The pattern of CNI nephrotoxicity differs between treatments

Immunosuppressants have greatly improved the outcomes of organ transplantation and calcineurin inhibitors (CNI) have been used extensively to prevent graft rejection since their development over 40 years ago.¹ The most commonly used CNIs are cyclosporine A (CsA) and tacrolimus (Tac), and in the United States, Tac is the most commonly prescribed immunosuppressant (in combination with mycophenolate agents and/or steroids) after kidney transplantation in adults.² CsA was approved by the FDA for immunosuppression following transplantation in 1983, and Tac in 1994. But like many great drugs, there are drawbacks. For CNIs, one of the major adverse effects is nephrotoxicity, which has been investigated extensively and it is known that CsA and Tac in part have a different side effect pattern, but details are still lacking.³ In this issue of Acta Physiologica, Demirci et al. have investigated how CsA and Tac affect the renal compartments, and if there are differences in the mechanisms behind the nephrotoxicity caused by CNIs.⁴ A recent review by Attachaipanich et al. in Acta Physiologica regarding cardiotoxicity after CNI treatment indicate that the cardiovascular toxicity profiles between CsA and Tac differ substantially,⁵ implying that this could be true for other organs as well. Understanding the differences in CsA and Tac nephrotoxicity could improve patient treatment, allowing adapted treatment for each patient and hopefully reducing allograft damage caused by CNIs, alongside careful consideration of the non-renal side effects of the two drugs as well.

Although both CsA and Tac have immunosuppressive properties through the inhibition of the calcineurin/NFAT pathway, the compounds are quite different. CsA is a lipophilic cyclic peptide and Tac is a macrolide antibiotic and they are both derived from fungi. CsA binds to cyclophilins and Tac to FK-binding proteins present in the cytoplasm and both the complexes inhibit calcineurin. Calcineurin is regulated by calcium and calmodulin and activates transcription factors in the NFAT family inducing an immune response with proliferation of T lymphocytes. Calcineurin is not only expressed by lymphocytes but also other cells in the body; hence, the effects of CNIs are not exclusive for lymphocytes. Calcineurin is, for example, involved in regulating the renal potassium and sodium transport in the kidneys, which is reviewed in this number of Acta Physiologica.⁶

To give further insight into the different effects of CsA and Tac on the kidneys, Demirci et al. has explored the effects of CsA and Tac in a rat model, and after 4 weeks of treatment investigating the early chronic phase of nephrotoxicity. The histopathology of the rats has been investigated in great detail in combination with omics techniques (RNA sequencing, global proteomics and phosphoproteomics) to understand the underlying molecular mechanisms. Clinical translatability was investigated in renal biopsies from patients with CNI-caused nephrotoxicity using histopathology. Interestingly, the authors found that although both drugs caused significant damage to the kidneys, there were differences in which and how the renal compartments were affected by the two CNIs. Both drugs lead to similar histopathological damage, such as fibrosis, inflammation, glomerular tuft retraction, and podocyte synechiae in the rats. However, CsA mainly affected the proximal tubules and Tac the microvasculature (glomerular filtration barrier). On the molecular level, the pathways implicating these differences include for Tac; increased activity of the renin–angiotensin system, reduced eNOS function, and impaired VEGF signaling pointing toward endothelial dysfunction. This is further strengthened by the increased loss of endothelial fenestrations in Tac-treated rats. The podocytes were more severely affected by Tac treatment compared to CsA treatment, further implying that Tac has more severe effects on the filtration barrier compared to CsA treatment. In contrast, CsA displayed more damage to the tubules, with increased heterolysosome accumulation in the proximal tubules, and omic signatures pointing at cytotoxic UPR (unfolded protein response) signaling and altered autophagic flux. It is worthy to note that the pathway analysis of the omics did not overlap between the CsA- and Tac-treated rats, although several common pathological changes were observed by the histopathology analysis. Validation in the human setting investigating the histopathological changes in biopsies with CNI-induced nephrotoxicity displayed the normal findings of arteriolar toxicity and glomerulosclerosis and also confirmed the specific glomerular and tubular alterations found in the rat model.⁴

Overall, this study gives new and valid information about the mechanistic differences in nephrotoxicity caused by CsA and Tac. This could be beneficial in the future for patients when selecting treatment regimens to reduce the nephrotoxic effects of the CNIs. The findings in the rat studies are important and are partly validated by the findings in the human biopsies, but further validation in human studies is needed to fully translate the findings to the human setting. In particular, omic data from patient kidney biopsies to compare with the rat signatures would be of great value. To further translate the compartmentalized findings in the kidney, single cell transcriptomics would be of value as indeed also proteomics. In addition, it is important to consider the dosage and time frame of treatment in the rat model when interpreting the translatability to the human setting.

In conclusion, this study contributes to the understanding of the differences in nephrotoxicity between the most commonly used CNIs, giving further insight into the molecular mechanisms behind the differences. Since CNIs are such cornerstones of immunosuppressive therapy in solid organ transplantation, these results highlight the need for personalization of treatment in this field and the article gives substantial input to such a path forward.

JN and KE drafted, wrote and edited the paper together.

The authors have nothing to disclose.