oxypurinol and Kidney-Failure--Chronic

The spectrum of kidney and urinary tract disorders related to purines comprises acute hyperuricosuric nephropathy, chronic urate nephropathy and urolithiasis. Two factors in the development of acute hyperuricosuric nephropathy are increased uric acid concentration and low pH in the tubular fluid. Chronic urate nephropathy still possess several problems: incidence (although this seems to be decreasing, presumably owing to effective prevention), the source of interstitial urate, the cause of the interstitial deposition of urate, and the role of urate deposits in the pathogenesis of the interstitial nephropathy. The relation of the experimental nephropathy to the pathogenesis of chronic urate nephropathy in the human is not yet clear but a model is proposed according to which interstitial urate derives from two sources: hyperuricaemic plasma and hyperuricosuric tubular fluid. Urolithiasis related to purines leads to uric acid-urate stones, xanthine stones, 2,8-dihydroxyadenine stones, iatrogenic xanthine and oxipurinol stones, and possibly calcium stones. Pathogenetic factors in uric acid lithiasis are hyperuricosuria (whether due to an inborn enzyme abnormality or of unknown aetiology) and low urinary pH; oliguria is a contributory factor. There remain several open questions about uric acid lithiasis: incidence, the shift of its location from lower to upper urinary tract, the interplay of pathogenetic factors, and the role of compounds which inhibit crystallization.

Topics: Adenine Phosphoribosyltransferase; Allopurinol; Animals; Calcium; Gout; Humans; Hydrogen-Ion Concentration; Hypoxanthine Phosphoribosyltransferase; Kidney Calculi; Kidney Diseases; Kidney Failure, Chronic; Oxypurinol; Purines; Sodium; Solubility; Uric Acid; Urologic Diseases; Xanthine Oxidase; Xanthines

Topics: Adult; Allopurinol; Chromatography, High Pressure Liquid; Drug Overdose; Female; Gout; Gout Suppressants; Humans; Kidney Failure, Chronic; Oxypurinol; Ribonucleosides; Risk Factors; Transsexualism

A 73-year-old woman with chronic renal failure developed generalized muscular weakness and pain 6 days after the start of allopurinol treatment(200 mg/day). Routine laboratory tests revealed elevated levels of serum creatine kinase, and the patient was clinically diagnosed as rhabdomyolysis, due probably to severe myositis. A high level of serum oxipurinol, the chief active metabolite of allopurinol, was also revealed. The muscular weakness was relieved in seven weeks with intermittent hemodiafiltration.

Topics: Aged; Allopurinol; Female; Hemodiafiltration; Humans; Kidney Failure, Chronic; Myositis; Oxypurinol; Rhabdomyolysis

Allopurinol is a xanthine oxidase inhibitor widely used to control plasma uric acid levels. Episodes of hypersensitivity to the drug are not rare. A severe form of this with a generalized exanthem, fever and liver involvement has been termed the allopurinol hypersensitivity syndrome (AHS). Patch testing and lymphocyte stimulation testing (LST) are not helpful in confirming this sensitivity. Allopurinol works as a substrate of xanthine oxidase, and is rapidly oxidized into oxypurinol in vivo. Therefore, the biological half-life of oxypurinol is markedly longer than that of allopurinol. In addition, conspicuous pre-existing renal impairment has been noted in many AHS patients. Thus, it is possible that AHS is a manifestation of hypersensitivity to oxy-, not allopurinol. Here, we now report three cases of AHS in which there were significant lymphoproliferative reactions to oxypurinol but not allopurinol.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Cystitis; Drug Hypersensitivity; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Oxypurinol; Xanthine Oxidase

1. A compound identified as orotidine has been found in the erythrocytes of all subjects on allopurinol. 2. The erythrocyte orotidine concentrations were much higher in patients with renal failure or with the Lesch-Nyhan syndrome. 3. In addition, increased amounts of oxypurinol-7-riboside were excreted in the urine by both of these groups compared with control subjects or with patients with normal renal function on allopurinol. 4. A good correlation was found between urinary oxypurinol-7-riboside excretion and erythrocyte orotidine concentrations. 5. Increased erythrocyte levels of the pyrimidine-sugar UDP-glucose were also found in patients with the highest orotidine levels. 6. The combined results suggest a derangement of pyrimidine nucleotide metabolism during allopurinol therapy. We propose that erythrocyte orotidine formation results primarily from inhibition of orotidine-5'-monophosphate decarboxylase by oxypurinol-7-ribotide.

Topics: Allopurinol; Erythrocytes; Female; Humans; Kidney Failure, Chronic; Lesch-Nyhan Syndrome; Male; Nucleotides; Oxypurinol; Ribonucleosides; Uridine

Monitoring of plasma oxypurinol has been proposed to prevent allopurinol side effects. An 89-year-old man developed a severe desquamative rash, fever, eosinophilia, hepatocellular injury and renal failure after allopurinol administration. Eight hours after the last dose, plasma allopurinol was undetectable and plasma oxypurinol was 50 mumol/l. This is the first case in which severe allopurinol hypersensitivity occurred despite a simultaneous plasma oxypurinol concentration within recommended levels (below 100 mumol/l).

Topics: Aged; Aged, 80 and over; Allopurinol; Chemical and Drug Induced Liver Injury; Dermatitis, Exfoliative; Drug Eruptions; Drug Hypersensitivity; Humans; Kidney Failure, Chronic; Male; Oxypurinol; Pyrimidines

Topics: Acute Kidney Injury; Allopurinol; Chromatography, High Pressure Liquid; Female; Gout; Humans; Hypoxanthine Phosphoribosyltransferase; Kidney Failure, Chronic; Male; Oxypurinol

This paper illustrates several important points relating to the use of allopurinol in renal failure, or situations of purine overproduction: It is very easy to give too much allopurinol. Most of the side effects (bone marrow depression, exfoliative dermatitis, etc) are the result of overdosage due to the retention of oxipurinol, an effect exaggerated by thiazide diuretics. Monitoring of plasma oxipurinol levels (ideally less than 100 mumol/l) by high-pressure liquid chromatography is helpful for adjusting dosage in renal failure. Some estimate of the anticipated purine excess is equally vital in deciding dosage during tumour lysis if the risk of urate nephropathy is not to be substituted for the certainty of xanthine nephropathy. In this situation the use of allopurinol may even be questioned. Patients with HGPRT deficiency are exquisitely sensitive to allopurinol, and careful monitoring of the effect on urinary purine levels is essential if xanthine colic is to be avoided.

Topics: Adult; Allopurinol; Child; Child, Preschool; Creatinine; Female; Humans; Infant; Kidney Failure, Chronic; Male; Middle Aged; Monitoring, Physiologic; Oxypurinol; Purines; Uric Acid

Topics: Allopurinol; Humans; Kidney; Kidney Failure, Chronic; Oxypurinol; Renal Dialysis; Uric Acid

Drugs that are administered to man may be biotransformed to yield metabolites that are pharmacologically active. These metabolites may accumulate in patients with end-stage renal disease if renal excretion is a major elimination pathway for the metabolite. This is true even if the active metabolite is a minor metabolite of the parent drug as long as the minor metabolite is not further biotransformed but is mainly excreted in the urine. Minor metabolite accumulation may also occur if it is further biotransformed by a pathway that is inhibited in uremia. Some clinical consequences of accumulation of the active drug metabolites of procainamide, meperidine, clofibrate, allopurinol, sulfadiazine and nitrofurantoin in patients with renal failure are discussed. The high incidence of adverse drug reactions seen in renal failure may be explained, in part, by the accumulation of active drug metabolites. Examples of active drug metabolites that do not accumulate in patients with renal failure because of further biotransformations are also included.

Topics: Acetylation; Biotransformation; Clofibrate; Humans; Kidney Failure, Chronic; Meperidine; Methyldopa; Nitrofurantoin; Oxypurinol; Pharmaceutical Preparations; Procainamide; Sulfonamides

Topics: Acute Kidney Injury; Analgesics; Anti-Bacterial Agents; Anti-Inflammatory Agents; Humans; Kidney Failure, Chronic; Oxypurinol