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.

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.

Treatment resistant M-type phospholipase A2 receptor associated membranous nephropathy responds to obinutuzumab: a report of two cases.

BACKGROUND: Membranous Nephropathy (MN) is a common cause of nephrotic syndrome (NS) in adults. Recognition of MN as an antibody mediated autoimmune disease has enabled the introduction of anti-B-cell therapy. Rituximab, a type I anti-CD20 antibody has been used in the management of MN, but has a 35-45% failure rate. Obinutuzumab, a fully humanised type II anti-CD20 monoclonal antibody produces greater CD20 depletion and is superior to rituximab in the treatment of certain B-cell malignancies. In the two reports published to date involving nine patients with M-type phospholipase A2 receptor (PLA2R) associated MN (six of whom were rituximab resistant), treatment with obinutuzumab lead to immunological remission (IR) in 75% of patients, with improvement of proteinuria, normalisation of serum albumin and stable renal function in all patients. CASE PRESENTATION: We report on two cases of PLA2R-associated MN, two males aged 33 and 36-years, who presented with NS and bilateral sub massive pulmonary emboli requiring anticoagulation. Both were diagnosed serologically as PLA2R-associated MN where a renal biopsy was initially deferred due to bleeding risk on anticoagulation, but later confirmed. Both patients were refractory to multiple lines of therapy including rituximab, but achieved IR, normalistation of serum albumin, improved proteinuria and stable renal function with obinutuzumab. CONCLUSIONS: Our cases add to the current limited literature on the successful use of obinutuzumab in PLA2R associated MN refractory to standard therapy including rituximab.

Exploring the impact and utility of genomic sequencing in established CKD.

Clinical genetics is increasingly recognized as an important area within nephrology care. Clinicians require awareness of genetic kidney disease to recognize clinical phenotypes, consider use of genomics to aid diagnosis, and inform treatment decisions. Understanding the broad spectrum of clinical phenotypes and principles of genomic sequencing is becoming increasingly required in clinical nephrology, with nephrologists requiring education and support to achieve meaningful patient outcomes. Establishment of effective clinical resources, multi-disciplinary teams and education is important to increase application of genomics in clinical care, for the benefit of patients and their families. Novel applications of genomics in chronic kidney disease include pharmacogenomics and clinical translation of polygenic risk scores. This review explores established and emerging impacts and utility of genomics in kidney disease.

Monogenic and polygenic concepts in chronic kidney disease (CKD).

Kidney function is strongly influenced by genetic factors with both monogenic and polygenic factors contributing to kidney function. Monogenic disorders with primarily autosomal dominant inheritance patterns account for 10% of adult and 50% of paediatric kidney diseases. However, kidney function is also a complex trait with polygenic architecture, where genetic factors interact with environment and lifestyle factors. Family studies suggest that kidney function has significant heritability at 35-69%, capturing complexities of the genome with shared environmental factors. Genome-wide association studies estimate the single nucleotide polymorphism-based heritability of kidney function between 7.1 and 20.3%. These heritability estimates, measuring the extent to which genetic variation contributes to CKD risk, indicate a strong genetic contribution. Polygenic Risk Scores have recently been developed for chronic kidney disease and kidney function, and validated in large populations. Polygenic Risk Scores show correlation with kidney function but lack the specificity to predict individual-level changes in kidney function. Certain kidney diseases, such as membranous nephropathy and IgA nephropathy that have significant genetic components, may benefit most from polygenic risk scores for improved risk stratification. Genetic studies of kidney function also provide a potential avenue for the development of more targeted therapies and interventions. Understanding the development and validation of genomic scores is required to guide their implementation and identify the most appropriate potential implications in clinical practice. In this review, we provide an overview of the heritability of kidney function traits in population studies, explore both monogenic and polygenic concepts in kidney disease, with a focus on recently developed polygenic risk scores in kidney function and chronic kidney disease, and review specific diseases which are most amenable to incorporation of genomic scores.

The Heritability of Kidney Function Using an Older Australian Twin Population.

Introduction: Twin studies are unique population models which estimate observed rather than inferred genetic components of complex traits. Nonmonogenic chronic kidney disease (CKD) is a complex disease process with strong genetic and environmental influences, amenable to twin studies. We aimed to assess the heritability of CKD using twin analysis and modeling within Older Australian Twin Study (OATS) data. Methods: OATS had 109 dizygotic (DZ) and 126 monozygotic (MZ) twin pairs with paired serum creatinine levels. Heritability of kidney function as estimated glomerular filtration rate (eGFR CKD Epidemiology Collaboration [CKD-EPI]) was modeled using the ACE model to estimate additive heritability (A), common (C), and unique (E) environmental factors. Intratwin pair analysis using mixed effects logistic regression allowed analysis of variation in eGFR from established CKD risk factors. Results: The median age was 69.71 (interquartile range 78.4-83.0) years, with 65% female, and a mean CKD-EPI of 82.8 ml/min (SD 6.7). The unadjusted ACE model determined kidney function to be 33% genetically determined (A), 18% shared genetic-environmental (C), and 49% because of unique environment (E). This remained unchanged when adjusted for age, hypertension, and sex. Hypertension was associated with eGFR; however, intertwin variance in hypertension did not explain variance in eGFR. Two or more hypertension medications were associated with decreased eGFR (P = 0.009). Conclusion: This study estimates observed heritability at 33%, notably higher than inferred heritability in genome-wide association study (GWAS) (7.1%-18%). Epigenetics and other genomic phenomena may explain this heritability gap. Difference in antihypertension medications explains part of unique environmental exposures, though discordance in hypertension and diabetes does not.