Chronic cyclosporine nephropathy: The Achilles' heel of immunosuppressive therapy

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 of kidney, heart, liver, and kidney/pancreas have reached unprecedented levels largely due to cyclosporine-based immunosuppressive regimens. Most transplant centers around the world achieve 85 to 90% one-year graft survival for kidney transplants and very few patients suffer loss of life because of modern medical management [1, 2]. These impressive results with cyclosporine have

successfully managed with precise pharmacologic monitoring and improved dosing, these presumptions depend on the assumption

extended the indications for cyclosporine usage from organ transplantation to the treatment of autoimmune and primary

patients with autoimmune diseases, extrarenal organ transplant recipients, renal allograft recipients, and experimental animals, consists of areas of striped tubulointerstitial fibrosis, tubular

renal diseases. However, nephrotoxicity due to cyclosporine continues to be a major problem [3]. In spite of improved one- and two-year renal allograft graft survival rates, the average half-life of eight years for a cadaver kidney transplant that is functioning at

atrophy and afferent arteriolopathy [16, 17]. The process begins in the outer medulla with extension to the medullary rays and thus is often difficult to diagnose on a core renal biopsy. The hallmark of

chronic rejection [6]. However, the adverse effects of cyclosporine

some patients can be observed with doses of cyclosporine as low as 2 to 4 mg/kg. Many of the retrospective clinical reports concerning the pres-

that cyclosporine-induced nephropathy is functional, dose-related, and reversible. These acute hemodynamic effects may not be the only consequences of cyclosporine on the kidney. It is clear that the morphologic lesion produced by cyclosporine therapy in

cyclosporine nephropathy rests on the demonstration of approone year has changed little with the addition of cyclosporine- priate vascular lesions in the afferent arteriole (cyclosporinebased immunosuppression [4, 1. Conventional wisdom suggests associated arteriolopathy) [161. These vascular lesions of chronic that chronic allograft failure in kidney transplants is largely due to cyclosporine nephropathy are not necessarily dose-related and in

on long-term kidney structure and function have not been ex-

cluded as an important part of the chronic allograft failure

syndrome. An important role for cyclosporine on chronic progres- ence or absence of chronic cyclosporine nephropathy in renal sive renal dysfunction when used outside the renal transplant transplantation are based on renal function alone [181. There are situation is well accepted. This communication will review the few pathologic data available to separate chronic allograft rejecentity of chronic cyclosporine nephropathy. The current literature tion from chronic cyclosporine nephropathy. This distinction is about this subject will be analyzed and its presumed pathogenesis based on the demonstration of arteriolar vessel changes as will be reviewed with an emphasis on recent studies indicating that opposed to the arterial lesions of chronic rejection [16]. In cyclosporine-induced renal fibrosis may be an inevitable conse- addition, there is also no a priori reason that both processes cannot exist together. Thus, for the most part, renal function as quence of effective immunosuppressive therapy. estimated by serum creatinine or even by more precise GFR Renal effects of cyclosporine measurements has been used as a surrogate marker for the It is well-known that cyclosporine causes a dose-related de- presence or absence of chronic cyclosporine nephropathy. Clearly, crease in renal function in experimental animals and humans. This adaptive mechanisms within the kidney can keep the GFR is largely thought to be due to the drug's hemodynamic effects to relatively stable for long periods in the face of progressive and produce afferent arteriolar vasoconstriction and in the extreme, important tubulointerstitial disease as exemplified by diabetic

decreased glomerular filtration rate (GFR), manifested clinically nephropathy, autosomal dominant polycystic kidney disease, and by rises in serum creatinine [7, 8]. While there are many candidate non-cyclosporine-treated renal transplants [19]. mediators for cyclosporine-induced vasoconstriction such as endothelin, thromboxane A2, nitric oxide synthase inhibition and Chronic cyclosporine nephropathy activation of the sympathetic nervous system, these effects are Chronic cyclosporine nephropathy is defined as a clinicopathreversible with dose reduction or appropriate pharmacologic ologic entity produced by exposure of the patient to cyclosporirie. maneuvers [9—14]. The studies of Curtis et al [151 have shown that characterized by tubulointerstitial fibrosis in a striped pattern, even in renal transplant patients who are perceived to be doing beginning in the medulla and progressing to the medullary rays of well under cyclosporine immunosuppression, drug withdrawal the cortex. It is associated with degenerative hyaline changes in leads to rapid improvement in renal hemodynamics. While some the walls of afferent arteriolar-sized blood vessels extending from have argued that these cyclosporine-induced renal effects can be the pre-glomerular area proximally up the afferent arteriole [161. Usually, but not inevitably, this pathologic finding is associated

with some degree of renal dysfunction. It is clear that this Received for publication January 2, 1996 and in revised form February 27, 1996 Accepted for publication February 28, 1996

© 1996 by the International Society of Nephrology

clinicopathologic entity does not preclude the coexistence of other processes such as renal allograft rejection. Dc novo or recurrent hemolytic uremic syndrome may be associated with cyclosporine [20, 211. There is glomerular fibrin deposition with fibrin thrombi.

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Bennett et al: Chronic cyclosporine nephropathy

This unusual type of cyclosporine-associated renal dysfunction will not be discussed further. Chronic cyclosporine nephropathy in heart transplantation The pivotal studies of Myers et al [22] described the renal, structural, and functional changes in the native kidneys of heart transplant recipients. Careful documentation of renal function revealed a progressive decrease in GFR with a concomitant drop in renal plasma flow and increase in renal vascular resistance. This

was associated with hypertension. Biopsies in a subset of these patients showed glomeruloscierosis, striped interstitial fibrosis, and afferent arteriolopathy. The original study was criticized because of the high doses of cyclosporine that were used for induction and subsequently for maintenance therapy. The starting dose of 17 mg/kg/day with adjustment downward, was higher than that used in modern cardiac transplantation [23]. Nonetheless, when patients who subsequently underwent heart transplantation at Stanford with cyclosporine doses of 10 mg/kg or less were compared with the high dose patients, both groups had hypertension and decreased GFR. The decrease in GFR was approximately 45% from baseline, even in the low dose cyclosporine group, when compared to a historical control group which used azathioprine and prednisone without cyclosporine. Renal biopsy samples from patients treated with lower dose cyclosporine had the same pathologic changes as those seen with higher doses and no difference in the degree of involvement could be shown [241. When high dose and low dose groups were compared two years after transplantation, the mean serum creatinine was 2.1 mg/dl in the high dose group, 1.6 mg/dl in the low dose group, and 1.2 mg/dl in the no cyclosporine group [25]. It was further demonstrated that sequential native kidney biopsies in both cyclosporine groups showed progressive histopathologic changes. There was a cumulative incidence of end-stage renal disease of approximately 10% from the decade of 1980—1990 [25]. There were no differences in cardiac function among the groups to explain the renal dysfunction. Furthermore, the authors established that cyclosporme-induced chronic nephropathy can progress despite drug with-

before transplantation, the serum creatinine at hospital discharge

rose from 1.2 mg/dl to 3.3 mg/dl at seven years, and 1.6% of patients had developed end-stage renal disease by 18 months with an additional patient developing end-stage renal disease after five

years. No pathologic material was available, but the doses of cyclosporine used in the study were similar to current clinical doses of 10 mg/kg/day for induction and then 5 to 10 mg/kg/day dependent on blood levels.

An autopsy study of 15 patients established that interstitial fibrosis can be present in terminal heart failure patients before heart transplantation and it does not inevitably progress [29]. There was no relationship between renal histology and cyclosporme-treated heart transplant recipients' blood pressures and serum creatinine levels. In this study, it was confirmed that cyclosporine can cause progressive arteriolar hyalinization and glomerulosclerosis.

The remainder of studies in heart transplant recipients involve renal 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 or estimated by the reciprocal of serum creatinine. Doses again were contemporary, and no histopathology was available. Gonwa et a! [31] cited a 1 to 2% incidence of end-stage renal disease at four centers with > 1000 patients, although the duration of follow-up and 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 renal functional studies were performed in 10 cyclosporine-treated heart transplant recipients who had been on the drug for two years. GFR and effective renal plasma flow were below normal values in transplant recipients, and the averages were 35 mI/min/ 1.73 m2 and 325 ml/min/1.73 m2, respectively. Light microscopy of

autopsy specimens from patients with no history of renal disease

and from patients who had died from dilated cardiomyopathy without heart transplantation revealed no structural renal abnormalities. However, in cyclosporine-treated patients, arteriolopathy and glomerulosclerosis were seen. Thus, cyclosporine given drawal. for more than two years induced in all patients moderate renal Other studies have looked at renal function without concomi- failure associated with obliterative arteriolopathy and glomerular tant renal pathologic studies in heart transplant recipients. Zietse ischemia. As cyclosporine nephropathy developed, subpopulaet al [26] in 1994 followed 187 patients treated with initial doses of tions of glomeruli of different sizes emerged. Some glomeruli cyclosporine of 8 mg/kg/day. At two years post-transplant, serum were small and had segmental or global sclerosis, and other creatinine was >2 mg/dl in 52% of the patients. At four years, glomeruli were large. Follow-up of these same patients by Rugserum creatinine was >3.5 mg/dl in 13% of the patients. There genenti et al [331 showed stabilization of GFR and renal plasma was no relationship of renal dysfunction to CSA blood level, the flow over a two-year follow-up period. No histopathology was use of calcium antagonists, blood pressure, or the pre-transplant recorded in the follow-up study. serum creatinine. In two publications by Greenburg et al [27, 28], Nephrotoxicity is frequent and a major cause of progressive heart transplant patients were frequently shown to have azotemia renal injury in lung transplantation. In 30 recipients followed for and acute renal failure at one week post transplant. No CsA- at least six months, 50% developed hypertension, 9 patients had treated patients in this series who had 36 months of follow-up creatinines > 3 mg/dl, and 2 had developed end-stage renal showed normal renal function. One patient had progressed to disease [34]. Likewise, of 67 heart-lung transplant patients survivend-stage renal disease. Renal function was improved in five ing at least six months, 3 developed end-stage renal failure, while patients in whom dose reduction was attempted, although patho- the mean serum creatinine rose from baseline 0.96 to 1.88 at logic documentation of histologic improvement is not available. four-year follow-up [35]. These 43 cyclosporine-treated cardiac transplant recipients had a Chronic cyclosporine nephropathy in renal transplantation 58% incidence of azotemia compared to 34% of 41 non-cyclosporine-treated patients and 4% of 25 patients undergoing cardioThe effect of cyclosporine on renal structure and function in renal allografts is often difficult to discern. Much of the problem pulmonary bypass without immunosuppression. In a later study of 228 adults who survived more than one year involves the complicated differential diagnosis of renal dysfuncafter cardiac transplantation and who had normal renal function tion in this setting [16]. Chronic rejection, recurrent renal disease,

Bennett et al: Chronic cyclosporine nephropathy

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and nonspecific factors such as hypertension, hyperlipidemia and age can lead to progressive renal structural and functional deterioration. Discerning the role, if any, of cyclosporine in isolation is difficult. Based largely on retrospective data showing stability of

prine-treated patients is of concern [41]. Experimental data from denervated renal isografts which progressively fail over 12 months from cyclosporine-induced renal failure do not support a sparing of renal transplants from CSA toxicity [7]. Other studies without

serum creatinine over time, it has been stated that the renal

histopathology or controls, such as those of Lewis et al [42],

transplant is relatively spared from the ravages of chronic cyclosporine treatment [18]. Many of these studies are methodologically flawed because both structure and function were not measured, some studies used structure alone, and some studies used functional parameters alone. Jacobsen et a! [36] studied 19 renal transplant patients who received cyclosporine for two years. The daily dose of cyclosporine was 15 mg/kg to start, dropping to 6 mg/kg at two years. GFR was 42 mI/mm compared to 106 ml/min in 13 healthy two kidney gender- and age-matched control patients. Eighteen of the 19 patients had increased tubulointerstitial fibrosis by morphometric determination when compared to normal kidneys. All of the recipients were non-diabetic, and there was no correlation between the degree of renal dysfunction and the

Slomovitz et al [43] and Lewis et al [30], showed elevated serum creatinine levels and decreased GFRs for a solitary kidney that

were abnormal but stable. Since histopathology was not performed, cyclosporine-associated tubulointerstitial disease with arteriolopathy cannot be excluded. Thus, chronic rejection de-

extent of tubulointerstitial fibrosis. Ruiz et al [37] studied 59

fined on clinical grounds alone, that is, renal dysfunction, minimizes any role for cyclosporine. It is possible that cyclosporine-induced injury may play a role in chronic allograft failure that is caused predominantly by chronic rejection. Mihatsch et al studied 90 patients and compared renal pathology in a group who had serum creatinine levels less than 2 mg/dl, with a group who had biopsy-proven rejection with serum creatinine levels greater than 2 mg/dl, and with a pathologically defined cyclosporine-nephrotoxicity group with serum creatiriine

cyclosporine-treated kidney transplant patients at 15 weeks post-

levels greater than 2 mg/dI [17]. Of the variables examined, factors

transplant and compared them with 46 recipients who did not that lead to acute cyclosporine nephrotoxicity such as high trough receive cyclosporine and with 15 pre-transplant donor kidney blood levels, had predictive value for chronic cyclosporine biopsies. The daily dose of cyclosporine at the time of biopsy was changes even in patients whose biopsies showed histologic evi-

12 mg/kg. Both transplant groups had increased tubulointerstitial dence of acute rejection. Table 1 summarizes the available studies fibrosis when compared to control kidneys. The interstitial fibrosis concerning the long-term effects of cyclosporine on renal strucwas more extensive and the serum creatinine level higher in the ture and/or function. cyclosporine group after six months. Klintmalm et al [38] studied While it has been thought that arteriolopathy and tubulointer38 biopsies in 24 cyclosporine-treated renal transplant patients stitial fibrosis are irreversible changes, some recent studies have and compared them to 43 biopsies from 43 patients treated with

azathioprine and steroids over a one to four year observation questioned this assumption. A preliminary study of 21 patients with biopsy-proven cyclosporine nephrotoxicity showed that with period. Doses of cyclosporine, again, were high initially and 50 percent dose reductions in 12 patients and complete cyclospotapered to 10 mg/kg/day at four months. Serum creatinine averrifle withdrawal in 9 patients, GFR improved from a mean of 42 aged 2.1 mg/dl in the cyclosporine-treated patients and 1.5 mg/dl in the azathioprine-treated group. Blind analysis of the renal to 67 mI/mm. In 5 patients who had repeat biopsies, arteriolar biopsies showed severe interstitial fibrosis and tubular atrophy in lesions disappeared and "onion skin" vascular changes decreased. the cyclosporine patients when compared with biopsies from the There was only one acute rejection episode noted with these

azathioprine patients, although the same number of rejection dosage adjustments [4I. Morozumi et al [45] in 1992 showed that in 9 of 20 patients crises occurred in each patient group. The renal histologic findings correlated with high trough cyclosporine levels and cumulative transplanted 10 years earlier, there was no difference in mean cyclosporine whole blood levels and duration of treatment becyclosporine dose in the first six months. Other groups in the early 1980s reported that renal biopsies tween those who had demonstrable arteriolopathy and those who did not. However, vascular lesions were reversible in patients in showed progressive changes of chronic cyclosporine nephropathy. Sommer et al [39] reported that cyclosporine arteriolopathy whom the drug was discontinued and renal function became caused graft loss in 7.5% of 200 recipients. This represented 40% of all allografts that failed. Graft losses not attributable to chronic rejection also demonstrated interstitial fibrosis.

normal. Thus, despite 15 years of cyclosporinc-based immunosuppres-

Perhaps the most cited study is the retrospective analysis of 1415 kidney transplant recipients by Burke et al [40]. This study

studies available that document the long-term renal safety of this compound or the effect of cyclosporine-induced renal structural and functional changes on the longevity of renal transplants. The difficulty in implicating cyclosporinc in chronic allograft failure

followed serum creatinine levels, up to four years after transplantation. Values were elevated but unchanged during the period of study. Only 25% were followed for more than four years and the

sion in renal transplant recipients, there are no prospective

has arisen because of the complexity of its role in an allograft

average follow-up was three years. The main drawback of this under immunologic attack. yclosporine-induced renal sympathetic nerve stimulation has study was the absence of renal histopathology. The diagnosis of "chronic rejection" in this study was based simply on progressive been implicated in the development of hypertension in recipients renal dysfunction in the absence of improvement following cyclo- of non-renal organ transplants [46, 47]. It has been suggested that sporine dose reduction. Furthermore, the four centers which renal denervation protects the transplanted kidney versus extracontributed to this report, all had different immunosuppressive renal situations in which cyclosporine is prescribed. Recent exregimens. Long-term increases in serum creatinine in cyclospor- perimental studies, however, have shown that renal denervation inc-treated HL-A identical renal transplants compared to azathio- does not protect against chronic cyclosporinc nephropathy [7, 481.

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Bennett et al: Chronic cyclosporine nephropathy

Table 1. Summary of published articles on long term effects of cyclosporine on renal structure and/or function Length of N Bantle et al 11501

Mean GFR reduced by 27%

11

Burke et al [1511

1415

Klintmalm [38]

24 pts with CsA 43 pts with azathioprine

(AZA) Jacobson Ct al [36]

Lewis et xi [30]

Renal function

19

119

from baseline: but stable over study period Mean scrum ereatinine 1.9 mg/dl: stable over study period

Mean serum creatinine 2.1 mg/dl with CsA, 1.5 mg/dl with

AZA

Renal pathology

23 mo

None

Regimens varied among 4 centers

Mean follow-up 3 yrs

Retrospective clinical definition of chronic rejection, CsA nephrotoxicity

Masked pathology; more fibrosis

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

1—4 yrs

Rejections equal. Fibrosis correlated with high cumulative CsA and trough levels in first 6 mos

2 yrs

and tubular atrophy in CsA pts

GFR 42 mI/mm; P < 0.001 vs. healthy controls

18 pts had increased fibrosis compared to controls

12—15 mg/kg initial

Mean serum creatinine 2.1 mg/dl

None

10—14 mg/kg

None

Mourad et al [44J

21 pts with biopsy-proven

GFR improved from 42 to 67 mI/mm when CsA decreased or stopped Creatinine increased in CsA group (P < 0.01)

In 5 pts, arteriolar

Slomowitz [43]

29

Snider et al [152]

Summer et al [39]

145 with CsA 194 with AZA 200 consecutive cadaver

Initial GRF 29 ml/ mm in Pt who lost grafts vs. 46 mI/mm in those with stable function Mean serum creatinine did not differ between groups None given

transplants Sumrani et al [41]

HI-A identical 72 with AZA 34 with CsA

Creatinine 2.4 at 5 yrs in CsA pts with progressive rise vs stable ereatinine 1.4, in azathioprine pts

4-6 mg/kg at 2 mo adjusted to trough levels 7 mg/kg at 6 mo 4.3 mg/kg at 4 yr Mean dose 4.8 mg/kg

GFR stable over 1 year period

59 CsA 46 AZA

Remarks

3—5 mg/kg

44

Ruiz et al [37]

follow-up

None

Lewis et al [421

CsA nephrotoxicity

CsA dose mg/kg

lesions

disappeared

Both groups had increased fibrosis compared to pre-transplant donor controls 5 graft losses, 3 rejection plus CsA toxicity, 2 CsA toxicity alone

None reported

Dose reduced in 50 percent; CsA discontinued 9 pts

Up to 4 yr

Reciprocal creatinine stable; 32 pts withdrew because of nephrotoxicity

Studied 2 mo to 9 yr posttransplant

11.8 mg/kg at time of biopsy

15 weeks of CSA

Tailored to trough

32 mos

level 150—250 ng/ml; dose 3.5—

4.9 mg/kg S mg/kg/day initial

Up to 6 yrs

tapered to blood level target 16 serial biopsies showed progressive CsA nephrotoxieity

None

Chronic cyclosporine nephropathy in autoimmune disease Because of the success of cyclosporine in solid organ transplan-

10 mg/kg/day in

1 year

double or triple therapy regimens 10—15 mg/kg

initially; 4 mg/kg

Cyclosporine toxicity

cause of graft loss in 15 pts

Up to 5 yrs

Pt and graft survival better with CsA

at 1 yr

with normal renal function because of worries about nephrotoxicity. Since rejection is not an issue in autoimmune disease, the pathologic and functional changes produced by cyclosporine are instructive. One of the first uses of cyclosporine was in patients

tation, it was logical to extend this potent immunosuppressive drug to other refractory conditions thought to be of immunologic with refractory autoimmune uveitis. The NIH group 1491 reported origin. In these patients, most clinical trials only enrolled people 17 patients who received cyclosporine in initial daily doses of 10

Bennett et al: Chronic cyclosporine nephropathy

1093

mg/kg. The dose was titrated to keep the serum creatinine level

terstitial fibrosis have been seen associated with decreased GFR [62]. Serial biopsies one year apart have shown increases in renal Duration of therapy was from two to four years. All patients had fibrous tissue inversely correlated with creatinine clearance [63, arteriotar changes on renal biopsies performed after 18 to 24 64]. In psoriatic patients, there were correlations between acute months of therapy. In 6 patients, further follow-up biopsies were episodes of nephrotoxicity and chronic changes, but no relationavailable. Three of these showed progressive tubulointerstitial and ship to dose, duration of therapy or blood levels. An excellent arteriolar changes in the presence of stable inulin clearances. prospective study by Young et al with serial biopsies and GFR Despite the fact that all patients had normal creatinine clearance measurements showed a decline of 3.1 ml/min/i.73 m2/year along before initiation of cyclosporine therapy, 14 of 17 patients had with progressive structural changes [65]. Angiotensin II elevations markedly reduced renal function, and in 2 of the 17 these renal were noted in patients with cyclosporine A (CsA)-associated function deteriorations were progressive. Two of 17 improved hemodynamic abnormalities [66]. Similar findings to the psoriasis when the drug was stopped, and 12 of 17 remained stable after series were noted in atopic dermatitis treated with cyclosporine dose reduction. There was little relationship between the patho- [67]. logic changes, the dose, and the whole blood trough blood levels In a two-year placebo controlled study in multiple sclerosis [49, 50]. Sixteen other patients were treated with cyclosporine patients, serum creatinine rose from baseline normal values to initially, 6 mg/kg/day tapered to 2 mg/kg/day, and followed for five greater than ito 5 times baseline or greater than 2 mg/dl in 21% years. The GFR was reduced from 119 mI/mm to 98 mI/mm of 273 patients randomized to CsA with blood pressure elevations without a return to the pre-treatment level when the drug was in 50%. No biopsies were done [68]. Low dose cyclosporine stopped. No pathologic studies were performed in this series [51]. produced chronic cyclosporine nephropathy in serial biopsies In 1991, Anderson et al [52] reported on 10 patients who initially from rheumatoid arthritis patients with no previous renal disease, received 10 mg/kg/day of CsA that was reduced to 5 mg/kg/day for as well as in increases in serum creatinine [69—75]. A 24-month three years. Eight of the 10 patients had lymphocytic infiltrates serial biopsy in 11 patients were compared to 22 matched autopsy with arteriolar hyalinosis on renal biopsy. Creatinine clearances controls who had received gold and/or penicillamine [76]. Alwere slightly reduced from baseline values. though creatinine clearance decreased from lii mi/mm to 82 Another major use of cyclosporine has been at the onset of mi/mm, structural nephropathy was minimal. Mild tubular atroinsulin-dependent diabetes mellitus. There are a variety of proto- phy was common but arteriolopathy was only found in 3 biopsies

less than 2 mg/kg or less than 50% above the baseline value.

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 13

months of therapy with cyclosporine was evaluated. There were typical histopathological abnormalities in 40% of patients which were not progressive when doses were low and adjusted for serum creatinine levels. The morphologic changes correlated with age, dose and the trough blood level. Functional abnormalities were reversible when doses were reduced. Mihatsch et al [55] in 1991 studied 40 type 1 diabetic patients treated with cyclosporine 7 to

9 mg/kg/day for at least one year. Twenty-five percent of the patients had vascular and interstitial pathologic changes of chronic cyclosporine nephropathy. Renal function, as measured by serum creatinine level, was decreased by 43% at the time of biopsy when compared to baseline values. The patients of Mihatsch were different than the patients of Assari et at whose patients were biopsied when in remission from type I diabetes [54]. There was a weak positive correlation of high trough cyclosporine levels with chronic cyclosporine nephropathy. Feutren and Mihatsch reported an extensive series of autoimmune patients with pathologically defined chronic cyclosporine

[76]. Structural nephropathy of a similar degree was seen in controls. Similar data exist for patients with myasthenia gravis and other autoimmune diseases in blinded clinical trials [77—82].

Chronic cyclosporine nephropathy in liver transplantation Several series have been reported in which renal function has been followed in liver transplant patients [83—86]. While GFR decreases soon after liver transplantation, renal dysfunction is seldom progressive, at least up to three or four years of follow-up. However, renal histopathobogic changes have not been extensively studied. In one recent study where autopsy pathology in 7 liver transplant patients was compared to that of gender and age matched controls, cyclosporine caused progressive fibrosis and arteriolopathy independent of serum creatinine levels and blood pressure [87].

In a large series of liver transplant patients [88], the greatest decline in creatinine clearance occurred at 18 months. However, at three years post-transplant, serum creatinine was less than 1.7 mg/dl in only 23% of patients. There was no relationship between

nephropathy [56]. Initial cyclosporinc dose, male gender and kidney dysfunction and the daily dose of cyclosporine or the cpisodes of acute nephrotoxicity correlated with the presence of measured whole blood trough blood levels. Thus, in liver transchronic changes. It is noteworthy that patients in this series were plantation, as in other solid organ transplantation, cyclosporine young and without previous renal dysfunction or atherosclerosis. induces important structural and functional lesions. In diabetic subjects who achieved five years of normoglycemia by

pancreas alone transplants, serious tubulointerstitial and gbmerulosclerotic lesions developed in native kidneys. This contrasted with a lack of renal abnormalities in control diabetics with similar baseline renal function followed for the five year period [57].

Series of psoriasis patients who received low doses of cyclosporifle, initially 5 mg/kg/day, tapered to 1 to 2 mg/kg/day, have shown

moderate arteriolopathy and scarring [6, 58—61]. In the studies that have reported renal pathology, arteriolopathy and tuhuloin-

Bone marrow transplantation In bone marrow transplantation, where cyclosporine is used as prophylaxis against graft versus host disease, Dieterle et a! [89] reported renal pathology in autopsied or biopsied bone marrow transplant recipients. Striped interstitial fibrosis was present in 25 patients, and arteriolopathy was present in 36 patients of the 51 patients studied. Serum creatinine levels increased 40 to 80% by three months post-transplant and stabilized. The renal pathology

seemed to be worse when total body radiation was used to

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Bennett et al: Chronic cyclosporine nephropathy

condition the bone marrow transplant recipient even when the

Animal models of chronic cyclosporine nephrotoxicity have

kidneys are shielded. Bone marrow recipients tended to be been difficult to develop. Even in animals treated with cyclospoyounger and without pre-existing atherosclerotic disease when compared to recipients of other organs. This demonstrated that chronic cyclosporine nephropathy may occur without those risk factors. An autopsy study of 112 bone marrow transplant recipients showed that 54% has vascular and interstitial toxic lesions with severe thrombotic microangiopathy in 25% [901.

Primary renal disease and cyclosporine

When cyclosporine is used to treat nephrotic syndrome or glomerular diseases, any renal function deterioration is not easily distinguished from progression of the primary diseases process. Delaney, Dukes and Edmunds [91] reported 10 adult patients with nephrotic syndrome of various causes treated with cyclosporine 5 mg/kg for up to five years. Three patients had mild elevations of

serum creatinine while in one patient abnormal renal function improved. No follow-up biopsies were done. In children, GFR falls within the first three months by 21% but remains stable thereafter up to two years [92]. In 42 nephrotic children with preand post-treatment renal biopsies, Habib and Niaudet were able to demonstrate progressive tubulointerstitial changes and arteriolopathy in the absence of progressive focal glomerulosclerosis lesions suggesting cyclosporine nephrotoxicity in 9 patients [93, 94]. Interestingly, there was normal renal function and no correlation between the pathologic lesions and the treatment dose, duration, or trough blood levels. Meyrier et al found that minimal change nephrotic syndrome patients tolerated cyclosporine up to 5.5 mg/kg well without histologic evidence of nephrotoxicity, whereas patients with focal and segmental glomerulosclerosis particularly with pre-existing renal insufficiency were at risk of cyclosporine nephrotoxicity [5I. This subject has recently been debated [96, 97]. A randomized controlled trial of cyclosporine in membranous nephropathy has showed slowing of progressive renal dysfunction and decreased proteinuria in patients with refractory nephrotic syndrome. No follow-up renal histology was available [98]. Biopsies of patients with lupus nephritis 18 to 24 months after steroids and 5 mg/kg/ day cyclosporine revealed no evidence of chronic cyclosporine nephropathy [99]. Thus, cyclosporine can produce chronic nephropathy when the drug is used to treat renal diseases although the risk to long-term renal reserve is unclear.

Pathophysiology of chronic cyclosporine nephropathy Cyclosporine is known to produce decreases in renal blood flow

due to constriction of the afferent arteriole proximal to the glomerulus [8]. Although most of these studies have been performed in experimental animals, similar phenomena occur in humans. The profound impairment of renal hemodynamics from even a single dose of cyclosporine in chronically treated renal transplant patients has been documented by Perico et al [10]. In stable patients who have cyclosporine discontinued, renal blood flow improves by 30% and renovascular resistance and blood pressure reciprocally drop [151. Thus, some degree of renal vasoconstriction probably occurs in all patients who receive effective immunosuppressive therapy with eyclosporine. When this hemodynamically-mediated phenomenon causes a rise in serum creatinine, which is reversible with dosage adjustment, the clinical diagnosis of acute cyclosporine ncphrotoxicity is made.

rifle for long periods of time, or with extremely high doses, the adverse renal hemodynamic effects are not associated with major structural abnormalities in the kidney [100]. Tubular function, in response to the vasoconstriction, is well preserved, at least as measured by the fractional excretion of sodium and lithium [8]. There is little evidence for acute tubular necrosis produced by cyclosporine. While prolonged vasoconstriction could contribute to chronic cyclosporine nephropathy by producing chronic ischemia, this relationship has been difficult to demonstrate in experimental studies. Thus, most studies in salt replete animals even with extremely high blood levels for periods as long as 12 months have failed to reproduce the clinicopathologic findings of chronic cyclosporine nephropathy observed in humans [100]. There are many suggested mediators for cyclosporine-induced vasoconstriction, including thromboxane A2, reduction of vasodilator prostaglandins, activation of renal sympathetic nerves, endothelin, angiotensin 11, platelet-derived growth factor, and reduced nitric oxide production [10, 12, 14, 101—108]. In the isolated

perfused rat kidney, Rossi et al [109] showed that cyclosporineinduced vasoconstriction could be blocked by alpha-adrencrgic blockers as well as by calcium channel blockers [109]. Many in vivo

studies have evaluated the ability of pharmacologic antagonists of mediators to reverse cyclosporine-induced vasoconstriction [110— 113]. While there are usually improvements in renal hemodynamics, the effect of any individual or combination of mediators on the chronic nephrotoxic lesion remains unknown. Clinically, multivariate analysis of renal biopsies from cyclosporine-treated patients with autoimmune disease has shown that initial dose, male gender, and episodes of acute renal dysfunction are major risk factors for the chronic pathologic manifestations of

cyclosporine nephropathy [56]. Mihatsch et a! [161 observed obliterative arteriolopathy with downstream glomerulosclerosis in cyclosporine-treated patients. They proposed that the arteriolopa. thy with ultimate vascular occlusion produces a pattern of striped interstitial fibrosis with nephron dropout, tubular atrophy, and, if

progressive, compromised renal function. Myers et al [23] also suggested that chronic afferent vascular injury leads to compromisc in the integrity of afferent arterioles, leading to the irreversible changes that are observed. This logical, but undocumented, pathophysiology has recently been brought into question by several unrelated observations.

Ghiggheri et al [114] have shown that very small doses of cyclosporine, much less than would produce toxicity clinically, can stimulate collagen synthesis in vitro in a variety of cell systems.

Wolf and Nielson showed increased levels of type I and type 4 collagen mRNA in murine kidneys treated with CsA for four weeks when serum creatinine was normal [115]. In an animal model of chronic cyclosporine nephrotoxicity produced by one week of salt depletion, structural lesions are seen that resemble the human renal pathology of chronic cyclosporine nephropathy [116, 117]. Indeed, afferent arteriolopathy with hyalinization and striped tubulointerstitial fibrosis are seen when cyclosporine treated animals arc subjected to salt depletion. Renal hemodynamic changes are associated with this lesion. However, when the drug is stopped, GFR returns towards baseline values over two to four weeks while tubulointerstitial pathologic changes remain

Bennett et a!: Chronic cyclosporine nephropathy

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

Because the structural changes in this model are related to the manipulation of salt depletion, the renin-angiotensin system has been examined for its role in chronic cyclosporine nephropathy [1191. Blockade by angiotensin converting enzyme inhibition as well as angiotensin II receptor blockade strikingly reduces the tubulointerstitial fibrosis and arteriolopathy in this model despite failure to normalize glomerular filtration rate [100, 120]. Kon, Hunley and Fogo [105] have recently shown that endothelin A and B receptor blockade normalizes renal hemodynamics but has no effect on the structural lesions produced in the low salt cyclospo-

rifle model, whereas angiotensin converting enzyme inhibition normalizes renal structure without changing renal functional parameters. Young et al [121, 122] have shown that macrophage infiltration occurs early in this chronic model and is associated with up-regulation of the macrophage chemoattraetant, osteopontin in proximal tubular cells. Jackson, O'Connor and Humes [123] and Rogers et a! [124] have previously shown that infiltrating cells

could be a source of vasoconstrictive prostaglandins or other mediators of inflammation. Thus, salt depletion might turn on angiotensin II dependent growth factors for fibroblasts, lymphokines, and cytokines and provide a link between the acute vascular

effects of cyclosporine and chronic tubulointerstitial damage [125]. yclosporine increases the recruitment of renin-containing cells along the afferent arteriole [126, 127] and the expression of

ATI receptors and renin [128]. These observations are further strengthened by the experiments of Johnson Ct a! [129], who showed that angiotensin 11 infusions can also produce tubulointerstitial nephropathy similar to what is observed in the cyclosporinc-treated animals associated with up-regulation of osteopontin

in tubular cells. Furthermore, the location of the angiotensin II type 1 receptor in the outer medulla and medullary rays [1301

1095

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 of corticosteroids goes on within the renal parenchyma of an individual patient. Preliminary evidence has shown that glucocorticoids reduce the morphologic changes induced in the chronic salt-depleted rat model [138]. Further study of this area should prove fruitful with major clinical implications for long-term immunosuppressive withdrawal protocols. It is of interest that cyclosporine has been observed to be protective against ischemic reperfusion effects on mitochondria in some systems such as the isolated rat heart [139] and forebrain [1401. Perhaps the presence of cyclosporine modifies isehemic induced damage that would otherwise be produced by rejection, organ procurement conditions, or the hemodynamic effects of the drug per Se. There are other possible mechanisms of cyclosporine nephrotoxicity that have not been completely explored. Cyclosporine is an inhibitor of the multi-drug resistance transporter, p-glycoprotein, which is expressed on resistant tumor cells rendering them more sensitive to chemotherapy. This transporter is also constitutively expressed on the epithelial cells of renal tubular epithehum [141]. Cyclosporine, tacrolimus, and many related compounds such as verapamil, inhibit this transporter and thus at least theoretically could allow the accumulation of chemotherapeutic agents, and perhaps other endogenous or exogenous molecules. Cyclosporine, its metabolites, and even some of its non-immunosuppressive analogues, can inhibit this transporter which might account for nephrotoxicity through indirect mechanisms. Verapamil by competition for this transporter might reduce cyclosporifle accumulation in tubular cells rather than by inhibition of cyclosporine metabolism per Se. Further studies are obviously needed in this area. Possible pathogenetic constructs and working hypotheses are depicted in Figures 1 and 2. Clinical issues in chronic cyclosporine nephropathy

corresponds to the location of damage in the chronic cyclosporine

At the present time, it is not possible to say what role chronic

model. When patients are converted from cyclosporine to azathioprine, the number of renin containing cells and juxtaglomerular apparatus hyperplasia markedly decreased over the ensuing

cyclosporine treatment plays in the chronic failure of renal allografts. Clearly, the drug may produce renal pathologic changes

that are deleterious. Toxic effects of cyclosporine could coexist with those produced by chronic rejection or alternatively inadeThe most accepted mechanism for the immunosuppressive quate doses of cyclosporine might actually contribute to progresaction of cyclosporine is the drug's interference with interleukin 2 sive graft failure. There have been no properly controlled studies gene transcription by interference by a cyclosporine-cyclophilin to examine this point. The only data that exists are retrospective complex inhibiting calcineurin phosphatase. It has been suggested analyses of large data sets which do not examine this issue directly. that cyclosporine may produce its immunosuppression not only This is an important question, because cyclosporine has some through inhibition of calcineurin phosphatase, hut also through efficacy in primary renal diseases. It would obviously not be transforming growth factor (TGF) beta-mediated mechanisms desirable to have chronic tubulointerstitia! disease accelerate as [132, 133]. This is of interest since TGFf3 may play a role in the glomerular lesions are brought under control. interstitial fibrosis of the chronic cyclosporine model [134]. CyData on eyclosporine withdrawal protocols have been conflictclosporine enhances the expression of TGF in the juxtaglomer- ing. Multiple reports show a 20 to 50% incidence of postular cells of the rat kidney [135]. Therefore, as suggested by the conversion acute rejection with about 20% of these being irrework of Khanna et a! [136, 137], cyclosporine immunosuppressive versible when the drug is abruptly withdrawn [142]. Other studies actions could also lead to the production of cytokines that lead to are more supportive of withdrawal protocols. Pedersen et a! [143] renal interstitial scarring. On the one hand, effective immunosup- withdrew cyelosporine and followed the patients for one year and pression with cyclosporine prevents rejection-induced inflamma- compared them with patients in whom cyclosporine was contintory changes that enhance fibrosis, whereas, on the other hand, ued. At the end of one year follow-up, biopsies showed little the immunosuppressive action of the drug depends on liberation difference in tubulointerstitial fibrosis, although vasculopathy and of cytokines that are pivotal in the renal scarring process. blood pressure were improved in the patients in whom cyclospoThe role of other inhibitors of renal scarring, such as cortico- rine was discontinued. Hollander et al [144] in a randomized study year [131].

1096

Bennett et a!: Chronic cyclosporine nephropathy

CSA

Rejection

Fig. 1. Proposed pathogenesis of chronic cyclosporine nephropathy in kidney transplantation.

Tubular cell

Cancer cell Chemotherapeutic agent

Fig. 2. Alternative hypothesis for cyclosporine nephrotoxicity. P-glycoprotein, the multi-drug resistance (MDR) transporter is constitutively expressed in proximal tubular epithelium. This transporter is inhibited by cyclosporine, tacrolimus, and other drugs such as verapamil.

Inhibition of MDR has been used to "chemosensitize" cancer cells. It could be responsible for accumulation of an endogenous toxin or toxic metabolite.

should give us insights into the nature of cyclosporine-induced sporine three months post-transplant compared to control pa- scarring processes and their potential for modification by medical showed superior renal function in patients withdrawn from cyclo-

tients in whom the drug was continued over five years of follow-

up. These prospective data contrast with large retrospective studies that conclude that inadequate cyclosporine doses, not toxicity, leads to worse graft outcome [18]. In the retrospective studies cyclosporine may have been reduced because of drug-

induced renal dysfunction as opposed to the conclusion that inadequate immunosuppression leads to graft loss. These latter studies are also flawed, by the lack of any corroborating pathologic data. The role of corticosteroids in cyclosporine withdrawal protocols remains to be established. A multicenter study, with combinations of appropriate renal functional markers and renal pathologic studies, is needed to directly examine these questions at least in the kidney transplant patient in whom biopsies are easy to obtain. Calcium antagonists may modify the metabolism of cyclosporine allowing lower doses to achieve adequate immunosuppression as well as providing renal vasodilation [145—147]. Dihydropyridine calcium channel blockers may slow interstitial fibrosis in renal transplant recipients without affecting cyclosporine metabolism. The mechanisms of this beneficial effect is unclear [1481 although protection from daily drug related vasoconstriction is possible [149].

Continued work in the basic science laboratories and clinics

management. 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 from

the Oregon Health Sciences Foundation, Portland, Oregon. The authors acknowledge 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 Health Sciences University, 3314 SW US Veterans Hospital Road, Portland, Oregon 97201, USA.

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