Impact of a Mineralocorticoid Receptor Antagonist on Chronic Histological Changes in Renal Allograft

Chronic allograft nephropathy (CAN) is the main cause of long term kidney transplant failure. Its main histological determinant is interstitial fibrosis and tubular atrophy, but mechanisms of these changes are not completely elucidated and seem to be multifactorial. It seems that these histological changes develop as a consequence of immunological and non-immunological mechanisms. Study from Nankivell and al. defined two phases of CAN, early, attributed to immunological mechanisms; acute rejection, persistent subclinical rejection and ischemic- reperfusion injury, and late injury, characterized with progressive arteriolar hyalinosis, glomerulosclerosis andInterstitial fibrosis and tubular atrophy (IF/TA), which was attributed in part to calcineurin inhibitor use and in part to ongoing immunologic injury.

In vitro studies and animal studies have shown epithelial mesenchimal transition as one of possible mechanisms and early markers of subsequent IF/TA. EMT is defined as process where completely differentiated epithelial cells undergo transition into fibroblast phenotype cells.

It is known that on molecular level RAAS has crucial role in development of progressive renal injury and fibrosis. Role of angiotensin II in progression of chronic kidney injury is established and well known. It mediates kidney injury by increasing intraglomerular capillary pressure leading to ultrafiltration of plasma proteins and by promoting cell growth and fibroproliferative effects.

It is hypothesized that aldosterone as a component of RAAS may also have direct role in proinflammatory and profibrotic mechanisms of initiation and progression of kidney injury. Aldosterone is a mineralocorticoid hormone produced in adrenal cortex zona glomerulosa and has crucial role as a regulator of extracellular fluid volume and sodium and potassium balance.

It has been shown in the rat models that aldosterone activates mTOR kinase, which promotes cell proliferation and contributes in early phases of injury healing. However, a prolonged activation of mTOR seems to promote development of interstitial fibrosis.