Design and evaluation of a visual genomic explainer: a mixed-methods study.

OBJECTIVE: To design and assess a visual genomic explainer focusing on plain language and engaging imagery. The explainer aimed to support doctors' comprehension of complex genomic concepts and results and act as a resource promoting the integration of genomic testing into mainstream care. DESIGN: Prospective genomic resource development and questionnaire. SETTING: Regional and tertiary hospitals in Australia and Ireland, private and community-based clinicians in Australia. PARTICIPANTS: Recruitment of paediatricians and nephrologists in Australia and paediatricians in Ireland was multi-faceted. Emails with survey links were circulated through training bodies, advanced trainee networks, departmental heads, and professional societies. MAIN OUTCOME MEASURES: Comprehension, engagement and perception of the visual explainer. RESULTS: Most clinicians surveyed (95% (53) Australian group, 100% (29) Irish group) felt that genomics would be a useful tool in their practice. 77% of Australian paediatric respondents and 73% of Irish paediatric respondents felt that genomics was underutilised. Challenges encountered with genomic testing included poor patient comprehension of the testing process and results along with difficulties perceived by clinicians in explaining complex results. 89% of Australian paediatricians and 100% of Irish paediatricians surveyed would recommend the use of the explainer to other professionals in their field. CONCLUSION: This genomic resource was acceptable to clinicians and could be a useful tool to support paediatricians integrating genomic testing into mainstream care.

Defining childhood hypertension: is it too complicated? An evaluation of the potential impact of different approaches in an Australian paediatric population.

OBJECTIVES: Current American Academy of Pediatrics (AAP) and European Society of Hypertension (ESH) thresholds defining hypertension in children use blood pressure (BP) normalised to age, sex and height. However, scare data exists regarding the relative importance of these variables to accurately model the 95th quantile of BP. We hypothesised that height alone may fit the population data equally well compared to more complex definitions. We also compare the potential impact of various thresholds for defining hypertension in an Australian population. METHODS: Longitudinal data from the Raine Study were used, with 2248 participants contributing 7479 valid BP values across the 3/5/10/14/17-year study visits. BP was measured after 5 min rest, ≥3 times at each visit, using a Dinamap device. Quantile regression was used to predict the 95th percentile of BP, with nonlinear modelling of covariates through restricted cubic spline terms. RESULTS: At a single visit, 6-16% of young children exceeded the ESH threshold and 12-23% the AAP threshold. The transition to fixed thresholds (≥13 years AAP, ≥16 years ESH), increased the number of males (AAP only) and reduced the number of females considered hypertensive. A quantile regression model constructed with Raine Study data using height-only as the explanatory variable better predicted BP than the respective model using age-only (or a combination of the two). CONCLUSIONS: There may be large differences in the prevalence of hypertension according to AAP and ESH criteria, with a marked sex-discrepancy emerging from the point of fixed threshold application in adolescence. It may not be necessary to normalise BP by both age and height, the latter being a better predictor of childhood BP. Simpler methods may be preferable in clinical practice but require validation against clinical outcomes.

Shaping the future of kidney genetics in Australia: proceedings from the KidGen policy implementation workshop 2023.

The KidGen Collaborative's Policy Implementation Workshop 2023 celebrated the 10th anniversary of Australia's first kidney genetics clinic in Brisbane. This event marked the establishment of a national network now comprising 19 kidney genetics clinics across Australia, all dedicated to providing equitable access to genomic testing for families affected by genetic kidney diseases. The workshop reflected on past progress and outlined future objectives for kidney genetics in Australia, recognising the collaborative efforts of clinical teams, researchers, and patients. Key insights from the workshop are documented in the proceedings.

Noninvasive pediatric blood pressure assessment: exploring the clinicians' perspective.

BACKGROUND: Obtaining accurate and reliable blood pressure (BP) readings in pediatric patients is challenging, given difficulties in adhering to measurement guidelines, limited device validation and variable patient cooperation. This study aimed to investigate clinicians' perspectives surrounding noninvasive pediatric BP assessment to identify opportunities for improvement in BP technology and clinical practice. METHOD: Based on an adapted version of the extended Technology Acceptance Model 2, semi-structured interviews were conducted with clinicians involved in noninvasive pediatric BP assessment in a major Australian children's hospital. Transcripts were analyzed thematically and guided by Technology Acceptance Model 2. RESULTS: Clinician responses ( n  = 20) revealed that poor patient tolerance of BP measurement resulting from excessive cuff inflation is a major hindrance to reliable pediatric BP assessment. Clinicians described low trust in BP readings from automated devices, often relating to poor patient tolerance to cuff inflation, thereby diminishing the clinical utility of these readings in informing treatment decisions. Auscultatory measurement was regarded as more trustworthy and better tolerated, but less convenient to perform as compared with oscillometric measurement. CONCLUSION: A dissonance exists between (1) low trust and clinical utility of the most common and easy-to-use BP measurement approach (automated devices), versus (2) higher trust and clinical utility, but efficiency and user-related impediments, for the auscultatory method. Based on our results, we have developed the Blood Pressure Acceptance Model, which can be used to explain and predict clinicians' acceptance of BP technology. Further work is needed to improve the tolerability and accuracy of automated BP devices in real-world pediatric settings.

A decision-making framework for genomic testing in paediatric nephrology.

AIM: Technological advances and increased access have led to genomics expanding beyond the genetics clinic. Consequently, nephrologists can now order genomic testing for their patients. Consistent decision-making around patient and test selection is required to ensure equitable access while maximising the utility of genomic testing. However, there are currently no frameworks to guide decision-making for testing in this context. We aimed to develop an ethical decision-making framework for genomic testing in paediatric nephrology. METHODS: A three-stage approach was used: (i) review of the literature on decision-making for genomic testing in nephrology and other disciplines; (ii) ethnographic observation of approaches to genomic testing in the general nephrology and renal genetics clinics at an Australian paediatric hospital; (iii) review and revision of the framework with key stakeholders, including clinical geneticists, genetic counsellors, paediatric nephrologists and families from the renal genetics service. The initial framework was modified until consensus from key stakeholders was reached. RESULTS: A decision-making framework was created with questions designed to explore the impact of genomic testing on patient management, clinical validity, patient characteristics, alternatives to genomic testing, genetic counselling, resource availability, implications for family members, psychosocial considerations, patient autonomy, research, support services and insurance. Case studies were developed to demonstrate the framework's application. CONCLUSIONS: This framework was designed to guide decisions around patient selection for genomic testing in nephrology in the Australian health-care setting, with potential utility in other institutions and medical disciplines. It may help facilitate consistent approaches to genomic testing, to maximise equity and utility.

Re-Envisioning the Culture of Undergraduate Biology Education to Foster Black Student Success: A Clarion Call.

The purpose of this paper is to present an argument for why there is a need to re-envision the underlying culture of undergraduate biology education to ensure the success, retention, and matriculation of Black students. The basis of this argument is the continued noted challenges with retaining Black students in the biological sciences coupled with existing research that implicates science contexts (i.e., the cultural norms, values, and beliefs manifesting through policies and practices) as being the primary source of the challenges experienced by Black students that lead to their attrition. In presenting this argument, we introduce the Re-Envisioning Culture Network, a multigenerational, interdisciplinary network comprised of higher education administrators, faculty, staff, Black undergraduate students majoring in biology, Black cultural artists, community leaders, and STEM professionals to work together to curate and generate resources and tools that will facilitate change. In introducing the REC Network and disseminating its mission and ongoing endeavors, we generate a clarion call for educators, researchers, STEM professionals, students, and the broader community to join us in this endeavor in fostering transformative change.

Genomic testing for suspected monogenic kidney disease in children and adults: A health economic evaluation.

PURPOSE: To assess the relative cost-effectiveness of genomic testing compared with standard non-genomic diagnostic investigations in patients with suspected monogenic kidney disease from an Australian health care system perspective. METHODS: Diagnostic and clinical information was used from a national cohort of 349 participants. Simulation modelling captured diagnostic, health, and economic outcomes during a time horizon from clinical presentation until 3 months post-test results based on the outcome of cost per additional diagnosis and lifetime horizon based on cost per quality-adjusted life-year (QALY) gained. RESULTS: Genomic testing was Australian dollars (AU$) 1600 more costly per patient and led to an additional 27 diagnoses out of a 100 individuals tested, resulting in an incremental cost-effectiveness ratio of AU$5991 per additional diagnosis. Using a lifetime horizon, genomic testing resulted in an additional cost of AU$438 and 0.04 QALYs gained per individual compared with standard diagnostic investigations, corresponding to an incremental cost-effectiveness ratio of AU$10,823 per QALY gained. Sub-group analyses identified that the results were largely driven by the cost-effectiveness in glomerular diseases. CONCLUSION: Based on established or expected thresholds of cost-effectiveness, our evidence suggests that genomic testing is very likely to be cost saving for individuals with suspected glomerular diseases, whereas no evidence of cost-effectiveness was found for non-glomerular diseases.

Correcting Hypernatremia in Children.

BACKGROUND: In children with hypernatremia, current clinical guidelines recommend a reduction in serum sodium of 0.5 mmol/L per hour or less to avoid complications of cerebral edema. However, no large-scale studies have been conducted in the pediatric setting to inform this recommendation. Therefore, this study aimed to report the association between the rate of correction of hypernatremia, neurological outcomes, and all-cause mortality in children. METHODS: A retrospective cohort study was conducted from 2016 to 2019 at a quaternary pediatric center in Melbourne, Victoria, Australia. All children with at least one serum sodium level ≥150 mmol/L were identified through interrogation of the hospital's electronic medical record. Medical notes, neuroimaging reports, and electroencephalogram results were reviewed for evidence of seizures and/or cerebral edema. The peak serum sodium level was identified and correction rates over the first 24 hours and overall were calculated. Unadjusted and multivariable analyses were used to examine the association between the rate of sodium correction and neurological complications, the requirement for neurological investigation, and death. RESULTS: There were 402 episodes of hypernatremia among 358 children over the 3-year study period. Of these, 179 were community-acquired and 223 developed during admission. A total of 28 patients (7%) died during admission. Mortality was higher in children with hospital-acquired hypernatremia, as was the frequency of intensive care unit admission and hospital length of stay. Rapid correction (>0.5 mmol/L per hour) occurred in 200 children and was not associated with greater neurological investigation or mortality. Length of stay was longer in children who received slow correction (<0.5 mmol/L per hour). CONCLUSIONS: Our study did not find any evidence that rapid sodium correction was associated with greater neurological investigation, cerebral edema, seizures, or mortality; however, slow correction was associated with a longer hospital length of stay.

Pathological consequences of DNA damage in the kidney.

DNA lesions that evade repair can lead to mutations that drive the development of cancer, and cellular responses to DNA damage can trigger senescence and cell death, which are associated with ageing. In the kidney, DNA damage has been implicated in both acute and chronic kidney injury, and in renal cell carcinoma. The susceptibility of the kidney to chemotherapeutic agents that damage DNA is well established, but an unexpected link between kidney ciliopathies and the DNA damage response has also been reported. In addition, human genetic deficiencies in DNA repair have highlighted DNA crosslinks, DNA breaks and transcription-blocking damage as lesions that are particularly toxic to the kidney. Genetic tools in mice, as well as advances in kidney organoid and single-cell RNA sequencing technologies, have provided important insights into how specific kidney cell types respond to DNA damage. The emerging view is that in the kidney, DNA damage affects the local microenvironment by triggering a damage response and cell proliferation to replenish injured cells, as well as inducing systemic responses aimed at reducing exposure to genotoxic stress. The pathological consequences of DNA damage are therefore key to the nephrotoxicity of DNA-damaging agents and the kidney phenotypes observed in human DNA repair-deficiency disorders.

Clinical and diagnostic utility of genomic sequencing for children referred to a Kidney Genomics Clinic with microscopic haematuria.

BACKGROUND: Microscopic haematuria in children is associated with the risk of progression to chronic kidney disease. Genetic disease is an important potential aetiology. Genomic sequencing presents the most effective diagnostic route for these conditions, but access remains inequitable internationally. METHODS: We conducted a retrospective review of the electronic medical records of a Kidney Genomics Clinic (KGC) from January 2016 to December 2021. RESULTS: Sixty patients were referred to the KGC with haematuria over this period. Forty-three percent of patients had analysis of a limited haematuria panel (COL4A1, COL4A3, COL4A4, COL4A5, MYH9) with 58% receiving a genetic diagnosis. Forty-two percent of referred patients had further analysis of genes implicated in the development of kidney disease, and 36% received a diagnosis. Eight percent of patients underwent cascade testing for a known familial variant, and all received a diagnosis. Children with the highest levels of haematuria (> 500 × 106/L red blood cells) had the highest diagnostic yield (67%). Proteinuria, defined as a urinary protein to creatinine ratio > 20, increased the diagnostic yield from 31 to 65%. Importantly, negative genetic analysis can still have significant clinical utility for patients by altering surveillance and further management; the genetic result had clinical utility in 60% of patients. CONCLUSIONS: Our KGC review highlights the substantial clinical utility and diagnostic yield of genomic analysis for microscopic haematuria in paediatric patients. Whilst the management of variants of uncertain significance can be challenging, a multidisciplinary team including genetic counselling can help ensure these patients are followed up meaningfully. A higher resolution version of the Graphical abstract is available as Supplementary information.

Kidney Organoids Generated Using an Allelic Series of NPHS2 Point Variants Reveal Distinct Intracellular Podocin Mistrafficking.

BACKGROUND: NPHS2 variants are the most common cause of steroid-resistant nephrotic syndrome in children >1 month old. Missense NPHS2 variants were reported to cause mistrafficking of the encoded protein, PODOCIN, but this conclusion was on the basis of overexpression in some nonpodocyte cell lines. METHODS: We generated a series of human induced pluripotent stem cell (iPSC) lines bearing pathogenic missense variants of NPHS2 , encoding the protein changes p.G92C, p.P118L, p.R138Q, p.R168H, and p.R291W, and control lines. iPSC lines were also generated from a patient with steroid-resistant nephrotic syndrome (p.R168H homozygote) and a healthy heterozygous parent. All lines were differentiated into kidney organoids. Immunofluorescence assessed PODOCIN expression and subcellular localization. Podocytes were transcriptionally profiled and PODOCIN-NEPHRIN interaction interrogated. RESULTS: All variant lines revealed reduced levels of PODOCIN protein in the absence of reduced transcription. Although wild-type PODOCIN localized to the membrane, distinct variant proteins displayed unique patterns of subcellular protein trafficking, some unreported. P118L and R138Q were preferentially retained in the endoplasmic reticulum (ER); R168H and R291W accumulated in the Golgi. Podocyte profiling demonstrated minimal disease-associated transcriptional change. All variants displayed podocyte-specific apoptosis, which was not linked to ER stress. NEPHRIN-PODOCIN colocalization elucidated the variant-specific effect on NEPHRIN association and hence NEPHRIN trafficking. CONCLUSIONS: Specific variants of endogenous NPHS2 result in distinct subcellular PODOCIN localization within organoid podocytes. Understanding the effect of each variant on protein levels and localization and the effect on NEPHRIN provides additional insight into the pathobiology of NPHS2 variants. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_01_05_JASN2022060707.mp3.

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.

Theory Designed Strategies to Support Implementation of Genomics in Nephrology.

(1) Background: Genomic testing is increasingly utilized as a clinical tool; however, its integration into nephrology remains limited. The purpose of this study was to identify barriers and prioritize interventions for the widespread implementation of genomics in nephrology. (2) Methods: Qualitative, semi-structured interviews were conducted with 25 Australian adult nephrologists to determine their perspectives on interventions and models of care to support implementation of genomics in nephrology. Interviews were guided by a validated theoretical framework for the implementation of genomic medicine-the Consolidated Framework of Implementation Research (CFIR). (3) Results: Nephrologists were from 18 hospitals, with 7 having a dedicated multidisciplinary kidney genetics service. Most practiced in the public healthcare system (n = 24), a large number were early-career (n = 13), and few had genomics experience (n = 4). The top three preferred interventions were increased funding, access to genomics champions, and education and training. Where interventions to barriers were not reported, we used the CFIR/Expert Recommendations for Implementing Change matching tool to generate theory-informed approaches. The preferred model of service delivery was a multidisciplinary kidney genetics clinic. (4) Conclusions: This study identified surmountable barriers and practical interventions for the implementation of genomics in nephrology, with multidisciplinary kidney genetics clinics identified as the preferred model of care. The integration of genomics education into nephrology training, secure funding for testing, and counselling along with the identification of genomics champions should be pursued by health services more broadly.

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

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].