Molecular-level HLA mismatch is associated with rejection and worsened graft survival in heart transplant recipients – a retrospective study

The aim was to evaluate the association of molecular-level human leukocyte antigen (HLA) mismatching with post-transplant graft survival, rejection, and cardiac allograft vasculopathy (CAV). We retrospectively analyzed all primary cardiac transplant recipients between 01/1984-06/2016. 1167 patients fulfilled inclusion criteria and had HLA typing information available. In 312 donor-recipient pairs, typing at serological split antigen level was available. We used the Epitope MisMatch Algorithm to calculate the number of amino acid differences in antibody-verified HLA eplets (amino acid mismatch load (AAMM)) between donor and recipient. Patients with a higher HLA-DR AAMM load had inferior 1-year graft survival (hazard ratio [HR], 1.14; 95% confidence interval [CI], 1.01–1.28). The HLA-AB AAMM load showed no impact on graft survival. In the subgroup with available split-level information, we observed an inferior graft survival for a higher HLA-DR AAMM load 3 months after transplantation (HR, 1.22; 95% CI, 1.04–1.44) and a higher risk for rejection for an increasing HLA-AB (HR, 1.70; 95% CI, 1.29–2.24) and HLA-DR (HR, 1.32; 95% CI, 1.09–1.61) AAMM load. No impact on the development of CAV was found. Molecular-level HLA mismatch analysis could serve as a tool for risk stratification after heart transplantation and might take us one step further into precision medicine.     

C4d immunostaining is an independent predictor of cardiac allograft vasculopathy and death in heart transplant recipients

Antibody‐mediated rejection (AMR) occurs in 10–20% of patients after heart transplantation. C4d immunostaining is one parameter used in its diagnosis. This study aimed to determine whether C4d staining has prognostic significance for mortality, coronary allograft vasculopathy (CAV), cell‐mediated rejection (CMR), and graft dysfunction in patients post‐transplantation. Consecutive patients receiving an endomyocardial biopsy between 2007 and 2008 were selected. Left ventricular function, angiography, episodes of AMR/CMR, and death were noted. C4d was graded from 0 to 3 (immunostaining). Cox proportional models (recurrent events analysis) were used to evaluate C4d staining with mortality, graft dysfunction, CAV (≥grade 2), and episodes of ≥2R‐CMR. We analyzed 2525 biopsy specimens (n = 217). During a follow‐up of 4.5 ± 2 years, 35 died, 49 had graft dysfunction, seven had ≥grade 2 CAV, and 95 episodes of CMR occurred. A one‐grade increase in C4d staining was associated with an increase in mortality (HR 1.57; 95% CI 1.0–2.5), a higher risk of CAV (HR 2.4, 95% CI 1.04–5.4), and a trend toward graft dysfunction (HR 1.42; 95% CI 1.0–2.09). C4d was not associated with CMR. C4d immunostaining was a significant predictor of CAV and death but not subsequent episodes of CMR. There was also a trend toward increased graft failure.     

The effect of pre–heart transplant body mass index on posttransplant outcomes: An analysis of the ISHLT Registry Data

We evaluated the effect of pre–heart transplant body mass index (BMI) on posttransplant outcomes using the International Society for Heart and Lung Transplantation Registry. Kaplan‐Meier analysis and a multivariable Cox proportional hazard regression model were used for all‐cause mortality, and cause‐specific hazard regression for cause‐specific mortality and morbidity. We assessed 38 498 recipients from 2000 to 2014 stratified by pretransplant BMI. Ten‐year survival was 56% in underweight, 59% in normal weight, 57% in overweight, 52% in obese class I, 54% in class II, and 47% in class III patients (P < 0.001). Mortality was increased in underweight (HR 1.29, 95% CI 1.24‐1.35), obese class I (HR 1.19, 95% CI 1.13‐1.26), class II (HR 1.20, 95% CI 1.08‐1.32), and class III patients (HR 1.45, 95% CI 1.15‐1.83). Obesity was independently associated with increased death from myocardial infarction, chronic rejection, infection, and renal dysfunction. An underweight BMI lead to increased death from infection, acute and chronic rejection, malignancy, and bleeding. Obese patients had a higher incidence of renal dysfunction, diabetes, stroke, acute rejection, cardiac allograft vasculopathy, and malignancy, and underweight recipients had increased acute rejection. We have shown that pretransplant obese and underweight patients have increased post–heart transplant mortality and morbidity. This has implications for candidate selection and posttransplant management.     

Diminished impact of cytomegalovirus infection on graft vasculopathy development in the antiviral prophylaxis era – a retrospective study

Evidence concerning an association between cytomegalovirus (CMV) infection and accelerated cardiac allograft vasculopathy (CAV) is inconclusive. Data were analyzed retrospectively from 297 consecutive heart transplants between 1.1.2002 and 31.12.2012. Patients ≤18 years of age, survival, and follow‐up ≤1‐year post‐transplant and patients with early CAV were excluded. CMV‐infection was diagnosed and monitored closely in the first year. CAV was diagnosed by coronary angiography via left heart catheterization, and results were categorized according to the International Society of Heart and Lung Transplantation (ISHLT) scoring system. Risk factors for CAV were tested in a multivariable model. Median follow‐up was 7.5 years (IQR: 5.6–10.3). CMV infection in the first year after transplantation occurred in 26% of patients (n = 78), CMV disease in 5% (n = 15). CAV ≥1 ISHLT was detected in 36% (n = 108). Incidence of CAV >1 ISHLT and severity of CAV increased over time. No statistically significant association between CMV infection and disease within the first year and risk of CAV after 1‐year post‐HTx was detected in the univariate (P = 0.16) and multivariable [hazard ratio (HR), 1.36; confidence interval (CI), 0.89–2.07; P = 0.16] Cox regression. In the multivariable Cox regression, donor age (HR, 1.04; 95% CI, 1.02–1.06; P < 0.01) and acute cellular rejection (ACR) ≥2R in the first year after HTx (HR, 1.77; 95% CI, 1.06–2.95; P = 0.03) were independent risk factors for CAV development. In our cohort, CMV infection and disease in the first year after transplantation did not significantly influence the risk of CAV in the long‐term follow‐up.     

Cyclosporine versus Tacrolimus Treated Liver Transplant Recipients with Chronic Hepatitis C: Outcomes Analysis of the UNOS/OPTN Database

Recurrent hepatitis C virus (HCV) remains a problematic cause of morbidity and mortality for liver transplant patients. Immunosuppression including calcineurin‐inhibitors has been implicated in the acceleration of recurrent HCV. Recent studies suggest that outcomes may be better with cyclosporine (CSA‐ME) compared to tacrolimus (TAC), but the data are inconclusive. We retrospectively analyzed data received from the United Network for Organ Sharing on 8809 chronic HCV liver transplant recipients receiving either cyclosporine microemulsion (CSA‐ME) or tacrolimus (TAC) as maintenance immunosuppression prior to discharge. We analyzed patient death, graft failure, failure due recurrent disease and acute cellular rejection (ACR) for CSA‐ME versus TAC treated patients. Three‐year unadjusted patient and graft survival rates were 76.8% and 71.5%, respectively, in the CSA‐ME group versus 79.9% and 75.0% in the TAC group. Propensity score‐adjusted results suggest CSA‐ME treated patients are at increased risk of patient death and graft failure [Hazards ratio (HR) = 1.17; 95% CI = 1.01–1.36 and HR = 1.19; 95% CI = 1.04–1.35, respectively] and biopsy‐confirmed AR (HR = 2.03; 95% CI = 1.54–2.67) compared to TAC treated patients. These results provide evidence to reconsider the targeted administration of CSA‐ME to HCV‐infected liver transplant recipients.     

Thalidomide treatment prevents chronic graft rejection after aortic transplantation in rats – an experimental study

Cardiac allograft vasculopathy (CAV) affects approximately 30% of cardiac transplant patients at 5 years post‐transplantation. To date, there are few CAV treatment or prevention options, none of which are highly effective. The aim of the study was to investigate the effect of thalidomide on the development of CAV. The effect of thalidomide treatment on chronic rejection was assessed in rat orthotopic aortic transplants in allogeneic F344 or syngeneic Lew rats (n = 6 per group). Animals were left untreated or received thalidomide for 30 days post‐transplant, and evidence of graft CAV was determined by histology (trichrome and immunohistochemistry) and intragraft cytokine measurements. Animals that received thalidomide treatment post‐transplant showed markedly reduced luminal obliteration, with concomitant rescue of smooth muscle cells (SMCs) in the aortic media of grafts. Thalidomide counteracted neointimal hyperplasia by preventing dedifferentiation of vascular SMCs. Measurement of intragraft cytokine levels after thalidomide treatment revealed downregulation of matrix metalloproteinase 8 and monocyte chemotactic protein 1, cytokines involved in tissue remodelling and inflammation, respectively. Importantly, no negative side effects of thalidomide were observed. Thalidomide treatment prevents CAV development in a rodent model and is therefore potentially useful in clinical applications to prevent post‐transplant heart rejection.     

Association of diagnosed obstructive sleep apnea with kidney transplant outcomes

Obstructive sleep apnea (OSA) is common but underdiagnosed among patients with kidney disease. This study examines whether the diagnosis of OSA in kidney transplant recipients (KTR) affected death, death‐censored graft failure (DCGF), and acute rejection (AR). We analyzed the records of KTR who underwent transplant between 2000 and 2015. A total of 4014 kidney transplants were performed during the study period. Of these, 415 (10.3%) had a diagnosis of pretransplant OSA. Pretransplant OSA was associated with a higher risk of death in unadjusted analyses. After adjustment for potential confounders, pretransplant OSA was not associated with risk of death (HR = 1.04, 95% CI: 0.80‐1.36). Similarly, pretransplant OSA was associated with a slightly higher incidence of DCGF or AR but neither associations were significant (HR: 1.23, 95% CI: 0.85‐1.47 for DCGF; HR 1.10, 95% CI: 0.90‐1.36 for AR). A total of 117 (3.3%) were diagnosed with de novo OSA after transplant. Similar to the pretransplant OSA, unadjusted HR for death was significantly higher in the de novo OSA group (HR: 1.48, 95% CI: 1.19‐1.84); however, after adjustment, de novo OSA was not significantly associated with risk of death (HR: 1.15, 95% CI: 0.92‐1.45). Similarly, DCGF and AR rates were not significantly associated with de novo OSA (HR: 1.10, 95% CI: 0.84‐1.44 for DCGF; HR 1.10, 95% CI: 0.90‐1.33 for AR). Our work did not detect significant associations between OSA and risk of death, graft failure, and rejection but the estimates might be underestimated due to underdiagnosis of OSA.     

Reduced‐Dose Tacrolimus with Mycophenolate Mofetil vs. Standard‐Dose Tacrolimus in Liver Transplantation: A Randomized Study

We conducted a multicenter randomized study in liver transplantation to compare standard‐dose tacrolimus to reduced‐dose tacrolimus with mycophenolate mofetil to reduce the occurrence of tacrolimus side effects. Two primary outcomes (censored criteria) were monitored during 48 weeks post‐transplantation: occurrence of renal dysfunction or arterial hypertension or diabetes (evaluating benefit) and occurrence of acute graft rejection (evaluating risk). Interim analyses were performed every 40 patients to stop the study in the case of increased risk of graft rejection. One hundred and ninety‐five patients (control: 100; experimental: 95) had been included when the study was stopped. Acute graft rejection occurred in 46 (46%) and 28 (30%) patients in control and experimental groups, respectively (HR = 0.59; 95% CI: [0.37–0.94]; p = 0.024). Renal dysfunction or arterial hypertension or diabetes occurred in 80 (80%) and 61 (64%) patients in control and experimental groups, respectively (HR = 0.68; 95% CI: [0.49–0.95]; p = 0.021). Renal dysfunction occurred in 42 (42%) and 23 (24%) patients in control and experimental groups, respectively (HR = 0.49; 95% CI: [0.29–0.81]; p = 0.004). Leucopoenia (p = 0.001), thrombocytopenia (p = 0.017) and diarrhea (p = 0.002) occurred more frequently in the experimental group. Reduced‐dose tacrolimus with mycophenolate mofetil reduces the occurrence of renal dysfunction and the risk of graft rejection. This immunosuppressive regimen could replace full‐dose tacrolimus in adult liver transplantation.     

Death in the first year after kidney transplantation: implications for patients on the transplant waiting list

BACKGROUND: As the kidney transplant waiting list continues to expand, maintaining the medical fitness of transplant candidates will become increasingly difficult. METHODS: To identify patients who are at greatest risk during the wait-list period, we performed a Cox regression analysis to determine risk factors for mortality in the first posttransplantation year among 23,546 adult first kidney transplant recipients recorded in the United States Renal Data System between January 1995 and September 1997. RESULTS: In this study population, 4.6% of the patients died in the first posttransplantation year, and cardiac causes were the leading cause (27%) of death. Patients with diabetes (hazard ratio [HR]=1.58; 95% confidence interval [CI], 1.39-1.80), peripheral vascular disease (HR=1.41; 95% CI, 1.11-1.80), or angina (HR=1.38; 95% CI, 1.15-1.65), and patients with a longer duration of end-stage renal disease (HR=1.06 per year; 95% CI, 1.04-1.09) had a higher risk for mortality. Additionally, patients with early acute rejection (HR=1.47; 95% CI, 1.23-1.76), delayed graft function (HR=1.46; 95% CI, 1.25-1.71), and a lower glomerular filtration rate after transplantation were also at increased risk for death within the first posttransplantation year. CONCLUSIONS: Patients with comorbid disease, patients with a long duration of end-stage renal disease, and potential recipients of organs at high risk for graft dysfunction should be carefully screened for medical complications before transplantation to achieve the most favorable outcomes. Alternate organ allocation strategies that facilitate patient assessment close to the time of transplantation or that prioritize high-risk patients may also improve outcomes.     

The relative risk of overall graft loss and acute rejection among African American renal transplant recipients is attenuated with advancing age

Schold JD, Srinivas TR, Braun WE, Shoskes DA, Nurko S, Poggio ED. The relative risk of overall graft loss and acute rejection among African American renal transplant recipients is attenuated with advancing age.
Clin Transplant 2011: 25: 721–730. © 2010 John Wiley & Sons A/S. Abstract: Background: Graft loss rates are elevated among African American (AA) kidney transplant recipients. This may be attributable to immunological responses, socioeconomic disparities, comorbid conditions and access to care, but it is unclear whether risks are uniform in the AA population. Methods: We utilized multivariable models with the national SRTR database for adult recipients transplanted from 2000 to 2009 (n = 112 120) to investigate whether risks of graft loss, death and acute rejection between AAs and Caucasians vary with age. Results: Relative to Caucasians, AA recipients had significantly higher risk of overall graft loss among patients aged 18–49 (AHR = 1.37, 95% CI 1.30–1.43) but comparable risk among patients aged >65 (AHR = 1.04, 95% CI 0.96–1.13). Among recipients aged 18–34, AAs had higher risk of acute rejection (AOR = 1.33, 95% CI 1.12–1.57) but similar likelihood among recipients aged >65 (AOR = 0.94, 95% CI 0.75–1.17). Differences between race groups, as well as the relatively higher risks among younger AAs, were most pronounced following one yr post‐transplantation and diminished with presence of other risk factors. Conclusions: Elevated risks of overall graft loss and acute rejection are present among younger but not older AA kidney transplant recipients. These findings may have important implications for treatment decisions, follow‐up protocols and designation of “high‐risk” patients.     

Mortality after kidney transplant failure: the impact of non-immunologic factors

BACKGROUND: One third of cadaveric kidney transplant recipients suffer graft loss within five years of transplantation. Non-immunologic factors that predict mortality among non-transplant patients also may be potentially modifiable risk factors for mortality among patients with transplant failure. METHODS: Applying multivariate survival analysis to data from the United States Renal Data System, we determined the effect of immunologic or transplant related factors and non-immunologic factors on mortality in patients who initiated dialysis after kidney transplant failure in the United States between April 1995 and September 1998. RESULTS: A total of 4741 patients were followed for a median +/- standard deviation of 15 +/- 11 months after initiation of dialysis after transplant failure. The majority of the 1016 (21%) deaths were due to cardiac (36%) or infectious (17%) causes. Patients in the following groups had an increased risk for all-cause mortality: older patients [hazard ratio (HR) = 1.04 per year, 95% confidence interval (95% CI) 1.03-1.04], women (HR = 1.31, 95% CI 1.10-1.56), patients of white race (HR = 1.94, 95% CI 1.32-2.84), patients with diabetes (HR = 1.76, 95% CI 1.43-2.16), peripheral vascular disease (HR = 1.94, 95% CI 1.54-2.43), congestive heart failure (HR = 1.26, 95% CI 1.05-1.53), drug use (HR = 2.23; 95% CI 1.08-4.60), smokers (HR = 1.35, 95% CI 1.01-1.81), first transplant recipients (HR = 1.32, 95% CI 1.02-1.69), and patients with a higher glomerular filtration rate (GFR) at dialysis initiation (HR = 1.04 per mL/min higher, 95% CI 1.02-1.06). Those with private insurance (HR = 0.67, 95% CI 0.49-0.93) and higher serum albumin (HR = 0.73 per g/dL higher, 95% CI 0.64-0.83) had a decreased risk for all-cause mortality. Acute rejection, antibody induction, donor source, duration of graft survival and the maximum attained GFR during transplantation did not predict all-cause mortality. CONCLUSIONS: Non-immunologic factors predicted mortality among patients with transplant failure but immunologic and transplant related factors did not. Prevention, early diagnosis and treatment of co-morbid conditions and the complications of chronic kidney disease may improve the survival of patients with transplant failure.     

De novo noncutaneous malignancies after kidney transplantation are associated with an increased risk of graft failure: results from a time‐dependent analysis on 672 patients

The aim of this study was to evaluate the association between cancer occurrence and risk of graft failure in kidney transplant recipients. From November 1998 to November 2013, 672 adult patients received their first kidney transplant from a deceased donor and had a minimum follow‐up of 6 months. During a median follow‐up of 4.7 years (3523 patient‐years), 47 patients developed a nonmelanoma skin cancer (NMSC) and 40 a noncutaneous malignancy (NCM). A total of 59 graft failures were observed. The failure rate was 6 per 100 patient‐year (pt‐yr) after NCM versus 1.5 per 100 pt‐yr in patients without NCM. In a time‐dependent multivariable model, the occurrence of NCM appeared to be associated with failure (HR = 3.27; 95% CI = 1.44–7.44). The effect of NCM on the cause‐specific graft failure was different (P = 0.002) when considering events due to chronic rejection (HR = 0.55) versus other causes (HR = 15.59). The reduction of the immunosuppression after NCM was not associated with a greater risk of graft failure. In conclusion, our data suggest that post‐transplant NCM may be a strong risk factor for graft failure, particularly for causes other than chronic rejection.     

Outcomes of Simultaneous Heart–Kidney Transplant in the US: A Retrospective Analysis Using OPTN/UNOS Data

Simultaneous heart–kidney transplantation (SHK) remains uncommon in the US. We examined outcomes of SHK compared to heart transplant alone (HTA) and deceased donor kidney transplant (DDKT).
Data from OPTN/UNOS heart and kidney data bases were used to identify 16 710 HTA, 263 SHK transplants and 68 833 DDK transplants between 1998 and 2007. Outcomes included patient survival (PS), acute cardiac and renal rejection and renal graft survival (rGS).
The adjusted risk of death was 44% lower with SHK compared to HTA. Over half of SHK were performed in cases where pretransplant dialysis was not initiated. In these cases, there was no significant difference in the risk of death between SHK and HTA (HR 1.01; 95% CI 0.67–1.50).
Recipients of SHK had worse 1-year rGS and PS and had a higher relative risk of overall renal graft loss compared to DDKT recipients. One-year rates of cardiac (14.5%) and renal (6.5%) rejection were lower in SHK compared to HTA and DDKT, respectively.
Recipients of SHK had a lower adjusted risk of death compared to HTA recipients, particularly in patients who required pretransplant dialysis. These data suggest that SHK should be considered in heart transplant candidates with renal failure requiring dialysis, whereas the utility of SHK in cases of renal failure not requiring dialysis warrants further study.     

Antidepressant medication use before and after kidney transplant: implications for outcomes – a retrospective study

We examined a novel database wherein national US transplant registry identifiers were linked to records from a large pharmaceutical claims warehouse (2008–2015) to characterize antidepressant use before and after kidney transplantation, and associations [adjusted hazard ratio (aHR) 95% CI] with death and graft failure. Among 72 054 recipients, 12.6% filled antidepressant medications in the year before transplant, and use was more common among women and patients who were white, unemployed, and had limited functional status. Pre‐transplant antidepressant use was associated with 39% higher 1‐year mortality (aHR 1.39, 95% CI 1.18–1.64) and 15% higher all‐cause graft loss risk (aHR 1.15, 95% CI 1.02–1.30). More than 50% of patients who filled antidepressants pre‐transplant continued fill post‐transplant. Antidepressant use in the first year after transplant was associated with twofold higher risk of death (aHR 1.94, 95% CI 1.60–2.35), 38% higher risk of death‐censored graft failure, and 61% higher risk of all‐cause graft failure in the subsequent year. Pre‐listing antidepressant use was also associated with increased mortality, but transplantation conferred a survival benefit regardless of prelisting antidepressant use status. While associations may in part reflect underlying behaviors or comorbidities, kidney transplant candidates and recipients treated with antidepressant medications should be monitored and supported to reduce the risk of adverse outcomes.     

Multivariate analysis of the effectiveness of using antibody induction therapy according to the degree of HLA mismatches

OBJECTIVE: HLA mismatches have a strong impact on acute rejection and renal allograft survival. The objective of this study was to evaluate the effectiveness of antibody induction according to the degree of HLA mismatches. METHODS: Of 20,429 deceased donor (DD) transplantations and 12,859 living donor (LD) transplantations reported to the United Network for Organ Sharing (UNOS) between 1999 and 2001, 51% of DD and 45% of LD transplant recipients received induction therapy. Propensity scores (PS) were calculated to indicate independent factors associated with the use of induction. Levels of HLA match examined for DD transplant recipients were 0 ABDR (n = 3239), 0 DR (n = 4210), and DR mismatched transplants (n = 12,980), and 0 (n = 1133), 1 (n = 3836), and 2 (n = 7890) haplotype mismatches for LD transplant recipients. Outcome parameters were reported as hazard ratios (HR) for graft loss and odds ratios (OR) for first-year acute rejection. RESULTS: Recipients with HLA mismatches were more likely to receive induction antibody for DR mismatch in DDs (PS = 1.11, 95% confidence interval [CI] 1.04-1.19) and for haplotype mismatch in LDs (PS = 1.36, 95% CI 1.22-1.52). Induction reduced the likelihood of acute rejection for DD transplant recipients regardless of the level of HLA mismatch (OR = 0.70; 95% CI 0.57-0.85 in 0 ABDR MM; OR = 0.76, 95% CI 0.64-0.89 in 0 DR MM; and OR = 0.69, 95% CI 0.62-0.77 in DR MM), and for 2 haplotype mismatched LD transplant recipients (OR = 0.82, 95% CI 0.70-0.96); in other LD transplant recipients, reductions in acute rejection rates were observed but not statistically significant. Induction reduced the risk of graft loss for DR mismatched DD transplant recipients by about 12% (HR = 0.88; 95% CI 0.80-0.97). CONCLUSIONS: Antibody induction resulted in a significant reduction of acute rejection and graft loss for patients with HLA mismatch.     

Factors at de novo donor‐specific antibody initial detection associated with allograft loss: a multicenter study

We aimed to evaluate patient factors including nonadherence and viral infection and de novo donor‐specific antibody (dnDSA) characteristics [total immunoglobulin G (IgG), C1q, IgG3, and IgG4] as predictors of renal allograft failure in a multicenter cohort with dnDSA. We performed a retrospective observational study of 113 kidney transplant recipients with dnDSA and stored sera for analysis. Predictors of death‐censored allograft loss were assessed by Cox proportional modeling. Death‐censored allograft survival was 77.0% (87/113) during a median follow‐up of 2.2 (IQR 1.2–3.7) years after dnDSA detection. Predictors of allograft failure included medication nonadherence [HR 6.5 (95% CI 2.6–15.9)], prior viral infection requiring immunosuppression reduction [HR 5.3 (95% CI 2.1–13.5)], IgG3 positivity [HR 3.8 (95% CI 1.5, 9.3)], and time post‐transplant (years) until donor‐specific antibody (DSA) detection [HR 1.2 (95% CI 1.0, 1.3)]. In the 67 patients who were biopsied at dnDSA detection, chronic antibody‐mediated rejection [HR 11.4 (95% CI 2.3, 56.0)] and mixed rejection [HR 7.4 (95% CI 2.2, 24.8)] were associated with allograft failure. We conclude that patient factors, including a history of viral infection requiring immunosuppression reduction or medication nonadherence, combined with DSA and histologic parameters must be considered to understand the risk of allograft failure in patients with dnDSA.     

Impact of cytomegalovirus prophylaxis on rejection following orthotopic liver transplantation.

With improved cytomegalovirus (CMV) prophylaxis, CMV disease after liver transplantation has decreased dramatically, and patient and graft survival have improved. We examined the impact of CMV prophylaxis on biopsy proven rejection after orthotopic liver transplantation by analyzing data on 192 liver recipients over 5 years (1994-1999). Risk factors assessed for biopsy proven rejection including donor and recipient age, CMV serostatus; CMV prophylaxis; immunosuppression; bacteremia and blood product use were examined over a 2-year follow-up. Multivariate analysis of risk factors for rejection showed that bacteremia (HR 3.57, 95% CI 1.39-9.36, P=0.008), donor age (HR 1.20, 95% CI 1.06-1.36, per 10 year increase, P=0.004), and use of cyclosporine as initial immunosuppression compared to tacrolimus (HR 1.98, 95% CI 1.27-3.09, P=0.003) were associated with increased risk; ganciclovir prophylaxis for 3 months (HR 0.51, 95% CI 0.33 to 0.79, P=0.003) and recipient age (HR 0.78; 95% CI 0.63-0.96, for each 10 year increase, P=0.03) were associated with decreased risk. We conclude that, the use of CMV prophylaxis with ganciclovir significantly reduces the incidence of biopsy proven rejection in liver transplant recipients.     

Risk factors for allograft failure in United kingdom renal transplant recipients treated with cyclosporine A

BACKGROUND: After the introduction of cyclosporine A (CsA), 2-year graft survival of transplanted kidneys improved from less than 60% to more than 80%, but long-term graft survival and graft half-life have shown less change. This study investigates the impact of a range of demographic and treatment factors on long-term graft survival in renal recipients treated with CsA from all renal transplant centers in the United Kingdom. METHODS: Data were obtained from the Long-Term Efficacy and Safety Surveillance study of renal transplant recipients receiving CsA (Neoral; Novartis, Basel, Switzerland). A total of 1,757 de novo patients with a functioning graft at 1 year were evaluated. The endpoints considered were the need for regular dialysis or death. A stepwise stratified Cox model was used to identify the factors associated with outcome. RESULTS: Seven independent risk factors for allograft failure were identified: older recipient (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.2-2.6), male recipient (HR 1.8, 95% CI 1.2-2.7), younger donor (HR 1.7, 95% CI 1.2-2.5), above average creatinine (HR 1.9, 95% CI 1.3-2.8), chronic allograft nephropathy (HR 7.0, 95% CI 4.7-10.4), diabetic recipient (HR 2.2, 95% CI 1.2-4.1), and neoplasm after transplant (HR 1.7, 95% CI 1.2-2.6). CONCLUSION: Seven independent risk factors were found to influence graft survival. Only two of these can be modified by clinical intervention, elevated serum creatinine at 1 year and the occurrence of chronic allograft nephropathy. To influence these two factors, the optimization of immunosuppressive therapy is essential.     

Development and outcomes of de novo donor‐specific antibodies in low,moderate, and high immunological risk kidney transplant recipients

De novo donor‐specific antibodies (dnDSA) play an important role in antibody‐mediated rejection (ABMR) and graft failure, yet their development in kidney transplant recipients (KTx) of higher immunological risk has not been characterized. We prospectively determined the incidence of dnDSA at 3 and 12 months posttransplant and assessed their associations with outcomes in recipients stratified by low, moderate, and high immunological risk. Adult KTx were screened for DSA pretransplant, months 3 and 12 posttransplant, and when clinically indicated. Outcomes included incidence of dnDSA, death‐censored graft survival (DCGS), and ABMR. Of 371 recipients, 154 (42%) were transplanted across a pretransplant DSA that became undetectable by 12 months posttransplant in 78% of cases. dnDSA were detected in 16% (95% confidence interval [CI]: 12‐20%) by 3 months and 23% (95% CI: 18‐29%) by 12 months posttransplant. Incidence at 12 months was higher in the moderate (30%) and high‐risk groups (29%) compared to the low‐risk group (16%). dnDSA were associated with an increased risk of ABMR (hazard ratio [HR] 2.2; 95% CI: 1.1‐4.4; P = .04) but were not an independent risk factor for DCGS. In conclusion, dnDSA were more frequent in transplant recipients of higher immune risk and associated with an increased risk of ABMR.     

Long‐term patient survival and kidney allograft survival in post‐transplant diabetes mellitus: a single‐center retrospective study

A decade ago, observations suggested that post‐transplant diabetes mellitus (PTDM) was linked to allograft loss and shorter patient survival. Increasing awareness, improvements in care, and changes in the immunosuppressive regimen may have modified this association. Single‐center analysis of 1990 (age>18; transplantation date 1996–2012) primary kidney recipients (KTR). Patients with <12 months follow‐up were excluded. Diabetes was diagnosed according to ADA criteria and characterized as follows: No diabetes, PTDM in the first post‐transplant year not treated with glucose‐lowering medications (GLM) at 12 months, PTDM in the first post‐transplant year treated with GLM at 12 months, and pretransplant diabetes. Cox proportional hazards models were used to examine the relationship of PTDM with allograft and patient survival. Mean follow‐up time was 6.8 years for allograft survival and 7.4 years for patient survival. PTDM treated with medication at year one was not associated with allograft survival (HR 1.28, 95% CI 0.97–1.69), but was significantly associated with overall mortality and death with functioning graft (DWFG) (HR overall: 1.81, 95% CI 1.36–2.39; HR DWFG: 1.59 95% CI 1.05–2.38). In this cohort, KTR with PTDM being treated with glucose‐lowering medication at 12 months experienced significantly shorter overall survival and survival with functioning graft.