Human Leukocyte antigen-DR Mismatches Research Articles

Management strategies and outcomes in renal transplant recipients recovering from COVID-19: A retrospective, multicentre, cohort study

SummaryBackgroundThere is an enormous knowledge gap on management strategies, clinical outcomes, and follow-up after kidney transplantation (KT) in recipients that have recovered from coronavirus disease (COVID-19).MethodsWe conducted a multi-center, retrospective analysis in 23 Indian transplant centres between June 26, 2020 to December 1, 2021 on KT recipients who recovered after COVID-19 infections. We analyzed clinical and biopsy-confirmed acute rejection (AR) incidence and used cox-proportional modeling to estimate multivariate-adjusted hazard ratios (HR) for predictors of AR. We also performed competing risk analysis. Additional outcome measures included graft loss, all-cause mortality, waiting time from a positive real-time polymerase test (RT-PCR) to KT, laboratory parameters, and quality of life in follow-up.FindingsAmong 372 KT which included 38(10·21%) ABO-incompatible, 12(3·22%) sensitized, 64(17·20%) coexisting donors with COVID-19 history and 20 (5·37%) recipients with residual radiographic abnormalities, the incidence of AR was 34 (9·1%) with 1(0·26%) death censored graft loss, and 4(1·07%) all-cause mortality over a median (interquartile range) follow-up of 241 (106–350) days. In our cox hazard proportional analysis, absence of oxygen requirement during COVID-19 compared to oxygen need [HR = 0·14(0·03–0·59); p-value = 0·0071], and use of thymoglobulin use compared to other induction strategies [HR = 0·17(0·03–0.95); p-value = 0·044] had a lower risk for AR. Degree of Human leukocyte antigen (HLA) DR mismatch had the highest risk of AR [HR = 10.2(1·74–65·83); p-value = 0·011]. With competing risk analysis, with death as a competing event, HLA DR mismatch, and oxygen requirement continued to be associated with AR. Age, gender, obesity, inflammatory markers, dialysis vintage, steroid use, sensitization and ABO-incompatibility have not been associated with a higher risk of AR. The median duration between COVID-19 real time polymerase test negativity to transplant was 88(40–145) days (overall), and ranged from 88(40–137), 65(42–120), 110(49–190), and 127(64–161) days in World Health Organization ordinal scale ≤ 3, 4, 5, and 6–7, respectively. There was no difference in quality of life, tacrolimus levels, blood counts, and mean serum creatinine assessed in patients with a past COVID-19 infection independent of severity.InterpretationOur findings support that the outcomes of KT after COVID-19 recovery are excellent with absence of COVID-19 sequelae during follow-up. Additionally, there does not seem to be a need for changes in the induction/immunosuppression regimen based on the severity of COVID-19.FundingSanofi

Incidence, risk factors, and long-term outcomes associated with antibody-mediated rejection - The long-term Deterioration of Kidney Allograft Function (DeKAF) prospective cohort study.

Major gaps remain in our understanding of antibody-mediated rejection (AMR) after kidney transplant. We examined the incidence, risk factors, response to treatment, and effects on outcomes of AMR at seven transplant programs in the long-term Deterioration of Kidney Allograft Function prospective study cohort. Among 3131 kidney recipients, there were 194 observed AMR cases (6.2%) during (mean±SD) 4.85±1.86years of follow-up. Time to AMR was 0.97±1.17 (median, 0.48) years. Risk factors for AMR included younger recipient age, human leukocyte antigen DR mismatches, panel-reactive antibody >0%, positive T- or B-cell cross-match, and delayed graft function. Compared with no AMR, the adjusted time-dependent hazard ratio for death-censored graft failure is 10.1 (95% confidence interval, 6.5-15.7) for all AMR patients, 4.0 (2.5, 9.1) for early AMR (<90days after transplant), and 24.0 (14.0-41.1) for late AMR (≥90days after transplant). Patients were treated with different therapeutic combinations. Of 194 kidney transplant recipients with AMR, 50 (25.8%) did not respond to treatment, defined as second AMR within 100days or no improvement in estimated glomerular filtration rate by 42days. Long-term outcomes after AMR are poor, regardless of the initial response to treatment. Better prevention and new therapeutic strategies are needed to improve long-term allograft survival.

(511) - The Number of Human Leukocyte Antigen DR Mismatch Is Associated with Early Post-Transplant Acute Cellular Rejection Among Heart Transplantation Recipients

s S193 The purpose of the study was to evaluate T2, T1 and extracellular volume (ECV) quantification as novel tissue markers to diagnose acute cardiac rejection. Methods: CMR was prospectively performed in heart transplant patients before or just after routine EMB and before acute rejection therapy. Images were acquired on a 1.5 Tesla scanner including T2 mapping (T2 preparedSSFP) and T1 mapping using a modified look locker inversion recovery sequence ( MOLLI) at basal, mid and apical level in short axis view. T2 and T1 values were measured before and 15 minutes (for T1 mapping) after contrast administration. The results are expressed by the median and the 5th and the 95th percentiles. Results: twenty six patients (age 52±14 years) were included providing 40 comparisons CMR/EMB. Acute rejection (cellular, humoral or clinical symptoms) was diagnosed in 13 patients. Patients with AR had significantly higher global T2 values at 3 levels (58 ms [52-61] vs 55ms [49-55], P= 0.0049 at basal; 57 ms [54-61] vs 51 ms [5054], P= 0.0010 at median and 60 ms [54-66] vs 54 ms [50-57], P= 0.0119 at apical level). The area under the curve (AUC) for each level was: 0.78; 0.84 and 0.77 respectively. Patients with AR had significantly higher ECV at basal and median level: 35% [33-41] vs 27% [25-31] P= 0.0021 and 33% [28-38] vs 27%[24-31], P= 0.015 respectively. The AUC for each level was; 0.83 and 0.75 respectively. The sensitivity, specificity and diagnosis accuracy for basal T2 (cutoff : 58 ms) were 70%, 96 % and 79% respectively; basal ECV: (cutoff 31%) 89%, 77% and 81% respectively. The best AUC ( 0.88) was obtained when we combined basal T2 and basal ECV. Conclusion: In heart transplant patients, a combined CMR approach using T2 mapping and ECV quantification provides a high diagnostic accuracy for acute rejection diagnosis and could potentially decrease the number of routine EMB. Further studies are required to confirm these data.

Human Leukocyte Antigen-DR Mismatch Is Associated With Increased In-Hospital Mortality After a Heart Transplant

Although previous studies have investigated the effect of human leukocyte antigen matching on long-term outcomes after heart transplants, its role in the prognosis after a heart transplant remains unclear, particularly with respect to short-term survival. We evaluated the human leukocyte antigen mismatch on in-hospital mortality of 158 consecutive patients who had undergone a heart transplant between 2000 and 2008. Human leukocyte antigens-A, -B, and -DR were determined by means of serologic and molecular techniques. Univariate analysis and a multiple logistic regression models evaluated the effect of human leukocyte antigen variants on mortality, independent of clinical variables. In-hospital mortality was 11.4%. Higher prevalence of acute kidney injury (50.0% vs 12.9%), higher levels of troponins 48 hours after transplant (15.6 ± 12.0 ng/mL vs 9.7 ± 9.4 ng/mL), prolonged ischemia (188.2 ± 32.5 min vs 162.6 ± 40.7 min), higher frequency of reoperation (61.1% vs 17.9%), and higher human leukocyte antigen-DR mismatch (1.61 ± 0.5 vs 1.30 ± 0.6) were found in patients who died. By logistic regression analysis, humanleukocyte antigen-DR mismatch is associated with in-hospital mortality (OR=5.159, 95% CI=1.348-19.754), independent of the effect of covariates such as recipient age, mismatch sex, mismatch human leukocyte antigen-A, human leukocyte antigen-B, acute kidney injury, reoperation, ischemia duration, and levels of troponins. Human leukocyte antigen-DR mismatch is associated with in-hospital mortality in heart transplant.

A New Kidney Allocation Policy in Chile. Computer Based Simulations

Introduction: Kidney allocation involves ethical and technical aspects that have to be addressed in order to reach a balance between fairness, equity and efficiency. Models based on large populations may not be applicable to small countries, so local rules have to be developed and tried before implementation. In Chile kidneys are allocated based on ABO matching, first to medical priorities and then according to a point scheme that considers human leukocyte antigen (HLA) match (60%), time on the waiting list (20%) and panel reactive antibodies (PRA) (20%), additionally paediatric recipients receive extra points. A new policy being developed maintains ABO matching and medical priorities as first step but incorporates several other steps namely prior donors; 0 mismatch recipients; paediatric recipients and finally all other recipients according to a point scheme that incorporates recipient age, HLA match, PRA, and time on waiting list on similar proportions. The aim of this study is to compare the resulting transplants of the new allocation policy to the older. Methods: Computer generated simulations using actual patients (N=1176) on the Chilean waiting list as of September 2011 and 300 donors generated on the previous 3 years, were analyzed. Several simulations were performed randomly distributing the order of the donors in order to eliminate the importance of this factor on the results. Results: The new policy resulted in a significant decrease in the recipient age from 46 years to 41 and an increase in the number of 0 mismatched transplants from 4% to 6%. The mean HLA mismatch increased from 2,51 to 3,19 and HLA DR mismatch from 0,43 to 0,75. Finally waiting time increased from a mean of 40,2 months to 44,3 months. Conclusions: These results support the idea that improvements in the overall quality of transplants being performed can be achieved by changes in allocation policies. With the changes proposed younger patients are being privileged and compatibility is not (exception being made of 0 mismatched donor-recipient pairs). Increase in waiting time observed is probably due to the transplantation of longstanding patients on the wait list that were not candidates previously due to poor matching. Computer generated simulations can help decide which policies are best suited for each country based on their local characteristics.

A New Kidney Allocation Policy in Chile. Computer Based Simulations

Introduction: Kidney allocation involves ethical and technical aspects that have to be addressed in order to reach a balance between fairness, equity and efficiency. Models based on large populations may not be applicable to small countries, so local rules have to be developed and tried before implementation. In Chile kidneys are allocated based on ABO matching, first to medical priorities and then according to a point scheme that considers human leukocyte antigen (HLA) match (60%), time on the waiting list (20%) and panel reactive antibodies (PRA) (20%), additionally paediatric recipients receive extra points. A new policy being developed maintains ABO matching and medical priorities as first step but incorporates several other steps namely prior donors; 0 mismatch recipients; paediatric recipients and finally all other recipients according to a point scheme that incorporates recipient age, HLA match, PRA, and time on waiting list on similar proportions. The aim of this study is to compare the resulting transplants of the new allocation policy to the older. Methods: Computer generated simulations using actual patients (N=1176) on the Chilean waiting list as of September 2011 and 300 donors generated on the previous 3 years, were analyzed. Several simulations were performed randomly distributing the order of the donors in order to eliminate the importance of this factor on the results. Results: The new policy resulted in a significant decrease in the recipient age from 46 years to 41 and an increase in the number of 0 mismatched transplants from 4% to 6%. The mean HLA mismatch increased from 2,51 to 3,19 and HLA DR mismatch from 0,43 to 0,75. Finally waiting time increased from a mean of 40,2 months to 44,3 months. Conclusions: These results support the idea that improvements in the overall quality of transplants being performed can be achieved by changes in allocation policies. With the changes proposed younger patients are being privileged and compatibility is not (exception being made of 0 mismatched donor-recipient pairs). Increase in waiting time observed is probably due to the transplantation of longstanding patients on the wait list that were not candidates previously due to poor matching. Computer generated simulations can help decide which policies are best suited for each country based on their local characteristics.

Posttransplant Major Histocompatibility Complex Class I Chain-Related Gene A Antibodies and Long-Term Graft Outcomes in a Multicenter Cohort of 779 Kidney Transplant Recipients

The impact of major histocompatibility class I chain-related A (MICA) antibodies on renal graft outcomes is unclear. The goal of this work was to assess the impact of posttransplant MICA antibodies, assayed at 1 year, with two commercially available kits, on long-term renal graft outcomes. We retrospectively tested sera from 779 kidney transplant recipients with two single-antigen flow bead assays 1 year after transplantation. Samples were considered positive for MICA if they were positive in both tests or positive for MICA specificities that were present in one kit only. The main outcome was 4-year death-censored graft survival. The prevalence of MICA antibodies was 5.4% at 1 year. MICA+ patients were more frequently human leukocyte antigen (HLA) sensitized and regrafted. Four-year death-censored graft survival was not different between MICA+ and MICA- patients (97% vs. 94%, P=0.28). By Cox multivariate analysis, independent risk factors for graft loss were as follows: number of HLA DR mismatches, acute rejection within the first year posttransplantation, 1-year serum creatinine, and the presence of HLA antibodies at 1 year, but not the presence of MICA antibodies. These data do not support an independent pathogenic role for MICA in long-term renal graft injury and question the interest of posttransplant monitoring of MICA antibodies with single-antigen flow bead assays currently available.

Impact of Human Leukocyte Antigen-DR Mismatch Status on Kidney Graft Survival in a Predominantly African-American Population Under the Newer Immunosuppressive Era

Background Human leukocyte antigen (HLA)-DR has been shown to be immunogenic and associated with poor long-term graft function. However, under potent induction immunosuppression with antithymocyte globulin, the impact of the HLA-DR remains unclear. Method We reviewed 672 renal transplant recipients who received their transplants between 1998 and 2007. All patients received antithymocyte globulin as induction therapy followed by tacrolimus + prednisone + mycophenolate mofetil for maintenance immunosuppression. We divided the patients into three groups according to HLA-DR mismatch status (zero, one, or two mismatches). Results The three groups were different in total number of mismatches, deceased donor transplant, and delayed graft function, respectively. By Kaplan-Meier survival analysis, actuarial graft survival was significantly lower in the HLA-DR two mismatches group (72%) compared to HLA-DR zero mismatches group (78.5%) or HLA-DR one mismatch group (78.5%; P = .05, by log-rank test). Using Cox regression analysis, the risk of graft failure with two HLA-DR mismatches as compared with zero HLA-DR mismatches was 1.6 (95% confidence interval = 1.0–2.44, P = .049). When adjusted for age, wait time, race, type of transplant, retransplant status, T-cell flow crossmatch, delayed graft function, acute rejection, HLA-A and HLA-B, the effect of HLA-DR on survival was not significant ( P = .55). Conclusion The independent effect of HLA-DR mismatches on adverse graft survival is diminished under potent antibody induction and maintenance immunosuppression in our predominantly African-American population.

Experience From an Active Preemptive Kidney Transplantation Program—809 Cases Revisited

Preemptive kidney transplantation (PKT) is increasingly acknowledged. We wanted to investigate the results of an active PKT policy in an unselected end-stage renal disease population with high prevalence of PKT. From 1989 to 2007, 3400 first kidney transplantations were performed in which 809 were PKTs (24%). PKT patients were 7.4 years younger (P<0.001), had more live donors (LD; 64% vs. 35%, P<0.001), and fewer were panel reactive human leukocyte antigen antibody positive (2% vs. 6%, P<0.001). In the Cox regression analyses of patient mortality, uncensored and death-censored graft failures, all potential risk factors tested were statistically significant, except for recipient sex (i.e., recipient and donor age, PKT, deceased donor [DD], diabetes nephropathy, human leukocyte antigen-DR mismatch, and panel reactive antibody positivity). For patient mortality, PKT and DD had a hazard ratio (HR) of 0.75 (P=0.001) and 1.38 (P<0.001), respectively. The results were similar for uncensored and death-censored graft failures. Risk analyses were also performed separately for DD and LD cohorts. The results were comparable, except that PKT was not a significant risk factor in the LD cohort (HR=0.82, P=0.12 for mortality and HR=0.83, P=0.051 for uncensored graft failure). However, in DD recipients, patient mortality (HR=0.70, P=0.004) and uncensored graft failure (HR=0.68, P<0.001) were significantly reduced with PKT. PKT reduced the risk of patient mortality and uncensored graft failure in DD recipients. Our study confirms the advantages of PKT in an unselected end-stage renal disease population with a high prevalence of PKT.

Haplotypic Structure of ABCB1/MDR1 Gene Modifies the Risk of the Acute Allograft Rejection in Renal Transplant Recipients

Bioavailability of tacrolimus (Tac) and cyclosporine is determined by cytochrome P450IIIA and by P-glycoprotein encoded by the CYP3A4/CYP3A5 and ABCB1 genes. Polymorphisms in these genes have been suggested to influence acute rejection and pharmacokinetics in renal transplantation. We aimed to validate these findings in a haplotype analysis. A total of 832 renal transplant recipients were genotyped for the CYP3A4 -288A>G, CYP3A5 +6986G>A, ABCB1 +1236C>T, +2677G>T>A, and +3435C>T polymorphisms. Their association with acute rejection and with pharmacokinetic parameters was analyzed in haplotype models. Apart from human leukocyte antigen-DR mismatches, delayed graft function and age at renal transplantation, acute rejection was also predicted by the [ABCB1 +1236C; +2677G; +3435T] haplotype. Allograft survival was determined by donor age, age at renal transplantation, delayed graft function, cold ischemia, and history of more than two acute rejections. Homozygotes for the [CYP3A4 -288A; CYP3A5 +6986G] haplotype achieved earlier therapeutic concentrations of Tac and a higher concentration to dose ratio at week 1. ABCB1 haplotypes did not influence pharmacokinetic parameters. ABCB1 haplotypes modify the risk of acute rejection, suggesting that ABCB1 allelic arrangement is a stronger regulator of P-glycoprotein activity than single polymorphisms. The risk of acute rejection determined by ABCB1 is independent of pharmacokinetic parameters. CYP3A haplotypes control the bioavailability of Tac, but do not modify the risk of acute rejection.

Tacrolimus Exposure and Evolution of Renal Allograft Histology in the First Year After Transplantation

Tacrolimus has a narrow therapeutic window and is characterized by a large inter-individual variability in bioavailability. The impact of tacrolimus exposure on subclinical evolution of graft histology has not been studied in renal recipients. This analysis included 239 protocol biopsies (obtained at implantation, 3 and 12 months) of 120 consecutive kidney recipients treated with tacrolimus, mycophenolate mofetil (MMF) and corticosteroids. Biopsies were scored according to the Banff 2001 criteria and a chronicity score was calculated. Prospective pharmacokinetic data were included in the analysis (5544 tacrolimus predose blood concentrations and tacrolimus AUC(0-12) at 3 and 12 months). Higher donor age and higher number of human leukocyte antigen-DR (HLA-DR) mismatches were independent predictors of subclinical acute rejection at 3 months, present in 8.7% of patients. The number of HLA-DR mismatches was independently associated with biopsy-proven clinical acute rejection. Biopsy-proven acute rejection episodes and low mean tacrolimus exposure were independently associated with higher increase in chronicity scores between 3 and 12 months after transplantation. This observational study suggests that rejection phenomena and immune-mediated mechanisms remain important in the early progression of chronic allograft pathology. Tacrolimus doses or systemic exposure were not associated with lesions of calcineurin inhibitor nephrotoxicity, suggesting that other factors determine susceptibility to tacrolimus nephrotoxicity.

Inhibition of NF-κB during human dendritic cell differentiation generates anergy and regulatory T-cell activity for one but not two human leukocyte antigen DR mismatches

We examined the in vitro inhibition of human monocyte-derived dendritic cells (DC) maturation via NF-kappaB blockade on T-cell allostimulation, cytokine production, and regulatory T-cell generation. DC were generated from CD14+ monocytes isolated from peripheral blood using GM-CSF and IL-4 for differentiation and TNF-alpha, IL-1beta, and PGE2 as maturational stimuli with or without the NF-kappaB inhibitors, BAY 11-7082 (BAY-DC) or Aspirin (ASA-DC). Stimulator and responder cells were one versus two HLA-DR mismatched in direct versus indirect presentation assays. Both BAY-DC and ASA-DC expressed high levels of HLA-DR and CD86 but always expressed less CD40 compared with controls. Some experiments showed slightly lower levels of CD80. Both BAY- and ASA-allogeneic DC and autologous alloantigen pulsed DC were weaker stimulators of T cells (by MLR) compared with controls, and there was reduced IL-2 and IFN-gamma production by T cells stimulated with BAY-DC or ASA-DC (by ELISPOT) (more marked results were always observed with ASA-treated DC). In addition, NF-kappaB blockade of DC maturation caused the generation of T cells with regulatory function (T regs) but only when T cells were stimulated by either allogeneic (direct presentation) or alloantigen pulsed autologous DC (indirect presentation) with one HLA-DR mismatch and not with two HLA-DR mismatches (either direct or indirect presentation). However, the T regs generated from these ASA-DC showed similar FoxP3 mRNA expression to those from nontreated DC. Extension of this study to human organ transplantation suggests potential therapies using one DR-matched NF-kappaB blocked DC to help generate clinical tolerance.

Risk Factors for Reaching Renal Endpoints in the Assessment of Lescol in Renal Transplantation (ALERT) Trial

The aim of the study was to identity risk factors for long-term renal transplant function and development of chronic allograft nephropathy (CAN) in renal transplant recipients included in the Assessment of Lescol in Renal Transplantation (ALERT) trial. The ALERT trial was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin, 40 and 80 mg/day, in renal transplant recipients who were randomized to receive fluvastatin (Lescol) (n = 1,050) or placebo (n = 1,052) over 5 to 6 years of follow-up. Renal endpoints including graft loss or doubling of serum creatinine or death were analyzed by univariate and multivariate regression analysis in the placebo group. There were 137 graft losses (13.5%) in the placebo group, mainly caused by CAN (82%). Univariate risk factors for graft loss or doubling of serum creatinine were as follows: serum creatinine, proteinuria, hypertension, pulse pressure, time since transplantation, donor age, human leukocyte antigen-DR mismatches, treatment for rejection, low high-density lipoprotein cholesterol, and smoking. Multivariate analysis revealed independent risk factors for graft loss as follows: serum creatinine (relative risk [RR], 3.12 per 100-microM increase), proteinuria (RR, 1.64 per 1-g/24 hr increase), and pulse pressure (RR, 1.12 per 10 mm Hg), whereas age was a protective factor. With patient death in the composite endpoint, diabetes mellitus, smoking, age, and number of transplantations were also risk factors. Independent risk factors for graft loss or doubling of serum creatinine or patient death are mainly related to renal transplant function, proteinuria, and blood pressure, which emphasizes the importance of renoprotective treatment regimens in this population.

Human leukocyte antigen-DR and ABO mismatch are associated with accelerated homograft valve failure in children: implications for therapeutic interventions

Objective This study examines the incidence and factors associated with the failure of homograft valves and identifies those factors that are modifiable. Methods From 1990 to 2001, 96 homograft valves were implanted in the right ventricular outflow tract of 83 children (mean age 5.1 ± 5.6 years). Clinical and blinded serial echocardiographic follow-up was performed on all 90 valves in the 77 survivors. Results Eighteen homograft valves were replaced as the result of pulmonary insufficiency (3), stenosis (9), or both (6). Freedom from reoperation was 71% at 9 years (95% confidence interval, 58%-84%). Forty-eight valves developed progressive pulmonary insufficiency of at least 2 grades, 26 valves developed transvalvular gradients of 50 mm Hg or greater, and 14 of these valves were also insufficient. The freedom from echocardiographic failure (progressive pulmonary insufficiency ≥2 grades or ≥50 mm Hg gradient) was only 27% at 5 years (95% confidence interval, 17%-37%). In a multivariate analysis (Cox regression), use of an aortic homograft ( P = .001) and short antibiotic preservation time ( P = .04) were associated with reoperation. Younger age ( P = .01), ABO mismatch ( P = .04), and diagnosis ( P = .005) were associated with echocardiographic failure. In the subanalysis of patients with human leukocyte antigen typing, age ( P = .002), aortic homograft ( P = .04), and human leukocyte antigen-DR mismatch ( P = .03) were associated with echocardiographic valve failure. Conclusion Many homografts rapidly become insufficient and require replacement. In our analysis of both reoperation and echocardiographic failure, several immunologic factors are consistently associated with homograft failure. Matching for human leukocyte antigen-DR, blood group, and avoiding short preservation times (thus minimizing antigenicity) offers the potential to extend the life of these valves.

Increased immunogenicity and cause of graft loss of old donor kidneys.

Donor age was identified recently as a major factor that determines long-term outcome after transplantation, but the mechanism that is responsible for increased graft loss of old donor kidneys is unknown. The influence of donor age on graft survival was assessed retrospectively in 514 consecutive first cadaveric transplants that were treated with cyclosporine maintenance immunosuppression. Donor age > or =50 yr (relative risk [RR] = 1.7; 95% confidence interval [CI], 1.2 to 2.6), acute rejection (RR = 2.0; 95% CI, 1.3 to 3.0), and type of rejection (RR = 3.3; 95% CI, 2.0 to 5.3) had a significant impact on graft survival. However, when subsets of patients who entered subsequent intervals after transplantation were analyzed, donor age was not an independent predictive factor of graft loss. Donor age (RR = 1.53; 95% CI, 1.19 to 1.98), human leukocyte antigen-DR mismatch (RR = 2.28; 95% CI, 1.78 to 2.92), and recipient age (RR = 1.34; 95% CI, 1.05 to 1.72) were associated significantly with acute rejection episodes. Delayed graft function alone was not associated independently with the occurrence of early acute rejection (RR = 1.24; 95% CI, 0.96 to 1.61). The timing of the rejection episodes of old donor kidneys was not different, and the excess rejection prevalence was attributable entirely to interstitial (grade I) types of rejection. Interstitial rejection episodes in kidneys from old donors had a significant (P < 0.05) negative impact on graft survival. Beyond the first year, poor renal function and proteinuria were significant risk factors for graft loss, regardless of rejection. Our data fit best the hypothesis that increased graft loss of older donor kidneys results from an increased incidence of acute interstitial rejection episodes in the early posttransplantation months. It is proposed that kidneys from older donors are more immunogenic than kidneys from young donors and that acute rejection episodes result in functional deterioration. Contrary to interstitial rejection in kidneys from younger donors, kidneys from old donors seem to have an impaired ability to restore tissue.

Correlation of donor characteristics with transplant coronary artery disease as assessed by intracoronary ultrasound and coronary angiography

The mechanisms responsible for transplant coronary artery disease (CAD) and its predisposing factors remain incompletely understood. The influence of donor characteristics as predisposing factors has not been studied systematically. We examined the correlation of donor demographic, clinical, and immunologic parameters with transplant CAD assessed by both intracoronary ultrasound (ICUS) and coronary angiography in 116 heart transplant recipients (age 44.7 ± 12.0 years) studied 3.4 years (range 1.0 to 14.6) after transplantation. Quantitative ultrasound data were obtained by calculating mean intimai thickness from several distinct coronary sites. Coronary angiograms were categorized visually as normal or showing any transplant CAD. By multivariate regression analysis, donor undersize of > 20% of recipient weight (p < 0.02) and duration after transplantation (p < 0.005) were independently correlated with the amount of ICUS intimai thickness (r = 0.36, p = 0.0007), and older donor age with angiographic evidence for the disease (r = 0.34, p < 0.006). In a subgroup analysis of the 39 patients studied 1 year after transplantation, white donor race (p < 0.05), fewer human leukocyte antigen-DR mismatches (p < 0.002), shorter ischemic time (p < 0.04), and donor smoking history (p < 0.02) were independent predictors for severity of ICUS intimai thickening (r = 0.92, p = 0.0009); higher donor age (p < 0.006) and higher arterial partial pressure of oxygen (p < 0.003) were independent predictors for angiographic disease (r = 0.67, p < 0.002). In conclusion, donor characteristics may contribute to the probably multifactorial pathogenesis of transplant CAD.