Mayer G. Nephrol Dial Transplant. 2021 Jun 22;36(Suppl 2):1-2. doi: 10.1093/ndt/gfaa366.
In 2015, former US president Barack Obama launched a Precision Medicine Initiative ‘in order to bring us closer to curing diseases like cancer and diabetes – and to give all of us access to the personalized information we need to keep ourselves and our families healthier’.
The concept to account for individual variability when preventing or treating diseases is not new. In 1903, Sir William Osler stated that ‘the good physician treats the disease; the great physician treats the patient, who has the disease’ and blood typing to guide transfusion therapy has been routine practice for more than a century. However, the availability of large-scale biologic databases holding information from powerful methods for characterizing individuals (such as proteomics, metabolomics, genomics, diverse cellular assays and even mobile health technology) and computational analysis tools to handle big data has massively increased our options.
Evidence-based medicine, the current mainstay of clinical practise, usually relies on findings obtained in cohorts included in large observational or interventional trials, and even though studies apply inclusion and exclusion criteria, these do no eliminate interindividual heterogeneity in prognosis and/or response to therapy. Consequently, when transferring population data into clinical practise in individuals, we are limited to probabilistic estimates even though we aim for determinism. Therefore we have to develop appropriate analysis tools to advance. Nonetheless, cohort-derived evidence-based and (individualized) precision medicine are obviously not two different concepts but rather the latter is a logical further development of the former.
Nephrology has already partially adopted the precision medicine approach. In kidney transplantation, donor-to-recipient matching is continuously refined and a better understanding of the molecular pathogenesis of Fabry’s disease allows tailoring therapy even to the individual genotype (for further details, see the articles by Oberbauer et al. and Brand et al. in this supplement). In other areas such as haemodialysis, clinical practise is still largely based on population-oriented guidelines. We aim for uniform targets for Kt/V, haemoglobin ranges or use low dialysate calcium concentration. Along with the fact that we have to critically question the clinical significance of some of these parameters (see the article by Meyer in this supplement), it is interesting that we forget that uniform procedures and targets actually can inadvertently result in individualized therapy. Even when using the same (low) dialysate calcium concentration to avoid calcium loading, mass balance over a session varies greatly due to the (neglected) variability in the patient’s pre-dialysis serum concentration.
Precision medicine in the care of patients with chronic kidney disease (CKD) is the topic of several currently ongoing large research projects, some of them funded by the European Union, such as Beat-DKD [3] or DC-ren [4]. In CKD, recent large-scale clinical trials have shown that therapies like sodium-glucose cotransporter 2 inhibitors dramatically reduce the residual risk of progression in a substantial proportion of patients [5–7]. Nonetheless, some individuals still loose glomerular filtratin rate (GFR) and the next step will be to look for optimized therapies in these ‘non-responders’ (actually, on an individual level we do not know if these patients do not respond or whether we just insufficiently control their disease because they suffer from additional pathophysiologically relevant drivers of progression). If we want to address these individuals, we first will have to understand what makes them different. Stratification by estimated GFR (eGFR) and albuminuria (both rather, at least partially, being markers of function and prognosis than pathophysiology) will not be sufficient and we need further insights into the interaction between disease pathophysiology and drug mode of action in individuals [8]. Future clinical trials will have to take this information into account when deciding on their inclusion and exclusion criteria to avoid the risk of failure. CKD is additionally challenging, as we see not only interindividual heterogeneity in disease progression and effect of therapies, but also intraindividual variability over time [9]. Phases of stable eGFR are followed by periods of deterioration and vice versa. Again, our current guideline-based approach to start therapy and continue over time regardless of patient status is challenged and needs a critical reappraisal, as outlined by Fliser et al. and by the articles by Lambers Heerspink, Wanner, Rosenkranz and Tesar in this supplement of Nephrology, Dialysis and Transplantation. On behalf of the authors, I hope that we are able to provide an overview of the current state of the art of precision medicine in nephrology that hopefully will stimulate further research in this exciting area.
