A deeper understanding of disease mechanisms will help address a growing global problem.
Chronic kidney disease (CKD) is a global health crisis with an estimated 850 million people affected worldwide. Rising faster than all non-infectious diseases including cardiovascular disease, CKD is 20 times more prevalent than cancer. Most people don’t even realize their kidneys are impaired until damage has severely progressed, leaving them at risk of heart attack, stroke and progression to kidney failure.
Early detection and treatment can alter or slow the course of the disease, preventing disability or death. Unfortunately, there have been few advances in either diagnosis or treatments, and neither have been able to keep up with the rapid rise of acute and chronic kidney disease seen globally.
Current methods of diagnosing kidney disease
The kidney is a complex organ responsible for maintaining balance and stability in multiple aspects of the human body, encompassing many interrelated yet distinct functions. Current recommendations for diagnosing kidney disease include measurement of glomerular filtration rate (GFR) and determining the presence and level of albuminuria. GFR is considered the most accurate measure of the kidney’s health.
Direct GFR measurement is a complicated and lengthy process which isn’t practical. Instead, clinicians use a formula to estimate GFR (eGFR) based on the serum creatinine. Measuring creatinine levels with a simple blood test can help identify CKD as early as possible and indicate that the kidneys aren’t properly filtering this waste product that mainly comes from the normal breakdown of muscle tissue.
Although eGFR measurement may indicate that the kidneys are malfunctioning — and how severely — it doesn’t tell why a person has the disease, how it will likely affect a person’s health in the future or how to optimally treat it. Furthermore, creatine levels can also be affected by other factors including diet, muscle mass, pregnancy, age, chronic disease and even some medications.
Measuring urinary protein excretion along with imaging, and potentially performing a kidney biopsy, may give clues to the cause of malfunction. However, urinary protein excretion is variable and can be affected by many things, making it difficult to measure in a standardized way. Biopsies are invasive and give only a snapshot of what is happening.
In short, current diagnostic tests are limited in understanding causes and telling us how to best treat a patient. They do not provide us with an indication of chronicity or prognosis, if there are hemodynamic changes causing kidney injury or if the patient is more or less likely to respond to a certain treatment.
“A biomarker, or panel of biomarkers, that could provide information about the risk of progression earlier in the disease course would be immensely useful in identifying those who may benefit from earlier intervention and could also help to enrich clinical trials, where negative findings in previous studies may be partly attributable to the inclusion of patients at low risk of progression.”
Chee Kay Cheung, Consultant Nephrologist, John Walls Renal Unit, Leicester General Hospital, UK, and George Clinical Renal and Metabolic Scientific Leader
Looking forward in kidney diagnosis and treatment
Modern medicine is rapidly moving toward precision medicine — the ability to create individualized diagnostic tests and treatment plans for patients based on the unique characteristics influencing the progression of their disease and the way their body will react to specific therapies. This concept is well advanced in certain types of cancer such as the HER-2 status in breast cancer patients, and we are beginning to see this in nephrology, for example, with antiPLA2R antibody status in membranous nephropathy.
Work is ongoing to identify reliable pathway-specific biomarkers in the mechanisms of kidney disease that are better prognostic and predictive indicators. Understanding the characteristics that can affect treatment outcomes, such as age, sex, race, disease etiology and severity, comorbidities, concomitant exposures and genetic variants, will help pinpoint drug targets and lead to more effective treatments. More specific and sensitive biomarkers will also improve the efficiency of clinical trials by providing more precise inclusion criteria, decreasing sample sizes needed for investigation, and helping to more rapidly translate research into clinical practice.
Recent advances in molecular biology show promise
Success of cancer researchers to identify genetic/molecular markers that have led to precision disease management is encouraging kidney researchers. Because chronic kidney diseases are rarely caused by a single gene, the challenge is to identify a set of genes, or a marker panel, that will pinpoint the pathogenesis of an individual’s disease. This will require large amounts of longitudinally collected data and extensive collection of renal tissues and other samples.
The international research community is working to redefine kidney disease in molecular terms. It requires collaboration on international registries of large numbers of patients from all demographics with comprehensive tissue sampling and accurate data. Deeper insight into the precise molecular pathways of kidney disease will increase accuracy in screening, diagnosis and prognosis.
Moving forward, both academia and the industry must continue to invest both time and resources to the cause. Large multicenter studies will be required, and publicly available data hubs established. Emerging large biological and clinical databases will allow diverse types of data including molecular, tissue and clinical parameters to be mined for the relationships between genes, proteins and molecular mechanisms that drive the pathology of kidney disease and its progression.
Technological advances in AI and machine learning will be able to accelerate the robust computations necessary to extract the actionable knowledge from large-scale datasets and move nephrology forward to meet the growing global challenges faced.
