Quality of life of adolescents with end-stage renal disease and kidney transplant.

The health-related quality of life (HRQOL) of adolescents with end-stage renal disease (ESRD) is an important marker of disease burden. Our aims were to investigate HRQOL in a group of children and adolescents with ESRD and to compare them with the reference population norms. Ours was a cross-sectional study of 81 patients aged 10 years to 21 years with ESRD (68 with kidney transplants and 13 on dialysis) at five Spanish paediatric nephrology centres. HRQOL was investigated with the Spanish version of the child health and illness profile, adolescent edition (CHIP-AE). Clinical variables such as underlying diagnosis, number of rejection episodes, pre-emptive transplantation, anaemia and height were also analysed. No differences were found between patients with kidney transplants and their healthy peers in any domain or sub-domain of CHIP-AE. The group on dialysis scored lower than healthy controls and patients with transplants for satisfaction with health. Discomfort was higher in patients with transplants who had suffered one rejection episode. Physical discomfort was increased in anaemic patients with transplants. Short patients scored less in the satisfaction domain, with lower self-esteem and lower satisfaction with health. Adolescents with kidney transplants had better satisfaction with health than the group on dialysis, which matched the level of a healthy population. Further long-term prospective research is warranted.

Essential fatty acid deficiency profile in patients with nephrotic-range proteinuria.

Plasma free fatty acids are bound to albumin, filtered through the glomeruli, and reabsorbed at the proximal nephron. The aim of the present investigation was to determine if urinary loss of fatty acids results in essential fatty acid (EFA) deficiency in patients with nephrotic-range proteinuria. We studied 12 patients aged 9 months to 23 years (eight male, four female) four suffering from congenital nephrotic syndrome (NS) and eight from different renal diseases. Six patients were studied postrenal transplantation. Proteinuria ranged between 41 and 829 mg/m2/h. Results were compared with data obtained in 83 healthy children. The patients had significantly lower values for plasma arachidonic acid content and EFA index (omega3 + omega6/omega7 + omega9). Deficiency in polyunsaturated fatty acids (PUFA) was especially manifest in infants with congenital NS. Plasma content of arachidonic and docosahexaenoic acids related negatively with the degree of proteinuria. In the lineal regression model, the degree of proteinuria explained 60% of the variability of plasma values of those fatty acids. We conclude that plasma fatty acid status should be regularly monitored in patients with nephrotic-range proteinuria, especially in young infants with congenital NS, who represent a population at special risk with regard to neurological development.

Osteogenesis imperfecta: anthropometric, skeletal and mineral metabolic effects of long-term intravenous pamidronate therapy.

BACKGROUND: Administration of bisphosphonates represents a beneficial therapy in children and adolescents with severe osteogenesis imperfecta (OI) because it significantly reduces the annual rate of bone fractures. AIM: To evaluate the anthropometric, skeletal and mineral metabolic effects of long-term intravenous pamidronate therapy in OI. METHODS: Ten patients, aged 5 mo to 25 y, with OI received cyclical intravenous pamidronate. The yearly dose of pamidronate was approximately 9 mg/kg/d at all ages. Duration of treatment varied from a minimum of 2 y to a maximum of 5 y. Growth, bone mass and mineral metabolic parameters were studied at baseline and repeated every year thereafter. Bone mass was assessed by calculation of bone mineral apparent density (L2-L4 BMAD). This represents the first study on the changes in size-adjusted measures of bone mass observed with such therapy. RESULTS: While on therapy, all children and adolescents grew normally but did not experience any manifest catch-up growth. A significant decrease in the incidence of bone fractures was observed. In seven patients with severe forms, L2-L4 BMAD increased by 80% after the first 2 y of therapy but tended to stabilize or even decrease over the following years despite maintenance of therapy. A significant inverse correlation could be established between urinary Ca excretion and L2-L4 BMAD (r = -0.30, p < 0.05). CONCLUSION: Our results confirm that cyclical pamidronate infusions reduce the incidence of bone fractures and allow normal growth. The improvement in bone mass initially observed after the first 2 y of therapy is not always sustained over the following years despite maintenance of therapy.

An analysis of renal tubular acidosis by the Stewart method.

Renal tubular acidosis (RTA) comprises a group of disorders characterized by a low capacity for net acid excretion and persistent hyperchloremic, metabolic acidosis. To investigate the role of chloride, we performed hypotonic (0.45%) saline-loading experiments in 12 children with alkali-treated distal RTA (dRTA) and compared the results with data obtained from 17 healthy control subjects. In patients, but not in controls, saline loading induced both hyperchloremia and metabolic acidosis. Hyperchloremia was associated with high total and high distal fractional reabsorption of chloride [C(H20)/(C(H20)+C(Cl))]. The increase in plasma chloride varied inversely with the fractional excretion of chloride (C(Cl)) and correlated with the decrease in blood pH. However, the urinary excretion of bicarbonate did not correlate with either changes in blood pH or plasma bicarbonate concentration. Our findings suggest that the mechanism of hyperchloremia was enhanced Cl(-)/HCO(3) (-) exchange by the distal tubule. The resulting metabolic acidosis is better explained by changes in the strong ion difference (the Stewart theory) than by changes in the urine bicarbonate excretion (the traditional theory).

Bone mineral density and bone turnover in patients with Bartter syndrome.

The aim of this investigation was to evaluate bone mineral density (BMD), by use of DXA, and bone turnover, in patients with Bartter syndrome (BS). Ten patients (2 with BS type II and 8 with BS type III) were included in the procedure. Age at study varied between 2 and 30 years. During the studies usual treatment with indomethacin, spironolactone, and potassium chloride was maintained. Results were compared with those obtained in the 20 asymptomatic parents. Height of the patients at the time of the study did not differ from reference values (Z-score -1.2 to +0.8). Three patients (1 with BS type II and 2 with BS type III) presented reduced lumbar spine BMD or overt osteopenia (BMD Z-scores: -2.3, -1.3, and -1.1). BMD did not correlate significantly with age. Paternal and maternal femoral neck BMD values correlated significantly with lumbar spine BMD of the patients (r=0.65, P<0.05, and r=0.80, P<0.01). Lumbar spine BMD Z-scores correlated negatively with urinary Ca excretion when values both from patients and parents were jointly analyzed (r=-0.43, P<0.05). Plasma calcium concentration was significantly higher (P<0.001) and plasma phosphate Z-score was significantly lower (P<0.05) in the patients than in the parents. However, no significant differences were observed in values for intact PTH, 1,25 (OH)(2)D(3) and 25 (OH)D(3). Intact PTH values correlated positively with BMD Z-scores at lumbar spine (r=0.45, P<0.05) and at femoral neck (r=0.63, P<0.01). Age-corrected biochemical markers of bone formation (plasma alkaline phosphatase and osteocalcin concentrations) were normal whereas age-corrected markers of bone reabsorption (urinary PYD and DPD excretion) were significantly higher than parental values (P<0.01 and <0.05, respectively). We conclude that: (1) reduced BMD is not an exclusive feature of neonatal BS and it can be also observed in classic BS; (2) the loss of bone mineral is not progressive, probably because of the hypocalciuric effect of indomethacin therapy; and (3) this study did not determine whether loss of bone mass is the cause or the consequence of hypercalciuria although the beneficial effect of indomethacin therapy implies the latter.

A founder mutation in the CLCNKB gene causes Bartter syndrome type III in Spain.

The term "Bartter syndrome" encompasses a group of closely related inherited tubulopathies characterized by markedly reduced NaCl transport by the distal nephron. At present, five different genetic variants have been demonstrated. The majority of patients with so-called classic Bartter syndrome carry inactivating mutations of the CLCNKB gene encoding the basolateral ClC-Kb chloride channel (Bartter syndrome type III). The purpose of this study was to investigate the underlying mutation in cases of classic Bartter syndrome followed at our center. Ten patients, including two sisters, with clinical and biochemical features of classic Bartter syndrome were included in the mutational analysis. They originated from different regions of Spain with either Basque or Spanish ancestry. There was no history of consanguineous marriage in any of the kindreds. The parents and siblings of each patient, as well as a population of 300 healthy control adult subjects, were also analyzed. All ten patients were found to be homozygous for an identical missense mutation in the CLCNKB gene, substituting a threonine for an alanine at codon 204 (A204T) in the putative fifth transmembrane domain of the protein. None of the 300 control subjects were homozygous for the A204T allele. Overall, the A204T mutation was detected on 2/600 control chromosomes. Despite sharing a common mutation, the clinical manifestations of the syndrome in the patients varied from lack of symptoms to severe growth retardation. Demonstration of a point mutation within the CLCNKB gene as the apparently unique cause of Bartter syndrome type III in Spain is highly suggestive of a founder effect. Our results also support the lack of correlation between genotype and phenotype in this disease.

Long-term renal follow-up of extremely low birth weight infants.

There is evidence that low birth weight caused by intrauterine growth retardation adversely affects normal renal development. Very little information on this issue is available on children born very prematurely. This investigation examined clinical and functional renal parameters in 40 children (23 boys, 17 girls) ranging in age between 6.1 and 12.4 years and weighing less than 1000 g at birth. Results were compared to those obtained in 43 healthy children of similar age and gender. Study subjects were significantly smaller and thinner than control subjects (mean height SDS: -0.36 vs. +0.70; and mean BMI SDS: -0.56 vs. +1.18). Systolic, diastolic, and mean blood pressures did not differ from those of controls. Renal sonography revealed no abnormality, and mean percentiles for renal length and volume appeared normal. In comparison with controls, plasma creatinine concentration (0.62+/-0.1 vs. 0.53+/-0.1 mg/dl) and estimated creatinine clearance (117+/-17 vs. 131+/-17 ml min(-1) 1.73 m(-2)) differed significantly. No significant differences were observed in microalbuminuria values, but five study subjects (12.5%) presented values above the upper limit of normality. A defect in tubular phosphate transport was also evident: TmP/GFR (3.6+/-0.4 vs. 4.2+/-0.8 mg/dl) and TRP (83+/-5% vs. 90+/-4%) were significantly lower, and urinary P excretion, estimated by the ratio UP/UCr, was significantly higher (1.2+/-0.4 vs. 0.9+/-0.4 mg/mg) than controls. Urinary calcium excretion, estimated by the UCa/UCr ratio, was also significantly higher (0.15+/-0.07 vs. 0.12+/-0.09 mg/mg). These data clearly demonstrate that both GFR and tubular phosphate transport are significantly diminished in school-age children born with extreme prematurity, probably as a consequence of impaired postnatal nephrogenesis.

Acidosis increases magnesiuria in children with distal renal tubular acidosis.

In experimental animals, metabolic acidosis increases renal magnesium (Mg) excretion, whereas metabolic alkalosis reduces it. The objective of this study was to examine renal magnesium handling (U(Mg)) in children with primary distal renal tubular acidosis (DRTA). We measured U(Mg) in 11 children (3 females, 8 males, aged 6.9+/-4.9 years) with primary DRTA. They were studied either during spontaneous acidosis post treatment removal (3 patients) or after ammonium chloride (100 mmol/m2) induced acidosis (8 patients), and then following oral sodium bicarbonate load (4 g/1.73 m2). During acidosis (plasma pH 7.28+/-0.09, bicarbonate 13.2+/-4.3 mEq/l), U(Mg) was elevated (U(Mg/Cr) 0.18+/-0.06 mg/mg, normal values 0.1+/-0.06, P=0.003) although plasma Mg (P(Mg)) was in the normal range (1.93+/-0.31 mg/dl, controls 1.77+/-0.19, P=NS). After acute correction of metabolic acidosis (plasma pH 7.44+/-0.05, bicarbonate 25.6+/-1.6 mEq/l, P<0.001; urine pH 7.52+/-0.28, bicarbonate 86.9+/-39.1 mEq/l), U(Mg) decreased significantly (P=0.003), returning to control values after about 2 h (U(Mg/Cr) 0.09+/-0.06 mg/mg). Bicarbonate load resulted not only in reduction in U(Mg) but also in a decrease in urinary calcium excretion (U(Ca/Cr)) from 0.46+/-0.17 mg/mg to 0.14+/-0.12 mg/mg (P<0.001). We conclude that in children with primary DRTA, urinary Mg excretion is markedly increased and that this defect, like the hypercalciuric defect, is correctable by sodium bicarbonate administration.

Influence of diet on atherogenic risk in children with renal transplants.

Cardiovascular disease is one of the main causes of morbidity and mortality in recipients of renal transplants. Although the risk for cardiovascular disease is in part genetically determined, it may also be influenced by diet. The aim of the present study was to analyze the cross-sectional association of dietary intake of nutrients with biochemical markers of atherogenic risk. The influence of diet on the plasma profile of fatty acids was specifically investigated. Twenty-nine children and adolescents (mean age 14 years, range 6-18 years) with stable renal transplants and on a normal diet recorded their food intake for a period of 3 days. The mean calorie intake was 40.6 kcal/kg per day (protein provided 16% of total calories, carbohydrates 45%, and fat 39%). Plasma levels of total cholesterol and low-density lipoprotein-cholesterol were significantly and positively related to intake of monounsaturated fatty acids ( r=0.66, P =0.007 and r =0.62, P =0.02, respectively) and to plasma levels of elaidic acid, a trans fatty acid ( r=0.43, P =0.02 and r =0.54, P =0.01, respectively). Insulin resistance, estimated from values of plasma glucose ( r=0.70, P =0.03), plasma insulin ( r=0.59, P =0.02), and HOMA index ( r=0.62, P =0.01), was also directly related to the intake of monounsaturated fatty acids. Plasma plasminogen activator inhibitor-1 activity correlated positively with total fat intake ( r=0.59, P =0.04). Plasma levels of homocysteine were negatively related to the intake of carbohydrates ( r=-0.62, P =0.02). We conclude that reasonable dietary recommendations to minimize the atherogenic risk in children with stable renal transplants should include a protein intake adjusted to the requirements for age, a large intake of carbohydrates leading to a low glycemic load, and a fat intake of less than 30% of the total calorie intake. The amount of monounsaturated and trans fatty acids in the diet should be especially limited. A sufficient intake of polyunsaturated fatty acids, with an adequate ratio between omega 6 and omega 3 components, should also be provided.

Genetic and metabolic determinants of increased plasma plasminogen activator inhibitor-1 activity in children with renal transplants.

Recent studies have shown that activity of plasminogen activator inhibitor-1 (PAI-1), a prothrombotic protein, may be increased in transplanted patients. The aim of the present investigation was to determine PAI-1 activity in pediatric recipients of renal transplants and to establish the relative contribution of both genetic and metabolic factors. In 29 children and adolescents with stable renal transplants, we related plasma PAI-1 activity to an indicator of inflammatory status [plasma concentration of C-reactive protein (CRP)] and to elements of the insulin resistance syndrome [body mass index (BMI), fasting insulinemia, HOMA index and plasma triglyceride, HDL-cholesterol, apolipoproteins A-1 and B concentrations]. Polymorphisms of PAI-1, apolipoprotein E (apoE) and angiotensin-converting enzyme (ACE) genes were also investigated. In all patients the study was repeated 1 year later. PAI-1 activity remained constantly elevated (23.4+/-22.8 and 18.6+/-7.8 U/ml in the first and second study, respectively, P=NS). Plasma PAI-1 activity correlated positively with CRP ( P=0.001), BMI z score ( P=0.02), fasting insulinemia ( P=0.009), and HOMA index ( P=0.006). No significant correlations were found in this population between plasma PAI-1 activity and age, gender, time elapsed after transplantation and plasma homocysteine, total cholesterol, LDL-cholesterol, HDL-cholesterol, apolipoprotein B, and apolipoprotein A-1. Plasma PAI-1 activity was not related to the cumulative dose of prednisone, cyclosporin A, or tacrolimus. Plasma PAI-1 activity was significantly higher in 5 children with apoE3/apoE4 genotype. No apparent influences of the PAI-1 4G/4G and ACE I/D genotypes were observed. In a multiple stepwise regression model, fasting insulinemia and apoE3/apoE4 genotype accounted for 45% of the observed plasma PAI-1 variability. We conclude that increased PAI-1 activity in children with stable renal transplants is determined both by genetic factors and by metabolic factors, the latter mainly linked to the insulin resistance syndrome.

Renin-angiotensin system polymorphisms and renal scarring.

The purpose of the study was to determine whether DNA polymorphisms at the renin-angiotensin-aldosterone (RAS) genes were associated with evolution to renal scar formation and, consequently, with reflux nephropathy (RN) in patients with vesicoureteral reflux (VUR). Some authors have suggested that the DD genotype of the angiotensin-converting enzyme (ACE) gene would be an adverse renal prognosis factor. We recruited 246 patients (aged 3 months to 22 years) from four Spanish hospitals. These included 69 patients with VUR, 110 with RN (determined by absence/presence of renal scarring on dimercaptosuccinc acid scan), 27 with chronic renal failure due to RN, and 40 patients (control group) with urinary tract infection and normal findings on renal ultrasonography and voiding cystoureterogram. The ACE I/D, angiotensin II type 1 receptor AT1 A1166C, angiotensin II type 2 receptor A3123C AT2, and angiotensinogen AGT M235T polymorphisms were determined on the basis of polymerase chain reaction amplification. ACE serum levels were determined by spectrophotometric methods. We found no statistical differences in the distribution of RAS polymorphisms between the different groups. The ACE D allele was linked to higher ACE serum levels. We found no association between ACE I/D polymorphism and presence of hypertension, proteinuria, grade of VUR, or unilateral/bilateral VUR. Patients with the DD genotype had a lower incidence of febrile urinary tract infection as a first symptom of VUR/RN (P<0.05). We conclude that genetic polymorphisms of RAS components are not independent prognostic indicators of renal scarring in patients with VUR.

Hyperhomocysteinemia in children with renal transplants.

Many studies have demonstrated a strong association between elevated plasma total homocysteine (tHcys) levels and vascular disease. The aim of the present study was to determine the plasma levels of tHcys in pediatric recipients of renal transplants, to establish possible correlations with renal function, lipid profile, and folate and vitamin B12 status, and to assess whether the C677T and A1298C polymorphisms in the 5, l0-methylenetetrahydrofolate reductase (MTHFR) gene were associated with a particular risk. A total of 26 transplanted children and adolescents were investigated. tHcys levels were elevated in transplanted patients (12.9+/-4.8 micro mol/l) and 73% of these displayed values above the 97th percentile of healthy children. Plasma tHcys correlated negatively with creatinine clearance ( r=-0.58, P<0.001) and plasma vitamin B(12) ( r=-0.40, P<0.05) and positively with plasma triglycerides ( r=0.53, P<0.005). No significant correlations were found between plasma tHcys level and age, gender, time elapsed after transplantation and plasma values of glucose, insulin, folic acid, total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, apolipoprotein B, and apolipoprotein A-1. Plasma tHcys level was clearly increased in 3 patients with a MTHFR 677TT/1298AA genotype. In a multiple stepwise regression model plasma creatinine and triglyceride levels and MTHFR 677TT/1298 AA genotype accounted for 60% of the observed plasma tHcys variability. The MTHFR 677CT/1298 AC genotype was not a significant predictor of tHcys plasma levels. We conclude that a moderate degree of hyperhomocysteinemia is often present in renal transplant children and that folate supplementation must be considered in this population.

Pronóstico en la vida adulta de la nefropatía iga diagnosticada en la edad pediátrica / Long-term prognosis of childhood IgA nephropathy in adult life

Fundamento: Evaluar el pronóstico a largo plazo de la nefropatía IgA en una población de niños y establecer los factores clínicos de riesgo asociados con la progresión a la insuficiencia renal crónica en la vida adulta. Pacientes y método: Estudio retrospectivo. Constituyen la muestra adultos jóvenes diagnosticados de nefropatía IgA a los 10,6 (DE, 2,9) años de edad, con un seguimiento medio de 11,8 (DE, 2,9) años. Resultados: La presentación clínica más frecuente fueron los brotes de macrohematuria-proteinuria (75,9 por ciento), con elevación plasmática de IgA en el 25,9 por ciento de los casos. Casi todos los niños presentaban una afección histológica de grados I (44,8 por ciento) o II (44,8 por ciento) al diagnóstico. Evolutivamente, se observó una remisión clínica completa en 21 casos (36,2 por ciento), mientras que el 50 por ciento de los pacientes continuaban con diversas alteraciones urinarias. Ocho pacientes (13,8 por ciento) progresaron a la insuficiencia renal crónica terminal (IRCT). La supervivencia renal, definida por un filtrado glomerular superior a 50 ml/min/1,73 m2, fue del 100, del 93,3 y del 81,1 por ciento a los 5, 10 y 15 años del diagnóstico, respectivamente. Conclusiones: A largo plazo se observó un pronóstico renal desfavorable en un 14 por ciento de los niños con nefropatía IgA. La hipertensión arterial al inicio, la elevación de la creatinina plasmática y la aparición de proteinuria en la adolescencia fueron las variables clínicas de riesgo. Las lesiones histológicas leves al diagnóstico de la nefropatía IgA en el niño no excluyeron una evolución renal desfavorable (AU)