A Case of Exercise-Induced Acute Renal Failure in a Patient With

509

Case Report

A Case of Exercise-Induced Acute Renal Failure in a Patient with Idiopathic Renal Hypouricemia Developed during Antihypertensive Therapy with Losartan and Trichlormethiazide

Osamu ITO, Yutaka HASEGAWA, Kazuto SATO, Hideaki MITSUI＊, Fumiaki YUDA＊＊, Hiroshi SATO＊＊＊, Sadayoshi ITO＊＊＊, and Ken-ichi KUDO

Exercise-induced acute renal failure (ARF) developed in a 45-year-old man during antihypertensive therapy with losartan and trichlormethiazide. The antihypertensive therapy was stopped and marked hypouricemia became apparent during improvement of his renal function. The daily urinary excretion of uric acid was normal and an increased fractional excretion of uric acid was observed. Renal biopsy revealed that the kidney was recovering from acute tubular necrosis with interstitial ﬁbrosis. Based on the results of pyrazinamide and benzbromarone tests, we classiﬁed this case as one of presecretory reabsorption defect of uric acid. Antihypertesive therapy with benidipine and candesartan was initiated, and the patient has not had any ARF episodes since. Because idiopathic renal hypouricemia can be associated with exercise-induced ARF and chronic renal dysfunction, careful antihypertensive therapy and follow-up evaluation of renal function might be necessary for hypertensive patients with idiopathic renal hypouricemia. (Hypertens Res 2003; 26: 509–513)

Key Words: exercise-induced acute renal failure, idiopathic renal hypouricemia, urate transport, hypertension, losartan

tubular transport of uric acid (7). Enomoto et al. recently Introduction provided evidence that patients with idiopathic renal hypouricemia have defects in a gene (SLC22A12) encoding for Hyperuricemia is one of the common complications in es- the urate transporter (URAT1) (8). This disorder usually has sential hypertension. It has been recognized that hyper- no clinical manifestation other than formation of uric acid uricemia is an independent risk factor for cardiovascular stones of the urinary tract (6). However, an important com- morbidity and mortality in hypertensive patients (1). The plication of this disorder is exercise-induced acute renal fail- control of hyperuricemia might be important for antihyper- ure (ARF), which was ﬁrst reported by Erley et al. in 1989 tensive therapy (2). In this regard, losartan, an angiotensin II (9). More than 50 cases of exercise-induced ARF in patients (AII) receptor antagonist, is considered to be useful for the with idiopathic renal hypouricemia have been reported, and treatment of hypertensive patients with hyperuricemia be- most of these have been young adults or children from Japan cause of its uricosuric property (3–5). (9–19). We here report a case of exercise-induced ARF in a Idiopathic renal hypouricemia is a rare disorder with an middle-aged man with idiopathic renal hypouricemia. He incidence of 0.15% in Japan (6). The patients exhibit an in- had been treated with losartan and trichlormethiazide as an crease in uric acid excretion due to an isolated defect in renal antihypertensive therapy.

From the Department of Internal Medicine, ＊Department of Radiology, and ＊＊Department of Pathology, Yamagata City Hospital Saiseikan, Yamagata, Japan, and ＊＊＊Department of Nephrology, Endocrinology and Hypertension, Tohoku University School of Medicine, Sendai, Japan. Address for Reprints: Osamu Ito, M.D., Ph.D., Department of Internal Medicine, Yamagata City Hospital Saiseikan, Nanoka-machi 1–3–26, Yamagata 990–8533, Japan. E-mail: [email protected] Received December 11, 2002; Accepted in revised form January 8, 2003. 510 Hypertens Res Vol. 26, No. 6 (2003)

Table 1. Laboratory Data of the Patients on Admission

White blood cell 6,540/µl AST 28 IU/l BUN 26.9 mg/dl Red blood cell 452×104 /µl ALT 46 IU/l Creatinine 3.4 mg/dl Hemoglobin 14.6 g/dl LDH 251 IU/l Uric acid 2.0 mg/dl Hematocrit 41.7% ALP 181 IU/l Sodium 140 mEq/l Platelet 32.4×104 /µl γ-GTP 36 IU/l Potassium 4.5 mEq/l Total cholesterol 184 mg/dl Total protein 8.0 g/dl Chloride 102 mEq/l Triglyceride 132 mg/dl Albumine 5.0 g/dl Calcium 9.2 mg/dl Glucose 85 mg/dl CPK 124 IU/l Phosphate 3.1 mg/dl Myoglobin 127.8 ng/ml C-reactive protein 0.53 mg/dl AST, asparate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; ALP, alkaline phosphatase; γ-GTP, γ- glutamyltranspeptidase; CPK, creatine phosphokinase; BUN, blood urea nitrogen.

Case Report A 45-year-old man was referred to Yamagata City Hospital for the evaluation of ARF on August 27, 2001. Hypertension had been diagnosed 2 years prior and an antihypertensive therapy with losartan (25 mg/day) and trichlormethiazide (1 mg/day) had been initiated 4 months prior. On August 20, he complained of nausea, malaise and slight fever after a Karate training session. He had done such training twice a week since his high school days, but this was his first episode of ARF. On August 25, he visited a doctor and laboratory evaluation revealed a serum creatinine (S-Cr) level of 6.0 mg/dl and blood urea nitrogen (BUN) level of 38.1 mg/dl. On ad- Fig. 1. Changes in the patient’s serum concentration of cre- mission, his blood pressure was 156/113 mmHg and his atinine (S-Cr) and uric acid (S-UA). On 6 days after onset, pulse was 77 beats/min. The results of a physical examina- he visited a doctor and his S-Cr was 6.0 mg/dl. On admis- tion were entirely unremarkable. Urine volume was 1,500 sion, his S-Cr and S-UA were 3.4 mg/dl and 2.0 mg/dl, re- ml/day. Urinalysis revealed a specific gravity of 1.009 and spectively. With conservative therapy, the S-Cr decreased to pH 5.5. Urinary protein and occult blood were negative. Uri- 1.0 mg/dl and nearly stabilized. Serum uric acid decreased nary sediment showed hyaline granular casts and no uric to a subnormal concentration of 0.7–0.8 mg/dl. acid crystals. Neither glycosuria nor aminoaciduria was seen. Laboratory data were as follows (Table 1): hemoglobin 14.6 g/dl, hematocrit 41.7%, white blood cell count 6,540 /µl with A diagnosis of exercise-induced ARF associated with idio- normal differentiation, platelet count 32.4×104/µl, S-Cr 3.4 pathic renal hypouricemia was made. mg/dl, BUN 26.9 mg/dl, uric acid 2.0 mg/dl, sodium 140 After recovery from ARF, magnetic resonance angiogra- mEq/l, potassium 4.5 mEq/l, chloride 102 mEq/l, calcium phy and arteriography demonstrated double renal artery in 9.2 mg/l, phosphate 3.1 mg/l, asparate aminotransferase 28 the left kidney. However, plasma renin activity was 1.7 IU/l, lactate dehydrogenase 251 IU/l, creatinine phosphoki- ng/ml/h and plasma aldosterone concentration was 76 pg/ml. nase 124 IU/l, and myoglobin 128 ng/ml. Chest X-ray and A renal vein sampling during treatment with captopril (37.5 electrocardiogram appeared normal. Plain CT showed bilat- mg/day) showed that the level of plasma renin activity was eral enlargement of the kidneys without hydronephrosis. similar in the right and left renal vein (8.6 and 8.0 ng/ml/h). The clinical course is illustrated in Fig. 1. The antihyper- These results served to rule out the possibility of renovascu- tensive therapy with losartan and trichlormethiazide was lar hypertension or secondary hypertension. stopped and a new therapy with benidipine was initiated. A renal biopsy was performed on November 11. Light-mi- With a conservative therapy, S-Cr decreased to 1.0 mg/dl croscopic examinations revealed the kidney to be recovering and nearly stabilized. The glomerular filtration rate (GFR) from acute tubular necrosis. The histological findings includ- was 73.2 ml/min/1.73 m2. Serum uric acid decreased to a ed normal glomeruli, atherosclerotic arterioles and interstitial subnormal concentration of 0.7–0.8 mg/dl. The daily urinary fibrosis with little cellular infiltration over a wide area. There excretion of uric acid was in a normal range from 500 to 600 was no urate deposition (Fig. 2). Pyrazinamide and benzbro- mg and the fractional excretion of uric acid (FEUA) was 55%. marone tests were also performed. Pyrazinamide (3 g) de- Ito et al: Renal Hypouricemia and Antihypertensive Drugs 511

Table 2. Pyrazinamide and Benzbromarone Tests

Serum uric acid Serum creatinine U-UA/U-Cr FEUA Time (min) (mg/dl) (mg/dl) (%) (%) Pyrazinamide test －30–0 0.7 1.0 39.3 56.1 －00–30 0.7 1.0 39.0 55.7 －30–60 0.7 1.0 40.3 57.6 －60–90 0.7 1.0 37.6 53.7 －90–120 0.7 1.0 38.4 54.9 Benzbromarone test －60–0 0.8 1.0 40.2 50.3 －00–60 0.8 1.0 43.4 54.2 －60–120 0.7 1.0 41.5 59.3 120–180 0.7 1.0 39.5 56.4

U-UA, urinary concentration of uric acid; U-Cr, urinary concentration of creatinine; FEUA, fractional excretion of uric acid.

creased FEUA from 56.1% to 53.7%. Benzbromarone (100 mg) increased FEUA from 50.3% to 59.3% (Table 2). Based on the results of these tests, we classiﬁed the present case as one of presecretory reabsorption defect of uric acid (7).

Discussion Idiopathic renal hypouricemia is a rare disorder, although its precise incidence is unclear. Hisatome et al. reported that renal hypouricemia was found in 0.15% of individuals in an outpatient Japanese population (6). The incidence of renal hypouricemia in other patient populations is not known, although 50% of case reports of renal hypouricemia involve Japanese patients (14). Exercise-induced ARF in patients with idiopathic renal hypouricemia was first reported by Erley et al. in 1989 (9). Since that time, more than 50 cases of exercise-induced ARF with idiopathic renal hypouricemia have been reported, and most of these were cases from Japan (9–19). Ishikawa et al. reported 13 patients with exercise-induced ARF, and 3 (23%) of these were associated with idiopathic renal hypouricemia (10). In view of these findings, patients with idiopathic renal hypouricemia can be considered to have a 200-fold greater predisposition to exercise-induced ARF than those without renal hypouricemia. Although the long-term prognosis of these patients is not well known, chronic renal dysfunction, as revealed by such conditions as decreased GFR and decreased urine-concentrating ability, has been reported in patients with renal hypouricemia and Fig. 2. Light micrograph of the renal biopsy specimen ob- concomitant exercise-induced ARF (17). Decreased GFR tained from the present patient. Staining was done with and interstitial fibrosis over a wide area of the kidney were hematoxylin-eosin. Magnifications are ×100 (upper) and revealed in the present case. ×400 (lower). The histological findings included normal The mechanism of exercise-induced ARF in renal hy- glomeruli, atherosclerotic arterioles, and interstitial fibrosis pouricemia is unclear, although several hypotheses have with little cellular infiltration over a wide area. There was been proposed. The first hypothesis is that exercise-induced no urate deposition. ARF in renal hypouricemia is a result of acute uric acid nephropathy (12, 14). During exercise, the production of uric acid is increased and dehydration concentrates urine. The 512 Hypertens Res Vol. 26, No. 6 (2003) concentration of uric acid in urine is markedly increased in a pertensive patients and in normotensive subjects at genetic patient with renal hypouricemia, and this may result in acute risk for hypertension (21). ACE inhibitors and AII receptor uric acid nephropathy. In this regard, Erley et al. (9) reported antagonists may decrease the production of oxygen free radi- that acute tubular necrosis with intratubular urate crystals cals and the morbidity of exercise-induced ARF in patients was found in a renal biopsy specimen, whereas no other re- with renal hypouricemia. It is unknown whether losartan ports have identified this crystal in such specimens. The sec- shows a uricosuric property in patients with idiopathic renal ond hypothesis, proposed by Murakami et al. (13), empha- hypouricemia. Benzbromarone and probenecid inhibit sizes the role of uric acid as an antioxidant. The renal han- URAT1 expressed in Xenopus oocytes (8) and urate trans- dling of uric acid seems to be a protective mechanism port in the brush-border membrane of the human kidney against the renal injury by oxygen free radicals. Both the uric (22). In addition to these uricosuric drugs, losartan also in- acid pool and the total amount of uric acid mobilized into the hibits URAT1 (8) and urate transport in the brush-border proximal tubular cells are very small in patients with renal membrane of the human kidney (23). Benzbromarone and hypouricemia. Renal perfusion is diminished during exer- probenecid can increase FEUA in patients classified as having cise, and reperfusion is achieved after exercise, which mim- a presecretory reabsorption defect of uric acid (7), who con- ics ischemia-reperfusion injury. In this state, an excessive stitute the majority of cases of exercise-induced ARF production of oxygen free radicals may lead to extensive (12–19). Therefore, it is possible that losartan may increase kidney damage. It has also been proposed that an intrarenal FEUA even in patients with idiopathic renal hypouricemia. In perfusion defect due to regional vasoconstriction participates this regard, other AII receptor antagonists are considered to in the mechanisms of this type of ARF. Ishikawa et al. (10) be more safe for the patients with idiopathic renal hy- reported that renal CT revealed a delayed wedge-shaped pouricemia, because these drugs have no uricosuric property patchy contrast enhancement during exercise-induced ARF (23, 24). in patients with idiopathic renal hypouricemia. Hasegawa et Although idiopathic renal hypouricemia is a rare disorder, al. (15) reported that renal CT showed the delayed wedge- it can be associated with exercise-induced ARF and chronic shaped patchy contrast enhancement after exercise in a pa- renal dysfunction. Careful antihypertensive therapy and fol- tient with idiopathic renal hypouricemia, even though the low-up evaluation of renal function might be necessary for level of exercise did not induce ARF. 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