PubMed · 12092090
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K O Weselman, C A Agudelo. 2001. Gout basics.. https://pubmed.ncbi.nlm.nih.gov/12092090/
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OBJECTIVE: To report the use of single-dose rasburicase in an obese patient. CASE SUMMARY: A 53-year-old obese African American woman weighing 136 kg (ideal body weight [IBW] 55 kg) with new-onset chronic myelomonocytic leukemia in leukocytic blast crisis was treated with hydroxyurea 5 g daily. In addition, she received allopurinol 300 mg daily for prevention of tumor lysis syndrome (TLS). The following day, allopurinol was discontinued and rasburicase was administered at a dose of 0.2 mg/kg of IBW for a serum uric acid level of 11.9 mg/dL. The patient's serum uric acid level decreased to 1.9 mg/dL 48 hours after a single dose. DISCUSSION: Rasburicase is indicated for the initial management of elevated plasma uric acid levels in patients with hematologic and solid tumor malignancies who are at risk for TLS. This case is unique because the patient received one dose of rasburicase followed by allopurinol rather than 5 daily doses of rasburicase. Additionally, the dose was based on IBW rather than actual body weight. Efficacy of this approach is apparent from the uric acid levels and the lack of hemodialysis requirements. CONCLUSIONS: A single dose of rasburicase (based on IBW) followed by allopurinol can effectively prevent TLS based on serum uric acid concentration. This approach resulted in a substantial cost savings.
Uric acid released from dying cells has been shown recently to act as a danger signal for the immune system, stimulating dendritic cell maturation and enhancing T-cell responses to foreign antigens. Stimulation of dendritic cell maturation by uric acid has been proposed as a mechanism by which the immune system could generate responses against tumors. We show here that uric acid levels are elevated in tumors undergoing immune rejection and that the inhibition of uric acid production, by systemic administration of allopurinol, or the removal of uric acid, by administration of uricase, delayed tumor immune rejection, whereas subcutaneous administration of crystalline uric acid enhanced the rejection process.
Osmotic diuretics are used successfully to alleviate acute tubular necrosis (ATN) produced by chemotherapeutic agents and aminoglycoside antibiotics. The beneficial action of these agents likely involves rapid elimination of the nephrotoxic agents from the kidney by promoting diuresis. Adenosine A1 receptor (A1AR) subtype present on renal proximal tubular epithelial and cortical collecting duct cells mediates the antidiuretic and cytoprotective actions of adenosine. These receptors are induced by activation of nuclear factor (NF)-kappaB, a transcription factor reported to mediate hyperosmotic stress-induced cytoprotection in renal medullary cells. In this study, we tested the hypothesis that induction of the A1AR in renal proximal tubular cells by NF-kappaB contributes to the cytoprotection afforded by osmotic diuretics. Exposure of porcine renal proximal tubular epithelial (LLC-PK1) cells to mannitol or NaCl produced a significant increase in A1AR. This increase was preceded by adenosine release and NF-kappaB activation. Expression of an IkappaB-alpha mutant, which acts as a superrepressor of NF-kappaB, abrogated the increase in A1AR. Cells exposed to mannitol demonstrated increased reactive oxygen species (ROS) generation, which was attenuated by inhibiting xanthine oxidase with allopurinol. Allopurinol attenuated both the increase in A1AR expression and NF-kappaB activation produced by osmotic diuretics, indicating a role of adenosine metabolites in these processes. Treatment of LLC-PK1 cells with cisplatin (8 microm) resulted in apoptosis, which was attenuated by mannitol but exacerbated by selective A1AR blockade. Administration of mannitol to mice increases A1AR expression and activation of NF-kappaB in renal cortical sections. Taken together, these data provide novel mechanisms of nephroprotection by osmotic diuretics, involving both activation and induction of the A1AR, the latter mediated through activation of a xanthine oxidase pathway leading to ROS generation and promoting activation of NF-kappaB.