Congenital nephrotic syndrome (CNS) is clinically and genetically heterogeneous, with mutations in WT1, NPHS1 and NPHS2 accounting for part of cases. We recently delineated a new autosomal recessive entity comprising CNS with diffuse mesangial sclerosis and distinct ocular anomalies with microcoria as the leading clinical feature (Pierson syndrome). On the basis of homozygosity mapping to markers on chromosome 3p14-p22, we identified homozygous or compound heterozygous mutations of LAMB2 in patients from five unrelated families. Most disease-associated alleles were truncating mutations. Using immunohistochemistry and western blotting we could demonstrate that the respective LAMB2 mutations lead to loss of laminin beta2 expression in kidney and other tissues studied. Laminin beta2 is known to be abundantly expressed in the glomerular basement membrane (GBM) where it is thought to play a key role in anchoring as well as differentiation of podocyte foot processes. Lamb2 knockout mice were reported to exhibit congenital nephrosis in association with anomalies of retina and neuromuscular junctions. By studying ocular laminin beta2 expression in unaffected controls, we detected the strongest expression in the intraocular muscles corresponding well to the characteristic hypoplasia of ciliary and pupillary muscles observed in patients. Moreover, we present first clinical evidence of severe impairment of vision and neurodevelopment due to LAMB2 defects. Our current data suggest that human laminin beta2 deficiency is consistently and specifically associated with this particular oculorenal syndrome. In addition, components of the molecular interface between GBM and podocyte foot processes come in the focus as potential candidates for isolated and syndromic CNS.

Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin b2, which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families. The majority of disease-causing LAMB2 mutations are truncating, consistent with the hypothesis that loss of laminin b2 function is the molecular basis of Pierson syndrome. Although truncating mutations are distributed across the entire gene, missense mutations are clearly clustered in the N-terminal LN domain, which is important for intermolecular interactions. There is an association of missense mutations and small in frame deletions with a higher mean age at onset of renal disease and with absence of neurologic abnormalities, thus suggesting that at least some of these may represent hypomorphic alleles. Nevertheless, genotype alone does not appear to explain the full range of clinical variability, and therefore hitherto unidentified modifiers are likely to exist.

Prenatal MMC closure significantly lowers further adverse evolution of the II CM. Further studies are needed, especially on preventive measures for preterm labor and iatrogenic preterm prelabor rupture of membranes (iPPRM) in the postoperative course of IUMR.

No abstract

Neutrophil gelatinase-associated lipocalin (NGAL) is postulated to be a potentially new and highly specific/sensitive marker of acute kidney injury (AKI). The aim of this study was to assess the impact of inflammation on serum and urine NGAL in newborns that were treated due to infection. We determined serum and urine NGAL concentrations in 73 infants (51 with sepsis; 22 with severe sepsis) admitted to the Intensive Care Unit in the first month of life, for three consecutive days during the course of treatment for infection. 29 neonates without infection served as the control group. Septic patients, in particular, severe sepsis patients, had increased serum and urinary NGAL levels in the three subsequent days of observation. Five septic patients who developed AKI had elevated serum and urinary NGAL values to a similar extent as septic neonates without AKI. A strong correlation was found between the concentration of serum and urinary NGAL and inflammatory markers, such as CRP and procalcitonin. Serum and urinary NGAL levels were also significantly associated with NTISS (neonatal therapeutic intervention scoring system) values. We conclude that increased serum and urinary NGAL values are not solely a marker of AKI, and more accurately reflect the severity of inflammatory status.