Abstract We describe a case of exercise-induced acuterenal failure (ARF) in a patient with hypouricemia. Fol-lowing recovery from ARF, the patient’s serum urateconcentration was 0.6–0.9 mg/dl, and the ratio of urateclearance to creatinine clearance (Cua/CCr) was41.9%–56.6%. There was no change in the Cua/CCr fol-lowing the administration of pyrazinamide or probene-cid, suggesting defects of tubular urate/anion exchang-ers. Because the renal biopsy revealed acute tubular ne-crosis without uric acid crystals, the ARF of this patientmight be due to oxygen free radicals resulting from exer-cise stress and hypouricemia.

Key words Renal hypouricemia · Acute renal failure ·Urate transport

Introduction

Renal hypouricemia is the hereditary condition of in-creased renal urate clearance caused by an isolated in-born error of membrane transport for urate in the renalproximal tubule [1]. Although most patients with renalhypouricemia have no clinical symptoms or complica-tions, exercise-induced acute renal failure (ARF) hassometimes been reported. We present a patient with renalhypouricemia and exercise-induced ARF.

Case report

A previously healthy 12-year-old boy was admitted to another hospi-tal because of nausea, vomiting, and loin and abdominal pain after 6 h of baseball training. Laboratory study revealed elevation of bloodurea nitrogen (BUN) and serum creatinine, and a normal serum uratelevel. He was diagnosed as having colitis and dehydration, and wasgiven intravenous fluids. On the following day, his BUN and serum

creatinine levels increased further, and his urine volume decreased,therefore he was transferred to our hospital. On physical examina-tion, his blood pressure was 148/90 mmHg. His body weight was 49 kg (3 kg more than before his illness). The urine volume was 650 ml on the day of admission. Physical examination was entirelynormal except for mild abdominal tenderness.

Laboratory study revealed a serum sodium of 137 mEq/l, serum potassium 4.5 mEq/l, serum chloride 98 mEq/l, serum BUN 51.6 mg/dl, serum creatinine 4.3 mg/dl, serum calcium 8.6 mg/dl, serum phosphate 5.9 mg/dl, serum uric acid 5.2 mg/dl(normal 3.3–7.0 mg/dl), serum creatine kinase 100 U/l, serummyoglobin 42.2 ng/ml (normal <50 ng/ml), and fractional excre-tion of sodium 1.3%. Urinalysis revealed a specific gravity of1.010, 1+ protein, no blood, no glucose, pH 6.0, 1–4 red bloodcells/high-power field, no uric acid crystallization, and myoglobinless than 10 ng/ml (normal <10 ng/ml). The urinary β2-micro-globulin concentration was 1,040 µg/l (normal <200 µg/l). A com-plete blood count, blood gas analysis, and liver enzymes were nor-mal. Pre-contrast renal computed tomographic scan revealed bilat-eral diffuse enlargement of the kidneys.

He underwent intravenous restrictive fluid and furosemide ad-ministration. The nausea, vomiting, and loin and abdominal painwere resolved in 48 h. BUN and creatinine declined to within nor-mal ranges after 10 days. The serum concentration of uric acid af-ter recovery of ARF was consistently below the normal range(0.6–0.9 mg/dl). The daily urinary uric acid excretion was 326–426mg/day (normal 250–450 mg/day). He was diagnosed as having re-nal hypouricemia with exercise-induced ARF. A renal biopsy takenon the 20th hospital day showed normal glomeruli, mild interstitialedema, a partial destruction of tubular epithelial cells, and no evi-dence of urate deposition or urate crystals in the tubular lumen,findings compatible with healing of acute tubular necrosis.

Two months after ARF, renal clearances of urate and creatininewere measured before and after pyrazinamide and probenecid ad-ministration. Written informed consent was obtained from his par-ents. He was maintained on an unrestricted diet during the studies.Pyrazinamide and probenecid tests were performed by previouslyreported methods [2]. The patient was hydrated orally with waterin amounts sufficient to provide a steady rate of urine flow of atleast 1 ml/min. Blood samples were drawn in the middle of eachurine collection period. Urine was collected by spontaneous voiding. Serum and urinary urate concentrations were determinedby a uricase assay, and creatinine levels in serum and urine weredetermined by enzymatic assay. Urate clearance (Cua) (normal5–15 ml/min) and creatinine clearance (CCr) (normal in our insti-tute 120–160 ml/min) were determined before and after oral ad-ministration of 3.0 g pyrazinamide or 2.0 g probenecid.

The patient’s basal Cua/CCr ratio was 41.9%–56.6% (normal6%–10%). There was no change in the Cua/CCr following pyrazina-mide or probenecid administration (Table 1).

T. Watanabe (✉ ) · T. Abe · Y. OdaDepartment of Pediatrics, Niigata City General Hospital, 2-6-1 Shichikuyama, Niigata 950-8739, Japane-mail: twata@coral.ocn.ne.jpTel.: +81-025-241-5151, Fax: +81-025-248-3507

Pediatr Nephrol (2000) 14:851–852 © IPNA 2000

B R I E F R E P O RT

Toru Watanabe · Tokinari Abe · Yoshihiko Oda

Exercise-induced acute renal failure in a patient with renal hypouricemia

Received: 15 March 1999 / Revised: 10 September 1999 / Accepted: 14 September 1999

Discussion

Although the complete mechanisms of urate handling ofhuman renal tubules remain unclear, new insights havebeen obtained from recent advances in renal tubular phys-iology [1]. Two urate/anion exchangers (high-affinity andlow-affinity urate exchangers) in the apical membrane ofproximal tubules contribute to urate reabsorption [1].Roch-Ramel et al. [3] demonstrated that the antiuricosu-ric effect of pyrazinamide resulted from stimulation of tu-bular urate reabsorption through the urate/anion exchang-ers, not an inhibition of tubular urate secretion. They alsoshowed that the uricosuric effect of probenecid resultsfrom an inhibition of tubular urate reabsorption throughthe apical low-affinity urate/anion exchangers [3]. Fromthese observations, no change in Cua/CCr following pyra-zinamide or probenecid administration means dysfunc-tion of both high- and low-affinity urate/anion exchang-ers. Therefore, our patient has tubular defects of bothlow- and high-affinity urate/anion exchangers.

Exercise-induced ARF has been sometimes describedas a complication of renal hypouricemia [4–11]. Al-though the precise mechanism of exercise-induced ARFin renal hypouricemia remains unknown, two hypotheseshave been proposed: uric acid nephropathy and oxygenradical stress. Yuen and Hasbargen [9] hypothesized thatARF occurred with exercise in patients with renal hypo-uricemia because of the increase in uric acid productionduring exercise, leading to uric acid nephropathy [9].However, although renal biopsy findings have been re-ported in seven cases in the English literature, includingours, uric acid nephropathy was found in only one pa-tient [4]. The other renal biopsies revealed acute tubularnecrosis (present case; [5, 8]) or normal tissue [5] withno uric acid crystals or uric acid deposition. Murakami etal. [7] suggested an increase in oxygen free radicals pro-duced during exercise leads to renal tissue damage in pa-tients with renal hypouricemia. Because uric acid isthought to be a powerful antioxidant and is a scavengerof free radicals [7], patients with renal hypouricemiamay be at risk from oxygen free radicals damaging thekidneys during exercise. Recently, Ueda et al. [10] re-ported a case of renal hypouricemia with exercise-induced ARF and cerebral infarction. In this patient, re-

versible cerebral infarction was detected by brain com-puted tomography and single-photon emission computedtomography. This suggests that damage by oxygen freeradicals may affect not only the kidney, but also thebrain in patients with renal hypouricemia.

These observations suggest that oxygen free radicalsplay an important role in the development of ARF duringexercise in patients with renal hypouricemia. Further in-vestigations are necessary to clarify the role of oxygenfree radicals in the induction of exercise-induced ARF inpatients with renal hypouricemia.

References

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2. Hisatome I, Kato T, Miyakoda H, Takami T, Abe T, Tanaka Y,Kosaka Y, Ogino H, Mitani Y, Yoshida A, Kotake H, Shigem-asa C, Mashiba H, Sato R, Takeda A (1993) Renal hypourice-mia with both drug-insensitive secretion of urate: a novel typeof renal hypouricemia. Nephron 64:447–451

3. Roch-Ramel F, Guisan B, Diezi J (1997) Effects of uricosuricand antiuricosuric agents on urate transport in human brush-border membrane vesicles. J Pharmacol Exp Ther 280:839–845

4. Erley CMM, Hirschberg RR, Hoefer W, Schaefer K (1989)Acute renal failure due to uric acid nephropathy in a patientwith renal hypouricemia. Klin Wochenschr 67:308–312

5. Ishikawa I, Sakurai Y, Masuzaki S, Sugishita N, Shinoda A,Shikura N (1990) Exercise-induced acute renal failure in 3 pa-tients with renal hypouricemia. Jpn J Nephrol 32:923–928

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Table 1 Pyrazinamide and pro-benecid tests (SCr serum creat-inine, Cua uric acid clearance)

Period SCr Sua CCr Cua Cua/CCr Urine output(min) (mg/dl) mg/dl) (ml/min) (ml/min) (%) (ml)

Pyrazinamide test–30 to 0 0.5 0.7 192.8 80.8 41.9 30

30–60 0.5 0.6 146.6 68.0 46.4 25060–90 0.4 0.6 123.7 48.9 39.5 11090–120 0.4 0.6 156.0 58.7 37.6 160

Probenecid test–60 to 0 0.6 0.9 129.6 61.3 47.3 60

0–60 0.5 0.8 169.8 70.6 44.9 28060–120 0.5 0.9 99.7 41.8 41.8 80

120–180 0.5 0.8 130.6 50.5 38.6 60