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.

Background Hypertension and cardiovascular disease are common in children undergoing dialysis. Studies suggest that hemodiafiltration (HDF) may reduce cardiovascular mortality in adults, but data for children are scarce. Methods The HDF, Heart and Height study is a nonrandomized observational study comparing outcomes on conventional hemodialysis (HD) versus postdilution online HDF in children. Primary outcome measures were annualized changes in carotid intima-media thickness (cIMT) SD score and height SD score. Results We enrolled 190 children from 28 centers; 78 on HD and 55 on HDF completed 1-year follow-up. The groups were comparable for age, dialysis vintage, access type, dialysis frequency, blood flow, and residual renal function. At 1 year, cIMT SD score increased significantly in children on HD but remained static in the HDF cohort. On propensity score analysis, HD was associated with a +0.47 higher annualized cIMT SD score compared with HDF. Height SD score increased in HDF but remained static in HD. Mean arterial pressure SD score increased with HD only. Factors associated with higher cIMT and mean arterial pressure SD-scores were HD group, higher ultrafiltration rate, and higher b2-microglobulin. The HDF cohort had lower b2-microglobulin, parathyroid hormone, and high-sensitivity C-reactive protein at 1 year; fewer headaches, dizziness, or cramps; and shorter postdialysis recovery time. Conclusions HDF is associated with a lack of progression in vascular measures versus progression with HD, as well as an increase in height not seen in the HD cohort. Patient-related outcomes improved among children on HDF correlating with improved BP control and clearances. Confirmation through randomized trials is required.

The aim of our study was to determine the outcome of children with severe Henoch-Schönlein nephritis (HSN) and immunoglobulin A (IgA) nephritis (IgAN) treated with early plasmapheresis alone. Children with acute renal impairment, heavy proteinuria or both and histology greater than grade 3 were treated with early plasmapheresis alone. Glomerular filtration rate (GFR) estimated from plasma creatinine (eGFR), urine albumin:creatinine ratio (UA/UC) and blood pressure 2 weeks after treatment and were measured at the last follow-up. Sixteen children (14 HSN, 2 IgAN) had a mean eGFR of 56 (17-136) ml/min per 1.73 m2 and UA/UC of 590 (12-1,379) mg/mmol. Fifteen were referred at presentation and one after 2 months, and all commenced plasmapheresis within 6 (2-13) days. All had at least nine exchanges of 90 ml/kg over 2 weeks. At 2 weeks, the eGFR had increased by 51 (95% CI 34-68; P=0.002), and the UA/UC fell by 457 (95% CI 241-673; P=0.0001). At last review after 4 (1-7.5) years, the late-referred child had required a renal transplant but the other 15 had normal eGFRs (98-142), did not require hypotensive medication, and had normal or minimally elevated UA/UC (maximum 42). Children with severe HSN and IgAN recover well if treated with plasmapheresis alone without the need for immunosuppressive therapy. A randomised trial is needed.

This retrospective study investigated the outcome of 27 children (19 male) with Henoch-Schönlein purpura nephritis (HSN) of International Study of Kidney Disease in Children (ISKDC) grade 3b or higher treated with long-term immunosuppressive therapy in a single centre over a 10-year period. The mean age at presentation was 9.7 years. The median estimated glomerular filtration rate (eGFR) was 91.3 ml/min per 1.73 m(2), with the median urine protein creatinine ratio (UP:UC) 556 mg/mmol. The treatment protocol comprised daily steroids and cyclophosphamide for 8-12 weeks followed by azathioprine and a reducing regimen of alternate-day steroids for 8-12 months. After a mean follow-up period of 7 years following presentation, 37% made a complete recovery, 40.7% had persistent proteinuria, 7.4% had persistent proteinuria and were on antihypertensive therapy and 14.8% had progressed to end-stage kidney failure (ESKF). Children with poor outcome were older at presentation (p 0.005), had more crescents (p 0.015) and had heavier proteinuria 6 months post initial biopsy (p 0.023). All of the four children with ESKF had nephrotic range proteinuria and greater than 50% crescents on initial biopsy. Despite long-term immunosuppression, the majority of children with HSN grade 3b or higher will have persistent renal abnormalities on long-term follow-up.

Background: Gitelman syndrome (GS) is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. GS is caused by biallelic pathogenic variants in SLC12A3, encoding the Na+-Cl- cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of CLCNKB, HNF1B, FXYD2, or KCNJ10 may result in the same renal phenotype of GS, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a GS phenotype, the genotype is unknown. Methods: We identified mitochondrial DNA (mtDNA) variants in three families with GS-like electrolyte abnormalities, then investigated 156 families for variants in MT-TI and MT-TF, which encode the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. Mitochondrial dysfunction was induced In NCC-expressing HEK293 cells to assess the effect on thiazide-sensitive 22Na+ transport. Results: Genetic investigations revealed four mtDNA variants in 13 families: m.591C>T (n=7), m.616T>C (n=1), m.643A>G (n=1) (all in MT-TF) and m.4291T>C (n=4, in MT-TI). Variants were near homoplasmic in affected individuals. All variants were classified as pathogenic, except for m.643A>G, which was classified as a variant of uncertain significance. Importantly, affected members of six families with an MT-TF variant additionally suffered from progressive chronic kidney disease. Dysfunction of oxidative phosphorylation complex IV reduced maximal mitochondrial respiratory capacity in patient fibroblasts. In vitro pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake. Conclusion: Pathogenic mtDNA variants in MT-TF and MT-TI can cause a GS-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained GS-like tubulopathies.