Chronic cyclosporine nephropathy: The Achilles' heel of immunosuppressive therapy

Bennett, William M.; DeMattos, Angelo M; Meyer, Mary M.; Andoh, Takeshi F.; Barry, John M.

doi:10.1038/ki.1996.415

Cited by 413 publications

(238 citation statements)

References 102 publications

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“…Renal biopsy is the only standard tool with which to evaluate these structural alterations. Arteriolar lesions are considered to be the hallmark of cyclosporin toxicity [3,21] Late alterations consist of fibrous thickening of the small vessels, especially of the arterioles and of the glomerular basement membranes [17,341, and in the long run stripped interstitial fibrosis [34]. In this study, all patients underwent a renal biopsy and all showed these findings.…”

Section: Discussionmentioning

confidence: 98%

Effect of adding Mycophenolate mofetil in paediatric renal transplant recipients with chronical cyclosporine nephrotoxicity

et al. 2000

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Cyclosporine (CyA) has made a great impact on 1-year allograft survival, however, after years, renal function deteriorates, possibly due to chronic toxicity. Recently, Mycophenolate mofetil (MMF) was introduced as a nonnephrotoxic immunosuppressant that might be effective in chronical transplant arteriolopathy. We therefore started MMF at a dose of 600 mg/m2 b. i. d. in 18 pediatric renal transplant recipients (10.8 f 3.9 (SD) years of age at transplantation, 11/18 with a history of rejections) with biopsy-proven chronic arteriolopathy and other signs of CyA toxicity at a mean follow up time of 6.2 k 2.7 (range 2.3-11.8) years after transplantation. One month prior to conversion, mean serum creatinine was 171 the time of conversion (188 f 100 pmol/l, P = 0.003, paired t-test). At last follow-up (median 13.7 months, range 5.0 to 25.0 months) after conversion, mean serum creatinine decreased significantly to 127 t 69 pmolil ( P = 0,0003, paired t-test). The CyA dosage was reduced from a mean of 150 * 39 mg/ m2 per day to 59 f 13 mg/m2 per day 96 pmol/l, lower than at in 7 patients, and CyA was discontinued in 11 patients after a median period of nine months (range 1-18 months). After a median period of 21 days, a pharrnacokinetic profile was performed in all patients. The mean MMF dose was 1117 f 319 mg/m2 per day (range 675-1774 mg/m2 per day). The mean Mycophenolic acid (MPA) trough concentration was 4.0 k 2.0 pg/ml, range 1.4-7.9 pg/ml. Mean 12 h MPA AUC was 70.6 k 28.1 (range 31.9-127) pg x h/ml. Except for one patient with diarrhea associated with a high AUC, and for one patient with a steroid-sensitive rejection episode after 566 days, no other patient experienced side effects or a rejection episode. Prednisolone was left unaltered at 2-4 mg/m2 per day. We conclude that MMF allows safe reduction of CyA with markedly better graft function, suggesting that chronical CyA-toxicity partially accounts for deteriorating allograft function.

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Section: Discussionmentioning

confidence: 98%

Effect of adding Mycophenolate mofetil in paediatric renal transplant recipients with chronical cyclosporine nephrotoxicity

et al. 2000

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“…Chronic CNI nephrotoxicity is the Achilles' heel of current immunosuppressive regimens (114). Myers et al were the first to demonstrate that cyclosporine not only induces reversible alterations in renal vascular resistance, but is associated with irreversible damage of the renal architecture (22).…”

Section: Chronic Cni Nephrotoxicitymentioning

confidence: 99%

Calcineurin Inhibitor Nephrotoxicity

Naesens

Kuypers²,

Sarwal³

2009

Clinical Journal of the American Society of Nephrology

1,207

968

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The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis. The authors also review the available literature on the physiologic and molecular mechanisms underlying acute and chronic calcineurin inhibitor nephrotoxicity, and demonstrate that its development is related to both reversible alterations and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. The main question-whether nephrotoxicity is secondary to the actions of cyclosporine and tacrolimus on the calcineurin-NFAT pathway-remains largely unanswered. The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cyclosporine or tacrolimus could be more important than systemic exposure. Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-␤ and ACE. Better insight into the mechanisms underlying calcineurin inhibitor nephrotoxicity might pave the way toward more targeted therapy or prevention of calcineurin inhibitor nephrotoxicity.Clin J Am Soc Nephrol 4: 481-508, 2009. doi: 10.2215/CJN.04800908 T he introduction of the calcineurin inhibitor (CNI) cyclosporine in human kidney transplantation in the late 1970s revolutionized transplantation medicine, and made transplantation a preferable therapeutic intervention for end-stage renal diseases (1,2). In 1984, the potent immunosuppressive properties of another CNI, tacrolimus, were discovered, and tacrolimus was used successfully in human liver, kidney, and heart allograft recipients (3,4). Currently, 94% of kidney transplant recipients are discharged after transplantation with a CNI-based immunosuppressive regimen (5).The immunosuppressive properties of cyclosporine and tacrolimus result from inhibition of calcineurin, a calcium-and calmodulin-dependent phosphatase (protein phosphatase 3 [PPP3C], formerly PP2B). Intracellularly, these completely different molecules bind to cyclophylin and FKBP12 for cyclosporine and tacrolimus, respectively (6 -9). The competitive binding of cyclosporine-cyclophylin and tacrolimus-FKBP12 complexes to calcineurin inhibits phosphatase activity of calcineurin. This inhibition then suppresses the transcription of IL-2 via inhibition of the dephosphorylation and impaired translocation of the nucl...

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“…2 The introduction of calcineurin inhibitors (CNIs)-cyclosporine (CsA) and tacrolimus (Tac)-in the last two decades has resulted in a significant decrease in acute rejection and an improvement in short-term graft survival 3 with most centers now achieving 85% to 90% 1-year graft survival. 4 However, long-term graft loss due to chronic allograft nephropathy (CAN) remains a major problem in renal transplantation. 5 While there appear to be many contributors to CAN, many studies emphasize the nephrotoxicity associated with CNIs.…”

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confidence: 99%

Calcineurin Inhibitor–Free Immunosuppression in Renal Transplantation

Parada

Mota

Nunes

et al. 2005

Transplantation Proceedings

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Purpose. To describe our initial results using a calcineurin inhibitor-free immunosuppression protocol in renal transplants. Patients and methods. Between October 2001 and June 2003, 56 recipients of a renal allografts were started on an immunosuppression protocol without calcineurin inhibitors, consisting of basiliximab, sirolimus, mycophenolate mofetil, and steroids. We analyzed patient and graft survival, acute rejection episodes, and renal function. Results. The mean follow-up was 19.6 months. Actuarial patient survival at 1 and 2 years was 98.1% and 95.3%, respectively. Actuarial graft survival at 1 and 2 years was 92.9% and 87.6%, respectively. Acute rejection occurred in 27.8% of the patients, usually Banff 1 (73.3%). There was stable renal function with mean serum creatinine of 1.3, 1.4, 1.3, and 1.3 mg/dL at 1, 6, 12, and 24 months after transplant. Conclusions. The use of immunosuppression free of calcineurin inhibitors is effective and safe. Further follow-up is needed to evaluate the impact on long-term results.K IDNEY TRANSPLANT OUTCOMES have steadily improved over the past decade 1 due to modern immunosuppression protocols and better prophylaxis and treatment of common posttransplant infections. 2 The introduction of calcineurin inhibitors (CNIs)-cyclosporine (CsA) and tacrolimus (Tac)-in the last two decades has resulted in a significant decrease in acute rejection and an improvement in short-term graft survival 3 with most centers now achieving 85% to 90% 1-year graft survival. 4 However, long-term graft loss due to chronic allograft nephropathy (CAN) remains a major problem in renal transplantation. 5 While there appear to be many contributors to CAN, many studies emphasize the nephrotoxicity associated with CNIs. 6 -8 Several studies of CNI-free immunosuppression 2,9 -13 or early CsA withdrawal 14 -16 have been reported, with good patient and graft survival and without drug-induced nephrotoxicity. In this report, we describe our initial results using a CNI-free immunosuppression protocol in renal transplants. PATIENTS AND METHODSBetween October 2001 and June 2003, 56 recipients of a first renal allograft were enrolled in this prospective study, which had obtained local ethics committee approval and written informed consent from each patient. Exclusion criteria consisted of prior transplantation or exposure to immunosuppressants, type I diabeties, severe hyperlipidemia prior to transplantation (serum cholesterol level greater than 350 mg/dL or serum triglycerides over 400 mg/dL), white blood cells less than 3000/mm 3 , or platelets less than 100,000/mm 3 .Immunosuppressive protocol included basiliximab 20 mg (days 0 and 4), mycophenolate mofetil (1 g two times per day), steroids, and sirolimus (5 mg daily after a 20 mg loading dose). Sirolimus doses were then adjusted to achieve target through levels between 10 and 15 ng/mL for 6 months and 5 to 10 ng/mL thereafter. All clinical rejections were biopsy-proven and Banff scored prior to initiation of therapy with high-dose steroids. Prim...

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Chronic cyclosporine nephropathy: The Achilles' heel of immunosuppressive therapy

Cited by 413 publications

References 102 publications

Effect of adding Mycophenolate mofetil in paediatric renal transplant recipients with chronical cyclosporine nephrotoxicity

Effect of adding Mycophenolate mofetil in paediatric renal transplant recipients with chronical cyclosporine nephrotoxicity

Calcineurin Inhibitor Nephrotoxicity

Calcineurin Inhibitor–Free Immunosuppression in Renal Transplantation

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