- Email: [email protected]
Effect of cyclosporine on the kidney
Effect of cyclosporine on the kidney P. A. K e o w n , MD, C. R. Stiller, MD, a n d A. C. W a l l a c e , MD From the Departments of Medicine and Pathology, University Hospital, and The University of Western Ontario, London, Ontario, Canada
In contrast to conventional immunosuppressive agents, cyclosporine does not limit myeloproliferation, but inhibits the immune response by a direct effect on the helper/ inducer T-lymphocyte. Cyclosporine suppresses activation events both at the cell membrane and in the cytosol, but a major site of action now appears to be the inhibition of lymphokine gene transcription, ~thus preventing the elaboration of essential intercellular messengers of the immune response such as interleukin-1, IL-2, and ,y-interferon. In the experimental animal, cyclosporine is highly effective in preventing graft rejection and in suppressing autoimmune disease with minimal toxicity and little renal effect. The nephrotoxicity observed in humans was thus unexpected and disappointing, and has proved the major concern accompanying the clinical use of this valuable agent. 2 We examined the pathophysiology of this unique nephrotoxicity, the spectrum of clinical injury induced, and the therapeutic approach that has been adopted to optimize the use of this drug. PATHOPHYSIOLOGY NEPHROTOXICITY
flow-probe techniques have now confirmed that cyclosporine causes a sharp decrease in both renal cortical and medullary blood flow, which is sustained throughout the duration of treatment? It would appear that this is also a principal mechanism in humans, in whom comparable data exist to demonstrate that cyclosporine causes an increase in renovascular resistance, 4 whereas renal plasma flow is significantly diminished in cardiac allograft recipients with renal functional impairment2 Regulation of renal blood flow is dependent on a complex interaction between neurogenic and hormonal stimuli. Alpha adrenergic stimulation maintains vasoconstrictor tone, and angiotensin II, derived from the decapeptide angiotensin I by the action of converting enzyme, has a potent direct vasoconstrictor effect on the preglomerular afferent arteriole, reducing glomerular blood flow and hence glomerular filtration? Closely linked to the reninIL TXA2
Interleukin Thromboxane A
[
OF CYCLOSPORINE
Studies in experimental animals and in humans indicate that cyclosporine has an acute dose-dependent effect on renal function, producing a marked reduction in glomerular filtration with oliguria, and an elevation in the blood urea nitrogen/creatinine ratio. Tubular function is also affected, causing decreased urinary sodium excretion, hyperuricemia, hyperkalemia, and type IV renal tubular acidosis? These functional effects are rapidly reversible with drug withdrawal, suggesting an underlying acute alteration in glomerular capillary perfusion and consequent proximal tubular reabsorption. Studies in animals using radiolabeled microspheres or Dr. P. A. Keown is a Career Scientist of the Ontario Ministry of Health. Reprint requests: Dr. P. A. Keown, Executive Director, British Columbia Transplant Programme, D 10, Room 19, Heather Pavilion, Vancouver General Hospital, Vancouver, British Columbia, Canada.
angiotensin system is the prostaglandin-thromboxane cascade. 7 These compounds participate in several physiologic processes within the kidney, including autoregulation of renal blood ftow and glomerular filtration, modulation of renin release, tubular ion transport, and water metabolism. Prostaglandins PGE2, PGD2, and PGI2 are potent vasodilators, modulating tone in pre- and postglomerular arterioles to reduce renal resistance and increase renal blood flow, whereas thromboxane A2 is a potent vasoconstrictor with opposing effects. 7 The effect of cyclosporine on these regulatory systems is currently being studied. Murray and Paller 8 have shown that, when administered rapidly at high intravenous doses, cyclosporine may cause renal vasoconstriction via a-adrenergic stimulation, an effect that may be prevented by renal denervation or pretreatment with prazosin. Whether this mechanism is relevant at therapeutic doses in humans is questionable, however, because cyclosporine nephrotoxicity is evident in the denervated grafted kidney. The role of the renin-angiotensin system is
1029
10 3 0
Keown, Stiller, and Wallace
The Journal of Pediatrics December 1987
Tablo. Algorithm for clinical use of cyclosporine in kidney transplantation
Allograft dysfunction Acute
Diagnostic category
Fever, oliguria, weight gain; diffuse infiltration; immunology positive
Acute vasculopathy
Oliguria, graft failure, microvascular platelet occlusion Combined features of rejection and toxicity
Uncertain Nephrotoxicity Chronic
Characteristic features
Acute rejection
Chronic toxicity
Chronic rejection
Therapeutic approach
Mild focal infiltrate, tubular injury; immunology negative Vascular thickening, intimal proliferation, interstitial fibrosis, unresponsive to CsA
Vascular thickening, intimal proliferation, interstitial fibrosis, unresponsive to CsA
tCsA levels to 200 ng/mL with MP 250 mg IV • 3 days; if no response, ALG • 5-7 days or monoclonal antibody ~CsA, institute alternative immunosuppression ~CsA to 100 ng/mL; if no response, MP 250 mg Iv • 3 days ~CsA to 100 ng/mL No clearly beneficial therapy; optimize CsA therapy, use triple (CsA, AZA, prednisone) drug regimen to reduce CsA dose or convert to AZA No clearly beneficial therapy; commence low-protein diet, avoid overimmunosuppression, prepare for retransplantation
ALG, anti-lymphocyteglobulin;CsA, cyclosporine;MP, methylprednisolone;AZA, azathioprine.
also unclear. Although cyclosporine causes a sharp elevation in plasma renin and aldosterone values, this rise is not sustained, 9 and converting enzyme inhibition is ineffective in preventing the cyclosporine effect. The role of the prostaglandin cascade is intriguing, but is also not entirely defined. In contrast to nonsteroidal agents, which produce a comparable acute inhibition of renal function as a result of prostaglandin inhibition, cyclosporine triggers a marked increase in TXA2 production, with a smaller compensatory increase in PGI2 and PGE2 (unpublished data). In initial studies, we have been able to demonstrate that selective blockade of TXA2 synthesis mitigates the cyclosporineinduced deterioration of renal function, restoring blood flow and glomerular filtration toward normal. Although reduced renal perfusion appears to explain the short-term events, the pathogenesis of the fibrosing injury accompanying prolonged drug administration in humans remains obscure. Three possible mechanisms have been advanced. Fibrosis, with secondary tubular injury, has been ascribed to the fibrogenic effect of cyclosporine resulting from direct fibroblast stimulation. Fibrosis may also be seen in other grafted tissues, notably the heart, but does not predominate in other native organs. The possibility of a polar metabolite causing direct tubulotoxicity has also been considered, but no satisfactory candidate has yet been identified. Although these events may contribute, a vascular cause currently appears most plausible. It is possible that persistent renal vasoconstriction and sodium
retention, triggered by physiologic events described, lead to sustained low-renin hypertension. This, in combination with chronic endothelial damage related to low-grade platelet activation on the vessel wall, secondary perhaps to dysregulation of prostaglandin-thromboxane metabolism, results in renal parenchymal ischemia, with the characteristic degenerative changes in the nephron and interstitium. Such a vascular cause would be most consistent with the segmental, or "striped," picture characteristically described in this disease. 1~ CLINICAL
TOXICITY AND RISK FACTORS
The nephrotoxicity of cyclosporine may be divided into four discrete syndromes on the basis of physiologic and pathologic criteria (Table). Initial nonfunction of graft. The detrimental effect of cyclosporine on initial renal graft function was reported in early studies, and has been substantiated in subsequent randomized trials. ~1 Both the incidence and duration of initial graft nonfunction are increased, and secondary oliguria has been reported in up to 30% of cases. Certain risk factors have been identified, including prolonged graft storage (>24 hours) or surgical reanastomosis time (>45 minutes), H and the immunologic status of the recipient in terms of prior transplants and degree of sensitization, which appear to interact with cyclosporine to increase the risk of nonfunction (unpublished data), while elevated drug concentrations in blood or serum in the early postop-
Volume 111 Number 6, part 2
erative period may delay renal functional recovery. 1~ To minimize early toxicity, the starting dose of cyclosporine has been progressively reduced to about 10 mg/kg/d orally in adults and 12 to 15 mg/kg/d in children, subsequently adjusted to maintain trough concentrations in serum of 150 to 250 ng/mL by radioimmunoassay (whole blood, 250 to 350 ng/mL). Intravenous administration by intermittent or continuous infusion at one-third the oral dose may prove more beneficial while absorption is unreliable, and is routinely used in several centers. To avoid toxicity completely during this critical period, however, induction immunosuppression with anti-lymphocyte globulin, followed by conversion to cyclosporine between days 2 and 7, may ultimately prove to be the most effective therapy. In studies thus far available, this combination appears to provide optimal immunosuppression, with minimal toxicity or morbidity, 12 but caution is essential in the use of these powerful agents to avoid over immunosuppression. Acute nephrotoxieity, Acute, reversible nephrotoxicity may occur in either the native or transplanted kidney, and is characterized by an increase in serum creatinine and BUN/creatinine ratio, with hyperuricemia, hyperkalemia, and mild oliguria? Acute nephrotoxicity is generally observed in association with rising or elevated serum concentrations of cyclosporine (>200 ng/mL), and is frequent with levels >400 ng/mL. A clear temporal relationship can usually be established, with changes in cyclosporine level preceding those in serum creatinine by a few days. Several drugs exhibit pharmacokinetic or pharmacodynamic interactions with cyclosporine that enhance acute nephrotoxicity. Ketoconazole and erythromycin inhibit cyclosporine metabolism, causing a rise in blood levels; nonsteroidal anti-inflammatory drugs, aminoglycosides, trimethoprim-sulfamethoxazole, and amphotericin B interact at the level of the kidney by a number of discrete mechanisms. ~3Distinction between acute cyclosporine toxicity and mild acute rejection in the transplanted kidney may be difficult. Both occur with greatest frequency in the first 3 months, but acute rejection is subsequently rare. Nephrotoxicity is characterized by a slow rise in creatinine values accompanied by elevated serum cyclosporine concentrations; oliguria, fever, and low cyclosporine levels are more common in rejection. ~3 Final differentiation, however, may depend on demonstration of typical changes of edema, vasculitis, and interstitial mononuclear cell infiltrate in rejection, or tubular epithelial cell injury characterized by vacuolization, calcification, and mitochondrial injury in cyclosporine nephrotoxicity. Acute cyclosporine nephrotoxicity usually resolves rapidly after appropriate dose reduction, and is rarely of clinical importance when trough serum levels are maintained between 50 and 150 ng/mL.
Effect o f cyclosporine on kidney
10 3 1
Acute vasculopathy. Acute vasculopathy is a rare manifestation of cyclosporine toxicity, and occurs within the first 2 to 3 weeks of therapy. First described after bone marrow transplantation and subsequently after other solid organ grafts, this entity resembles hemolytic-uremic syndrome and comprises thrombocytopenia, red cell fragmentation, and acute renal failure. An isolated variant has been described after renal transplantation, in which systemic thrombocytopenia is accompanied by microvascular occlusion by platelet and fibrin deposits within the graft, and amorphous eosinophilic material is interposed beneath the endothelium. 14It is probable that this form of vasculopathy reflects initial endothelial injury by an immune process, permitting secondary platelet activation at this site, related to the perturbation of normal regulatory mechanisms by cyclosporine. Ferguson et al. 14 have reported that this complication occurs in 8% of their patients after renal transplantation and is now their most common cause of graft loss. They postulate that the high frequency may be related to the routine use of anti-lymphocyte globulin for induction immunosuppression, causing subtle endothelial injury. In our experience, however, it is considerably less common, and we have seen only two cases (1.2%) in the last 2 years that could not be ascribed to acute rejection. The acute vascular injury is accompanied clinically by a rapid deterioration in renal function with oligoanuria, frequently without fever or graft tenderness. The entity is not responsive to conventional anti-rejection therapy, but temporary replacement of cyclosporine with anti-l~ymphocyte globulin, followed by conversion to maintenance azathioprine or triple therapy, may salvage graft function. Heparin or streptokinase infusion into the graft has also been used, but is not yet of demonstrated benefit. Chronic nephropathy with interstitial fibrosis. The chronic fibrosing injury was first observed in initial adult studies when cyclosporine was used in doses exceeding 12.5 mg/kg/d, and with careful pharmacokinetic monitoring and appropriate dose reduction has become a less serious clinical concern. This form of injury has so far been found unique in humans, and its cause remains unclear. Histologically, it is characterized by an increase in interstitial connective tissue, tubular atrophy, and vascular sclerosis? Thickening of the tubular and glomerular basement membranes may be seen, with glomerular retraction resembling focal glomerulosclerosis, s Glomerular filtration in patients receiving cyclosporine is normally lower than in those receiving alternative immunosuppression. 11 The decrease in renal function is most marked during the first 12 months, but then appears to plateau and remain stable." Patients can be clinically divided into three groups on the basis of long-term renal
10 3 2
Keown, Stiller, and Wallace
function. The first, representing the majority of patients, experiences no progressive change in glomerular filtration rate, and the serum creatinine concentration remains stable, although elevated, throughout the transplant course. In the second group, there is a slow and progressive rise in creatinine concentration, which generally responds to a decrease in the cyclosporine dose and then remains stable. The third group, however, is characterized by a marked and continuing rise in serum creatinine despite reduction in cyclosporine to levels that no longer ensure satisfactory immunosuppression. Deteriorating renal function is accompanied by increasing hypertension, which is poorly responsive to treatment and may necessitate multiple agent therapy. Ultimately, renal dysfunction, hypertension, and intractable headache may require discontinuation of the medication. Such patients represent approximately 10% of those receiving long-term cyclosporine therapy. Retrospective analysis shows that many have sustained prior graft damage in the form of protracted perfusion, warm ischemia, or acute rejection, or have unacceptably high (>300 to 400 ng/mL) serum cyclosporine levels for prolonged periods during treatment? s Two therapeutic approaches have been used in such cases. In the first, azathioprine is substituted for cyclosporine, with or without a period of overlap. 16 Withdrawal of the drug usually results in a marked improvement in renal function, which returns toward normal over the subsequent 30 days, and the accompanying hypertension may ameliorate or resolve. Azathioprine is a less effective immunosuppressant, however, and this approach may be inadequate to maintain immune control in organ transplantation. Acute graft rejection may be precipitated in up to 80% of patients after conversion, with appreciable graft loss, Iv and relapse of autoimmune disease may occur, leading to destruction of residual islet tissue in type 1 diabetes mellitus. To avoid this outcome, conversion to a triple-therapy regimen consisting of prednisone, azathioprine, and low doses (1 to 3 m g / k g / d ) of cyclosporine has been more widely examined. ~8 Beneficial interactions between these agents have been shown in vitro and in experimental animal studies. Clinical experience is still limited, but the preliminary use of this combination in renal transplantation is encouragingJ 7 SUMMARY Cyclosporine constitutes a major advance in pharmacologic immunosuppression, the benefit of which is now established for solid organ transplantation and is rapidly emerging for many forms of autoimmune disease. By virtue of its potency and selectivity, there has been a marked reduction in steroid requirement with a concomitant reduction in morbidity and mortality.
The Journal of Pediatrics December 1987
The undesirable effect of cyclosporine on the kidney may thus be considered within this context. The short-term functional effect observed to some degree in most patients receiving this drug is rapidly reversible, and is unaccompanied by long-term detriment in studies now extending over 6 years. Progressive deterioration still occurs in a small proportion of patients, but may often be reversed by carefully controlled conversion to alternative combination immunosuppression therapy. For each developing application, the ultimate value of cyclosporine must be determined individually in relation to the severity of the disease process. The challenge that now confronts us is to determine the manner in which this agent may be most safely and effectively used. REFERENCES
1. GraneUi-Piperno A, Andrus L, Steinman R. Lymphokine and non-lymphokine mRNA levels in stimulated human T cells. J Exp Med 1986;163:922-37. 2. Stom TB, Loertscher R. Cyclosporine-induced nephroto• ty: Inevitable and intractable? N Engl J Med 1984;311: 728-9. 3. Keown PA, Stiller CR, Wallace AC. Nephrotoxicity of eyclosporine A. In: Williams GM, Burdick JF, Solez K, eds. Kidney transplant rejection. New York: Marcel Dekker, 1986:423. 4. Curtis J J, Luke RG, Dubovsky E, et al. Cyclosporine in therapeutic doses increases renal allograft vascular resistance. Lancet 1986;2:477-9. 5. Myers BD, Ross J, Newton L, et al. Cyclosporine-associated chronic nephropathy. N Engl J Med 1984;311:699-705. 6. Lifschitz MD, Stein JH. Renal vasoactive hormones. In: Brenner BM, Rector FC, eds. The kidney, vol 1. Philadelphia: WB Saunders, 1981:650. 7. Levenson DJ, Simmons CE, Brenner BM. Arachidonic acid metabolism, prostaglandins and the kidney. Am J Med 1982;72:354-74. 8. Murray BM, Paller MS. Beneficial effects of renal denervation and prazosin on GFR and renal blood flow after cyclosporine in rats. Clin Nephrol 1986;25(suppl 1):37-9. 9. Siegle H, Ryffel R, Petric R, et al. Cyclosporine, the renin-angiotensin-aldosterone system, and renal adverse reactions. In: Kahan BD, ed. Cyclosporine: biological activity and clinical applications. Orlando, Fla.: Grune & Stratton, 1984:503. 10. Mihatsch M J, Thiel G, Spichtin HP, et al. Morphologic findings in kidney transplants after treatment with cyclospofine. Transplant Proc 1983;15(suppl 1):2821-35. 11. Canadian Multieentre Transplant Study Group. A randomized clinical trial of cyclosporine in cadaveric renal transplantation. N Engl J Med 1983;309:809-15. 12. Kupin WL, Venkataehalam KK, Oh HK, et al. Sequential use of Minnesota antilymphoblast globulin and cyclosporine in cadaveric renal transplantation. Transplantation 1985; 40:601-4. 13. Kahan BD. Individualization of cyclosporine therapy using pharmacokinetic and pharmacodynamic parameters. Transplantation 1985;40:457-77. 14. Sommer BG, Innes JT, Whitehurst RM, et al. Cyclosporine
Volume 111 Number 6, part 2
associated renal arteriopathy resulting in loss of allograft function. Am J Surg 1985;149:756-65. 15. Keown PA, Stiller CR, Sinclair NR, et al. The clinical relevance of cyclosporine blood levels as measured by radioimmunoassay. In: Kahan BD, ed. Cyclosporine: biological activity and clinical applications. Orlando, Fla.: Grune & Stratton, 1984:222. 16. Rocher LL, Milford EL, Kirkman RL, et al. Conversion from cyclosporine to azatbioprine in renal allograft recipients. Transplantation 1984;38:669-74.
Effect o f cyclosporine on kidney
10 3 3
17. Flechner SM, Lorber M, Van Buren C, et al. The case against conversion to azathioprine in cyclosporine-treated renal recipients. Transplant Proc 1985;17(suppl 1):276-81. 18. Simmons RL, Canafax DM, Strand M, et al. Management and prevention of cyclosporine nephrotoxicity after renal transplantation: use of low doses of cyclosporine, azathioprine, and prednisone. Transplant Proc 1985; 17 (suppl 1) :26675.
In contrast to conventional immunosuppressive agents, cyclosporine does not limit myeloproliferation, but inhibits the immune response by a direct effect on the helper/ inducer T-lymphocyte. Cyclosporine suppresses activation events both at the cell membrane and in the cytosol, but a major site of action now appears to be the inhibition of lymphokine gene transcription, ~thus preventing the elaboration of essential intercellular messengers of the immune response such as interleukin-1, IL-2, and ,y-interferon. In the experimental animal, cyclosporine is highly effective in preventing graft rejection and in suppressing autoimmune disease with minimal toxicity and little renal effect. The nephrotoxicity observed in humans was thus unexpected and disappointing, and has proved the major concern accompanying the clinical use of this valuable agent. 2 We examined the pathophysiology of this unique nephrotoxicity, the spectrum of clinical injury induced, and the therapeutic approach that has been adopted to optimize the use of this drug. PATHOPHYSIOLOGY NEPHROTOXICITY
flow-probe techniques have now confirmed that cyclosporine causes a sharp decrease in both renal cortical and medullary blood flow, which is sustained throughout the duration of treatment? It would appear that this is also a principal mechanism in humans, in whom comparable data exist to demonstrate that cyclosporine causes an increase in renovascular resistance, 4 whereas renal plasma flow is significantly diminished in cardiac allograft recipients with renal functional impairment2 Regulation of renal blood flow is dependent on a complex interaction between neurogenic and hormonal stimuli. Alpha adrenergic stimulation maintains vasoconstrictor tone, and angiotensin II, derived from the decapeptide angiotensin I by the action of converting enzyme, has a potent direct vasoconstrictor effect on the preglomerular afferent arteriole, reducing glomerular blood flow and hence glomerular filtration? Closely linked to the reninIL TXA2
Interleukin Thromboxane A
[
OF CYCLOSPORINE
Studies in experimental animals and in humans indicate that cyclosporine has an acute dose-dependent effect on renal function, producing a marked reduction in glomerular filtration with oliguria, and an elevation in the blood urea nitrogen/creatinine ratio. Tubular function is also affected, causing decreased urinary sodium excretion, hyperuricemia, hyperkalemia, and type IV renal tubular acidosis? These functional effects are rapidly reversible with drug withdrawal, suggesting an underlying acute alteration in glomerular capillary perfusion and consequent proximal tubular reabsorption. Studies in animals using radiolabeled microspheres or Dr. P. A. Keown is a Career Scientist of the Ontario Ministry of Health. Reprint requests: Dr. P. A. Keown, Executive Director, British Columbia Transplant Programme, D 10, Room 19, Heather Pavilion, Vancouver General Hospital, Vancouver, British Columbia, Canada.
angiotensin system is the prostaglandin-thromboxane cascade. 7 These compounds participate in several physiologic processes within the kidney, including autoregulation of renal blood ftow and glomerular filtration, modulation of renin release, tubular ion transport, and water metabolism. Prostaglandins PGE2, PGD2, and PGI2 are potent vasodilators, modulating tone in pre- and postglomerular arterioles to reduce renal resistance and increase renal blood flow, whereas thromboxane A2 is a potent vasoconstrictor with opposing effects. 7 The effect of cyclosporine on these regulatory systems is currently being studied. Murray and Paller 8 have shown that, when administered rapidly at high intravenous doses, cyclosporine may cause renal vasoconstriction via a-adrenergic stimulation, an effect that may be prevented by renal denervation or pretreatment with prazosin. Whether this mechanism is relevant at therapeutic doses in humans is questionable, however, because cyclosporine nephrotoxicity is evident in the denervated grafted kidney. The role of the renin-angiotensin system is
1029
10 3 0
Keown, Stiller, and Wallace
The Journal of Pediatrics December 1987
Tablo. Algorithm for clinical use of cyclosporine in kidney transplantation
Allograft dysfunction Acute
Diagnostic category
Fever, oliguria, weight gain; diffuse infiltration; immunology positive
Acute vasculopathy
Oliguria, graft failure, microvascular platelet occlusion Combined features of rejection and toxicity
Uncertain Nephrotoxicity Chronic
Characteristic features
Acute rejection
Chronic toxicity
Chronic rejection
Therapeutic approach
Mild focal infiltrate, tubular injury; immunology negative Vascular thickening, intimal proliferation, interstitial fibrosis, unresponsive to CsA
Vascular thickening, intimal proliferation, interstitial fibrosis, unresponsive to CsA
tCsA levels to 200 ng/mL with MP 250 mg IV • 3 days; if no response, ALG • 5-7 days or monoclonal antibody ~CsA, institute alternative immunosuppression ~CsA to 100 ng/mL; if no response, MP 250 mg Iv • 3 days ~CsA to 100 ng/mL No clearly beneficial therapy; optimize CsA therapy, use triple (CsA, AZA, prednisone) drug regimen to reduce CsA dose or convert to AZA No clearly beneficial therapy; commence low-protein diet, avoid overimmunosuppression, prepare for retransplantation
ALG, anti-lymphocyteglobulin;CsA, cyclosporine;MP, methylprednisolone;AZA, azathioprine.
also unclear. Although cyclosporine causes a sharp elevation in plasma renin and aldosterone values, this rise is not sustained, 9 and converting enzyme inhibition is ineffective in preventing the cyclosporine effect. The role of the prostaglandin cascade is intriguing, but is also not entirely defined. In contrast to nonsteroidal agents, which produce a comparable acute inhibition of renal function as a result of prostaglandin inhibition, cyclosporine triggers a marked increase in TXA2 production, with a smaller compensatory increase in PGI2 and PGE2 (unpublished data). In initial studies, we have been able to demonstrate that selective blockade of TXA2 synthesis mitigates the cyclosporineinduced deterioration of renal function, restoring blood flow and glomerular filtration toward normal. Although reduced renal perfusion appears to explain the short-term events, the pathogenesis of the fibrosing injury accompanying prolonged drug administration in humans remains obscure. Three possible mechanisms have been advanced. Fibrosis, with secondary tubular injury, has been ascribed to the fibrogenic effect of cyclosporine resulting from direct fibroblast stimulation. Fibrosis may also be seen in other grafted tissues, notably the heart, but does not predominate in other native organs. The possibility of a polar metabolite causing direct tubulotoxicity has also been considered, but no satisfactory candidate has yet been identified. Although these events may contribute, a vascular cause currently appears most plausible. It is possible that persistent renal vasoconstriction and sodium
retention, triggered by physiologic events described, lead to sustained low-renin hypertension. This, in combination with chronic endothelial damage related to low-grade platelet activation on the vessel wall, secondary perhaps to dysregulation of prostaglandin-thromboxane metabolism, results in renal parenchymal ischemia, with the characteristic degenerative changes in the nephron and interstitium. Such a vascular cause would be most consistent with the segmental, or "striped," picture characteristically described in this disease. 1~ CLINICAL
TOXICITY AND RISK FACTORS
The nephrotoxicity of cyclosporine may be divided into four discrete syndromes on the basis of physiologic and pathologic criteria (Table). Initial nonfunction of graft. The detrimental effect of cyclosporine on initial renal graft function was reported in early studies, and has been substantiated in subsequent randomized trials. ~1 Both the incidence and duration of initial graft nonfunction are increased, and secondary oliguria has been reported in up to 30% of cases. Certain risk factors have been identified, including prolonged graft storage (>24 hours) or surgical reanastomosis time (>45 minutes), H and the immunologic status of the recipient in terms of prior transplants and degree of sensitization, which appear to interact with cyclosporine to increase the risk of nonfunction (unpublished data), while elevated drug concentrations in blood or serum in the early postop-
Volume 111 Number 6, part 2
erative period may delay renal functional recovery. 1~ To minimize early toxicity, the starting dose of cyclosporine has been progressively reduced to about 10 mg/kg/d orally in adults and 12 to 15 mg/kg/d in children, subsequently adjusted to maintain trough concentrations in serum of 150 to 250 ng/mL by radioimmunoassay (whole blood, 250 to 350 ng/mL). Intravenous administration by intermittent or continuous infusion at one-third the oral dose may prove more beneficial while absorption is unreliable, and is routinely used in several centers. To avoid toxicity completely during this critical period, however, induction immunosuppression with anti-lymphocyte globulin, followed by conversion to cyclosporine between days 2 and 7, may ultimately prove to be the most effective therapy. In studies thus far available, this combination appears to provide optimal immunosuppression, with minimal toxicity or morbidity, 12 but caution is essential in the use of these powerful agents to avoid over immunosuppression. Acute nephrotoxieity, Acute, reversible nephrotoxicity may occur in either the native or transplanted kidney, and is characterized by an increase in serum creatinine and BUN/creatinine ratio, with hyperuricemia, hyperkalemia, and mild oliguria? Acute nephrotoxicity is generally observed in association with rising or elevated serum concentrations of cyclosporine (>200 ng/mL), and is frequent with levels >400 ng/mL. A clear temporal relationship can usually be established, with changes in cyclosporine level preceding those in serum creatinine by a few days. Several drugs exhibit pharmacokinetic or pharmacodynamic interactions with cyclosporine that enhance acute nephrotoxicity. Ketoconazole and erythromycin inhibit cyclosporine metabolism, causing a rise in blood levels; nonsteroidal anti-inflammatory drugs, aminoglycosides, trimethoprim-sulfamethoxazole, and amphotericin B interact at the level of the kidney by a number of discrete mechanisms. ~3Distinction between acute cyclosporine toxicity and mild acute rejection in the transplanted kidney may be difficult. Both occur with greatest frequency in the first 3 months, but acute rejection is subsequently rare. Nephrotoxicity is characterized by a slow rise in creatinine values accompanied by elevated serum cyclosporine concentrations; oliguria, fever, and low cyclosporine levels are more common in rejection. ~3 Final differentiation, however, may depend on demonstration of typical changes of edema, vasculitis, and interstitial mononuclear cell infiltrate in rejection, or tubular epithelial cell injury characterized by vacuolization, calcification, and mitochondrial injury in cyclosporine nephrotoxicity. Acute cyclosporine nephrotoxicity usually resolves rapidly after appropriate dose reduction, and is rarely of clinical importance when trough serum levels are maintained between 50 and 150 ng/mL.
Effect o f cyclosporine on kidney
10 3 1
Acute vasculopathy. Acute vasculopathy is a rare manifestation of cyclosporine toxicity, and occurs within the first 2 to 3 weeks of therapy. First described after bone marrow transplantation and subsequently after other solid organ grafts, this entity resembles hemolytic-uremic syndrome and comprises thrombocytopenia, red cell fragmentation, and acute renal failure. An isolated variant has been described after renal transplantation, in which systemic thrombocytopenia is accompanied by microvascular occlusion by platelet and fibrin deposits within the graft, and amorphous eosinophilic material is interposed beneath the endothelium. 14It is probable that this form of vasculopathy reflects initial endothelial injury by an immune process, permitting secondary platelet activation at this site, related to the perturbation of normal regulatory mechanisms by cyclosporine. Ferguson et al. 14 have reported that this complication occurs in 8% of their patients after renal transplantation and is now their most common cause of graft loss. They postulate that the high frequency may be related to the routine use of anti-lymphocyte globulin for induction immunosuppression, causing subtle endothelial injury. In our experience, however, it is considerably less common, and we have seen only two cases (1.2%) in the last 2 years that could not be ascribed to acute rejection. The acute vascular injury is accompanied clinically by a rapid deterioration in renal function with oligoanuria, frequently without fever or graft tenderness. The entity is not responsive to conventional anti-rejection therapy, but temporary replacement of cyclosporine with anti-l~ymphocyte globulin, followed by conversion to maintenance azathioprine or triple therapy, may salvage graft function. Heparin or streptokinase infusion into the graft has also been used, but is not yet of demonstrated benefit. Chronic nephropathy with interstitial fibrosis. The chronic fibrosing injury was first observed in initial adult studies when cyclosporine was used in doses exceeding 12.5 mg/kg/d, and with careful pharmacokinetic monitoring and appropriate dose reduction has become a less serious clinical concern. This form of injury has so far been found unique in humans, and its cause remains unclear. Histologically, it is characterized by an increase in interstitial connective tissue, tubular atrophy, and vascular sclerosis? Thickening of the tubular and glomerular basement membranes may be seen, with glomerular retraction resembling focal glomerulosclerosis, s Glomerular filtration in patients receiving cyclosporine is normally lower than in those receiving alternative immunosuppression. 11 The decrease in renal function is most marked during the first 12 months, but then appears to plateau and remain stable." Patients can be clinically divided into three groups on the basis of long-term renal
10 3 2
Keown, Stiller, and Wallace
function. The first, representing the majority of patients, experiences no progressive change in glomerular filtration rate, and the serum creatinine concentration remains stable, although elevated, throughout the transplant course. In the second group, there is a slow and progressive rise in creatinine concentration, which generally responds to a decrease in the cyclosporine dose and then remains stable. The third group, however, is characterized by a marked and continuing rise in serum creatinine despite reduction in cyclosporine to levels that no longer ensure satisfactory immunosuppression. Deteriorating renal function is accompanied by increasing hypertension, which is poorly responsive to treatment and may necessitate multiple agent therapy. Ultimately, renal dysfunction, hypertension, and intractable headache may require discontinuation of the medication. Such patients represent approximately 10% of those receiving long-term cyclosporine therapy. Retrospective analysis shows that many have sustained prior graft damage in the form of protracted perfusion, warm ischemia, or acute rejection, or have unacceptably high (>300 to 400 ng/mL) serum cyclosporine levels for prolonged periods during treatment? s Two therapeutic approaches have been used in such cases. In the first, azathioprine is substituted for cyclosporine, with or without a period of overlap. 16 Withdrawal of the drug usually results in a marked improvement in renal function, which returns toward normal over the subsequent 30 days, and the accompanying hypertension may ameliorate or resolve. Azathioprine is a less effective immunosuppressant, however, and this approach may be inadequate to maintain immune control in organ transplantation. Acute graft rejection may be precipitated in up to 80% of patients after conversion, with appreciable graft loss, Iv and relapse of autoimmune disease may occur, leading to destruction of residual islet tissue in type 1 diabetes mellitus. To avoid this outcome, conversion to a triple-therapy regimen consisting of prednisone, azathioprine, and low doses (1 to 3 m g / k g / d ) of cyclosporine has been more widely examined. ~8 Beneficial interactions between these agents have been shown in vitro and in experimental animal studies. Clinical experience is still limited, but the preliminary use of this combination in renal transplantation is encouragingJ 7 SUMMARY Cyclosporine constitutes a major advance in pharmacologic immunosuppression, the benefit of which is now established for solid organ transplantation and is rapidly emerging for many forms of autoimmune disease. By virtue of its potency and selectivity, there has been a marked reduction in steroid requirement with a concomitant reduction in morbidity and mortality.
The Journal of Pediatrics December 1987
The undesirable effect of cyclosporine on the kidney may thus be considered within this context. The short-term functional effect observed to some degree in most patients receiving this drug is rapidly reversible, and is unaccompanied by long-term detriment in studies now extending over 6 years. Progressive deterioration still occurs in a small proportion of patients, but may often be reversed by carefully controlled conversion to alternative combination immunosuppression therapy. For each developing application, the ultimate value of cyclosporine must be determined individually in relation to the severity of the disease process. The challenge that now confronts us is to determine the manner in which this agent may be most safely and effectively used. REFERENCES
1. GraneUi-Piperno A, Andrus L, Steinman R. Lymphokine and non-lymphokine mRNA levels in stimulated human T cells. J Exp Med 1986;163:922-37. 2. Stom TB, Loertscher R. Cyclosporine-induced nephroto• ty: Inevitable and intractable? N Engl J Med 1984;311: 728-9. 3. Keown PA, Stiller CR, Wallace AC. Nephrotoxicity of eyclosporine A. In: Williams GM, Burdick JF, Solez K, eds. Kidney transplant rejection. New York: Marcel Dekker, 1986:423. 4. Curtis J J, Luke RG, Dubovsky E, et al. Cyclosporine in therapeutic doses increases renal allograft vascular resistance. Lancet 1986;2:477-9. 5. Myers BD, Ross J, Newton L, et al. Cyclosporine-associated chronic nephropathy. N Engl J Med 1984;311:699-705. 6. Lifschitz MD, Stein JH. Renal vasoactive hormones. In: Brenner BM, Rector FC, eds. The kidney, vol 1. Philadelphia: WB Saunders, 1981:650. 7. Levenson DJ, Simmons CE, Brenner BM. Arachidonic acid metabolism, prostaglandins and the kidney. Am J Med 1982;72:354-74. 8. Murray BM, Paller MS. Beneficial effects of renal denervation and prazosin on GFR and renal blood flow after cyclosporine in rats. Clin Nephrol 1986;25(suppl 1):37-9. 9. Siegle H, Ryffel R, Petric R, et al. Cyclosporine, the renin-angiotensin-aldosterone system, and renal adverse reactions. In: Kahan BD, ed. Cyclosporine: biological activity and clinical applications. Orlando, Fla.: Grune & Stratton, 1984:503. 10. Mihatsch M J, Thiel G, Spichtin HP, et al. Morphologic findings in kidney transplants after treatment with cyclospofine. Transplant Proc 1983;15(suppl 1):2821-35. 11. Canadian Multieentre Transplant Study Group. A randomized clinical trial of cyclosporine in cadaveric renal transplantation. N Engl J Med 1983;309:809-15. 12. Kupin WL, Venkataehalam KK, Oh HK, et al. Sequential use of Minnesota antilymphoblast globulin and cyclosporine in cadaveric renal transplantation. Transplantation 1985; 40:601-4. 13. Kahan BD. Individualization of cyclosporine therapy using pharmacokinetic and pharmacodynamic parameters. Transplantation 1985;40:457-77. 14. Sommer BG, Innes JT, Whitehurst RM, et al. Cyclosporine
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associated renal arteriopathy resulting in loss of allograft function. Am J Surg 1985;149:756-65. 15. Keown PA, Stiller CR, Sinclair NR, et al. The clinical relevance of cyclosporine blood levels as measured by radioimmunoassay. In: Kahan BD, ed. Cyclosporine: biological activity and clinical applications. Orlando, Fla.: Grune & Stratton, 1984:222. 16. Rocher LL, Milford EL, Kirkman RL, et al. Conversion from cyclosporine to azatbioprine in renal allograft recipients. Transplantation 1984;38:669-74.
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17. Flechner SM, Lorber M, Van Buren C, et al. The case against conversion to azathioprine in cyclosporine-treated renal recipients. Transplant Proc 1985;17(suppl 1):276-81. 18. Simmons RL, Canafax DM, Strand M, et al. Management and prevention of cyclosporine nephrotoxicity after renal transplantation: use of low doses of cyclosporine, azathioprine, and prednisone. Transplant Proc 1985; 17 (suppl 1) :26675.