A NEW AKI TO CKD PROGRESSION IN VIVO EXPERIMENTAL MODEL

Abstract Background and Aims Chronic kidney disease (CKD) represents an enormous problem for healthcare systems. It is estimated that in USA more than 37 million people suffer from this disease. Risk factors include hypertension, diabetes mellitus, older age, proteinuria and previous episodes of acute kidney injury (AKI). Indeed, several studies have shown that AKI increases the risk of CKD, independently of other risk factors, especially when the episode is severe or recurrent. Under these circumstances, maladaptive responses may occur leading to structural and functional abnormalities. Renal fibrosis is the hallmark for maladaptive repair and is considered the final common outcome of progressive kidney disease. We hypothesized that after multiple renal insults, the mechanisms of adaptive repair could be less effective generating a progressive accumulation of extracellular matrix and a progressive deterioration of kidney function. Method We used 8 weeks old male Wistar rats and we analyse their evolution during 9 months. Animals were subdivided into 4 experimental groups: Control group: SHAM operated rats, saline solution, i.p.; “CDDP5-I/R60-I/R60” group: 5 mg/kg cisplatin i.p., after renal function normalization, 60-minute ischemia-reperfusion (I/R60) on left kidney, and 2 weeks later 60-minute ischemia-reperfusion (I/R60) on right kidney; “5/6 RMR” group: 5/6 renal mass reduction; “UNX” group: nephrectomy. Blood and urine were collected at: day 0 (basal); day 4 (AKI development); day 8 (normalized renal function after AKI and induction of renal ischemia); day 9 (1 day after ischemia); day 13, day 20 and monthly thereafter. Renal function was analyzed by sCr, creatinine clearance, blood urea nitrogen and proteinuria determination using colorimetric methods. Tissue samples were stained with Masson´s trichrome and Sirius Red at days 13, 20, 56, 165 and 270 and renal fibrosis was quantified using Image J program. Results The addition of several AKI episodes induces a progressive accumulation of extracellular matrix. In addition, the “CDDP5-I/R60-I/R60” group presented an initial reduction in renal function that remained stable in the last 6 months of the study. On the contrary, we observed a spontaneous and progressive decline of kidney function in the “5/6 RMR” group, which nevertheless presented a significant lower degree of interstitial fibrosis than the “CDDP5-I/R60-I/R60” group. Conclusion We have generated a new in vivo experimental model of AKI to CKD transition combining nephrotoxic and ischemic AKI. We demonstrate that after recurrent episodes of AKI, kidneys show progressive interstitial fibrosis which however does not correlate with a progressive decline of renal function.