Familial Variability of Disease Severity in Adult Patients With ADPKD.

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic nephropathy and has striking familial variability of disease severity. Methods: To better comprehend familial phenotypic variability, we analyzed clinical and pedigree data on 92 unrelated ADPKD kindreds with ≥2 affected individuals (N = 292) from an Irish population. All probands underwent genetic sequencing. Age at onset of kidney failure (KF), decline in estimated glomerular filtration rate (eGFR), predicting renal outcome in polycystic kidney disease (PROPKD) score, and imaging criteria were used to assess and grade disease severity as mild, intermediate, or severe. One mild and 1 severe case per family defined marked intrafamilial variability of disease severity. Results: Marked intrafamilial variability was observed in at least 13% of the 92 families, with a higher proportion of families carrying PKD1-nontruncating (PKD1-NT) variants. In families with ≥2 members affected by KF, the average intrafamilial age difference was 7 years, and there was no observed difference in intrafamilial variability of age at KF between allelic groups. The prespecified criteria showed marked familial variability in 7.7%, 8.4%, and 24% for age at KF, the PROPKD score, and imaging criteria, respectively. In our multivariate mixed-effects model, the intrafamilial variability in kidney survival was independent of the measured genotypic factors associated with prognosis and survival (P = <0.001). Conclusion: Using objective measures, we quantified marked intrafamilial variability in ADPKD disease phenotype in at least 13% of families. Our findings indicate that intrafamilial phenotypic variability remains incompletely understood and necessitates a more thorough identification of relevant clinical and genotypic factors.

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.

Outcomes of a Fatigue Management Intervention for People With Post COVID-19 Condition.

OBJECTIVE: Fatigue is identified as one of the most prevalent and persistent problems reported by people with post COVID-19 condition that negatively impacts on everyday living and resumption of pre-COVID-19 lifestyle. A pilot occupational therapy fatigue management intervention was designed for patients presenting with post COVID-19 condition fatigue. DESIGN: A retrospective analysis was carried out after the delivery of the fatigue management intervention. Self-reported measures of fatigue, well-being, and health status were taken at baseline and repeated at 2 wks after intervention. Baseline and postintervention scores were compared using nonparametric analysis. RESULTS: Sixty participants (73% female), median age 50.5 yrs (range, 17-74), 93% reporting symptoms persisting for 12 wks or longer, completed the fatigue management intervention. All participants reported moderate to severe fatigue impacting on everyday activity at baseline. The greatest impact of fatigue was on engagement in leisure and work activity. Statistically significant improvement in fatigue ( P < 0.001), well-being ( P < 0.001), and health status ( P < 0.001) were noted after the intervention. CONCLUSIONS: Findings indicate the potential of occupational therapy fatigue management interventions to enable self-management strategies and reduce the negative impact of fatigue among people with post COVID-19 condition.

Improving kidney care for people with severe mental health difficulties: a thematic analysis of twenty-two healthcare providers' perspectives.

Introduction: People with severe mental health difficulties (SMHDs) and concurrent kidney disease have less access to quality kidney care and worse clinical outcomes. Our research investigates the barriers and facilitators to effective kidney care for people with SMHDs, and how care might be improved for this underserved population. Methods: We conducted semi-structured interviews with twenty-two physical (n = 14) and mental (n = 8) healthcare professionals with experience working with people with SMHDs and concurrent kidney disease. Interview data were analysed and interpreted using reflexive thematic analysis. Results: Four themes were generated from the data: 1. "It's about understanding their limitations and challenges, without limiting their rights" describes how some people with SMHDs need additional support when accessing kidney care due to challenges with their mental state, motivation, cognitive difficulties, or mistrust of the healthcare system. 2. "There are people falling through the cracks" describes how the separation of physical and mental healthcare, combined with under-resourcing and understaffing, results in poorer outcomes for people with SMHDs. 3. "Psychiatry is a black spot in our continuing medical education" describes how many renal healthcare providers have limited confidence in their understanding of mental health and their ability to provide care for people with SMHDs. 4. "When they present to a busy emergency department with a problem, the staff tend to go '…psych patient"" describes how stigma towards people with SMHDs can negatively impact quality of care. Conclusion: Healthcare professionals accounts' describe how people with SMHDs and kidney disease can have favourable outcomes if they have appropriate hospital, community and social supports. Findings indicate that effective management of kidney disease for people with SMHDs requires integrated physical and mental health care, which takes an individualised "whole person" approach to addressing the interaction between kidney disease and mental health.

Pilot Study of a Wearable Hydration Monitor in Haemodialysis Patients: Haemodialysis Outcomes & Patient Empowerment Study 02.

Introduction: We aimed to assess the validity and reproducibility of a wearable hydration device in a cohort of maintenance dialysis patients. Methods: We conducted a prospective, single-arm observational study on 20 haemodialysis patients between January and June 2021 in a single centre. A prototype wearable infrared spectroscopy device, termed the Sixty device, was worn on the forearm during dialysis sessions and nocturnally. Bioimpedance measurements were performed 4 times using the body composition monitor (BCM) over 3 weeks. Measurements from the Sixty device were compared with the BCM overhydration index (litres) pre- and post-dialysis and with standard haemodialysis parameters. Results: 12 out of 20 patients had useable data. Mean age was 52 ± 12.4 years. The overall accuracy for predicting pre-dialysis categories of fluid status using Sixty device was 0.55 [K = 0.00; 95% CI: -0.39-0.42]. The accuracy for the prediction of post-dialysis categories of volume status was low [accuracy = 0.34, K = 0.08; 95% CI: -0.13-0.3]. Sixty outputs at the start and end of dialysis were weakly correlated with pre- and post-dialysis weights (r = 0.27 and r = 0.27, respectively), as well as weight loss during dialysis (r = 0.31), but not ultrafiltration volume (r = 0.12). There was no difference between the change in Sixty readings overnight and the change in Sixty readings during dialysis (mean difference 0.09 ± 1.5 kg), [t(39) = 0.38, p = 0.71]. Conclusion: A prototype wearable infrared spectroscopy device was unable to accurately assess changes in fluid status during or between dialysis sessions. In the future, hardware development and advances in photonics may enable the tracking of interdialytic fluid status.

Mitochondrial ROS Triggers KIN Pathogenesis in FAN1-Deficient Kidneys.

Karyomegalic interstitial nephritis (KIN) is a genetic adult-onset chronic kidney disease (CKD) characterized by genomic instability and mitotic abnormalities in the tubular epithelial cells. KIN is caused by recessive mutations in the FAN1 DNA repair enzyme. However, the endogenous source of DNA damage in FAN1/KIN kidneys has not been identified. Here we show, using FAN1-deficient human renal tubular epithelial cells (hRTECs) and FAN1-null mice as a model of KIN, that FAN1 kidney pathophysiology is triggered by hypersensitivity to endogenous reactive oxygen species (ROS), which cause chronic oxidative and double-strand DNA damage in the kidney tubular epithelial cells, accompanied by an intrinsic failure to repair DNA damage. Furthermore, persistent oxidative stress in FAN1-deficient RTECs and FAN1 kidneys caused mitochondrial deficiencies in oxidative phosphorylation and fatty acid oxidation. The administration of subclinical, low-dose cisplatin increased oxidative stress and aggravated mitochondrial dysfunction in FAN1-deficient kidneys, thereby exacerbating KIN pathophysiology. In contrast, treatment of FAN1 mice with a mitochondria-targeted ROS scavenger, JP4-039, attenuated oxidative stress and accumulation of DNA damage, mitigated tubular injury, and preserved kidney function in cisplatin-treated FAN1-null mice, demonstrating that endogenous oxygen stress is an important source of DNA damage in FAN1-deficient kidneys and a driver of KIN pathogenesis. Our findings indicate that therapeutic modulation of kidney oxidative stress may be a promising avenue to mitigate FAN1/KIN kidney pathophysiology and disease progression in patients.

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.

High rates of psychological distress, mental health diagnoses and suicide attempts in people with chronic kidney disease in Ireland.

BACKGROUND: People with chronic kidney disease (CKD) experience high levels of psychological distress, which is associated with higher mortality and adverse health outcomes. Little is known about the rates of a range of mental health difficulties or rates of suicide attempts in people with CKD. METHODS: Individuals with CKD (n = 268; age range 18-94 years, mean = 49.96 years) on haemodialysis (n = 79), peritoneal dialysis (n = 46), transplant recipients (n = 84) and who were not on renal replacement therapy (RRT; n = 59) were recruited through the Irish Kidney Association social media pages and three Irish hospitals. Participants completed surveys to gather demographics and mental health histories, the Hospital Anxiety and Depression Scale (HADS) and the 12-item Short Form Health Survey (SF-12) to measure health-related quality of life (HRQoL). RESULTS: A total of 23.5% of participants self-reported they had received a mental health diagnosis, with depression (14.5%) and anxiety (14.2%) being the most common, while 26.4% of participants had experienced suicidal ideation and 9.3% had attempted suicide. Using a clinical cut-off ≥8 on the HADS subscales, current levels of clinically significant anxiety and depression were 50.7% and 35.4%, respectively. Depression levels were slightly higher for those on haemodialysis compared with those with a transplant and those not on RRT. Depression, anxiety and having a mental health diagnosis were all associated with lower HRQoL. CONCLUSIONS: People with CKD in Ireland experience high levels of psychological distress, mental health difficulties, suicidal ideation and suicide attempts. The identification of and intervention for mental health difficulties in CKD should be prioritised in clinical care.

Clinical and genetic characteristics of Dent's disease type 1 in Europe.

BACKGROUND: Dent's disease type 1 (DD1) is a rare X-linked nephropathy caused by CLCN5 mutations, characterized by proximal tubule dysfunction, including low molecular weight proteinuria (LMWP), hypercalciuria, nephrolithiasis-nephrocalcinosis, progressive chronic kidney disease (CKD) and kidney failure (KF). Current management is symptomatic and does not prevent disease progression. Here we describe the contemporary DD1 picture across Europe to highlight its unmet needs. METHODS: A physician-based anonymous international e-survey supported by several European nephrology networks/societies was conducted. Questions focused on DD1 clinical features, diagnostic procedure and mutation spectra. RESULTS: A total of 207 DD1 male patients were reported; clinical data were available for 163 with confirmed CLCN5 mutations. Proteinuria was the most common manifestation (49.1%). During follow-up, all patients showed LMWP, 66.4% nephrocalcinosis, 44.4% hypercalciuria and 26.4% nephrolithiasis. After 5.5 years, ≈50% of patients presented with renal dysfunction, 20.7% developed CKD stage ≥3 and 11.1% developed KF. At the last visit, hypercalciuria was more frequent in paediatric patients than in adults (73.4% versus 19.0%). Conversely, nephrolithiasis, nephrocalcinosis and renal dysfunction were more prominent in adults. Furthermore, CKD progressed with age. Despite no clear phenotype/genotype correlation, decreased glomerular filtration rate was more frequent in subjects with CLCN5 mutations affecting the pore or CBS domains compared with those with early-stop mutations. CONCLUSIONS: Results from this large DD1 cohort confirm previous findings and provide new insights regarding age and genotype impact on CKD progression. Our data strongly support that DD1 should be considered in male patients with CKD, nephrocalcinosis/hypercalciuria and non-nephrotic proteinuria and provide additional support for new research opportunities.

Adrenal insufficiency is common amongst kidney transplant recipients receiving maintenance prednisolone and can be predicted using morning cortisol.

BACKGROUND: Long-term glucocorticoid therapy is a key component of immunosuppression for kidney transplant recipients (KTRs), leading to significant cumulative glucocorticoid exposure. The aims of this study are to investigate the prevalence of adrenal insufficiency (AI) in KTRs taking prednisolone and to develop a screening algorithm to identify patients at the highest risk of AI. METHODS: In this cross-sectional cohort study, 67 KTRs receiving prednisolone underwent a short synacthen test (SST) and measurement of cumulative glucocorticoid exposure. RESULTS: A total of 72% (n = 48) of participants failed the SST. Participants with AI had a higher daily prednisolone dose (4.9 versus 4.2 mg/day; P = .002) and greater cumulative glucocorticoid exposure (289 versus 111 mg/kg; P = .03) than those with intact adrenal function. Participants with AI had lower baseline cortisol than participants with intact adrenal function (143 versus 303 nmol/L; P < .001). Morning cortisol of >288 nmol/L predicted a normal SST with 100% specificity [95% confidence interval (CI) 92-100] and 70% sensitivity (95% CI 56-78%), therefore excluding AI. CONCLUSIONS: Our results suggest KTRs are at a higher risk for AI than previously reported. A morning serum cortisol measurement is a useful screening tool in this cohort, reducing the need for stimulatory testing by 44%. KTRs with AI need education regarding glucocorticoid sick rules, similar to patients with other forms of AI.

Rare disease gene association discovery from burden analysis of the 100,000 Genomes Project data.

To discover rare disease-gene associations, we developed a gene burden analytical framework and applied it to rare, protein-coding variants from whole genome sequencing of 35,008 cases with rare diseases and their family members recruited to the 100,000 Genomes Project (100KGP). Following in silico triaging of the results, 88 novel associations were identified including 38 with existing experimental evidence. We have published the confirmation of one of these associations, hereditary ataxia with UCHL1 , and independent confirmatory evidence has recently been published for four more. We highlight a further seven compelling associations: hypertrophic cardiomyopathy with DYSF and SLC4A3 where both genes show high/specific heart expression and existing associations to skeletal dystrophies or short QT syndrome respectively; monogenic diabetes with UNC13A with a known role in the regulation of ß cells and a mouse model with impaired glucose tolerance; epilepsy with KCNQ1 where a mouse model shows seizures and the existing long QT syndrome association may be linked; early onset Parkinson's disease with RYR1 with existing links to tremor pathophysiology and a mouse model with neurological phenotypes; anterior segment ocular abnormalities associated with POMK showing expression in corneal cells and with a zebrafish model with developmental ocular abnormalities; and cystic kidney disease with COL4A3 showing high renal expression and prior evidence for a digenic or modifying role in renal disease. Confirmation of all 88 associations would lead to potential diagnoses in 456 molecularly undiagnosed cases within the 100KGP, as well as other rare disease patients worldwide, highlighting the clinical impact of a large-scale statistical approach to rare disease gene discovery.

Epigenome-wide meta-analysis identifies DNA methylation biomarkers associated with diabetic kidney disease.

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.

Investigating the Relationship between Multiple Mini-Interview Communication Skills Outcomes and First-Year Communication Skills Performance and Reflections in Students at the Ontario Veterinary College.

An important outcome for veterinary education is ensuring that graduates can provide an appropriate level of care to patients and clients by demonstrating core competencies such as communication skills. In addition, accreditation requirements dictate the need to assess learning outcomes and may drive the motivation to incorporate relevant and appropriate methods of entry assessments for incoming students. Predicting the success of Doctor of Veterinary Medicine (DVM) students based on entry assessment performance has been scantly investigated and can be challenging. Specifically, no research presently exists on predicting DVM students' first-year performance in relation to communication skills at the time of program entry. Objectives of this exploratory study were to investigate (a) the relationship between communication skills outcomes from multiple mini-interview (MMI) data and first-year academic performance related to communication and (b) the relationship between communication skills outcomes from MMI data and self-reported first-year communication reflections. A retrospective single-class study was conducted. Data were analyzed using descriptive statistics, correlation statistics, regression models, and paired t-tests to identify relationships among variables. Paired t-tests showed that students felt more prepared to meet second-year expectations over first-year expectations. Spearman's correlation revealed an association between MMI communication scores and one pre-year 1 survey question related to professionalism. Noo relationships were observed between MMI communication scores and marks from a self-reflection assignment in a communications course, or grades from a clinical medicine course that included clinical communication. The merit for further exploration of the relationship between communication competencies and student performance is discussed.

Interventions for increasing immunosuppressant medication adherence in solid organ transplant recipients.

BACKGROUND: Non-adherence to immunosuppressant therapy is a significant concern following a solid organ transplant, given its association with graft failure. Adherence to immunosuppressant therapy is a modifiable patient behaviour, and different approaches to increasing adherence have emerged, including multi-component interventions. There has been limited exploration of the effectiveness of interventions to increase adherence to immunosuppressant therapy. OBJECTIVES: This review aimed to look at the benefits and harms of using interventions for increasing adherence to immunosuppressant therapies in solid organ transplant recipients, including adults and children with a heart, lung, kidney, liver and pancreas transplant. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 14 October 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs), quasi-RCTs, and cluster RCTs examining interventions to increase immunosuppressant adherence following a solid organ transplant (heart, lung, kidney, liver, pancreas) were included. There were no restrictions on language or publication type. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles and abstracts of identified records, evaluated study quality and assessed the quality of the evidence using the GRADE approach. The risk of bias was assessed using the Cochrane tool. The ABC taxonomy for measuring medication adherence provided the analysis framework, and the primary outcomes were immunosuppressant medication initiation, implementation (taking adherence, dosing adherence, timing adherence, drug holidays) and persistence. Secondary outcomes were surrogate markers of adherence, including self-reported adherence, trough concentration levels of immunosuppressant medication, acute graft rejection, graft loss, death, hospital readmission and health-related quality of life (HRQoL). Meta-analysis was conducted where possible, and narrative synthesis was carried out for the remainder of the results. MAIN RESULTS: Forty studies involving 3896 randomised participants (3718 adults and 178 adolescents) were included. Studies were heterogeneous in terms of the type of intervention and outcomes assessed. The majority of studies (80%) were conducted in kidney transplant recipients. Two studies examined paediatric solid organ transplant recipients. The risk of bias was generally high or unclear, leading to lower certainty in the results. Initiation of immunosuppression was not measured by the included studies. There is uncertain evidence of an association between immunosuppressant medication adherence interventions and the proportion of participants classified as adherent to taking immunosuppressant medication (4 studies, 445 participants: RR 1.09, 95% CI 0.95 to 1.20; I² = 78%). There was very marked heterogeneity in treatment effects between the four studies evaluating taking adherence, which may have been due to the different types of interventions used. There was evidence of increasing dosing adherence in the intervention group (8 studies, 713 participants: RR 1.14, 95% CI 1.03 to 1.26, I² = 61%).  There was very marked heterogeneity in treatment effects between the eight studies evaluating dosing adherence, which may have been due to the different types of interventions used. It was uncertain if an intervention to increase immunosuppressant adherence had an effect on timing adherence or drug holidays. There was limited evidence that an intervention to increase immunosuppressant adherence had an effect on persistence. There was limited evidence that an intervention to increase immunosuppressant adherence had an effect on secondary outcomes. For self-reported adherence, it is uncertain whether an intervention to increase adherence to immunosuppressant medication increases the proportion of participants classified as medically adherent to immunosuppressant therapy (9 studies, 755 participants: RR 1.21, 95% CI 0.99 to 1.49; I² = 74%; very low certainty evidence). Similarly, it is uncertain whether an intervention to increase adherence to immunosuppressant medication increases the mean adherence score on self-reported adherence measures (5 studies, 471 participants: SMD 0.65, 95% CI -0.31 to 1.60; I² = 96%; very low certainty evidence). For immunosuppressant trough concentration levels, it is uncertain whether an intervention to increase adherence to immunosuppressant medication increases the proportion of participants who reach target immunosuppressant trough concentration levels (4 studies, 348 participants: RR 0.98, 95% CI 0.68 to 1.40; I² = 40%; very low certainty evidence). It is uncertain whether an intervention to increase adherence to immunosuppressant medication may reduce hospitalisations (5 studies, 460 participants: RR 0.67, 95% CI 0.44 to 1.02; I² = 64%; low certainty evidence). There were limited, low certainty effects on patient-reported health outcomes such as HRQoL. There was no clear evidence to determine the effect of interventions on secondary outcomes, including acute graft rejection, graft loss and death. No harms from intervention participation were reported. AUTHORS' CONCLUSIONS: Interventions to increase taking and dosing adherence to immunosuppressant therapy may be effective; however, our findings suggest that current evidence in support of interventions to increase adherence to immunosuppressant therapy is overall of low methodological quality, attributable to small sample sizes, and heterogeneity identified for the types of interventions. Twenty-four studies are currently ongoing or awaiting assessment (3248 proposed participants); therefore, it is possible that findings may change with the inclusion of these large ongoing studies in future updates.

An intermediate-effect size variant in UMOD confers risk for chronic kidney disease.

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.

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.

Complexities in diagnosing and treating endophthalmitis in the post stem cell transplant setting.

Endophthalmitis is a rare but sight-threatening manifestation of systemic infection. Immunosuppression is a well-recognised risk factor for development of endophthalmitis. Determining the aetiology can be complex, particularly in the context of immunosuppression, we present the diagnostic and treatment dilemmas associated with a patient who complains of blurred vision 2 weeks following an allogeneic stem cell transplant for refractory Hodgkin's disease. We demonstrate that in the context of immunosuppression post stem cell transplantation, a broad differential should be maintained until a microbiological diagnosis can be confirmed. In particular, we evaluate how clinical suspicion can diverge from typical fundoscopic findings in the diagnosis of endophthalmitis.

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.