AN IMMUNOSUPPRESSIVE TRIUMVIRATE TO MINIMIZE RENAL INJURIES ASSOCIATED WITH CALCINEURIN ANTAGONIST THERAPY
1999; Wolters Kluwer; Volume: 68; Issue: 1 Linguagem: Inglês
10.1097/00007890-199907150-00004
ISSN1534-6080
Autores Tópico(s)Drug-Induced Hepatotoxicity and Protection
ResumoSoccal PM, Gasche Y, Favre H, Spiliopoulos A, Nicod LP. Improvement of Drug-Induced Chronic Renal Failure in Lung Transplantation. Transplantation 1999; 68: 164. The renal dysfunction produced by the calcineurin antagonists (CNA), cyclosporine (CsA) and tacrolimus, poses a significant challenge to immunosuppressive therapy (1). There are at least two, possibly independent, lesions associated with CNA drugs: a vasomotor component of afferent arteriolar constriction reducing glomerular perfusion, and a structural component replacing vascular smooth muscle cells with hyaline material and/or tubular and interstitial tissues with fibrosis (2). The correlation between the degree of calcineurin inhibition and the extent of renal impairment, as well as the failure to identify an immunosuppressive CNA analog that spares the kidney, both suggest a causal relation. However, it is not known what molecular role calcineurin plays in the spectrum of nephrotoxic effects: namely, the stimulation of the local renin-angiotensin system; the increased production of the profibrogenic transforming growth factor-β, the vasculoproliferative cytokine platelet-derived growth factor and/or the vasoconstrictors thromboxane and endothelin; as well as the decreased synthesis of vasodilators, including prostacyclin and nitric acid. Furthermore, it is unclear why certain factors exacerbate the CNA-induced injury: elderly donor age, pretransplantation renal compromise, adverse organ harvest or implantation circumstances, and/or prolonged kidney allograft storage times (3). Interestingly, CNA drugs seem to produce a greater degree of dysfunction of native kidneys than of renal transplants, even when one takes account of the compromised pretransplantation renal function in these patients and the higher doses typically used in vital organ transplant recipients (4). Indeed, progressive renal damage is not uncommon among heart or liver transplant recipients, whereas the dysfunction tends to stabilize after 6 months in renal transplant patients (5). The differential susceptibility in recipients of vital organ transplants has been ascribed to a distinct effect of CNA to stimulate the intact sympathetic innervation of native kidneys. Due to our failure to precisely define the pathophysiologic mechanisms of, and to thereby design, effective countermeasure therapies against the renal injury, CNA dose minimization or even long-term CNA elimination represents the most pragmatic strategy. CNA dose reduction within the first 3 posttransplantation months frequently ameliorates the subacute toxic injury, particularly when the patient displays an unexpectedly high absorption and/or a slow drug clearance rate (6). However, Burke et al. (7) observed that despite judicious CsA dose reduction, there existed a threshold associated with emergence of allograft rejection in most transplant recipients. To intensify the immunoprophylaxis and overcome the rejection risk, azathioprine (Aza)-a non-nephrotoxic anti-proliferative agent-was initially combined with CsA in the immunosuppressive regimen. Unfortunately it failed to permit substantial CsA dose reduction (8), probably due both to its low potency and to its only additive immunosuppressive interaction with CsA (9). The stronger antiproliferative agent mycophenolate mofetil (MMF) proffers a second option to buffer the effects of CNA dose reduction, as reported in 14 lung transplant recipients by Soccal et al. in this issue of Transplantation. Reduction of CNA doses to produce trough concentrations that were half of the usual maintenance level yielded a 20% improvement in the mean glomerular filtration rate, namely, an increase from 59.5±11.7 to 71.3±15.7 ml/min. Although no early breakthrough rejection episodes occurred, the new level of glomerular filtration rate was less than 65% of the pretransplantation value of 108.8±9.7 ml/min, and the dose reduction maneuver only modestly improved the hypertensive state. Soccal et al. propose that the incomplete reversal of renal toxicity by CNA dose reduction was due to an improvement in the functional (but not the structural) components of the injury, a hypothesis that would have been advanced if they had performed native kidney biopsies. In a similar clinical setting, Myers et al. (4) observed that CsA dose reduction rapidly improved both the renal function and the histopathologic findings of arteriolopathy but did not alter the long-term adverse progression of tubulointerstitial disease. These findings are consistent with the observations of Collins et al. (10) that vascular remodeling may reverse the arteriolar lesions produced by CsA, whereas the fibrotic changes are permanent. The present publication does not address other reasons why the CNA dose reduction failed to more fully reverse the renal dysfunction. First, was the mean follow-up period reported by Soccal et al. of just over 1 year sufficient to realize the full benefits of the maneuver? Second, was a 50% decrease in trough CNA concentrations sufficient? Even greater dose reductions may be necessary to restore kidney function since Feutren et al. (11) described renal injuries among psoriatic patients who were treated with only 5 mg/kg/day CsA. Would an 80% reduction in CNA concentration have been more effective? Third, was the apparent benefit on kidney function observed by Soccal et al. due at least in part to amelioration of salt retention, of an ill-defined cardiac toxicity, and/or of hyperlipidemia-three widely recognized, dose-dependent adverse cardiovascular effects of CNA (3). A logical extension from CNA dose reduction is conversion to a non-CNA-based regimen-drug withdrawal. Morris et al. (12) observed improved renal function upon conversion of kidney transplant recipients from a CsA- to an Aza-based regimen at 3 months. However, subsequent reports noted a disturbing incidence of breakthrough rejection episodes and possibly premature graft failure (13), unless the conversion was performed in special low-risk circumstances-a close donor-recipient match, initiation at 1 year (although 30% of patients at this time show structural evidence of the injury), good graft function, and a slow rate of CsA withdrawal using a prolonged overlap period with Aza administration (14). Similarly in low-risk patients, Zanker et al. (15) described a CNA-free maintenance immunosuppressive regimen, utilizing an MMF-steroid combination. However, despite CNA elimination from the long-term regimen, only a modest degree of improvement in renal function has generally been observed. Thus, it seems likely that the renal injury will never reverse completely if the patient has ever been treated with full therapeutic amounts of CNA, a hypothesis that is suggested by the study of Franceschini et al. (16) in an animal model. Indeed the issue is whether at least some of the benefits of CNA therapy can be realized, and the hazards minimized, both in the short- and the long-term, by utilizing parsimonious amounts of CNA. We have proposed that substantial CNA dose reduction may be achieved by exploiting the synergistic interaction among three agents that disrupt the cytokine paradigm of immune activation (17)-CsA to inhibit proinflammatory cytokine synthesis, anti-interleukin (IL)-2R monoclonal antibodies to block ligand binding to IL-2R, and the powerful protein translation inhibitor sirolimus (SRL) to disrupt cytokine signal transduction. Based on this paradigm, induction immunosuppression with anti-IL-2R monoclonal antibody in conjunction with full doses of SRL provides at least a 2-month window for recovery of normal renal function without the potential deleterious effects of CNA drugs. Thereafter, 50-100 mg b.i.d. doses of CsA are introduced judiciously, namely, amounts 60-80% lower than usual (18). This protocol has yielded not only freedom from acute allograft rejection episodes (in contradistinction to the 45% incidence with the combination of anti-IL-2R and MMF; 19) but also significantly better cadaveric renal allograft function at 6 months than that previously obtained with de novo treatment with CNA-SRL-steroid or CNA-steroid regimens. Careful concentration-controlled clinical trials are underway to establish the threshold of parsimonious CsA exposure that minimizes both the arteriolopathic and the tubulointerstitial adverse effects but realizes the immunosuppressive benefits of calcineurin antagonist therapy. Barry D. Kahan The University of Texas Medical School; Department of Surgery; Division of Immunology and Organ Transplantation; Houston, Texas 77030
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