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  • A New Criterion for Pediatric AKI Based on the Reference Change Value of Serum Creatinine
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-09-01
    Xin Xu; Sheng Nie; Aihua Zhang; Mao Jianhua; Hai-Peng Liu; Huimin Xia; Hong Xu; Zhangsuo Liu; Shipin Feng; Wei Zhou; Xuemei Liu; Yonghong Yang; Yuhong Tao; Yunlin Feng; Chunbo Chen; Mo Wang; Yan Zha; Jian-Hua Feng; Qingchu Li; Shuwang Ge; Jianghua Chen; Yongcheng He; Siyuan Teng; Chuanming Hao; Bi-Cheng Liu; Ying Tang; Li-Jun Wang; Jin-Lei Qi; Wenjuan He; Pinghong He; Youhua Liu; Fan Fan Hou

    Background Current definitions of AKI do not take into account serum creatinine’s high variability in children. Methods We analyzed data from 156,075 hospitalized children with at least two creatinine tests within 30 days. We estimated reference change value (RCV) of creatinine on the basis of age and initial creatinine level in children without kidney disease or known AKI risk, and we used these data to develop a model for detecting pediatric AKI on the basis of RCV of creatinine. We defined pediatric AKI according to pediatric reference change value optimized for AKI in children (pROCK) as creatinine increase beyond RCV of creatinine, which was estimated as the greater of 20 μmol/L or 30% of the initial creatinine level. Results Of 102,817 children with at least two serum creatinine tests within 7 days, 5432 (5.3%) had AKI as defined by pROCK compared with 15,647 (15.2%) and 10,446 (10.2%) as defined by pediatric RIFLE (pRIFLE) and Kidney Disease Improving Global Outcomes (KDIGO), respectively. Children with pROCK-defined AKI had significantly increased risk of death (hazard ratio, 3.56; 95% confidence interval, 3.15 to 4.04) compared with those without AKI. About 66% of patients with pRIFLE-defined AKI and 51% of patients with KDIGO-defined AKI, mostly children with initial creatinine level of <30 μmol/L, were reclassified as non-AKI by pROCK, and mortality risk in these children was comparable with risk in those without AKI by all definitions. Conclusions pROCK criterion improves detection of “true” AKI in children compared with earlier definitions that may lead to pediatric AKI overdiagnosis.

    更新日期:2018-09-01
  • Noninvasive Immunohistochemical Diagnosis and Novel MUC1 Mutations Causing Autosomal Dominant Tubulointerstitial Kidney Disease
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-09-01
    Martina Živná; Kendrah Kidd; Anna Přistoupilová; Veronika Barešová; Mathew DeFelice; Brendan Blumenstiel; Maegan Harden; Peter Conlon; Peter Lavin; Dervla M. Connaughton; Hana Hartmannová; Kateřina Hodaňová; Viktor Stránecký; Alena Vrbacká; Petr Vyleťal; Jan Živný; Miroslav Votruba; Jana Sovová; Helena Hůlková; Victoria Robins; Rebecca Perry; Andrea Wenzel; Bodo B. Beck; Tomáš Seeman; Ondřej Viklický; Sylvie Rajnochová-Bloudíčková; Gregory Papagregoriou; Constantinos C. Deltas; Seth L. Alper; Anna Greka; Anthony J. Bleyer; Stanislav Kmoch

    Background Autosomal dominant tubulointerstitial kidney disease caused by mucin-1 gene (MUC1) mutations (ADTKD-MUC1) is characterized by progressive kidney failure. Genetic evaluation for ADTKD-MUC1 specifically tests for a cytosine duplication that creates a unique frameshift protein (MUC1fs). Our goal was to develop immunohistochemical methods to detect the MUC1fs created by the cytosine duplication and, possibly, by other similar frameshift mutations and to identify novel MUC1 mutations in individuals with positive immunohistochemical staining for the MUC1fs protein. Methods We performed MUC1fs immunostaining on urinary cell smears and various tissues from ADTKD-MUC1–positive and –negative controls as well as in individuals from 37 ADTKD families that were negative for mutations in known ADTKD genes. We used novel analytic methods to identify MUC1 frameshift mutations. Results After technique refinement, the sensitivity and specificity for MUC1fs immunostaining of urinary cell smears were 94.2% and 88.6%, respectively. Further genetic testing on 17 families with positive MUC1fs immunostaining revealed six families with five novel MUC1 frameshift mutations that all predict production of the identical MUC1fs protein. Conclusions We developed a noninvasive immunohistochemical method to detect MUC1fs that, after further validation, may be useful in the future for diagnostic testing. Production of the MUC1fs protein may be central to the pathogenesis of ADTKD-MUC1.

    更新日期:2018-09-01
  • Association of Ambulatory Blood Pressure with All-Cause and Cardiovascular Mortality in Hemodialysis Patients: Effects of Heart Failure and Atrial Fibrillation
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-09-01
    Christopher C. Mayer; Julia Matschkal; Pantelis A. Sarafidis; Stefan Hagmair; Georg Lorenz; Susanne Angermann; Matthias C. Braunisch; Marcus Baumann; Uwe Heemann; Siegfried Wassertheurer; Christoph Schmaderer

    Background Evidence on the utility of ambulatory BP monitoring for risk prediction has been scarce and inconclusive in patients on hemodialysis. In addition, in cardiac diseases such as heart failure and atrial fibrillation (common among patients on hemodialysis), studies have found that parameters such as systolic BP (SBP) and pulse pressure (PP) have inverse or nonlinear (U-shaped) associations with mortality. Methods In total, 344 patients on hemodialysis (105 with atrial fibrillation, heart failure, or both) underwent ambulatory BP monitoring for 24 hours, starting before a dialysis session. The primary end point was all-cause mortality; the prespecified secondary end point was cardiovascular mortality. We performed linear and nonlinear Cox regression analyses for risk prediction to determine the associations between BP and study end points. Results During the mean 37.6-month follow-up, 115 patients died (47 from a cardiovascular cause). SBP and PP showed a U-shaped association with all-cause and cardiovascular mortality in the cohort. In linear subgroup analysis, SBP and PP were independent risk predictors and showed a significant inverse relationship to all-cause and cardiovascular mortality in patients with atrial fibrillation or heart failure. In patients without these conditions, these associations were in the opposite direction. SBP and PP were significant independent risk predictors for cardiovascular mortality; PP was a significant independent risk predictor for all-cause mortality. Conclusions This study provides evidence for the U-shaped association between peripheral ambulatory SBP or PP and mortality in patients on hemodialysis. Furthermore, it suggests that underlying cardiac disease can explain the opposite direction of associations.

    更新日期:2018-09-01
  • Acute Declines in Renal Function during Intensive BP Lowering and Long-Term Risk of Death
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-09-01
    Elaine Ku; Joachim H. Ix; Kenneth Jamerson; Navdeep Tangri; Feng Lin; Jennifer Gassman; Miroslaw Smogorzewski; Mark J. Sarnak

    Background During intensive BP lowering, acute declines in renal function are common, thought to be hemodynamic, and potentially reversible. We previously showed that acute declines in renal function ≥20% during intensive BP lowering were associated with higher risk of ESRD. Here, we determined whether acute declines in renal function during intensive BP lowering were associated with mortality risk among 1660 participants of the African American Study of Kidney Disease and Hypertension and the Modification of Diet in Renal Disease Trial. Methods We used Cox models to examine the association between percentage decline in eGFR (<5%, 5% to <20%, or ≥20%) between randomization and months 3–4 of the trials (period of therapy intensification) and death. Results In adjusted analyses, compared with a <5% eGFR decline in the usual BP arm (reference), a 5% to <20% eGFR decline in the intensive BP arm was associated with a survival benefit (hazard ratio [HR], 0.77; 95% confidence interval [95% CI], 0.62 to 0.96), but a 5% to <20% eGFR decline in the usual BP arm was not (HR, 1.01; 95% CI, 0.81 to 1.26; P<0.05 for the interaction between intensive and usual BP arms for mortality risk). A ≥20% eGFR decline was not associated with risk of death in the intensive BP arm (HR, 1.18; 95% CI, 0.86 to 1.62), but it was associated with a higher risk of death in the usual BP arm (HR, 1.40; 95% CI, 1.04 to 1.89) compared with the reference group. Conclusions Intensive BP lowering was associated with a mortality benefit only if declines in eGFR were <20%.

    更新日期:2018-09-01
  • Race, Ethnicity, and End-of-Life Care in Dialysis Patients in the United States
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-09-01
    Robert N. Foley; Donal J. Sexton; Paul Drawz; Areef Ishani; Scott Reule

    Background End-of-life care is a prominent consideration in patients on maintenance dialysis, especially when death appears imminent and quality of life is poor. To date, examination of race- and ethnicity-associated disparities in end-of-life care for patients with ESRD has largely been restricted to comparisons of white and black patients. Methods We performed a retrospective national study using United States Renal Data System files to determine whether end-of-life care in United States patients on dialysis is subject to racial or ethnic disparity. The primary outcome was a composite of discontinuation of dialysis and death in a nonhospital or hospice setting. Results Among 1,098,384 patients on dialysis dying between 2000 and 2014, the primary outcome was less likely in patients from any minority group compared with the non-Hispanic white population (10.9% versus 22.6%, P<0.001, respectively). We also observed similar significant disparities between any minority group and non-Hispanic whites for dialysis discontinuation (16.7% versus 31.2%), as well as hospice (10.3% versus 18.1%) and nonhospital death (34.4% versus 46.4%). After extensive covariate adjustment, the primary outcome was less likely in the combined minority group than in the non-Hispanic white population (adjusted odds ratio, 0.55; 95% confidence interval, 0.55 to 0.56; P<0.001). Individual minority groups (non-Hispanic Asian, non-Hispanic black, non-Hispanic Native American, and Hispanic) were significantly less likely than non-Hispanic whites to experience the primary outcome. This disparity was especially pronounced for non-Hispanic Native American and Hispanic subgroups. Conclusions There appear to be substantial race- and ethnicity-based disparities in end-of-life care practices for United States patients receiving dialysis.

    更新日期:2018-09-01
  • EGF Receptor–Dependent YAP Activation Is Important for Renal Recovery from AKI
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-09-01
    Jianchun Chen; Huaizhou You; Yan Li; You Xu; Qian He; Raymond C. Harris

    Background Increasing evidence indicates that renal recovery from AKI stems from dedifferentiation and proliferation of surviving tubule epithelial cells. Both EGF receptor (EGFR) and the Hippo signaling pathway are implicated in cell proliferation and differentiation, and previous studies showed that activation of EGFR in renal proximal tubule epithelial cells (RPTCs) plays a critical role in recovery from ischemia-reperfusion injury (IRI). In this study, we explored RPTC activation of Yes-associated protein (YAP) and transcriptional coactivator with PDZ binding motif (TAZ), two key downstream effectors of the Hippo pathway, and their potential involvement in recovery from AKI. Methods We used immunofluorescence to examine YAP expression in kidney biopsy samples from patients with clinical AKI and controls (patients with minimal change disease). Studies of RPTC activation of YAP and TAZ used cultured human RPTCs that were exposed to hypoxia-reoxygenation as well as knockout mice (with inducible deletions of Yap, Taz, or both occurring specifically in RPTCs) that were subjected to bilateral IRI. Results YAP was activated in RPTCs in kidneys from post-AKI patients and post-IRI mouse kidneys. Inhibition of the interaction of YAP and the TEA domain (TEAD) transcription factor complex by verteporfin or conditional deletion of YAP in RPTCs delayed renal functional and structural recovery from IRI, whereas TAZ deletion had no effect. Activation of the EGFR-PI3K-Akt pathway in response to IRI signaled YAP activation, which promoted cell cycle progression. Conclusions This study shows that EGFR-PI3K-Akt–dependent YAP activation plays an essential role in mediating epithelial cell regeneration during kidney recovery from AKI.

    更新日期:2018-09-01
  • Structural Basis of Highly Specific Interaction between Nephrin and MAGI1 in Slit Diaphragm Assembly and Signaling
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-09-01
    Zhuangfeng Weng; Yuan Shang; Zeyang Ji; Fei Ye; Lin Lin; Rongguang Zhang; Jinwei Zhu

    Background The slit diaphragm is a specialized adhesion junction between opposing podocytes, establishing the final filtration barrier that prevents passage of proteins from the capillary lumen into the urinary space. Nephrin, the key structural and signaling adhesion molecule expressed in the slit diaphragm, contains an evolutionally conserved, atypical PDZ-binding motif (PBM) reported to bind to a variety of proteins in the slit diaphragm. Several mutations in NPHS1 (the gene encoding nephrin) that result in nephrin lacking an intact PBM are associated with glomerular diseases. However, the molecular basis of nephrin-PBM–mediated protein complexes is still unclear. Methods Using a combination of biochemic, biophysic, and cell biologic approaches, we systematically investigated the interactions between nephrin-PBM and PDZ domain–containing proteins in the slit diaphragm. Results We found that nephrin-PBM specifically binds to one member of the membrane-associated guanylate kinase family of scaffolding proteins, MAGI1, but not to another, MAGI2. The complex structure of MAGI1-PDZ3/nephrin-PBM reveals that the Gly at the −3 position of nephrin-PBM is the determining feature for MAGI1-PDZ3 recognition, which sharply contrasts with the typical PDZ/PBM binding mode. A single gain-of-function mutation within MAGI2 enabled nephrin-PBM binding. In addition, using our structural analysis, we developed a highly efficient inhibitory peptide capable of specifically blocking the nephrin/MAGI1 interaction. Conclusions MAGI1 interacts with nephrin-PBM with exquisite specificity. A newly developed, potent inhibitory peptide that blocks this interaction may be useful for future functional investigations in vivo. Our findings also provide possible explanations for the diseases caused by NPHS1 mutations.

    更新日期:2018-09-01
  • Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-09-01
    Amelie T. van der Ven; Dervla M. Connaughton; Hadas Ityel; Nina Mann; Makiko Nakayama; Jing Chen; Asaf Vivante; Daw-yang Hwang; Julian Schulz; Daniela A. Braun; Johanna Magdalena Schmidt; David Schapiro; Ronen Schneider; Jillian K. Warejko; Ankana Daga; Amar J. Majmundar; Weizhen Tan; Tilman Jobst-Schwan; Tobias Hermle; Eugen Widmeier; Shazia Ashraf; Ali Amar; Charlotte A. Hoogstraaten; Hannah Hugo; Thomas M. Kitzler; Franziska Kause; Caroline M. Kolvenbach; Rufeng Dai; Leslie Spaneas; Kassaundra Amann; Deborah R. Stein; Michelle A. Baum; Michael J.G. Somers; Nancy M. Rodig; Michael A. Ferguson; Avram Z. Traum; Ghaleb H. Daouk; Radovan Bogdanović; Natasa Stajić; Neveen A. Soliman; Jameela A. Kari; Sherif El Desoky; Hanan M. Fathy; Danko Milosevic; Muna Al-Saffar; Hazem S. Awad; Loai A. Eid; Aravind Selvin; Prabha Senguttuvan; Simone Sanna-Cherchi; Heidi L. Rehm; Daniel G. MacArthur; Monkol Lek; Kristen M. Laricchia; Michael W. Wilson; Shrikant M. Mane; Richard P. Lifton; Richard S. Lee; Stuart B. Bauer; Weining Lu; Heiko M. Reutter; Velibor Tasic; Shirlee Shril; Friedhelm Hildebrandt

    Background Congenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12% of patients with CAKUT. Methods We applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT. Results In 29 families (13%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient’s CAKUT phenotype. In three families (1%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8%). Conclusions We identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.

    更新日期:2018-09-01
  • ABCC6 Deficiency Promotes Development of Randall Plaque
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-09-01
    Emmanuel Letavernier; Gilles Kauffenstein; Léa Huguet; Nastassia Navasiolava; Elise Bouderlique; Ellie Tang; Léa Delaitre; Dominique Bazin; Marta de Frutos; Clément Gay; Joëlle Perez; Marie-Christine Verpont; Jean-Philippe Haymann; Viola Pomozi; Janna Zoll; Olivier Le Saux; Michel Daudon; Georges Leftheriotis; Ludovic Martin

    Background Pseudoxanthoma elasticum (PXE) is a genetic disease caused by mutations in the ABCC6 gene that result in low pyrophosphate levels and subsequent progressive soft tissue calcifications. PXE mainly affects the skin, retina, and arteries. However, many patients with PXE experience kidney stones. We determined the prevalence of this pathology in patients with PXE and examined the possible underlying mechanisms in murine models. Methods We conducted a retrospective study in a large cohort of patients with PXE and analyzed urine samples and kidneys from Abcc6−/− mice at various ages. We used Yasue staining, scanning electron microscopy, electron microscopy coupled to electron energy loss spectroscopy, and Fourier transform infrared microspectroscopy to characterize kidney calcifications. Results Among 113 patients with PXE, 45 (40%) had a past medical history of kidney stones. Five of six computed tomography scans performed showed evidence of massive papillary calcifications (Randall plaques). Abcc6−/− mice spontaneously developed kidney interstitial apatite calcifications with aging. These calcifications appeared specifically at the tip of the papilla and formed Randall plaques similar to those observed in human kidneys. Compared with controls, Abcc6−/− mice had low urinary excretion of pyrophosphate. Conclusions The frequency of kidney stones and probably, Randall plaque is extremely high in patients with PXE, and Abcc6−/− mice provide a new and useful model in which to study Randall plaque formation. Our findings also suggest that pyrophosphate administration should be evaluated for the prevention of Randall plaque and kidney stones.

    更新日期:2018-09-01
  • Phosphorylation of Acetyl-CoA Carboxylase by AMPK Reduces Renal Fibrosis and Is Essential for the Anti-Fibrotic Effect of Metformin
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-09-01
    Mardiana Lee; Marina Katerelos; Kurt Gleich; Sandra Galic; Bruce E. Kemp; Peter F. Mount; David A. Power

    Background Expression of genes regulating fatty acid metabolism is reduced in tubular epithelial cells from kidneys with tubulointerstitial fibrosis (TIF), thus decreasing the energy produced by fatty acid oxidation (FAO). Acetyl-CoA carboxylase (ACC), a target for the energy-sensing AMP-activating protein kinase (AMPK), is the major controller of the rate of FAO within cells. Metformin has a well described antifibrotic effect, and increases phosphorylation of ACC by AMPK, thereby increasing FAO. Methods We evaluated phosphorylation of ACC in cell and mouse nephropathy models, as well as the effects of metformin administration in mice with and without mutations that reduce ACC phosphorylation. Results Reduced phosphorylation of ACC on the AMPK site Ser79 occurred in both tubular epithelial cells treated with folate to mimic cellular injury and in wild-type (WT) mice after induction of the folic acid nephropathy model. When this effect was exaggerated in mice with knock-in (KI) Ser to Ala mutations of the phosphorylation sites in ACC, lipid accumulation and fibrosis increased significantly compared with WT. The effect of ACC phosphorylation on fibrosis was confirmed in the unilateral ureteric obstruction model, which showed significantly increased lipid accumulation and fibrosis in the KI mice. Metformin use was associated with significantly reduced fibrosis and lipid accumulation in WT mice. In contrast, in the KI mice, the drug was associated with worsened fibrosis. Conclusions These data indicate that reduced phosphorylation of ACC after renal injury contributes to the development of TIF, and that phosphorylation of ACC is required for metformin’s antifibrotic action in the kidney.

    更新日期:2018-09-01
  • Interactions between Macrophages and Cyst-Lining Epithelial Cells Promote Kidney Cyst Growth in Pkd1-Deficient Mice
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-09-01
    Yang Yang; Meihan Chen; Jie Zhou; Jiayi Lv; Shuwei Song; LiLi Fu; Jiejian Chen; Ming Yang; Changlin Mei

    Background Autosomal-dominant polycystic kidney disease (ADPKD) is the leading inherited renal disease worldwide. The proproliferative function of macrophages is associated with late-stage cyst enlargement in mice with PKD; however, the way in which macrophages act on cyst-lining epithelial cells (CLECs) has not been well elucidated. Methods We generated a rapid-onset PKD mouse model by inactivating Pkd1 on postnatal day 10 (P10) and compared cell proliferation and differential gene expression in kidney tissues of the PKD mice and wild-type (WT) littermates. Results The cystic phenotype was dominant from P18. A distinct peak in cell proliferation in polycystic kidneys during P22–P30 was closely related to late-stage cyst growth. Comparisons of gene expression profiles in kidney tissues at P22 and P30 in PKD and WT mice revealed that arginine metabolism was significantly activated; 204 differentially expressed genes (DEGs), including Arg1, an arginine metabolism–associated gene, were identified in late-stage polycystic kidneys. The Arg1-encoded protein, arginase-1 (ARG1), was predominantly expressed in macrophages in a time-dependent manner. Multiple-stage macrophage depletion verified that macrophages expressing high ARG1 levels accounted for late-stage cyst enlargement, and inhibiting ARG1 activity significantly retarded cyst growth and effectively lowered the proliferative indices in polycystic kidneys. In vitro experiments revealed that macrophages stimulated CLEC proliferation, and that L–lactic acid, primarily generated by CLECs, significantly upregulated ARG1 expression and increased polyamine synthesis in macrophages. Conclusions Interactions between macrophages and CLECs promote cyst growth. ARG1 is a key molecule involved in this process and is a potential therapeutic target to help delay ADPKD progression.

    更新日期:2018-09-01
  • Biallelic Expression of Mucin-1 in Autosomal Dominant Tubulointerstitial Kidney Disease: Implications for Nongenetic Disease Recognition
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-09-01
    Karl X. Knaup; Thomas Hackenbeck; Bernt Popp; Johanna Stoeckert; Andrea Wenzel; Maike Büttner-Herold; Frederick Pfister; Markus Schueler; Didem Seven; Annette M. May; Jan Halbritter; Hermann-Josef Gröne; André Reis; Bodo B. Beck; Kerstin Amann; Arif B. Ekici; Michael S. Wiesener

    Background Providing the correct diagnosis for patients with tubulointerstitial kidney disease and secondary degenerative disorders, such as hypertension, remains a challenge. The autosomal dominant tubulointerstitial kidney disease (ADTKD) subtype caused by MUC1 mutations (ADTKD-MUC1) is particularly difficult to diagnose, because the mutational hotspot is a complex repeat domain, inaccessible with routine sequencing techniques. Here, we further evaluated SNaPshot minisequencing as a technique for diagnosing ADTKD-MUC1 and assessed immunodetection of the disease-associated mucin 1 frameshift protein (MUC1-fs) as a nongenetic technique. Methods We re-evaluated detection of MUC1 mutations by targeted repeat enrichment and SNaPshot minisequencing by haplotype reconstruction via microsatellite analysis in three independent ADTKD-MUC1 families. Additionally, we generated rabbit polyclonal antibodies against MUC1-fs and evaluated immunodetection of wild-type and mutated allele products in human kidney biopsy specimens. Results The detection of MUC1 mutations by SNaPshot minisequencing was robust. Immunostaining with our MUC1-fs antibodies and an MUC1 antibody showed that both proteins are readily detectable in human ADTKD-MUC1 kidneys, with mucin 1 localized to the apical membrane and MUC1-fs abundantly distributed throughout the cytoplasm. Notably, immunohistochemical analysis of MUC1-fs expression in clinical kidney samples facilitated reliable prediction of the disease status of individual patients. Conclusions Diagnosing ADTKD-MUC1 by molecular genetics is possible, but it is technically demanding and labor intensive. However, immunohistochemistry on kidney biopsy specimens is feasible for nongenetic diagnosis of ADTKD-MUC1 and therefore, a valid method to select families for further diagnostics. Our data are compatible with the hypothesis that specific molecular effects of MUC1-fs underlie the pathogenesis of this disease.

    更新日期:2018-09-01
  • Efficient Gene Transfer to Kidney Mesenchymal Cells Using a Synthetic Adeno-Associated Viral Vector
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-09-01
    Yoichiro Ikeda; Zhao Sun; Xiao Ru; Luk H. Vandenberghe; Benjamin D. Humphreys

    Background After injury, mesenchymal progenitors in the kidney interstitium differentiate into myofibroblasts, cells that have a critical role in kidney fibrogenesis. The ability to deliver genetic material to myofibroblast progenitors could allow new therapeutic approaches to treat kidney fibrosis. Preclinical and clinical studies show that adeno-associated viruses (AAVs) efficiently and safely transduce various tissue targets in vivo; however, protocols for transduction of kidney mesenchymal cells have not been established. Methods We evaluated the transduction profiles of various pseudotyped AAV vectors expressing either GFP or Cre recombinase reporters in mouse kidney and human kidney organoids. Results Of the six AAVs tested, a synthetic AAV called Anc80 showed specific and high-efficiency transduction of kidney stroma and mesangial cells. We characterized the cell specificity, dose dependence, and expression kinetics and showed the efficacy of this approach by knocking out Gli2 from kidney mesenchymal cells by injection of Anc80-Cre virus into either homozygous or heterozygous Gli2-floxed mice. After unilateral ureteral obstruction, the homozygous Gli2-floxed mice had less fibrosis than the Gli2 heterozygotes had. We observed the same antifibrotic effect in β-catenin–floxed mice injected with Anc80-Cre virus before obstructive injury, strongly supporting a central role for canonical Wnt signaling in kidney myofibroblast activation. Finally, we showed that the Anc80 synthetic virus can transduce the mesenchymal lineage in human kidney organoids. Conclusions These studies establish a novel method for inducible knockout of floxed genes in mouse mesangium, pericytes, and perivascular fibroblasts and are the foundation for future gene therapy approaches to treat kidney fibrosis.

    更新日期:2018-09-01
  • Pretransplant C3d-Fixing Donor-Specific Anti-HLA Antibodies Are Not Associated with Increased Risk for Kidney Graft Failure
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-09-01
    Elena G. Kamburova; Bram W. Wisse; Irma Joosten; Wil A. Allebes; Arnold van der Meer; Luuk B. Hilbrands; Marije C. Baas; Eric Spierings; Cornelis E. Hack; Franka E. van Reekum; Arjan D. van Zuilen; Marianne C. Verhaar; Michiel L. Bots; Adriaan C.A.D. Drop; Loes Plaisier; Marc A.J. Seelen; Jan Stephan Sanders; Bouke G. Hepkema; Annechien J.A. Lambeck; Laura B. Bungener; Caroline Roozendaal; Marcel G.J. Tilanus; Christina E. Voorter; Lotte Wieten; Elly M. van Duijnhoven; Mariëlle A.C.J. Gelens; Maarten H.L. Christiaans; Frans J. van Ittersum; Shaikh A. Nurmohamed; Neubury M. Lardy; Wendy Swelsen; Karlijn A.M.I. van der Pant; Neelke C. van der Weerd; Ineke J.M. ten Berge; Frederike J. Bemelman; Andries J. Hoitsma; Paul J.M. van der Boog; Johan W. de Fijter; Michiel G.H. Betjes; Sebastiaan Heidt; Dave L. Roelen; Frans H. Claas; Henny G. Otten

    Background Complement-fixing antibodies against donor HLA are considered a contraindication for kidney transplant. A modification of the IgG single-antigen bead (SAB) assay allows detection of anti-HLA antibodies that bind C3d. Because early humoral graft rejection is considered to be complement mediated, this SAB-based technique may provide a valuable tool in the pretransplant risk stratification of kidney transplant recipients. Methods Previously, we established that pretransplant donor-specific anti-HLA antibodies (DSAs) are associated with increased risk for long-term graft failure in complement-dependent cytotoxicity crossmatch-negative transplants. In this study, we further characterized the DSA-positive serum samples using the C3d SAB assay. Results Among 567 pretransplant DSA-positive serum samples, 97 (17%) contained at least one C3d-fixing DSA, whereas 470 (83%) had non–C3d-fixing DSA. At 10 years after transplant, patients with C3d-fixing antibodies had a death-censored, covariate-adjusted graft survival of 60%, whereas patients with non–C3d-fixing DSA had a graft survival of 64% (hazard ratio, 1.02; 95% confidence interval, 0.70 to 1.48 for C3d-fixing DSA compared with non–C3d-fixing DSA; P=0.93). Patients without DSA had a 10-year graft survival of 78%. Conclusions The C3d-fixing ability of pretransplant DSA is not associated with increased risk for graft failure.

    更新日期:2018-09-01
  • Detection of Splicing Abnormalities and Genotype-Phenotype Correlation in X-linked Alport Syndrome
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-08-01
    Tomoko Horinouchi; Kandai Nozu; Tomohiko Yamamura; Shogo Minamikawa; Takashi Omori; Keita Nakanishi; Junya Fujimura; Akira Ashida; Mineaki Kitamura; Mitsuhiro Kawano; Wataru Shimabukuro; Chizuko Kitabayashi; Aya Imafuku; Keiichi Tamagaki; Koichi Kamei; Kenjirou Okamoto; Shuichiro Fujinaga; Masafumi Oka; Toru Igarashi; Akinori Miyazono; Emi Sawanobori; Rika Fujimaru; Koichi Nakanishi; Yuko Shima; Masafumi Matsuo; Ming Juan Ye; Yoshimi Nozu; Naoya Morisada; Hiroshi Kaito; Kazumoto Iijima

    Background X-linked Alport syndrome (XLAS) is a progressive hereditary nephropathy caused by mutations in the COL4A5 gene. Genotype-phenotype correlation in male XLAS is relatively well established; relative to truncating mutations, nontruncating mutations exhibit milder phenotypes. However, transcript comparison between XLAS cases with splicing abnormalities that result in a premature stop codon and those with nontruncating splicing abnormalities has not been reported, mainly because transcript analysis is not routinely conducted in patients with XLAS. Methods We examined transcript expression for all patients with suspected splicing abnormalities who were treated at one hospital between January of 2006 and July of 2017. Additionally, we recruited 46 males from 29 families with splicing abnormalities to examine genotype-phenotype correlation in patients with truncating (n=21, from 14 families) and nontruncating (n=25, from 15 families) mutations at the transcript level. Results We detected 41 XLAS families with abnormal splicing patterns and described novel XLAS atypical splicing patterns (n=14) other than exon skipping caused by point mutations in the splice consensus sequence. The median age for developing ESRD was 20 years (95% confidence interval, 14 to 23 years) among patients with truncating mutations and 29 years (95% confidence interval, 25 to 40 years) among patients with nontruncating mutations (P=0.001). Conclusions We report unpredictable atypical splicing in the COL4A5 gene in male patients with XLAS and reveal that renal prognosis differs significantly for patients with truncating versus nontruncating splicing abnormalities. Our results suggest that splicing modulation should be explored as a therapy for XLAS with truncating mutations.

    更新日期:2018-08-01
  • C5b9 Formation on Endothelial Cells Reflects Complement Defects among Patients with Renal Thrombotic Microangiopathy and Severe Hypertension
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-08-01
    Sjoerd A.M.E.G. Timmermans; Myrurgia A. Abdul-Hamid; Judith Potjewijd; Ruud O.M.F.I.H. Theunissen; Jan G.M.C. Damoiseaux; Chris P. Reutelingsperger; Pieter van Paassen; on behalf of the Limburg Renal Registry; M. Christiaans; T. Fung; M. Gelens; J. Kooman; K. Leunissen; E. Litjens; J. van der Net; F. van der Sande; E. Duijnhoven; S. Boorsma; J. Huitema; J. Wirtz; F. de Heer; M. Krekels; F. Stifft; G. Verseput; N. ter Braak; L. Frenken; S. Gaertner

    Background Severe hypertension can induce thrombotic microangiopathy (TMA) in the renal vasculature, the occurrence of which has been linked to mechanical stress to the endothelium. Complement defects may be the culprit of disease in patients who present with severe renal disease and often progress to ESRD, despite BP control. Methods We studied a well defined cohort of 17 patients with hypertension-associated TMA to define the prevalence of complement defects by a specific ex vivo serum-based microvascular endothelial cell assay. Results Compared with normal human serum and samples from patients with hypertensive arterionephrosclerosis, 14 of 16 (87.5%) serum samples collected at presentation from 16 patients with hypertension-associated TMA induced abnormal C5b9 formation on microvascular endothelial cells. We detected rare variants in complement genes in eight of 17 (47%) patients. ESRD occurred in 14 of 17 (82%) patients, and recurrent TMA after transplant occurred in seven of 11 (64%) donor kidneys. Eculizumab improved the renal function in three patients and prevented TMA recurrence in an allograft recipient. Conclusions These observations point to complement defects as the key causative factor of ESRD and recurrent TMA after transplant in patients presenting with severe hypertension. Complement defects can be identified by measurements of complement activation on microvascular endothelial cells, which should substantially influence treatment and prognosis.

    更新日期:2018-08-01
  • Early Proteinuria Lowering by Angiotensin-Converting Enzyme Inhibition Predicts Renal Survival in Children with CKD
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-08-01
    Sophie M. van den Belt; Hiddo J.L. Heerspink; Valentina Gracchi; Dick de Zeeuw; Elke Wühl; Franz Schaefer; on behalf of the ESCAPE Trial Group; A. Anarat; A. Bakkaloglu; F. Ozaltin; A. Peco-Antic; U. Querfeld; J. Gellermann; P. Sallay; D. Drozdz; K.-E. Bonzel; A.-M. Wingen; A. Zurowska; I. Balasz; A. Trivelli; F. Perfumo; D.E. Müller-Wiefel; K. Möller; G. Offner; B. Enke; E. Wühl; C. Gimpel; O. Mehls; F. Schaefer; S. Emre; S. Caliskan; S. Mir; S. Wygoda; K. Hohbach-Hohenfellner; N. Jeck; G. Klaus; G. Ardissino; S. Testa; G. Montini; M. Charbit; P. Niaudet; A. Caldas-Afonso; A. Fernandes-Teixeira; J. Dušek; M.C. Matteucci; S. Picca; A. Mastrostefano; M. Wigger; U.B. Berg; G. Celsi; M. Fischbach; J. Terzic; J. Fydryk; T. Urasinski; R. Coppo; Licia Peruzzi; K. Arbeiter; A. Jankauskiené; R. Grenda; M. Litwin; R. Janas; G. Laube; T.J. Neuhaus

    Background Although pharmacotherapeutic proteinuria lowering was found to be nephroprotective in adults, the predictive value of early drug-induced proteinuria reduction for long-term renal survival in pediatric CKD is unknown. We analyzed data from the ESCAPE Trial for a potential association between initial antiproteinuric effect of standardized angiotensin-converting enzyme (ACE) inhibition and renal disease progression in children with CKD. Methods In total, 280 eligible children with CKD stages 2–4 (mean age 11.7 years old, median eGFR 46 ml/min per 1.73 m2, 71% congenital renal malformations) received a fixed dose of ramipril (6 mg/m2 per day) and were subsequently randomized to conventional or intensified BP control. We assessed initial proteinuria reduction from baseline to first measurement on ramipril (at 2.5±1.3 months). We used multivariable Cox modeling to estimate the association between initial proteinuria reduction and the risk of reaching a renal end point (50% eGFR decline or ESRD), which occurred in 80 patients during 5 years of observation. Results Ramipril therapy lowered proteinuria by a mean of 43.5% (95% confidence interval, 36.3% to 49.9%). Relative to proteinuria reduction <30%, 30%–60% and >60% reduction resulted in hazard ratios (95% confidence intervals) of 0.70 (0.40 to 1.22) and 0.42 (0.22 to 0.79), respectively. This association was independent of age, sex, CKD diagnosis, baseline eGFR, baseline proteinuria, initial BP, and concomitant BP reduction. Conclusions The early antiproteinuric effect of ACE inhibition is associated with long-term preservation of renal function in children with CKD. Proteinuria lowering should be considered an important target in the management of pediatric CKD.

    更新日期:2018-08-01
  • The Prognostic Value of Histopathologic Lesions in Native Kidney Biopsy Specimens: Results from the Boston Kidney Biopsy Cohort Study
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-08-01
    Anand Srivastava; Ragnar Palsson; Arnaud D. Kaze; Margaret E. Chen; Polly Palacios; Venkata Sabbisetti; Rebecca A. Betensky; Theodore I. Steinman; Ravi I. Thadhani; Gearoid M. McMahon; Isaac E. Stillman; Helmut G. Rennke; Sushrut S. Waikar

    Background Few studies have evaluated whether histopathologic lesions on kidney biopsy provide prognostic information beyond clinical and laboratory data. Methods We enrolled 676 individuals undergoing native kidney biopsy at three tertiary care hospitals into a prospective, observational cohort study. Biopsy specimens were adjudicated for semiquantitative scores in 13 categories of histopathology by two experienced renal pathologists. Proportional hazards models tested the association between histopathologic lesions and risk of kidney disease progression (≥40% eGFR decline or RRT). Results Mean baseline eGFR was 57.5±36.0 ml/min per 1.73 m2. During follow-up (median, 34.3 months), 199 individuals suffered kidney disease progression. After adjustment for demographics, clinicopathologic diagnosis, and laboratory values, the following lesions (hazard ratio; 95% confidence interval) were independently associated with progression: inflammation in nonfibrosed interstitium (0.52; 0.32 to 0.83), moderate and severe versus minimal interstitial fibrosis/tubular atrophy (2.14; 1.24 to 3.69 and 3.42; 1.99 to 5.87, respectively), moderate and severe versus minimal global glomerulosclerosis (2.17; 1.36 to 3.45 and 3.31; 2.04 to 5.38, respectively), moderate and severe versus minimal arterial sclerosis (1.78; 1.15 to 2.74 and 1.64; 1.04 to 2.60, respectively), and moderate and severe versus minimal arteriolar sclerosis (1.63; 1.08 to 2.46 and 2.33; 1.42 to 3.83, respectively). An 11-point chronicity score derived from semiquantitative assessments of chronic lesions independently associated with higher risk of kidney disease progression (hazard ratio per one-point increase, 1.19; 95% confidence interval, 1.12 to 1.27). Conclusions Across a diverse group of kidney diseases, histopathologic lesions on kidney biopsy provide prognostic information, even after adjustment for proteinuria and eGFR.

    更新日期:2018-08-01
  • Decline in Kidney Function among Apparently Healthy Young Adults at Risk of Mesoamerican Nephropathy
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-08-01
    Marvin Gonzalez-Quiroz; Evangelia-Theano Smpokou; Richard J. Silverwood; Armando Camacho; Dorien Faber; Brenda La Rosa Garcia; Amin Oomatia; Michael Hill; Jason Glaser; Jennifer Le Blond; Catharina Wesseling; Aurora Aragon; Liam Smeeth; Neil Pearce; Dorothea Nitsch; Ben Caplin

    Background Epidemic levels of CKD of undetermined cause, termed Mesoamerican nephropathy in Central America, have been found in low- and middle-income countries. We investigated the natural history of, and factors associated with, loss of kidney function in a population at high risk for this disease. Methods We conducted a 2-year prospective, longitudinal study with follow-up every 6 months in nine rural communities in northwestern Nicaragua and included all men (n=263) and a random sample of women (n=87) ages 18–30 years old without self-reported CKD, diabetes, or hypertension. We used growth mixture modeling to identify subgroups of eGFR trajectory and weighted multinomial logistic regression to examine associations with proposed risk factors. Results Among men, we identified three subpopulations of eGFR trajectory (mean baseline eGFR; mean eGFR change over follow-up): 81% remained stable (116 ml/min per 1.73 m2; −0.6 ml/min per 1.73 m2 per year), 9.5% experienced rapid decline despite normal baseline function (112 ml/min per 1.73 m2; −18.2 ml/min per 1.73 m2 per year), and 9.5% had baseline dysfunction (58 ml/min per 1.73 m2; −3.8 ml/min per 1.73 m2 per year). Among women: 96.6% remained stable (121 ml/min per 1.73 m2; −0.6 ml/min per 1.73 m2 per year), and 3.4% experienced rapid decline (132 ml/min per 1.73 m2; −14.6 ml/min per 1.73 m2 per year; n=3 women). Among men, outdoor and agricultural work and lack of shade availability during work breaks, reported at baseline, were associated with rapid decline. Conclusions Although Mesoamerican nephropathy is associated with agricultural work, other factors may also contribute to this disease.

    更新日期:2018-08-01
  • Strong Association of the HLA-DR/DQ Locus with Childhood Steroid-Sensitive Nephrotic Syndrome in the Japanese Population
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-08-01
    Xiaoyuan Jia; Tomoko Horinouchi; Yuki Hitomi; Akemi Shono; Seik-Soon Khor; Yosuke Omae; Kaname Kojima; Yosuke Kawai; Masao Nagasaki; Yoshitsugu Kaku; Takayuki Okamoto; Yoko Ohwada; Kazuhide Ohta; Yusuke Okuda; Rika Fujimaru; Ken Hatae; Naonori Kumagai; Emi Sawanobori; Hitoshi Nakazato; Yasufumi Ohtsuka; Koichi Nakanishi; Yuko Shima; Ryojiro Tanaka; Akira Ashida; Koichi Kamei; Kenji Ishikura; Kandai Nozu; Katsushi Tokunaga; Kazumoto Iijima; for the Research Consortium on Genetics of Childhood Idiopathic Nephrotic Syndrome in Japan; Takayuki Okamoto; Hayato Aoyagi; Tomohiko Ueno; Masanori Nakanishi; Nariaki Toita; Kimiaki Uetake; Norio Kobayashi; Shoji Fujita; Kazushi Tsuruga; Naonori Kumagai; Hiroki Kudo; Eriko Tanaka; Mari Okada; Kenji Ishikuyra; Koichi Kamei; Masao Ogura; Mai Sato; Yuji Kano; Kenichiro Miura; Yaeko Motoyoshi; Emi Sawanobori; Anna Kobayashi; Manabu Kojika; Yoko Ohwada; Riku Hamada; Hiroshi Hataya; Miwa Goto; Kazuhide Ohta; Soichi Tamamura; Yukiko Mori; Kazumoto Iijima; Kandai Nozu; Hiroshi Kaito; Tomohiko Yamamura; Shogo Minamikawa; Keita Nakanishi; Junya Fujimura; China Nagano; Nana Sakakibara; Ryojiro Tanaka; Kyoko Kanda; Taku Nakagawa; Takayuki Shibano; Kohei Maekawa; Masuji Hattori; Yuya Hashimura; Shingo Ishimori; Rika Fujimaru; Hiroaki Ueda; Akira Ashida; Hideki Matsumura; Toshihiro Sawai; Tomoyuki Sakai; Yusuke Okuda; Yuko Shima; Shigeru Itoh; Koji Nagatani; Yoshikazu Kaku; Manao Nishimura; Ken Hatae; Maiko Hinokiyama; Rie Kuroki; Yasufumi Ohtsuka; Shinji Nishimura; Hitoshi Nakazato; Hiroshi Tamura; Koichi Nakanishi

    Background Nephrotic syndrome is the most common cause of chronic glomerular disease in children. Most of these patients develop steroid-sensitive nephrotic syndrome (SSNS), but the loci conferring susceptibility to childhood SSNS are mainly unknown. Methods We conducted a genome-wide association study (GWAS) in the Japanese population; 224 patients with childhood SSNS and 419 adult healthy controls were genotyped using the Affymetrix Japonica Array in the discovery stage. Imputation for six HLA genes (HLA-A, -C, -B, -DRB1, -DQB1, and -DPB1) was conducted on the basis of Japanese-specific references. We performed genotyping for HLA-DRB1/-DQB1 using a sequence-specific oligonucleotide-probing method on a Luminex platform. Whole-genome imputation was conducted using a phased reference panel of 2049 healthy Japanese individuals. Replication was performed in an independent Japanese sample set including 216 patients and 719 healthy controls. We genotyped candidate single-nucleotide polymorphisms using the DigiTag2 assay. Results The most significant association was detected in the HLA-DR/DQ region and replicated (rs4642516 [minor allele G], combined Pallelic=7.84×10−23; odds ratio [OR], 0.33; 95% confidence interval [95% CI], 0.26 to 0.41; rs3134996 [minor allele A], combined Pallelic=1.72×10−25; OR, 0.29; 95% CI, 0.23 to 0.37). HLA-DRB1*08:02 (Pc=1.82×10−9; OR, 2.62; 95% CI, 1.94 to 3.54) and HLA-DQB1*06:04 (Pc=2.09×10−12; OR, 0.10; 95% CI, 0.05 to 0.21) were considered primary HLA alleles associated with childhood SSNS. HLA-DRB1*08:02-DQB1*03:02 (Pc=7.01×10−11; OR, 3.60; 95% CI, 2.46 to 5.29) was identified as the most significant genetic susceptibility factor. Conclusions The most significant association with childhood SSNS was detected in the HLA-DR/DQ region. Further HLA allele/haplotype analyses should enhance our understanding of molecular mechanisms underlying SSNS.

    更新日期:2018-08-01
  • Failed Target Weight Achievement Associates with Short-Term Hospital Encounters among Individuals Receiving Maintenance Hemodialysis
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-08-01
    Magdalene M. Assimon; Lily Wang; Jennifer E. Flythe

    Background Hospitalizations and 30-day readmissions are common in the hemodialysis population. Actionable clinical markers for near-term hospital encounters are needed to identify individuals who require swift intervention to avoid hospitalization. Aspects of volume management, such as failed target weight (i.e, estimated dry weight) achievement, are plausible modifiable indicators of impending adverse events. The short-term consequences of failed target weight achievement are not well established. Methods Statistically deidentified data were taken from a cohort of Medicare-enrolled, prevalent hemodialysis patients treated at a large dialysis organization from 2010 to 2012. We used a retrospective cohort design with repeated intervals, each consisting of 180-day baseline, 30-day exposure assessment, and 30-day follow-up period, to estimate the associations between failed target weight achievement and the risk of 30-day emergency department visits and hospitalizations. We estimated adjusted risk differences using inverse probability of exposure weighted Kaplan–Meier methods. Results A total of 113,561 patients on hemodialysis contributed 788,722 study intervals to analyses. Patients who had a postdialysis weight >1.0 kg above the prescribed target weight in ≥30% (versus <30%) of exposure period treatments had a higher absolute risk (risk difference) of 30-day: emergency department visits (2.13%; 95% confidence interval, 2.00% to 2.32%); and all-cause (1.47%; 95% confidence interval, 1.34% to 1.62%), cardiovascular (0.31%; 95% confidence interval, 0.24% to 0.40%), and volume-related (0.15%; 95% confidence interval, 0.11% to 0.21%) hospitalizations. Conclusions In the absence of objective measures of volume status, recurrent failure to achieve target weight is an easily identifiable clinical risk marker for impending hospital encounters among patients on hemodialysis.

    更新日期:2018-08-01
  • Dialysis versus Medical Management at Different Ages and Levels of Kidney Function in Veterans with Advanced CKD
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-08-01
    Manjula Kurella Tamura; Manisha Desai; Kristopher I. Kapphahn; I-Chun Thomas; Steven M. Asch; Glenn M. Chertow

    Background Appropriate patient selection and optimal timing of dialysis initiation among older adults with advanced CKD are uncertain. We determined the association between dialysis versus medical management and survival at different ages and levels of kidney function. Methods We assembled a nationally representative 20% sample of United States veterans with eGFR<30 ml/min per 1.73 m2 between 2005 and 2010 (n=73,349), with follow-up through 2012. We used an extended Cox model to determine associations among the time-varying exposures, age (<65, 65–74, 75–84, and ≥85 years), eGFR (<6, 6–<9, 9–<12, 12–<15, and 15–<29 ml/min per 1.73 m2), and provision of dialysis, and survival. Result Over the mean±SEM follow-up of 3.4±2.2 years, 15% of patients started dialysis and 52% died. The eGFR at which dialysis, compared with medical management, associated with lower mortality varied by age (P<0.001). For patients aged <65, 65–74, 75–84, and ≥85 years, dialysis associated with lower mortality for those with eGFR not exceeding 6–<9, <6, 9–<12, and 9–<12 ml/min per 1.73 m2, respectively. Dialysis initiation at eGFR<6 ml/min per 1.73 m2 associated with a higher median life expectancy of 26, 25, and 19 months for patients aged 65, 75, and 85 years, respectively. When dialysis was initiated at eGFR 9–<12 ml/min per 1.73 m2, the estimated difference in median life expectancy was <1 year for these patients. Conclusions Provision of dialysis at higher levels of kidney function may extend survival for some older patients.

    更新日期:2018-08-01
  • Mechanisms Underlying Increased TIMP2 and IGFBP7 Urinary Excretion in Experimental AKI
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-08-01
    Ali C.M. Johnson; Richard A. Zager

    Background Recent clinical data support the utility/superiority of a new AKI biomarker (“NephroCheck”), the arithmetic product of urinary TIMP × IGFBP7 concentrations. However, the pathophysiologic basis for its utility remains ill defined. Methods To clarify this issue, CD-1 mice were subjected to either nephrotoxic (glycerol, maleate) or ischemic AKI. Urinary TIMP2/IGFBP7 concentrations were determined at 4 and 18 hours postinjury and compared with urinary albumin levels. Gene transcription was assessed by measuring renal cortical and/or medullary TIMP2/IGFBP7 mRNAs (4 and 18 hours after AKI induction). For comparison, the mRNAs of three renal “stress” biomarkers (NGAL, heme oxygenase 1, and p21) were assessed. Renal cortical TIMP2/IGFBP7 protein was gauged by ELISA. Proximal tubule–specific TIMP2/IGFBP7 was assessed by immunohistochemistry. Results Each AKI model induced prompt (4 hours) and marked urinary TIMP2/IGFBP7 increases without an increase in renal cortical concentrations. Furthermore, TIMP2/IGFBP7 mRNAs remained at normal levels. Endotoxemia also failed to increase TIMP2/IGFBP7 mRNAs. In contrast, each AKI model provoked massive NGAL, HO-1, and p21 mRNA increases, confirming that a renal “stress response” had occurred. Urinary albumin rose up to 100-fold and strongly correlated (r=0.87–0.91) with urinary TIMP2/IGFBP7 concentrations. Immunohistochemistry showed progressive TIMP2/IGFBP7 losses from injured proximal tubule cells. Competitive inhibition of endocytic protein reabsorption in normal mice tripled urinary TIMP2/IGFBP7 levels, confirming this pathway’s role in determining urinary excretion. Conclusions AKI-induced urinary TIMP2/IGFBP7 elevations are not due to stress-induced gene transcription. Rather, increased filtration, decreased tubule reabsorption, and proximal tubule cell TIMP2/IGFBP7 urinary leakage seem to be the most likely mechanisms.

    更新日期:2018-08-01
  • Somatic Mutations in Renal Cyst Epithelium in Autosomal Dominant Polycystic Kidney Disease
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-08-01
    Adrian Y. Tan; Tuo Zhang; Alber Michaeel; Jon Blumenfeld; Genyan Liu; Wanying Zhang; Zhengmao Zhang; Yi Zhu; Lior Rennert; Che Martin; Jenny Xiang; Steven P. Salvatore; Brian D. Robinson; Sandip Kapur; Stephanie Donahue; Warren O. Bobb; Hanna Rennert

    Background Autosomal dominant polycystic kidney disease (ADPKD) is a ciliopathy caused by mutations in PKD1 and PKD2 that is characterized by renal tubular epithelial cell proliferation and progressive CKD. Although the molecular mechanisms involved in cystogenesis are not established, concurrent inactivating constitutional and somatic mutations in ADPKD genes in cyst epithelium have been proposed as a cellular recessive mechanism. Methods We characterized, by whole-exome sequencing (WES) and long-range PCR techniques, the somatic mutations in PKD1 and PKD2 genes in renal epithelial cells from 83 kidney cysts obtained from nine patients with ADPKD, for whom a constitutional mutation in PKD1 or PKD2 was identified. Results Complete sequencing data by long-range PCR and WES was available for 63 and 65 cysts, respectively. Private somatic mutations of PKD1 or PKD2 were identified in all patients and in 90% of the cysts analyzed; 90% of these mutations were truncating, splice site, or in-frame variations predicted to be pathogenic mutations. No trans-heterozygous mutations of PKD1 or PKD2 genes were identified. Copy number changes of PKD1 ranging from 151 bp to 28 kb were observed in 12% of the cysts. WES also identified significant mutations in 53 non-PKD1/2 genes, including other ciliopathy genes and cancer-related genes. Conclusions These findings support a cellular recessive mechanism for cyst formation in ADPKD caused primarily by inactivating constitutional and somatic mutations of PKD1 or PKD2 in kidney cyst epithelium. The potential interactions of these genes with other ciliopathy- and cancer-related genes to influence ADPKD severity merits further evaluation.

    更新日期:2018-08-01
  • GAPVD1 and ANKFY1 Mutations Implicate RAB5 Regulation in Nephrotic Syndrome
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-08-01
    Tobias Hermle; Ronen Schneider; David Schapiro; Daniela A. Braun; Amelie T. van der Ven; Jillian K. Warejko; Ankana Daga; Eugen Widmeier; Makiko Nakayama; Tilman Jobst-Schwan; Amar J. Majmundar; Shazia Ashraf; Jia Rao; Laura S. Finn; Velibor Tasic; Joel D. Hernandez; Arvind Bagga; Sawsan M. Jalalah; Sherif El Desoky; Jameela A. Kari; Kristen M. Laricchia; Monkol Lek; Heidi L. Rehm; Daniel G. MacArthur; Shrikant Mane; Richard P. Lifton; Shirlee Shril; Friedhelm Hildebrandt

    Background Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of CKD. The discovery of monogenic causes of SRNS has revealed specific pathogenetic pathways, but these monogenic causes do not explain all cases of SRNS. Methods To identify novel monogenic causes of SRNS, we screened 665 patients by whole-exome sequencing. We then evaluated the in vitro functional significance of two genes and the mutations therein that we discovered through this sequencing and conducted complementary studies in podocyte-like Drosophila nephrocytes. Results We identified conserved, homozygous missense mutations of GAPVD1 in two families with early-onset NS and a homozygous missense mutation of ANKFY1 in two siblings with SRNS. GAPVD1 and ANKFY1 interact with the endosomal regulator RAB5. Coimmunoprecipitation assays indicated interaction between GAPVD1 and ANKFY1 proteins, which also colocalized when expressed in HEK293T cells. Silencing either protein diminished the podocyte migration rate. Compared with wild-type GAPVD1 and ANKFY1, the mutated proteins produced upon ectopic expression of GAPVD1 or ANKFY1 bearing the patient-derived mutations exhibited altered binding affinity for active RAB5 and reduced ability to rescue the knockout-induced defect in podocyte migration. Coimmunoprecipitation assays further demonstrated a physical interaction between nephrin and GAPVD1, and immunofluorescence revealed partial colocalization of these proteins in rat glomeruli. The patient-derived GAPVD1 mutations reduced nephrin-GAPVD1 binding affinity. In Drosophila, silencing Gapvd1 impaired endocytosis and caused mistrafficking of the nephrin ortholog. Conclusions Mutations in GAPVD1 and probably in ANKFY1 are novel monogenic causes of NS. The discovery of these genes implicates RAB5 regulation in the pathogenesis of human NS.

    更新日期:2018-08-01
  • The Human FSGS-Causing ANLN R431C Mutation Induces Dysregulated PI3K/AKT/mTOR/Rac1 Signaling in Podocytes
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-08-01
    Gentzon Hall; Brandon M. Lane; Kamal Khan; Igor Pediaditakis; Jianqiu Xiao; Guanghong Wu; Liming Wang; Maria E. Kovalik; Megan Chryst-Stangl; Erica E. Davis; Robert F. Spurney; Rasheed A. Gbadegesin

    Background We previously reported that mutations in the anillin (ANLN) gene cause familial forms of FSGS. ANLN is an F-actin binding protein that modulates podocyte cell motility and interacts with the phosphoinositide 3-kinase (PI3K) pathway through the slit diaphragm adaptor protein CD2-associated protein (CD2AP). However, it is unclear how the ANLN mutations cause the FSGS phenotype. We hypothesized that the R431C mutation exerts its pathogenic effects by uncoupling ANLN from CD2AP. Methods We conducted in vivo complementation assays in zebrafish to determine the effect of the previously identified missense ANLN variants, ANLNR431C and ANLNG618C during development. We also performed in vitro functional assays using human podocyte cell lines stably expressing wild-type ANLN (ANLNWT) or ANLNR431C. Results Experiments in anln-deficient zebrafish embryos showed a loss-of-function effect for each ANLN variant. In human podocyte lines, expression of ANLNR431C increased cell migration, proliferation, and apoptosis. Biochemical characterization of ANLNR431C-expressing podocytes revealed hyperactivation of the PI3K/AKT/mTOR/p70S6K/Rac1 signaling axis and activation of mTOR-driven endoplasmic reticulum stress in ANLNR431C-expressing podocytes. Inhibition of mTOR, GSK-3β, Rac1, or calcineurin ameliorated the effects of ANLNR431C. Additionally, inhibition of the calcineurin/NFAT pathway reduced the expression of endogenous ANLN and mTOR. Conclusions The ANLNR431C mutation causes multiple derangements in podocyte function through hyperactivation of PI3K/AKT/mTOR/p70S6K/Rac1 signaling. Our findings suggest that the benefits of calcineurin inhibition in FSGS may be due, in part, to the suppression of ANLN and mTOR. Moreover, these studies illustrate that rational therapeutic targets for familial FSGS can be identified through biochemical characterization of dysregulated podocyte phenotypes.

    更新日期:2018-08-01
  • The Calcium-Dependent Protease Calpain-1 Links TRPC6 Activity to Podocyte Injury
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-08-01
    Kim A.T. Verheijden; Ramon Sonneveld; Marinka Bakker-van Bebber; Jack F.M. Wetzels; Johan van der Vlag; Tom Nijenhuis

    Background The hallmark of podocytopathies, such as FSGS, is podocyte injury resulting in proteinuria. Transient receptor potential channel C6 (TRPC6) is a calcium-conducting ion channel expressed at the slit diaphragm. TRPC6 gain-of-function mutations and glomerular TRPC6 overexpression are associated with proteinuria. However, the pathways linking TRPC6 to podocyte injury, which is characterized by loss of the slit diaphragm protein nephrin, activation of several intracellular pathways (including calcineurin-NFAT signaling), and cytoskeletal rearrangement, remain elusive. Methods We tested whether the calcium-dependent protease calpain-1 mediates TRPC6-dependent podocyte injury in human and experimental FSGS and cultured podocytes. Results Compared with kidneys of healthy controls, kidneys of patients with FSGS had increased TRPC6 expression, increased calpain and calcineurin activity, and reduced expression of the calpain target Talin-1, which links the actin cytoskeleton to integrins and is critical for podocyte cytoskeletal stability. In a rat model of human FSGS, increased glomerular and urinary calpain activity associated with reduced Talin-1 abundance, enhanced calcineurin activity, and increased proteinuria. Treatment with the calpain inhibitor calpeptin prevented these effects. In cultured podocytes, pharmacologic stimulation of TRPC6-dependent calcium influx increased calpain-1 and calcineurin activity and reduced Talin-1 expression, and knockdown of TRPC6 or calpain-1 prevented these effects. Conclusions We elucidated a novel mechanism that links TRPC6 activity to calpain-1 activation and through Talin-1 loss and possibly, calcineurin activation, the podocyte injury characterizing FSGS. Therefore, calpain-1 and/or TRPC6 inhibition could be future therapeutic options to treat patients with FSGS or other podocytopathies.

    更新日期:2018-08-01
  • A Controlled Increase in Dietary Phosphate Elevates BP in Healthy Human Subjects
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-08-01
    Jaber Mohammad; Roberto Scanni; Lukas Bestmann; Henry N. Hulter; Reto Krapf

    Background Despite epidemiologic evidence for increased cardiovascular morbidity and mortality associated with both high dietary and serum phosphate in humans with normal renal function, no controlled phosphate intervention studies of systemic hemodynamics have been reported. Higher serum 25(OH) vitamin D levels are associated with better cardiovascular outcomes, but vitamin D increases intestinal phosphate absorption. Methods We conducted a prospective outpatient study with blinded assessment in 20 young adults with normal renal function randomized to high phosphate (regular diet plus 1 mmol/kg body wt per day of Na as neutral sodium phosphate) or low phosphate (regular diet plus lanthanum, 750 mg thrice/day, plus 0.7 mmol/kg body wt per day of Na as NaCl) for 11 weeks. After 6 weeks, all subjects received vitamin D3 (600,000 U) by intramuscular injection. Outcome parameters were 24-hour ambulatory systolic and diastolic BP (SBP and DBP), pulse rate (PR), biomarkers, and measures of endothelial and arterial function. Results Compared with the low-phosphate diet group, the high-phosphate diet group had a significant increase in mean±SEM fasting plasma phosphate concentration (0.23±0.11 mmol/L); 24-hour SBP and DBP (+4.1; 95% confidence interval [95% CI], 2.1 to 6.1; and +3.2; 95% CI, 1.2 to 5.2 mm Hg, respectively); mean 24-hour PR (+4.0; 95% CI, 2.0 to 6.0 beats/min); and urinary metanephrine and normetanephrine excretion (54; 95% CI, 50 to 70; and 122; 95% CI, 85 to 159 µg/24 hr, respectively). Vitamin D had no effect on any of these parameters. Neither high- nor low-phosphate diet nor vitamin D affected endothelial function or arterial elasticity. Conclusions Increased phosphate intake (controlled for sodium) significantly increases SBP, DBP, and PR in humans with normal renal function, in part, by increasing sympathoadrenergic activity.

    更新日期:2018-08-01
  • Region-Based Convolutional Neural Nets for Localization of Glomeruli in Trichrome-Stained Whole Kidney Sections
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-08-01
    John D. Bukowy; Alex Dayton; Dustin Cloutier; Anna D. Manis; Alexander Staruschenko; Julian H. Lombard; Leah C. Solberg Woods; Daniel A. Beard; Allen W. Cowley Jr.

    Background Histologic examination of fixed renal tissue is widely used to assess morphology and the progression of disease. Commonly reported metrics include glomerular number and injury. However, characterization of renal histology is a time-consuming and user-dependent process. To accelerate and improve the process, we have developed a glomerular localization pipeline for trichrome-stained kidney sections using a machine learning image classification algorithm. Methods We prepared 4-μm slices of kidneys from rats of various genetic backgrounds that were subjected to different experimental protocols and mounted the slices on glass slides. All sections used in this analysis were trichrome stained and imaged in bright field at a minimum resolution of 0.92 μm per pixel. The training and test datasets for the algorithm comprised 74 and 13 whole renal sections, respectively, totaling over 28,000 glomeruli manually localized. Additionally, because this localizer will be ultimately used for automated assessment of glomerular injury, we assessed bias of the localizer for preferentially identifying healthy or damaged glomeruli. Results Localizer performance achieved an average precision and recall of 96.94% and 96.79%, respectively, on whole kidney sections without evidence of bias for or against glomerular injury or the need for manual preprocessing. Conclusions This study presents a novel and robust application of convolutional neural nets for the localization of glomeruli in healthy and damaged trichrome-stained whole-renal section mounts and lays the groundwork for automated glomerular injury scoring.

    更新日期:2018-08-01
  • Single-Cell Transcriptomics of a Human Kidney Allograft Biopsy Specimen Defines a Diverse Inflammatory Response
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-08-01
    Haojia Wu; Andrew F. Malone; Erinn L. Donnelly; Yuhei Kirita; Kohei Uchimura; Sai M. Ramakrishnan; Joseph P. Gaut; Benjamin D. Humphreys

    Background Single-cell genomics techniques are revolutionizing our ability to characterize complex tissues. By contrast, the techniques used to analyze renal biopsy specimens have changed little over several decades. We tested the hypothesis that single-cell RNA-sequencing can comprehensively describe cell types and states in a human kidney biopsy specimen. Methods We generated 8746 single-cell transcriptomes from a healthy adult kidney and a single kidney transplant biopsy core by single-cell RNA-sequencing. Unsupervised clustering analysis of the biopsy specimen was performed to identify 16 distinct cell types, including all of the major immune cell types and most native kidney cell types, in this biopsy specimen, for which the histologic read was mixed rejection. Results Monocytes formed two subclusters representing a nonclassical CD16+ group and a classic CD16− group expressing dendritic cell maturation markers. The presence of both monocyte cell subtypes was validated by staining of independent transplant biopsy specimens. Comparison of healthy kidney epithelial transcriptomes with biopsy specimen counterparts identified novel segment-specific proinflammatory responses in rejection. Endothelial cells formed three distinct subclusters: resting cells and two activated endothelial cell groups. One activated endothelial cell group expressed Fc receptor pathway activation and Ig internalization genes, consistent with the pathologic diagnosis of antibody-mediated rejection. We mapped previously defined genes that associate with rejection outcomes to single cell types and generated a searchable online gene expression database. Conclusions We present the first step toward incorporation of single-cell transcriptomics into kidney biopsy specimen interpretation, describe a heterogeneous immune response in mixed rejection, and provide a searchable resource for the scientific community.

    更新日期:2018-08-01
  • A Single-Cell Transcriptome Atlas of the Mouse Glomerulus
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-08-01
    Nikos Karaiskos; Mahdieh Rahmatollahi; Anastasiya Boltengagen; Haiyue Liu; Martin Hoehne; Markus Rinschen; Bernhard Schermer; Thomas Benzing; Nikolaus Rajewsky; Christine Kocks; Martin Kann; Roman-Ulrich Müller

    Background Three different cell types constitute the glomerular filter: mesangial cells, endothelial cells, and podocytes. However, to what extent cellular heterogeneity exists within healthy glomerular cell populations remains unknown. Methods We used nanodroplet-based highly parallel transcriptional profiling to characterize the cellular content of purified wild-type mouse glomeruli. Results Unsupervised clustering of nearly 13,000 single-cell transcriptomes identified the three known glomerular cell types. We provide a comprehensive online atlas of gene expression in glomerular cells that can be queried and visualized using an interactive and freely available database. Novel marker genes for all glomerular cell types were identified and supported by immunohistochemistry images obtained from the Human Protein Atlas. Subclustering of endothelial cells revealed a subset of endothelium that expressed marker genes related to endothelial proliferation. By comparison, the podocyte population appeared more homogeneous but contained three smaller, previously unknown subpopulations. Conclusions Our study comprehensively characterized gene expression in individual glomerular cells and sets the stage for the dissection of glomerular function at the single-cell level in health and disease.

    更新日期:2018-08-01
  • Prevention of Fatal C3 Glomerulopathy by Recombinant Complement Receptor of the Ig Superfamily
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-08-01
    Xiaoxu Wang; Menno Van Lookeren Campagne; Kenneth J. Katschke Jr.; Damodar Gullipalli; Takashi Miwa; Yoshiyasu Ueda; Yuan Wang; Matthew Palmer; Guolan Xing; Wen-Chao Song

    Background C3 glomerulopathy (C3G) is a life-threatening kidney disease caused by dysregulation of the alternative pathway of complement (AP) activation. No approved specific therapy is available for C3G, although an anti-C5 mAb has been used off-label in some patients with C3G, with mixed results. Thus, there is an unmet medical need to develop other inhibitors of complement for C3G. Methods We used a murine model of lethal C3G to test the potential efficacy of an Fc fusion protein of complement receptor of the Ig superfamily (CRIg-Fc) in the treatment of C3G. CRIg-Fc binds C3b and inhibits C3 and C5 convertases of the AP. Mice with mutations in the factor H and properdin genes (FHm/mP−/−) develop early-onset C3G, with AP consumption, high proteinuria, and lethal crescentic GN. Results Treatment of FHm/mP−/− mice with CRIg-Fc, but not a control IgG, inhibited AP activation and diminished the consumption of plasma C3, factor B, and C5. CRIg-Fc–treated FHm/mP−/− mice also had significantly improved survival and reduced proteinuria, hematuria, BUN, glomerular C3 fragment, C9 and fibrin deposition, and GN pathology scores. Conclusions Therapeutics developed on the basis of the mechanism of action of soluble CRIg may be effective for the treatment of C3G and should be explored clinically.

    更新日期:2018-08-01
  • Nephrotoxicity of Cancer Immunotherapies: Past, Present and Future
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-08-01
    Mark A. Perazella; Anushree C. Shirali

    Nephrotoxicity from cancer therapies is common and increasingly encountered in clinical practice, such that the subfield of “onco-nephrology” has emerged. Conventional chemotherapeutic drugs and novel agents targeting specific genes/proteins are effective cancer therapies but suffer from a number of adverse kidney effects. An effective avenue of cancer treatment is immunotherapy, which uses drugs that augment immune system–mediated recognition and targeting of tumor cells. As such, leveraging the immune system to target malignant cells represents an important modality in eradicating cancer. IFN and high-dose IL-2 are older immunotherapies used in clinical practice to treat various malignancies, whereas new cancer immunotherapies have emerged over the past decade that offer even more effective treatment options. The immune checkpoint inhibitors are an exciting addition to the cancer immunotherapy armamentarium. Chimeric antigen receptor T cells are also a new immunotherapy used to treat various hematologic malignancies. However, as with the conventional and targeted cancer agents, the immunotherapies are also associated with immune-related adverse effects, which includes nephrotoxicity.

    更新日期:2018-08-01
  • Donald Seldin: A Transformative Leader in Medicine and Nephrology
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-08-01
    Robert Alpern; Gerhard Giebisch

    On April 25, 2018, Dr. Donald Seldin passed away at the age of 97, and the world lost a great treasure. Born in Coney Island, Brooklyn, Seldin attended James Madison High School and established his intellectual roots early on. He then attended New York University, where he was particularly interested in poetry and philosophy, but being a product of the depression, he decided to pursue a more profitable occupation. That together with his interest in science led him to medicine. This decision would have a profound effect on many aspects of the world that we now know.

    更新日期:2018-08-01
  • Fibroblast Growth Factor-23 and Risks of Cardiovascular and Noncardiovascular Diseases: A Meta-Analysis
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-07-01
    Amarnath Marthi; Killian Donovan; Richard Haynes; David C. Wheeler; Colin Baigent; Christopher M. Rooney; Martin J. Landray; Sharon M. Moe; Jun Yang; Lisa Holland; Romina di Giuseppe; Annet Bouma-de Krijger; Borislava Mihaylova; William G. Herrington

    Background Fibroblast growth factor-23 (FGF-23) has been hypothesized to play a role in the increased risk of cardiovascular disease in patients with CKD. Methods We identified prospective studies reporting associations between FGF-23 concentration and risk of cardiovascular events. Maximally adjusted risk ratios (RRs) were extracted for each outcome and scaled to a comparison of the top versus bottom third of the baseline FGF-23 concentration, and the results aggregated. Results Depending on the assay used, median FGF-23 concentrations were 43–74 RU/ml and 38–47 pg/ml in 17 general population cohorts; 102–392 RU/ml in nine cohorts of patients with CKD not requiring dialysis; and 79–4212 RU/ml and 2526–5555 pg/ml in eight cohorts of patients on dialysis. Overall, comparing participants in the top and bottom FGF-23 concentration thirds, the summary RRs (95% confidence intervals [95% CIs]) were 1.33 (1.12 to 1.58) for myocardial infarction, 1.26 (1.13 to 1.41) for stroke, 1.48 (1.29 to 1.69) for heart failure, 1.42 (1.27 to 1.60) for cardiovascular mortality, and 1.70 (1.52 to 1.91) for all-cause mortality. The summary RR for noncardiovascular mortality, calculated indirectly, was 1.52 (95% CI, 1.28 to 1.79). When studies were ordered by average differences in FGF-23 concentration between the top and bottom thirds, there was no trend in RRs across the studies. Conclusions The similarly-sized associations between increased FGF-23 concentration and cardiovascular (atherosclerotic and nonatherosclerotic) and noncardiovascular outcomes, together with the absence of any exposure–response relationship, suggest that the relationship between FGF-23 and cardiovascular disease risk may be noncausal.

    更新日期:2018-06-30
  • Transethnic, Genome-Wide Analysis Reveals Immune-Related Risk Alleles and Phenotypic Correlates in Pediatric Steroid-Sensitive Nephrotic Syndrome
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-07-01
    Hanna Debiec; Claire Dossier; Eric Letouzé; Christopher E. Gillies; Marina Vivarelli; Rosemary K. Putler; Elisabet Ars; Evelyne Jacqz-Aigrain; Valery Elie; Manuela Colucci; Stéphanie Debette; Philippe Amouyel; Siham C. Elalaoui; Abdelaziz Sefiani; Valérie Dubois; Tabassome Simon; Matthias Kretzler; Jose Ballarin; Francesco Emma; Matthew G. Sampson; Georges Deschênes; Pierre Ronco

    Background Steroid-sensitive nephrotic syndrome (SSNS) is a childhood disease with unclear pathophysiology and genetic architecture. We investigated the genomic basis of SSNS in children recruited in Europe and the biopsy-based North American NEPTUNE cohort. Methods We performed three ancestry-matched, genome-wide association studies (GWAS) in 273 children with NS (Children Cohort Nephrosis and Virus [NEPHROVIR] cohort: 132 European, 56 African, and 85 Maghrebian) followed by independent replication in 112 European children, transethnic meta-analysis, and conditional analysis. GWAS alleles were used to perform glomerular cis-expression quantitative trait loci studies in 39 children in the NEPTUNE cohort and epidemiologic studies in GWAS and NEPTUNE (97 children) cohorts. Results Transethnic meta-analysis identified one SSNS-associated single-nucleotide polymorphism (SNP) rs1063348 in the 3′ untranslated region of HLA-DQB1 (P=9.3×10−23). Conditional analysis identified two additional independent risk alleles upstream of HLA-DRB1 (rs28366266, P=3.7×10−11) and in the 3′ untranslated region of BTNL2 (rs9348883, P=9.4×10−7) within introns of HCG23 and LOC101929163. These three risk alleles were independent of the risk haplotype DRB1*07:01-DQA1*02:01-DQB1*02:02 identified in European patients. Increased burden of risk alleles across independent loci was associated with higher odds of SSNS. Increased burden of risk alleles across independent loci was associated with higher odds of SSNS, with younger age of onset across all cohorts, and with increased odds of complete remission across histologies in NEPTUNE children. rs1063348 associated with decreased glomerular expression of HLA-DRB1, HLA-DRB5, and HLA-DQB1. Conclusions Transethnic GWAS empowered discovery of three independent risk SNPs for pediatric SSNS. Characterization of these SNPs provide an entry for understanding immune dysregulation in NS and introducing a genomically defined classification.

    更新日期:2018-06-30
  • Residual Function Effectively Controls Plasma Concentrations of Secreted Solutes in Patients on Twice Weekly Hemodialysis
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-07-01
    Sheldon C. Leong; Justin N. Sao; Abigail Taussig; Natalie S. Plummer; Timothy W. Meyer; Tammy L. Sirich

    Background Most patients on hemodialysis are treated thrice weekly even if they have residual kidney function, in part because uncertainty remains as to how residual function should be valued and incorporated into the dialysis prescription. Recent guidelines, however, have increased the weight assigned to residual function and thus reduced the treatment time required when it is present. Increasing the weight assigned to residual function may be justified by knowledge that the native kidney performs functions not replicated by dialysis, including solute removal by secretion. This study tested whether plasma concentrations of secreted solutes are as well controlled in patients with residual function on twice weekly hemodialysis as in anuric patients on thrice weekly hemodialysis. Methods We measured the plasma concentration and residual clearance, dialytic clearance, and removal rates for urea and the secreted solutes hippurate, phenylacetylglutamine, indoxyl sulfate, and p-cresol sulfate in nine patients on twice weekly hemodialysis and nine patients on thrice weekly hemodialysis. Results Compared with anuric patients on thrice weekly dialysis with the same standard Kt/Vurea, patients on twice weekly hemodialysis had lower hippurate and phenylacetylglutamine concentrations and similar indoxyl sulfate and p-cresol sulfate concentrations. Mathematical modeling revealed that residual secretory function accounted for the observed pattern of solute concentrations. Conclusions Plasma concentrations of secreted solutes can be well controlled by twice weekly hemodialysis in patients with residual kidney function. This result supports further study of residual kidney function value and the inclusion of this function in dialysis adequacy measures.

    更新日期:2018-06-30
  • Everolimus with Reduced Calcineurin Inhibitor Exposure in Renal Transplantation
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-07-01
    Julio Pascual; Stefan P. Berger; Oliver Witzke; Helio Tedesco; Shamkant Mulgaonkar; Yasir Qazi; Steven Chadban; Federico Oppenheimer; Claudia Sommerer; Rainer Oberbauer; Yoshihiko Watarai; Christophe Legendre; Franco Citterio; Mitchell Henry; Titte R. Srinivas; Wen-Lin Luo; AnaMaria Marti; Peter Bernhardt; Flavio Vincenti; on behalf of the TRANSFORM Investigators; Alan Jardine; Tim Friede; Rafael Maldonado; Pablo Massari; Silvina Aleman; Silvia Maurich; Luis E. Gaite; Pablo Raffaele; Nora Imperiali; Scott Campbell; Steven Chadban; Peter Hughes; Ashley Irish; John Kanellis; Wai Lim; Philip J O’Connell; Graeme Russ; Zoltan Endre; Peter Mount; Paul Hengster; Peter Neudorfer; Rainer Oberbauer; Johann Pratschke; Dirk Kuypers; Jean-Louis Bosmans; Emine N. Broeders; Laurent Weekers; Helio Tedesco Silva Jr.; Elias D. Neto; Valter D. Garcia; Emil P. Dimitrov; Alvaro Kompatzki; Carlos Benavides; Johanna Schweineberg; Nikolina Basic Jukic; Mladen Knotek; Sanjin Racki; Ondrej Viklicky; M.A. Bakr; Christophe Legendre; Elisabeth Cassuto; Vincent Pernin; Vincent Vuiblet; Mathias Buchler; Claudia Sommerer; Peter Weithofer; Thomas Rath; Oliver Witzke; Markus van der Giet; Wolfgang Arns; Lutz Renders; Antje Habicht; Daniel Seehofer; Bernhard Banas; Frank Lehner; Johann Pratschke; Ioannis Boletis; Dimitrios Goumenos; Vasileios Papanikolaou; Spyros Drakopoulos; Dinesh Khullar; Veerbhadra Guptha; Shibu Jacob; Alan Fernandes Almeida; Eytan Mor; Richard Nakache; Mario Carmellini; Paolo Rigotti; Giacomo Colussi; Giuseppe Tisone; Paola Todeschini; Luigi Biancone; Franco Citterio; Vincenzo Cantaluppi; Loreto Gesualdo; Umberto Maggiore; Yoshihiko Watarai; Naotake Akutsu; Takashi Kenmochi; Duck Jong Han; Myoung Soo Kim; Sung Joo Kim; Torki AlOtaibi; Dania Chelala; Hilal Abou Zeinab; Khalil Jaber; Ghazali Ahmad Kutty; Hin Seng Wong; Francisco Javier Monteon Ramos; J.W. de Fijter; Stefan P. Berger; F.J. Bemelman; A.D. van Zuilen; L. Hilbrands; M.H.L. Christiaans; Anders Hartmann; Romina Danguilan; Angel Joaquin Amante; Kazimierz Ciechanowski; Maciej Glyda; Marek Karczewski; Alicja Debska-Slizien; Fernando Nolasco; Jose Guerra; Joana Santos; Patricia Joao Matias; Arnaldo Figueiredo; Yan G. Moysyuk; Aleksey V. Pinchuk; Ilya V. Aleksandrov; Vladimir E. Zagainov; Elena I. Boretskaya; Vladimir L. Medvedev; Ashraf Attia; Wael Habhab; Meteb Bugami; Neven Vavic; Igor Mitic; Goran Paunovic; Terence Kee; Tatiana Baltesova; Eva Lackova; Zuzana Zilinska; Ivana Dedinska; Miha Arnol; Elmi Muller; Julio Pascual; Federico Oppenheimer; Asuncion Sancho; Alex Gutierrez Dalmau; Domingo Marrero; Josep M. Cruzado; Amado Andres Belmonte; Juan Carlos Ruiz San Millan; Antonio Osuna; Ana Fernandez; Lars Wennberg; Bengt von Zur Muhlen; Bengt Gustafsson; Uyen Huynh-Do; Meng-Kun Tsai; Ming Ju Wu; Tsung Ching Chou; Prajej Ruangkanchanasetr; Sakarn Bunnag; Atiporn Ingsathit; Aydin Turmen; Ahmet V. Celik; Huseyin Kocak; Alexander Wiseman; Phillippe Gauthier; Fuad Shihab; Stevenson Bynon; Bernard Fischbach; Goran B. Klintmalm; Richard Knight; Kenneth L. Brayman; Jason Wellen; Stanley J. Jordan; Yasir Qazi; Ronald Cotton; Venkat Peddi; David Leeser; Mohamed E. Akoad; Shamkant Mulgaonkar; Martha Pavlakis; Reginald Gohh; Charles Bratton; Nahel Elias; Debra Sudan; Mary Waybill; Johnny Hong; Silas Norman; Ivo Tzvetanov; Dean Kim; Mitchell Henry; Jeffrey Rogers; Chandrasekar Santhanakrishnan; Nicolae Leca; Tomasz Kozlowski; Flavio Vincenti; Enver Akalin; Clifton E. Kew; David Shaffer; Liise K Kayler; Steven Steinberg; Stuart M. Flechner; Donald Hricik; Michael de Vera; Didier Mandelbrot

    Background Everolimus permits reduced calcineurin inhibitor (CNI) exposure, but the efficacy and safety outcomes of this treatment after kidney transplant require confirmation. Methods In a multicenter noninferiority trial, we randomized 2037 de novo kidney transplant recipients to receive, in combination with induction therapy and corticosteroids, everolimus with reduced-exposure CNI (everolimus arm) or mycophenolic acid (MPA) with standard-exposure CNI (MPA arm). The primary end point was treated biopsy-proven acute rejection or eGFR<50 ml/min per 1.73 m2 at post-transplant month 12 using a 10% noninferiority margin. Results In the intent-to-treat population (everolimus n=1022, MPA n=1015), the primary end point incidence was 48.2% (493) with everolimus and 45.1% (457) with MPA (difference 3.2%; 95% confidence interval, −1.3% to 7.6%). Similar between-treatment differences in incidence were observed in the subgroups of patients who received tacrolimus or cyclosporine. Treated biopsy-proven acute rejection, graft loss, or death at post-transplant month 12 occurred in 14.9% and 12.5% of patients treated with everolimus and MPA, respectively (difference 2.3%; 95% confidence interval, −1.7% to 6.4%). De novo donor-specific antibody incidence at 12 months and antibody-mediated rejection rate did not differ between arms. Cytomegalovirus (3.6% versus 13.3%) and BK virus infections (4.3% versus 8.0%) were less frequent in the everolimus arm than in the MPA arm. Overall, 23.0% and 11.9% of patients treated with everolimus and MPA, respectively, discontinued the study drug because of adverse events. Conclusions In kidney transplant recipients at mild-to-moderate immunologic risk, everolimus was noninferior to MPA for a binary composite end point assessing immunosuppressive efficacy and preservation of graft function.

    更新日期:2018-06-30
  • Gabapentin and Pregabalin Use and Association with Adverse Outcomes among Hemodialysis Patients
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-07-01
    Julie H. Ishida; Charles E. McCulloch; Michael A. Steinman; Barbara A. Grimes; Kirsten L. Johansen

    Background Gabapentin and pregabalin are used to manage neuropathic pain, pruritus, and restless legs syndrome in patients on hemodialysis. These patients may be especially predisposed to complications related to these agents, which are renally cleared, but data regarding the risk thereof are lacking. Methods From the US Renal Data System, we identified 140,899 Medicare-covered adults receiving hemodialysis with Part D coverage in 2011. Using Cox regression models in which we adjusted for demographics, comorbidities, duration of exposure, number of medications, and use of potentially confounding concomitant medications, we investigated the association between gabapentin and pregabalin, modeled as separate time-varying exposures, and time to first emergency room visit or hospitalization for altered mental status, fall, and fracture. We evaluated risk according to daily dose categories: gabapentin (>0–100, >100–200, >200–300, and >300 mg) and pregabalin (>0–100 and >100 mg). Results In 2011, 19% and 4% of patients received gabapentin and pregabalin, respectively. Sixty-eight percent of gabapentin or pregabalin users had a diagnosis of neuropathic pain, pruritus, or restless legs syndrome. Gabapentin was associated with 50%, 55%, and 38% higher hazards of altered mental status, fall, and fracture, respectively, in the highest dose category, but even lower dosing was associated with a higher hazard of altered mental status (31%–41%) and fall (26%–30%). Pregabalin was associated with up to 51% and 68% higher hazards of altered mental status and fall, respectively. Conclusions Gabapentin and pregabalin should be used judiciously in patients on hemodialysis, and research to identify the most optimal dosing is warranted.

    更新日期:2018-06-30
  • Clinical and Pathology Findings Associate Consistently with Larger Glomerular Volume
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-07-01
    Aleksandar Denic; Jerry Mathew; Venkata V. Nagineni; R. Houston Thompson; Bradley C. Leibovich; Lilach O. Lerman; John C. Lieske; Mariam P. Alexander; Joshua J. Augustine; Walter K. Kremers; Andrew D. Rule

    Background Glomerular volume increases when demand exceeds nephron supply, which may lead to glomerulosclerosis. It is unclear if determinants of glomerular volume are consistent between populations that differ by severity of comorbidities. Methods We studied kidney biopsy specimens from living kidney donors (n=2453) and patients who underwent radical nephrectomy for a renal tumor (n=780). We scanned specimen sections into high-resolution digital images, manually traced glomerular profiles, and calculated mean glomerular volumes using the Weibel–Gomez stereologic formula (separately for nonsclerosed glomeruli and globally sclerosed glomeruli). We then assessed the relationship of glomerular volume with age, clinical characteristics, and nephrosclerosis on biopsy specimen. Results Compared with kidney donors, patients with tumors were older and more frequently men, obese, diabetic, or hypertensive, had more glomerulosclerosis and interstitial fibrosis on biopsy specimen, and had 12% larger nonsclerosed glomeruli (P<0.001). In both populations, male sex, taller height, obesity, hypertension, and proteinuria associated with larger nonsclerosed glomeruli to a similar extent. In patients with tumors, diabetes, glomerulosclerosis >25%, and interstitial fibrosis >25% also associated with larger nonsclerosed glomeruli. Independent clinical predictors of larger nonsclerotic glomeruli were family history of ESRD, male sex, taller height, obesity, diabetes, and proteinuria. After adjustment for these characteristics, nonsclerotic glomerular volume did not differ between populations and was stable up to age 75 years, after which it decreased with age. Many of these findings were also evident with globally sclerotic glomerular volume. Conclusions Characteristics associated with glomerular volume are consistent between patient populations with low and high levels of comorbidity.

    更新日期:2018-06-30
  • ESRD among Immigrants to Ontario, Canada: A Population-Based Study
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-07-01
    Jeffrey Perl; Eric McArthur; Vivian S. Tan; Danielle M. Nash; Amit X. Garg; Ziv Harel; Alvin H. Li; Manish M. Sood; Joel G. Ray; Ron Wald

    Background The epidemiology of ESRD requiring maintenance dialysis (ESRD-D) in large, diverse immigrant populations is unclear. Methods We estimated ESRD-D prevalence and incidence among immigrants in Ontario, Canada. Adults residing in Ontario in 2014 were categorized as long-term Canadian residents or immigrants according to administrative health and immigration datasets. We determined ESRD-D prevalence among these adults and calculated age-adjusted prevalence ratios (PRs) comparing immigrants to long-term residents. Among those who immigrated to Ontario between 1991 and 2012, age-adjusted ESRD-D incidence was calculated by world region and country of birth, with immigrants from Western nations as the referent group. Results Among 1,902,394 immigrants and 8,860,283 long-term residents, 1700 (0.09%) and 8909 (0.10%), respectively, presented with ESRD-D. Age-adjusted ESRD-D prevalence was higher among immigrants from sub-Saharan Africa (PR, 2.17; 95% confidence interval [95% CI], 1.84 to 2.57), Latin America and the Caribbean (PR, 2.11; 95% CI, 1.90 to 2.34), South Asia (PR, 1.45; 95% CI, 1.32 to 1.59), and East Asia and the Pacific (PR, 1.34; 95% CI, 1.22 to 1.46). Immigrants from Somalia (PR, 4.18; 95% CI, 3.11 to 5.61), Trinidad and Tobago (PR, 2.88; 95% CI, 2.23 to 3.73), Jamaica (PR, 2.88; 95% CI, 2.40 to 3.44), Sudan (PR, 2.84; 95% CI, 1.53 to 5.27), and Guyana (PR, 2.69; 95% CI, 2.19 to 3.29) had the highest age-adjusted ESRD-D PRs relative to long-term residents. Immigrants from these countries also exhibited higher age-adjusted ESKD-D incidence relative to Western Nations immigrants. Conclusions Among immigrants in Canada, those from sub-Saharan Africa and the Caribbean have the highest ESRD-D risk. Tailored kidney-protective interventions should be developed for these susceptible populations.

    更新日期:2018-06-30
  • Serum 6-Bromotryptophan Levels Identified as a Risk Factor for CKD Progression
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-07-01
    Adrienne Tin; Girish Nadkarni; Anne M. Evans; Cheryl A. Winkler; Erwin Bottinger; Casey M. Rebholz; Mark J. Sarnak; Lesley A. Inker; Andrew S. Levey; Michael S. Lipkowitz; Lawrence J. Appel; Dan E. Arking; Josef Coresh; Morgan E. Grams

    Background Metabolite levels reflect physiologic homeostasis and may serve as biomarkers of disease progression. Identifying metabolites associated with APOL1 risk alleles—genetic variants associated with CKD risk commonly present in persons of African descent—may reveal novel markers of CKD progression relevant to other populations. Methods We evaluated associations between the number of APOL1 risk alleles and 760 serum metabolites identified via untargeted profiling in participants of the African American Study of Kidney Disease and Hypertension (AASK) (n=588; Bonferroni significance threshold P<6.5×10−5) and replicated findings in 678 black participants with CKD in BioMe, an electronic medical record–linked biobank. We tested the metabolite association with CKD progression in AASK, BioMe, and the Modification of Diet in Renal Disease (MDRD) Study. Results One metabolite, 6-bromotryptophan, was significant in AASK (P=4.7×10−5) and replicated in BioMe (P=5.7×10−3) participants, with lower levels associated with more APOL1 risk alleles. Lower levels of 6-bromotryptophan were associated with CKD progression in AASK and BioMe participants and in white participants in the MDRD Study, independent of demographics and clinical characteristics, including baseline GFR (adjusted hazard ratio per two-fold higher 6-bromotryptophan level, AASK, 0.76; 95% confidence interval [95% CI], 0.64 to 0.91; BioMe, 0.61; 95% CI, 0.43 to 0.85; MDRD, 0.52; 95% CI, 0.34 to 0.79). The interaction between the APOL1 risk alleles and 6-bromotryptophan was not significant. The identity of 6-bromotryptophan was confirmed in experiments comparing its molecular signature with that of authentic standards of other bromotryptophan isomers. Conclusions Serum 6-bromotryptophan is a consistent and novel risk factor for CKD progression.

    更新日期:2018-06-30
  • Blocking Properdin Prevents Complement-Mediated Hemolytic Uremic Syndrome and Systemic Thrombophilia
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-07-01
    Yoshiyasu Ueda; Takashi Miwa; Damodar Gullipalli; Sayaka Sato; Daisuke Ito; Hangsoo Kim; Matthew Palmer; Wen-Chao Song

    Background Properdin (P) is a positive regulator of the alternative pathway of complement activation. Although P inhibition is expected and has been shown to ameliorate the alternative pathway of complement-mediated tissue injury in several disease models, it unexpectedly exacerbated renal injury in a murine model of C3 glomerulopathy. The role of P in atypical hemolytic uremic syndrome (aHUS) is uncertain. Methods We blocked P function by genetic deletion or mAb-mediated inhibition in mice carrying a factor H (FH) point mutation, W1206R (FHR/R), that causes aHUS and systemic thrombophilia with high mortality. Results P deficiency completely rescued FHR/R mice from premature death and prevented thrombocytopenia, hemolytic anemia, and renal disease. It also eliminated macrovessel thrombi that were prevalent in FHR/R mice. All mice that received a function-blocking anti-P mAb for 8 weeks survived the experimental period and appeared grossly healthy. Platelet counts and hemoglobin levels were significantly improved in FHR/R mice after 4 weeks of anti-P mAb treatment. One half of the FHR/R mice treated with an isotype control mAb but none of the anti-P mAb-treated mice developed stroke-related neurologic disease. Anti-P mAb-treated FHR/R mice showed largely normal renal histology, and residual liver thrombi were detected in only three of 15 treated mice. Conclusions These results contrast with the detrimental effect of P inhibition observed in a murine model of C3 glomerulopathy and suggest that P contributes critically to aHUS pathogenesis. Inhibition of P in aHUS may be of therapeutic benefit.

    更新日期:2018-06-30
  • A NOX4/TRPC6 Pathway in Podocyte Calcium Regulation and Renal Damage in Diabetic Kidney Disease
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-07-01
    Daria V. Ilatovskaya; Gregory Blass; Oleg Palygin; Vladislav Levchenko; Tengis S. Pavlov; Michael N. Grzybowski; Kristen Winsor; Leonid S. Shuyskiy; Aron M. Geurts; Allen W. Cowley Jr.; Lutz Birnbaumer; Alexander Staruschenko

    Background Loss of glomerular podocytes is an indicator of diabetic kidney disease (DKD). The damage to these cells has been attributed in part to elevated intrarenal oxidative stress. The primary source of the renal reactive oxygen species, particularly H2O2, is NADPH oxidase 4 (NOX4). We hypothesized that NOX4-derived H2O2 contributes to podocyte damage in DKD via elevation of podocyte calcium. Methods We used Dahl salt-sensitive (SS) rats with a null mutation for the Nox4 gene (SSNox4−/−) and mice with knockout of the nonselective calcium channel TRPC6 or double knockout of TRPC5 and TRPC6. We performed whole animal studies and used biosensor measurements, electron microscopy, electrophysiology, and live calcium imaging experiments to evaluate the contribution of this pathway to the physiology of the podocytes in freshly isolated glomeruli. Results Upon induction of type 1 diabetes with streptozotocin, SSNox4−/− rats exhibited significantly lower basal intracellular Ca2+ levels in podocytes and less DKD-associated damage than SS rats did. Furthermore, the angiotensin II–elicited calcium flux was blunted in glomeruli isolated from diabetic SSNox4−/− rats compared with that in glomeruli from diabetic SS rats. H2O2 stimulated TRPC-dependent calcium influx in podocytes from wild-type mice, but this influx was blunted in podocytes from Trpc6-knockout mice and, in a similar manner, in podocytes from Trpc5/6 double-knockout mice. Finally, electron microscopy revealed that podocytes of glomeruli isolated from Trpc6-knockout or Trpc5/6 double-knockout mice were protected from damage induced by H2O2 to the same extent. Conclusions These data reveal a novel signaling mechanism involving NOX4 and TRPC6 in podocytes that could be pharmacologically targeted to abate the development of DKD.

    更新日期:2018-06-30
  • Caspase-3 Is a Pivotal Regulator of Microvascular Rarefaction and Renal Fibrosis after Ischemia-Reperfusion Injury
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-07-01
    Bing Yang; Shanshan Lan; Mélanie Dieudé; Jean-Paul Sabo-Vatasescu; Annie Karakeussian-Rimbaud; Julie Turgeon; Shijie Qi; Lakshman Gunaratnam; Natalie Patey; Marie-Josée Hébert

    Background Ischemia-reperfusion injury (IRI) is a major risk factor for chronic renal failure. Here, we characterize the different modes of programmed cell death in the tubular and microvascular compartments during the various stages of IRI-induced AKI, and their relative importance to renal fibrogenesis. Methods We performed unilateral renal artery clamping for 30 minutes and contralateral nephrectomy in wild-type mice (C57BL/6) or caspase-3−/− mice. Results Compared with their wild-type counterparts, caspase-3−/− mice in the early stage of AKI had high urine cystatin C levels, tubular injury scores, and serum creatinine levels. Electron microscopy revealed evidence of tubular epithelial cell necrosis in caspase-3−/− mice, and immunohistochemistry showed upregulation of the necroptosis marker receptor-interacting serine/threonine-protein kinase 3 (RIPK3) in renal cortical sections. Western blot analysis further demonstrated enhanced levels of phosphorylated RIPK3 in the kidneys of caspase-3−/− mice. In contrast, caspase-3−/− mice had less microvascular congestion and activation in the early and extension phases of AKI. In the long term (3 weeks after IRI), caspase-3−/− mice had reduced microvascular rarefaction and renal fibrosis, as well as decreased expression of α-smooth muscle actin and reduced collagen deposition within peritubular capillaries. Moreover, caspase-3−/− mice exhibited signs of reduced tubular ischemia, including lower tubular expression of hypoxia-inducible factor-1α and improved tubular injury scores. Conclusions These results establish the pivotal importance of caspase-3 in regulating microvascular endothelial cell apoptosis and renal fibrosis after IRI. These findings also demonstrate the predominant role of microvascular over tubular injury as a driver of progressive renal damage and fibrosis after IRI.

    更新日期:2018-06-30
  • Epithelial and Endothelial Pannexin1 Channels Mediate AKI
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-07-01
    Jakub Jankowski; Heather M. Perry; Christopher B. Medina; Liping Huang; Junlan Yao; Amandeep Bajwa; Ulrike M. Lorenz; Diane L. Rosin; Kodi S. Ravichandran; Brant E. Isakson; Mark D. Okusa

    Background Pannexin1 (Panx1), an ATP release channel, is present in most mammalian tissues, but the role of Panx1 in health and disease is not fully understood. Panx1 may serve to modulate AKI; ATP is a precursor to adenosine and may function to block inflammation, or ATP may act as a danger-associated molecular pattern and initiate inflammation. Methods We used pharmacologic and genetic approaches to evaluate the effect of Panx1 on kidney ischemia-reperfusion injury (IRI), a mouse model of AKI. Results Pharmacologic inhibition of gap junctions, including Panx1, by administration of carbenoxolone protected mice from IRI. Furthermore, global deletion of Panx1 preserved kidney function and morphology and diminished the expression of proinflammatory molecules after IRI. Analysis of bone marrow chimeric mice revealed that Panx1 expressed on parenchymal cells is necessary for ischemic injury, and both proximal tubule and vascular endothelial Panx1 tissue-specific knockout mice were protected from IRI. In vitro, Panx1-deficient proximal tubule cells released less and retained more ATP under hypoxic stress. Conclusions Panx1 is involved in regulating ATP release from hypoxic cells, and reducing this ATP release may protect kidneys from AKI.

    更新日期:2018-06-30
  • Mechanisms of Crystalloid versus Colloid Osmosis across the Peritoneal Membrane
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-07-01
    Johann Morelle; Amadou Sow; Charles-André Fustin; Catherine Fillée; Elvia Garcia-Lopez; Bengt Lindholm; Eric Goffin; Fréderic Vandemaele; Bengt Rippe; Carl M. Öberg; Olivier Devuyst

    Background Osmosis drives transcapillary ultrafiltration and water removal in patients treated with peritoneal dialysis. Crystalloid osmosis, typically induced by glucose, relies on dialysate tonicity and occurs through endothelial aquaporin-1 water channels and interendothelial clefts. In contrast, the mechanisms mediating water flow driven by colloidal agents, such as icodextrin, and combinations of osmotic agents have not been evaluated. Methods We used experimental models of peritoneal dialysis in mouse and biophysical studies combined with mathematical modeling to evaluate the mechanisms of colloid versus crystalloid osmosis across the peritoneal membrane and to investigate the pathways mediating water flow generated by the glucose polymer icodextrin. Results In silico modeling and in vivo studies showed that deletion of aquaporin-1 did not influence osmotic water transport induced by icodextrin but did affect that induced by crystalloid agents. Water flow induced by icodextrin was dependent upon the presence of large, colloidal fractions, with a reflection coefficient close to unity, a low diffusion capacity, and a minimal effect on dialysate osmolality. Combining crystalloid and colloid osmotic agents in the same dialysis solution strikingly enhanced water and sodium transport across the peritoneal membrane, improving ultrafiltration efficiency over that obtained with either type of agent alone. Conclusions These data cast light on the molecular mechanisms involved in colloid versus crystalloid osmosis and characterize novel osmotic agents. Dialysis solutions combining crystalloid and colloid particles may help restore fluid balance in patients treated with peritoneal dialysis.

    更新日期:2018-06-30
  • Cellular Origin and Functional Relevance of Collagen I Production in the Kidney
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-07-01
    Simone Buchtler; Alexandra Grill; Stefanie Hofmarksrichter; Petra Stöckert; Gabriela Schiechl-Brachner; Manuel Rodriguez Gomez; Sophia Neumayer; Kathrin Schmidbauer; Yvonne Talke; Barbara M. Klinkhammer; Peter Boor; Alexander Medvinsky; Kerstin Renner; Hayo Castrop; Matthias Mack

    Background Interstitial fibrosis is associated with chronic renal failure. In addition to fibroblasts, bone marrow–derived cells and tubular epithelial cells have the capacity to produce collagen. However, the amount of collagen produced by each of these cell types and the relevance of fibrosis to renal function are unclear. Methods We generated conditional cell type–specific collagen I knockout mice and used (reversible) unilateral ureteral obstruction and adenine-induced nephropathy to study renal fibrosis and function. Results In these mouse models, hematopoietic, bone marrow–derived cells contributed to 38%–50% of the overall deposition of collagen I in the kidney. The influence of fibrosis on renal function was dependent on the type of damage. In unilateral ureteral obstruction, collagen production by resident fibroblasts was essential to preserve renal function, whereas in the chronic model of adenine-induced nephropathy, collagen production was detrimental to renal function. Conclusions Our data show that hematopoietic cells are a major source of collagen and that antifibrotic therapies need to be carefully considered depending on the type of disease and the underlying cause of fibrosis.

    更新日期:2018-06-30
  • Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-07-01
    Markus Reichold; Enriko D. Klootwijk; Joerg Reinders; Edgar A. Otto; Mario Milani; Carsten Broeker; Chris Laing; Julia Wiesner; Sulochana Devi; Weibin Zhou; Roland Schmitt; Ines Tegtmeier; Christina Sterner; Hannes Doellerer; Kathrin Renner; Peter J. Oefner; Katja Dettmer; Johann M. Simbuerger; Ralph Witzgall; Horia C. Stanescu; Simona Dumitriu; Daniela Iancu; Vaksha Patel; Monika Mozere; Mehmet Tekman; Graciana Jaureguiberry; Naomi Issler; Anne Kesselheim; Stephen B. Walsh; Daniel P. Gale; Alexander J. Howie; Joana R. Martins; Andrew M. Hall; Michael Kasgharian; Kevin O’Brien; Carlos R. Ferreira; Paldeep S. Atwal; Mahim Jain; Alexander Hammers; Geoffrey Charles-Edwards; Chi-Un Choe; Dirk Isbrandt; Alberto Cebrian-Serrano; Ben Davies; Richard N. Sandford; Christopher Pugh; David S. Konecki; Sue Povey; Detlef Bockenhauer; Uta Lichter-Konecki; William A. Gahl; Robert J. Unwin; Richard Warth; Robert Kleta

    Background For many patients with kidney failure, the cause and underlying defect remain unknown. Here, we describe a novel mechanism of a genetic order characterized by renal Fanconi syndrome and kidney failure. Methods We clinically and genetically characterized members of five families with autosomal dominant renal Fanconi syndrome and kidney failure. We performed genome-wide linkage analysis, sequencing, and expression studies in kidney biopsy specimens and renal cells along with knockout mouse studies and evaluations of mitochondrial morphology and function. Structural studies examined the effects of recognized mutations. Results The renal disease in these patients resulted from monoallelic mutations in the gene encoding glycine amidinotransferase (GATM), a renal proximal tubular enzyme in the creatine biosynthetic pathway that is otherwise associated with a recessive disorder of creatine deficiency. In silico analysis showed that the particular GATM mutations, identified in 28 members of the five families, create an additional interaction interface within the GATM protein and likely cause the linear aggregation of GATM observed in patient biopsy specimens and cultured proximal tubule cells. GATM aggregates-containing mitochondria were elongated and associated with increased ROS production, activation of the NLRP3 inflammasome, enhanced expression of the profibrotic cytokine IL-18, and increased cell death. Conclusions In this novel genetic disorder, fully penetrant heterozygous missense mutations in GATM trigger intramitochondrial fibrillary deposition of GATM and lead to elongated and abnormal mitochondria. We speculate that this renal proximal tubular mitochondrial pathology initiates a response from the inflammasome, with subsequent development of kidney fibrosis.

    更新日期:2018-06-30
  • The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-07-01
    Silvana Bazúa-Valenti; Lorena Rojas-Vega; María Castañeda-Bueno; Jonatan Barrera-Chimal; Rocío Bautista; Luz G. Cervantes-Pérez; Norma Vázquez; Consuelo Plata; Adrián R. Murillo-de-Ozores; Lorenza González-Mariscal; David H. Ellison; Daniela Riccardi; Norma A. Bobadilla; Gerardo Gamba

    Background Hypercalciuria can result from activation of the basolateral calcium-sensing receptor (CaSR), which in the thick ascending limb of Henle’s loop controls Ca2+ excretion and NaCl reabsorption in response to extracellular Ca2+. However, the function of CaSR in the regulation of NaCl reabsorption in the distal convoluted tubule (DCT) is unknown. We hypothesized that CaSR in this location is involved in activating the thiazide-sensitive NaCl cotransporter (NCC) to prevent NaCl loss. Methods We used a combination of in vitro and in vivo models to examine the effects of CaSR on NCC activity. Because the KLHL3-WNK4-SPAK pathway is involved in regulating NaCl reabsorption in the DCT, we assessed the involvement of this pathway as well. Results Thiazide-sensitive 22Na+ uptake assays in Xenopus laevis oocytes revealed that NCC activity increased in a WNK4-dependent manner upon activation of CaSR with Gd3+. In HEK293 cells, treatment with the calcimimetic R-568 stimulated SPAK phosphorylation only in the presence of WNK4. The WNK4 inhibitor WNK463 also prevented this effect. Furthermore, CaSR activation in HEK293 cells led to phosphorylation of KLHL3 and WNK4 and increased WNK4 abundance and activity. Finally, acute oral administration of R-568 in mice led to the phosphorylation of NCC. Conclusions Activation of CaSR can increase NCC activity via the WNK4-SPAK pathway. It is possible that activation of CaSR by Ca2+ in the apical membrane of the DCT increases NaCl reabsorption by NCC, with the consequent, well known decrease of Ca2+ reabsorption, further promoting hypercalciuria.

    更新日期:2018-06-30
  • IL-10 Receptor Signaling Empowers Regulatory T Cells to Control Th17 Responses and Protect from GN
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-07-01
    Paul Diefenhardt; Anna Nosko; Malte A. Kluger; Johannes V. Richter; Claudia Wegscheid; Yasushi Kobayashi; Gisa Tiegs; Samuel Huber; Richard A. Flavell; Rolf A.K. Stahl; Oliver M. Steinmetz

    Background Th17 cells are central pathogenic mediators of autoimmune disease, including many forms of GN. IL-10 receptor signaling (IL-10R) in regulatory T cells (Tregs) has been implicated in the downregulation of Th17 cells, but the underlying molecular mechanisms and functional relevance of this process remain unclear. Methods We generated mice with Treg-specific IL-10Ra deficiency and subjected these mice to nephrotoxic serum–induced nephritis as a model of crescentic GN. Immune responses and Treg phenotypes were extensively analyzed. Results Compared with controls, mice with IL-10Ra−/− Tregs showed a spontaneously overshooting Th17 immune response. This hyper-Th17 phenotype was further boosted during GN and associated with aggravated renal injury. Notably, abrogation of IL-10Ra signaling in Tregs increased dendritic cell activation and production of Th17-inducing cytokines. In contrast, Treg trafficking and expression of chemokine receptor CCR6 remained unaffected, indicating mechanisms of Th17 control, differing from those of previously identified CCR6+ Treg17 cells. Indeed, the capacity for direct in vitro suppression of Th17 responses by IL-10Ra−/− Tregs was significantly impaired. As underlying pathology, analyses conducted in vitro and in vivo using double-fluorescent reporter mice revealed strikingly decreased IL-10 production by IL-10Ra−/− Tregs. To assess, whether reduced IL-10 could explain the hyper Th17 phenotype, competitive cotransfer experiments were performed. Supporting our concept, IL-10Ra−/− T cells differentiated into Th17 cells at much higher frequencies than wild type T cells did during GN. Conclusions IL-10R engagement optimizes Treg-mediated suppression of Th17 immunity. We hypothesize a feed-forward loop, in which IL-10Ra signaling reinforces IL-10 secretion by Tregs which potently controls Th17 development via direct and indirect mechanisms. IL-10R thus may be a promising therapeutic target for the treatment of GN.

    更新日期:2018-06-30
  • The Complexity and Heterogeneity of Monoclonal Immunoglobulin–Associated Renal Diseases
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-07-01
    Sanjeev Sethi; S. Vincent Rajkumar; Vivette D. D’Agati

    Monoclonal gammopathies are characterized by the overproduction of monoclonal Ig (MIg) detectable in the serum or urine resulting from a clonal proliferation of plasma cells or B lymphocytes. The underlying hematologic conditions range from malignant neoplasms of plasma cells or B lymphocytes, including multiple myeloma and B-cell lymphoproliferative disorders, to nonmalignant small clonal proliferations. The term MGUS implies presence of an MIg in the setting of a “benign” hematologic condition without renal or other end organ damage. The term MGRS was recently introduced to indicate monoclonal gammopathy with MIg-associated renal disease in the absence of hematologic malignancy. Most MIg-associated renal diseases result from the direct deposition of nephrotoxic MIg or its light- or heavy-chain fragments in various renal tissue compartments. Immunofluorescence microscopy is essential to identify the offending MIg and define its tissue distribution. Mass spectrometry is helpful in difficult cases. Conditions caused by direct tissue deposition of MIg include common disorders, such as cast nephropathy, amyloidosis, and MIg deposition diseases, as well as uncommon disorders, such as immunotactoid glomerulopathy, proliferative GN with MIg deposits, light-chain proximal tubulopathy, and the rare entities of crystal-storing histiocytosis and crystalglobulinemia. Indirect mechanisms of MIg-induced renal disease can cause C3 glomerulopathy or thrombotic microangiopathy without tissue MIg deposits. Treatment of MIg-associated renal disease is aimed at eliminating the clonal plasma cell or B-cell population as appropriate. Both the renal and the underlying hematologic disorders influence the management and prognosis of MIg-associated renal diseases.

    更新日期:2018-06-30
  • Sirtuins in Renal Health and Disease
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-07-01
    Marina Morigi; Luca Perico; Ariela Benigni

    Sirtuins belong to an evolutionarily conserved family of NAD+-dependent deacetylases that share multiple cellular functions related to proliferation, DNA repair, mitochondrial energy homeostasis, and antioxidant activity. Mammalians express seven sirtuins (SIRT1–7) that are localized in different subcellular compartments. Changes in sirtuin expression are critical in several diseases, including metabolic syndrome, diabetes, cancer, and aging. In the kidney, the most widely studied sirtuin is SIRT1, which exerts cytoprotective effects by inhibiting cell apoptosis, inflammation, and fibrosis together with SIRT3, a crucial metabolic sensor that regulates ATP generation and mitochondrial adaptive response to stress. Here, we provide an overview of the biologic effects of sirtuins and the molecular targets thereof regulating renal physiology. This review also details progress made in understanding the effect of sirtuins in the pathophysiology of chronic and acute kidney diseases, highlighting the key role of SIRT1, SIRT3, and now SIRT6 as potential therapeutic targets. In this context, the current pharmacologic approaches to enhancing the activity of SIRT1 and SIRT3 will be discussed.

    更新日期:2018-06-30
  • The Authors Reply
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-06-01
    Lin-Li Lv; Ye Feng; Bi-Cheng Liu

    We thank Gleadle et al. for their interest in our article and comments. We agree that the isolation method for urine exosomes is a very important issue.

    更新日期:2018-06-01
  • Nanoparticle Tracking Analysis of Urine to Detect Exosomes Can Be Confounded by Albuminuria
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-06-01
    Jonathan Gleadle; Kym McNicholas; Jordan Li; Michael Michael; Darling Rojas-Canales

    In the article by Lv et al.1 published in the Journal of the American Society of Nephrology, the authors describe enhanced urinary exosomal release in experimental models of acute and chronic renal injury. They also describe increased exosomal release in patients with IgA nephropathy and a correlation between exosomal concentration and proteinuria. These findings are of clear interest, but we have reservations about some of the methodology used to ascertain this observation. They use nanoparticle tracking analysis (NTA) of urine and describe enhanced particle concentration in patients who are proteinuric. We have recently reported similar observations using NTA in 32 patients with varying levels of albuminuria.2 We found that albuminuria confounded particle analysis by NTA, because albumin-containing solutions contain particles of exosome-like size, and such particles can mimic exosomes in standard NTA. Immunodepletion of albumin from proteinuric urine resulted in a substantial reduction in the concentration of particles detected by NTA as did urine purification using iodixanol density gradients. More importantly, NTA measurements of pure albumin solutions yielded a substantial number of particles with a diameter of 105 nm. This reinforces the need for great caution in the interpretation of NTA results in fluids that have significant levels of protein. It also emphasizes the importance of stringent methods of purification, such as density gradients, in exosome analysis as recommended by the International Society for Extracellular Vesicles.3

    更新日期:2018-06-01
  • The Authors Reply
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-06-01
    Steven G. Coca; Girish N. Nadkarni; Kinsuk Chauhan; Chirag R. Parikh

    We appreciate the suggestions by Hickson et al.1 for additional analysis by race and sex on plasma biomarkers and their association with renal outcomes in the Action to Control Cardiovascular Disease (ACCORD) trial and the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial cohorts.2

    更新日期:2018-06-01
  • Biomarkers Associated with Progression of Diabetic Kidney Disease: Do They Hold the Same Meaning for Blacks and Women?
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-06-01
    LaTonya J. Hickson; Joyce E. Balls-Berry; Allan S. Jaffe; Andrew D. Rule

    We read with interest the study by Coca et al.,1 which examined the association of plasma TNF receptor-1 (TNFR-1), TNFR-2, and kidney injury molecule-1 (KIM-1) on renal outcomes in patients with type 2 diabetes mellitus. These investigations were performed on plasma samples from two previously conducted clinical trials involving patients with incident and progressive diabetic kidney disease (DKD) (n=1636). The findings support prior studies. In 2012, Niewczas et al.2 connected circulating markers of the proinflammatory cytokine (TNF-α) and the TNF pathway to the inflammatory state in DKD as a potential biomarker of DKD progression. These novel investigations (n=410) revealed the predictive capacity of plasma TNFR-1 and TNFR-2 in determining future DKD ESRD events. Since then, these studies have been replicated in predominantly white cohorts, with a few in other racial groups including American Indians and Chinese. One study by Chode et al.3 involved blacks (n=359), but it did not determine renal outcomes.

    更新日期:2018-06-01
  • NPHP1 (Nephrocystin-1) Gene Deletions Cause Adult-Onset ESRD
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-06-01
    Rozemarijn Snoek; Jessica van Setten; Brendan J. Keating; Ajay K. Israni; Pamala A. Jacobson; William S. Oetting; Arthur J. Matas; Roslyn B. Mannon; Zhongyang Zhang; Weijia Zhang; Ke Hao; Barbara Murphy; Roman Reindl-Schwaighofer; Andreas Heinzl; Rainer Oberbauer; Ondrej Viklicky; Peter J. Conlon; Caragh P. Stapleton; Stephan J.L. Bakker; Harold Snieder; Edith D.J. Peters; Bert van der Zwaag; Nine V.A.M. Knoers; Martin H. de Borst; Albertien M. van Eerde

    Background Nephronophthisis (NPH) is the most prevalent genetic cause for ESRD in children. However, little is known about the prevalence of NPH in adult-onset ESRD. Homozygous full gene deletions of the NPHP1 gene encoding nephrocystin-1 are a prominent cause of NPH. We determined the prevalence of NPH in adults by assessing homozygous NPHP1 full gene deletions in adult-onset ESRD. Methods Adult renal transplant recipients from five cohorts of the International Genetics and Translational Research in Transplantation Network (iGeneTRAiN) underwent single-nucleotide polymorphism genotyping. After quality control, we determined autosomal copy number variants (such as deletions) on the basis of median log2 ratios and B-allele frequency patterns. The findings were independently validated in one cohort. Patients were included in the analysis if they had adult-onset ESRD, defined as start of RRT at ≥18 years old. Results We included 5606 patients with adult-onset ESRD; 26 (0.5%) showed homozygous NPHP1 deletions. No donor controls showed homozygosity for this deletion. Median age at ESRD onset was 30 (range, 18–61) years old for patients with NPH, with 54% of patients age ≥30 years old. Notably, only three (12%) patients were phenotypically classified as having NPH, whereas most patients were defined as having CKD with unknown etiology (n=11; 42%). Conclusions Considering that other mutation types in NPHP1 or mutations in other NPH-causing genes were not analyzed, NPH is a relatively frequent monogenic cause of adult-onset ESRD. Because 88% of patients had not been clinically diagnosed with NPH, wider application of genetic testing in adult-onset ESRD may be warranted.

    更新日期:2018-06-01
  • Post-Transplant Natural Antibodies Associate with Kidney Allograft Injury and Reduced Long-Term Survival
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-06-01
    Sarah B. See; Olivier Aubert; Alexandre Loupy; Yokarla Veras; Xavier Lebreton; Baoshan Gao; Christophe Legendre; Dany Anglicheau; Emmanuel Zorn

    Background The development of antibodies specific to HLA expressed on donor tissue (donor-specific antibodies [DSAs]) is a prominent risk factor for kidney graft loss. Non-HLA antibodies with pathogenic potential have also been described, including natural antibodies (Nabs). These IgG Nabs bind to immunogenic self-determinants, including oxidation-related antigens. Methods To examine the relationship of Nabs with graft outcomes, we assessed Nabs in blinded serum specimens collected from a retrospective cohort of 635 patients who received a transplant between 2005 and 2010 at Necker Hospital in Paris, France. Serum samples were obtained immediately before transplant and at the time of biopsy-proven rejection within the first year or 1 year after transplant. Nabs were detected by ELISA through reactivity to the generic oxidized epitope malondialdehyde. Results Univariate Cox regression analysis identified the development of post-transplant Nabs (defined as 50% increase in reactivity to malondialdehyde) as a significant risk factor for graft loss (hazard ratio, 2.68; 95% confidence interval, 1.49 to 4.82; P=0.001). Post-transplant Nabs also correlated with increased mean Banff scores for histologic signs of graft injury in post-transplant biopsy specimens. Multivariable Cox analyses confirmed Nabs development as a risk factor independent from anti-HLA DSAs (hazard ratio, 2.07; 95% confidence interval, 1.03 to 4.17; P=0.04). Moreover, patients with Nabs and DSAs had a further increased risk of kidney graft loss. Conclusions These findings reveal an association between Nabs, kidney graft injury, and eventual graft failure, suggesting the involvement of Nabs in immune mechanisms of rejection.

    更新日期:2018-06-01
  • Incidence, Risk Factors, and Sequelae of Post-kidney Transplant Delirium
    J. Am. Soc. Nephrol. (IF 8.547) Pub Date : 2018-06-01
    Christine E. Haugen; Alexandra Mountford; Fatima Warsame; Rachel Berkowitz; Sunjae Bae; Alvin G. Thomas; Charles H. Brown IV; Daniel C. Brennan; Karin J. Neufeld; Michelle C. Carlson; Dorry L. Segev; Mara McAdams-DeMarco

    Background Frail kidney transplant (KT) recipients may be particularly vulnerable to surgical stressors, resulting in delirium and subsequent adverse outcomes. We sought to identify the incidence, risk factors, and sequelae of post-KT delirium. Methods We studied 125,304 adult KT recipients (1999–2014) to estimate delirium incidence in national registry claims. Additionally, we used a validated chart abstraction algorithm to identify post-KT delirium in 893 adult recipients (2009–2017) from a cohort study of frailty. Delirium sequelae were identified using adjusted logistic regression (length of stay ≥2 weeks and institutional discharge [skilled nursing or rehabilitation facility]) and adjusted Cox regression (death-censored graft loss and mortality). Results Only 0.8% of KT recipients had a delirium claim. In the cohort study, delirium incidence increased with age (18–49 years old: 2.0%; 50–64 years old: 4.6%; 65–75 years old: 9.2%; and ≥75 years old: 13.8%) and frailty (9.0% versus 3.9%); 20.0% of frail recipients aged ≥75 years old experienced delirium. Frailty was independently associated with delirium (odds ratio [OR], 2.05; 95% confidence interval [95% CI], 1.02 to 4.13; P=0.04), but premorbid global cognitive function was not. Recipients with delirium had increased risks of ≥2-week length of stay (OR, 5.42; 95% CI, 2.76 to 10.66; P<0.001), institutional discharge (OR, 22.41; 95% CI, 7.85 to 63.98; P<0.001), graft loss (hazard ratio [HR], 2.73; 95% CI, 1.14 to 6.53; P=0.03), and mortality (HR, 3.12; 95% CI, 1.76 to 5.54; P<0.001). Conclusions Post-KT delirium is a strong risk factor for subsequent adverse outcomes, yet it is a clinical entity that is often missed.

    更新日期:2018-06-01
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