A comprehensive review of acute cardio-renal syndrome: need for novel biomarkers

Abstract

Cardiorenal syndrome represents a wide-spectrum disorder involving the heart and kidneys as the primary affected organs. India has an increasingly high burden of acute CRS, coinciding with the rise in global statistics. Up to 2022, approximately 46.1% of all cardiorenal patients have been diagnosed with acute CRS in India. Acute CRS involves a sudden deterioration of kidney functionalities, referred to as acute kidney injury (AKI) in acute heart failure patients. The pathophysiology of CRS involves hyperactivation of the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS) following acute myocardial stress. The pathological phenotype of acute CRS is associated with perturbed inflammatory, cellular, and neurohormonal markers in circulation. These complications increase the risk of mortality in clinically diagnosed acute CRS patients, making it a worldwide healthcare burden. Hence, effective diagnosis and early prevention are crucial to prevent the progression of CRS in AHF patients. Present biomarkers, such as serum creatinine (sCr), cystatin C (CysC), glomerular filtration rate (GFR), blood urea nitrogen (BUN), serum and/or urine neutrophil gelatinase-associated lipocalin (NGAL), B-type natriuretic peptide (BNP), and NT-proBNP, are clinically used to diagnose AKI stages in CRS patients but are limitedly sensitive to the early detection of the pathology. Therefore, the need for protein biomarkers is emerging for early intervention in CRS progression. Here, we summarized the cardio-renal nexus in acute CRS, with an emphasis on the present clinicopathological biomarkers and their limitations. The objective of this review is to highlight the need for novel proteomic biomarkers that will curb the burgeoning concern and direct future research trials.

Keywords: biomarkers; cardiorenal syndrome; fibrosis; heart failure; kidney failure; proteomics.

FIGURE 1

CRS prevalence in India. Proportion of acute CRS in the Indian population.

FIGURE 2

Burden of CRS in symptomatic patients with acute heart failure worldwide. A consensus study from 2005 to 2020.

FIGURE 3

Gender-based distribution of CRS patients in acute heart failure patients worldwide.

FIGURE 4

Overview of the pathophysiological mechanism of CRS in the setting of acute heart failure. In AHF patients, reduced CO causes renal hypoperfusion and subsequent activation of the renin-angiotensin-aldosterone system (RAAS). As a countermeasure, activation of the sympathetic nervous system (SNS) alongside RAAS enhances the systemic and local inflammatory response. Acute injury to both the heart and kidney releases a spectrum of molecules to circulation, designated as CRS biomarkers. CRS biomarkers from the heart include cardiac troponin (cTn) T or I, natriuretic peptide type-B (BNP), N-terminal proBNP, soluble ST2 (suppression of tumorigenicity 2), galectin-3, and hepcidin. Kidney injury biomarkers for CRS include serum NGAL, KIM-1, and NAG. A reduced GFR and impaired renal function contribute to the release of certain molecules into urine and this serves as an indicator of AKI. Such urinary biomarkers include urinary NGAL, collagen I to VI, KIM-1, cystatin-C, IGFBP7, galectin-3, and TIMP2.

FIGURE 5

Molecular mechanism underlying the inflammatory and fibrotic response in CRS pathophysiology. Acute injury to the heart and subsequently to the kidney causes the release of SDF-1 to circulation. Hyperactivation of RAAS induces the SDF-1- CXCR4 interaction and the infiltration of immune and fibrotic cells to local inflammatory sites. This further aggravates inflammation and fibrosis in damaged organs, reducing their functionalities.