Acute renal failure after exercise in a patient with renal hypouricemia

A 22-year-old man had recurrent exercise-induced acute renal failure (ARF). He was found to have isolated renal hypouricemia: serum uric acid level was 0.7–1.0 mg/dl and fractional excretion of uric acid (FE_UA) was 37%–43%. He showed no suppression of FE_UA following the the administration of pyrazinamide, and no increase of FE_UA after benzbromarone, suggesting a subtotal defect. We investigated renal function, FE_UA, and serum nitric oxide after a treadmill exercise test in our patient and two control subjects. On the day after the exercise test, plain and enhanced abdominal computed tomography (CT) scans were performed in our patient. During the arterial phase, early equilibration phase, equilibration phase, and 2, 6, and 24 h after the injection of contrast medium, renal CT scans were performed at the same slice level. Although ARF was not induced by this level of exercise, the CT scans showed patchy contrast enhancement 2, 6, and 24 h after contrast medium administration. This finding suggests that patchy renal vasoconstriction may occur in patients with renal hypouricemia after strenuous exercise, even in the setting of normal creatinine clearance. Received: June 19, 1998 / Accepted: September 4, 1998     

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.     

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.     

Cholangiocarcinoma and severe renal hypouricemia: a study of the renal mechanisms.

Hypouricemia in malignant neoplasms is rarely reported. We present a previously unreported case of cholangiocarcinoma associated with severe persistent hypouricemia (serum uric acid levels ranged from 0.07 to 0.08 mmol/L [1.16 to 1.40 mg/100 mL], and increased urate clearance (50.90 to 57.33 mL/min v a mean value in 20 normal subjects of 9.75 +/- 1.65 mL/min). High fractional urate clearance (Cus/Ccr = 0.50 to 0.58 v 0.09 +/- 0.01 in normals) was suppressed only slightly following pyrazinamide (PZA), to 0.29 versus 0.007, and was surprisingly enhanced by probenecid (PB) to 1.78 versus 0.63 in normals. No other renal tubular or metabolic abnormalities were detected. This previously unreported association of a high PZA-nonsuppressible urate excretion with a postprobenecid urate clearance exceeding glomerular filtration rate suggests that a combined renal tubular defect is responsible for hypouricemia. The patient described here provides evidence to support the presence of a presecretory reabsorptive defect in association with a "relatively high" urate secretion by the renal tubule. This report adds to the list of hypouricemic conditions and presents an important clue to elucidate urate handling mechanisms in man.     

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.     

Recurrent URAT1 gene mutations and prevalence of renal hypouricemia in Japanese

Recent identification of the urate transporter in the kidney (URAT1, encoded by SLC22A12) led to the molecular elucidation of idiopathic renal hypouricemia, which is a predisposition toward exercise-induce acute renal failure. One Japanese patient with renal hypouricemia demonstrated compound heterozygous mutations of the URAT1 gene (Q297X and IVS2+1G>A). It was suggested that these two mutations are recurrent mutations of the URAT1 gene in a Japanese population. In addition, we expect the prevalence of renal hypouricemia, 0.23%, from the analysis of serum urate levels in 1,730 Japanese children.     

Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion

Renal hypouricemia is an inherited and heterogeneous disorder characterized by increased urate clearance (CUA). The authors recently established that urate was reabsorbed via URAT1 on the tubular apical membrane and that mutations in SLC22A12 encoding URAT1 cause renal hypouricemia. This study was undertaken to elucidate and correlate clinical and genetic features of renal hypouricemia. The SLC22A12 gene was sequenced in 32 unrelated idiopathic renal hypouricemia patients, and the relationships of serum urate levels, and CUA/creatinine clearance (Ccr) to SLC22A12 genotype were examined. Uricosuric (probenecid and benzbromarone) and anti-uricosuric drug (pyrazinamide) loading tests were also performed in some patients. Three patients had exercise-induced acute renal failure (9.4%), and four patients had urolithiasis (12.5%). The authors identified eight new mutations and two previously reported mutations that result in loss of function. Thirty patients had SLC22A12 mutations; 24 homozygotes and compound heterozygotes, and 6 heterozygotes. Mutation G774A dominated SLC22A12 mutations (74.1% in 54 alleles). Serum urate levels were significantly lower and CUA/Ccr was significantly higher in heterozygotes compared with healthy subjects; these changes were even more significant in homozygotes and compound heterozygotes. These CUA/Ccr relations demonstrated a gene dosage effect that corresponds with the difference in serum urate levels. In contrast to healthy subjects, the CUA/Ccr of patients with homozygous and compound heterozygous SLC22A12 mutations was unaffected by pyrazinamide, benzbromarone, and probenecid. The findings indicate that SLC22A12 was responsible for most renal hypouricemia and that URAT1 is the primary reabsorptive urate transporter, targeted by pyrazinamide, benzbromarone, and probenecid in vivo.     

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 due to an isolated renal defect of urate transport

A 22-year-old man was found to have low serum urate concentration (1.1-1.7 mg/dl). His urate clearance was markedly increased (26.9-35.5 ml/min) and was not decreased after administration of pyrazinamide, but was even more increased after administration of benzbromarone. No other renal tubular abnormalities were detected. The young man has one sister and two brothers. His sister also has hypouricemia and hyperuricosuria. We suggest that the present case had a genetically determined renal abnormality affecting tubular presecretory reabsorption of urate.     

Two cases of persistent hypouricemia associated with diabetes mellitus.

Two patients with diabetes mellitus had persistent hypouricemia due to increased urate clearance; the degree of the apparent renal hypouricemia with uricosuria was quite mild. At the onset of diabetes, their serum urate levels were normal. Even after good diabetes control in both cases, hypouricemia continued. Based on the pharmacological evaluation in both patients, pyrazinamide administration could partially decrease urate clearance, however, suppression by pyrazinamide was less than in normal subjects, and probenecid increased urate clearance. These results suggest that the present cases had a renal abnormality affecting tubular presecretory reabsorption of urate, which might be due to diabetes mellitus.     

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.     

Renal tubular dysfunction in epileptic children on valproic acid therapy

To investigate the effects of valproic acid (VPA) on renal tubular function, we examined 15 ambulatory children with epilepsy who received VPA for at least 6 months. None of the patients had mental retardation. Fourteen age- and sex-matched children were used as a control group. No statistically significant differences were found between patients and control subjects with respect to blood urea nitrogen (BUN), creatinine (Cr), uric acid, creatinine clearance (C_cr), tubular reabsorption of phosphorus (TRP), urinary Ca:creatinine ratio, urinary pH and mean urinary β₂-microglobulin concentrations (P>0.05). Protein and glucose in patient urine samples were negative. Urine microscopic examinations and amino acid chromatographies of patients were also normal. However, significant differences were found between patient and control groups with respect to mean urinary N-acetyl-beta-d-glucosamine:creatinine ratio (NAG:Cr) and mean urinary malondialdehyde:creatinine (MDA:Cr) ratio (P<0.05). In conclusion, ambulatory children with epilepsy taking VPA therapy may develop proximal renal tubular dysfunction. Although this finding is clini-cally insignificant, it should be kept in mind during VPA therapy. Received: 11 November 1999 / Revised: 21 September 2000 / Accepted: 26 October 2000     

Renal uric acid excretion in patients with chronic pyelonephritis

In 25 patients in different stages of chronic pyelonephritis the renal clearance of uric acid, osmotically active substances and endogenous creatinine and their mutual relationship were investigated. It was found that the ratioC _ua/C _cr×100 rises in a hyperbolic relation with the decline of endogenous creatinine clearance. The rise of the ratioC _ua/C _cr×100 rose in a linear relationship to the fractional excretion of all osmotically active substances (C _osm/C _cr×100). The findings support the idea that osmotic diuresis in the residual nephron is one of the factors conditioning the relative increase of renal uric acid excretion.     

Glycine attenuates apoptotic cell death in uranyl acetate-induced acute renal failure in rats

Background. Although uranyl acetate (UA) is known to induce apoptosis in renal tubular cells, the pathophysiological role of apoptotic cell death in UA-induced acute renal failure (ARF) is not clear. In this study, we examined whether glycine, which is known to provide protection against nephrotoxic acute renal failure, attenuated tubular damage in UA-induced ARF in rats, and, if so, whether the attenuation of tubular damage was associated with reduced apoptotic cell death. Methods. Sprague-Dawley rats were allocated to three groups; normal controls, UA-treated, and UA plus glycine-treated. Acute renal failure was induced by the intravenous injection of UA (5 mg/kg). UA plus glycine-treated rats were given glycine at 1 g/kg, i.v. over 3 min at the same time as the UA injection. Serum creatinine concentration (Scr) and tubular damage score were examined 5 days after UA administration. Apoptosis was evaluated by counting the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL)-positive cells in the outer stripe of the outer medulla. Results. Glycine significantly decreased the UA-induced increases in Scr (3.73 ± 0.31 vs 2.74 ± 0.11 mg/dl; P < 0.05) and the tubular damage score (3.83 ± 0.13 vs 2.58 ± 0.01; P < 0.01). UA significantly increased the number of TUNEL-positive cells in the outer stripe of the outer medulla (0.16 ± 0.04 vs 7.45 ± 0.46/high power field at ×400 magnification; P < 0.01 vs normal control value). Glycine infusion significantly lessened the number of TUNEL-positive cells (5.84 ± 0.31/ high power field at ×400 magnification; P < 0.01 vs UA-treated rats). A significant correlation was found between the number of TUNEL-positive cells and the tubular damage score (r = 0.93; P < 0.01). Conclusion. Glycine ameliorated the severity of UA-induced ARF and the degree of apoptotic cell death. This finding suggested that the protective effect of glycine in UA-induced ARF may be mediated, at least in part, through a reduction of apoptosis. Received: January 22, 1999 / Accepted: July 7, 1999     

Hypouricemia due to increased tubular urate secretion

A 45-year-old woman had hypouricemia (serum uric acid, 1.0-2.3 mg/dl) with increased uric acid clearance (29.8 +/- 9.3 ml/min/1.73 m2). Uric acid clearance to creatinine clearance ratio (Cua/Ccr) was suppressed markedly by pyrazinamide to 2.3% and surprisingly enhanced by probenecid to 227.8%. No other renal tubular or metabolic abnormalities were detected. This previously unreported high postprobenecid Cua/Ccr suggests that markedly increased urate secretion by the renal tubule is responsible for hypouricemia in this patient.     

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.     

Familial renal hypouricemia with intact reabsorption of uric acid

Three patients with renal hypouricemia in the same family are described. Serum urate levels in the mother were in the low normal range and were below normal in her 2 sons. In all 3 patients, the ratios of renal urate clearance to creatinine clearance were abnormally elevated. Clear responses to either pyrazinamide or probenecid administration were observed in these ratios. These results suggest that these 3 patients had renal hypouricemia with normal reabsorption of urate as judged by the criteria for differentiating abnormalities in renal urate handling. This corresponds to the previously postulated mechanism as renal urate hypersecretion. Possible limitations to the diagnostic use of probenecid and pyrazinamide are also discussed.     

Dopamine increases renal oxygenation: a clinical study in post‐cardiac surgery patients

Background: Imbalance of the renal medullary oxygen supply/demand relationship can cause ischaemic acute renal failure (ARF). The use of dopamine for prevention/treatment of ischaemic ARF has been questioned. It has been suggested that dopamine may increase renal oxygen consumption (RVO₂) due to increased solute delivery to tubular cells, which may jeopardise renal oxygenation. Information on the effects of dopamine on renal perfusion, filtration and oxygenation in man is, however, lacking. We evaluated the effects of dopamine on renal blood flow (RBF), glomerular filtration rate (GFR), RVO₂ and renal O₂ demand/supply relationship, i.e. renal oxygen extraction (RO₂Ex). Methods: Twelve uncomplicated, mechanically ventilated and sedated post‐cardiac surgery patients with pre‐operatively normal renal function were studied. Dopamine was sequentially infused at 2 and 4 ug/kg/min. Systemic haemodynamics were evaluated by a pulmonary artery catheter. Absolute RBF was measured using two independent techniques: by the renal vein thermodilution technique and by infusion clearance of paraaminohippuric acid (PAH), with a correction for renal extraction of PAH. The filtration fraction (FF) was measured by the renal extraction of ⁵¹Cr‐EDTA. Results: Neither GFR, tubular sodium reabsorption nor RVO₂ was affected by dopamine, which increased RBF (45–55%) with both methods, decreased renal vascular resistance (30–35%), FF (21–26%) and RO₂Ex (28–34%). The RBF/CI ratio increased with dopamine. Dopamine decreased renal PAH extraction, suggestive of a flow distribution to the medulla. Conclusions: In post‐cardiac surgery patients, dopamine increases the renal oxygenation by a pronounced renal pre‐and post‐glomerular vasodilation with no increases in GFR, tubular sodium reabsorption or renal oxygen consumption.     

New approaches to the treatment of acute renal failure

At present, the clinician is left in a relatively dependent position when encountering a patient with established acute renal failure (ARF). Clearly, interventional therapies that can significantly influence the process of recovery from ARF are limited. Although a variety of manipulations and drugs will protect against the loss of renal function when administered prior to the initiation of a renal insult, the clinician usually encounters a patient after ARF has been established. Thus, pertubations that will protect against the development of ARF or modify the severity of the renal insult are not applicable. Moreover, it is clear that the mortality and morbidity for patients with ARF is unacceptably high. Although a variety of supportive measures such as peritoneal/hemodialysis or continuous arteriovenous hemofiltration are now applicable to patients of almost any size or weight, patients continue to diewith but perhaps notof ARF. This article will review several new agents that act to enhance the restoration of renal function and result in accelerated recovery of both glomerular and tubular function, following an established acute renal insult: adenine nucleotides, thyroxin, and calcium channel blockers.     

Non-urate transporter 1-related renal hypouricemia and acute renal failure in an Israeli–Arab family

Idiopathic renal hypouricemia (IRHU) is a rare hereditary disease, predisposing the individual to exercise-induced acute renal failure (EIARF) and nephrolithiasis, and it is characterized by increased clearance of renal uric acid. Most of the described patients are Japanese, who have loss-of-function mutations in the SLC22A12 gene coding for the human urate transporter 1 (URAT1) gene. An 18-year-old youth, who was admitted for EIARF due to IRHU, and six consanguineous Israeli–Arab family members were included in the study. The family members were tested for fractional excretion of uric acid and molecular analysis of the URAT1 gene. Four family members, including the proband, had very low levels of blood uric acid and high rate of fractional excretion (FE urate> 100%) of uric acid. Genetic analysis of the affected family members did not reveal a mutation in the coding regions and intron–exon boundaries of SCL22A12. Haplotype analysis excluded SCL22A12 involvement in the pathogenesis, suggesting a different gene as a cause of the disease. We herein describe the first Israeli–Arab family with IRHU. A non-URAT1 genetic defect that causes decreased reabsorption or, more probably, increased secretion of uric acid, induces IRHU. Further studies are required in order to elucidate the genetic defect. Hilla Bahat and Dganit Dinour contributed equally to the work.