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

Purpose of review: This review will summarize and synthesize recent findings in regard to monogenic kidney disorders, including how that evidence is being translated into practice. It will add to existing key knowledge to provide context for clinicians in consolidating existing practice and approaches. Recent findings: Whilst there are long established factors, which indicate increased likelihood of identifying a monogenic cause for kidney disease, these can now be framed in terms of the identification of new genes, new indications for genomic testing and new evidence for clinical utility of genomic testing in nephrology. Further, inherent in the use of genomics in nephrology are key concepts including robust informed consent, variant interpretation and return of results. Recent findings of variants in genes related to complex or broader kidney phenotypes are emerging in addition to understanding of de novo variants. Phenocopy phenomena are indicating a more pragmatic use of broader gene panels whilst evidence is emerging of a role in unexplained kidney disease. Clinical utility is evolving but is being successfully demonstrated across multiple domains of outcome and practice. Summary: We provide an updated framework of evidence to guide application of genomic testing in chronic kidney disease (CKD), building upon existing principles and knowledge to indicate how the practice and implementation of this can be applied today. There are clearly established roles for genomic testing for some patients with CKD, largely those with suspected heritable forms, with these continuing to expand as new evidence emerges

Clinical versus research genomics in kidney disease

Key differences exist between clinical and research genomics. As genomic testing is adopted in nephrology clinical care, we propose focusing on clinical genomics approaches to obtain genetic diagnoses in order to ensure optimal use of resources and maximum patient benefit

Antenatally diagnosed ADPKD

[Extract] Advances in antenatal ultrasonographyhave substantially improved the counseling of pregnantwomen.1�4With this advancement comes a diagnosticdilemma in the approach to antenatal diagnoses of cystickidney disease. The differential diagnosis of enlargedcystic echogenic kidneys includes autosomal dominantpolycystic kidney disease (ADPKD), autosomal recessivepolycystic kidney disease, renal cysts and diabetessyndrome, and other syndromic disorders

Cellular milieu in clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is globally the most prevalent renal cancer. The cells of origin in ccRCC have been identified as proximal tubular epithelial cells (PTEC); however, the transcriptomic pathways resulting in the transition from normal to malignant PTEC state have remained unclear. Immunotherapy targeting checkpoints have revolutionized the management of ccRCC, but a sustained clinical response is achieved in only a minority of ccRCC patients. This indicates that our understanding of the mechanisms involved in the malignant transition and resistance to immune checkpoint therapy in ccRCC is unclear. This review examines recent single-cell transcriptomics studies of ccRCC to clarify the transition of PTEC in ccRCC development, and the immune cell types, states, and interactions that may limit the response to targeted immune therapy, and finally suggests stromal cells as key drivers in recurrent and locally invasive ccRCC. These and future single-cell transcriptomics studies will continue to clarify the cellular milieu in the ccRCC microenvironment, thus defining actional clinical, therapeutic, and prognostic characteristics of ccRCC

Association of polygenic scores with chronic kidney disease phenotypes in a longitudinal study of older adults

Risk of chronic kidney disease (CKD) is influenced by environmental and genetic factors and increases sharply in individuals 70 years and older. Polygenic scores (PGS) for kidney disease-related traits have shown promise but require validation in well-characterized cohorts. Here, we assessed the performance of recently developed PGSs for CKD-related traits in a longitudinal cohort of healthy older individuals enrolled in the Australian ASPREE randomized controlled trial of daily low-dose aspirin with CKD risk at baseline and longitudinally. Among 11,813 genotyped participants aged 70 years or more with baseline eGFR measures, we tested associations between PGSs and measured eGFR at baseline, clinical phenotype of CKD, and longitudinal rate of eGFR decline spanning up to six years of follow-up per participant. A PGS for eGFR was associated with baseline eGFR, with a significant decrease of 3.9 mL/min/1.73m2 (95% confidence interval -4.17 to -3.68) per standard deviation (SD) increase of the PGS. This PGS, as well as a PGS for CKD stage 3 were both associated with higher risk of baseline CKD stage 3 in cross-sectional analysis (Odds Ratio 1.75 per SD, 95% confidence interval 1.66-1.85, and Odds Ratio 1.51 per SD, 95% confidence interval 1.43-1.59, respectively). Longitudinally, two separate PGSs for eGFR slope were associated with significant kidney function decline during follow-up. Thus, our study demonstrates that kidney function has a considerable genetic component in older adults, and that new PGSs for kidney disease-related phenotypes may have potential utility for CKD risk prediction in advanced age

The Evolving Role of Diagnostic Genomics in Kidney Transplantation

Monogenic forms of heritable kidney disease account for a significant proportion of chronic kidney disease (CKD) across both pediatric and adult patient populations and up to 11% of patients under 40 years reaching end-stage kidney failure (KF) and awaiting kidney transplant. Diagnostic genomics in the field of nephrology is ever evolving and now plays an important role in assessment and management of kidney transplant recipients and their related donor pairs. Genomic testing can help identify the cause of KF in kidney transplant recipients and assist in prognostication around graft survival and rate of recurrence of primary kidney disease. If a gene variant has been identified in the recipient, at-risk related donors can be assessed for the same and excluded if affected. This paper aims to address the indications for genomic testing in the context for kidney transplantation, the technologies available for testing, the conditions and groups in which testing should be most often considered, and the role for the renal genetics multidisci-plinary team in this process

Participant Choice towards Receiving Potential Additional Findings in an Australian Nephrology Research Genomics Study

The choices of participants in nephrology research genomics studies about receiving additional findings (AFs) are unclear as are participant factors that might influence those choices. Methods: Participant choices and factors potentially impacting decisions about AFs were examined in an Australian study applying research genomic testing following uninformative diagnostic genetic testing for suspected monogenic kidney disease. Results: 93% of participants (195/210) chose to receive potential AFs. There were no statistically significant differences between those consenting to receive AFs or not in terms of gender (p = 0.97), median age (p = 0.56), being personally affected by the inherited kidney disease of interest (p = 0.38), or by the inheritance pattern (p = 0.12–0.19). Participants were more likely to choose not to receive AFs if the family proband presented in adulthood (p = 0.01), if there was family history of another genetic disorder (p = 0.01), and where the consent process was undertaken by an adult nephrologist (p = 0.01). Conclusion: The majority of participants in this nephrology research genomics study chose to receive potential AFs. Younger age of the family proband, family history of an alternate genetic disorder, and consenting by some multidisciplinary team members might impact upon participant choices

Cost-effectiveness of targeted exome analysis as a diagnostic test in glomerular diseases

Background: Despite the emergence of diagnostic and clinical utility evidence in nephrology, publicly funded access to genomic testing is restricted in most health care systems. To establish genomic sequencing as a clinical test, an evaluation of cost-effectiveness is urgently required. Methods: An economic evaluation, informed by a primary clinical study and available clinical evidence and guidelines in nephrology, was performed to evaluate the cost-effectiveness and optimal timing of exome sequencing (ES) in adults and children with suspected monogenic glomerular diseases compared with nongenomic investigations (NGIs). Six diagnostic strategies reflecting current practice and recommended models of care in Australia were modeled: (i) NGIs, (ii) late gene panel followed by ES, (iii) late ES, (iv) early gene panel, (v) early gene panel followed by ES, and (vi) early ES. Results: ES with targeted analysis achieved a diagnosis in 23 of 63 (36.5%) adults and 10 of 24 (41.6%) children. NGIs were estimated to diagnose 4.0% of children, with an average estimated cost of AU$6120 per child. Integrating ES as a first-line test in children was cost saving, with an incremental cost saving of AU$3230 per additional diagnosis compared with NGIs. In adults, NGIs was estimated to diagnose 8% of patients, with an average estimated cost of AU$1830 per person. In adults, integrating ES early resulted in an incremental cost per additional diagnosis of AU$5460 relative to NGIs. Conclusions: Early ES with targeted analysis was effective for diagnosing monogenic kidney disease, with substantial cost savings in children

La asociación : revista de primera enseñanza: Año XI Número 541 - (07/07/23)

There have been few new therapies for patients with chronic kidney disease in the last decade. However, the management of patients affected by genetic kidney disease is rapidly evolving. Inherited or genetic kidney disease affects around 10% of adults with end-stage kidney disease and up to 70% of children with early onset kidney disease. Advances in next-generation sequencing have enabled rapid and cost-effective sequencing of large amounts of DNA. Next-generation sequencing-based diagnostic tests now enable identification of a monogenic cause in around 20% of patients with early-onset chronic kidney disease. A definitive diagnosis through genomic testing may negate the need for prolonged diagnostic investigations and surveillance, facilitate reproductive planning and provide accurate counselling for at-risk relatives. Genomics has allowed the better understanding of disease pathogenesis, providing prognostic information and facilitating development of targeted treatments for patients with inherited or genetic kidney disease. Although genomic testing is becoming more readily available, there are many challenges to implementation in clinical practice. Multidisciplinary renal genetics clinics serve as a model of how some of these challenges may be overcome. Such clinics are already well established in most parts of Australia, with more to follow in future. With the rapid pace of new technology and gene discovery, collaboration between expert clinicians, laboratory and research scientists is of increasing importance to maximize benefits to patients and health-care systems

Per-treatment post-hoc analysis of clinical trial outcomes with Tolvaptan in autosomal dominant polycystic kidney disease

Introduction: In pivotal trials of patients with autosomal dominant polycystic kidney disease at risk of rapid progression, tolvaptan slowed estimated glomerular filtration rate (eGFR) decline in early-to-moderate (TEMPO 3:4 [NCT00428948]) and moderate-to-late stage (REPRISE [NCT02160145]) chronic kidney disease (CKD). Discontinuation was less frequent in REPRISE (15.0%) than TEMPO 3:4 (23.0%), given that in REPRISE, only subjects who tolerated tolvaptan 60/30 mg daily initiated the double-blind phase. We evaluated whether the greater treatment effect in REPRISE was attributable to different completion rates. Methods: We conducted post hoc analyses of TEMPO 3:4 and REPRISE completers, defined as subjects who took trial drug to the end of the treatment period in TEMPO 3:4 (3 years) or REPRISE (1 year). Efficacy (rate of change in eGFR for tolvaptan versus placebo) was analyzed as in each trial. Subjects from TEMPO 3:4 and REPRISE were also matched by propensity score for age, gender, and baseline eGFR to explore potential additional determinants of treatment effect. Results: The annualized tolvaptan treatment effect in TEMPO 3:4 completers (difference versus placebo of 0.98 mL/min/1.73 m2/year) and REPRISE completers (difference of 1.23) was similar to that of the respective total trial populations (TEMPO 3:4: 0.94; REPRISE: 1.27). The treatment effect of tolvaptan was also similar between matched subjects. Conclusion: Greater treatment completion rate did not drive greater treatment effect in REPRISE. The more advanced CKD of REPRISE subjects may be more relevant. More rapid decline in kidney function in later-stage CKD enabled the effects of tolvaptan to be more easily discerned