Genetic Testing and FOX News

Genetic testing is transforming kidney care, arguably with similar impact as the adoption of kidney biopsies in the 1950s. It is incumbent on nephrologists to teach the genetics of kidney disease and the accessibility of genetic testing. Proper usage of genetic testing can avoid “diagnostic odysseys” with multiple nonspecific investigations, some of them invasive like a kidney biopsy and repeated consultations with multiple different specialists [1]

Segment-specific expression of 2P domain potassium channel genes in human nephron.

BackgroundThe 2P domain potassium (K2P) channels are a recently discovered ion channel superfamily. Structurally, K2P channels are distinguished by the presence of two pore forming loops within one channel subunit. Functionally, they are characterized by their ability to pass potassium across the physiologic voltage range. Thus, K2P channels are also called open rectifier, background, or leak potassium channels. Patch clamp studies of renal tubules have described several open rectifier potassium channels that have as yet eluded molecular identification. We sought to determine the segment-specific expression of transcripts for the 14 known K2P channel genes in human nephron to identify potential correlates of native leak channels.MethodsHuman kidney samples were obtained from surgical cases and specific nephron segments were dissected. RNA was extracted and used as template for the generation of cDNA libraries. Real-time polymerase chain reaction (PCR) (TaqMan) was used to analyze gene expression.ResultsWe found significant (P < 0.05) expression of K2P10 in glomerulus, K2P5 in proximal tubule and K2P1 in cortical thick ascending limb of Henle's loop (cTAL) and in distal nephron segments. In addition, we repeatedly detected message for several other K2P channels with less abundance, including K2P3 and K2P6 in glomerulus, K2P10 in proximal tubule, K2P5 in thick ascending limb of Henle's loop, and K2P3, K2P5, and K2P13 in distal nephron segments.ConclusionK2P channels are expressed in specific segments of human kidney. These results provide a step toward assigning K2P channels to previously described native renal leaks

The pathophysiology of distal renal tubular acidosis

The kidneys have a central role in the control of acid-base homeostasis owing to bicarbonate reabsorption and production of ammonia and ammonium in the proximal tubule and active acid secretion along the collecting duct. Impaired acid excretion by the collecting duct system causes distal renal tubular acidosis (dRTA), which is characterized by the failure to acidify urine below pH 5.5. This defect originates from reduced function of acid-secretory type A intercalated cells. Inherited forms of dRTA are caused by variants in SLC4A1, ATP6V1B1, ATP6V0A4, FOXI1, WDR72 and probably in other genes that are yet to be discovered. Inheritance of dRTA follows autosomal-dominant and -recessive patterns. Acquired forms of dRTA are caused by various types of autoimmune diseases or adverse effects of some drugs. Incomplete dRTA is frequently found in patients with and without kidney stone disease. These patients fail to appropriately acidify their urine when challenged, suggesting that incomplete dRTA may represent an intermediate state in the spectrum of the ability to excrete acids. Unrecognized or insufficiently treated dRTA can cause rickets and failure to thrive in children, osteomalacia in adults, nephrolithiasis and nephrocalcinosis. Electrolyte disorders are also often present and poorly controlled dRTA can increase the risk of developing chronic kidney disease

Burosumab in management of X-linked hypophosphataemia: a retrospective cohort study of growth and serum phosphate levels

BACKGROUND: Burosumab, an antifibroblast growth factor 23 monoclonal antibody, improves rickets severity, symptoms and growth in children with X-linked hypophosphataemia (XLH) followed up to 64 weeks in clinical trials. International dosing guidance recommends targeting normal serum phosphate concentration; however, some children may not achieve this despite maximal dosing. This study compares clinical outcomes in children with XLH on long-term burosumab treatment who achieved normal phosphate versus those who did not. METHODS: Single-centre retrospective review of a large paediatric cohort with XLH treated with burosumab. We evaluated growth and biochemical markers of bone health in those who did compared with those who did not achieve normal plasma phosphate concentration. RESULTS: Fifty-five children with XLH with median age of 11.7 (IQR 6.8-15.5) years were included. 27 (49%) had low plasma phosphate concentration, and 27 (49%) had normal phosphate after a median burosumab treatment duration of 3.3 (IQR 2.6-3.7) years. 1 (2%) did not have a recent phosphate level recorded. No difference in growth was found between normal and abnormal phosphate groups (p=0.9). CONCLUSIONS: Young children with XLH experience sustained growth on long-term burosumab treatment, although without normal plasma phosphate concentration in many. Consideration should be made to changing burosumab dosing recommendations to target normalisation of alkaline phosphatase, as opposed to plasma phosphate concentration

Analysis of photocatalytic reactors employing the photonic efficiency and the removal efficiency parameters: degradation of radiation absorbing and nonabsorbing pollutants.

The photocatalytic degradation of radiation absorbing and nonabsorbing pollutants in slurry reactors is analyzed in terms of two performance parameters: the observed photonic efficiency (OPE) and the remoVal efficiency (RE) [Sagawe et al. Chem. Eng. Sci. 2003, 58, 2587]. The OPE proposal permits a simpe approach to analyze complex reacting systems. Conversely, to calculate the RE, the modeling of radiation absorption and scattering inside the reactors is necessary, which requires the determination of the optical properties of the catalyst and the modeling of the optical effects of the reactor walls. The degradation of dichloroacetic acid, phenol, and 4-nitrophenol was studied employing aeroxide TiO2 P25 from Evonik-Degussa in well-mixed batch reactors irradiated by UV lamps. 4-Nitrophenol has the particular characteristic to compete with titania for the absorption of photons in the employed wavelength range of irradiation. Two reaction kinetics proposals were considered to interpret experimental data: a ?photocatalytic? Langmuir-Hinshelwood model (the L-HPh model) and a ?photocatalytic? Langmuir-Hinshelwood linear model (the L-HPh/1 model). The good agreement observed between experimental results and model simulations confirms the usefulness of the proposed OPE approximation and the more accurate information provided by the RE performance parameter. The inclusion of 4-nitrophenol allowed inference of the situation that would be encountered when treating real samples contaminated with strong radiation absorbing compounds.Fil: Sagawe, Gerd. Leibniz Universitat Hannover; AlemaniaFil: Satuf, María Lucila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Brandi, Rodolfo Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Muschner, Jan P.. Leibniz Universitat Hannover; AlemaniaFil: Federer, Christian. Leibniz Universitat Hannover; AlemaniaFil: Alfano, Orlando Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; ArgentinaFil: Bockenhauer, Detlef. Leibniz Universitat Hannover; AlemaniaFil: Cassano, Alberto Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; Argentin

Consensus Expert Recommendations for the Diagnosis and Management of Autosomal Recessive Polycystic Kidney Disease: Report of an International Conference

Autosomal recessive polycystic kidney disease (ARPKD; MIM 263200) is a severe, typically early onset form of cystic disease that primarily involves the kidneys and biliary tract. Phenotypic expression and age at presentation can be quite variable1. The incidence of ARPKD is 1 in 20,000 live births2, and its pleotropic manifestations are potentially life-threatening. Optimal care requires proper surveillance to limit morbidity and mortality, knowledgeable approaches to diagnosis and treatment, and informed strategies to optimize quality of life. Clinical management therefore is ideally directed by multidisciplinary care teams consisting of perinatologists, neonatologists, nephrologists, hepatologists, geneticists, and behavioral specialists to coordinate patient care from the perinatal period to adulthood. In May 2013, an international team of 25 multidisciplinary specialists from the US, Canada, Germany, and the United Kingdom convened in Washington, DC, to review the literature published from 1990 to 2013 and to develop recommendations for diagnosis, surveillance, and clinical management. Identification of the gene PKHD1, and the significant advances in perinatal care, imaging, medical management, and behavioral therapies over the past decade, provide the foundational elements to define diagnostic criteria and establish clinical management guidelines as the first steps towards standardizing the clinical care for ARPKD patients. The key issues discussed included recommendations regarding perinatal interventions, diagnostic criteria, genetic testing, management of renal and biliary-associated morbidities, and behavioral assessment. The meeting was funded by the National Institutes of Health and an educational grant from the Polycystic Kidney Disease Foundation. Here we summarize the discussions and provide an updated set of diagnostic, surveillance, and management recommendations for optimizing the pediatric care of patients with ARPKD. Specialist care of ARPKD-related complications including dialysis, transplantation, and management of severe portal hypertension will be addressed in a subsequent report. Given the paucity of information regarding targeted therapies in ARPKD, this topic was not addressed in this conference.

Genetic aspects of congenital nephrotic syndrome : a consensus statement from the ERKNet-ESPN inherited glomerulopathy working group

Congenital nephrotic syndrome (CNS) is a heterogeneous group of disorders presenting with massive proteinuria within the first 3 months of life almost inevitably leading to end-stage kidney disease. The Work Group for the European Reference Network for Kidney Diseases (ERKNet) and the European Society for Pediatric Nephrology (ESPN) has developed consensus statement on genetic aspects of CNS diagnosis and management. The presented expert opinion recommends genetic diagnostics as the key diagnostic test to be ordered already during the initial evaluation of the patient, discusses which phenotyping workup should be performed and presents known genotype-phenotype correlations.Peer reviewe

A Neanderthal haplotype introgressed into the human genome confers protection against membranous nephropathy

Class 2 HLA and PLA2R1 alleles are exceptionally strong genetic risk factors for membranous nephropathy (MN), leading, through an unknown mechanism, to a targeted autoimmune response. Introgressed archaic haplotypes (introduced from an archaic human genome into the modern human genome) might influence phenotypes through gene dysregulation. Here, we investigated the genomic region surrounding the PLA2R1 gene. We reconstructed the phylogeny of Neanderthal and modern haplotypes in this region and calculated the probability of the observed clustering being the result of introgression or common descent. We imputed variants for the participants in our previous genome-wide association study and we compared the distribution of Neanderthal variants between MN cases and controls. The region associated with the lead MN risk locus in the PLA2R1 gene was confirmed and showed that, within a 507 kb region enriched in introgressed sequence, a stringently defined 105 kb haplotype, intersecting the coding regions for PLA2R1 and ITGB6, is inherited from Neanderthals. Thus, introgressed Neanderthal haplotypes overlapping PLA2R1 are differentially represented in MN cases and controls, with enrichment In controls suggesting a protective effect