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APOL1 genotype-associated morphologic changes among patients with focal segmental glomerulosclerosis

Zee, Jarcy; McNulty, Michelle T; Hodgin, Jeffrey B; Zhdanova, Olga; Hingorani, Sangeeta; Jefferson, Jonathan Ashley; Gibson, Keisha L; Trachtman, Howard; Fornoni, Alessia; Dell, Katherine M; Reich, Heather N; Bagnasco, Serena; Greenbaum, Larry A; Lafayette, Richard A; Gipson, Debbie S; Brown, Elizabeth; Kretzler, Matthias; Appel, Gerald; Sambandam, Kamalanathan K; Tuttle, Katherine R; Chen, Dhruti; Atkinson, Meredith A; Hogan, Marie C; Kaskel, Frederick J; Meyers, Kevin E; O'Toole, John; Srivastava, Tarak; Sethna, Christine B; Hladunewich, Michelle A; Lin, J J; Nast, Cynthia C; Derebail, Vimal K; Patel, Jiten; Vento, Suzanne; Holzman, Lawrence B; Athavale, Ambarish M; Adler, Sharon G; Lemley, Kevin V; Lieske, John C; Hogan, Jonathan J; Gadegbeku, Crystal A; Fervenza, Fernando C; Wang, Chia-Shi; Matar, Raed Bou; Singer, Pamela; Kopp, Jeffrey B; Barisoni, Laura; Sampson, Matthew G
BACKGROUND:The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1's natural absence in laboratory animals makes studying its pathobiology challenging. METHODS:In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes. RESULTS:Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features. CONCLUSIONS:While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes.
PMID: 33646395
ISSN: 1432-198x
CID: 4801182

Acute Peritoneal Dialysis During the COVID-19 Pandemic at Bellevue Hospital in New York City

Caplin, Nina J; Zhdanova, Olga; Tandon, Manish; Thompson, Nathan; Patel, Dhwanil; Soomro, Qandeel; Ranjeeta, Fnu; Joseph, Leian; Scherer, Jennifer; Joshi, Shivam; Dyal, Betty; Chawla, Harminder; Iyer, Sitalakshmi; Bails, Douglas; Benstein, Judith; Goldfarb, David S; Gelb, Bruce; Amerling, Richard; Charytan, David M
Background:The COVID-19 pandemic strained hospital resources in New York City, including those for providing dialysis. New York University Medical Center and affiliations, including New York City Health and Hospitals/Bellevue, developed a plan to offset the increased needs for KRT. We established acute peritoneal dialysis (PD) capability, as usual dialysis modalities were overwhelmed by COVID-19 AKI. Methods:Observational study of patients requiring KRT admitted to Bellevue Hospital during the COVID surge. Bellevue Hospital is one of the largest public hospitals in the United States, providing medical care to an underserved population. There were substantial staff, supplies, and equipment shortages. Adult patients admitted with AKI who required KRT were considered for PD. We rapidly established an acute PD program. A surgery team placed catheters at the bedside in the intensive care unit; a nephrology team delivered treatment. We provided an alternative to hemodialysis and continuous venovenous hemofiltration for treating patients in the intensive-care unit, demonstrating efficacy with outcomes comparable to standard care. Results:From April 8, 2020 to May 8, 2020, 39 catheters were placed into ten women and 29 men. By June 10, 39% of the patients started on PD recovered kidney function (average ages 56 years for men and 59.5 years for women); men and women who expired were an average 71.8 and 66.2 years old. No episodes of peritonitis were observed; there were nine incidents of minor leaking. Some patients were treated while ventilated in the prone position. Conclusions:Demand compelled us to utilize acute PD during the COVID-19 pandemic. Our experience is one of the largest recently reported in the United States of which we are aware. Acute PD provided lifesaving care to acutely ill patients when expanding current resources was impossible. Our experience may help other programs to avoid rationing dialysis treatments in health crises.
PMID: 35372895
ISSN: 2641-7650
CID: 5219412

Impending Shortages of Kidney Replacement Therapy for COVID-19 Patients

Goldfarb, David S; Benstein, Judith A; Zhdanova, Olga; Hammer, Elizabeth; Block, Clay A; Caplin, Nina J; Thompson, Nathan; Charytan, David M
PMID: 32345750
ISSN: 1555-905x
CID: 4412262

Acute peritoneal dialysis during the COVID-19 pandemic in new york city [Meeting Abstract]

Caplin, N J; Tandon, M; Zhdanova, O; Amerling, R; Thompson, N
Introduction: The dramatic spread of COVID-19 in March 2020 threatened to overwhelm ICU capacity. At the peak we had more than 120 patients in the ICU. About 40% of the ICU patients required RRT due to AKI. Our ability to provide RRT with CVVH and IHD was severely limited by critical shortages of equipment and personnel. We rapidly established an acute PD program at Bellevue hospital for AKI patients. The acute PD program turned out to be instrumental in the BH response to COVID AKI. Case Description: Patients All patients who needed RRT in the ICU were eligible to receive PD catheters except for those with prior abdominal surgery. 36/38 patients who received catheters were Covid (+). Proning was not always planned; we did not use this as a contraindication. We were able to successfully perform adequate PD on patients who were proned with minimal complications. Surgical Support Catheters were placed using a limited cut down to the peritoneal membrane through the rectus muscle at bedside; most of the patients were intubated and sedated. Training and Initial Experience A nurse affiliated with Bellevue's outpatient dialysis unit helped make videos and trained the lead nephrologist on how to perform PD and how to use a Cycler. 25 people were on the PD team and we were able to provide exchanges 24 hours per day. Exchanges were initially performed manually every 1-2 hours. Eventually we acquired 18 cyclers which greatly eased the workload. Outcomes As of May 8, 2020 63 patients were evaluated, 38 PD catheters were placed with 35 used for exchanges. 2 patients had catheters placed but recovered renal function prior to starting PD. 1/38 was nonfunctioning and changed to IHD. 15/35 survived >30 days; 8 recovered renal function; 20 expired <30 days.
Discussion(s): Because of the shortage of our typically used dialysis modalities we were compelled to start an acute PD program. No patient on PD required additional dialytic support with IHD or CVVH. PD was well tolerated by ventilated patients with hemodynamic instability. Acute PD more than adequately filled the gap in treatment options during this unprecedented crisis
ISSN: 1533-3450
CID: 4750112

DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients with FSGS

Trachtman, Howard; Nelson, Peter; Adler, Sharon; Campbell, Kirk N; Chaudhuri, Abanti; Derebail, Vimal Kumar; Gambaro, Giovanni; Gesualdo, Loreto; Gipson, Debbie S; Hogan, Jonathan; Lieberman, Kenneth; Marder, Brad; Meyers, Kevin Edward; Mustafa, Esmat; Radhakrishnan, Jai; Srivastava, Tarak; Stepanians, Miganush; Tesar, Vladimír; Zhdanova, Olga; Komers, Radko
BACKGROUND:) and angiotensin II type 1 receptor antagonist, with those of the angiotensin II type 1 receptor antagonist irbesartan in patients with primary FSGS. METHODS:, and urinary protein-to-creatinine ratio (UP/C) ≥1.0 g/g received sparsentan (200, 400, or 800 mg/d) or irbesartan (300 mg/d) for 8 weeks, followed by open-label sparsentan only. End points at week 8 were reduction from baseline in UP/C (primary) and proportion of patients achieving FSGS partial remission end point (FPRE) (UP/C: ≤1.5 g/g and >40% reduction [secondary]). RESULTS:=0.04). After 8 weeks of treatment, BP was reduced with sparsentan but not irbesartan, and eGFR was stable with both treatments. Overall, the incidence of adverse events was similar between groups. Hypotension and edema were more common among sparsentan-treated patients but did not result in study withdrawals. CONCLUSIONS:Patients with FSGS achieved significantly greater reductions in proteinuria after 8 weeks of sparsentan versus irbesartan. Sparsentan was safe and well tolerated.
PMID: 30361325
ISSN: 1533-3450
CID: 3385302

Complete Remission in the Nephrotic Syndrome Study Network

Gipson, Debbie S; Troost, Jonathan P; Lafayette, Richard A; Hladunewich, Michelle A; Trachtman, Howard; Gadegbeku, Crystal A; Sedor, John R; Holzman, Lawrence B; Moxey-Mims, Marva M; Perumal, Kalyani; Kaskel, Frederick J; Nelson, Peter J; Tuttle, Katherine R; Bagnasco, Serena M; Hogan, Marie C; Dell, Katherine M; Appel, Gerald B; Lieske, John C; Ilori, Titilayo O; Sethna, Christine B; Fervenza, Fernando C; Hogan, Susan L; Nachman, Patrick H; Rosenberg, Avi Z; Greenbaum, Larry A; Meyers, Kevin E C; Hewitt, Stephen M; Choi, Michael J; Kopp, Jeffrey B; Zhdanova, Olga; Hodgin, Jeffrey B; Johnstone, Duncan B; Adler, Sharon G; Avila-Casado, Carmen; Neu, Alicia M; Hingorani, Sangeeta R; Lemley, Kevin V; Nast, Cynthia C; Brady, Tammy M; Barisoni-Thomas, Laura; Fornoni, Alessia; Jennette, J Charles; Cattran, Daniel C; Palmer, Matthew B; Gibson, Keisha L; Reich, Heather N; Mokrzycki, Michele H; Sambandam, Kamalanathan K; Zilleruelo, Gaston E; Licht, Christoph; Sampson, Matthew G; Song, Peter; Mariani, Laura H; Kretzler, Matthias
BACKGROUND AND OBJECTIVES: This analysis from the Nephrotic Syndrome Study Network (NEPTUNE) assessed the phenotypic and pathology characteristics of proteinuric patients undergoing kidney biopsy and defined the frequency and factors associated with complete proteinuria remission (CRever). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We enrolled adults and children with proteinuria >/=0.5 g/d at the time of first clinically indicated renal biopsy at 21 sites in North America from April 2010 to June 2014 into a prospective cohort study. NEPTUNE central pathologists assigned participants to minimal-change disease (MCD), FSGS, membranous nephropathy, or other glomerulopathy cohorts. Outcome measures for this analysis were (1) CRever with urine protein-to-creatinine ratio (UPC) <0.3 g/g with preserved native kidney function and (2) ESRD. Continuous variables are reported as median and interquartile range (IQR; 25th, 75th percentile). Cox proportional hazards modeling was used to assess factors associated with CRever. RESULTS: We enrolled 441 patients: 116 (27%) had MCD, 142 (32%) had FSGS, 66 (15%) had membranous nephropathy, and 117 (27%) had other glomerulopathy. The baseline UPC was 4.1 g/g (IQR, 1.9, 7.7) and the eGFR was 81 ml/min per 1.73 m(2) (IQR, 50, 105). Median duration of observation was 19 months (IQR, 11, 30). CRever occurred in 46% of patients, and 4.6% progressed to ESRD. Multivariate analysis demonstrated that higher prebiopsy proteinuria (hazard ratio, 0.3; 95% confidence interval, 0.2 to 0.5) and pathology diagnosis (FSGS versus MCD; hazard ratio, 0.2; 95% confidence interval, 0.1 to 0.5) were inversely associated with CRever. The effect of immunosuppressive therapy on remission varied by pathology diagnosis. CONCLUSIONS: In NEPTUNE, the high frequency of other pathology in proteinuric patients affirms the value of the diagnostic kidney biopsy. Clinical factors, including level of proteinuria before biopsy, pathology diagnosis, and immunosuppression, are associated with complete remission.
PMID: 26656320
ISSN: 1555-905x
CID: 2041412

Design of the Nephrotic Syndrome Study Network (NEPTUNE) to evaluate primary glomerular nephropathy by a multidisciplinary approach

Gadegbeku, Crystal A; Gipson, Debbie S; Holzman, Lawrence B; Ojo, Akinlolu O; Song, Peter X K; Barisoni, Laura; Sampson, Matthew G; Kopp, Jeffrey B; Lemley, Kevin V; Nelson, Peter J; Lienczewski, Chrysta C; Adler, Sharon G; Appel, Gerald B; Cattran, Daniel C; Choi, Michael J; Contreras, Gabriel; Dell, Katherine M; Fervenza, Fernando C; Gibson, Keisha L; Greenbaum, Larry A; Hernandez, Joel D; Hewitt, Stephen M; Hingorani, Sangeeta R; Hladunewich, Michelle; Hogan, Marie C; Hogan, Susan L; Kaskel, Frederick J; Lieske, John C; Meyers, Kevin E C; Nachman, Patrick H; Nast, Cynthia C; Neu, Alicia M; Reich, Heather N; Sedor, John R; Sethna, Christine B; Trachtman, Howard; Tuttle, Katherine R; Zhdanova, Olga; Zilleruelo, Gaston E; Kretzler, Matthias
The Nephrotic Syndrome Study Network (NEPTUNE) is a North American multicenter collaborative consortium established to develop a translational research infrastructure for nephrotic syndrome. This includes a longitudinal observational cohort study, a pilot and ancillary study program, a training program, and a patient contact registry. NEPTUNE will enroll 450 adults and children with minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy for detailed clinical, histopathological, and molecular phenotyping at the time of clinically indicated renal biopsy. Initial visits will include an extensive clinical history, physical examination, collection of urine, blood and renal tissue samples, and assessments of quality of life and patient-reported outcomes. Follow-up history, physical measures, urine and blood samples, and questionnaires will be obtained every 4 months in the first year and biannually, thereafter. Molecular profiles and gene expression data will be linked to phenotypic, genetic, and digitalized histological data for comprehensive analyses using systems biology approaches. Analytical strategies were designed to transform descriptive information to mechanistic disease classification for nephrotic syndrome and to identify clinical, histological, and genomic disease predictors. Thus, understanding the complexity of the disease pathogenesis will guide further investigation for targeted therapeutic strategies.Kidney International advance online publication, 16 January 2013; doi:10.1038/ki.2012.428.
PMID: 23325076
ISSN: 0085-2538
CID: 220962

The inducible deletion of Drosha and microRNAs in mature podocytes results in a collapsing glomerulopathy

Zhdanova, Olga; Srivastava, Shekhar; Di, Lie; Li, Zhai; Tchelebi, Leila; Dworkin, Sara; Johnstone, Duncan B; Zavadil, Jiri; Chong, Mark M; Littman, Dan R; Holzman, Lawrence B; Barisoni, Laura; Skolnik, Edward Y
Micro-RNAs (miRNAs) are short (average 22 nucleotides) noncoding regulatory RNAs that inhibit gene expression by targeting complementary 3'-untranslated regions of protein-encoding mRNAs for translational repression or degradation. miRNAs play key roles in both the function and differentiation of many cell types. Drosha and Dicer, two RNAase III enzymes, function in a stepwise manner to generate a mature miRNA. Previous studies have shown that podocyte-specific deletion of Dicer during development results in proteinuric renal disease and collapsing glomerulopathy (CG); however, Dicer has functions other than the generation of miRNAs. Here we found that the podocyte-specific deletion of Drosha results in a similar phenotype to Dicer mutants, confirming that the Dicer mutant phenotype is due to the loss of miRNAs. Moreover, the inducible deletion of Drosha in 2- to 3-month-old mice (Tet-On system) resulted in CG. Thus, continuous generation of miRNAs are required for the normal function of mature podocytes and their loss leads to CG. Identifying these miRNAs may provide new insight into disease pathogenesis and novel therapeutic targets in various podocytopathies
PMID: 21544061
ISSN: 1523-1755
CID: 137467

Nucleoside diphosphate kinase B knock-out mice have impaired activation of the K+ channel KCa3.1, resulting in defective T cell activation

Di, Lie; Srivastava, Shekhar; Zhdanova, Olga; Sun, Yi; Li, Zhai; Skolnik, Edward Y
Nucleoside diphosphate kinases (NDPKs) are encoded by the Nme (non-metastatic cell) gene family. Although they comprise a family of 10 genes, NDPK-A and -B are ubiquitously expressed and account for most of the NDPK activity. We previously showed that NDPK-B activates the K(+) channel KCa3.1 via histidine phosphorylation of the C terminus of KCa3.1, which is required for T cell receptor-stimulated Ca(2+) flux and proliferation of activated naive human CD4 T cells. We now report the phenotype of NDPK-B(-/-) mice. NDPK-B(-/-) mice are phenotypically normal at birth with a normal life span. Although T and B cell development is normal in NDPK-B(-/-) mice, KCa3.1 channel activity and cytokine production are markedly defective in T helper 1 (Th1) and Th2 cells, whereas Th17 function is normal. These findings phenocopy studies in the same cells isolated from KCa3.1(-/-) mice and thereby support genetically that NDPK-B functions upstream of KCa3.1. NDPK-A and -B have been linked to an astonishing array of disparate cellular and biochemical functions, few of which have been confirmed in vivo in physiological relevant systems. NDPK-B(-/-) mice will be an essential tool with which to definitively address the biological functions of NDPK-B. Our finding that NDPK-B is required for activation of Th1 and Th2 CD4 T cells, together with the normal overall phenotype of NDPK-B(-/-) mice, suggests that specific pharmacological inhibitors of NDPK-B may provide new opportunities to treat Th1- and Th2-mediated autoimmune diseases
PMID: 20884616
ISSN: 1083-351x
CID: 116205

Inhibition of the K+ channel KCa3.1 ameliorates T cell-mediated colitis

Di, Lie; Srivastava, Shekhar; Zhdanova, Olga; Ding, Yi; Li, Zhai; Wulff, Heike; Lafaille, Maria; Skolnik, Edward Y
The calcium-activated K(+) channel KCa3.1 plays an important role in T lymphocyte Ca(2+) signaling by helping to maintain a negative membrane potential, which provides an electrochemical gradient to drive Ca(2+) influx. To assess the role of KCa3.1 channels in lymphocyte activation in vivo, we studied T cell function in KCa3.1(-/-) mice. CD4 T helper (i.e., Th0) cells isolated from KCa3.1(-/-) mice lacked KCa3.1 channel activity, which resulted in decreased T cell receptor-stimulated Ca(2+) influx and IL-2 production. Although loss of KCa3.1 did not interfere with CD4 T cell differentiation, both Ca(2+) influx and cytokine production were impaired in KCa3.1(-/-) Th1 and Th2 CD4 T cells, whereas T-regulatory and Th17 function were normal. We found that inhibition of KCa3.1(-/-) protected mice from developing severe colitis in two mouse models of inflammatory bowel disease, which were induced by (i) the adoptive transfer of mouse naive CD4 T cells into rag2(-/-) recipients and (ii) trinitrobenzene sulfonic acid. Pharmacologic inhibitors of KCa3.1 have already been shown to be safe in humans. Thus, if these preclinical studies continue to show efficacy, it may be possible to rapidly test whether KCa3.1 inhibitors are efficacious in patients with inflammatory bowel diseases such as Crohn's disease and ulcerative colitis
PMID: 20080610
ISSN: 0027-8424
CID: 106594