Abstract. Familial juvenile hyperuricemic nephropathy (FJHN [MIM 162000]) is an autosomal-dominant disorder characterized by abnormal tubular handling of urate and late development of chronic interstitial nephritis leading to progressive renal failure. A locus for FJHN was previously identified on chromosome 16p12 close to the MCKD2 locus, which is responsible for a variety of autosomal-dominant medullary cystic kidney disease (MCKD2). UMOD, the gene encoding the Tamm-Horsfall/uromodulin protein, maps within the FJHN/MCKD2 critical region. Mutations in UMOD were recently reported in nine families with FJHN/ MCKD2 disease. A mutation in UMOD has been identified in 11 FJHN families (10 missense and one in-frame deletion)-10 of which are novel-clustering in the highly conserved exon 4. The consequences of UMOD mutations on uromodulin expression were investigated in urine samples and renal biopsies from nine patients in four families. There was a markedly increased expression of uromodulin in a cluster of tubule profiles, suggesting an accumulation of the protein in tubular cells. Consistent with this observation, urinary excretion of wild-type uromodulin was significantly decreased. The latter findings were not observed in patients with FJHN without UMOD mutations. In conclusion, this study points to a mutation clustering in exon 4 of UMOD as a major genetic defect in FJHN. Mutations in UMOD may critically affect the function of uromodulin, resulting in abnormal accumulation within tubular cells and reduced urinary excretion.Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal-dominant disorder characterized by hyperuricemia and decreased urinary excretion of urate, followed by the development of chronic interstitial nephritis most often leading to progressive renal failure (1,2). The link between early hyperuricemia and subsequent progression of renal disease remains unclear.Urate is the end product of purine metabolism in humans, who have lost the expression of the uricase gene during evolution (3). Urate is freely filtered by the glomerulus and essentially reabsorbed, because only 10% of the filtered load is present in the final urine (4). The transport mechanisms of urate are localized in the proximal tubule (PT), whereas no experimental evidence supports urate permeability in the more distal segments of the nephron (5). URAT1, the long-hypothesized apical urate-anion exchanger involved in the reabsorption of urate by PT cells, was recently identified (6). Inactivating mutations of URAT1 located on 11q13 are responsible

We sought to ascertain the long-term outcome and genotype-phenotype correlations available for primary hyperoxaluria type 1 in a large retrospective cohort study. We examined the clinical history of 155 patients (129 families primarily from Western Europe, North Africa, or the Middle East) as well as the enzymatic or genetic diagnosis. The median age at first symptom was 4 years, and at diagnosis 7.7 years, at which time 43% had reached end-stage renal disease. Presentations included: (1) early nephrocalcinosis and infantile renal failure, (2) recurrent urolithiasis and progressive renal failure diagnosed during childhood, (3) late onset with occasional stone passage diagnosed in adulthood, (4) diagnosis occurring on post-transplantation recurrence, and (5) family screening. The cumulative patient survival was 95, 86, and 74% at ages 10, 30, and 50 years, respectively, with the cumulative renal survival of 81, 59, 41, and 10% at ages 10, 20, 30, and 50 years, respectively; 72 patients had undergone a total of 97 transplantations. Among the 136 patients with DNA analysis, the most common mutation was p.Gly170Arg (allelic frequency 21.5%), with a median age at end-stage renal disease of 47 years for homozygotes, 35 years for heterozygotes, and 21 years for other mutations. Our results underscore the severe prognosis of primary hyperoxaluria type 1 and the necessity for early diagnosis and treatment, as well as confirm a better prognosis of the p.Gly170Arg mutation.

No abstract

Nephronophthisis is an autosomal recessive chronic tubulointerstitial disease that progresses to end-stage renal disease (ESRD) in about 10% of cases during infancy. Mutations in the INVS (NPHP2) gene were found in a few patients with infantile nephronophthisis. Mutations of NPHP3, known to be associated with adolescent nephronophthisis, were found in two patients with early-onset ESRD. Here we screened 43 families with infantile nephronophthisis (ESRD less than 5 years of age) for NPHP2 and NPHP3 mutations and determined genotype-phenotype correlations. In this cohort there were 16 families with NPHP2 mutations and NPHP3 mutations in seven. Three patients carried only one heterozygous mutation in NPHP3. ESRD arose during the first 2 years of life in 16 of 18 patients with mutations in NPHP2, but in only two patients with mutations in NPHP3. Renal morphology, characterized by hyper-echogenic kidneys on ultrasound and tubular lesions with interstitial fibrosis on histology, was similar in the two patient groups. The kidney sizes were highly diverse and ultrasound-visualized cysts were present in a minority of cases. Extra-renal anomalies were found in 80% of the entire cohort including hepatic involvement (50%), cardiac valve or septal defects (20%) and recurrent bronchial infections (18%). We show that NPHP3 mutations in both infantile and adolescent nephronophthisis point to a common pathophysiological mechanism despite their different clinical presentations.

Aetiology could not be established prenatally in the absence of familial data. Kidney size and amniotic fluid volume were the best prenatal predictors of outcome.

We prospectively determined cystine crystal volume (Vcys) in urine specimens from all consecutive patients with cystine urolithiasis followed at our institution over the past decade, in order to assess its predictive value as to the risk of recurrent cystine stone formation. A total of 57 patients (29 males, 28 females) with homozygous cystinuria entered in the study between January 1990 and December 2000, including 15 children aged less than 15 years and 42 patients aged 15 years or more. The clinical and radiological course was followed until December 2001, for a total of 243 patient-years of follow-up. From study entry until the end of follow-up, we serially examined first voided morning urine specimens in all patients, with determination of the number of cystine crystals per mm3, and the average size of crystals, thus allowing us to calculate Vcys using a simple formula based on crystal geometry. Recurrence was diagnosed on the basis of serial radiographic examinations using X-rays and echography. Overall, cystine crystals were present in 179 (39%) of the 460 examined urine specimens. Cystine crystalluria was significantly more frequent among the 27 patients who developed new cystine stones (SF) than in the other 30 who remained stone-free (63.3 vs 25.5% of samples, P<0.001). The presence of crystals in > or =50% of serially examined urine samples was more frequently found in patients with recurrent stone formation than in non-recurrent patients (24/27 vs 2/30, P<0.001). The average Vcys value was significantly higher in recurrent SF than in stone-free patients (8,173 +/- 1,544 vs 233 +/- 150 micro3/mm3, P<0.001) and there was no overlap in the individual values of recurrent vs stone-free patients. A Vcys value > or =3,000 micro3/mm3 was observed at least once prior to each of the 63 stone recurrences observed in 27 patients (2.3 per patient on the average). In addition, Vcys reflected the efficacy of treatment, with Vcys mean values of 12,097 +/- 3,214 micro3/mm3 at baseline, falling to 2,648 +/- 658 micro3/mm3 on basic therapy (hyperdiuresis plus alkalinization) alone, 1,141 +/- 522 micro3/mm3 on tiopronin therapy (median dose 1,000 mg/day) and 791 +/- 390 micro3/mm3 on D-penicillamine therapy (median dose 900 mg/day) whereas captopril had no effect (5,114 +/- 2,128 micro3/mm3). Based on the results of the present study, cystine crystalluria appears to accurately reflect active stone formation in cystinuric patients. Determination of total Vcys provides a simple, cheap and accurate means of predicting the risk of cystine stone recurrence with a Vcys value > or =3000 micro3/mm3 as the threshold risk value. We propose that serial Vcys determination be performed simultaneously with the measurement of urine pH and specific gravity to optimally monitor the medical treatment of cystine patients.

IV CsA is a safe and effective treatment in children with recurrent nephrotic syndrome after renal transplantation.

Augmentation cystoplasty is a safe and effective method of restoring lower urinary tract function in the pediatric renal transplant population with a small noncompliant bladder.