The HIDDEN Protocol: An Australian Prospective Cohort Study to Determine the Utility of Whole Genome Sequencing in Kidney Failure of Unknown Aetiology

Abstract

Early identification of genetic kidney disease allows personalised management, clarification of risk for relatives, and guidance for family planning. Genetic disease is underdiagnosed, and recognition of genetic disease is particularly challenging in patients with kidney failure without distinguishing diagnostic features. To address this challenge, the primary aim of this study is to determine the proportion of genetic diagnoses amongst patients with kidney failure of unknown aetiology, using whole genome sequencing (WGS). A cohort of up to 100 Australian patients with kidney failure of unknown aetiology, with onset <50 years old and approved by a panel of study investigators will be recruited via 18 centres nationally. Clinically accredited WGS will be undertaken with analysis targeted to a priority list of ∼388 genes associated with genetic kidney disease. The primary outcome will be the proportion of patients who receive a molecular diagnosis (diagnostic rate) via WGS compared with usual -care (no further diagnostic investigation). Participant surveys will be undertaken at consent, after test result return and 1 year subsequently. Where there is no or an uncertain diagnosis, future research genomics will be considered to identify candidate genes and new pathogenic variants in known genes. All results will be relayed to participants via the recruiting clinician and/or kidney genetics clinic. The study is ethically approved (HREC/16/MH/251) with local site governance approvals in place. The future results of this study will be disseminated and inform practical understanding of the potential monogenic contribution to kidney failure of unknown aetiology. These findings are anticipated to impact clinical practice and healthcare policy.Study Registration[https://dora.health.qld.gov.au], identifier [HREC/16/MH/251].

Uniform Manifold Approximation and Projection-based Assessment of Chronic Kidney Disease Aetiologies based on Urinary Peptidomics

“…Last, potential technique constraints (e.g. variants within promoter regions are undetected by whole exome sequencing) may also have to be considered when assessing the correspondent diagnostic yield of genetic tests, although in part these can be addressed, such as in the ongoing whole genome sequencing study by Soraru et al (2022) (34).…”

Genomic Testing in Patients with Kidney Failure of an Unknown Cause

“…The inclusion criteria required participants to have reached stage 5 CKD (eGFR <15 ml/min per 1.73 m 2 using CKD Epidemiology Collaboration equation) at the age of ≤50 years, with no identifiable cause for their CKD. 20 Exclusion criteria included participants with an existing kidney clinical or phenotypic diagnosis, including likely or proven diabetic nephropathy, renovascular disease, renal sarcoidosis, primary nephrotic-range proteinuric disorder, tuberculosis, paraproteinemia (except when excluded on kidney biopsy), exposure to nephrotoxin causing kidney dysfunction, obstructive uropathy, nephromegaly (>14 cm for adults; normagram for pediatric patients), and a family history of cystic kidneys or identified glomerular disorder on kidney biopsy that clarifies a diagnosis (Figure 1). The exclusion criteria also included isolated congenital anomaly of the kidney and urinary tract, which were excluded given the known relatively low yield of monogenic etiology (Figure 1).…”

Which patients with CKD will benefit from genomic sequencing? Synthesizing progress to illuminate the future

“…One area of substantial interest is whether or not broad genomic testing might have a diagnostic role in instances of otherwise unexplained CKD or kidney failure. At least two prospective studies are currently underway examining this question [ 27 , 28 ]. Whilst awaiting those prospective studies to report, new information from retrospective studies is adding evidence to this space.…”