*4.2. Chronic CNI Nephrotoxicity*

Some other studies identified potential specific biomarkers for chronic CNI nephrotoxicity, which are outlined in Table 9.

Chronic ischemia due to the vasoconstrictive effect of CNI triggers an alteration in expression of proteins involved in pro-inflammatory response and oxidative stress; however, the renal histology of chronic CNI nephrotoxicity is not peculiar (it may in fact merely determine IFTA) and this hampers efforts to identify specific biomarkers [176].

A metabolomic study compared urine from healthy subjects and KTx recipients with biopsy-proven chronic TAC nephrotoxicity and proposed symmetric dimethylarginine and serine as marker of this type of kidney injury (ROC analysis AUC of 0.95 and 0.81, respectively) [177].

uNGAL was proved to correlate with duration of CsA therapy in children with CNI nephrotoxicity [178]. A SNP in the FK-506-binding protein (FKBP), rs6041749 C variant, appeared to enhance FKBP1A gene transcription compared to the T variant and was associated with an increased risk of CAD in a Chinese cohort of TAC-treated KTx recipients, although with an unclear mechanism [179].

Other studies in rat models have reported increased urinary levels of TNAα, LIM-1, and FN in the early phase of CsA nephrotoxicity and late increases of urinary Osteopontin and TGF-β in chronic nephrotoxicity [180].

Decreased expression of Slc12a3 and KS-WNK1, leading to impaired sodium transport in distal tubules and chronic activation of renin-angiotensin system, was associated with CsA and TAC nephrotoxicity in another rat model [181]. Potential biomarkers identified in the last two experimental studies need to be validated in humans.


**Table 9.** Potential biomarkers for chronic calcineurin-inhibitor (CNI) nephrotoxicity.
