Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. A rare Mendelian syndrome, pseudohypoaldosteronism type II (PHAII), featuring hypertension, hyperkalemia, and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption versus K+ and H+ excretion1. We used exome sequencing to identify mutations in Kelch-like 3 (KLHL3) or Cullin 3 (CUL3) in 41 PHAII kindreds. KLHL3 mutations are either recessive or dominant, while CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-Kelch proteins such as KLHL3 are components of Cullin/RING E3 ligase complexes (CRLs) that ubiquitinate substrates bound to Kelch propeller domains2–8. Dominant KLHL3 mutations are clustered in short segments within the Kelch propeller and BTB domains implicated in substrate9 and Cullin5 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 (NCC) in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3/CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite combined complexities of locus heterogeneity, mixed models of transmission, and frequent de novo mutation, and establish a fundamental role for KLHL3/CUL3 in blood pressure, K+, and pH homeostasis.

As hypertensive target-organ damage has been associated with diminished diurnal blood pressure (BP) variation in adults, we compared diurnal BP patterns of hypertensive adolescents with left ventricular hypertrophy with normotensive and hypertensive adolescents with normal left ventricular mass. In addition, the frequency of microalbuminuria (Malb), hyperfiltration, and reduced renal functional reserve (RFR) was evaluated in adolescents with normal BP and untreated borderline and mild essential hypertension. Thirty-three normotensive (NT) adolescents, 14.5+/-2.1 years (mean +/- SD), and 29 untreated borderline and mildly hypertensive (HT) adolescents, 14.6+/-2.4 years, wore the SpaceLabs 90207 ambulatory BP monitor for 24 h. Left ventricular mass was measured by M-mode echocardiography and then indexed (LVMI) to the cube of height. Creatinine clearance (Clcr) and urine Malb was measured on 24 h collection and RFR by change in creatinine clearance after an oral protein load. Diurnal BP change was expressed as the absolute and percent day-night BP fall and cusum derived plot height (CPH) and circadian alteration magnitude (CDCAM). Groups were compared using analysis of covariance with adjustments for race, gender, and body mass index. All NT and 19 HT subjects (HT-1) had normal LVMI at 22.2+/-5.3 and 25.8+/-3.8 g/m3, respectively. Ten HT (HT-2) had increased LVMI of 36.9+/-5.2 g/m3. No significant difference was found for absolute or percent day-night BP fall or CDCAM between groups. Nocturnal systolic BP was correlated most closely with LVMI (r = 0.41, p = .001). Clcr, Malb, and RFR did not differ between the groups. In conclusion, adolescents with borderline and mild essential hypertension and left ventricular hypertrophy have similar levels of diurnal BP fall, urine Malb excretion, and RFR compared to normotensive and hypertensive adolescents with normal left ventricular mass.

There are limited data on the impact of COVID‐19 in children with a kidney transplant (KT). We conducted a prospective cohort study through the Improving Renal Outcomes Collaborative (IROC) to collect clinical outcome data about COVID‐19 in pediatric KT patients. Twenty‐two IROC centers that care for 2732 patients submitted testing and outcomes data for 281 patients tested for SARS‐CoV‐2 by PCR. Testing indications included symptoms and/or potential exposures to COVID‐19 ( N = 134, 47.7%) and/or testing per hospital policy ( N = 154, 54.8%). Overall, 24 (8.5%) patients tested positive, of which 15 (63%) were symptomatic. Of the COVID‐19‐positive patients, 16 were managed as outpatients, six received non‐ICU inpatient care and two were admitted to the ICU. There were no episodes of respiratory failure, allograft loss, or death associated with COVID‐19. To estimate incidence, subanalysis was performed for 13 centers that care for 1686 patients that submitted all negative and positive COVID‐19 results. Of the 229 tested patients at these 13 centers, 10 (5 asymptomatic) patients tested positive, yielding an overall incidence of 0.6% and an incidence among tested patients of 4.4%. Pediatric KT patients in the United States had a low estimated incidence of COVID‐19 disease and excellent short‐term outcomes.

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Atypical hemolytic uremic syndrome (aHUS) is a complex complement-mediated disease that progresses to end-stage renal failure (ESRF) in 50% of cases. Dysregulation of the alternative pathway (AP) of the complement cascade manifests as microangiopathic anaemia and thrombocytopenia. Multiple genes in the AP have been implicated in disease pathogenesis. Here, we report the clinical presentation of an affected patient that was inconsistent with genotype-phenotype data for carriers of CD46 mutations. Tests of AP function in this patient suggested additional genetic factors, and in-depth studies revealed a de novo heterozygous deletion that creates a novel CFH/CFHR1 fusion protein.

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