RENAL genetics is an emerging specialty in the fast moving field of clinical genetics, with genetic kidney disease increasingly recognised as an important cause of chronic kidney disease. Multidisciplinary renal genetics clinics across Australia are changing how patients are diagnosed and managed at all stages of their disease.

Early active management of chronic kidney disease can slow the decline in kidney function, but this is only possible when patients are accurately diagnosed, particularly in the early stages of disease. Recognising the impact early detection has on outcomes, Kidney Health Australia has led a campaign to highlight the high population prevalence of undiagnosed chronic kidney disease, with screening for at-risk populations, including a blood test, urinalysis and blood pressure measurement.

For those who are known to have kidney disease, a definitive genomic diagnosis can have a real impact on affected patients and their family members. Along with the standard management of chronic kidney disease, there are a limited number of phenotype-specific disease modifying agents such as tolvaptan, for autosomal dominant polycystic kidney disease; eculizumab, for atypical haemolytic uraemic syndrome; and angiotensin-converting enzyme (ACE) inhibitors for Alport syndrome (a genetic condition characterised by kidney disease, hearing loss, and eye abnormalities).

But the benefits to patients go beyond the medical management of their kidney disease. A definitive genomic diagnosis permits closure of a “diagnostic odyssey”, informs reproductive decisions, allows screening for extra-renal manifestations of disease and can inform the medical work-up for living related kidney donors. A recent Australian case report by McBride and colleagues demonstrated how familial genomic sequencing after the birth of a child with nephrocalcinosis facilitated prenatal and early neonatal management, resulting in normal kidney development for a subsequent sibling.

As the cost of genomic sequencing has decreased, the list of genes associated with the development of kidney disease has increased, with more than 360 genes now implicated. Genomic sequencing remains relatively expensive and should be used judiciously, ideally only when there is likely to be a clinically relevant diagnostic yield or when a definitive diagnosis will affect management.

Choosing the appropriate test is not straightforward. Direct comparisons between Australian laboratories and overseas services are complex for the non-geneticist, requiring an in depth understanding of sequencing approach, quality, turnaround times and the ability to re-analyse data. In a patient with haematuria, for example, an overseas panel test for three genes implicated in Alport syndrome, COL4A5, COL4A3 and COL4A4, may seem the most fiscally appropriate test. However, whole exome sequencing with targeted analysis for genes of interest would also permit examination of potential modifiers of the Alport phenotype such as ACTN4 and NPHS2, as suggested by expert consensus guidelines. Furthermore, if the above are negative, phenotypes such as Dent disease, caused by variants in CLCN4 or OCRL, can be analysed.

Identifying patients who are likely to benefit from an accurate genetic diagnosis is complex, dynamic and influenced by a number of factors extraneous to their clinical phenotype. These factors include the impact of an accurate diagnosis on treatment options, transplant planning, reproductive decisions, screening for extra-renal disease, kidney donor work-up, and prognostication. Phenotype selection and definition are also key. Groopman and colleagues recently demonstrated a 10% diagnostic rate in an unselected cohort of patients with chronic kidney disease, whereas Mallett and colleagues demonstrated a 43% diagnostic rate when recruiting patients actually suspected of having a genetic kidney disease diagnosis.

Certain groups of patients are more likely to benefit from genomic sequencing, including individuals with haematuria or proteinuria, with a potential diagnosis of Alport syndrome; children with steroid-resistant nephrotic syndrome, who may not benefit from immunosuppression; those with cystic kidney disease, who may benefit from surveillance for extra-renal involvement; children with early onset nephrolithiasis, who may require preventive therapy; and those with a family history of kidney disease for whom an early diagnosis can facilitate optimised chronic kidney disease management.

On the one hand, nephrologists are enthusiastic early adopters of clinical genomics, readily adopting a technology that has the potential to change the paradigm of chronic disease management and improve clinical outcomes. On the other hand, counselling about the impact of genomic sequencing before and after a test requires specialised knowledge that has not previously been part of a nephrologist’s skillset. Counselling patients as to the relative benefits of different sequencing options and results can be highly complex, representing a potential extension of scope for many nephrologists. Working as part of multidisciplinary and multiskilled teams is, however, well within scope, and this has resulted in formation of multidisciplinary renal genetics clinics for exactly these reasons.

Thus, if considering genetic kidney disease in a patient or family, or considering a genomic test, also think about referring to a multidisciplinary renal genetics clinic. These clinics can provide a comprehensive counselling and diagnostic service in parallel with and in support of a primary medical or nephrology team continuing ongoing clinical management.

Multidisciplinary renal genetics in Australia began at the Royal Brisbane and Women’s Hospital in 2013 and, in Victoria, at the Royal Children’s Hospital in 2016, supported by the Royal Children’s Hospital Foundation. The KidGen collaborative is a national network of renal genetics clinics across Australia offering multidisciplinary assessment of patients with sequencing supported by a combination of hospital funding, research grants and philanthropy. Patients are reviewed by a paediatric or adult nephrologist, clinical geneticist and a genetic counsellor. This combined approach means that patients and families are counselled as to the benefits and limitations of genomic sequencing and the impact of the diagnosis. Participation in cutting edge kidney research at Murdoch Children’s Research Institute, the University of Queensland, Australian Genomics and Melbourne Genomics are also enabled through this clinic network. KidGen offers regular Renal Genetics Workshops, where physicians can learn how to assess patients with genetic kidney disease, as well as patient engagement events and educational symposia. A list of KidGen clinics is available online at along with information about how to refer patients to these services.

Clinical genomics may be fast moving and disruptive, but it presents opportunities to improve clinical care and strengthen multidisciplinary teams so that patients realise benefits. Australia already has the infrastructure in place to make genomics an integral part of medical care for patients with kidney disease, ensuring nationwide, equitable access to a clinical paradigm that offers state-of-the-art medical care.

Dr Cathy Quinlan is a consultant paediatric nephrologist in the Royal Children’s Hospital and clinician scientist at the Murdoch Children’s Research Institute and the University of Melbourne. She is Victorian lead for Renal Genetics with the Melbourne Genomics Health Alliance, Australian Genomics Health Alliance and KidGen Collaborative. She can be found on Twitter @KidneyCathy

Associate Professor Andrew Mallett is a nephrologist and Clinical Council Co-Chair at the Royal Brisbane and Women’s Hospital, Associate Professor and Clinical Fellow at the University of Queensland, and Rare Disease Flagship Lead at the Australian Genomics Health Alliance and KidGen Collaborative.

KidGen is a collaboration between clinical, diagnostic and research teams in Australia with the aim of better understanding the causes of genetic kidney disease. By developing renal genetics clinics across Australia, we work with patients and diagnostic providers to determine the genetic basis of kidney diseases. Having identified potentially causative genetic lesions, we can model and verify these changes in biological model systems, furthering our understanding of kidney development and disease. KidGen can be found on Twitter @KidGenAustralia


The statements or opinions expressed in this article reflect the views of the authors and do not represent the official policy of the AMA, the MJA or InSight+ unless so stated.

Leave a Reply

Your email address will not be published. Required fields are marked *