Genetic testing for kidney disease of unknown etiology

Hays, T. R.; Groopman, Emily; Gharavi, Ali G.

doi:10.1016/j.kint.2020.03.031

Cited by 51 publications

(53 citation statements)

References 101 publications

(137 reference statements)

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“…This idea has been supported by several recent studies that demonstrated significant diagnostic capabilities of genetic testing in patients with a variety of chronic kidney diseases. For example, genetic testing was shown to provide an accurate diagnosis in up to 40% of patients with kidney disease of unknown etiology [38]. Separately, recent gene sequencing studies have consistently demonstrated that variants in COL4A3 , COL4A4 , and COL4A5 commonly result in sporadic and familial adult FSGS, which should be identified as Alport syndrome based on the reclassification proposal [39, 40].…”

Section: Discussionmentioning

confidence: 99%

Study Design and Baseline Characteristics of the CARDINAL Trial: A Phase 3 Study of Bardoxolone Methyl in Patients with Alport Syndrome

et al. 2021

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Introduction: Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons (<5 per 10,000) in the European Union [1, 2]. It is the second most common inherited cause of kidney failure and is characterized by progressive loss of kidney function that often leads to end-stage kidney disease. Currently, there are no approved disease-specific agents for therapeutic use. We designed a phase 3 study (CARDINAL; NCT03019185) to evaluate the safety, tolerability, and efficacy of bardoxolone methyl in patients with Alport syndrome. Methods: The CARDINAL phase 3 study is an international, multicenter, double-blind, placebo-controlled, randomized registrational trial. Eligible patients were of ages 12–70 years with confirmed genetic or histologic diagnosis of Alport syndrome, eGFR 30–90 mL/min/1.73 m2, and urinary albumin to creatinine ratio (UACR) ≤3,500 mg/g. Patients with B-type natriuretic peptide values >200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to bardoxolone methyl or placebo, with stratification by baseline UACR. Results: A total of 371 patients were screened, and 157 patients were randomly assigned to receive bardoxolone methyl (n = 77) or placebo (n = 80). The average age at screening was 39.2 years, and 23 (15%) were <18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m2, and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was −4.9 mL/min/1.73 m2 despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy. Discussion/Conclusion: CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry.

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Section: Discussionmentioning

confidence: 99%

Study Design and Baseline Characteristics of the CARDINAL Trial: A Phase 3 Study of Bardoxolone Methyl in Patients with Alport Syndrome

et al. 2021

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“…Karyotyping directly visualizes the entire set of 46 chromosomes during prometaphase or metaphase with a high sensitivity for aneuploidies, large deletions and duplications, and translocations. CMA is more sensitive for the detection of microdeletions or microduplications that are over 20-400 kilobases (Kb) in size, but cannot detect balanced translocations or inversions [13][14][15] . CMA in combination with karyotype is the test of choice when a structural variant is clinically suspected, as in developmental delay and multiple congenital anomalies.…”

Section: Diagnostic Genetic Testing and Diagnostic Yieldmentioning

confidence: 99%

“…1. Approach to genetic testing in children with kidney disease, which is modified from the suggested algorithm for kidney disease of unknown etiology by Hay et al 15) . CAKUT, congenital anomalies of the kidney and urinary tract; CMA, chromosomal microarray; SNRS, steroid-resistant nephrotic syndrome; VUS, variants of unknown significance; WES, whole exome sequencing.…”

Section: Diagnostic Approach and Interpretation Of Genetic Testingmentioning

confidence: 99%

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Clinical Genetic Testing in Children with Kidney Disease

Kang¹,

Lee²

2021

Child Kidney Dis

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Chronic kidney disease, the presence of structural and functional abnormalities in the kidneys, is associated with a lower quality of life and increased morbidity and mortality in children. Genetic etiologies account for a substantial proportion of pediatric chronic kidney disease. With recent advances in genetic testing techni ques, an increasing number of genetic causes of kidney disease continue to be found. Genetic testing is recommended in children with steroid-resistant ne phro tic syndrome, congenital malformations of the kidney and urinary tract, cystic disease, or kidney disease with extrarenal manifestations. Diagnostic yields differ according to the category of clinical diagnosis and the choice of test. Here, we review the characteristics of genetic testing modalities and the implications of genetic testing in clinical genetic diagnostics.

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“…Knowledge of the underlying kidney disease is crucial for ESRD management in the context of transplantation, as the primary etiology may affect graft survival in terms of recurrence and or rejection 7 – 10 . Moreover, a genetic diagnosis may be of pivotal importance for family counseling and in the setting of kidney transplantation, particularly when living related donation is involved 9 , 11 .…”

Section: Introductionmentioning

confidence: 99%

An accessible insight into genetic findings for transplantation recipients with suspected genetic kidney disease

Wang

Xiang

et al. 2021

npj Genom. Med.

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Determining the etiology of end-stage renal disease (ESRD) constitutes a great challenge in the context of renal transplantation. Evidence is lacking on the genetic findings for adult renal transplant recipients through exome sequencing (ES). Adult patients on kidney transplant waitlist were recruited from 2017 to 2019. Trio-ES was conducted for the families who had multiple affected individuals with nephropathy or clinical suspicion of a genetic kidney disease owing to early onset or extrarenal features. Pathogenic variants were confirmed in 62 from 115 families post sequencing for 421 individuals including 195 health family members as potential living donors. Seventeen distinct genetic disorders were identified confirming the priori diagnosis in 33 (28.7%) families, modified or reclassified the clinical diagnosis in 27 (23.5%) families, and established a diagnosis in two families with ESRD of unknown etiology. In 14.8% of the families, we detected promising variants of uncertain significance in candidate genes associated with renal development or renal disease. Furthermore, we reported the secondary findings of oncogenes in 4.4% of the patients and known single-nucleotide polymorphisms associated with pharmacokinetics in our cohort to predict the drug levels of tacrolimus and mycophenolate. The diagnostic utility of the genetic findings has provided new clinical insight in most families that help with preplanned renal transplantation.

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Genetic testing for kidney disease of unknown etiology

Cited by 51 publications

References 101 publications

Study Design and Baseline Characteristics of the CARDINAL Trial: A Phase 3 Study of Bardoxolone Methyl in Patients with Alport Syndrome

Study Design and Baseline Characteristics of the CARDINAL Trial: A Phase 3 Study of Bardoxolone Methyl in Patients with Alport Syndrome

Clinical Genetic Testing in Children with Kidney Disease

An accessible insight into genetic findings for transplantation recipients with suspected genetic kidney disease

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