Patient and graft survival in older kidney transplant recipients: does age matter?

An increasing gap between supply and demand of donor kidneys for transplantation exists. There is concern regarding the allocation of scarce organs to elderly patients, because the benefit obtained by the transplant may be less in elderly compared with younger recipients. It was the objective of this study to determine differences in patient and organ survival between organ recipients >65 yr and 50 to 64 yr of age at transplantation. A retrospective cohort of 627 patients >50 yr who received a kidney transplant between 1993 and 2000 was assembled. Detailed information on patient demographics, comorbidities, and immunological and donor characteristics was ascertained before transplantation. Five-year patient and graft survival were evaluated by Kaplan-Meier survival curves and multivariate Cox proportional-hazard models. Five-year patient mortality was similar between patients aged >65 and 60 to 64 at transplantation (relative risk [RR] = 1.07; 95% confidence interval [CI], 0.66 to 1.74). Patients aged 50 to 59 yr showed a clear trend toward lower 5-yr mortality (RR = 0.66; 95% CI, 0.43 to 1.03). Compared with patients >65 yr, 5-yr graft loss was not different in patients aged 60 to 64 (RR = 1.28; 95% CI, 0.82 to 2.02) or those aged 50 to 59 yr at transplantation (RR = 1.02; 95% CI, 0.68 to 1.53). After thorough control for confounding, 5-yr graft survival was not materially different by age group. Discrimination against older candidates for kidney transplantation on age-related grounds alone is not warranted.     

The association of living donor source with patient and graft survival among kidney transplant recipients in the ERA-EDTA Registry – a retrospective study

In this study we aimed to compare patient and graft survival of kidney transplant recipients who received a kidney from a living-related donor (LRD) or living-unrelated donor (LUD). Adult patients in the ERA-EDTA Registry who received their first kidney transplant in 1998–2017 were included. Ten-year patient and graft survival were compared between LRD and LUD transplants using Cox regression analysis. In total, 14 370 patients received a kidney from a living donor. Of those, 9212 (64.1%) grafts were from a LRD, 5063 (35.2%) from a LUD and for 95 (0.7%), the donor type was unknown. Unadjusted five-year risks of death and graft failure (including death as event) were lower for LRD transplants than for LUD grafts: 4.2% (95% confidence interval [CI]: 3.7–4.6) and 10.8% (95% CI: 10.1–11.5) versus 6.5% (95% CI: 5.7–7.4) and 12.2% (95% CI: 11.2–13.3), respectively. However, after adjusting for potential confounders, associations disappeared with hazard ratios of 0.99 (95% CI: 0.87–1.13) for patient survival and 1.03 (95% CI: 0.94–1.14) for graft survival. Unadjusted risk of death-censored graft failure was similar, but after adjustment, it was higher for LUD transplants (1.19; 95% CI: 1.04–1.35). In conclusion, patient and graft survival of LRD and LUD kidney transplant recipients was similar, whereas death-censored graft failure was higher in LUD. These findings confirm the importance of both living kidney donor types.     

Chronic graft-versus-host disease in pancreas after kidney transplant recipients – An unrecognized entity

Graft-versus-host disease (GVHD), a common complication after peripheral blood stem cell or bone marrow transplantation, rarely occurs in kidney and pancreas transplant recipients. The true incidence may be confounded by the rarity of the disorder, with a resultant lack of appreciation of the diagnosis as a potential cause of common clinical manifestations such as cytopenias and immune dysfunction. Reports of GVHD in kidney and pancreas transplant recipients almost uniformly describe patients in the early posttransplant period (days to months) with the typical manifestations of acute GVHD involving the skin, liver, and intestines. In contrast, reports of solid organ transplant recipients with clinical features more consistent with chronic GVHD (cGVHD) are lacking, raising concern of underrecognition of this severe complication. Occurrence later after transplant may be even more likely to result in lack of recognition. We report 2 cases of possible cGVHD occurring in recipients of pancreas after kidney transplantation, which were diagnosed at 5.5 and 42 months after pancreas transplant. Both patients presented with severe pancytopenia, multiple opportunistic infections, and features suggestive of cGVHD. Transplant professionals should be aware of the possibility of acute and cGVHD in pancreas after kidney transplant recipients and be able to recognize the clinical manifestations.     

Use of induction therapy in pediatric heart transplant recipients in Switzerland – Analysis of the Swiss national database

BackgroundData on individualized immunosuppressive protocols for the pediatric heart recipients are missing in Europe. To contribute to this very small but specialized field, we describe the use of induction therapy (IT) in pediatric heart transplant patients in Switzerland and the retrospective outcomes.MethodThis is a retrospective national database analysis of children <19 years of age at time of heart transplantation (HT) from 05/2008–01/2018. Use of IT or no IT, use of steroids, calculated panel reactive antibodies (cPRA) and outcomes (Mortality, post-transplant lymphoproliferative disease (PTLD), rejection rates) were studied within a mean follow-up period of 2.9 years (0.2–8.1 years).ResultsAll 32 patients (12♂, 20♀), median age at HT of 6.4 years (24 days - 18 years) received IT using either polyclonal antibodies (ATG; 72%) or interleukin-2 receptor antagonist (anti-IL-2R mAb; 28%). Length of treatment was median of 4 (1–63) days. At time of HT all patients received steroids, while at discharge 32% and one year after HT 19%. Kaplan-Meier analysis of survival revealed a one-year survival of 86%. Three out of 7 patients with elevated cPRA (43%) died. Median time to first treated rejection was 19.4 months (±60.5 SD) without significant difference if treated with anti-IL-2R mAb or ATG (p:0.5). No development of PTLD, chronic renal failure needing ongoing renal replacement therapy or diabetes mellitus were recorded.DiscussionThis is the first report of the national practice use of IT within Switzerland. It reveals a high use of IT, no development of PTLD and a low use of steroids at one-year post HT.     

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.     

Observational study of risk factors associated with clinical outcome among elderly kidney transplant recipients in Sweden – a decade of follow-up

Kidney transplantation (Ktx) in elderly has become increasingly accepted worldwide despite their higher burden of comorbidities. We investigated important risk factors affecting long-term patient and graft survival. We included all (n = 747) Ktx patients >60 years from 2000 to 2012 in Sweden. Patients were age-stratified, 60–64, 65–69 and >70 years. Follow-up time was up to 10 years (median 7.9 years, 75% percentile >10 years). Primary outcome was 10-year patient survival in age-stratified groups. Secondary outcomes were 5-year patient and graft survival in age-stratified groups and the impact of risk factors including Charlson comorbidity index (CCI) on patient and graft survival. Mortality was higher in patients >70 years, after 10 years (HR 1.94; 95% CI 1.24–3.04; P = 0.004). Males had a higher 10-year risk of death (HR 1.39; CI 95% 1.04–1.86; P = 0.024). Five-year patient survival did not differ between age groups. In multivariate Cox analysis (n = 500), hazard ratio for 10-year mortality was 4.6 in patients with CCI ≥7 vs. <4 (95% CI 2.42–8.62; P = 0.0001). Higher CCI identified ESKD patients with 4.6 times higher risk of death after Ktx. We suggest that this index should be used as a part of the preoperative evaluation in elderly.     

Does etiology of end-stage renal disease affect sleep quality in kidney transplant recipients?

BACKGROUND: That hypertension (HTN) as a leading cause of end-stage renal disease (ESRD) is linked to sleep disorders in the general population can be the basis of a hypothesis that HTN may be a contributing factor to the poor quality of sleep in some kidney transplant recipients. This study was designed to investigate the correlation between ESRD secondary to HTN and sleep quality among kidney transplant recipients. METHODS: In this case control study, 201 kidney transplant recipients were divided into group I (ESRD) secondary to HTN, (n=82) and group II (ESRD secondary to other causes, n=119). The groups were matched for medical comorbidities, demographic and clinical data, and symptoms of anxiety and depression. Sleep quality assessed by means of the Pittsburgh Sleep Quality Index (PSQI) was compared between the study groups. RESULTS: The mean (SD) of the total PSQI score was significantly high in group I compared with group II (7.42 +/- 2.36 vs 6.60 +/- 3.07, P=.042). Similar results were observed for the sleep duration scores in the groups (1.22 +/- 1.12 vs 0.86 +/- 1.12, P=.026). In group I, all the other PSQI components were higher than those in group II, difference that were statistically significant. CONCLUSION: Sleep quality and duration was poorer among our kidney transplant recipients with ESRD secondary to HTN compared with the controls. Further studies, however, are required to investigate whether HTN is responsible for the reported poor quality of sleep in some kidney transplant recipients.     

Type of proton-pump inhibitor and risk of iron deficiency in kidney transplant recipients – results from the TransplantLines Biobank and Cohort Study

Proton-pump inhibitors (PPIs) have been associated with iron deficiency (ID) in kidney transplant recipients (KTRs). Gastric acid plays a pivotal role in the intestinal absorption of non-heme iron, but the pharmacodynamics of PPIs differs in potency of acid suppression. We hypothesized that the risk of ID might be lower in KTRs using a less potent PPI. In a cohort of 724 KTRs from the TransplantLines Biobank and Cohort Study (NCT03272841), PPI use was associated with ID [odds ratio (OR) 2.02; 95% CI 1.36–2.98]. Compared with no PPI use, the point estimate of the odds ratio for risk of ID for pantoprazole (OR 1.55; 95%CI 0.78–3.10) was lower than for esomeprazole and omeprazole (3.58; 95%CI 1.73–7.40 and 1.96; 95%CI 1.31–2.94, respectively). When comparing pantoprazole users with omeprazole users on an equipotent dose (≤20 omeprazole equivalents (OE)/day) omeprazole, but not pantoprazole was associated with ID, although the lack of a significant effect of pantoprazole on the risk of ID could be caused by a lack of power. Furthermore, risk of ID was higher among users of a high PPI dose (≥ 20 OE/day) and OE as continuous variable was also independently associated with ID, indicating that risk of ID is higher while using a more potent PPI. Further investigation seems warranted to confirm whether pantoprazole leads to less ID in KTRs.     

Urinary sulfate excretion and risk of late graft failure in renal transplant recipients – a prospective cohort study

Hydrogen sulfide (H₂S), produced from metabolism of dietary sulfur-containing amino acids, is allegedly a renoprotective compound. Twenty-four-hour urinary sulfate excretion (USE) may reflect H₂S bioavailability. We aimed to investigate the association of USE with graft failure in a large prospective cohort of renal transplant recipients (RTR). We included 704 stable RTR, recruited at least 1 year after transplantation. We applied log-rank testing and Cox regression analyses to study association of USE, measured from baseline 24 h urine samples, with graft failure. Median age was 55 [45–63] years (57% male, eGFR was 45 ± 19 ml/min/1.73 m²). Median USE was 17.1 [13.1–21.1] mmol/24 h. Over median follow-up of 5.3 [4.5–6.0] years, 84 RTR experienced graft failure. RTR in the lowest sex-specific tertile of USE experienced a higher rate of graft failure during follow-up than RTR in the middle and highest sex-specific tertiles (18%, 13%, and 5%, respectively, log-rank P < 0.001). In Cox regression analyses, USE was inversely associated with graft failure [HR per 10 mmol/24 h: 0.37 (0.24–0.55), P < 0.001]. The association remained independent of adjustment for potential confounders, including age, sex, eGFR, proteinuria, time between transplantation and baseline, BMI, smoking, and high sensitivity C-reactive protein [HR per 10 mmol/24 h: 0.51 (0.31–0.82), P = 0.01]. In conclusion, this study demonstrates a significant inverse association of USE with graft failure in RTR, suggesting high H₂S bioavailability as a novel, potentially modifiable factor for prevention of graft failure in RTR.     

Long-term survival and late graft loss in pediatric liver transplant recipients—a 15-year single-center experience

Increasing numbers of children undergo successful liver transplantation. Limited data exist on long-term survival and late graft loss. Survival and graft loss were studied in 376 primary liver graft recipients who survived more than 3 months after transplantation (80.5% of all primary graft recipients). Patient records were reviewed retrospectively for causes of graft loss. Risk factors were identified by analyzing graft, recipient, and posttransplant variables using multivariate Cox regression. One-, 5-, and 10-year actuarial graft survival rates in the study population were 94.6%, 87.3%, and 86.3%, respectively. Corresponding patient survival rates were 95.7%, 91.4%, and 90.4%. Forty-seven (12.5%) grafts were lost subsequently, 15 by patient death with preserved graft function. Survival rate after late retransplantation was 63.3%. Causes of late graft loss were infection (21.2%), posttransplant lymphoproliferative disease (PTLD, 21.2%), chronic rejection (17%), biliary complications (14.8%), and recurrence of malignant disease (8.5%). Independent risk factors for late graft loss and patient death included liver malignancy as primary disease, steroid resistant rejection, and PTLD. Graft loss rate was significantly increased for reduced-size grafts. Patients undergoing transplantation after 1991 and recipients of full-size grafts were more likely to survive. In conclusion, the long-term outcome for pediatric primary liver graft recipients surviving the early postoperative period is excellent except for patients with liver malignancy. There is no increased risk of late graft loss with the use of split or living related donor grafts. Technical complications are only a minor factor in late graft loss, but complications related to immunosuppression and infection remain a major hazard and must be addressed. (Liver Transpl 2002;8:615-622.)     

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.     

Is the strength of single HLA antigen mismatch variable in kidney transplant survival?

The survival rate among 458 cadaver kidney grafts with "full-house" four HLA-A,B antigens detected in the donor, three being identical to those of the recipient and only one mismatched, was studied specifically in relation to antigen incompatibility. At the A locus, the A3 incompatibility was associated with a lower transplant survival (44% at 2 years) than all of the others, and particularly more than the A11 (80% at 2 years) (P less than 0.003 but without significance after correction multiplying by the number of tested alleles). At the B locus, there was no significant difference in survival rate among the alleles. These results are only preliminary and need confirmation based on longer series permitting possible cross-reactions which exit between donor and recipient antigens to be taken into consideration.     

Variability of mycophenolic acid elimination in the renal transplant recipients – population pharmacokinetic approach

Abstract

The aim of this study was to develop a population pharmacokinetic (PK) model for clearance of mycophenolic acid (MPA) in adult renal transplant recipients, to quantify the PK parameters and the influence of covariates on the MPA pharmacokinetic parameters. Parameters associated with plasma concentrations of MPA at steady-state were analyzed in 70 renal transplant recipients (mean age 42.97 years; mean total body weight 75.33?kg) using nonlinear mixed-effect modeling (NONMEM). Characteristics of patients screened for influence on the pharmacokinetic parameters were gender, age, body weight, time after transplantation, whether the patient was diagnosed as having diabetes mellitus, organ source (living or deceased donor), biochemical parameters and co-therapy (tacrolimus, cyclosporine, prednisolone, omeprazole, bisoprolol, carvedilol, nifedipine). A validation set of 25 renal transplant recipients was used to estimate the predictive performance of population pharmacokinetic model. Typical mean value of MPA oral clearance, estimated by base model (without covariates) was 0.741?L?h^?1. During population modeling, the full model showed that clearance of the MPA was significantly influenced by age, total daily dose of MPA, creatinine clearance, albumin level, status and gender of a donor, and the nifedipine and tacrolimus co-therapy. In the final model, clearance of MPA was reported to be significantly influenced by age, total daily dose of MPA and thenifedipine co-therapy. The derived model describes adequately MPA clearance in terms of characteristics of our patients, offering basis for individual pharmacotherapy approach.     

The impact of severe acute kidney injury requiring renal replacement therapy on survival and renal function of heart transplant recipients – a UK cohort study

Severe acute kidney injury (AKI), defined as requiring renal replacement therapy (RRT), is associated with higher mortality postheart transplantation, but its long-term renal consequences are not known. Anonymized data of 3365 patients, who underwent heart transplantation between 1995 and 2017, were retrieved from the UK Transplant Registry. Multivariable binary logistic regression was performed to identify risk factors for severe AKI requiring RRT, Kaplan–Meier analysis to compare survival and renal function deterioration of the RRT and non-RRT groups, and multivariable Cox regression model to identify predicting factors of mortality and end-stage renal disease (ESRD). 26.0% of heart recipients received RRT post-transplant. The RRT group has lower survival rates at all time points, especially in the immediate post-transplant period. However, conditional on 3 months survival, older age, diabetes and coronary heart disease, but not post-transplant RRT, were the risk factors for long-term survival. The predicting factors for ESRD were insulin-dependent diabetes, renal function at transplantation, eGFR decline in the first 3 months post-transplant, post-transplant severe AKI and transplantation era. Severe AKI requiring RRT post-transplant is associated with worse short-term survival, but has no impact on long-term mortality. It also accelerates recipients’ renal function deterioration in the long term.     

Outcomes of kidney retransplantation in recipients with prior posttransplant lymphoproliferative disorders: An analysis of the 2000–2019 UNOS/OPTN database

This study utilized the UNOS database to assess clinical outcomes after kidney retransplantation in patients with a history of posttransplant lymphoproliferative disease (PTLD). Among second kidney transplant patients from 2000 to 2019, 254 had history of PTLD in their first kidney transplant, whereas 28,113 did not. After a second kidney transplant, PTLD occurred in 2.8% and 0.8% of patients with and without history of PTLD, respectively (p = .001). Over a median follow-up time of 4.5 years after a second kidney transplant, 5-year death-censored graft failure was 9.5% vs. 12.6% (p = .21), all-cause mortality was 8.3% vs. 11.8% (p = .51), and 1-year acute rejection was 11.0% vs. 9.3% (p = .36) in the PTLD vs. non-PTLD groups, respectively. There was no significant difference in death-censored graft failure, mortality, and acute rejection between PTLD and non-PTLD groups in adjusted analysis and after propensity score matching. We conclude that graft survival, patient survival, and acute rejection after kidney retransplantation are comparable between patients with and without history of PTLD, but PTLD occurrence after kidney retransplantation remains higher in patients with history of PTLD.     

The impact of COVID-19 on kidney transplantation and the kidney transplant recipient – One year into the pandemic

The COVID-19 pandemic has significantly changed the landscape of kidney transplantation in the United States and worldwide. In addition to adversely impacting allograft and patient survival in postkidney transplant recipients, the current pandemic has affected all aspects of transplant care, including transplant referrals and listing, organ donation rates, organ procurement and shipping, and waitlist mortality. Critical decisions were made during this period by transplant centers and individual transplant physicians taking into consideration patient safety and resource utilization. As countries have begun administering the COVID vaccines, new and important considerations pertinent to our transplant population have arisen. This comprehensive review focuses on the impact of COVID-19 on kidney transplantation rates, mortality, policy decisions, and the clinical management of transplanted patients infected with COVID-19.     

Exploring the biology of vascular calcification in chronic kidney disease: what's circulating?

Chronic kidney disease (CKD) is associated with fatal cardiovascular consequences in part due to ectopic calcification of soft tissues particularly arteries, capillaries, and cardiac valves. An increasing body of evidence from experimental studies and in vivo data suggest that (I) a mineral imbalance with hyperphosphatemia and high-circulating calcium x phosphate product, (II) a deficiency of systemic or local calcification inhibitors, (III) death or 'damage' of vascular smooth muscle cells (VSMCs), and/or (IV) phenotypic transformation of VSMCs to osteo/chondrocytic cells may all act in concert to initiate and sustain vascular calcification. In CKD patients inhibitory systems are overwhelmed by a multitude of agents that induce VSMC damage and cell death resulting in the release of vesicles capable of nucleating basic calcium phosphate. Studies with genetically altered mice have identified both local and systemic calcification inhibitors that act to maintain VSMC differentiation or regulate vesicle properties. However, for many of these proteins the mechanisms and sites of action are still under investigation. In particular, it is unclear whether factors present in the circulation have an inhibitory role there and whether circulating levels of these proteins influence or are indicative of underlying disease processes in individual patients. A greater understanding of the origins and roles of potential circulating inhibitors may result in novel strategies aimed at the prevention or reversal of the life-limiting calcifying vasculopathies seen in CKD patients.     

IFNy + and IFNy − Treg subsets with stable and unstable Foxp3 expression in kidney transplant recipients with good long-term graft function

BackgroundTreg are a heterogenous cell population. In the present study we attempted to identify Treg subsets that might contribute to stable and good long-term graft function.MethodLymphocyte and Treg subsets were studied in 136 kidney transplant recipients with good long-term graft function and in 52 healthy control individuals using eight-color-fluorescence flow cytometry. Foxp3 TSDR methylation status was investigated in enriched IFNy + and IFNy − Treg preparations using high resolution melt analysis.ResultsCompared with healthy controls, patients showed strong associations of IFNy secreting Helios + and Helios − Treg with Treg that co-expressed perforin and/or CTLA4 (CD152; p < 0.01). Moreover they showed associations of IFNy − Helios + Treg with Treg that produced TGFβ and/or perforin and of IFNy − Helios − Treg with TGFβ production (all p < 0.01). Only in patients, but not in healthy controls, were IFNy − Helios + and Helios − Treg associated with higher CD45 +, CD3 +, (CD4 +), CD19 + lymphocyte counts (p < 0.001). In addition IFNy − Helios + Treg were associated with CD16 + 56 + lymphocytes (p < 0.001). Enriched IFNy − Treg from female but not male patients showed an association of Foxp3 methylation with higher total Treg and higher Helios + IFNy −, CXCR3 + Lselectin + (CD183 + CD62L +), CXCR3 − Lselectin + and CD28 + HLADR + Treg subsets (p < 0.01). Enriched IFNy + Treg from male patients showed an association of demethylated Foxp3 with total Treg and IL10 − TFGβ + Treg counts, and in enriched IFNy − Treg an association of methylated Foxp3 with APO1/FasR + FasL + (CD95 + CD178 +) Treg (p < 0.01).ConclusionsKidney recipients with good long-term graft function possess IFNy + and IFNy − Treg with stable and unstable Foxp3 expression in the blood. They co-express CD28, HLADR, CTLA4, CXCR3, Lselectin, TGFβ, perforin and FasL and might contribute to the establishment and maintenance of good long-term graft function.