Frey, Felix J.

Marti, Hans-Peter

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Nephrol Dial Transplant (2005) 20: 13–15doi:10.1093/ndt/gfh639Nephrotoxicity of rapamycin: an emerging problemin clinical medicineHans-Peter Marti1 and Felix J. Frey21Division of Nephrology, Department of Medicine, University Hospital of Zurich, Zurich and 2Department of Nephrologyand Hypertension, Inselspital, University of Berne, Berne, SwitzerlandKeywords: cyclosporine; everolimus; nephrotoxicity;rapamycin; renal allograft; sirolimusIntroductionRapamycin represents substantial progress as a main-tenance immunosuppressive agent to prevent rejectionepisodes and to decrease steroid and calcineurininhibitor (CNI) exposure [1–3]. This drug is com-monly administered in combination with mycophenol-ate mofetil, an inhibitor of inosine monophosphatedehydrogenase, or with azathioprine, a purine anti-metabolite. Furthermore, rapamycin is prescribed asa substitute for or in combination with CNI.The macrocyclic lactone rapamycin or sirolimus(Rapamune) and its more polar derivative ever-olimus (Certican) exhibit a similar mode of actionbut a different pharmacokinetic behaviour. Everolimusshows a shorter elimination half-life (30 vs 60 h) anda higher bioavailability [4,5].In the absence of concomitant use of CNI,rapamycin was shown repeatedly to spare renalfunction. To the surprise of the transplant community,evidence for rapamycin-associated nephrotoxicity hasbeen accumulating in the last few years. In line withsuch observations, Crew et al. [6] describe two patientswith thrombotic microangiopathy as a result ofrapamycin exposure and suggest potential mechanismsof the disorder in this edition of NDT. Thus, deﬁnitely,the question has to be addressed whether nephrotoxi-city of rapamycin represents a relevant problem inclinical practice.Evidence of rapamycin nephrotoxicityin kidney transplantationRandomized phase-III trials (US trial and global trial)conducted over 24 months and comprising almost1300 renal allograft recipients treated with cyclosporininvestigated the efﬁcacy and safety of the concurrentadministration of sirolimus in doses of 2 or 5mg/day vsplacebo or azathioprine [7]. Mean values of serumcreatinine concentrations in patients treated withsirolimus were higher than in subjects treated withplacebo or azathioprine (175 vs 137 mmol/l) [7]. Theaddition of sirolimus revealed a pharmacokineticinteraction, since 20% lower doses of cyclosporinwere required to achieve target levels in patientstreated with cyclosporin and rapamycin than inpatients exposed to cyclosporin plus azathioprine orplacebo. Nevertheless, the 1 year graft survival rates inpatients on rapamycin were similar and the rejectionrates lower, suggesting nephrotoxicity of rapamycinrather than under-immunosuppression.In a prospective study, high-risk renal allograftrecipients (79% African-Americans, 59% delayed graftfunction, high proportion of marginal kidneys) wererandomized to receive, following thymoglobulin induc-tion, either standard tacrolimus (10–15 ng/ml) plusreduced sirolimus (5–10 ng/ml; group I, n¼ 16)or reduced tacrolimus (5–10 ng/ml) plus standardsirolimus (10–15 ng/ml; group II, n¼ 23) [8]. Althoughthe outcome at 6 months was identical between the twogroups, 38% of patients from group I neededdiscontinuation of tacrolimus due to biopsy-proventacrolimus nephrotoxicity. Therefore, a reduced qual-ity of the grafts may render them more susceptible tonephrotoxicity of this drug combination.Furthermore, two cases of acute oliguric renalallograft failure due to suspected acute tubular necro-sis (one case biopsy-conﬁrmed) associated with thecombined use of tacrolimus and sirolimus weredescribed [9].In a recent retrospective analysis, the inﬂuence ofimmunosuppression on delayed graft function (DGF)was investigated in 144 kidney transplant patientstreated with tacrolimus with or without rapamycin [1].DGF occurred almost three times more often insubjects treated with rapamycin than without (25%vs 8.9%), and was correlated positively with drug doseCorrespondence and offprint requests to: Professor Felix J. Frey,Department of Nephrology and Hypertension, Inselspital Berne,University of Berne, 3010 Berne, SwitzerlandEmail: felix.frey@insel.chNephrol Dial Transplant (2005) 20: Editorial Comments 13Nephrol Dial Transplant Vol. 20 No. 1  ERA–EDTA 2005; all rights reserved(odds ratio: 1.1 per mg). In addition, a subset ofrapamycin-treated patients developed cast nephrop-athy, reminiscent of myeloma cast nephropathy. Theseobservations are in line with the results from anotherretrospective clinical study examining 132 renal allo-graft recipients who developed DFG (23.4%) from atotal of 563 adults [10]. Recipients of sirolimus werehalf as likely to resolve DGF or twice as likely toremain on dialysis as subjects without this agent [10].In a recent 12 month analysis of 634 cyclosporin-treated heart transplant patients, the concurrentadministration of everolimus and cyclosporin led to asigniﬁcant increase in serum creatinine levels beginningon day 28, as compared with the use of azathioprine[11]. Importantly, cyclosporin drug concentrationswere not different among the different groups.Thus, in patients with an allograft, the combina-tion of a CNI (cyclosporine) and sirolimus/everolimusis deﬁnitely associated with higher serum creatinineconcentrations than a CNI combined with the otherimmunosuppressive agents.Nephrotoxicity of rapamycinin glomerulonephritisReports of rapamycin-associated nephrotoxicity innative kidneys are sparse due to its preferential usein transplantation medicine. The largest clinical studyincluded 11 patients suffering from chronic glomer-ulonephritis (GN) with moderate kidney failure andproteinuria (1 g/day) [12]. Within the ﬁrst 6 weeks ofrapamycin therapy (5mg/day), six subjects developedacute kidney failure with improvement of kidneyfunction after discontinuation of rapamycin in ﬁvecases. However, no biopsies were performed in thesepatients and the mechanism of rapamycin-associatednephrotoxicity remained unclear.In addition, a recent investigation described fourpatients with chronic allograft dysfunction who devel-oped biopsy-conﬁrmed post-transplantation GN withnephrotic-range proteinuria 2–9 months after conver-sion of a CNI-containing regimen to rapamycin [13].Stabilization of kidney function and complete remis-sion of proteinuria occurred in all cases after reintro-duction of CNI.Mechanisms of rapamycin-associatednephrotoxicityRapamycin may display direct tubular or, to a lesserdegree, glomerular toxicity and may also potentiateCNI nephrotoxicity.Sirolimus and everolimus bind to FKBP12 andinhibit mTOR, later identiﬁed as FRAP kinase [4],a key regulator of cell proliferation, growth, apoptosisand survival in response to growth factors and cyto-kines [1,4,14]. FRAP kinase belongs to the phospha-tidylinositol kinases, crucial for the progression of thecell cycle from G1 to S phase by signalling through thep70 S6 kinase and eIF4E-binding protein [4].Rapamycin exposure leads primarily to cell-cyclearrest in the early G1 phase of T and B lymphocytes[4,10]. Following transplantation, rapamycin preventsacute rejection by inhibition of cytokine and growthfactor-mediated lymphocyte proliferation, especiallythe proliferation and clonal expansion of interleukin-2-stimulated T lymphocytes [15]. Importantly, othercells are also a direct target of this drug, includ-ing endothelial, smooth muscle, mesangial and renaltubular cells [1,12,16]. Furthermore, rapamycin maypromote the ‘default way’ of apoptosis by inhibitingthe activity of ‘survival factors’ and of p70 S6 kinase[15,17].Importantly, rapamycin inhibits growth factor-induced proliferation of cultured proximal tubular cellsand supports their apoptosis by blocking the survivaleffects of the same growth factors [15]. Accordingly,rapamycin impaired recovery from experimental acuterenal failure induced by renal artery occlusion due tothe combined effects of increased tubular cell loss(apoptosis) and inhibition of regenerative proliferation[15]. These effects were attributable to the inhibition ofp70 S6 kinase [15].In addition, rats given rapamycin (3 mg/kg/p.o.) for2 weeks on a low-salt diet developed magnesium wast-ing and structural renal lesions consisting of tubularcollapse, vacuolization and nephrocalcinosis [18].Thus, during periods of renal allograft injury,rapamycin may be harmful due to its negative effectson tubular cell regeneration and survival [1,15].The same may be true at the glomerular level ininﬂammatory states that require intact cell prolifera-tion for repair and/or compensatory mechanisms [12].In addition, rapamycin may potentiate tubular toxicityof proteinuria per se [12].Toxicity of rapamycin, indeed, depends upon thetype of GN, as ﬁrst reported by our group in experi-mental GN models [19]. We demonstrated thateverolimus highly accentuated acute mesangial prolif-erative anti-Thy1.1 nephritis, reﬂected by severeglomerular destruction with areas of necrosis, kidneyfailure and increased proteinuria. In contrast, a signiﬁ-cant reduction of proteinuria was achieved as a resultof everolimus exposure in the non-proliferative acutepuromycin aminonucleoside nephrosis [19]. In additionto the antiproliferative effect, everolimus also inhibitsmesangial cell migration, mediated by preventing thedecrease in the CDK-inhibitor p27 KIP1 induced bygrowth factors [20]. In this respect, particular cautionmay be warranted for the use of rapamycin inantibody-mediated forms of proliferative GN.Pharmacokinetic and possibly also pharmacody-namic interactions of CNI and sirolimus are anotherpotential mechanism of nephrotoxicity. Because ofthe shared metabolism by the P-450 (CYP) 3A4 andcompetition for the extrusion by the p-glycoproteinmechanism, blood and tissue levels of both cyclosporinand rapamycin can be increased if administeredconcurrently [1,7,21–24]. Possibly, the same is truefor the tacrolimus and rapamycin combinationwith respect to an intracellular accumulation resulting14 Nephrol Dial Transplant (2005) 20: Editorial Commentsin direct tissue injury [1,8,12,25]. However, unlikethe cyclosporin/sirolimus combination, sirolimus/tacrolimus pharmacokinetics appears to remainessentially unchanged following their simultaneousadministration [23,24].In addition, a possible potentiation of CNI nephro-toxicity by sirolimus or everolimus per se unrelatedto changes in drug levels was proposed also [11]. Thismay be especially true in cases of tissue regenerationfollowing injury.ConclusionsRapamycin and its derivative everolimus appear not tobe nephrotoxic to the healthy, predominantly quies-cent kidney. However, in vitro studies and observationsin animals and humans indicate that these agents arenephrotoxic in disease states. Evidence is growing thatthe same mechanisms that lead to excellent immuno-suppression may also impair recovery of tissue injury.Therefore, the administration of rapamycin mayexacerbate pre-existing or newly occurring renallesions.This might explain why renal function deterioratesin patients with kidneys in the process of repairingtubular cells (delayed graft function and acute tubularnecrosis), endothelial cells (thrombotic microangio-pathy and GN) or mesangial cells (GN).Acknowledgements. This work was supported by the SwissNational Foundation for Scientiﬁc Research by grant nos.404640-101082 (NFP-46) to H.-P.M. and 3100-102153 to F.J.F.Conﬂict of interest statement. Both authors are supported by thecompanies Novartis Pharma AG, Switzerland and Wyeth, USA.[See related article by Crew et al. (this issue pp. 203–209)]References1. Smith KD, Wrenshall LE, Nicosia RF et al. Delayed graftfunction and cast nephropathy associated with tacrolimus plusrapamycin use. 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Nephrotoxicity of rapamycin: an emerging problem in clinical medicine

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