Single-dose pharmacokinetics of cefpirome in patients receiving hemodialysis and in patients treated by continuous ambulatory peritoneal dialysis.

Cefpirome is eliminated primarily by renal excretion, compelling dosage reduction in kidney failure. We studied the elimination kinetics after intravenous administration of 1 gm cefpirome in patients undergoing hemodialysis (n = 9) and after intravenous (n = 6) or intraperitoneal administration (n = 6) of 1 gm cefpirome in subjects treated by continuous ambulatory peritoneal dialysis (CAPD). Four hours of hemodialysis removed 48% +/- 9% of the drug present in the body at the start of hemodialysis. Consequently, a supplementary dose equal to 50% of the daily dose recommended in end stage renal disease (ESRD) should be administered after each hemodialysis treatment. In patients receiving CAPD, therapeutic levels in both serum and dialysate were reached after intravenous and intraperitoneal administration. The bioavailability after intraperitoneal administration was 84%. After systemic administration, the elimination of cefpirome in the dialysate was negligible. Consequently, systemic dosage of cefpirome in patients receiving CAPD and in patients with ESRD should be identical.

Diquat intoxication: report of two cases and review of the literature.

Animal experiments have suggested that diquat is less toxic than the more widely used paraquat. In this paper, nine previously reported cases of diquat intoxication are reviewed, together with the description of our personal observations in two additional patients. These two patients, like four other patients described in the literature, died from complications involving the gastrointestinal tract, brain and kidneys. Thus, diquat intoxication is apparently not as innocent as was originally thought. In this paper, special attention has been given to the major clinical differences between diquat and paraquat intoxication. In contrast with the latter, severe diquat intoxication induces gastrointestinal fluid sequestration and is associated with cerebral hemorrhagic lesions and a higher incidence of severe acute renal failure. Despite an asymptomatic clinical interval of up to 48 hours after ingestion, hemoperfusion should be started as soon as possible to prevent toxic levels of diquat in tissue.

Pharmacokinetics of recombinant hirudin in hemodialyzed end-stage renal failure patients.

Recently, 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 (HD1) 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 HD1, 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 +/- 2.01, 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.

Ofloxacin pharmacokinetics in chronic renal failure and dialysis.

Data on the pharmacokinetics of ofloxacin in chronic renal failure, in patients who were not dialysed or were receiving haemodialysis or continuous ambulatory peritoneal dialysis (CAPD), are reviewed. In addition, a large pool of data obtained in patients with a wide range of renal dysfunction is provided. The good absorption of ofloxacin after oral administration is not influenced by renal failure. Total plasma clearance (CL) is largely dependent on renal elimination of the drug, and renal clearance (CLR) and urinary recovery are reduced in parallel with reductions in renal function. Consequently, the serum half-life progressively increases when creatinine clearance decreases. Although there is wide variation in the published absolute values for the CL and CLR of ofloxacin, all studies show a similar pattern in the pharmacokinetic behaviour of the drug in chronic renal failure. A proposed protocol for ofloxacin dosage adjustment in chronic renal failure is reported which differs slightly but significantly from that recommended by the manufacturer. This new dosage regimen was derived from the pharmacokinetic results after single and multiple oral administration of the drug to patients with chronic renal failure. Since no clinically relevant losses of ofloxacin occur during haemodialysis or continuous ambulatory peritoneal dialysis (CAPD), the same protocol should be followed in these patients as in undialysed patients with terminal chronic renal failure.

Membrane plasma exchange in patients with metastatic cancer.

Seven patients suffering from metastatic cancer and all showing objectively measurable tumours were treated with eight sessions of membrane plasma exchange. No other oncological treatment was administered during the period of plasma exchange. The procedure itself was well tolerated and subjective improvement was reported by some patients. No objective tumour regression was observed. Immune complex-like material and inflammatory proteins were efficiently removed. In some patients a decrease in the number of T lymphocytes, due to relative depletion of T mu cells, was noted.

An update on uremic toxins.

The author reviews trends and evolution in biochemical methodology, clinical symptomatology description, experimental models and definitions of uremic toxins. The assumption is made of one specific toxic effect for one specific toxin.

Polymorphonuclear cell function and infection in dialysis.

End-stage renal disease is characterized by enhanced susceptibility for infectious diseases, carrying an important risk of morbidity and mortality. In the host's defense against bacterial infection, a central role is played by phagocytic ingestion of bacteria, followed by their destruction after metabolic production of oxygen free radical species. Our studies have concentrated on the energy delivery by the hexose monophosphate shunt (HMS) to NAD(P)H-oxidase, the enzyme responsible for free radical production. This evaluation was realized by measuring, in whole blood, the CO2 produced from standard quantities of radiolabeled glucose, with data normalized for the number of polymorphs in each sample. Our studies indicate that: (1) glycolysis is disturbed in uremic outpatients from a SCrea of 6 mg/dl and a CCr of 15 ml/min; (2) similar functional disturbances are found in pre-dialysis blood samples of hemodialyzed patients; (3) this functional disturbance is further intensified during dialysis with cuprophan, which is not the case for non-complement activating dialyzers; (4) the response is especially suppressed towards Staphylococcus Aureus, the bacterial species responsible for the majority of infections in uremia; (5) that functional disturbances are mainly related to uremic toxicity, dialyzer membrane bio(in)compatibility, and uremic anemia. Biochemical disturbances in PMNL, induced by a multifactorial patho-physiologic process, may therefore be related to the enhanced incidence of infection in uremic patients.

Results of urometabolic evaluation in 127 patients with renal calculous disease.

One hundred twenty-seven selected stone formers were evaluated. With the simple ambulatory tests proposed by Pak for metabolic screening and a complete urologic evaluation an anomaly was found in more than 90 per cent of the cases. The patients were divided into three groups: (1) patients operated on for staghorn stones; (2) patients with episodes of spontaneous stone eliminations or young people with only one stone episode; and (3) patients operated on for stone disease. No significant differences were noted except for the occurrence of urinary tract infection and for struvite and calcium oxalate occurrence in the different groups. Urinary tract infection combined with a metabolic disorder appear to make the evolution from small kidney stone to staghorn stone a reality.

LDH isozymes of human T and B lymphocytes.

Peripheral lymphocytes were obtained from five normal healthy adults. T and B lymphocytes were separated by rosette formation. LDH (L-lactate: NAD-+ oxidoreductase, EC 1.1.1.27) isozymes were studied on both populations after agar gel electrophoresis. The mean B lymphocyte pattern was: LDH-1, 7.2%; LDH-2, 25.0%; LDH-3, 39.2%; LDH-4, 21.9%; LDH-5, 6.6%. The mean T lymphocyte pattern was: LDH-1, 25.8%; LDH-2, 35.1%; LDH-3, 28.3%; LDH-4, 9.4%, LDH-5, 1.3%. This makes the T lymphocytes look more aerobic than the B lymphocytes. Daudicells had the following pattern: LDH-1, 8.4%; LDH-2, 19.1%; LDH-3, 26.6%, LDH-4, 24.9%; LDH-5, 20.9%.

Serum uremic toxins from patients with chronic renal failure displace the binding of L-tryptophan to human serum albumin.

The level of free tryptophan (Trp) and its metabolites in serum appears to be related to some pathologic states, such as chronic renal failure and neuropsychiatric disorders, so that a precise characterization of tryptophan binding to serum albumin is of interest. In the present paper, the binding of L-tryptophan to defatted human serum albumin at 37 degrees C and at pH 7.4 was studied by means of equilibrium dialysis. The competition between L-tryptophan and serum solutes extracted from uremic patients undergoing hemodialysis, before dialysis treatment, was also investigated. Solutes were extracted from uremic pools of sera using two different deproteinization methods: serum ultrafiltration and heat denaturation of serum proteins followed by ultrafiltration. We found 1.10 +/- 0.03 binding sites for Trp to defatted albumin with an association constant 11.37 +/- 1.03 x 10(3) M-1. The competition experiments suggested that the number of Trp binding sites were not significantly modified by the addition of solutes obtained with the method of ultrafiltration with respect to the binding of L-tryptophan to albumin in the absence of competitors, while their affinity constant was markedly reduced (2.66 +/- 0.18 x 10(3) M-1). Moreover, a significant reduction of the affinity constant was observed when competitors for Trp were obtained using heat deproteinization associated with ultrafiltration (1.91 +/- 0.15 x 10(3) M-1 vs. 2.66 +/- 0.18 x 10(3) M-1; P < 0.005). These results might be ascribed to the fact that the last procedure has a higher yield with a more complete liberation of uremic toxins from serum proteins, so that they became probably totally free thus competing at higher extent with L-tryptophan for albumin binding sites.

Binding of indole-3-acetic acid to human serum albumin and competition with L-tryptophan.

Indole-3-acetic acid (IAA) is a product of tryptophan (Trp) metabolism and is found to be markedly increased in uremic sera. IAA binding to defatted human serum albumin at 37 degrees C and pH 5, 7.4, and 8.5 was studied by equilibrium dialysis, and data were analyzed assuming two independent high affinity binding sites plus a class of low affinity sites. The estimated values of the association constant of dominant site were: 7.96 x 10(3) M-1 at pH 5, 11.57 x 10(3) M-1 at pH 7.4, and 6.30 x 10(3) M-1 at pH 8.5. The competition between IAA and Trp for albumin binding at pH 7.4 was investigated. The results suggest that one specific albumin site is common for IAA and Trp, but the data were not adequately predicted by a purely competitive scheme. A better prediction was achieved assuming that the binding of IAA to a site different from the common site inhibits Trp binding.

Plasma vitamin A in haemodialysis patients.

Different high performance liquid chromatographic systems were applied to the investigation of vitamin A metabolism in subjects undergoing haemodialysis. Plasma levels of retinol, retinyl esters and retinoic acid were measured. There was a significant elevation of plasma retinol and dialysis failed to normalise this level. No correlation with plasma concentrations of creatinine or urea was found. No differences in retinyl ester and retinoic acid levels were observed between healthy subjects and haemodialysis patients. These results suggest that retinol accumulation is not caused by a deficiency in its oxidative metabolism.

Screening of UV-absorbing solutes in uremic serum by reversed phase HPLC--change of blood levels in different therapies.

In order to screen UV-absorbing solutes in large numbers of uremic serum samples, an automated liquid chromatographic method was developed. The method proved to be reliable and reproducible in more than 500 analyses. HPLC separation was performed using gradient elution on a 25-cm Ultrasphere Octyl reversed phase column, with 5 microns particles. Characteristic profiles for the uremic state were obtained in the analyses of serum samples of 43 uremic patients before and just after artificial kidney treatment; hemodialysis (n = 14), hemodiafiltration (n = 13) and hemofiltration (n = 16). In these profiles 20-40 peaks were resolved of which nine were 'quantitated' by peak height relative to a standard. Of these solutes creatinine, uracil, uric acid, hypoxanthine, indoxylsulfate, tryptophan and hippuric acid were identified. The heterogeneity of the population of uremic patients, with respect to the UV-absorbing solutes, was estimated. Significant differences of solute blood level changes during hemodialysis, hemodiafiltration and hemofiltration, were observed.

The compartmental syndrome: a serious complication of acute rhabdomyolysis.

The compartmental syndrome is not a rare complication of non-traumatic rhabdomyolysis. Early recognition and prompt surgical decompression of the affected area are essential. We feel that a lack of familiarity with the syndrome among nephrologists may contribute to delay in diagnosis and treatment and reduce the chances for functional neuromuscular recovery. Our experience with three cases following overdosage of alcohol (case 1), barbiturates (case 2) and a mixture of alcohol and sedatives (case 3) is reported. The pathogenesis, symptomatology and treatment of the compartmental syndrome in this setting are discussed.

Shunt nephritis.

A case of nephritis occurring in a 40-year old patient with a ventriculojugular shung infected with staphylococcus albus is described. Circulating antistaphylococcal antibodies could be demonstrated. Renal manifestations disappeared after treatment with systemic antibiotics and surgical removal of the shunt.

Inhibition of phagocytosis by a middle molecular fraction from ultrafiltrate.

The in vitro phagocytic activity of normal human blood was maximally inhibited by an uremic toxin isolated by Sephadex G 15 column chromatography from the ultrafiltrate obtained during a sequential hemodiafiltration procedure in an anephric patient. The phagocytic activity of the blood was studied by measuring the labelled CO2 production from glucose metabolism during the phagocytosis of latex, zymosan and inulin; phagocytosis was not influenced by urea levels of 4 g/l and creatinine levels of 15 mg/100 ml, whereas it was inhibited for 59% by uremic serum and for 90% by a D fraction. The D fraction blocking phagocytosis is of the so-called middle molecular weight range; the presumed molecular weight is between 113 and 1029; the elution volume Ve is 25.28/ml and the available distribution coefficient KAV 0.52.

Impairment of phagocytic activity of macrophages as studied by the skin window test in patients on regular hemodialysis treatment.

In 7 patients with less than 4 months of regular hemodialysis treatment (RDT), in 28 patients with more than 4 months RDT and in 9 normal subjects, the skin window technic of Rebuck and Crowley was used to study the cellular response and the phagocytic activity of macrophages. Phagocytosis of carbon particles is decreased in the patients with less than 4 months dialysis, whereas it is not significantly different from the normals in those being dialyzed for longer periods.

Oral diazoxide contraindicated in severe hypertension with renal failure.

Diazoxide was given orally to nine hypertensive patients with renal failure and its effect on blood pressure and on glucose metabolism was studied. There was no long-term antihypertensive effect. During treatment insulin release and glucose assimilation after an intravenous glucose load were frankly impaired, but this impairment was reversible after stopping the treatment. Two major complications (diabetic ketoacidosis and pancreatitis) were observed. In view of these observations, the authors are of the opinion that oral diazoxide is contraindicated in the treatment of hypertension in patients with renal failure.

Cardiac output-changes during hemodialysis with ultrafiltration.

Cardiovascular hemodynamics were studied noninvasively before, during and after hemodialysis with ultrafiltration in 18 patients on chronic hemodialysis. The cardiac output (CO) was determined by a continuous wave Doppler method. Overall, no major CO changes were seen (7.8 +/- 0.6 l/min post- versus 7.4 +/- 0.5 l/min pre-dialysis). Mean blood pressure rose slightly but significantly from 103 +/- 4 mmHg before to 113 +/- 3 mmHg after hemodialysis (p less than 0.01). Important interindividual differences in the intradialytic evolution of CO were observed. In patients with previous myocardial infarction or dilated cardiomyopathy (n = 12), CO rose significantly from 7.3 +/- 0.7 l/min before to 8.4 +/- 0.6 l/min after hemodialysis (p less than 0.05), while in patients without manifest myocardial disease (n = 6) CO decreased from 7.5 +/- 0.7 l/min to 6.6 +/- 0.9 l/min (NS). Comparison of the evolution of CO in both groups by variance analysis revealed a significant difference (p less than 0.01). It is concluded that, in response to hemodialysis with ultrafiltration, CO probably will increase in patients with myocardial infarction or congestive cardiomyopathy, but probably will decrease in patients without.

Short dialysis with a polyacrylonitrilmembrane (RP 6) without the use of a closed recirculating dialyzate delivery system.

Because of excessive eltrafiltration (UF), the RP 6 dialyzer requires a closed recirculating dialyzate delivery system. The purpose of this study is to present the characteristics of the RP 6 dialyzer on a single needle system which programs the UF rate of this dialyzer. The single needle system consists of one blood pu-mp and two roller pump heads, switched on and off at preselected maximum and minimum out let pressures (OP). It is possible to decrease the UF rate by lowering the OP in the bubble trap chamber. By varying OP from 0 to 100 mm Hg, we obtained an UF rate in vitro of 6.5 ml per minute. The clearance values, in ml/min, obtained at OP 0 to -100 NN Hg, QB 300 and QD 500 are (in ml/min): urea: 160.0, creatinine: 145.0, sucrose-C14: 105.4, sodiumiothalamate-i125: 79.9, cyanocobalamin-co58: 73.7 and inulin-3H: 40.7. The priming volume (corn-oil) at OP 0 to -100 MM Hg, QB 250, QD 500 varies between 140 ml (at the minimum OP) and 150 ml (at the maximum OP). We performed 370 dialyses. The dialysis runs were well tolerated: moderate hypotension occurred in 4% and cramps in 1.6% of the dialyses. In most cases no fluid perfusion was necessary. The residual blood volume (Technetium99m) is estimated at 8.2 ml(n equale 11).