Gregory Malat

Comparison of four different immunosuppression protocols without long-term steroid therapy in kidney recipients monitored by surveillance biopsy: five-year outcomes.

Induction and maintenance immunosuppression protocols with or without long-term steroid therapy in kidney transplant recipients are variable and are transplant center-specific. The aim of this prospective randomized pilot study was to compare 5-year outcomes in kidney recipients maintained on 4 different calcineurin inhibitor (CNI)-based immunosuppression protocols without long-term steroid therapy. Two hundred consenting patients who received kidney transplants between June 2000 and October 2004 were enrolled in 4 immunosuppression protocol groups, with 50 patients in each group: cyclosporine (CSA)/mycophenolate mofetil (MMF), CSA/sirolimus (SRL), tacrolimus (TAC)/MMF, and TAC/SRL. Induction therapy was done with basiliximab and methylprednisolone. Steroids were withdrawn on post-transplant day 2, and long-term steroid therapy was not used. Demographic characteristics among the four groups were comparable; approximately 50% of the recipients were African American and > or =80% of the kidneys transplanted were from deceased donors. Clinical acute rejection (CAR) was confirmed by biopsy and treated with intravenous pulse steroid therapy. Steroid-unresponsive CAR was treated with Thymoglobulin. Surveillance biopsies were performed at 1, 6, 12, 24, 36, 48, and 60 months to evaluate subclinical acute rejection (SCAR), chronic allograft injury (CAI), and other pathological changes per the Banff 2005 schema. The primary end point was CAR, and secondary end points were 5-year patient and graft survival rates, renal function, SCAR, CAI, and adverse events. In the first year post-transplant, the incidence of CAR was 18% in the CSA/MMF group, 8% in the CSA/SRL group, 14% in the TAC/MMF group, and 4% in the TAC/SRL group (CSA/MMF vs. TAC/SRL; p=0.05). The incidence of SCAR was 22% in the CSA/MMF group, 8% in the CSA/SRL group, 16% in the TAC/MMF group, and 6% in the TAC/SRL group (CSA/MMF vs. CSA/SRL and TAC/SRL; p=0.05). After the first year, the incidences of CAR and SCAR decreased and were comparable in all 4 groups. At 5 years post-transplant, cumulative CAI due to interstitial fibrosis/tubular atrophy (IF/TA), hypertension (HTN), and chronic calcineurin inhibitor (CNI) toxicity was observed in 54%, 48%, and 8% of the CSA/MMF group vs. 16%, 36%, and 12% of the CSA/SRL group vs. 38%, 24% and 6% of the TAC/MMF group vs. 14%, 25% and 12% of the TAC/SLR group (IF/TA: CSA/MMF vs. CSA/SRL and TAC/SRL; p=0.04, HTN: CSA/MMF vs. TAC/MMF and TAC/SRL; p=0.05, CNI toxicity: TAC/SRL and CSA/SRL vs. TAC/MMF; p=0.05). Five-year patient and graft survival rates were 82% and 60% in the CSA/MMF group, 82% and 60% in the CSA/SRL group, 84% and 62% in the TAC/MMF group, and 82% and 64% in the TAC/SRL group (p=0.9). Serum creatinine levels and creatinine clearances at 5 years were comparable among the groups. Our data show that the rates of CAR and SCAR in the first year post-transplant were significantly lower in the CSA/SRL and TAC/SRL groups and that cumulative CAI rates due to IF/TA and HTN at 5 years were significantly lower in the TAC/MMF, TAC/SRL, and CSA/SRL groups than in the CSA/MMF group. Despite significant differences in the incidences of CAR and SCAR and prevalence of different types of CAI at 5 years, renal function and patient and graft survival rates at 5 years were comparable among kidney recipients maintained on 4 different immunosuppression protocols without long-term steroid therapy.

Long-term outcome of early steroid withdrawal after kidney transplantation in African American recipients monitored by surveillance biopsy

Generally chronic steroid therapy is standard care for African American (AA) kidney recipients because of their higher incidence of rejections and lower long‐term graft survival. This prospective study evaluated the long‐term safety and efficacy of early steroid withdrawal (ESW) in AA recipients. A total of 206 recipients were studied; 103 AA and 103 non‐AA recipients monitored by serial surveillance biopsies from 1 to 60 months posttransplantation to evaluate subclinical acute rejections (SCAR) and chronic allograft injury (CAI). Biopsy‐proven clinical acute rejections (BPAR) and SCAR were treated. Primary end point was BPAR and secondary end points were 5‐year SCAR, CAI and survival. Incidences of BPAR was 16% versus 14% (p = 1.0), prevalence of CAI due to hypertension was 48% versus 30% (p = 0.05) and interstitial fibrosis/tubular atrophy was 47% versus 32% (p = 0.05) and the mean serum creatinine levels were 2.1 versus 1.8 mg/dL (p = 0.05) at 5‐years in AA versus non‐AA recipients. The incidence of SCAR was 23% versus 11% at 1 month (p = 0.04), 12% versus 3% at 3 years (p = 0.04) and 10% versus 1% at 5 years (p = 0.04) in AA and non‐AA recipients, respectively. Five‐year patient survivals were 81% and 88% (p = 0.09) and graft survivals were 71% and 73%(p = 0.19) in AA and non‐AA groups, respectively. After early steroid withdrawal AA kidney recipients have significantly lower renal function and higher SCAR and CAI but 5‐year graft survival are comparable to non‐AA recipients.

African American kidney transplantation survival: the ability of immunosuppression to balance the inherent pre- and post-transplant risk factors.

Among organ transplant recipients, the African American population historically has received special attention. This is because secondary to their disposition to certain disease states, for example hypertension, an African American patient has a propensity to reach end-stage renal disease and require renal replacement earlier than a Caucasian patient. Regardless of the initiative to replace dialysis therapy with organ transplantation, the African American patient has many barriers to kidney transplantation, thus extending their time on dialysis and waiting time on the organ transplant list. These factors are among the many negative causes of decreased kidney graft survival, realized before kidney transplantation.Unfortunately, once the African American recipient receives a kidney graft, the literature documents that many post-transplant barriers exist which limit successful outcomes. The primary post-transplant barrier relates to designing proper immunosuppression protocols. The difficulty in designing protocols revolves around (i) altered genetic metabolism/lower absorption, (ii) increased immuno-active cytokines and (iii) detrimental effects of noncompliance. Based on the literature, dosing of immunosuppression must be aggressive and requires a diligent practitioner. Research has indicated that, despite some success with proven levels of immunosuppression, the African American recipient usually requires a higher ‘dose per weight’ regimen. However, even with aggressive immunosuppressant dosing, African Americans still have worse outcomes than Caucasian recipients. Additionally, many of the targeted sites of action that immunosuppression exerts its effects on have been found to be amplified in the African American population. Finally, noncompliance is the most discouraging inhibitor of long-term success in organ transplantation. The consequences of non-compliance are biased by ethnicity and affect the African American population more severely.All of these factors are discussed further in this review in the hope of identifying an ideal healthcare model for caring for the African American transplant recipient, from diagnosing chronic kidney disease through to successful kidney graft outcomes. An indepth review of the literature is described and organized in a fashion that highlights all of the issues affecting success in African Americans. The compilation of the literature in this review will enable the reader to get closer to understanding the caveats of kidney transplantation in the African American patient, but falls short of delivering an actual ‘equation’ for post-transplant care in an African American kidney recipient.

High frequency of rejections in HIV-positive recipients of kidney transplantation: a single center prospective trial.

Background This is a single institution report of the incidence of combined acute antibody-mediated rejection (ABMR) + acute cellular rejection (ACR) [mixed rejection] in HIV (+) kidney transplant recipients. Methods We prospectively enrolled 92 HIV (+) patients who received a kidney transplant between 2001 and 2009. There were three cohorts: no rejection [n=26], ACR [n=53], and mixed rejections (ABMR and ACR) [n=13]. Immunosuppression comprised of basiliximab, cyclosporine, sirolimus, and steroid minimization. Fisher exact tests for categorical variables, t test for continuous variables, and Kaplan-Meier estimates were used to describe events. Results Mixed rejections were seen in all 13 HIV (+) kidney transplant recipients (14%) with a median time to ABMR of 48 days. Acute cellular rejection occurred in 28% at 1 month and 55% at 12 months. eGFR was lower for recipients who experienced ABMR versus those experiencing ACR and those never experiencing rejection up to 3 years (14 ± 9.4 vs 19 ± 3.3 vs 29 ± 7.3 mL/min, respectively). Kaplan-Meier showed that graft survival up to 9 years was worse in recipients experiencing mixed rejection. Suboptimal donors with terminal creatinine greater than 2.5 mg/dL was associated with increased incidence of mixed rejections versus cellular rejections and no rejection (42% vs 17% vs. 8%, respectively). Conclusions Our single center study showed a relatively higher incidence of mixed rejection compared with that reported for non-HIV transplant recipients. A donor terminal serum creatinine greater than 2.5 mg/dL predicted mixed rejection, which was associated with poor outcomes. Donor selection and optimization of immunosuppression may be critical in these patients.

Validation of the Maryland Aggregate Pathology Index (MAPI), a pre‐implantation scoring system that predicts graft outcome

Predicting graft outcome after renal transplantation based on donor histological features has remained elusive and is subject to institutional variability. We have shown in a retrospective study that the Maryland Aggregate Pathology Index score reliably predicts graft outcome. We sought to validate the scoring system in our center and a second transplant center. We analyzed 140 deceased donor kidneys pre‐implantation biopsies from center 1 and 65 from center 2. The patients had a mean follow‐up of 695 ± 424 and 656 ± 305 d respectively. Although MAPI scores were similar, there were significant differences in donor and recipient parameters between both centers. Despite this, MAPI was predictive of graft outcome for both centers by Cox univariate, multivariate and time dependent ROC analysis. For center 1 and 2, three yr graft survival within each MAPI group was statistically equivalent. The three‐yr graft survival at center 1 for low, intermediate, and high MAPI groups were 84.3%, 56.5%, and 50.0%, respectively, p ≤ 0.0001, and at center 2 were 83.3%, 33.3%, and 33.3%, p = 0.006. MAPI, which is based on a pre‐implantation biopsy, demonstrated similar predictive and outcome results from both centers. As expanded criteria donors (ECD) criteria have redefined marginal kidneys, MAPI has the potential to further define ECD kidneys, increase utilization, and ultimately improve outcomes.

Low rates of vaccination in listed kidney transplant candidates.

Despite clear consensus and strong recommendations, vaccination rates of kidney transplant (KT) recipients have remained below targets. As vaccination is most effective if it is given prior to transplantation and the initiation of immunosuppression, patients should ideally have their vaccination status assessed and optimized in the pre‐transplant period. We performed a retrospective chart review to characterize vaccination rates and factors associated with gaps in vaccination in a single‐center population of waitlisted patients being evaluated for kidney transplantation. We evaluated 362 KT patients. Three‐quarters were receiving dialysis at the time of evaluation. Immunization rates were low with 35.9% of patients having completed vaccination for Pneumococcus, 55% for influenza, 6.9% for zoster, and 2.5% for tetanus. On multivariable analysis, patients who received other vaccines, including influenza, tetanus, or zoster vaccine (odds ratio [OR] 10.55, 95% confidence interval [CI] 5.65–19.71) were more likely to receive pneumococcal vaccine. Blacks (OR 0.24, 95% CI 0.12–0.47) were less likely to receive pneumococcal vaccine compared to whites. Patients on dialysis, and those active on the waiting list were more likely to receive pneumococcal vaccine than other groups (OR 2.81, 95% CI 1.44–5.51, and OR 1.84, 95% CI 1.08–3.14, respectively). We found that the overall immunization rate against common vaccine‐preventable infections was low among patients evaluated for kidney transplantation. A significant gap remains between recommendations and vaccine uptake in clinical practice among this high‐risk population.

Kidney donor risk index (KDRI) fails to predict kidney allograft survival in HIV (+) recipients.

Introduction We used the United Network of Organ Sharing Standard Transplant Analysis and Research Files (STAR files) to investigate the utility of the Kidney Donor Risk Index (KDRI) versus delayed graft function (DGF) to predict graft survival in the HIV (+) kidney transplant recipients. Methods Individual matching (one case to five controls) was used to investigate predictive ability of the KDRI for graft survival in HIV (+) recipients (cases) as compared to HIV (−) recipients (controls) leaving 400 HIV (+) recipients matched with 1,904 HIV (−) recipients. Cox proportional hazard regression model was used to test association of the KDRI and DGF with graft survival. The relationship of the KDRI with graft survival was also explored by using Kaplan-Meier analysis. Results HIV (+) and HIV (−) cohorts were well matched in terms of race, HCV co-infection, panel reactive antibody, and wait time except HIV + were more frequently diabetic. Donor qualities were similar between the cohorts, including method of allograft preservation pretransplant, HLA matching, and calculated KDRI. There was no significant difference in survival based on the KDRI quintiles among the HIV (+) cohort (logrank sum P=0.4986). Graft survival within the HIV (+) cohort was significantly worse in the DGF (+) group than the DGF (−) group (logrank P<0.01). Discussion We found that the KDRI did not predict graft survival for HIV (+) kidney transplant recipients; however, the presence of DGF continues to have a negative impact on the graft survival. Future predictive models should include DGF as a variable.

Nonmelanoma Skin Cancer in Nonwhite Organ Transplant Recipients

Importance Organ transplant recipients have a higher incidence of skin cancer. This risk is magnified over time and with continued exposure to immunosuppression. Skin cancer in nonwhite patients is associated with greater morbidity and mortality owing to diagnosis at a more advanced stage, which suggests that nonwhite organ transplant recipients are at even higher risk. Objective To describe demographic and clinical factors and the incidence of skin cancer in nonwhite organ transplant recipients. Design, Setting, and Participants We performed a retrospective medical record review of patients who were organ transplant recipients (154 were white and 259 nonwhite [black, Asian, Hispanic, Pacific Islander]) seen from November 1, 2011, to April 18, 2016 at an academic referral center. Main Outcomes and Measures Variables were analyzed and compared between racial groups, including sex, age, race/ethnicity, Fitzpatrick type, type and location of skin cancer, type of organ transplanted, time to diagnosis of skin cancer after transplantation, and history of condyloma acuminata and/or verruca vulgaris. Results Most of the 413 patients (62.7%) evaluated were nonwhite organ transplant recipients; 264 were men, and 149 were women. Their mean (SD) age was 60.09 (13.59) years. Nineteen skin cancers were identified in 15 patients (5.8%) representing 3 racial/ethnic groups: black (6 patients), Asian (5), and Hispanic (4). All squamous cell carcinomas in blacks were diagnosed in the in situ stage, located on sun-protected sites, and occurred in patients whose lesions tested positive for human papilloma virus (HPV) and/or who endorsed a history of condyloma acuminata or verruca vulgaris. Most skin cancers in Asians were located on sun-exposed areas and occurred in individuals who emigrated from equatorial locations. Conclusions and Relevance Nonwhite organ transplant recipients are at risk for developing skin cancer posttransplantation. Follow-up in a specialized transplant dermatology center and baseline total-body skin examination should be part of posttransplantation care in all organ transplant recipients, including nonwhite patients. A thorough inspection of the groin and genitalia is imperative in black organ transplant recipients. History of HPV infection, particularly in black organ transplant recipients, and sun exposure/emigration history in Asian organ transplant recipients should be documented. Vigilant photoprotection may be of lesser importance in the prevention of skin cancer in black organ transplant recipients. Risk factors for nonwhite organ transplant recipients differ between races/ethnicities and warrant further study in efforts to better counsel and prevent skin cancer in these patients.

Vismodegib for Locally Advanced Basal Cell Carcinoma in a Heart Transplant Patient

IMPORTANCE Immunosuppressed patients with solid organ transplants have an increased risk for nonmelanoma skin cancer. Vismodegib has been reported to be effective for select locally advanced or metastatic basal cell carcinomas. However, there is no data documenting the use and safety of vismodegib in immunosuppressed organ transplant patients. OBSERVATIONS We describe a 78-year-old white man with a history of orthotopic heart transplant, immunosuppressed with low-dose cyclosporine, who presented to a specialty dermatology transplant clinic with multiple, recurrent, locally aggressive facial basal cell carcinomas. Through a multidisciplinary approach, the patient was started on vismodegib therapy. The pharmacokinetics of cyclosporine in the setting of vismodegib administration and weekly monitoring of cyclosporine levels ensured that therapeutic immunosuppression levels were achieved without toxic effects. CONCLUSIONS AND RELEVANCE To our knowledge, this is the first report that details vismodegib use in an immunosuppressed heart transplant patient receiving cyclosporine therapy. With a growing immunosuppressed organ transplant population at high risk for basal cell carcinoma, therapeutic options for locally advanced or metastatic disease are limited. Vismodegib appears to be a safe option for patients receiving cyclosporine therapy with routine monitoring. Future research is needed to evaluate the safety profile of vismodegib with other immunosuppressive agents.

Successful Treatment of Acute Severe Graft-Versus-Host-Disease in a Pancreas-After-Kidney Transplant Recipient: Case Report

The development of acute graft-versus-host-disease (GVHD) in recipients of pancreas transplants is a rare and quite often a fatal post-transplantation complication. We present a 38-year-old male with a longstanding history of type 1 diabetes mellitus and end-stage kidney disease, with a living unrelated kidney transplant from his wife for 3 years, who received an enteric-drained 5-antigen HLA-mismatched deceased-donor pancreas. Five weeks after transplantation, he presented with spiking fevers, severe skin rash, diarrhea, pancytopenia, and increasingly abnormal liver function tests. Skin biopsies were consistent with grade 3 acute GVHD. The patient was treated for GVHD with escalated doses of tacrolimus, pulse doses of steroids, and basiliximab. He was discharged after a 4-week hospital stay with complete resolution of his rash, fever, abnormal liver enzymes, and leukopenia. He remained in good health with excellent kidney and pancreas allograft function 3 years later.