DIAGNOSTICS AND TECHNIQUES: Edited by Maarten W. Taal
The era of ‘evidence-based medicine’ emphasized the need for robust evidence to ensure that treatments afford benefit with limited or acceptable levels of harm, but neglected variation in individual response to therapy. The most extreme expression of this approach was the proposal, based on evidence from several large randomized trials that large populations assessed to be at increased risk of cardiovascular disease should be treated with a combination ‘polypill’ of drugs to reduce risk in the population but largely ignoring the characteristics of individuals . Increasingly, it is now recognized that whereas randomized prospective trials provide essential evidence on how best to treat the ‘average’ patient, many of those included in positive trials did not derive individual benefit . This problem has been most eloquently illustrated in drug trials but is equally relevant for diagnostic tests and other therapeutic interventions. No diagnostic test has a sensitivity and specificity of 100% and people respond differently to interventions like physical therapy or surgery.
Rapid developments in the fields of genomics and other ‘omics’ technologies have ushered in a new era in medicine in which the goal is to offer therapy specifically designed for each individual patient based on a detailed analysis of their genetic background, disease characteristics (assessed using genomic, proteomic and multiplex biomarker assay techniques) and clinical features. The challenge is to develop techniques that allow clinicians to apply the evidence from large clinical trials in a manner that maximizes benefit and minimizes harm for the individual. This challenge is particularly relevant in renal medicine. Despite trial evidence for treatments to slow chronic kidney disease (CKD) progression, many patients still progress to end-stage kidney disease and outcomes on dialysis remain poor. I have, therefore, selected topics for this issue of the ‘Diagnostics and Techniques’ section to explore the promise of personalized medicine in a broad range of areas in nephrology.
The development of an equation to estimate glomerular filtration rate (GFR) from serum creatinine using variables readily available to clinical laboratories to facilitate automated reporting of estimated GFR  fundamentally changed our approach to kidney disease and resulted in a global increase in awareness of CKD and its multiple adverse consequences for health. Nevertheless, it was recognized that general application of creatinine-based estimating equations resulted in substantial overestimation or underestimation of GFR in individuals with extremes of body habitus or age, and from different ethnic groups. New equations that perform better have been developed  but the limitations of serum creatinine remain. Steubl and Inker  provide an update on recent developments in the search for alternative glomerular filtration markers to creatinine to enable accurate estimation of GFR in a greater proportion of people and conclude that a combination of markers will probably be required.
Though dialysis prolongs life, it is associated with substantial comorbidity, poor quality of life and reduced survival. Two articles in this section explore novel approaches to addressing these problems. Optimization of fluid status has long been recognized as a key priority in maintaining health for people on dialysis. Tabinor and Davies  review recent evidence on the use bioimpedance spectroscopy to assess fluid status and individualize interventions to achieve ‘euvolaemia.’ Though no improvement in the outcomes of survival or cardiovascular events has been observed in relatively small studies published to date, the use of bioimpedance spectroscopy was associated with an improvement in fluid overload and a reduction in blood pressure in some studies, though others have reported an adverse impact on residual renal function. Thus further studies are warranted to explore the potential benefits of this technology and determine the optimal means to integrate its use into clinical practice. Selby and colleagues discuss interventions for improving intradialytic haemodynamic stability, increasingly recognized as a key factor influencing outcomes and quality of life [7,8]. Cooling dialysis fluid has been identified as a simple intervention to reduce intradialytic hypotension but results in uncomfortable thermal symptoms in some patients, emphasizing the need for a personalized approach. Future progress will likely depend on the development of biofeedback systems that constantly regulate dialysis therapy variables such as ultrafiltration rate and sodium balance to adjust the dialysis to the individual's physiological responses.
The remaining articles deal with important aspects of therapeutics. Due to the fine balance between benefit and risk, anticoagulation for the prevention of embolic events associated with atrial fibrillation is recognized as a problem area, particularly in persons with advanced CKD. Kalra et al. review the recent literature on this topic and report that the use of vitamin K antagonists (VKAs) in patients with advanced CKD and atrial fibrillation was associated with minimal benefit and increased risk of bleeding, though these outcomes may be attributable in part to difficulty maintaining treatment within the therapeutic range. In randomized trials, direct acting oral anticoagulants (DOACs) have shown similar efficacy and reduced bleeding complications versus VKAs, though persons with advanced CKD were excluded. On the basis of pharmacokinetic studies, some DOACs have been licensed by the Federal Drugs Agency for use at a reduced dose in advanced CKD but outcome studies are needed and a similar licence has not yet been granted in Europe. The authors propose a personalized approach using risk scores to assess an individual's risk of embolic events versus bleeding complications. Heerspink and colleagues argue that variation in individual responses to drugs is an important contributor to the observed residual risk of CKD progression and cardiovascular events observed in persons with diabetes and kidney disease despite treatment with evidence-based drugs such as renin–angiotensin–aldosterone system inhibitors (RAASi) . They review evidence that variation in drug response is because of individual characteristics such as genetic factors and volume status rather than drug characteristics or dose. They further contend that biomarker-based enrichment strategies to identify those at the highest risk or most likely to respond to a particular drug are needed to improve future trial design and clinical treatment to deliver individualized therapy so that more patients derive benefit. Finally, Hamidi and Kretzler  propose that current clinicopathological classifications of glomerular disease are inadequate to predict outcomes and guide therapy. They argue for the use of modern systems biology techniques applied to kidney biopsies to achieve detailed molecular characterization (genome, transcriptome, proteome, metabolome, lipidome, and epigenome) of glomerular disease in individuals using an approach similar to that which is enabling successful individualized therapy in the field of oncology. Novel prognostic markers identified in this manner will enable more precise clinical trials and will identify patients most likely respond to a particular drug. This creates the possibility of a precise, personalized approach in which each individual is treated according to the molecular characteristics of their glomerulopathy.
More than a century ago, one of the fathers of modern medicine, Sir William Osler, recognized the importance of a personalized approach when he said ‘Variability is the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike and behave alike under the abnormal conditions which we know as disease.’ The concept of personalized medicine is, therefore, not new but Osler practiced in a period when there were limited therapies and little evidence to support their use. In the modern era, we have the advantage of multiple treatments (though more are needed) and a large evidence base. Additionally, we are now developing the tools to apply the evidence in an individualized manner to achieve the ultimate goal of providing ‘the right medicine for the right person at the right time and the right dose’ or as Osler put it, ‘The good physician treats the disease; the great physician treats the patient who has the disease.’
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1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326:1419.
2. Kent DM, Hayward RA. Limitations of applying summary results of clinical trials to individual patients: the need for risk stratification. JAMA 2007; 298:1209–1212.
3. Levey AS, Coresh J, Greene T, et al. Chronic Kidney Disease Epidemiology Collaboration. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 2006; 145:247–254.
4. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009; 150:604–612.
5. Steubl D, Inker LA. How best to estimate GFR? Novel filtration markers and their application. Curr Opin Nephrol Hypertens 2018.
6. Tabinor M, Davies S. The use of bioimpedance spectroscopy to guide fluid management in patients receiving dialysis. Curr Opin Nephrol Hypertens 2018.
7. Gullapudi VRL, Kazmi I, Selby NM. Techniques to improve intradialytic haemodynamic stability. Curr Opin Nephrol Hypertens 2018.
8. McIntyre CW. Recurrent circulatory stress: the dark side of dialysis. Semin Dial 2010; 23:449–451.
9. Kalra PA, Burlacu A, Ferro CJ, Covic A. Which anticoagulants should be used for stroke prevention in atrial fibrillation and severe CKD? Curr Opin Nephrol Hypertens 2018; [Epub ahead of print].
10. Idzerda NMA, Pena MJ, Heerspink HJL. Personalized medicine in diabetic kidney disease: a novel approach to improve trial design and patient outcomes. Curr Opin Nephrol Hypertens 2018.
11. Hamidi H, Kretzler M. Systems biology approaches to identify disease mechanisms and facilitate targeted therapy in the management of glomerular disease. Curr Opin Nephrol Hypertens 2018.