Hyperuricosuria with Hypouricemia, an Isolated Defect of the Urate

923

Exercise-induced acute renal failure in

3 patients with renal hypouricemia

ISAO ISHIKAWA, YUSEI SAKURAI, SHIGEKI MASUZAKI,

NAOYASU SUGISHITA, AKIRA SHINODA and NAOTO SHIKURA

Division of Nephrology, Department of Internal Medicine and Division of Clinical Research, Medical Research Institute, Kanazawa Medical University, Uchinada, Kahoku, Ishikawa 920-02, Japan

Key words: acute renal failure, renal hypouricemia, exercise, wedge-shaped patchy contrast enhancement, CT scan

Abstract

Three cases of exercise-induced non-oliguric acute renal failure in patients with renal hypouricemia, an isolated defect of the renal urate transport system, are described. During acute renal failure, the serum uric acid levels were 5.6, 2.7 and 5.8 mg/dl, respectively, and were within normal limits. The values representing the fractional excretion of uric acid (FEUA)were 28.7, 60.0 and 12.7%, with accompanying serum creatinine levels of 8.1, 3.9 and 3.3 mg/dl, respectively. After recovery, the serum uric acid fell to 0.6, 0.7 and 1.0 mg/dl and the FEUA increased to 79.3, 52.8 and 43.2%, respectively. Two of the patients examined exhibited decreased reabsorption of filtered urate. These 3 examples of renal hypouricemia represented 23% of 13 cases of mild exercise-induced acute renal failure encountered within our experience.

developed bilateral loin pain and abdominal pain, Introduction the character of which was continuous and lan- Hyperuricosuria with hypouricemia, an isolated cinating. The pain became severe and he was seen defect of the urate transport system, is a rare at the emergency room of our hospital at 22:40 on condition with an incidence of only 0.15% [1]. The At the time of initial examination, newly described syndrome, acute renal failure with bilateral knock pain was remarkable in both loin pain and patchy renal vasoconstriction [2], is costovertebral areas and there was + + protein in one type of exercise-related acute renal failure. We the normally colored urine and 40 RBCs in the describe here 3 patients with renal hypouricemia, sediment. The patient had no oliguria. Other which was discovered before exercise-induced acute analyses yielded the following data: serum renal failure in one case, and after the onset of creatinine, 7.3 mg/dl; BUN, 62 mg/dl; potassium, acute renal failure in the other 2 cases. Two of 4.6 mEq/l; calcium, 8.8 mg/dl; phosphorus, 4.0 these patients exhibited acute renal failure with loin mg/dl; uric acid, 5.5 mg/dl; and fractional excre- pain and patchy renal vasoconstriction. tion of urate (FEUA), 28.7%. The serum and urine uric acid (urate) levels were determined by Case reports uricase assay (normal male concentration: 3.4-7.1 mg/dl). On 40 ml of 67% sodium Case #1. A 17-year-old student entered a 400 iothalamate was infused intravenously and after meter race at a school athletics meeting on 12,18 and 48 hours, renal CT scans were repeated At 1:00 am on at the same slice level. These scans (Fig. 1) revealed he complained of nausea and vomiting, and then diffuse to patchy contrast enhancement which per- Received January 17, 1990 sisted for at least 48 hours. The serum creatinine

Japanese Journal of Nephrology Vol. 32, No. 8, 1990 75 924 Isao Ishikawa, et al.

Fig. 1. a: Renal CT scan, carried out 18 hours after infusion of 40 ml of 67076 sodium iothalamate, showing diffuse to patchy contrast enhancement in a patient with acute renal failure accompanied by severe loin pain and patchy renal vasoconstriction. The serum creatinine level was 8.1 mg/dl and the serum uric acid level, 5.6 mg/dl. b: Faint contrast enhancement was observed at 41 hours after administration of the contrast medium.

76 Japanese Journal of Nephrology Vol. 32, No. 8, 1990 Acute Renal Failure and Hypouricemia 925 reached a peak concentration of 8.1 mg/dl before mg/dl and the FEUA was 79.3%. A renal biopsy administration of the contrast medium and fell to performed on revealed the kidneys to 6.7 mg/dl by The concentration of be recovering from acute tubular necrosis; no serum uric acid peaked at 5.6 mg/dl and then evidence of urate deposition was noted. The decreased to 5.1 mg/dl by (Table 1). highest serum levels of myoglobin and creatinine Renal dysfunction lasted for 18 days with a serum phosphokinase were 85 ng/ml (normal: 60 ng/ml) creatinine level on of 0.9 mg/dl. and 250 U/l (normal 218 U/1), respectively. There On the same date, the serum uric acid was 0.6 were no significant elevations of the influenza,

Table 1. Serum uric acid, creatinine and FEUA in cases of exercise-induced acute renal failure

I. Patients with renal hypouricemia

II. Patients without renal hypouricemia

Japanese Journal of Nephrology Vol. 32, No. 8, 1990 77 926 Isao Ishikawa, et al.

herpes and Coxsackie virus titers. low in the right kidney. However, no delayed film Case #2. A 22-year-old man experienced flu-like was obtained. symptoms and took 400 mg of aspirin aluminium, Benzbromarone and pyrazinamide tests were 150 mg of ethenzamide and 300 mg of acetamino- performed on November 12 to investigate the urate phen between He twice handling in the kidney. After determining the renal participated in a 100-meter track race at a local clearance of urate and creatinine, 100 mg of athletic meeting on a national benzbromarone was administered in a single dose sports holiday. Four hours later, he complained and two 60-min clearances were measured. Three of nausea and vomited once. g of pyrazinamide was then given orally, and one he suffered from malaise, loin pain, epigastric hour later, three 20-min clearances were measured. pain and slight fever, prompting him to visit a Benzbromarone increased the ratio of urate hospital on Urinalysis revealed the clearance to creatinine clearance from 49.1 to presence of a trace of protein with normal sedi- 59.4%. Subsequently, this ratio did not decrease ment. The results of blood tests were as follows: (59.2%) in response to pyrazinamide (Table 2). BUN, 36 mg/dl; serum creatinine, 3.9 mg/dl; uric The results of a renal biopsy carried out on acid, 2.7 mg/dl; calcium, 8.8 mg/dl; and phos- November 14, 1987, were compatible with the phorus, 4.3 mg/dl. The serum creatinine decreased kidneys being at the healing stage of acute tubular to 3.1, 1.4 and 1.0 mg/dl and the serum uric acid necrosis. to 1.7, 1.0 and 0.4 mg/dl on and Case #3. A 16-year-old student complained of 27, respectively. The FEUA values were 60.0, 52.8 edema of the lower legs on On and 58.0% on respectively. he performed 100 press-ups and 100 sit-ups A plain CT scan performed on October 15 showed following which he experienced pain in his ex- that bilateral enlargement of the kidneys had taken tremities. Dark urine was not noted, but with the place, but without massive deposition of urate since onset of vomiting, he visited a doctor. Urinalysis the density in the medulla was not anomalously revealed + + + protein and no RBCs in the sedi- high. An enhanced CT scan on October 22, carried ment. His blood chemistry was found to be as out at 10 min after contrast administration, follows: BUN, 17 mg/dl; serum creatinine, 1.0 resulted in the detection of a wedge-shaped density mg/dl; uric acid, 1.4 mg/dl; calcium, 8.8 mg/dl;

Table 2. Effect of benzbromarone and pyrazinamide (PZA) on uric acid excretion

S-UA, serum uric acid; S-Cr, serum creatinine; CUA, uric acid clearance; Ccr, creatinine clearance.

78 Japanese Journal of Nephrology Vol. 32, No. 8, 1990 Acute Renal Failure and Hypouricemia 927

phosphorus 3.9 mg/dl, sodium, 142 mEq/l; and Although it is well known that physical exercise potassium, 4.0 mEq/l. At 2:00 am on may induce hyperuricemia [6], our patients with he became dyspneic and was subsequently trans- renal hypouricemia exhibited only mild elevation ferred to our hospital where severe metabolic of their serum uric acid during acute renal failure. acidosis was diagnosed. His creatinine phospho- The fractional excretion of urate was relatively low

kinase was 1,182 U/1 and other findings were: (33.8 •} 24.1 %) compared to the serum creatinine serum uric acid, 5.8 mg/dl; serum creatinine, 3.3 levels during the period of acute renal failure, and mg/dl; calcium, 8.3 mg/dl; phosphorus, 10.5 returned to high levels (58.4 •} 18.7%) after mg/dl; and FEUA, 12.7%. He was non-oliguric recovery. This suggests that the glomerular damage and his urinalysis was normal for protein and is greater than the tubular damage in mild cases

sediment. Dialysis was immediately instituted to of exercise-induced acute renal failure. treat congestive heart failure and severe metabolic In 1982, Ishikawa et al. [2] described a new acidosis. On 1986, his serum creatinine acute renal failure syndrome. Acute renal failure level was 0.7 mg/dl, serum uric acid 1.0 mg/dl, with severe loin pain and patchy renal vasoconstric- and FEUA 43.2%. The effects of benzbromarone tion is a clinical syndrome which occurs most often and pyrazinamide on the urate transport were in young, previously healthy individuals. Such

examined on 1986. Benzbromarone in- patients come to the emergency room, usually late creased the ratio of urate clearance to creatinine at night, complaining of severe bilateral loin pain clearance from 57.7 to 69.5%, while subsequent with nausea, vomiting and slight fever after mild

pyrazinamide administration changed the ratio to exercise. Myoglobinuria and darkened urine are 78.5% (Table 2). Urate excretion was thus slightly not characteristic. However, there is mild or accelerated by benzbromarone, and was not in- moderate elevation of the creatinine phosphokinase hibited by pyrazinamide. A renal biopsy on concentration, suggesting that massive rhabdo- revealed no evidence of glomerulo- myolysis does not occur. CT scans performed 1-2 nephritis or urate deposition. days after the introduction of contrast medium We have encountered 12 other cases of acute reveal patchy wedge-shaped contrast enhancement, renal failure with severe loin pain and renal indicative of patchy renal vasoconstriction. Such vasoconstriction, several of which have been acute renal failure is usually of a mild and non- reported previously [2-5]. In 10 of these cases, for oliguric form and has a good prognosis. The which relevant data were obtained, the uric acid etiology in case 1 was compatible with that of the was 11.4 •} 4.2 mg/dl (mean •} SD) and the serum acute renal failure syndrome, as described above, creatinine 3.1 •} 1.6 mg/dl (Table 1). No renal with severe loin pain and patchy renal vasoconstric- hypouricemia was noted in these 10 patients. tion. In case 2, although CT demonstration of

patchy wedge-shaped contrast enhancement was not definitive, this syndrome was suspected. The Discussion cause of the acute renal failure in case 3 remained In the present 3 cases, renal hypouricemia was unknown because of the immediate need for found to have occurred before the onset of acute dialysis treatment and consequent failure to test renal failure in one patient and after onset in the for the existence of patchy wedge-shaped renal other two. In cases 2 and 3, benzbromarone and damage. However, the patient's history of exercise pyrazinamide tests revealed that the reabsorption and elevation of creatinine phosphokinase sug- of filtered urate was decreased. No other tubular gested at least that he had experienced exercise- dysfunction, except for urate transport after related acute renal dysfunction. None of the recovery, was detected in these 3 cases, and none patients described here displayed evidence of were administered uricosuric drugs (except for case massive rhabdomyolysis. 2) or showed evidence of enzymatic defects. Serum uric acid levels were determined during Isolated metabolic dysfunction of the urate and after acute renal dysfunction in 10 of 12 transport system is thus thought to be the causative patients suffering from acute renal failure accom- agent here. In case 3, other family members were panied by severe loin pain and patchy renal found to exhibit renal hypouricemia. vasoconstriction. In these 10 patients, the average Japanese Journal of Nephrology Vol. 32, No. 8, 1990 79 928 Isao Ishikawa, et al.

serum uric acid level was initially 11.4 •} 4.2 mg/dl hypouricemia and that due to the exercise. (serum creatinine, 3.1 •} 1.6 mg/dl), but dropped Exercise-induced acute renal failure is to 6.1 •} 1.2 mg/dl (serum creatinine, 1.1 •} 0.1 sometimes accompanied by the relatively rare mg/dl) after recovery. These figures are in sharp condition, renal hypouricemia. Our examinations contrast to the 4.7 •} 1.7 mg/dl of serum uric acid revealed that 3 of 13 patients with mild exercise- (serum creatinine, 5.1 •} 2.6 mg/dl) measured related acute renal failure including acute renal during the episode of acute renal failure in the 3 failure with severe loin pain and patchy renal patients with renal hypouricemia. In the latter, vasoconstriction, displayed renal hypouricemia . after recovery from acute renal failure, the serum uric acid level was 0.8 •} 0.2 mg/dl (serum Acknowledgement creatinine, 1.1 •} 0.3 mg/dl). Thus, out of 13 We are grateful to Dr. Shigehiko Sato, Ushitsu General patients presenting with exercise-induced acute Hospital, for referring case #2 to us. renal failure, 3 (23 Wo) exhibited renal hypouricemia. This incidence of hypouricemia seems to be References too high to allow the conclusion that the associa- tion of renal failure and renal hypouricemia could 1. Hisatome I, Ogino K, Kotake H, Ishiko R, Saito M, have occurred by chance in the 3 persons described. Hasegawa J, Mashiba H, Nakamoto S: Cause of per- The relationship between renal hypouricemia sistent hypouricemia in outpatients. Nephron 51:13-16, 1989 and exercise-induced acute renal failure is 2. Ishikawa I, Onouchi Z, Yuri T, Saito Y, Shinoda A, unknown. Recently, it has been demonstrated that Yamamoto I: Acute renal failure with severe loin pain suprofen-induced uricosuria can cause acute and patchy renal vasoconstriction; in Acute renal nephropathy and flank pain [7], the latter being failure, edited by Eliahou HE. London, Libbey, pp a symptom of uric acid nephropathy. However, 224-229, 1982 3. Ishikawa I, Saito Y, Shinoda A, Onouchi Z: Evidence among the present 13 patients (including case 3) for patchy renal vasoconstriction in man: Observation displaying acute renal failure with loin pain and by CT scan. Nephron 27: 31-34, 1981 patchy renal vasoconstriction, 8 did not take 4. Ishikawa I, Ishii H, Saito T, Yuri T, Shinoda A, nonsteroideal anti-inflammatory drugs. Renal Urashima S: Increased patchy renal accumulation of 99mTc hyperuricosuria with hypouricemia may be related -methylene diphosphonate in a patient with severe loin pain after exercise. Nephron 47: 29-31, 1987 to the development of exercise-induced acute renal 5. Ishikawa I, Masuzaki S, Saito T, Yuri T, Shinoda A, failure, since it is possible that renal dysfunction Tsujigiwa M: Magnetic resonance imaging in renal is caused by impairment of renal perfusion accom- infarction and ischemia. Nephron 51: 99-102, 1989 panying tubular precipitation of uric acid [8]. 6. Lijnen P, Hespel P, Vanden Eynde E, Amery A: Biochemical variables in plasma and urine before and This idea is only speculation since our biopsies after prolonged physical exercise. Enzyme 33:134-142 , yielded no evidence for tubular urate precipitation 1985 and the CT scans did not reveal that urate deposi- 7. Abraham PA, Halstenson CE, Opsahl JA, Matzke tion had taken place within the medulla. However, GR, Keane WF: Suprofen-induced uricosuria: A recently, a case which required dialysis in connec- potential mechanism for acute nephropathy and flank tion with acute renal failure resulting from uric acid pain. Am J Nephrol 8: 90-95, 1988 8. Conger JD, Falk SA, Guggenheim SJ, Burke TJ: nephropathy without hypeuricemia has been A micropuncture study of the early phase of acute urate reported [9]. The etiological relationship between nephropathy. J Clin Invest 58: 681-689, 1976 renal hypouricemia and exercise-induced acute 9. Erley ChMM, Hirschberg RR, Hoefer W, Schaefer K: renal failure could thus involve a "double load" Acute renal failure due to uric acid nephropathy in a of hyperuricosuria, that due to the renal patient with renal hypouricemia. Klin Wochenschr 67: 308-312, 1989

80 Japanese Journal of Nephrology Vol. 32, No. 8, 1990