Publications by authors named "Darshana Dadhania"

81 Publications

Gut microbiota profiles and fecal beta-glucuronidase activity in kidney transplant recipients with and without post-transplant diarrhea.

Clin Transplant 2021 Feb 19:e14260. Epub 2021 Feb 19.

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

Post-transplant diarrhea is a common complication after solid organ transplantation and is frequently attributed to the widely prescribed immunosuppressant mycophenolate mofetil (MMF). Given recent work identifying the relationship between MMF toxicity and gut bacterial β-glucuronidase activity, we evaluated the relationship between gut microbiota composition, fecal β-glucuronidase activity, and post-transplant diarrhea. We recruited 97 kidney transplant recipients and profiled the gut microbiota in 273 fecal specimens using 16S rRNA gene sequencing. We further characterized fecal β-glucuronidase activity in a subset of this cohort. Kidney transplant recipients with post-transplant diarrhea had decreased gut microbial diversity and decreased relative gut abundances of 12 genera when compared to those without post-transplant diarrhea (adjusted P value<0.15, Wilcoxon rank sum test). Among the kidney transplant recipients with post-transplant diarrhea, those with higher fecal β-glucuronidase activity had a more prolonged course of diarrhea (≥7 days) compared to patients with lower fecal β-glucuronidase activity (91% vs 40%, P=0.02, Fisher's exact test). Our data reveal post-transplant diarrhea as a complex phenomenon with decreased gut microbial diversity and commensal gut organisms. This study further links commensal bacterial metabolism with an important clinical outcome measure, suggesting fecal β-glucuronidase activity could be a novel biomarker for gastrointestinal-related MMF toxicity.
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http://dx.doi.org/10.1111/ctr.14260DOI Listing
February 2021

Kidney recipients with allograft failure, transition of kidney care (KRAFT): A survey of contemporary practices of transplant providers.

Am J Transplant 2021 Feb 8. Epub 2021 Feb 8.

New York Presbyterian Hospital- Weill Cornell Medicine, New York, NY.

Kidney allograft failure and return to dialysis carries a high risk of morbidity. A practice survey was developed by the AST Kidney Pancreas Community of Practice workgroup and distributed electronically to the AST members. There were 104 responders that represented 92 kidney transplant centers. Most survey respondents were transplant nephrologists at academic centers. The most common approach to immunosuppression management was to withdraw the anti-metabolite first (73%), while 12% responded they would withdraw calcineurin inhibitor first. More than 60% reported that the availability of a living donor is the most important factor in the decision to taper immunosuppression, followed by the risk of infection, risk of sensitization, frailty, and side effects of medications. More than half of respondents reported that embolization was either not available or offered to less than 10% as an option for surgical intervention. More than half reported that ≤50% of failed allograft patients were re-listed before dialysis, and less than a quarter of transplant nephrologists perform frequent follow-ups with their failed allograft patients after dialysis. This survey demonstrates a heterogeneity in the care of patients with a failing allograft and the need for more evidence to guide improvements in clinical practice related to transition of care.
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http://dx.doi.org/10.1111/ajt.16523DOI Listing
February 2021

Consensus conference on heart-kidney transplantation.

Am J Transplant 2021 Feb 2. Epub 2021 Feb 2.

Stanford University, Palo Alto, California, USA.

Simultaneous heart-kidney transplant (sHK) has enabled the successful transplantation of patients with end-stage heart disease and concomitant kidney disease, with non-inferior outcomes to heart transplant (HT) alone. The decision for sHK is challenged by difficulties in differentiating those patients with a significant component of reversible kidney injury due to cardiorenal syndrome who may recover kidney function after HT, from those with intrinsic advanced kidney disease who would benefit most from sHK. A consensus conference on sHK took place on June 1, 2019 in Boston, Massachusetts. The conference represented a collaborative effort by experts in cardiothoracic and kidney transplantation from centers across the United States to explore the development of guidelines for the interdisciplinary criteria for kidney transplantation in the sHK candidate, to evaluate the current allocation of kidneys to follow the heart for sHK, and to recommend standardized care for the management of sHK recipients. The conference served as a forum to unify criteria between the different specialties and to forge a pathway for patients who may need dual organ transplantation. Due to the continuing shortage of available donor organs, ethical problems related to multi-organ transplantation were also debated. The findings and consensus statements are presented.
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http://dx.doi.org/10.1111/ajt.16512DOI Listing
February 2021

COVID-19 infection in former living kidney donors.

Clin Transplant 2021 Jan 22:e14230. Epub 2021 Jan 22.

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

The COVID-19 pandemic brought living donor kidney transplant programs across the United States to a near halt in March 2020. As programs have begun to reopen, potential donor candidates often inquire about their risk of a COVID-19 infection and its potential impact on kidney function after donation. To address their concerns, we surveyed 1740 former live kidney donors at four transplant centers located in New York and Michigan. Of these, 839 (48.2%) donors responded, their mean age was 46 ± 12.5 years, 543 (65%) were females, and 611 (73%) were white. Ninety-two donors (11%) had symptoms suggestive of a COVID-19 infection with fever (48%) and fatigue (43%) being the most common. Among those with symptoms, 42 donors underwent testing and 16 tested positive. Testing was more common among donors with private insurance, and a positive test result was more common among young black donors. Only one donor surveyed required hospitalization and none required dialysis. Fourteen donors have recovered completely and two partially. Our survey highlights that a COVID-19 infection in former donors results in a mild disease with good recovery. These data will be useful for transplant programs to counsel living donors who are considering kidney donation during this pandemic.
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http://dx.doi.org/10.1111/ctr.14230DOI Listing
January 2021

A 2020 Banff Antibody-mediatedInjury Working Group examination of international practices for diagnosing antibody-mediated rejection in kidney transplantation - a cohort study.

Transpl Int 2021 Mar;34(3):488-498

Division of Nephrology/Transplant Nephrology, Johns Hopkins University, Baltimore, MD, USA.

The Banff antibody-mediated rejection (ABMR) classification is vulnerable to misinterpretation, but the reasons are unclear. To better understand this vulnerability, we evaluated how ABMR is diagnosed in practice. To do this, the Banff Antibody-Mediated Injury Workgroup electronically surveyed an international cohort of nephrologists/surgeons (n = 133) and renal pathologists (n = 99). Most providers (97%) responded that they use the Banff ABMR classification at least sometimes, but DSA information is often not readily available. Only 41.1% (55/133) of nephrologists/surgeons and 19.2% (19/99) of pathologists reported that they always have DSA results when the biopsy is available. Additionally, only 19.6% (26/133) of nephrologists/surgeons responded that non-HLA antibody or molecular transcripts are obtained when ABMR histologic features are present but DSA is undetected. Several respondents agreed that histologic features concerning for ABMR in the absence of DSA and/or C4d are not well accounted for in the current classification [31.3% (31/99) pathologists and 37.6% (50/133) nephrologist/surgeons]. The Banff ABMR classification appears widely accepted, but efforts to improve the accessibility of DSA information for the multidisciplinary care team are needed. Further clarity is also needed in Banff ABMR nomenclature to account for the spectrum of ABMR and for histologic features suspicious for ABMR when DSA is absent.
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http://dx.doi.org/10.1111/tri.13813DOI Listing
March 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

COVID-19 outcomes in patients waitlisted for kidney transplantation and kidney transplant recipients.

Am J Transplant 2020 Oct 12. Epub 2020 Oct 12.

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

The COVID-19 pandemic has brought unprecedented challenges to the transplant community. The reduction in transplantation volume during this time is partly due to concerns over potentially increased susceptibility and worsened outcomes of COVID-19 in immunosuppressed recipients. The consequences of COVID-19 on patients waitlisted for kidney transplantation, however, have not previously been characterized. We studied 56 waitlisted patients and 80 kidney transplant recipients diagnosed with COVID-19 between March 13 and May 20, 2020. Despite similar demographics and burden of comorbidities between waitlisted and transplant patients, waitlisted patients were more likely to require hospitalization (82% vs. 65%, P = .03) and were at a higher risk of mortality (34% vs. 16%, P = .02). Intubation was required in one third of hospitalized patients in each group, and portended a very poor prognosis. The vast majority of patients who died were male (84% waitlist, 100% transplant). Multivariate analysis demonstrated waitlist status, age, and male sex were independently associated with mortality. COVID-19 has had a dramatic impact on waitlisted patients, decreasing their opportunities for transplantation and posing significant mortality risk. Understanding the impact of COVID-19 on waitlist patients in comparison to transplant recipients may aid centers in weighing the risks and benefits of transplantation in the setting of ongoing COVID-19.
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http://dx.doi.org/10.1111/ajt.16351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675359PMC
October 2020

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
October 2020

Impact of Functional Status on Outcomes of Simultaneous Pancreas-kidney Transplantation: Risks and Opportunities for Patient Benefit.

Transplant Direct 2020 Sep 21;6(9):e599. Epub 2020 Aug 21.

Emory University, Atlanta, GA.

Background: The impact of functional status on survival among simultaneous pancreas-kidney transplant (SPKT) candidates and recipients is not well described.

Methods: We examined national Scientific Registry of Transplant Recipients (SRTR) data for patients listed for SPKT in the United States (2006-2019). Functional status was categorized by center-reported Karnofsky Performance Score (KPS). We used Cox regression to quantify associations of KPS at listing and transplant with subsequent patient survival, adjusted for baseline patient and transplant factors (adjusted hazard ratio, aHR). We also explored time-dependent associations of SPKT with survival risk after listing compared with continued waiting in each functional status group.

Results: KPS distributions among candidates (N = 16 822) and recipients (N = 10 316), respectively, were normal (KPS 80-100), 62.0% and 57.8%; capable of self-care (KPS 70), 23.5% and 24.7%; requires assistance (KPS 50-60), 12.4% and 14.2%; and disabled (KPS 10-40), 2.1% and 3.3%. There was a graded increase in mortality after listing and after transplant with lower functional levels. Compared with normal functioning, mortality after SPKT rose progressively for patients capable of self-care (aHR, 1.18), requiring assistance (aHR, 1.31), and disabled (aHR, 1.55). In time-dependent regression, compared with waiting, SPKT was associated with 2-fold mortality risk within 30 days of transplant. However, beyond 30 days, SPKT was associated with reduced mortality, from 52% for disabled patients (aHR, 0.48) to 70% for patients with normal functioning (aHR, 0.30).

Conclusions: While lower functional status is associated with increased mortality risk among SPKT candidates and recipients, SPKT can provide long-term survival benefit across functional status levels in those selected for transplant.
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http://dx.doi.org/10.1097/TXD.0000000000001043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447442PMC
September 2020

Gut commensal microbiota and decreased risk for bacteriuria and urinary tract infection.

Gut Microbes 2020 Nov;12(1):1805281

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

Urinary tract infection (UTI) is a common complication in kidney transplant recipients and can lead to significant morbidity and mortality. Recent evidence supports a role for the gut as a source for UTIs but little is known about the relationship between gut commensal bacteria and UTI development. We hypothesized that the abundance of gut commensal bacteria is associated with a lower risk of developing bacteriuria and UTIs. We performed gut microbiome profiling using 16S rRNA gene sequencing of the V4-V5 hypervariable region on 510 fecal specimens in 168 kidney transplant recipients. Fifty-one kidney transplant recipients (30%) developed bacteriuria within the first 6 months after transplantation ( Bacteriuria Group) and 117 did not (No Bacteriuria Group). The relative abundances of and were significantly higher in the fecal specimens from the No Bacteriuria Group than those from the Bacteriuria Group (Adjusted value<.01). The combined relative abundance of and was inversely correlated with the relative abundance of (r = -0.13, = .003). In a multivariable Cox Regression, a top tercile cutoff of the combined relative abundance of and of ≥13.7% was independently associated with a decreased risk for bacteriuria (hazard ratio 0.3, = .02) and UTI (hazard ratio 0.4, = .09). In conclusion, we identify bacterial taxa associated with decreased risk for bacteriuria and UTI in kidney transplant recipients, which supports future studies on modulating the gut microbiota as a novel treatment for preventing UTIs.
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http://dx.doi.org/10.1080/19490976.2020.1805281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524266PMC
November 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

The 2018 Banff Working Group classification of definitive polyomavirus nephropathy: A multicenter validation study in the modern era.

Am J Transplant 2021 02 5;21(2):669-680. Epub 2020 Aug 5.

Department of Pathology, Weill-Cornell Medical Center/ New York Presbyterian Hospital, New York, New York, USA.

Polyomavirus nephropathy (PVN) remained inadequately classified until 2018 when the Banff Working Group published a new 3-tier morphologic classification scheme derived from in-depth statistical analysis of a large multinational patient cohort. Here we report a multicenter "modern-era" validation study that included 99 patients with definitive PVN transplanted post January 1, 2009 and followed the original 2018 study design. Results validate the PVN classification, that is, the 3 PVN disease classes predicted clinical presentation, allograft function, and outcome independent of therapeutic intervention. PVN class 1 compared to classes 2 and 3 was diagnosed earlier (16.9 weeks posttransplant [median], P = .004), and showed significantly better function at 24 months postindex biopsy (serum creatinine 1.75 mg/dl, geometric mean, vs class 2: P = .037, vs class 3: P = .013). Class 1 presented during long-term follow-up with a low graft failure rate: 5% class 1, vs 30% class 2, vs 50% class 3 (P = .009). Persistent PVN was associated with an increased risk for graft failure (and functional decline in class 2 at 24 months postdiagnosis; serum creatinine with persistence: 2.48 mg/dL vs 1.65 with clearance, geometric means, P = .018). In conclusion, we validate the 2018 Banff Working Group PVN classification that provides significant clinical information and enhances comparative data analysis.
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http://dx.doi.org/10.1111/ajt.16189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891590PMC
February 2021

Association of HLA Typing and Alloimmunity With Posttransplantation Membranous Nephropathy: A Multicenter Case Series.

Am J Kidney Dis 2020 09 28;76(3):374-383. Epub 2020 Apr 28.

Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY.

Rationale & Objectives: Posttransplantation membranous nephropathy (MN) represents a rare complication of kidney transplantation that can be classified as recurrent or de novo. The clinical, pathologic, and immunogenetic characteristics of posttransplantation MN and the differences between de novo and recurrent MN are not well understood.

Study Design: Multicenter case series.

Setting & Participants: We included 77 patients from 5 North American and European medical centers with post-kidney transplantation MN (27 de novo and 50 recurrent). Patients with MN in the native kidney who received kidney allografts but did not develop recurrent MN were used as nonrecurrent controls (n = 43). To improve understanding of posttransplantation MN, we compared de novo MN with recurrent MN and then contrasted recurrent MN with nonrecurrent controls.

Findings: Compared with recurrent MN, de novo MN was less likely to be classified as primary MN (OR, 0.04; P < 0.001) and had more concurrent antibody-mediated rejection (OR, 12.0; P < 0.001) and inferior allograft survival (HR for allograft failure, 3.2; P = 0.007). HLA-DQ2 and HLA-DR17 antigens were more common in recipients with recurrent MN compared with those with de novo MN; however, the frequency of these recipient antigens in recurrent MN was similar to that in nonrecurrent MN controls. Among the 93 kidney transplant recipients with native kidney failure attributed to MN, older recipient age (HR per each year older, 1.03; P = 0.02), recipient HLA-A3 antigen (HR, 2.5; P = 0.003), steroid-free immunosuppressive regimens (HR, 2.84; P < 0.001), and living related allograft (HR, 1.94; P = 0.03) were predictors of MN recurrence.

Limitations: Retrospective case series, limited sample size due to rarity of the disease, nonstandardized nature of data collection and biopsies.

Conclusions: De novo and recurrent MN likely represent separate diseases. De novo MN is associated with humoral alloimmunity and guarded outcome. Potential predisposing factors for recurrent MN include recipients who are older, recipient HLA-A3 antigen, steroid-free immunosuppressive regimen, and living related donor kidney.
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http://dx.doi.org/10.1053/j.ajkd.2020.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483441PMC
September 2020

COVID-19 in solid organ transplant recipients: Initial report from the US epicenter.

Am J Transplant 2020 07 10;20(7):1800-1808. Epub 2020 May 10.

Department of Medicine, Division of Digestive & Liver Diseases, Columbia University College of Physicians & Surgeons, New York, New York, USA.

Solid organ transplant recipients may be at a high risk for SARS-CoV-2 infection and poor associated outcomes. We herein report our initial experience with solid organ transplant recipients with SARS-CoV-2 infection at two centers during the first 3 weeks of the outbreak in New York City. Baseline characteristics, clinical presentation, antiviral and immunosuppressive management were compared between patients with mild/moderate and severe disease (defined as ICU admission, intubation or death). Ninety patients were analyzed with a median age of 57 years. Forty-six were kidney recipients, 17 lung, 13 liver, 9 heart, and 5 dual-organ transplants. The most common presenting symptoms were fever (70%), cough (59%), and dyspnea (43%). Twenty-two (24%) had mild, 41 (46%) moderate, and 27 (30%) severe disease. Among the 68 hospitalized patients, 12% required non-rebreather and 35% required intubation. 91% received hydroxychloroquine, 66% azithromycin, 3% remdesivir, 21% tocilizumab, and 24% bolus steroids. Sixteen patients died (18% overall, 24% of hospitalized, 52% of ICU) and 37 (54%) were discharged. In this initial cohort, transplant recipients with COVID-19 appear to have more severe outcomes, although testing limitations likely led to undercounting of mild/asymptomatic cases. As this outbreak unfolds, COVID-19 has the potential to severely impact solid organ transplant recipients.
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http://dx.doi.org/10.1111/ajt.15941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264777PMC
July 2020

An overview of frailty in kidney transplantation: measurement, management and future considerations.

Nephrol Dial Transplant 2020 07;35(7):1099-1112

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

The construct of frailty was first developed in gerontology to help identify older adults with increased vulnerability when confronted with a health stressor. This article is a review of studies in which frailty has been applied to pre- and post-kidney transplantation (KT) populations. Although KT is the optimal treatment for end-stage kidney disease (ESKD), KT candidates often must overcome numerous health challenges associated with ESKD before receiving KT. After KT, the impacts of surgery and immunosuppression represent additional health stressors that disproportionately impact individuals with frailty. Frailty metrics could improve the ability to identify KT candidates and recipients at risk for adverse health outcomes and those who could potentially benefit from interventions to improve their frail status. The Physical Frailty Phenotype (PFP) is the most commonly used frailty metric in ESKD research, and KT recipients who are frail at KT (~20% of recipients) are twice as likely to die as nonfrail recipients. In addition to the PFP, many other metrics are currently used to assess pre- and post-KT vulnerability in research and clinical practice, underscoring the need for a disease-specific frailty metric that can be used to monitor KT candidates and recipients. Although frailty is an independent risk factor for post-transplant adverse outcomes, it is not factored into the current transplant program risk-adjustment equations. Future studies are needed to explore pre- and post-KT interventions to improve or prevent frailty.
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http://dx.doi.org/10.1093/ndt/gfaa016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417002PMC
July 2020

Long-term Kidney Transplantation Outcomes Network (APOLLO): Design and Rationale.

Kidney Int Rep 2020 Mar 13;5(3):278-288. Epub 2019 Dec 13.

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

Introduction: Much of the higher risk for end-stage kidney disease (ESKD) in African American individuals relates to ancestry-specific variation in the apolipoprotein L1 gene (). Relative to kidneys from European American deceased-donors, kidneys from African American deceased-donors have shorter allograft survival and African American living-kidney donors more often develop ESKD. The National Institutes of Health (NIH)-sponsored Long-term Kidney Transplantation Outcomes Network (APOLLO) is prospectively assessing kidney allograft survival from donors with recent African ancestry based on donor and recipient genotypes.

Methods: APOLLO will evaluate outcomes from 2614 deceased kidney donor-recipient pairs, as well as additional living-kidney donor-recipient pairs and unpaired deceased-donor kidneys.

Results: The United Network for Organ Sharing (UNOS), Association of Organ Procurement Organizations, American Society of Transplantation, American Society for Histocompatibility and Immunogenetics, and nearly all U.S. kidney transplant programs, organ procurement organizations (OPOs), and histocompatibility laboratories are participating in this observational study. APOLLO employs a central institutional review board (cIRB) and maintains voluntary partnerships with OPOs and histocompatibility laboratories. A Community Advisory Council composed of African American individuals with a personal or family history of kidney disease has advised the NIH Project Office and Steering Committee since inception. UNOS is providing data for outcome analyses.

Conclusion: This article describes unique aspects of the protocol, design, and performance of APOLLO. Results will guide use of genotypic data to improve the assessment of quality in deceased-donor kidneys and could increase numbers of transplanted kidneys, reduce rates of discard, and improve the safety of living-kidney donation.
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http://dx.doi.org/10.1016/j.ekir.2019.11.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056919PMC
March 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

Separating the signal from the noise in metagenomic cell-free DNA sequencing.

Microbiome 2020 02 11;8(1):18. Epub 2020 Feb 11.

Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA.

Background: Cell-free DNA (cfDNA) in blood, urine, and other biofluids provides a unique window into human health. A proportion of cfDNA is derived from bacteria and viruses, creating opportunities for the diagnosis of infection via metagenomic sequencing. The total biomass of microbial-derived cfDNA in clinical isolates is low, which makes metagenomic cfDNA sequencing susceptible to contamination and alignment noise.

Results: Here, we report low biomass background correction (LBBC), a bioinformatics noise filtering tool informed by the uniformity of the coverage of microbial genomes and the batch variation in the absolute abundance of microbial cfDNA. We demonstrate that LBBC leads to a dramatic reduction in false positive rate while minimally affecting the true positive rate for a cfDNA test to screen for urinary tract infection. We next performed high-throughput sequencing of cfDNA in amniotic fluid collected from term uncomplicated pregnancies or those complicated with clinical chorioamnionitis with and without intra-amniotic infection.

Conclusions: The data provide unique insight into the properties of fetal and maternal cfDNA in amniotic fluid, demonstrate the utility of cfDNA to screen for intra-amniotic infection, support the view that the amniotic fluid is sterile during normal pregnancy, and reveal cases of intra-amniotic inflammation without infection at term. Video abstract.
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http://dx.doi.org/10.1186/s40168-020-0793-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014780PMC
February 2020

Gut uropathogen abundance is a risk factor for development of bacteriuria and urinary tract infection.

Nat Commun 2019 12 4;10(1):5521. Epub 2019 Dec 4.

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

The origin of most bacterial infections in the urinary tract is often presumed to be the gut. Herein, we investigate the relationship between the gut microbiota and future development of bacteriuria and urinary tract infection (UTI). We perform gut microbial profiling using 16S rRNA gene deep sequencing on 510 fecal specimens from 168 kidney transplant recipients and metagenomic sequencing on a subset of fecal specimens and urine supernatant specimens. We report that a 1% relative gut abundance of Escherichia is an independent risk factor for Escherichia bacteriuria and UTI and a 1% relative gut abundance of Enterococcus is an independent risk factor for Enterococcus bacteriuria. Strain analysis establishes a close strain level alignment between species found in the gut and in the urine in the same subjects. Our results support a gut microbiota-UTI axis, suggesting that modulating the gut microbiota may be a potential novel strategy to prevent UTIs.
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http://dx.doi.org/10.1038/s41467-019-13467-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893017PMC
December 2019

MANAGEMENT OF HYPERPARATHYROIDISM IN KIDNEY TRANSPLANTATION CANDIDATES: A NEED FOR CONSENSUS.

Endocr Pract 2020 Mar 4;26(3):299-304. Epub 2019 Nov 4.

To assess the evolving standards of care for hyperparathyroidism in kidney transplant candidates. An 11-question, Institutional Review Board-approved survey was designed and reviewed by multiple institutions. The questionnaire was made available to the American Society of Transplantation's Kidney Pancreas Community of Practice membership via their online hub from April through July 2019. Twenty percent (n = 41) of kidney transplant centers responded out of 202 programs in the United States. Forty-one percent (n = 17) of respondents believed medical literature supports the concept that a serum parathyroid hormone level greater than 800 pg/mL could endanger the survival of a transplanted kidney and therefore makes transplantation in an affected patient relatively or absolutely contraindicated. Sixty-six percent (n = 27) said they occasionally recommend parathyroidectomy for secondary hyperparathyroidism prior to transplantation, and 66% (n = 27) recommend parathyroidectomy after transplantation based on persistent, unsatisfactory posttransplantation parathyroid hormone levels. Forty-six percent (n = 19) prefer subtotal parathyroidectomy as their choice; 44% (n = 18) had no standard preference. Endocrine surgery and otolaryngology were the most common surgical specialties consulted to perform parathyroidectomy in kidney transplant candidates. The majority of respondents (71%, n = 29) do not involve endocrinologists in the management of kidney transplantation candidates. Our survey shows wide divergence of clinical practice in the area of surgical management of kidney transplantation candidates with hyperparathyroidism. We suggest that medical/surgical societies involved in the transplantation care spectrum convene a multidisciplinary group of experts to create a new section in the kidney transplantation guidelines addressing the collaborative management of parathyroid disease in transplantation candidates. = American Association of Clinical Endocrinologists; = American Association of Endocrine Surgeons; = American Head and Neck Society; = chronic kidney disease; = chronic kidney disease-mineral and bone disorder; = end-stage renal disease; = hyperparathyroidism; = Kidney Disease Improving Global Outcomes; = kidney transplantation; = kidney transplant candidate; = parathyroid hormone; = parathyroidectomy; = ultrasonography.
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http://dx.doi.org/10.4158/EP-2019-0392DOI Listing
March 2020

Identification of Antibiotic Administration as a Potentially Novel Factor Associated With Tacrolimus Trough Variability in Kidney Transplant Recipients: A Preliminary Study.

Transplant Direct 2019 Sep 23;5(9):e485. Epub 2019 Aug 23.

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

Tacrolimus trough variability is an important risk factor for kidney allograft outcomes. Recent evidence suggests that the gut microbiota is associated with tacrolimus dosing requirements and direct metabolism of tacrolimus. We hypothesize that administration of antibiotics, which are known to alter the gut microbiota, is associated with tacrolimus trough variability.

Methods: We conducted a retrospective chart review of subjects who received kidney transplants at our institution from 2012 to 2013 and evaluated subjects who received antibiotics during the first month of transplantation (Abx Group, N = 60) and subjects who did not (No Abx Group, N = 200). We evaluated whether antibiotic administration in the Abx Group had increased tacrolimus trough concentrations and concentration over tacrolimus dosage (C/D) after antibiotic administration. We also evaluated tacrolimus variability as measured by standard deviation (SD) and coefficient of variation between the Abx Group and No Abx Group.

Results: In the Abx Group, tacrolimus trough concentration over tacrolimus dosage (C/D) increased 7 and 15 days after antibiotic administration ( = 0.001, = 0.07, respectively, Wilcoxon signed-rank test). From postoperative day 31-45, the variability in tacrolimus trough levels in the Abx Group as measured by SD and coefficient of variation was significantly higher than the variability in the No Abx Group ( = 0.03, = 0.02, Wilcoxon rank sum test, respectively).

Conclusions: Our identification of antibiotic administration as a potentially new risk factor for tacrolimus trough variability suggests the need to carefully follow tacrolimus trough levels after antibiotic administration.
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http://dx.doi.org/10.1097/TXD.0000000000000930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739039PMC
September 2019

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

Gastrointestinal pathogen colonization and the microbiome in asymptomatic kidney transplant recipients.

Transpl Infect Dis 2019 Dec 24;21(6):e13167. Epub 2019 Oct 24.

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

Background: In kidney transplant recipients, gastrointestinal (GI) pathogens in feces are only evaluated during diarrheal episodes. Little is known about the prevalence of GI pathogens in asymptomatic individuals in this population.

Methods: We recruited 142 kidney transplant recipients who provided a non-diarrheal fecal sample within the first 10 days after transplantation. The specimens were evaluated for GI pathogens using the BioFire FilmArray GI Panel (BioFire Diagnostics, LLC), which tests for 22 pathogens. The fecal microbiome was also characterized using 16S rRNA gene sequencing of the V4-V5 hypervariable region. We evaluated whether detection of Clostridioides difficile and other GI pathogens was associated with post-transplant diarrhea within the first 3 months after transplantation.

Results: Among the 142 subjects, a potential pathogen was detected in 43 (30%) using the GI Panel. The most common organisms detected were C difficile (n = 24, 17%), enteropathogenic Escherichia coli (n = 8, 6%), and norovirus (n = 5, 4%). Detection of a pathogen on the GI panel or detection of C difficile alone was not associated with future post-transplant diarrhea (P > .05). The estimated number of gut bacterial species was significantly lower in subjects colonized with C difficile than those not colonized with a GI pathogen (P = .01).

Conclusion: Colonization with GI pathogens, particularly C difficile, is common at the time of kidney transplantation but does not predict subsequent diarrhea. Detection of C difficile carriage was associated with decreased microbial diversity and may be a biomarker of gut dysbiosis.
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http://dx.doi.org/10.1111/tid.13167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917898PMC
December 2019

A cell-free DNA metagenomic sequencing assay that integrates the host injury response to infection.

Proc Natl Acad Sci U S A 2019 09 26;116(37):18738-18744. Epub 2019 Aug 26.

Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853;

High-throughput metagenomic sequencing offers an unbiased approach to identify pathogens in clinical samples. Conventional metagenomic sequencing, however, does not integrate information about the host, which is often critical to distinguish infection from infectious disease, and to assess the severity of disease. Here, we explore the utility of high-throughput sequencing of cell-free DNA (cfDNA) after bisulfite conversion to map the tissue and cell types of origin of host-derived cfDNA, and to profile the bacterial and viral metagenome. We applied this assay to 51 urinary cfDNA isolates collected from a cohort of kidney transplant recipients with and without bacterial and viral infection of the urinary tract. We find that the cell and tissue types of origin of urinary cfDNA can be derived from its genome-wide profile of methylation marks, and strongly depend on infection status. We find evidence of kidney and bladder tissue damage due to viral and bacterial infection, respectively, and of the recruitment of neutrophils to the urinary tract during infection. Through direct comparison to conventional metagenomic sequencing as well as clinical tests of infection, we find this assay accurately captures the bacterial and viral composition of the sample. The assay presented here is straightforward to implement, offers a systems view into bacterial and viral infections of the urinary tract, and can find future use as a tool for the differential diagnosis of infection.
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http://dx.doi.org/10.1073/pnas.1906320116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744880PMC
September 2019

Cardiovascular disease care fragmentation in kidney transplantation: a call for action.

Kidney Int 2019 09 10;96(3):568-571. Epub 2019 Jun 10.

Division of Nephrology, Department of Medicine, Weill Cornell Medical Center, New York, New York, USA.

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http://dx.doi.org/10.1016/j.kint.2019.04.042DOI Listing
September 2019

Perceptions and Practices Regarding Frailty in Kidney Transplantation: Results of a National Survey.

Transplantation 2020 02;104(2):349-356

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

Background: Given the potential utility of frailty, a clinical phenotype of decreased physiologic reserve and resistance to stressors, to predict postkidney transplant (KT) outcomes, we sought to understand the perceptions and practices regarding frailty measurement in US KT programs.

Methods: Surveys were emailed to American Society of Transplantation Kidney/Pancreas Community of Practice members and 202 US transplant programs (November 2017 to April 2018). Program characteristics were gleaned from Scientific Registry of Transplant Recipients.

Results: The 133 responding programs (response rate = 66%) represented 77% of adult KTs and 79% of adult KT candidates in the United States. Respondents considered frailty to be a useful concept in evaluating candidacy (99%) and endorsed a need to develop a frailty measurement specific to KT (92%). Frailty measurement was more common during candidacy evaluation (69%) than during KT admission (28%). Of the 202 programs, 38% performed frailty assessments in all candidates while 23% performed assessments only for older candidates. There was heterogeneity in the frailty assessment method; 18 different tools were utilized to measure frailty. The most common tool was a timed walk test (19%); 67% reported performing >1 tool. Among programs that measure frailty, 53% reported being less likely to list frail patients for KT.

Conclusions: Among US KT programs, frailty is recognized as a clinically relevant construct and is commonly measured at evaluation. However, there is considerable heterogeneity in the tools used to measure frailty. Efforts to identify optimal measurement of frailty using either an existing or a novel tool and subsequent standardization of its measurement and application across KT programs should be considered.
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http://dx.doi.org/10.1097/TP.0000000000002779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834867PMC
February 2020

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

Cardiovascular disease in the kidney transplant recipient: epidemiology, diagnosis and management strategies.

Nephrol Dial Transplant 2019 05;34(5):760-773

Weill Cornell Medicine-New York Presbyterian Hospital, New York, NY, USA.

Kidney transplantation (KT) is the optimal therapy for end-stage kidney disease (ESKD), resulting in significant improvement in survival as well as quality of life when compared with maintenance dialysis. The burden of cardiovascular disease (CVD) in ESKD is reduced after KT; however, it still remains the leading cause of premature patient and allograft loss, as well as a source of significant morbidity and healthcare costs. All major phenotypes of CVD including coronary artery disease, heart failure, valvular heart disease, arrhythmias and pulmonary hypertension are represented in the KT recipient population. Pre-existing risk factors for CVD in the KT recipient are amplified by superimposed cardio-metabolic derangements after transplantation such as the metabolic effects of immunosuppressive regimens, obesity, posttransplant diabetes, hypertension, dyslipidemia and allograft dysfunction. This review summarizes the major risk factors for CVD in KT recipients and describes the individual phenotypes of overt CVD in this population. It highlights gaps in the existing literature to emphasize the need for future studies in those areas and optimize cardiovascular outcomes after KT. Finally, it outlines the need for a joint 'cardio-nephrology' clinical care model to ensure continuity, multidisciplinary collaboration and implementation of best clinical practices toward reducing CVD after KT.
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http://dx.doi.org/10.1093/ndt/gfz053DOI Listing
May 2019