Kidney International, Vol. 50 (1996), pp. 1089—1100

PERSPECTIVES IN CLINICAL NEPHROLOGY

Chronic cyclosporine nephropathy: The Achilles' heel of

immunosuppressive therapy

In the past 15 years, short-term success rates for allografts ofkidney, heart, liver, and kidney/pancreas have reached unprece-dented levels largely due to cyclosporine-based immunosuppres-sive regimens. Most transplant centers around the world achieve85 to 90% one-year graft survival for kidney transplants and veryfew patients suffer loss of life because of modern medical man-agement [1, 2]. These impressive results with cyclosporine haveextended the indications for cyclosporine usage from organtransplantation to the treatment of autoimmune and primaryrenal diseases. However, nephrotoxicity due to cyclosporine con-tinues to be a major problem [3]. In spite of improved one- andtwo-year renal allograft graft survival rates, the average half-life ofeight years for a cadaver kidney transplant that is functioning atone year has changed little with the addition of cyclosporine-based immunosuppression [4, 1. Conventional wisdom suggeststhat chronic allograft failure in kidney transplants is largely due tochronic rejection [6]. However, the adverse effects of cyclosporineon long-term kidney structure and function have not been ex-cluded as an important part of the chronic allograft failuresyndrome. An important role for cyclosporine on chronic progres-sive renal dysfunction when used outside the renal transplantsituation is well accepted. This communication will review theentity of chronic cyclosporine nephropathy. The current literatureabout this subject will be analyzed and its presumed pathogenesiswill be reviewed with an emphasis on recent studies indicating thatcyclosporine-induced renal fibrosis may be an inevitable conse-quence of effective immunosuppressive therapy.

Renal effects of cyclosporine

It is well-known that cyclosporine causes a dose-related de-crease in renal function in experimental animals and humans. Thisis largely thought to be due to the drug's hemodynamic effects toproduce afferent arteriolar vasoconstriction and in the extreme,decreased glomerular filtration rate (GFR), manifested clinicallyby rises in serum creatinine [7, 8]. While there are many candidatemediators for cyclosporine-induced vasoconstriction such as en-dothelin, thromboxane A2, nitric oxide synthase inhibition andactivation of the sympathetic nervous system, these effects arereversible with dose reduction or appropriate pharmacologicmaneuvers [9—14]. The studies of Curtis et al [151 have shown thateven in renal transplant patients who are perceived to be doingwell under cyclosporine immunosuppression, drug withdrawalleads to rapid improvement in renal hemodynamics. While somehave argued that these cyclosporine-induced renal effects can be

Received for publication January 2, 1996and in revised form February 27, 1996Accepted for publication February 28, 1996

© 1996 by the International Society of Nephrology

successfully managed with precise pharmacologic monitoring andimproved dosing, these presumptions depend on the assumptionthat cyclosporine-induced nephropathy is functional, dose-re-lated, and reversible. These acute hemodynamic effects may notbe the only consequences of cyclosporine on the kidney. It is clearthat the morphologic lesion produced by cyclosporine therapy inpatients with autoimmune diseases, extrarenal organ transplantrecipients, renal allograft recipients, and experimental animals,consists of areas of striped tubulointerstitial fibrosis, tubularatrophy and afferent arteriolopathy [16, 17]. The process begins inthe outer medulla with extension to the medullary rays and thus isoften difficult to diagnose on a core renal biopsy. The hallmark ofcyclosporine nephropathy rests on the demonstration of appro-priate vascular lesions in the afferent arteriole (cyclosporine-associated arteriolopathy) [161. These vascular lesions of chroniccyclosporine nephropathy are not necessarily dose-related and insome patients can be observed with doses of cyclosporine as lowas 2 to 4 mg/kg.

Many of the retrospective clinical reports concerning the pres-ence or absence of chronic cyclosporine nephropathy in renaltransplantation are based on renal function alone [181. There arefew pathologic data available to separate chronic allograft rejec-tion from chronic cyclosporine nephropathy. This distinction isbased on the demonstration of arteriolar vessel changes asopposed to the arterial lesions of chronic rejection [16]. Inaddition, there is also no a priori reason that both processescannot exist together. Thus, for the most part, renal function asestimated by serum creatinine or even by more precise GFRmeasurements has been used as a surrogate marker for thepresence or absence of chronic cyclosporine nephropathy. Clearly,adaptive mechanisms within the kidney can keep the GFRrelatively stable for long periods in the face of progressive andimportant tubulointerstitial disease as exemplified by diabeticnephropathy, autosomal dominant polycystic kidney disease, andnon-cyclosporine-treated renal transplants [19].

Chronic cyclosporine nephropathyChronic cyclosporine nephropathy is defined as a clinicopath-

ologic entity produced by exposure of the patient to cyclosporirie.characterized by tubulointerstitial fibrosis in a striped pattern,beginning in the medulla and progressing to the medullary rays ofthe cortex. It is associated with degenerative hyaline changes inthe walls of afferent arteriolar-sized blood vessels extending fromthe pre-glomerular area proximally up the afferent arteriole [161.Usually, but not inevitably, this pathologic finding is associatedwith some degree of renal dysfunction. It is clear that thisclinicopathologic entity does not preclude the coexistence of otherprocesses such as renal allograft rejection. Dc novo or recurrenthemolytic uremic syndrome may be associated with cyclosporine[20, 211. There is glomerular fibrin deposition with fibrin thrombi.

1089

1090 Bennett et al: Chronic cyclosporine nephropathy

This unusual type of cyclosporine-associated renal dysfunctionwill not be discussed further.

Chronic cyclosporine nephropathy in heart transplantationThe pivotal studies of Myers et al [22] described the renal,

structural, and functional changes in the native kidneys of hearttransplant recipients. Careful documentation of renal functionrevealed a progressive decrease in GFR with a concomitant dropin renal plasma flow and increase in renal vascular resistance. Thiswas associated with hypertension. Biopsies in a subset of thesepatients showed glomeruloscierosis, striped interstitial fibrosis,and afferent arteriolopathy. The original study was criticizedbecause of the high doses of cyclosporine that were used forinduction and subsequently for maintenance therapy. The startingdose of 17 mg/kg/day with adjustment downward, was higher thanthat used in modern cardiac transplantation [23]. Nonetheless,when patients who subsequently underwent heart transplantationat Stanford with cyclosporine doses of 10 mg/kg or less werecompared with the high dose patients, both groups had hyperten-sion and decreased GFR. The decrease in GFR was approxi-mately 45% from baseline, even in the low dose cyclosporinegroup, when compared to a historical control group which usedazathioprine and prednisone without cyclosporine. Renal biopsysamples from patients treated with lower dose cyclosporine hadthe same pathologic changes as those seen with higher doses andno difference in the degree of involvement could be shown [241.When high dose and low dose groups were compared two yearsafter transplantation, the mean serum creatinine was 2.1 mg/dl inthe high dose group, 1.6 mg/dl in the low dose group, and 1.2mg/dl in the no cyclosporine group [25]. It was further demon-strated that sequential native kidney biopsies in both cyclosporinegroups showed progressive histopathologic changes. There was acumulative incidence of end-stage renal disease of approximately10% from the decade of 1980—1990 [25]. There were no differ-ences in cardiac function among the groups to explain the renaldysfunction. Furthermore, the authors established that cyclospor-me-induced chronic nephropathy can progress despite drug with-drawal.

Other studies have looked at renal function without concomi-tant renal pathologic studies in heart transplant recipients. Zietseet al [26] in 1994 followed 187 patients treated with initial doses ofcyclosporine of 8 mg/kg/day. At two years post-transplant, serumcreatinine was >2 mg/dl in 52% of the patients. At four years,serum creatinine was >3.5 mg/dl in 13% of the patients. Therewas no relationship of renal dysfunction to CSA blood level, theuse of calcium antagonists, blood pressure, or the pre-transplantserum creatinine. In two publications by Greenburg et al [27, 28],heart transplant patients were frequently shown to have azotemiaand acute renal failure at one week post transplant. No CsA-treated patients in this series who had 36 months of follow-upshowed normal renal function. One patient had progressed toend-stage renal disease. Renal function was improved in fivepatients in whom dose reduction was attempted, although patho-logic documentation of histologic improvement is not available.These 43 cyclosporine-treated cardiac transplant recipients had a58% incidence of azotemia compared to 34% of 41 non-cyclos-porine-treated patients and 4% of 25 patients undergoing cardio-pulmonary bypass without immunosuppression.

In a later study of 228 adults who survived more than one yearafter cardiac transplantation and who had normal renal function

before transplantation, the serum creatinine at hospital dischargerose from 1.2 mg/dl to 3.3 mg/dl at seven years, and 1.6% ofpatients had developed end-stage renal disease by 18 months withan additional patient developing end-stage renal disease after fiveyears. No pathologic material was available, but the doses ofcyclosporine used in the study were similar to current clinicaldoses of 10 mg/kg/day for induction and then 5 to 10 mg/kg/daydependent on blood levels.

An autopsy study of 15 patients established that interstitialfibrosis can be present in terminal heart failure patients beforeheart transplantation and it does not inevitably progress [29].There was no relationship between renal histology and cyclospor-me-treated heart transplant recipients' blood pressures and serumcreatinine levels. In this study, it was confirmed that cyclosporinecan cause progressive arteriolar hyalinization and glomeruloscle-rosis.

The remainder of studies in heart transplant recipients involverenal function only. Studies of 203 recipients by Lewis et al [30],Gonwa et al [31], showed initial decreases in GFR of approxi-mately 30% with stabilization of GFR measured directly orestimated by the reciprocal of serum creatinine. Doses again werecontemporary, and no histopathology was available. Gonwa et a![31] cited a 1 to 2% incidence of end-stage renal disease at fourcenters with > 1000 patients, although the duration of follow-upand the current renal function of these patients is unknown.

A particularly important study was performed by Bertani et al[32]. Renal biopsies were obtained at the same time that renalfunctional studies were performed in 10 cyclosporine-treatedheart transplant recipients who had been on the drug for twoyears. GFR and effective renal plasma flow were below normalvalues in transplant recipients, and the averages were 35 mI/min/1.73 m2 and 325 ml/min/1.73 m2, respectively. Light microscopy ofautopsy specimens from patients with no history of renal diseaseand from patients who had died from dilated cardiomyopathywithout heart transplantation revealed no structural renal abnor-malities. However, in cyclosporine-treated patients, arteriolopa-thy and glomerulosclerosis were seen. Thus, cyclosporine givenfor more than two years induced in all patients moderate renalfailure associated with obliterative arteriolopathy and glomerularischemia. As cyclosporine nephropathy developed, subpopula-tions of glomeruli of different sizes emerged. Some glomeruliwere small and had segmental or global sclerosis, and otherglomeruli were large. Follow-up of these same patients by Rug-genenti et al [331 showed stabilization of GFR and renal plasmaflow over a two-year follow-up period. No histopathology wasrecorded in the follow-up study.

Nephrotoxicity is frequent and a major cause of progressiverenal injury in lung transplantation. In 30 recipients followed forat least six months, 50% developed hypertension, 9 patients hadcreatinines > 3 mg/dl, and 2 had developed end-stage renaldisease [34]. Likewise, of 67 heart-lung transplant patients surviv-ing at least six months, 3 developed end-stage renal failure, whilethe mean serum creatinine rose from baseline 0.96 to 1.88 atfour-year follow-up [35].

Chronic cyclosporine nephropathy in renal transplantationThe effect of cyclosporine on renal structure and function in

renal allografts is often difficult to discern. Much of the probleminvolves the complicated differential diagnosis of renal dysfunc-tion in this setting [16]. Chronic rejection, recurrent renal disease,

Bennett et al: Chronic cyclosporine nephropathy 1091

and nonspecific factors such as hypertension, hyperlipidemia andage can lead to progressive renal structural and functional dete-rioration. Discerning the role, if any, of cyclosporine in isolation isdifficult. Based largely on retrospective data showing stability ofserum creatinine over time, it has been stated that the renaltransplant is relatively spared from the ravages of chronic cyclo-sporine treatment [18]. Many of these studies are methodologi-cally flawed because both structure and function were not mea-sured, some studies used structure alone, and some studies usedfunctional parameters alone. Jacobsen et a! [36] studied 19 renaltransplant patients who received cyclosporine for two years. Thedaily dose of cyclosporine was 15 mg/kg to start, dropping to 6mg/kg at two years. GFR was 42 mI/mm compared to 106 ml/minin 13 healthy two kidney gender- and age-matched control pa-tients. Eighteen of the 19 patients had increased tubulointerstitialfibrosis by morphometric determination when compared to nor-mal kidneys. All of the recipients were non-diabetic, and there wasno correlation between the degree of renal dysfunction and theextent of tubulointerstitial fibrosis. Ruiz et al [37] studied 59cyclosporine-treated kidney transplant patients at 15 weeks post-transplant and compared them with 46 recipients who did notreceive cyclosporine and with 15 pre-transplant donor kidneybiopsies. The daily dose of cyclosporine at the time of biopsy was12 mg/kg. Both transplant groups had increased tubulointerstitialfibrosis when compared to control kidneys. The interstitial fibrosiswas more extensive and the serum creatinine level higher in thecyclosporine group after six months. Klintmalm et al [38] studied38 biopsies in 24 cyclosporine-treated renal transplant patientsand compared them to 43 biopsies from 43 patients treated withazathioprine and steroids over a one to four year observationperiod. Doses of cyclosporine, again, were high initially andtapered to 10 mg/kg/day at four months. Serum creatinine aver-aged 2.1 mg/dl in the cyclosporine-treated patients and 1.5 mg/dlin the azathioprine-treated group. Blind analysis of the renalbiopsies showed severe interstitial fibrosis and tubular atrophy inthe cyclosporine patients when compared with biopsies from theazathioprine patients, although the same number of rejectioncrises occurred in each patient group. The renal histologic findingscorrelated with high trough cyclosporine levels and cumulativecyclosporine dose in the first six months.

Other groups in the early 1980s reported that renal biopsiesshowed progressive changes of chronic cyclosporine nephropathy.Sommer et al [39] reported that cyclosporine arteriolopathycaused graft loss in 7.5% of 200 recipients. This represented 40%of all allografts that failed. Graft losses not attributable to chronicrejection also demonstrated interstitial fibrosis.

Perhaps the most cited study is the retrospective analysis of1415 kidney transplant recipients by Burke et al [40]. This studyfollowed serum creatinine levels, up to four years after transplan-tation. Values were elevated but unchanged during the period ofstudy. Only 25% were followed for more than four years and theaverage follow-up was three years. The main drawback of thisstudy was the absence of renal histopathology. The diagnosis of"chronic rejection" in this study was based simply on progressiverenal dysfunction in the absence of improvement following cyclo-sporine dose reduction. Furthermore, the four centers whichcontributed to this report, all had different immunosuppressiveregimens. Long-term increases in serum creatinine in cyclospor-inc-treated HL-A identical renal transplants compared to azathio-

prine-treated patients is of concern [41]. Experimental data fromdenervated renal isografts which progressively fail over 12 monthsfrom cyclosporine-induced renal failure do not support a sparingof renal transplants from CSA toxicity [7]. Other studies withouthistopathology or controls, such as those of Lewis et al [42],Slomovitz et al [43] and Lewis et al [30], showed elevated serumcreatinine levels and decreased GFRs for a solitary kidney thatwere abnormal but stable. Since histopathology was not per-formed, cyclosporine-associated tubulointerstitial disease witharteriolopathy cannot be excluded. Thus, chronic rejection de-fined on clinical grounds alone, that is, renal dysfunction, mini-mizes any role for cyclosporine.

It is possible that cyclosporine-induced injury may play a role inchronic allograft failure that is caused predominantly by chronicrejection. Mihatsch et al studied 90 patients and compared renalpathology in a group who had serum creatinine levels less than 2mg/dl, with a group who had biopsy-proven rejection with serumcreatinine levels greater than 2 mg/dl, and with a pathologicallydefined cyclosporine-nephrotoxicity group with serum creatiriinelevels greater than 2 mg/dI [17]. Of the variables examined, factorsthat lead to acute cyclosporine nephrotoxicity such as high troughblood levels, had predictive value for chronic cyclosporinechanges even in patients whose biopsies showed histologic evi-dence of acute rejection. Table 1 summarizes the available studiesconcerning the long-term effects of cyclosporine on renal struc-ture and/or function.

While it has been thought that arteriolopathy and tubulointer-stitial fibrosis are irreversible changes, some recent studies havequestioned this assumption. A preliminary study of 21 patientswith biopsy-proven cyclosporine nephrotoxicity showed that with50 percent dose reductions in 12 patients and complete cyclospo-rifle withdrawal in 9 patients, GFR improved from a mean of 42to 67 mI/mm. In 5 patients who had repeat biopsies, arteriolarlesions disappeared and "onion skin" vascular changes decreased.There was only one acute rejection episode noted with thesedosage adjustments [4I.

Morozumi et al [45] in 1992 showed that in 9 of 20 patientstransplanted 10 years earlier, there was no difference in meancyclosporine whole blood levels and duration of treatment be-tween those who had demonstrable arteriolopathy and those whodid not. However, vascular lesions were reversible in patients inwhom the drug was discontinued and renal function becamenormal.

Thus, despite 15 years of cyclosporinc-based immunosuppres-sion in renal transplant recipients, there are no prospectivestudies available that document the long-term renal safety of thiscompound or the effect of cyclosporine-induced renal structuraland functional changes on the longevity of renal transplants. Thedifficulty in implicating cyclosporinc in chronic allograft failurehas arisen because of the complexity of its role in an allograftunder immunologic attack.

yclosporine-induced renal sympathetic nerve stimulation hasbeen implicated in the development of hypertension in recipientsof non-renal organ transplants [46, 47]. It has been suggested thatrenal denervation protects the transplanted kidney versus extra-renal situations in which cyclosporine is prescribed. Recent ex-perimental studies, however, have shown that renal denervationdoes not protect against chronic cyclosporinc nephropathy [7, 481.

1092 Bennett et al: Chronic cyclosporine nephropathy

Table 1. Summary of published articles on long term effects of cyclosporine on renal structure and/or function

Chronic cyclosporine nephropathy in autoimmune disease

Because of the success of cyclosporine in solid organ transplan-tation, it was logical to extend this potent immunosuppressivedrug to other refractory conditions thought to be of immunologicorigin. In these patients, most clinical trials only enrolled people

with normal renal function because of worries about nephrotox-icity. Since rejection is not an issue in autoimmune disease, thepathologic and functional changes produced by cyclosporine areinstructive. One of the first uses of cyclosporine was in patientswith refractory autoimmune uveitis. The NIH group 1491 reported17 patients who received cyclosporine in initial daily doses of 10

N Renal function Renal pathology CsA dose mg/kgLength offollow-up Remarks

Bantle et al 11501 11 Mean GFR None 3—5 mg/kg 23 moreduced by 27%from baseline:but stable overstudy period

Burke et al [1511 1415 Mean scrumereatinine 1.9mg/dl: stableover studyperiod

None Regimens variedamong 4 centers

Mean follow-up 3yrs

Retrospective clinicaldefinition ofchronic rejection,CsA nephrotoxicity

Klintmalm [38] 24 pts with CsA43 pts withazathioprine(AZA)

Mean serumcreatinine 2.1mg/dl with CsA,1.5 mg/dl withAZA

Masked pathology;more fibrosisand tubularatrophy in CsApts

17.5 mg/kg initial 10mg/kg at 4 mo

1—4 yrs Rejections equal.Fibrosis correlated

with highcumulative CsAand trough levels infirst 6 mos

Jacobson Ct al [36] 19 GFR 42 mI/mm; P< 0.001 vs.healthy controls

18 pts hadincreased fibrosiscompared tocontrols

12—15 mg/kg initial4-6 mg/kg at 2mo

2 yrs

Lewis et xi [30] 119 Mean serumcreatinine2.1 mg/dl

None 10—14 mg/kgadjusted totrough levels7 mg/kg at 6 mo4.3 mg/kg at 4 yr

Up to 4 yr Reciprocal creatininestable; 32 ptswithdrew becauseof nephrotoxicity

Lewis et al [421 44 GFR stable over 1year period

None Mean dose4.8 mg/kg

Studied 2 mo to 9yr post-transplant

Mourad et al [44J 21 pts withbiopsy-provenCsAnephrotoxicity

GFR improvedfrom 42 to 67mI/mm whenCsA decreased

In 5 pts, arteriolarlesionsdisappeared

Dose reduced in 50percent; CsAdiscontinued 9pts

Ruiz et al [37] 59 CsA46 AZA

or stoppedCreatinine

increased in CsABoth groups had

increased fibrosis11.8 mg/kg at time

of biopsy15 weeks of CSA

group(P < 0.01)

compared topre-transplantdonor controls

Slomowitz [43] 29 Initial GRF 29 ml/mm in Pt wholost grafts vs. 46mI/mm in thosewith stablefunction

5 graft losses, 3rejection plusCsA toxicity, 2CsA toxicityalone

Tailored to troughlevel 150—250ng/ml; dose 3.5—4.9 mg/kg

32 mos

Snider et al [152]

Summer et al [39]

145 with CsA194 with AZA

200 consecutivecadavertransplants

Mean serumcreatinine didnot differbetween groups

None given

None reported

16 serial biopsiesshowedprogressive CsAnephrotoxieity

S mg/kg/day initialtapered to bloodlevel target

10 mg/kg/day indouble or tripletherapy regimens

Up to 6 yrs

1 year Cyclosporine toxicitycause of graft lossin 15 pts

Sumrani et al [41] HI-A identical72 with AZA34 with CsA

Creatinine 2.4 at 5yrs in CsA ptswith progressiverise vs stableereatinine 1.4, inazathioprine pts

None 10—15 mg/kginitially; 4 mg/kgat 1 yr

Up to 5 yrs Pt and graft survivalbetter with CsA

Bennett et al: Chronic cyclosporine nephropathy 1093

mg/kg. The dose was titrated to keep the serum creatinine levelless than 2 mg/kg or less than 50% above the baseline value.Duration of therapy was from two to four years. All patients hadarteriotar changes on renal biopsies performed after 18 to 24months of therapy. In 6 patients, further follow-up biopsies wereavailable. Three of these showed progressive tubulointerstitial andarteriolar changes in the presence of stable inulin clearances.Despite the fact that all patients had normal creatinine clearancebefore initiation of cyclosporine therapy, 14 of 17 patients hadmarkedly reduced renal function, and in 2 of the 17 these renalfunction deteriorations were progressive. Two of 17 improvedwhen the drug was stopped, and 12 of 17 remained stable afterdose reduction. There was little relationship between the patho-logic changes, the dose, and the whole blood trough blood levels[49, 50]. Sixteen other patients were treated with cyclosporineinitially, 6 mg/kg/day tapered to 2 mg/kg/day, and followed for fiveyears. The GFR was reduced from 119 mI/mm to 98 mI/mmwithout a return to the pre-treatment level when the drug wasstopped. No pathologic studies were performed in this series [51].In 1991, Anderson et al [52] reported on 10 patients who initiallyreceived 10 mg/kg/day of CsA that was reduced to 5 mg/kg/day forthree years. Eight of the 10 patients had lymphocytic infiltrateswith arteriolar hyalinosis on renal biopsy. Creatinine clearanceswere slightly reduced from baseline values.

Another major use of cyclosporine has been at the onset ofinsulin-dependent diabetes mellitus. There are a variety of proto-cots that have been used, including doses from 7.5 to 10 mg/kg/day[53]. In a study reported by Assan et a! [54] in 1994, a mean of 13months of therapy with cyclosporine was evaluated. There weretypical histopathological abnormalities in 40% of patients whichwere not progressive when doses were low and adjusted for serumcreatinine levels. The morphologic changes correlated with age,dose and the trough blood level. Functional abnormalities werereversible when doses were reduced. Mihatsch et al [55] in 1991studied 40 type 1 diabetic patients treated with cyclosporine 7 to9 mg/kg/day for at least one year. Twenty-five percent of thepatients had vascular and interstitial pathologic changes ofchronic cyclosporine nephropathy. Renal function, as measuredby serum creatinine level, was decreased by 43% at the time ofbiopsy when compared to baseline values. The patients of Mi-hatsch were different than the patients of Assari et at whosepatients were biopsied when in remission from type I diabetes[54]. There was a weak positive correlation of high troughcyclosporine levels with chronic cyclosporine nephropathy.

Feutren and Mihatsch reported an extensive series of autoim-mune patients with pathologically defined chronic cyclosporinenephropathy [56]. Initial cyclosporinc dose, male gender andcpisodes of acute nephrotoxicity correlated with the presence ofchronic changes. It is noteworthy that patients in this series wereyoung and without previous renal dysfunction or atherosclerosis.In diabetic subjects who achieved five years of normoglycemia bypancreas alone transplants, serious tubulointerstitial and gb-merulosclerotic lesions developed in native kidneys. This con-trasted with a lack of renal abnormalities in control diabetics withsimilar baseline renal function followed for the five year period[57].

Series of psoriasis patients who received low doses of cyclospo-rifle, initially 5 mg/kg/day, tapered to 1 to 2 mg/kg/day, have shownmoderate arteriolopathy and scarring [6, 58—61]. In the studiesthat have reported renal pathology, arteriolopathy and tuhuloin-

terstitial fibrosis have been seen associated with decreased GFR[62]. Serial biopsies one year apart have shown increases in renalfibrous tissue inversely correlated with creatinine clearance [63,64]. In psoriatic patients, there were correlations between acuteepisodes of nephrotoxicity and chronic changes, but no relation-ship to dose, duration of therapy or blood levels. An excellentprospective study by Young et al with serial biopsies and GFRmeasurements showed a decline of 3.1 ml/min/i.73 m2/year alongwith progressive structural changes [65]. Angiotensin II elevationswere noted in patients with cyclosporine A (CsA)-associatedhemodynamic abnormalities [66]. Similar findings to the psoriasisseries were noted in atopic dermatitis treated with cyclosporine[67].

In a two-year placebo controlled study in multiple sclerosispatients, serum creatinine rose from baseline normal values togreater than ito 5 times baseline or greater than 2 mg/dl in 21%of 273 patients randomized to CsA with blood pressure elevationsin 50%. No biopsies were done [68]. Low dose cyclosporineproduced chronic cyclosporine nephropathy in serial biopsiesfrom rheumatoid arthritis patients with no previous renal disease,as well as in increases in serum creatinine [69—75]. A 24-monthserial biopsy in 11 patients were compared to 22 matched autopsycontrols who had received gold and/or penicillamine [76]. Al-though creatinine clearance decreased from lii mi/mm to 82mi/mm, structural nephropathy was minimal. Mild tubular atro-phy was common but arteriolopathy was only found in 3 biopsies[76]. Structural nephropathy of a similar degree was seen incontrols. Similar data exist for patients with myasthenia gravis andother autoimmune diseases in blinded clinical trials [77—82].

Chronic cyclosporine nephropathy in liver transplantationSeveral series have been reported in which renal function has

been followed in liver transplant patients [83—86]. While GFRdecreases soon after liver transplantation, renal dysfunction isseldom progressive, at least up to three or four years of follow-up.However, renal histopathobogic changes have not been extensivelystudied.

In one recent study where autopsy pathology in 7 liver trans-plant patients was compared to that of gender and age matchedcontrols, cyclosporine caused progressive fibrosis and arteriolopa-thy independent of serum creatinine levels and blood pressure[87].

In a large series of liver transplant patients [88], the greatestdecline in creatinine clearance occurred at 18 months. However,at three years post-transplant, serum creatinine was less than 1.7mg/dl in only 23% of patients. There was no relationship betweenkidney dysfunction and the daily dose of cyclosporine or themeasured whole blood trough blood levels. Thus, in liver trans-plantation, as in other solid organ transplantation, cyclosporineinduces important structural and functional lesions.

Bone marrow transplantation

In bone marrow transplantation, where cyclosporine is used asprophylaxis against graft versus host disease, Dieterle et a! [89]reported renal pathology in autopsied or biopsied bone marrowtransplant recipients. Striped interstitial fibrosis was present in 25patients, and arteriolopathy was present in 36 patients of the 51patients studied. Serum creatinine levels increased 40 to 80% bythree months post-transplant and stabilized. The renal pathologyseemed to be worse when total body radiation was used to

1094 Bennett et al: Chronic cyclosporine nephropathy

condition the bone marrow transplant recipient even when thekidneys are shielded. Bone marrow recipients tended to beyounger and without pre-existing atherosclerotic disease whencompared to recipients of other organs. This demonstrated thatchronic cyclosporine nephropathy may occur without those riskfactors. An autopsy study of 112 bone marrow transplant recipi-ents showed that 54% has vascular and interstitial toxic lesionswith severe thrombotic microangiopathy in 25% [901.

Primary renal disease and cyclosporine

When cyclosporine is used to treat nephrotic syndrome orglomerular diseases, any renal function deterioration is not easilydistinguished from progression of the primary diseases process.Delaney, Dukes and Edmunds [91] reported 10 adult patients withnephrotic syndrome of various causes treated with cyclosporine 5mg/kg for up to five years. Three patients had mild elevations ofserum creatinine while in one patient abnormal renal functionimproved. No follow-up biopsies were done. In children, GFRfalls within the first three months by 21% but remains stablethereafter up to two years [92]. In 42 nephrotic children with pre-and post-treatment renal biopsies, Habib and Niaudet were ableto demonstrate progressive tubulointerstitial changes and arteriol-opathy in the absence of progressive focal glomerulosclerosislesions suggesting cyclosporine nephrotoxicity in 9 patients [93,94]. Interestingly, there was normal renal function and no corre-lation between the pathologic lesions and the treatment dose,duration, or trough blood levels. Meyrier et al found that minimalchange nephrotic syndrome patients tolerated cyclosporine up to5.5 mg/kg well without histologic evidence of nephrotoxicity,whereas patients with focal and segmental glomerulosclerosisparticularly with pre-existing renal insufficiency were at risk ofcyclosporine nephrotoxicity [5I.

This subject has recently been debated [96, 97]. A randomizedcontrolled trial of cyclosporine in membranous nephropathy hasshowed slowing of progressive renal dysfunction and decreasedproteinuria in patients with refractory nephrotic syndrome. Nofollow-up renal histology was available [98]. Biopsies of patientswith lupus nephritis 18 to 24 months after steroids and 5 mg/kg/day cyclosporine revealed no evidence of chronic cyclosporinenephropathy [99]. Thus, cyclosporine can produce chronic ne-phropathy when the drug is used to treat renal diseases althoughthe risk to long-term renal reserve is unclear.

Pathophysiology of chronic cyclosporine nephropathy

Cyclosporine is known to produce decreases in renal blood flowdue to constriction of the afferent arteriole proximal to theglomerulus [8]. Although most of these studies have been per-formed in experimental animals, similar phenomena occur inhumans. The profound impairment of renal hemodynamics fromeven a single dose of cyclosporine in chronically treated renaltransplant patients has been documented by Perico et al [10]. Instable patients who have cyclosporine discontinued, renal bloodflow improves by 30% and renovascular resistance and bloodpressure reciprocally drop [151. Thus, some degree of renalvasoconstriction probably occurs in all patients who receiveeffective immunosuppressive therapy with eyclosporine. Whenthis hemodynamically-mediated phenomenon causes a rise inserum creatinine, which is reversible with dosage adjustment, theclinical diagnosis of acute cyclosporine ncphrotoxicity is made.

Animal models of chronic cyclosporine nephrotoxicity havebeen difficult to develop. Even in animals treated with cyclospo-rifle for long periods of time, or with extremely high doses, theadverse renal hemodynamic effects are not associated with majorstructural abnormalities in the kidney [100]. Tubular function, inresponse to the vasoconstriction, is well preserved, at least asmeasured by the fractional excretion of sodium and lithium [8].There is little evidence for acute tubular necrosis produced bycyclosporine. While prolonged vasoconstriction could contributeto chronic cyclosporine nephropathy by producing chronic isch-emia, this relationship has been difficult to demonstrate in exper-imental studies. Thus, most studies in salt replete animals evenwith extremely high blood levels for periods as long as 12 monthshave failed to reproduce the clinicopathologic findings of chroniccyclosporine nephropathy observed in humans [100].

There are many suggested mediators for cyclosporine-inducedvasoconstriction, including thromboxane A2, reduction of vasodi-lator prostaglandins, activation of renal sympathetic nerves, en-dothelin, angiotensin 11, platelet-derived growth factor, and re-duced nitric oxide production [10, 12, 14, 101—108]. In the isolatedperfused rat kidney, Rossi et al [109] showed that cyclosporine-induced vasoconstriction could be blocked by alpha-adrencrgicblockers as well as by calcium channel blockers [109]. Many in vivostudies have evaluated the ability of pharmacologic antagonists ofmediators to reverse cyclosporine-induced vasoconstriction [110—113]. While there are usually improvements in renal hemodynam-ics, the effect of any individual or combination of mediators on thechronic nephrotoxic lesion remains unknown.

Clinically, multivariate analysis of renal biopsies from cyclo-sporine-treated patients with autoimmune disease has shown thatinitial dose, male gender, and episodes of acute renal dysfunctionare major risk factors for the chronic pathologic manifestations ofcyclosporine nephropathy [56]. Mihatsch et a! [161 observedobliterative arteriolopathy with downstream glomerulosclerosis incyclosporine-treated patients. They proposed that the arteriolopa.thy with ultimate vascular occlusion produces a pattern of stripedinterstitial fibrosis with nephron dropout, tubular atrophy, and, ifprogressive, compromised renal function. Myers et al [23] alsosuggested that chronic afferent vascular injury leads to compro-misc in the integrity of afferent arterioles, leading to the irrevers-ible changes that are observed.

This logical, but undocumented, pathophysiology has recentlybeen brought into question by several unrelated observations.Ghiggheri et al [114] have shown that very small doses ofcyclosporine, much less than would produce toxicity clinically, canstimulate collagen synthesis in vitro in a variety of cell systems.Wolf and Nielson showed increased levels of type I and type 4collagen mRNA in murine kidneys treated with CsA for fourweeks when serum creatinine was normal [115]. In an animalmodel of chronic cyclosporine nephrotoxicity produced by oneweek of salt depletion, structural lesions are seen that resemblethe human renal pathology of chronic cyclosporine nephropathy[116, 117]. Indeed, afferent arteriolopathy with hyalinization andstriped tubulointerstitial fibrosis are seen when cyclosporinetreated animals arc subjected to salt depletion. Renal hemody-namic changes are associated with this lesion. However, when thedrug is stopped, GFR returns towards baseline values over two tofour weeks while tubulointerstitial pathologic changes remain

Bennett et a!: Chronic cyclosporine nephropathy 1095

unchanged thus dissociating structure from function [117]. Re-cently, it has been shown that arteriolopathy produced in thismodel, while seemingly irreversible in short term follow-up(weeks), can remit somewhat months after the drug is discontin-ued [118].

Because the structural changes in this model are related to themanipulation of salt depletion, the renin-angiotensin system hasbeen examined for its role in chronic cyclosporine nephropathy[1191. Blockade by angiotensin converting enzyme inhibition aswell as angiotensin II receptor blockade strikingly reduces thetubulointerstitial fibrosis and arteriolopathy in this model despitefailure to normalize glomerular filtration rate [100, 120]. Kon,Hunley and Fogo [105] have recently shown that endothelin A andB receptor blockade normalizes renal hemodynamics but has noeffect on the structural lesions produced in the low salt cyclospo-rifle model, whereas angiotensin converting enzyme inhibitionnormalizes renal structure without changing renal functionalparameters. Young et al [121, 122] have shown that macrophageinfiltration occurs early in this chronic model and is associatedwith up-regulation of the macrophage chemoattraetant, osteopon-tin in proximal tubular cells. Jackson, O'Connor and Humes [123]and Rogers et a! [124] have previously shown that infiltrating cellscould be a source of vasoconstrictive prostaglandins or othermediators of inflammation. Thus, salt depletion might turn onangiotensin II dependent growth factors for fibroblasts, lympho-kines, and cytokines and provide a link between the acute vasculareffects of cyclosporine and chronic tubulointerstitial damage[125]. yclosporine increases the recruitment of renin-containingcells along the afferent arteriole [126, 127] and the expression ofATI receptors and renin [128]. These observations are furtherstrengthened by the experiments of Johnson Ct a! [129], whoshowed that angiotensin 11 infusions can also produce tubuloin-terstitial nephropathy similar to what is observed in the cyclospor-inc-treated animals associated with up-regulation of osteopontinin tubular cells. Furthermore, the location of the angiotensin IItype 1 receptor in the outer medulla and medullary rays [1301corresponds to the location of damage in the chronic cyclosporinemodel. When patients are converted from cyclosporine to aza-thioprine, the number of renin containing cells and juxtaglomer-ular apparatus hyperplasia markedly decreased over the ensuingyear [131].

The most accepted mechanism for the immunosuppressiveaction of cyclosporine is the drug's interference with interleukin 2gene transcription by interference by a cyclosporine-cyclophilincomplex inhibiting calcineurin phosphatase. It has been suggestedthat cyclosporine may produce its immunosuppression not onlythrough inhibition of calcineurin phosphatase, hut also throughtransforming growth factor (TGF) beta-mediated mechanisms[132, 133]. This is of interest since TGFf3 may play a role in theinterstitial fibrosis of the chronic cyclosporine model [134]. Cy-closporine enhances the expression of TGF in the juxtaglomer-ular cells of the rat kidney [135]. Therefore, as suggested by thework of Khanna et a! [136, 137], cyclosporine immunosuppressiveactions could also lead to the production of cytokines that lead torenal interstitial scarring. On the one hand, effective immunosup-pression with cyclosporine prevents rejection-induced inflamma-tory changes that enhance fibrosis, whereas, on the other hand,the immunosuppressive action of the drug depends on liberationof cytokines that are pivotal in the renal scarring process.

The role of other inhibitors of renal scarring, such as cortico-

steroids, have not been clearly evaluated in cyclosporine nephro-toxicity. It is possible that a complex relationship between a!-lograft rejection, renal scarring, and modifying effects ofcorticosteroids goes on within the renal parenchyma of an indi-vidual patient. Preliminary evidence has shown that glucocorti-coids reduce the morphologic changes induced in the chronicsalt-depleted rat model [138]. Further study of this area shouldprove fruitful with major clinical implications for long-termimmunosuppressive withdrawal protocols. It is of interest thatcyclosporine has been observed to be protective against ischemicreperfusion effects on mitochondria in some systems such as theisolated rat heart [139] and forebrain [1401. Perhaps the presenceof cyclosporine modifies isehemic induced damage that wouldotherwise be produced by rejection, organ procurement condi-tions, or the hemodynamic effects of the drug per Se.

There are other possible mechanisms of cyclosporine nephro-toxicity that have not been completely explored. Cyclosporine isan inhibitor of the multi-drug resistance transporter, p-glycopro-tein, which is expressed on resistant tumor cells rendering themmore sensitive to chemotherapy. This transporter is also consti-tutively expressed on the epithelial cells of renal tubular epithe-hum [141]. Cyclosporine, tacrolimus, and many related com-pounds such as verapamil, inhibit this transporter and thus at leasttheoretically could allow the accumulation of chemotherapeuticagents, and perhaps other endogenous or exogenous molecules.Cyclosporine, its metabolites, and even some of its non-immuno-suppressive analogues, can inhibit this transporter which mightaccount for nephrotoxicity through indirect mechanisms. Vera-pamil by competition for this transporter might reduce cyclospo-rifle accumulation in tubular cells rather than by inhibition ofcyclosporine metabolism per Se. Further studies are obviouslyneeded in this area. Possible pathogenetic constructs and workinghypotheses are depicted in Figures 1 and 2.

Clinical issues in chronic cyclosporine nephropathy

At the present time, it is not possible to say what role chroniccyclosporine treatment plays in the chronic failure of renalallografts. Clearly, the drug may produce renal pathologic changesthat are deleterious. Toxic effects of cyclosporine could coexistwith those produced by chronic rejection or alternatively inade-quate doses of cyclosporine might actually contribute to progres-sive graft failure. There have been no properly controlled studiesto examine this point. The only data that exists are retrospectiveanalyses of large data sets which do not examine this issue directly.This is an important question, because cyclosporine has someefficacy in primary renal diseases. It would obviously not bedesirable to have chronic tubulointerstitia! disease accelerate asglomerular lesions are brought under control.

Data on eyclosporine withdrawal protocols have been conflict-ing. Multiple reports show a 20 to 50% incidence of post-conversion acute rejection with about 20% of these being irre-versible when the drug is abruptly withdrawn [142]. Other studiesare more supportive of withdrawal protocols. Pedersen et a! [143]withdrew cyelosporine and followed the patients for one year andcompared them with patients in whom cyclosporine was contin-ued. At the end of one year follow-up, biopsies showed littledifference in tubulointerstitial fibrosis, although vasculopathy andblood pressure were improved in the patients in whom cyclospo-rine was discontinued. Hollander et al [144] in a randomized study

1096 Bennett et a!: Chronic cyclosporine nephropathy

Rejection

Fig. 1. Proposed pathogenesis of chroniccyclosporine nephropathy in kidneytransplantation.

Tubular cell Cancer cell

Fig. 2. Alternative hypothesis for cyclosporinenephrotoxicity. P-glycoprotein, the multi-drugresistance (MDR) transporter is constitutivelyexpressed in proximal tubular epithelium. Thistransporter is inhibited by cyclosporine,tacrolimus, and other drugs such as verapamil.Inhibition of MDR has been used to"chemosensitize" cancer cells. It could beresponsible for accumulation of an endogenoustoxin or toxic metabolite.

showed superior renal function in patients withdrawn from cyclo-sporine three months post-transplant compared to control pa-tients in whom the drug was continued over five years of follow-up. These prospective data contrast with large retrospectivestudies that conclude that inadequate cyclosporine doses, nottoxicity, leads to worse graft outcome [18]. In the retrospectivestudies cyclosporine may have been reduced because of drug-induced renal dysfunction as opposed to the conclusion thatinadequate immunosuppression leads to graft loss. These latterstudies are also flawed, by the lack of any corroborating patho-logic data. The role of corticosteroids in cyclosporine withdrawalprotocols remains to be established. A multicenter study, withcombinations of appropriate renal functional markers and renalpathologic studies, is needed to directly examine these questionsat least in the kidney transplant patient in whom biopsies are easyto obtain.

Calcium antagonists may modify the metabolism of cyclospo-rine allowing lower doses to achieve adequate immunosuppres-sion as well as providing renal vasodilation [145—147]. Dihydro-pyridine calcium channel blockers may slow interstitial fibrosis inrenal transplant recipients without affecting cyclosporine metab-olism. The mechanisms of this beneficial effect is unclear [1481although protection from daily drug related vasoconstriction ispossible [149].

Continued work in the basic science laboratories and clinics

should give us insights into the nature of cyclosporine-inducedscarring processes and their potential for modification by medicalmanagement.

WILLIAM M. BENNEJT, ANGELO DEMATTOS, MARY M. MEYER,TAKESHI ANDOH, and JOHN M. BARRY

Portland, Oregon, USA

Acknowledgments

Studies cited from the authors' laboratory were supported by funds fromthe Oregon Health Sciences Foundation, Portland, Oregon. The authorsacknowledge the word processing help of Gayle Cox.

Reprint requests to William M. Bennett, M.D., Division of Nephrology,Hypertension and Clinical Pharmacology, Mail Code PP262, Oregon HealthSciences University, 3314 SW US Veterans Hospital Road, Portland, Oregon97201, USA.

References

1. TURASAKI P1, PARK MS, DANOVITCH GM: Histocompatibility testing,crossmatching, and allocation of cadaveric kidney transplants, inHandbook of Kidney Transplantation, edited by DANOVITCH GM,Boston, Little, Brown and Co., 1992, pp 43—66

2. DUNN J, GOLDEN D, VAN BUREN CT, Lewis RM, LAWEN J, KAHANBD: Causes of graft loss beyond two years in the cyclosporine era.Transplantation 49:349—353, 1990

CSA

Chemotherapeuticagent

Bennett et al: Chronic cyclosporine nephropathy 1097

3. BENNETF WM:The nephrotoxicity of immunosuppressive drugs. ClinNephrol 43:S3—S7, 1995

4. TERASAKI P1, CECKA JM, CH0 Y: Overview, in Clinical Transplants1990, edited by TERASAKI P1, Los Angeles, UCLA Tissue TypingLaboratory, 1990

5. OPELZ G, SCHWARZ V ENGELMANN A, BACK D, WILK M, KEPPEL E:Long-term impact of HLA matching on kidney graft survival incyclosporine-treated recipients. Transplant Proc 23:373—375, 1991

6. MODENA FM, HOSTETrER TH, SALAHUDEEN AK, NAJARIAN JS,MATAS AJ, ROSENBERG ME: Progression of kidney disease in chronicrenal transplant rejection. Transplantation 52:239—244, 1991

7. REMUZZI G, PERIC0 N: Cyclosporine-induced renal dysfunction inexperimental animals and humans. Kidney mt 48(Suppl 52):S70—S74,1995

8. ENGLISH J, EVAN A, HOUGIITON DC, BENNETT WM: yclosporine-induced acute renal dysfunction in the rat. Evidence of arteriolarvasoconstriction with preservation of tubular function. Transplanta-tion 44:135—141, 1987

9. SKORECKE KL, RUTLEDGE WP, SCHRIER RW: Acute cyclosporinenephrotoxicity—Prototype for a renal membrane signalling disorder.Kidney mt 42: 1—10, 1992

10. PERICO N, RUGGENENTI P, GASPARI F, MoscoNl L, BENIGNI A,AMUCHASTEGUI CS, GASPARINI F, REMUZZI G: Daily renal hypoper-fusion induced by cyclosporine in patients with renal transplantation.Transplantation 54:56—60, 1992

11. CONGER JD, KIM GE, ROBINETTE JB: Effects of ANG II, ETA, andTxA, receptor antagonists on cyclosporin A renal vasoconstriction.Am J Physiol 267:F443—F449, 1994

12. BOBADILLA NA, TAPIA E, FRANCO M, LOPEZ P, MENDOZA S,GARCIA-TORRES R, ALVARADO JA, HERRERA-ACOSTA J: Role ofnitric oxide in renal hemodynamic abnormalities of cyclosporinnephrotoxicity. Kidney mt 46:773—779, 1994

13. GAILEGO MJ, GARCIA VILLALON AL, LOPEZ FARRE AJ, GARCIA JL,GARRON MP, CASADO 5, HERNANDO L, CARAMELO CA: Mechanismsof the endothelial toxicity of cyclosporin A. Role of nitric oxide.cGMP, and Ca2. Circ Res 74:477—484, 1994

14. BUNCHMAN TE, BR0OKSHIRE CA: Cyclosporine-induced synthesis ofendothelin by cultured human endothelial cells. J Clin Invest 88:310—314, 1991

15. CURTIS JJ, LUKE RG, DUBOVSKY E, DIETI-IELM AG, WHELCHEL JD,JONES P: Cyclosporin in therapeutic doses increases renal allograftvascular resistance. Lancet 2:477—479, 1986

16. MIHATSCH MJ, RYFFEL B, GUDAT F: The differential diagnosisbetween rejection and cyclosporine toxicity. Kidney mt 48(Suppl52):S63—S69, 1995

17. MIHATSCH MJ, STEINER K, ABEYWICKRAMA KH, LANDMANN J, THIELG: Risk factors for the development of chronic cyclosporine-neph-rotoxicity. Clin Nephrol 29:165—175, 1988

18. LEWIS RM: Long-term use of cyclosporine A does not adverselyimpact on clinical outcomes following renal transplantation. Kidneymt 48(Suppl 52):575—S78, 1995

19. BRENNER BM, COHEN RA, MIlFORD EL: In renal transplantation,one size may not fit all. JAm Soc Nephrol 3:162—169, 1992

20. WOLFE JA, MCCANN RL, SANFILIPPO F: Cyclosporine-associatedmicroangiopathy in renal transplantation: a severe hut potentiallyreversible form of early graft injury. Transplantation 41:541—544,1986

21. VAN BUREN D, VAN BLJREN CT, FLECHNER SM, MADDOX AM,VERANI R, KAHAN BD: Dc novo hemolytic uremic syndrome in renaltransplant recipients immunosuppressed with cyclosporinc. Surgery98:54—62, 1985

22. MYERS BD, Ross J, NEWION L, LUETSCHER J, PERLROIII M:yclosporine-associatcd chronic nephropathy. N Engl J Med 311:699—705, 1984

23. MYERS BD, SIBLEY R, N[wroN L, TOMLANOVICH SJ, Bosinos C,STINSON F, LUETSCHER iA WHITNEY DJ, KRASNY D, COPLON NS,PERLROTII MG: The long-term course of cyclosporine-associatedchronic nephropathy. Kidney mt 33:590—600, 1988

24. MYERS BD, NEWTON L, BOSHKOS C, MACOVIAK JA, FRIST WH,DERBY GC, PIRI,ROTI1 MG, SIBLEY RK: Chronic injury of humanrenal mierovessels with low-dose cyclosporine therapy. Transplanta-tion 46:694—703, 1988

25. MYERS BD, NEWTON L: Cyclosporine-induced chronic nephropathy:

An obliterative microvascular renal injury. JAm Soc Nephrol 2:S45—S52, 1991

26. ZIETSE R, BALK AH, VAN DER DORPEL MA, MEETER K, Bos E,WEIMAR W: Time course of the decline in renal function in cyclo-sporine-treated heart transplant recipients. Am J Nephrol 14:1—5,1994

27. GREENBERG A, THoMI'soN ME, GRIFFITH BJ, HARDESTY RL, KOR-MOS RL, EL-SHAHAWY MA, JANOSKY JE, PUSCHETT JB: Cyclosporinenephrotoxicity in cardiac allograft patients—A seven-year follow-up.Transplantation 50:589—593, 1990

28. GREENBERG A, EGEL JW, THOMPSON ME, HARDESTY RL, GRIFFITHBP, BAIINSON HT, BERNSTEIN RL, HASTILI.O A, HESS ML, PusclIE'rrJB: Early and late forms of cyclosporine nephrotoxicity: Studies incardiac transplant recipients. Am J Kidney Dis 9:12—22, 1987

29. FALKENHAIN ME, Coslo FG: yclosporine (C5A) causes progressiveglomerular sclerosis (GS) and arteriolar hyalinosis (AH) in kidneysof heart (HTx) and liver (LTx) transplant recipients. (abstract) JAmSoc Nephrol 5:1003, 1994

30. LEWIS RM, VAN BUREN CT, RADOVANCEVIC B, FRAZIER OH,JANNEY RP, POWERS PL, GOLDEN DL, GIANNAKIS JG, MACRIS MP,KERMAN RH, KAHAN BD: Impact of long-term cyclosporine immu-nosuppressive therapy on native kidneys versus renal allografts:Serial renal function in heart and kidney transplant recipients. JHeart Lung Transplant 10:63—70, 1991

31. GONWA TA, MAI ML, PILCIIER J, JOHNSON C, PIERSON 5, CAPEHARTJE, All VIZATOS PA: Stability of long-term renal function in hearttransplant patients treated with induction therapy and low-dosecyclosporine. J Heart Lung Transplant 11:926—928, 1992

32. BERTANI T, FERRAZZI P, SCHIEPPATI A, RUGGENENTI P, GAMBA A,PARENZAN L, MECCA G, PERICO N, IMBERTI 0, REMUZZI A, RE-MUZZI G: Nature and extent of glomerular injury induced bycyclosporine in heart transplant patients. Kidney Int 40:243—250, 1991

33. RUGGENENTI P, PERICO N, AMUCHASTEGUI CS, FERRAZZI P, MAM-PRIN F, REMUZZI G: Following an initial decline, glomerular filtra-tion rate stabilizes in heart transplant patients on chronic cyclospo-rine. Am J Kidney Dis 24:549—553, 1994

34. ZALTZMAN JS, PEI Y, MAURER J, PATTERSON A, CATTRAN DC:Cyclosporine nephrotoxicity in lung transplant recipients. Transplan-tation 54:875—878, 1992

35. Pvi-nsos JM, PETERSEN J, Kuo P, VALANTINE V, ROBBINS RC,THEODORE J: The incidence of renal failure in one hundred consec-utive heart-lung transplant recipients. Am J Kidney Dis 26:643—648,1995

36. JACOBSON SH, JAREMKO G, DURAJ FF, WILCZEK HE: Renal fibrosisin cyclosporine A treated renal allograft recipients: morphologicalfindings in relation to renal hemodynamics. Nephron (in press)

37. RUIZ P, KOLBECK PC, SCROGGS MW, SANFILIPPO F: Associationsbetween cyclosporine therapy and interstitial fibrosis in renal al-lograft biopsies. Transplantation 45:91—95, 1988

38. KLINTMALM G, SUNDFI.IN B, BOHMAN SO, WILCZEK H: Interstitialfibrosis in renal allografts after 12 to 46 months of cyclosporintreatment: Beneficial effect of low doses in early post-transplantationperiod. Lancet 2:950—954, 1984

39. SUMMER BG, INNES JT, WHITEIIURST RM, SHARMA HM, FERGUSONRM: Cyclosporine-associated renal arteriopathy resulting in loss ofallograft function. Am J Surg 149:756—764, 1985

40. BURKE JFJ, PIRSCH JD, RAMOS EL, SALOMON DR, STABLEIN DM,VAN BEREN DII, WEST JC: Long-term efficacy and safety of cyclo-sporine in renal-transplant recipients. N Engl J Med 331:358—363,1994

41. SUMRANI N, DELANEY V, DING Z, Burl' K, HONG J: HLA-identicalrenal transplants: Impact of cyelosporine on intermediate-term sur-vival and renal function. Am J Kidney Dis 16:417—422, 1990

42. LEWIs R, PODBIELSKI J, MUNSELI. M, KATZ 5, VAN BURFN C,KERMAN R, KAIIAN BD: Stability of renal allograft glomerularfiltration rate in the cyclosporine era: 2-year follow-up. TransplantProc 26:2619—2621, 1994

43. SLOMOWITZ LA, WIlKINSON A, HAWKINS R, DANOvI1'cH G: Evalu-ation of kidney function in renal transplant patients receivinglong-term cyclosporine. Am I Kidney Dis 15:530—534, 1990

44. MOURAD G, VEI,A C, RIBSTEIN J, MIMRAN A: Chronic cyclosporinenephrotoxieity is reversible in renal transplant recipients. (abstract)Nephml Dial Transplant 8:1045, 1993

1098 Bennett et a!: Chronic cyclosporine nephropathy

45. Morozuii K, THIEL G, ALBERT FW, BANFI G, GUDAT F, MII-IATSCHMJ: Studies on morphological outcome of cyclosporine-associatedarteriolopathy after discontinuation of cyclosporine in renal al-lografts. Clin Nephrol 38:1—8, 1992

46. SCHERRER U, Vissir't SF, MORGAN BJ, ROLLINS JA, TINDALL RSA,RING S, HANSON F, MOHANTY PK, VICTOR RG: Cyclosporine-induced sympathetic activation and hypertension after heart trans-plantation. N Engi J Med 323:693—699, 1990

47. MARK AL: Cyclosporine, sympathetic activity, and hypertension.NEngIJ Med 323:748—750, 1990

48. ELZINGA LW, ROSEN S, LINDSLEY J, BURDMANN EA, BENNEYF WM:The role of the sympathetic nervous system in a model of chroniccyclosporine nephropathy. (abstract) JAm Soc Nephrol 3:722, 1992

49. PALESTINE AG, AUSTIN 1-IAI, BALOW JE, ANTONOVYCH IT, SABNISSG, PREUSS HG, NUSSENBLArF RB: Renal histopathologic alter-ations in patients treated with cyclosporine for uveitis. N Engi J Med314:1293—1298, 1986

50. AUSTIN HAl, PALESTINE AG, SABNIS SG, BALOW JE, PREUSS HG,NUSSENBLATIT RB, ANTONOVYCI-I TT: Evolution of ciclosporin neph-rotoxicity in patients treated for autoimmune uveitis. Am J Nephrol9:392—402, 1989

51. DERAY G, BENI-IMIDA M, LU HOANG P, MAKSUD P, AUPETI-I' B,BAUMELOU A, JACOBS C: Renal function and blood pressure inpatients receiving long-term, low-dose cyclosporine therapy for idio-pathic autoimmune uvcitis. Ann Intern Med 117:578—583, 1992

52. ANDERSEN CB, LARSEN 5, ELMGREEN J, TVEDE N, ANDERSEN V:Cyclosporine-induced renal morphologic and immunohistologicchanges in patients with chronic uveitis. APMJS 99:576—582, 1991

53. FELDT-RASMUSSEN B, JENSEN T, DIEPERINK H, MANDRUP-POULSENT, NERUP J, BENDTZEN K, ANDERSEN V, KEMP E, LEYSSAC PP:Nephrotoxicity of cyclosporin A in patients with newly diagnosedtype 1 diabetes mellitus. Diabetic Med 7:429—433, 1990

54. ASSAN R, TIMSIT J, FEU-I'REN G, BOUGNERES P, CZERNICHOW P.HANNEDOUCHE T, BOITARD C, NOEL LH, MIHATSCH MJ, BACH JF:The kidney in cyclosporin A-treated diabetic patients: A long-termclinicopathological study. Clin Nephrol 41:41—49, 1994

55. MIHATSCH MJ, HELMCHEN U, CASANOVA P, HABIB R, LARSEN 5,MAGIL A, NOEL LH, RAPOLA J, ULRICH J, WALLACE AC: Kidneybiopsy findings in cyclosporine-treated patients with insulin-depen-dent diabetes mellitus. Kim Wochenschr 69:354—359, 1991

56. FEUTREN G, MIHATSCH MJ: Risk factors for cyclosporine-inducednephropathy in patients with autoimmunc diseases. N Engl J Med326:1654—1660, 1992

57. Foun-o F, STEFFES MW, MIHATSCH MJ, STROM EH, SUTHERLANDDER, MAUER M: Cyclosporine associated lesions in native kidneysof diabetic pancreas transplant recipients. Kidney mt 48:489—495,1995

58. POWLES AV, COOK T, HULME B, BAKER BS, LEwIS HM, THOMAS E,VALDIMARSSON H, FRY L: Renal function and biopsy findings after 5years' treatment with low-dose cyclosporin for psoriasis. BrJ Derma-to! 128:159—165, 1993

59. SVARSTAD E, HELLAND 5, MORKEN T, BOSTAD L, MYKING A,IvERSEN BM, OFSTAD J: Renal effects of maintenance low-dosecyclosporin A treatment in psoriasis. Nephrol Dial Transplant 9:1462—1467, 1994

60. BAGNIS C, DERAY G, KADRI A, LU HOANG F, MAKSUD P, JACOBS C:Ciclosporine (CsA) nephrotoxicity in patients with idiopathic uveitis:A five years follow-up. (abstract) JAm Soc IVephrol 5:388, 1994

61. PEI Y, SCHOLEY JW, KATZ A, SCHACIIFEI( R, MURPHY GF, CAYFRAND: Chronic nephrotoxicity in psoriatic patients treated with low-dosecyclosporine. Am J Kidney Dis 23:528—536, 1994

62. MESSANA JM, JOHNSON KJ, MIIIArscH MJ: Renal structure andfunction effects after low dose cyclosporine in psoriasis patients: Apreliminary report. Clin Nephrol 43:150—153, 1995

63. ZACI-IARIAE H, HANSEN HE, KRAGBALLE K, OLSEN S: Morphologicrenal changes during cyclosporine treatment of psoriasis. Studies onpretreatment and posttreatment kidney biopsy specimens. JAm AcadDermatol 26:415—419, 1992

64. ZACHARIAE H, OLSEN TS: Efficacy of cyclosporin A (CyA) inpsoriasis: An overview of dose/response, indications, contraindica-tions and side-effects. C/in Nephroi 43:154—158, 1995

65. YOuNG EW, ELLIS CN, MESSANA JM, JOHNSON KJ, LEICHTMAN AB,MIHATSCII MJ, HAMILTON TA, GROISSER DS, FRADIN MS, Voo-

RHEES JJ: A prospective study of renal structure and function inpsoriasis patients treated with cyclosporin. Kidney mt 46:1216—1222,1994

66. EDWARDS BD, CHALMERS RJG, O'DRISCOLL JB, MITCHELL DM,SMITH RJ, LAWSON RS, TESTA HJ, BALLARDIE FW: Angiotensin II asa risk factor for cyclosporin nephrotoxicity in patients with psoriasis.C/in Nephrol 41:350—356, 1994

67. SOWDEN JM, BERTH-JONES J, ROSS JS, MOTLEY RJ, MARKS R,FINLAY AY, SALEK MS, GRAHAM-BROWN RAC, ALLEN BR, CAMPRDR: Double-blind, controlled, crossover study of cyclosporin inadults with severe refractory atopic dermatitis. Lancet 338:137—140,1991

68. THE MULTIPLE SCLEROSIS STUDY GROUP: Efficacy and toxicity ofcyclosporine in chronic progressive multiple sclerosis: A randomized,double-blinded, placebo-controlled clinical trial. Ann Neurol 27:591—605, 1990

69. SUND 5, FORRE 0, BERG KJ, KVIEN TK, H0vIG T: Morphologicaland functional renal effects of long-term low-dose cyclosporin Atreatment in patients with rheumatoid arthritis. Clin Nephrol 41:33—40, 1994

70. MIIIATSCH MJ, HOVIG T, LEMOINE R, ALEXOPOULOU I, FORRE 0,MIESCHER P, FAVRE H, LUDWIN D, TUGWELL F, BJERKHOEL N, VONGRAFFENRIED B, FEUTREN G: Renal morphology after cyclosporin Atherapy in rheumatoid arthritis patients. Br J Rheumatol 32:65—71,1993

71. MADHOK R, TORLEY HI, CAPELL HA: A study of the longtermefficacy and toxicity of cyclosporine A in rheumatoid arthritis. JRheumatol 18:1485—1489, 1991

72. AHERN MJ, HARRISON W, HOI.LINGSWORTI-I P, BRADLEY J, LAING B,BAYLISS C: A randomised double-blind trial of cyclosporin andazathioprine in refractory rheumatoid arthritis. Aust NZ J Med21:844—849, 1991

73. LANDEWE RBM, G0EI THE HS, VAN RIJTHOVEN AWAM, BREED-VELD FC, DIJKMANS BAC: A randomized, double-blind, 24-weekcontrolled study of low-dose cyclosporine versus chloroquine forearly rheumatoid arthritis. Arthritis Rheum 37:637—643, 1994

74. LUDWIN D, ALEXOPOULOU I: yclosporin A nephropathy in patientswith rheumatoid arthritis. Br J Rheumatol 32:60—64, 1993

75. COHEN DJ, APPEL GB: Cyclosporine: Nephrotoxic effects and guide-lines for safe use in patients with rheumatoid arthritis. Semin ArthritisRheum 21:43—48, 1992

76. LANDEWE RBM, DIJKMANS BAC, VAN DER WOUDE FJ, BREEDVELDFC, MIHATSCH MJ, BRUIJN JA: Longterm low dose cyclosporine inpatients with rheumatoid arthritis: Renal function loss withoutstructural nephropathy. J Rheumatol 23:61—64, 1996

77. CLEMENTS PJ, LACHENBRUCH PA, STERZ M, DANOVITCH G,HAWKINS R, IPPOLITI A, PAuI.tjs HE: Cyclosporine in systemicsclerosis. Results of a forty-eight-week open safety study in tenpatients. Arthritis Rheum 36:75—83, 1993

78. WIESNER RH, LUDWIG J, LINDOR KD, JORGENSEN RA, BALDUS WP,HOMBURGER HA, DICKSON ER: A controlled trial of cyclosporine inthe treatment of primary hiliary cirrhosis. N EngI J Med 322:1419—1424, 1990

79. LOMBARD M, PORTMANN B, NEUBERGER J, WILLIAMS R, TYGSTRUPN, RANEK L, RING-LARSEN H, RODES J, NAVASA M, TRUPO C, PAPEG, SCHOU G, BADSBERG JH, ANDERSEN PK: yclosporin A treatmentin primary hiliary cirrhosis: Results of a long-term placebo controlledtrial. Gastroenterology 104:519—526, 1993

80. KOLKIN 5, NAHMAN NSJ, MENDELL JR: Chronic nephrotoxicitycomplicating cyclosporine treatment of chronic inflammatory demy-elinating polyradiculoneuropathy. Neurology 37:147—149, 1987

81. FIANNEDOUCHE TP, DEIriAoo AG, GNIONSAHE AD, BOIFARD C,NoEl. LH, GRUNFELD JP: Nephrotoxicity of cyclosporine in autoim-mune diseases. Adv Nephrol 19:169—186, 1990

82. TINDALL RSA, ROLLINS JA, PHIlLIPS JT, GREENLEE RG, WEII,s L,BEIUNDIUK G: Preliminary results of a double-blind, randomized,placebo-controlled trial of cyclosporine in myasthenia gravis. N EngiJ Med 316:719—724, 1987

83. PIATZ KP, MUELLER AR, BLUMHARDT G, BACHMANN S, BECHSTEINWO, KAHL A, NEUI IAUS P: Nephrotoxicity following orthotopic livertransplantation. A comparison between cyclosporinc and FK506Transplantation 58:170—178, 1994

84. WFIEATLEY HC, DATZMAN M, WILLIAMS JW, MILES DE, HATCI I FE:

Bennett et al: Chronic cyclosporine nephropathy 1099

Long-term effects of cyclosporine on renal function in liver trans-plant recipients. Transplantation 43:641—647, 1987

85. DJSCHE FE, NEUBERGER J, KEATING J, PARSONS V, CALNE RY,WILLIAMS R: Kidney pathology in liver allograft recipients afterlong-term treatment with cyclosporin A. Lab Invest 58:395—402, 1988

86. MONSOUR HPJ, WOOD RP, DYER CH, GALATI JS, OzAKI CF, CLARKJH: Renal insufficiency and hypertension as long-term complicationsin liver transplantation. Semin Liver Dis 15:123—132, 1995

87. MCCAULEY J, BRONSTHER 0, FUNG J, TOD0 5, STARZL TE: Treat-ment of cyclosporin-induced haemolytic uraemic syndrome withFK506. Lancet 2:1516, 1989

88. GONWA TA, MORRIS CA, GOLDSTEIN RM, HUSBERG BS, KLINTMALMGB: Long-term survival and renal function following liver transplan-tation in patients with and without hepatorenal syndrome—Experi-ence in 300 patients. Transplantation 51:428—430, 1991

89. DIETERLE A, GRATwOHL A, NIZZE H, HUSER B, MII-IATSCH MJ,THIEL G, TICHELLI A, SIGNER E, NISSEN C, SPECK B: Chroniccyclosporine-associated nephrotoxicity in bone marrow transplantpatients. Transplantation 49:1093—1100, 1990

90. NIZZE H, MIHATSCH MJ, ZOLLINGER HU, BROCHERIOU C, GOKELJM, HENRY K, SLOANE JP, ST0vIN PG: Cyclosporine-associatednephropathy in patients with heart and bone marrow transplants.Clin Nephrol 30:248—260, 1988

91. DELANEY MP, DUKES DC, EDMUNDS ME: Cyclosporin A in refrac-tory idiopathic nephrotic syndrome: 5 years clinical experience.Postgrad Med J 70:891—894, 1994

92. HULTON SA, JADRESIC L, SHAH V, TROMPETER RS, DILLON MJ,BARRAIT TM: Effect of cyclosporin A on glomerular filtration rate inchildren with minimal change nephrotic syndrome. Pediatr Nephrol8:404—407, 1994

93. HABIB R, NIAUDET P: Comparison between pre- and posttreatmentrenal biopsies in children receiving ciclosporine for idiopathic ne-phrosis. Cliii Nephrol 42:141—146, 1994

94. NIAUDET P, HABIB R: Cyclosporine in the treatment of idiopathicnephrosis. JAm Soc Nephrol 5:1049—1056, 1994

95. MEYRIER A, NOEL LH, AURICHE P, CALLARD P, BRONEER D:Long-term renal tolerance of cyclosporin A treatment in adultidiopathic nephrotic syndrome. Kidney mt 45:1446—1456, 1994

96. PONTICELLI C: Focal segmental glomerular sclerosis. To treat or notto treat? 1. It is worthwhile to give the adult patient with nephroticsyndrome the benefit of an adequate therapeutic trial? Nephrol DialTransplant 10:2351—2354, 1995

97. MEYRIER A: Focal segmental glomerulosclerosis: To treat or not totreat? 2. Focal and segmental glomerulosclerosis is not a disease, butan untreatable lesion of unknown pathophysiology. Its treatmentmust not be uselessly hazardous. Nephrol Dial Transplant 10:2355—2359, 1995

98. CATrRAN DC, GREENWOOD C, RITCHIE 5, BERNSTEIN K, CHURCHILLDN, CLARK WF, MORRIN PA, LAVOIE S: A controlled trial ofcyclosporine in patients with progressive membranous nephropathy.Kidney mt 47:1130—1 135, 1995

99. FAVRE H, MIESCHER PA, HUANG YP, CHATELANAT F, MIHATSCHMJ: Ciclosporin in the treatment of lupus nephritis. Am J Nephrol9:57—60, 1989

100. LAFAYETITE RA, MAYER 0, MEYER TW: The effects of bloodpressure reduction on cyclosporine nephrotoxicity in the rat. J AmSoc Nephrol 3:1892—1899, 1993

101. STAHL RAK, ADLER S, BAKER PJ, JOHNSON Ri, CHEN YP, PRITZL P,COUSER WG: Cyc1osporin A inhibits prostaglandin E2 formation byrat mesangial cells in culture. Kidney mt 35:1161—1167, 1989

102. LANESE DM, CONGER JD: Effects of endothelin receptor antagoniston cyclosporine-induced vasoconstriction in isolated rat renal arte-rioles. J Clin Invest 91:2144—2149, 1993

103. AUCH-SCHWELK W, DUSKE E, HINK U, BETZ M, UNKELBACH M,FLECK E: Vasomotor responses in cyclosporin A-treated rats afterchronic angiotensin blockade. Hypertension 23:832—837, 1994

104. MARUMO T, NAKAKI T, FIISHIKAWA K, SUZUKI H, KATO R, SARUTAT: Cyclosporin A inhibits nitric oxide synthase induction in vascularsmooth muscle cells. Hypertension 25:764—768, 1995

105. KON V, HUNLI-TY TE, FoGo A: Combined antagonism of endothelinA/B receptors links endothelin to vasoconstriction whereas angioten-sin II effects fibrosis. Studies in chronic cyclosporine nephrotoxicityin rats. Transplantation 60:89—95, 1995

106. BOKEMEYER D, KRAMER Hi, MEYER-LEHNERT H: Atrial natriuretiepeptide blunts the cellular effects of cyclosporine in smooth muscle.Hypertension 21:166—172, 1993

107. TAKENAKA T, HASHIMOTO Y, EPSTEIN M: Diminished aeetyleholine-induced vasodilation in renal mierovessels of cyclosporine-treatedrats. JAm Soc Nephrol 3:42—50, 1992

108. SHEHATA M, EL NAHAS AM, BARKWORTH E, COPE GH, RAF-FERYAT: Increased platelet-derived growth factor in the kidneys ofcyelosporin-treated rats. Kidney mt 46:726—732, 1994

109. R0SSI NF, CHURCHILL PC, MCDONALD FD, ELLIS VR: Mechanismof cyclosporin A-induced renal vasoconstrietion in the rat. J Phar-macol Exp Ther 250:896-901, 1989

110. GALLEGO MJ, LOPEZ FARRE A, RIESCO A, MONTON M, GRANDESSM, BARAT A, HERNANDO L, CASADO 5, CARAMELO CA: Blockadeof endothelium-dependent responses in conscious rats by cyclosporinA: Effect of L-arginine. Am J Physiol 264:H708—H714, 1993

111. DE NICOLA L, THOMSON SC, WEAD LM, BROWN MR, GABBAI FB:Arginine feeding modifies cyclosporine nephrotoxicity in rats. J ClinInvest 92:1859—1865, 1993

112. MARTIN M, NEUMANN D, HOFF T, RESCH K, DEWITI' DL, G0PPEI.T-STRUEBE M: Interleukin-1-induced cyclooxygenase 2 expression issuppressed by cyclosporin A in rat mesangial cells. Kidney mt45:150—158, 1994

113. LUSCHER TF, WENZEL RR: Endothelin in renal disease: Role ofendothelin antagonists. Nephrol Dial Transplant 10:162—166, 1995

114. GHIGGERI GM, ALTIERI F, OLEGGINI R, SPADA F, GINEVRI F,PERFUMO F, GUSMANO R: Selective enhancement by eyelosporin Aof collagen expression by mesangial cells "in culture." Eur J Phar-macol 270:195—201, 1994

115. WOLF G, NEILSON EG: Increases in levels of collagen types I and IVmessenger ribonucleic acid in murine kidneys after treatment withciclosporin. Nephron 60:87—91, 1992

116. ROSEN S, GREENFELD Z, BREZIS M: Chronic cyclosporine-inducednephropathy in the rat. A medullary ray and inner stripe injury.Transplantation 49:445—452, 1990

117. ELZINGA LW, ROSEN S, BENNETT WM: Dissociation of glomerularfiltration rate from tubulointerstitial fibrosis in experimental chroniceyelosporine nephropathy: Role of sodium intake. JAm Soc Nephrol4:214—221, 1993

118. FRANCESCHINI N, ALPERS CE, ANDOH TF, BURDMANN EA, BENNETTWM: Arteriolopathy persists after drug withdrawal in rats withchronic cyclosporine nephrotoxicity. (abstract) J Am Soc Nephrol5:778, 1994

119. MASON J, MULLER-SCHWEINITZER E, DUPONT M, CASELLAS D,MIHATSCH M, MOORE L, KASKEL F: Cyclosporine and the renin-angiotensin system. Kidney mt 39(Suppl 32):S28—S32, 1991

120. BURDMANN EA, ANDOH TF, NAST CC, EvAN A, CONNORS BA,COFFMAN TM, LINDSLEY J, BENNETT WM: Prevention of experimen-tal cyclosporin-indueed interstitial fibrosis by losartan and enalapril.Am J Physiol 269:F491—F499, 1995

121. YOUNG BA, BURDMANN EA, JOHNSON RJ, ANDOH T, BENNETT WM,COUSER WG, ALPERS CE: yclosporine A induced arteriolopathy ina rat model of chronic cyelosporine nephropathy. Kidney Int 48:431—438, 1995

122. YOUNG BA, BURDMANN EA, JOHNSON RJ, ALPERS CE, GIACHELLICM, ENG F, ANDOH T, BENNETF WM, COUSER WG, LINDSLEY J,DUYN I: Cellular proliferation and macrophage influx precedeinterstitial fibrosis in eyelosporine nephrotoxicity. Kidney Tht 48:439—448, 1995

123. JACKSON NM, O'CONNOR RP, HUMES HD: Interactions of cyclospo-rifle with renal proximal tubule cells and cellular membranes.Transplantation 46:109—1 14, 1988

124. ROGERS TS, ELZINGA L, BENNETT WM, KELLEY VE: Selectiveenhancement of thromboxane in macrophages and kidneys in cyclo-sporine-induced nephrotoxieity. Dietary protection by fish oil. Trans-plantation 45:153—156, 1988

125. WOLF C, NEILSON EG: Angiotensin II as a renal growth factor.JAmSoc Nephrol 3:1531—1540, 1993

126. MOORE LC, CASELLAS D, BEAUDOIN R, KUPFERMAN J, BEAUDOIN D,BIZGALIS A, KASKEL FJ: Dose-dependent renin recruitment byeyelosporines A and C in rat afferent arterioles (AA). (abstract)JAmSoc Nephrol 5:927, 1995

127. JACKSON NM, HSU CH, VISSCHER GE, VENKATACHALAM MA,

1100 Bennett ci al: Chronic cyclosporine nephropathy

HOMES HD: Alterations in renal structure and function in a ratmodel of cyclosporine nephrotoxicity. J Pharinacol Exp Ther 242:749—756, 1987

128. TUFRO-MCREDDIE A, GOMEZ RA, NORLING LL, OMAR AA, MOORELC, KASKEI. FJ: Effect of CsA on the expression of renin andangiotensin type 1 receptor genes in the rat kidney. Kidney liii43:615—622, 1993

129. JoHNsoN RJ, AI,PERS CE, YOSHIMURA A, LOMBARDI D, PRITzI. P,FLOEGE J, SCHWARTZ SM: Renal injury from angiotensin lI-medi-ated hypertcnsion. Hypertension 19:464—474, 1992

130. MEISTER B, LIPPOLDT A, BUNNEMANN B, INAGAMI T, GANTEN D,FOXy K: Cellular expression of angiotensin type-i receptor mRNAinthe kidney. Kidney mt 44:331—336, 1993

131. GARDINER DS, WATSON MA, JUNOR BJR, BRIGGS JD, MORE TAR,LINDOL' GBM: The effect of conversion from cyclosporin to azathio-prine on rcnin-containing cells in renal allograft biopsies. NephrolDial Transplant 6:363—367, 1991

132. AILUJA SS, SI LEt VASTAV S, DANIELPOUR D, BALOw JE, BOUMPAS DT:

Regulation of transforming growth factor- and its receptor bycyclosporine in human T lymphocytes. Transplantation 60:718—723,1995

133. KETTELER M, N0BI.E NA, BORDER WA: Transforming growth fac-tor- and thc kidney. J Nephrol 8:143—147, 1995

134. SIIIHAB FS, ANDOH TF, TANNER AM, NOBLE NA, FRANCESCIIINI N,BENNETT WM: Role of transforming growth factor-pi in experimen-tal chronic cyclosporine nephropathy. Kidney mt (in press)

135. SHEHATA M, COPE GH, JOHNSON TS, RAFTERY AT, EL NAI-lAs AM:Cyclosporine enhances the expression of TGF-p in the juxtaglomer-ular cells of the rat kidney. Kidney mt 48:1487—1496, 1995

136. KHANNA A, Li B, STENZEL KH, SUTHANTHIRAN M: Regulation ofnew DNA synthesis in mammalian cells by cyclosporine. Transplan-tation 57:577—582, 1994

137. KHANNA A, LI B, SEHAJPAL PK, SHARMA VK, SUTHANTI-IIRAN M:Mechanism of action of cyclosporine: A new hypothesis implicatingtransforming growth factor-p. Transplant Rev 9:41—48, 1995

138. ENGLISH JA, BURDMANN EA, ANDOII TF, STILL MAN I, FRANCESCHLNIN, LINDSEFY J, ROSEN 5, BENNETt WM: Effect of prednisone onexperimental chronic cyclosporine nephrotoxicity. (abstract) Cliii Res42:94A, 1994

139. GRIFFIm5 EJ, HALESTRAP AP: Protection by cyclosporin A ofischemia/reperfusion-induced damage in isolated rat hearts. J MolCell Cardiol 25:1461—1469, 1993

140. UCI-tINo H, ELMER E, UCHINO K, LINDVALL 0, SIESJO BK: (yclo-sporin A dramatically ameliorates CAl hippocampal damage follow-ing transient forebrain isehaemia in the rat. Ada Physiol Scand155:469—471, 1995

141. GARCIA DEL MORAL R, O'VALLF F, ANDIJJAR M, AGUILAR M,

LUCENA MA, LOPEZ-HIDALGO J, RAMIREZ C, MEDINA-CANO MT,AGUILAR D, GOMEZ-MORALES M: Relationship between P-glycopro-tein expression and cyclosporin A in kidney. An immunohistologicaland cell culture study. Am J Pathol 146:398—408, 1995

142. HIESSE C, NEYRAT N, DEGLISE-FAVRE A, LANTZ 0, BENSADOUN H,BENOIT G, CHARPENTIER B, FRIES D: Randomized prospective trialof elective cyclosporine withdrawal from triple therapy at 6 monthsafter cadaveric renal transplantation. Transplant Proc 23:987—989,1991

143. PEDERSEN EB, HANSEN HE, KORNERUP HJ, MADSEN S, SORENSENAW: Long-term graft survival after conversion from cyclosporin toazathioprine 1 year after renal transplantation. A prospective, ran-domized study from 1 to 6 years after transplantation. Nephrol DialTransplant 8:250—254, 1993

144. HOLLANDER AAMJ, VAN SAASE JLCM, Koorrv AMM, VAN DORPWT, VAN BOCKEI, HJ, VAN ES LA, VAN DER WOUDE FJ: Beneficialeffects of conversion from cyclosporin to azathioprine after kidneytransplantation. Lancet 345:610— 614, 1995

145. FERGUSON CJ, WILLIAMS JD, HILLIS AN, PARRY-JONES D, SALAMANJR: Effects of the calcium channel blocker diltiazem on cyclosporinnephrotoxicity in renal transplant patients. C/in Transplant 6:39 1—398, 1992

146. PALMER BF, DAWIDSON I, SAGALOWSKY A, SANDOR Z, Lu CY:Improved outcome of cadaveric renal transplantation due to calciumchannel blockers. Transplantation 52:640—645, 1991

147. CHRYSOSTOMOU A, WALKER RG, RUSS GR, D'APICE AJF, KINCAID-SMITH P, MATIIEW TH: Diltiazem in renal allograft recipientsreceiving cyclosporine. Transplantation 55:300—304, 1993

148. MCCULLOCH TA, HARPER SJ, DONNELLY PK, MOORHOUSE J, BELLPRF, WALLS J, FEEHALLY J, FURNESS PN: Influence of nifedipine oninterstitial fibrosis in renal transplant allografts treated with cyclo-sporin A. J Clin Pathol 47:839—842, 1994

149. RUGGENENTI F, PEFSICO N, MOSCONI L, GASPARI F, BENIGNI A,AMUCHASTEGUL CS, BRUzzI I, REMUZZI 0: Calcium channel block-ers protect transplant patients from cyclosporine-induced daily renalhypoperfusion. Kidney mt 43:706—711, 1993

150. BANTLE JP, PALLLR MS, BOUDREAU RJ, OLIVARI MT, FERRIS TF:Long-term effects of cyclosporine on renal function in organ trans-plant recipients. J Lab C/in Med 115:233—240, 1990

151. VAN BUREN DH, BURKE JF, LEWIS RM: Renal function in patientsreceiving long-term cyclosporine therapy. JAm Soc Nephrol 4:S17—S22, 1994

152. SNIDER J, FRANCIS DMA, KINCAID-SMITH P, WALKER RG: Long-term graft survival and renal function in cyclosporin-treated renalallograft recipients: Lack of evidence of nephrotoxicity. C/in Trans-plant 7:25—27, 1993