Cystinuria.

UNLABELLED: Cystinuria is an autosomal recessive disorder characterized by impaired transport of cystine, lysine, ornithine and arginine in the proximal renal tubule and in the epithelial cells of the gastrointestinal tract. Following recent progress in the genetic understanding of the disease, the traditional classification, based on the excretion of cystine and dibasic amino acids in obligate heterozygotes, may no longer be considered valid. A new classification is therefore needed: type A due to two mutations of SLC3A1 on chromosome 2, and type B due to two mutations of SLC7A9 on chromosome 19. The possibility of a third type, AB, with one mutation on each of the above-mentioned genes, is left open, but is unlikely. Clinical data show that cystinuria is more severe in males than in females in terms of stone production and early age of onset. The two types of cystinuria (A and B) have a similar outcome. A mild renal failure is present in 17% of patients. Medical treatment of this disorder is possible, but requires a composite approach: urine dilution and alkalization, and the use of drugs to form chemical bonds with the sulphydryl domains of the cystine molecule, which lower the amount of free cystine in the urine. CONCLUSION: Following new achievements in the genetics of cystinuria, a new classification has been proposed. Cystinuria is more severe in males than in females, but only rarely leads to renal insufficiency. The two types of cystinuria have a similar clinical outcome. A combined medical treatment may be effective in reducing renal stone incidence.

Epidemiology, clinical presentation, and pathophysiology of atypical and recurrent hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) includes a heterogeneous group of hemolytic disorders. Among the identified causes of HUS are infections, particularly infections with Shiga toxin-producing ESCHERICHIA COLI (STEC), complement disorders, and disorders interfering with the degradation of von Willebrand factor (VWF). Other causes for atypical HUS include the cobalamin metabolism; pregnancy/hemolysis, elevated liver enzymes, and low platelets syndrome (HELLP); drugs; and other disorders (e.g., systemic diseases appearing as HUS, such as systemic lupus erythematosus and rejection after transplantation). The group not related to STEC is often also called atypical HUS. Most of the occurrences of infectious HUS have only one episode. Recurrent episodes (recurrent HUS) have strong relationships to diseases of the complement system. In these two subgroups the prognosis is poor, with severe renal insufficiency, together with the need for renal replacement therapy. Severe arterial hypertension is common. Treatment options are limited. To better define this group of patients, the European Society for Pediatric Nephrology supported an initiative to develop a European HUS registry. In this registry, 167 patients were acquired; 73 were female (43.8%). The year of onset of the disease ranged from 1974 to 2005. The prevalence of atypical HUS/recurrent HUS can be calculated as 3.3 per million child population (< 18 years). Underlying disorders included factor H, factor I, MCP-1, pneumococci, and von Willebrand factor disturbances. In 33 patients at least one renal transplantation was performed (total, 55 kidneys); 18% were successful and 73% demonstrated recurrence or thrombosis. Treatment options were plasma substitution or plasmapheresis. Despite continued efforts, transplantation is not recommended at present for these patients. Living-related transplantation should be abandoned. New therapeutic strategies are urgently needed.

Long-term renal function in heart transplant children on cyclosporine treatment.

Renal function deterioration is a reason of concern in heart transplantation. Our aim was to evaluate long-term renal function in heart transplant children on cyclosporine (CsA) treatment and to investigate the effect of several variables possibly involved in renal function deterioration. Creatinine clearances were retrospectively reviewed in 50 children (median follow 99.7 months after heart transplant). Gender, age, and body weight at transplant, rejection episodes, CsA cumulative dose, and trough levels were analyzed. After an initial increase of the glomerular filtration rate (GFR), renal function worsened in most patients; 28% of the children developed renal insufficiency (defined as GFR <80 ml/min per 1.73 m2), which was already evident in the first 3 years. Neither CsA dose, trough levels, nor other patient characteristics were found to be associated with renal function deterioration. In this study renal failure occurred in one-third of the patients. The lack of association of CsA with renal insufficiency may be explained by several reasons, including the limitations of the retrospective design of the study. However, it is possible that the nephrotoxic effect of CsA is more likely to occur in a set of predisposed patients. These must be soon identified to evaluate early a calcineurin inhibitor-sparing strategy.

Shiga toxins present in the gut and in the polymorphonuclear leukocytes circulating in the blood of children with hemolytic-uremic syndrome.

Hemolytic-uremic syndrome, the main cause of acute renal failure in early childhood, is caused primarily by intestinal infections from some Escherichia coli strains that produce Shiga toxins. The toxins released in the gut are targeted to renal endothelium after binding to polymorphonuclear leukocytes. The presence of Shiga toxins in the feces and the circulating neutrophils of 20 children with hemolytic uremic syndrome was evaluated by the Vero cell cytotoxicity assay and flow cytometric analysis, respectively. The latter showed the presence of Shiga toxins on the polymorphonuclear leukocytes of 13 patients, 5 of whom had no other microbiologic or serologic evidence of infection by Shiga toxin-producing Escherichia coli. A positive relationship was observed between the amounts of Shiga toxins released in the intestinal lumen and those released in the bloodstream. The toxins were detectable on the neutrophils for a median period of 5 days after they were no longer detectable in stools. This investigation confirms that the immunodetection of Shiga toxins on neutrophils is a valuable tool for laboratory diagnosis of Shiga toxin-producing Escherichia coli infection in hemolytic-uremic syndrome and provides clues for further studies on the role of neutrophils in the pathogenesis of this syndrome.

Impaired activity of the gamma-glutamyl cycle in nephropathic cystinosis fibroblasts.

Cystinotic patients have been shown to excrete in their urine high levels of pyroglutamate, an intermediate metabolite of the adenosine triphosphate (ATP)-dependent gamma-glutamyl cycle, which is responsible for glutathione (GSH) synthesis. Human fibroblasts were used to study the mechanisms leading to pyroglutamate accumulation in nephropathic cystinosis (NC). We show that inhibition of ATP synthesis caused a marked intracellular accumulation of pyroglutamate, reflecting decreased GSH synthesis. Despite similar degrees of ATP depletion, pyroglutamate increased more in cystinotic fibroblasts than in controls, while GSH decreased to lower levels. In addition, cystinotic cells exposed to oxidative stress (hydrogen peroxide) were unable to increase their GSH concentration above baseline. These results could not be attributed to differences in mitochondrial oxidative activity or to increased apoptotic cell death. Together, these results support the hypothesis that cysteine derived from lysosomal cystine efflux limits the activity of the gamma-glutamyl cycle and GSH synthesis.

Left ventricular geometry in children with mild to moderate chronic renal insufficiency.

Left ventricular hypertrophy (LVH) is the most important independent marker of cardiovascular risk in adults with chronic kidney disease. Cardiovascular morbidity seems increased even in children with chronic renal insufficiency (CRI), but the age and stage of CRI when cardiac alterations become manifest are unknown. For assessing the prevalence and factors associated with abnormal LV geometry in children with CRI, echocardiograms, ambulatory BP monitoring, and biochemical profiles were obtained in 156 children aged 3 to 18 yr with stages 2 through 4 chronic kidney disease (GFR 49 +/- 19 ml/min per 1.73 m2) and compared with echocardiograms obtained in 133 healthy children of comparable age and gender. LV mass was indexed to height2.7. Concentric LV remodeling was observed in 10.2%, concentric LVH in 12.1%, and eccentric LVH in 21% of patients. LVH was more common in boys (43.3 versus 19.4%; P < 0.005). Probability of LVH independently increased with male gender (odds ratio [OR] 2.62; P < 0.05) and standardized body mass index (OR 1.56; P = 0.01). Low hemoglobin, low GFR, young age, and high body mass index were independent correlates of LV mass index (0.005 < P < 0.05). LV concentricity (relative wall thickness) was positively associated with serum albumin (P < 0.05). Probability of abnormal LV geometry increased with C-reactive protein >10 mg/dl (OR 26; P < 0.001). In conclusion, substantial cardiac remodeling of both concentric and eccentric type is present at young age and early stages of CRI in children. Prevalence of LVH is related to male gender, anemia, and ponderosity but not to BP. Additional effects of volume status and inflammation on cardiac geometry are also evident.

"Bartter-like" phenotype in Kearns-Sayre syndrome.

Kearns-Sayre syndrome (KSS) is a mitochondrial disease caused by large deletions in mitochondrial DNA (mtDNA). In most patients the disease is characterized by mtDNA heteroplasmy, where a mixture of wild-type and mutated mtDNA co-exist within cells in variable proportion, modulating the severity of the phenotype in different tissues. We report on the case of a 14-year-old child with classical symptoms of KSS and a renal phenotype characterized by hypokalaemic alkalosis, hypomagnesaemia, hyperreninaemia, hyperaldosteronism and nephrocalcinosis, resembling Bartter syndrome. Analysis of mtDNA demonstrated an 8,661 bp deletion involving eight mitochondrial genes. Uneven degrees of mtDNA heteroplasmy were demonstrated in several tissues, ranging from 24% to 60% of deleted/total mtDNA. Variable degrees of expression of mitochondrial enzymes were also found in biopsy specimens of renal and skeletal muscle by histocytochemistry. In particular, preserved cytochrome c oxidase was observed in tubular structures within medullary rays. It is proposed that a "Bartter-like" phenotype can arise in some patients with KSS as a result of heteroplasmy. In these cases aldosterone-responsive tubular structures have been spared during renal embryogenesis, allowing for the development of hypokalaemic alkalosis in response to salt and water losses from the more damaged tubular segments.

One-year angiotensin-converting enzyme inhibition plus mycophenolate mofetil immunosuppression in the course of early IgA nephropathy: a multicenter, randomised, controlled study.

Angiotensin converting-enzyme inhibition (ACEI) is a widely accepted treatment during established renal diseases and beneficial effects have also been reported in IgA nephropathy (IgAN). Immunosuppression with myco-phenolate mofetil (MMF) has recently been introduced in the treatment of immune-mediated renal diseases showing promising results. Preliminary clinical reports are also suggestive that MMF is effective in severe forms of IgAN. We propose a randomised prospective trial aimed to compare long-term renal survival of early IgAN in the course of ACEI therapy with or without MMF immunosuppression.

Cyclosporine therapy monitored with abbreviated area under curve in nephrotic syndrome.

Cyclosporin A (CsA) is an effective therapy for children with long-lasting nephrotic syndrome (NS). Long-term treatment can result in chronic CsA nephropathy (CsAN) and there is controversy concerning its incidence and severity. Trough levels are commonly used to monitor the drug concentration. We report a retrospective clinical and histological analysis of 18 children (12 males, 6 females) with steroid-dependent nephrotic syndrome (15 patients) and partially steroid-sensitive nephrotic syndrome (3 patients) treated with CsA for a long-term period (mean 4.9 years, range 2.2-6.9). Before CsA treatment all patients had normal creatinine clearance. CsA was started at a dose of 5 mg/kg per day administered orally in two divided doses and adjusted to maintain the mean CsA blood concentration between 250 and 350 ng/ml obtained from abbreviated area under the curve (AUC). A renal biopsy was performed after a mean period of 3.9 years (range 2.2-6.2) from the start of CsA treatment. Tubular, interstitial, and arteriolar lesions were evaluated in order to assess CsAN. The mean CsA dose and the mean CsA blood concentration were 4.4 mg/kg per day (range 3.6-5.8) and 276.6 ng/ml (range 162-346), respectively. No child had a worsening creatinine clearance during CsA treatment and follow-up after CsA discontinuation. If compared with the year before the start of CsA treatment, NS relapses and prednisone (PDN) dose significantly decreased during CsA treatment, 4/year versus 0.8/year (P <0.0001) and 0.9 mg/kg per day versus 0.2 mg/kg per day (P <0.0001), respectively. Histological analysis showed 15 patients with minimal change disease and 3 with focal segmental glomerulosclerosis. Clear-cut lesions diagnostic of CsAN were never found and only mild lesions were observed in 5 children (suggestive of CsAN in 2 patients and consistent with CsAN in 3 patients). Long-term CsA treatment is confirmed to be effective in preventing NS relapses and reducing PDN dose. Renal function is not a reliable indicator of CsAN. With the mean CsA blood concentrations used in our patients CsAN presented a low incidence (28%) and was generally mild. Renal biopsy should be performed 2-3 years from the start of long-term CsA treatment, especially if the mean CsA blood concentrations are not regularly monitored.

Chronic peritoneal dialysis catheters in children: a fifteen-year experience of the Italian Registry of Pediatric Chronic Peritoneal Dialysis.

OBJECTIVE: To analyze data on 503 chronic peritoneal dialysis (CPD) catheters implanted between 1986 and 2000 in pediatric patients enrolled in the Italian Registry of Pediatric Chronic Peritoneal Dialysis (the Registry), comparing three different time periods: 1986-1990, 1991-1995, and 1996-2000. DESIGN: Retrospective study. SETTING: 23 dialysis centers participating in the Registry. METHODS: Data were collected from questionnaires filled in every year. The information for each peritoneal catheter included type, site and technique of insertion, exit-site orientation, exit-site care, complications, survival, and reason for removal. PATIENTS: 503 catheters were implanted in 363 pediatric patients aged younger than 15 years at the start of CPD: 97 catheters in patients under 2 years of age, 67 in patients aged 2-5 years, and 339 in patients over 5 years of age. Mean patient age at onset of CPD was 8.0 +/- 5.1 years. All catheters were surgically implanted and omentectomy was performed in 82.4% of cases. The catheters used were Tenckhoff [468 (93.0%): 443 double cuff, 25 single cuff] and double-cuffed Valli [35 (7.0%)]. The entry site was in the midline in 153 cases (30.4%) and paramedian in 350 (69.6%). RESULTS: During 9048 dialysis-months we observed 451 catheter-related complications, yielding an incidence of 1 episode/20.1 CPD-months: 330 catheter infections (exit-site and/or tunnel infections), 26 leakages, 26 dislocations, 24 obstructions, 22 cuff extrusions, 6 hemoperitoneums, 17 others. 171 catheters were removed due to catheter-related causes; exit-site and/or tunnel infections were the main cause for removal (75.4%), followed by obstruction, dislocation, outer-cuff extrusion, and leakage. Younger children (< 2 years) had a higher risk of infectious causes of catheter removal compared to children aged 2-5 years (p = 0.004) and over 5 years of age (p = 0.002). During the 15-year observation period, a significant reduction in the incidence of leakage was observed and risk of leakage was lower in catheters with paramedian entry site compared to catheters with midline entry site. Removal and replacement of peritoneal catheters during the same surgical operation was performed in 76.3% of catheter removals. Catheter survival rate was 78.1% at 12 months, 58.5% at 24 months, 43.8% at 36 months, and 34.6% at 48 months. No difference in catheter survival was observed in younger children (< 2 years) compared with the two other age groups: < 2 years versus 2-5 years hazard ratio 0.7, 95% confidence interval (95%CI) 0.4-1.2; < 2 years versus > 5 years hazard ratio 0.8, 95%CI 0.5-1.1. CONCLUSIONS: In this survey, we observed better catheter survival in comparison with data reported by the Registry in 1998. Catheter survival improved especially in younger children (< 2 years), a group that previously had a decreased catheter survival rate compared to older age groups. In addition to the progressive increase in experience acquired by dialysis centers, this upward trend may also be related to greater use of double-cuffed catheters, with paramedian exit site, and a higher frequency of omentectomy.

Flow cytometry detection of Shiga toxins in the blood from children with hemolytic uremic syndrome.

BACKGROUND: Hemolytic uremic syndrome (HUS) is the main cause of acute renal failure in early childhood. Most cases are due to intestinal infections from Escherichia coli strains (STEC) which produce by Shiga toxin (Stxs). Stx1 and Stx2 produced by STEC in the gut are absorbed into the circulation and, after binding on polymorphonuclear leukocytes (PMNs), are targeted to renal endothelium. The aim of the present work was the development of a method to detect Stxs bound on circulating PMNs and to diagnose STEC infections in patients with HUS. METHODS: White blood cells isolated after erythrocytic lysis were incubated with anti-Stxs mouse monoclonal antibodies in the presence of human serum to saturate Fc receptors on PMNs. After incubation with fluorescein isothiocyanate-goat anti-mouse immunoglobulin G, flow cytometric analysis was used to demonstrate the cell-bound fluorescence. RESULTS: The method was quick (3 h), sensitive (femtomoles), and capable of detecting both Stxs. The presence of Stxs was detected on PMNs from six patients with HUS: four patients had serologic or microbiological evidence of STEC infection, whereas the other two patients had no evidence of STEC infection when employing the standard diagnostic methods. CONCLUSIONS: The method described is rapid, simple, and based on commercially available reagents, and it might be more sensitive than the standard methods for diagnosis of STEC infection. It also allows the detection of Stxs in blood, a key step to monitor the pathogenesis of HUS.

Blood pressure in the long-term follow-up of children with hemolytic uremic syndrome.

The hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure (ARF) in young children. Most patients recover from the acute phase of the illness but they may develop arterial hypertension(AH) after many years, even in the absence of signs of renal impairment during short-term follow-up. In this study, we performed casual blood pressure (BP) measurement, 24-h blood pressure monitoring (ABPM), and a Bruce walking treadmill study (ET) in 24 children (aged 5-15 years, 13 males, 11 females) with a history of HUS and normal renal function during follow-up (median 5.8 years, range 1.8-12.4 years). There were 22 children(91%) with prodromal diarrhea associated with HUS and 20 (83%) underwent dialysis during the acute illness. All children had normal casual BP measurement. Of 13 children (54%) with normal ABPM, 5 patients (38%) had an abnormal BP response during the ET study. There were 4 (58%) of the 7 patients with AH by ABPM (29%)and an abnormal BP response during ET. These findings suggest that ET could be a useful means of identifying children with a history of HUS that could be at risk of future AH even if they had normal renal function, casual BP, and ABPM during long-term follow-up. These results should be confirmed with a large prospective clinical study.

Parathyroid hormone levels in pubertal uremic adolescents treated with growth hormone.

We have previously described severe hyperparathyroidism during the pubertal growth spurt in three uremic adolescents treated with recombinant human growth hormone (rhGH). Here we investigate the possible role of puberty in the genesis of hyperparathyroidism during rhGH treatment of a large cohort of patients. Data from 67 uremic patients treated with rhGH from five Italian pediatric nephrology centers were retrospectively recorded every 3 months starting 1 year before rhGH administration. The mean (+/-SD) rhGH treatment observation period was 19.9+/-5.9 months. The mean age at the start of rhGH treatment was 8.3+/-3.6 years. Of the 67 patients, 15 reached pubertal stage 2 during the 1st year of rhGH treatment and 12 of these 15 progressed to pubertal stage 3. The relative increase in parathyroid hormone (PTH) levels after rhGH initiation was greater in pubertal [1.95, 95% confidence interval (CI) 1.43-2.66] than in prepubertal patients (1.19, 95% CI 1.01-1.40). Increases in PTH levels were significantly different between the two groups (Delta=1.64, 95% CI 1.16-3.19, P=0.007). Multiple regression analysis showed an inverse correlation between PTH and calcium levels and a positive correlation between PTH and pubertal stage 3. There was no correlation with phosphate levels and calcitriol dosage. In conclusion, these results suggest that in uremic adolescents treated with rhGH puberty may influence PTH levels.

Risk factors for poor renal prognosis in children with hemolytic uremic syndrome.

Many factors have been proposed as predictors of poor renal prognosis in children with hemolytic uremic syndrome (HUS), but their role is still controversial. Our aim was to detect the most reliable early predictors of poor renal prognosis to promptly identify children at major risk of bad outcome who could eventually benefit from early specific treatments, such as plasmapheresis. Prognostic factors identifiable at onset of HUS were evaluated by survival analysis and a proportional hazard model. These included age at onset, prodromal diarrhea (D), leukocyte count, central nervous system (CNS) involvement, and evidence of Shiga toxin-producing Escherichia coli (STEC) infection. Three hundred and eighty-seven HUS cases were reported; 276 were investigated for STEC infection and 189 (68%) proved positive. Age at onset, leukocyte count, and CNS involvement were not associated with the time to recovery. Absence of prodromal D and lack of evidence of STEC infection were independently associated with a poor renal prognosis; only 34% of patients D(-)STEC(- )recovered normal renal function compared with 65%-76% of D(+)STEC(+), D(+)STEC(-) and D(-)STEC(+ )patients. In conclusion, absence of both D and evidence of STEC infection are needed to identify patients with HUS and worst prognosis, while D(-) but STEC(+) patients have a significantly better prognosis.

Epidermal basement membrane alpha 5(IV) expression in females with Alport syndrome and severity of renal disease.

BACKGROUND: X-linked Alport syndrome is a progressive nephritis caused by mutations of the COL4A5 gene. This gene encodes the collagen alpha 5(IV) chain, which is abnormally distributed in the glomerular basement membrane (GBM) and epidermal basement membrane (EBM). It has been reported a negative correlation between alpha 5(IV) chain distribution in EBM and the degree of proteinuria in heterozygous females with Alport syndrome. METHODS: In the present study, we evaluated the distribution of the alpha 5(IV) chain in the EBM and the degree of proteinuria in 22 females with X-linked Alport syndrome. The distribution of the cutaneous alpha 5(IV) chain was measured by a confocal laser microscope using an anti-alpha 5(IV) monoclonal antibody. The expression ratio of alpha 5(IV) distribution was quantified dividing the extension of the positive signal and the maximal extension of the specimen. Urinary protein excretion was expressed as urinary protein over urinary creatinine ratio. RESULTS: Proteinuria was present in five of the 22 patients. In two patients with proteinuria, alpha 5(IV)chain was normally distributed; in the remaining three, the expression ratio of alpha 5(IV)chain was 35%, 47%, and 48%. Of the 17 patients without proteinuria, two displayed a complete absence of the alpha 5(IV) chain in EBM, five displayed a normal staining, and the remaining 10 had an expression ratio between 18% and 65%. CONCLUSION: Our data suggest that there is no correlation between the severity of the glomerular involvement (expressed by proteinuria) and the staining of the alpha 5 chain in the EBM in females with X-linked Alport syndrome.

X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a "European Community Alport Syndrome Concerted Action" study.

Alport syndrome (AS) is a type IV collagen hereditary disease characterized by progressive hematuric nephritis, hearing loss, and ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease characterized by much less severe disease in girls and women. A "European Community Alport Syndrome Concerted Action" (ECASCA) group was established to delineate the Alport syndrome phenotype in each gender and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X-linked transmission, were collected. Characteristics of heterozygous girls and women belonging to the 195 families with proven COL4A5 mutation are compared with those of hemizygous boys and men. Hematuria was observed in 95% of carriers and consistently absent in the others. Proteinuria, hearing loss, and ocular defects developed in 75%, 28%, and 15%, respectively. The probability of developing end-stage renal disease or deafness before the age of 40 yr was 12% and 10%, respectively, in girls and women versus 90 and 80%, respectively, in boys and men. The risk of progression to end-stage renal disease appears to increase after the age of 60 yr in women. Because of the absence of genotype-phenotype correlation and the large intrafamilial phenotypic heterogeneity, early prognosis of the disease in X-linked Alport syndrome carriers remains moot. Risk factors for developing renal failure have been identified: the occurrence and progressive increase in proteinuria, and the development of a hearing defect.

Mutational spectrum of the CTNS gene in Italy.

Classic nephropathic or infantile cystinosis (NC) is an autosomal recessive disorder; the gene coding for the integral membrane protein cystinosin, which is responsible for membrane transport of cystine (CTNS), was cloned. Mutation analysis of the CTNS gene of Caucasian patients revealed a common 57-kb deletion, and several other mutations spread throughout the entire gene. In the present study, we report the CTNS mutations identified in 42 of 46 Italian families with NC. The percentage of mutations characterized in this study is 86%. The mutational spectrum of the Italian population is different from that of populations of North European origin: the 57-kb deletion is present in a lower percentage, while the splicing mutations represent 30% of mutation detected in our sample. In all, six novel mutations have been identified, and the origin of one recurrent mutation has been traced.

Long-term linear growth of children with severe steroid-responsive nephrotic syndrome.

The present study was designed to evaluate the risk of permanent linear growth impairment in a selected group of 42 children with steroid-dependent nephrotic syndrome (SDNS) and 14 children with frequently relapsing nephrotic syndrome (FRNS). Longitudinal height measurements were available in all patients from the onset of the disease for a mean follow-up of 11.7+/-3.5 years. During the prepubertal period, patients lost 0.49+/-0.6 height SD score (HtSDS) ( P<0.001). Twenty-three patients have reached their final height with an average loss of 0.92+/-0.8 HtSDS from the onset of their disease ( P<0.001) and 0.68+/-0.7 from their target HtSDS ( P<0.001). The pubertal growth spurt was mildly delayed in male but not female patients. Steroid therapy, calculated as the mean duration of prednisone (PDN) treatment or as the average cumulative PDN dose, was the only predictor of poor growth evolution. Partial catch-up growth occurred after PDN withdrawal. Children with early onset NS and adolescent patients, who were still receiving PDN after the age of 9 years in girls and 11 years in boys, were at higher risk for HtSDS loss. In conclusion, children with severe steroid-responsive NS are at risk of permanent growth retardation secondary to prolonged courses of steroid treatment.