Utility of fractional excretion of magnesium in diagnosing renal magnesium wasting in pediatric nephrology practice.

BACKGROUND: Fractional excretion of magnesium (FEMg) is commonly used to diagnose of renal magnesium (Mg) wasting, but it can be affected by serum Mg (SMg) and serum creatinine concentration (SCr). We investigated the sensitivity and specificity of FEMg to diagnose Mg wasting in subgroups with different SMg and eGFR (estimated glomerular filtration rate) in pediatric nephrology practice. METHODS: One hundred and nineteen patients (59 males and 60 females, median 15 years) seen in our pediatric clinic were investigated for FEMg, SMg, eGFR, and urine Mg-to-creatinine ratio (Mg/Cr). Normal eGFR was defined as ≥ 90 ml/min/1.73 m2 or for infants SCr < chronic kidney disease stage 2. Urine Mg/Cr was compared with age-specific reference values. RESULTS: Sixteen of all patients (13 %) had hypomagnesemia. All had FEMg greater than the cut-off value of 2 %. Only 4 patients had elevated urine Mg/Cr. Of 65 patients with normal SMg and eGFR, 19 had FEMg above the cut-off value of 4 %. Of these, 13 patients had elevated urine Mg/Cr i.e. Mg wasting (sensitivity and specificity of FEMg, 93 % and 88 %, respectively). Among 38 patients with normal SMg and low eGFR, 30 had FEMg > 4 %, but only 6 had elevated urine Mg/Cr (sensitivity 100 % and specificity 25 %). Overall, hypomagnesemic patients and normomagnesemic patients with elevated urine Mg/Cr were diagnosed with Mg wasting (36/119, 30 %). CONCLUSIONS: FEMg has variable sensitivity and specificity depending on SMg and eGFR in the diagnosis of Mg wasting. Mg wasting is not uncommon in pediatric nephrology practice.

A girl with membranous nephropathy associated with ventriculoperitoneal shunt infection.

Glomerulopathy associated with shunt infection is commonly membranoproliferative glomerulonephritis, whereas the causative organisms of secondary membranous nephropathy are usually viruses. We report a case of membranous nephropathy associated with shunt infection. The patient was born at 29-week gestation with a birth weight of 1178 g. Ventriculoperitoneal shunt surgery had been performed for congenital hydrocephalus. Thereafter, she had experienced seven shunt infections. At the age 13 years, proteinuria was detected in a school urinary screening. Urinalysis at our hospital demonstrated 3 + protein and 3 + blood. Laboratory testing demonstrated a serum creatinine 0.5 m/dl, albumin 2.5 g/dl, C-reactive protein (CRP) 13.7 mg/dl, and C3 182 mg/dl. Prior to repeat urinalysis, the patient developed vomiting and was admitted with suspected shunt infection. On admission, her body temperature was 36.0 ºC. Physical examination was unremarkable other than small stature and a palpable mass in the left upper quadrant. Urinalysis demonstrated 2 + protein and 1 + blood with no cells or casts. The urinary protein excretion was 3 g/day. Abnormal laboratory tests included erythrocyte sedimentation rate 102 mm/hr, CRP 11.67 mg/dl, IgG 2442 mg/dl, C3 177 mg/dl, and C4 44 mg/dl. Antibiotic therapy was initiated for a presumptive diagnosis of shunt infection and the shunt catheter was removed. Cultures obtained after antibiotic administration were negative. Proteinuria persisted after control of the shunt infection. Histology of a renal biopsy demonstrated membranous nephropathy with diffuse granular IgG staining and subepithelial deposits. Three possible pathomechanisms for her membranous nephropathy were considered.

A girl with a mutation of the ciliary gene CC2D2A presenting with FSGS and nephronophthisis.

Mutations in the ciliary gene TTC21B, NPHP4, and CRB2 cause familial focal and segmental glomerulosclerosis (FSGS). We report a girl with a mutation of the ciliary gene CC2D2A presenting with FSGS and nephronophthisis. The patient had mental retardation, postaxial polydactyly, and ataxic breathing, and was diagnosed as having compound heterozygous CC2D2A missense mutations at age 5. Retrospectively, azotemia at 1 year and proteinuria at 5 years were recorded but not investigated. At age 6, she was referred to the pediatric nephrology service because of hypertension, pretibial pitting edema, heavy proteinuria, and hematuria. eGFR was 66 ml/min/1.73 m2, total protein 5.3 g/dl, albumin 2.4 g/dl, and cholesterol 317 mg/dl. Ultrasonography showed normal-sized kidneys with a cyst in the right. Losartan was started. On renal biopsy, 8 out of 24 glomeruli were globally sclerosed, and three showed segmental sclerosis and/or hyalinosis with no immune deposits. Mild tubular dilatation, tubular atrophy, and interstitial fibrosis were observed. On electron microscopy, glomeruli showed focal foot process effacement with no electron dense deposits. Since losartan did not exert an obvious effect, treatment with prednisolone was tried. Urine protein decreased from 6.6 to 3.7 g/gCr. Prednisolone was discontinued after 10 days, however, because she developed duodenal ulcer perforation that necessitated omentoplasty. Subsequently, she was treated with losartan only. Her renal function deteriorated and peritoneal dialysis was initiated 8 months later. FSGS in this patient could be primary glomerular associated with CC2D2A mutation, rather than the consequences of tubulointerstitial fibrosis.

Ask-Upmark kidney in a girl with neurofibromatosis type 1.

Ask-Upmark kidney (AUK) is a scarred segment of the kidney, characterized by formation of primitive tubular and glomerular structures, and sporadically diagnosed as a cause of hypertension (HTN). A 6-year-old girl with neurofibromatosis type 1 (NF1) and moyamoya syndrome had severe HTN. Based on past history, she had HTN at the age of 1.5 years. Laboratory examination revealed slightly elevated plasma and renal venous renin activity without lateralization. No evidence of pheochromocytoma, or coarctation of the aorta was found. Contrast-enhanced computed tomography (CT) showed an area of hypoperfusion in the upper and middle poles with reduced size of the right kidney. The results of dimercaptosuccinic acid scintigraphy were in accordance with those of contrast-enhanced CT. Selected renal arteriography revealed a paucity of peripheral vascularity in the same parts of the right kidney. In the absence of a history of urinary tract infection and vesicoureteral reflux by cystography, we presumed that the severe HTN may be due to segmental hypoplasia of the kidney, AUK, with a possible contribution from NF1. Although renal artery stenosis and pheochromocytoma are well-known causes of HTN in NF1, this case demonstrates that HTN can be caused by AUK in patients with NF1.

Trajectory of Estimated Glomerular Filtration Rate Predicts Renal Injury in Children with Multicystic Dysplastic Kidney.

BACKGROUND/AIMS: Children with a solitary functioning kidney have a risk of renal injury caused by hyperfiltration. Timely intervention with renin-angiotensin inhibitors may be beneficial. We examined whether trajectory of estimated glomerular filtration rate (eGFR) would predict renal injury, defined as microalbuminuria/proteinuria, hypertension, and/or a decline in eGFR. METHODS: Seventeen patients (male 7, female 10) with multicystic dysplastic kidney (MCDK; median age 13 years, range 6-19 years) followed in our clinic were examined retrospectively. An eGFR decline was defined as a fall to < 90 mL/min/1.73 m2 or a decline of > 5 mL/min/1.73 m2/year for those with baseline eGFR of ≥90 or < 90 mL/min/1.73 m2 respectively. RESULTS: Nine patients had renal injury at the time of investigation. Compared with 8 patients without renal injury, those with renal injury tended to be older (14.7 ± 4.2 vs. 11.4 ± 4.6 years) and the birth weight was smaller (2,538 ± 281 vs. 2,966 ± 361 g, p < 0.05). The frequency of contralateral congenital anomaly of kidney and urinary tract (cyst, hydronephrosis, or vesicoureteral reflux) were not different. The trajectory of eGFR in those without renal injury was either an increase (n = 3) or unidentifiable (n = 5), whereas that in the renal injury group was exclusively an increase followed by decline (p < 0.05). The average age of the onset of eGFR decline was 9.4 ± 4.2 years and that of the start of renal injury (albuminuria/proteinuria 5, eGFR decline 4, hypertension 1) was 12.5 ± 4.2 years. CONCLUSION: All the children with MCDK who developed renal injury had eGFR trajectory of increase followed by decline. Renal injury followed the peak eGFR by 3 years on average. This observation is in agreement with the hyperfiltration theory and underscores the importance of following eGFR trajectory closely.

Visit-to-visit blood pressure variability in children and adolescents with renal disease.

BACKGROUND: Increase in blood pressure (BP) variability (BPV) is associated with cardiovascular events, target organ damage, and arterial stiffness in adults. We previously reported that 24-h BPV may be associated with arterial stiffness and underlie white-coat hypertension (WCH). In this study, we examined whether visit-to-visit variability (VVV) could predict WCH and whether VVV correlated with eGFR, eGFR slope, and albuminuria/proteinuria in children and adolescents with renal diseases. METHODS: VVV was determined as average real variability of office BP measurements between visits, and 24-h BPV as the standard deviation of 24-h ambulatory BP. In 35 renal patients (25 boys and 10 girls, 7-18 years of age), divided into normotension (NT), WCH, and hypertension (HTN), the relationships between VVV and 24-h BPV and VVV in each BP category were studied. In separate 48 renal patients (24 boys and 24 girls, 2-18 years of age), the correlation between VVV and eGFR, eGFR slope, urine albumin or protein excretion was examined. RESULTS: Systolic VVV was significantly correlated with systolic office BP index. There was no correlation between VVV and 24-h BPV or 24-h pulse pressure. In addition, VVV was not different among NT, WCH, and HTN. Systolic VVV was significantly negatively correlated with eGFR but not with eGFR slope, albuminuria, or proteinuria. A cut-off value of systolic VVV for detecting eGFR < 60 ml/min per 1.73 m2 was 8.5. CONCLUSION: VVV could not predict WCH. Systolic VVV correlated with eGFR but not with eGFR slope, albuminuria/proteinuria. Increased VVV could be a marker of decreased eGFR.

Polycythemia, capillary rarefaction, and focal glomerulosclerosis in two adolescents born extremely low birth weight and premature.

BACKGROUND: Low birthweight infants have a reduced number of nephrons and are at high risk of chronic kidney disease. Preterm birth and/or intrauterine growth restriction (IUGR) may also affect peritubular capillary development, as has been shown in other organs. CASE-DIAGNOSIS/TREATMENT: We report two patients with a history of preterm birth and extremely low birthweight who showed polycythemia and renal capillary rarefaction. Patient 1 and 2, born at 25 weeks of gestation with a birthweight of 728 and 466 g, showed mild proteinuria at age 8 and 6 years, respectively. In addition to increasing proteinuria, hemoglobin levels became elevated towards adolescence and their serum erythropoietin (EPO) was high despite polycythemia. Light microscopic examination of renal biopsy specimens showed glomerular hypertrophy, focal segmental glomerulosclerosis, and only mild tubulointerstitial fibrosis. A decrease in the immunohistochemical staining of CD31 and CD34 endothelial cells in renal biopsy specimens was consistent with peritubular capillary rarefaction. CONCLUSIONS: Since kidney function was almost normal and fibrosis was not severe, we consider that the capillary rarefaction and polycythemia associated with elevated EPO levels were largely attributable to preterm birth and/or IUGR.

Targeting the ERK signaling pathway as a potential treatment for insulin resistance and type 2 diabetes.

Extracellular signal-regulated kinase (ERK) has been implicated in the development of insulin resistance associated with obesity and type 2 diabetes mellitus. We have now examined the potential of pharmacological targeting of the ERK pathway with MEK (ERK kinase) inhibitors (PD184352 and PD0325901) for the treatment of obesity-associated insulin resistance. The effects of PD184352 and PD0325901 on the expression of adipocytokines and lipolysis activity were thus examined in 3T3-L1 adipocytes maintained in long-term culture as a model of adipocyte hypertrophy. Leptin receptor-deficient (db/db) mice and high-fat diet-fed KKAy mice, both of which are models of type 2 diabetes, were also treated orally with PD184352 to examine its effects on the diabetic condition. ERK activity was increased in hypertrophic 3T3-L1 adipocytes as well as in adipose tissue of db/db mice and high-fat diet-fed KKAy mice, and this enhanced ERK signaling was associated with dysregulation of adipocytokine expression and increased lipolysis activity. Specific blockade of the ERK pathway in hypertrophic 3T3-L1 adipocytes by MEK inhibitors ameliorated the dysregulation of adipocytokine expression and suppressed the enhanced lipolysis activity. Furthermore, repeated oral administration of PD184352 normalized hyperglycemia and hyperlipidemia and improved insulin sensitivity and glucose tolerance in the diabetic mice. These results suggest that sustained activation of the ERK pathway in adipocytes is associated with the pathogenesis of type 2 diabetes and that selective blockade of this pathway with MEK inhibitors warrants further study as a promising approach to the treatment of insulin resistance and type 2 diabetes.

Renal complications in 6p duplication syndrome: microarray-based investigation of the candidate gene(s) for the development of congenital anomalies of the kidney and urinary tract (CAKUT) and focal segmental glomerular sclerosis (FSGS).

6p duplication syndrome is a rare chromosomal disorder that frequently manifests renal complications, including proteinuria, hypoplastic kidney, and hydronephrosis. We report a girl with the syndrome, manifesting left hydronephrosis, proteinuria/hematuria, and focal segmental glomerular sclerosis (FSGS) resulting in chronic end-stage renal failure, successfully treated with renal transplantation. Microarray comparative genomic hybridization showed the derivative chromosome 6 to have a 6.4-Mb duplication at 6p25.3-p25.1 with 32 protein-coding genes and a 220-Kb deletion at 6p25.3 with two genes of no possible relation to the renal pathology. Review of the literature shows that variation of renal complications in the syndrome is compatible with congenital anomalies of the kidney and urinary tract (CAKUT). FSGS, observed in another patient with 6p duplication syndrome, could be a non-coincidental complication. FOXC1, located within the 6.4-Mb duplicated region at 6p25.3-p25.2, could be a candidate gene for CAKUT, but its single gene duplication effect would not be sufficient. FSGS would be a primary defect associated with duplicated gene(s) albeit no candidate could be proposed, or might occur in association with CAKUT.

Leukemia kidney infiltration can cause secondary polycythemia by activating hypoxia-inducible factor (HIF) pathway.

UNLABELLED: Secondary polycythemia with increased production of erythropoietin (EPO) is known to occur in kidney diseases such as hydronephrosis and cystic disease, but the mechanism remains unclear. We report an 18-year-old female with isolated renal relapse of acute lymphoblastic leukemia accompanied by polycythemia. At the relapse, she presented with bilateral nephromegaly, mild renal dysfunction, and erythrocytosis with increased serum EPO levels up to 52.1 mIU/mL (9.1-32.8). Renal biopsy demonstrated diffuse lymphoblastic infiltration. The expression of hypoxia-inducible factor (HIF)-1α, which is undetectable in normal kidney, was observed in the renal tubule epithelium compressed by lymphoblastic cells. These findings suggest that erythrocytosis was caused by renal ischemia due to leukemic infiltration. Polycythemia probably became apparent because of the lack of leukemic involvement of the bone marrow. With chemotherapy, the serum EPO level rapidly decreased to normal range accompanied by the normalization of kidney size and function. Renal leukemic infiltration may enhance EPO production, although not recognized in the majority of cases because of bone marrow involvement. CONCLUSION: Our case has clarified the mechanism of previously reported polycythemia associated with renal diseases as renal ischemia. Furthermore, we have added renal ischemia resulting from tumor infiltration to the list of causes of secondary polycythemia.

Eosinophilic cystitis presented as a manifestation of hypereosinophilic syndrome: a case report and review of the literature.

BACKGROUND: Hypereosinophilic syndrome (HES) is a group of disorders marked by the sustained overproduction of eosinophils, in which eosinophilic infiltration and inflammatory substance release cause damage to multiple organs. Eosinophilic cystitis (EC) is an inflammatory disorder caused by eosinophilic infiltration of the bladder wall. Although EC is often associated with eosinophilia, it has been rarely reported as a manifestation of HES. We report a case of EC as a primary manifestation of HES. The patient was a 27-year-old male with a history of complete intracardiac repair of tetralogy of Fallot who presented with an acute onset of dysuria accompanied by eosinophilia (7.5 × 10(3)/µl, 60% of white blood cells). Ultrasonography and MRI of the bladder showed a bladder mass, a biopsy of which revealed eosinophilic infiltration and degranulation. METHODS: We performed a literature search in PubMed from 2001 to 2012 to find patients with EC who may have had HES. RESULTS: There were 4 patients with HES who had EC including the present case. Of 14 patients reported as EC in whom the eosinophil count was described, 5 had eosinophils of ≥1,500/µl. None of the 5 patients had secondary causes for eosinophilia. Of the 9 patients with definite or probable HES, 7 patients (78%) were male and 5 patients (56%) showed a concomitant eosinophilic gastrointestinal disorder. CONCLUSION: HES may not be uncommon as the cause of EC. Thorough evaluation and close monitoring are warranted in EC patients with elevated eosinophils.

Persistent hypertension despite successful dilation of a stenotic renal artery in a boy with neurofibromatosis type 1.

Hypertension is one of the major complications in neurofibromatosis type 1 (NF1). It is known to be caused by renal artery stenosis or pheochromocytoma. However, more than half of hypertensive patients with NF1 do not have either disorder. We report here on a 13-year-old male with NF1 who had hypertension and a stenosis of the right renal artery associated with elevated renal vein renin on the diseased side. He underwent percutaneous transluminal renal angioplasty. In spite of successful dilation of the artery and normalized renin level, high blood pressure persisted beyond 6 months requiring antihypertensive medication. His wide pulse pressure suggested arterial stiffness due to NF1 vasculopathy. We posit that the cause of hypertension in this patient was considered to be arterial stiffness ascribed to NF1 vasculopathy rather than renal artery stenosis. Increased pulse pressure supports the hypothesis. This marker of arterial stiffness can be assessed non-invasively and should be evaluated routinely in NF1.

Cyclic stretch induces proliferation and TGF-beta1-mediated apoptosis via p38 and ERK in ureteric bud cells.

We previously reported that p38 mitogen-activated protein kinase (p38) and phosphorylated ERK are upregulated in cyst epithelium of human renal dysplasia and obstructive uropathy in fetal lambs (Omori S, Fukuzawa R, Hida M, Awazu M. Kidney Int 61: 899-906, 2002; Omori S, Kitagawa H, Koike J, Fujita H, Hida M, Pringle KC, Awazu M. Kidney Int 73: 1031-1037, 2008). Dysplastic epithelium is characterized by proliferation, apoptosis, and upregulation of Pax2 and transforming growth factor (TGF)-beta1. In the present study, we investigated whether cyclic mechanical stretching of ureteric bud cells, a mimic of the hydrodynamic derangement after fetal urinary tract obstruction, reproduces events seen in vivo. Cyclic stretch activated p38 and ERK and upregulated Pax2 expression in a time-dependent manner in ureteric bud cells. Stretch-stimulated Pax2 expression was suppressed by a p38 inhibitor, SB203580, or a MEK inhibitor, PD98059. 5-Deoxyuridine incorporation was increased by stretch at 24 h, which was also abolished by SB203580 or PD98059. On the other hand, apoptosis was not induced at 24 h by stretch but was significantly increased at 48 h. TGF-beta1 secretion was increased by stretch at 24 h, which was inhibited by SB203580 or PD98059. Inhibition of p38 or ERK as well as anti-TGF-beta antibody abolished the stretch-induced apoptosis. Finally, exogenous TGF-beta1 induced apoptosis of ureteric bud cells, which was inhibited by SB203580 and PD98059. In conclusion, cyclic stretch induces Pax2 upregulation, proliferation, and TGF-beta1-mediated apoptosis, features characteristic of dysplastic epithelium, via p38 and ERK in ureteric bud cells.

Tubulointerstitial nephritis and uveitis syndrome: a case with an autoimmune reactivity against retinal and renal antigens.

Tubulointerstitial nephritis and uveitis (TINU) generally occurs at young age and has a female preponderance. Renal biopsy reveals interstitial infiltration of inflammatory cells and edema, and the associated intraocular inflammation typically consists of an anterior, bilateral uveitis. The pathogenesis of TINU likely involves both humoral and cellular immunity and is mediated by medications, infectious agents, or other unknown causes. A previous report detected a renal antigen recognized by the serum of a TINU patient. In this report the authors extend these observations to document seroreactivity against a retinal antigen of similar size.

Hyponatremia, hypophosphatemia, and hypouricemia in a girl with macrophage activation syndrome.

Macrophage activation syndrome, a life-threatening complication of rheumatic disorders, is accompanied by the overproduction of cytokines. We describe a girl with macrophage activation syndrome complicating systemic-onset juvenile arthritis who developed hyponatremia, hypophosphatemia, and hypouricemia associated with a high level of serum tumor necrosis factor alpha. Renal proximal tubule dysfunction was considered to be the cause, which may be attributable to tumor necrosis factor alpha.

Extracellular signal-regulated kinase inhibition slows disease progression in mice with polycystic kidney disease.

The expression of mitogen-activated protein kinases (MAPK) in DBA/2-pcy/pcy (pcy) mice, a murine model of polycystic kidney disease was investigated. Proliferating cell nuclear antigen-positive cells were recognized in cyst epithelium from embryonic day 14.5 to 25 wk of age. Extracellular signal-regulated kinase (ERK) was expressed in the renal tubules of control and pcy mice, but stronger immunostaining was observed in cyst epithelium. Phosphorylated ERK was detected only in pcy mice and was localized predominantly in the cysts. p38 MAPK (p38) was no longer expressed after birth in controls but was detected in the cyst epithelium and in occasional tubular cells of pcy mice at all stages examined. c-Jun N-terminal kinase (JNK) was expressed in all tubular segments of controls after neonatal day 7, whereas in pcy kidneys, tubules became positive for JNK after 8 wk, and the cysts expressed little JNK. Administration of an oral MAP/ERK kinase inhibitor, PD184352, 400 mg/kg per d, to 10-wk-old pcy mice daily for the first week and then every third day for 6 additional weeks significantly decreased BP, kidney weight, serum creatinine level, and water intake and significantly increased urine osmolality. The cystic index and expression of phosphorylated ERK and ERK were significantly lower in PD184352-treated pcy mice. These results demonstrate that the expression of MAPK is dysregulated in cyst epithelium and that inhibition of ERK slowed the progression of renal disease in pcy mice.

Trapidil inhibits platelet-derived growth factor-induced migration via protein kinase A and RhoA/Rho-associated kinase in rat vascular smooth muscle cells.

Trapidil suppresses platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell (VSMC) proliferation by inhibiting Raf-1/extracellular signal-regulated kinase (ERK) via cAMP/protein kinase A (PKA). We examined whether trapidil inhibits PDGF-induced VSMC migration and investigated its mechanisms of action. VSMC migration was inhibited to a similar extent by trapidil and forskolin. A PKA inhibitor N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide (H89) blocked the inhibition by forskolin to a greater degree than that by trapidil. Trapidil but not forskolin suppressed PDGF-stimulated RhoA activation. In the presence of both H89 and (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride monohydrate, an inhibitor of Rho-associated kinase (ROCK), trapidil and forskolin inhibited migration to a similar extent. Thus, in addition to cAMP/PKA activation, trapidil inhibits RhoA/ROCK activation, which may be important in trapidil's inhibitory effect on migration.

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 W258 X 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.