Clin Biochem, Vol. 24, pp. 97-99, 1991

0009-9120/91 $3.00 + .00 Copyright © 1991 The Canadian Society of Clinical Chemists.

Printed in Canada. All rights reserved.

Cyclosporine Monitoring in Autoimmune and Other Diseases DAVID LUDWlN Department of Medicine, McMaster University and St. Joseph's Hospital, Hamilton, Ontario, Canada Cyclosporine (CsA) is being increasingly used for the treatment of disorders other than transplantation. In contrast to transplant recipients, most of these patients can have CsA therapy discontinued without life-threatening consequences, and the dose of CsA can therefore be restricted in order to limit the incidence and severity of toxicity, including nephrotoxicity. The utility of either CsA blood levels or pharmacokinetic profiling to ensure adequacy of therapy or to prevent incipient as well as overt toxicity has not been confirmed in this group of patients, and prevention of nephrotoxicity usually depends on limiting the dose of CsA and careful assessment of renal function. Frequent measurement of CsA levels beyond the initiation period in patients with autoimmune and other nontransplant diseases cannot be currently justified, and should be reserved for those situations where drug interactions, unexpected toxicity or the possibility of inadequate therapy is likely.

nal toxicity. The use of CsA is characterized by a relatively narrow therapeutic window, and the predictability of the pharmacokinetics after drug administration is limited by inter- and intrapatient variability (13). Therapies undergoing investigation, such as the use of verapamil or the prostaglandin agonists, may prove to be beneficial. Many factors predispose to the development of renal toxicity, such as the age of the patient, the nature of the underlying and comorbid disorders, as well as whether other medications are being administered (12). Monitoring of CsA a d m i n i s t r a t i o n

KEY WORDS: cyclosporine; autoimmunity; kidney disease. Introduction

he use of cyclosporine (CsA) for the treatment of disorders other than transplantation has T increased dramatically in the past few years (1,2). The efficacy of CsA has either been established or is undergoing investigation in a wide variety of conditions considered to have an immunological involvement (3-11). Although the initial use of CsA in these circumstances was limited to patients with disorders considered classically autoimmune in nature, the indications have been widened so that CsA is now used for many disparate diseases (including, for example, atopic dermatitis and drug resistance in cancer chemotherapy). Although the indications for the administration of CsA have been expanded, concern about the resultant toxicity has not diminished. Indeed, the frequent need to administer the drug for prolonged periods (as CsA therapy seldom results in disease remission) is thought to increase the risk of long-term problems, including renal dysfunction (12). Unfortunately, despite intensive investigation, little progress has been achieved in developing reliable mechanisms for minimizing re-

Correspondence: David Ludwin, M.D., Department of Medicine, St. Joseph's Hospital, 50 Charlton Ave. E., Hamilton, Ontario, Canada L8N 4A6. Manuscript received May 23, 1990; revised July 14, 1990; accepted July 28, 1990. CLINICAL BIOCHEMISTRY, VOLUME 24, FEBRUARY 1991

In general, attempts have been made to minimize toxicity by monitoring either the effects of CsA administration or its pharmacokinetics (13). Initially, the expertise developed with transplantation was extrapolated to the treatment of the autoimmune disorders. Frequent measurements of blood CsA levels using a variety of methodologies has been the cornerstone of therapy in many transplant centres, and this practice was continued for nontransplant patients, using the guidelines established for (usually) renal transplantation. In contrast to transplant recipients, however, it was usually possible to withdraw CsA therapy from nontransplant patients without life-threatening consequences. Furthermore, these patients could often have CsA introduced gradually and in lower doses, even if this practice was accompanied by reduced efficacy of the therapy. While numerous complications are associated with CsA therapy, renal toxicity is important and frequently encountered and for this reason, attention has been focused on detecting renal dysfunction (13). In general, if doses are low enough to avoid nephrotoxicity, other significant problems (such as hepatotoxicity) are less common. Renal toxicity has been monitored in three ways: (1) measurement of changes in renal function, (2) assessment of renal histological changes, and (3) measurement of CsA in serum or whole blood. RENAL FUNCTION

The measurement of renal function is problematical, and the traditional use of serum creatinine as 97

LUDWIN

an accurate marker of function is clearly unreliable (14-16). Unfortunately, more accurate tests (such as inulin or radioisotope clearance techniques) are limited by their complexity, cost or toxicity, thus precluding their frequent use. For this reason, despite its significant limitations, serum creatinine remains an important marker of renal function and is extensively used for the clinical management of patients with renal disorders. RENAL HISTOLOGY

Relatively few renal biopsies have been performed in patients receiving CsA for nontransplant indications, and biopsies have usually been performed in patients either as part of a study protocol or because of the existence of significant renal dysfunction (12,17,18). The biopsy procedure may be associated with a small but significant risk of morbidity and mortality, and can seldom be repeated more than once or twice. Its utility for the monitoring of patients receiving CsA therapy may be further hampered by difficulty in the interpretation of any histological changes detected, and the attribution of these abnormalities to CsA therapy. In spite of these limitations, however, it may become important in an individual patient to perform a biopsy where the long-term administration of CsA is being contemplated aider a successful initial course of therapy, usually in order to ensure that CsA is administered in the absence of significant renal damage, and where the risks of biopsy are thought to be justified by the potential information gained. CsA LEVELS The use of CsA levels to monitor therapy is currently the subject of debate (19). The relationship between CsA toxicity and elevated levels is not a perfect one, although some investigators have suggested that raised CsA levels are predictive of renal dysfunction (20,21). The debate about the methodology has centred around such problems as the optimal test for the measurement of CsA levels, or the tissue to be sampled (19). It has been suggested that the utility of these methods can be improved by studying pharmacokinetic data (e.g., area under the curve) generated during introduction of therapy or by employing computer simulation models, but these refinements have not been tested and validated in prospective studies in the nontransplant population (13,22,23). C s A DOSE

Initially, nontransplant patients receiving CsA were given doses of CsA comparable to those used in transplantation. Significant toxicity was noted, and the dosage was gradually decreased to levels generally considered too low for antirejection therapy. 98

Despite this, efficacy has been demonstrated using these doses (9), and current guidelines suggest that the maximum dose of CsA should not exceed 5 mg/kg/day (12). These guidelines, however, have to be individualized for patients with different conditions and disease severity.

Detection of minimal CsA nephrotoxicity It has been suggested that patients with autoimmune diseases treated with CsA may develop significant renal histological damage in the absence of marked renal functional changes (17). However, as discussed above, the determination of changes in renal function are limited by the availability of reliable tests. Furthermore, minimal changes in serum creatinine may correspond to marked changes in function, even when the levels remain within the normal range. Palestine et al. (17) noted significant histological changes attributable to CsA in a series of patients thought to have minimal deterioration in renal function, but the rise in mean serum creatinine level from 88 ~mol/L to 133 ~mol/L in their patients could not be considered minimal. Furthermore, the doses used in their study (10 mg/kg) were higher than those currently employed by most physicians. Finally, the potential for kidneys with minimal to mild CsA renal histological damage to progress to end stage renal failure is unknown. Nevertheless, their findings raise the question of the ability of any test other than renal biopsy to detect significant renal dysfunction.

Current guidelines for CsA administration While many questions about the optimal method for monitoring the administration of CsA to nontransplant patients remain, a consensus has developed regarding the safe administration of CsA to nontransplant patients (24). Patients should be carefully screened to exclude factors predisposing to CsA toxicity, and the drug should be administered with caution if any are detected. The initial dose of CsA should be between 2.5 and 5 mg/kg/day, and should not exceed 5 mg/kg/day unless clinically indicated. Renal function should be carefully followed by the repeated measurement of serum creatinine levels. If possible, the initial serum creatinine should be validated using a more accurate measure of renal function, and this should be repeated on at least one further occasion. If the serum creatinine is reliable as a measurement of renal function, then CsA should be gradually introduced over a period of months, and the maximum creatinine not allowed to rise by more than 30% over baseline values. The use of CsA levels or renal biopsy is indicated only in special circumstances.

Conclusions The prevention of CsA-induced renal damage remains a critical part of therapy with this agent, and CLINICAL BIOCHEMISTRY, VOLUME 24, FEBRUARY 1991

CYCLOSPORINE MONITORINGIN AUTOIMMUNE AND OTHER DISEASES

1. Talal N. Cyclosporine as an immunosuppressive agent for autoimmune disease: theoretical concepts and therapeutic strategies. Transplant Proc 1988; 20 (Suppl. 14): 11-5. 2. Bach JF. Cyclosporine in autoimmune diseases. Transplant Proc 1989; 21 (Suppl. 1): 97-113. 3. Stiller CR, Dupre J, Gent M, et al. Effects of cyclosporine immunosuppression in insulin-dependent diabetes mellitus of recent onset. Science 1984; 223: 13627. 4. Ponticelli C, Rivolta E. Cyclosporine in autoimmune renal diseases. Contrib Nephrol 1989; 69: 182-9. 5. Prummel MF, Mourits MP, Berghout A, et al. Prednisone and cyclosporine in the treatment of severe Graves' ophthalmopathy. N Engl J Med 1989; 321: 1353-9. 6. Rabinowitz AP, Sacks Y, Carmel R. Autoimmune cytopenias in pernicious anemia: a report of four cases and review of the literature. Eur J Haematol 1990; 44: 18-33. 7. Gupta AK, Matheson EL, Ellis CN, et al. Cyclosporine in the treatment of psoriatic arthritis. Arch Dermatol 1989; 125: 507-10. 8. Sachar DB. Cyclosporine treatment for inflammatory bowel disease: a step backward or a leap forward? N Engl J Med 1989; 321: 894-6. 9. Tugwell P, Bombardier C, Bennett KJ, et al. A multicentre, double blind, randomized trial of cyclosporine and placebo therapy in patients with rheumatoid arthritis. Lancet 1990; 335: 1051-5. 10. Austin HA, Palestine AG, Sabnis SG, et al. Evolution of cyclosporine nephrotoxicity in patients treated for autoimmune uveitis. A m J Nephrol 1989; 9: 392-402.

11. Goulon M, Elkharrat D, Lokiec F, Gajdos P. Results of a one-year open trial of cyclosporine in ten patients with severe myasthenia gravis. Transplant Proc 1988; 20 (Suppl. 4): 211-7. 12. Hannedouche TP, Delgado AG, Gnionsahe AD, et al. Nephrotoxicity of cyclosporine in autoimmune diseases. Adv Nephrol 1990; 19: 169-86. 13. Kahan BD. Pharmacokinetics and pharmacodynamics of cyclosporine. Transplant Proc 1989; 21 (Suppl. 1): 9-15. 14. Levey A, Perrone RD, Madias NE. Serum creatinine and renal function. A n n u Rev Med 1988; 39: 465-90. 15. Gabriel R. Time to scrap creatinine clearance? Br J Med 1986; 293: 1119-20. 16. Ross E, Wilkinson A, Hawkins R, Danovitch G. The plasma creatinine concentration is not an accurate reflection of the glomerular filtration rate in stable renal transplant patients receiving cyclosporine. A m J Kid Dis 1987; 10: 113-7. 17. Palestine AG, Austin HA, Balow JE, et al. Renal histopathologic alterations in patients treated with cyclosporine for uveitis. N Engl J Med 1986; 314: 1293-8. 18. Mihatsch MJ, Thiel G, Ryffel B. Morphologic diagnosis of cyclosporine nephrotoxicity. Semin Diagn Pathol 1988; 5: 104-21. 19. Keown PA. Optimizing cyclosporine therapy: dose, levels and monitoring. TransplantProc 1988; 20 (Suppl. 2): 382-9. 20. Bougneres PF, Carel JC, Castano L, et al. Factors associated with early remission of Type I diabetes in children treated with cyclosporine. N Engl J Med 1988; 318: 663-70. 21. Mihatsch MJ, Steiner K, Abeywickrama KH, Landmann J, Thiel G. Risk factors for the development of chronic cyclosporine nephrotoxicity. Clin Nephro11988; 29: 165-75. 22. Rodighiero V. Therapeutic drug monitoring of cyclosporine: practical applications and limitations. Clin Pharmacokinet 1989; 16: 27-37. 23. Frey FJ, Horber FF, Frey BM. Trough levels and concentration time curves of cyclosporine in patients undergoing renal transplantation. Clin Pharmacol Ther 1988; 43: 55-62. 24. Consensus conference on the use of cyclosporine in psoriasis (Editorial). Br J Dermatol 1990; 122 (Suppl. 36): 1-3.

CLINICAL BIOCHEMISTRY,VOLUME 24, FEBRUARY 1991

99

various methods have been used to monitor the administration of CsA and its effects on the kidney. Appropriate studies t h a t test the utility of CsA blood level m e a s u r e m e n t s to pr event CsA nephrotoxicity have not been performed. It is hoped t h a t advances in our u n d e r s t a n d i n g of the pathophysiology of CsA nephrotoxicity will allow b e t t e r tests to be developed.

References

Cyclosporine monitoring in autoimmune and other diseases.

Cyclosporine (CsA) is being increasingly used for the treatment of disorders other than transplantation. In contrast to transplant recipients, most of...
309KB Sizes 0 Downloads 0 Views