Targets, trends, excesses, and deficiencies: refocusing clinical investigation to improve patient outcomes

Abstract

Clinical trials in nephrology have focused on achieving targets, supplementing deficiencies, and correcting excesses in order to improve patient outcomes. The majority of interventions have failed to demonstrate benefit and some have caused harm. It may be that therapies aiming to 'normalize' parameters may actually disturb evolutionary adaptation, thus causing harm. By refocusing on the physiology of disease, and complexity of adaptation, we may design better trials. We review successful and unsuccessful trials in nephrology and other disciplines and suggest a set of principles by which to design future clinical trials:(1) acknowledge heterogeneity of chronic kidney disease populations and appropriately characterize populations for studies; (2) develop better validated biomarkers (through proteomics, genomics, and metabolomics) to identify responders and nonresponders to interventions; (3) design interventions that mimic physiological processes without collateral detrimental effects; (4) reconsider the status of the randomized-controlled trial as the only 'gold standard' and perform large-scale pragmatic trials comparing current care with the intervention(s) of interest, and (5) broaden nephrology research culture so that the majority of patients are enrolled into observational cohorts and intervention studies, which foster greater knowledge acquisition and dissemination. Improved understanding of pathophysiological mechanisms, in conjunction with more innovative but stringent clinical trial design, will ultimately lead to improved patient outcomes.

Targets for parathyroid hormone in secondary hyperparathyroidism: is a “one-size-fits-all” approach appropriate? A prospective incident cohort study

“…A recent publication has demonstrated a positive association between patient-doctor contact and outcomes [ 25 ]. Last but not least, our study reinforces the recent publication by Levin that has recommended acknowledging the heterogeneity of chronic kidney disease populations and appropriately characterizing populations for studies [ 26 ].…”

A randomized control trial to assess the impact of vitamin D supplementation compared to placebo on vascular stiffness in chronic kidney disease patients

“…The relationship of serum levels to disease, type of therapeutic supplementation (fixed dose or based on targeting serum levels) is unknown in CKD populations. Moreover, in various nephrology studies, attempts at targeting deficiencies or excesses of measured serum values in CKD patients in large randomized control trials has not met with success [ 44 – 47 ]. Thus, we have developed and designed a robust randomized control trial to attempt to address deficiencies in the literature, and to better understand mechanisms and complex biological interactions in this patient group.…”

The EVOLVE study is negative, so what does this ‘bitter pill’ of disappointment mean now for renal patients?

“…Can replacement with fixed doses of compounds known to be deficient in CKD, ever lead to improved outcomes? Will it be possible to fund such studies, given that some of the simple, sometimes complementary, therapies offer little financial return for industry – the traditional funder of first, or last, resort for nephrology ? Should we not now concentrate on nested care ‘bundles’ of interventions in one well‐conducted study, and by so doing, grasp the opportunity to show that we can actually influence patient‐level (as opposed to biochemical) outcomes positively?…”