Andrea Kerti

Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome

Monogenic disorders result from defects in a single gene. According to Mendels laws, these disorders are inherited in either a recessive or dominant fashion. Autosomal-recessive disorders require a disease-causing variant on both alleles, and according to our current understanding, their pathogenicities are not influenced by each other. Here we present an autosomal-recessive disorder, nephrotic syndrome type 2 (MIM 600995), in which the pathogenicity of an NPHS2 allele encoding p.Arg229Gln depends on the trans-associated mutation. We show that, contrary to expectations, this allele leads to a disease phenotype only when it is associated specifically with certain 3′ NPHS2 mutations because of an altered heterodimerization and mislocalization of the encoded p.Arg229Gln podocin. The disease-associated 3′ mutations exert a dominant-negative effect on p.Arg229Gln podocin but behave as recessive alleles when associated with wild-type podocin. Therefore, the transmission rates for couples carrying the disease-associated mutations and p.Arg229Gln may be substantially different from those expected in autosomal-recessive disorders.

Measurement of pulse wave velocity in children and young adults: a comparative study using three different devices

To estimate the value of pulse wave velocity (PWV) in pediatric cardiovascular disease, prospective studies are needed. Various instruments based on different measurement principles are proposed for use in children, hence the need to test the comparability of these devices in this younger population. The objective of this study was to compare PWV measured by oscillometry (Vicorder (VIC)) with the gold standard of applanation tonometry (PulsePen (PP), Sphygmocor (SC)). PWV was measured in 98 children and young adults (age: 16.7(6.3–26.6) years (median(range)) with the above three devices at the same visit under standardized conditions. Mean PWV measured by VIC was significantly lower than that measured by SC and PP. There was no difference following path length correction of the VIC measurement (using the distance between the jugular notch and the center of the femoral cuff), (PP: 6.12(1.00), SC: 5.94(0.91), VIC: 6.14(0.75) m s−1). Velocities measured by the three devices showed highly significant correlations. Bland–Altman analysis revealed excellent concordance between all three devices, however, there was a small but significant proportional error in the VIC measurements showing a trend toward lower PWV measured by VIC at higher PWV values. Our study provides data on the three most frequently used instruments in pediatrics. Following path length correction of the VIC, all three devices provided comparable results. Thus, our work allows extrapolating data between previously established normal PWV values for children and forthcoming studies using these instruments to assess children at long-term risk of cardiovascular disease. The small proportional error of VIC needs additional technical development to improve the accuracy of the measurements.

Cardiovascular risk assessment in children with chronic kidney disease.

Chronic kidney disease (CKD) is a major factor contributing to cardiovascular (CV) morbidity and mortality with the highest risk in patients on dialysis. An estimation of CV risk is important not only to identify potential modifiable risk factors but also to evaluate the effect of treatments aimed to reduce the risk. Non-invasive methods of measuring vascular changes and circulating biomarkers are available to assess the presence and severity of cardiovascular damage. These include measures of structural (carotid intima-media thickness and coronary artery calcification score) and functional (aortic pulse wave velocity, 24-h ambulatory blood pressure monitoring, ambulatory arterial stiffness index, heart rate variability and flow-mediated dilatation) changes in the vessel wall. In addition, a number of circulating biomarkers of vascular damage and its progression have been studied. Many of these tests are well validated as surrogate markers of future cardiovascular events and death in adult CKD patients, but need technical adaptation, standardization and validation for use in children. With our current state of knowledge, these are best reserved for research studies and scarce clinical resources may be better utilized for preventative strategies to reduce the modifiable risk factors for calcification from early CKD stages.

Cardiovascular risk assessment in children following kidney transplantation

Dégi A, Kerti A, Kis É, Cseprekál O, Tory K, Szabó AJ, Reusz GS. Cardiovascular risk assessment in children following kidney transplantation.

The 83,557insA variant of the gene coding 11β-hydroxysteroid dehydrogenase type 1 enzyme associates with serum osteocalcin in patients with endogenous Cushing's syndrome

OBJECTIVE The type 1 and type 2 isoenzymes of the 11β-hydroxysteroid dehydrogenase (HSD11B) play an important role in the prereceptor regulation of glucocorticoid bioavailability and action. The potential importance of gene variants coding HSD11B has not been previously evaluated in patients with endogenous hypercortisolism. The aim of the present study was to explore presumed associations between the 83,557insA variant of the HSD11B1 gene and circulating hormone concentrations, bone turnover and bone mineral density (BMD) in patients with endogenous Cushings syndrome (CS). PATIENTS AND METHODS Forty one patients with ACTH-producing pituitary adenomas (Cushings disease-CD), 32 patients with cortisol-producing adrenal tumors (ACS) and 129 healthy control subjects were genotyped for the 83,557insA variant of the HSD11B1 gene using restriction fragment length analysis. BMD was measured by dual-energy X-ray absorptiometry. Serum cortisol, ACTH, osteocalcin (OC) and C-terminal crosslinks (CTX) of human collagen type I (C-telopeptide) were measured by electrochemiluminescence immunoassay. RESULTS No statistically significant differences were found in the allelic frequencies of the 83,557insA polymorphism among patients with CD, ACS and healthy controls. Among all patients with CS, heterozygous carriers of the 83,557insA had significantly higher serum OC as compared to non-carriers. Patients with ACS carrying the 83,557insA variant had higher plasma ACTH concentrations compared to non-carriers. The 83,557insA variant failed to associate with BMD in patients and controls. CONCLUSIONS Our present findings indicate that the 83,557insA variant of the HSD11B1 gene may influence serum markers of bone turnover, but not BMD in patients with endogenous Cushings syndrome.

Ambulatory arterial stiffness index in children after kidney transplantation

Given the increase in CV morbidity after RTx and the scarcity of CV events in pediatrics, surrogate markers should be assessed to characterize CV damage in this population. AASI is a marker of arterial stiffness in adults, predicting cardio‐ and cerebrovascular morbidity. Our aim was to assess the determinants of AASI in RTx children (n = 54, 15.5 ± 3.5 yr) and to examine its relationship to central PWV. AASI was calculated from 24 h ABPM. PWV was determined by applanation tonometry, body composition by multifrequency bioimpedance measurement. The dipping state, volume overload, and time on dialysis were the main predictors of AASI (p < 0.05). Children with established HT (n = 34) had increased AASI, extracellular body water, and BNP (p < 0.05). In contrast to AASI, PWV did not differ between HT and normotensive RTx patient groups. There was no correlation between AASI and PWV. PWV was increased in children who spent more than one yr on dialysis prior to RTx. In conclusion, increased AASI in HT RTx children better characterizes the actual volume‐ and pressure‐dependent arterial rigidity rather than long‐term morphological changes in large arteries as reflected by PWV.

QMPSF is sensitive and specific in the detection of NPHP1 heterozygous deletions

Abstract Background: Nephronophthisis, an autosomal recessive nephropathy, is responsible for 10% of childhood chronic renal failure. The deletion of its major gene, NPHP1, with a minor allele frequency of 0.24% in the general population, is the most common mutation leading to a monogenic form of childhood chronic renal failure. It is challenging to detect it in the heterozygous state. We aimed to evaluate the sensitivity and the specificity of the quantitative multiplex PCR of short fluorescent fragments (QMPSF) in its detection. Methods: After setting up the protocol of QMPSF, we validated it on 39 individuals diagnosed by multiplex ligation-dependent probe amplification (MLPA) with normal NPHP1 copy number (n=17), with heterozygous deletion (n=13, seven parents and six patients), or with homozygous deletion (n=9). To assess the rate of the deletions that arise from independent events, deleted alleles were haplotyped. Results: The results of QMPSF and MLPA correlated perfectly in the identification of 76 heterozygously deleted and 56 homozygously deleted exons. The inter-experimental variability of the dosage quotient obtained by QMPSF was low: control, 1.05 (median; range, 0.86−1.33, n = 102 exons); heterozygous deletion, 0.51 (0.42−0.67, n = 76 exons); homozygous deletion, 0 (0−0, n = 56 exons). All patients harboring a heterozygous deletion were found to carry a hemizygous mutation. At least 15 out of 18 deletions appeared on different haplotypes and one deletion appeared de novo. Conclusions: The cost- and time-effective QMPSF has a 100% sensitivity and specificity in the detection of NPHP1 deletion. The potential de novo appearance of NPHP1 deletions makes its segregation analysis highly recommended in clinical practice.