The Interplay between inflammation and fibrosis in kidney transplantation

Abstract

Serial surveillance renal allograft biopsies have shown that early subclinical inflammation constitutes a risk factor for the development of interstitial fibrosis. More recently, it has been observed that persistent inflammation is also associated with fibrosis progression and chronic humoral rejection, two histological conditions associated with poor allograft survival. Treatment of subclinical inflammation with steroid boluses prevents progression of fibrosis and preserves renal function in patients treated with a cyclosporine-based regimen. Subclinical inflammation has been reduced after the introduction of tacrolimus based regimens, and it has been shown that immunosuppressive schedules that are effective in preventing acute rejection and subclinical inflammation may prevent the progression of fibrosis and chronic humoral rejection. On the other hand, minimization protocols are associated with progression of fibrosis, and noncompliance with the immunosuppressive regime constitutes a major risk factor for chronic humoral rejection. Thus, adequate immunosuppressive treatment, avoiding minimization strategies and reinforcing educational actions to prevent noncompliance, is at present an effective approach to combat the progression of fibrosis.

Figure 1

Renal transplant-induced fibrosis involves a complex multifactorial inflammatory process with the participation and interaction of infiltrated cells with different cell types in the kidney and is orchestrated by a network of cytokines/chemokines, growth factors, adhesion molecules, and signalling processes. These events include several phases in a dynamic process in which many of these events occur simultaneously, often in a mutually stimulating fashion.

Figure 2

Progression of fibrosis after kidney transplantation. Fibrosis is already present in a proportion of grafts, especially in renal allograft obtained from expanded criteria donors. Ischemia/reperfusion (I/R) injury and alloimmune response trigger inflammation and its severity is modulated by immunosuppressive treatment. Subclinical inflammation can be ameliorated by treatment with steroid boluses or by increasing exposure to immunosuppressive drugs. Quiescent interstitial fibrosis/tubular atrophy (IF/TA) may represent the healing of the inflammatory insult while inflammation in areas of fibrosis (i-F/TA) and antibody-mediated rejection (ABMR) due to the appearance of de novo donor specific antibodies (DSA) may represent an ongoing inflammatory response that is associated with decreased allograft survival.