INTRODUCTION: Hepatocyte nuclear factor 1-beta (HNF1B) gene variants or the chromosome 17q12 deletion (17q12del) represent the most common monogenic cause of developmental kidney disease. Although neurodevelopmental disorders have been associated with the 17q12del, specific genotype-phenotype associations with respect to kidney function evolution have not yet been fully defined. Here, we aimed to determine whether 17q12del or specific HNF1B variants were associated with kidney survival in a large patient population with HNF1B disease. METHODS: This was a retrospective observational study involving 521 patients with HNF1B disease from 14 countries using the European Reference Network for rare kidney diseases with detailed information on the HNF1B genotype (HNF1B variants or the 17q12del). Median follow-up time was 11 years with 6 visits per patient. The primary end point was progression to chronic kidney disease (CKD) stage 3 (estimated glomerular filtration rate [eGFR] < 60 ml/min per 1.73 m2). Secondary end points were the development of hypomagnesemia or extrarenal disorders, including hyperuricemia and hyperglycemia. RESULTS: Progression toward CKD stage 3 was significantly delayed in patients with the 17q12del compared to patients with HNF1B variants (hazard ratio [HR]: 0.29, 95% confidence interval [CI]: 0.19-0.44, P < 0.001). Progression toward CKD stage 3 was also significantly delayed when HNF1B variants involved the HNF1B Pit-1, Oct-1, and Unc-86 homeodomain (POUh) DNA-binding and transactivation domains rather than the POU-specific domain (POUs) DNA-binding domain (HR: 0.15 [95% CI: 0.06-0.37), P < 0.001 and HR: 0.25 (95% CI: 0.11-0.57), P = 0.001, respectively). Finally, the 17q12del was positively associated with hypomagnesemia and negatively associated with hyperuricemia, but not with hyperglycemia. CONCLUSION: Patients with the 17q12del display a significantly better kidney survival than patients with other HNF1B variants; and for the latter, variants in the POUs DNA-binding domain lead to the poorest kidney survival. These are clinically relevant HNF1B kidney genotype-phenotype correlations that inform genetic counseling.

• Publikační typ
• časopisecké články MeSH

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10-12) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10-14), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10-103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10-49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10-93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10-23 and OR = 3.39, P = 5.2 × 10-82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk.

• MeSH
• alely MeSH
• Asijci genetika   MeSH
• běloši genetika   MeSH
• celogenomová asociační studie * MeSH
• interferonové regulační faktory genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• membranózní glomerulonefritida diagnóza   genetika   imunologie   MeSH
• molekulární modely MeSH
• NF-kappa B - podjednotka p50 genetika   MeSH
• receptory pro fosfolipasy A2 genetika   MeSH
• sekvence aminokyselin MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Management of children with congenital nephrotic syndrome (CNS) is challenging. Bilateral nephrectomies followed by dialysis and transplantation are practiced in most centres, but conservative treatment may also be effective. METHODS: We conducted a 6-year review across members of the European Society for Paediatric Nephrology Dialysis Working Group to compare management strategies and their outcomes in children with CNS. RESULTS: Eighty children (50% male) across 17 tertiary nephrology units in Europe were included (mutations in NPHS1, n = 55; NPHS2, n = 1; WT1, n = 9; others, n = 15). Excluding patients with mutations in WT1, antiproteinuric treatment was given in 42 (59%) with an increase in S-albumin in 70% by median 6 (interquartile range: 3-8) g/L (P < 0.001). Following unilateral nephrectomy, S-albumin increased by 4 (1-8) g/L (P = 0.03) with a reduction in albumin infusion dose by 5 (2-9) g/kg/week (P = 0.02). Median age at bilateral nephrectomies (n = 29) was 9 (7-16) months. Outcomes were compared between two groups of NPHS1 patients: those who underwent bilateral nephrectomies (n = 25) versus those on conservative management (n = 17). The number of septic or thrombotic episodes and growth were comparable between the groups. The response to antiproteinuric treatment, as well as renal and patient survival, was independent of NPHS1 mutation type. At final follow-up (median age 34 months) 20 (80%) children in the nephrectomy group were transplanted and 1 died. In the conservative group, 9 (53%) remained without dialysis, 4 (24%; P < 0.001) were transplanted and 2 died. CONCLUSION: An individualized, stepwise approach with prolonged conservative management may be a reasonable alternative to early bilateral nephrectomies and dialysis in children with CNS and NPHS1 mutations. Further prospective studies are needed to define indications for unilateral nephrectomy.

• MeSH
• albuminy terapeutické užití   MeSH
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• membránové proteiny genetika   MeSH
• mutace MeSH
• nefrektomie * MeSH
• nefrologie metody   MeSH
• nefrotický syndrom genetika   chirurgie   terapie   MeSH
• pediatrie metody   MeSH
• předškolní dítě MeSH
• prospektivní studie MeSH
• proteinurie terapie   MeSH
• retrospektivní studie MeSH
• sepse komplikace   MeSH
• trombóza komplikace   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Geografické názvy
• Evropa MeSH

Publikace se zabývá aktuální léčbou a diagnózou X-vázané hypofosfatemické rachitidy. Půmocka odborníkům v péči o pacienty.

• MeSH
• biologická terapie metody   MeSH
• familiární hypofosfatemická rachitida diagnóza   terapie   MeSH
• konzervativní terapie metody   MeSH
• kosti a kostní tkáň patologie   MeSH
• léčivé přípravky MeSH
• ortopedické výkony metody   MeSH
• Publikační typ
• přehledy MeSH
• směrnice pro lékařskou praxi MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• ortopedie
• pediatrie

Nephronophthisis-related ciliopathies (NPHP-RC) are recessive diseases characterized by renal dysplasia or degeneration. We here identify mutations of DCDC2 as causing a renal-hepatic ciliopathy. DCDC2 localizes to the ciliary axoneme and to mitotic spindle fibers in a cell-cycle-dependent manner. Knockdown of Dcdc2 in IMCD3 cells disrupts ciliogenesis, which is rescued by wild-type (WT) human DCDC2, but not by constructs that reflect human mutations. We show that DCDC2 interacts with DVL and DCDC2 overexpression inhibits β-catenin-dependent Wnt signaling in an effect additive to Wnt inhibitors. Mutations detected in human NPHP-RC lack these effects. A Wnt inhibitor likewise restores ciliogenesis in 3D IMCD3 cultures, emphasizing the importance of Wnt signaling for renal tubulogenesis. Knockdown of dcdc2 in zebrafish recapitulates NPHP-RC phenotypes, including renal cysts and hydrocephalus, which is rescued by a Wnt inhibitor and by WT, but not by mutant, DCDC2. We thus demonstrate a central role of Wnt signaling in the pathogenesis of NPHP-RC, suggesting an avenue for potential treatment of NPHP-RC.

• MeSH
• adaptorové proteiny signální transdukční genetika   metabolismus   MeSH
• beta-katenin antagonisté a inhibitory   metabolismus   MeSH
• buňky NIH 3T3 MeSH
• cilie genetika   patologie   MeSH
• cystická onemocnění ledvin genetika   MeSH
• dánio pruhované genetika   MeSH
• exony MeSH
• fenotyp MeSH
• fosfoproteiny genetika   metabolismus   MeSH
• HEK293 buňky MeSH
• ledviny patologie   MeSH
• lidé MeSH
• mutace MeSH
• myši MeSH
• proteiny asociované s mikrotubuly genetika   metabolismus   MeSH
• signální dráha Wnt genetika   MeSH
• transmisní elektronová mikroskopie MeSH
• výpočetní biologie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Electrolyte disorders can result in life-threatening complications. The kidneys are tasked with maintaining electrolyte homoeostasis, yet the low glomerular filtration rate of neonatal kidneys, tubular immaturity, and high extrarenal fluid losses contribute to increased occurrence of electrolyte disorders in neonates. Understanding the physiologic basis of renal electrolyte handling is crucial in identifying underlying causes and initiation of proper treatment. This article reviews key aspects of renal physiology, the diagnostic workup of disorders of plasma sodium and potassium, and the appropriate treatment, in addition to inherited disorders associated with neonatal electrolyte disturbances that illuminate the physiology of renal electrolyte handling.

• MeSH
• hodnoty glomerulární filtrace MeSH
• ledviny metabolismus   patofyziologie   MeSH
• lidé MeSH
• nemoci ledvin etiologie   metabolismus   patofyziologie   MeSH
• novorozenec MeSH
• vodní a elektrolytová nerovnováha komplikace   metabolismus   MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH