The unsolved cyclosporine-induced kidney injury: is paricalcitol a feasible new renoprotective option?
2010; Elsevier BV; Volume: 77; Issue: 12 Linguagem: Inglês
10.1038/ki.2010.93
ISSN1523-1755
Autores Tópico(s)Pregnancy and Medication Impact
ResumoThe management of cyclosporine A (CsA)-induced nephrotoxicity remains one of the main challenges in kidney transplantation. The animal study by Park et al. proposes that paricalcitol, a vitamin D analog with renoprotective actions reported in other conditions, attenuates CsA-induced kidney injury via the suppression of inflammatory, fibrotic, and apoptotic factors. Before paricalcitol can be considered a feasible new therapeutic option for post-transplantation nephropathy, these interesting data require further studies assessing other mechanisms of CsA-induced nephrotoxicity. The management of cyclosporine A (CsA)-induced nephrotoxicity remains one of the main challenges in kidney transplantation. The animal study by Park et al. proposes that paricalcitol, a vitamin D analog with renoprotective actions reported in other conditions, attenuates CsA-induced kidney injury via the suppression of inflammatory, fibrotic, and apoptotic factors. Before paricalcitol can be considered a feasible new therapeutic option for post-transplantation nephropathy, these interesting data require further studies assessing other mechanisms of CsA-induced nephrotoxicity. Key concerns in kidney transplantation (KTx) are allograft rejection and side effects of immunosuppressive agents. The introduction of calcineurin inhibitors, particularly cyclosporine A (CsA), has greatly improved morbidity and mortality in kidney-transplanted patients, particularly as a result of more efficient prevention of acute rejection. However, the clinical use of CsA is associated with serious undesirable side effects, such as nephrotoxicity and arterial hypertension.1.Naesens M. Kuypers D.R. Sarwal M. Calcineurin inhibitor nephrotoxicity.Clin J Am Soc Nephrol. 2009; 4: 481-508PubMed Google Scholar,2.Textor S.C. Taler S.J. Canzanello V.J. et al.Posttransplantation hypertension related to calcineurin inhibitors.Liver Transpl. 2000; 6: 521-530Crossref PubMed Scopus (110) Google Scholar In fact, chronic allograft nephropathy is an independent risk factor for graft loss and mortality after KTx, and cardiovascular complications are the main cause of death after transplantation.2.Textor S.C. Taler S.J. Canzanello V.J. et al.Posttransplantation hypertension related to calcineurin inhibitors.Liver Transpl. 2000; 6: 521-530Crossref PubMed Scopus (110) Google Scholar,3.Mange K.C. Cizman B. Joffe M. et al.Arterial hypertension and renal allograft survival.JAMA. 2000; 283: 633-638Crossref PubMed Scopus (253) Google Scholar Thus, extended long-term graft survival has not been achieved. The recognition of these serious adverse effects raised interest in CsA-sparing schemes. Strategies to limit CsA exposure include avoidance, minimization, and withdrawal.4.Flechner S.M. Kobashigawa J. Klintmalm G. Calcineurin inhibitor-sparing regimens in solid organ transplantation: focus on improving renal function and nephrotoxicity.Clin Transplant. 2008; 22: 1-15Crossref PubMed Google Scholar Calcineurin inhibitor avoidance is associated with increased acute rejection rates, and these protocols have been discarded. CsA reduction is associated with a modest improvement in renal function, but the chronic allograft nephropathy increases if the exposure remains. The preferable CsA withdrawal protocols are early and late replacement, especially with sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR). The choice depends mainly on two important factors: the risk of rejection and the undesirable side effects—in particular, kidney injury. In general, when there is low risk of rejection and/or high nephrotoxicity, replacement might be performed earlier in order to protect the kidney. Early withdrawal, before significant graft damage, has generally improved creatinine clearance and markers of fibrosis, with decreased chronic allograft lesions. Late CsA withdrawal has achieved variable results, possibly because withdrawal was attempted after the kidney damage was too extensive. However, there is no consensus in the medical–scientific community concerning the choice of combined protocols (early or late replacement) and their real benefits, particularly because of the lack of knowledge concerning the biomolecular mechanisms that support the decision. Sirolimus (SRL), an inhibitor of mTOR, is a new option in KTx management. However, although the cardiorenal side effects of SRL are apparently less than those of CsA, other serious adverse effects, such as lipid abnormalities and thrombocytopenia, have been reported for this mTOR inhibitor, and even the benefits previously reported have been recently discussed with regard to evidence of nephrotoxicity and proteinuria.5.Rangan G.K. Sirolimus-associated proteinuria and renal dysfunction.Drug Saf. 2006; 29: 1153-1161Crossref PubMed Scopus (38) Google Scholar Even considering that substitution of CsA by SRL is promising, validation in long-term follow-up studies in large cohorts is yet required in order to consistently determine whether the changes will result in a significant improvement in patient and graft survival. On the other hand, according to some single-center studies, which should be further confirmed in large randomized multicenter trials, CsA withdrawal from SRL-based therapy is associated with an increased risk of acute rejection in the short term, which remains one of the key concerns in transplantation. In any case, at the moment, CsA immunotherapy remains one of the central pillars of solid-organ transplantation, and the unsolved CsA-induced kidney injury remains one of the main problems in KTx management. Chronic allograft nephropathy is a severe post-transplantation complication with a multifactorial cause. The article by Park et al.6.Park J.W. Bae E.H. Kim I.J. et al.Paricalcitol attenuates cyclosporine-induced kidney injury in rats.Kidney Int. 2010; 77: 1076-1085Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar (this issue) begins with a description of some of the mechanisms underlying CsA-induced nephropathy (CIN), thus explaining the rationale for their study. The irreversible decline in renal function includes both renal vasoconstriction and structural damage.1.Naesens M. Kuypers D.R. Sarwal M. Calcineurin inhibitor nephrotoxicity.Clin J Am Soc Nephrol. 2009; 4: 481-508PubMed Google Scholar,6.Park J.W. Bae E.H. Kim I.J. et al.Paricalcitol attenuates cyclosporine-induced kidney injury in rats.Kidney Int. 2010; 77: 1076-1085Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar CsA causes overactivity of the renin–angiotensin–aldosterone system (RAAS), thus reducing the renal blood flow. Angiotensin II promotes various actions, including proinflammatory and profibrogenic actions, through transforming growth factor-β1 (TGF-β1). Furthermore, as Park et al. mention,6.Park J.W. Bae E.H. Kim I.J. et al.Paricalcitol attenuates cyclosporine-induced kidney injury in rats.Kidney Int. 2010; 77: 1076-1085Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar the production of reactive oxygen species causes cellular injury and promotes cell death by apoptosis; moreover, CsA directly upregulates TGF-β1 expression in tubular epithelial cells, independently of the hemodynamic effects of the RAAS in chronic CIN.1.Naesens M. Kuypers D.R. Sarwal M. Calcineurin inhibitor nephrotoxicity.Clin J Am Soc Nephrol. 2009; 4: 481-508PubMed Google Scholar,6.Park J.W. Bae E.H. Kim I.J. et al.Paricalcitol attenuates cyclosporine-induced kidney injury in rats.Kidney Int. 2010; 77: 1076-1085Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar Park et al. tested the possibility of CIN attenuation by paricalcitol through inhibition of pathways dependent on TGF-β1 signaling, including inflammation, proliferation, and apoptosis6.Park J.W. Bae E.H. Kim I.J. et al.Paricalcitol attenuates cyclosporine-induced kidney injury in rats.Kidney Int. 2010; 77: 1076-1085Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar (Figure 1a). The management of CIN includes minimization or withdrawal strategies (which must be done vigilantly because of the risk of acute rejection) and control of concomitant dyslipidemia and hypertension, particularly with the use of modulators of the RAAS and calcium channel blockers. However, as long as the precise biomolecular mechanisms underlying the cardiorenal effects of CsA remain to be fully clarified, the choice of the most appropriate antihypertensive/renoprotective drug will remain a largely empirical decision that considers blood pressure control, side effects, and potential interference with immunosuppression. Under these conditions, the renal and cardiovascular impairment will progress, thus originating one or both of two more serious consequences: graft loss and death due to cardiorenal complications. In the past decades, there has been a manifest change in attitude toward transplantation, with particular attention to long-term kidney function and overall quality of life. In this context, the search for better renoprotective post-KTx therapies should continue, and new options have been tested. Paricalcitol (19-nor-1,25-hydroxyvitamin D2) is an active non-hypercalcemic vitamin D analog that, besides the expected regulation of calcium and phosphate levels and the control of bone metabolism, plays a role in protection from progressive renal dysfunction. Recent studies have indicated that vitamin D analogs are able to reduce proteinuria in chronic kidney disease patients apart from the beneficial effects on mineral metabolism, further demonstrating an inhibitory action on the RAAS and anti-inflammatory and immunomodulator properties.7.Li M. Batuman V. Vitamin D: a new hope for chronic kidney disease?.Kidney Int. 2009; 76: 1219-1221Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar,8.Doorenbos C.R. van den Born J. Navis G. et al.Possible renoprotection by vitamin D in chronic renal disease: beyond mineral metabolism.Nat Rev Nephrol. 2009; 5: 691-700Crossref PubMed Scopus (87) Google Scholar Thus, paricalcitol has been viewed as a new hope in nephropathy, but the exact mechanisms underlying the protective action remain to be fully elucidated. Park et al. previously reported a renoprotective effect of paricalcitol in gentamicin-induced nephrotoxicity in rats9.Park J.W. Bae E.H. Kim I.J. et al.Renoprotective effects of paricalcitol on gentamicin-induced kidney injury in rats.Am J Physiol Renal Physiol. 2010; 298: F301-F313Crossref PubMed Scopus (57) Google Scholar and have now tested whether identical action could be replicated in a model of CsA-induced kidney injury, focusing on hypothetical anti-inflammatory, antiproliferative, and antiapoptotic effects. The nephropathy model studied was characterized by a functional impairment and structural damage, accompanied by markers of inflammation. The authors proposed that the renoprotective activity of paricalcitol was due to inhibition of nuclear factor-κB and nitric oxide (NO) signaling and that this anti-inflammatory action further causes reduction of TGF-β1 expression and the restoration of renal tubular-cell damage. According to the authors, on the basis of the data of their study, the inhibition of TGF-β1 pathways by paricalcitol, due to prevention of CsA-induced TGF-β1 expression and TGF-β1-induced Smad-2/3 and mitogen-activated protein kinase signaling, might be responsible for the attenuation of CsA-induced renal tubular-cell apoptosis and fibrosis.6.Park J.W. Bae E.H. Kim I.J. et al.Paricalcitol attenuates cyclosporine-induced kidney injury in rats.Kidney Int. 2010; 77: 1076-1085Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar These findings suggest that the restoration of renal functional parameters and structural changes by paricalcitol may in part be due to the abolishment of inflammatory, fibrotic, and apoptotic responses (Figure 1a). Since several mechanisms underlying the attenuation by paricalcitol of gentamicin-induced kidney injury in rats9.Park J.W. Bae E.H. Kim I.J. et al.Renoprotective effects of paricalcitol on gentamicin-induced kidney injury in rats.Am J Physiol Renal Physiol. 2010; 298: F301-F313Crossref PubMed Scopus (57) Google Scholar are the same as those proposed for the prevention of CIN,6.Park J.W. Bae E.H. Kim I.J. et al.Paricalcitol attenuates cyclosporine-induced kidney injury in rats.Kidney Int. 2010; 77: 1076-1085Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar paricalcitol might be better viewed as a general renoprotector, and other therapeutic strategies with higher specificity to CsA nephrotoxicity might be needed. Although an ample characterization of the model was performed, vitamin D levels were not addressed, which might be relevant when a vitamin D analog is used as pharmacological treatment. Similar confirmation should be performed in KTx patients under CsA-based immunosuppressive therapy, in order to estimate whether vitamin D suppression is a key factor for the kidney injury and, consequently, a feasible target for renoprotective pharmacological post-transplantation therapy. Furthermore, as a complement to the study by Park et al.,6.Park J.W. Bae E.H. Kim I.J. et al.Paricalcitol attenuates cyclosporine-induced kidney injury in rats.Kidney Int. 2010; 77: 1076-1085Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar the protective role of paricalcitol against other relevant contributors to CIN might also be estimated, including: the well-accepted renal vascular impairment due to increased vasoconstrictors, such as thromboxane A2 and endothelin 1, and/or decreased vasodilators, such as prostacyclin and NO; oxidative stress, namely through inducible NO synthase production of NO that will react with superoxide (O2·−), thus generating peroxynitrite (ONOO−), a deleterious reactive species; the activity of the RAAS, particularly due to angiotensin II overproduction and/or overactivity; and the activity of the sympathetic nervous system, via noradrenaline and adrenaline production and reactivity (Figure 1b). According to several previous reports in experimental models and in humans, these are pivotal factors for CsA-induced nephrotoxicity and, thus, deserve better clarification.10.McNally P.G. Feehally J. Pathophysiology of cyclosporin A nephrotoxicity: experimental and clinical observations.Nephrol Dial Transplant. 1992; 7: 791-804PubMed Google Scholar In conclusion, the efficacy of paricalcitol in the prevention and attenuation of CsA-induced nephrotoxicity needs to be confirmed by more ample research in animal models in order for it to be further considered as suitable for study in prospective randomized trials. At the very least, urologists and nephrologists need to be aware of the potential renoprotective effects of paricalcitol against CIN, and preclinical data, such as those reported by Park et al.,6.Park J.W. Bae E.H. Kim I.J. et al.Paricalcitol attenuates cyclosporine-induced kidney injury in rats.Kidney Int. 2010; 77: 1076-1085Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar must be considered in the design of clinical trials in post-transplantation CsA-induced kidney injury. The author declared no competing interests.
Referência(s)