SummaryRecently, hirudin was used for the first time as an anticoagulant during hemodialysis in men. Pharmacokinetic data of this compound in end-stage renal failure are however not available. In this study, the pharmacokinetics of recombinant hirudin (HBW 023) was evaluated in hemodialysis-treated end-stage renal failure patients. HBW 023 was administered as a bolus at the start of a single dialysis (0.02 to 0.08 mg/kg) in 20 patients, and plasma hirudin levels were followed during this and the 5 following dialyses, without additional hirudin administration. The initial dialysis (HDj) was performed with a low flux polysulfone dialyzer; the following dialyses (up to HD6) with a high flux polysulfone dialyzer and regular heparin. Hirudin levels averaged 504.0 ± 214.0 and 527.7 ± 217.1 ng/ml in the middle and at the end of HDj, and then gradually decreased to 15.2 ± 15.2 ng/ml at the end of HD6. Pharmacokinetic data were compared to those obtained in healthy controls (n = 5), receiving the same dose, and reaching the same peak hirudin level. Hirudin half-life was >30 times longer in hemodialysis patients (51.8 ± 15.6 vs. 1.7 ± 1.5 h, p <0.001), whereas area under the curve was >60 times higher (34,669 ± 14,898 vs. 545 ± 205 ng/ml X h, p <0.001). Distribution volume was lower in hemodialysis patients (11.0 ± 3.1 vs. 14.1 ± 2.0 1, p <0.05). Hirudin disappearance rate was the same during high flux polysulfone dialysis as during interdialytic periods. Hirudin removal was markedly higher in those patients still maintaining some residual renal function and parameters of hirudin removal were significantly correlated to residual creatinine clearance. It is concluded that hirudin removal from the body is markedly depressed in hemodialyzed end-stage renal failure patients and that even minor residual renal function may increase this removal rate.

Implementation of the current guidelines for referral of CKD patients to nephrologists would lead to an overload of the nephrology care capacities. Large differences in estimated GFRs with different corrections for serum creatinine are observed, resulting in important CKD classification differences. Standardization of serum creatinine assays is mandatory before guidelines, and especially the routine provision of the estimated GFR by the abbreviated MDRD formula, can be implemented in clinical practice.

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The evolution of extracorporeal treatment of end-stage renal failure has enforced focus on the purity of dialysis fluid. A major challenge of high-flux haemodialysis (HD) and haemodiafiltration relates to the necessity for ultrapure dialysis fluid and for sterile non-pyrogenic substitution fluid. The present review focuses especially on the possible microbial contamination including, next to intact micro-organisms, a variety of microbial derivatives. It is pointed out that there are conditions (e.g. contamination by non-culturable micro-organisms or bacterial derivatives other than lipopolysaccharides) where the detection of biologically relevant contaminants can be missed when applying the recommended standard detection methods such as bacterial culture and limulus amoebocyte lysate test. Possible approaches for action upon positive sampling results, exceeding the levels recommended in the latest ISO 11663:2009, are described in detail and illustrated with flow charts. The issue of purity of dialysis fluids is highly relevant, since the chronic exposure of HD patients to low levels of cytokine-inducing microbial components can significantly contribute to the micro-inflammatory status of these patients.

The first experience with hirudin as an alternative anticoagulant for heparin in hemodialysis is reported. Recombinant hirudin (HBW 023) was administered in 20 patients as a bolus before dialysis with low flux polysulfone dialyzers (PS400), the dosage being adapted stepwise from patient to patient by 0.02 mg/kg to the occurrence of clotting or bleeding. Four different administration schedules were studied. The first three schedules (0.02 mg/kg, N = 1; 0.04 mg/kg, N = 1; 0.06 mg/kg, N = 4) were discontinued because of clotting. The 0.08 mg/kg schedule was maintained without clotting event in 14 patients. Bleeding was not observed. Plasma hirudin averaged 503.9 +/- 214.0 and 527.7 +/- 217.1 ng/ml after two and four hours of dialysis, and decreased during an interdialytic interval of 44 hours to 223.2 +/- 86.2 ng/ml. Modified antithrombin III (P < 0.05) and activated partial thromboplastin times were lower (P < 0.01) under hirudin compared to heparin; these coagulation parameters were closer to normal during hirudin treatment. The patients developing clotting could be distinguished from those without clotting by the registration of the activated clotting times (9.2 +/- 3.0 vs. 18.7 +/- 3.2 min after 2 hr, P < 0.01; 8.1 +/- 3.0 vs. 16.2 +/- 3.8 min after 4 hr of dialysis, P < 0.05); cut-off value below which clotting is to be expected was 12 min). It is concluded that administration of hirudin as a bolus before the start of dialysis, at a dosage of 0.08 mg/kg, is not complicated by clotting or by bleeding. Coagulation tendency can optimally be monitored by the registration of the activated clotting time.(ABSTRACT TRUNCATED AT 250 WORDS)

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Anemia negatively impacts cardiovascular comorbidity and hospitalization. In animals, recombinant erythropoietin (RhuEPO) leads to faster recovery after acute tubular necrosis. This study evaluates the effect of RhuEPO (Recormon, Hoffman-La Roche, Basel, Switzerland) on the correction of anemia and kidney function after renal transplantation. Patients receiving a renal transplant were randomized to receive or not receive RhuEPO 100 U/kg three times per week if the hemoglobin (Hb) level was less than 12.5 g/dL. The time to reach an Hb level greater than 12.5 g/dL was 66.5+/-14.5 days versus 52.6+/-23.7 days in the non-EPO and EPO groups, respectively (P=0.05). After 3 months, Hb levels were not different between the non-EPO and EPO groups (12.6+/-1.5 g/dL vs. 12.0+/-1.5 g/dL, respectively), although there was a higher increase in the EPO group (4.1+/-1.1 g/dL vs. 3.2+/-1.1 g/dL, P=0.02). In a Cox regression analysis, EPO use (relative risk 7.2, P=0.004) and dose (relative risk=0.63, P=0.04) were retained as independent variables predicting the time to reach an Hb level greater than 12.5 g/dL. In the EPO group, 14 of 22 patients reached the target Hb level of more than 12.5 g/dL versus 12 of 18 patients in the non-EPO group (P=not significant). Serum creatinine levels were not different between groups. RhuEPO in the immediate posttransplantation period seems to have no relevant clinical impact on the correction of anemia. There was no difference in the evolution of serum creatinine levels. In view of the cost, the use of RhuEpo in the posttransplantation period should be limited to high-risk patients.

In this in-vivo study, dialysate and serum endotoxin was evaluated before and after haemodialysis with small-pore (PS400) and large-pore (PS600) polysulphone dialysers, and before and after haemodiafiltration with the PS600 filter. The source of the endotoxin was the presence in dialysate of Pseudomonads at a concentration of 10(3)-10(4) CFU/ml. Endotoxin was measured by a modified chromogenic limulus amoebocyte lysate (LAL) assay. In spite of dialysate endotoxin concentrations greater than 100 pg/ml, no changes in pre- versus posttreatment LAL reactivity were observed in PS400 dialysis and PS600 haemodiafiltration. In contrast, PS600 haemodialysis was related to an increase in serum LAL reactivity from 1.3 +/- 1.5 to 3.8 +/- 2.0 pg/ml (n = 15, P less than 0.01), and five patients (33.3%) showed a post-dialysis value in excess of 5 pg/ml. Our data are consistent with the absence of in-vivo endotoxin transfer during haemodialysis with small-pore dialyser membranes, and during haemodiafiltration with membranes with larger pores. An increase in LAL reactivity during haemodialysis with membranes with larger pores is, however, present, presumably due to the occurrence of backdiffusion/filtration with that specific strategy.