Explore the vast range of titles available.

Background/Aims: To assess the relationship between bone and vascular disease and its changes over time after renal transplantation. Metabolic bone disease (MBD) is common in chronic kidney disease (CKD) and is associated with cardiovascular (CV) disease. Following transplantation (Tx), improvement in CV disease has been reported; however, data regarding changes in bone disease remain controversial. Methods: Bone turnover and arterial stiffness (pulse wave velocity (PWV)) were assessed in 47 Tx patients (38 (3-191) months after Tx). Results: Bone alkaline phosphatase (BALP), osteocalcin (OC) and beta-crosslaps were significantly higher in Tx patients, and decreased significantly after one year. There was a negative correlation between BALP, OC and steroid administered (r=-0.35;r=-0.36 respectively). PWV increased in the Tx group (1.15 SD). In patients with a follow up of <24 months, PWV was correlated with BALP and beta-crosslaps (r=0.53; r=0.69 respectively) while in the ≥24 months group, PWV was correlated with cholesterol (r=0.38). Conclusions: Increased bone turnover and arterial stiffness are present following kidney transplantation. While bone turnover decreases with time, arterial stiffness correlates initially with bone turnover, after which the influence of cholesterol becomes significant. Non-invasive estimation of bone metabolism and arterial stiffness may help to assess CKD-MBD following renal transplantation.

Kálmán Tory, Corinne Antignac and colleagues report that a variant of NPHS2 , encoding p.Arg229Gln, causes nephrotic syndrome only when present in trans with particular mutations in the 3′ coding region of NPHS2 . Mechanistically, the authors show that these 3′ mutations behave as recessive alleles when present with wild-type NPHS2 but exert a dominant-negative effect on the p.Arg229Gln variant, resulting in protein mislocalization. Monogenic disorders result from defects in a single gene. According to Mendel's 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.

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.

Background The pathogenicity of the NPHS2 homozygous p.R229Q variant in steroid-resistant nephrotic syndrome (SRNS) is doubtful. While it has been reported in unaffected controls, it is enriched in patients with SRNS, suggesting pathogenicity. Case-Diagnosis/Treatment A family with three members homozygous for the NPHS2 p.R229Q variant is presented: a 37-year-old patient who was diagnosed with proteinuria at age 7 months, focal segmental glomerulosclerosis (FSGS) at age 20 years, and end-stage renal disease (ESRD) at age 33 years, his 59 year-old father and his 40 year-old brother, both unaffected with no proteinuria. The affected son also harbors a heterozygous de novo, truncating PAX2 mutation (c.76dupG, p.V26Gfs*28), which can explain his chronic renal failure but which is rarely associated with FSGS. Conclusions This family provides further evidence that homozygous p.R229Q in itself may not cause FSGS. Nevertheless, the rare association of FSGS to a PAX2 mutation may reflect the modifier effect of p.R229Q in the homozygous state. Such a modifier effect can also explain its enrichment in SRNS patients. Patients with homozygous p.R229Q should be screened for the causative mutation in a second gene.

Background The most frequently mutated gene of steroid-resistant nephrotic syndrome (SRNS) is NPHS2 . Current guidelines propose the sequencing of all NPHS2 exons only in childhood-onset SRNS. Methods A cohort of 38 Hungarian patients with childhood-onset nephrotic-range proteinuria was screened for NPHS2 mutations. The frequency of the p.V290M mutation in late-onset SRNS was examined in the French and PodoNet cohorts. Results Of the 38 Hungarian patients screened, seven carried NPHS2 mutations on both alleles, of whom two—diagnosed with proteinuria through school screening programs at the age of 9.7 and 14 years, respectively—did not develop nephrotic syndrome in childhood. The first, an 18-year-old boy, homozygous for p.V290M, has never developed edema. The second, a 31-year-old woman—compound heterozygous for p.V290M and p.R138Q—was first detected with hypoalbuminemia (<30 g/l) and edema at the age of 24.3 and 27.5 years, respectively. Both patients currently have a normal glomerular filtration rate. The mutation p.V290M was carried by three of the 38 patients in the Hungarian cohort, by two of the 95 patients with late-onset SRNS in the PodoNet cohort and by none of the 83 patients in the French cohort. Conclusions We propose that not only the p.R229Q variant, but also the p.V290M mutation should be screened in Central and Eastern European patients with late-onset SRNS.

Arterial stiffness (Ast) individually predicts cardiovascular (CV) mortality. Ast increases via vascular calcification and can be characterized by pulse wave velocity (PWV). We assessed the influence of mineral and bone metabolism on Ast in dialyzed (D) and renal transplanted (Tx) children by measuring fetuin-A and bone markers [bone-specific alkaline phosphatase (BALP); beta-CrossLaps (β)]. Normalized PWV/height (PWV/h) of 11 D and 17 Tx patients was measured by applanation tonometry. Levels of calcium (Ca), phosphate (P), fetuin-A, and bone markers were analyzed. Ca × P/fetuin-A ratio was calculated to characterize the balance of calcification and inhibition. Cumulative dose of calcitriol was also assessed. Fetuin-A was lower in D and Tx compared with healthy controls. Bone markers and Ca × P/fetuin-A of D were significantly higher than those of Tx and controls. In D PWV/h correlated with Ca × P/fetuin-A and BALP ( r  = 0.8; p  = 0.005, r  = 0.6, p  = 0.05, respectively); BALP correlated with Ca × P/fetuin-A ( r  = 0.7, p  = 0.01). In Tx, there was a correlation between calcitriol administered before transplantation and PWV/h ( r  = 0.5, p  = 0.04). Increased bone turnover was coupled with an increased potential of calcium-phosphate precipitation, as shown by the increased Ca × P/fetuin-A. It might explain the connection between disturbed mineral and bone metabolism and Ast. Tx might be beneficial on Ast, though follow-up studies are needed.

Wall motion abnormalities during acute ST-segment elevation myocardial infarction (STEMI) and the improvement after recanalization depend on the conditions of the coronary occlusion. Fifty-seven patients with first-ever STEMI due to one-artery occlusion, treated with primary PCI, were evaluated. Area at risk and left ventricular wall motion abnormalities were localized with coronary angiography and echocardiography and then compared in relation to the time elapsed from the onset of symptoms at the time of infarction and at 3 months. Left ventricular diameters and ejection fractions were evaluated in relation to the ischemic time. Three hundred forty-one affected left ventricular segments were detected with angiography, while echocardiography showed 206 segments with motion abnormality. No correlation was found between the regional wall motion index in the area at risk and the time elapsed from the beginning of symptoms. However, the improvement in wall motion abnormalities at the follow-up was dependent on the ischemic time (r=-0.29, p<0.03). The early subgroup showed significant improvement in left ventricular ejection fraction at follow-up (p=0.03), whereas in the late subgroup, a significant increase in left ventricle diameters was observed. Our results first demonstrate in humans that in the early hours from the occlusion of the coronary artery, the extent and severity of the wall motion abnormalities inside the area at risk show large variability without relation to the elapsed time since the onset of symptoms. On the other hand, the results of follow-up echocardiography proved that the wall motion improvement was highly dependent on the ischemic time.