Surveillance of Non melanoma 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.

Homocysteine and B-group vitamins in renal transplant patients

Increased plasma homocysteine is an independent risk factor for cardiovascular disease. We have investigated homocysteine and B-group vitamin levels in renal transplant patients. Fasting blood was collected from 55 renal transplant recipients with good renal function and 32 age/sex matched control subjects. Total homocysteine was increased in transplant recipients in comparison to controls (10.9+/-1.5 vs. 6.7+/-1.3 micromol/l, P < 0.001). There was no difference in homocysteine between patients receiving cyclosporin (n = 39, homocysteine 11.0+/-1.5 micromol/l) and patients receiving prednisolone + azathioprine (n = 16, 10.8+/-1.6 micromol/l, mean+/-S.D.), although there was a significant correlation between homocysteine and serum cyclosporin concentration in the sub-group of patients receiving that immunosuppressive regimen (r = 0.42, P < 0.05). Levels of B-group vitamins were similar in patients and controls. Plasma homocysteine is increased in renal transplant recipients even in the presence of minor degrees of renal impairment and normal levels of B-group vitamins.

Influence of ABCB1 polymorphisms and haplotypes on tacrolimus nephrotoxicity and dosage requirements in children with liver transplant

AIMS
The aim of this study was to investigate the in?uence of genetic polymorphisms in ABCB1 on the incidence of nephrotoxicity and tacrolimus dosage-requirements in paediatric patients following liver transplantation.
METHODS
Fifty-one paediatric liver transplant recipients receiving tacrolimus were genotyped for ABCB1 C1236>T, G2677>T and C3435>T polymorphisms. Dose-adjusted tacrolimus trough concentrations and estimated glomerular ?ltration rates (EGFR) indicative of renal toxicity were determined and correlated with the corresponding genotypes.
RESULTS
The present study revealed a higher incidence of the ABCB1 variant-alleles examined among patients with renal dysfunction (30% reduction in EGFR) at 6 months post-transplantation (1236T allele: 63.3% vs 37.5% in controls,P = 0.019; 2677T allele: 63.3% vs. 35.9%, p = 0.012; 3435T allele: 60% vs. 39.1%,P = 0.057). Carriers of the G2677->T variant allele also had a signi?cant reduction (%) in EGFR at 12 months post-transplant (mean difference = 22.6%; P = 0.031). Haplotype analysis showed a signi?cant association between T-T-T haplotypes and an increased incidence of nephrotoxicity at 6 months post-transplantation (haplotype-frequency = 52.9% in nephrotoxic patients vs 29.4% in controls; P = 0.029). Furthermore, G2677->T and C3435->T polymorphisms and T-T-T haplotypes were signi?cantly correlated with higher tacrolimus dose-adjusted pre-dose concentrations at various time points examined long after drug initiation.
CONCLUSIONS
These ?ndings suggest that ABCB1 polymorphisms in the native intestine signi?cantly in?uence tacrolimus dosage-requirement in the stable phase after transplantation. In addition, ABCB1 polymorphisms in paediatric liver transplant recipients may predispose them to nephrotoxicity over the ?rst year posttransplantation. Genotyping future transplant recipients for ABCB1 polymorphisms, therefore, could have the potential to individualize better tacrolimus immunosuppressive therapy and enhance drug safety

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.

Tacrolimus is not associated with gingival overgrowth in renal transplant patients

BACKGROUND: Cyclosporin A is used extensively to prevent the rejection of allogenic renal transplants. However, it is associated with a variety of undesirable side effects including gingival overgrowth. Tacrolimus (FK506), has been marketed as an effective alternative immunosuppressant to cyclosporin A and recent subjective reports suggest patients taking it complain infrequently of gingival problems. This clinical investigation was undertaken to confirm whether or not tacrolimus adversely affected the gingival health of renal transplant recipients.

METHODS: Renal transplant patients (RTPs) under the care of the Renal Transplantation Service at the Manchester Royal Infirmary, who had received a renal allograft at least 18 months earlier, were recruited for this study. All but one of the RTPs had been taking tacrolimus since transplantation. The other had commenced tacrolimus therapy two months after receiving her allograft. A hospital based control group was recruited from non transplanted individuals attending the Turner Dental School, Manchester. Each patient underwent a detailed dental assessment and had dental impressions taken. The extent of gingival overgrowth was determined from plaster models.

RESULTS: 25 renal transplant recipients and 26 control patients were included in the study. None of the individuals in either the tacrolimus or control groups had clinically significant overgrowth. The patients in the tacrolimus group with the highest overgrowth scores were those also taking calcium antagonists as treatment for hypertension.

CONCLUSION: This study demonstrates that tacrolimus has no adverse effects on the gingival tissues and thus has potential as an alternative immunosuppressant for individuals susceptible to developing cyclosporin A-induced gingival overgrowth.

The influence of transforming growth factor-beta1 gene polymorphisms on the severity of gingival overgrowth associated with concomitant use of cyclosporin A and a calcium channel blocker

The purpose of this study was to determine whether the prevalence and severity of gingival overgrowth in renal transplant recipients concomitantly treated with cyclosporin and a calcium channel blocker was associated with functional polymorphisms within the signal sequence of the transforming growth factor-(TGF)beta1 gene.

Is screening for Factor V Leiden and Prothrombin G20210A Mutations in Renal Transplantation worthwhile? Results of a large single-center U.K. study

This single center study is the largest series of renal transplant recipients and donors screened for the commonest prothrombotic genotypes. A total of 562 transplant recipients and 457 kidney donors were genotyped for the factor V Leiden and prothrombin G20210A mutations. The prevalence of heterozygous factor V Leiden was 3.4% and 2.6% and prothrombin G20210A was 2.0% and 1.1% in recipients and donors, respectively, similar frequencies to that of the general U.K. population. The 30-day and 1-year graft survival rates in recipients with thrombophilic mutations were 93% and 93%, compared with 88% and 82% in patients without these mutations (log-rank P =0.34). Thrombophilia in recipients (odds ratio 0.55; confidence interval 0.06-2.29; P =0.56) or in donors (odds ratio 1.53; confidence interval 0.27-5.74; P =0.46) did not correlate with graft loss at 30 days after transplantation. In contrast to recent reports, this study did not demonstrate an association between thrombophilia and renal allograft loss, and routine screening is not recommended.

Level of renal function and serum erythropoietin levels independently predict anaemia post-renal transplantation

Background. Post-renal transplant anaemia is a potentially reversible cardiovascular risk factor. Graft function, immunosuppressive agents and inhibition of the renin-angiotensin system have been implicated in its aetiology. The evaluation of erythropoietin (EPO) levels may contribute to understanding the relative contributions of these factors. Methods. Two-hundred and seven renal transplant recipients attending the Belfast City Hospital were studied. Clinical and laboratory data were extracted from the medical records and laboratory systems. Results. Of the 207 patients (126 male), 47 (22.7%) were found to be anaemic (males, haemoglobin (Hb) <12 g/dl, females Hb <11g/dl). The anaemic group had a significantly higher mean serum creatinine level (162.8 µmol/l vs 131.0 µmol/l, P <0.001) and lower mean estimated glomerular filtration rate (eGFR) (41.5 ml/min vs 54.9 ml/min, P <0.001) than the non-anaemic group. Individual immunosuppressive regimens were comparable between those with and those without anaemia. Angiotensin converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) administration was not more prevalent in those with anaemia compared with those without (36.2 vs 38.8, P = 0.88). There was a significant inverse correlation between Hb levels and serum EPO levels (R = -0.29, P <0.001), but not between EPO levels and eGFR (R = 0.02, P = 0.74). Higher EPO levels were predictive of anaemia, independent of eGFR in multivariate analysis. Conclusion. Anaemia is common in post-renal transplant patients. The levels of renal function and serum EPO and not immunosuppressive regimens or ACE-I/ARB use, are strong and independent predictors of anaemia. © The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Evaluation of Five Interleukin Genes for Association with End-Stage Renal Disease in White Europeans

Background: Genetic variation within interleukin genes has been reported to be associated with end-stage renal disease (ESRD). These findings have not been consistently replicated. No study has yet reported the comprehensive investigation of IL1A, IL1B, IL1RN, IL6 and IL10 genes. Methods: 664 kidney transplant recipients (cases) and 577 kidney donors (controls) were genotyped to establish if common variants in interleukin genes are associated with ESRD. Single nucleotide polymorphism (SNP) genotype data for each gene were downloaded for a northern and western European population from the International HapMap Project. Haploview was used to visualize linkage disequilibrium and select tag SNPs. Thirty SNPs were genotyped using MassARRAY (R) iPLEX Gold technology and data were analyzed using the chi(2) test for trend. Independent replication was conducted in 1,269 individuals with similar phenotypic characteristics. Results: Investigating all common variants in IL1A, IL1B, IL1RN, IL6 and IL10 genes revealed a statistically significant association (rs452204 p(empirical) = 0.02) with one IL1RN variant and ESRD. This IL1RN SNP tags three other variants, none of which have previously been reported to be associated with renal disease. Independent replication in a separate transplant population of comparable size did not confirm the original observation. Conclusions: Common variants in these five candidate interleukin genes are not major risk factors for ESRD in white Europeans. Copyright (C) 2010 S. Karger AG, Basel

Incidence, determinants and outcome of chronic kidney disease after adult heart transplantation in the United Kingdom

Background: We investigated the incidence of chronic kidney disease (CKD) in the United Kingdom heart transplant population, identified risk factors for the development of CKD, and assessed the impact of CKD on subsequent survival.

Methods: Data from the UK Cardiothoracic Transplant Audit and UK Renal Registry were linked for 1732 adult heart transplantations, 1996 to 2007. Factors influencing time to CKD, defined as National Kidney Foundation CKD stage 4 or 5 or preemptive kidney transplantation, were identified using a Cox proportional hazards model. The effects of distinct CKD stages on survival were evaluated using time-dependent covariates.

Results: A total of 3% of patients had CKD at transplantation, 11% at 1-year and more than 15% at 6 years posttransplantation and beyond. Earlier transplantations, shorter ischemia times, female, older, hepatitis C virus positive, and diabetic recipients were at increased risk of developing CKD, along with those with impaired renal function pretransplantation or early posttransplantation. Significant differences between transplantation centers were also observed. The risk of death was significantly higher for patients at CKD stage 4, stage 5 (excluding dialysis), or on dialysis, compared with equivalent patients surviving to the same time point with CKD stage 3 or lower (hazard ratios of 1.66, 8.54, and 4.07, respectively).

Conclusions: CKD is a common complication of heart transplantation in the UK, and several risk factors identified in other studies are also relevant in this population. By linking national heart transplantation and renal data, we have determined the impact of CKD stage and dialysis treatment on subsequent survival in heart transplant recipients.

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.

Early diagnosis improves survival in kidney cancer

Kidney cancers account for 2-3% of all adult malignancies in the UK. Men are predominantly affected by renal cancer with an average age at diagnosis of 64 years. Renal (or clear) cell carcinoma (RCC) accounts for 90% of kidney cancers. Early diagnosis improves survival with five-year survival rates for renal cancer of 70-94% for localised tumours in the UK. RCC should be suspected in the presence of localising symptoms such as flank pain, a loin mass or haematuria; constitutional upset including weight loss, pyrexia and/or night sweats; or with unexplained laboratory tests. Smoking, obesity and hypertension are the most important and most common risk factors. Environmental exposure to asbestos, cadmium and trichloroethylene are less common risk factors. Patients on chronic dialysis and renal transplant recipients are at increased risk of RCC in their native kidneys. If kidney cancer is suspected on history, physical examination or initial screening tests then a red flag ultrasound examination of the renal tracts should be requested. Dipstick urinalysis is of great value as asymptomatic haematuria may be the only abnormal test in the presence of non-specific symptoms such as weight loss or loin pain. Visible or non-visible haematuria, in the absence of proteinuria, suggests an underlying structural abnormality is present in the kidneys, ureters or bladder. Surgical removal of RCCs, where feasible, may result in cure in up to 40-60% of cases. Individuals too frail for major surgery may benefit from thermal ablation and cryotherapy. Agents that target the VEGF and mTOR pathways are considered first line in the treatment of metastatic RCC. Sunitinib, recommended by NICE, is administered orally and acts by inhibiting the VEGF receptor.

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.