorporeal immunoadsorption is a safe and effective way of removing IgG-type antibodies, with potential application to reduction of HLA antibodies in transplant candidates.

Five long-term hemodialysis patients with clinical iron overload were treated with 300 U/kg of recombinant human erythropoietin (rHuEPO) intravenously (IV) after each hemodialysis. The patients were phlebotomized after each hemodialysis at any time the predialysis hematocrit was 35% or greater. Over a period of 1 year, the average phlebotomy rate varied from 0.5 to 1.1 U/wk with a mean phlebotomy rate of 45.8 +/- 5.6 U/yr (range, 27 to 57 U). The mean serum ferritin decreased from 8,412 +/- 1,599 micrograms/L (ng/mL) to 3,007 +/- 1,129 micrograms/L (ng/mL), and the mean iron removal over this period was 9.5 g. Liver iron deposition, as measured by density on computed tomographic (CT) scan, improved, while skin color lightened significantly. Patients tolerated phlebotomy with no major symptoms or complications and exhibited no change in the hemogram or serum chemistries. In patients with severe iron overload, changes in serum ferritin with erythropoietin treatment alone may not reflect true change in iron burden. Use of high-dose erythropoietin and phlebotomy is an effective and safe (at least for 1 year) method of reducing iron overload in long-term hemodialysis patients.

We report on the outcome of six consecutive adult patients who presented with microangiopathic anemia and thrombocytopenia. Clinical parameters on admission included platelet counts less than 45,000/mm3, microangiopathic red blood cell morphology, mental status abnormalities, and in three, rapidly progressive azotemia requiring dialysis. All patients underwent plasma exchange therapy as part of their treatments. Patients with renal failure underwent plasma exchange with a hollow fiber plasma separator, while those without renal failure were treated with a cytocentrifuge. All received fresh frozen plasma as replacement solution and were treated with glucocorticoids as well. For all six patients, plasmapheresis and conventional drug therapy resulted in remission that has lasted for 16 +/- 5 months (range 8 to 24 months). Early cessation of plasmapheresis in two patients resulted in rapid relapse. Patients who required dialysis now have a mean creatinine of 2.0 +/- 0.9 mg/dL (range 1.2 to 3.5). With similar volumes of exchange, and the same number of treatments, less fresh frozen plasma was used in the three patients treated with the hollow fiber separator than in patients treated with the cytocentrifuge (6.3 +/- 3.7 v 14.8 +/- 4.3 U/exchange, P less than 0.05). We conclude that plasmapheresis is a useful therapeutic modality for the treatment of thrombocytopenia and microangiopathic hemolytic anemia. In addition the use of a hollow fiber plasma separator for plasmapheresis is safe and efficient, particularly when concurrent dialysis is required.

Iron overload from repeated transfusions of RBCs in long-term hemodialysis patients is a problem of increasing clinical significance. We report on the prevalence of and diagnostic criteria for identification of hemodialysis patients with iron overload. In 150 unselected hemodialysis patients, 62 (41%) had ferritin levels greater than 2,000 ng/mL (normal = 10 to 360 ng/mL). In 16 of these patients, accurate transfusion histories were obtained and ferritin levels correlated with calculated transfusional iron burden (r = 0.553, P less than .05). These patients could be divided into two distinct groups on the basis of their response to a single dose (2 g, IV) of deferoxamine: "high" responders had twice the level of feroxamine (the chelated product of deferoxamine and iron) of the "low" responders (P less than .001). High responders also had significantly higher prevalence of the "hemochromatosis" alleles A3, B7, and B14 than a large group of dialysis patients awaiting transplantation (71% v 37%, P less than .001). In two patients with iron overload and clinically significant bone disease, bone histology revealed prominent iron staining at the calcification front. We conclude that transfusional iron overload is a significant clinical problem in long-term hemodialysis patients, that may also be associated with bone pathology.

We analyzed biochemical data derived from 911 patients with renal insufficiency observed at our institution for periods up to 7 years. During early renal failure (RF) (creatinine less than 5 mg/dL), the rate of change of hematocrit, total CO2 (tCO2) and urea per unit change of creatinine was significantly higher than during moderate (creatinine between 5 and 10 mg/dL) or advanced (creatinine greater than 10 mg/dL) RF. For example, the rate of change of hematocrit (%, volume/volume [v/v]) was (mean +/- SEM) -2.15 +/- 0.15% for each 1 mg/dL increase in creatinine in the range of creatinine less than 5 mg/dL, whereas for the range of creatinine greater than 10 mg/dL, the rate of change was only -0.48 +/- 0.06% (P less than 0.001). Similarly, the rate of change of tCO2 was -1.68 +/- 0.09 mEq/L for each 1 mg/dL increment in creatinine concentration during early RF, and -0.19 +/- 0.09 mEq/L per unit increase in creatinine during advanced RF (P less than 0.001). Chloride concentration initially increased as a function of creatinine in early RF, but decreased in advanced RF, whereas the anion gap increased throughout the course of RF. Mean serum phosphate concentration also increased steadily, but remained below the upper range of normal (4.7 mg/dL) during early RF without the use of phosphate binders. These data suggest that different biochemical parameters change at different rates as a function of the severity of renal dysfunction, and that although phosphate retention may occur, hyperphosphatemia is not a hallmark of early RF.

Rates of progression of renal failure were calculated for a group of 277 patients who had five or more clinic visits. The goals of therapy in the absence of ongoing immunological processes were control of blood pressure to diastolic pressures less than 85 mm Hg and serum phosphate less than 1.60 mmol/L (5 mg/dL). The mean rate of progression expressed as the slope of the reciprocal creatinine versus time was -0.0054 +/- 0.0009 dL/mg/mo (mean +/- SEM), and the median was -0.00315 dL/mg/mo. Approximately 25% of these patients had rates of progression less than -0.001 dL/mg/mo. The rate of progression was inversely correlated with the creatinine concentration at entry (P less than 0.004) and with the frequency of clinic visits (P less than 0.01). The "renal survival" time from a creatinine of 880 mumol/L (10 mg/dL) to dialysis was 10.0 +/- 1.2 months (mean +/- SEM). These data provide rates of progression for a group of patients without specific dietary intervention but with vigorous control of blood pressure and phosphorus.