*4.1. Kidney Biomarkers*

In nephrology, the most used predictive biomarkers are eGFR and albuminuria. Both these biomarkers can be considered as "dynamic" predictive biomarkers. In fact, their levels change over time with the effects of treatment, such that they can be efficiently used for monitoring the course of CKD and the appropriateness of the therapy followed by the patient. In the past few decades, several interventional studies were carried out testing the effect of nephroprotective drugs on hard endpoints such as mortality, CV events, and ESKD in patients with CKD [89–96]. Although interventions differed between studies, with principally antihypertensive drugs and albuminuria-lowering agents being tested, all these trials pointed out that the CV, mortality, and ESKD risk reductions were strictly associated with a reduction in albuminuria after the start of treatment. Moreover, the magnitude of treatment effect was greater in patients with higher albuminuria levels at the time of the initial visit [95,96]. These findings are reinforced by the evidence that albuminuria changes also played a potentially beneficial role in negative clinical trials. In the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE), which failed in demonstrating the advantage of adding Aliskiren to an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin-receptor blocker (ARB) on CV and renal outcomes, patients who showed an albuminuria reduction in the Aliskiren arm (37%) were largely protected against CKD progression compared with those who did not show a reduction in albuminuria levels [97]. All these pieces of evidence testified that albuminuria has great predictive and prognostic power in CKD patients and, although further studies are needed to find the correct threshold of albuminuria reduction that can confer CV and renal risk protection after an appropriate treatment, there is a general consensus that a 30% reduction in its levels from baseline to six months could be acceptable [98]. With respect to eGFR, it was demonstrated that a doubling of serum creatinine level, which corresponds approximately to a 57% eGFR decline, was able to predict CKD progression in previous clinical trials in diabetic CKD patients [99]. The importance of that evidence is highlighted by the fact that, in these previous trials, eGFR decline correlated with renal outcomes after exposure to nephroprotective treatments, thus affirming its role as a predictive biomarker, in addition to a prognostic biomarker [100]. Since then, the association of lesser eGFR declines with CKD outcomes was tested. A post hoc analysis of the Reduction of End Points in Non-Insulin-Dependent Diabetes with the Angiotensin II Antagonist Losartan (RENAAL) and Irbesartan Diabetic Nephropathy Trial

(IDNT) clinical trials, two studies that evaluated the efficacy of ARB treatment in patients with diabetes mellitus and nephropathy, showed that 30% and 40% eGFR declines may improve the power of clinical trials if the drug investigated does not determine an acute (within three months of the start of treatment) drop in eGFR [101]. A larger meta-analysis of 37 clinical trials in CKD patients documented a strong association between 30% and 40% eGFR decline in the first 12 months of treatment and the onset of kidney disease progression [100].
