Serafín Málaga

Cystatin C and beta2-microglobulin: markers of glomerular filtration in critically ill children

IntroductionParameters allowing regular evaluation of renal function in a paediatric intensive care unit (PICU) are not optimal. The aim of the present study was to analyse the utility of serum cystatin C and beta2-microglobulin (B2M) in detecting decreased glomerular filtration rate in critically ill children.MethodsThis was a prospective, observational study set in an eight-bed PICU. Twenty-five children were included. The inverses of serum creatinine, cystatin C, and B2M were correlated with creatinine clearance (CrC) using a 24-hour urine sample and CrC estimation by Schwartz formula (Schwartz). The diagnostic value of serum creatinine, cystatin C, and B2M to identify a glomerular filtration rate under 80 ml/minute per 1.73 m2 was evaluated using receiver operating characteristic (ROC) curve analysis.ResultsMean age was 2.9 years (range, 0.1 to 13.9 years). CrC was less than 80 ml/minute per 1.73 m2 in 14 children, and Schwartz was less than 80 ml/minute per 1.73 m2 in 9 children. Correlations between inverse of B2M and CrC (r = 0.477) and between inverse of B2M and Schwartz (r = 0.697) were better than correlations between inverse of cystatin C and CrC (r = 0.390) or Schwartz (r = 0.586) and better than correlations between inverse of creatinine and CrC (r = 0.104) or Schwartz (r = 0.442). The ability of serum cystatin C and B2M to identify a CrC rate and a Schwartz CrC rate under 80 ml/minute per 1.73 m2 was better than that of creatinine (areas under the ROC curve: 0.851 and 0.792 for cystatin C, 0.802 and 0.799 for B2M, and 0.633 and 0.625 for creatinine).ConclusionSerum cystatin C and B2M were confirmed as easy and useful markers, better than serum creatinine, to detect acute kidney injury in critically ill children.

Effect of a low sodium diet on urinary elimination of cystine in cystinuric children.

Restriction of sodium intake has been shown to decrease urinary elimination of cystine in adult subjects with cystinuria. This simple therapeutic recommendation may be particularly useful in pediatric patients whose compliance with high fluid ingestion and repeated doses of alkali is usually poor. We studied the effect of sodium intake in 5 cystinuric children (3 males) aged 5.9-9.3 years. Urinary excretion of cystine (means +/- SD) was determined at the end of two sequential 1-week periods in which sodium content of diet was modified. Reduction of sodium intake brought about significant decreases in natriuresis (6.0 +/- 2.1 vs. 1.5 +/- 0.5 mEq/kg/day, p < 0.03) and urine cystine concentration (328.0 +/- 190.7 vs. 14.1 +/- 7.4 mg/l, p < 0.02) while urine volume output remained unchanged (58.0 +/- 36.0 vs. 70.3 +/- 33.0 ml/kg/day). These findings confirm that elimination of cystine is highly influenced by sodium intake in cystinuric children and suggest that a low sodium diet may play a key-role in the treatment of pediatric patients with cystinuria.

Idiopathic hypercalciuria in children: Pathophysiologic considerations of renal and absorptive subtypes

Sixteen children with idiopathic hypercalciuria and seven control children were observed. Patients were classified into two groups by means of an orally administered calcium loading test. Individuals with renal hypercalciuria (five children) had a high fasting urinary calcium/creatinine concentration ratio (0.27 +/- 0.05), a mild increase of this value after calcium administration (0.29 +/- 0.07, P less than 0.05), and elevated mean serum parathyroid hormone (PTH) concentrations (0.95 +/- 1.14 ng/ml). Patients with absorptive hypercalciuria (11 children) had fasting urinary calcium/creatinine concentration ratio of 0.11 +/- 0.04, a large increase of this index after calcium loading (0.25 +/- 0.06, P less than 0.0005), and normal levels of serum PTH (0.29 +/- 0.10 ng/ml). Next, we examined the effects of two different calcium intakes on urinary calcium excretion, serum calcium, PTH, and 1,25-dihydroxyvitamin D3 concentrations. In patients with absorptive hypercalciuria, the increased calcium intake resulted in significant increments of calciuria (P less than 0.0005), mild elevation of serum calcium concentration (P less than 0.05), and reduction of serum 1,25-dihydroxyvitamin D3 concentrations (P less than 0.005). By contrast, these values were not modified in children with renal hypercalciuria. Serum PTH did not change within each group. After dietary calcium supplementation, serum ratios of 1,25-dihydroxyvitamin D3 to calcium, phosphate, and PTH concentrations decreased significantly only in the group of children with absorptive hypercalciuria. Our data support the contention that 1,25-dihydroxyvitamin D3 metabolism is different in the two groups of patients with hypercalciuria.

Predictors of Final Adult Height after Renal Transplantation during Childhood: A Single-Center Study

Aim: Assessment of final adult height and its predictive factors in children transplanted (RTx) and followed up in a single center. Methods: A cohort of 32 patients (17 boys, 15 girls) who received RTx before the age of 15 years and had reached a final adult height was selected. Twenty patients received a single RTx, 9 patients received two RTx, and 3 patients received three RTx. Seven children were transplanted preemptively, while the remaining 25 children received peritoneal dialysis for relatively short periods of time. In 11 patients, recombinant human growth hormone (rhGH) was administered either before (n = 8) or after (n = 3) RTx. Results: In 13 patiens (41%), the final height standard deviation score for chronological age (hSDS) was –2.3±0.5, below the 95% confidence limits for target height (group A), while in 19 patients (59%), it was –0.7±0.8, within the 95% confidence limits for target height (group B). The hSDS values at the start of dialysis and at the time of first RTx were significantly lower in group A than in group B. A higher hSDS at the start of dialysis and at the time of first RTx had a significant positive influence on the final height (FH), whereas a longer duration of dialysis had a significant negative effect on the FH. Administration of rhGH after RTx played an important role in the achievement of a normal FH in 3 girls. No differences were observed between group A and B with respect to age at start of dialysis, chronological or bone age at first RTx, number of rejection episodes, duration of the study period from last RTx to FH, glomerular filtration rate during this study period, or percentage of time on prednisone therapy. Conclusions: The FH is almost exclusively predetermined by the height achieved at the start of dialysis and at the time of first RTx. Therefore, to reach target adult height after RTx, the best strategy is to shorten the time of dialysis and to start rhGH administration at a young age and as early as possible during the course of chronic renal failure. Administration of rhGH after RTx is also highly effective, but, given its potential danger, still remains a matter of investigation.

Nutritional status of children with moderate chronic renal failure

Nutritional status was evaluated in 15 children (11 males) with moderate chronic renal failure (CRF). Two 3-day prospective dietary records, anthropometric measures and biochemical determinations were performed 3 months apart. Energy, protein, carbohydrate, fat, polyunsaturated, monounsaturated and saturated fatty acid intakes, expressed as percentages of international recommendations, were 87±14, 223±42, 73±12, 110±27, 55±31, 129±51 and 111±26%, respectively. The relative distribution of calories was 15±2% from proteins, 48±5% from carbohydrates and 37±5% from lipids. Anthropometric indices, expressed as standard deviation score, were: weight −0.50±0.8, height −0.94±1.3, growth velocity −0.61±1.8, triceps skinfold thickness −0.30±0.6, subscapular skinfold thickness −0.19±0.8, mid-arm muscle circumference 0.38±0.3 and body mass index −0.22±1.0. Serum concentrations of albumin, total protein, transferrin, IgG, IgA, IgM, C3 and C4 and blood lymphocyte counts were within normal limits. The mean serum insulin-like growth factor-I concentration, expressed as standard deviation score, as 0.74±1.5. No anthropometric or biochemical signs of malnutrition were found in children with moderate CRF. However, their dietary intake of calories and carbohydrates was low and the protein and saturated fatty acid intake excessively high.

Towards guidelines for dialysis in children with end-stage renal disease.

Abstract There are few data describing the current practices of treatment selection for children with end-stage renal disease (ESRD). In an effort to establish a consensus among Spanish pediatric nephrologists for inclusion and exclusion criteria for renal replacement therapy in children with ESRD, in 1995 we surveyed members of the Spanish Pediatric Nephrology Association. Although only 43% of members responded, pediatric nephrologists and bioethicists studied the results and compiled a list of ten guidelines for treatment of children with ESRD. The proposed guidelines are meant to be a starting point for further discussion. An emphasis on flexibility, individual case assessment, and consideration of the best interests of the patient must remain central to any treatment plan. Decision making should ideally be shared by parents, professionals, the child, when appropriate, and ethics committees, as necessary.

C-reactive protein is elevated in the offspring of parents with essential hypertension

Background: Hypertension is a risk factor for cardiovascular disease (CVD). Studies in adults have shown that high sensitivity C-reactive protein (CRP) levels are associated with increased risk of CVD and essential hypertension (EHT). Genetic background is widely accepted as a risk factor for CVD. The aim of the present study was to analyse the association of high sensitivity CRP levels with other cardiovascular risk factors in children and young adults with at least one parent with EHT. Methods: Fifty one healthy children and young adults (28 boys) with at least one parent with hypertension and 69 (41 boys) whose parents did not have hypertension were recruited prospectively from primary care centres. High sensitivity CRP, fasting lipid profile, blood pressure (BP) and anthropometric variables were obtained for all participants. Results: CRP values were higher in the study group than in controls (logCRP mean difference: −0.69; 95% confidence interval: −1.05 to −0.33), even when differences were adjusted for age, gender, body mass index (BMI) and triglyceride levels (p = 0.01). No differences were observed in BP values between groups. In the study group, 35.3% of the participants had a CRP level ⩾1 mg/l compared to 14.5% in the control group (p = 0.009). CRP showed a significant correlation with body weight (rho = 0.28, p = 0.04), BMI (rho = 0.32; p = 0.02) and ponderosity index (rho = 0.28; p<0.05). Conclusions: CRP is significantly higher in the offspring of parents with EHT. A significant positive relationship exists between BMI and serum CRP levels in this high risk group of children and young adults.

Analysis of chromosome 6p in Spanish families with recessive polycystic kidney disease

Abstract Several previous reports have suggested that autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in a single gene (the PKDH1 gene). Linkage analysis showed a positive linkage for polymorphic markers at the short arm of chromosome 6 (6p) in all families. PKHD1 has not been cloned. Recombinants in the critical region would permit the narrowing of the 6p interval containing the PKHD1 gene, thus facilitating the final identification (cloning) of this gene. Our study included 30 Spanish families. Each family consisted of both parents and at least two children, with at least one diagnosed with ARPKD by clinical and pathological parameters. DNA was obtained and 6p microsatellite markers were used to establish haplotypes for each family. A positive linkage to chromosome 6p was found for all families. In 2 cases, recombinants in the region containing the PKHD1 gene were found. These families will help narrow the size of the 6p region, facilitating the efforts to position and clone the PKHD1 gene. In conclusion, our analysis of Spanish ARPKD families confirms the lack of linkage heterogeneity. This suggests that mutations at a single locus on chromosome 6p21.1-p12 are responsible for the broad clinical spectrum of variable phenotypes.

THE SYNDROME OF RENAL TUBULAR ACIDOSIS AND NERVE DEAFNESS. DISCORDANT MANIFESTATIONS IN DIZYGOTIC TWIN BROTHERS

The syndrome of renal tubular acidosis (RTA) and nerve deafness is a distinct nosological entity that is inherited as an autosomal recessive trait. We studied a pair of dizygotic twin brothers both with nerve deafness but only one with RTA. Distal RTA was diagnosed in twin A because of inappropriately high urinary pH (6.9) and low net acid excretion (40.0 μEq/min per 1.73 m2) in the presence of hyperchloraemic metablic acidosis, and fractional bicarbonate excretion of 1.6% at a normal serum bicarbonate concentration. The urine minus bloodPCO2 differences (U-BPCO2) during a neutral sodium phosphate load and in alkaline urine induced by bicarbonate supplementation were: 11 and 0 mm Hg, respectively. Twin A developed nephrocalcinosis and, after a 9.5-year follow-up period, was 5.3 cm taller than his brother. Twin B remained asymptomatic. Periodic determinations of blood pH and serum bicarbonate were normal and urine pH decreased to 4.6 in the face of ammonium chloride-induced metabolic acidosis. The U-BPCO2 assessed in alkaline urine was 33.5 mm Hg. Audiograms demonstrated bilateral nerve deafness in both brothers. The presence of deafness without RTA has not been previously reported in this syndrome. This report also shows that a primary distal acidification defect is responsible for the RTA observed in this syndrome.

A labor and cost effective next generation sequencing of PKHD1 in autosomal recessive polycystic kidney disease patients

The Sanger sequencing of patients with recessive polycystic kidney disease is challenging due to the length and heterogeneous mutational spectrum of the PKHD1 gene. Next generation sequencing (NGS) might thus be of special interest to search for PKHD1 mutations. The study involved a total of 22 patients with autosomal recessive polycystic kidney disease (ARPKD) and 8 parents of non-available ARPKD patients. Five pools of 6 samples each were sequenced with the Personal Genome Machine (PGM, Ion Torrent). For each DNA pool, a total of 109 fragments that covered the entire PKHD1 coding sequence were amplified in only two tubes followed by library preparation and NGS with the PGM. To validate the technique, each pool contained the DNA of at least one patient with known mutation. The putative mutations identified in each pool were confirmed and assigned to specific individuals through Sanger sequencing. All but one of the 109 amplicons were successfully read, and we identified the two PKHD1 mutations in 11 of the ARPKD cases, one mutation in 9 patients, and no mutation in only 2 patients. Six of the 8 parents from non-available patients were mutation carriers. The reported procedure would facilitate the large scale analysis of PKHD1 with a significant reduction in cost and labor.