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Page 12 of 19 Cervantes-Gracia et al. Vessel Plus 2020;4:27 I http://dx.doi.org/10.20517/2574-1209.2020.22

expression in many animal models [168,169] . Resident kidney cells, such as tubular epithelial cells, endothelial
cells, mesangial cells and podocytes can all produce and release IL-6. A study has shown that, in a model of
ischemia-reperfusion injury, after leukocytes penetrated the injured kidney, maladaptive IL-6 was produced
in response to their TLR-4 receptors interacting with high mobility group box 1 protein released by the
[170]
injured renal cells . Raised levels of the pro-inflammatory cytokines, IL-8 and IL-6, have been seen early
[171]
on in AKI patients and were linked to prolonged mechanical ventilation .
The transmembrane protein, kidney injury molecule 1 (KIM-1), recognizes apoptotic cells and leads
them to lysosomes. Additionally, it acts as a receptor for oxidized lipoproteins and is therefore adept at
recognizing apoptotic cell signals. KIM-1 is undetectable in normal kidney tissue but is highly expressed
following toxic or ischaemic injury in differentiated proximal tubule epithelial cells from rodent and
human kidneys [172,173] . Plasma cystatine-C (CysC), is a low molecular weight protein produced at a
predictable rate by all nucleated cells. CysC is filtered across the glomerular membrane but is neither
reabsorbed nor secreted during its passage through the nephron. Given that CysC is almost entirely
catabolized in the proximal tubule, it is impossible to measure its renal clearance. However, the plasma or
serum concentration of CysC accurately reflects the GFR and significant increases in CysC are detected
in CIN patients after 8 h. However, a similar increment has also been seen in several other conditions,
including thyroid dysfunction, age, an increase in muscle mass, systemic inflammation, corticosteroids
[174]
administration and neoplasia limiting its utility as a CIN biomarker.
The key diagnostic criterion for CIN is the elevation of serum creatinine concentration by more than 25%
over baseline, after eliminating any other possible causes. Other laboratory findings may also be present such
as hyperkalaemia and acidosis. Although patients may have normal urine output, they can also suffer from
anuria (failure of the kidneys to produce urine) or oliguria (low output of urine > 80 mL/day, < 400 mL/day).
Findings on urine analysis are normally non-specific [175] . Normally a delay of 24-48 h is seen between
contrast exposure and changes in serum creatinine concentration, which makes creatinine a late indicator
[176]
of renal function changes .

Since a close correlation among inflammatory molecules and kidney injury in CIN has been observed, as
described above, they have also been proposed as potential CIN biomarkers [Table 1]. IL-8 and IL-6, have
been seen early on in AKI patients and were linked to prolonged mechanical ventilation [171] . Successive
studies have recognized renal NGAL as a unique, specific biomarker for the early detection of AKI in
critically ill patients and after CM administration [154-157] . Other proposed biomarkers, despite being effective
predictors of AKI, such as uNGAL triggered preceding increases in serum creatinine concentration [157,158]
are still experimental. Other potential biomarkers have been deemed as non-specific, such as L-FABP,
although significantly increased in CIN patients after 24 h, where potential confounders lower its
[159]
specificity .

CONCLUSION
Oxidative stress influences cardiovascular morbidity mainly through increased peripheral vascular
resistance [Figure 1]. However, although the generation of ROS could affect renal blood flow by facilitating
the production of vasoconstrictors and impacting the effects of vasodilators, the influence of oxidative
stress in the development of CIN is uncertain.

Inflammation results in the alteration of homeostasis in both the circulatory and renal systems. These
alterations can be intrinsic of cellular damage or can be mediated by external factors such as CM. Immune
response to CM cytotoxicity causes a rapid increase in the migration and accumulation of cytokines such
as ILs and TNF-a in the progression of both CVD and CIN. Additionally, the presence of cellular types
found in response to inflammation is a feature in early development of CVD and CIN. The main interplay