Podocytes are highly specialized cells in the vertebrate kidney. They participate in the formation of the size-exclusion barrier of the glomerulus/glomus and recruit mesangial and endothelial cells to form a mature glomerulus. At least six transcription factors (wt1, foxc2, hey1, tcf21, lmx1b and mafb) are known to be involved in podocyte specification, but how they interact to drive the differentiation program is unknown. The Xenopus pronephros was used as a paradigm to address this question. All six podocyte transcription factors were systematically eliminated by antisense morpholino oligomers. Changes in the expression of the podocyte transcription factors and of four selected markers of terminal differentiation (nphs1, kirrel, ptpru and nphs2) were analyzed by in situ hybridization. The data were assembled into a transcriptional regulatory network for podocyte development. Although eliminating the six transcription factors individually interfered with aspects of podocyte development, no single gene regulated the entire differentiation program. Only the combined knockdown of wt1 and foxc2 resulted in a loss of all podocyte marker gene expression. Gain-of-function studies showed that wt1 and foxc2 were sufficient to increase podocyte gene expression within the glomus proper. However, the combination of wt1, foxc2 and Notch signaling was required for ectopic expression in ventral marginal zone explants. Together, this approach demonstrates how complex interactions are required for the correct spatiotemporal execution of the podocyte gene expression program.

Objective: Investigate whether residential prenatal exposure to heavy metal hazardous air pollutants (HMHAPs) is associated with an increased risk of hypospadias. Methods: Data on non-syndromic hypospadias cases (n = 8981) and control patients delivered in Texas were obtained from the Texas Birth Defects Registry and matched 1:10 by birth year. Average exposure concentrations of HMHAPs were obtained from the 2005 U.S. Environmental Protection Agency National-Scale Air Toxics Assessment and categorized into quintiles. Odds ratios and 95% confidence intervals were estimated. STROBE reporting guidelines were followed. Results: We observed associations between hypospadias and prenatal HMHAP exposure. Manganese demonstrated significant increased risk of hypospadias at the medium, medium-high and high exposure quintiles; lead in the medium-high and high exposure quintiles. Cadmium, mercury and nickel demonstrated a significant inverted “U-shaped” association for exposures with significant associations in the medium and medium-high quintiles but not in the medium-low and high quintiles. Arsenic and chromium demonstrated a significant bivalent association for risk of hypospadias in a lower quintile as well as a higher quintile with non-significant intermediate quintiles. Conclusions: Using data from one of the world’s largest active surveillance birth defects registries, we identified significant associations between hypospadias and HMHAP exposures. These results should be used in counseling for maternal demographic risk factors as well as avoidance of heavy metals and their sources.

Purpose: To correlate sonographic renal parenchymal measurements among patients with ureteropelvic junction obstruction (UPJO) labeled Society of Fetal Urology (SFU) hydronephrosis grades 1 to 4 and to examine whether sonographic renal parenchymal measurements could be used to differentiate conservative versus surgical management. Materials and Methods: Retrospective chart review and sonographic renal parenchymal measurements (renal length, medullary pyramid thickness, and renal parenchymal thickness ) were performed in patients with SFU grades 1 to 4 hydronephrosis secondary to UPJO managed between 2009 and 2014. Exclusion criteria included other concomitant genitourinary pathology or incomplete follow-up. Anterior-posterior renal pelvic diameter (APRPD) and radionuclide renography were also evaluated when available. Results: 104 patient with ureteropelvic junction obstruction underwent 244 RBUS (1,464 sonographic renal parenchymal measurements in 488 kidneys). Medullary pyramid thickness and renal parenchymal thickness progressively decreased from SFU grades 1 to 4 (p<0.05). A similar trend was appreciated when comparing SFU grades 1 and 2 vs. 3 and 4, as well as SFU grades 3 vs. 4 (p<0.05). SFU grade 3 and 4 patients who underwent pyeloplasty had longer renal length in comparison to those who were managed conservatively (p<0.02). Conclusions: This is the first study that evaluates these objective, quantifiable sonographic renal parenchymal measurements in children with unilateral UPJO. These sonographic renal parenchymal measurements correlate closely with worsening of hydronephrosis graded by the SFU and APRPD classification systems. Prospective studies are needed to elucidate the role of sonographic renal parenchymal measurements in the management of children with UPJO. □