*4.3. Ultrasound Biomarkers*

Evidence is also emerging for a possible role of the renal resistive index (RRI) as a dynamic predictive biomarker. RRI is a Doppler ultrasonographic index, whose increase reflects both renal and systemic vascular impairment [105]. RRI was also found to predict the onset of CV and kidney outcomes in patients with CKD or essential hypertension [106,107]. RRI values are changed over time by different drug classes, such as RAAS-i and SGLT2-i; novel studies will hopefully reveal in the future if these treatment-induced modifications could also predict hard CV and renal endpoints [108,109].

## *4.4. Predictive Role of Proteomics, Metabolomics, and Genomics*

A polymorphism of the angiotensin-converting enzyme gene caused by an insertion/deletion (ACE/ID) modifies the systemic and renal activity of the RAAS, which was recognized to be a trigger of kidney damage [110]. The ACE/DD–ACE/ID polymorphism was able to predict the response to losartan in type 2 diabetic patients enrolled in the RENAAL trial, that is, patients with worse prognosis (D allele carriers) had the best response to losartan [111]. Complex biomarkers and classifiers have a predictive role, in addition to a prognostic role. A set of 21 serum metabolites were selected from a larger panel through a penalized regression analysis, and they were shown to correctly predict the albuminuria response to ARB treatment in type 2 diabetic patients [112]. This classifier revealed that the enzyme nitric oxide synthase 3 (NOS3) is crucial to forecast the response to ARB therapy in diabetic CKD, since it is involved in the molecular mechanism of action of these drugs. A proteomic predictive classifier was developed from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, using plasma proteomics profiles of fibrosis and kidney damage that allowed predicting the albuminuria change in patients treated with RAAS-i [113]. The principal characteristics of prognostic and predictive biomarkers are depicted in Table 1.





chemoattractant

inhibitors; RENAAL, Reduction of End Points in

angiotensin-receptor

 blockers.

 protein-1; MPO,

Myeloperoxidase;

 RRT, Renal Replacement

Non-Insulin-Dependent

 Therapies; RAAS,

 Diabetes with the Angiotensin II Antagonist Losartan; CRIC, Chronic Renal Insu

Renin–Angiotensin–Aldosterone

 System; SGLT2-i,

sodium–glucose

 cotransporter fficiency Cohort; ARBs

 2
