Effect of Fosfomycin on Cyclosporine Nephrotoxicity

Abstract

Fosfomycin (Fos) has emerged as a potential treatment against multidrug-resistant organisms, however, there has been little work done on its influence on calcineurin inhibitor nephrotoxicity (CIN). This study was designed to evaluate the effect of Fos in combination with cyclosporine (CsA) on CIN. Two sets of experiments were undertaken. In the first, Wistar rats received different doses of Fos: 0, 62.5, 125, 250, and 500 mg/kg. In the second, rats were divided into four groups: control, CsA 15 mg/kg s.c., CsA + fosfomycin 62.5 mg/kg (CsA + LF), and CsA + Fos 500 mg/kg (CsA + HF). CsA was administrated daily for 14 days, whereas Fos administration started on the ninth day followed by two more doses, delivered 48 h apart. The administration of different Fos doses did not alter renal function. In contrast, CsA induced arteriolopathy, hypoperfusion, a reduction in the glomerular filtration rate, and downregulation of eNOS, angiotensinogen, and AT1R mRNA levels. Lower doses of Fos did not modify CIN. Instead, the CsA + HF group exhibited greater hypoperfusion, arteriolopathy, and oxidative stress, and increased mRNA levels of pro-inflammatory cytokines. This study shows that Fos administered by itself at different doses did not cause renal injury, but when it was given repeatedly at high dosages (500 mg/kg) in combination with CsA, it increased CIN through the promotion of greater oxidative stress and renal inflammation.

Nephroprotective effects of cilastatin in people at risk of acute kidney injury: A systematic review and meta-analysis

“…The nephroprotective effects of cilastatin have been demonstrated in several pre-clinical studies [18][19][20][21][22] and mechanistic effects have been further examined in a number of human studies. [23][24][25][26][27][28][29] The mechanism of action for cilastatin involves counteracting metabolism of nephrotoxic substances in the proximal tubule of the kidney, thereby blocking the uptake of these agents and preventing tubular necrosis through several pathways, including via reactive oxygen species, inflammation, and apoptosis. In addition to reducing nephrotoxin accumulation in renal tubular cells, cilastatin is believed to attenuate leukotriene mediated interstitial inflammation.…”

“…The approval of imipenem-cilastatin for clinical use has enabled several studies in humans that suggest cilastatin has nephroprotective effects against drug toxicity, including from fosfomycin, vancomycin, and cisplatin (23)(24)(25), among subjects undergoing solid organ transplantation (26)(27)(28), bone marrow transplantation (29), cancer therapy (30), treatment of nosocomial pneumonia (31,32), and childhood bacterial infections (33). A previous meta-analysis of studies testing imipenem-cilastatin among kidney transplant recipients receiving cyclosporin reported better kidney function and lower incidence of acute renal failure among patients who received imipenem-cilastatin than those who did not.…”

“…18,[20][21][22] Studies have also shown that cilastatin lowers the risk of kidney injury in rats undergoing kidney transplantation and in those receiving chemotherapeutic agents, without reducing the potency of the anticancer effect of these drugs. 20,22 The approval of imipenem-cilastatin for clinical use has enabled several studies in humans that suggest cilastatin may protect against drug-induced nephrotoxicity, including from fosfomycin, vancomycin, and cisplatin, [23][24][25] among patients undergoing solid organ transplantation, [26][27][28] bone marrow transplantation, 29 cancer therapy, 30 treatment of nosocomial pneumonia, 31,32 and childhood bacterial infections. 33 A previous meta-analysis of studies testing imipenem-cilastatin among kidney transplant recipients receiving cyclosporin reported better kidney function and lower incidence of AKI among patients who received imipenem-cilastatin when compared to a control group.…”