Molecular analysis of Frasier syndrome: mutation in the WT1 gene in a girl with gonadal dysgenesis and nephronophthisis.

The Wilms' tumor gene (WT1) encodes a protein that is believed to exert transcriptional and tumor-suppressor activities. Mutations in this gene have occasionally been associated with Wilms' tumor (<15% patients) and, more consistently, with three syndromes characterized by urogenital abnormalities (WAGR, Denys-Drash and Frasier syndromes). We report 17 years follow-up of a 29 year-old phenotypic female with 46,XY karyotype, gonadal dysgenesis and nephronophthisis in order to identify possible germline alterations of the WT1 gene. Frasier syndrome was suspected and confirmed by genetic analysis. Sequence analysis permitted the identification of an A40-->G mutation in position +5 in the donor splice site of intron 9. During surgery for streak gonads extirpation, a microscopic gonadoblastoma was found, a typical complication of Frasier syndrome.

Familial hypercalcemia and hypercalciuria: no mutations in the Ca2+-sensing receptor gene.

A 6-year-old boy presented with persistent hypercalcemia, hypercalciuria and nephrocalcinosis from early infancy. His 40-year-old father also had hypercalcemia and hypercalciuria. In both individuals serum values of intact parathyroid hormone (PTH) were repeatedly normal. Although these findings suggest a functional abnormality of the calcium-sensing receptor (CaR), no mutations in coding regions of the CaR gene could be demonstrated.

Branchio-oto-renal syndrome: identification of a novel mutation in the EYA1 gene.

Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by the association of branchial cysts or fistulae, external ear malformation and/or preauricular pits, hearing loss, and renal anomalies. Mutations in the EYA1 gene, a human homologue of the Drosophila 'eyes absent' gene, have been identified as cause of the syndrome. We report here two families with BOR syndrome. In one family, with the complete phenotype, a novel splice site mutation in exon 15 (1599 +1 G to A) is described. No mutations in the EYA1 gene were found in a second family presenting with ear pits, deafness, and renal anomalies, but lacking branchial fistulae. These and other findings from the literature suggest the existence of genetic heterogeneity of the BOR, BO, and other related phenotypes, with two or more genes involved.

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

BACKGROUND: To evaluate long-term prognosis in a group of children with IgA nephropathy and to analyse which clinical factors were associated with progression to chronic renal failure in adulthood. PATIENTS AND METHOD: Retrospective study. 58 young adults with IgA nephropathy diagnosed at 10.6(SD 2.9) years old and studied after a follow-up of 11.8 (SD 2.9) years. RESULTS: Relapses of macroscopic hematuria and proteinuria were the most frequent symptoms at onset (75.9%). In 25.9% of patients high plasmatic IgA levels were also detected. Most cases had grade I (44.8%)or grade II (44.8%) histological lesions at diagnosis. At the last control, clinical remision was observed in 21 patients (36.2%) and 50% of the whole group remained with abnormal urine. 8 patients(13.8%) reached terminal renal failure. Mean renal survival (defined as glomerular filtration rate above 50 ml/min/1.73 m2)was 100, 93.3 and 81.1% at 5, 10 and 15 years of evolution, respectively. CONCLUSIONS: About 14% of children with IgA nephropathy had long-term renal bad prognosis. Hypertension at onset, plasma creatinine elevation and proteinuria during adolescence were significant risk factors associated with chronic renal failure during adulthood. Minimal lesions at IgA nephropathy diagnosis in children did not exclude long-term poor prognosis.

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

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.

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.

Registro Español Pediátrico de Insuficiencia Renal Terminal (REPIR), 1998 / The Spanish pediatric registry of renal patients

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Implantación de filtros en el sector suprarrenal de la vena cava / Percutaneous placement of suprarenal greenfield vena cava filters

Se presentan dos casos de implantación de filtros en el sector suprarrenal de la vena cava inferior. Este sitio de implantación es infrecuente. La principal indicación es la trombosis aguda de la vena cava extendida hasta el nivel de las venas renales. En ambos casos se implantaron filtros de Greenfield por abordaje percutáneo transyugular. La evolución postoperatoria fue favorable. El seguimiento de 9 y 19 meses respectivamente, demostró vena cava inferior permeable, ausencia de tromboembolismo pulmonar y función renal normal

Implantación de filtros en el sector suprarrenal de la vena cava / Percutaneous placement of suprarenal greenfield vena cava filters

Se presentan dos casos de implantación de filtros en el sector suprarrenal de la vena cava inferior. Este sitio de implantación es infrecuente. La principal indicación es la trombosis aguda de la vena cava extendida hasta el nivel de las venas renales. En ambos casos se implantaron filtros de Greenfield por abordaje percutáneo transyugular. La evolución postoperatoria fue favorable. El seguimiento de 9 y 19 meses respectivamente, demostró vena cava inferior permeable, ausencia de tromboembolismo pulmonar y función renal normal (AU)

Salt-losing nephropathy associated with inappropriate secretion of atrial natriuretic peptide--a new clinical syndrome.

A state of normokalemic renal sodium wasting associated with an apparently inappropriate secretion of atrial natriuretic peptide (ANP) has not been previously recognized. We here report an 11-year-old boy who presented with a chronic "salt-losing" nephropathy manifested by normonatremic or mildly hyponatremic extracellular fluid volume depletion, hypodipsia, absence of salt appetite, normokalemic metabolic alkalosis, hyper-reninemic hyperaldosteronism, hypertrophy of the juxtaglomerular apparatus, and highly conserved capacities for concentrating diluting the urine. Plasma ANP values were paradoxically elevated (between 10 and 47 fmol/ml), despite the coexistence of intravascular volume depletion and increased plasma levels of renin and aldosterone. Although the patient had some clinical similarities to Bartter's syndrome, fractional sodium chloride (NaCl) reabsorption during hypotonic saline diuresis was normal and no clinical amelioration was observed while on indomethacin therapy. Neither a tumor nor cardiac or cerebral abnormalities, which could be responsible for the increased ANP secretion, were detected. These clinical, biochemical, and histological features have not been previously described together and may represent a new clinical syndrome. The pathophysiology of this entity remains unknown, but an attractive, although unproven, hypothesis is that the renal defect in NaCl reabsorption in this patient could be related to an inappropriate and unregulated secretion of ANP.

Acute and chronic effects of cisplatin therapy on renal magnesium homeostasis.

Although the acute renal toxicity of cisplatin has been well documented, long-term follow-up studies in cisplatin-treated children are scanty. We have evaluated the incidence and characteristics of both acute and chronic nephrotoxicity in 22 children (median age 8 years) treated with cisplatin as part of different chemotherapeutic protocols. All patients exhibited a significant and progressive decrease in plasma magnesium (Mg) values soon after cisplatin administration. Magnesiuria also increased immediately after therapy. Hypomagnesemia (plasma Mg < 1.4 mg/dl) occurred in 10 patients and it was dose-dependent. Minimal and mean cumulated doses inducing hypomagnesemia were 300 and 500 mg/m2, respectively. In 18 children we followed renal function prospectively for a mean time of 2.3 years after arrest of cisplatin therapy. Chronic hypomagnesemia and moderate elevation of plasma creatinine were observed in 6 children, hypocalciuria in 5 children, and hypokalemia in 1 child. Presence of hypomagnesemia was unrelated to the total dose received or the time elapsed since cisplatin therapy. Renal function studies, performed in the 6 children with chronic hypomagnesemia, revealed different degrees of impairment in Mg reabsorption. The functional characteristics of chronic cisplatin nephrotoxicity found in the present series-contrary to prior reports-are not comparable to those present in the inherited Gitelman's syndrome.

Renal magnesium handling in infants and children.

Renal handling of magnesium (Mg) has been incompletely studied during infancy and childhood due to the difficulty, until recently, of measuring the diffusible fraction of plasma Mg. In the present investigation this methodology has been used to assess Mg homeostasis in 45 healthy infants, aged 1 to 12 months, and in 63 healthy children, aged 1 to 15 years. When compared to children, infants had significantly higher plasma values (mean +/- SD) for both total (0.76 +/- 0.08 versus 0.70 +/- 0.06 mmol l-1; p < 0.001) and ultrafilterable Mg (0.51 +/- 0.07 versus 0.49 +/- 0.04 mmol l-1; p < 0.05). No significant correlations were present between values of plasma Mg and plasma concentrations of calcium, creatinine, total protein or albumin. The ratio Umg/Ucr, calculated in the second morning urine (median, 3rd-97th centiles), was also significantly higher during infancy (0.023, 0.009-0.07 versus 0.015, 0.006-0.04; p < 0.001). On the contrary, fractional excretion of Mg (median, 3rd-97th centiles) was identical in both age groups and did not correlate significantly with age (infants: 3.2, 1.0-7.8%, children 3.4, 1.6-8.1%; p = NS). During a Mg infusion, carried out in six children, we could establish an approximative value for renal Mg threshold (plasma ultrafilterable Mg = 0.50 mmol l-1) close to that found in adults. These results indicate that no functional immaturity is present during infancy for renal tubular reabsorption of Mg and that the high Umg/Ucr ratio observed in this age group is a phenomenon not dependent on a higher urinary Mg excretion but probably related to a lower urinary creatinine excretion per unit of lean body mass.

Renal tubular handling of potassium in children with insulin-dependent diabetes mellitus.

To clarify the mechanism by which renal potassium (K) excretion is reduced in children with insulin-dependent diabetes mellitus, we studied two groups of patients: (A) at diagnosis and (B) after at least 1 year of follow-up. Group A (15 children) was studied twice: on the day of admission and after 1 month of insulin therapy. On admission, urinary K excretion, fractional K excretion, and transtubular K concentration gradient (TTKG) were significantly decreased, but became normal after extended insulin therapy. TTKG was inversely correlated with blood glucose (P < 0.001) and hemoglobin A1c (HbA1c, P < 0.001). Group B (73 children with a mean follow-up of 54 +/- 36 months) was subdivided according to the TTKG: 30 patients had a low TTKG < 4.0 (median 3.2) and 43 patients had a normal TTKG > or = 4.0 (median 5.2). Patients had a low TTKG and those with a normal TTKG had an identical duration of follow-up and similar values for plasma renin activity, aldosterone concentration, calciuria, magnesiuria, albumin excretion rate, and creatinine clearance. However, those with a low TTKG had significantly higher blood HbA1c levels, urine volume, and glucosuria. Logistic regression analysis showed that the only independent variables predicting a low TTKG were blood HbA1c and glucosuria (P < 0.001). These data confirm that a reduced renal K excretion is a characteristic feature of diabetic children; this is reversible with appropriate insulin therapy, largely depends on the metabolic control of the disease, and, specifically, on the degree of hyperglycemia and/or glucosuria.

Magnesium homeostasis in premature and full-term neonates.

Renal handling of magnesium (Mg) has not been comprehensively studied in the newborn period due to the difficulty, until recently, of measuring the diffusible fraction of plasma Mg (UfMg). In the present study this methodology was used to assess Mg homeostasis in 84 newborn infants of different postconceptional age (26-42 weeks), weight (720-4,830 g) and postnatal age (1-72 days). Very premature infants (postconceptional age less than 35 weeks) had significantly higher values of plasma Mg than mature newborn infants. Plasma Mg related inversely to postconceptional age, weight, plasma total protein and plasma calcium, and directly to plasma potassium. Stepwise multiple regression analysis revealed that postconceptional age was the unique factor contributing to variations in plasma Mg. Plasma values of UfMg were the same in preterm as in term infants but, when expressed as a fraction of total plasma Mg (UfMg/Mg), they were significantly lower in very preterm infants. Fractional excretion of Mg and the ratio of urine Mg to urine creatinine did not vary as a function of postconceptional age. These results indicate that plasma UfMg is kept constant at different gestational ages despite variations in total plasma Mg; furthermore, no functional immaturity is present for renal tubular reabsorption of Mg, even in very low birth weight infants.

Pathophysiology of the renal acidification defect present in the syndrome of familial hypomagnesaemia-hypercalciuria.

A distal acidification defect is frequently observed in the syndrome of familial hypomagnesaemia-hypercalciuria and hence this condition can be confused with primary distal renal tubular acidosis (RTA). This study demonstrates that in four unrelated patients with familial hypomagnesaemia-hypercalciuria the acidification defect is functionally different from that present in primary distal RTA. All patients exhibited hypomagnesaemia, hypermagnesuria, hypercalciuria, hyposthenuria, nephrocalcinosis and slight reduction of glomerular filtration rate (GFR). A moderate degree of metabolic acidosis was also present and basal data showed an inappropriately high urine pH (5.7-5.9) and a positive urine anion gap (Na + K-Cl = 11-28 mmol/l). Stimulation of distal acidification induced a fall in urine pH (4.7-5.6), but ammonium excretion remained low despite factoring by GFR (26-46 mumol/min per 1.73 m2, 35-54 mumol/100 ml GF). The urine to blood PCO2 gradient also remained low after sodium bicarbonate loading (1.3-17.7 mmHg). These results are best explained by both defective ammonia transfer to the deep nephron and impaired hydrogen ion secretion at the level of the medullary collecting duct, and probably are secondary effects of the medullary interstitial nephropathy.