PAX2 mutations in renal-coloboma syndrome: mutational hotspot and germline mosaicism.

The renal-coloboma syndrome (RCS, MIM 120330) is an autosomal dominant disorder caused by PAX2 gene mutations. We screened the entire coding sequence of the PAX2 gene for mutations in nine patients with RCS. We found five heterozygous PAX2 gene mutations: a dinucleotide insertion (2G) at position 619 in one sporadic RCS case, a single nucleotide insertion (619 + G) in three unrelated cases, and a single nucleotide deletion in a familial case. In this familial case, three affected sibs showed a striking ocular phenotypic variability. Each of the sibs carried a 619insG mutation, whilst unaffected parents did not, suggesting the presence of germline mosaicism. Interestingly, the 619insG mutation has been previously reported in several patients and is also responsible for the Pax21Neu mouse mutant, an animal model of human RCS. This study confirms the critical role of the PAX2 gene in human renal and ocular development. In addition, it emphasises the high variability of ocular defects associated with PAX2 mutations ranging from subtle optic disc anomalies to microphthalmia. Finally, the presence of PAX2 germline mosaicism highlights the difficulties associated with genetic counselling for PAX2 mutations.

Comparison of progressive antithrombin activity and the concentration of three thrombin inhibitors in nephrotic syndrome.

In order to compare the plasmatic progressive antithrombin activity to the concentration of three thrombin inhibitors, antithrombin III (AT III), alpha 2 macroglobulin (alpha 2 M), alpha 1 anti-trypsin (alpha 1, AT) in nephrotic syndrome, a prospective study was carried out on a group of 28 children affected with the disease. A dramatic reduction of the level of AT III and of alpha 1 AT, two inhibitors of molecular weight close to that of albumin, was observed. The decreased level of AT III was counterbalanced by an increase in alpha 2 M. This phenomenon accounts for the increased progressive antithrombin activity observed in all the affected children. It is suggested that the above compensatory mechanism explains the absence of thrombotic accidents in this series and that the benefit of heparin therapy is doubtful in these conditions.

Severe idiopathic nephrotic syndrome with tubular dysfunction (report of nine pediatric cases).

The association of idopathic nephrotic syndrome (INS) with tubular dysfunction is uncommon. The authors report on 9 pediatric cases (6 girls and 3 boys). All the patients (age 12 to 48 months) presented initially with a pure INS. The syndrome was clinically severe and either initially or secondarily resistant to steroid and immunosuppressive therapy. In 6 cases initial renal biopsies showed minimal glomerular lesions and in one case, segmental and focal hyalinization was observed. Symptoms of tubular insufficiency appeared progressively and included: proximal and distal hyperchloremic acidosis (9/9 cases), renal glycosuria (9/9 cases), hypokalemia with hyperkaluria (7/9 cases), hypohposphatemia (4/9 cases), global hyperaminoaciduria (4/9 cases), tubular proteinura (2/9 cases). Control of water and electrolyte balance was difficult. The urinary concentration of fibrinogen breakdown products was very high throughout the course of the disease. In all cases, anemia preceded the inevitable alteration of glomerular filtration which resulted in four cases of terminal renal failure after an average evolution of 2 to 3 years. Renal biopsies during the later stages of evolution demonstrated five cases of glomerular hyalinization with interstitial fibrosis associated in 3 cases with histiocytic infiltration. Immunologic studies were negative. The authors discuss the physiopathologic aspects of the disease including the possibility of thrombosis of intrarenal veins and compare their observations with those of Royer et al. [1963].

Clinical implications from studies of HLA antigens in idiopathic nephrotic syndrome in children.

HLA class I and II antigen frequencies were determined in two large cohorts of children with idiopathic nephrotic syndrome (NS) from Southwest France (n = 199) and Southwest Germany (n = 152) and compared with unrelated healthy individuals from the same geographical areas. Strength of HLA association was expressed by the relative risk (RR) estimated by Odd's ratio. We examined 105 steroid-resistant and 242 steroid-sensitive NS patients who were subdivided in non-relapsers, infrequent relapsers and frequent relapsers or steroid-dependent patients. In steroid-sensitive patients significant associations were found with HLA-DR7 (RR 5.1 in French, 3.2 in Germans), -DQ2 (RR 4.7/2.3) and with the phenotypic combination HLA-DR3/DR7 (RR 5.6/7.7). Significant negative associations were encountered with HLA-DR2, -DR6 and -DQ1. The associations were stronger in frequent relapsers/steroid-dependent patients than in infrequent relapsers and were not significant in non-relapsers. In steroid-resistant patients the only significant association found was with the combined occurrence of HLA-DR3/DR7. We propose that in childhood NS tissue typing for selected HLA class II antigens is helpful in prediciting the clinical course.

[Results of the evaluation of platelet sodium-proton exchange in the young hypertensive subject]. / Résultats de l'évaluation de l'antiport sodium-proton plaquettaire chez le sujet jeune hypertendu.

In order to assess the relationships between increased cellular sodium-proton (Na+/H+) exchange and cardiovascular abnormalities in essential hypertension (EH), 21 young subjects as part of an ongoing longitudinal study were tested for the platelets Na+/H+ exchange using the amiloride sensitive sodium dependent component of platelet volume change under cytoplasmic acidification induced by a sodium propionate medium; cell volumes were determined by electronic cell sizing (Livne et al., Lancet 1987; i: 533-6). 24 normal subjects with normotension and without familial history of hypertension were taken as controls. Data of ambulatory blood pressure recording (ABPR) defined 2 groups according to the presence of normotension (group I, n = 10), or of hypertension (group II, n = 11): established (n = 2) or borderline (n = 9) hypertension. Hypertensive subjects (group II) had increased values of Na+/H+ exchange (k coefficient, mean (SEM): 0.287 (0.07) vs 0.228 (0.05) in control group (p less than 0.01). Na+/H+ rates were significantly related to ABPR data (r = 0.46, p less than 0.02 with diastolic charge during ABPR), but not to left ventricular mass index in g/m2 by echocardiography. Increased rates of platelets Na+/H+ exchange which were related to diastolic blood pressure levels by ABPR, and perhaps to the level of peripheric vascular resistances, may play a significant role in the development of EH in the early stages.

[Fetal and neonatal effects of maternal treatment with angiotensin converting enzyme inhibitor]. / Effets foetaux et néonatals d'un traitement maternel par inhibiteur de l'enzyme de conversion de l'angiotensine.

BACKGROUND. Exposure of pregnant women to angiotensin converting enzyme inhibitor may have side effects on the fetus or newborn, mainly oligoamnios and impaired renal function. CASE REPORT N zero 1. A 34 year-old woman was given enalapril from the onset of her pregnancy because of hypertension from the age of 18 years. Oligoamnios was diagnosed in the fetus on gestational week 28; enalapril was then replaced by nifedipine but this drug was badly tolerated so that the woman was again given enalapril 8 days later. The baby (1700 g) was born by cesarean section at gestational week 34 because of acute distress syndrome; he developed hypotension, anuria, generalized oedema and was placed in intensive care. Treatment included ventilation, sympathomimetic agents, and diuretics. An exchange-transfusion followed by peritoneal dialysis was performed a few hours later. Renal function returned to normal between the 3rd and 5th day. Unilateral kidney hypoplasia was diagnosed at the age of 2 years. CASE N zero 2. A 24 year-old woman was given enalapril at the third trimester of a twin pregnancy. Delivery was full term at 37 weeks. The first baby, a boy weighing 2610 g, suffered from hypoglycemia and vomiting followed by hypotension and oliguria that required exchange-transfusion and repeated peritoneal dialysis. This boy has developed moderate chronic renal failure and hypertension. The second baby, a girl weighing 2,165 g, suffered from respiratory distress syndrome followed by hypotension and oliguria, but her renal function returned to normal within a few days. CONCLUSIONS. The use of angiotension converting enzyme inhibitor by pregnant women places the fetus at severe risk: treatment with this type of drug should be stopped as soon as pregnancy is confirmed.

[Terminal and pre-terminal chronic renal insufficiency in newborns in French neonatal intensive care units: survey of the French pediatric nephrologic society of resuscitation and emergency]. / Insuffisance rénale chronique terminale et préterminale du nouveau-né dans les services de réanimation français: enquête de la Société de néphrologie pédiatrique auprès du Groupe francophone de réanimation et d'urgences pédiatriques.

OBJECTIVES: The aim of this study was to describe the intensive care unit neonatologists' attitudes about a neonate with terminal or pre-terminal renal failure. METHODS: A questionnaire was sent to all French neonatal intensive care units. Physicians were asked to describe their attitude about neonatal chronic renal failure (Would you agree with dialysis and graft for these children?). Physicians were also presented with two clinical observations involving neonates with varying degrees of renal insufficiency and a complicating comorbidity, including neurological abnormality or socioeconomic circumstances. RESULTS: Responses were obtained from 92% of the university neonatal care units. The will to take care of a neonate with end-stage renal failure till the renal graft, varied greatly from a centre to another one. Three (9%) university-teams said they had a strong will to bring the baby from the neonatal period to the time of renal graft. Eleven other centres (32%) did not have any will for accompanying the baby till the renal graft. Eight centres (24%) would be rather favourable to the idea of dialysis and graft, and 12 others (35%) would be rather unfavourable. CONCLUSION: The results of this study show great differences between French neonatologists when they are faced to newborns with end stage renal failure. Ethical, medical and organisational difficulties are matters of controversy. The epidemiological impact of the perinatal discussion could be a 20% variation of all the renal grafts in children.

[Value of MR imaging of the fetal kidney]. / Apport de l'IRM dans l'étude du rein foetal.

Sonography is the imaging modality of choice for initial evaluation of the fetus. However, the role of MR imaging for fetal evaluation is expanding. Based on a review of seven cases, the role of MRI to further characterize renal abnormalities detected at US, especially hyperechoic kidneys, is demonstrated.

[Quantitative renal scintigraphy with technetium-labelled dimercaptosuccinic acid in children]. / Scintigraphie rénale quantitative à l'acide dimercaptosuccinique marqué. Chez l'enfant.

Separate measurement of renal function is essential in children with urinary tract disease. This can be done satisfactorily by means of kidney scintigraphy with technetium 99m-labelled dimercaptosuccinic acid. A retrospective study of the records of 415 children, which comprised renal function tests, radiology and scintigraphy, confirmed the value of the radioisotope technique. Graphs of height, kidney uptake and kidney uptake density in relation to age were established, showing highly significant correlations with renal function tests and intravenous urography results, but many dissociations were encountered. Separate renal function evaluation by radioisotope scintigraphy seems to be more reliable than evaluation extrapolated from measurement of the cortical areas at intravenous urography. In vesico-ureteral reflux scintigraphy makes it possible to detect reflux nephropathy at an earlier stage than with other methods.

Population pharmacokinetics of mycophenolic acid in kidney transplant pediatric and adolescent patients.

Current data on mycophenolate mofetil (MMF) suggest that there is a pharmacokinetic/pharmacodynamic relationship between the mycophenolic acid (MPA) area under the curve (AUC) during treatment and both the risk of acute rejection and the occurrence of side effects. The aim of this study was to characterize the population pharmacokinetics of MPA in kidney transplant patients between the ages of 2 and 21 years and to propose a limited sampling strategy to estimate individual MPA AUCs. Forty-one patients received long-term oral MMF continuous therapy as part of a triple immunosuppressive regimen, which also included cyclosporine or tacrolimus (n=3) and corticosteroids. Therapy was initiated at a dose of 600 mg/m twice daily. The population parameters were calculated from an initial group of 32 patients. The data were analyzed by nonlinear mixed-effect modeling using a 2-compartment structural model with first-order absorption and a lag time. The interindividual variability in the initial volume of distribution was partially explained by the fact that this parameter was weight-dependent. Fifteen concentration-time profiles from 13 patients were used to evaluate the predictive performance of the Bayesian approach and to devise a limited sampling strategy. The protocol, involving two sampling times, 1 and 4 hours after oral administration, allows the precise and accurate determination of MPA AUCs (bias -0.9 microg.h/mL; precision 6.02 microg.h/mL). The results of this study combine the relationships between the pharmacokinetic parameters of MPA and patient covariates, which may be useful for dose adjustment, with a convenient sampling procedure that may aid in optimizing pediatric patient care.