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.     

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.     

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.     

Mechanism of hypouricemia in Hodgkin's disease. Isolated defect in postsecretory reabsorption of uric acid

We present a patient with hypouricemia associated with Hodgkin's disease. Serum uric acid level ranged from 1.4 to 2.2 mg/dl and fractional excretion of uric acid was 26.5%. No other renal tubular abnormalities were found. The pyrazinamide suppression test came off normal. However, during the benzbromarone test, the uricosuric response was reduced. The abnormal renal handling of urate became normal following therapy of Hodgkin's disease. The findings suggest that hypouricemia in Hodgkin's disease is caused by an impairment of postsecretory tubular reabsorption of uric acid.     

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.     

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.     

Effect of valsartan on renal handling of uric acid in healthy subjects

OBJECTIVE: To evaluate the effect of valsartan on renal handling of uric acid in healthy subjects. METHODS: A randomized, single-blind, placebo-controlled clinical trial was performed in twelve healthy volunteers. Six received a morning dose of valsartan 80 mg orally during 14 to 21 days and the other six received placebo. Before and after valsartan or placebo, clearance, fractional excretion and excretion uric acid rates were calculated. Presecretory reabsorption, tubular secretion and postsecretory reabsorption of uric acid were assessed by pharmacological tests using pyrazinamide or probenecid. RESULTS: There were no differences in clearance, fractional excretion and excretion uric acid rates with valsartan and placebo. Valsartan did not affect presecretory reabsorption (p = 0.92), tubular secretion (p = 0.62) or postsecretory reabsorption (p = 0.52) of uric acid. CONCLUSION: Valsartan did not significantly affect renal handling of uric acid in healthy subjects.     

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     

Familial renal hypouricaemia: two additional cases with uric acid lithiasis.

Two families are reported affected with hereditary renal hypouricaemia associated with uric acid lithiasis. The propositi of both families were found also to have hyperabsorptive hypercalciuria. Based on the study of the effect of pyrazinamide and probenecid on uric acid excretion in both propositi, it is suggested that the defect in uric acid reabsorption is most probably at the pre-secretory site.     

Insulin-dependent diabetes and renal hypouricemia

We studied 14 patients (11 women and 3 men) from 18 to 33 years old, suffering from type I diabetes mellitus with normal renal function (creatinine clearance 106.91 +/- 28.73 ml/min) and serum uric acid below 2.5 mg/dl (2.34 +/- 0.11 mg/dl) as well as a high uric acid clearance (23.04 +/- 5.92 ml/min) and fractional urate excretion (21.4 +/- 2.6) versus urate clearance 9.82 ml/min and fractional urate excretion 8.80 +/- 1.3 in 14 normal control subjects. The study of the uricosuric mechanisms was conducted by the combination of probenecid (PB) test which inhibits the reabsorption of secreted urate, and pyrazinamide (PZA) test, which inhibits its tubular secretion. The results of studies indicate that the increase in urate clearance was accounted for by increased PZA-nonsuppressible urate suggesting a decreased reabsorption of filtered urate. Increased PZA-suppressible urate excretion combined with impaired response to a uricosuric drug is consistent with impaired reabsorption of secreted urate. According to our findings, increased urate excretion in diabetic patients may be attributed to the inhibition of both filtered and secreted reabsorption. This reabsorptive tubular abnormality is consistent with the view of an interference of tubular reabsorption of glucose with the tubular capacity for uric acid reabsorption.     

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.     

Cyclosporine inhibits renal uric acid transport in renal transplants not in children treated for nephrotic syndrome

Children with various grades of renal insufficiency (CON group) maintained uric acid excretion over a range of glomerular filtration rate (GFR) from 27 to 160 ml/min*1.73m2 despite a decreased filtered load which was paralleled by glomerular filtration of uric acid. This was achieved by a compensatory decrease of net uric acid reabsorption (TUA) and an increasing fractional excretion of uric acid (FEUA) with decreasing GFR. Although there was a decreased GFR in the group of children after transplantation (NTx group) there was no difference in TUA and FEUA between the NTx group and the CON group. Uric acid transport was not affected in children treated with Cyclosporine (CyA) for nephrotic syndrome (NEPH group) compared to the CON group. Decreased fractional phosphate reabsorption in the NTx group suggests proximal tubule damage associated with disturbed uric acid handling. Under conditions of water diuresis hyperuricemia seen in NTx may result from an indirect effect of renal ischemic damage due to the transplantation procedure causing disturbance of proximal tubular uric acid (active) secretion/reabsorption.     

Pseudoaldosteronism with increased serum cortisol associated with pneumonia, hypouricemia, hypocalcemia, and hypophosphatemia

We describe here the interesting case of a 73-year-old hypertensive man with pseudoaldosteronism. He had been taking glycyrrhizin at a dose of 75 mg/day for 12 years because of mild liver damage, but had never experienced any previous symptoms associated with hypokalemia. He was referred to our hospital because of hypokalemic tetraparesis and rhabdomyolysis. At that time, we noted mineralocorticoid excess characterized by hypokalemia due to urinary K loss, exacerbation of hypertension due to increased tubular Na reabsorption, metabolic alkalosis, and suppression of both plasma renin activity and plasma aldosterone concentration. His urinary free cortisol excretion rate and the urinary ratio of free cortisol to free cortisone were markedly elevated. Thus we diagnosed pseudoaldosteronism that was related to the long-term use of glycyrrhizin. When he developed pseudoaldosteronism, he also contracted pneumonia, and exhibited elevated levels of serum cortisol and creatinine clearance (CCr) as well as hypouricemia, hypocalcemia, and hypophosphatemia. All normalized after the recovery from pneumonia and the administration of spironolactone. The extracellular volume expansion associated with increased tubular Na reabsorption by the aldosterone-sensitive distal nephron and the resulting increase in CCr caused an inhibition of proximal tubular reabsorption of uric acid, Ca, and inorganic phosphate, leading to their renal loss and therefore hypouricemia, hypocalcemia, and hypophosphatemia, respectively. In this patient, the increased circulating cortisol associated with the stress of inflammation caused by pneumonia triggered the development of pseudoaldosteronism.     

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.     

Decreased renal clearance of xanthine and hypoxanthine in a patient with renal hypouricemia: a new defect in renal handling of purines.

Renal handling of urate, xanthine and hypoxanthine was studied in a hypouricemic patient who had increased plasma concentrations of xanthine and hypoxanthine. The patient, a 50-year-old man, had been suffering from Parkinson's disease, while neither systemic disorders nor particular renal diseases known to affect plasma purine levels were found. His serum urate level was 58 +/- 6 mumol/l (healthy controls for males, 310 +/- 48 mumol/l, mean +/- SD) and the renal uric acid clearance was 3 times higher than that of the controls, establishing a diagnosis of renal hypouricemia. Xanthine and hypoxanthine concentrations in the plasma were elevated to 1.3 +/- 0.1 mumol/l (controls, 0.5 +/- 0.3) and 5.9 +/- 3.5 mumol/l (controls, 1.6 +/- 0.4), respectively. Both renal xanthine and hypoxanthine clearance was only half the value of the controls, indicating reduced urinary excretion of xanthine, and hypoxanthine appears to be responsible for their elevation in plasma. A probenecid loading test revealed no response of urinary urate excretion but normal responses of xanthine and hypoxanthine excretion. However, urinary excretion of urate, xanthine or hypoxanthine did not respond at all to pyrazinamide administration. These findings indicate that the patient had a defective renal handling of xanthine and hypoxanthine as well as urate.     

Acute renal failure after exercise in a child with renal hypouricaemia

We describe a 12-year-old boy with renal hypouricaemia who presented with acute renal failure after a 6-h sports training session. Back and loin pain were noted at presentation. Although serum creatinine and blood urea nitrogen were elevated, the serum uric acid concentration was normal (2.6 mg/dl). This decreased to 0.3 mg/dl after recovery. The pyrazinamide and probenecid tests revealed that the cause of renal hypouricaemia in this patient was totally defective uric acid reabsorption. Acute renal failure after exercise is a rare but serious complication in paediatric patients with renal hypouricaemia.     

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.     

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.     

Hypouricemia related to a hypersecretional tubulopathy

We present 1 patient with hypouricemia and hyperuricosuria. Serum uric acid level ranged between 1.5 and 1.9 mg/dl and uric acid fractional excretion between 20 and 28%. Apart from that the renal function was normal. The pyrazinamide suppression test gave a normal response showing nearly complete suppression of urate excretion. The uricosuric response to sulfinpyrazone was normal too. The renal tubular response to extracellular fluid volume contraction induced by furosemide indicated a normal tubular sensitivity to extracellular fluid volume variations. From these results we conclude that our patient has a specific tubulopathy characterized by uric acid hypersecretion.     

Functional analysis of novel allelic variants in URAT1 and GLUT9 causing renal hypouricemia type 1 and 2

Background

Renal hypouricemia is a rare heterogeneous inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury and nephrolithiasis. Type 1 is caused by a loss-of-function mutation in the SLC22A12 gene (URAT1), while type 2 is caused by defects in the SLC2A9 gene (GLUT9).

Methods and results

In this article we present clinical, biochemical and molecular genetics of two Czech patients. The serum uric acid in the probands was 57 and 98 µmol/l and expressed as an increase in the fractional excretion of uric acid (40 and 18 %). The sequencing analysis of SLC22A12 and SLC2A9 revealed novel variants p.R92C and p.R203C in URAT1 and p.G72D in GLUT9. Functional studies were performed for these novel variants and for previously reported variants p.I118HfsX27, p.G216R and p.N333S in GLUT9 responsible for renal hypouricemia in three probands from Czech Republic and United Kingdom. Functional studies showed significantly decreased urate uptake for all variants. However, urate uptake of GLUT9 variants prepared for both isoforms were not significantly different.

Conclusions

This is the first complex function characterization of non-synonymous allelic variants in patients with renal hypouricemia regarding both GLUT9 isoforms. Our finding of defects in the SLC2A9 and SLC22A12 genes show the following: renal hypouricemia is not restricted to East Asia populations; urate uptake of GLUT9 variants prepared for both isoforms were not significantly different; renal hypouricemia type 2 has more wide clinical variability than type 1; the phenotypic severity of renal hypouricemia is not correlated with results of functional characterizations of URAT1 and GLUT9 variants.