Making Sense and Cents of Precision Medicine in Fight Against Kidney Failures

According to the National Population Health Survey 2021, over 300,000 people in Singapore suffer from chronic kidney disease but another 200,000 could be undiagnosed[1]. Adding on to that, kidney failure imposes heavy personal and social costs, and is a significant burden on the healthcare system. In 2021, dialysis costs in Singapore were estimated to be about S$300 million[2], and the mean annual costs for patients with type 2 diabetes who had chronic kidney diseases were S$3,385[3].

As next-generation sequencing becomes faster and less cost prohibitive, it is becoming increasingly clear that precision medicine can be a powerful tool in the field of kidney disease as it can provide earlier or more accurate diagnosis, allowing for more targeted or earlier interventions—and ultimately leading to better long-term outcomes. In the long run, it has the potential to decrease the burden of kidney failure in our society. Yet, despite these benefits of precision medicine, genetic testing is currently not commonly or consistently offered in local nephrology clinics.

Missed Opportunities in Fight Against Kidney Failures

“For patients with nephrotic syndrome, genetic testing is typically performed only after the second or third line of immunosuppressants have been empirically administered and proven ineffective,” said Associate Professor Ng Kar Hui, Paediatrics Nephrology, Dialysis and Renal Transplantation, National University Hospital.

A/Prof Ng continued, “In our earlier studies, we noted that 20% of patients with steroid-resistant nephrotic syndrome (NS) had genetic causes. These cases generally do not respond well to immunosuppression. In the absence of genetic testing, 20% of these NS patients would have received unnecessary immunosuppressive drugs. With early genetic testing, the immunosuppressive strategy can be more directed and rational.” Additionally, in some children, if the genetic results can be available in two weeks, the need for a kidney biopsy can be avoided.”

Professor David Matchar, Programme in Health Services and Systems Research, Duke-NUS Medical School added, “We can reap cost savings from reduced unnecessary usage of expensive immunosuppressants, as well as the treatment costs of their long-term side effects like infections, malignancy and infertility. Ultimately, these translate into gains for both patients and the healthcare system.”

Patients with protein and/or blood in their urine for which initial evaluations have revealed no known causes, can also benefit from genetic testing. Without genetic testing, such patients would have been given either no definite diagnosis, a presumptive benign diagnosis, or be subjected to a kidney biopsy. However, some of these cases can be traced to genetic reasons with a proportion of them developing impairment of the kidney function in the future—and ultimately being labelled as having “kidney failure with an unknown cause”. Yet, with genetic testing, early accurate diagnosis can lead to early interventions that change the course of disease markedly.

Sharing the experience of one of her patients, who is a 10-year-old boy, A/Prof Ng said, “He had large amounts of urinary protein which were detected when a urine test was performed for other reasons. All initial laboratory tests investigating causes for high urinary protein results came back negative. Eventually, through genetic testing, we uncovered a genetic condition related to coenzyme Q10 deficiency. With this, our young patient avoided the need for a kidney biopsy and was started on a disease-specific treatment involving coenzyme Q10—a supplement readily available in retail pharmacies. This significantly decreased his urinary protein to near normal levels—a remarkable achievement in renal medicine because this means likely preservation of his kidney function for a long time.”

In the event that a genetic condition has no available disease-specific treatment, an earlier diagnosis will nonetheless increase awareness among patients and their families, as well as enable kidney protective measures to be instituted early. These include avoidance of drugs that may damage kidneys, vigilant blood pressure control, surveillance for other kidney insults like diabetes mellitus, avoidance of smoking and obesity and possibly early initiation of medicines with kidney-protecting effects.

Infrastructure for Primary Glomerular Disease Genetic Testing

Poor accessibility to genetic tests is a big reason why genetic testing is not consistently performed locally in patients who can benefit from it. While this is partly driven by the high costs of genetic tests, the low genetic literacy amongst kidney specialist doctors and the lack of a conducive genetic ecosystem in healthcare play an important part. Prof Matchar said, “That is why we are doing this clinical implementation pilot (CIP) to enable our ecosystem and make it more conducive.”

Kidney specialists are not able to order and interpret genetic tests because they have not been adequately trained. Plus, genetics has been such a rapidly advancing field that most of what was learnt in undergraduate and postgraduate studies have become obsolete. Prof Matchar said, “We also have a dire lack of genetic counsellors who can provide genetic counselling, which is mandatory before a genetic test is ordered and after the genetic result is available. In addition, there is a general lack of local genetic sequencing laboratories and experts to analyse genetic data, suitable data storage capabilities and healthcare financing structures.”

Garnering Support from Clinicians, Patients and Families, Genetic Experts

To make genetic testing more accessible, the relevant stakeholders must come together and recognise the need to change things. “For example, nephrologists need to be educated about genetics, so that they can articulate benefits of genetic testing to their patients and families. Then they need to be trained in genetic counselling. Genetic experts will need to support them in interpreting the genetic results and providing suitable recommendations to the patients.” said A/Prof Ng.

“We believe that if we can set up a robust infrastructure comprising local accredited laboratories, genetic counsellors, trained nephrologists, standardised clinical algorithms and processes, and a framework that supports regular and sustainable cross-communications between genetic experts, kidney doctors, scientists and data analysts, we can provide high quality genetic testing services to our patients. And if we can also augment the health financing structure surrounding genetic testing, we would have a good chance of sustaining patient interest and increasing the uptake of genetic testing,” Prof Matchar added. “It may sound very operational and somewhat tedious, but these are all highly essential—not just for kidney diseases, but also all other diseases that call for genetic testing.”

The CIP may still be underway, but interest in genetics and genetic testing is slowly and surely gaining momentum among kidney specialists—particularly the nephrologists in the adult services. “We have several nephrologists who can now independently perform genetic counselling. We are also increasingly seeing cases which have previously baffled doctors for years being solved by genetic testing now. These are significant milestones and certainly a great source of motivation for the team. It validates the importance of this CIP as well as the efforts of our Co-Principal Investigators (PIs)—Associate Professor Jason Choo, Dr Lim Ru Sin, Dr Chan Gek Cher and Dr Esther Leow—and their teams,” said A/Prof Ng.

On the patient side, the CIP is also working on getting the genetic testing consent framework up and educational materials in place. A/Prof Ng said, “We are exploring various things—printed materials, chatbots or possibly even a series of videos that patients and their families can watch before they go for their genetic counselling sessions. The hope is that these initiatives enable us to increase the uptake of genetic testing, as well as streamline processes so that they are less labour-intensive, and more sustainable and scalable in the future.”

Click here to read how A/Prof Ng and Prof Matchar first embarked on their first steps to study the clinical implementation of genetic testing for primary glomerular disease.

This project is supported by the National Research Foundation, Singapore, through the Singapore Ministry of Health’s National Medical Research Council and the Precision Health Research, Singapore (PRECISE), under PRECISE’s Clinical Implementation Pilot grant scheme.