Cyclosporine A nephropathy, its pathogenesis and management

CsA, obtained from a fungus called Tolypocladium inflatum came into medical use in 1983. Organ transplants have shown great success after the use of Cyclosporine, especially in 3and 5-year graft survival. However, nephrotoxicity seen in the early and late periods complicates its use. It is very important to distinguish especially early toxicity from rejection attacks; because the treatments of both processes are completely different. While vasocostriction in the renal artery system is prominent in the early period, the underlying factor for late toxicity is the thickening of the arteriolar intima and the consequent decrease in tissue oxygenation. The article discusses the variants of toxicity caused by the use of cyclosporin A. Morphological changes with the use of cyclosporin A are shown in rat models. The results of our own observations on the use of prostaglandin, which demonstrated the effect of vasodilation, are also presented, which can probably be used for further studies in order to reduce the nephrotoxicity of cyclosporin A. In particular, we found that PGE2 significantly reduced vasoconstriction and reduced the toxic effect due to CsA. The limitations was the usage of these agents once, so we couldn’t continue and only gave them intravenously. However, the results obtained were found to be significant.

Since CsA is metabolized in the liver via the P450 cytochrome enzyme system, it interacts with many drugs that alter this enzyme system. Ketoconazole, cimetidine, erythromycin and corticosteroids increase blood levels of CsA by inhibiting P450 enzyme. Phenytoin, rifampicin, isoniazid, and trimethoprim decrease CsA levels by inducing P450 [10][11][12].
The nephrotoxic effect of CsA is enhanced when Amphotericin B is co-administered with aminoglycosides, melphalan and Co-trimoxasole [12].
In addition, there is no difference between CsA and conventional immunosuppressive therapy in terms of the risk of developing lymphoma and non-lymphoma malignant diseases [13,14].  Organ transplants have shown great success after the use of Cyclosporine, especially in 3-and 5-year graft survival. However, nephrotoxicity seen in the early and late periods complicates its use. It is very important to distinguish especially early toxicity from rejection attacks; because the treatments of both processes are completely different. While vasocostriction in the renal artery system is prominent in the early period, the underlying factor for late toxicity is the thickening of the arteriolar intima and the consequent decrease in tissue oxygenation. The article discusses the variants of toxicity caused by the use of cyclosporin A. Morphological changes with the use of cyclosporin A are shown in rat models. The results of our own observations on the use of prostaglandin, which demonstrated the effect of vasodilation, are also presented, which can probably be used for further studies in order to reduce the nephrotoxicity of cyclosporin A. In particular, we found that PGE2 significantly reduced vasoconstriction and reduced the toxic effect due to CsA. The limitations was the usage of these agents once, so we couldn't continue and only gave them intravenously. However, the results obtained were found to be significant. Vol. 10, No. 4, 2021
A) Functional toxicity. A slight decrease in renal function can be observed in almost all patients with daily administration of 10 mg/kg oral CsA after transplantation. The serum creatinine level is slightly increased. It returns to normal with decreasing the CsA dose [13]. Hypertension develops in half of the patients [15]. CsA is thought to exert a selective vasoconstriction on renal vessels, particularly on arterioles [13]. Its mechanism has been tried to be explained in four ways: 1) direct effect on renal vessels [13]; 2) adrenergic system stimulation [16-18]; 3) stimulation of the tubuloglomerular feedback mechanism [19,20]; 4) effects on renal prostaglandin synthesis [3,13]. B) Tubular toxicity. The findings are not different from those seen in functional nephrotoxicity. But the serum creatinine level is hi gher, it can be more than twice the normal [13,15].
The main etiological factor in the development of tubular toxicity is high CsA levels. This level is usually above 200 ng/ml [15]. C) Vascular-interstitial toxicity. The patient has a slow but progressive deterioration in kidney function, resulting in hypertension. Initially, the glomerular filtration rate and renal plasma flow decrease. Then serum creatinine increases; proteinuria is mild or absent. With the discontinuation of CsA, some patients may have an improvement in renal function, but most do not. As a sign of vascular damage, some patients have increased plasma levels of endothelial-derived factor VIII and antithrombin [13,15].
Renal vasoconstriction is shown as the main cause of CsA-induced nephrotoxicity ( fig. 3). For this reason, the first thing that comes to mind for the prevention or treatment of renal toxicity is to reduce the dose of CsA or to replace it with another immunosuppressive. Although FK506induced nephrotoxicity is observed, it is not as severe as CsA Запрошені статті / Guest Articles as is known. That's why Tacrolimus seems like an option. The newly introduced co-stimulator blockers are another option. However, the high risk of infection in these should not be ignored.
In a study we conducted on rats, we tried PGI2 (prostacyclin) and PGE2, which have vasodilator effects, in this context. In particular, we found that PGE2 significantly reduced vasoconstriction and reduced the toxic effect due to CsA. Our problem here was that we only used these agents once, so we couldn't continue and only gave them intravenously. However, the results obtained were found to be significant. Vol. 10, No. 4, 2021

Conflicts of interests.
Author declares the absence of any conflicts of interests and their own financial interest that might be construed to influence the results or interpretation of their manuscript.