Type I IgE receptor, interleukin 4 receptor and interleukin 13 polymorphisms in children with nephrotic syndrome.

Polymorphisms in the genes encoding the high-affinity IgE receptor, the interleukin 4 (IL4) receptor and IL13 can be associated with the development of asthma and allergy. Although several studies have described an association between atopy and idiopathic childhood nephrotic syndrome (NS), it is not clear whether this association is of a causal nature. Furthermore, it is not known whether these polymorphisms are associated with the clinical course of NS. A total of 84 children (52 male and 32 female; mean age 12.1 years) with NS were included in the present study. Of these, 78 could be classified as either atopic or non-atopic. Atopy was defined by elevated IgE levels (>100 k-units/l) and/or a positive history of atopy (33 of 78 patients). DNA was extracted from blood collected in EDTA tubes, and polymorphisms at positions 50 and 551 of the IL4 receptor, position 110 of IL13 and position 181 of the high-affinity IgE receptor were investigated by sequence-specific PCR or direct sequencing. Although we noted a strong tendency towards a higher allele frequency of polymorphisms in children with atopy and NS compared with children with NS but without atopy (IL4 50, 30% compared with 18%; IL4 551, 39% compared with 31%; IL13 110, 45% compared with 33%; IgE 181, 12% compared with 13%), these differences did not reach statistical significance. There were no differences in the frequency of polymorphisms between the different clinical courses of NS (frequent relapsers, steroid-dependent or steroid-resistant NS). We conclude that polymorphisms in the IL4 receptor, the high-affinity IgE receptor and IL13 do not seem to predict the clinical course of NS, despite the fact that serum IgE elevations are more frequent in patients with NS than in normal control subjects. The investigated polymorphisms may contribute to the IgE switch in patients with NS.

Antenatal oligohydramnios of renal origin: postnatal therapeutic and prognostic challenges.

Urinary tract anomalies (UTA) including polycystic kidney disease nowadays can be detected antenatally by ultrasound. The concomitant presence of oligohydramnios has been regarded as a severe risk factor for renal dysfunction and pulmonary hypoplasia, although clinical data after birth are scarce. We report the postnatal course and long-term follow-up of 10 infants with oligohydramnios due to congenital UTA from two pediatric nephrology centers. The underlying final diagnoses were autosomal-recessive polycystic kidney disease (ARPKD, n = 2), familial tubular dysgenesis (n = 2) and bilateral renal hypoplasia (n = 6) including 3 children with posterior urethral valves. Two children died in the neonatal period while 8 children are currently alive at a median age of 2.5 (range 1.1-10) years. In the postnatal period, respiratory failure necessitating mechanical ventilation occurred in 7 infants (including the 2 non-survivors). All surviving children had chronic renal failure, which could be managed conservatively in 6 children (median GFR 45 (range 15-53) ml/min/1.73 m2) while 2 reached end-stage renal disease; one undergoing preemptive kidney transplantation and one peritoneal dialysis. Seven of 8 children reached normal developmental milestones. In conclusion, the presence of antenatal oligohydramnios in infants with UTA does not always carry a poor prognosis. The high incidence of perinatal complications, the complexity of underlying causes and the prevalence of postnatal chronic renal dysfunction calls for a multidisciplinary approach in the management of these children.

Unfavorable response to cyclophosphamide in steroid-dependent nephrotic syndrome.

Development of steroid dependency represents a significant therapeutic challenge in steroid-sensitive nephrotic syndrome. Previous studies have shown conflicting results concerning the benefit of a 12-week treatment with cyclophosphamide (CPO), with 24%-67% of patients achieving long-term remission. We therefore analyzed the clinical response of 20 consecutive children with steroid-dependent nephrotic syndrome (SDNS) (12 male, median age at start of treatment 5.9 years, range 3.2-14.7 years) treated at our institution with CPO (2 mg/kg per day) for 12 weeks since 1989. Median duration of follow-up was 5.8 (range 1.1-9.25) years. Only 6 of 20 children (30%) showed a long-term remission of >2 years, while 14 of 20 (70%) developed relapses again. Of these, 12 patients (86%) again developed steroid dependency, requiring further alternative treatment. Our data show that a 12-week course of CPO leads to unfavorable results in the majority of patients with SDNS. We therefore conclude that there is a need for further optimization of therapy in SDNS.

Functional characterization of the molecular defects causing nephrogenic diabetes insipidus in eight families.

X-Linked nephrogenic diabetes insipidus (NDI) is a rare inherited disorder characterized by the excretion of abnormal large volumes of diluted urine mainly caused by mutations in the V2 vasopressin receptor (AVPR2) gene. By screening NDI patients for mutations within the AVPR2 gene we have identified three novel (I46K, F105V, I130F) and four recurrent (D85N, R106C, R113W, Q225X) mutations. In addition, a recurrent missense mutation (A147T) within the aquaporin-2 gene was identified in a female patient with autosomal recessive NDI associated with sensorineural deafness. Selected clinical data of the NDI patients were compared with the results from the in vitro studies. Functional analysis of I46K and I130F revealed reduced maximum agonist-induced cAMP responses as a result of an improper cell surface targeting. In contrast, the F105V mutation is delivered to the cell surface and displayed an unchanged maximum cAMP response, but impaired ligand binding abilities of F105V were reflected in a shifted concentration-response curve toward higher vasopressin concentrations. As the extracellularly located F105 is highly conserved among the vasopressin/oxytocin receptor family, functional analysis of this residue implicates an important role in high affinity agonist binding.

Iron homeostasis in relapsing steroid-sensitive nephrotic syndrome of childhood.

AIM: Urinary transferrin loss is a typical feature in relapse of the idiopathic nephrotic syndrome, however, the impact on serum iron homeostasis and hematological parameters has not been studied systematically so far. PATIENTS AND METHODS: Therefore, we investigated serum iron (Fe), erythropoietin (EPO), ferritin (FN), transferrin (TF), total iron-binding capacity (TEBK), transferrin saturation and the soluble transferrin receptor (sTFR) combined with hematological parameters (hemoglobin, MCV, MCH) in 42 children with relapsing, steroid-sensitive nephrotic syndrome (NS) in remission (RM, n = 26) and relapse (RL, n = 16), including 13 patients who were studied in both states. Thirty-three age-matched healthy children served as controls. RESULTS: Fe, TEBK and TF were significantly reduced in RL compared to RM in cross-sectional as well as in paired studies while ferritin, hematological parameters and EPO levels remained unchanged. A significant increase, however, of the soluble transferrin-receptor could be demonstrated in cross-sectional analysis comparing RL to RM and healthy controls (3568+/-713 mg/ml vs 2625+/-576 vs 2646+/-697; p < 0.001 respectively) as well as in paired analysis of 13 patients in RL and RM (p < 0.001). CONCLUSION: We conclude that transient transferrin and iron deficiency occurs in RL of INS but this seems to be counterbalanced by upregulation of the sTFR, a mechanism that might be important in preventing the development of iron deficiency anemia during the active nephrotic state.

Preemptive liver transplantation in primary hyperoxaluria type 1: timing and preliminary results.

Preemptive isolated liver transplantation (PLTX) can cure the metabolic defect in primary hyperoxaluria type 1 (PH1) but there are no uniformally accepted recommendations concerning the timing of this transplantation procedure. We have performed PLTX successfully in 4 children (age 3-9 years) with PH1 with no mortality or morbidity due to the transplantation procedure. Plasma and urinary oxalate levels normalised rapidly and renal function remained stable including one patient with advanced chronic renal failure who showed a stable course for more than 24 months. Although treatment must be individualised in this severe metabolic disorder and PLTX has to be viewed as invasive procedure, we feel PLTX should be offered and discussed not too late in the treatment of PH1 to prevent or at least delay the progression to end stage renal disease and systemic oxalosis.

[The treatment with levamisole of frequently recurring steroid-sensitive idiopathic nephrotic syndrome in children]. / Die Behandlung des häufig rezidivierenden steroidsensiblen idiopathischen nephrotischen Syndroms im Kindesalter mit Levamisol.

BACKGROUND AND OBJECTIVE: The treatment of frequently relapsing steroid-sensitive nephrotic syndrome in children with established immunosuppressive drugs (steroids, cyclophosphamide, cyclosporin A) sometimes presents problems because of the expected incidence of side effects. Stimulation of the immune system with the anthelminthic drug levamisole in this disease has been documented. Aim of this study was to assess in a prospective but uncontrolled series of observations its value and side effects. PATIENTS AND METHODS: 25 patients (15 boys, ten girls; median age 10 [3.5-22] years) were given levamisole, 2 mg/kg/48 h. Before this treatment was started eight of the children/adolescents (32%) had frequent relapses and 17 (68%) had become steroid-dependent. Treatment was started during steroid-induced remission and continued for 3-24 (median 6) month, while steroids were discontinued after four weeks. RESULTS: Relapse frequency per patient month was reduced from a mean of 0.5 (0.33-0.83) before to 0.31 (0-0.67) during levamisole administration (P < 0.001). In 12 patients (48%) no or considerably fewer relapses were observed. Patients with exclusively frequent relapses responded to levamisole better than those with steroid dependence (7/8 [87.5%] vs. 5/18 [27.7%], P = 0.01). Side effects were reversible leukopenia in two patients and nonspecific skin rash as well as epigastric pain in one patient. CONCLUSION: Levamisole is an efficacious addition or alternative, with a low incidence of side effects, in the treatment of frequently relapsing nephrotic syndrome, particularly so in yet steroid-dependent patients.

[Acute reversible encephalopathy with brain edema and serial seizures in pseudohypoparathyroidism]. / Akute reversible Enzephalopathie mit Hirnödem und Anfallserie bei Pseudohypoparathyreoidismus.

A 16 year old patient with the typical clinical signs of Albright's hereditary dystrophia developed series of epileptic seizures with loss of consciousness, tonic muscle contractions and bite of the tongue. After termination of the seizures there was coma without focal neurological signs. CT scan revealed diffuse brain edema. Electroencephalographic studies showed generalized slowing. In laboratory tests the only abnormalities were marked hypocalcemia (1.15 mmol/l) and hyperphosphatemia. Blood parathyroid hormone (PTH) was elevated. PTH-Test confirmed the diagnosis of pseudohypoparathyroidism. The patient was treated with calcium and 1,25-dihydroxy-cholecalciferol. After few days the severe encephalopathy, CT and electroencephalographic changes were completely reversible. Hereditary disturbances of the parathyroid hormone metabolism are rare diseases. Hypocalcemia must be included into the differential diagnosis of seizures and brain edema to avoid invasive diagnostic and irrational treatment.