Publications by authors named "Enver Akalin"

88 Publications

A Safe Anti-A2 Titer for a Successful A2 Incompatible Kidney Transplantation: A Single-center Experience and Review of the Literature.

Transplant Direct 2021 Feb 26;7(2):e662. Epub 2021 Jan 26.

Montefiore-Einstein Center for Transplantation, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY.

Background: Kidney allocation system allows blood type B candidates accept kidneys from A2/A2B donors. There is no mandate by UNOS on which the anti-A2 level is acceptable. We aimed to investigate the safety of kidney transplant in blood group B patients with anti-A2 titers ≤16.

Methods: We performed 41 A2-incompatible kidney transplants in blood group B recipients between May 2015 and September 2019. Clinical outcomes were compared with a control group of 75 blood group B recipients who received blood group compatible kidney transplantation at the same period.

Results: Of the 41 recipients, 85% were male, 48% African American, with a median age of 53 (20-73) y. Thirty-eight (93%) were deceased-donor and 3 (7%) were living-donor kidney transplant recipients. Pretransplant anti-A2 IgG titers were 2 in 16, 4 in 9, 8 in 6, and 16 in 5 and too weak to titer in 5 recipients. Eight patients had pretransplant donor-specific antibodies. During a median follow-up of 32.6 mo (6-57.3) patient and graft survival were 100% and 92% in the A2-incompatible kidney transplant group, and 91% and 92% in the blood group compatible group, respectively. Twelve A2-incompatible recipients underwent a 21 clinically indicated kidney biopsies at a median 28 d (6-390) after transplantation. None of the patients developed acute antibody-mediated rejection and 2 patients (5%) had acute T-cell-mediated rejection. Interestingly, peritubular capillary C4d positivity was seen in 7 biopsies which did not have any findings of acute rejection or microvascular inflammation but not in any of the rejection-free biopsies in the control group. C4d positivity was persistent in 5 of those patients who had follow-up biopsies.

Conclusions: A2-incompatible transplantation is safe in patients with anti-A2 titers ≤16 with excellent short-term kidney allograft outcomes. C4d positivity is frequent in allograft biopsies without acute rejection.
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http://dx.doi.org/10.1097/TXD.0000000000001099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837880PMC
February 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

CCR5 inhibition in critical COVID-19 patients decreases inflammatory cytokines, increases CD8 T-cells, and decreases SARS-CoV2 RNA in plasma by day 14.

Int J Infect Dis 2021 Feb 10;103:25-32. Epub 2020 Nov 10.

Vaccine & Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA.

Objective: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now a global pandemic. Emerging results indicate a dysregulated immune response. Given the role of CCR5 in immune cell migration and inflammation, we investigated the impact of CCR5 blockade via the CCR5-specific antibody leronlimab on clinical, immunological, and virological parameters in severe COVID-19 patients.

Methods: In March 2020, 10 terminally ill, critical COVID-19 patients received two doses of leronlimab via individual emergency use indication. We analyzed changes in clinical presentation, immune cell populations, inflammation, as well as SARS-CoV-2 plasma viremia before and 14 days after treatment.

Results: Over the 14-day study period, six patients survived, two were extubated, and one discharged. We observed complete CCR5 receptor occupancy in all donors by day 7. Compared with the baseline, we observed a concomitant statistically significant reduction in plasma IL-6, restoration of the CD4/CD8 ratio, and resolution of SARS-CoV2 plasma viremia (pVL). Furthermore, the increase in the CD8 percentage was inversely correlated with the reduction in pVL (r = -0.77, p = 0.0013).

Conclusions: Our study design precludes clinical efficacy inferences but the results implicate CCR5 as a therapeutic target for COVID-19 and they form the basis for ongoing randomized clinical trials.
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http://dx.doi.org/10.1016/j.ijid.2020.10.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654230PMC
February 2021

COVID-19 and Solid Organ Transplantation: A Review Article.

Transplantation 2021 01;105(1):37-55

Division of Nephrology, Abdominal Transplant Program, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY.

The coronavirus pandemic has significantly impacted solid organ transplantation (SOT). Early in the outbreak period, transplant societies recommended suspending living kidney transplant programs in communities with widespread transmission to avoid exposing recipients to increased risk of immunosuppression, while recommendations were made to reserve deceased-donor kidney transplantation for likely life-saving indications. SOT recipients may be at high risk from COVID-19 disease due to chronic immunosuppressive treatment and other medical comorbidities. Mortality rates reported between 13 to over 30% in SOT recipients. In addition to high rates of complications and mortality attributable to COVID-19 infections, the pandemic has also led to additional complexities in transplantation including new questions regarding screening of donors and recipients, decision making to accept a patient for kidney transplant or wait after pandemic. The clinical implications of COVID-19 infection may also differ depending on the type of the transplanted organ and recipient comorbidities which further impacts decisions on continuing transplantation during the pandemic. Transplant activity during a pandemic should be tailored with careful selection of both donors and recipients. Furthermore, while tremendous strides have been made in treatment strategies and vaccinations, the impact of these in transplant recipients may be attenuated in the setting of their immunosuppression. In this review, we aim to summarize several aspects of COVID-19 in transplantation, including the immune response to SARS-CoV-2, SARS-CoV-2 diagnostics, clinical outcomes in SOT recipients, and end-stage kidney disease patients, transplant activity during the pandemic, and treatment options for COVID-19 disease.
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http://dx.doi.org/10.1097/TP.0000000000003523DOI Listing
January 2021

COVID-19 infection in kidney transplant recipients at the epicenter of pandemics.

Kidney Int 2020 12 16;98(6):1559-1567. Epub 2020 Oct 16.

Division of Nephrology, Montefiore Medical Center Transplant Center, Albert Einstein College of Medicine, Bronx, New York, USA; Einstein-Montefiore Abdominal Transplant Center, Bronx, New York, USA. Electronic address:

We investigated the prevalence and clinical outcomes of COVID-19 in recipients of kidney transplants in the Bronx, New York, one of the epicenters of the pandemic. Between March 16 and June 2, 2020, 132 kidney transplant recipients tested positive by SARS-CoV-2 RT-PCR. From May 3 to July 29, 2020, 912 kidney transplant recipients were screened for SARS-CoV-2 IgG antibodies during routine clinic visits, of which 16.6% tested positive. Fifty-five of the 152 patients had previously tested positive by RT-PCR, while the remaining 97 did not have significant symptoms and had not been previously tested by RT-PCR. The prevalence of SARS-CoV-2 infection was 23.4% in the 975 patients tested by either RT-PCR or SARS-CoV-2 IgG. Older patients and patients with higher serum creatinine levels were more likely diagnosed by RT-PCR compared to SARS-CoV-2 IgG. Sixty-nine RT-PCR positive patients were screened for SARS-CoV-2 IgG antibodies at a median of 44 days post-diagnosis (Inter Quartile Range 31-58) and 80% were positive. Overall mortality was 20.5% but significantly higher (37.8%) in the patients who required hospitalization. Twenty-three percent of the hospitalized patients required kidney replacement therapy and 6.3% lost their allografts. In multivariable analysis, older age, receipt of deceased-donor transplantation, lack of influenza vaccination in the previous year and higher serum interleukine-6 levels were associated with mortality. Thus, 42% of patients with a kidney transplant and with COVID-19 were diagnosed on antibody testing without significant clinical symptoms; 80% of patients with positive RT-PCR developed SARS-CoV-2 IgG and mortality was high among patients requiring hospitalization.
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http://dx.doi.org/10.1016/j.kint.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561527PMC
December 2020

Defining the roles and responsibilities of the kidney transplant medical director: A necessary step for future training, mentoring, and professional development.

Am J Transplant 2020 Oct 5. Epub 2020 Oct 5.

University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

The management of a kidney transplant program has evolved significantly in the last decades to become a highly specialized, multidisciplinary standard of care for end-stage kidney disease. Transplant center job descriptions have similarly morphed with increasing responsibilities to address a more complex patient mix, increasing medical and surgical therapeutic options, and increasing regulatory burden in the face of an ever-increasing organ shortage. Within this evolution, the role of the Kidney Transplant Medical Director (KTMD) has expanded beyond the basic requirements described in the United Network for Organ Sharing bylaws. Without a clear job description, transplant nephrology trainees may be inadequately trained and practicing transplant nephrologists may face opaque expectations for the roles and responsibilities of Medical Director. To address this gap and clarify the key areas in which the KTMD interfaces with the kidney transplant program, American Society of Transplantation (AST) formed a Task Force of 14 AST KTMDs to review and define the role of the KTMD in key aspects of administrative, regulatory, budgetary, and educational oversight of a kidney transplant program.
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http://dx.doi.org/10.1111/ajt.16332DOI Listing
October 2020

High terminal creatinine donors should not preclude simultaneous kidney and pancreas transplantation.

Am J Surg 2020 Sep 28. Epub 2020 Sep 28.

Albert Einstein College of Medicine, Bronx, NY, USA; Montefiore-Einstein Center for Transplantation, Montefiore Medical Center, Bronx, NY, USA. Electronic address:

Background: Simultaneous pancreas and kidney transplantation (SPK) in the setting of end-stage renal disease offers unmatched outcomes in insulin dependent diabetic patients. Donor pool expansion through the transplantation of kidneys with acute kidney injury (AKI) is controversial.

Methods: 59 SPK transplants were classified by presence of donor AKI, defined as donor terminal creatinine ≥ 1.5x the initial creatinine or donor terminal creatinine > 4.0 mg/dL. Endpoints included graft and patient survival, delayed graft function (DGF), serum creatinine, glomerular filtration rate (GFR), Hemoglobin A1c (HbA1c) and acute rejection.

Results: The donor AKI group (n = 35) had significantly higher rates of DGF (38 v. 9%, p = 0.01). There was no difference in creatinine or GFR at 1, 3, 6 and 12 months. HbA1c was comparable at 3, 6 and 12 months. There was no significant difference in the percentage of patients that required anti-diabetic agents after transplant (14 v. 4%, p = 0.56).

Conclusions: We observed increased rates of DGF in SPK recipients with donor AKI. However, equivalent outcomes of pancreas and kidney function in both groups were observed.
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http://dx.doi.org/10.1016/j.amjsurg.2020.09.031DOI Listing
September 2020

Commercial insurance delays direct-acting antiviral treatment for hepatitis C kidney transplantation into uninfected recipients.

Transpl Infect Dis 2021 Feb 3;23(1):e13449. Epub 2020 Sep 3.

Albert Einstein College of Medicine, Bronx, NY, USA.

Introduction: The advent of direct-acting antivirals (DAAs) has created an avenue for transplantation of hepatitis C virus (HCV)-infected donors into uninfected recipients (D+/R-). The donor transmission of HCV is then countered by DAA administration during the post-operative period. However, initiation of DAA treatment is ultimately dictated by insurance companies.

Methods: A retrospective chart review of 52 D+/R- kidney recipients who underwent DAA treatment post-transplant was performed. Patients were grouped according to their prescription coverage plans, managed by either commercial or government pharmacy benefit managers (PBMs).

Results: Thirty-nine patients had government PBMs and 13 had commercial PBMs. Demographics were similar between the two groups. All patients developed HCV viremia, but cleared the virus after treatment with DAA. Patients with government PBMs were treated earlier compared to those with commercial PBMs (11 days vs 26 days, P = .01). Longer time to DAA initiation resulted in higher peak viral loads (β = 0.39, R  = .15, P = .01) and longer time to HCV viral load clearance (β = 0.41, R  = .17, P = .01).

Conclusions: D+/R- transplantation offers patients an alternative strategy to increase access. However, treatment can be profoundly delayed by a third-party payer authorization process that may be subjecting patients to unnecessary risks and worsened outcomes.
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http://dx.doi.org/10.1111/tid.13449DOI Listing
February 2021

Trajectories of glomerular filtration rate and progression to end stage kidney disease after kidney transplantation.

Kidney Int 2021 01 8;99(1):186-197. Epub 2020 Aug 8.

Université de Paris, INSERM, PARCC, Paris Translational Research Centre for Organ Transplantation, Paris, France; Kidney Transplant Department, Necker Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France. Electronic address:

Although the gold standard of monitoring kidney transplant function relies on glomerular filtration rate (GFR), little is known about GFR trajectories after transplantation, their determinants, and their association with outcomes. To evaluate these parameters we examined kidney transplant recipients receiving care at 15 academic centers. Patients underwent prospective monitoring of estimated GFR (eGFR) measurements, with assessment of clinical, functional, histological and immunological parameters. Additional validation took place in seven randomized controlled trials that included a total of 14,132 patients with 403,497 eGFR measurements. After a median follow-up of 6.5 years, 1,688 patients developed end-stage kidney disease. Using unsupervised latent class mixed models, we identified eight distinct eGFR trajectories. Multinomial regression models identified seven significant determinants of eGFR trajectories including donor age, eGFR, proteinuria, and several significant histological features: graft scarring, graft interstitial inflammation and tubulitis, microcirculation inflammation, and circulating anti-HLA donor specific antibodies. The eGFR trajectories were associated with progression to end stage kidney disease. These trajectories, their determinants and respective associations with end stage kidney disease were similar across cohorts, as well as in diverse clinical scenarios, therapeutic eras and in the seven randomized control trials. Thus, our results provide the basis for a trajectory-based assessment of kidney transplant patients for risk stratification and monitoring.
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http://dx.doi.org/10.1016/j.kint.2020.07.025DOI Listing
January 2021

Uromodulin to Osteopontin Ratio in Deceased Donor Urine is Associated with Kidney Graft Outcomes.

Transplantation 2020 Jul 27. Epub 2020 Jul 27.

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 graft failure (dcGF).

Secondary Outcomes: delayed graft function (DGF) and 6-month 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 graft failure 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 (MHCII) in mouse macrophages.

Results: Doubling of UMOD increased dcGF risk (adjusted hazard ratio (aHR) of 1.1 (95% 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 B-coefficient 3.19 (95% CI: 1.28-5.11)]. UMOD increased MHCII 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.

Trial Registration Number: NCT01848249.
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http://dx.doi.org/10.1097/TP.0000000000003299DOI Listing
July 2020

The COVID-19 pandemic: A community approach.

Clin Transplant 2020 11 28;34(11):e14059. Epub 2020 Sep 28.

Transplanation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

An unprecedented global pandemic caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has quickly overwhelmed the health care systems worldwide. While there is an absence of consensus among the community in how to manage solid organ transplant recipients and donors, a platform provided by the American Society of Transplantation online community "Outstanding Questions in Transplantation," hosted a collaborative multicenter, multinational discussions to share knowledge in a rapidly evolving global situation. Here, we present a summary of the discussion in addition to the latest published literature.
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http://dx.doi.org/10.1111/ctr.14059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435543PMC
November 2020

COVID-19 and kidney transplantation: Results from the TANGO International Transplant Consortium.

Am J Transplant 2020 11 4;20(11):3140-3148. Epub 2020 Aug 4.

Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Kidney transplant recipients may be at a high risk of developing critical coronavirus disease 2019 (COVID-19) illness due to chronic immunosuppression and comorbidities. We identified hospitalized adult kidney transplant recipients at 12 transplant centers in the United States, Italy, and Spain who tested positive for COVID-19. Clinical presentation, laboratory values, immunosuppression, and treatment strategies were reviewed, and predictors of poor clinical outcomes were determined through multivariable analyses. Among 9845 kidney transplant recipients across centers, 144 were hospitalized due to COVID-19 during the 9-week study period. Of the 144 patients, 66% were male with a mean age of 60 (±12) years, and 40% were Hispanic and 25% were African American. Prevalent comorbidities included hypertension (95%), diabetes (52%), obesity (49%), and heart (28%) and lung (19%) disease. Therapeutic management included antimetabolite withdrawal (68%), calcineurin inhibitor withdrawal (23%), hydroxychloroquine (71%), antibiotics (74%), tocilizumab (13%), and antivirals (14%). During a median follow-up period of 52 days (IQR: 16-66 days), acute kidney injury occurred in 52% cases, with respiratory failure requiring intubation in 29%, and the mortality rate was 32%. The 46 patients who died were older, had lower lymphocyte counts and estimated glomerular filtration rate levels, and had higher serum lactate dehydrogenase, procalcitonin, and interleukin-6 levels. In sum, hospitalized kidney transplant recipients with COVID-19 have higher rates of acute kidney injury and mortality.
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http://dx.doi.org/10.1111/ajt.16185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405285PMC
November 2020

Assessment of Organ Quality in Kidney Transplantation by Molecular Analysis and Why It May Not Have Been Achieved, Yet.

Front Immunol 2020 12;11:833. Epub 2020 May 12.

Division of Nephrology, University Hospital Zürich, Zurich, Switzerland.

Donor organ shortage, growing waiting lists and substantial organ discard rates are key problems in transplantation. The critical importance of organ quality in determining long-term function is becoming increasingly clear. However, organ quality is difficult to predict. The lack of good measures of organ quality is a serious challenge in terms of acceptance and allocation of an organ. The underlying review summarizes currently available methods used to assess donor organ quality such as histopathology, clinical scores and machine perfusion characteristics with special focus on molecular analyses of kidney quality. The majority of studies testing molecular markers of organ quality focused on identifying organs at risk for delayed graft function, yet without prediction of long-term graft outcome. Recently, interest has emerged in looking for molecular markers associated with biological age to predict organ quality. However, molecular gene sets have not entered the clinical routine or impacted discard rates so far. The current review critically discusses the potential reasons why clinically applicable molecular quality assessment using early kidney biopsies might not have been achieved yet. Besides a critical analysis of the inherent limitations of surrogate markers used for organ quality, i.e., delayed graft function, the intrinsic methodological limitations of studies assessing organ quality will be discussed. These comprise the multitude of unpredictable hits as well as lack of markers of nephron mass, functional reserve and regenerative capacity.
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http://dx.doi.org/10.3389/fimmu.2020.00833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236771PMC
May 2020

The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection.

Am J Transplant 2020 09 28;20(9):2318-2331. Epub 2020 May 28.

Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell-mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation.
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http://dx.doi.org/10.1111/ajt.15898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496245PMC
September 2020

Glycemic management and clinical outcomes in underserved minority kidney transplant recipients with type 2 and posttransplantation diabetes: A single-center retrospective study.

Diabetes Res Clin Pract 2020 Jul 20;165:108221. Epub 2020 May 20.

Department of Medicine, Division of Endocrinology, Albert Einstein College of Medicine, Bronx, NY, United States.

Aims: Little is known about glycemic management, particularly with novel cardio-nephroprotecive agents, in underserved minority kidney transplant recipients with pre-transplant type 2 (T2DM) and posttransplantation diabetes mellitus (PTDM). We assessed glycemic management and outcomes in this high-risk population.

Methods: We reviewed records of patients who received kidney transplants between June 2012 and December 2014 at a single center. Hemoglobin A1c (HbA1c) and prescribed glucose-lowering medications were examined, and mortality was compared between T2DM, PTDM, and no diabetes (NoDM) patients.

Results: We followed 302 patient records (41.1% Hispanic, 41.1% non-Hispanic black) for a median (IQR) of 45.5 (37.0, 53.0) months post-transplant. Pre-transplant T2DM was present in 152 (50.3%), while 58 (19.2%) developed PTDM and 92 (30.4%) remained NoDM. At 1-year post-transplant, the average HbA1c was 8.1 ± 1.8% in T2DM and 6.6 ± 1.3% in PTDM. No glucose-lowering agents were prescribed in 3.4% of T2DM and 44.8% of PTDM. When treated, both received mostly insulin and metformin. Diabetes, HbA1c and insulin therapy were not independently associated with risk of mortality.

Conclusions: Glycemic management was suboptimal and relied on older medications. Further studies are needed to assess longer-term outcomes of more rigorous glycemic management, and the value of novel cardio-nephroprotective agents in kidney transplant recipients.
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http://dx.doi.org/10.1016/j.diabres.2020.108221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415727PMC
July 2020

Banff 2019 Meeting Report: Molecular diagnostics in solid organ transplantation-Consensus for the Banff Human Organ Transplant (B-HOT) gene panel and open source multicenter validation.

Am J Transplant 2020 09 27;20(9):2305-2317. Epub 2020 Jun 27.

Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

This meeting report from the XV Banff conference describes the creation of a multiorgan transplant gene panel by the Banff Molecular Diagnostics Working Group (MDWG). This Banff Human Organ Transplant (B-HOT) panel is the culmination of previous work by the MDWG to identify a broadly useful gene panel based on whole transcriptome technology. A data-driven process distilled a gene list from peer-reviewed comprehensive microarray studies that discovered and validated their use in kidney, liver, heart, and lung transplant biopsies. These were supplemented by genes that define relevant cellular pathways and cell types plus 12 reference genes used for normalization. The 770 gene B-HOT panel includes the most pertinent genes related to rejection, tolerance, viral infections, and innate and adaptive immune responses. This commercially available panel uses the NanoString platform, which can quantitate transcripts from formalin-fixed paraffin-embedded samples. The B-HOT panel will facilitate multicenter collaborative clinical research using archival samples and permit the development of an open source large database of standardized analyses, thereby expediting clinical validation studies. The MDWG believes that a pathogenesis and pathway based molecular approach will be valuable for investigators and promote therapeutic decision-making and clinical trials.
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http://dx.doi.org/10.1111/ajt.16059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496585PMC
September 2020

A CRISPR-based assay for the detection of opportunistic infections post-transplantation and for the monitoring of transplant rejection.

Nat Biomed Eng 2020 06 13;4(6):601-609. Epub 2020 Apr 13.

Institute for Medical Engineering and Science and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.

In organ transplantation, infection and rejection are major causes of graft loss. They are linked by the net state of immunosuppression. To diagnose and treat these conditions earlier, and to improve long-term patient outcomes, refined strategies for the monitoring of patients after graft transplantation are needed. Here, we show that a fast and inexpensive assay based on CRISPR-Cas13 accurately detects BK polyomavirus DNA and cytomegalovirus DNA from patient-derived blood and urine samples, as well as CXCL9 messenger RNA (a marker of graft rejection) at elevated levels in urine samples from patients experiencing acute kidney transplant rejection. The assay, which we adapted for lateral-flow readout, enables-via simple visualization-the post-transplantation monitoring of common opportunistic viral infections and of graft rejection, and should facilitate point-of-care post-transplantation monitoring.
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http://dx.doi.org/10.1038/s41551-020-0546-5DOI Listing
June 2020

Preoperative C-Peptide Predicts Weight Gain After Pancreas Transplantation.

Prog Transplant 2020 06 3;30(2):117-124. Epub 2020 Apr 3.

Albert Einstein College of Medicine, Bronx, NY, USA.

Background: Transplant recipients are susceptible to cardiovascular complications, obesity, and increased insulin resistance after transplant. Here we assess weight gain in diabetic recipients after pancreas transplantation.

Methods: This is a single-center study of 32 simultaneous pancreas and kidney and 5 pancreas after kidney transplant recipients from 2014 to 2018. Starting C-peptide levels ≤ 0.1 ng/mL were used to denote insulin nondetectability (n = 25) and C-peptide levels > 0.1 ng/mL as insulin detectability (n = 12). Hemoglobin A, body mass index (BMI), and weight following transplantation were assessed.

Results: Hemoglobin A at 1 year was 5.9% in the insulin nondetectable recipients and 5.6% in the insulin detectable group ( = .56). Average BMI after transplant was higher in the insulin detectable group 28.6 versus 24.4 kg/m ( = .03) despite no difference in starting BMIs (24.9 versus 24.0 kg/m, = .42). The insulin detectable group also had a larger percentage weight change from their starting weight 13.1% versus 0.9 % at 1 year ( = .02). Linear regression demonstrated that starting C-peptide was a significant predictor of weight gain posttransplant.

Conclusions: Patients with elevated C-peptides at time of transplant are susceptible to rapid weight gain postoperatively. These patients may benefit from aggressive nutritional management.
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http://dx.doi.org/10.1177/1526924820913518DOI Listing
June 2020

The use of LCP-Tacrolimus (Envarsus XR) in simultaneous pancreas and kidney (SPK) transplant recipients.

Am J Surg 2020 04 24;219(4):583-586. Epub 2020 Feb 24.

Albert Einstein College of Medicine, Bronx, NY, USA; Montefiore-Einstein Center for Transplantation, Montefiore Medical Center, Bronx, NY, USA. Electronic address:

Background: Extended release LCP-tacrolimus (LCPT) allows once-daily dosing in transplant recipients. The improved bioavailability may be beneficial for simultaneous pancreas-kidney recipients (SPK).

Methods: This is a study of 39 SPK recipients on standard immediate-release tacrolimus (IR-TAC, n = 21) or LCPT (n = 18). Coefficient of variability (CV = 100∗standard deviation/mean) was calculated to assess drug levels. Hemoglobin A1c (HbA1c), tacrolimus and creatinine levels were measured postoperatively.

Results: There was no difference in tacrolimus CV in the IR-TAC and LCPT groups at 1 month or 3 months postoperatively; however, a greater difference was observed at 1 year (41.0 vs. 33.1%; p = 0.19). There were six episodes of acute rejection in the IR-TAC group compared to zero episodes in the LCPT group (p = 0.01). HbA1c was significantly higher in the IR-TAC group compared to LCPT at 3 (5.5 vs. 4.9%, p = 0.01), 6 (5.6 vs. 4.9%, p = 0.01) and 12 months (5.8 vs. 5.1%, p = 0.07).

Conclusions: Significantly lower rates of rejection were observed in patients receiving LCPT. The once daily dosing may facilitate medication adherence and result in improved long-term outcomes.
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http://dx.doi.org/10.1016/j.amjsurg.2020.02.027DOI Listing
April 2020

Transplantation of viral-positive hepatitis C-positive kidneys into uninfected recipients offers an opportunity to increase organ access.

Clin Transplant 2020 04 10;34(4):e13833. Epub 2020 Mar 10.

Albert Einstein College of Medicine, Bronx, NY, USA.

The advent of direct-acting antivirals (DAAs) has provided the impetus to transplant kidneys from hepatitis C virus-positive donors into uninfected recipients (D+/R-). Thirty D+/R- patients received DAA treatment. Sustained virologic response (SVR12) was defined as an undetectable viral load in 12 weeks after treatment. An age-matched cohort of uninfected donor and recipient pairs (D-/R-) transplanted during same time period was used for comparison. The median day of viral detection was postoperative day (POD) 2. The detection of viremia in D+/R- patients was 100%. The initial median viral load was 531 copies/μL (range: 10-1 × 10 copies/μL) with a median peak viral load of 3.4 × 10 copies/μL (range: 804-1.0 × 10 copies/μL). DAAs were initiated on median POD 9 (range: 5-41 days). All 30 patients had confirmed SVR12. During a median follow-up of 10 months, patient and graft survival was 100%, and acute rejection was 6.6% with no major adverse events related to DAA treatment. Delayed graft function was significantly decreased in D+/R- patients as compared to the age-matched cohort (27% vs 60%; P = .01). D+/R- transplantation offers patients an alternative strategy to increase access.
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http://dx.doi.org/10.1111/ctr.13833DOI Listing
April 2020

Recurrence of FSGS after Kidney Transplantation in Adults.

Clin J Am Soc Nephrol 2020 02 23;15(2):247-256. Epub 2020 Jan 23.

Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts;

Background And Objectives: FSGS recurrence after kidney transplantation is a major risk factor for graft loss. However, the natural history, clinical predictors, and response to treatment remain unclear because of small sample sizes and poor generalizability of single-center studies, and disease misclassification in registry-based studies. We therefore aimed to determine the incidence, predictors, and treatment response of recurrent FSGS in a large cohort of kidney transplant recipients.

Design, Setting, Participants, & Measurements: The Post-Transplant Glomerular Disease (TANGO) project is an observational, multicenter, international cohort study that aims to investigate glomerular disease recurrence post-transplantation. Transplant recipients were screened for the diagnosis of idiopathic FSGS between 2005 and 2015 and details were recorded about the transplant, clinical outcomes, treatments, and other risk factors.

Results: Among 11,742 kidney transplant recipients screened for FSGS, 176 had a diagnosis of idiopathic FSGS and were included. FSGS recurred in 57 patients (32%; 95% confidence interval [95% CI], 25% to 39%) and 39% of them lost their graft over a median of 5 (interquartile range, 3.0-8.1) years. Multivariable Cox regression revealed a higher risk for recurrence with older age at native kidney disease onset (hazard ratio [HR], 1.37 per decade; 95% CI, 1.09 to 1.56). Other predictors were white race (HR, 2.14; 95% CI, 1.08 to 4.22), body mass index at transplant (HR, 0.89 per kg/m; 95% CI, 0.83 to 0.95), and native kidney nephrectomies (HR, 2.76; 95% CI, 1.16 to 6.57). Plasmapheresis and rituximab were the most frequent treatments (81%). Partial or complete remission occurred in 57% of patients and was associated with better graft survival.

Conclusions: Idiopathic FSGS recurs post-transplant in one third of cases and is associated with a five-fold higher risk of graft loss. Response to treatment is associated with significantly better outcomes but is achieved in only half of the cases.
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http://dx.doi.org/10.2215/CJN.08970719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015092PMC
February 2020

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

Peritransplant eculizumab does not prevent delayed graft function in deceased donor kidney transplant recipients: Results of two randomized controlled pilot trials.

Am J Transplant 2020 02 8;20(2):564-572. Epub 2019 Oct 8.

Nephrology Division, Department of Medicine and Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.

Animal models and observational human data indicate that complement, including C5a, pathogenically participates in ischemia reperfusion (IR) injury that manifests as delayed graft function (DGF) following deceased donor kidney transplantation. We report on the safety/efficacy of anti-C5 monoclonal antibody eculizumab (Ecu) administered in the operating room prior to reperfusion, to prevent DGF in recipients of deceased donor kidney transplants in two related, investigator-sponsored, randomized controlled trials. Eight recipients from a single center were enrolled in a pilot study that led to a 19-subject multicenter trial. Together, 27 deceased donor kidney transplant recipients, 16 Ecu-treated and 11 controls, were treated with rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil with or without glucocorticoids, and followed for 6 months. Data analysis showed no epidemiological or transplant-related differences between study arms. Ecu was well tolerated with a similar severe adverse event incidence between groups. The DGF rate did not differ between Ecu-treated (44%) and control (45%, P = 1.0) subjects. Serum creatinine reduction in the first week after transplantation, and graft function up to 180-days post-transplant, were also similar. Ecu administration was safe but did not reduce the rate of DGF in a high-risk population of deceased donor recipients.
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http://dx.doi.org/10.1111/ajt.15580DOI Listing
February 2020

Preformed Donor-specific Antibodies Against HLA Class II and Graft Outcomes in Deceased-donor Kidney Transplantation.

Transplant Direct 2019 May 15;5(5):e446. Epub 2019 Apr 15.

Schuster Family Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Background: Many kidney transplant centers in the United States report both HLA class I and II antibodies detected by sensitive solid-phase assays (SPAs) to United Network for Organ Sharing as unacceptable antigens, significantly reducing the compatible donor organ pool and prolonging waiting time for highly sensitized patients. However, the clinical relevance of all detected donor-specific antibodies (DSAs) by SPA is not unequivocal, because fluorescence intensity does not always accurately reflect antibody pathogenicity. Our center does not exclude patients from transplantation based on DSA class II.

Methods: We performed a retrospective analysis in 179 deceased-donor kidney transplant recipients with solely DSA class II before transplant and patients without DSA and compared graft survival, rejection, and clinical outcomes. Patient survival was also compared with matched controls on the waiting list.

Results: Patients transplanted with DSA class II showed a clear survival benefit compared with matched patients who remained on dialysis or were waitlisted on dialysis/transplanted at 5 years (100%, 34%, and 73%, respectively). After a mean follow-up of 5.5 years, there was no significant difference in death-censored graft survival between transplanted patients without DSA and those with preformed DSA class II (adjusted HR 1.10; 95% confidence interval, 0.41-2.97), although the incidence of rejection was higher in recipients with DSA class II (adjusted HR 5.84; 95% confidence interval, 2.58-13.23; < 0.001). Serum creatinine levels at 1, 3, and 5 years posttransplant did not differ between groups. No predictors of rejection were found, although patients who received basiliximab induction therapy had higher incidence of rejection (100%) compared with those who received antithymocyte globulin (52%).

Conclusions: We conclude that for highly sensitized patients, deceased-donor kidney transplantation with DSA class II yields a survival benefit over prolonged waiting time on dialysis. Instead of listing DSA class II as unacceptable antigens, an individual approach with further immunologic risk assessment is recommended.
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http://dx.doi.org/10.1097/TXD.0000000000000893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511444PMC
May 2019

Young donors with severe acute kidney injury offer an opportunity to expand the donor pool.

Am J Surg 2019 07 12;218(1):7-13. Epub 2019 Apr 12.

Albert Einstein College of Medicine, Bronx, NY, USA; Montefiore-Einstein Center for Transplantation, Montefiore Medical Center, Bronx, NY, USA.

Background: This study assessed our experience transplanting kidneys from young donors with severe acute kidney injury.

Methods: We performed a single center retrospective analysis of 315 kidney transplants between 1/1/2014-12/31/2016. Donor kidneys were classified according to the Acute Kidney Injury Network (AKIN) criteria. A case-matched cohort was created using recipient age, history of diabetes, donor specific antibody, donor age and donor after cardiac death. Primary endpoints were graft function measured by eGFR at 90 days and at 1-year.

Results: Stage 3 AKIN recipients had significantly greater eGFR at one year (63.9 ml/min v. 51.2 ml/min, p < 0.001) compared to those with Stage 0 AKIN. This difference was abrogated when compared to a case matched cohort (eGFR at 90 days or 1 year; p > 0.05). Donor and recipient characteristics on eGFR at 1 year were analyzed using linear and logistic regression. Only donor age had a significant impact on recipient eGFR.

Conclusions: Donor kidneys with severe acute injury can achieve optimal 1-year outcomes. Donor age is the most significant predictor of eGFR >45 ml/min after transplant.
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http://dx.doi.org/10.1016/j.amjsurg.2019.04.005DOI Listing
July 2019

Molecular signatures and clinical outcomes of transplant glomerulopathy stratified by microvascular inflammation and donor-specific antibody.

Clin Transplant 2019 03 29;33(3):e13469. Epub 2019 Jan 29.

Montefiore Medical Center Transplant Center, Albert Einstein College of Medicine, New York City, New York.

Background: We investigated clinical outcomes and molecular signatures of transplant glomerulopathy (TG) stratified by microvascular inflammation (MVI) and donor-specific antibody (DSA) status.

Methods: We performed a retrospective review of 749 kidney transplant patients who received a for-cause kidney biopsy from 2009 to 2014. We classified TG as MVI positive (MVI+) or MVI negative (MVI-), and with or without DSA. We obtained gene expression profiles for 44 biopsies by Affymetrix HuGene 1.0 ST expression arrays.

Results: A total of 100 patients had TG; 49 were MVI+, and 51 were MVI-. After a median post-biopsy follow-up of 2.08 years (range 0.43-4.59), Kaplan-Meier survival analysis demonstrated worse allograft survival in MVI+ TG patients compared with MVI- TG patients (P = 0.01), and time to graft failure was significantly shorter in MVI+ patients (1.08 ± 1.01 years vs 2.3 ± 1.8 years; P = 0.002). DSA status did not affect graft survival within MVI+ or MVI- groups. Analysis of pathogenesis-based transcripts (PBT) showed that MVI+ TG biopsies had increased expression of gamma interferon and rejection (GRIT) and DSA-associated transcripts (DSAST), as observed in antibody-mediated rejection. MVI- TG biopsies had increased expression of cytotoxic and regulatory T cell- and B cell-associated transcripts but not GRIT or DSAST. DSA status had no effect on expression of any PBTs studied in MVI- TG biopsies.

Conclusions: Graft survival in TG is significantly worse in the presence of MVI. Gene expression profiles of MVI+ TG resemble antibody-mediated rejection while gene expression profiles of MVI- TG resemble cell-mediated rejection regardless of DSA status.
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http://dx.doi.org/10.1111/ctr.13469DOI 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

A large, international study on post-transplant glomerular diseases: the TANGO project.

BMC Nephrol 2018 09 12;19(1):229. Epub 2018 Sep 12.

Renal Division, Brigham & Women's Hospital, Harvard Medical School, 221 Longwood Ave, Boston, MA, 02115, USA.

Background: Long-term outcomes in kidney transplantation (KT) have not significantly improved during the past twenty years. Despite being a leading cause of graft failure, glomerular disease (GD) recurrence remains poorly understood, due to heterogeneity in disease pathogenesis and clinical presentation, reliance on histopathology to confirm disease recurrence, and the low incidence of individual GD subtypes. Large, international cohorts of patients with GD are urgently needed to better understand the disease pathophysiology, predictors of recurrence, and response to therapy.

Methods: The Post-TrANsplant GlOmerular Disease (TANGO) study is an observational, multicenter cohort study initiated in January 2017 that aims to: 1) characterize the natural history of GD after KT, 2) create a biorepository of saliva, blood, urine, stools and kidney tissue samples, and 3) establish a network of patients and centers to support novel therapeutic trials. The study includes 15 centers in America and Europe. Enrollment is open to patients with biopsy-proven GD prior to transplantation, including IgA nephropathy, membranous nephropathy, focal and segmental glomerulosclerosis, atypical hemolytic uremic syndrome, dense-deposit disease, C3 glomerulopathy, complement- and IgG-positive membranoproliferative glomerulonephritis or membranoproliferative glomerulonephritis type I-III (old classification). During phase 1, patient data will be collected in an online database. The biorepository (phase 2) will involve collection of samples from patients for identification of predictors of recurrence, biomarkers of disease activity or response to therapy, and novel pathogenic mechanisms. Finally, through phase 3, we will use our multicenter network of patients and centers to launch interventional studies.

Discussion: Most prior studies of post-transplant GD recurrence are single-center and retrospective, or rely upon registry data that frequently misclassify the cause of kidney disease. Systematically determining GD recurrence rates and predictors of clinical outcomes is essential to improving post-transplant outcomes. Furthermore, accurate molecular phenotyping and biomarker development will allow better understanding of individual GD pathogenesis, and potentially identify novel drug targets for GD in both native and transplanted kidneys. The TANGO study has the potential to tackle GD recurrence through a multicenter design and a comprehensive biorepository.
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http://dx.doi.org/10.1186/s12882-018-1025-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136179PMC
September 2018