Marie-France Gagnadoux

A Cluster of Mutations in the UMOD Gene Causes Familial Juvenile Hyperuricemic Nephropathy with Abnormal Expression of Uromodulin

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.

Treatment of cystinuria.

Abstract Cystine urolithiasis is the only clinical expression of cystinuria, an autosomal recessive genetic defect of the transepithelial transport of cystine and other dibasic amino acids in the kidney. Stones form due to the increased excretion of cystine, which is poorly soluble at normal urine pH. Cystine stones are often resistent to extracorporeal shock wave lithotripsy, so that percutaneous surgery or ureteroscopy are the preferred techniques of stone extraction. Medical preventative treatment is based on high diuresis (≥1.5 l/m2 per day) well distributed throughout the day and night, and urine alkalinization up to pH 7.5 by means of sodium bicarbonate and/or potassium citrate. When these basal measures are ineffective at preventing stone recurrence or dissolving pre-existing stones, sulfhydryl agents such as D-penicillamine or tiopronin, which form highly soluble mixed disulfides with cystine moieties, are to be added to urine dilution and alkalinization, especially when cystine excretion is in excess of 750 mg/day (3 mmol/day). Frequent clinical and ultrasound follow-up is needed to encourage patient compliance and assess efficacy and tolerance of treatment.

Intravenous cyclosporine therapy in recurrent nephrotic syndrome after renal transplantation in children.

Background. Early recurrence of massive proteinuria after renal transplantation occurs in 20% to 30% of patients with steroid-resistant idiopathic nephrotic syndrome and is responsible for graft failure in approximately half of cases. We report our experience with the use of intravenous (IV) cyclosporine (CsA) in children with recurrent proteinuria after renal transplantation. Methods. Between March 1991 and August 2001, 36 renal transplantations were performed in 35 patients with steroid-resistant idiopathic nephrotic syndrome in our institution. Recurrence, defined by proteinuria higher than 50 mg/kg per day in the absence of acute rejection or urinary tract infection, was observed in 17 grafts performed in 16 patients. In patients with recurrence, CsA was administered IV, at an initial dose of 3 mg/kg per day, which was afterward adapted to maintain whole-blood levels between 250 and 350 ng/mL. Results. In 14 of 17 cases (82%) with recurrence, proteinuria completely disappeared after 20.8±8.4 (range 12–40) days. The treatment was ineffective in the remaining three patients with persistent proteinuria at the end of the second month posttransplantation. Plasma exchanges were performed in four patients during the first 2 months, and proteinuria regressed in three cases and persisted in one. Persistent remission was observed in 11 patients with a follow-up of 3.7±3 (range 0.3–9) years. Actuarial graft survival was 92% and 70% at 1 and 5 years. Conclusion. IV CsA is a safe and effective treatment in children with recurrent nephrotic syndrome after renal transplantation.

Glomerular Lesions in the Transplanted Kidney in Children

The glomerular pathology of 634 transplant specimens (526 biopsies and 108 transplantectomies) from 410 children was studied. Three types of glomerulopathies were observed: (1) recurrent glomerulonephritis (GN) (40 of 142 patients with glomerular nephropathy), (2) de novo GN (52 grafts), and (3) transplant glomerulopathy (29 grafts). The study of recurrent GN is considered of great interest because of the possible insight into the nature of the original disease and the opportunity to observe the evolution of the disease in sequential biopsies of the transplant. The two major forms of de novo GN were membranous GN and IgG linear deposits along glomerular and tubular basement membranes. Transplant glomerulopathy, although distinctive morphologically, may resemble membranoproliferative GN (MPGN) or thrombotic microangiopathy.

Elevated Plasma 1,25-Dihydroxyvitamin D Concentrations in Infants with Hypercalcemia and an Elfin Facies

We measured plasma concentrations of 1,25-dihydroxyvitamin D (1,25-(OH)2D) in the course of a 6-to-37-month survey of four children with hypercalcemia and an elfin facies (Williams syndrome). Levels of 1,25-(OH)2D were elevated (160 to 470 pg per milliliter) during the hypercalcemic phase of the disease, when the children were five to nine months old, and they decreased thereafter. Plasma 1,25 (OH)2D levels were higher than those found in three children (16 to 60 months old) with the elfin facies syndrome and no hypercalcemia (42 to 71 pg per milliliter) and eight children (1 to 36 months old) with hypercalcemia and no dysmorphy (12 to 140 pg per milliliter), including two children with vitamin D intoxication. Hypercalcemia in the three children with elfin facies was controlled by a low-calcium diet. Serum calcium levels fell to the normal range, and plasma 1,25-(OH)2D levels were normal for age (18 to 105 pg per milliliter) at 14 to 47 months of age, even after appropriate therapy had been discontinued. These observations suggest that hypercalcemia may be the consequence of abnormal synthesis or degradation of 1,25-(OH)2D in children with the elfin facies syndrome.

Renal transplantation in children with augmentation cystoplasty: long-term results.

PURPOSE We assessed the long-term results of renal transplantation in children with augmentation cystoplasty. MATERIALS AND METHODS We retrospectively reviewed the complications and followup in 14 pediatric renal transplant recipients with augmentation cystoplasty. The etiology of bladder dysfunction included posterior urethral valves in 10 cases, neurogenic bladder in 3 and vesicoureteral reflux in 1. All transplants were cadaver donor kidneys. Mean patient age at transplantation was 12.1 years (range 5 to 18). Augmentation cystoplasty was performed before and after transplantation in 10 and 4 cases, respectively. Detubularized ileum was used in 5 cases, tubular ileum in 4, tubular sigmoid in 4 and stomach in 1. RESULTS Of the 14 transplanted kidneys 10 (71%) were functioning at a mean followup of 80 months (range 12 to 151). Serum creatinine was less than 1.4 mg./dl. in 9 patients. Four grafts were lost to chronic rejection. The 5 and 10-year graft survival rates were 84 and 73%, respectively. Two patients with a functioning kidney died of causes unrelated to augmentation cystoplasty. Complications included symptomatic urinary infections in 4 patients, hyperchloremic metabolic acidosis in 2, nephrolithiasis in the allograft in 2 and the hematuria-dysuria syndrome in 1. All patients were continent. CONCLUSIONS 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.

Microsurgical creation and follow-up of arteriovenous fistulae for chronic haemodialysis in children

Three hundred and eighty children underwent 434 angioaccesses. Of these angioaccesses, 113 were constructed in 74 children weighing under 10 kg. Most accesses (n=340) were distal arteriovenous fistulae (AVF). After microsurgery there was a 96% immediate patency. Seventy percent of AVF, excluding distal ulnarbasilic AVF, were functional, sometimes after secondary superficialization of the vein. Eighty-five per cent of the distal radial-cephalic AVF are still patent after 2 years, 60% are still patent after 4 years. These radial-cephalic AVF required 65 repeat anastomoses, and 12 ligations of the proximal-radial artery in order to reduce to 50% the high blood flow (pre-reduction average index = 900 ml/min per m2). The patency rate of arteriovenousbridge grafts was not encouraging. The severity of stenoses in the proximal-venous trunks, sometimes related to previous catheterization, is emphasized. Advantages of the radial-cephalic wrist AVF in children are highlighted.

Mutations of NPHP2 and NPHP3 in infantile nephronophthisis

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.

Long term results of liver-kidney transplantation in children with primary hyperoxaluria.

Abstract. From 1990 to 2000, we performed eight liver-kidney transplants in eight children, aged 1–16 years, with end-stage renal failure (ESRF) due to primary hyperoxaluria (PH1). The duration of dialysis before transplantation ranged from 2 to 42 months (mean 14 months) and was <1 year in four patients. Only the first patient underwent postoperative hemodialysis; in the other five, we chose to induce maximal diuresis from the first hours with intravenous and intragastric hyperhydration (≥3 l/m2 per day). High water intake with nocturnal tube hydration was maintained for 6 months to 5 years, as long as oxaluria exceeded 0.5 mmol/day. A quadruple sequential immunosuppressive regimen was used. Two patients died during liver graft surgery. The other six patients are alive and well, with a mean follow-up of 7.4 years (range 5–11 years). Patient and graft survival is 75% at 5 years. At latest follow-up, liver tests were normal in all six patients; creatinine clearance ranged from 55 to 95 ml/min per 1.73 m2 (mean=74). Oxaluria was lower than 0.4 mmol/day in all patients (mean=0.22). The six patients underwent 15 renal biopsies, 1–11 years after transplantation. Chronic transplant nephropathy was present in four patients and mild cyclosporin nephrotoxicity in another. No oxalate crystals were seen and repeat ultrasonography has been consistently normal in all patients. The three patients with bone oxalosis showed progressive complete healing of bone lesions. All six children or adolescents now live a normal life. From this series, we conclude that early combined liver-kidney transplantation is the treatment of choice for children with ESRF due to primary hyperoxaluria.

Immunopathological findings in idiopathic nephrosis: clinical significance of glomerular "immune deposits".

Idiopathic nephrosis (IN), which includes minimal change (MCD), diffuse mesangial proliferation (DMP) and focal segmental glomerular sclerosis (FSGS), is classically characterized by the absence of significant deposits by immunofluorescence microcopy (IF), except for the focal lesions of segmental sclerosis and/or hyalinosis of FSGS, which fix IgM and C3 antiserums. Since IF is available in most centres, an increasing number of unexpected findings has been reported. In order to evaluate the clinical significance of the glomerular deposits revealed by IF in some instances, we reviewed the renal biopsy findings of 222 consecutive children presenting with IN and in whom IF microscopy was available. By light microscopy, 122 patients showed MCD, 10 DMP, and 90 FSGS with DMP (11 cases) or without (79 cases). By IF, 125 specimens were negative and served as controls; 54 showed mesangial IgM deposits, 24 mesangial IgG deposits (associated with Clq deposits in 16), 15 scattered granules of C3 and 4 predominant deposits of mesangial IgA. We correlated these findings with initial response to steroid therapy and outcome and could find no significant difference between the various categories defined by IF and the control group. Repeat biopsies, performed in 21 cases, showed the persistence of deposits in 11 and their transformation in 10. The particular problem raised by the patients who present with IN and mesangial IgA deposits is discussed. Our results demonstrate that patients presenting with IN and “positive IF”, whether showing IgM, IgG and Clq, C3 or IgA, do not represent distinct clinicopathological entities.