Original Article
Risk Factors for Cyclosporine-Induced Nephropathy in Patients with Autoimmune Diseases
N Engl J Med 1992; 326:1654-1660June 18, 1992
- Abstract
- Abstract
Background.
Cyclosporine is an immunosuppressive drug that is used to treat patients with autoimmune disease as well as patients who have received allografts. The drug can cause renal damage, but the incidence of and risk factors for nephropathy in patients treated with cyclosporine for autoimmune or inflammatory diseases are not known.
Methods.
We analyzed data from renal biopsies performed in 192 patients (129 adults and 63 children) who had been treated with cyclosporine for insulin-dependent diabetes mellitus of recent onset, uveitis, psoriasis, Sjögren's syndrome, or polychondritis. The mean (±SD) initial dose of cyclosporine was 8.2±2.8 mg per kilogram of body weight per day, and the duration of treatment was 4 to 39 months (median, 13).
Results.
Forty-one patients (37 adults and 4 children) had cyclosporine-induced nephropathy, defined as at least moderate focal interstitial fibrosis with tubular atrophy, arteriolar alterations, or both. As compared with patients in whom nephropathy did not develop, these patients received a larger initial dose of cyclosporine (9.3±2.8 vs. 8.0±2.8 mg per kilogram per day), had a larger maximal increase in the serum creatinine concentration above base-line values (101±77 percent vs. 50±33 percent), and were older (31 ±13 vs. 23±12 years). These three variables were shown by multivariate logistic-regression analysis to be significant risk factors. The duration of the elevation in the serum creatinine concentration and the occurrence of elevated blood pressure were not additional risk factors.
Conclusions.
Nephropathy is an important potential effect of cyclosporine therapy. The risk of its development in patients with autoimmune diseases who are treated with cyclosporine can be minimized by allowing a dose no higher than 5 mg per kilogram per day and avoiding increases in serum creatinine of more than 30 percent above the patient's base-line value. (N Engl J Med 1992;326:1654–60.)
Media in This Article
Figure 1
Renal-Biopsy Specimen Showing Typical Signs of Cyclosporine-Induced Nephropathy.Figure 2
Incidence of Cyclosporine-Induced Nephropathy in Relation to the Maximal Increase in the Serum Creatinine and Urea Concentrations during Cyclosporine Therapy.Article Activity
- Article
RENAL damage is an important potential side effect of cyclosporine therapy and has been a reason for caution when one is considering its use in the treatment of patients with autoimmune diseases. Primarily described in patients who have undergone renal transplantation,1 cyclosporine-induced nephropathy has also occurred in patients after cardiac transplantation2 and in patients with autoimmune diseases who had no underlying renal disease3 , 4 but who had been treated with cyclosporine in doses of 10 mg per kilogram of body weight per day or more.
Chronic cyclosporine-induced nephropathy is thought to be irreversible. It is characterized primarily by focal interstitial fibrosis and tubular atrophy. Renal arteriolar abnormalities, consisting of either necrosis of smooth-muscle cells and nodular protein deposits in the walls of afferent glomerular arterioles or arteriolar intimal hyalinosis,5 may also be seen. The goal of this study was to determine the incidence of and risk factors for cyclosporine-induced nephropathy in patients with autoimmune or inflammatory diseases.
Methods
Patients' Characteristics and Treatment
We retrospectively analyzed clinical and renal-biopsy data on 192 patients (113 males and 79 females), including 63 children (≤15 years of age). Morphologic findings in 137 of the biopsies have been reported previously.3 , 4 , 6 7 8 All the patients had participated in clinical trials with cyclosporine between 1982 and 1989; each of the trials had been approved by the appropriate institutional review committees, and all patients or their parents gave informed consent for the therapeutic trial and the renal biopsy.
There were 152 patients with insulin-dependent diabetes mellitus of recent onset, 23 patients with noninfectious posterior uveitis (including 8 with Behçet's syndrome), 11 patients with severe psoriasis, 5 patients with Sjögren's syndrome (sicca syndrome), and 1 patient with polychondritis. The patients with diabetes had had symptoms for less than six months (median, three) before the initiation of cyclosporine therapy. These patients were in clinical remission for several months before the biopsies were done, and none of the biopsies showed diabetic nephropathy. The remission of diabetes had occurred after an average of four months of cyclosporine treatment.9 , 10 All patients had normal serum creatinine concentrations for their age and sex before cyclosporine therapy was initiated.
The duration of cyclosporine therapy in the 192 patients ranged from 4 to 39 months (median, 13). In most patients the initial dose of cyclosporine was higher (mean [±SD], 8.2±2.8 mg per kilogram per day) than the dose now recommended (Table 1Table 1
Characteristics of Patients with Autoimmune or Inflammatory Diseases Treated with Cyclosporine.*) and was increased during the first several months of therapy, the maximal dose being given a median of two months after therapy was begun. In the majority of patients the dose at the time of biopsy was lower than the maximum (Table 1). The patients with uveitis received the highest dose of cyclosporine, and the patients with psoriasis the lowest. None of the patients received concomitant medications known to interfere with the pharmacokinetics of cyclosporine or to potentiate its nephrotoxicity. Most patients were examined and had routine plasma measurements every 2 to 4 weeks during the first 12 months of treatment and every 1 to 2 months thereafter. Seventeen of the patients with uveitis were examined every two to three months. In 138 patients the trough blood cyclosporine concentrations were measured at each examination by a nonspecific, polyclonal radioimmunoassay (Ciclo-Kit, Sandoz),11 and in 83 percent of these 138 patients the measurements were performed in the same laboratory.Renal Biopsy
In all but 10 patients, the renal biopsy was performed not because of renal dysfunction but as part of the research protocol to assess the safety of continuing cyclosporine treatment in consenting patients who had benefited from the therapy. The remaining 10 patients (9 with uveitis and 1 with polychondritis) underwent biopsies because serious renal dysfunction developed while they were receiving cyclosporine therapy.
All but 14 biopsy specimens were reexamined by a pathologist who was unaware of the clinical or laboratory data. His assessment was ultimately used to categorize the biopsy specimens. The following features were recorded on the basis of light-microscopical examination: the number of glomeruli, globally sclerotic glomeruli, and glomeruli with segmental sclerosis; the severity (measured with a 5-point scale in which a score of 0 indicated no abnormalities and a score of 4, severe abnormalities) and characteristics of arteriolar alterations, interstitial fibrosis, interstitial infiltration, and tubular atrophy.
In these biopsy specimens, the renal tubules, interstitium, and arterioles showed a wide spectrum of changes, from the absence of abnormalities to severe lesions. Since these changes are nonspecific,5 , 12 , 13 cyclosporine-induced nephropathy was defined as the presence of moderate or more severe alterations of the tubulointerstitial space, the glomerular arterioles, or both (Fig. 1Figure 1
Renal-Biopsy Specimen Showing Typical Signs of Cyclosporine-Induced Nephropathy.). Tubulointerstitial lesions were characterized by focal (striped) interstitial fibrosis outside perivascular areas, accompanied by tubular atrophy within the areas of fibrosis. Tubular atrophy was considered to be present when the tubular diameter was reduced and basement membranes were thickened. The arteriolar alterations could be of two types: intimal hyalinosis characterized by eccentric subendothelial deposits of hyaline material or typical cyclosporine-induced arteriolopathy defined by the presence of a ring of nodular hyaline deposits on the outer side of the wall of the afferent arteriole. Arteriolar alterations were considered moderate when circular deposits viere seen in one arteriole and severe when more than one arteriole was affected. An advisory board of seven nephropathologists agreed that the presence of cyclosporine-induced nephropathy as defined above should result in the discontinuation of cyclosporine treatment in the absence of life-threatening conditions, whereas the relevance of milder lesions to treatment was uncertain.Statistical Analysis
The results are presented as means ±SD, except for the duration of therapy, which is reported as the median and range. Patients with cyclosporine-induced nephropathy were compared with control patients without nephropathy after treatment with cyclosporine who were matched as closely as possible with respect to age, sex, disease status, and duration of cyclosporine therapy. Thirty-two of the matched control patients had diabetes, five had psoriasis, three had uveitis, and one had Sjögren's syndrome. The statistical significance of differences between the patients with cyclosporine-induced nephropathy and the matched control patients was assessed with Student's t-test. Multiple correlations were analyzed with Pearson's correlation coefficients. The analysis of risk factors was based on univariate and multivariate logisticregression analysis, calculated by Statistical Analysis System software (SAS version 6.03, procedures Probit and Logistic).14 All statistical tests were two-tailed. Since no a priori hypothesis had been formulated, statistical significance has only a descriptive value.
Results
Incidence and Features of Cyclosporine-induced Nephropathy
Forty-one of the 192 patients had evidence of cyclosporine-induced nephropathy. Twenty-five of the 41 patients had diabetes, 14 patients had uveitis, and 1 patient each had polychondritis and Sjögren's syndrome. In 37 of these 41 patients, interstitial fibrosis and tubular atrophy were the predominant findings; 9 of these 37 also had moderate or severe arteriolar alterations. Four of the 41 patients had moderate arteriolar alterations but no detectable interstitial fibrosis or tubular atrophy. The patients with cyclosporineinduced nephropathy did not have more glomeruli with global or with focal sclerosis than the patients without nephropathy; more than 5 percent of glomeruli showed global sclerosis in 15 percent and 16 percent, respectively. No patient had hypertrophic glomeruli.
Characteristics of Cyclosporine Treatment
In the 41 patients with cyclosporine-induced nephropathy, the initial dose of cyclosporine was 9.3± 2.8 mg per kilogram per day (range, 5.0 to 17.9), and it was 8.0±2.8 mg per kilogram per day (range, 1.2 to 16.8) in the 152 patients without nephropathy. The duration of cyclosporine treatment was 6 to 40 months (median, 14) in the patients with nephropathy and 4 to 38 months (median, 13) in the other patients. The maximal dose of cyclosporine, the average dose before biopsy, the dose at the time of biopsy, and the cumulative dose were closely correlated with each other and with the initial dose (P<0.001), and all were higher in the group with cyclosporine-induced nephropathy. The results were similar when the patients with nephropathy were compared with the matched control patients, except that there was no significant difference between the two groups with respect to the dose of cyclosporine at the time of the renal biopsy (Table 2Table 2
Characteristics of Patients with Cyclosporine-induced Nephropathy and Matched Control Patients without Nephropathy Treated with Cyclosporine.*).The incidence of cyclosporine-induced nephropathy ranged from 0 in the 11 patients who received an initial dose of cyclosporine that was less than 5 mg per kilogram per day to 40 percent in the 10 patients whose initial dose was at least 15 mg per kilogram per day (Table 3Table 3
Incidence of Cyclosporine-Induced Nephropathy in Relation to Cyclosporine Therapy in Patients with Autoimmune or Inflammatory Diseases.*). The presence of nephropathy was more closely related to the initial or maximal dose of cyclosporine than to the dose at the time of biopsy, the average dose before biopsy, or the length of time that the maximal dose was administered (Table 3). The latter may be explained by the maintenance of high doses only in patients who tolerated treatment well. The initial dose and the maximal dose were significantly associated with the risk of cyclosporine-induced nephropathy (P<0.001 by univariate analysis). The frequency of nephropathy was 12 percent among the 43 patients whose cumulative dose of cyclosporine was less than 2 g per kilogram, 18 percent among the 72 patients who received 2 to less than 3 g per kilogram, 24 percent among the 38 patients who received 3 to less than 4 g per kilogram, and 36 percent among the 39 patients who received 4 g per kilogram or more.The mean trough concentrations of cyclosporine in the blood during the first three months of therapy were 421±167 ng per milliliter in the patients with nephropathy, 396±171 ng per milliliter in those without nephropathy, and 389±180 ng per milliliter in the matched control patients. The risk of nephropathy was not significantly associated with the blood cyclosporine concentration at any point (P = 0.54 by univariate analysis).
Laboratory Values
The maximal increases in serum creatinine and urea concentrations above the patient's own base-line values, as well as the decrease in the hemoglobin level, were significantly greater in the patients with cyclosporine-induced nephropathy than in the matched control patients (Table 2), as well as in the group without nephropathy. The difference between the groups was the greatest for serum creatinine. The mean maximal increases in serum creatinine were 101±77 percent (range, 0 percent to 459) in the 41 patients with nephropathy and 50±33 percent (range, -13 to +170) in the 151 patients without it, corresponding to maximal serum creatinine concentrations of 158±56 μmol per liter (range, 76 to 442) and 111±27 μmol per liter (range, 56 to 189), respectively. The maximal increase in serum creatinine was correlated (P<0.002) with the maximal dose of cyclosporine. The median duration of the elevation in the serum creatinine concentration to 50 percent or more above base-line values was longer in the patients with nephropathy than in those without it (171 days [range, 5 to 792] vs. 31 days [range, 2 to 551]). The increase in serum creatinine did not occur abruptly, since the maximal increase occurred after a median of seven months of therapy.
The increase in the serum creatinine concentration was reversible. At the time of the biopsy, a point at which the patients were still receiving cyclosporine but at a lower dose than the initial one, the changes from base-line values in the serum creatinine concentration and all other laboratory values were less than the maximal increases in both the patients with nephropathy and the matched control patients (Table 2). Cyclosporine therapy was discontinued in 15 patients with nephropathy 2 months (range, 0 to 18) after the biopsy. Their mean serum creatinine concentration 8 months (range, 1 to 26) after the discontinuation of cyclosporine was 14±6 percent above base line, whereas their maximal value during therapy was 92±10 percent above base line. The serum creatinine concentration at the time of the last measurement in these 15 patients was 87±5 μmol per liter.
The incidence of cyclosporine-induced nephropathy was significantly related (P<0.001 by univariate analysis) to the maximal increase in serum creatinine or serum urea (Fig. 2Figure 2
Incidence of Cyclosporine-Induced Nephropathy in Relation to the Maximal Increase in the Serum Creatinine and Urea Concentrations during Cyclosporine Therapy.). Cyclosporine-induced nephropathy was found in only 3 of the 42 patients (7 percent) who had a maximal increase in serum creatinine of less than 30 percent above base-line values, whereas it was present in 15 of the 26 patients (59 percent) who had an increase in serum creatinine of 100 percent or more. In addition, the serum uric acid, potassium, magnesium, and bilirubin concentrations did not change significantly in either the patients with nephropathy or the matched control patients.Arterial Blood Pressure
Elevated blood pressure was defined as a systolic blood pressure of 160 mm Hg or higher or a diastolic blood pressure of 95 mm Hg or higher at one or more follow-up visits. Fourteen of the 34 patients (41 percent) with cyclosporine-induced nephropathy in whom blood pressure was measured and 13 of the 34 matched control patients (38 percent) had elevated blood pressure. Among the 127 patients without nephropathy who had adequate records of blood-pressure measurements, only 26 (20 percent) had elevated blood pressure. The risk of cyclosporine-induced nephropathy was significantly associated with the increase in diastolic blood pressure (P = 0.037 by univariate analysis).
Age
The mean age of the 41 patients with cyclosporine-induced nephropathy was 31±13 years; 4 of the patients were children (10 percent). The mean age of the 151 patients who did not have nephropathy, 58 of whom were children (38 percent), was 23±12 years. Age was significantly associated with the risk of nephropathy (P<0.001 by univariate analysis). Despite the fact that the children received a higher dose of cyclosporine, they had a smaller increase in serum creatinine concentration and a lower incidence of nephropathy than the adults (Table 4Table 4
Incidence of Cyclosporine-induced Nephropathy in Adults and Children with Autoimmune or Inflammatory Diseases.*).Multivariate Analysis
The following variables were included in the multivariate analysis: age; the initial, maximal, average, and cumulative dose of cyclosporine; the dose at biopsy; the maximal increase in serum creatinine; the occurrence or absence of elevated blood pressure; the duration of cyclosporine therapy; and the duration of an increase in the serum creatinine concentration of 50 percent or more above base line. The other variables were not included, either because they were not significantly associated with the risk of nephropathy when analyzed individually or because they were not documented for many patients.
In order to estimate the effect of treatment, the multivariate analysis was first carried out with the inclusion of the measures of treatment and the patients' characteristics. In a second step, other treatment-related variables, such as the maximal increase in serum creatinine, were added to assess their prognostic importance. The multivariate analysis was also carried out separately for adults and children because, as described above, there was a difference between these two groups (Table 4). In adults, the maximal increase in serum creatinine, the initial dose of cyclosporine, and age all contributed significantly to the risk of cyclosporine-induced nephropathy (Table 5Table 5
Multivariate Analysis of the Risk of Cyclosporine-induced Nephropathy in Patients with Autoimmune and Inflammatory Diseases.*). The duration of treatment, the cumulative dose of cyclosporine, the duration of the increase in serum creatinine, or the occurrence of elevated blood pressure did not have an additional significant influence on the risk of nephropathy. The results in children could not be analyzed in the same way because nephropathy developed in too few of the children. When the analysis included all 192 patients, the same factors were found to be significantly involved in the risk of nephropathy (Table 5). However, the contribution of the dose of cyclosporine was greater and that of age was less in the logistic function calculated for adults than in that for all patients. In the analysis of both the group as a whole and the adults alone, the model was significantly improved by adding the maximal increase in serum creatinine to the patients' characteristics and treatment (P<0.001 by goodness-of-fit testing performed according to Akaike14).The relation between the dose of cyclosporine, the maximal increase in serum creatinine, and age as major risk factors is shown in Figure 3Figure 3
Estimated Risk of Cyclosporine-induced Nephropathy in Relation to the Maximal Increase in the Serum Creatinine Concentration, According to the Dose of Cyclosporine in a 31-Year-Old Patient (the Mean Age of the Adult Population) (Upper Panel), and in Relation to Age in Adults with a Maximal Increase in Serum Creatinine of 30 Percent (Lower Panel).. As an example, a 31-year-old patient (the mean age of the adult patients) who had a 30 percent increase in serum creatinine during treatment with cyclosporine would have an average risk of nephropathy of 4 percent (95 percent confidence interval, 1 percent to 12 percent) if treated with 5 mg of cyclosporine per kilogram per day and of 29 percent (95 percent confidence interval, 15 percent to 48 percent) if treated with 10 mg per kilogram per day.Discussion
The aim of this retrospective analysis was to identify the factors that increased the likelihood of cyclosporine-associated structural damage to the kidney in a group of patients without preexisting renal disease who were being treated for autoimmune and inflammatory diseases. As previously reported,5 , 6 , 15 cyclosporine-induced nephropathy was identified by the presence of focal (striped) interstitial fibrosis with tubular atrophy, arteriolar alterations, or both. A group of renal pathologists thought that the presence of such lesions justified the recommendation that cyclosporine therapy should be discontinued. Because none of these morphologic abnormalities are specific for cyclosporine-induced nephropathy5 , 12 , 13 and since renal biopsies were not done before cyclosporine therapy was begun, only patients with a low probability of disease-associated renal involvement were studied.
In this series of patients treated with doses of cyclosporine now regarded as high, interstitial fibrosis with tubular atrophy was the predominant feature of cyclosporine-induced nephropathy. The incidence of glomeruli with global or segmental sclerosis was not related to the incidence of nephropathy, and no hypertrophic glomeruli were detected. The glomerulosclerosis reported in heart-transplant recipients2 , 16 , 17 was most likely due to extensive tubulointerstitial or arteriolar injury18 in patients exposed to high doses of cyclosporine soon after transplantation.
The maximal degree of renal dysfunction during cyclosporine therapy, measured as the percent increase in serum creatinine above the patient's baseline value, was the best predictor of cyclosporine-induced nephropathy. The reliability of measurements of serum creatinine as an indirect measurement of the glomerular filtration rate has been questioned.19 , 20 However, increases in serum creatinine were reported to correlate well with decreases in the glomerular filtration rate.21 The impairment of renal function did not seem to be a direct consequence of the morphologic abnormalities, since it was reversible in most patients after a reduction in the dose or discontinuation of cyclosporine therapy, even when morphologic lesions were present.
The dose of cyclosporine and age were additional risk factors for nephropathy. The incidence of nephropathy was lower in children than in adults, probably because the clearance of cyclosporine is greater in children, and therefore their blood concentrations for the same dose are lower.22 In the light of this study, the high incidence of cyclosporine-induced nephropathy in previous studies is most easily explained by the high initial doses of cyclosporine (≥10 mg per kilogram per day), despite the fact that the dose had often been reduced by the time of the biopsy,3 , 4 , 16 , 17 and by the absence of guidelines for adjusting the dose in relation to increases in serum creatinine. This analysis is in line with the data obtained in a different group of patients with autoimmune diseases who were treated with ≤5 mg of cyclosporine per kilogram per day, in whom no unequivocal signs of cyclosporineinduced nephropathy were detected.15 However, these results may not be valid for patients after renal transplantation, when denervation may decrease the sensitivity of the kidney to cyclosporine,23 , 24 or after bone marrow transplantation, when total-body irradiation can induce arteriolar alterations and increase renal sensitivity to cyclosporine.25 , 26 Overall, these results suggest that cyclosporine-induced nephropathy may not be the result of long-term and cumulative toxic effects on the arterioles and tubules, but rather the consequence of brief insults brought about by the administration of excessive doses of cyclosporine.
In summary, nephropathy is an important potential side effect of cyclosporine therapy. This retrospective analysis suggests that in patients with autoimmune or inflammatory diseases and normal renal function, the likelihood of its development can be minimized by using doses no higher than 5 mg per kilogram and avoiding increases in serum creatinine concentrations that are more than 30 percent above the patient's base-line value through the use of appropriate dose adjustments. The risk of nephropathy is not affected by the length of treatment, at least during the first year. The validity of these guidelines is currently being evaluated in a prospective fashion by analysis of renal-biopsy specimens from patients with autoimmune diseases who were treated with low doses of cyclosporine for a longer time.
Supported in part by a grant from Sandoz Pharma Ltd., Basel.
*The following were participants in the study: Pathologists: L.H. Noel, E. Sansino, and R. Habib (Paris); T. Antonovych (Washington, D.C.); S. Bohman (Stockholm, Sweden); D. Belghiti (Créteil, France); U. Helmchen (Hamburg, Germany); S. Larsen (Copenhagen, Denmark); J. Ulrich (Vienna, Austria); A.C. Wallace (London, Ont.); J. Rapola (Helsinki, Finland); P. Casanova (Marseille, France); A. Magil (Vancouver, B.C.); and K. Porter (London); Clinicians: J.F. Bach, R. Assan, C. Boitard, P. Bougnères, P. Czernichow, L. Dubertret, P. Vexiau, and M. Pehuet-Figioni (Paris); R. Nussenblatt (Bethesda, Md.); F.A. Gries (Dusseldorf, Germany); H.M. Moutsopoulos (Ioánnina, Greece); J. Nerup (Gentofte, Denmark); J. Dupre and C. Stiller (London, Ont.); G. Schernthaner (Vienna); V.A. Koivisto (Helsinki); J. Juhlin (Uppsala, Sweden); B. Vialettes (Marseille); K. Dawson (Vancouver); H. du Rostu (Nantes, France); and L. Fry (London); Statisticians: E. Nüesch (Basel) and M. Rainizio (Imperia, Italy); and. Registry Management: E. Curschellas and B. von Graffenried (Basel).
We are indebted to Professor June Mason for her fruitful comments, to Dr. J. Schädelin for his support, and to Drs. A. Lallemand, O. Reigneau, and T. Arvidsson and Mmes. L. Gomez, C. Bon, A. Barnes, and P. Isenring for their help.
Source Information
International Kidney Biopsy Registry of Cyclosporine in Autoimmune Diseases*
From the Department of Clinical Research/Immunology, Sandoz Pharma Ltd. (G.F.), and the Institute of Pathology, University of Basel (M.J.M.), both in Basel, Switzerland. Address reprint requests to Dr. Feutren at Clinical Research/ Immunology, Sandoz Pharma Ltd., 4002 Basel, Switzerland.
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