Search

The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare large-effect variants in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD), while common low-impact variants strongly associate with kidney function and the risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in UMOD contribute to CKD. Here, candidate intermediate-effect UMOD variants were identified using large-population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations, patient samples, and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in the Genome Aggregation Database (gnomAD), with minor allele frequency (MAF) ranging from 10-5 to 10-3. Among them, the missense variant p.Thr62Pro is detected in ~1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD, and is associated with kidney failure in the 100,000 Genomes Project (odds ratio [OR] = 3.99 [1.84 to 8.98]) and the UK Biobank (OR = 4.12 [1.32 to 12.85). Compared with canonical ADTKD mutations, the p. Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD and an intermediate reduction of urinary uromodulin levels, in line with an intermediate trafficking defect in vitro and modest induction of endoplasmic reticulum (ER) stress. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD-associated kidney diseases and provides insights into the mechanisms of ADTKD and the genetic architecture of CKD. [ABSTRACT FROM AUTHOR]

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 genomicsequencing 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. [ABSTRACT FROM AUTHOR]

Socioeconomic status ( SES) has been linked to worse end-stage kidney disease survival. The effect of SES on survival on chronic dialysis, including the impact of transplantation, was examined. A retrospective, observational study investigated the association of SES with dialysis patient survival, with censoring at time of transplantation. Adult patients commencing dialysis from 1990 to 2009 in an Irish tertiary center received a spatial SES score using the 2011 Pobal Haase- Pratschke Deprivation Index and were compared by quartile. Cox proportional hazard models and Kaplan- Meier survival analysis examined any association of SES with survival. The 1794 patients included had a median follow-up of 3.8 years. Patients in the lowest SES area quartile were significantly younger than the highest, mean age 56.7 vs. 59 years, P = 0.006, respectively. There was no association between SES area score and survival in an unadjusted model (hazard ratio [ HR] 1.00, 95% confidence interval [ CI] 0.99-1.01). Survival in the highest SES area quartile was superior to the lowest SES in a multivariable adjusted model including age, gender, and dialysis modality ( HR 0.83, 95% CI 0.70-0.99, P = 0.04). These results were only mildly attenuated by censoring at time of transplantation (highest SES area quartile deprived vs. lowest SES area quartile, HR 0.85, 95% CI 0.70-1.03, P = 0.09). Superior patient survival was identified in the highest SES areas compared with the lowest following age-adjusted analyses, despite the older population in the most affluent areas. Further research should focus on identifying modifiable targets for intervention that account for this socioeconomic-related survival advantage. [ABSTRACT FROM AUTHOR]

Herein we present one of the largest single-center reports of the response of hemodialysis patients to a two-vaccine hepatitis B virus vaccination protocol in a European dialysis population. A hepatitis B recombinant DNA vaccine, HBvaxPRO®®, was given at a dose of 40 µµg intramuscularly using a four-dose schedule at 0, 1, 2, and 12 months. Responses were (1) a titer >100 mIU//mL == patient immune, (2) a titer level 10--99 mIU//mL == give a booster dose and recheck level 2 months later, and (3) 0 ££ 10 mIU//mL == repeat vaccination course using a different vaccine, Engerix-B®®. We compared responder groups in terms of titer levels for each vaccine and variables including age, gender, serum albumin, parathyroid hormone (PTH), calcium, phosphate, hemoglobin, years on dialysis, and type of dialysis access. Of the 176 patients who received the first vaccine course, 71 patients achieved immunity, that is, 40%% uptake for the first vaccine. Of the 105 who failed, 72 received the second vaccine with 46 responders, that is, 64%% uptake for the second vaccine. Overall, 143 of the 176 patients who entered the vaccination program completed the protocol with 117 achieving immunity, representing an 82%% success rate. The only variable overall to show significance in achieving seroconversion was serum albumin ( p == 0.03). Using a two-vaccine protocol, hepatitis B vaccination response was high in our population of end-stage renal disease patients. [ABSTRACT FROM AUTHOR]

Secondary hyperparathyroidism and abnormal calcium/phosphate balance are common complications of ESRD and significant cardiovascular risk factors. It has also been demonstrated that malnourished dialysis patients have a much higher mortality than well-nourished patients. There is a lack of research looking at combined mortality with altered mineral metabolism and a low serum albumin. Using our renal database, we analyzed outcomes on 1,007 chronic dialysis patients, commencing dialysis between January 1990 and December 2004. The association between median values of serum phosphate, calcium, albumin (between three and six months post-commencement of dialysis), and long-term survival was examined. Cox proportional hazards models were used to determine the combined effects of these variables on patient outcome. The results showed that 18% of patients had serum phosphorous >1.8 mmol/L (5.5 g/dL), and the five-year survival of these patients was 48.4% compared with 58.6% for those with a serum phosphorous <1.8 mmol/L (p = 0.047). For serum albumin, 34.9% had a value <35 g/L, and this group also had a highly significant risk of increased mortality (p < 0.001). When combined with corrected calcium, 40.9% of patients reached all three target levels and had the greatest long-term survival (five-year survival of 62.5% for all three targets reached, compared to 30.7% for 0 or 1 targets reached). Poor control of calcium/phosphorous balance appears to have long-term deleterious effects on patient survival in ESRD patients. This risk of death is increased by poor serum albumin levels reflecting inadequate nutrition. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background. Coronary artery disease(CAD) is prevalent among endstage renal failure patients and remains the major cause of mortality following renal transplantation. Death with a functioning transplant institute remains the most common cause of kidney graft failure. In this study we attempt to evaluate the effectiveness of the clinical history and current screening techniques available in predicting posttransplant CAD and also assess the role of coronary angiography as a pretransplant screening technique. METHODS: Clinical data of 190 renal transplant patients was analyzed. Any clinical history of cardiac disease and all preoperative cardiac screening data was recorded for each patient. The study endpoints were the subsequent development of myocardial infarction(MI), undergoing coronary artery bypass graft(CABG) or death. RESULTS: Factors that were significantly associated with reaching a study end-point included: age at transplant[Hazard Ratio(HR) 1.91, P < 0.001], history of heart failure(HR 8.22, P < 0.001), presence of CAD on coronary angiography(HR 5.55, P = 0.033), anterior Q wave on electrocardiograph{ECG}(HR 8.6, P < 0.001), carotid artery disease(HR 3.74, P = 0.030) and history of a cerebrovascular accident(HR of 4.32, P = 0.008). The screening techniques of exercise stress testing and echocardiography were not conclusive as predictive variables of outcome. CONCLUSION: Clinical history and ECG results are good, practical and low-cost screening methods. In our study exercise stress testing and echocardiography were found to be of limited value. Coronary angiography is appropriate in certain high-risk groups but not necessary as part of screening in all potential renal transplant recipients. [ABSTRACT FROM AUTHOR]

Introduction: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of chronic kidney disease (CKD) and end‐stage renal disease (ESRD). We aimed to compare renal transplant outcomes in people with ESRD due to ADTKD to those with other causes of renal failure. Methods: Patients with clinical characteristics consistent with ADTKD by the criteria outlined in the 2015 KDIGO consensus were included. We compared ADTKD transplant outcomes with those of 4633 non‐ADTKD renal transplant recipients. Results: We included 31 patients who met diagnostic criteria for ADTKD in this analysis, 23 of whom had an identified mutation (28 were categorized as definite‐ADTKD and 3 as suspected ADTKD). Five patients received a second transplant during follow‐up. In total, 36 grafts were included. We did not identify significant differences between groups in terms of graft or patient survival after transplantation. Twenty‐five transplant biopsies were performed during follow‐up, and none of these showed signs of recurrent ADTKD post‐transplant. Conclusion: In patients with ESRD due to ADTKD, we demonstrate that transplant outcomes are comparable with the general transplant population. There is no evidence that ADTKD can recur after transplantation. [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]