Adult presentation of a rare mitochondrial tRNA Val gene mutation-an expanding clinical phenotype.

BACKGROUND AND PURPOSE: Late-onset mitochondrial disorders are diagnostically challenging with significant heterogeneity in disease presentation. A case is reported of a 67-year-old gentleman who presented with a 3-month history of seizures, recurrent encephalopathy, ataxia and weight loss, preceded by recent initiation of haemodialysis for end-stage chronic kidney disease. METHODS: Extensive work-up including serological, cerebrospinal fluid, magnetic resonance imaging and electroencephalography was performed. Whole exome sequencing and muscle biopsy confirmed the diagnosis. RESULTS: Magnetic resonance imaging brain demonstrated a single non-enhancing T2 fluid attenuated inversion recovery hyperintense cortical/subcortical signal change in the right temporal lobe and cerebellar atrophy. Given the subacute presentation of uncertain aetiology, he was empirically treated for autoimmune/paraneoplastic encephalitis. Despite radiological resolution of the cortical abnormality 2 weeks later, there was no clinical improvement. Further collateral history unveiled a mildly ataxic gait and longstanding hearing loss suggestive of a genetic cause. Whole exome sequencing revealed a likely pathogenic, heteroplasmic mitochondrial DNA variant in the MT-TV gene, m.1659T>C, present at higher levels of heteroplasmy in muscle (91%) compared to other mitotic tissues. A high fat/protein diet and multivitamins including co-enzyme Q10 were commenced. Treatment of the nutritional deficiency and avoidance of intermittent fasting due to unreliable oral intake secondary to encephalopathy probably contributed to the clinical improvement seen over the ensuing few months, with resolution of his encephalopathy and return to his baseline gait and weight. CONCLUSION: An adult case is reported with an acute neurological presentation mimicking encephalitis, caused by a heteroplasmic m.1659T>C MT-TV variant, previously reported once in a child who displayed a different clinical phenotype.

Long-term renal function following radical cystectomy and ileal conduit creation.

BACKGROUND: Treatment for bladder cancer includes radical cystectomy (RC) and urinary diversion; RC is associated with long-term morbidity, kidney impairment and mortality. AIM: To identify risk factors associated with postoperative long-term kidney function and mortality. METHODS: Retrospective study of patients with RC and urinary diversion in Beaumont Hospital from 1996 to 2016. We included patients who had follow-up at least 2 years post-procedure. We assessed estimated glomerular filtration rate (eGFR) preoperatively and yearly post-procedure, dialysis commencement and mortality. Cox and Fine-Gray regression analyses were applied; p-value < 0.05 was considered significant. RESULTS: We included 264 patients, median age 68.3 years, 73.7% males. The most common diagnosis was bladder cancer 93.3%, TNM stages T ≥ 2 75.9%, N ≥ 1 47.6% and M1 28%. The median eGFR preoperative was 65.8 ml/min/1.73m2 and after 2 years 58.2 ml/min/1.73m2 (p: 0.009); 5.3% required chronic dialysis and 32.8% had a decrease > 10 ml/min/1.73m2. Risk factors associated with ESKD and start dialysis included younger age (HR: 0.90, CI 95% 0.87-0.94) and lower pre-operative eGFR (HR: 0.97, CI 95% 0.94-1.00). Overall mortality was 43.2% and 54.1% at 5 and 10 years, respectively; risk factors were older age (HR: 1.04, CI 95% 1.02-1.06), tumour stage T ≥ 2 (HR: 2.22, CI 95% 1.39-3.54) and no chemotherapy (HR: 1.72, CI 95% 1.18-2.51). Limitations include retrospective design, absence of control group and single centre experience. CONCLUSIONS: Patients with RC are at risk of progressive kidney function deterioration and elevated mortality and the main risk factors associated were age and preoperative eGFR. Regular monitoring of kidney function will permit early diagnosis and treatment.

High frequency and mortality of head and neck malignancy in organ transplant recipients in Ireland - A national cohort study.

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.

Persistent DNA damage underlies tubular cell polyploidization and progression to chronic kidney disease in kidneys deficient in the DNA repair protein FAN1.

Defective DNA repair pathways contribute to the development of chronic kidney disease (CKD) in humans. However, the molecular mechanisms underlying DNA damage-induced CKD pathogenesis are not well understood. Here, we investigated the role of tubular cell DNA damage in the pathogenesis of CKD using mice in which the DNA repair protein Fan1 was knocked out. The phenotype of these mice is orthologous to the human DNA damage syndrome, karyomegalic interstitial nephritis (KIN). Inactivation of Fan1 in kidney proximal tubule cells sensitized the kidneys to genotoxic and obstructive injury characterized by replication stress and persistent DNA damage response activity. Accumulation of DNA damage in Fan1 tubular cells induced epithelial dedifferentiation and tubular injury. Characteristic to KIN, cells with chronic DNA damage failed to complete mitosis and underwent polyploidization. In vitro and in vivo studies showed that polyploidization was caused by the overexpression of DNA replication factors CDT1 and CDC6 in FAN1 deficient cells. Mechanistically, inhibiting DNA replication with Roscovitine reduced tubular injury, blocked the development of KIN and mitigated kidney function in these Fan1 knockout mice. Thus, our data delineate a mechanistic pathway by which persistent DNA damage in the kidney tubular cells leads to kidney injury and development of CKD. Furthermore, therapeutic modulation of cell cycle activity may provide an opportunity to mitigate the DNA damage response induced CKD progression.

The utility of a genetic kidney disease clinic employing a broad range of genomic testing platforms: experience of the Irish Kidney Gene Project.

BACKGROUND AND AIMS: Genetic testing presents a unique opportunity for diagnosis and management of genetic kidney diseases (GKD). Here, we describe the clinical utility and valuable impact of a specialized GKD clinic, which uses a variety of genomic sequencing strategies. METHODS: In this prospective cohort study, we undertook genetic testing in adults with suspected GKD according to prespecified criteria. Over 7 years, patients were referred from tertiary centres across Ireland to an academic medical centre as part of the Irish Kidney Gene Project. RESULTS: Among 677 patients, the mean age was of 37.2 ± 13 years, and 73.9% of the patients had family history of chronic kidney disease (CKD). We achieved a molecular diagnostic rate of 50.9%. Four genes accounted for more than 70% of identified pathogenic variants: PKD1 and PKD2 (n = 186, 53.4%), MUC1 (8.9%), and COL4A5 (8.3%). In 162 patients with a genetic diagnosis, excluding PKD1/PKD2, the a priori diagnosis was confirmed in 58% and in 13% the diagnosis was reclassified. A genetic diagnosis was established in 22 (29.7%) patients with CKD of uncertain aetiology. Based on genetic testing, a diagnostic kidney biopsy was unnecessary in 13 (8%) patients. Presence of family history of CKD and the underlying a priori diagnosis were independent predictors (P < 0.001) of a positive genetic diagnosis. CONCLUSIONS: A dedicated GKD clinic is a valuable resource, and its implementation of various genomic strategies has resulted in a direct, demonstrable clinical and therapeutic benefits to affected patients.

Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype.

Autosomal dominant polycystic kidney disease (ADPKD), characterized by progressive cyst formation/expansion, results in enlarged kidneys and often end stage kidney disease. ADPKD is genetically heterogeneous; PKD1 and PKD2 are the common loci (∼78% and ∼15% of families) and GANAB, DNAJB11, and ALG9 are minor genes. PKD is a ciliary-associated disease, a ciliopathy, and many syndromic ciliopathies have a PKD phenotype. In a multi-cohort/-site collaboration, we screened ADPKD-diagnosed families that were naive to genetic testing (n = 834) or for whom no PKD1 and PKD2 pathogenic variants had been identified (n = 381) with a PKD targeted next-generation sequencing panel (tNGS; n = 1,186) or whole-exome sequencing (WES; n = 29). We identified monoallelic IFT140 loss-of-function (LoF) variants in 12 multiplex families and 26 singletons (1.9% of naive families). IFT140 is a core component of the intraflagellar transport-complex A, responsible for retrograde ciliary trafficking and ciliary entry of membrane proteins; bi-allelic IFT140 variants cause the syndromic ciliopathy, short-rib thoracic dysplasia (SRTD9). The distinctive monoallelic phenotype is mild PKD with large cysts, limited kidney insufficiency, and few liver cysts. Analyses of the cystic kidney disease probands of Genomics England 100K showed that 2.1% had IFT140 LoF variants. Analysis of the UK Biobank cystic kidney disease group showed probands with IFT140 LoF variants as the third most common group, after PKD1 and PKD2. The proximity of IFT140 to PKD1 (∼0.5 Mb) in 16p13.3 can cause diagnostic confusion, and PKD1 variants could modify the IFT140 phenotype. Importantly, our studies link a ciliary structural protein to the ADPKD spectrum.

Integration of genetic and histopathology data in interpretation of kidney disease.

For many years renal biopsy has been the gold standard for diagnosis in many forms of kidney disease. It provides rapid, accurate and clinically useful information in most individuals with kidney disease. However, in recent years, other diagnostic modalities have become available that may provide more detailed and specific diagnostic information in addition to, or instead of, renal biopsy. Genomics is one of these modalities. Previously prohibitively expensive and time consuming, it is now increasingly available and practical in a clinical setting for the diagnosis of inherited kidney disease. Inherited kidney disease is a significant cause of kidney disease, in both the adult and paediatric populations. While individual inherited kidney diseases are rare, together they represent a significant burden of disease. Because of the heterogenicity of inherited kidney disease, diagnosis and management can be a challenge and often multiple diagnostic modalities are needed to arrive at a diagnosis. We present updates in genomic medicine for renal disease, how genetic testing integrates with our knowledge of renal histopathology and how the two modalities may interact to enhance patient care.

Diagnostic utility of genetic testing in patients undergoing renal biopsy.

High-throughput DNA testing is becoming established as a standard diagnostic test in the renal clinic. Previously published studies on cohorts of patients with unexplained chronic kidney disease of a suspected genetic aetiology have suggested a diagnostic yield for genomic sequencing of up to 18%. Here we determine the yield of targeted gene panel in a clinically unscreened cohort of patients referred for percutaneous native renal biopsy. Patients who underwent renal biopsy for investigation of chronic kidney disease were sequenced using a genomic sequencing panel covering 227 genes in which variation is known to be associated with monogenic chronic kidney disease (CKD). Candidate disease-causing variants were assessed for pathogenicity using guidelines from the American College for Medical Genetics and Genomics. Fifty CKD patients were recruited and sequenced. A molecular diagnosis was obtained for two patients (4%). A molecular diagnosis is possible using genomic testing in ∼4% of clinically unscreened patients undergoing renal biopsy. Genetic screening may be useful for diagnosis in a subset of CKD patients but is most valuable when applied to patients with suspected heritable forms of kidney disease.

The impact of switching to mTOR inhibitor-based immunosuppression on long-term non-melanoma skin cancer incidence and renal function in kidney and liver transplant recipients.

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.

Cancer survival in kidney transplant recipients in Ireland.

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.

Polygenic risk score of non-melanoma skin cancer predicts post-transplant skin cancer across multiple organ types.

Polygenic risk scores (PRSs) calculated from genome-wide association studies (GWASs) of non-melanoma skin cancer (NMSC) in a general, non-transplant setting have recently been shown to predict risk of and time to post-renal transplant skin cancer. In this study, we set out to test these findings in a cohort of heart, lung, and liver transplant patients to see whether these scores could be applied across different organ transplant types. Using the PRS from Stapleton et al (2018), PRS was calculated for each sample across a European ancestry heart, lung, and liver transplant cohorts (n = 523) and tested as predictor of time to NMSC post-transplant. The top PRS, squamous cell carcinoma (SCC) pT1 x 10-5 , (n SNPs = 1953), SCC pT1 x 10-6 , and SCC pT1 x 10-6 (n SNPs = 1061) were significantly predictive in the time to NMSC, SCC, and basal cell carcinoma (BCC) analysis across organ (P = .006, .02, and .02, respectively). We observed here a similar direction of effect and effect size [NMSC HR = 1.31(1.08-1.59)] to that in the original discovery study with increased polygenic burden leading to a faster time to developing NMSC. In summary, we found that PRS of NMSC calculated from GWAS of NMSC in non-transplant populations independently replicated in this cohort of heart, lung, and liver transplant.

Utility of Genomic Testing after Renal Biopsy.

BACKGROUND: Renal biopsy is the mainstay of renal pathological diagnosis. Despite sophisticated diagnostic techniques, it is not always possible to make a precise pathological diagnosis. Our aim was to identify a genetic cause of disease in patients who had undergone renal biopsy and determine if genetic testing altered diagnosis or treatment. METHODS: Patients with suspected familial kidney disease underwent a variety of next-generation sequencing (NGS) strategies. The subset of these patients who had also undergone native kidney biopsy was identified. Histological specimens were reviewed by a consultant pathologist, and genetic and pathological diagnoses were compared. RESULTS: Seventy-five patients in 47 families underwent genetic sequencing and renal biopsy. Patients were grouped into 5 diagnostic categories based on pathological diagnosis: tubulointerstitial kidney disease (TIKD; n = 18); glomerulonephritis (GN; n = 15); focal segmental glomerulosclerosis and Alport Syndrome (n = 11); thrombotic microangiopathy (TMA; n = 17); and nonspecific pathological changes (n = 14). Thirty-nine patients (52%) in 21 families (45%) received a genetic diagnosis; 13 cases (72%) with TIKD, 4 (27%) with GN, 6 (55%) with focal segmental glomerulosclerosis/Alport syndrome, and 10 (59%) with TMA and 6 cases (43%) with nonspecific features. Genetic testing resulted in changes in understanding of disease mechanism in 21 individuals (54%) in 12 families (57%). Treatment would have been altered in at least 26% of cases (10/39). CONCLUSIONS: An accurate genetic diagnosis can result in changes in clinical diagnosis, understanding of pathological mechanism, and treatment. NGS should be considered as a complementary diagnostic technique to kidney biopsy in the evaluation of patients with kidney disease.

An Exome Sequencing Study of 10 Families with IgA Nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is a heterogeneous disorder with a strong genetic component. The advent of whole exome sequencing (WES) has accelerated the discovery of genetic risk factors underlying familial disorders. OBJECTIVES: We set out to test whether damaging variants in known kidney disease genes explain a proportion of IgAN cases recruited in Ireland. METHODS: We performed WES in 10 Irish families with multiple affected members having kidney disease where at least one member had biopsy confirmed IgAN. Candidate variants were identified based on being shared between affected family members, minor allele frequency, function and predicted pathogenicity. Pathogenicity of variants was determined according to American College of Medical Genetics and Genomics guidelines. RESULTS: We detected candidate variants in 3 of 10 families. We identified a likely pathogenic variant in COL4A5 in one family and a variant of unknown significance (VUS) in COL4A3 in another. Variants in COL4A5 and COL4A3 are known to cause Alport syndrome. In the third family, we identified a VUS in LMX1B, a gene associated with Nail-patella syndrome. CONCLUSIONS: We identified a number of cases of familial IgAN where the families harbored variants in known kidney disease-related genes indicating that potentially a number of cases of familial IgAN are mistaken for other familial kidney disorders. However, the majority of families studied did not carry a candidate variant in a known kidney disease causing gene indicating that there may be >1 underlying genetic mechanism present in these families.

Karyomegalic Interstitial Nephritis: Cancer Risk Following Transplantation.

A brother and sister presented individually in their forties with progressive renal failure, bronchiectasis and mild derangements of their liver function tests. Both developed end-stage renal disease before the age of 50. Both siblings were found to carry a pathogenic, recessive, compound heterozygote mutation in the gene FAN1, which causes karyomegalic interstitial nephritis. Both siblings underwent renal transplantation. The sister developed small cell carcinoma of the lung 18 months after transplantation. Despite intensive chemotherapy she died 6 months later. Six years after transplant, the brother has developed prostate cancer and over 30 individual skin cancers. To our knowledge, only 6 other patients with FAN1 mutations have undergone solid organ transplantation. Outcomes have been poor, with only 3 patients surviving beyond 1 year. While cancer is a significant risk for all patients in the post-transplant period, only 0.01% of patients develop >10 skin cancers. Transplantation may be an unrecognised risk in patients with FAN1 mutations.

Neutrophil gelatinase-associated lipocalin (NGAL) is localised to the primary cilium in renal tubular epithelial cells - A novel source of urinary biomarkers of renal injury.

BACKGROUND: Primary cilia have been shown to play a central role in regulating epithelial cell differentiation during injury and repair. Growing evidence implicates structural and functional abnormalities of primary cilia in kidney epithelial cells in the onset and development of various kidney diseases including polycystic kidney disease (PKD). Neutrophil-gelatinase associated lipocalin (NGAL) has been identified as a reliable urinary biomarker of kidney injury. However, the mechanism by which this protein accumulates in patient urine samples has not been fully elucidated. METHODS: Human renal tubular epithelial cells (RPTECs) were exposed to previously characterized deciliating agents to assess mechanisms of primary cilium loss. Confocal immunofluorescent imaging was employed to visualise the effects on cilia. Western blot analysis was utilised to quantify the ciliary protein Arl13b in both RPTEC whole cell lysates and supernatants. Co-immunoprecipitation was used to demonstrate co-localisation of Arl13b and NGAL in urinary samples from a clinical Chronic Allograft Nephropathy (CAN) cohort. RESULTS: Immunofluorescent analysis revealed that NGAL was localised to the primary cilium in RPTECs, co-localizing with a ciliary specific protein, Arl13b. Deciliation experiments showed that loss of the cilia coincided with loss of NGAL from the cells. CONCLUSION: The accumulation of NGAL in supernatants in vitro and in the urine of CAN patients was concurrent with loss of Arl13b, a specific ciliary protein. The findings of this study propose that increased NGAL urinary concentrations are directly linked to deciliation of the renal epithelial cells as a result of injury.

Post-transplant malignancy in solid organ transplant recipients in Ireland, The Irish Transplant Cancer Group.

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.

Variation in Nonmelanoma Skin Cancer Incidence by Treatment Modality Among Patients Receiving Multiple Kidney Transplants.

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.

Polygenic risk score as a determinant of risk of non-melanoma skin cancer in a European-descent renal transplant cohort.

Renal transplant recipients have an increased risk of non-melanoma skin cancer (NMSC) compared to in the general population. Here, we show polygenic risk scores (PRS) calculated from genome-wide association studies (GWAS) of NMSC in a general, nontransplant setting, can predict risk of, and time to posttransplant skin cancer. Genetic variants, reaching predefined P-value thresholds were chosen from published squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) nontransplant GWAS. Using these GWAS, BCC and SCC PRS were calculated for each sample across three European ancestry renal transplant cohorts (n = 889) and tested as predictors of case:control status and time to NMSC posttransplant. BCC PRS calculated at P-value threshold 1 × 10-5 was the most significant predictor of case:control status of NMSC posttransplant (OR = 1.61; adjusted P = .0022; AUC [full model adjusted for clinical predictors and PRS] = 0.81). SCC PRS at P-value threshold 1 × 10-5 was the most significant predictor of time to posttransplant NMSC (adjusted P = 9.39 × 10-7 ; HR = 1.41, concordance [full model] = 0.74). PRS of nontransplant NMSC is predictive of case:control status and time to NMSC posttransplant. These results are relevant to how genomics can risk stratify patients to help develop personalized treatment regimens.

Successful kidney transplantation normalizes platelet function.

BACKGROUND: Uraemic platelet dysfunction is not completely understood, in part due to non-physiological platelet function assays. We have developed a physiological flow-based assay that quantifies platelet function in microlitre volumes of blood under arterial shear. The aim of this study was to characterize platelet function before and after kidney transplantation. METHODS: Ten patients scheduled for living donor kidney transplant surgery and nine healthy controls were analysed using the assay. The motional parameters of platelet behaviour on von Willebrand factor (VWF) were recorded using customized platelet tracking software. The assay was repeated 3-8 weeks post-transplant in the transplant group and at an interval of >3 weeks in normal healthy volunteers. RESULTS: Platelet-VWF interactions were markedly reduced in the 10 pre-transplant patients compared with the healthy controls. In seven patients with immediate graft function, dynamic platelet function returned to normal (despite a small decrease in haemoglobin and haematocrit), but remained markedly abnormal in the three patients with delayed graft function (DGF). CONCLUSIONS: Dynamic platelet function returned to normal following transplantation in those with immediate graft function. This early improvement was not observed in those with DGF. There may be important clinical implications, as patients with DGF are more likely to undergo invasive procedures, including transplant biopsies and insertion of central venous catheters.