No clear evidence of ACEi efficacy on the progression of chronic kidney disease in children with hypodysplastic nephropathy--report from the ItalKid Project database.

BACKGROUND: Chronic kidney diseases (CKD) tend to progress to end-stage renal failure (ESRF). As it has been demonstrated that angiotensin-converting enzyme inhibitors (ACEi) have a renoprotective effect in adults with proteinuric disease and may be effective in reducing hyperfiltration and proteinuria, they are also frequently used as anti-progression agents in paediatric patients with CKD despite the lack of data confirming their role in the nephropathies peculiar to children. The aim of this study was to investigate whether patients with hypodysplastic CKD (the most common cause of ESRF in children) treated with ACEi show a significantly slower decline in creatinine clearance (Ccr). METHODS: The analysis was based on the information available in the database of the ItalKid Project, a nationwide, population-based registry of chronic renal insufficiency (CRI) in children in Italy. Of the 822 patients with CRI due to hypodysplasia, we selected those who had been continuously treated with ACEi; the control patients were identified from the same diagnostic group and matched for gender, age and baseline Ccr. RESULTS: Progression was analysed as the slope of Ccr in a total of 164 patients: 41 cases and 123 matched controls. There were no significant between-group differences in blood pressure, duration of follow-up or pre-study slope of Ccr (-0.31+/-2.26 vs -0.33+/-3.58 ml/min/1.73 m2/year; P=NS). After an average of 4.9+/-2.3 years, the mean slope of Ccr was 40% lower in the ACEi-treated cases in comparison to controls (-1.08+/-2.08 vs -1.80+/-4.42 ml/min/1.73 m2/year), however, this difference was not statistically significant (P=0.31). CONCLUSIONS: We conclude that ACEi treatment does not significantly modify the naturally progressive course of hypodysplastic nephropathy in children and further studies are necessary before such treatment is routinely proposed for anti-progression purposes in children with CKD.

Growth in children with chronic renal failure on intermittent versus daily calcitriol.

Calcitriol (C) treatment strategies for secondary hyperparathyroidism remain controversial regarding efficacy and safety. In children, intermittent C administration has been suspected of impairing body growth. In a prospective, randomized multicenter study, we compared the effect of daily versus twice weekly C on plasma intact parathyroid hormone (iPTH) levels and growth in 24 prepubertal children with chronic renal insufficiency (mean creatinine clearance 20+/-9 ml/min per 1.73 m(2)). After a 3-week washout period, the patients were randomly assigned to 10 ng/kg per day or 35 ng/kg twice a week oral C. The C dose was kept constant for 2 months and could then be adapted to maintain an iPTH target range of 140-280 pg/ml. Median (range) baseline iPTH levels were 567 (114-1209) pg/ml in the daily and 332 (93-614) pg/ml in the intermittent treatment group ( P=NS). After 12 months, iPTH had decreased to 255 (85-710) and 179 (51-443) pg/ml ( P<0.01). The average weekly dose of C was 76+/-34 and 62+/-34 ng/kg ( P=NS). Five episodes of calcium phosphate product>/=70 occurred in the daily group and four in the intermittent group. The change in height standard deviation score during the study period was not affected by either treatment modality (-0.18+/-0.34 vs. -0.05+/-0.52, P=NS). Daily and intermittent C do not differentially affect growth rate and are equally effective in controlling secondary hyperparathyroidism in children with chronic renal failure.

Urea percentiles in children with chronic renal failure. Data from the ItalKid project.

In chronic renal failure high serum urea levels (sUrea) are correlated with the onset of uremic symptoms. Urea has generally been considered relatively non-toxic, functioning more as a surrogate for other toxic solutes; however, it has been recently reported that it can contribute to uremic toxicity. Clinically sUrea are often difficult to interpret because of the wide range of kidney functions. To obtain a practical and easily accessible tool to evaluate sUrea, we have produced percentile curves for different ranges of chronic renal failure, defined with creatinine clearance ( C(Cr)) obtained with the Schwartz formula. Data were obtained from the Italian Pediatric Registry of Chronic Renal Failure (ItalKid); its inclusion criteria are: (1) C(Cr )<75 ml/min per 1.73 m(2), (2) age <20 years at time of registration, and (3) conservative treatment. To obtain the percentiles, the following patients were excluded: patients with an underlying disease, a concomitant treatment, or a disorder that could affect urea metabolism, per se, and/or food intake, and patients aged <2 years. The study group included 690 subjects (mean age 9.56+/-4.54 years, 485 males). In total, 2,085 observations (C(Cr )and sUrea) were available for the construction of the percentile curves. A median of 258 (range 99-380) observations was obtained for each of the eight different categories of C(Cr )(intervals of 10 ml/min per 1.73 m(2)). The 10th, 25th, 50th, 75th, and 90th percentiles were calculated and a graph was produced. Patients with the highest urea percentiles showed significantly higher plasma levels of phosphorus and parathyroid hormone and significantly lower hemoglobin concentrations and bicarbonate levels. Our percentile curves may help to identify subjects with inappropriate sUrea for a given C(Cr).

Proteinuria as a predictor of disease progression in children with hypodysplastic nephropathy. Data from the Ital Kid Project.

Little is known about the role of proteinuria in the progression of childhood renal diseases. We analyzed the decline in creatinine clearance ( C(Cr)) and kidney survival in 225 children (185 males) with chronic renal failure (CRF) due to isolated hypodysplasia or hypodysplasia associated with urological abnormalities. The data were based on the information available in the Italian Pediatric Registry of CRF (ItalKid Project), which includes patients from all of Italy aged <20 years with C(Cr )levels of <75 ml/min per 1.73 m(2). Patients aged <2 years and those with C(Cr )levels of <20 ml/min per 1.73 m(2) or a follow-up of <1 year were excluded from the analysis, as were those receiving angiotensin-converting enzyme inhibitors. At baseline, the patients had a mean age of 7.8+/-4.2 years, a mean C(Cr )of 50+/-16.3 ml/min per 1.73 m(2), a median urinary protein/urinary creatinine (uPr/uCr) ratio of 0.38 (range 0.02-7.21), and a mean duration of follow-up of 3.5+/-1.1 years. The patients were divided into three groups on the basis of their baseline proteinuria levels: group A normal (uPr/uCr <0.2) n=83; group B low (uPr/uCr 0.2-0.9) n=71; and group C mild (uPr/uCr >0.9) n=71. Patients in groups A and B showed a significantly slower decline in C(Cr )than those in group C (slope +0.16+/-3.64 and -0.54+/-3.67 vs. -3.61+/-5.47, P<0.0001) and a higher rate of kidney survival after 5 years (96.7% and 94.1% vs. 44.9%, P<0.01). By multivariate analysis, the baseline uPr/uCr ratio ( P<0.01) and age ( P<0.0001) correlated with a faster decline in C(Cr )irrespective of baseline C(Cr). There was no correlation with mean arterial blood pressure. We conclude that proteinuria is an independent predictor of progression to end-stage renal failure also in children whose renal impairment is due to congenital hypodysplasia.

Epidemiology of chronic renal failure in children: data from the ItalKid project.

OBJECTIVE: The ItalKid Project is a prospective, population-based registry that was started in 1990 with the aim of assessing the epidemiology of childhood chronic renal failure (CRF), describing the natural history of the disease, and identifying factors that influence its course. This article reports the epidemiologic results. METHODS: Prevalent and incident cases of CRF in children and adolescents were identified throughout Italy (total population base: 16.8 million children) by regularly asking all of the pediatric hospitals and adult nephrology units potentially involved in caring for children with kidney disease to report all cases that meet the inclusion criteria and then to update the clinical information regarding all previously reported patients on an annual basis. The inclusion criteria were 1) creatinine clearance (Ccr; according to Schwartz's formula) <75 mL/min/1.73 m2 bsa (predialysis) and 2) an age of <20 years at the time of registration. RESULTS: By December 31, 2000, 1197 patients (803 boys) had been registered. The mean incidence was 12.1 cases per million (range: 8.8-13.9), and the (point) prevalence was 74.7 per million of the age-related population. The mean age at registration was 6.9 +/- 5.4 years, and the mean Ccr was 41.7 +/- 20.5 mL/min/1.73 m2. The leading causes of CRF were hypodysplasia associated with urinary tract malformations (53.6%) and isolated hypodysplasia (13.9%), whereas glomerular disease accounted for as few as 6.8%. Hypodysplasia associated with primary vesicoureteral reflux (VUR) alone was responsible for as many as 25.8% of the cases, thus being the leading single cause with a female-to-male ratio of 1:3.2. The diagnosis of VUR was established early in life at an overall median age of 3 months (range: 0-180). However, the diagnosis was made significantly later among girls, whose median age at diagnosis was 9 months (range: 0-156; 95% confidence interval: 21.2-49.3) as against 2 months among boys (range: 0-180; 95% confidence interval: 10.9-21.2). As many as 23.6% of the registered patients had at least 1 severe associated disease (excluding urological abnormalities). A steep decline in renal survival occurred during puberty and early postpuberty, leading almost 70% of the patients to end-stage renal failure by the age of 20 years. When the population was subdivided on the basis of Ccr at the time of registration, the probability of kidney survival at 20 years of age was significantly different, being 63% in patients with mild renal failure (Ccr 51-75 mL/min), 30% in those with moderate renal failure (Ccr 25-50 mL/min), and 3% in those with severe renal failure (Ccr <25 mL/min). The incidence of renal replacement therapy was 7.3/y/100 patients, and the case-fatality rate on conservative treatment was 1.41%. CONCLUSIONS: This study provides important and recent epidemiologic information concerning CRF in children and adolescents: a mean annual incidence of 12.1 new patients per million of the age-related population with a very high proportion (57.6%) of hypodysplastic renal diseases with or without urinary tract malformation. By the age of 20 years, the cumulative probability of end-stage renal disease in the population as a whole was 68%. The probability of kidney survival sharply declined during puberty and early postpuberty. This is the first prospective evaluation of the incidence and outcome of CRF in children, including those with mild and moderate renal impairment.

Long-term outcome of vesicoureteral reflux associated chronic renal failure in children. Data from the ItalKid Project.

PURPOSE: The nephropathy associated with vesicoureteral reflux (VUR) is one of the leading causes of chronic renal failure (CRF) in children. We describe the clinical course of the disease based on information available in the ItalKid Project database, and analyze the predictive value of baseline renal function, age at VUR diagnosis and urinary protein excretion in relation to the risk of progressive renal failure. MATERIALS AND METHODS: As of December 31, 2001 the registry included a total of 343 patients (261 males) with a diagnosis of primary VUR, which was the leading single cause of CRF, accounting for 25.4% of all patients with CRF. RESULTS: The estimated risk of end stage renal disease (ESRD) by age 20 years was 56%. The patients with a creatinine clearance (Ccr) of less than 40 ml per minute at baseline had an estimated 4-fold greater risk of ESRD developing in comparison with those whose Ccr was 40 to 75 ml per minute. No significant difference in probability of disease progression to ESRD was found between subjects diagnosed with VUR at age 6 months or less and those diagnosed later (older than 6 months). Furthermore, children with normal urinary protein excretion (a urinary protein [uPr]/urinary creatinine [uCr] ratio of less than 0.2 in 36 patients) and low grade proteinuria (uPr/uCr 0.2 to 0.8 in 34 patients) at baseline showed a significantly slower decrease in mean Ccr than those with moderate proteinuria (uPr/uCr greater than 0.8 in 34 patients). Hypertension and/or antihypertensive treatment (including antiprogressive drugs) were reported in 29.1% of patients. CONCLUSIONS: The results of the present study define the long-term risk of ESRD in a large population of children with CRF and VUR, and provide some critical information for identifying the prognosis.