Raymond M. Hakim

Vascular access for hemodialysis. Patency rates and results of revision.

Over a 4-year interval, 324 arteriovenous conduits were created in 256 patients with end-stage renal disease as access for chronic hemodialysis. These included 154 Cimino fistulae, 163 polytetrafluoroethylene (PTFE) grafts, and seven miscellaneous grafts. Satisfactory patency rates were demonstrated for as long as 4 years for both Cimino fistulae and PTFE grafts by life-table analysis. Failures of Cimino fistulae usually occurred early in the postoperative period, secondary to attempts to use inadequate veins. Thrombosis caused the majority of PTFE graft failures and was generally the result of venous stenosis. Correction of such venous stenosis is mandatory to restore graft patency and can result in prolonged graft survival.

Malnutrition in Hemodialysis Patients

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 patients 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.

Effect of the Dialysis Membrane in the Treatment of Patients with Acute Renal Failure

BACKGROUND The mortality rate among patients with acute renal failure remains high, and the role of the biocompatibility of the dialysis membrane in the resolution of this disorder is not known. METHODS We prospectively studied 72 patients with acute renal failure who required hemodialysis and assigned them to two treatment groups. One group underwent dialysis with the widely used cuprophane dialysis membrane, which activates the complement system and leukocytes, and the other group underwent dialysis with a synthetic polymethyl methacrylate membrane, which has a more limited effect on complement and leukocytes. Scores on the Acute Physiology, Age, and Chronic Health Evaluation (APACHE II) were calculated at the initiation of dialysis. Survival and the recovery of renal function were determined with the use of proportional-hazards and exact logistic-regression analyses. RESULTS When dialysis was initiated, the patients in the two groups were similar in terms of age, APACHE II scores, the prevalence of oliguria, and biochemical indexes of renal failure. Twenty-three of the 37 patients (62 percent) in the group undergoing dialysis with the polymethyl methacrylate membrane recovered renal function, as compared with 13 of the 35 patients (37 percent) in the group undergoing dialysis with the cuprophane membrane (P = 0.04 after adjustment for the APACHE II score). The median number of dialysis treatments required before the recovery of renal function was 5 in the former group and 17 in the latter group (P = 0.02). Twenty-one patients (57 percent) undergoing dialysis with the polymethyl methacrylate membrane survived, as compared with 13 patients (37 percent) undergoing dialysis with the cuprophane membrane (P = 0.11). Of the 20 patients in each group who initially had nonoliguric acute renal failure, the survival rates were 80 percent with the polymethyl methacrylate membrane and 40 percent with the cuprophane membrane (P = 0.01). CONCLUSIONS Among patients with acute renal failure requiring hemodialysis, the use of the polymethyl methacrylate membrane, as compared with the cuprophane membrane, resulted in improved recovery of renal function.

Warfarin Use Associates with Increased Risk for Stroke in Hemodialysis Patients with Atrial Fibrillation

Use of warfarin, clopidogrel, or aspirin associates with mortality among patients with ESRD, but the risk-benefit ratio may depend on underlying comorbidities. Here, we investigated the association between these medications and new stroke, mortality, and hospitalization in a retrospective cohort analysis of 1671 incident hemodialysis patients with preexisting atrial fibrillation. We followed patient outcomes from the time of initiation of dialysis for an average of 1.6 yr. Compared with nonuse, warfarin use associated with a significantly increased risk for new stroke (hazard ratio 1.93; 95% confidence interval 1.29 to 2.90); clopidogrel or aspirin use did not associate with increased risk for new stroke. Analysis using international normalized ratio (INR) suggested a dose-response relationship between the degree of anticoagulation and new stroke in patients on warfarin (P = 0.02 for trend). Warfarin users who received no INR monitoring in the first 90 d of dialysis had the highest risk for stroke compared with nonusers (hazard ratio 2.79; 95% confidence interval 1.65 to 4.70). Warfarin use did not associate with statistically significant increases in all-cause mortality or hospitalization. In conclusion, warfarin use among patients with both ESRD and atrial fibrillation associates with an increased risk for stroke. The risk is greatest in warfarin users who do not receive in-facility INR monitoring.

Increased Expression of an Adhesion-Promoting Surface Glycoprotein in the Granulocytopenia of Hemodialysis

To identify the mechanisms accounting for hemodialysis-induced granulocytopenia, we undertook quantitative kinetic studies of a granulocyte-adhesion-promoting surface glycoprotein (Mo1). In eight patients undergoing maintenance hemodialysis, there was a fivefold increase in the mean cell-surface expression of Mo1 within 15 minutes after the start of dialysis with a new cuprophane membrane. The peak increase in surface Mo1 coincided with the maximal drop in neutrophil count and with the peak rise in the plasma levels of the complement-activation products C5a desArg and C3a desArg. During dialysis on a membrane being reused for the fifth time, no significant complement activation, no increase in Mo1 expression, and no change in neutrophil count were seen. C5a desArg (but not C3a desArg) induced a comparable increase in Mo1 expression on normal granulocytes in vitro at concentrations similar to those measured in vivo. Chemotactic peptide-induced granulocyte aggregation (a reflection of increased cell-to-cell adhesiveness) was specifically blocked by mouse monoclonal antibodies to Mo1 in vitro. These data suggest that the increased expression of Mo1 on granulocytes in vivo is in part mediated by C5a (and C5a desArg). The quantitative increase in granulocyte-surface Mo1 may provide a mechanism for initiating leukoaggregation, sequestration of granulocytes, and neutropenia during hemodialysis.

Intradialytic parenteral nutrition improves protein and energy homeostasis in chronic hemodialysis patients

Decreased dietary protein intake and hemodialysis-associated protein catabolism are among several factors that predispose chronic hemodialysis (CHD) patients to protein calorie malnutrition. Since attempts to increase protein intake by dietary counseling are usually ineffective, intradialytic parenteral nutrition (IDPN) has been proposed as a potential therapeutic approach in malnourished CHD patients. In this study, we examined protein and energy homeostasis during hemodialysis in seven CHD patients at two separate hemodialysis sessions, with and without IDPN administration. Patients were studied 2 hours before, during, and 2 hours following a hemodialysis session, using a primed constant infusion of L-(1-(13)C) leucine and L-(ring-(2)H(5)) phenylalanine. Our results showed that IPDN promoted a large increase in whole-body protein synthesis and a significant decrease in whole-body proteolysis, along with a significant increase in forearm muscle protein synthesis. The net result was a change from an essentially catabolic state to a highly positive protein balance, both in whole-body and forearm muscle compartments. We conclude that the provision of calories and amino acids during hemodialysis with IDPN acutely reverses the net negative whole-body and forearm muscle protein balances, demonstrating a need for long-term clinical trials evaluating IDPN in malnourished CHD patients.

Oxidative stress in uremia.

Purpose of reviewOxidative stress has been described as ‘a disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. In uremic patients, an increase in oxidative stress may occur because of the loss of residual renal function, and may be exacerbated by dialysis. This review will focus on the emerging biochemical evidence of an increase in oxidative stress in uremic patients, the relationship with renal replacement therapy, and the potential linkages to acute-phase inflammation, malnutrition, and adverse cardiovascular outcomes in uremic patients. Recent findingsMany studies from multiple research laboratories around the world have recently utilized in-vivo biomarkers to describe increased oxidative stress in uremic patients. An emerging literature suggests that there are links between an increase in oxidative stress, endothelial dysfunction, an increase in acute-phase inflammation, and an accelerated risk of cardiovascular complications in dialysis patients. Additional uremia-associated metabolic abnormalities, including hyperhomocysteinemia, intravenous iron exposure, and biocompatibility changes related to dialysis, may contribute to an increase in oxidative stress. Finally, two well-conducted pilot clinical randomized trials have suggested that antioxidant therapy may have efficacy in reducing cardiovascular events in uremic patients. SummaryThe implications of the findings of a generalized increase in oxidative stress associated with uremia have led to the suggestion that antioxidative therapy may be efficacious in reducing cardiovascular complications. Pilot studies have suggested potential efficacy for this approach. However, further large-scale randomized clinical trials will be required to establish a compelling, evidence-based approach to the use of antioxidants in patients with uremia.

Anticoagulant and Antiplatelet Usage Associates with Mortality among Hemodialysis Patients

Many prescribe anticoagulants and antiplatelet medications to prevent thromboembolic events and access thrombosis in dialysis patients despite limited evidence of their efficacy in this population. This retrospective cohort study examined whether use of warfarin, clopidogrel, and/or aspirin affected survival in 41,425 incident hemodialysis patients during 5 yr of follow-up. The prescription frequencies for warfarin, clopidogrel, and aspirin were 8.3, 10.0, and 30.4%, respectively, during the first 90 d of initiating chronic hemodialysis. Compared with the 24,740 patients receiving none of these medications, Cox proportional hazards analysis suggested that exposure to these medications was associated with increased risk for mortality (warfarin hazard ratio [HR] 1.27 [95% confidence interval (CI) 1.18 to 1.37]; clopidogrel HR 1.24 [95% CI 1.13 to 1.35]; and aspirin HR 1.06 [95% CI 1.01 to 1.11]). The increased mortality associated with warfarin or clopidogrel use remained in stratified analyses. A covariate- and propensity-adjusted time-varying analysis, which accounted for longitudinal changes in prescription, produced similar results. In addition, matching for treatment facility and attending physician revealed similar associations between prescription and mortality. We conclude that warfarin, aspirin, or clopidogrel prescription is associated with higher mortality among hemodialysis patients. Given the possibility of confounding by indication, randomized trials are needed to determine definitively the risk and benefit of these medications.

Efficacy of oral iron therapy in patients receiving recombinant human erythropoietin

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)

Hemodialysis-associated platelet activation and thrombocytopenia

The interactions between platelets and dialysis membranes were studied prospectively in 10 patients undergoing long-term stable dialysis. Transient but significant thrombocytopenia and platelet activation were found during dialysis with the commonly used cuprophane membrane. Platelet counts decreased from 231 +/- 21 X 10(3)/mm3 before dialysis to 127 +/- 28 X 10(3)/mm3 at 90 minutes following initiation of dialysis (p less than or equal to 0.007). Thromboxane B2, an index of platelet activation, also increased from a baseline level of 1.06 +/- 0.2 pg/10(6) platelets to 7.3 +/- 3.0 pg/10(6) platelets at 90 minutes (p less than or equal to 0.04). Cuprophane membranes were also shown to induce complement activation with C3a desArg, the stable derivative of C3 activation, showing a threefold increase from baseline 15 minutes after initiation of dialysis. In contrast, during dialysis with a non-complement-activating dialyzer membrane, polymethylmethacrylate, thrombocytopenia and platelet activation were not observed. These data suggest that platelet activation and thrombocytopenia during hemodialysis are associated with complement activation during hemodialysis in a manner similar to dialysis-associated neutropenia.