Non-immune interventions to protect kidney allografts in the long term
2010; Elsevier BV; Volume: 78; Linguagem: Inglês
10.1038/ki.2010.427
ISSN1523-1755
AutoresPaolo Cravedi, Norberto Perico, Giuseppe Remuzzi,
Tópico(s)Neurological Complications and Syndromes
ResumoChronic rejection, the primary cause of late renal allograft loss, results from a complex interplay between immunological and non-immunological factors. During the past few decades, transplant research has focused almost exclusively on identifying more powerful and minimally toxic immunosuppressive strategies to prevent acute rejection and alloimmune response toward the graft, whereas poor attention has been paid to non-immunological factors. However, the discrepancy between remarkable improvements in the prevention of acute rejection and failure to ameliorate long-term graft outcomes suggests that non-immunological injuries may have an important role in the progressive loss of graft function. As kidney graft resembles the remnant kidney, in which a low nephron mass initiates a self-perpetuating process of progressive renal function loss, the same therapeutic tools able to retard progression of chronic renal disease are expected to be effective in kidney transplant patients as well. Indeed, high blood pressure (BP) levels, along with increased urinary protein excretion and hyperlipidemia, have been associated with reduced graft survival. Hence, strict BP control, renin–angiotensin system blockade to reduce proteinuria, and statins for hyperlipidemia control should probably represent the standard of care for kidney transplant patients. Furthermore, a multimodal nephroprotective strategy that includes smoking cessation, and tight glucose control for diabetes, might eventually be crucial to improve long-term graft outcomes. Chronic rejection, the primary cause of late renal allograft loss, results from a complex interplay between immunological and non-immunological factors. During the past few decades, transplant research has focused almost exclusively on identifying more powerful and minimally toxic immunosuppressive strategies to prevent acute rejection and alloimmune response toward the graft, whereas poor attention has been paid to non-immunological factors. However, the discrepancy between remarkable improvements in the prevention of acute rejection and failure to ameliorate long-term graft outcomes suggests that non-immunological injuries may have an important role in the progressive loss of graft function. As kidney graft resembles the remnant kidney, in which a low nephron mass initiates a self-perpetuating process of progressive renal function loss, the same therapeutic tools able to retard progression of chronic renal disease are expected to be effective in kidney transplant patients as well. Indeed, high blood pressure (BP) levels, along with increased urinary protein excretion and hyperlipidemia, have been associated with reduced graft survival. Hence, strict BP control, renin–angiotensin system blockade to reduce proteinuria, and statins for hyperlipidemia control should probably represent the standard of care for kidney transplant patients. Furthermore, a multimodal nephroprotective strategy that includes smoking cessation, and tight glucose control for diabetes, might eventually be crucial to improve long-term graft outcomes. A recent analysis of the US Transplantation Data, united Network for Organ Sharing Renal Transplant Registry database including more than 138,000 cases showed that, despite remarkable improvements in short-term graft outcomes, the graft loss rate after the first year posttransplant has not remarkably changed over the last 10 years.1Kaneku H.K. Terasaki P.I. Thirty year trend in kidney transplants: UCLA and UNOS Renal Transplant Registry.Clin Transpl. 2006; : 1-27PubMed Google Scholar Thus, prolonging survival of kidney graft in the long term is the major task of modern transplant medicine. Most grafts fail after a period of progressive function loss, the histological counterpart of which is represented by glomerulosclerosis, tubular atrophy, interstitial fibrosis, and arteriosclerosis.1Kaneku H.K. Terasaki P.I. Thirty year trend in kidney transplants: UCLA and UNOS Renal Transplant Registry.Clin Transpl. 2006; : 1-27PubMed Google Scholar Apparently, the natural history of this process has not been significantly modified by the development of more potent and selective immunosuppressive strategies, suggesting that other factors beside immunologic ones may adversely affect long-term graft outcome.2Remuzzi G. Perico N. Protecting single-kidney allografts from long-term functional deterioration.J Am Soc Nephrol. 1998; 9: 1321-1332PubMed Google Scholar Functional and structural changes of chronic renal allograft failure share similarities with those observed in other forms of chronic progressive kidney disease, in which decline of functioning nephron mass has been considered the key event. Indeed, transplantation of a single kidney supplies only half the number of nephrons commonly available to a healthy subject. This implies an increased workload per nephron to maintain body homeostasis.2Remuzzi G. Perico N. Protecting single-kidney allografts from long-term functional deterioration.J Am Soc Nephrol. 1998; 9: 1321-1332PubMed Google Scholar,3Brenner B.M. Nephron adaptation to renal injury or ablation.Am J Physiol. 1985; 249: F324-F337PubMed Google Scholar Indeed, reductions in nephron number below 50% may induce glomerular hypertension and hyperfiltration in surviving units, which in turn leads to graft injury.4Azuma H. Nadeau K. Mackenzie H.S. et al.Nephron mass modulates the hemodynamic, cellular, and molecular response of the rat renal allograft.Transplantation. 1997; 63: 519-528Crossref PubMed Scopus (112) Google Scholar The transplanted kidney is also subject to further reduction in the pool of functioning nephrons due to surgical and ischemic injury, acute rejection,2Remuzzi G. Perico N. Protecting single-kidney allografts from long-term functional deterioration.J Am Soc Nephrol. 1998; 9: 1321-1332PubMed Google Scholar and chronic toxicity of calcineurin5Naesens M. Kuypers D.R. Sarwal M. Calcineurin inhibitor nephrotoxicity.Clin J Am Soc Nephrol. 2009; 4: 481-508Crossref PubMed Scopus (1004) Google Scholar and mammalian target of rapamycine (mTOR) inhibitors.6Tomlanovich S.J. Vincenti F. Sirolimus: defining nephrotoxicity in the renal transplant recipient.Clin J Am Soc Nephrol. 2007; 2: 198-199Crossref PubMed Scopus (20) Google Scholar This sequence of events resembles the self-perpetuating cycle responsible for progressive renal failure in experimental models of reduced nephron number and in patients with chronic kidney disease.7Remuzzi G. Benigni A. Remuzzi A. Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes.J Clin Invest. 2006; 116: 288-296Crossref PubMed Scopus (510) Google Scholar Thus, taking advantage of strategies developed to preserve renal function in patients with chronic kidney disease7Remuzzi G. Benigni A. Remuzzi A. Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes.J Clin Invest. 2006; 116: 288-296Crossref PubMed Scopus (510) Google Scholar might be crucial to improve renal graft outcome in the long term. Hypertension is frequent among renal transplant recipients and can be observed even starting from the first week after transplantation, when the doses of immunosuppressive agents such as steroids and calcineurin inhibitors are usually high.8Tedla F. Hayashi R. McFarlane S.I. et al.Hypertension after renal transplant.J Clin Hypertens (Greenwich). 2007; 9: 538-545Crossref PubMed Scopus (15) Google Scholar The prevalence of hypertension in the pre-cyclosporine (CsA) era ranged between 40 and 60% (ref. 9Kasiske B.L. Vazquez M.A. Harmon W.E. et al.Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation.J Am Soc Nephrol. 2000; 15: S1-S86Google Scholar) and, after the introduction of CsA in the mid-1980s, it increased up to 80–90%.10Schwenger V. Zeier M. Ritz E. Hypertension after renal transplantation.Curr Hypertens Rep. 2001; 3: 434-439Crossref PubMed Scopus (31) Google Scholar,11Curtis J.J. Cyclosporine and posttransplant hypertension.J Am Soc Nephrol. 1992; 2: S243-S245PubMed Google Scholar A retrospective analysis on 277 kidney transplant recipients showed that each 10-mm Hg increase in either systolic or diastolic blood pressure (BP) at 1 year after transplant had an independent negative effect on graft survival.12Mange K.C. Cizman B. Joffe M. et al.Arterial hypertension and renal allograft survival.JAMA. 2000; 283: 633-638Crossref PubMed Scopus (263) Google Scholar Nevertheless, there are no randomized, controlled trials comparing different antihypertensive drugs or optimal BP goals in transplant recipients. On the basis of large clinical trials in non-transplant patients with and without kidney disease, the Kidney Disease Outcomes Quality Initiative guidelines recommend BP goals of 125/75 mm Hg for transplant recipients with proteinuria and 130/85 mm Hg in the absence of proteinuria.13Bakris G.L. Williams M. Dworkin L. et al.Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group.Am J Kidney Dis. 2000; 36: 646-661Abstract Full Text Full Text PDF PubMed Scopus (1240) Google Scholar Treatment should start with non-pharmacologic interventions—such as weight reduction, exercise, smoking cessation, and dietary sodium restriction—but simultaneous initiation of non-pharmacologic and pharmacologic treatment is frequently required to reach target levels.13Bakris G.L. Williams M. Dworkin L. et al.Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group.Am J Kidney Dis. 2000; 36: 646-661Abstract Full Text Full Text PDF PubMed Scopus (1240) Google Scholar,14Svetkey L.P. Erlinger T.P. Vollmer W.M. et al.Effect of lifestyle modifications on blood pressure by race, sex, hypertension status, and age.J Hum Hypertens. 2005; 19: 21-31Crossref PubMed Scopus (142) Google Scholar The choice among different classes of antihypertensive agents generally depends on the individual patient. The use of calcium channel blockers is often considered a first-line therapy, especially early after transplant, because they are effective in counteracting the vasoconstrictive effects of high-dose calcineurin inhibitors given peri-transplantation.15Harper S.J. Moorhouse J. Veitch P.S. et al.Nifedipine improves immediate, and 6- and 12-month graft function in cyclosporin A (CyA) treated renal allograft recipients.Transpl Int. 1992; 5: S69-S72PubMed Google Scholar However, considering that the new immunosuppressive regimens are employing CsA and tacrolimus doses remarkably lower than in the past, the main indication for the chronic use of dihydropiridinic-calcium channel blocker is no longer present.16Ekberg H. Tedesco-Silva H. Demirbas A. et al.Reduced exposure to calcineurin inhibitors in renal transplantation.N Engl J Med. 2007; 357: 2562-2575Crossref PubMed Scopus (1437) Google Scholar Conversely, in proteinuric chronic kidney disease patients dihydropiridinic-calcium channel blocker has been associated with increased risk of renal disease progression and death, thus should not be considered as the ideal therapy for BP control in the long term.17Wright Jr, J.T. Bakris G. Greene T. et al.Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial.JAMA. 2002; 288: 2421-2431Crossref PubMed Scopus (1629) Google Scholar,18Agodoa L.Y. Appel L. Bakris G.L. et al.Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial.JAMA. 2001; 285: 2719-2728Crossref PubMed Scopus (858) Google Scholar The use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in renal transplant recipients is now more frequent than in the past.19Ram C.V. Angiotensin receptor blockers: current status and future prospects.Am J Med. 2008; 121: 656-663Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar The cardioprotective and renoprotective effects of renin–angiotensin system (RAS) blockade in the general population20Braunwald E. Domanski M.J. Fowler S.E. et al.Angiotensin-converting-enzyme inhibition in stable coronary artery disease.N Engl J Med. 2004; 351: 2058-2068Crossref PubMed Scopus (1023) Google Scholar and in patients with chronic kidney disease21Ruggenenti P. Perna A. Mosconi L. et al.Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia).Lancet. 1997; 349: 1857-1863Abstract Full Text Full Text PDF PubMed Scopus (1744) Google Scholar make the use of these agents attractive in the renal transplant recipients, although data in this clinical setting are limited so far. Moreover, a particular caution should be taken when using these agents in kidney transplant patients, as in the presence of artery stenosis of the graft the use of RAS inhibitors may dramatically increase the risk of kidney function impairment and hyperkalemia.22Salzberg D.J. Is RAS blockade routinely indicated in hypertensive kidney transplant patients?.Curr Hypertens Rep. 2007; 9: 422-429Crossref PubMed Scopus (6) Google Scholar In renal transplant recipients, however, the multifactorial nature of hypertension often requires multiple drugs, including α- or β-blockers, centrally acting drugs, and also diuretics.9Kasiske B.L. Vazquez M.A. Harmon W.E. et al.Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation.J Am Soc Nephrol. 2000; 15: S1-S86Google Scholar,23Ojo A.O. Cardiovascular complications after renal transplantation and their prevention.Transplantation. 2006; 82: 603-611Crossref PubMed Scopus (352) Google Scholar The prevalence of proteinuria in kidney transplant patients ranges between 10 and 25%.9Kasiske B.L. Vazquez M.A. Harmon W.E. et al.Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation.J Am Soc Nephrol. 2000; 15: S1-S86Google Scholar The three most common causes of persistent proteinuria after kidney transplantation are chronic graft injury, recurrent glomerulonephritis, and drug-related nephrotoxicity.24Bear R.A. Aprile M. Sweet J. et al.Proteinuria in renal transplant recipients: incidence, cause, prognostic importance.Transplant Proc. 1988; 20: 1235-1236PubMed Google Scholar Calcineurin inhibitors have been considered as the immunosuppressive drugs with the highest risk of nephrotoxicity; hence, mTOR inhibitors were thought to be an alternative to prevent acute rejection without exposing patient to drug-induced renal injury.25Morath C. Arns W. Schwenger V. et al.Sirolimus in renal transplantation.Nephrol Dial Transplant. 2007; 22: viii61-viii65Crossref PubMed Scopus (95) Google Scholar Recently, however, growing evidence has suggested a potential nephrotoxicity also with mTOR inhibitors. Indeed, they have been associated with an increased risk of proteinuria, possibly resulting from a direct toxicity on glomerular and tubular epithelial cells.6Tomlanovich S.J. Vincenti F. Sirolimus: defining nephrotoxicity in the renal transplant recipient.Clin J Am Soc Nephrol. 2007; 2: 198-199Crossref PubMed Scopus (20) Google Scholar Independently from its origin, proteinuria represents a strong independent risk factor for graft loss.24Bear R.A. Aprile M. Sweet J. et al.Proteinuria in renal transplant recipients: incidence, cause, prognostic importance.Transplant Proc. 1988; 20: 1235-1236PubMed Google Scholar Indeed, it is not only a marker of progressive renal injury, but it also contributes to progression of kidney dysfunction and fibrosis through aberrant proximal tubule protein uptake and direct tubular cell toxicity.7Remuzzi G. Benigni A. Remuzzi A. Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes.J Clin Invest. 2006; 116: 288-296Crossref PubMed Scopus (510) Google Scholar Drugs that interfere with the RAS have been shown to be superior to non-RAS inhibitors in reducing proteinuria and progression of renal disease in experimental models of renal mass reduction and in patients with chronic nephropathies.7Remuzzi G. Benigni A. Remuzzi A. Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes.J Clin Invest. 2006; 116: 288-296Crossref PubMed Scopus (510) Google Scholar Intriguingly, RAS inhibitor therapy may exert renoprotection independently from its effect on proteinuria. Indeed, AT1 receptors mediate inflammation and are involved in the profibrotic action exhibited by potent cytokines.26Ruiz-Ortega M. Ruperez M. Esteban V. et al.Angiotensin II: a key factor in the inflammatory and fibrotic response in kidney diseases.Nephrol Dial Transplant. 2006; 21: 16-20Crossref PubMed Scopus (275) Google Scholar Angiotensin II is also synthesized by the proximal renal tubule cells and exhibits powerful hemodynamic and non-hemodynamic effects,27Brewster U.C. Perazella M.A. The renin-angiotensin-aldosterone system and the kidney: effects on kidney disease.Am J Med. 2004; 116: 263-272Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar all implicated in the progression of chronic kidney disease. Similarities between remnant kidney models, chronic kidney disease and transplant nephropathy represent a strong background for the use of RAS inhibitors to protect renal function also in transplantation. In a model of chronic renal transplant rejection in the rat, therapy with angiotensin-converting enzyme inhibitor trandolapril induced complete normalization of graft function and partial remission of proteinuria, as well as stabilized kidney structural changes even if started late in the course of the disease (Figure 1).28Noris M. Mister M. Pezzotta A. et al.ACE inhibition limits chronic injury of kidney transplant even with treatment started when lesions are established.Kidney Int. 2003; 64: 2253-2261Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar These effects were associated with reduced allograft infiltrates and attenuated expression of molecules involved in macrophage and lymphocyte recruitment.28Noris M. Mister M. Pezzotta A. et al.ACE inhibition limits chronic injury of kidney transplant even with treatment started when lesions are established.Kidney Int. 2003; 64: 2253-2261Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar A recent analysis of 2031 patients, who received their first renal allograft at the Medical University of Vienna between 1990 and 2003, showed that RAS inhibitor therapy was associated with a significantly higher patient (74 versus 53%, P<0.001) and graft (59 versus 43%, P=0.002) survival at 10 years after transplant as compared with non-RAS inhibitor therapy.29Heinze G. Mitterbauer C. Regele H. et al.Angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor antagonist therapy is associated with prolonged patient and graft survival after renal transplantation.J Am Soc Nephrol. 2006; 17: 889-899Crossref PubMed Scopus (218) Google Scholar This is at variance with a previous systematic review of 21 studies consisting of 1549 patients on the effect of RAS inhibitor therapy after kidney transplantation that failed to show any beneficial effect on patient and graft survival over a median follow-up of 27 months.30Hiremath S. Fergusson D. Doucette S. et al.Renin angiotensin system blockade in kidney transplantation: a systematic review of the evidence.Am J Transplant. 2007; 7: 2350-2360Crossref PubMed Scopus (147) Google Scholar However, it clearly pointed out the remarkably good safety profile of this therapy in recipients of a kidney transplant as well.30Hiremath S. Fergusson D. Doucette S. et al.Renin angiotensin system blockade in kidney transplantation: a systematic review of the evidence.Am J Transplant. 2007; 7: 2350-2360Crossref PubMed Scopus (147) Google Scholar Of note, angiotensin receptor blockers may be particularly effective in those renal transplant patients who develop AT1 receptor-activating antibodies that may represent a risk factor for acute vascular rejection.31Dragun D. Muller D.N. Brasen J.H. et al.Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection.N Engl J Med. 2005; 352: 558-569Crossref PubMed Scopus (679) Google Scholar To better define whether RAS inhibitor therapy may reduce mortality and prolong allograft survival in renal transplant recipients, the Canadian angiotensin-converting enzyme inhibitor trial (ISRCTN-78129473) will randomize in a blinded manner 528 kidney transplant patients with proteinuria and an estimated glomerular filtration rate between 20 and 55 ml/min per 1.73 m2 to either ramipril or placebo. The primary outcome will be a composite measure incorporating doubling of serum creatinine, end-stage renal disease, or death. Results from this trial will provide crucial information on management of kidney transplant patients with proteinuria by RAS blockade.32Knoll G.A. Cantarovitch M. Cole E. et al.The Canadian ACE-inhibitor trial to improve renal outcomes and patient survival in kidney transplantation—study design.Nephrol Dial Transplant. 2008; 23: 354-358Crossref PubMed Scopus (46) Google Scholar Hyperlipidemia is a frequent finding in kidney transplant recipients, affecting ∼60% of patients.9Kasiske B.L. Vazquez M.A. Harmon W.E. et al.Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation.J Am Soc Nephrol. 2000; 15: S1-S86Google Scholar Its pathogenesis is multifactorial and includes posttransplantation weight gain and the use of immunosuppressive drugs, such as mTOR inhibitors and steroids.33Tsimihodimos V. Dounousi E. Siamopoulos K.C. Dyslipidemia in chronic kidney disease: an approach to pathogenesis and treatment.Am J Nephrol. 2008; 28: 958-973Crossref PubMed Scopus (107) Google Scholar Notably, higher triglyceride levels have been associated with poorer graft outcomes.34Del Castillo D. Cruzado J.M. Manel Diaz J. et al.The effects of hyperlipidaemia on graft and patient outcome in renal transplantation.Nephrol Dial Transplant. 2004; 19: iii67-iii71PubMed Google Scholar Therapeutic agents to control low-density lipoprotein cholesterol and triglycerides include statins as well as fenofibrates. Intriguingly, statins have been implicated as nephroprotective agents beyond their lipid-lowering ability because of their potential to regulate fibrogenic mechanisms, as well as their impact on endothelial dysfunction.35Perico N. Benigni A. Remuzzi G. Present and future drug treatments for chronic kidney diseases: evolving targets in renoprotection.Nat Rev Drug Discov. 2008; 7: 936-953Crossref PubMed Scopus (81) Google Scholar The Assessment of Lescol in Renal Transplantation (ALERT) trial randomized 2102 renal transplant recipients with total cholesterol 156–351 mg/dl to fluvastatin or placebo over a 5-year follow-up period. Treatment was safe and effective in lowering total and low-density lipoprotein cholesterol.36Holdaas H. Fellstrom B. Jardine A.G. et al.Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial.Lancet. 2003; 361: 2024-2031Abstract Full Text Full Text PDF PubMed Scopus (798) Google Scholar Moreover, although the trial had insufficient power to detect a significant reduction in the primary end point of cardiac death, non-fatal myocardial infarction, or coronary intervention procedure, there was a significant 35% reduction in the secondary end point of cardiac death and non-fatal myocardial infarction with fluvastatin.36Holdaas H. Fellstrom B. Jardine A.G. et al.Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial.Lancet. 2003; 361: 2024-2031Abstract Full Text Full Text PDF PubMed Scopus (798) Google Scholar The treatment, however, had no effect on graft survival or function.37Fellstrom B. Holdaas H. Jardine A.G. et al.Effect of fluvastatin on renal end points in the Assessment of Lescol in Renal Transplant (ALERT) trial.Kidney Int. 2004; 66: 1549-1555Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar Yet, a recent randomized controlled study in 89 kidney transplant recipients showed a beneficial effect of fluvastatin (80 mg/day) over placebo on the incidence of transplant vasculopathy (7 versus 33%; P=0.02) over 6-month follow-up.38Seron D. Oppenheimer F. Pallardo L.M. et al.Fluvastatin in the prevention of renal transplant vasculopathy: results of a prospective, randomized, double-blind, placebo-controlled trial.Transplantation. 2008; 86: 82-87Crossref PubMed Scopus (23) Google Scholar Intriguingly, experimental and clinical evidence suggest that statins may have an additive beneficial effect with RAS inhibitors on kidney graft outcomes.35Perico N. Benigni A. Remuzzi G. Present and future drug treatments for chronic kidney diseases: evolving targets in renoprotection.Nat Rev Drug Discov. 2008; 7: 936-953Crossref PubMed Scopus (81) Google Scholar However, a clear role for lowering lipid levels in renoprotection cannot be discerned until large, randomized controlled trials are conducted. As such, prevention of cardiovascular disease remains the primary goal of lipid management in renal transplantation. Compliance with the immunosuppressive regimen is a major issue for many transplant patients and might account for late acute rejection episodes and graft loss. Indeed, non-compliance to immunosuppressive medications has been reported up to 22–48% (refs 39Chisholm M.A. Identification of medication-adherence barriers and strategies to increase adherence in recipients of renal transplants.Manag Care Interface. 2004; 17: 44-48PubMed Google Scholar,40Vlaminck H. Maes B. Evers G. et al.Prospective study on late consequences of subclinical non-compliance with immunosuppressive therapy in renal transplant patients.Am J Transplant. 2004; 4: 1509-1513Crossref PubMed Scopus (175) Google Scholar). Causes of non-compliance may include forgetfulness, lack of knowledge about new drug modifications, and patient's beliefs about the effectiveness of immunosuppressants and their concerns about their side effects.41Gheith O.A. El-Saadany S.A. Abuo Donia S.A. et al.Compliance of kidney transplant patients to the recommended lifestyle behaviours: single centre experience.Int J Nurs Pract. 2008; 14: 398-407Crossref PubMed Scopus (7) Google Scholar Thus, a clear explanation of therapy rationale is crucial in improving patients' compliance and transplant outcomes. Costs for therapy represent another important hurdle to patient compliance. In a large cohort of kidney transplant recipients, 42% were smokers at the time of transplantation and 12% continued thereafter.42Yavuz A. Tuncer M. Gurkan A. et al.Cigarette smoking in renal transplant recipients.Transplant Proc. 2004; 36: 108-110Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar In light of high cardiovascular risk of this patient population, health education programs should further stress this point. Moreover, evidence exists that smoke habit is associated with reduced renal survival in general population and in transplant patients.43Mercado C. Jaimes E.A. Cigarette smoking as a risk factor for atherosclerosis and renal disease: novel pathogenic insights.Curr Hypertens Rep. 2007; 9: 66-72Crossref PubMed Scopus (55) Google Scholar Another important tool to improve patient and graft outcomes is physical activity. However, only a minority of kidney transplant patients practices regular exercise.41Gheith O.A. El-Saadany S.A. Abuo Donia S.A. et al.Compliance of kidney transplant patients to the recommended lifestyle behaviours: single centre experience.Int J Nurs Pract. 2008; 14: 398-407Crossref PubMed Scopus (7) Google Scholar Along the same line, the importance of dietary advice should be pointed out,44Martins C. Pecoits-Filho R. Riella M.C. Nutrition for the post-renal transplant recipients.Transplant Proc. 2004; 36: 1650-1654Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar considering the high diabetogenic effects of steroids, calcineurin inhibitors and, possibly, also of mTOR inhibitors,45Johnston O. Rose C.L. Webster A.C. et al.Sirolimus is associated with new-onset diabetes in kidney transplant recipients.J Am Soc Nephrol. 2008; 19: 1411-1418Crossref PubMed Scopus (313) Google Scholar and the negative impact of posttransplant diabetes mellitus on patient and graft outcomes.46Sezer S. Akgul A. Altinoglu A. et al.Posttransplant diabetes mellitus: impact of good blood glucose regulation on renal transplant recipient outcome.Transplant Proc. 2006; 38: 533-536Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar In patients with chronic proteinuric nephropathies, multimodal therapy, including maximized RAS inhibition and BP control, along with the use of statins stabilized renal function decline that was otherwise predicted to invariably progress toward end-stage renal failure.47Ruggenenti P. Perticucci E. Cravedi P. et al.Role of remission clinics in the longitudinal treatment of CKD.J Am Soc Nephrol. 2008; 19: 1213-1224Crossref PubMed Scopus (177) Google Scholar Similarities between chronic graft injury and chronic renal disease suggest that the same therapeutic tools effective in retarding renal disease progression could be effective in improving outcomes of kidney grafts as well. Thus, a multifactorial therapeutic approach, including optimal control of hypertension, proteinuria, and dyslipidemia, could also be used for kidney transplant patients with chronic graft injury, although evidence from formal trials in this patient population is still limited. Transplant practitioners should maximize metabolic control in primary diabetic patients and in those with posttransplant diabetes mellitus. Finally, patients should be warned of the importance of having a lifestyle that includes physical activity and avoidance of smoking, especially in light of their cardiovascular risk, that is around 50-fold higher than the one of healthy subjects (Figure 2).23Ojo A.O. Cardiovascular complications after renal transplantation and their prevention.Transplantation. 2006; 82: 603-611Crossref PubMed Scopus (352) Google Scholar
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