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Journal of the American Society of Nephrology
Journal Prestige (SJR): 4.819
Citation Impact (citeScore): 7
Number of Followers: 31  
 
  Full-text available via subscription Subscription journal
ISSN (Print) 1046-6673 - ISSN (Online) 1533-3450
Published by American Society of Nephrology Homepage  [2 journals]
  • This Month's Highlights

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      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2021030385
      Issue No: Vol. 32, No. 5 (2021)
       
  • Kidney Transplant Rejection Clusters and Graft Outcomes: Revisiting Banff
           in the Era of "Big Data"

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      Authors: Vasquez-Rios, G; Menon, M. C.
      Pages: 1009 - 1011
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2021030348
      Issue No: Vol. 32, No. 5 (2021)
       
  • Monkeying about with Nephron Formation

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      Authors: Smyth I. M.
      Pages: 1011 - 1013
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2021030320
      Issue No: Vol. 32, No. 5 (2021)
       
  • Urinary Vesicles: Are They Ready for Real-World Use'

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      Authors: Hunter, R. W; Dear, J. W.
      Pages: 1013 - 1015
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2021030332
      Issue No: Vol. 32, No. 5 (2021)
       
  • Obituary for Robert Schrier

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      Authors: Berl T.
      Pages: 1016 - 1017
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2021020239
      Issue No: Vol. 32, No. 5 (2021)
       
  • COVID-19 and Dialysis Patients: Unsolved Problems in Early 2021

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      Authors: Kliger, A. S; Silberzweig, J.
      Pages: 1018 - 1020
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2020121766
      Issue No: Vol. 32, No. 5 (2021)
       
  • SARS-CoV-2 Vaccines in Kidney Transplant Recipients: Will They Be Safe and
           Effective and How Will We Know'

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      Authors: Heldman, M. R; Limaye, A. P.
      Pages: 1021 - 1024
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2021010023
      Issue No: Vol. 32, No. 5 (2021)
       
  • The Urine Anion Gap: Common Misconceptions

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      Authors: Uribarri, J; Oh, M. S.
      Pages: 1025 - 1028
      Abstract: Two papers, one in 1986 and another one in 1988, reported a strong inverse correlation between urinary anion gap (UAG) and urine ammonia excretion (UNH4) in patients with metabolic acidosis and postulated that UAG could be used as an indirect measure of UNH4. This postulation has persisted until now and is widely accepted. In this review, we discuss factors regulating UAG and examine published evidence to uncover errors in the postulate and the design of the original studies. The essential fact is that, in the steady state, UAG reflects intake of Na, K, and Cl. Discrepancy between intake and urinary output of these electrolytes (i.e., UAG) indicates selective extrarenal loss of these electrolytes or nonsteady state. UNH4 excretion, which depends, in the absence of renal dysfunction, mainly on the daily acid load, has no consistent relationship to UAG either theoretically or in reality. Any correlation between UAG and UNH4, when observed, was a fortuitous correlation and cannot be extrapolated to other situations. Furthermore, the normal value of UAG has greatly increased over the past few decades, mainly due to increases in dietary intake of potassium and widespread use of sodium salts with anions other than chloride as food additives. The higher normal values of UAG must be taken into consideration in interpreting UAG.
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2020101509
      Issue No: Vol. 32, No. 5 (2021)
       
  • COVID-19 and AKI: Where Do We Stand'

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      Authors: Palevsky P. M.
      Pages: 1029 - 1032
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2020121768
      Issue No: Vol. 32, No. 5 (2021)
       
  • Kinetics of Anti-SARS-CoV-2 IgG Antibodies in Hemodialysis Patients Six
           Months after Infection

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      Authors: Sakhi, H; Dahmane, D, Attias, P, Kofman, T, Bouvier, M, Lapidus, N, Fourati, S, El Karoui, K, Mondor NephroCov Study Group, Audard, Bentaarit, Boueilh, Gallien, Grimbert, Hüe, Joher, Jouan, Lamriben, Lelievre, Lepeule, Mahevas, Matignon, Melica, Oniszczuk, Pawlotsky, Stehle, Vindrios, Wemmert
      Pages: 1033 - 1036
      Abstract: BackgroundThe humoral response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the hemodialysis population, including its dynamics over time, remains poorly understood.MethodsTo analyze initial and long-term humoral responses against SARS-CoV-2 in a hemodialysis population, we retrospectively evaluated findings from SARS-CoV-2 IgG serologic assays targeting the nucleocapsid antigen or spike antigen up to 6 months of follow-up in patients on hemodialysis in the Paris, France, region who had recovered from coronavirus disease 2019 (COVID-19).ResultsOur analysis included 83 patients (median age 65 years); 59 (71%) were male and 28 (34%) had presented with severe COVID-19. We observed positive initial SARS-CoV-2 IgG antinucleocapsid serology in 74 patients (89%) at a median of 67 days postdiagnosis. By multivariable analysis, immunocompromised status was the only factor significantly associated with lack of an IgG antinucleocapsid antibody response. Follow-up data were available at 6 months postdiagnosis for 60 of 74 patients (81%) with positive initial antinucleocapsid serology, and 15 (25%) of them had negative antinucleocapsid serology at month 6. In total, 14 of 15 sera were tested for antispike antibodies, 3 of 14 (21%) of which were also negative. Overall, 97% of antinucleocapsid-antibody–positive specimens were also antispike-antibody positive. Female sex, age >70 years, and nonsevere clinical presentation were independently associated with faster IgG antinucleocapsid titer decay in multivariable analysis. After adjustment for sex and age >70 years, nonsevere clinical presentation was the only factor associated with faster decay of IgG antispike antibodies.ConclusionsThis study characterizes evolution of the SARS-CoV-2 antibody response in patients on hemodialysis and identifies factors that are associated with lack of seroconversion and with IgG titer decay.
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2020111618
      Issue No: Vol. 32, No. 5 (2021)
       
  • Deletion of Myeloid Interferon Regulatory Factor 4 (Irf4) in Mouse Model
           Protects against Kidney Fibrosis after Ischemic Injury by Decreased
           Macrophage Recruitment and Activation

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      Authors: Sasaki, K; Terker, A. S, Pan, Y, Li, Z, Cao, S, Wang, Y, Niu, A, Wang, S, Fan, X, Zhang, M.-Z, Harris, R. C.
      Pages: 1037 - 1052
      Abstract: BackgroundAKI is characterized by abrupt and reversible kidney dysfunction, and incomplete recovery leads to chronic kidney injury. Previous studies by us and others have indicated that macrophage infiltration and polarization play key roles in recovery from AKI. The role in AKI recovery played by IFN regulatory factor 4 (IRF4), a mediator of polarization of macrophages to the M2 phenotype, is unclear.MethodsWe used mice with myeloid or macrophage cell–specific deletion of Irf4 (M Irf4 –/– ) to evaluate Irf4’s role in renal macrophage polarization and development of fibrosis after severe AKI.ResultsSurprisingly, although macrophage Irf4 deletion had a minimal effect on early renal functional recovery from AKI, it resulted in decreased renal fibrosis 4 weeks after severe AKI, in association with less-activated macrophages. Macrophage Irf4 deletion also protected against renal fibrosis in unilateral ureteral obstruction. Bone marrow–derived monocytes (BMDMs) from M Irf4 –/– mice had diminished chemotactic responses to macrophage chemoattractants, with decreased activation of AKT and PI3 kinase and increased PTEN expression. PI3K and AKT inhibitors markedly decreased chemotaxis in wild-type BMDMs, and in a cultured macrophage cell line. There was significant inhibition of homing of labeled Irf4 –/– BMDMs to postischemic kidneys. Renal macrophage infiltration in response to AKI was markedly decreased in M Irf4 –/– mice or in wild-type mice with inhibition of AKT activity.ConclusionsDeletion of Irf4 from myeloid cells protected against development of tubulointerstitial fibrosis after severe ischemic renal injury in mice, due primarily to inhibition of AKT-mediated monocyte recruitment to the injured kidney and reduced activation and subsequent polarization into a profibrotic M2 phenotype.
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2020071010
      Issue No: Vol. 32, No. 5 (2021)
       
  • Crumbs2 Is an Essential Slit Diaphragm Protein of the Renal Filtration
           Barrier

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      Authors: Möller-Kerutt, A; Rodriguez-Gatica, J. E, Wacker, K, Bhatia, R, Siebrasse, J.-P, Boon, N, Van Marck, V, Boor, P, Kubitscheck, U, Wijnholds, J, Pavenstädt, H, Weide, T.
      Pages: 1053 - 1070
      Abstract: BackgroundCrumbs2 is expressed at embryonic stages as well as in the retina, brain, and glomerular podocytes. Recent studies identified CRB2 mutations as a novel cause of steroid-resistant nephrotic syndrome (SRNS).MethodsTo study the function of Crb2 at the renal filtration barrier, mice lacking Crb2 exclusively in podocytes were generated. Gene expression and histologic studies as well as transmission and scanning electron microscopy were used to analyze these Crb2 podKO knockout mice and their littermate controls. Furthermore, high-resolution expansion microscopy was used to investigate Crb2 distribution in murine glomeruli. For pull-down experiments, live cell imaging, and transcriptome analyses, cell lines were applied that inducibly express fluorescent protein–tagged CRB2 wild type and mutants.Results Crb2 podKO mice developed proteinuria directly after birth that preceded a prominent development of disordered and effaced foot processes, upregulation of renal injury and inflammatory markers, and glomerulosclerosis. Pull-down assays revealed an interaction of CRB2 with Nephrin, mediated by their extracellular domains. Expansion microscopy showed that in mice glomeruli, Crb2 and Nephrin are organized in adjacent clusters. SRNS-associated CRB2 protein variants and a mutant that lacks a putative conserved O-glycosylation site were not transported to the cell surface. Instead, mutants accumulated in the ER, showed altered glycosylation pattern, and triggered an ER stress response.ConclusionsCrb2 is an essential component of the podocyte’s slit diaphragm, interacting with Nephrin. Loss of slit diaphragm targeting and increasing ER stress are pivotal factors for onset and progression of CRB2-related SRNS.
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2020040501
      Issue No: Vol. 32, No. 5 (2021)
       
  • Anti-CD20 mAb-Induced B Cell Apoptosis Generates T Cell Regulation of
           Experimental Myeloperoxidase ANCA-Associated Vasculitis

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      Authors: Gan, P.-Y; Dick, J, OSullivan, K. M, Oudin, V, Cao Le, A, Koo Yuk Cheong, D, Shim, R, Alikhan, M, Kitching, A. R, Ooi, J. D, Holdsworth, S. R.
      Pages: 1071 - 1083
      Abstract: BackgroundMyeloperoxidase ANCA-associated vasculitis is a major cause of ESKD. Efficacy of anti-CD20 mAb treatment was tested in a mouse model of the disease.MethodsMPO immunization induced anti-MPO autoimmunity, and a subnephritogenic dose of sheep anti-mouse GBM globulin triggered GN.ResultsAnti-CD20 mAb treatment increased the numbers and immunomodulatory capacity of MPO-specific T regulatory cells (Tregs) and attenuated T cell–mediated and humoral anti-MPO autoimmunity and GN. Disabling of Tregs negated the therapeutic benefit of anti-CD20 treatment. The mechanism of enhancement of Treg activity could be attributed to anti-CD20 mAb effects on inducing B cell apoptosis. Administering anti-CD20 mAb-induced apoptotic splenocytes to mice developing anti-MPO GN was as effective as anti-CD20 mAb treatment in inducing Tregs and attenuating both anti-MPO autoimmunity and GN. A nonredundant role for splenic macrophages in mediating the anti-CD20 mAb-induced immunomodulation was demonstrated by showing that administration of anti-CD20 mAb ex vivo–induced apoptotic splenocytes to unmanipulated mice attenuated autoimmunity and GN, whereas deletion of splenic marginal zone macrophages prevented anti-CD20 mAb-induced immunomodulation and treatment efficacy. Six days after administering anti-CD20 mAb to mice with murine anti-MPO GN, cell-mediated anti-MPO responses and GN were attenuated, and Tregs were enhanced, but ANCA levels were unchanged, suggesting humoral autoimmunity was redundant at this time point.ConclusionsCollectively, these data suggest that, as well as reducing humoral autoimmunity, anti-CD20 mAb more rapidly induces protective anti-MPO Treg-mediated immunomodulation by splenic processing of anti-CD20–induced apoptotic B cells.
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2020060834
      Issue No: Vol. 32, No. 5 (2021)
       
  • Data-driven Derivation and Validation of Novel Phenotypes for Acute Kidney
           Transplant Rejection using Semi-supervised Clustering

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      Authors: Vaulet, T; Divard, G, Thaunat, O, Lerut, E, Senev, A, Aubert, O, Van Loon, E, Callemeyn, J, Emonds, M.-P, Van Craenenbroeck, A, De Vusser, K, Sprangers, B, Rabeyrin, M, Dubois, V, Kuypers, D, De Vos, M, Loupy, A, De Moor, B, Naesens, M.
      Pages: 1084 - 1096
      Abstract: BackgroundOver the past decades, an international group of experts iteratively developed a consensus classification of kidney transplant rejection phenotypes, known as the Banff classification. Data-driven clustering of kidney transplant histologic data could simplify the complex and discretionary rules of the Banff classification, while improving the association with graft failure.MethodsThe data consisted of a training set of 3510 kidney-transplant biopsies from an observational cohort of 936 recipients. Independent validation of the results was performed on an external set of 3835 biopsies from 1989 patients. On the basis of acute histologic lesion scores and the presence of donor-specific HLA antibodies, stable clustering was achieved on the basis of a consensus of 400 different clustering partitions. Additional information on kidney-transplant failure was introduced with a weighted Euclidean distance.ResultsBased on the proportion of ambiguous clustering, six clinically meaningful cluster phenotypes were identified. There was significant overlap with the existing Banff classification (adjusted rand index, 0.48). However, the data-driven approach eliminated intermediate and mixed phenotypes and created acute rejection clusters that are each significantly associated with graft failure. Finally, a novel visualization tool presents disease phenotypes and severity in a continuous manner, as a complement to the discrete clusters.ConclusionsA semisupervised clustering approach for the identification of clinically meaningful novel phenotypes of kidney transplant rejection has been developed and validated. The approach has the potential to offer a more quantitative evaluation of rejection subtypes and severity, especially in situations in which the current histologic categorization is ambiguous.
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2020101418
      Issue No: Vol. 32, No. 5 (2021)
       
  • The Rhesus Macaque Serves As a Model for Human Lateral Branch
           Nephrogenesis

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      Authors: Schuh, M. P; Alkhudairy, L, Potter, A, Potter, S. S, Chetal, K, Thakkar, K, Salomonis, N, Kopan, R.
      Pages: 1097 - 1112
      Abstract: BackgroundMost nephrons are added in late gestation. Truncated extrauterine nephrogenesis in premature infants results in fewer nephrons and significantly increased risk for CKD in adulthood. To overcome the ethical and technical difficulties associated with studies of late-gestation human fetal kidney development, third-trimester rhesus macaques served as a model to understand lateral branch nephrogenesis (LBN) at the molecular level.MethodsImmunostaining and 3D rendering assessed morphology. Single-cell (sc) and single-nucleus (sn) RNA-Seq were performed on four cortically enriched fetal rhesus kidneys of 129–131 days gestational age (GA). An integrative bioinformatics strategy was applied across single-cell modalities, species, and time. RNAScope validation studies were performed on human archival tissue.ResultsThird-trimester rhesus kidney undergoes human-like LBN. scRNA-Seq of 23,608 cells revealed 37 transcriptionally distinct cell populations, including naïve nephron progenitor cells (NPCs), with the prior noted marker genes CITED1, MEOX1, and EYA1 (c25). These same populations and markers were reflected in snRNA-Seq of 5972 nuclei. Late-gestation rhesus NPC markers resembled late-gestation murine NPC, whereas early second-trimester human NPC markers aligned to midgestation murine NPCs. New, age-specific rhesus NPCs (SHISA8) and ureteric buds (POU3F4 and TWIST) predicted markers were verified in late-gestation human archival samples.ConclusionsRhesus macaque is the first model of bona fide LBN, enabling molecular studies of late gestation, human-like nephrogenesis. These molecular findings support the hypothesis that aging nephron progenitors have a distinct molecular signature and align to their earlier human counterparts, with unique markers highlighting LBN-specific progenitor maturation.
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2020101459
      Issue No: Vol. 32, No. 5 (2021)
       
  • Protective Role of the M-Sec-Tunneling Nanotube System in Podocytes

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      Authors: Barutta, F; Kimura, S, Hase, K, Bellini, S, Corbetta, B, Corbelli, A, Fiordaliso, F, Barreca, A, Papotti, M. G, Ghiggeri, G. M, Salvidio, G, Roccatello, D, Audrito, V, Deaglio, S, Gambino, R, Bruno, S, Camussi, G, Martini, M, Hirsch, E, Durazzo, M, Ohno, H, Gruden, G.
      Pages: 1114 - 1130
      Abstract: BackgroundPodocyte dysfunction and loss are major determinants in the development of proteinuria. FSGS is one of the most common causes of proteinuria, but the mechanisms leading to podocyte injury or conferring protection against FSGS remain poorly understood. The cytosolic protein M-Sec has been involved in the formation of tunneling nanotubes (TNTs), membrane channels that transiently connect cells and allow intercellular organelle transfer. Whether podocytes express M-Sec is unknown and the potential relevance of the M-Sec–TNT system in FSGS has not been explored.MethodsWe studied the role of the M-Sec–TNT system in cultured podocytes exposed to Adriamycin and in BALB/c M-Sec knockout mice. We also assessed M-Sec expression in both kidney biopsies from patients with FSGS and in experimental FSGS (Adriamycin-induced nephropathy).ResultsPodocytes can form TNTs in a M-Sec–dependent manner. Consistent with the notion that the M-Sec–TNT system is cytoprotective, podocytes overexpressed M-Sec in both human and experimental FSGS. Moreover, M-Sec deletion resulted in podocyte injury, with mitochondrial abnormalities and development of progressive FSGS. In vitro, M-Sec deletion abolished TNT-mediated mitochondria transfer between podocytes and altered mitochondrial bioenergetics. Re-expression of M-Sec reestablishes TNT formation and mitochondria exchange, rescued mitochondrial function, and partially reverted podocyte injury.ConclusionsThese findings indicate that the M-Sec–TNT system plays an important protective role in the glomeruli by rescuing podocytes via mitochondrial horizontal transfer. M-Sec may represent a promising therapeutic target in FSGS, and evidence that podocytes can be rescued via TNT-mediated horizontal transfer may open new avenues of research.
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2020071076
      Issue No: Vol. 32, No. 5 (2021)
       
  • Renal Inflammation Induces Salt Sensitivity in Male db/db Mice through
           Dysregulation of ENaC

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      Authors: Veiras, L. C; Shen, J. Z. Y, Bernstein, E. A, Regis, G. C, Cao, D, Okwan-Duodu, D, Khan, Z, Gibb, D. R, Dominici, F. P, Bernstein, K. E, Giani, J. F.
      Pages: 1131 - 1149
      Abstract: BackgroundHypertension is considered a major risk factor for the progression of diabetic kidney disease. Type 2 diabetes is associated with increased renal sodium reabsorption and salt-sensitive hypertension. Clinical studies show that men have higher risk than premenopausal women for the development of diabetic kidney disease. However, the renal mechanisms that predispose to salt sensitivity during diabetes and whether sexual dimorphism is associated with these mechanisms remains unknown.MethodsFemale and male db/db mice exposed to a high-salt diet were used to analyze the progression of diabetic kidney disease and the development of hypertension.ResultsMale, 34-week-old, db/db mice display hypertension when exposed to a 4-week high-salt treatment, whereas equivalently treated female db/db mice remain normotensive. Salt-sensitive hypertension in male mice was associated with no suppression of the epithelial sodium channel (ENaC) in response to a high-salt diet, despite downregulation of several components of the intrarenal renin-angiotensin system. Male db/db mice show higher levels of proinflammatory cytokines and more immune-cell infiltration in the kidney than do female db/db mice. Blocking inflammation, with either mycophenolate mofetil or by reducing IL-6 levels with a neutralizing anti–IL-6 antibody, prevented the development of salt sensitivity in male db/db mice.ConclusionsThe inflammatory response observed in male, but not in female, db/db mice induces salt-sensitive hypertension by impairing ENaC downregulation in response to high salt. These data provide a mechanistic explanation for the sexual dimorphism associated with the development of diabetic kidney disease and salt sensitivity.
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2020081112
      Issue No: Vol. 32, No. 5 (2021)
       
  • Association between Longer Travel Distance for Transplant Care and Access
           to Kidney Transplantation and Graft Survival in the United States

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      Authors: Whelan, A. M; Johansen, K. L, Brar, S, McCulloch, C. E, Adey, D. B, Roll, G. R, Grimes, B, Ku, E.
      Pages: 1151 - 1161
      Abstract: BackgroundTransplant candidates may gain an advantage by traveling to receive care at a transplant center that may have more favorable characteristics than their local center. Factors associated with longer travel distance for transplant care and whether the excess travel distance (ETD) is associated with access to transplantation or with graft failure are unknown.MethodsThis study of adults in the United States wait-listed for kidney transplantation in 1995–2015 used ETD, defined as distance a patient traveled beyond the nearest transplant center for initial waiting list registration. We used linear regression to examine patient and center characteristics associated with ETD and Fine–Gray models to examine the association between ETD (modeled as a spline) and time to deceased or living donor transplantation or graft failure.ResultsOf 373,365 patients, 11% had an ETD≥50 miles. Traveling excess distance was more likely among patients who were of non-Black race or those whose nearest transplant center had lower annual living donor transplant volume. At an ETD of 50 miles, we observed a lower likelihood of deceased donor transplantation (subhazard ratio [SHR], 0.85; 95% confidence interval [95% CI], 0.84 to 0.87) but higher likelihood of living donor transplantation (SHR, 1.14; 95% CI, 1.12 to 1.16) compared with those who received care at their nearest center. ETD was weakly associated with higher risk of graft failure.ConclusionsPatients who travel excess distances for transplant care have better access to living donor but not deceased donor transplantation and slightly higher risk of graft failure. Traveling excess distances is not clearly associated with better outcomes, especially if living donors are unavailable.
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2020081242
      Issue No: Vol. 32, No. 5 (2021)
       
  • Safety and Efficacy of Daratumumab in Patients with Proliferative GN with
           Monoclonal Immunoglobulin Deposits

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      Authors: Zand, L; Rajkumar, S. V, Leung, N, Sethi, S, El Ters, M, Fervenza, F. C.
      Pages: 1163 - 1173
      Abstract: BackgroundTreatment of proliferative GN with monoclonal Ig deposits (PGNMID) is not established. A monoclonal anti-CD38 antibody (daratumumab) is effective in treating multiple myeloma. Abnormal plasma cell clones may play a role in the pathogenesis of PGNMID.MethodsWe evaluated daratumumab’s safety and efficacy in an open-label, phase 2 trial in 11 adults with PGNMID and one with C3 glomerulopathy (C3G) with monoclonal gammopathy. Patients had an eGFR >20 ml/min per 1.73 m2 and proteinuria >1 g/d. They received daratumumab intravenously (16 mg/kg) once weekly for 8 weeks, and then every other week for eight additional doses. Primary outcome was safety, defined as major infections, grade 3 or 4 anemia, leukopenia, or thrombocytopenia. Secondary outcomes were rate of complete remission (proteinuria
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2020101541
      Issue No: Vol. 32, No. 5 (2021)
       
  • Kidney Failure Prediction Models: A Comprehensive External Validation
           Study in Patients with Advanced CKD

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      Authors: Ramspek, C. L; Evans, M, Wanner, C, Drechsler, C, Chesnaye, N. C, Szymczak, M, Krajewska, M, Torino, C, Porto, G, Hayward, S, Caskey, F, Dekker, F. W, Jager, K. J, van Diepen, M, the EQUAL Study Investigators, EQUAL Study Investigators, Cupisti, Sagliocca, Ferraro, Musiała, Mele, Naticchia, Cosaro, Woodman, Ranghino, Stucchi, Jonsson, Schneider, Pignataro, Schrander, Torp, McKeever, Szymczak, Blom, De Blasio, Pani, Tsalouichos, Ullah, McLaren, van Dam, Iwig, Antonio, Di Iorio, Rogland, Perras, Alessandra, Harron, Wallquist, Siegert, Barrett, Gaillard, Garofalo, Abaterusso, Beerenhout, OToole, Somma, Marx, Summersgill, Blaser, Dalessandro, Emde, Zullo, Pozzi, Geddes, Verburgh, Bergamo, Ciurlino, Motta, Glowski, McGlynn, Vargas, Krieter, Russo, Fuchs, Sands, Hoogeveen, Irmler, Dimeny, Favaro, Platen, Olczyk, Hoorn, Vigotti, Ansali, Conte, Cianciotta, Giacchino, Cappellaio, Pizzarelli, Sundelin, Uhlin, Greco, Roy, Porto, Bigatti, Marinangeli, Cabiddu, Hirst, Fumagalli, Caloro, Piccoli, Capasso, Gambaro, Tognarelli, Bonforte, Conte, Toscano, Del Rosso, Welander, Augustyniak-Bartosik, Boots, Schmidt-Gürtler, King, McNally, Schlee, Boom, Naujoks, Masri-Senghor, Murtagh, Rayner, Miskowiec-Wisniewska, Schlee, Capizzi, Bascaran Hernandez, Baragetti, Manitius, Turner, Eijgenraam, Kooman, Beige, Pondel, Wilcox, Berdeprado, Röthele, Wong, Rotmans, Banda, Mazur, Hahn, Jedrzejak, Nowanska, Blouin, Neumeier, Jones, Anding-Rost, Gröntoft, Oldrizzi, Haydock, Vogt, Wilkinson, Gesualdo, Schramm, Biancone, Nowak, Raasveld, Durlik, Magnano, Vervloet, Ricardi, Carmody, Di Bari, Laudato, Luisa Sirico, Stendahl, Svensson, Weetman, van Buren, Joinson, Ferraresi, Dutton, van Diepen, Matthews, Provenzano, Hopf, Malaguti, Wuttke, Morgan, Palmieri, Frischmuth, Bleakley, Murrone, Cockwell, Leurs, Roderick, Voskamp, Kashioulis, Ichtiaris, Blankestijn, Kirste, Schulz, Mason, Kalra, Cirillo, Dattolo, Acampora, Sajith, Nigro, Boero, Scarpioni, Sicoli, Malandra, Aign, Cäsar, van Esch, Chapman, Biribauer, Navjee, Crosbie, Brown, Tickle, Manan, Röser, Savoldi, Bertoli, Borrelli, Boorsma, Heidenreich, Melander, Maxia, Maffei, Mangano, Palm, Konings, Mathavakkannan, Schwedler, Delrieux, Renker, Schättel, Dorota, Cicchetti, Nieszporek, Stephan, Schmiedeke, Weinreich, Leimbach, Rappa, Almquist, Stövesand, Bahner, Jensen, Palazzo, De Simone, Seeger, Kuan, Heleniak, Aydin
      Pages: 1174 - 1186
      Abstract: BackgroundVarious prediction models have been developed to predict the risk of kidney failure in patients with CKD. However, guideline-recommended models have yet to be compared head to head, their validation in patients with advanced CKD is lacking, and most do not account for competing risks.MethodsTo externally validate 11 existing models of kidney failure, taking the competing risk of death into account, we included patients with advanced CKD from two large cohorts: the European Quality Study (EQUAL), an ongoing European prospective, multicenter cohort study of older patients with advanced CKD, and the Swedish Renal Registry (SRR), an ongoing registry of nephrology-referred patients with CKD in Sweden. The outcome of the models was kidney failure (defined as RRT-treated ESKD). We assessed model performance with discrimination and calibration.ResultsThe study included 1580 patients from EQUAL and 13,489 patients from SRR. The average c statistic over the 11 validated models was 0.74 in EQUAL and 0.80 in SRR, compared with 0.89 in previous validations. Most models with longer prediction horizons overestimated the risk of kidney failure considerably. The 5-year Kidney Failure Risk Equation (KFRE) overpredicted risk by 10%–18%. The four- and eight-variable 2-year KFRE and the 4-year Grams model showed excellent calibration and good discrimination in both cohorts.ConclusionsSome existing models can accurately predict kidney failure in patients with advanced CKD. KFRE performed well for a shorter time frame (2 years), despite not accounting for competing events. Models predicting over a longer time frame (5 years) overestimated risk because of the competing risk of death. The Grams model, which accounts for the latter, is suitable for longer-term predictions (4 years).
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2020071077
      Issue No: Vol. 32, No. 5 (2021)
       
  • Podometrics in Japanese Living Donor Kidneys: Associations with Nephron
           Number, Age, and Hypertension

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      Authors: Haruhara, K; Sasaki, T, de Zoysa, N, Okabayashi, Y, Kanzaki, G, Yamamoto, I, Harper, I. S, Puelles, V. G, Shimizu, A, Cullen-McEwen, L. A, Tsuboi, N, Yokoo, T, Bertram, J. F.
      Pages: 1187 - 1199
      Abstract: BackgroundPodocyte depletion, low nephron number, aging, and hypertension are associated with glomerulosclerosis and CKD. However, the relationship between podometrics and nephron number has not previously been examined.MethodsTo investigate podometrics and nephron number in healthy Japanese individuals, a population characterized by a relatively low nephron number, we immunostained single paraffin sections from 30 Japanese living-kidney donors (median age, 57 years) with podocyte-specific markers and analyzed images obtained with confocal microscopy. We used model-based stereology to estimate podometrics, and a combined enhanced–computed tomography/biopsy-specimen stereology method to estimate nephron number.ResultsThe median number of nonsclerotic nephrons per kidney was 659,000 (interquartile range [IQR], 564,000–825,000). The median podocyte number and podocyte density were 518 (IQR, 428–601) per tuft and 219 (IQR, 180–253) per 106 μm3, respectively; these values are similar to those previously reported for other races. Total podocyte number per kidney (obtained by multiplying the individual number of nonsclerotic glomeruli by podocyte number per glomerulus) was 376 million (IQR, 259–449 million) and ranged 7.4-fold between donors. On average, these healthy kidneys lost 5.63 million podocytes per kidney per year, with most of this loss associated with glomerular loss resulting from global glomerulosclerosis, rather than podocyte loss from healthy glomeruli. Hypertension was associated with lower podocyte density and larger podocyte volume, independent of age.ConclusionsEstimation of the number of nephrons, podocytes, and other podometric parameters in individual kidneys provides new insights into the relationships between these parameters, age, and hypertension in the kidney. This approach might be of considerable value in evaluating the kidney in health and disease.
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2020101486
      Issue No: Vol. 32, No. 5 (2021)
       
  • BP in Young Adults with CKD and Associations with Cardiovascular Events
           and Decline in Kidney Function

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      Authors: Kula, A. J; Prince, D. K, Flynn, J. T, Bansal, N.
      Pages: 1200 - 1209
      Abstract: BackgroundBP is an important modifiable risk factor for cardiovascular events and CKD progression in middle-aged or older adults with CKD. However, studies describing the relationship between BP with outcomes in young adults with CKD are limited.MethodsIn an observational study, we focused on 317 young adults (aged 21–40 years) with mild to moderate CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. Exposures included baseline systolic BP evaluated continuously (per 10 mm Hg increase) and in categories (
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2020081156
      Issue No: Vol. 32, No. 5 (2021)
       
  • Comparing Approaches to Normalize, Quantify, and Characterize Urinary
           Extracellular Vesicles

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      Authors: Blijdorp, C. J; Tutakhel, O. A. Z, Hartjes, T. A, van den Bosch, T. P. P, van Heugten, M. H, Rigalli, J. P, Willemsen, R, Musterd-Bhaggoe, U. M, Barros, E. R, Carles-Fontana, R, Carvajal, C. A, Arntz, O. J, van de Loo, F. A. J, Jenster, G, Clahsen-van Groningen, M. C, Cuevas, C. A, Severs, D, Fenton, R. A, van Royen, M. E, Hoenderop, J. G. J, Bindels, R. J. M, Hoorn, E. J.
      Pages: 1210 - 1226
      Abstract: BackgroundUrinary extracellular vesicles (uEVs) are a promising source for biomarker discovery, but optimal approaches for normalization, quantification, and characterization in spot urines are unclear.MethodsUrine samples were analyzed in a water-loading study, from healthy subjects and patients with kidney disease. Urine particles were quantified in whole urine using nanoparticle tracking analysis (NTA), time-resolved fluorescence immunoassay (TR-FIA), and EVQuant, a novel method quantifying particles via gel immobilization.ResultsUrine particle and creatinine concentrations were highly correlated in the water-loading study (R 2 0.96) and in random spot urines from healthy subjects (R 2 0.47–0.95) and patients (R 2 0.41–0.81). Water loading reduced aquaporin-2 but increased Tamm-Horsfall protein (THP) and particle detection by NTA. This finding was attributed to hypotonicity increasing uEV size (more EVs reach the NTA size detection limit) and reducing THP polymerization. Adding THP to urine also significantly increased particle count by NTA. In both fluorescence NTA and EVQuant, adding 0.01% SDS maintained uEV integrity and increased aquaporin-2 detection. Comparison of intracellular- and extracellular-epitope antibodies suggested the presence of reverse topology uEVs. The exosome markers CD9 and CD63 colocalized and immunoprecipitated selectively with distal nephron markers. Conclusions uEV concentration is highly correlated with urine creatinine, potentially replacing the need for uEV quantification to normalize spot urines. Additional findings relevant for future uEV studies in whole urine include the interference of THP with NTA, excretion of larger uEVs in dilute urine, the ability to use detergent to increase intracellular-epitope recognition in uEVs, and CD9 or CD63 capture of nephron segment–specific EVs.
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2020081142
      Issue No: Vol. 32, No. 5 (2021)
       
  • IgM Autoantibodies to Complement Factor H in Atypical Hemolytic Uremic
           Syndrome

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      Authors: Cugno, M; Berra, S, Depetri, F, Tedeschi, S, Griffini, S, Grovetti, E, Caccia, S, Cresseri, D, Messa, P, Testa, S, Giglio, F, Peyvandi, F, Ardissino, G.
      Pages: 1227 - 1235
      Abstract: BackgroundAtypical hemolytic uremic syndrome (aHUS), a severe thrombotic microangiopathy, is often related to complement dysregulation, but the pathomechanisms remain unknown in at least 30% of patients. Researchers have described autoantibodies to complement factor H of the IgG class in 10% of patients with aHUS but have not reported anti-factor H autoantibodies of the IgM class.MethodsIn 186 patients with thrombotic microangiopathy clinically presented as aHUS, we searched for anti-factor H autoantibodies of the IgM class and those of the IgG and IgA classes. We used immunochromatography to purify anti-factor H IgM autoantibodies and immunoenzymatic methods and a competition assay with mapping mAbs to characterize interaction with the target protein.ResultsWe detected anti-factor H autoantibodies of the IgM class in seven of 186 (3.8%) patients with thrombotic microangiopathy presented as aHUS. No association was observed between anti-factor H IgM and homozygous deletions involving CFHR3-CFHR1. A significantly higher proportion of patients with bone marrow transplant–related thrombotic microangiopathy had anti-factor H IgM autoantibodies versus other patients with aHUS: three of 20 (15%) versus four of 166 (2.4%), respectively. The identified IgM autoantibodies recognize the SCR domain 19 of factor H molecule in all patients and interact with the factor H molecule, inhibiting its binding to C3b.ConclusionsDetectable autoantibodies to factor H of the IgM class may be present in patients with aHUS, and their frequency is six-fold higher in thrombotic microangiopathy forms associated with bone marrow transplant. The autoantibody interaction with factor H’s active site may support an autoimmune mechanism in some cases previously considered to be of unknown origin.
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2020081224
      Issue No: Vol. 32, No. 5 (2021)
       
  • Impact of the COVID-19 Pandemic on Nephrology Fellow Training and
           Well-Being in the United States: A National Survey

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      Authors: Pivert, K. A; Boyle, S. M, Halbach, S. M, Chan, L, Shah, H. H, Waitzman, J. S, Mehdi, A, Norouzi, S, Sozio, S. M.
      Pages: 1236 - 1248
      Abstract: BackgroundThe coronavirus disease 2019 (COVID-19) pandemic’s effects on nephrology fellows’ educational experiences, preparedness for practice, and emotional wellbeing are unknown.MethodsWe recruited current adult and pediatric fellows and 2020 graduates of nephrology training programs in the United States to participate in a survey measuring COVID-19’s effects on their training experiences and wellbeing.ResultsOf 1005 nephrology fellows-in-training and recent graduates, 425 participated (response rate 42%). Telehealth was widely adopted (90% for some or all outpatient nephrology consults), as was remote learning (76% of conferences were exclusively online). Most respondents (64%) did not have in-person consults on COVID-19 inpatients; these patients were managed by telehealth visits (27%), by in-person visits with the attending faculty without fellows (29%), or by another approach (9%). A majority of fellows (84%) and graduates (82%) said their training programs successfully sustained their education during the pandemic, and most fellows (86%) and graduates (90%) perceived themselves as prepared for unsupervised practice. Although 42% indicated the pandemic had negatively affected their overall quality of life and 33% reported a poorer work-life balance, only 15% of 412 respondents who completed the Resident Well-Being Index met its distress threshold. Risk for distress was increased among respondents who perceived the pandemic had impaired their knowledge base (odds ratio [OR], 3.04; 95% confidence interval [CI], 2.00 to 4.77) or negatively affected their quality of life (OR, 3.47; 95% CI, 2.29 to 5.46) or work-life balance (OR, 3.16; 95% CI, 2.18 to 4.71).ConclusionsDespite major shifts in education modalities and patient care protocols precipitated by the COVID-19 pandemic, participants perceived their education and preparation for practice to be minimally affected.
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2020111636
      Issue No: Vol. 32, No. 5 (2021)
       
  • Protocadherin 7-Associated Membranous Nephropathy

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      Authors: Sethi, S; Madden, B, Debiec, H, Morelle, J, Charlesworth, M. C, Gross, L, Negron, V, Buob, D, Chaudhry, S, Jadoul, M, Fervenza, F. C, Ronco, P.
      Pages: 1249 - 1261
      Abstract: BackgroundMembranous nephropathy (MN) results from deposition of antigen-antibody complexes along the glomerular basement membrane (GBM). PLA2R, THSD7A, NELL1, and SEMA3B account for 80%–90% of target antigens in MN.MethodsWe performed laser microdissection and mass spectrometry (MS/MS) in kidney biopsies from 135 individuals with PLA2R-negative MN, and used immunohistochemistry/immunofluorescence and confocal microscopy to confirm the MS/MS finding, detect additional cases, and localize the novel protein. We also performed MS/MS and immunohistochemistry on 116 controls and used immunofluorescence microscopy to screen biopsy samples from two validation cohorts. Western blot and elution studies were performed to detect antibodies in serum and biopsy tissue.ResultsMS/MS studies detected a unique protein, protocadherin 7 (PCDH7), in glomeruli of ten (5.7%) PLA2R-negative MN cases, which also were negative for PLA2R, THSD7A, EXT1/EXT2, NELL1, and SEMA3B. Spectral counts ranged from six to 24 (average 13.2 [SD 6.6]). MS/MS did not detect PCDH7 in controls (which included 28 PLA2R-positive cases). In all ten PCDH7-positive cases, immunohistochemistry showed bright granular staining along the GBM, which was absent in the remaining cases of PLA2R-negative MN and control cases. Four of 69 (5.8%) cases in the validation cohorts (all of which were negative for PLA2R, THSD7A, EXT1, NELL1, and SEMA3B) were PCDH7-positive MN. Kidney biopsy showed minimal complement deposition in 12 of the 14 PCDH7-associated cases. Confocal microscopy showed colocalization of PCDH7 and IgG along the GBM. Western blot analysis using sera from six patients showed antibodies to nonreduced PCDH7. Elution of IgG from frozen tissue of PCDH7-associated MN showed reactivity against PCDH7.ConclusionsMN associated with the protocadherin PCDH7 appears to be a distinct, previously unidentified type of MN.
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2020081165
      Issue No: Vol. 32, No. 5 (2021)
       
  • Procurement Biopsy Data Quality Limits Comparability of United States and
           French Deceased Donor Kidney Biopsies

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      Authors: Husain, S. A; Mohan, S.
      Pages: 1263 - 1264
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2020121788
      Issue No: Vol. 32, No. 5 (2021)
       
  • Authors Reply

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      Authors: Reese, P. P; Aubert, O, Loupy, A.
      Pages: 1264 - 1265
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2021020207
      Issue No: Vol. 32, No. 5 (2021)
       
  • Receptor-Mediated Endocytosis and Differentiation in Proximal Tubule Cell
           Systems

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      Authors: Berquez, M; Krohn, P, Luciani, A, Devuyst, O.
      Pages: 1265 - 1267
      PubDate: 2021-05-01T06:48:23-07:00
      DOI: 10.1681/ASN.2021020253
      Issue No: Vol. 32, No. 5 (2021)
       
 
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