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NDT Advance Access originally published online on November 24, 2006
Nephrology Dialysis Transplantation 2007 22(3):880-885; doi:10.1093/ndt/gfl634
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Renal outcome after ciclosporin-induced nephrotoxicity

Isabelle Tostivint1, Sophie Tezenas du Montcel2, Marie Chantal Jaudon4, Alain Mallet2, Phuc Le Hoang3, Bahram Bodaghi3, Gilbert Deray1 and Corinne Isnard Bagnis1

1Department of Nephrology, Pitié Salpétrière Hospital, 2Department of Biostatistics and Medical Information, Pitié Salpétrière Medical University, 3Department of Ophtalmology, and 4Department of Biochemistry, Pitié Salpétrière Hospital, Paris, France

Correspondence and offprint requests to: Dr Isabelle Tostivint, Service de Néphrologie, Hôpital Pitié Salpétrière, 83 Boulevard de l’Hôpital, 75013 Paris, France. Email: isabelle.tostivint{at}psl.aphp.fr



   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Background. Renal outcome after ciclosporin (CsA) is not clear in most studies involving patients with many renal comorbid conditions. We first report on renal function recovery after CsA in previously healthy kidney patients.

Methods. Uveitis patients, enroled in a unique single centre cohort follow-up study initiated in 1987, were prospectively evaluated for plasma creatinine and glomerular filtration rate (GFR) before, during (>2 years) and after (>6 months) CsA therapy. We hypothesized that CsA alters renal function progressively over time according to two additive exponential components (irreversible and reversible) and used a mixed linear model with exponential speed parameters maximizing the likelihood.

Results. Twenty-seven patients treated for 60±34 months (CsA 5.1±2.5 mg/kg/day) were followed up for 56±42 months after CsA withdrawal. Baseline creatinine was 0.92±0.15 mg/dl. The reversible effect of CsA was quantified as a 0.11±0.07 mg/dl increase in creatinine/100 mg CsA/day (P<0.001) and a 6.0±3.7 ml/min/1.73 m2 decrease in GFR/100 mg CsA/day (P<0.0001). The irreversible effect was quantified as a 0.03±0.05 mg/dl increase in creatinine/100 g cumulative CsA received (P<0.007) and a decrease of 3.3±3.9 ml/min/1.73 m2 GFR/100 g CsA.

Conclusions. Although significant decrease in GFR is induced by low-dose CsA therapy in previously healthy kidney patients, renal function recovery is possible after CsA withdrawal and best predicted by CsA daily dosage. Irreversible loss in GFR is correlated to cumulated CsA exposure. The lowest CsA dosage and shortest exposure time effect as well as unlimited renal monitoring are required in order to provide the best long-term renal outcome.

Keywords: ciclosporin; glomerular filtration rate; hypertension; nephrotoxicity; reversibility; uveitis



   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Despite the new drugs available, ciclosporin (CsA) is still the cornerstone of immunosuppressive therapy in the field of solid organ transplantation and immune diseases including Birdshot uveitis [1]. The main side effect is dose-dependent nephrotoxicity. In previously healthy kidney patients, a 30% decline in glomerular filtration rate (GFR) occurs soon after initiation of treatment together with a high incidence of hypertension (80%) [2]. In autoimmune Birdshot uveitis patients, even low-dose CsA treatment (3–5 mg/kg/day) is associated with a 30% drop in GFR [3]. CsA induces both an acute haemodynamic intrarenal effect and also fixed arteriolar lesions leading to ischaemic nephropathy [3,4]. Pathological data showed significant interstitial striped fibrosis, arteriolopathy and tubular atrophy [3,4]. In many subgroups of patients treated with CsA, namely those with abnormal renal function before treatment (heart or lung or kidney transplanted patients), CsA therapy may induce end-stage renal failure in as many as 10% of the patients after 10 years [5–8], related with multiple comorbidities [9–15] which impede the analysis of the specific nephrotoxic effect of CsA. In rheumatoid arthritis patients, renal function is often affected by the use of other concomitant nephrotoxic drugs or secondary to associated nephropathy (AA amyloïdosis, auto-immune interstitial nephritis, IgA deposit nephropathy) [16]. Chronic plaque psoriasis patients are exposed to drug- or disease-associated renal alteration the same way [17]. In diabetes mellitus patients, GFR changes during CsA therapy may be related to diabetic nephropathy [18], pre-renal or post-renal injury. Therefore, pertinent data on CsA-associated renal tolerance can only be drawn from studies involving healthy kidney patients exposed to no other renal insult. Whether once established, CsA dose-dependent renal toxicity is reversible is still prospective, although the occurrence of interstitial fibrosis in the kidney would argue against reversibility.

The aim of the study was to analyse the evolution of renal function and blood pressure (BP) in our cohort of sight-threatening posterior uveitis patients, before, during and after CsA withdrawal. Since the absence of any related disease and no concomitant nephrotoxic drug were the inclusion criteria for this therapy with CsA, the evolution of BP and renal function can be related with the evolution of CsA nephropathy (for some patients biopsy proven) after withdrawal.



   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Patients' selection and study design
After institutional review boards’ approval and patients’ informed consent, we enroled 91 patients between April 1986 and June 2002 in a non-randomized, open-labelled single-centre prospective cohort study. Inclusion criteria were age >18 years, sight-threatening idiopathic autoimmune intermediate or posterior Birdshot uveitis resistant to steroid treatment. Patients enroled before 1990 received a higher initial dose of CsA (5 mg/kg/day) compared with patients enroled later (3 mg/kg/day). CsA was administered in two daily divided doses, and always gradually tapered after each out-patient visit at the ophthalmology clinic, provided that ocular inflammatory activity grade decreased and best-corrected visual acuity was stable or improved. Overall CsA exposure was different for each patient according to ocular outcome. Renal outcome during CsA therapy was published previously [2,3].

In the present work, we analysed renal outcome in a subgroup (CsA therapy >2 years) of this cohort of patients if their follow-up after CsA withdrawal was superior to 6 months. Primary end point was renal function assessed by creatinine level and modified diet in renal diseases (MDRD) formula [19] during and after treatment by CsA. Secondary end points were incidence of hypertension, hyperuricaemia and hyperlipidaemia. Data were collected at baseline after 1, 3, 6 and 12 months, and on a yearly basis thereafter during treatment and after CsA withdrawal until the end of the follow-up. Clinical data (age, sex, height, body weight, systolic and diastolic BP), renal function parameters (serum creatinine level and GFR assessed with the MDRD equation) and steroid treatment were recorded at baseline and at each following visit. Concentration of residual circulating CSA and the 2-h CSA rate were measured (after 1, 3 and 6 months and 1 year.

The end of the study was defined by the end of the follow-up.

Renal function assessment methods
The serum creatinine level was measured by auto-analyser using the Jaffe colorimetric assay. MDRD equation was used to assess the GFR [19].

Statistical analysis
Because of the known dual effects of CsA in the kidney (acute haemodynamic, supposedly reversible and chronic interstitial fibrosis, supposedly irreversible), we hypothesized that renal function varied with respect to time according to two components. The first component referred to an irreversible effect of CsA on renal function. Irreversible decline in renal function (either creatinine level or GFR) over time was assumed to obey a first order process triggered by the cumulative dose of CsA received to date: the long-term decline in renal function was proportional (factor di) to the cumulative dose, and the rate of decline was proportional (factor 1/{tau}i) to the difference between the long-term decline and the current decline (see caption of Figures 1 and 2). Time constant parameter {tau}i, expressed in days, accounts for the dynamics of the process: the higher the parameter, the slower the decline.


Figure 1
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  		Fig. 1. Reversible effect ({Delta}Rr, black line) and irreversible effect ({Delta}Ri, dotted line) on creatinine level, for two patients A (cumulative CsA dose: 411.7 g) and B (cumulative CsA dose: 178.2 g), with contrasted dosing history of CsA (triangle symbol). Time varying CsA given dose per time unit is denoted as q, cumulative dose is denoted as Q. Function {Delta}Rr satisfies the differential equation d{Delta}Ri/dt=1/{tau}i(diQ–{Delta}Ri) with di=4.8 (13.5) for patient A (for patient B), while {triangleup}Rr satisfies d{Delta}Rr/dt=1/{tau}r(drq–{Delta}Rr) with dr=12.7 (24.7) for patient A (B). The current creatinine level (thick line) is expressed as R=R0+{Delta}Ri+{Delta}Rr, where R0 is the baseline creatinine level. Observed creatinine level is displayed with round symbols at observed times.

 

Figure 2
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  		Fig. 2. Reversible effect ({Delta}Rr, black line) and irreversible effect ({triangleup}Ri, dotted line) on GFR level, for patients A and B with contrasted dosing history of CsA (triangle symbol). Same equations as Figure 1 apply, R now standing for GFR values with di=–8.6 (–13.5) for patient A (B) and with dri=–12.4 (–14.1) for patient A (B). Current creatinine level: thick line. Observed creatinine level: round symbol.

 
The second component referred to the reversible effect of CsA on renal function; it was assumed to obey a first order process triggered by the daily dose: the long-term reversible effect on renal function was proportional to the daily CsA dose (factor dr), and the rate of variation of this effect was proportional (factor 1/{tau}r) to the difference between the long-term effect and the current effect. For each time interval where CsA dose was constant, renal function evolved according to a negative exponential function. After CsA withdrawal, renal function progressively improved and the reversible effect vanished.

We hypothesized that the reversible and irreversible effects of CsA treatment on renal function are additive. Analyses were based on linear mixed models (Mixed Procedure on SAS) with random effects across patients for long-term effects di and dr and fixed time parameters {tau}i and {tau}r.

Assessment of irreversible and reversible effects was based on tests to zero of means and if necessary of variances of di and dr. Observed values are expressed as mean±SD or percentage (n) whereas values estimated by the model are given with their estimation SD and coefficient of variation (CV) (SD divided by the mean). P-values <0.05 were considered statistically significant. Statistical analyses were performed using the SAS 8.1 statistical package (SAS Institute, Cary, NC).



   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Twenty-seven patients were followed during 10.7±4.5 years. Baseline parameters are summarized in Table 1. No patient had proteinuria or urine sediment abnormalities before CsA therapy was initiated. None of the patients had received any other nephrotoxic drug (including non-steroidal anti-inflammatory drugs). Baseline renal function was normal or subnormal without renal failure (14 patients had an MDRD between 60 and 80 ml/min) (Table 1). Mean treatment duration was 5.0±2.8 years. Ten patients received steroids in association with CsA (37%). Mean initial daily CsA dose was 5.1±2.5 [0.9–10] mg/kg/day.


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  		Table 1. Baseline characteristics of patients (n=27 unless otherwise specified)

 
Renal function during CsA therapy and after CsA withdrawal
Plasma creatinine level before treatment was 0.92±0.15 mg/dl (81.0±13.6 µmol/l). Mean observed creatinine values at different time points over the study are summarized in Table 2. The reversible effect of CsA on renal function assessed by creatinine level is quantified as a 0.11±0.07 mg/dl mean increase for 100 mg CsA/day (9.36±6.37 µmol/l, P<0.001), with an inter-individual CV of 68% and a time constant of 146 days. The mean irreversible effect is quantified as a 0.03±0.05 mg/dl per 100 g CsA (2.7±4.1 µmol/l, P<0.007), with a 149% CV, and a time constant of 122 days. Given that the patients received a mean cumulative dose of CsA of 476.6±332.9 g, the mean irreversible effect can be quantified as an increase of 13.0 µmol/l. Figure 1 displays typical estimated and observed creatinine time courses for two different patients.


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  		Table 2. Mean creatinine levels, GFR and daily CsA dosages during follow up

 
The GFR, assessed by MDRD, before treatment is 81.0±15.2 ml/min/1.73 m2. The mean observed MDRD values at several time points during the study are summarized in Table 2. The reversible effect of CsA is quantified as a mean 6.0±3.7 ml/min/1.73 m2 decrease for 100 mg CsA/day (P<0.0001), a 61% CV and a 101 days time constant. The mean irreversible effect on GFR amounts to 3.3±3.9 ml/mn/1.73 m2 (P<0.0007), with an inter-individual CV of 119%, and a time constant of 163 days. The mean irreversible effect can be quantified as a decrease of 15.8 ml/min/1.73 m2. GFR time courses for two patients are displayed in Figure 2.

Effects of CsA on blood pressure and metabolic parameters
Before treatment, all patients but five were normotensive [antihypertensive therapy consisted of diuretics, ß-blocker, angiotensin converting enzyme (ACE)], but 19 patients became hypertensive (diastolic BP >95 mmHg or systolic BP >160 mmHg or both) during CsA therapy. Hypertensive patients were treated with either an adrenergic receptor blocking agent, an ACE inhibitor, a calcium channel blocker or a diuretic. After CsA withdrawal, 21 patients were hypertensive at the end of the follow-up.

None of our patients had gout while being treated with CsA. Uric acid, serum cholesterol, triglyceride, potassium and total bilirubin levels increased significantly over time. Fasting glucose levels and serum calcium remained unchanged during the follow-up. After CsA withdrawal, all the parameters normalized quickly.



   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our study first provides data on renal function before, during therapy and after CsA withdrawal in prospectively followed idiopathic autoimmune uveitis patients with previously healthy kidneys. That GFR deteriorates during CsA therapy has already been demonstrated [2,3]. Our data clearly indicate that long-term low-dose CsA therapy is associated with cumulative dose-dependent irreversible toxicity. That renal parameters may improve after CsA withdrawal is also established. Our data show for the first time a significant improvement of GFR after very-long-term CsA therapy in patients with proven interstitial fibrosis. Improvement in renal parameters is completed after 6 months of CsA withdrawal. Indeed, some of the patients involved in this study had been evaluated in a previous histopathological protocol evaluating renal tolerance to CsA with renal biopsies before and after 2 years of CsA therapy. Histopathological data showed significant interstitial fibrosis (P<0.003) and tubular atrophy (P<0.003) after 2 years [3]. It is difficult to imagine that the improvement profile is only due to the withdrawal of the acute haemodynamic effect of the CsA, because the amelioration takes around 6 months to be patent. We can better hypothesize that there is a remodelling of the CsA-induced lesions, a phenomenon that takes time to happen.

We hypothesized that CsA-induced renal function impairment occurs according to two components, and we designed a model that fits with this hypothesis. The first component reflects the reversible part of CsA-induced nephrotoxicity, and is proportional to the daily dose received. The second one reflects the irreversible part of CsA-induced nephrotoxicity, and is proportional to the cumulated CsA dosage.

Recently, experimental data have been published documenting possible reversibility of chronic-CsA-induced nephrotoxicity in rats [20]. Li et al. [21] describes the decrease in osteopontin expression and macrophage infiltration after CsA withdrawal in rats in parallel with renal recovery. Li et al. [21] further showed that CsA withdrawal is associated with a fading of apoptotic cell renal infiltration and with changes in pro-apoptotic molecule expression such as TGF ß1 and Fas, which may contribute to one of the mechanisms underlying the reversibility of chronic CsA nephrotoxicity. Kang et al. [22] showed the role of vascular endothelial growth factor in CsA-induced lesion repair in rats.

In transplanted kidney patients, Mozorumi described the outcome of CsA-induced renal lesions showing that remodelling of the vascular-CsA-induced lesions is possible in contrast with the fixed interstitial fibrosis [23]. Reversibility of vascular dysfunction is supposed to be related to a better kidney perfusion. In this study, interstitial fibrosis is evaluated to 10 times more severe than expected age-related lesions.

The limits of our study are the absence of a control population. A decline in the renal function is always observed in normal population with aging and quantified to approximately a 1 ml/min/year decrease in GFR [24]. In hypertensive subjects, it has been shown that the rate of loss of renal function is accelerated [25]. Despite the absence of a control group, it is obvious that the rate of decline observed in our patients is much higher than expected in healthy subjects (about three times), and may reflect CsA toxicity added to the consequences of hypertension. Notably these patients have been closely followed and clinical and biological parameters monitored regularly. This stresses the need for a prolonged follow-up in patients treated with or having received CsA therapy, considering those subjects as high risk for renal function decline.

Pathological study of renal biopsies after CsA withdrawal would have added informative data to our study. But repeated biopsies (renal biopsy had been performed in some of our patients before initiation of CsA therapy) or renal biopsies at the end of the follow-up seemed unethical.

Our results are of major consequence, considering the increasing interest in CsA as an immunosuppressive drug and the widening of CsA indications. Chronic urticaria [26], chronic inflammatory demyelinating polyradiculoneuropathy [27], unresponsive asthma [28] and autoimmune hepatitis [29,30] are now encountered indications for long-term CsA therapy. In children, myocarditis [31], ulcerative colitis [32] and severe aplastic anaemia [33] are currently treated with CsA, with a long-term benefit/risk ratio on renal function that is not evaluated.

Our study draws attention to the potential renal consequences of CsA therapy. In previously healthy kidney patients, closely monitored during and after CsA withdrawal, a significant decline in GFR is observed, related to total CsA exposure. Very recent studies have demonstrated that an independent, graded association is observed between a reduced estimated GFR and the risk of death and cardiovascular events [34], and that even mild renal disease is now considered a major risk factor for cardiovascular complications [34]. Therefore, the lowest CsA dosage and shortest exposure time affording therapeutic effect are required in order to provide best long-term renal and cardiovascular outcome. We would like to suggest that CsA-treat patients should be considered as highly exposed to renal function decline even years after CsA withdrawal. Screening and treatment for hypertension and proteinuria is essential both during and after treatment.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Received for publication: 27. 2.06
Accepted in revised form: 5.10.06


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