Clinical Genetic Screening in Adult Patients with Kidney Disease.
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ABSTRACT:
SUBMITTER: Cocchi E
PROVIDER: S-EPMC7536756 | biostudies-literature | 2020 Oct
REPOSITORIES: biostudies-literature
Publications
Clinical Genetic Screening in Adult Patients with Kidney Disease.
Cocchi Enrico E Cocchi Enrico E Nestor Jordan Gabriela JG Gharavi Ali G AG
Clinical journal of the American Society of Nephrology : CJASN 20200709 10
Expanded accessibility of genetic sequencing technologies, such as chromosomal microarray and massively parallel sequencing approaches, is changing the management of hereditary kidney diseases. Genetic causes account for a substantial proportion of pediatric kidney disease cases, and with increased utilization of diagnostic genetic testing in nephrology, they are now also detected at appreciable frequencies in adult populations. Establishing a molecular diagnosis can have many potential benefits ...[more]
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Project description:PurposeGenetic testing results are currently obtained approximately 1 year after referral to a medical genetics team for autosomal dominant polycystic kidney disease (ADPKD). We evaluated a mainstream genetic testing (MGT) pathway whereby the nephrology team provided pre-test counseling and selection of patients with suspected ADPKD for genetic testing prior to direct patient interaction by a medical geneticist.Sources of informationA multidisciplinary team of nephrologists, genetic counselors, and medical geneticists developed an MGT pathway for ADPKD using current testing criteria for adult patient with suspected ADPKD and literature from MGT in oncology.MethodsAn MGT pathway was assessed using a prospective cohort and compared to a retrospective cohort of 56 patients with ADPKD who received genetic testing using the standard, traditional pathway prior to implementing the MGT for ADPKD. The mainstream pathway was evaluated using time to diagnosis, diagnostic yield, and a patient survey to assess patient perceptions of the MGT pathway.Key findingsWe assessed 26 patients with ADPKD using the MGT and 18 underwent genetic testing with return of results. Of them, 52 patients had data available for analysis in the traditional control cohort. The time for return of results using our MGT pathway was significantly shorter with a median time to results of 6 months compared to 12 months for the traditional pathway. We identified causative variants in 61% of patients, variants of uncertain significance in 28%, and 10% had negative testing which is in line with expectations from the literature. The patient surveys showed high satisfaction rates with the MGT pathway.LimitationsThis report is an evaluation of a new genetic testing pathway restricted to a single, publicly funded health care center. The MGT pathway involved a prospective collection of a limited number of patients with ADPKD with comparison to a retrospective cohort of patients with ADPKD evaluated by standard testing.ImplicationsA MGT pathway using clearly defined criteria and commercially available gene panels for ADPKD can be successfully implemented in a publicly funded health care system to reduce the time required to obtain genetic results.
| S-EPMC8558595 | biostudies-literature
Project description:BackgroundMolecular mechanisms of kidney stone formation remain unknown in most patients. Previous studies have shown a high heritability of nephrolithiasis, but data on the prevalence and characteristics of genetic disease in unselected adults with nephrolithiasis are lacking. This study was conducted to fill this important knowledge gap.MethodsWe performed whole exome sequencing in 787 participants in the Bern Kidney Stone Registry, an unselected cohort of adults with one or more past kidney stone episodes [kidney stone formers (KSFs)] and 114 non-kidney stone formers (NKSFs). An exome-based panel of 34 established nephrolithiasis genes was analysed and variants assessed according to American College of Medical Genetics and Genomics criteria. Pathogenic (P) or likely pathogenic (LP) variants were considered diagnostic.ResultsThe mean age of KSFs was 47 ± 15 years and 18% were first-time KSFs. A Mendelian kidney stone disease was present in 2.9% (23/787) of KSFs. The most common genetic diagnoses were cystinuria (SLC3A1, SLC7A9; n = 13), vitamin D-24 hydroxylase deficiency (CYP24A1; n = 5) and primary hyperoxaluria (AGXT, GRHPR, HOGA1; n = 3). Of the KSFs, 8.1% (64/787) were monoallelic for LP/P variants predisposing to nephrolithiasis, most frequently in SLC34A1/A3 or SLC9A3R1 (n = 37), CLDN16 (n = 8) and CYP24A1 (n = 8). KSFs with Mendelian disease had a lower age at the first stone event (30 ± 14 versus 36 ± 14 years; P = .003), were more likely to have cystine stones (23.4% versus 1.4%) and less likely to have calcium oxalate monohydrates stones (31.9% versus 52.5%) compared with KSFs without a genetic diagnosis. The phenotype of KSFs with variants predisposing to nephrolithiasis was subtle and showed significant overlap with KSFs without diagnostic variants. In NKSFs, no Mendelian disease was detected and LP/P variants were significantly less prevalent compared with KSFs (1.8% versus 8.1%).ConclusionMendelian disease is uncommon in unselected adult KSFs, yet variants predisposing to nephrolithiasis are significantly enriched in adult KSFs.
| S-EPMC11483609 | biostudies-literature
Project description:BackgroundFabry disease (FD), an X-linked lysosomal storage disorder caused by a deficiency in alfa-galactosidase A (α-Gal A) activity due to mutations in the GLA gene, has a prevalence of 0-1.69% in patients undergoing haemodialysis; however, its prevalence in patients with chronic kidney disease (CKD) Stages 1-5 is unknown.MethodsSerum α-Gal A activity analysis and direct sequencing of GLA were used to screen for FD in 2122 male patients with CKD, including 1703 patients with CKD Stage 5D and 419 with CKD Stages 1-5. The correlation between serum α-Gal A activity and confounding factors in patients with CKD Stages 1-5 was evaluated.ResultsFD prevalence rates in patients with CKD Stage 5D and CKD Stages 1-5 were 0.06% (1/1703) and 0.48% (2/419), respectively. A patient with CKD Stage 5D exhibited a novel GLA mutation, p.Met208Arg, whereas two patients with CKD Stages 1-5 had c.370delG and p.Met296Ile. p. Met208Arg caused moderate structural changes in the molecular surface region near the substituted amino acid residue but did not affect the catalytic residues Asp170 and Asp231 in α-Gal A. Serum α-Gal A activity in patients with CKD Stages 1-5 was inversely correlated with age (P < 0.0001) but directly correlated with estimated glomerular filtration rate (P < 0.0001).ConclusionsFD prevalence was much higher in male patients with CKD Stages 1-5 than in those with CKD Stage 5D. FD screening in patients with CKD Stages 1-5 may improve patient survival, decreasing the number of patients with CKD Stage 5D.
| S-EPMC8719579 | biostudies-literature
Project description:Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a clinical entity defined by interstitial fibrosis with tubular damage, bland urinalysis and progressive kidney disease. Mutations in UMOD and MUC1 are the most common causes of ADTKD but other rarer (REN, SEC61A1), atypical (DNAJB11) or heterogeneous (HNF1B) subtypes have been described. Raised awareness, as well as the implementation of next-generation sequencing approaches, have led to a sharp increase in reported cases. ADTKD is now believed to be one of the most common monogenic forms of kidney disease and overall it probably accounts for ∼5% of all monogenic causes of chronic kidney disease. Through international efforts and systematic analyses of patient cohorts, critical insights into clinical and genetic spectra of ADTKD, genotype-phenotype correlations as well as innovative diagnostic approaches have been amassed during recent years. In addition, intense research efforts are addressed towards deciphering and rescuing the cellular pathways activated in ADTKD. A better understanding of these diseases and of possible commonalities with more common causes of kidney disease may be relevant to understand and target mechanisms leading to fibrotic kidney disease in general. Here we highlight recent advances in our understanding of the different subtypes of ADTKD with an emphasis on the molecular underpinnings and its clinical presentations.
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Project description:BackgroundChronic kidney disease (CKD) affects ∼10% of the adult population. The majority of patients with CKD are managed by primary care physicians, and despite the availability of effective treatment options, the use of evidence-based interventions for CKD in this setting remains suboptimal. Clinical pathways have been identified as effective tools to guide primary care physicians in providing evidence-based care. We aimed to describe the availability, characteristics and credibility of clinical pathways for adult CKD using a scoping review methodology.MethodsWe searched Medline, Embase, CINAHL and targeted Internet sites from inception to 31 October 2014 to identify studies and resources that identified adult CKD clinical pathways for primary care settings. Study selection and data extraction were independently performed by two reviewers.ResultsFrom 487 citations, 41 items were eligible for review: 7 published articles and 34 grey literature resources published between 2001 and 2014. Of the 41 clinical pathways, 32, 24 and 22% were from the UK, USA and Canada, respectively. The majority (66%, n = 31) of clinical pathways were static in nature (did not have an online interactive feature). The majority (76%) of articles/resources reported using one or more clinical practice guidelines as a resource to guide the clinical pathway content. Few articles described a dissemination and evaluation plan for the clinical pathway, but most reported the targeted end-users.ConclusionsOur scoping review synthesized available literature on CKD clinical pathways in the primary care setting. We found that existing clinical pathways are diverse in their design, content and implementation. These results can be used by researchers developing or testing new or existing clinical pathways and by practitioners and health system stakeholders who aim to implement CKD clinical pathways in clinical practice.
| S-EPMC5837585 | biostudies-literature
Project description:Background and objectivePrevious studies have reported a strong genetic contribution to kidney stone risk. This study aims to identify genetic associations of kidney stone disease within a large-scale electronic health record system.MethodsWe performed genome-wide association studies (GWASs) for nephrolithiasis from genotyped samples of 5571 cases and 83 692 controls. This analysis included a primary GWAS focused on nephrolithiasis and subsequent subgroup GWASs stratified by stone composition types. For significant risk variants, we performed association analyses with stone composition and first-time 24-h urine parameters. To assess disease severity, we investigated the associations with age at first stone diagnosis, age at first stone-related procedure, and time between first and second stone-related procedures.Key findings and limitationsThe primary GWAS analysis identified ten significant loci, all located on chromosome 16 within coding regions of the UMOD gene. The strongest signal was rs28544423 (odds ratio 1.17, 95% confidence interval 1.11-1.23, p = 2.7 × 10-9). In subgroup GWASs stratified by six kidney stone composition subtypes, 19 significant loci were identified including two loci in coding regions (brushite; NXPH1, rs79970906 and rs4725104). The UMOD single nucleotide polymorphism rs28544423 was associated with differences in 24-h excretion of urinary analytes, and the minor allele was positively associated with calcium oxalate dihydrate stone composition (p < 0.05). No associations were found between UMOD variants and disease severity. Limitations include an omitted variable bias and a misclassification bias.Conclusions and clinical implicationsWe replicated germline variants associated with kidney stone disease risk at UMOD and reported novel variants associated with stone composition. Genetic variants of UMOD are associated with differences in 24-h urine parameters and stone composition, but not disease severity.Patient summaryWe identify genetic variants linked to kidney stone disease within an electronic health record (EHR) system. These findings suggest a role for the EHR to enable a precision-medicine approach for stone disease.
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Project description:IntroductionChronic kidney disease (CKD) is a significant public health problem, with rising incidence and prevalence worldwide, and is associated with increased morbidity and mortality. Early identification and treatment of CKD can slow its progression and prevent complications, but it is not clear whether CKD screening is cost-effective. The aim of this study is to conduct a systematic review of the cost-effectiveness of CKD screening strategies in general adult populations worldwide, and to identify factors, settings and drivers of cost-effectiveness in CKD screening.MethodsStudies examining the cost-effectiveness of CKD screening in the general adult population were identified by systematic literature search on electronic databases (MEDLINE OVID, Embase, Cochrane Library and Web of Science) for peer-reviewed publications, hand-searched reference lists and grey literature of relevant sites, focusing on the following themes: (i) CKD, (ii) screening and (iii) cost-effectiveness. Studies comprising health economic evaluations performed for CKD screening strategies, compared with no CKD screening or usual-care strategy in adult individuals, were included. Study characteristics, model assumptions and CKD screening strategies of selected studies were identified. The primary outcome of interest is the incremental cost-effectiveness ratio (ICER) of CKD screening, in cost per quality-adjusted life year (QALY) and life-year gained (LYG), expressed in 2022 US dollars equivalent.ResultsTwenty-one studies were identified, examining CKD screening in general and targeted populations. The cost-effectiveness of screening for CKD was found to vary widely across different studies, with ICERs ranging from $113 to $430 595, with a median of $26 662 per QALY and from $6516 to $38 372, with a median of $29 112 per LYG. Based on the pre-defined cost-effectiveness threshold of $50 000 per QALY, the majority of the studies found CKD screening to be cost-effective. CKD screening was especially cost-effective in those with diabetes ($113 to $42 359, with a median of $27 471 per QALY) and ethnic groups identified to be higher risk of CKD development or progression ($23 902 per QALY in African American adults and $21 285 per QALY in Canadian indigenous adults), as indicated by a lower ICER. Additionally, the cost-effectiveness of CKD screening improved if it was performed in older adults, populations with higher CKD risk scores, or when setting a higher albuminuria detection threshold or increasing the interval between screening. In contrast, CKD screening was not cost-effective in populations without diabetes and hypertension (ICERs range from $117 769 to $1792 142, with a median of $202 761 per QALY). Treatment effectiveness, prevalence of CKD, cost of CKD treatment and discount rate were identified to be the most common influential drivers of the ICERs.ConclusionsScreening for CKD is especially cost-effective in patients with diabetes and high-risk ethnic groups, but not in populations without diabetes and hypertension. Increasing the age of screening, screening interval or albuminuria detection threshold, or selection of population based on CKD risk scores, may increase cost-effectiveness of CKD screening, while treatment effectiveness, prevalence of CKD, cost of CKD treatment and discount rate were influential drivers of the cost-effectiveness.
| S-EPMC10765095 | biostudies-literature
Project description:ObjectivesFabry's disease is an X-linked inherited, rare, progressive, lysosomal storage disorder, affecting multiple organs due to the deficient activity of α-galactosidase A (α-Gal A) enzyme. The prevalence has been reported to be 0.15-1% in hemodialysis patients; however, the information on the prevalence in chronic kidney disease not on dialysis is lacking. This study aimed to determine the prevalence of Fabry's disease in chronic kidney disease.MethodsThe patients older than 18 years, enclosing KDIGO 2012 chronic kidney disease definitions, not on dialysis, were enrolled. Dried blood spots on Guthrie papers were used to analyze α-Gal A enzyme and genetic analysis was performed in individuals with enzyme activity ≤1.2 μmol/L/h.ResultsA total of 1453 chronic kidney disease patients not on dialysis from seven clinics in Turkey were screened. The mean age of the study population was 59.3 ± 15.9 years. 45.6% of patients were female. The creatinine clearance of 77.3% of patients was below 60 mL/min/1.73 m2, 8.4% had proteinuria, and 2.5% had isolated microscopic hematuria. The mean value of patients' α-Gal A enzyme was detected as 2.93 ± 1.92 μmol/L/h. 152 patients had low levels of α-Gal A enzyme activity (≤1.2 μmol/L/h). In mutation analysis, A143T and D313Y variants were disclosed in three male patients. The prevalence of Fabry's disease in chronic kidney disease not on dialysis was found to be 0.2% (0.4% in male, 0.0% in female).ConclusionFabry's disease should be considered in the differential diagnosis of chronic kidney disease with unknown etiology even in the absence of symptoms and signs suggestive of Fabry's disease.
| S-EPMC6014365 | biostudies-literature
Project description:BackgroundPatients with autosomal dominant polycystic kidney disease (ADPKD) have an increased risk of cardiovascular morbidity and mortality. Impaired left ventricular (LV) global longitudinal strain (GLS) can be a sign of subclinical cardiac dysfunction even in patients with otherwise preserved ejection fraction (EF). Transmitral early filling velocity to early diastolic strain rate (E/SRe) is a novel measure of LV filling pressure, which is often affected early in cardiac disease.MethodsA total of 110 ADPKD patients not on dialysis were included in this prospective study. All patients underwent an extensive echocardiographic examination including two-dimensional speckle tracking. GLS and strain rates were measured. The distribution of GLS and E/SRe was determined and patient characteristics were compared by median levels of GLS (- 17.8%) and E/SRe (91.4 cm). Twenty healthy participants were included as control group.ResultsThere was a significantly worse GLS in the ADPKD patients (mean: - 17.8 ± 2.5%) compared to the healthy controls (mean: - 21.9 ± 1.9%), p < 0.001. The same was true for E/SRe (mean: 10.0 ± 0.3 cm) compared to the control group (mean: 6.5 ± 0.3 cm), p < 0.001. In simple logistic regression, male gender (OR: 4.74 [2.10-10.71], p < 0.001), fasting glucose (odds ratio (OR) 1.05 [1.01-1.10], p = 0.024), htTKV (OR: 1.07 [1.01-1.13], p = 0.013), HDL cholesterol (OR: 0.97 [0.94, 0.996], p = 0.025), triglycerides (OR: 1.01 [1.00-1.02], p = 0.039), hemoglobin (OR: 1.50 [1.11-2.04], p = 0.009), and β-blocker use (OR: 1.07 [1.01, 1.13], p = 0.013) were all associated with higher GLS. After multivariate logistic regression with backward model selection, only male gender (OR: 5.78 [2.27-14.71], p < 0.001) and β-blocker use (OR: 14.00 [1.60, 122.51], p = 0.017) remained significant. In simple logistic regression models, BMI (OR: 1.11 [1.02-1.20], p = 0.015), systolic blood pressure (OR: 1.03 [1.00-1.06], p = 0.027) and β-blocker use (OR: 17.12 [2.15-136.20], p = 0.007) were associated with higher E/SRe - a novel measure of left ventricular filling pressure. After backward elimination, only β-blocker use (OR: 17.22 [2.16, 137.14], p = 0.007) remained significant.ConclusionHigher GLS and E/SRe are common in ADPKD patients, even in patients with preserved eGFR and normal left ventricular EF. GLS and E/SRe may aid in cardiovascular risk stratification in patients with ADPKD as they represent early markers of cardiac dysfunction.
| S-EPMC6697983 | biostudies-literature
Project description:PURPOSE OF REVIEW:Calcium is an essential ion for the maintenance of normal bone health and physiologic functions. The extracellular and intracellular levels of calcium are maintained through hormonal regulation called homeostasis. Balance, the net intake minus excretion of calcium, is maintained by hormonal regulation of intestinal absorption and fecal/urinary excretion. Homeostasis and balance are disconnected in patients with chronic kidney disease (CKD). The purpose of this review is to understand how calcium homeostasis and balance are impaired in CKD. RECENT FINDINGS:Two formal calcium balance studies have found that an oral intake of 800-1000 mg of calcium in adults with CKD leads to neutral calcium balance, whereas amounts greater than that lead to positive calcium balance. In patients with CKD, the main determinant of positive calcium balance is the intake and the lack of urinary calcium excretion. SUMMARY:Calcium balance is different in patients with advanced CKD compared with patients without CKD. Thus, the oral intake of calcium in the form of diet and binders should not exceed 800-1000 mg/day to achieve neutral calcium balance in adult patients with CKD stages 3b/4.
| S-EPMC6454891 | biostudies-literature