Craig C. Porter

Mutations in Kelch-like 3 and Cullin 3 cause hypertension and electrolyte abnormalities

Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K+ and H+ excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin–RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na–Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na–Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K+ and pH homeostasis.

Dialysis and pediatric acute kidney injury: choice of renal support modality

Dialytic intervention for infants and children with acute kidney injury (AKI) can take many forms. Whether patients are treated by intermittent hemodialysis, peritoneal dialysis or continuous renal replacement therapy depends on specific patient characteristics. Modality choice is also determined by a variety of factors, including provider preference, available institutional resources, dialytic goals and the specific advantages or disadvantages of each modality. Our approach to AKI has benefited from the derivation and generally accepted defining criteria put forth by the Acute Dialysis Quality Initiative (ADQI) group. These are known as the risk, injury, failure, loss, and end-stage renal disease (RIFLE) criteria. A modified pediatrics RIFLE (pRIFLE) criteria has recently been validated. Common defining criteria will allow comparative investigation into therapeutic benefits of different dialytic interventions. While this is an extremely important development in our approach to AKI, several fundamental questions remain. Of these, arguably, the most important are “When and what type of dialytic modality should be used in the treatment of pediatric AKI?” This review will provide an overview of the limited data with the aim of providing objective guidelines regarding modality choice for pediatric AKI. Comparisons in terms of cost, availability, safety and target group will be reviewed.

Ontogenic changes and regulation of renal angiotensin II type 1 receptor gene expression during fetal and newborn life.

ABSTRACT: Factors regulating the expression of the angiotensin II subtype 1 (AT1) receptor during fetal life have not been investigated previously. The present study was designed 1) to characterize the ontogeny of AT1 receptor gene expression in the kidney of fetal and newborn sheep and 2) to determine the influence of both glucocorticoids and renal nerves in modulating AT1 gene expression during fetal life and during the transition from fetal to newborn life. We first isolated and cloned a PCR product that has 98 and 94% homology with the cDNA encoding the bovine and pig AT1 receptors, respectively, and 99 and 98% homology with the corresponding deduced protein sequences. Probing with this cDNA, we demonstrated that renal AT1 mRNA expression did not change significantly during the last trimester of gestation in fetal sheep or immediately after birth but decreased significantly 10 d after birth. We also demonstrated that renal denervation in the fetus had no effect on renal AT1 gene expression in 24-h-old newborn lambs. On the other hand, we observed in 130-d twin fetuses that continuous intraperitoneal infusion (1 mL/h) of cortisol (3 mg/h or 6.2 μmol/h) for 48 h in one of the twins increased the fetal plasma cortisol concentration from 32.0 ± 7.1 to 1126 ± 231 nmol/L and produced a significant decrease (p<0.005) in renal AT1 gene expression compared with the control twin receiving an intraperitoneal infusion of 0.9% NaCl. In summary, this study demonstrates that renal AT1gene expression is elevated during fetal life and decreases after birth. It is also shown that glucocorticoids, but not renal nerves, contribute to the regulation of renal AT1 gene expression during development.

Hemolytic-uremic syndrome: a population-based study in Washington, DC and Baltimore, Maryland.

A population-based study of hemolytic-uremic syndrome (HUS) revealed that 20 child residents of Washington, DC and Baltimore, Maryland were hospitalized with HUS from January 1979 through September 1983. The number of cases peaked during the summer and fall; none occurred during the winter. Incidence of hospitalized cases was higher in Whites and girls than in Blacks or boys, and the average annual incidence was 1.08 cases/100,000 children less than 5 year old. This study demonstrates that HUS is not unique to the West Coast, as previously suggested.

Developmental Regulation of the |[alpha]|1B-Adrenoceptor in the Sheep Kidney

ABSTRACT: The expression of renal α1B-adrenoceptor (α1B-AR) mRNA was studied and contrasted with the expression of renal renin mRNA in fetal and newborn sheep. Fetal sheep between 90 and 91, 116 and 118, and 139 and 141 d gestation (term is 145 d gestation) as well as newborn lambs between 1 and 2 d old and 8 and 10 d old were studied (n = 3 for each age range). The role of the renal nerves in regulating changes in α1B-AR gene expression was also investigated by measuring renal cortical α1B-AR mRNA levels and receptor kd and maximum number of binding sites in 24-h-old lambs that were either denervated (n = 6) or sham-operated (n = 5) 3 d before birth. During development, renal α1B-AR mRNA levels show a marked increase in term fetuses; this increase persists into the first 2 d of life and is distinct from the developmental pattern seen for renal renin mRNA levels. Denervation of term fetuses does not alter the expression of renal α1B-AR mRNA in newborn lambs when compared with sham-operated controls but decreases significantly the expression of the renin gene (p < 0.05). These results suggest that the α1B-AR gene is developmentally regulated in the kidney in a pattern distinct from that seen for renin. Furthermore, the renal nerves, which play an important role in the regulation of renin gene expression at the time of birth, do not appear to be an important factor in the regulation of the α1B-AR during the maturation from fetal to newborn life.

Accelerated recovery from immune-mediated thrombocytopenia with plasmapheresis

Autoimmune thrombocytopenia unresponsive to corticosteroid therapy developed in a 16-year-old female with long-standing Sjögrens syndrome. Serial plasma exchange caused a linear decrease in platelet antibody titer associated with a concomitant rise in platelet count. Statistical analysis of sequential platelet counts revealed an increase with plasmapheresis and immunosuppression that was significantly greater than that achieved with immunosuppression alone (p less than 0.005).