A priori clinical diagnosis of CKD is defined as pre-WES clinical diagnosis per referral by primary nephrologist. CAKUT, congenital anomalies of the kidney and urinary tract; CKD, chronic kidney disease; ESKD, end-stage kidney disease; GN, glomerulonephritis; SRNS, steroid-resistant nephrotic syndrome; TIKD, tubulointerstitial kidney disease; WES, whole exome sequencing. a Age at first presentation to medical services with evidence of CKD. b Age at start of renal replacement therapy, i.e., dialysis or kidney transplantation. DM Connaughton et al.: Monogenic causation of chronic kidney disease in Ireland c l i n i c a l i n v e s t i g a t i o n Kidney International (2019) 95, 914-928 DM Connaughton et al.: Monogenic causation of chronic kidney disease in Ireland c l i n i c a l i n v e s t i g a t i o n
A specific biomarker that can separate active renal vasculitis from other causes of renal dysfunction is lacking, with a kidney biopsy often being required. Soluble CD163 (sCD163), shed by monocytes and macrophages, has been reported as a potential biomarker in diseases associated with excessive macrophage activation. Thus, we hypothesized that urinary sCD163 shed by crescent macrophages correlates with active glomerular inflammation. We detected sCD163 in rat urine early in the disease course of experimental vasculitis. Moreover, microdissected glomeruli from patients with small vessel vasculitis (SVV) had markedly higher levels of CD163 mRNA than did those from patients with lupus nephritis, diabetic nephropathy, or nephrotic syndrome. Both glomeruli and interstitium of patients with SVV strongly expressed CD163 protein. In 479 individuals, including patients with SVV, disease controls, and healthy controls, serum levels of sCD163 did not differ between the groups. However, in an inception cohort, including 177 patients with SVV, patients with active renal vasculitis had markedly higher urinary sCD163 levels than did patients in remission, disease controls, or healthy controls. Analyses in both internal and external validation cohorts confirmed these results. Setting a derived optimum cutoff for urinary sCD163 of 0.3 ng/mmol creatinine for detection of active renal vasculitis resulted in a sensitivity of 83%, specificity of 96%, and a positive likelihood ratio of 20.8. These data indicate that urinary sCD163 level associates very tightly with active renal vasculitis, and assessing this level may be a noninvasive method for diagnosing renal flare in the setting of a known diagnosis of SVV.
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 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 was the most significant predictor of time to posttransplant NMSC (adjusted P = 9.39 × 10 ; 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.
Pressure related complications such as abdominal wall hernias occur with relative frequency in patients on peritoneal dialysis. Less frequently, a transudative pleural effusion containing dialysate can develop. This phenomenon appears to be due to increased intra-abdominal pressure in the setting of congenital or acquired diaphragmatic defects. We report three cases of pleuroperitoneal leak that occurred within a nine-month period at our institution. We review the literature on this topic, and discuss management options. The pleural effusion resolved in one patient following drainage of the peritoneum and a switch to haemodialysis. One patient required emergency thoracocentesis. The third patient developed a complex effusion requiring surgical intervention. The three cases highlight the variability of this condition in terms of timing, symptoms and management. The diagnosis of a pleuroperitoneal leak is an important one as it is managed very differently to most transudative pleural effusions seen in this patient population. Surgical repair may be necessary in those patients who wish to resume peritoneal dialysis, or in those patients with complex effusions. Pleuroperitoneal leak should be considered in the differential diagnosis of a pleural effusion, particularly a right-sided effusion, in a patient on peritoneal dialysis.
Preeclampsia commonly complicates pregnancies after renal transplantation but is not associated with long-term renal dysfunction or graft loss.
We demonstrate high rates of r-FSGS and describe modest success from with treatments for r-FSGS.
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. Graphical abstract
Introduction: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of renal impairment resulting from mutations in the MUC1, UMOD, HNF1B, REN, and SEC61A1 genes. Neither the national or global prevalence of these diseases has been determined. We aimed to establish a database of patients with ADTKD in Ireland and report the clinical and genetic characteristics of these families. Methods: We identified patients via the Irish Kidney Gene Project and referral to the national renal genetics clinic in Beaumont Hospital who met the clinical criteria for ADTKD (chronic kidney disease, bland urinary sediment, and autosomal dominant inheritance). Eligible patients were then invited to undergo genetic testing by a variety of methods including panel-based testing, whole exome sequencing and, in five families who met the criteria for diagnosis of ADTKD but were negative for causal genetic mutations, we analyzed urinary cell smears for the presence of MUC1fs protein. Results: We studied 54 individuals from 16 families. We identified mutations in the MUC1 gene in three families, UMOD in five families, HNF1beta in two families, and the presence of abnormal MUC1 protein in urine smears in three families (one of which was previously known to carry the genetic mutation). We were unable to identify a mutation in 4 families (3 of whom also tested negative for urinary MUC1fs). Conclusions: There are 4443 people with ESRD in Ireland, 24 of whom are members of the cohort described herein. We observe that ADTKD represents at least 0.54% of Irish ESRD patients.
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