How genomic medicine is modernising nephrology

John A Sayer

6 September 2016

In our guest blog, Prof John A Sayer highlights some of the ways genomic medicine is transforming the medical specialty of nephrology. The factsheet Nephrology and genomics is one in the series of Genomics in mainstream medicine resources developed to help clinicians understand how genomics can be used in their clinical specialty.

Nephrology - the study of the kidney - has grown to become a major medical specialty. Traditionally associated with physiology (salt and water balance, blood pressure maintenance) nephrology now encompasses the treatment of a wide spectrum of, often multisystem, diseases and therapies for end stage renal disease (ESRD), namely haemodialysis, peritoneal dialysis and renal transplantation. 

The advent of genomic medicine, which is cross cutting across all medical specialties, allows nephrology to become a truly modern medical specialty.

Genomics has perhaps crept into nephrology by the back door, at least in some instances. Renal transplantation offers the best chance of improvement in mortality for patients with ESRD, and is underpinned by the science of tissue typing. This relies on understanding a set of highly polymorphic genes that control immunity called the Major Histocompatibility Complex (MHC). Located on Chromosome 6p, the MHC includes two highly polymorphic gene families,  the Human Leukocyte Antigens (HLA). The typing of donor and recipient HLAs is important in all forms of transplantation, and is used to select donors prior to renal transplantation. Cellular based assays examining protein expression have now been replaced by genomic DNA testing which allows definition of a genotype to determine the HLA type at the DNA level. The introduction of Next Generation Sequencing strategies now allows HLA typing of donors and recipients to be faster and more economical. Thus, using high throughput technologies, a complex immunological assay has been transformed, into a rapid series of genetic tests.

UK nephrology has led the way in the investigation of rare renal diseases. A renal registry, known as RaDaR is an initiative by UK kidney specialists designed to pull together information from patients who have certain rare kidney diseases. This will give a much better understanding of how these illnesses affect people. Genetic understanding of rare disease is important and allows both a diagnosis and the adoption of personalised approaches to treatment. For example the diagnosis and treatment of atypical haemolytic uraemic syndrome (aHUS) has been revolutionized by modern genetics and genomics. We now know that most patients with aHUS carry mutations in complement genes which result in over activation of the complement system. This knowledge led to identification of a targeted drug therapy using a complement inhibitor Eculizumab. Proven mutations in complement genes predict response to Eculizumab, while the presence of mutations in the non-complement gene, DGKE , is a marker of non-response in a subgroup of patients. This allows treatments to be personalised for this serious cause of ESRD.

The introduction of Next Generation Sequencing strategies now allows HLA typing of donors and recipients to be faster and more economical. Thus, using high throughput technologies, a complex immunological assay has been transformed, into a rapid series of genetic tests

Cystic kidney diseases are perhaps the best known group of inherited renal diseases. In fact autosomal dominant polycystic kidney disease is the most common life threatening inherited disease worldwide. Genetics and genomics have now identified a set of kidney disease genes which account for a range of childhood and adult inherited cystic kidney diseases, and variants in some of these genes may have wider ranging implications. For example, UMOD, which encodes uromodulin and is associated with Medullary Cystic Kidney Disease Type 2, may also be important in renal salt handling and variants may contribute to chronic kidney disease and hypertension in the general population. Uromodulin may be a novel therapeutic target to control blood pressure and preserve renal function.

The future of nephrology looks bright, with an increasing move towards genetic and genomic understanding of disease, which will allow new insights into renal physiology, which is where this great specialty started. As this moves from research to mainstream all nephrologists will need to develop their practice. For those wishing to find out more a recent introduction to genomics in nephrology developed in the UK as part of an RCP Working Group provides a useful signpost to appropriate resources.