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.     

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     

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.     

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     

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.     

The W258X mutation in SLC22A12 is the predominant cause of Japanese renal hypouricemia

Recently, a urate transporter, hURAT1 (human uric acid transporter 1) encoded by SLC22A12, was isolated from the human kidney. hURAT1 is presumed to play the central role in reabsorption of urate from glomerular filtrate. In the present study, we analyzed SLC22A12 in seven unrelated Japanese patients with renal hypouricemia whose serum level of urate was less than 1.0 mg/dl, and their family members. We performed direct DNA sequencing of the exon and exon-intron boundaries of SLC22A12 using genomic DNA. Six of the seven patients (86%) possess mutations in SLC22A12. In five patients, a homozygous G to A transition at nucleotide 774 within exon 4 of SLC22A12, which forms a stop codon (TGA) at codon 258 (TGG), was identified (W258X). In one patient, the C to T transition within exon 3, which changes threonine at codon 217 to methionine (T217 M), and the W258X mutation were found (compound heterozygote). Thus, among 12 mutational alleles in six patients, 11 were the W258X mutation (92%). Family members with the heterozygous W258X mutation (carriers) show relatively low levels of serum urate. The present study demonstrates that homozygous W258X mutation is the predominant genetic cause of idiopathic renal hypouricemia in Japanese patients.     

Acute renal failure in children with idiopathic nephrotic syndrome

Acute renal failure (ARF) is an uncommon but alarming complication of idiopathic nephrotic syndrome. The renal failure could be secondary to causes evident from the history and evaluation, such as severe intravascular volume depletion, acute tubular necrosis, allergic interstitial nephritis, bilateral renal vein thrombosis, acute pyelonephritis, or rapid progression of the original glomerular disease. It may be termed idiopathic if the underlying cause is undetermined. We present three children with idiopathic nephrotic syndrome who were admitted with acute renal failure. One case was due to drug-induced allergic interstitial nephritis. The other two were idiopathic in nature. Improvement in renal function occurred in the three patients over a variable period of 10 days to 4 weeks. After careful exclusion of well-known causes of acute renal failure, idiopathic acute renal failure (IARF) should be considered as a diagnostic possibility in these patients. The exact pathophysiology of IARF is not understood. Possible proposed explanations include interstitial edema, tubular obstruction, altered glomerular permeability, and unrecognized hypovolemia.     

Immunosuppression can arrest progressive renal failure due to idiopathic membranous glomerulonephritis

The effect of pulse intravenous methylprednisolone therapy followed by oral immunosuppression was evaluated in ten patients with idiopathic membranous glomerulonephritis who had developed progressive renal failure--a group generally considered to have a poor prognosis. The patients (six male, four female, mean age 50 years) were monitored over 9-30 months during which time creatinine clearance reduced from (mean +/- SEM) 83 +/- 10 to 29 +/- 6 ml/min, and plasma creatinine increased from 135 +/- 22 to 297 +/- 35 mumol/l. All patient were nephrotic with mean 24-h urinary protein excretion ranging from 5.8 to 19.6 g. Treatment administered was pulse intravenous methyl-prednisolone 1 g X 3 then oral prednisolone 30 mg and azathioprine 50 mg (nine patients) or cyclophosphamide 50 mg (one patient). Mean prednisolone dosage was 25 mg at 3 months, 16 mg at 6, and 10 mg at 12 months. Patients have been followed up for between 12 and 57 months on therapy. Creatinine clearance increased to 39 +/- 6, 47 +/- 5 and 48 +/- 18 ml/min after 3, 6 and 12 months treatment with a fall in proteinuria to 6.2 +/- 1.7, 5.7 +/- 1.4, and 3.1 +/- 1.1 g/24h. The deterioration of renal function was reversed in six patients (associated with a reduction in proteinuria to less than 1 g/24 hours in five), slowed in three (with a significant reduction in proteinuria in two), and only one patient with more advanced renal failure before treatment progressed to end-stage failure without any retardation of the rate of deterioration or change in proteinuria.(ABSTRACT TRUNCATED AT 250 WORDS)     

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     

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.     

Oxidative stress, inflammation and early cardiovascular damage in children with chronic renal failure

The relationship between inflammation, oxidant stress and cardiovascular damage in children with chronic renal failure (CRF) has not previously been investigated. The aim of this study was to investigate markers of oxidative stress, inflammation and early cardiovascular abnormalities. Therefore, erythrocyte superoxide dismutase (SOD) and catalase (CAT) activities; blood glutathione (GSH) and serum malondialdehyde (MDA) levels; C-reactive protein (CRP) and proinflammatory cytokines (IL-6, TNF-α,); and left ventricular masses (LVM) and intima media thicknesses (IMT) were measured in children with CRF. A total of 29 children with CRF (19 nondialysis, 10 peritoneal dialysis) were included. The control group consisted of 25 healthy subjects. CRF children had significantly increased IL-6, TNF-α, CRP and MDA concentrations and decreased SOD, CAT and GSH levels compared with controls (P<0.05). Nondialysis and peritoneal dialysis subgroups had similar oxidative stress and inflammation biomarkers (P>0.05). Erythrocyte CAT was positively correlated with CRP, TNF-α, and IL2-R in the study group. Positive correlations were found between cytokine concentrations, CRP and urea/creatinine levels. Significantly increased LVM and IMT values were found in CRF children (P<0.05). In conclusion, increased oxidant stress and inflammation together with early cardiovascular damage were found in CRF children. Further studies with more patients are needed to verify these results.     

Renoprotective Effect of Spirulina fusiformis on Cisplatin-Induced Oxidative Stress and Renal Dysfunction in Rats

Cisplatin is an effective chemotherapeutic agent used in the treatment of a wide array of both pediatric and adult malignancies. Dose-dependent and cumulative nephrotoxicity is the major toxicity of this compound, sometimes requiring a reduction in dose or discontinuation of treatment. Recent evidences have implicated oxidative and nitrosative stress in cisplatin-induced nephrotoxicity. Spirulina fusiformis, blue-green algae, is claimed to be a potential antioxidant. The present study was designed to explore the renoprotective potential of Spirulina fusiformis against cisplatin-induced oxidative stress and renal dysfunction. Spirulina fusiformis (500,1000,1500 mg/kg^?1 p.o.) was administered 2 days before and until 3 days after cisplatin challenge (5 mg/kg^?1 i.p.). Renal injury was assessed by measuring serum creatinine, blood urea nitrogen, creatinine and urea clearance, and serum nitrite levels. Renal oxidative stress was determined by renal TBARS levels, reduced glutathione levels, and by enzymatic activity of superoxide dismutase and catalase. A single dose of cisplatin produced marked renal oxidative and nitrosative stress and significantly deranged renal functions. Chronic Spirulina fusiformis treatment significantly and dose-dependently restored renal functions, reduced lipid peroxidation, and enhanced reduced glutathione levels, superoxide dismutase, and catalase activities. The results of the present study clearly demonstrate the pivotal role of reactive oxygen species and their relation to renal dysfunction and point to the therapeutic potential of Spirulina fusiformis in cisplatin-induced nephrotoxicity.     

Acute renal failure at the onset of idiopathic nephrotic syndrome in two children

Two children with idiopathic nephrotic syndrome (INS) developed acute renal failure (ARF) at the onset of the disease. Although the initial renal biopsy showed minimal change (MC) lesions with prominent interstitial edema, repeat renal biopsy revealed focal segmental glomerulosclerosis (FSGS). ARF has been reported to be a relatively rare complication in childhood INS. However, the initial manifestation of ARF may increase the risk for subsequent progression to FSGS in a proportion of children with INS with MC lesions. Received: April 3, 2000 / Accepted: October 31, 2000     

Challenges in diagnosing acute pancreatitis in renal transplant patients

Abstract: Acute pancreatitis is a recognized occurrence in patients with end‐stage renal disease, those on dialysis and those who have undergone renal transplantation. The incidence is significantly increased in comparison to the general population and carries significant mortality. We report two cases of acute pancreatitis that occurred in stable renal transplant recipients, and in which there was diagnostic difficulty. The etiology of the acute pancreatitis is not always identifiable in these patients. Classical symptoms and laboratory findings are often absent, which may cause diagnostic difficulty. Our experience suggests that in immunosuppressed patients with unexplained abdominal pain or abnormal liver function tests, acute pancreatitis should be considered at an early stage in order to initiate appropriate treatment and therefore minimize mortality and morbidity.     

Olmesartan associated with acute renal failure in a patient with bilateral renal artery stenosis

In patients with renal artery stenosis (RAS), the inhibition of renin-angiotensin-aldosterone system can cause deterioration of renal function. Here we present a 75-year-old man who developed acute renal failure after olmesartan treatment. Following discontinuation of olmesartan, his renal functions normalized. His renal Doppler ultrasonography and renal angiography showed findings consistent with bilateral RAS. In this case, unlike those previously reported, renal failure developed with olmesartan for the first time and after only a single dose, which is thought to be a new, safe, and tolerable antihypertensive agent. This is a well-defined effect of angiotensin-converting enzyme inhibitors, in patients with RAS. Also with the increasing use of angiotensin II receptor blockers (ARBs), renal failure associated with ARBs in patients with RAS is rising. The use of olmesartan also requires caution and close follow-up of renal functions for patients who have risk factors.     

Oxidative stress in children with kidney disease

The aim of this work was to study the dynamics of oxidative stress in the blood and urine of children with kidney diseases: glomerulonephritis (GN), pyelonephritis (PN), renal failure (RF), and lower urinary tract infections (LUTI). The concentration of conjugated dienes is increased in blood: GN 4 times and RF up to 2 times; and extremely increased in urine: GN 12 times and RF 4 times. The concentration of thiobarbituric acid reactive substances in urine shows a similar trend: GN 7 times, PN 2 times, RF 1.5 times, and LUTI almost 3 times. Urine chemiluminescence is also increased: GN 5 times, PN and LUTI 3 times, and RF 6 times. Kidney disease leads to 2.5-fold inhibition of antioxidant catalase activity in blood and 10-fold in urine. Total antioxidant activity of urine is induced in all groups: GN 18 times, PN 2 times, RF 1.5 times, and almost 4 times in the LUTI group. Experimental data confirm that products of lipid peroxidation, intensity of chemiluminescence, and total and enzyme antioxidant capacity in combination with clinical parameters are a proper test for the dynamics of oxidative stress and markers of intoxication in children with inflammatory and immunological active parenchymal kidney disorders. These data could be helpful for the optimization of complex and effective antioxidant therapy of children with kidney disease.     

Acute renal failure in the surgical setting

Acute renal failure (ARF) is an unwelcome complication of major surgical procedures that contributes to surgical morbidity and mortality. Acute renal failure associated with surgery may account for 18-47% of all cases of hospital-acquired ARF. The overall incidence of ARF in surgical patients has been estimated at 1.2%, although is higher in at-risk groups. Mortality of patients with ARF remains disturbingly high, ranging from 25% to 90%, despite advances in dialysis and intensive care support. Appreciation of at-risk surgical populations coupled with intensive perioperative care has the capacity to reduce the incidence of ARF and by implication mortality. Developments in understanding the pathophysiology of ARF may eventually result in newer therapeutic strategies to either prevent or accelerate recovery from ARF. At present the best form of treatment is prevention. In this review the epidemiology, pathophysiology, diagnosis, treatment and possible prevention of ARF will be discussed.     

An uncommon genetic syndrome with acute renal failure in a 30-year-old diabetic patient.

Case AB is a 31-year-old man who has had type 1 diabetes since theage of 7 years, severe visual impairment and hypoacousia. InAugust 1998 he was referred to a nephrologist because of progressiveimpairment of renal function. At his last evaluation by thediabetologist, his serum creatinine, previously 1.5–1.7mg/dl, had risen to 2.4 mg/dl. During his first nephrologicalevaluation 5 days later, the patient reported oligoanuria beginningapproximately 18 h earlier. On physical examination, the patient,who manifested a modest intellectual deficit, appeared co-operativeand in good clinical condition. His blood pressure, reportedas normal in the past, was 130/85 mmHg. Cardiac and pulmonaryassessments were normal, and oedema was absent. A moderate bladderglobus was present. The only symptoms the patient reported were occasional dysuriaand urgency during the last 3 months. Glycaemic control hadbeen good     

Cause of death in acute renal failure.

The cause of 636 deaths during acute renal failure (ARF) occurring between 1956 and 1989 were analysed. Deaths due to haemorrhage and to non-recovery of renal function have declined but cardiovascular deaths and withdrawal of active treatment have increased. The causes of death varied with the clinical situation in which ARF arose. The most important factor contributing to death was the underlying cause of ARF. 67% deaths due to sepsis resulted from infection present at the time of development of ARF. Deaths due to secondary complications have declined, indicating that the precipitating causes of ARF are the main determinant of overall mortality.