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.

Leukocyte response to phagocytic challenge was assessed in uremic and hemodialysis patients in a prospective and cross sectional study. Using latex, zymosan and staphylococcus as phagocytic challenge, the utilization of glucose-I-C14 and the generation of reactive oxygen species was measured in these patients. In uremic, non-dialysis dependent patients, the response to phagocytosis was significantly reduced when creatinine exceeded 6 mg/dl and prior to initiation of dialysis (mean serum creatinine 9.3 +/- 0.3 mg/dl) was less than half that of patients with normal renal function (P less than 0.01). In a prospective study of 15 patients initiated on dialysis, the metabolic response of their leukocytes was assessed sequentially. In eight patients, initiation of dialysis with cuprophane (Cu) membrane lead to a further decline (60%) in their metabolic response to phagocytosis at the end of four weeks of dialysis compared to pre-initiation of dialysis (P less than 0.01), whereas in seven other patients, dialysis with non-complement activating membranes did not result in a significant decline. Prospective cross-over studies of chronic hemodialysis patients corroborated these findings; eight patients dialyzed with new CU membranes had a significant decline of their metabolic response to phagocytic challenge acutely at the end of each dialysis and in pre-dialysis samples after two weeks of Cu dialysis, whereas their response returned back to baseline after two weeks of dialysis with non-complement activating membrane. In prospective and cross sectional studies, a decreased response to phagocytic stimulus was a predictor of hospitalization, primarily for infectious reasons.(ABSTRACT TRUNCATED AT 250 WORDS)

In this study, changes of protein binding of nine drugs were evaluated. In addition, theophylline and phenytoin, the two drugs with the most substantial and progressive decrease in protein binding, were further studied by high performance liquid chromatography (HPLC)-fractions of ultrafiltrate of normal and uremic serum, in an attempt to identify substances causing drug protein binding inhibition. There was a marked decline of the protein binding of theophylline, phenytoin and methotrexate (dialyzed patients vs. normals: -20.1, -16.0 and -15.1%, respectively). There was a rise in the protein binding of propranolol, cimetidine and clonidine. The changes observed for diazepam, prazosin and imipramine were less marked. For phenytoin, theophylline, methotrexate and diazepam, protein binding was inversely correlated to the serum creatinine (r = 0.87, 0.80, 0.79 and 0.67, P less than 0.001), and a less pronounced but still significant positive correlation was found for clonidine (r = 0.46, P less than 0.01). Ultrafiltrate, obtained during a hemofiltration session, inhibited protein binding of theophylline and phenytoin in a dose dependent way. After separation of this ultrafiltrate by HPLC, it appeared that for both theophylline and phenytoin at least a part of this inhibitory activity corresponded to the elution zone of hippuric acid. For theophylline two other inhibitory zones were further recognized: one corresponding to the elution zone of NaCl and one in which the responsible substance remained unidentified. Hippuric acid in solution inhibited protein binding of theophylline and phenytoin in a dose dependent way. In conclusion, protein binding of several drugs currently used in renal failure is affected in parallel with renal function, which might affect the therapeutic effectiveness of the drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

This study reports on the five years' evolution of the KT/V urea index and protein catabolic rate (PCR) in 16 CAPD patients who were treated with a constant daily dialysis dose. Total KT/V urea index decreased with time from a value of 0.96 +/- 0.06 at the start to 0.55 +/- 0.05 at five years of treatment. This decline was due to the opposite changes of two important parameters affecting the index. First, the contribution of the residual urinary KT/V gradually decreased from 28.6% at the start to 8 to 9% after four years. Second, the distribution volume of urea calculated as a constant fraction of body weight gradually increased. The body weight increased from 58.2 +/- 2.79 kg at start to 70.6 +/- 3.33 kg at five years. Peritoneal urea clearances and ultrafiltration rates remained stable. In 12 patients with stable body weight between 24 and 48 months, PCR decreased from 0.98 +/- 0.05 to 0.87 +/- 0.05 g/kg/day. A positive correlation between KT/V urea and PCR and a negative correlation between KT/V urea and number of hospitalization days, peritonitis rates and peripheral nerve conductivity was found. The same negative correlation was found when only the KT/V urea index obtained during the first year of treatment was considered. In conclusion, the KT/V urea index decreases in CAPD patients primarily because residual renal function decreases and body weight increases, while the peritoneal clearing for urea is maintained. The index correlates with some clinical parameters, and may have some prognostic value.

It is generally recognized that the uremic syndrome results in a depression of immune function, but the uremic solutes responsible remain largely unidentified. In this study, the effect of 18 known uremic retention solutes, including urea and creatinine, on hexose monophosphate shunt (HMS)-dependent glucose-1-C14 utilization (G1C-U), chemiluminescence production (CL-P) and flow cytometric parameters (FCP) of respiratory burst and phagocytosis were evaluated in granulocytes and/or monocytes. Among the compounds studied, only p-cresol depressed whole blood respiratory burst reactivity (G1C-U, CL-P) dose dependently at concentrations currently encountered in end-stage renal disease (ESRD) (P < 0.05 from 5 micrograms/ml on). The effect of p-cresol was enhanced by increasing incubation times from 10 to 120 minutes. HMS activity of isolated packed erythrocytes remained unaffected. FCP of respiratory burst activity (Bursttest, expressed as log fluorescence units, LFU) revealed a marked depression in the presence of p-cresol (from 700 +/- 167 to 291 +/- 128 LFU for granulocytes, from 278 +/- 102 to 146 +/- 52 LFU for monocytes, P < 0.01), whereas particle ingestion (Phagotest) remained unaffected. Cell-free myeloperoxidase activity was also markedly depressed in the presence of p-cresol. Polarity based HPLC-elution of a standard solution containing all the solutes studied, using a gradient from 100% formic acid to 100% methanol during 60 minutes, revealed elution of p-cresol after 46.6 minutes, pointing to its relative hydrophobicity. Conjugation of p-cresol to p-cresylsulfate anihilated the depressive effect of p-cresol on granulocyte function, and at the same time caused a shift in HPLC-elution pattern to a less lipophilic range.(ABSTRACT TRUNCATED AT 250 WORDS)