Living Donor Kidney Transplantation Improves Graft and Recipient Survival in Patients with Multiple Kidney Transplants.

BACKGROUND: Failed kidney transplant recipients benefit from a new graft as the general incident dialysis population, although additional challenges in the management of these patients are often limiting the long-term outcomes. Previously failed grafts, a long history of comorbidities, side effects of long-term immunosuppression and previous surgical interventions are common characteristics in the repeated kidney transplantation population, leading to significant complex immunological and technical aspects and often compromising the short- and long-term results. Although recipients' factors are acknowledged to represent one of the main determinants for graft and patient survival, there is increasing interest in expanding the donor's pool safely, particularly for high-risk candidates. The role of living kidney donation in this peculiar context of repeated kidney transplantation has not been assessed thoroughly. The aim of the present study is to analyse the effects of a high-quality graft, such as the one retrieved from living kidney donors, in the repeated kidney transplant population context. METHODS: Retrospective analysis of the outcomes of the repeated kidney transplant population at our institution from 1968 to 2019. Data were extracted from a prospectively maintained database and stratified according to the number of transplants: 1st, 2nd or 3rd+. The main outcomes were graft and patient survivals, recorded from time of transplant to graft failure (return to dialysis) and censored at patient death with a functioning graft. Duration of renal replacement therapy was expressed as cumulative time per month. A multivariate analysis considering death-censored graft survival, decade of transplantation, recipient age, donor age, living donor, transplant number, ischaemic time, time on renal replacement therapy prior to transplant and HLA mismatch at HLA-A, -B and -DR was conducted. In the multivariate analysis of recipient survival, diabetic nephropathy as primary renal disease was also included. RESULTS: A total of 2395 kidney transplant recipients were analysed: 2062 (83.8%) with the 1st kidney transplant, 279 (11.3%) with the 2nd graft, 46 (2.2%) with the 3rd+. Mean age of 1st kidney transplant recipients was 43.6 ± 16.3 years, versus 39.9 ± 14.4 for 2nd and 41.4 ± 11.5 for 3rd+ (p < 0.001). Aside from being younger, repeated kidney transplant patients were also more often males (p = 0.006), with a longer time spent on renal replacement therapy (p < 0.0001) and a higher degree of sensitisation, expressed as calculated reaction frequency (p < 0.001). There was also an association between multiple kidney transplants and better HLA match at transplantation (p < 0.0001). A difference in death-censored graft survival by number of transplants was seen, with a median graft survival of 328 months for recipients of the 1st transplant, 209 months for the 2nd and 150 months for the 3rd+ (p = 0.038). The same difference was seen in deceased donor kidneys (p = 0.048), but not in grafts from living donors (p = 0.2). Patient survival was comparable between the three groups (p = 0.59). CONCLUSIONS: In the attempt to expand the organ donor pool, particular attention should be reserved to high complex recipients, such as the repeated kidney transplant population. In this peculiar context, the quality of the donor has been shown to represent a main determinant for graft survival-in fact, kidney retrieved from living donors provide comparable outcomes to those from single-graft recipients.

Gene expression profiling and racial disparities in outcomes after heart transplantation.

BACKGROUND: African Americans (AAs) have lower survival rates after heart transplantation (HTx) than Caucasians. The aim of this analysis was to evaluate racial differences in gene expression and their associations with survival and the composite outcome of death, retransplant, rejection with hemodynamic compromise, and graft dysfunction in the Outcomes AlloMap Registry. METHODS: Registry participants included low-risk Caucasian and AA heart transplant recipients with a baseline and at least 1 follow-up gene expression test (AlloMap(C)) within the first year after HTx. The Kaplan-Meier method with delayed entry was used to describe differences in outcomes. Multivariable Cox hazard regression was used to evaluate the associations of overall gene expression profiling score, MARCH8 and FLT3 expression, and tacrolimus levels with each outcome, and stratified Cox models were developed to quantify race-specific associations. RESULTS: Among 933 eligible recipients, 737 (79%) were Caucasian and 196 (21%) were AA. Compared with Caucasians, AAs were significantly younger (55 vs 59 years, p < 0.001), with higher rates of non-ischemic cardiomyopathy (68% vs 50%, p < 0.001), sensitization (>10% panel reactive antibody, 16% vs 9.1%, p = 0.009), and human leukocyte antigen mismatches (7 vs 7, p = 0.01), but less frequent primary cytomegalovirus serostatus mismatch (14.31% vs 27.3%, p < 0.001). Overall, AAs had an increased adjusted mortality risk (hazard ratio [HR] 4.13, p = 0.007). Higher tacrolimus levels were associated with decreased mortality in AAs (HR 0.62, p = 0.009). Overall gene expression profiling score was associated with increased mortality among Caucasians (HR 1.21, p = 0.048). In Caucasians, but not AAs, overexpression of MARCH8 was associated with increased mortality (HR 2.90, p = 0.001). FLT3 upregulation was associated with increased mortality (HR 2.42, p = 0.033) in AAs. There was an inverse relationship between FLT3 expression and tacrolimus levels (-0.029 and -0.176, respectively) in Caucasians and AAs. CONCLUSIONS: AAs have a significantly higher mortality risk after HTx than Caucasians, even in the low-risk Outcomes AlloMap Registry population. AAs and Caucasians had differential outcomes based upon the varying expression of MARCH8 and FLT3 genes following HTx.

De novo donor-specific HLA antibodies in heart transplantation: Do transient de novo DSA confer the same risk as persistent de novo DSA?

BACKGROUND: It is estimated that 25%-35% of heart transplant recipients develop de novo donor-specific antibodies (dnDSA). One factor that appears to play a role in clinical outcomes is DSA persistence. The objective of this study was to determine the incidence of transient and persistent dnDSA in a Canadian heart transplant population and to evaluate their impact on coronary allograft vasculopathy (CAV), graft function, and mortality. METHODS: A retrospective study of consecutive adult and transitioned pediatric heart transplant recipients (2008-2015) in Toronto was performed. Clinical demographics were collected prospectively. HLA antibody testing was performed using Luminex single antigen assays. In statistical analysis, dnDSA was modeled as a time dependent covariate. RESULTS: During a median follow-up of 4.1 years, dnDSA were detected in 42 (23%) with a median time to detection of 329 days (156-740); 27 (64%) developed persistent dnDSA. Persistent dnDSA conferred an increased risk of death with a HR 4.0 (95%CI 1.4-12.1) when adjusted recipient age, CAV, and cytomegalovirus status. CONCLUSIONS: Transient dnDSA were not associated with adverse outcomes after heart transplantation. This suggests that transient dnDSA may not require enhanced immunosuppression, increased HLA antibody monitoring, or additional physiological assessment. By knowing the transient dnDSA status, clinicians may minimize both recipient morbidity and cost without increasing harm.

Donor specific HLA antibodies & allograft injury: mechanisms, methods of detection, manifestations and management.

The impact of donor specific HLA antibodies (DSA) on solid organ transplant outcomes has been recognised for over half a century. This article reviews the mechanisms of DSA formation, details the laboratory methods for detecting DSA, discusses the clinical and histological manifestations of DSA in the allograft and explores the options for management of DSA. The challenges posed by pre-existing and de novo DSA are explored with current therapeutic strategies described. A method for stratifying the risk associated with pre-existing DSA is explained and the importance of understanding immunological risk associated with transplantation to facilitate optimal personalised decision making for transplant recipients is highlighted. Future directions for further managing the risk associated with DSA are proposed.

Preformed donor-specific HLA antibodies are associated with increased risk of early mortality after liver transplantation.

There is limited evidence for a negative impact of preformed, donor-specific HLA antibodies (DSA) identified by cross-matching on outcomes after liver transplantation. Three recent studies have suggested an association between preformed DSA detected by Luminex and reduced graft or recipient survival in liver transplant cohorts with a high prevalence of hepatitis C. This study investigated the impact of preformed DSA identified by Luminex in the Scottish liver transplant population. All recipients of liver transplants in Scotland between 2007 and 2015 with samples available for day of transplant antibody testing and donor HLA typing were included (n=459); 96% of the cohort were white and 19% had a primary diagnosis of hepatitis C. The median follow-up time was 36 months. Preformed DSA were detected in 88 recipients. In multivariate analysis, preformed DSA with a median fluorescent intensity ≥10 000 were associated with recipient mortality at 1 year. There was no association between DSA and overall graft or recipient survival. This study adds to the growing body of evidence supporting a detrimental impact of preformed, high-level DSA in a subset of liver transplant recipients by identifying an association in an ethnically and demographically distinct liver transplant population.

Recipient obesity and outcomes after kidney transplantation: a systematic review and meta-analysis.

BACKGROUND: The prevalence of obesity is increasing globally and is associated with chronic kidney disease and premature mortality. However, the impact of recipient obesity on kidney transplant outcomes remains unclear. This study aimed to investigate the association between recipient obesity and mortality, death-censored graft loss and delayed graft function (DGF) following kidney transplantation. METHODS: A systematic review and meta-analysis was conducted using Medline, Embase and the Cochrane Library. Observational studies or randomized controlled trials investigating the association between recipient obesity at transplantation and mortality, death-censored graft loss and DGF were included. Obesity was defined as a body mass index (BMI) of ≥30 kg/m(2). Obese recipients were compared with those with a normal BMI (18.5-24.9 kg/m(2)). Pooled estimates of hazard ratios (HRs) for patient mortality or death-censored graft loss and odds ratios (ORs) for DGF were calculated. RESULTS: Seventeen studies including 138 081 patients were analysed. After adjustment, there was no significant difference in mortality risk in obese recipients [HR = 1.24, 95% confidence interval (CI) = 0.90-1.70, studies = 5, n = 83 416]. However, obesity was associated with an increased risk of death-censored graft loss (HR = 1.06, 95% CI = 1.01-1.12, studies = 5, n = 83 416) and an increased likelihood of DGF (OR = 1.68, 95% CI = 1.39-2.03, studies = 4, n = 28 847). CONCLUSIONS: Despite having a much higher likelihood of DGF, obese transplant recipients have only a slightly increased risk of graft loss and experience similar survival to recipients with normal BMI.

Factors influencing survival after kidney transplant failure.

BACKGROUND: The failure of a kidney transplant is now a common reason for initiation of dialysis therapy. Kidney transplant recipients commencing dialysis have greater morbidity and mortality than transplant-naïve, incident dialysis patients. This study aimed to identify variables associated with survival after graft failure. METHODS: All recipients of first, deceased donor kidney transplants performed in Northern Ireland between 1986 and 2005 who had a functioning graft at 12 months were included (n = 585). Clinical and blood-derived variables (age, gender, primary renal disease, diabetic status, smoking status, human leukocyte antigen (HLA) mismatch, acute rejection episodes, immunosuppression, cardiovascular disease, graft survival, haemoglobin, albumin, phosphate, C reactive protein, estimated glomerular filtration rate (eGFR), rate of eGFR decline, dialysis modality, and access) were collected prospectively and investigated for association with re-transplantation and survival. The association between re-transplantation and survival was explored by modelling re-transplantation as a time-dependent covariate. RESULTS: Median follow-up time was 12.1 years. Recipients with a failing graft (158/585) demonstrated rapid loss of eGFR prior to graft failure, reducing the time available to plan for alternative renal replacement therapy. Median survival after graft failure was 3.0 years. In multivariate analysis, age and re-transplantation were associated with survival after graft failure. Re-transplantation was associated with an 88% reduction in mortality. CONCLUSIONS: Optimal management of kidney transplant recipients with failing grafts requires early recognition of declining function and proactive preparation for re-transplantation given the substantial survival benefit this confers. The survival benefit associated with re-transplantation persists after prolonged exposure to immunosuppressive therapy.

Surveillance of nonmelanoma skin cancer incidence rates in kidney transplant recipients in Ireland.

BACKGROUND: The incidence of nonmelanomatous skin cancer (NMSC) is substantially higher among renal transplant recipients (RTRs) than in the general population. With a growing RTR population, a robust method for monitoring skin cancer rates in this population is required. METHODS: A modeling approach was used to estimate the trends in NMSC rates that adjusted for changes in the RTR population (sex and age), calendar time, the duration of posttransplant follow-up, and background population NMSC incidence rates. RTR databases in both Northern Ireland (NI) and the Republic of Ireland (ROI) were linked to their respective cancer registries for diagnosis of NMSC, mainly squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). RESULTS: RTRs in the ROI had three times the incidence (P<0.001) of NMSC compared with NI. There was a decline (P<0.001) in NMSC 10-year cumulative incidence rate in RTRs over the period 1994-2009, which was driven by reductions in both SCC and BCC incidence rates. Nevertheless, there was an increase in the incidence of NMSC with time since transplantation. The observed graft survival was higher in ROI than NI (P<0.05) from 1994-2004. The overall patient survival of RTRs was similar in NI and ROI. CONCLUSION: Appropriate modeling of incidence trends in NMSC among RTRs is a valuable surveillance exercise for assessing the impact of change in clinical practices over time on the incidence rates of skin cancer in RTRs. It can form the basis of further research into unexplained regional variations in NMSC incidence.

Estimated glomerular filtration rate decline as a predictor of dialysis in kidney transplant recipients.

BACKGROUND: It is now common for individuals to require dialysis following the failure of a kidney transplant. Management of complications and preparation for dialysis are suboptimal in this group. To aid planning, it is desirable to estimate the time to dialysis requirement. The rate of decline in the estimated glomerular filtration rate (eGFR) may be used to this end. METHODS: This study compared the rate of eGFR decline prior to dialysis commencement between individuals with failing transplants and transplant-naïve patients. The rate of eGFR decline was also compared between transplant recipients with and without graft failure. eGFR was calculated using the four-variable MDRD equation with rate of decline calculated by least squares linear regression. RESULTS: The annual rate of eGFR decline in incident dialysis patients with graft failure exceeded that of the transplant-naïve incident dialysis patients. In the transplant cohort, the mean annual rate of eGFR decline prior to graft failure was 7.3 ml/min/1.73 m(2) compared to 4.8 ml/min/1.73 m(2) in the transplant-naïve group (p < 0.001) and 0.35 ml/min/1.73 m(2) in recipients without graft failure (p < 0.001). Factors associated with eGFR decline were recipient age, decade of transplantation, HLA mismatch and histological evidence of chronic immunological injury. CONCLUSIONS: Individuals with graft failure have a rapid decline in eGFR prior to dialysis commencement. To improve outcomes, dialysis planning and management of chronic kidney disease complications should be initiated earlier than in the transplant-naïve population.

Do patients with chronic kidney disease get optimal cardiovascular risk reduction?

PURPOSE OF REVIEW: Cardiovascular events are the major cause of death in chronic kidney disease (CKD). Individuals with CKD have a substantially greater risk of cardiovascular disease compared with the general population but have largely been excluded from clinical trials. This review highlights the complex pathogenesis of cardiovascular disease, discusses the evidence for cardiovascular risk reduction and assesses the achievement of cardiovascular treatment targets in CKD. RECENT FINDINGS: There is evidence to support both blood pressure and cholesterol reduction in the CKD population. The risk of bleeding with antiplatelet drugs is high in CKD and these should be used with caution. Although there has been recent interest in targeting nonclassical cardiovascular risk factors in CKD, few trials have demonstrated any significant reduction in cardiovascular risk. Smoking cessation remains important but is poorly studied in CKD with many dialysis patients still smoking. SUMMARY: The pathogenesis of cardiovascular disease in CKD differs subtly from that of non-CKD patients. As renal function declines, the role and impact of treating classical risk factors may change and diminish. However, hypertension, hypercholesterolaemia and smoking cessation management should be optimized and may require multiple agents and approaches, particularly as CKD advances. Treatment of hypertension would appear to be one management area in which performance is less than ideal. Future work should focus on new management strategies and drug combinations that tackle the classical risk factors as well as better designed longitudinal and randomized control trials of nonclassical risk factors. Patients with CKD should be included in all cardiovascular intervention studies, given their poor outcomes without interventions.

Genetics of new-onset diabetes after transplantation.

New-onset diabetes after transplantation is a common complication that reduces recipient survival. Research in renal transplant recipients has suggested that pancreatic ß-cell dysfunction, as opposed to insulin resistance, may be the key pathologic process. In this study, clinical and genetic factors associated with new-onset diabetes after transplantation were identified in a white population. A joint analysis approach, with an initial genome-wide association study in a subset of cases followed by de novo genotyping in the complete case cohort, was implemented to identify single-nucleotide polymorphisms (SNPs) associated with the development of new-onset diabetes after transplantation. Clinical variables associated with the development of diabetes after renal transplantation included older recipient age, female sex, and percentage weight gain within 12 months of transplantation. The genome-wide association study identified 26 SNPs associated with new-onset diabetes after transplantation; this association was validated for eight SNPs (rs10484821, rs7533125, rs2861484, rs11580170, rs2020902, rs1836882, rs198372, and rs4394754) by de novo genotyping. These associations remained significant after multivariate adjustment for clinical variables. Seven of these SNPs are associated with genes implicated in ß-cell apoptosis. These results corroborate recent clinical evidence implicating ß-cell dysfunction in the pathophysiology of new-onset diabetes after transplantation and support the pursuit of therapeutic strategies to protect ß cells in the post-transplant period.

Comprehensive investigation of the caveolin 2 gene: resequencing and association for kidney transplant outcomes.

Caveolae are plasma membrane structures formed from a complex of the proteins caveolin-1 and caveolin-2. Caveolae interact with pro-inflammatory cytokines and are dysregulated in fibrotic disease. Although caveolae are present infrequently in healthy kidneys, they are abundant during kidney injury. An association has been identified between a CAV1 gene variant and long term kidney transplant survival. Chronic, gradual decline in transplant function is a persistent problem in kidney transplantation. The aetiology of this is diverse but fibrosis within the transplanted organ is the common end point. This study is the first to investigate the association of CAV2 gene variants with kidney transplant outcomes. Genomic DNA from donors and recipients of 575 kidney transplants performed in Belfast was investigated for common variation in CAV2 using a tag SNP approach. The CAV2 SNP rs13221869 was nominally significant for kidney transplant failure. Validation was sought in an independent group of kidney transplant donors and recipients from Dublin, Ireland using a second genotyping technology. Due to the unexpected absence of rs13221869 from this cohort, the CAV2 gene was resequenced. One novel SNP and a novel insertion/deletion in CAV2 were identified; rs13221869 is located in a repetitive region and was not a true variant in resequenced populations. CAV2 is a plausible candidate gene for association with kidney transplant outcomes given its proximity to CAV1 and its role in attenuating fibrosis. This study does not support an association between CAV2 variation and kidney transplant survival. Further analysis of CAV2 should be undertaken with an awareness of the sequence complexities and genetic variants highlighted by this study.

The complement cascade in kidney disease: from sideline to center stage.

Activation of the complement pathway is implicated in the pathogenesis of many kidney diseases. The pathologic and clinical features of these diseases are determined in part by the mechanism and location of complement activation within the kidney parenchyma. This review describes the physiology, action, and control of the complement cascade and explains the role of complement overactivation and dysregulation in kidney disease. There have been recent advances in the understanding of the effects of upregulation of the complement cascade after kidney transplantation. Complement plays an important role in initiating and propagating damage to transplanted kidneys in ischemia-reperfusion injury, antibody-mediated rejection, and cell-mediated rejection. Complement-targeting therapies presently are in development, and the first direct complement medication for kidney disease was licensed in 2011. The potential therapeutic targets for anticomplement drugs in kidney disease are described. Clinical and experimental studies are ongoing to identify further roles for complement-targeting therapy.

Epigenetics: time to translate into transplantation.

Substantial progress has been made in identifying genetic loci associated with multifactorial disorders, including variants that seem to impact outcomes following solid organ transplantation. Despite these advances, much of the heritability and susceptibility to chronic disease processes remains unexplained. Epigenetic modifications may exert their effect independently or complementary to genetic variants. Epigenetic modifications can change gene expression without altering the DNA sequence. These modifications are dynamic, potentially heritable, and can be induced by environmental stimuli or drugs. The impact of epigenetic phenomena on the outcomes of organ transplantation is currently poorly understood. Epigenetic modifications can occur during periods of illness; these may persist and potentially influence allograft outcomes. Epigenetic mechanisms influence the activation, proliferation, and differentiation of the immune cells involved in allograft rejection. The donor's epigenome may also impact transplant survival, and initial research has demonstrated that peritransplant conditions induce rapid epigenetic modification within the allograft. Further research will help to define the importance of epigenetic modifications in transplantation. This will potentially lead to the identification of useful biomarkers and the development of novel pharmacotherapies. This review explores the nature of epigenetic modification in disease and the emerging evidence for epigenetic influences on allograft survival.

Managing patients on dialysis in the community.

In an average GP practice there will be one or two patients currently on renal replacement therapy (RRT) and a larger number with progressive chronic kidney disease who will reach end stage renal disease (ESRD). The options for RRT are kidney transplantation, haemodialysis (HD) or peritoneal dialysis (PD). For many patients with ESRD, treatment at home allows greater flexibility and independence than can be facilitated by inpatient HD. PD can be broadly categorised into two types: continuous ambulatory peritoneal dialysis and automated peritoneal dialysis. Each PD patient has a personalised prescription depending on their body mass, residual renal function and the physical properties of their peritoneal membrane. On average patients can have four years of successful PD before needing to switch to an altemative mode of RRT. In home haemodialysis (HHD), the entire process is initiated and managed by the patient at home. HHD is an option for any motivated patient who can learn the necessary skills to manage their own HD and deal with the potential complications. The strongest clinical argument for choosing HHD is the ability to provide longer and more regular HD sessions. Daily HD results in an improvement in BP control, solute clearance and anaemia management, and thus confers a significant survival benefit to patients.