Calcineurin inhibitors: a double-edged sword

Abstract

Recently, research has directed its interests into identifying molecular pathways implicated in calcineurin inhibitor (CNI)-induced renal fibrosis. An emerging body of studies investigating calcineurin (CnA) activity has identified distinct actions of two main ubiquitously expressed isoforms: CnAα and CnAβ. CNIs have the capacity to inhibit both of these CnA isoforms. In the kidney, CnAα is required for development, whereas CnAβ predominantly modulates the immune response and glomerular hypertrophic signaling powered by activation of the transcription factor, Nuclear Factor of Activated T lymphocytes (NFAT). Interestingly, data has shown that a loss of CnAα activity contributes to the expression of profibrotic proteins in the kidney. Although this finding is of great significance, follow-up studies are needed to identify how loss of the CnAα isoform causes progressive renal damage. Additionally, it is also necessary to identify downstream mediators of CnAα signaling that assist in upregulation of these profibrotic proteins. The goal of this review is to provide insight into strides taken to close the gap in elucidating CnA isoform-specific mechanisms of CNI-induced renal fibrosis. It is with hope that these contributions will lead to the development of newer generation CNIs that effectively blunt the immune response while circumventing extensive renal damage noted with long-term CNI use.

Evaluating Efficacy and Safety of Tacrolimus Treatment in Membranous Nephropathy: Results of a Retrospective Study of 182 Patients

“…Tacrolimus-related nephrotoxicity is associated with reversible or irreversible histological damage to the kidney, which can occur in the glomeruli, arterioles, and tubular interstitium, but most lesions are non-specific. 33 , 34 In addition, elevated blood glucose, gastrointestinal symptoms, hepatotoxicity, hypertension, gouty arthritis, tremor, infection, and rarely epilepsy have been reported during treatment with tacrolimus. 35 In this study, 11.0% patients experienced a ≥50% increase in serum creatinine.…”

Frequency of Histological Patterns of Renal Allograft Biopsies– One Year of Renal Allograft Experience

“…Another matter of particular interest is the effect of calcineurin inhibitors as cornerstones for immunosuppression in the early phase following renal transplantation. 20 Their adverse effect profile renders the transplant non-viable in certain cases by causing acute kidney injury and ultimately graft rejection. This toxicity is seen acutely, and its role in chronic rejection is controversial.…”

From KDIGO 2012 towards KDIGO 2021 in idiopathic membranous nephropathy guidelines: what has changed over the last 10 years?

“…Even though the exact "point of no return" was not clearly defined, the above findings, combined with histological evidence of extensive interstitial fibrosis, tubular atrophy and glomerular sclerosis (according to some authors involving > 50% of the glomeruli), were considered to significantly reduce response probability, making the risks of immunoosuppressive drugs unacceptable [5,6]. In this regard it is important to consider the regimens proposed for IMN treatment: the pharmacokinetics of cyclophosphamide, the alkylating agent of preference, is altered in patients with reduced eGFR, requiring dose adjustment [5,7,8], while CNIs are nephrotoxic [9,10].…”

“…The use of alkylating agents has been linked to better chances of preserving eGFR, thus preventing end stage renal disease, as well as lower mortality rates. Patients receiving CNIs display a higher risk of severe deterioration of kidney function [14,19,[27][28][29] due to their timedependent and non-reversible nephrotoxicity, related to increased transforming growth factor β (TGF-β) activity and characterized by the development of interstitial fibrosis and glomerulosclerosis [9,10,34,35]. On the other hand, CNIs are more effective than alkylating agents in achieving rapid remission, while the difference is not significant in longer follow-up [19][20][21][22].…”