A case of acute renal failure after exercise with renal hypouricemia demonstrated compound heterozygous mutations of uric acid transporter 1

Familial renal hypouricemia is a hereditary disease characterized by extraordinary high renal uric acid (UA) clearance and is associated with acute renal failure (ARF). A 17-year-old Japanese male developed ARF after anerobic exercise. Renal function improved completely after approximately 2 weeks of hydration treatment. After remission, hypouricemia became evident (1.0 mg/dL) from the initial level of UA (4.8 mg/dL) and fractional excretion of uric acid (FEUA) was >50%. His parents showed normal levels of UA and FEUA. Polymerase chain reaction of a urate anion exchanger known to regulate UA level [SLC22A12 gene: UA transporter 1 (URAT1)] demonstrated compound heterozygous mutations (Q297X and R90H). Thus, we describe a Japanese male with hypouricemia complicated by anerobic exercise-induced ARF, with definite demonstration of a genetic abnormality in the responsible gene, URAT1.     

Patchy renal vasoconstriction after exercise in a child without renal hypouricemia

Here, I present a case of patchy renal vasoconstriction and renal injury in a girl without renal hypouricemia, following exercise and ingestion of an analgesic. For the previous 2 years, she had suffered from re-current abdominal pain following exercise. Postcontrast renal computed tomographic scan showed low-density patchy areas immediately after contrast medium injection, and then patchy wedge-shaped contrast enhancement 22 h later. These symptoms and signs are typical findings of patchy renal vasoconstriction. Although precise mechanisms for the development of patchy renal vasoconstriction after exercise in patients without renal hypouricemia remain obscure, both exercise and ingestion of an analgesic were active in the development of patchy renal vasoconstriction and renal injury in our patient. Received: 9 August 2001 / Revised: 10 December 2001 / Accepted: 11 December 2001     

Patients with renal hypouricemia with exercise-induced acute renal failure and chronic renal dysfunction

We here report the case of a 38-year-old male with back pain and vomiting occurring after exercise. Serum creatinine level was elevated, and he was admitted to our hospital with diagnosis of acute renal failure (ARF). He had experienced similar attacks at least 4 times, including the present episode, from the age of 22 years. After admission, the patient was managed only by resting, and remission was nearly attained in about 1 month. The renal biopsy specimen performed on day 15 showed findings of acute tubular necrosis, thickening of the tubular basement membrane, and interstitial fibrosis. After remission, the serum uric acid level was 0.7-0.8 mg/dl, fractional excretion of uric acid was 0.63, and the possibility of other diseases facilitating the excretion of uric acid was denied. Therefore, ARF associated with idiopathic renal hypouricemia was diagnosed. Since only mild responses were observed in a pyradinamide loading test and a benzbromarone loading test, the case was considered to be a presecretary reabsorption disorder type. Renal function tests showed the almost complete recovery of the glomerular filtration rate (GFR: 114 ml/min/1.73 m2), but the urine concentrating ability was markedly decreased (specific gravity 1.019 and osmolarity 516 mOsm/kgxH2O in Fishberg test). Past data from this patient indicated that this renal dysfunction had been persisting for ten years. We examined 9 patients with renal hypouricemia and focused on the differences between the two groups (with or without complications). Four patients had a history of exercise-induced ARF or calculus. The urine concentrating ability was significantly lower in these patients (group A) than in the other patients without complications (group B). The glomerular filtration rate in group A was within the normal range, but was lower than in group B. These results suggested the possibility that patients with renal hypouricemia with complications may have chronic renal dysfunction in the future.     

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

We describe a case of exercise-induced acute renal failure (ARF) in a patient with hypouricemia. Following recovery from ARF, the patient’s serum urate concentration was 0.6–0.9 mg/dl, and the ratio of urate clearance to creatinine clearance (C _ua/C _Cr) was 41.9%–56.6%. There was no change in the C _ua/C _Cr following the administration of pyrazinamide or probenecid, suggesting defects of tubular urate/anion exchangers. Because the renal biopsy revealed acute tubular necrosis without uric acid crystals, the ARF of this patient might be due to oxygen free radicals resulting from exercise stress and hypouricemia. Received: 15 March 1999 / Revised: 10 September 1999 / Accepted: 14 September 1999     

Exercise-induced acute renal failure associated with renal vasoconstriction]

Exercise-induced acute renal failure without rhabdomyolysis is not a rare condition. We experienced 6 cases (5 men and a woman) during last the 8 years. All cases complained of severe loin pain and nausea after mild to moderate exercises (for example, a track race in an athletic meeting). The elevation of serum and urinary myoglobin was undetected. In 4 of 5 patients with abdominal CT, renal patchy vasoconstriction (wedge-shaped low-density lesion) was observed. This was diagnosed as exercise-induced acute renal failure with loin pain (serum creatinine levels: 1.7-8.6 mg/dl). The renal function in 5 of the 6 cases normalized in about three weeks by fluid replacement therapy and hemodialysis support, which one patient received for 3 days. One patient required a long time for improvement of renal function and renal insufficiency persisted (serum creatinine 1.8 mg/dl). In 2 patients, the concentration of serum uric acid became very low after the recovery of renal function. These two patients were diagnosed as an isolated hyperuricosuric hypouricemia. More than half of the 6 patients had previously experienced the same episodes (loin pain and nausea) after exercise. Exercise-induced acute renal failure, probably due to renal patchy vasoconstriction, seems to be not a rare disease. The etiology of renal patchy vasoconstriction after exercises remains to be elucidated. The occurrence of acute renal failure must be taken into consideration when the youngster, especially with renal hypouricemia, complains of severe loin pain and nausea after exercise such as a track race.     

Oxidative imbalance in idiopathic renal hypouricemia

An important complication of idiopathic renal hypouricemia is exercise-induced acute renal failure (ARF). The most plausible explanation for this complication is that decreased antioxidant potential leads to kidney injury by reactive oxygen species (ROS). We demonstrated this oxidative imbalance by a concomitant assessment of ROS production and antioxidant system capability in a 15- year-old girl with idiopathic renal hypouricemia caused by a mutation in the urate transporter (URAT1) gene. Her serum level of ROS increased with decreasing antioxidant potential capacity soon after the initiation of anaerobic stress due to treadmill exercise. Thereafter, serum levels of ROS and antioxidant potential showed a parallel course, returning to the baseline values at 240 min after exercise. Some patients with idiopathic renal hypouricemia demonstrate oxidative imbalance soon after exercise with a predisposition to exercise-induced acute renal failure. Antioxidant properties may alter this imbalance by augmenting the antioxidant activity.     

Mutational analysis of idiopathic renal hypouricemia in Korea

Idiopathic renal hypouricemia is a hereditary disease characterized by abnormally high renal uric acid clearance. Most patients are clinically silent, but acute renal failure (ARF), urolithiasis, or hematuria may develop. A defect in the SLC22A12 gene, which encodes the renal uric acid transporter, URAT1, is the known major cause of this disorder. We performed a mutational analysis of the SLC22A12 gene in five Korean patients with idiopathic renal hypouricemia in this study. Two patients presented with microscopic hematuria, one with uric acid urolithiasis, and one with exercise-induced ARF. One patient was asymptomatic. Three different mutations, W258X, R90H and R477H, were detected in four of the patients. However, no mutation was found in the fifth ARF patient. This is the first study of SLC22A12 mutations in a country other than Japan. W258X was found to be the predominant SLC22A12 mutation in Korean renal hypouricemia patients, as has been reported in Japan.     

Reversible renal vasoconstriction in a patient with acute renal failure after exercise

Acute renal failure (ARF) with severe loin pain induced by anaerobic exercise is a rare condition that is accompanied by wedge-shaped contrast enhancement seen on computerized tomographic (CT) scan without evidence of rhabdomyolysis. An 18-year-old Korean male was transferred to our hospital for evaluation of mild azotemia, that developed after anaerobic exercise. The laboratory tests revealed that the serum creatinine was 2.1 mg/dl and the serum uric acid level was 1.6 mg/dl without any elevation of the serum myoglobin or creatine phosphokinase. Under the impression of exercise-induced ARF, we tried to determine the relationship between the occurrence of clinical symptoms, renal dysfunction and the characteristic CT findings by observing those changes prospectively before and after anaerobic exercise. After obtaining a written consent, the patient underwent a strenuous period of anaerobic exercise to induce the clinical symptoms. Before exercise, he was completely asymptomatic; his serum creatinine level was 0.9 mg/dl and CT scan of the kidneys showed no abnormalities. Loin pain developed 2 hours after exercise, and the serum creatinine level increased to 1.2 mg/dl 18 hours after the exercise. CT scan 18 hours after exercise showed multiple perfusion defects, and a 24-hour delayed CT scan showed multiple areas of wedge-shaped enhancement on both kidneys. These changes were completely resolved on the follow-up CT scan obtained 13 days after exercise with the return of a normal serum creatinine level. We conclude that reversible renal vasoconstriction is probably the main pathophysiologic mechanism of acute renal failure induced by anaerobic exercise.     

Exercise-induced acute renal failure with renal hypouricemia: a case report and a review of the literature

A previously healthy 16-year-old boy developed acute renal failure following a track race at a local athletic meeting. Several hours after the run, he expressed pain in the loins with nausea and vomiting. After 3 sessions of hemodialysis, he was referred to our hospital. On admission, serum creatinine was elevated to 2.3 mg/dl without an increase in serum uric acid level. After recovery from acute renal failure (ARF), hypouricemia (0.7 mg/dl) became evident in the patient. One year later, he suffered from ARF after a track race with the highest creatinine levels of 1.1 mg/dl. In order to clarify the cause and prognosis of ARF with renal hypouricemia, we summarized the clinical features in 18 patients previously described and our patient. Serum uric acid levels after recovery from ARF were below 1.0 mg/dl in all patients. Renal biopsy in 9 patients showed acute tubular necrosis in 8 patients and uric acid nephropathy in 1. The short-term prognosis of these patients seemed good, although 5 patients needed to undergo hemodialysis in their ARF courses. However, the recurrence of ARF episodes occurred in 6 patients (31.6%) including our patient, indicating that prevention of ARF might be necessary in these patients. More information is required to establish guidance for prevention of ARF.     

Renal hypouricemia in school-aged children: screening of serum uric acid level before physical training

We present two cases of a 12-year-old Japanese boy and a 14-year-old Japanese girl who had exercise-induced acute renal failure (ARF). They experienced general fatigue, nausea/vomiting, and vague discomfort in the abdomen after physical exercise at school. In case of the boy, abdominal pain subsided, but renal dysfunction lasted 17 days, with peak levels of creatinine 9.4 mg/dl and uric acid 11.3 mg/dl. On the other hand, as the girl had suffered from hypouricemia before, she followed a doctor’s guidance on prevention of ARF. Consequently, she was promptly diagnosed as having exercise-induced ARF associated with hypouricemia, and rapidly recovered from ARF within a week. The difference between their clinical courses suggested a possibility that previous laboratory evaluation of serum uric acid assisted in the management of exercise-induced ARF associated with hypouricemia. School-aged children, especially Japanese and Asian, may be advised to have their serum uric acid measured before starting physical training at school.     

Two cases of exercise-induced acute renal failure with idiopathic renal hypouricemia

Acute renal failure without oliguria developed in a 25-year-old male and a 19-year-old male after exercise. Marked hypouricemia became apparent during improvement of their renal function. Increased excretion of uric acid into the urine, increased fractional excretion of uric acid(clearance ratio of uric acid against creatinine), and normal concentration of plasma xanthine and hypoxanthine were observed in both cases. Probenecid and pyrazinamide loading test suggesting decreased reabsorption of uric acid in the proximal convoluted tubules revealed that presecretory reabsorption defect of uric acid resulted in the hypouricemia in both cases. These two cases were diagnosed as having idiopathic renal hypouricemia.     

Bone scintigraphy in acute renal failure with severe loin pain and patchy renal vasoconstriction.

To evaluate the patterns of renal images and the diagnostic value as a screening test of the whole-body bone and renal scintigraphy with technetium-99m-methylene diphosphonate (99mTc-MDP) or -pyrophosphate (99mTc-PYP), we performed bone scintigraphy in 6 patients with acute renal failure (ARF) with severe loin pain and patchy renal vasoconstriction on postcontrast renal computed tomography (CT). All 6 patients were young and previously healthy but experienced severe loin pain after track events. Five took analgesics. Postcontrast renal CT showed patchy low-density areas or diffuse enhancement immediately after radiocontrast injection and then patchy wedge-shaped enhancement 24 or 48 h later, which subsequently disappeared 72 h later. On the whole-body bone scintigrams with 99mTc-MDP or 99mTc-PYP before obtaining renal CT, there was no increased uptake of isotope in the soft tissue, and multiple patchy increased accumulations of the isotope in the kidney were observed in 5 patients. In 2 patients, renal scintigraphies with technetium-99m-dimercaptosuccinate showed photon-deficient areas in the same areas of patchy isotope accumulation in the whole-body bone scintigraphies. Whole-body image and renal scintigraphy with bone-seeking agents may be useful as a screening test and in the search for the theoretical evidence of ARF with severe loin pain and patchy renal vasoconstriction.     

Exercise-induced acute renal failure associated with renal hypouricaemia: results of a questionnaire-based survey in Japan.

BACKGROUND: A retrospective investigation was conducted to define the clinical features of exercise-induced acute renal failure (ARF) associated with renal hypouricaemia with the aim of clarifying further the clinical features of the disease entity. METHODS: A questionnaire was mailed to 43 institutions in Japan that had experienced case(s) of exercise-induced ARF associated with renal hypouricaemia. Fifty-four patients (48 males and six females) were identified from 38 institutions. RESULTS: Median age at the first episode of ARF was 17 years (range 11-46). The maximal serum uric acid and creatinine levels were 4.40+/-2.49 (range 0.4-13.3) and 5.45+/-3.33 mg/dl (range 1.10-17.7), respectively. The serum uric acid level after recovery was 0.70+/-0.25 mg/dl (range 0.1-1.4). The short-term prognosis seemed to be good and histological findings in 28 patients showed minimal change or acute tubular necrosis except for one patient with chronic lesions. ARF episodes occurred predominantly in September, October and May, mostly after strenuous exercise such as a short-distance race. The first symptoms were nausea/vomiting in 51 episodes, loin pain in 35, abdominal pain in 22, general fatigue in 16 and low-grade fever in seven. Thirteen patients (24.1%) experienced recurrent ARF at various intervals. Univariate and multivariate analyses failed to demonstrate any risk factor of ARF recurrence, although no female patients experienced ARF recurrence. CONCLUSIONS: The reason for the heterogeneity in ARF associated with renal hypouricaemia remains unknown. Further studies, especially on molecular mechanisms, are required to establish the best guidance against ARF recurrence.     

Urinary excretion of vitamin C in chronic renal failure and after renal transplantation

Urinary excretion of vitamin C was investigated in 44 patients with chronic renal diseases and in 25 patients after renal transplantation with various mean glomerular filtration rates. In both groups a hyperbolic relationship was observed between FE_{vitamin C} and C_Cr. In addition, direct relationships were found between FE_{vitamin C} and FE_Na, FE_K and FE_{H 2}O in both groups. Various chronic renal diseases and treatments had no influence on the investigated relationships. In 16 healthy subjects urinary excretion of sodium during maximal water diuresis did not increase but urinary excretion of vitamin C significantly increased. In 10 patients in the polyuric stage of chronic renal failure without dialysis treatment during Giordano-Giovanetti-Maggiora diet with addition of sodium chloride the urinary excretion of sodium increased but that of vitamin C was not influenced. The results obtained for the biochemical parameters tested suggest that the urinary excretion of vitamin C depends on the urinary excretion of water.     

Two cases of nephrotic syndrome (NS)-induced acute kidney injury (AKI) associated with renal hypouricemia

Renal hypouricemia is a clinical disorder attributed to an increased renal urate excretion rate and is well known to involve a high risk of urolithiasis and exercise-induced acute kidney injury (AKI). This report concerns two interesting cases of nephrotic syndrome (NS)-induced AKI associated with renal hypouricemia. A 64-year-old female (Case 1) and a 37-year-old male (Case 2) were hospitalized because of AKI (serum creatinine: 2.07 mg/dl and 3.3 mg/dl, respectively), oliguria and NS. They were treated with prednisolone and temporary hemodialysis. Renal function improved, but hypouricemia persisted during hospitalization. Histological findings in both cases led to a diagnosis of minimal change nephrotic syndrome and identification of the diuretic phase of tubulointerstitial damage because of findings such as acute tubular necrosis. Furthermore, distal tubules of Case 2 showed an amorphous mass, possibly a uric acid crystal. Analysis of the two cases with the URAT1 gene, encoded by SLC22A12, found a homozygous mutation in exon 4 (W258stop) of each one. Our cases show that patients with renal hypouricemia may be susceptible to AKI without involvement of exercise if they possess some facilitators. Renal hypouricemic patients should therefore be carefully examined for all complications from renal hypouricemia because of high risk of AKI.     

A case of acute renal failure in a patient with idiopathic hypouricemia]

This report is a 17-year-old man with an acute renal failure who complained of nausea, vomiting, bilateral loin pain and abdominal pain after scuffle. Renal biopsy specimen obtained from the left kidney revealed acute tubular necrosis. After recovering renal function he showed extreme hypouricemia (serum uric acid, 0.6 mg/dl) and elevated uric acid clearance (62-78 ml/min). The fractional excretion of uric acid (CUA/Ccr) could not be influenced by either oral pyrazinamide or probenecid. As no other renal tubular or metabolic abnormalities were detected, it is suggested that presecretory reabsorption defect or subtotal defect in uric acid transportation was responsible for the hypouricemia in this patient.     

The fractional excretion of urea: a new diagnostic test for acute renal allograft rejection

Fractional excretion of fsodium (FE_Na) has been used in the diagnosis of acute renal allograft failure on the assumption that poor allograft perfusion should result in a low FE_Na. However, many patient receive medications which affect the active transport of Na⁺ and thus FE_Na. In contrast, the fractional excretion of urea (FE_urea) is mostly dependent on passive forces and is therefore less influenced by drug therapy. To test the hypothesis that FE_urea might be more useful than FE_Na in evaluating graft failure, we compared FE_urea with FE_Na during 79 episodes of acute renal allograft dysfunction due to acute rejection (AR), cyclosporine nephrotoxicity (CsA-Nx), viral infection, or bacterial infection in 32 children and young adults with renal transplants. There was no significant difference between groups in FE_Na. However, FE_urea was significantly lower (P<0.05) in patients with CsA-Nx (32.6±1.9%) and viral infection (32.9±3.2%) than those with AR (45.1±1.7%) or bacterial infection (38.9±2.5%). FE_urea was < 35% in 20 of 28 (71.4%) episodes of CsA-Nx and 8 of 11 (72.2%) of viral infection, but only 5 of 36 (13.9%) of AR (P<0.05). FE_urea was also measured during stable graft function, 7–14 days prior to allograft dysfunction. CsA-Nx was associated with a 30.5±8.3% decrease in FE_urea. FE_urea did not change in patients with AR. Based on these findings, we present an algorithm to aid in the differential diagnosis of acute renal allograft failure.     

Diffusion-weighted MRI of exercise-induced acute renal failure (ALPE)

Acute renal failure with severe loin pain induced by anaerobic exercise (ALPE) is a rare condition that is accompanied by wedge-shaped contrast enhancement on computed tomography (CT) without evidence of rhabdomyolysis. In two pediatric cases with ALPE, we tried to determine the relationship between findings from CT and magnetic resonance imaging (MRI). Case 1 involved a 13-year-old Japanese girl with a diagnosis of ALPE with normo-uricemia. Contrast-enhanced CT after 24 and 48 h showed a wedge-shaped excretion delay for the contrast media. A clear wedge-shaped signal hyperintensity matching the CT images was obtained by diffusion-weighted MRI. Case 2 involved a 16-year-old boy who presented with a second attack of ALPE after diagnosis of ALPE with hypouricemia 1 year earlier. Only diffusion-weighted imaging was performed. Clear wedge-shaped signal hyperintensity was apparent, similar to Case 1. MRI is safer than contrast-enhanced CT for patients with ALPE. Diffusion-weighted MRI is a very useful examination for diagnosing ALPE, providing noninvasive detection of lesions peculiar to ALPE.     

Exercise-induced acute renal failure in 3 patients with renal hypouricemia

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.