Influence of donor sex and age on graft outcome in kidney transplantation.

BACKGROUND: There is a known recipient sex-dependent association between donor sex and kidney transplant survival. We hypothesized that donor age also modifies the association between donor sex and graft survival. METHODS: First, deceased donor kidney transplant recipients (1988-2019, n = 461 364) recorded in the Scientific Registry of Transplant Recipients, the Australia and New Zealand Dialysis and Transplant Registry and the Collaborative Transplant Study were analyzed. We used multivariable Cox regression models to estimate the association between donor sex and death censored graft loss, accounting for the modifying effects of recipient sex and donor age; donor age was categorized as 5-19, 20-34, 35-49, 50-59 and ≥60 years. Results from cohort-specific Cox models were combined using individual patient data meta-analysis. RESULTS: Among female recipients of donors aged <60 years, graft loss hazards did not differ by donor sex; recipients of female donors ≥60 years showed significantly lower graft loss hazards than recipients of male donors of the same age [combined adjusted hazard ratio (aHR) 0.90, 95% CI 0.86-0.94]. Among male recipients, female donors aged <50 years were associated with significantly higher graft loss hazards than same-aged male donors (5-19 years: aHR 1.11, 95% CI 1.02-1.21; 20-34 years: aHR 1.08, 95% CI 1.02-1.15; 35-49 years: aHR 1.07, 95% CI 1.04-1.10). There were no significant differences in graft loss by donor sex among male recipients of donors aged ≥50 years. CONCLUSION: Donor age modifies the association between donor sex and graft survival. Older female donors were associated with similar or lower hazards of graft failure than older male donors in both male and female recipients, suggesting a better functional reserve of older female donor kidneys.

A multinational cohort study uncovered sex differences in excess mortality after kidney transplant.

Worldwide and at all ages, males have a higher mortality risk than females. This mortality bias should be preserved in kidney transplant recipients unless there are sex differences in the effects of transplantation. Here we compared the excess risk of mortality (risk above the general population) in female versus male recipients of all ages recorded in three large transplant databases. This included first deceased donor kidney transplant recipients and accounted for the modifying effects of donor sex and recipient age. After harmonization of variables across cohorts, relative survival models were fitted in each cohort separately and results were combined using individual patient data meta-analysis among 466,892 individuals (1988-2019). When the donor was male, female recipients 0-12 years (Relative Excess Risk 1.54, 95% Confidence Interval 1.20-1.99), 13-24 years (1.17, 1.01-1.34), 25-44 years (1.11, 1.05-1.18) and 60 years and older (1.05, 1.02-1.08) showed higher excess mortality risks than male recipients of the same age. When the donor was female, the Relative Excess Risk for those over 12 years were similar to those when the donor was male. There is a higher excess mortality risk in female than male recipients with differences larger at younger than older ages and only statistically significant when the donor was male. While these findings may be partly explained by the known sex differences in graft loss risks, sex differences in the risks of death with graft function may also contribute. Thus, higher risks in females than males suggest that management needs to be modified to optimize transplant outcomes among females.

Outcome of Extended Right Lobe Liver Transplantations.

Split-liver transplantation offers a solution to the organ shortage problem. However, the outcomes of extended right lobe liver transplantation (ERLT) and whether it is a suitable alternative to full-size liver transplantation (FSLT) remain controversial. We compared the outcomes of ERLT and FSLT in adult recipients of 43,409 first deceased donor liver transplantations using Cox regression. We also analyzed 612 ERLT and 1224 FSLT 1:2 matched cases to identify factors that affect ERLT outcome. The risk of graft loss was significantly higher following ERLT than following FSLT during the first posttransplantation year in the matched and unmatched collective (hazard ratio [HR], 1.39 and 1.27 and P = 0.01 and 0.006, respectively). Every additional hour of cold ischemia time (CIT) increased the risk of 1-year graft loss by 10% in the ERLT group compared with only 3% in the FSLT group (P = 0.003 and <0.001, respectively). Importantly, the outcome of ERLT and FSLT did not differ significantly if the CIT was below 10 hours (HR, 0.71; P = 0.22). One-year graft and patient survival were lower in high-risk ERLT recipients with a Model for End-Stage Liver Disease (MELD) score of ≥20 (HR, 1.88; P = 0.03 and HR, 2.03; P = 0.02). In the male recipient-male donor combination, ERLT recipients had a higher risk of 1-year graft loss than FSLT recipients (HR, 2.44; P = 0.006). This was probably because of the significantly higher MELD score in ERLT recipients (P = 0.004). ERLT in adults is an adequate alternative to FSLT and offers an elegant solution to the problem of organ shortage as long as the cold storage is less than 10 hours and the recipient's MELD score is <20.

Maternal versus paternal living kidney transplant donation is associated with lower rejection in young pediatric recipients: A Collaborative Transplant Study report.

BACKGROUND: Approximately 1700 children per year with end-stage kidney disease undergo kidney transplantation in Europe and the United States of America; 30%-50% are living donor kidney transplantations. There may be immunological differences between paternal and maternal donors due to transplacental exchange of cells between the mother and fetus during pregnancy leading to microchimerism. We investigated whether the outcome of living-related kidney transplantation in young children is different after maternal compared with paternal organ donation. METHODS: Using the international Collaborative Transplant Study (CTS) database, we analyzed epidemiological data of 7247 children and adolescents aged <18 years who had received a kidney transplant from either mother or father. Risk of treated rejection episodes and death-censored graft failure were computed using the Kaplan-Meier method and multivariable Cox regression. RESULTS: In the recipient age group 1-4 years, the rate of treated rejection episodes in recipients of kidneys from maternal donors (N = 195) during the first 2 years post-transplant was significantly lower (hazard ratio HR = 0.47, p = .004) than in patients receiving kidneys from paternal donors (N = 179). This association between donor sex and risk of treated rejections was not observed in children aged 5-9 years. The 5-year death-censored graft survival in children aged 1-4 years with a maternal or paternal donor was comparable. CONCLUSIONS: Maternal kidney donation in young pediatric renal transplant recipients is associated with an approximately 50% lower rate of treated rejection than paternal kidney donation. Whether this phenomenon is due to maternal microchimerism-induced donor-specific hyporesponsiveness must be evaluated in prospective mechanistic studies.

Soluble Urokinase Receptor and Mortality in Kidney Transplant Recipients.

Main problem: Soluble urokinase plasminogen activator receptor (suPAR) is an immunological risk factor for kidney disease and a prognostic marker for cardiovascular events. Methods: We measured serum suPAR levels in a total of 1,023 kidney transplant recipients either before (cohort 1, n = 474) or at year 1 after transplantation (cohort 2, n = 549). The association of suPAR levels and all-cause and cardiovascular mortality was evaluated by multivariable Cox regression analysis. Results: The highest suPAR tertile compared to the two lower tertiles had a significantly higher risk of all-cause mortality in both cohorts separately (cohort 1: hazard ratio (HR) 1.92, 95% confidence interval (CI) 1.20-3.08, p = 0.007; cohort 2: HR = 2.78, 95% CI 1.51-5.13, p = 0.001) and combined (n = 1,023, combined HR = 2.14, 95% CI 1.48-3.08, p < 0.001). The association remained significant in the subgroup of patients with normal kidney function (cohort 2: HR = 5.40, 95% CI 1.42-20.5, p = 0.013). The increased mortality risk in patients with high suPAR levels was attributable mainly to an increased rate of cardiovascular death (n = 1,023, HR = 4.24, 95% CI 1.81-9.96, p < 0.001). Conclusion: A high suPAR level prior to and at 1 year after kidney transplantation was associated with an increased risk of patient death independent of kidney function, predominantly from cardiovascular cause.

Impact of HLA compatibility in recipients of kidneys from expanded criteria donors: A Collaborative Transplant Study Report.

Due to a widespread organ shortage, the use of expanded criteria donors (ECDs) in kidney transplantation has increased persistently, reaching approximately 40% in recent years. Whether human leucocyte antigen (HLA) matching between donor and recipient should be part of allocation algorithms in transplantation of ECD kidneys, and especially of ECD kidneys from ≥70-year-old donors, is still in question. To this end, 135,529 kidney transplantations performed between 2000 and 2017 and reported to the Collaborative Transplant Study were analysed and the impact of HLA-A+B+DR mismatches on death-censored graft and patient survival as well as on rejection episodes was investigated. Results were stratified according to donor status (standard criteria donor (SCD) versus ECD) and age of ECD. HLA incompatibility increased the five-year death-censored graft failure risk similarly strong in recipients of ECD and SCD transplants (hazard ratio (HR) per HLA mismatch 1.078 and 1.075, respectively; p < .001 for both). Its impact on rejection treatments during the first post-transplant year was also significant but slightly weaker for recipients of ECD transplants (risk ratio (RR) per HLA mismatch 1.10 for ECD transplants and 1.13 for SCD transplants; p < .001 for both). Mortality increased gradually from zero to six HLA mismatches in recipients of SCD transplants, whereas for ECD transplants a significant increase was notable only from zero to more than zero mismatches. A significant but slightly less pronounced impact of HLA incompatibility on graft failure was observed in transplants from ≥70- compared with <70-year-old ECDs (HR per mismatch 1.047 and 1.093; p = .009 and < 0.001, respectively). The influence of HLA mismatches on rejection treatments was the same for both ECD age groups (RR = 1.10, p < .001 and p = .004, respectively). Our data indicate that HLA matching should be part of allocation algorithms not only in transplantation of kidneys from SCDs but also from ECDs.

Association of graft survival with tacrolimus exposure and late intra-patient tacrolimus variability in pediatric and young adult renal transplant recipients-an international CTS registry analysis.

Adolescent and young adult age is a high-risk window with an alarmingly increased likelihood of premature kidney graft loss due to immunological rejection. Using the large database of the Collaborative Transplant Study, we analyzed whether a more intense and less variable exposure to tacrolimus could counteract this young age-related enhanced immunoreactivity. Kidney graft recipients aged 12-23 years (n = 964) with a 1-year tacrolimus trough level between 4.0 and 10.9 ng/ml had a 5-year graft survival rate of 85.1%, significantly better than the poor 66.1% rate in patients with a trough level below 4.0 ng/ml who showed a 2.38-fold increased risk of graft loss in the multivariable analysis (P < 0.001). This association was not apparent in young children aged 0-11 years (n = 455) and less pronounced in adults aged 24-34 years (n = 1466). However, an intra-patient variability of tacrolimus (IPV) trough level ≥1.5 at post-transplant years 1 and 2 was associated with an increased graft loss risk in both 12- to 23-year-old and 0- to 11-year-old recipients (P < 0.001 and P = 0.045). Patients with high IPV made up as many as 30% of kidney graft recipients, indicating that a more intense and less variable exposure to tacrolimus could improve graft survival strongly in this high-risk group.

Should kidney allografts from old donors be allocated only to old recipients?

In several deceased donor kidney allocation systems, organs from elderly donors are allocated primarily to elderly recipients. The Eurotransplant Senior Program (ESP) was implemented in 1999, and since then, especially in Europe, the use of organs from elderly donors has steadily increased. The proportion of ≥60-year-old donors reported to the Collaborative Transplant Study (CTS) by European centers has doubled, from 21% in 2000-2001 to 42% in 2016-2017. Therefore, in the era of organ shortage it is a matter of debate whether kidney organs from elderly donors should only be allocated to elderly recipients or whether <65-year-old recipients can also benefit from these generally as "marginal" categorized organs. To discuss this issue, a European Consensus Meeting was organized by the CTS on April 12, 2018, in Heidelberg, in which 36 experts participated. Based on available evidence, it was unanimously concluded that kidney organs from 65- to 74-year-old donors can also be allocated to 55- to 64-year-old recipients, especially if these organs are from donors with no history of hypertension, no increased creatinine, no cerebrovascular death, and no other reasons for defining a marginal donor, such as diabetes or cancer.

Late intra-patient tacrolimus trough level variability as a major problem in kidney transplantation: A Collaborative Transplant Study Report.

Intra-patient variability (IPV) of tacrolimus trough level has been associated with poor outcome after kidney transplantation. These findings were derived from single-center analyses and restricted mainly to measurements early after transplantation. We analyzed in a multicenter effort whether high IPV of tacrolimus levels at posttransplant years 1, 2, and 3 was associated with impaired clinical outcome. More than 6600 patients who received a deceased donor kidney transplant during 2000-2014 and had a functioning graft for >3 years were studied. Graft survival was significantly impaired with increasing IPV (P < 0.001). As compared to patients with a low IPV of <30%, the risk of graft loss during years 4-6 increased 32% in patients with an IPV of 30% to 44% and 66% in patients with an IPV of ≥45% (P = 0.002 and P < 0.001). About one-third of patients showed an IPV of ≥30% with substantially impaired outcome. Even in patients with good outcome during the first 3 posttransplant years, a high IPV was associated with inferior graft survival. Our data indicate that a fluctuating tacrolimus trough level at years 1, 2, and 3 posttransplant is a major problem in kidney transplantation.

Analyses of the short- and long-term graft survival after kidney transplantation in Europe between 1986 and 2015.

The evolution of kidney allograft survival remains insufficiently studied in the context of the changing donor and recipient demographics. Since European data are lacking we performed a cohort study (1986-2015) that, based on the Collaborative Transplant Study, included 108 787 recipients of brain-death kidney donors in 135 hospitals across 21 European countries. We analyzed the hazard rate of kidney failure after transplantation. Between 1986 and 1999, improvement in graft survival was more pronounced in the short term than in the long term: one-, five- and ten-year hazard rates after transplantation declined 64% (95% confidence interval, 61%-66%), 53% (49%-57%) and 45% (39%-50%), respectively. Between 2000 and 2015, hazard rates at one, five and ten years post-transplant declined respectively 22% (12-30%), 47% (36-56%) and 64% (45-76%). Improvement in graft survival in the first five years post-transplant was significantly less since 2000, while improvement after five years was comparable to before. During the 2000-2015 period improvement of graft survival was greater in the long than in the short term. These changes were independent of changing donor and recipient characteristics, and reflect the evolution in global kidney transplant management over the past decades. Unfortunately, after accounting for the evolution of donor and recipient characteristics, we found that short-term improvement in graft survival decreased since 2000, while long-term improvement remained unchanged in Europe. Thus, deceleration of short-term graft survival improvement in more recent years illustrates an unmet need for innovation.

Immunosuppression with mammalian target of rapamycin inhibitor and incidence of post-transplant cancer in kidney transplant recipients.

BACKGROUND: Evidence is limited regarding the effect of de novo therapy with mammalian target of rapamycin (mTOR) inhibitors on cancer risk after kidney transplantation. METHODS: Collaborative Transplant Study data from 78 146 adult recipients of first deceased-donor kidney transplants (1999-2013) were analysed (4279 mTOR inhibitor, 73 867 no mTOR inhibitor) using standard methods. Propensity score matching was performed for analysis of basal cell and squamous cell skin cancer. RESULTS: Standardized incidence ratios (SIR) versus a matched non-transplant population showed reduced tumour incidence in recipients with de novo mTOR inhibitor therapy compared with no mTOR inhibitor for non-melanoma skin cancer (NMSC) (SIR 5.1 versus 6.1; P =0.019) but not non-NMSC cancers (SIR 1.6 versus 1.7; P =0.35). Within propensity score-matched groups (n = 4265), multivariable Cox regression analysis showed a trend to reduced NMSC with mTOR inhibition [hazard ratio (HR) 0.77; P =0.063] but not for all non-NMSC tumours (HR 0.94; P= 0.59). A significant effect for mTOR inhibition was observed for basal cell carcinoma of the skin (HR 0.56; P= 0.004) but not squamous cell carcinoma (HR 0.87; P= 0.54). CONCLUSIONS: De novo mTOR inhibition was associated with a substantially and significantly reduced risk of basal cell carcinoma of the skin after kidney transplantation. A significant reduction of the incidence of other cancers was not found.

Efficacy and safety of antibody induction therapy in the current era of kidney transplantation.

BACKGROUND: Antibody induction with polyclonal rabbit-antithymocyte globulin (rATG) or an interleukin-2 receptor antagonist (IL-2RA) is widely used in kidney transplantation. METHODS: Collaborative Transplant Study data from 38 311 first deceased-donor kidney transplants (2004-13) were analysed. Transplants were classified as 'normal risk' or 'increased risk' according to current guidelines. Cox regression analysis was applied to subpopulations of propensity score-matched recipients. RESULTS: rATG or IL-2RA induction was given to 64% of increased-risk and 53% of normal-risk patients, respectively. rATG and IL-2RA induction were each associated with reduced risk for graft loss versus no induction in increased-risk patients [hazard ratio (HR) 0.85, P = 0.046 and HR 0.89, P = 0.011, respectively]. The HR values for incidence of treated rejection in increased-risk patients for rATG and IL-2RA versus no induction were 0.75 (P = 0.037) and 0.77 (P < 0.001), respectively. In the normal risk subpopulation, neither induction therapy significantly affected the risk of graft loss or treated rejection. Hospitalization for infection was increased by rATG (P < 0.001) and IL-2RA (P < 0.001) induction. In contrast to patients transplanted during 1994-2003, among patients transplanted during 2004-13, rATG did not significantly affect the risk of non-Hodgkin's lymphoma versus no induction (P = 0.68). CONCLUSION: Induction therapy following kidney transplantation should be targeted to increased-risk transplants. In this analysis, a beneficial effect of antibody induction in normal-risk transplants could not be demonstrated.

Malignancies in transplanted patients: Multidisciplinary evaluation and switch to mTOR inhibitors after kidney transplantation - experiences from a prospective, clinical, observational study.

Background Solid organ transplant recipients are at increased risk of developing malignancies. The objective of this prospective, observational, one-armed study was to study the feasibility to add a mammalian target of rapamycin (mTOR) inhibitor to the immunosuppressive regimen in transplanted patients with post-transplant malignancies. During the trial the need to improve identification of post-transplant malignancies and to reassure adequate oncological treatment of these patients became evident. Multidisciplinary team (MDT) evaluation of oncological and immunosuppressive treatments was implemented for all patients with malignancies after renal or combined renal and pancreas transplantation because of the trial. Material and methods At Uppsala University Hospital, Sweden, a MDT consisting of transplant surgeons, nephrologists, oncologists and dermatologists evaluated 120 renal or combined renal and pancreas-transplanted recipients diagnosed with malignancies from September 2006 to July 2012. To identify all malignancies, the population was linked to the Regional Tumor Registry (RTR). We recorded to which extent a switch to mTOR inhibitors was possible and how often the originally planned oncological managements were adjusted. All patients were followed for three years. (ClinicalTrials.gov: NCT02241564). Results In 76 of 120 patients (63%) a switch to mTOR inhibitors was possible. Immunosuppression was interrupted in seven patients (6%), reduced in three patients (2%) and remained unchanged in 34 of 120 patients (28%). Identification of post-transplant malignancies increased significantly after linkage to RTR (p = 0.015). The initially recommended oncological treatment was adjusted in 23 of 44 patients (52%) with solid or hematological malignancies; 36 of these patients (82%) were treated according to national guidelines. Conclusion In two thirds of the patients the immunosuppressive treatment could be changed to an mTOR inhibitor with anti-tumor effects in transplanted patients with post-transplant malignancies. The use of regional tumor registers considerably improved the identification of patients with post-transplant malignancies indicating that post-transplant malignancies might be timely underreported in transplant registers.

Differences in excess mortality by recipient sex after heart transplant: An individual patient data meta-analysis.

BACKGROUND: Identification of differences in mortality risk between female and male heart transplant recipients may prompt sex-specific management strategies. Because worldwide, males of all ages have higher absolute mortality rates than females, we aimed to compare the excess risk of mortality (risk above the general population) in female vs male heart transplant recipients. METHODS: We used relative survival models conducted separately in SRTR and CTS cohorts from 1988-2019, and subsequently combined using 2-stage individual patient data meta-analysis, to compare the excess risk of mortality in female vs male first heart transplant recipients, accounting for the modifying effects of donor sex and recipient current age. RESULTS: We analyzed 108,918 patients. When the donor was male, female recipients 0-12 years (Relative excess risk (RER) 1.13, 95% CI 1.00-1.26), 13-44 years (RER 1.17, 95% CI 1.10-1.25), and ≥45 years (RER 1.14, 95% CI 1.02-1.27) showed higher excess mortality risks than male recipients of the same age. When the donor was female, only female recipients 13-44 years showed higher excess risks of mortality than males (RER 1.09, 95% CI 1.00-1.20), though not significantly (p = 0.05). CONCLUSIONS: In the setting of a male donor, female recipients of all ages had significantly higher excess mortality than males. When the donor was female, female recipients of reproductive age had higher excess risks of mortality than male recipients of the same age, though this was not statistically significant. Further investigation is required to determine the reasons underlying these differences.

A Multinational Cohort Study Examining Sex Differences in Excess Risk of Death With Graft Function After Kidney Transplant.

BACKGROUND: Kidney transplant recipients show sex differences in excess overall mortality risk that vary by donor sex and recipient age. However, whether the excess risk of death with graft function (DWGF) differs by recipient sex is unknown. METHODS: In this study, we combined data from 3 of the largest transplant registries worldwide (Scientific Registry of Transplant Recipient, Australia and New Zealand Dialysis and Transplant Registry, and Collaborative Transplant Study) using individual patient data meta-analysis to compare the excess risk of DWGF between male and female recipients of a first deceased donor kidney transplant (1988-2019), conditional on donor sex and recipient age. RESULTS: Among 463 895 individuals examined, when the donor was male, female recipients aged 0 to 12 y experienced a higher excess risk of DWGF than male recipients (relative excess risk 1.68; 95% confidence interval, 1.24-2.29); there were no significant differences in other age intervals or at any age when the donor was female. There was no statistically significant between-cohort heterogeneity. CONCLUSIONS: Given the lack of sex differences in the excess risk of DWGF (other than in prepubertal recipients of a male donor kidney) and the known greater excess overall mortality risk for female recipients compared with male recipients in the setting of a male donor, future study is required to characterize potential sex-specific causes of death after graft loss.

Clinical outcome with low-dose valacyclovir in high-risk renal transplant recipients: a 10-year experience.

BACKGROUND: Cytomegalovirus (CMV) remains an important pathogen in transplant patients, and valacyclovir (VACV) prophylaxis 8 g/day has been used in high-risk CMV-seromismatched [D+/R-] renal transplant patients to decrease CMV disease. Neurotoxic adverse effects have limited its use, and the aim of the present study was to retrospectively evaluate low-dose VACV prophylaxis, 3 g/day for 90 days after transplantation, in 102 D+/R- renal transplant patients. METHODS: We compared patient and graft survival rates up to 5 years after transplantation with the data from the Collaborative Transplant Study Group (CTS) database. The incidence of CMV disease, rejection and neurotoxic adverse effects was analyzed up to 1 year after transplantation. RESULTS: The patient and graft survival rates up to 5 years were comparable with those derived from the CTS. CMV disease was diagnosed in 25% of the patients and 2% developed tissue-invasive CMV disease. The rejection frequency was 22% and neurotoxic adverse effects were seen in 2% of the patients. CONCLUSIONS: Low-dose VACV prophylaxis (3 g/day) for 90 days post-transplantation results in high patient and graft survival rates and reduces the incidence of CMV disease. Neurotoxic adverse effects are minimal. We believe that low-dose VACV prophylaxis should be considered to form one of the arms in future prospective comparison studies for the prevention of CMV disease in the high-risk D+/R- population of renal transplant patients.

Donor ABCB1 variant associates with increased risk for kidney allograft failure.

The impact of variation within genes responsible for the disposition and metabolism of calcineurin inhibitors (CNIs) on clinical outcomes in kidney transplantation is not well understood. Furthermore, the potential influence of donor, rather than recipient, genotypes on clinical endpoints is unknown. Here, we investigated the associations between donor and recipient gene variants with outcome among 4471 white, CNI-treated kidney transplant recipients. We tested for 52 single-nucleotide polymorphisms (SNPs) across five genes: CYP3A4, CYP3A5, ABCB1 (MDR1; encoding P-glycoprotein), NR1I2 (encoding the pregnane X receptor), and PPIA (encoding cyclophilin). In a discovery cohort of 811 patients from Birmingham, United Kingdom, kidney donor CC genotype at C3435T (rs1045642) within ABCB1, a variant known to alter protein expression, was associated with an increased risk for long-term graft failure compared with non-CC genotype (hazard ratio [HR], 1.69; 95% confidence interval [CI], 1.20-2.40; P=0.003). No other donor or recipient SNPs were associated with graft survival or mortality. We validated this association in 675 donors from Belfast, United Kingdom (HR, 1.68; 95% CI, 1.21-2.32; P=0.002), and in 2985 donors from the Collaborative Transplant Study (HR, 1.84; 95% CI, 1.08-3.13; P=0.006). In conclusion, these data suggest that an ABCB1 variant known to alter protein expression represents an attractive candidate for future study and risk stratification in kidney transplantation.

C3 polymorphisms and allograft outcome in renal transplantation.

BACKGROUND: Complement activation plays a role in the development of chronic allograft nephropathy, a common cause of late allograft loss. The role of two complement component 3 (C3) allotypes, called C3F (fast) and C3S (slow) on the basis of their electrophoretic motility, in the long-term outcome of renal allografts remains controversial. METHODS: We selected a random sample of 1147 donor and recipient pairs from the Collaborative Transplant Study DNA bank, and their DNA specimens were genotyped for the C3F and C3S alleles. The genotyping results were analyzed according to allograft outcome. Transplants were divided into four groups, according to the recipient and donor genotypes: SS recipient and FS or FF donor (the standard for comparison, since this combination has been reported to have the best outcome), SS recipient and donor, FS or FF recipient and SS donor, and FS or FF recipient and donor. RESULTS: Baseline characteristics of the four transplant groups were similar. The hazard ratios for allograft survival in the SS recipient and FS or FF donor group as compared with the other three groups (SS recipient and donor, FS or FF recipient and SS donor, and FS or FF recipient and donor) were not significant: 0.90 (95% confidence interval [CI], 0.7 to 1.14; P=0.33), 0.87 (95% CI, 0.65 to 1.16; P=0.33), and 0.89 (95% CI, 0.65 to 1.23; P=0.48), respectively. The four groups had similar patient-survival rates and similar cumulative rates of acute rejection and allograft dysfunction, as assessed by means of serum creatinine levels. CONCLUSIONS: Our results suggest that transplantation of FS or FF kidneys to SS recipients is not advantageous, possibly because chronic allograft nephropathy is a multifaceted disease involving the interplay of many biologic pathways.

Natural killer-cell receptor polymorphisms and posttransplantation non-Hodgkin lymphoma.

Posttransplantation non-Hodgkin lymphoma is a life-threatening complication after transplantation. Although pharmacologically suppressed adaptive immunity plays a major role in its development, the role of innate immunity in posttransplantation lymphoma is unknown. We assessed the 158 V/F polymorphism in the Fc-gamma receptor 3A gene (FCGR3A), killer cell immunoglobulin-like receptor (KIR) genotype, KIR ligand status, and a single nucleotide polymorphism affecting the production of interferon-gamma (IFN-gamma; +874 A/T) in 236 patients with posttransplantation lymphoma reported to the Collaborative Transplant Study. In addition, polymorphisms in the interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) genes previously associated with lymphoma development were also typed. Using a split-cohort approach, gene/allele frequency was related to the 5-year patient survival after the diagnosis of lymphoma and compared with 100 control solid organ transplant recipients. FCGR3A and KIR genotype significantly influenced survival after diagnosis of posttransplantation lymphoma: the hazard of dying was reduced in homozygous carriers of the high-affinity V allele (hazard ratio 0.49, 95% confidence interval 0.29-0.82, P = .006), whereas carrying a genotype including KIR2DL2/KIR2DS2 increased the risk of dying (hazard ratio 1.49, 95% confidence interval 1.07-2.05, P = .02). KIR ligands and cytokine polymorphisms had no effect on survival. None of the genetic loci analyzed emerged as risk factors for lymphoma development.