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PubMed2004

A single dose of rasburicase is sufficient for the treatment of hyperuricemia in patients receiving chemotherapy.

Hydration, urinary alkalization, and allopurinol are the standard of care in the treatment and prevention of hyperuricemia. Rasburicase is a new alternative for the management of hyperuricemia in cancer patients. Criteria for the use of rasburicase were developed by the Hematology/Oncology Pharmacy and Therapeutics Subcommittee of the Detroit Medical Center and implemented in 2003. The guidelines limit rasburicase use to one dose, with additional doses as needed, compared to the five doses recommended by the manufacturer, in cancer patients with hyperuricemia and bulky tumor who require immediate chemotherapy. During the period of March to September 2003, eight patients received rasburicase, according to the guidelines, for the management of hyperuricemia. One dose of rasburicase produced a rapid and sustained therapeutic effect of lowering the plasma uric acid levels in all patients. The levels remained below 4 mg/dL throughout the administration of chemotherapy for up to 96 h. Utilizing the guidelines resulted in a significant cost savings of 100,000 US dollars.

Adult↗
PubMed2002

Hyperuricemia and gout in renal transplant recipients.

Hyperuricemia, unlike clinical gout, is extremely common in renal transplant patients. The high prevalence of hyperuricemia is related to prolonged exposure to cyclosporine rather than to its dose or serum concentration. Serum creatinine levels do not show significant correlation with hyperuricemia, behaving more like a surrogate marker for cyclosporine dose and trough level. The low incidence of gout in renal transplant patients, despite the hyperuricemia, may be related to the prolonged immunosuppression effect.

Adult↗
PubMed2004

Management of hyperuricemia with rasburicase review.

Tumor lysis syndrome (TLS) is a serious complication in patients with hematological malignancies. Massive lysis of tumor cells can lead to hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcaemia. These metabolic disturbances may result in renal failure, because of precipitation of uric acid crystals and calcium phosphate salts in the kidney. The standard prophylaxis or treatment of hyperuricemia consists of decreasing uric acid production with allopurinol and facilitating its excretion by urinary alkalinization and hyperhydration. By inhibiting the enzyme xanthine oxidase, allopurinol blocks the conversion of hypoxanthine and xanthine into uric acid. An alternative treatment is urate oxidase which oxidates uric acid into allantoin. Allantoin is 5-10 times more soluble than uric acid and is therefore excreted easily. In several clinical trials rasburicase, the recombinant form of urate oxidase, has shown to be very effective in preventing and treating hyperuricemia. Rasburicase, in contrast with the non-recombinant form of urate oxidase uricozyme, is associated with a low incidence of hypersensitivity reactions. In addition to the demonstrated clinical benefit, rasburicase also proved to be a cost-effective option in the management of hyperuricemia.

Allopurinol↗
PubMedDate not supplied

Hyperuricemia causes glomerular hypertrophy in the rat.

BACKGROUND/AIMS: Rats with mild hyperuricemia develop systemic hypertension, interstitial renal disease, afferent arteriolopathy, and increased renin expression [Mazzali et al.: Am J Physiol 2002;6:F991-F997]. We hypothesized that hyperuricemia might also induce glomerular changes. METHODS: We reviewed renal biopsies of rats previously made hyperuricemic for 7 weeks with the uricase inhibitor, oxonic acid. Controls included normal rats and oxonic acid-treated rats administered allopurinol, benziodarone, hydrochlorothiazide, or enalapril. Glomeruli were examined for size (computer image analysis) and structure (histology). An additional group of rats were administered oxonic acid or control diet for 6 months. RESULTS: Renal biopsies showed that hyperuricemic rats had a 30% increase in glomerular tuft area (p < 0.01); these changes were prevented by allopurinol and benziodarone. Control of blood pressure with hydrochlorothiazide did not prevent the development of glomerular hypertrophy, whereas enalapril partially reduced the glomerular hypertrophy. Prolonged hyperuricemia was associated with the development of microalbuminuria (p < 0.05) and glomerulosclerosis (22 vs. 10%, p < 0.05) compared to control rats. CONCLUSIONS: Hyperuricemic rats develop glomerular hypertrophy that can be prevented in part by ACE inhibitor therapy. Prolonged hyperuricemia is associated with the development of glomerulosclerosis in the rat.

Animals↗
PubMed2005

Hyperuricemia and bone marrow transplantation.

Blood uric acid levels and purine metabolism are affected in many ways after bone marrow transplantation (BMT). Although BMT is usually performed when patients have a low residual disease burden, a proportion of them are still at risk of tumor lysis syndrome, even with limited disease or after nonmyeloablative conditioning regimens; moreover, an alteration in uric acid turnover can also be observed in patients with persistently normal uric acid blood levels. Apart from this obvious complication, multiple physiopathological events occurring after transplantation may derange uric acid homeostasis. Although there is only indirect evidence (derived from obstetric eclampsia and experimental gout arthritis), a transplant-related increase in cytokine production (particularly TNF, IL-1 and IL-6) may activate xanthine oxidase which, in turn, may be responsible for a further cytokine bout: deranged cytokine homeostasis is involved in the pathogenesis of some of the main acute post-BMT complications, such as hepatic veno-occlusive disease (VOD) and acute graft-versus-host disease (aGVHD). Hyperuricemia is also a well-known side effect of cyclosporine A, the reference drug for the prevention of post-BMT GVHD, which may affect uric acid turnover by reducing glomerular filtration and/or affecting tubular handling; the available evidence favors the former explanation. Hyperuricemia is found in long-term transplanted patients as part of a metabolic pattern reminiscent of the so-called 'X' or 'metabolic'syndrome related to insulin resistance: there is still no precise interpretation of this post-transplant complication nor any definite data concerning its real incidence and outcome. Hyperuricemia is frequently regarded as a marginal finding in the context of X syndrome, but it is pathogenetically linked to the other component of the syndrome and has proved to be autonomously responsible for tissue and vessel damage. Finally, BMT is a possible therapeutic strategy for some inherited forms of hyperuricemia, particularly Lesch- Nyhan disease, although there is still some perplexity concerning the possibility of preventing the development of neurological impairment.

Bone Marrow Transplantation↗
PubMed2004

Hyperuricemia and reticulocytopenia in association with autoimmune hemolytic anemia in two children.

Hyperuricemia developed in 2 children with autoimmune hemolytic anemia with reticulocytopenia at a time of hemolytic crisis. One likely cause of hyperuricemia is the destruction of nucleated RBC precursors by autoantibodies. It is advised that patients with autoimmune hemolytic anemia with reticulocytopenia be examined for hyperuricemia. This might explain the reason for reticulocytopenia and might prevent unnecessary bone marrow procedures. When hyperuricemia is present, supportive therapy might be needed to prevent renal damage.

Anemia, Hemolytic, Autoimmune↗
PubMedDate not supplied

Rasburicase for the treatment and prevention of hyperuricemia.

OBJECTIVE: To review the information currently available on rasburicase for treatment and prevention of hyperuricemia. DATA SOURCES: MEDLINE (1966-August 2002) was searched for primary and review articles. STUDY SELECTION/DATA EXTRACTION: Studies evaluating rasburicase, including abstracts and proceedings, were considered for inclusion. English-language literature was evaluated for the pharmacology, pharmacodynamics, pharmacokinetics, therapeutic use, and adverse effects of rasburicase. DATA SYNTHESIS: Rasburicase, a recombinant urate oxidase, has been shown to be effective in lowering uric acid and preventing uric acid accumulation in patients with hematologic malignancies who had hyperuricemia or who were at high risk for developing hyperuricemia. It has been approved for pediatric use in the US. CONCLUSIONS: In addition to allopurinol, hydration, and urinary alkalinization, rasburicase is a new alternative for the treatment and prevention of hyperuricemia in patients with hematologic malignancies. Its rapid onset of action and the ability to lower preexisting elevated uric acid levels are the advantages of rasburicase compared with allopurinol. It may allow the patient to receive chemotherapy treatment without delay.

Animals↗
PubMed2006

Febuxostat: a selective xanthine oxidase inhibitor for the treatment of hyperuricemia and gout.

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical trial data, safety profile, precautions, and place in therapy of febuxostat, a novel nonpurine xanthine oxidase inhibitor in development for the treatment of hyperuricemia and gout. DATA SOURCES: Available studies and abstracts were identified through MEDLINE (1990-November 2006), Science Citation Index, International Pharmaceutical Abstracts, Cochrane Databases, and the American College of Rheumatology and European League Against Rheumatism Web sites. Key search terms were febuxostat, TMX-67, TEI-6720, hyperuricemia, and gout. STUDY SELECTION AND DATA EXTRACTION: All available studies describing the pharmacology of febuxostat were included. Human studies formed the basis for discussion of clinical parameters, including pharmacokinetics, pharmacodynamics, efficacy, and safety of febuxostat. DATA SYNTHESIS: Febuxostat significantly reduces uric acid levels within 2 weeks after initiation of therapy and up to 48% by the end of 104 weeks of therapy. Approximately 60% of patients achieved the primary goal of serum uric acid less than 6 mg/dL during the last 3 months following once-daily administration of febuxostat 80 mg or 120 mg for at least 52 weeks. The most common adverse reactions to febuxostat were abnormal results from liver function tests, diarrhea, headache, arthralgias, and musculoskeletal symptoms. Due to its potency, patients are at an increased risk of experiencing gout flares for at least the first year of therapy. Up to 70% of patients in clinical trials experienced gout flares despite concomitant prophylactic treatment with colchicine or naproxen. Additional clinical trial evidence supports the efficacy and safety of febuxostat in the treatment of hyperuricemia and gout. CONCLUSIONS: Febuxostat is a promising alternative to allopurinol for the treatment of gout and hyperuricemia. The optimal length of prophylactic therapy, clinical significance of abnormal liver function tests results during therapy, and safety in patients with moderate or severe renal insufficiency warrant further investigation.

Febuxostat↗
PubMed2006

Reduced-dose rasburicase in the treatment of adults with hyperuricemia associated with malignancy.

Tumor lysis syndrome is a life-threatening complication of chemotherapy for patients with leukemia and large tumors with a high proliferative index, such as Burkitt's lymphoma. The syndrome is characterized by hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia. The standard of care for hyperuricemia consists of hydration with or without alkalinization and administration of allopurinol. When treated in this manner, patients often experience persistent hyperuricemia that lasts several days after the start of antineoplastic therapy; sometimes they develop uric acid nephropathy as a consequence. Rasburicase, a recombinant urate oxidase enzyme, quickly removes large amounts of uric acid from plasma. The drug is approved by the United States Food and Drug Administration for management of elevated plasma uric acid levels in pediatric patients with leukemia, lymphoma, or solid tumor malignancies who are receiving chemotherapy. We undertook a retrospective review of adult patients treated with a single dose of rasburicase 6 mg for hyperuricemia associated with malignancy. Ten patients received one 6-mg dose of rasburicase, and one patient received two 6-mg doses as an adjuvant therapy to normalize uric acid levels. In most of the patients, a single 6-mg dose of rasburicase was effective in correcting uric acid levels in the typical time between diagnosis and start of antineoplastic therapy.

Aged↗
PubMed2006

Spotlight on rasburicase in anticancer therapy-induced hyperuricemia.

Intravenous rasburicase (Elitek), Fasturtec) is the first recombinant uricolytic agent. It is indicated for the management of anticancer therapy-induced hyperuricemia in pediatric patients in the EU and US, and in adult patients in the EU. Rasburicase is effective and generally well tolerated in adult and pediatric patients with, or at risk of developing, anticancer therapy-induced hyperuricemia. It is associated with potentially serious hematologic adverse events and hypersensitivity reactions, which must be considered prior to and during administration; rasburicase is contraindicated in patients predisposed to hemolysis or methemoglobinemia and in patients with glucose-6-phosphate dehydrogenase deficiency. Unlike allopurinol, rasburicase acts on existing uric acid concentrations. Rasburicase treatment resulted in significantly less systemic exposure to uric acid and a quicker therapeutic response than allopurinol in pediatric patients; further studies are needed to determine the comparative efficacy and tolerability of rasburicase versus allopurinol in adult patients. Although further pharmacoeconomic data would be useful, rasburicase was most cost effective for the prevention of hyperuricemia in children and for treatment of this condition in adults. Thus, rasburicase is a useful option for the prophylaxis or treatment of anticancer therapy-induced hyperuricemia in both adult and pediatric patients.

Anticarcinogenic Agents↗
PubMed1990

Renal dysfunction and hyperuricemia at presentation and relapse of acute lymphoblastic leukemia.

Hyperuricemia is an unusual presenting feature of acute lymphoblastic leukemia (ALL) and is generally associated with a large leukemic cell burden. We describe three children with T-cell ALL who presented with acute renal failure and very high serum uric acid concentrations, despite a relatively small leukemic cell burden. Two of the three patients had normal complete blood counts without circulating blasts or other physical evidence of leukemia. An isolated renal relapse in one case was associated with hyperuricemia, increased renal excretion of uric acid, and renal dysfunction. An unusually high rate of purine catabolism of the lymphoblasts may cause hyperuricemia in these cases. Unexplained hyperuricemia should prompt a search for occult malignancy.

Acute Kidney Injury↗
PubMed2001

Difficult gout and new approaches for control of hyperuricemia in the allopurinol-allergic patient.

A major obstacle to the treatment of hyperuricemia in patients allergic to allopurinol is the limited availability of suitable, equally effective, alternative, urate-lowering drugs. Conventional uricosuric drugs, including probenecid and sulfinpyrazone, are recommended for allopurinol- intolerant patients with gout and "underexcretion" hyperuricemia who have normal renal function and no history of nephrolithiasis. Therapeutic options in those in whom traditional uricosuric drugs are contraindicated, ineffective, or poorly tolerated include slow oral desensitization to allopurinol and cautious administration of oxipurinol. Allopurinol desensitization is useful particularly in those who have failed other treatment modalities. If available (as in Europe, South Africa, and Japan), benzbromarone may be tried in patients with gout and mild-to-moderate renal insufficiency. Recombinant urate oxidase can be used in the short-term prophylaxis and treatment of chemotherapy- associated hyperuricemia in patients with lymphoproliferative and myeloproliferative disorders. Hyperuricemia and gout occur with increased frequency in cyclosporine-treated allograft transplant recipients. The management of gout in these patients is complicated by two main factors: cyclosporine-induced renal impairment, and interactions with medications used to preserve the allograft.

Allopurinol↗
PubMed1992

Hyperuricemia and gout among heart transplant recipients receiving cyclosporine.

PURPOSE: To determine the frequency and characteristics of hyperuricemia and gouty arthritis among cyclosporine-treated heart transplant recipients. PATIENTS AND METHODS: One hundred ninety-six surviving adult heart or heart/lung transplant recipients were evaluated. Medical records were reviewed to determine peak serum uric acid levels after transplantation, and to evaluate potential risk factors for hyperuricemia. Patients were surveyed by postal questionnaire for a history of gouty arthritis, with positive responses evaluated by telephone interview and/or examination of the patient. RESULTS: Hyperuricemia occurred in 72% of male and 81% of female patients and was not correlated with cyclosporine level, presence of hypertension, or degree of renal insufficiency. Eleven (6%) patients had gout prior to transplantation; 14 (8%) had onset of definite gout and seven (4%) had probable gout a mean of 17 months after transplantation. Polyarticular arthritis and/or tophi developed in six (43%) of the posttransplant-onset definite gout group within a mean of 31 months. CONCLUSION: Both hyperuricemia and gouty arthritis occur with increased frequency among cyclosporine-treated heart or heart/lung transplant recipients. The clinical course of gout in these patients is often accelerated, with management complicated by the patients' renal insufficiency and interaction with transplant-related medications.

Arthritis, Gouty↗
PubMed1994

Hyperuricemia and urate nephropathy in urate oxidase-deficient mice.

Urate oxidase, or uricase (EC 1.7.3.3), is a purine metabolic enzyme that catalyzes the conversion of uric acid to allantoin in most mammals except humans and certain other primates. The loss of urate oxidase in the human during primate evolution predisposes man to hyperuricemia, a metabolic disturbance that can lead to gouty arthritis and renal stones. To create a mouse model for hyperuricemia and gout, and to address the question of whether urate oxidase is essential in lower mammalian species, we have disrupted the urate oxidase gene in the mouse by homologous recombination in embryonic stem cells. Unlike the human situation, urate oxidase deficiency in mice causes pronounced hyperuricemia and urate nephropathy. More than half of the mutant mice died before 4 weeks of age, indicating that urate oxidase is essential in mice. These mutant mice may also serve as animal models for hyperuricemia and its related nephropathy in humans.

Allopurinol↗
PubMed1993

Glycogenosis type V (McArdle's disease) with hyperuricemia. A case report and clinical investigation.

A 28-year-old male with glycogenosis type V associated with continuous hyperuricemia during mild daily activities is reported. An aerobic exercise test using a bicycle ergometer revealed that purine metabolites, i.e., ammonia, inosine, hypoxanthine and xanthine, were transiently increased by the exercise and that a subsequent increment in uric acid continued until the following day. The accelerated purine degradation by the muscle exercise was thus shown to be able to cause the overt hyperuricemia in a patient with glycogenosis type V. Therapeutic use of fructose for glycogenosis was disappointing due to fructose-induced hyperuricemia. A search for myogenic hyperuricemia is essential for therapeutic trials.

Adult↗
PubMed1990

Underexcretory-type hyperuricemia, disproportionate to the reduced glomerular filtration rate, in two boys with mild proteinuria.

Two unrelated boys with mild persistent proteinuria and underexcretory-type hyperuricemia of more than 9.0 mg/dl (535 mumols/l) are described. The proteinuria was detected at age 10 and 6 years, respectively. The fractional excretion of uric acid in both was low at 2-3%, when the creatinine clearance was decreased by about 50%. Tissue examination revealed focal interstitial fibrosis in both patients and medullary urate crystals in one patient in whom medullary tissue was obtained on biopsy. An immunofluorescence study was negative for immunoglobulins, complements and fibrin. Treatment of hyperuricemia did not prevent further deterioration of their renal function. One of them underwent a renal transplantation and then his serum uric acid level returned to the normal range. Neither patient had a family history of hyperuricemia, gout or inherited progressive renal disease. Both patients are likely to be sporadic cases of familial nephropathy with gout, an autosomal dominant disease, due to a new mutation. Hyperuricemia due to diminished uric acid clearance may be a risk factor or predictor for the development of progressive renal disease in some subjects.

Child↗
PubMed1981

Renal pathogenesis of familial hyperuricemia: studies in two kindreds.

The pathogenesis of familial hyperuricemia has been investigated in two kindreds in whom hyperuricemia was present in members of successive generations. Enzymatic and metabolic studies, including the incorporation of isotopically labeled glycine into urinary uric acid and assessment of the total excretion of oxypurines in one family, excluded a metabolic etiology. No secondary cause of hyperuricemia was identified in either family. Fractional excretion of uric acid was less than 6.2% in all hyperuricemic individuals studied, while creatinine clearances were normal. Tubular secretion of uric acid and tubular reabsorption of uric acid were studied in an affected teenager from each family while receiving a purine-free diet. Inhibition of secretion of uric acid with pyrazinamide decreased fractional excretion of uric acid to 0.6% in patient S and to 0.7% in patient B. Tubular secretion of uric acid at maximal response to pyrazinamide in these patients was 0.393 and 0.410 mg/dl glomerular filtration rate(nl response 0.300 to 1.30 mg/min/100ml inulin clearance). Probenecid, an inhibitor of uric acid reabsorption, increased uric acid excretion by 3.9 mg/min and by 3.2 mg/min (nl response 1.7 +/- 0.3 mg/min) in patients S and B. Tubular reabsorption of uric acid distal to secretory sites was determined by assessing the uricosuric response to probenecid plus pyrazinamide. Uric acid excretion increased by only 0.08 mg/min in patient A and by 0.17 mg/min in patient B (nl response 0.9 mg/min). Ascorbic acid increased fractional excretion of uric acid by 7.2% in patient S but was not uricosuric in patient B or any hyperuricemic member of his family. These data suggest that hyperuricemia in these families is due to diminished renal clearance of uric acid and that the reduced clearance is due to increased tubular reabsorption of uric acid distal to secretory sites.

Adolescent↗
PubMed1998

Contribution of a missense mutation (Trp64Arg) in beta3-adrenergic receptor gene to multiple risk factors in Japanese men with hyperuricemia.

Epidemiological data reveal that hyperuricemia is a risk factor of atherosclerosis. The risk is possibly caused by a link between hyperuricemia and insulin resistance-related metabolic syndrome. Recently it has been proposed that a missense mutation (Trp64Arg) in the beta3-adrenergic receptor (beta3-AR) gene may contribute to the accumulation of multiple risk factors related to insulin resistance. The present study was undertaken to further clarify an association between the Trp64Arg mutation and the metabolic syndrome in 47 Japanese men with hyperuricemia, who are substantially at high risk of atherosclerosis. One patient (2%) had the homozygous mutation, 12 (26%) were heterozygous for the mutation, and 31 (72%) had no mutation found by the PCR-RFLP analysis. The Trp64Arg mutation was not related to past maximal body mass index (BMI), BMI and waist/hip ratio. The subjects with the heterozygous mutation showed a slightly higher incidence of impaired glucose tolerance and diabetes mellitus in the 75 g oral glucose challenge (67%), as compared with those without the mutation (39%). Serum insulin response at 60 min and the sum of serum insulin in the glucose challenge were greater in the former subjects than those in the latter subjects (P=0.041 and 0.076, respectively). An increase in serum lipoprotein(a) was also observed in the subjects with the heterozygous mutation, but the Trp64Arg mutation was not associated with other dyslipidemia, blood pressure or ischemic changes on the electrocardiogram. These results indicate that the heterozygous mutation of Trp64Arg in the beta3-AR gene partly contributes to the accumulation of multiple risk factors in male subjects with hyperuricemia. A larger prospective study is necessary to elucidate a possible role of the Trp64Arg mutation in atherosclerotic diseases in future.

Adult↗