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Type 1 diabetes affects over nine million individuals globally, with approximately 40% developing diabetic kidney disease. Emerging evidence suggests that epigenetic alterations, such as DNA methylation, are involved in diabetic kidney disease. Here we assess differences in blood-derived genome-wide DNA methylation associated with diabetic kidney disease in 1304 carefully characterised individuals with type 1 diabetes and known renal status from two cohorts in the United Kingdom-Republic of Ireland and Finland. In the meta-analysis, we identify 32 differentially methylated CpGs in diabetic kidney disease in type 1 diabetes, 18 of which are located within genes differentially expressed in kidneys or correlated with pathological traits in diabetic kidney disease. We show that methylation at 21 of the 32 CpGs predict the development of kidney failure, extending the knowledge and potentially identifying individuals at greater risk for diabetic kidney disease in type 1 diabetes. Approximately 40 percent of people with type 1 diabetes develop kidney disease, but the risk factors are not well understood. Here, the authors identify DNA methylation signatures associated with diabetic kidney disease, of which 21 biomarkers predict the development of kidney failure. [ABSTRACT FROM AUTHOR]

Background Non-traditional cardiovascular risk factors, including calcium and phosphate derangement, may play a role in mortality in renal transplant. The data regarding this effect are conflicting. Our aim was to assess the impact of calcium and phosphate derangements in the first 90 days post-transplant on allograft and recipient outcomes. Methods We performed a retrospective cohort review of all-adult, first renal transplants in the Republic of Ireland between 1999 and 2015. We divided patients into tertiles based on serum phosphate and calcium levels post-transplant. We assessed their effect on death-censored graft survival and all-cause mortality. We used Stata for statistical analysis and did survival analysis and spline curves to assess the association. Results We included 1525 renal transplant recipients. Of the total, 86.3% had hypophosphataemia and 36.1% hypercalcaemia. Patients in the lowest phosphate tertile were younger, more likely female, had lower weight, more time on dialysis, received a kidney from a younger donor, had less delayed graft function and better transplant function compared with other tertiles. Patients in the highest calcium tertile were younger, more likely male, had higher body mass index, more time on dialysis and better transplant function. Adjusting for differences between groups, we were unable to show any difference in death-censored graft failure [phosphate = 1.14, 95% confidence interval (CI) 0.92–1.41; calcium = 0.98, 95% CI 0.80–1.20] or all-cause mortality (phosphate = 1.10, 95% CI 0.91–1.32; calcium = 0.96, 95% CI 0.81–1.13) based on tertiles of calcium or phosphate in the initial 90 days. Conclusions Hypophosphataemia and hypercalcaemia are common occurrences post-kidney transplant. We have identified different risk factors for these metabolic derangements. The calcium and phosphate levels exhibit no independent association with death-censored graft failure and mortality. [ABSTRACT FROM AUTHOR]

Background Transplantation is a well-known risk factor for malignancy. However, outcomes of cancer in transplant recipients compared with non-transplant recipients are less well studied. We aim to study the survival in kidney transplant recipients who develop cancer and compare this with cancer outcomes in the general population. Methods We linked data from the National Cancer Registry Ireland with the National Kidney Transplant Database. The period of observation was from 1 January 1994 until 31 December 2014. Transplant recipients were considered at risk from the time of diagnosing cancer. We administratively censored data at 10 years post-cancer diagnosis. Survival was compared with all patients in the general population that had a recorded diagnosis of cancer. Results There were 907 renal transplant recipients and 426679 individuals in the general population diagnosed with cancer between 1 January 1994 and 31 December 2014. In those with non-melanoma skin cancer, the hazard ratio (HR) for 10-year, all-cause mortality [HR = 3.06, 95% confidence interval (CI) 2.66–3.52] and cancer-specific mortality (HR = 3.91, 95% CI 2.57–5.96) was significantly higher among transplant recipients than the general population. Patients who developed non-Hodgkin lymphoma (HR = 2.89, 95% CI 1.96–4.25) and prostate cancer (HR = 4.32, 95% CI 2.39–7.82) had increased all-cause but not cancer-specific mortality. Colorectal, lung, breast and renal cell cancer did not show an increased risk of death in transplant recipients. Conclusion Cancer-attributable mortality is higher in kidney transplant recipients with non-melanoma skin cancer compared with non-transplant patients. The American Joint Committee on Cancer staging should reflect the increased hazard of death in these immunosuppressed patients. [ABSTRACT FROM AUTHOR]

Summary: It is often quoted that while short‐term graft survival in kidney transplantation has improved in recent years, it has not translated into a commensurate improvement in long‐term graft survival. We considered whether this was true of the entire experience of the national kidney transplant program in Ireland. A retrospective analysis of the National Kidney Transplant Service (NKTS) database was undertaken to investigate patient and graft survival for all adult first deceased donor kidney transplant recipients in Ireland, 1971–2015. Three thousand two hundred and sixty recipients were included in this study. Kaplan–Meier methods were used to estimate survival at each time period post transplant for the various eras of transplantation. Uncensored graft survival has improved over the course of the program in Ireland at various time points despite risk factors for graft failure progressively increasing over successive eras. For example the graft survival at 15 years post transplant has increased from 10% in 1971–1975 to 45% by 1996–2000. Ireland has experienced a progressive improvement in long‐term graft survival following kidney transplantation. Whether these trends are attributable to biological or nonbiological factors is unclear but likely involves a combination of both. [ABSTRACT FROM AUTHOR]

Background The Kidney Donor Risk Index (KDRI)/Kidney Donor Profile Index (KDPI) is relied upon for donor organ allocation in the USA, based on its association with graft failure in time-to-event models. However, the KDRI/KDPI has not been extensively evaluated in terms of predictive metrics for graft failure and allograft estimated glomerular filtration rate (eGFR) outside of the USA. Methods We performed a retrospective analysis of outcomes in the Irish National Kidney Transplant Service Registry for the years 2006–13. Associations of the KDRI/KDPI score with eGFR at various time points over the follow-up and ultimate graft failure were modelled. Results A total of 772 patients had complete data regarding KDRI/KDPI calculation and 148 of these allografts failed over the follow-up. The median and 25–75th centile for KDRI/KDPI was 51 (26–75). On repeated-measures analysis with linear mixed effects models, the KDRI/KDPI (fixed effect covariate) associated with eGFR over 5 years: eGFR = −0.25 (standard error 0.02; P < 0.001). The variability in eGFR mathematically accounted for by the KDRI/KDPI score was only 21%. The KDRI/KDPI score did not add significantly to graft failure prediction above donor age alone (categorized as > and <50 years of age) when assessed by the categorical net reclassification index. Conclusions In this cohort, while the KDRI/KDPI was predictive of eGFR over the follow-up, it did not provide additive discrimination above donor age alone in terms of graft failure prediction. Therefore it is unlikely to help inform decisions regarding kidney organ allocation in Ireland. [ABSTRACT FROM AUTHOR]

Aim Whether socioeconomic status confers worse outcomes after kidney transplantation is unknown. Its influence on allograft and patient survival following kidney transplantation in Ireland was examined. Methods A retrospective, observational cohort study of adult deceased-donor first kidney transplant recipients from 1990 to 2009 was performed. Those with a valid Irish postal address were assigned a socioeconomic status score based on the Pobal Hasse- Pratschke deprivation index and compared in quartiles. Cox proportional hazards models and Kaplan-Meier survival analysis were used to investigate any significant association of socioeconomic status with patient and allograft outcomes. Results A total of 1944 eligible kidney transplant recipients were identified. The median follow-up time was 8.2 years (interquartile range 4.4-13.3 years). Socioeconomic status was not associated with uncensored or death-censored allograft survival (hazard ratio ( HR) 1.0, 95% confidence interval ( CI) 0.99-1.00, P = 0.33 and HR 1.0, 95% CI 0.99-1.00, P = 0.37, respectively). Patient survival was not associated with socioeconomic status quartile ( HR 1.0, 95% CI 0.93-1.08, P = 0.88). There was no significant difference among quartiles for uncensored or death-censored allograft survival at 5 and 10 years. Conclusion There was no socioeconomic disparity in allograft or patient outcomes following kidney transplantation, which may be partly attributable to the Irish healthcare model. This may give further impetus to calls in other jurisdictions for universal healthcare and medication coverage for kidney transplant recipients. [ABSTRACT FROM AUTHOR]

Aim Apolipoprotein A- I amyloidosis is a rare, autosomal dominant disorder characterized by progressive accumulation of amyloid fibrils in tissues, leading to renal and hepatic disease. We describe the clinical manifestations and pathologic features of kidney disease in three Irish families. Methods This observational study examines all known cases of chronic kidney disease due to hereditary apolipoprotein A- I amyloidosis in Ireland. Patients were identified by physician interview. In all of the affected individuals the disease was caused by the Gly26Arg heterozygous mutation. Immunohistochemistry confirmed that amyloid deposits were composed of apolipoprotein A- I fibrils. Family trees and clinical data were obtained via analysis of patient medical records. Results The vast majority of affected cases had demonstrable kidney disease, with variable liver disease. Renal disease most commonly manifested as slowly progressive renal impairment with mild proteinuria. In one kindred, a severe, debilitating peripheral neuropathy was common among affected family members. Histology demonstrated tubulointerstitial fibrosis with amyloid deposition in the medulla. There was very high penetrance within affected families. Of five patients who were transplanted, one transplant was lost after 5 years due to recurrent disease. One patient died from sepsis shortly after transplant. Conclusion Hereditary apolipoprotein A- I amyloidosis is characterized by slowly progressive renal disease. Amyloid is deposited in the renal medulla highlighting the need to examine the medulla on renal biopsy. Overall, kidney transplantation conferred a survival advantage. [ABSTRACT FROM AUTHOR]

It has been suggested that the left kidney is easier to transplant than the right kidney because of the longer length of the left renal vein, facilitating the formation of the venous anastomosis. There are conflicting reports of differing renal allograft outcomes based on the side of donor kidney transplanted (left or right).We sought to determine the effect of side of donor kidney on early and late allograft outcome in our renal transplant population. We performed a retrospective analysis of transplanted left–right deceased donor kidney pairs in Ireland between January 1, 1998 and December 31, 2008. We used a time to death-censored graft failure approach for long-term allograft survival and also examined serum creatinine at different time points post-transplantation. All outcomes were included from day of transplant onwards. A total of 646 transplants were performed from 323 donors. The incidence of delayed graft function was 16.1% in both groups and there was no significant difference in acute rejection episodes or serum creatinine from 1 month to 8 years post-transplantation. There were 47 death-censored allograft failures in the left-sided group compared to 57 in the right-sided group ( P = 0.24). These observations show no difference in renal transplant outcome between the recipients of left- and right-sided deceased donor kidneys. [ABSTRACT FROM AUTHOR]

Context: The international cohort of hemodialysis patients is aging and increasing in number. Nephrologists have a therapeutic relationship with their patients that may span decades. Often overlooked components of chronic disease management include symptom control and assessment of health-related quality of life (HRQoL).Objectives: This study describes the symptom profile of a large cohort of patients with end-stage renal disease on hemodialysis in England and Ireland and evaluates how symptom burden and other factors influence quality-of-life scores.Methods: A prospective cross-sectional observational study of hemodialysis patients was conducted in Ireland and England during 2011 and 2012. Two validated clinical tools were used to determine HRQoL and symptom burden. Demographic and clinical data were examined, and regression analysis was used to determine associations with HRQoL scores.Results: A total of 893 patients on hemodialysis (mean [SD] age 64 [16] years) had a high symptom burden and poor HRQoL compared with population norms. Specifically, 64% of patients reported pain (95% confidence interval 61%-67%) and 79% reported weakness (95% confidence interval 75%-81%). A total of 43 percent of patients reported between six and 10 symptoms in the week preceding the survey. HRQoL was significantly and independently associated with poor mobility and pain and remained significant after adjusting for variations in clinical characteristics. Being listed on a transplant wait-list register was positively associated with HRQoL.Conclusion: These findings illustrate the high symptom burden and poor HRQoL of the hemodialysis population. Emphasis during clinical reviews on pain assessment and on assessing mobility plus interventions, such as pain management and physiotherapy/occupational therapy, are practical ways for renal teams to help improve patients' quality of life. [ABSTRACT FROM AUTHOR]

Background: Solid organ transplant recipients are recognized to carry a high burden of malignancy and frequently this cancer develops in the head and neck region. Furthermore, cancer of the head and neck post-transplant carries a significantly increased mortality. In this study, we aim to conduct a national retrospective cohort study to investigate the impact of head and neck cancer in terms of frequency and mortality in a large group of solid organ transplant recipients over a 20 year time span and compare the mortality in transplant patients to non-transplant patients with head and neck cancer., Methods: Patients in the Republic of Ireland who underwent solid organ transplantation between 1994 and 2014 who developed post-transplant head and neck malignancy were identified from the records of two prospective, national databases (National Cancer Registry of Ireland (NCRI) and The Irish Transplant Cancer Group database) working in conjunction with each other. Incidence of head and neck malignancy post-transplant was compared with the general population by means of standardised incidence ratios (SIR). Cumulative incidence of all cause and cancer related mortality from head and neck keratinocytic was undertaken by a competing risks analysis., Results: A total of 3346 solid organ transplant recipients were identified, 2382 (71.2 %) kidney, 562 (16.8 %) liver, 214 (6.4 %) cardiac and 188 (5.6 %) lung. During the period of follow up of 428 patients developed head and neck cancer, representing (12.8 %) of the population. 97 % of these patients developed keratinocytic cancers, specifically, of head and neck. The frequency of post-transplant head and neck cancer was related to the duration of immunosuppression with 14 % of patients developing cancer at 10 years and 20 % having developed at least one cancer by 15 years. 12 (3 %) patients developed non-cutaneous head and neck malignancy. 10 (0.3 %) patients died due to head and neck keratinocytic malignancy post-transplant. Competing risk analysis demonstrated that organ transplantation conferred a strong independent effect of death, compared to non-transplant patients with head and neck keratinocytes. This applied specifically for kidney (HR 4.4, 95 % CI 2.5-7.8) and heart transplants (HR 6.5, 95 % CI 2.1-19.9), and overall, across the four transplant categories (P < 0.001). The SIR of developing keratinocyte cancer varied based on primary tumor site, gender, and type of transplant organ., Conclusion: Transplant patients demonstrate a particularly high rate of head and neck keratinocyte cancer with a very high rate of associated mortality. Physicians should be cognizant of the increased rate of malignancy in this population and monitor for red flag signs/symptoms., (Copyright © 2023. Published by Elsevier Inc.)

Background: The survival of incident dialysis patients' end-stage kidney disease in some European and American has been reported to improve in modern era compared to earlier periods. However, in Ireland, this has not been well documented., Aim: To investigate the survival outcomes of incident end-stage kidney failure dialysis patients in a tertiary center over a 24-year period, 1993-2017., Methods: A retrospective analysis was carried out utilizing the Beaumont Hospital Renal Database. Consecutive adults with incident dialysis were analyzed. Kaplan-Meier methods and the estimated mean survival times were used to evaluate survival at successive 4-year periods of time., Results: In total, 2106 patients were included, of whom 830 underwent subsequent renal transplantation during follow-up. During the study period, from 1993 up to 2017, the mean patients' age increased from 56.3 ± 17.4 in 1993-1996 to 60.6 ± 18.3 in 2014-2017. There was an overall decrement in mortality over successive time intervals which were mirrored by the improvements in median survival after commencement of dialysis treatment from 6.14 years during 1993-1996 to 8.01 years during 2009-2012. Patients' survival has steadily improved, with the 5-year survival has risen over time, by almost 15%. This positive signal persisted and became more pronounced after adjusting Kaplan-Meier curve to age, where the 5-year survival estimates were exceeding 80% in 2014-2017., Conclusion: Survival rates among incident dialysis patients have improved progressively between 1993 and 2017 in Beaumont Hospital in Dublin, Ireland. The factors which led to this improvement are not entirely clear, but likely to be multifactorial., (© 2020. Royal Academy of Medicine in Ireland.)

Background: Solid organ transplantation is associated with increased risk of non-melanoma skin cancer. Studies with short follow up times have suggested a reduced occurrence of these cancers in recipients treated with mammalian target of rapamycin inhibitors as maintenance immunosuppression. We aimed to describe the occurrence of skin cancers in renal and liver transplant recipients switched from calcineurin inhibitor to sirolimus-based regimes. Methods: We performed a retrospective study of sirolimus conversion within the Irish national kidney and liver transplant programs. These data were linked with the National Cancer Registry Ireland to determine the incidence of NMSC among these recipients. The incidence rate ratio (IRR) for post versus pre-conversion NMSC rates are referred in this study as an effect size with [95% confidence interval]. Results: Of 4,536 kidney transplants and 574 liver transplants functioning on the 1 January 1994 or transplanted between 1 January 1994 and 01 January 1994 and 01 January 2015, 85 kidney and 88 liver transplant recipients were transitioned to sirolimus-based immunosuppression. In renal transplants, the rate of NMSC was 131 per 1000 patient years pre-switch to sirolimus, and 68 per 1000 patient years post switch, with adjusted effect size of 0.48 [0.31 - 0.74] ( p  = .001) following the switch. For liver transplant recipients, the rate of NMSC was 64 per 1,000 patient years pre-switch and 30 per 1,000 patient years post switch, with an adjusted effect size of 0.49 [0.22 - 1.09] ( p .081). Kidney transplant recipients were followed up for a median 3.4 years. Liver transplants were followed for a median 6.6 years. Conclusions: In this study, the conversion of maintenance immunosuppression from calcineurin inhibitors to mTOR inhibitors for clinical indications did appear to reduce the incidence of NMSC in kidney and liver transplant recipients.

Objective: Solid organ transplant recipients are at increased risk of cancer compared to the general population. To date, this risk in Ireland has not been investigated. We conducted a national registry study of cancer incidence following solid organ transplantation., Methods: National centers for solid organ transplantation supplied their respective registry databases to cross-reference with episodes of malignancy from the National Cancer Registry Ireland (NCRI) between 1994 and 2014. Standardized incidence of cancer post-transplant was compared to the general population by means of standardized incidence ratios (SIRs), and between solid organ transplant types by incidence rate ratios., Results: A total of 3346 solid organ transplant recipients were included in this study. Kidney transplant recipients constituted the majority of participants (71.2%), followed by liver (16.8%), heart (6.4%), and lung (5.6%) transplants. The most common cancers within the composite of all transplant recipients included the following (SIR [95% CI]): squamous and basal cell carcinoma (20.05 [17.97, 22.31] and 7.16 [6.43, 7.96], respectively), non-Hodgkin lymphoma (6.23 [4.26, 8.59]), and renal cell carcinoma (3.36 [1.96, 5.38])., Conclusions: This study reports the incidence of cancer following solid organ transplantation in Ireland. These results have significant national policy implications for surveillance, and early diagnosis in this patient group., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Importance: Existing data suggest that nonmelanoma skin cancer (NMSC) is more common in renal transplant recipients than in maintenance dialysis patients. However, whether the risk of NMSC varies as the treatment modality for end-stage kidney disease (ESKD) changes between dialysis and transplantation is not well described., Objective: To determine whether the incidence of NMSC is attenuated during periods of graft loss with a return to dialysis in those who receive multiple kidney transplants., Design, Setting, and Participants: Retrospective analysis of data from recipients of kidney transplants from the Irish National Kidney Transplant Service database, linked with the Irish Cancer Registry, from 1994 to 2014. All analysis took place between January 10, 2018 and March 31, 2018. Standardized incidence ratios (SIRs) were calculated for NMSC incidence in comparison with the general population using Irish census data as the denominator. Incidence of NMSC was calculated with modality of treatment for ESKD varying over time; incidence rates and rate ratios associated with dialysis intervals were calculated using Poisson regression; and disease was defined according to International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes for cancer diagnosis., Exposures: Kidney transplantation., Main Outcomes and Measures: Incidence rates per 1000 patient-years and incident rate ratios of NMSC after kidney transplant., Results: Data from the records of 3821 deceased or living donor kidney transplant recipients were assessed; 2399 (62.8%) male and 1422 (37.2%) female recipients; mean (SD) age at time of first data recorded, 41.9 (16.0) years. A total of 3433 recipients were included who had a functioning transplant on January 1, 1994, or received a transplant after that date up to December 31, 2014: 3215 received 1 transplant, 522 a second kidney transplant, and 84 had 3 or more kidney transplants. Periods of treatment with a functioning transplant were associated with a higher incidence of NMSC diagnosis than periods of graft failure: adjusted incidence rate ratio (aIRR), 2.19 (95% CI, 1.56-3.07), P < .001. The aIRRs of NMSC fell from 41.7 (95% CI, 39.38-44.15) per 1000 patient-years in the first transplant to 19.29 (95% CI, 13.41-27.76) in the dialysis period following the first allograft failure. Incidence similarly rose and fell following each subsequent consecutive transplant., Conclusions and Relevance: In recipients of multiple kidney transplants, while the incidence of NMSC fell during periods defined by transplant failure, there was residual elevated risk. While ascertainment bias may have contributed to the observed trends, the stagnant incidence of invasive cancer overall highlights the need for continued cancer surveillance during graft failure.

Approximately 500 monogenic causes of chronic kidney disease (CKD) have been identified, mainly in pediatric populations. The frequency of monogenic causes among adults with CKD has been less extensively studied. To determine the likelihood of detecting monogenic causes of CKD in adults presenting to nephrology services in Ireland, we conducted whole exome sequencing (WES) in a multi-centre cohort of 114 families including 138 affected individuals with CKD. Affected adults were recruited from 78 families with a positive family history, 16 families with extra-renal features, and 20 families with neither a family history nor extra-renal features. We detected a pathogenic mutation in a known CKD gene in 42 of 114 families (37%). A monogenic cause was identified in 36% of affected families with a positive family history of CKD, 69% of those with extra-renal features, and only 15% of those without a family history or extra-renal features. There was no difference in the rate of genetic diagnosis in individuals with childhood versus adult onset CKD. Among the 42 families in whom a monogenic cause was identified, WES confirmed the clinical diagnosis in 17 (40%), corrected the clinical diagnosis in 9 (22%), and established a diagnosis for the first time in 16 families referred with CKD of unknown etiology (38%). In this multi-centre study of adults with CKD, a molecular genetic diagnosis was established in over one-third of families. In the evolving era of precision medicine, WES may be an important tool to identify the cause of CKD in adults., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: IgA nephropathy is the most common primary glomerulonephritis worldwide and a significant cause of end-stage renal disease (ESRD). While most cases of IgA nephropathy are considered sporadic, familial cases have been reported., Methods: We performed a national audit of 1,809 patients attending renal clinics and dialysis units to identify a family history among patients with kidney disease. We reviewed all renal biopsies performed at our institution spanning a 30-year period. Paediatric cases were not included., Results: We identified 14 families involving 41 affected individuals with biopsy-proven IgA nephropathy and at least one other member with either biopsy-proven IgA nephropathy or ESRD. Detailed family histories were obtained, medical records reviewed and family pedigrees constructed. Retrospective application of the MESTC criteria to all familial IgA biopsies was performed. Seven families had 2 or more members with biopsy-proven IgA nephropathy, equating to 23 (1.8%) of 1,283 biopsies with IgA nephropathy over the last 30 years. A complex inheritance pattern was observed, with autosomal dominant and autosomal recessive families identified with varying penetrance. There was a male preponderance (68%), and a complex heterogeneity in the clinical and histopathological features of familial IgA patients (age range 16-60 years; creatinine range 60-350 μmol/L). We observed a high rate (66%) of progression to ESRD, with a mean time to progression of 5.13 years (SD 1.8 years; range 2-8 years). Among those patients who had undergone transplantation, recurrence of disease was reported in 5 (50%) cases., Conclusion: These data suggests familial aggregation of IgA nephropathy, confirm the clinical and histopathological heterogeneity and raise the possibility of monogenic inheritance., (© 2018 S. Karger AG, Basel.)

Aim: Long-term survival of renal allografts has improved over the last 20 years. However, less is known about current expectations for long-term allograft function as determined by estimated glomerular filtration rate (eGFR). The aim of this study was to investigate factors which affect graft function at 5 years' post-renal transplantation. The statistically significant factors were then used to construct a predictive model for expected eGFR at five years' post-transplant., Methods: We retrospectively reviewed all adult patients who received a renal transplant in the Republic of Ireland between 1990 and 2004. Data collected included era of transplantation (1990-1994, 1995-1999, 2000-2004), donor and recipient age and gender, number of human leucocyte antigen mismatches, cold ischemia time (CIT), number of prior renal transplants, immunosuppressive regimen used and acute rejection episodes. Estimated GFR was calculated at 5 years after transplantation from patient data using the Modified Diet in Renal Disease (MDRD) equation. Consecutive sampling was used to divide the study population into two equal unbiased groups of 489 patients. The first group (derivation cohort) was used to construct a predictive model for eGFR five years' post-transplantation, the second (validation cohort) to test this model., Results: Nine hundred and seventy eight patients were analyzed. The median age at transplantation was 43 years (range 18-78) and 620 (63.4%) were male. One hundred and seventy five patients (17.9%) had received a prior renal transplant. Improved eGFR at five years' post-transplantation was associated with tacrolimus-based combination immunosuppression, younger donor age, male recipient, absence of cytomegalovirus disease and absence of acute rejection episodes as independently significant factors (p < 0.05). The predictive model developed using these factors showed good correlation between predicted and actual median eGFR at five years. The model explained 20% of eGFR variability. The validation model findings were consistent with the derivation model (21% variability of eGFR explained by model using same covariates on new data)., Conclusion: The predictive model we have developed shows good correlation between predicted and actual median eGFR at five years' post-transplant. Applications of this model include comparison of current and future therapy options such as new immunosuppressive regimens.

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.

Background and Objectives: The term C3 glomerulopathy describes renal disorders characterized by the presence of glomerular deposits composed of C3 in the absence of significant amounts of Ig. On the basis of electron microscopy appearance, subsets of C3 glomerulopathy include dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). The full spectrum of histologic change observed in C3 glomerulopathy has yet to be defined and pathologic predictors of renal outcome within this patient population remain largely unknown. This study thus characterized a large C3 glomerulopathy cohort and identified clinicopathologic predictors of renal outcome., Design, Setting, Participants, & Measurements: All patients with kidney biopsies fulfilling criteria for C3 glomerulopathy from two quaternary renal centers within the United Kingdom and Ireland between 1992 and 2012 were retrospectively reviewed. We recorded histologic, demographic, and clinical data and determined predictors of ESRD using the Cox proportional hazards model., Results: Eighty patients with C3 glomerulopathy were identified: 21 with DDD and 59 with C3GN. Patients with DDD were younger, more likely to have low serum C3 levels, and more likely to have crescentic GN than patients with C3GN. Patients with C3GN were older and had more severe arteriolar sclerosis, glomerular sclerosis, and interstitial scarring than patients with DDD. Of 70 patients with available follow-up data, 20 (29%) progressed to ESRD after a median of 28 months. Age >16 years, DDD subtype, and crescentic GN were independent predictors of ESRD within the entire cohort. Renal impairment at presentation predicted ESRD only among patients with DDD., Conclusions: Although detailed serologic and genetic data are lacking, this study nevertheless identifies important clinicopathologic distinctions between patients with DDD and C3GN. These include independent predictors of renal outcome. If replicated in other cohorts, these predictors could be used to stratify patients, enabling application of emerging mechanism-based therapies to patients at high risk for poor renal outcome.

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.

Allograft thrombosis is a devastating early complication of renal transplantation that ultimately leads to allograft loss. We report here on our experience of nine cases of immediate re-transplantation following early kidney transplant thrombosis at a single centre between January 1990 and June 2009. The mean age was 42.9 years at time of transplant. For seven patients, the allograft thrombosis was their first kidney transplant and seven of the nine cases had a deceased donor transplant. The initial transplants functioned for a mean of 1.67 days and the patients received a second allograft at a mean of 3.1 days after graft failure. All of the re-transplants worked immediately. Four allografts failed after a mean of 52.5 months (2-155 months). Two of these died with a functioning allograft, one failed owing to chronic allograft nephropathy and one owing to persistent acute cellular rejection. The remaining five patients still have a functioning allograft after a mean of 101.8 months (7-187 months). One year allograft and patient survival after re-transplantation were 87.5% and 100% respectively (after 5 years, both were 57%). Immediate re-transplantation following early kidney transplant thrombosis can be a success. It may be considered in selected cases after allograft thrombosis., (© 2011 The Authors. Nephrology © 2011 Asian Pacific Society of Nephrology.)

Background: Delayed graft function (DGF) is a common complication in cadaveric kidney transplants affecting graft outcome. However, the incidence of DGF differs widely between centres as its definition is very variable. The purpose of this study was to define a parameter for DGF and immediate graft function (IGF) and to compare the graft outcome between these groups at our centre., Methods: The renal allograft function of 972 first cadaveric transplants performed between 1990 and 2001 in the Republic of Ireland was examined. The DGF and IGF were defined by a creatinine reduction ratio (CRR) between time 0 of transplantation and day 7 post-transplantation of <70 and >70%, respectively. Recipients with reduced graft function (DGF) not requiring dialysis were defined as slow graft function (SGF) patients. The serum creatinine at 3 months, 6 months, 1, 2 and 5 years after transplantation was compared between these groups of recipients. The graft survival rates at 1, 3 and 5 years and the graft half-life for DGF, SGF and IGF recipients were also assessed., Results: Of the 972 renal transplant recipients, DGF was seen in 102 (10.5%) patients, SGF in 202 (20.8%) recipients and IGF in 668 (68.7%) patients. Serum creatinine levels were significantly different between the three groups at 3 and 6 months, 1, 2 and 5 years. Graft survival at 5 years for the DGF patients was 48.5%, 60.5% for SGF recipients and 75% for IGF patients with graft half-life of 4.9, 8.7 and 10.5 years, respectively., Conclusion: This study has shown that the CRR at day 7 correlates with renal function up to 5 years post-transplantation and with long-term graft survival. We have also demonstrated that amongst patients with reduced graft function after transplantation, two groups with significantly different outcomes exist.

Graft survival in the autosomal dominant polycystic kidney disease (ADPKD) transplant population at our center was compared to other end stage renal disease (ESRD) transplant recipients (excluding diabetics). There were 1512 adult cadaveric renal transplants carried out at our center between 1989 and 2002. After exclusions, 1372 renal grafts were included in the study. Using Kaplan-Meier methods, patient and graft survival were determined and compared between the two groups. Mean age at transplant was significantly older for the ADPKD group of patients. The age adjusted graft survival at 5 years was 79% for ADPKD patients compared to 68% in the controls. Patient survival for ADPKD patients improved from 89% at 5 years to 95% when age adjusted. Using the Cox proportional hazards models to compare ADPKD with other causes of ESRD (including recipient age and other variables) in a multifactorial model, ADPKD was significant at the 5% level (p=0.036). This study demonstrates a graft and patient survival advantage in ADPKD patients when age-matched compared to other ESRD patients.