Role of time from transplantation to biopsy in histologic ABMR: A single center report.

BACKGROUND: Allograft biopsies with lesions of Antibody-Mediated Rejection (ABMR) with Microvascular Inflammation (MVI) have shown heterogeneous etiologies and outcomes. METHODS: To examine factors associated with outcomes in biopsies that meet histologic ABMR criteria, we retrospectively evaluated for-cause biopsies at our center between 2011 and 2017. We included biopsies that met the diagnosis of ABMR by histology, along with simultaneous evaluation for anti-Human Leukocyte Antigen (HLA) donor-specific antibodies (DSA). We evaluated death-censored graft loss (DCGL) and used a principal component analysis (PCA) approach to identify key predictors of outcomes. RESULTS: Out of the histologic ABMR cohort (n = 118), 70 were DSA-positive ABMR, while 48 had no DSA. DSA(+)ABMR were younger and more often female recipients. DSA(+)ABMR occurred significantly later post-transplant than DSA(-)ABMR suggesting time-dependence. DSA(+)ABMR had higher inflammatory scores (i,t), chronicity scores (ci, ct) and tended to have higher MVI scores. Immunodominance of DQ-DSA in DSA(+)ABMR was associated with higher i+t scores. Clinical/histologic factors significantly associated with DCGL after biopsy were inputted into the PCA. Principal component-1 (PC-1), which contributed 34.8% of the variance, significantly correlated with time from transplantation to biopsy, ci/ct scores and DCGL. In the PCA analyses, i, t scores, DQ-DSA, and creatinine at biopsy retained significant correlations with GL-associated PCs. CONCLUSIONS: Time from transplantation to biopsy plays a major role in the prognosis of biopsies with histologic ABMR and MVI, likely due to ongoing chronic allograft injury over time.

Influence of patient characteristics and immunosuppressant management on mortality in kidney transplant recipients hospitalized with coronavirus disease 2019 (COVID-19).

The influence of patient characteristics and immunosuppression management on COVID-19 outcomes in kidney transplant recipients (KTRs) remains uncertain. We performed a single-center, retrospective review of all adult KTRs admitted to the hospital with confirmed COVID-19 between 03/15/2020 and 05/15/2020. Patients were followed from the date of admission up to 1 month following hospital discharge or study conclusion (06/15/2020). Baseline characteristics, laboratory parameters, and immunosuppression were compared between survivors and patients who died to identify predictors of mortality. 38 KTRs with a mean baseline eGFR of 52.5 ml/min/1.73 m2 were hospitalized during the review period. Maintenance immunosuppression included tacrolimus (84.2%), mycophenolate (89.5%), and corticosteroids (81.6%) in the majority of patients. Eleven patients (28.9%) died during the hospitalization. Older age (OR = 2.05; 1.04-4.04), peak D-dimer (OR = 1.20; 1.04-1.39), and peak white blood cell count (OR = 1.11; 1.02-1.21) were all associated with mortality among KTRs hospitalized for COVID-19. Increased mortality was also observed among KTRs with concomitant HIV infection (87.5% vs. 36.1%; p < .01). Conversely, immunosuppression intensity and degree of reduction following COVID-19 diagnosis were not associated with either survival or acute allograft rejection. Our findings potentially support a strategy of individualization of immunosuppression targets based on patient-specific risk factors, rather than universal immunosuppression reduction for KTRs at risk from COVID-19.

Conversion to belatacept maintenance immunosuppression in HIV-positive kidney transplant recipients.

There are only scattered case reports documenting belatacept use in HIV + kidney transplant recipients. We performed a retrospective review to describe short-term outcomes following conversion to belatacept in a cohort of HIV + patients. Patients were included if they were converted to belatacept between May 2015 and May 2019, had an HIV- donor, and received ≥4 doses of belatacept. All patients were treated with non-depleting induction and triple maintenance immunosuppression. Allograft and HIV-related outcomes were collected from the date of belatacept infusion until May 2020. Ten HIV + kidney transplant recipients were identified, who were converted to belatacept a median of 364 days post-transplant. At last follow-up (median 3.3 years), 8 patients remained on belatacept therapy, and all patients were alive with functioning allografts. Mean estimated glomerular filtration rates (eGFR) improved from 31.6 mL/min at baseline to 42.8 mL/min at 1 year (P = .03). Two patients developed acute rejection, with one necessitating conversion back to tacrolimus. All patients maintained undetectable HIV-1 viral loads at last follow-up. One patient each developed pneumocystis pneumonia and Kaposi sarcoma following conversion, which were responsive to standard medical therapy. In our cohort of stable HIV + kidney transplant recipients, conversion to belatacept was associated with excellent early patient and allograft survival and improved eGFR at 1 year.

Different outcomes after kidney transplantation between African Americans and Whites: A matter of income? A single-center study.

BACKGROUND: Our center has one of the largest representations of African Americans in listed and transplanted patients. We investigated if and how racial differences affect outcomes in our patient population. METHODS: We performed a retrospective analysis of all kidney transplants in African American and (non-Hispanic) White patients in our center from 1/1/2005 to 12/31/2014. Cox regression was performed to evaluate the adjusted hazard ratios for graft loss. We investigated the influence of socioeconomic status on transplant outcomes. We stratified our patients into three groups based on income: lower (<$50 000 annual household income), medium ($50 000-100 000 annual household income), and higher (>$100 000 annual household income. RESULTS: There were 1333 patients in our study, 696 Whites and 637 African Americans. The 1-, 5-, and 10-year graft survival between the two groups was 96.5% vs 91.1%, 89% vs 80.7%, and 77% vs 66.3%, respectively (P < .001 by Log Rank, Breslow and Taron-Ware). When we compared the two groups separately in each income category, we found no statistical difference between African Americans and Whites in graft survival. In the regression model, income and not race was the significant factor influencing graft survival (P < .001 vs P = .61).

Pre-liver transplant renal dysfunction and association with post-transplant end-stage renal disease: A single-center examination of updated UNOS recommendations.

Simultaneous liver-kidney allocation protocols allocate dual organs based on a sustained eGFR of 30 mL/min or less. A 2017-UNOS update includes CKD3 as dual organ candidates but only when the listing eGFR is <30 mL/min while recommending a "safety net" for prioritized kidney listing post-LT. We retrospectively reviewed adult LTs examine whether the UNOS proposal captured the LT population at highest risk for developing post-LT ESRD. Among 290 LT recipients, 67 had pre-LT CKD3, 141 had AKI, of whom 47 required dialysis (<4 weeks). During follow-up, 25 (8.62%) developed ESRD, while 70 (24.1%) died. In adjusted Cox models, CKD3 had an independent association with post-LT ESRD (adjusted HR 4.8; P = 0.001), independent of AKI. Interestingly, CKD3 with listing GFR >30 mL/min was still significantly associated with post-LT ESRD. AKI was associated with reduced post-LT survival (adjusted HR 1.9; P = 0.02), albeit only in the first-year post-LT. Severe AKI-D was associated with post-LT ESRD and mortality. The safety net would have captured only 60% of all post-LT ESRD cases in our cohort. Pre-LT CKD3 was associated with increased risk of post-LT ESRD above the recommended cutoff for listing GFR. These findings, if generalizable in larger cohorts have important implications for dual organ allocation.

Early conversion to belatacept after renal transplantation.

Belatacept is a non-nephrotoxic immunosuppressive agent, which may make it the ideal agent for patients with delayed or slow graft function on calcineurin inhibitors. There are limited data on conversion of patients to belatacept within 6 months of transplantation. Between January 2012 and December 2015, 16 patients were converted to belatacept for delayed or poor graft function (eGFR<30 mL/min/1.73 m2 , MDRD); three were HIV positive. Conversion protocols were analyzed in patients ≤4 months and 4-6 months post-transplantation. Mean serum creatinine levels after belatacept conversion were compared with preconversion levels. Patient survival was 100%, and graft survival was 88%. The mean creatinine fell from 3.9±1.82 mg/dL prebelatacept conversion to 2.1±1.1 mg/dL at 6 months and 1.9±0.47 mg/dL (median 1.8 mg/dL) at 12 months postconversion. There was no significant increased risk of rejection, infection, or malignancy. HIV parameters remained largely stable. Early conversion to belatacept in patients with DGF or slow graft function is safe and efficacious, in a single-center nonrandomized retrospective analysis.

Hepatitis C and Human Immunodeficiency Virus Kidney Transplantation: The Mount Sinai Experience.

Mount Sinai Hospital in New York has a long history in the field of organ transplantation. The first kidney transplant at Mount Sinai was performed in 1967 by the late Dr. Lewis Burrows and the first laparoscopic donor nephrectomy in New York was performed at Mount Sinai in 1996. Over 3000 kidney transplantations have been performed at Mount Sinai. In the early 1990s, the first hepatitis C virus (HCV) positive patient at Mount Sinai underwent a kidney transplant and the first kidney transplant in a patient with human immunodeficiency virus (HIV) in New York was performed at Mount Sinai in 2001. In general, these patients have done well after renal transplantation, with outcomes similar to those seen in non-infected patients. This chapter will describe the evolution of immunosuppressive regimens in HCV positive and HIV positive patients, and will describe the outcomes of kidney transplantation in these patients. Given the favorable outcomes, it is reasonable to continue to offer renal transplantation as a treatment for end stage renal disease patients with HCV and/or HIV.

A case of undulating fevers and elevated liver tests after pancreas-kidney transplantation.

The patient is a 50-year-old Caucasian woman with a history of a pancreas and two kidney transplants complicated by chronic rejection of her latest kidney allograft and currently undergoing hemodialysis, who was referred for fever of unknown origin and elevated liver tests. She suffered a self-limited acute diarrheal illness with fever 3 months prior to referral and then experienced a persistent, undulating fever pattern. An exhaustive evaluation involving many consultants was undertaken, but failed to determine the etiology of her symptoms. Given her history, persistently elevated liver tests, and abnormal but nonspecific liver biopsy findings, infection with hepatitis E virus (HEV) was entertained. Several serum and stool samples were sent to the Centers for Disease Control for detection of HEV that were positive and ultimately consistent with autochthonous chronic HEV infection. The patient was treated with ribavirin and achieved normalization of her transaminase activities and resolution of her fever after 1 month, and undetectable HEV polymerase chain reaction at treatment month 6 and 10, at which time treatment was stopped. There has been renewed interest in HEV in light of recent studies demonstrating the existence of a chronic form of HEV infection occurring in immunosuppressed patients, such as solid-organ-transplant recipients. This report highlights a case of chronic HEV infection in a pancreas-kidney-transplant recipient with an unusual clinical presentation and highlights the need for increased awareness of chronic HEV infection in the hepatology and transplant community.

Effect of high-dose intravenous immunoglobulin on anti-HLA antibodies in sensitized kidney transplant candidates.

Limited data exist on the effect of intravenous immunoglobulin (IVIg) on anti-HLA antibodies as determined by solid-phase assays. We reviewed our experience treating sensitized wait-listed kidney transplant recipients with IVIg as a method for desensitization and report our results utilizing Luminex single antigen (LSA) bead assay to quantify antibody reactivity (MFI). Fifteen patients with a cPRA > 40% received 2 g/kg IVIg per month for four months or until transplanted. LSA testing was performed before and after IVIg. Median MFI for anti-class I antibodies fell in 11 (73%) and increased in 4 (27%) patients after IVIg. Similar significant changes in MFI for anti-class II antibodies were observed in 10 patients (66%). Administration of IVIg was associated with a modest decrease in reactivity to both class I and II HLA antigens (median MFI change 493 and 1110, respectively; p < 0.0001) but did not significantly alter mean cPRA (85% before IVIg vs. 80% after IVIg; p = 0.1). Our data suggest a smaller effect of IVIg on HLA antibody reactivity than previously described, leading us to question how best to measure the efficacy of a desensitization protocol in current practice.

Antibodies reactive to non-HLA antigens in transplant glomerulopathy.

Although T and B cell alloimmunity contribute to transplant injury, autoimmunity directed at kidney-expressed, non-HLA antigens may also participate. Because the specificity, prevalence, and importance of antibodies to non-HLA antigens in late allograft injury are poorly characterized, we used a protein microarray to compare antibody repertoires in pre- and post-transplant sera from several cohorts of patients with and without transplant glomerulopathy. Transplantation routinely induced changes in antibody repertoires, but we did not identify any de novo non-HLA antibodies common to patients with transplant glomerulopathy. The screening studies identified three reactivities present before transplantation that persisted after transplant and strongly associated with transplant glomerulopathy. ELISA confirmed that reactivity against peroxisomal-trans-2-enoyl-coA-reductase strongly associated with the development of transplant glomerulopathy in independent validation sets. In addition to providing insight into effects of transplantation on non-HLA antibody repertoires, these results suggest that pretransplant serum antibodies to peroxisomal-trans-2-enoyl-coA-reductase may predict prognosis in kidney transplantation.

Differential outcomes in 3 types of acute antibody-mediated rejection.

INTRODUCTION: The aim of this study is to investigate the prevalence, predictors, and clinical outcomes of acute antibody-mediated rejection (AAMR). METHODS: Retrospective analysis of 833 adult patients who received kidney transplantation between 1/1/2001 and 8/15/2007. RESULTS: The prevalence of AAMR and acute cellular rejection was 2% and 8.2%, respectively. Eight patients had type I, seven type II, and two type III AAMR. All patients had at least one strong donor-specific anti-HLA antibodies (DSA) with a median fluorescence intensity (MFI) value of over 6000 and the mean number of strong DSAs was 2.0 +/- 0.7. Fifteen of 17 patients received pre-transplant desensitization treatment. During a median 28 months of follow-up (range: 12-38 months), two patients died (88% patient survival), and nine lost their allografts (35% graft survival). While all type I AAMR patients responded to treatment, all type III patients, and four of seven patients with type II AAMR lost their allografts earlier, and three type II AAMR patients later due to transplant glomerulopathy. CONCLUSIONS: AAMR is mainly seen in patients with pre-transplant strong DSAs. There is a striking difference in clinical outcomes of AAMR that types II and III AAMR patients have poor prognosis compared to type I AAMR patients.

Addition of plasmapheresis decreases the incidence of acute antibody-mediated rejection in sensitized patients with strong donor-specific antibodies.

BACKGROUND AND OBJECTIVES: The objective of this study was to investigate the effects of desensitization protocols using intravenous Ig with or without plasmapheresis in patients with donor-specific anti-HLA antibodies on prevention of antibody-mediated rejection and downregulation of donor-specific antibodies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Thirty-five complement-dependent cytotoxicity T cell cross-match-negative but complement-dependent cytotoxicity B cell and/or flow cytometry cross-match-positive kidney transplant recipients were treated with high-dosage intravenous Ig plus Thymoglobulin induction treatment. Donor-specific antibody strength was stratified as strong, medium, or weak by Luminex flow beads. Group 1 patients had weak/moderate and group 2 strong donor-specific antibodies RESULTS: Whereas no group 1 patients had acute rejection, 66% of group 2 had acute rejection (44% antibody-mediated rejection, 22% cellular rejection). The protocol was then changed to the addition of peritransplantation plasmapheresis to patients with strong donor-specific antibodies (group 3). This change resulted in a dramatic decrease in the acute rejection rate to 7%. During a median 18 mo of follow-up, patient survival was 100, 100, and 93% and graft survival was 100, 78, and 86% in groups 1, 2, and 3, respectively. During follow-up, 17 (52%) patients lost donor-specific antibodies completely, and 10 (30%) lost some of donor-specific antibodies and/or decreased the strength of existing donor-specific antibodies. CONCLUSIONS: These results indicated that in patients with strong donor-specific antibodies, the addition of plasmapheresis to high-dosage intravenous Ig decreases the incidence of acute rejection. The majority of the patients, whether they received intravenous Ig alone or with plasmapheresis, lost their donor-specific antibodies during follow-up.

Transplant glomerulopathy may occur in the absence of donor-specific antibody and C4d staining.

BACKGROUND AND OBJECTIVES: Transplant glomerulopathy (TGP) has been proposed to be a component of chronic antibody-mediated rejection (AMR). We have studied 36 patients with TGP and 51 patients with chronic allograft nephropathy (CAN) but without TGP for C4d staining and donor-specific anti-HLA antibodies (DSA) to investigate the alloantibody-mediated mechanisms. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Allograft biopsies were stained with C4d staining and DSAs were studied by Luminex Flow Beads. Allograft biopsies were done at a mean of 5.3 +/- 5.0 and 5.6 +/- 4.6 yr after transplantation in patients with CAN and TGP, respectively. RESULTS: The mean creatinine level at the time of the biopsy was 2.7 +/- 1.2 mg/dl in each group. Proteinuria of >1.0 g/d was more common in patients with TGP (61 versus 25%; P = 0.002). Whereas three patients with TGP had a history of acute AMR, none of the patients with CAN had. Mean chronicity score of the biopsies were 1.7 +/- 0.7 in patients with CAN and 1.9 +/- 0.8 in patients with TGP. Biopsies from only two (4%) patients with CAN and four (11%) patients with TGP had diffuse C4d positivity. DSA were found in 36% of TGP and 33% of CAN patients. CONCLUSIONS: These results suggest that a substantial number of patients with TGP did not have positive C4d staining or DSA, indicating that a non-alloantibody-mediated process may be involved in the development of TGP in some patients.

Routine use of ambulatory blood pressure monitoring in potential living kidney donors.

BACKGROUND AND OBJECTIVES: Most transplant centers exclude prospective living kidney donors with hypertension from donation. Centers routinely identify hypertension using BP measured in the clinic, but it is not clear that clinic BP accurately detects the presence or absence of hypertension in potential donors. We therefore conducted a prospective study to determine the impact of routine ambulatory BP monitoring on diagnosis of hypertension in potential donors and the value of other baseline characteristics in predicting ambulatory BP results. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We compared classification of hypertension status by clinic BP and by ambulatory BP monitoring in 178 potential living kidney donors. RESULTS: Of 63 individuals with hypertension by clinic BP, 62% had white-coat hypertension by ambulatory BP and were therefore eligible to donate. Of 115 individuals who were normotensive by clinic BP, 17% had masked hypertension by ambulatory BP and were excluded from donation. Individuals with masked hypertension were older, were more likely to be male, and had a somewhat higher clinic BP than individuals with sustained normotension. Individuals with white-coat hypertension had a somewhat lower clinic diastolic BP than individuals with sustained hypertension. CONCLUSIONS: Routine ambulatory BP monitoring may identify a large number of individuals with white-coat hypertension and a smaller but significant number of individuals with masked hypertension, ensuring adequate protection of potential donors and accurate assessment of donor risk. Differences in baseline characteristics are small and are not clinically useful in distinguishing individuals with masked hypertension from individuals with sustained normotension or individuals with white-coat hypertension from individuals with sustained hypertension, demonstrating the importance of ambulatory BP monitoring in this population.

Safety of using hepatitis B virus core antibody or surface antigen-positive donors in kidney or pancreas transplantation.

Hepatitis B virus core antibody (HBcAb) or surface antigen (HBsAg)-positive organ donors have the potential to transmit infection to transplant recipients. We investigated the safety of using HBcAb(+) or HBsAg(+) donors in kidney or pancreas transplant recipients with 1 yr lamivudine prophylaxis. While HBsAb(-) recipients of HBcAb(+) donors received prophylaxis, HBsAb(+) recipients did not. HBsAg(+) organs were only used in patients who were both HBcAb and HBsAb(+). Forty-six patients received HBcAb(+) and four received HBsAg(+) organs (47 kidney, two pancreas, and one kidney/pancreas). All but one recipient were HBsAg(-), 25 were HBsAb(+), and 19 HBcAb(+). During a median 36 months of follow-up (range 6-66 months), with 43 of a total 50 patients having at least 1 yr follow-up and were off lamivudine, and none of the patients developed hepatitis B viremia or seroconversion to HBsAg or HBsAb(+). These results suggest that HBcAb(+) or HBsAg(+) organs can be used safely in selected recipients with lamivudine prophylaxis without requiring hepatitis B immunglobulin.

Rapid steroid withdrawal in hepatitis C virus-positive kidney transplant recipients.

The effects of rapid steroid withdrawal (SW) on kidney transplantation (KT) outcome were investigated in 12 HCV+ patients in a prospective cohort study. These results were compared with 17 HCV+ patients who received KT in the prior 2 yr and treated with a standard prednisone taper protocol. SW patients received only 6 d of steroid treatment after transplantation. Eleven received Thymoglobulin and one Basiliximab induction treatment along with a calcineurin inhibitor and mycophenolate mofetil. Patient and graft survival was 92% in SW group (median follow-up 12 months, range 6-17), and 92 and 82% in the historic control group respectively (median follow-up 21 months, range 11-27). In the SW and control group, acute rejection rates were 9 and 18%, and mean creatinine levels at last follow-up 1.30 +/- 0.36 and 1.68 +/- 0.58 mg/dL respectively. Only two SW patients had an increase in liver function tests during follow-up (18%), compared with six patients in the control group (43%). This study demonstrates that rapid SW is safe for HCV+ KT recipients, without an increase in acute rejection episodes or liver function abnormalities in the short term.