Publications by authors named "Thangamani Muthukumar"

70 Publications

Serum MicroRNA Transcriptomics and Acute Rejection or Recurrent Hepatitis C Virus in Human Liver Allograft Recipients: A Pilot Study.

Transplantation 2021 May 11. Epub 2021 May 11.

Division of Nephrology and Hypertension, Joan and Sanford I. Weill Department of Medicine and Department of Transplantation Medicine, New York Presbyterian-Weill Cornell Medicine, New York, NY. Laboratory of RNA Molecular Biology, The Rockefeller University, New York, NY. Department of Psychiatry and Behavioral Science, Stony Brook University, Stony Brook, NY. Division of Biostatistics, Department of Public Health Sciences, University of California at Davis, Davis, CA. Rho Federal Systems, Chapel Hill, NC. Division of Transplantation Pathology, Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA.

Background: Acute rejection (AR) and recurrent HCV (R-HCV) are significant complications in liver allograft recipients. Noninvasive diagnosis of intragraft pathologies may improve their management.

Methods: We performed small RNA sequencing and miRNA microarray profiling of RNA from sera matched to liver allograft biopsies from patients with nonimmune, nonviral (NINV) native liver disease. Absolute levels of informative miRNAs in 91 sera matched to 91 liver allograft biopsies were quantified using customized RT-qPCR assays: 30 biopsy-matched sera from 26 unique NINV patients and 61 biopsy-matched sera from 41 unique R-HCV patients. The association between biopsy diagnosis and miRNA abundance was analyzed by logistic regression and calculating the area under the receiver operating characteristic curve.

Results: Nine miRNAs- miR-22, miR-34a, miR-122, miR-148a, miR-192, miR-193b, miR-194, miR-210 and miR-885-5p- were identified by both sRNA-seq and TLDA to be associated with NINV-AR. Logistic regression analysis of absolute levels of miRNAs and goodness-of-fit of predictors identified a linear combination of miR-34a + miR-210 (P<0.0001) as the best statistical model and miR-122 + miR-210 (P<0.0001) as the best model that included miR-122. A different linear combination of miR-34a + miR-210 (P<0.0001) was the best model for discriminating NINV-AR from R-HCV with intragraft inflammation, and miR-34a + miR-122 (P<0.0001) was the best model for discriminating NINV-AR from R-HCV with intragraft fibrosis.

Conclusions: Circulating levels of miRNAs, quantified using customized RT-qPCR assays, may offer a rapid and noninvasive means of diagnosing AR in human liver allografts and for discriminating AR from intragraft inflammation or fibrosis due to recurrent HCV.Supplemental Visual Abstract; http://links.lww.com/TP/C231.
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http://dx.doi.org/10.1097/TP.0000000000003815DOI Listing
May 2021

Deep sequencing of DNA from urine of kidney allograft recipients to estimate donor/recipient-specific DNA fractions.

PLoS One 2021 15;16(4):e0249930. Epub 2021 Apr 15.

Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Doha, Qatar.

Kidney transplantation is the treatment of choice for patients with end-stage kidney failure, but transplanted allograft could be affected by viral and bacterial infections and by immune rejection. The standard test for the diagnosis of acute pathologies in kidney transplants is kidney biopsy. However, noninvasive tests would be desirable. Various methods using different techniques have been developed by the transplantation community. But these methods require improvements. We present here a cost-effective method for kidney rejection diagnosis that estimates donor/recipient-specific DNA fraction in recipient urine by sequencing urinary cell DNA. We hypothesized that in the no-pathology stage, the largest tissue types present in recipient urine are donor kidney cells, and in case of rejection, a larger number of recipient immune cells would be observed. Extensive in-silico simulation was used to tune the sequencing parameters: number of variants and depth of coverage. Sequencing of DNA mixture from 2 healthy individuals showed the method is highly predictive (maximum error < 0.04). We then demonstrated the insignificant impact of familial relationship and ethnicity using an in-house and public database. Lastly, we performed deep DNA sequencing of urinary cell pellets from 32 biopsy-matched samples representing two pathology groups: acute rejection (AR, 11 samples) and acute tubular injury (ATI, 12 samples) and 9 samples with no pathology. We found a significant association between the donor/recipient-specific DNA fraction in the two pathology groups compared to no pathology (P = 0.0064 for AR and P = 0.026 for ATI). We conclude that deep DNA sequencing of urinary cells from kidney allograft recipients offers a noninvasive means of diagnosing acute pathologies in the human kidney allograft.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249930PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049329PMC
April 2021

Deceased-Donor Acute Kidney Injury and BK Polyomavirus in Kidney Transplant Recipients.

Clin J Am Soc Nephrol 2021 May 10;16(5):765-775. Epub 2021 Mar 10.

Division of Nephrology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland

Background And Objectives: BK polyomavirus (BKV) infection commonly complicates kidney transplantation, contributing to morbidity and allograft failure. The virus is often donor-derived and influenced by ischemia-reperfusion processes and disruption of structural allograft integrity. We hypothesized that deceased-donor AKI associates with BKV infection in recipients.

Design, Setting, Participants, & Measurements: We studied 1025 kidney recipients from 801 deceased donors transplanted between 2010 and 2013, at 13 academic centers. We fitted Cox proportional-hazards models for BKV DNAemia (detectable in recipient blood by clinical PCR testing) within 1 year post-transplantation, adjusting for donor AKI and other donor- and recipient-related factors. We validated findings from this prospective cohort with analyses for graft failure attributed to BKV within the Organ Procurement and Transplantation Network (OPTN) database.

Results: The multicenter cohort mean kidney donor profile index was 49±27%, and 26% of donors had AKI. Mean recipient age was 54±13 years, and 25% developed BKV DNAemia. Donor AKI was associated with lower risk for BKV DNAemia (adjusted hazard ratio, 0.53; 95% confidence interval, 0.36 to 0.79). In the OPTN database, 22,537 (25%) patients received donor AKI kidneys, and 272 (0.3%) developed graft failure from BKV. The adjusted hazard ratio for the outcome with donor AKI was 0.7 (95% confidence interval, 0.52 to 0.95).

Conclusions: In a well-characterized, multicenter cohort, contrary to our hypothesis, deceased-donor AKI independently associated with lower risk for BKV DNAemia. Within the OPTN database, donor AKI was also associated with lower risk for graft failure attributed to BKV.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_03_10_CJN18101120_final.mp3.
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http://dx.doi.org/10.2215/CJN.18101120DOI Listing
May 2021

Contemporary incidence and risk factors of post transplant Erythrocytosis in deceased donor kidney transplantation.

BMC Nephrol 2021 Jan 12;22(1):26. Epub 2021 Jan 12.

Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Post-Transplant erythrocytosis (PTE) has not been studied in large recent cohorts. In this study, we evaluated the incidence, risk factors, and outcome of PTE with current transplant practices using the present World Health Organization criteria to define erythrocytosis. We also tested the hypothesis that the risk of PTE is greater with higher-quality kidneys.

Methods: We utilized the Deceased Donor Study which is an ongoing, multicenter, observational study of deceased donors and their kidney recipients that were transplanted between 2010 and 2013 across 13 centers. Eryrthocytosis is defined by hemoglobin> 16.5 g/dL in men and> 16 g/dL in women. Kidney quality is measured by Kidney Donor Profile Index (KDPI).

Results: Of the 1123 recipients qualified to be in this study, PTE was observed at a median of 18 months in 75 (6.6%) recipients. Compared to recipients without PTE, those with PTE were younger [mean 48±11 vs 54±13 years, p < 0.001], more likely to have polycystic kidney disease [17% vs 6%, p < 0.001], have received kidneys from younger donors [36 ±13 vs 41±15 years], and be on RAAS inhibitors [35% vs 22%, p < 0.001]. Recipients with PTE were less likely to have received kidneys from donors with hypertension [16% vs 32%, p = 0.004], diabetes [1% vs 11%, p = 0.008], and cerebrovascular event (24% vs 36%, p = 0.036). Higher KDPI was associated with decreased PTE risk [HR 0.98 (95% CI: 0.97-0.99)]. Over 60 months of follow-up, only 17 (36%) recipients had sustained PTE. There was no association between PTE and graft failure or mortality, CONCLUSIONS: The incidence of PTE was low in our study and PTE resolved in majority of patients. Lower KDPI increases risk of PTE. The underutilization of RAAS inhibitors in PTE patients raises the possibility of under-recognition of this phenomenon and should be explored in future studies.
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http://dx.doi.org/10.1186/s12882-021-02231-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802150PMC
January 2021

Validation of a noninvasive prognostic signature for allograft failure following BK virus associated nephropathy.

Clin Transplant 2021 Feb 21;35(2):e14200. Epub 2021 Jan 21.

Division of Nephrology and Hypertension, Department of Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, USA.

Identifying kidney transplant recipients at risk for graft failure following BK virus nephropathy (BKVN) may allow personalization of therapy. We have reported that a noninvasive composite signature of urinary cell level of plasminogen activator inhibitor-1(PAI-1) mRNA and serum creatinine level, measured at the time of BKVN diagnosis, is prognostic of graft failure. In this investigation, we determined whether the composite signature is prognostic of graft failure in an independent cohort of 25 patients with BKVN. Of the 25 patients, 8 developed graft failure and 17 did not. We measured urinary cell levels of PAI-1 mRNA, 18S rRNA, and BKV VP1 mRNA at the time of BKVN diagnosis and evaluated clinical parameters including Banff pathology scores, acute rejection, and graft function. The area under the receiver operating characteristic curve for the noninvasive composite signature was 0.95 (P < .001) for prognosticating graft failure. The previously reported threshold of -0.858 predicted graft failure with a sensitivity of 75% and a specificity of 94%. Our current study validates the use of composite signature and the threshold of -0.858 to identify those at risk for graft failure following BKVN diagnosis, and supports future studies utilizing the composite signature score to personalize treatment of BKVN.
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http://dx.doi.org/10.1111/ctr.14200DOI Listing
February 2021

Dissecting the human kidney allograft transcriptome: single-cell RNA sequencing.

Curr Opin Organ Transplant 2021 Feb;26(1):43-51

Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, New York.

Purpose Of Review: Single-cell RNA sequencing (scRNA-seq) has provided opportunities to interrogate kidney allografts at a hitherto unavailable molecular level of resolution. Understanding of this technology is essential to better appreciate the relevant biomedical literature.

Recent Findings: Sequencing is a technique to determine the order of nucleotides in a segment of RNA or DNA. RNA-seq of kidney allograft tissues has revealed novel mechanistic insights but does not provide information on individual cell types and cell states. scRNA-seq enables to study the transcriptome of individual cells and assess the transcriptional differences and similarities within a population of cells. Initial studies on rejecting kidney allograft tissues in humans have identified the transcriptional profile of the active players of the innate and adaptive immune system. Application of scRNA-seq in a preclinical model of kidney transplantation has revealed that allograft-infiltrating myeloid cells follow a trajectory of differentiation from monocytes to proinflammatory macrophages and exhibit distinct interactions with kidney allograft parenchymal cells; myeloid cell expression of Axl played a major role in promoting intragraft myeloid cell and T-cell differentiation.

Summary: The current review discusses the technical aspects of scRNA-seq and summarizes the application of this technology to dissect the human kidney allograft transcriptome.
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http://dx.doi.org/10.1097/MOT.0000000000000840DOI Listing
February 2021

FOXP3 mRNA Profile Prognostic of Acute T-cell-mediated Rejection and Human Kidney Allograft Survival.

Transplantation 2020 Oct 7. Epub 2020 Oct 7.

Division of Nephrology and Hypertension, Department of Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, NY, USA.

Background: T-cell-mediated rejection (TCMR) is the most frequent type of acute rejection and is associated with kidney allograft failure. Almost 40% of TCMR episodes are nonresponsive to therapy and molecular mechanisms for the nonresponsiveness are unknown. Our single-center study identified that urinary cell FOXP3 mRNA abundance predicts TCMR reversibility and allograft survival.

Methods: We developed PCR assays and measured absolute copy numbers of transcripts for FOXP3, CD25, CD3E, perforin, and 18S rRNA in 3559 urines from 480 kidney allograft recipients prospectively enrolled in the multicenter Clinical Trials in Organ Transplantation-04. In this replication study, we investigated the association between mRNA profile and TCMR diagnosis, TCMR reversibility and allograft survival.

Results: 18S rRNA normalized levels of mRNA for FOXP3 (P=0.01, Kruskal-Wallis test), CD25 (P=0.01), CD3E (P<0.0001), and perforin (P<0.0001) were diagnostic of TCMR, but only FOXP3 mRNA level predicted TCMR reversibility (ROC AUC=0.764; 95% confidence interval, 0.611 to 0.917; P=0.008). Multivariable logistic regression analyses showed that urinary cell FOXP3 mRNA level predicted reversal, independent of clinical variables. A composite model of clinical variables and FOXP3 mRNA (AUC = 0.889; 95% CI, 0.781 to 0.997; P<0.001) outperformed FOXP3 mRNA or clinical variables in predicting TCMR reversibility (P=0.01, likelihood ratio test). Multivariable Cox proportional hazards regression analyses showed that FOXP3 mRNA level predicts kidney allograft survival (P=0.047), but not after controlling for TCMR reversal (P=0.477).

Conclusions: Urinary cell level of FOXP3 mRNA is diagnostic of TCMR, predicts TCMR reversibility, and is prognostic of kidney allograft survival via a mechanism involving TCMR reversal.
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http://dx.doi.org/10.1097/TP.0000000000003478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024419PMC
October 2020

Uromodulin to Osteopontin Ratio in Deceased Donor Urine Is Associated With Kidney Graft Outcomes.

Transplantation 2021 Apr;105(4):876-885

Division of Nephrology, School of Medicine, Johns Hopkins University, Baltimore, MD.

Background: Deceased-donor kidneys experience extensive injury, activating adaptive and maladaptive pathways therefore impacting graft function. We evaluated urinary donor uromodulin (UMOD) and osteopontin (OPN) in recipient graft outcomes.

Methods: Primary outcomes: all-cause graft failure (GF) and death-censored GF (dcGF). Secondary outcomes: delayed graft function (DGF) and 6-month estimated glomerular filtration rate (eGFR). We randomly divided our cohort of deceased donors and recipients into training and test datasets. We internally validated associations between donor urine UMOD and OPN at time of procurement, with our primary outcomes. The direction of association between biomarkers and GF contrasted. Subsequently, we evaluated UMOD:OPN ratio with all outcomes. To understand these mechanisms, we examined the effect of UMOD on expression of major histocompatibility complex II in mouse macrophages.

Results: Doubling of UMOD increased dcGF risk (adjusted hazard ratio [aHR], 1.1; 95% confidence interval [CI], 1.02-1.2), whereas OPN decreased dcGF risk (aHR, 0.94; 95% CI, 0.88-1). UMOD:OPN ratio ≤3 strengthened the association, with reduced dcGF risk (aHR, 0.57; 0.41-0.80) with similar associations for GF, and in the test dataset. A ratio ≤3 was also associated with lower DGF (aOR, 0.73; 95% CI, 0.60-0.89) and higher 6-month eGFR (adjusted β coefficient, 3.19; 95% CI, 1.28-5.11). UMOD increased major histocompatibility complex II expression elucidating a possible mechanism behind UMOD's association with GF.

Conclusions: UMOD:OPN ratio ≤3 was protective, with lower risk of DGF, higher 6-month eGFR, and improved graft survival. This ratio may supplement existing strategies for evaluating kidney quality and allocation decisions regarding deceased-donor kidney transplantation.
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http://dx.doi.org/10.1097/TP.0000000000003299DOI Listing
April 2021

Urinary Cell Transcriptome Profiling and Identification of ITM2A, SLAMF6, and IKZF3 as Biomarkers of Acute Rejection in Human Kidney Allografts.

Transplant Direct 2020 Aug 22;6(8):e588. Epub 2020 Jul 22.

Division of Nephrology and Hypertension, Departments of Medicine and Transplantation Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, NY.

Identification of a shared gene expression pattern between T cell-mediated rejection (TCMR) and antibody-mediated rejection (AMR) in human kidney allografts may help prioritize targets for the treatment of both types of acute rejection.

Methods: We performed RNA sequencing and bioinformatics of genome-wide transcriptome profiles of urinary cells to identify novel mRNAs shared between TCMR and AMR and of mechanistic relevance. Customized RT-QPCR assays were then used to validate their abundance in urinary cells. Urinary cell transcriptome profiles and mRNA abundance were assessed in 22 urine samples matched to 22 TCMR biopsies, 7 samples matched to 7 AMR biopsies, and 24 samples matched to 24 No Rejection (NR) biopsies and correlated with biopsy diagnosis.

Results: RNA sequencing data and bioinformatics identified 127 genes in urine to be shared between TCMR and AMR. We selected 3 novel mRNAs-ITM2A, SLAMF6, and IKZF3-for absolute quantification and validation by customized RT-QPCR assays. The abundance of all 3 mRNAs was significantly higher in urine matched to TCMR or AMR than in urine matched to NR biopsies. Receiver-operating-characteristic curve analysis showed that all 3 mRNAs distinguished TCMR or AMR from NR. Their abundance was similar in patients with TCMR and those with AMR.

Conclusions: State-of-the-art antirejection therapies are mostly effective to treat TCMR but not AMR. Our identification of mRNAs shared between TCMR and AMR and contributing to T cell-B cell interactions may help prioritize therapeutic targets for the simultaneous treatment of TCMR and AMR.
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http://dx.doi.org/10.1097/TXD.0000000000001035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377920PMC
August 2020

Kidney allograft recipients, immunosuppression, and coronavirus disease-2019: a report of consecutive cases from a New York City transplant center.

Nephrol Dial Transplant 2020 07;35(7):1250-1261

Division of Nephrology and Hypertension, Weill Cornell Medicine, New York, NY, USA.

Background: Kidney graft recipients receiving immunosuppressive therapy may be at heightened risk for coronavirus disease 2019 (Covid-19) and adverse outcomes. It is therefore important to characterize the clinical course and outcome of Covid-19 in this population and identify safe therapeutic strategies.

Methods: We performed a retrospective chart review of 73 adult kidney graft recipients evaluated for Covid-19 from 13 March to 20 April 2020. Primary outcomes included recovery from symptoms, acute kidney injury, graft failure and case fatality rate.

Results: Of the 73 patients screened, 54 tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-39 with moderate to severe symptoms requiring hospital admission and 15 with mild symptoms managed in the ambulatory setting. Hospitalized patients were more likely to be male, of Hispanic ethnicity and to have cardiovascular disease. In the hospitalized group, tacrolimus dosage was reduced in 46% of patients and mycophenolate mofetil (MMF) therapy was stopped in 61% of patients. None of the ambulatory patients had tacrolimus reduction or discontinuation of MMF. Azithromycin or doxycycline was prescribed at a similar rate among hospitalized and ambulatory patients (38% versus 40%). Hydroxychloroquine was prescribed in 79% of hospitalized patients. Graft failure requiring hemodialysis occurred in 3 of 39 hospitalized patients (8%) and 7 patients died, resulting in a case fatality rate of 13% among Covid-19-positive patients and 18% among hospitalized Covid-19-positive patients.

Conclusions: Data from our study suggest that a strategy of systematic triage to outpatient or inpatient care, early management of concurrent bacterial infections and judicious adjustment of immunosuppressive drugs rather than cessation is feasible in kidney transplant recipients with Covid-19.
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http://dx.doi.org/10.1093/ndt/gfaa154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454827PMC
July 2020

Urinary cell transcriptomics and acute rejection in human kidney allografts.

JCI Insight 2020 02 27;5(4). Epub 2020 Feb 27.

Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, New York, USA.

BACKGROUNDRNA sequencing (RNA-Seq) is a molecular tool to analyze global transcriptional changes, deduce pathogenic mechanisms, and discover biomarkers. We performed RNA-Seq to investigate gene expression and biological pathways in urinary cells and kidney allograft biopsies during an acute rejection episode and to determine whether urinary cell gene expression patterns are enriched for biopsy transcriptional profiles.METHODSWe performed RNA-Seq of 57 urine samples collected from 53 kidney allograft recipients (patients) with biopsies classified as acute T cell-mediated rejection (TCMR; n = 22), antibody-mediated rejection (AMR; n = 8), or normal/nonspecific changes (No Rejection; n = 27). We also performed RNA-Seq of 49 kidney allograft biopsies from 49 recipients with biopsies classified as TCMR (n = 12), AMR (n = 17), or No Rejection (n = 20). We analyzed RNA-Seq data for differential gene expression, biological pathways, and gene set enrichment across diagnoses and across biospecimens.RESULTSWe identified unique and shared gene signatures associated with biological pathways during an episode of TCMR or AMR compared with No Rejection. Gene Set Enrichment Analysis demonstrated enrichment for TCMR biopsy signature and AMR biopsy signature in TCMR urine and AMR urine, irrespective of whether the biopsy and urine were from the same or different patients. Cell type enrichment analysis revealed a diverse cellular landscape with an enrichment of immune cell types in urinary cells compared with biopsies.CONCLUSIONSRNA-Seq of urinary cells and biopsies, in addition to identifying enriched gene signatures and pathways associated with TCMR or AMR, revealed genomic changes between TCMR and AMR, as well as between allograft biopsies and urinary cells.
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http://dx.doi.org/10.1172/jci.insight.131552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101135PMC
February 2020

Incidence and Risk Factors for Acute and Chronic Kidney Injury after Adult Cord Blood Transplantation.

Biol Blood Marrow Transplant 2020 04 3;26(4):758-763. Epub 2020 Jan 3.

Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Weill Cornell Medical College, New York, New York.

Although cord blood transplantation (CBT) extends allograft access, patient comorbidities, chemoradiation, and nephrotoxic medications all contribute to acute kidney injury (AKI) risk. We analyzed AKI in adult myeloablative CBT recipients who underwent transplantation from 2006 to 2017 for hematologic malignancies using cyclosporine A (CSA)/mycophenolate mofetil immunosuppression. Maximum grades of AKI were calculated using Kidney Disease: Improving Global Outcomes (grade 1, 1.5 to <2-fold; grade 2, 2 to <3-fold; or grade 3, ≥3-fold over baseline) definitions. In total, 153 patients (median 51 years [range, 23-65], 114/153 [75%] acute leukemia, 27/153 [18%] African, 88/153 [58%] cytomegalovirus seropositive, median age-adjusted hematopoietic cell comorbidity index 3 [range, 0-9], median pretransplant albumin 4.0 g/dL [range, 2.6-5.2]) underwent transplantation. The day 100 cumulative incidence of grade 1-3 AKI was 83% (95% confidence interval [CI], 77%-89%) (predominantly grade 2, median onset 40 days, range 0 to 96), and grade 2-3 AKI incidence was 54% (95% CI, 46%-62%) (median onset 43 days, range 0 to 96). Mean CSA level preceding AKI onset was high (360 ng/mL, target range 300-350). In multivariate analysis, African ancestry, addition of haploidentical CD34 cells, low day -7 albumin, critical illness/intensive care admission, and nephrotoxic drug exposure (predominantly CSA and/or foscarnet) were associated with AKI. In a day 100 landmark analysis, 6% of patients with no prior AKI had chronic kidney disease (CKD) at 2 years versus 43% with prior grade 1 and 38% with prior grade 2-3 AKI (overall P= .02). Adult CBT recipients are at significant AKI risk, and AKI is associated with increased risk of CKD. Prevention strategies, early recognition, and prompt intervention are critical to mitigate kidney injury.
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http://dx.doi.org/10.1016/j.bbmt.2019.12.768DOI Listing
April 2020

Molecular determinants of nephron vascular specialization in the kidney.

Nat Commun 2019 12 13;10(1):5705. Epub 2019 Dec 13.

Division of Regenerative Medicine, Ansary Stem Cell Institute, Weill Cornell Medicine, New York, NY, 10065, USA.

Although kidney parenchymal tissue can be generated in vitro, reconstructing the complex vasculature of the kidney remains a daunting task. The molecular pathways that specify and sustain functional, phenotypic and structural heterogeneity of the kidney vasculature are unknown. Here, we employ high-throughput bulk and single-cell RNA sequencing of the non-lymphatic endothelial cells (ECs) of the kidney to identify the molecular pathways that dictate vascular zonation from embryos to adulthood. We show that the kidney manifests vascular-specific signatures expressing defined transcription factors, ion channels, solute transporters, and angiocrine factors choreographing kidney functions. Notably, the ontology of the glomerulus coincides with induction of unique transcription factors, including Tbx3, Gata5, Prdm1, and Pbx1. Deletion of Tbx3 in ECs results in glomerular hypoplasia, microaneurysms and regressed fenestrations leading to fibrosis in subsets of glomeruli. Deciphering the molecular determinants of kidney vascular signatures lays the foundation for rebuilding nephrons and uncovering the pathogenesis of kidney disorders.
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http://dx.doi.org/10.1038/s41467-019-12872-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910926PMC
December 2019

Mitophagy-dependent macrophage reprogramming protects against kidney fibrosis.

JCI Insight 2019 12 5;4(23). Epub 2019 Dec 5.

Division of Nephrology and Hypertension and.

Mitophagy, by maintaining mitochondrial quality control, plays a key role in maintaining kidney function and is impaired in pathologic states. Macrophages are well known for their pathogenic role in kidney fibrosis. Here, we report that PINK1/Parkin-mediated mitophagy in macrophages is compromised in experimental and human kidney fibrosis. We demonstrate downregulation of mitophagy regulators mitofusin-2 (MFN2) and Parkin downstream of PINK1 in kidney fibrosis. Loss of either Pink1 or Prkn promoted renal extracellular matrix accumulation and frequency of profibrotic/M2 macrophages. Pink1-/- or Prkn-/- BM-derived macrophages (BMDMs) showed enhanced expression of rictor. Mitochondria from TGF-β1-treated Pink1-/- BMDMs exhibited increased superoxide levels, along with reduced respiration and ATP production. In addition, mitophagy in macrophages involves PINK1-mediated phosphorylation of downstream MFN2, MFN2-facilitated recruitment of Parkin to damaged mitochondria, and macrophage-specific deletion of Mfn2 aggravates kidney fibrosis. Moreover, mitophagy regulators were downregulated in human CKD kidney and TGF-β1-treated human renal macrophages, whereas Mdivi1 treatment suppressed mitophagy mediators and promoted fibrotic response. Taken together, our study is the first to our knowledge to demonstrate that macrophage mitophagy plays a protective role against kidney fibrosis via regulating the PINK1/MFN2/Parkin-mediated pathway.
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http://dx.doi.org/10.1172/jci.insight.132826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962025PMC
December 2019

Urine Injury Biomarkers Are Not Associated With Kidney Transplant Failure.

Transplantation 2020 06;104(6):1272-1279

Division of Nephrology, School of Medicine, Johns Hopkins University, Baltimore, MD.

Background: Kidneys transplanted from deceased donors with serum creatinine-defined acute kidney injury (AKI) have similar allograft survival as non-AKI kidneys but are discarded at a higher rate. Urine injury biomarkers are sensitive markers of structural kidney damage and may more accurately predict graft outcomes.

Methods: In the 2010-2013 multicenter Deceased Donor Study of 2430 kidney transplant recipients from 1298 donors, we assessed the association of donor urine injury biomarkers microalbumin, neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, IL-18, and liver-type fatty acid binding protein with graft failure (GF) and death-censored GF (dcGF) using Cox proportional hazard models (median follow-up 4 y). We examined if serum creatinine-defined donor AKI modified this association to assess the relationship between subclinical donor AKI (elevated biomarkers without creatinine-defined AKI) and GF. Through chart review of a subcohort (1137 recipients), we determined associations between donor injury biomarkers and a 3-year composite outcome of GF, mortality, or estimated glomerular filtration rate ≤ 20mL/min/1.73m.

Results: Risk of GF, dcGF, and 3-year composite outcome did not vary with donor injury biomarker concentrations after adjusting for donor, transplant, and recipient characteristics (adjusted hazard ratio ranged from 0.96 to 1.01 per log-2 increase in biomarker). Subclinical injury in transplanted kidneys without AKI was not associated with GF.

Conclusions: AKI measured using injury biomarkers was not associated with posttransplant graft outcomes (at median 4 y posttransplant). When assessing posttransplant graft viability, clinicians can prioritize other donor and recipient factors over donor kidney injury, measured by either serum creatinine or urine injury biomarkers.
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http://dx.doi.org/10.1097/TP.0000000000002948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384615PMC
June 2020

Butyrate-producing gut bacteria and viral infections in kidney transplant recipients: A pilot study.

Transpl Infect Dis 2019 Dec 8;21(6):e13180. Epub 2019 Oct 8.

Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.

Background: The gut microbiome is being associated increasingly with development of infections besides Clostridium difficile infection. A recent study found an association between butyrate-producing gut (BPG) bacteria and less frequent development of lower respiratory viral infections in allogeneic hematopoietic stem cell transplant recipients (Haak et al, Blood 131(26): 2978, 2018). In this investigation, we examine the relationship between the abundance of BPG bacteria and the development of viral infections in a cohort of kidney transplant recipients.

Methods: We recruited 168 kidney transplant recipients who provided 510 fecal specimens in the first 3 months after transplantation and profiled the gut microbiota using 16S rRNA gene sequencing of the V4-V5 hypervariable region. We classified the kidney transplant recipients into higher BPG Bacteria Group and lower BPG Bacteria Group using the same criteria of 1% relative gut abundance of BPG bacteria as the Haak et al study.

Results: Administration of antibiotics against anaerobes was associated with a significant decrease in the relative gut abundance of BPG bacteria. The higher BPG Bacteria Group was associated with less development of respiratory viral infections (Hazard Ratio [HR]: 0.28, P = .01) but not with less development of CMV viremia (HR: 0.38, P = .13) or BK viremia (HR: 1.02, P = .98) at 2 years post transplantation.

Conclusion: Our pilot investigation supports future validation of the relationship between high relative gut abundance of BPG bacteria and decreased risk for development of respiratory viral infections.
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http://dx.doi.org/10.1111/tid.13180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917841PMC
December 2019

Landscape of innate immune system transcriptome and acute T cell-mediated rejection of human kidney allografts.

JCI Insight 2019 07 11;4(13). Epub 2019 Jul 11.

Division of Nephrology and Hypertension, Department of Medicine.

Acute rejection of human allografts has been viewed mostly through the lens of adaptive immunity, and the intragraft landscape of innate immunity genes has not been characterized in an unbiased fashion. We performed RNA sequencing of 34 kidney allograft biopsy specimens from 34 adult recipients; 16 were categorized as Banff acute T cell-mediated rejection (TCMR) and 18 as normal. Computational analysis of intragraft mRNA transcriptome identified significantly higher abundance of mRNA for pattern recognition receptors in TCMR compared with normal biopsies, as well as increased expression of mRNAs for cytokines, chemokines, interferons, and caspases. Intragraft levels of calcineurin mRNA were higher in TCMR biopsies, suggesting underimmunosuppression compared with normal biopsies. Cell-type-enrichment analysis revealed higher abundance of dendritic cells and macrophages in TCMR biopsies. Damage-associated molecular patterns, the endogenous ligands for pattern recognition receptors, as well markers of DNA damage were higher in TCMR. mRNA expression patterns supported increased calcium flux and indices of endoplasmic, cellular oxidative, and mitochondrial stress were higher in TCMR. Expression of mRNAs in major metabolic pathways was decreased in TCMR. Our global and unbiased transcriptome profiling identified heightened expression of innate immune system genes during an episode of TCMR in human kidney allografts.
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http://dx.doi.org/10.1172/jci.insight.128014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629252PMC
July 2019

MicroRNAs and Transplantation.

Clin Lab Med 2019 03 22;39(1):125-143. Epub 2018 Dec 22.

Division of Nephrology and Hypertension, Department of Medicine, New York-Presbyterian-Weill Cornell Medicine, 525 East 68th Street, Box 3, New York, NY 10065, USA; Division of Nephrology and Hypertension, Department of Transplantation Medicine, New York-Presbyterian-Weill Cornell Medicine, 525 East 68th Street, Box 3, New York, NY 10065, USA. Electronic address:

miRNAs, ∼20 to 22 nucleotide single-stranded RNA species that play a pivotal role in the regulation of protein-coding genes, are emerging as robust biomarkers for assessing allograft status. Herein, the authors briefly review the biogenesis and function of the miRNAs and provide an overview of the tools to quantify miRNAs in tissues and body fluids. They then review their studies of discovery and validation of alterations in miRNA expression within kidney allografts with or without acute rejection, as well as with or without fibrosis, and summarize published data on miRNA expression patterns in kidney transplant recipients.
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http://dx.doi.org/10.1016/j.cll.2018.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369703PMC
March 2019

Antibiotic prophylaxis for ureteral stent removal after kidney transplantation.

Clin Transplant 2019 03 15;33(3):e13491. Epub 2019 Feb 15.

Division of Nephrology and Hypertension, Weill Cornell Medical Center, NewYork-Presbyterian Hospital, New York, New York.

There are no guidelines for antibiotic prophylaxis for ureteral stent removal after kidney transplantation. We reviewed the charts of 277 adult kidney transplant recipients with ureteral stents transplanted at our center between September 2014 and December 2015 and investigated whether antibiotic prophylaxis for stent removal was associated with reduced incidence of urinary tract infections (UTI). We defined UTI as a urine culture ≥10  CFU/mL of bacterial isolates irrespective of symptoms. Primary outcome was the incidence of UTI within four weeks of stent removal. Among the 277 recipients, 199 (72%) were on sulfamethoxazole/trimethoprim (SMZ/TMP) as Pneumocystis jirovecii prophylaxis. At the time of ureteral stent removal, 56 recipients (20%) received additional antibiotic prophylaxis (ABX+) and 221 (80%) did not (ABX-). The difference in the incidence of UTI in the ABX(+) group (16%) and ABX(-) group (19%) was not statistically significant (P = 0.85). Variables independently associated with the development of UTI were recipient age (odds ratio [OR] 1.04, [95% confidence interval 1.01-1.07]) and UTI while stents were in situ (OR 3.9 [2.00-7.62]). Use of SMZ/TMP was protective (OR 0.35 [0.18-0.7]). Our study does not show a statistically significant benefit for additional antibiotic prophylaxis for ureteral stent removal. Antibiotic prophylaxis may be beneficial for recipients not on SMZ/TMP at the time of stent removal.
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http://dx.doi.org/10.1111/ctr.13491DOI Listing
March 2019

Deceased-donor acute kidney injury is not associated with kidney allograft failure.

Kidney Int 2019 01 20;95(1):199-209. Epub 2018 Nov 20.

Division of Nephrology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. Electronic address:

Deceased-donor acute kidney injury (AKI) is associated with organ discard and delayed graft function, but data on longer-term allograft survival are limited. We performed a multicenter study to determine associations between donor AKI (from none to severe based on AKI Network stages) and all-cause graft failure, adjusting for donor, transplant, and recipient factors. We examined whether any of the following factors modified the relationship between donor AKI and graft survival: kidney donor profile index, cold ischemia time, donation after cardiac death, expanded-criteria donation, kidney machine perfusion, donor-recipient gender combinations, or delayed graft function. We also evaluated the association between donor AKI and a 3-year composite outcome of all-cause graft failure or estimated glomerular filtration rate ≤ 20 mL/min/1.73 m in a subcohort of 30% of recipients. Among 2,430 kidneys transplanted from 1,298 deceased donors, 585 (24%) were from donors with AKI. Over a median follow-up of 4.0 years, there were no significant differences in graft survival by donor AKI stage. We found no evidence that pre-specified variables modified the effect of donor AKI on graft survival. In the subcohort, donor AKI was not associated with the 3-year composite outcome. Donor AKI was not associated with graft failure in this well-phenotyped cohort. Given the organ shortage, the transplant community should consider measures to increase utilization of kidneys from deceased donors with AKI.
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http://dx.doi.org/10.1016/j.kint.2018.08.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331055PMC
January 2019

Bortezomib for Reduction of Proteinuria in IgA Nephropathy.

Kidney Int Rep 2018 Jul 11;3(4):861-866. Epub 2018 Mar 11.

Department of Medicine, Division of Nephrology and Hypertension, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York, USA.

Introduction: IgA nephropathy is the most common glomerulonephritis in the world. We conducted a pilot trial (NCT01103778) to test the effect of bortezomib in patients with IgA nephropathy and significant proteinuria.

Methods: We treated 8 consecutive subjects from July 2011 until March 2016 with 4 doses of bortezomib. All subjects had biopsy-proven IgA nephropathy and proteinuria of greater than 1 g per day. They were given 4 doses of bortezomib i.v. at 1.3 mg/m of body surface area per dose. Changes in proteinuria and renal function were followed for 1 year after enrollment. The primary endpoint was full remission defined as proteinuria of less than 300 mg per day.

Results: All 8 subjects received and tolerated 4 doses of bortezomib over a 2-week period during enrollment. The median baseline daily proteinuria was 2.46 g (interquartile range: 2.29-3.16 g). At 1-year follow-up, 3 subjects (38%) had achieved the primary endpoint. The 3 subjects who had complete remission had Oxford classification T scores of 0 before enrollment. Of the remaining 5 subjects, 1 was lost to follow-up within 1 month of enrollment and 4 (50%) did not have any response or had progression of disease.

Conclusion: Proteasome inhibition by bortezomib may reduce significant proteinuria in select cases of IgA nephropathy. Subjects who responded to bortezomib had Oxford classification T score of 0 and normal renal function.
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http://dx.doi.org/10.1016/j.ekir.2018.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035125PMC
July 2018

RIPK3 promotes sepsis-induced acute kidney injury via mitochondrial dysfunction.

JCI Insight 2018 06 7;3(11). Epub 2018 Jun 7.

Division of Nephrology and Hypertension, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, New York, USA.

Sepsis causes acute kidney injury (AKI) in critically ill patients, although the pathophysiology remains unclear. The receptor-interacting protein kinase-3 (RIPK3), a cardinal regulator of necroptosis, has recently been implicated in the pathogenesis of human disease. In mice subjected to polymicrobial sepsis, we demonstrate that RIPK3 promotes sepsis-induced AKI. Utilizing genetic deletion and biochemical approaches in vitro and in vivo, we identify a potentially novel pathway by which RIPK3 aggravates kidney tubular injury independently of the classical mixed lineage kinase domain-like protein-dependent (MLKL-dependent) necroptosis pathway. In kidney tubular epithelial cells, we show that RIPK3 promotes oxidative stress and mitochondrial dysfunction involving upregulation of NADPH oxidase-4 (NOX4) and inhibition of mitochondrial complex I and -III, and that RIPK3 and NOX4 are critical for kidney tubular injury in vivo. Furthermore, we demonstrate that RIPK3 is required for increased mitochondrial translocation of NOX4 in response to proinflammatory stimuli, by a mechanism involving protein-protein interactions. Finally, we observed elevated urinary and plasma RIPK3 levels in human patients with sepsis-induced AKI, representing potential markers of this condition. In conclusion, we identify a pathway by which RIPK3 promotes kidney tubular injury via mitochondrial dysfunction, independently of MLKL, which may represent a promising therapeutic target in sepsis-induced AKI.
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http://dx.doi.org/10.1172/jci.insight.98411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124406PMC
June 2018

Management of Patients with Acute Methotrexate Nephrotoxicity with High-Dose Leucovorin.

Pharmacotherapy 2018 Jul 27;38(7):714-724. Epub 2018 Jun 27.

Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, New York.

Background: Acute kidney injury complicating high-dose methotrexate (HDMTX) therapy increases the risk for severe mucositis, myelosuppression, and death. It is unclear whether high-dose leucovorin and supportive therapy without the use of glucarpidase can reduce toxicity from HDMTX.

Study Design: The charts of all patients at Memorial Sloan Kettering Cancer Center whose methotrexate (MTX) drug levels at 48 or 72 hours after administration were 10 times or more the toxic level were reviewed between January 2000 and December 2011.

Results: Eighty-eight patients (median age 51 years, range 9-90 years) who received 100 courses of HDMTX were identified. Serum creatinine increased by 2-fold from baseline (median, range 1- to 10-fold), but all patients recovered kidney function. Serum levels of MTX were 69 μmol/L (median, range 2.2-400), 6.9 μmol/L (1.3-64), and 2.0 μmol/L (0.05-26) at 24, 48, and 72 hours, respectively, after administration. A statistically significant correlation existed between MTX levels at 48, 72, 96, and 120 hours after administration but not between 24 and 72 hours or subsequent time points. High-dose leucovorin was given in 81% of courses in accordance with institutional protocols in most cases. Myelosuppression was present in 42%; grade III or higher neutropenia in 29%, and thrombocytopenia in 25%. Infectious complications, oral mucositis, and diarrhea occurred in 21%, 17%, and 6% of patients, respectively. Five deaths occurred, none directly attributed to complications from MTX administration. Seven additional patients received glucarpidase at the discretion of a treating physician during the study period, and results are reported separately.

Conclusion: Patients who had 100 episodes of HDMTX-associated acute kidney injury were treated with a strategy that only included usual supportive measures and high-dose leucovorin. No deaths were directly attributed to complications related to HDMTX. Glucarpidase, an expensive drug, may not be necessary for a significant number of patients.
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http://dx.doi.org/10.1002/phar.2145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279619PMC
July 2018

Single nucleotide variant counts computed from RNA sequencing and cellular traffic into human kidney allografts.

Am J Transplant 2018 10 15;18(10):2429-2442. Epub 2018 May 15.

Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, New York.

Advances in bioinformatics allow identification of single nucleotide polymorphisms (variants) from RNA sequence data. In an allograft biopsy, 2 genomes contribute to the RNA pool, 1 from the donor organ and the other from the infiltrating recipient's cells. We hypothesize that imbalances in genetic variants of RNA sequence data of kidney allograft biopsies provide an objective measure of cellular infiltration of the allograft. We performed mRNA sequencing of 40 kidney allograft biopsies, selected to represent a comprehensive range of diagnostic categories. We analyzed the sequencing reads of these biopsies and of 462 lymphoblastoid cell lines from the 1000 Genomes Project, for RNA variants. The ratio of heterozygous to nonreference genome homozygous variants (Het/Hom ratio) on all autosomes was determined for each sample, and the estimation of stromal and immune cells in malignant tumors using expression data (ESTIMATE) score was computed as a complementary estimate of the degree of cellular infiltration into biopsies. The Het/Hom ratios (P = .02) and the ESTIMATE scores (P < .001) were associated with the biopsy diagnosis. Both measures correlated significantly (r = .67, P < .0001), even though the Het/Hom ratio is based on mRNA sequence variation, while the ESTIMATE score uses mRNA expression. Het/Hom ratio and the ESTIMATE score may offer unbiased and quantitative parameters for characterizing cellular traffic into human kidney allografts.
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http://dx.doi.org/10.1111/ajt.14870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160347PMC
October 2018

RIPK3 promotes kidney fibrosis via AKT-dependent ATP citrate lyase.

JCI Insight 2018 02 8;3(3). Epub 2018 Feb 8.

Division of Nephrology and Hypertension, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, New York, USA.

Renal fibrosis is a common pathogenic response to injury in chronic kidney disease (CKD). The receptor-interacting protein kinase-3 (RIPK3), a regulator of necroptosis, has been implicated in disease pathogenesis. In mice subjected to unilateral ureteral obstruction-induced (UUO-induced) or adenine diet-induced (AD-induced) renal fibrosis, models of progressive kidney fibrosis, we demonstrate increased kidney expression of RIPK3. Mice genetically deficient in RIPK3 displayed decreased kidney fibrosis and improved kidney function relative to WT mice when challenged with UUO or AD. In contrast, mice genetically deficient in mixed-lineage kinase domain-like protein (MLKL), a downstream RIPK3 target, were not protected from UUO-induced kidney fibrosis. We demonstrate a pathway by which RIPK3 promotes fibrogenesis through the AKT-dependent activation of ATP citrate lyase (ACL). Genetic or chemical inhibition of RIPK3 suppressed the phosphorylation of AKT and ACL in response to TGF-β1 in fibroblasts. Inhibition of AKT or ACL suppressed TGF-β1-dependent extracellular matrix production and myofibroblast differentiation in fibroblasts. Pharmacological inhibition of ACL suppressed UUO-induced kidney fibrosis. RIPK3 expression was highly regulated in human CKD kidney. In conclusion, we identify a pathway by which RIPK3 promotes kidney fibrosis independently of MLKL-dependent necroptosis as a promising therapeutic target in CKD.
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http://dx.doi.org/10.1172/jci.insight.94979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821177PMC
February 2018

Kidney allograft failure in the steroid-free immunosuppression era: A matched case-control study.

Clin Transplant 2017 Nov;31(11)

Division of Nephrology and Hypertension, Department of Medicine, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, NY, USA.

We studied the causes and predictors of death-censored kidney allograft failure among 1670 kidney recipients transplanted at our center in the corticosteroid-free maintenance immunosuppression era. As of January 1, 2012, we identified 137 recipients with allograft failure; 130 of them (cases) were matched 1-1 for recipient age, calendar year of transplant, and donor type with 130 recipients with functioning grafts (controls). Median time to allograft failure was 29 months (interquartile range: 18-51). Physician-validated and biopsy-confirmed categories of allograft failure were as follows: acute rejection (21%), glomerular disease (19%), transplant glomerulopathy (13%), interstitial fibrosis tubular atrophy (10%), and polyomavirus-associated nephropathy (7%). Graft failures were attributed to medical conditions in 21% and remained unresolved in 9%. Donor race, donor age, human leukocyte antigen mismatches, serum creatinine, urinary protein, acute cellular rejection, acute antibody-mediated rejection, BK viremia, and CMV viremia were associated with allograft failure. Independent predictors of allograft failure were acute cellular rejection (odds ratio: 18.31, 95% confidence interval: 5.28-63.45) and urine protein ≥1 g/d within the first year post-transplantation (5.85, 2.37-14.45). Serum creatinine ≤1.5 mg/dL within the first year post-transplantation reduced the odds (0.29, 0.13-0.64) of allograft failure. Our study has identified modifiable risk factors to reduce the burden of allograft failure.
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http://dx.doi.org/10.1111/ctr.13117DOI Listing
November 2017

In-Hospital Cardiovascular Complications After Pancreas Transplantation in the United States from 2003 to 2012.

Am J Cardiol 2017 Aug 30;120(4):682-687. Epub 2017 May 30.

Division of Nephrology and Hypertension, Weill Cornell Medicine, New York, New York; The Rogosin Institute, New York, New York.

Large database studies detailing the risk of perioperative cardiovascular complications after pancreas transplant has been limited, perhaps because these outcomes are not captured by transplant registries. Greater data on the incidence and risks of such outcomes could provide additional insight for referring physicians and inform potential recipients of their risk. We performed a serial, cross-sectional analysis of the National Inpatient Sample, the largest publicly available inpatient database in the United States, to assess for the risk of cardiovascular complications after pancreas transplants in the United States from 2003 to 2012 (n = 13,399). Using multivariable logistic regression models, the risk of cardiovascular outcomes after simultaneous pancreas-kidney transplants (SPK) was compared with solitary pancreas transplants (pancreas after kidney and pancreas transplant alone [PAK + PTA]). The unadjusted prevalence of in-hospital cardiovascular complications was higher in SPK than PAK + PTA (5.5% vs 3.7%, p <0.001). After multivariable adjustment, SPK remained associated with significantly higher odds of any cardiovascular complication (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.21 to 1.80, p = 0.01), and particularly stroke (OR 13.41, 95% CI 4.78 to 37.63, p <0.001), compared with PAK + PTA. However, there was no difference in perioperative mortality (OR 0.78, 95% CI 0.54 to 1.12, p = 0.18). In conclusion, these findings highlight the association between uremia and stroke in pancreas transplant patients, as well as the need for improved preoperative cardiac risk assessment and perioperative management, especially in those who underwent SPK.
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http://dx.doi.org/10.1016/j.amjcard.2017.05.038DOI Listing
August 2017

Exome Sequencing and Prediction of Long-Term Kidney Allograft Function.

PLoS Comput Biol 2016 Sep 29;12(9):e1005088. Epub 2016 Sep 29.

The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, United States of America; Department of Physiology and Biophysics, The Weill Cornell Medical College, New York, New York, United States of America.

Current strategies to improve graft outcome following kidney transplantation consider information at the human leukocyte antigen (HLA) loci. Cell surface antigens, in addition to HLA, may serve as the stimuli as well as the targets for the anti-allograft immune response and influence long-term graft outcomes. We therefore performed exome sequencing of DNA from kidney graft recipients and their living donors and estimated all possible cell surface antigens mismatches for a given donor/recipient pair by computing the number of amino acid mismatches in trans-membrane proteins. We designated this tally as the allogenomics mismatch score (AMS). We examined the association between the AMS and post-transplant estimated glomerular filtration rate (eGFR) using mixed models, considering transplants from three independent cohorts (a total of 53 donor-recipient pairs, 106 exomes, and 239 eGFR measurements). We found that the AMS has a significant effect on eGFR (mixed model, effect size across the entire range of the score: -19.4 [-37.7, -1.1], P = 0.0042, χ2 = 8.1919, d.f. = 1) that is independent of the HLA-A, B, DR matching, donor age, and time post-transplantation. The AMS effect is consistent across the three independent cohorts studied and similar to the strong effect size of donor age. Taken together, these results show that the AMS, a novel tool to quantify amino acid mismatches in trans-membrane proteins in individual donor/recipient pair, is a strong, robust predictor of long-term graft function in kidney transplant recipients.
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http://dx.doi.org/10.1371/journal.pcbi.1005088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042552PMC
September 2016

Development and validation of a prognostic index for allograft outcome in kidney recipients with transplant glomerulopathy.

Kidney Int 2016 Feb;89(2):450-8

We studied 92 patients with transplant glomerulopathy to develop a prognostic index based on the risk factors for allograft failure within five years of diagnosis (Development cohort). During 60 months (median) follow-up, 64 patients developed allograft failure. A chronic-inflammation score generated by combining Banff ci, ct and ti scores, serum creatinine and proteinuria at biopsy, were independent risk factors for allograft failure. Based on the Cox model, we developed a prognostic index and classified patients into risk groups. Compared to the low-risk group (median allograft survival over 60 months from diagnosis), patients in the medium risk group had a hazard ratio of 2.83 (median survival 25 months), while those in the high-risk group had a hazard ratio of 5.96 (median survival 3.7 months). We next evaluated the performance of the prognostic index in an independent external cohort of 47 patients with transplant glomerulopathy (Validation cohort). The hazard ratios were 2.18 (median survival 19 months) and 16.27 (median survival 1.6 months), respectively, for patients in the medium and high-risk groups, compared to the low-risk group (median survival 47 months). Our prognostic index model did well in measures of discrimination and calibration. Thus, risk stratification of transplant glomerulopathy based on our prognostic index may provide informative insight for both the patient and physician regarding prognosis and treatment.
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http://dx.doi.org/10.1038/ki.2015.288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814368PMC
February 2016