Precision medicine for kidney diseasePrecision medicine for kidney disease

Nephrology as a speciality was born when physician Richard Bright described chronic kidney disease symptoms and anatomical changes in the early 1800s, but we could only start following kidney patients in a more systematic way when creatinine by bioassays was easily available. When nephrologist Stewart Cameron described how reducing proteinuria by blood pressure control helped reduce the rate of decline of kidney function in the late 1970s it remained the therapeutic benchmark for many years. The tools used for kidney disease management mostly focused on reducing proteinuria hence the focus on the use of RAAS blockade to manage progressive proteinuria kidney disease.

Concurrently, the nephropathological descriptions of kidney disease were based on light microscopy features, we had diseases like minimal change disease, membranous nephropathy, focal segmental glomerulosclerosis, etc. We knew from our clinical experience that these diseases had heterogenic outcomes with some responding easily to therapy and some having delayed or no response.

A classic example was membranous nephropathy, which had a famous rule of thirds — 1/3 going to spontaneous remission, 1/3 progress, and 1/3 remained static — and for many years we did not know the reason for this. The treatment for membranous nephropathy for many years was broad-spectrum cytotoxic agents with high-dose steroids and this was only considered after three to six months of waiting period as we were hoping for spontaneous remission. There were some clinical and anatomical indicators to indicate those who go into remission spontaneously, but this was largely not reliable or reproducible.

Nephrology as a speciality had a breakthrough in 2009 with the discovery of antibodies that caused membranous nephropathy and since then there have been many such antibodies described. This led to treatment protocols where the use of antibody assays has been used to decide renal biopsy and treatments. These antibodies are now used for surveillance including post-renal transplantation.

In addition, the need for comprehensive screening for potential kidney donors has required us to undertake screening to look for any predisposition for kidney disease like APOL1 genotyping.

This led to major interest in developing biomarkers that help diagnose detect and predict kidney disease. A great example is the development of placental growth factor assays that help predict preeclampsia disease, which affects young women and predisposes them to poor maternal and foetal outcomes.

In addition, in this region where there is an explosive rise in kidney disease, the establishment of national genome projects in UAE, Qatar and Saudi Arabia, plus their unified national health records, will help us longitudinally follow patients and understand the reasons and predisposition for this rising kidney disease. In addition will help us deep dive into dose clusters of premature kidney disease and certain phenotypical features that occur in families.

Detection of circulating autoantibodies essential for diagnosis and follow-up

Dr. Gehad ElGhazali, MD, PhD, Professor of Clinical Immunology and Services, and Lead of the Diagnostic and Transplant Immunology laboratory at Purelab, and his colleagues from the lab worked to develop the UAE National calculated PRA calculator. This calculator opens opportunities to build a national allocation policy for deceased donors and develop a national waiting list.

In addition, his team supports nephrologists and rheumatologists not just from the Pure Health network but across the UAE healthcare system to manage patients with complex immune-mediated and genetic kidney disease.

Several autoantibodies have been identified as renal disease-associated biomarkers with some of them being possibly implicated in pathogenesis.

A great example since the discovery of a major target antigen in membranous nephropathy, there has been a radical change in how we manage this condition. Two autoantibodies that are directed against kidney-specific autoantigens in membranous nephropathy (M-type phospholipase A2 receptor, PLA2R and thrombospondin type-1 domain-containing 7 A, THSD7A) were identified. Anti-PLA2R autoantibodies are highly specific to primary membranous glomerulonephritis and are detected in about 70 per cent of patients, while anti-THSD7A were detected in a small percentage of primary membranous glomerulonephritis.

The detection of circulating autoantibodies is of importance in diagnosis and follow-up. Since autoimmune-mediated renal diseases can lead to end-stage renal disease, early diagnosis and management will improve long-term outcomes. Dr. Gehad and his team continue to support clinicians and academics in the UAE to help understand the reasons for this rise in kidney disease in the region.

Non-invasive omics approaches to reduce the need for renal biopsy

Autoantibody and immunoglobulin assays are valuable in the prediction, diagnosis, and monitoring of a range of immune-mediated kidney diseases. At Sidra Medicine, Dr. Mohammed Yousuf Karim, Chief of the Division of Hematopathology, and a Clinical Professor in Immunopathology at the College of Medicine, Qatar University, established the diagnostic Immunology laboratory, including a full range of enzyme immunoassay testing for connective tissue disease and vasculitis — important causes of glomerulonephritis leading to CKD. Another important cause of CKD in young people is type 1 diabetes (T1D). Immune testing includes GAD-65, insulin, islet antigen 2, and zinc transporter 8 antibodies. One or more of these 4-antibody panels are detectable in 96 per cent of T1D patients and may occur before clinical disease onset. These autoantibodies can also be present in relatives of T1D patients. In the Research Branch at Sidra Medicine, Dr. Ammira Akil is developing these autoantibody assays, with the plan to translate these into the diagnostic Immunology laboratory. The utility of autoantibodies extends to the selection of candidates for immunotherapy. Teplizumab, a monoclonal antibody binding to the CD3 ε chain is FDA-approved for T1D patients aged ≥8 years with stage 2 disease, able to delay onset of clinically diagnosed stage 3 T1D by a median of two years.

Polygenic risk scores involving HLA-typing for the prediction of T1D are now well established in large-scale European studies and are likely to soon enter the realms of clinical care. However, further research including non-European ancestries is necessary, and Dr. Akil is leading an international project at Sidra Medicine.

Traditional diagnosis and monitoring of renal disease are being challenged by more sophisticated “multi-omics” approaches, which are available in the research branch at Sidra Medicine. These technologies will likely enable more accurate diagnosis and improved stratification of prognosis and therapeutic response. Such methodologies include multiplex cytokine measurement, transcriptomics, multi-parameter flow cytometry, metabolomics, and proteomics. Such approaches can be applied on renal biopsy specimens, or non-invasively on urine as a window into the kidney. The latter is particularly applicable to disease monitoring, for example, where the use of urine protein-creatinine ratio is a relatively blunt tool that cannot reliably distinguish between ongoing inflammation and chronic damage. Dr. Karim foresees such non-invasive omics approaches may over time even start to obviate or reduce the need for renal biopsy.

Fostering collaborations to address unmet needs

Dr. Siddiq Anwar, Consultant Nephrologist and Associate Professor of Medicine at Sheikh Shakhbout Medical City (SSMC) and Khalifa University, concludes: “As we are beginning to understand the role of complex genetic variants to the predisposition of kidney disease and the role of antibodies in developing immune-mediated kidney diseases, then we can start tailoring medical treatment to specific disease processes and thereby optimising patient outcomes. In addition, we can define subgroups of patients who may and will not benefit from specific therapeutic strategies."

References available on request.

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