Chronic allograft nephropathy: An update
1999; Elsevier BV; Volume: 56; Issue: 3 Linguagem: Inglês
10.1046/j.1523-1755.1999.00611.x
ISSN1523-1755
Autores Tópico(s)Organ Transplantation Techniques and Outcomes
ResumoChronic allograft nephropathy: An update.Chronic allograft nephropathy is the most prevalent cause of renal transplant failure in the first post-transplant decade, but its pathogenesis has remained elusive. Clinically, it is characterized by a slow but variable loss of function, often in combination with proteinuria and hypertension. The histopathology is also not specific, but transplant glomerulopathy and multilayering of the peritubular capillaries are highly characteristic. Several risk factors have been identified, such as advanced donor age, delayed graft function, repeated acute rejection episodes, vascular rejection episodes, and rejections that occur late after transplantation. A common feature of chronic allograft nephropathy is that it develops in grafts that have undergone previous damage, although the mechanism(s) responsible for the progressive fibrosis and tissue remodeling has not yet been defined. Hypotheses to explain chronic allograft nephropathy include the immunolymphatic theory, the cytokine excess theory, the loss of supporting architecture theory, and the premature senescence theory. The most effective option to prevent chronic allograft nephropathy is to avoid graft injury from both immune and nonimmune mechanisms. Chronic allograft nephropathy is the most prevalent cause of renal transplant failure in the first post-transplant decade, but its pathogenesis has remained elusive. Clinically, it is characterized by a slow but variable loss of function, often in combination with proteinuria and hypertension. The histopathology is also not specific, but transplant glomerulopathy and multilayering of the peritubular capillaries are highly characteristic. Several risk factors have been identified, such as advanced donor age, delayed graft function, repeated acute rejection episodes, vascular rejection episodes, and rejections that occur late after transplantation. A common feature of chronic allograft nephropathy is that it develops in grafts that have undergone previous damage, although the mechanism(s) responsible for the progressive fibrosis and tissue remodeling has not yet been defined. Hypotheses to explain chronic allograft nephropathy include the immunolymphatic theory, the cytokine excess theory, the loss of supporting architecture theory, and the premature senescence theory. The most effective option to prevent chronic allograft nephropathy is to avoid graft injury from both immune and nonimmune mechanisms. Interest in late renal transplant loss has increased substantially as it has become evident that improvements in the one-year graft survival rate have not resulted in decreased graft attrition after the first year1.Gjertson D.W. Survival trends in long-term first cadaver-donor kidney transplants.in: Terasaki P.I. Cecka J.M. Clinical Transplants 1991. UCLA Tissue Typing Laboratory, Los Angeles1991: 225Google Scholar. Up to 40% of grafts develop progressive dysfunction after the initial few post-transplant months and ultimately fail within a decade, despite the use of immunosuppressive drugs in doses sufficient to prevent acute rejection2.Paul L.C. Chronic renal transplant loss.Kidney Int. 1995; 47: 1491-1499Abstract Full Text PDF PubMed Scopus (216) Google Scholar. This form of graft failure has been called chronic rejection3.Schweitzer E.J. Matas A.J. Gillingham K.J. Payne W.D. Gores P.F. Dunn D.L. Sutherland D.E.R. Najarian J.S. Causes of renal allograft loss: Progress in the 1980, challenges for the 1990s.Ann Surg. 1991; 214: 679-688Crossref PubMed Scopus (168) Google Scholar, however, immune and nonimmune factors are involved in its pathogenesis4.Tilney N.L. Paul L.C. Antigen-independent events leading to chronic graft dysfunction.in: Tilney N.L. Strom T.B. Paul L.C. Transplantation Biology: Cellular and Molecular Aspects. New York, Lippincott-Raven, Philadelphia1996: 629Google Scholar,5.Paul L.C. Tilney N.L. Alloantigen-dependent events in chronic rejection.in: Tilney N.L. Strom T.B. Paul L.C. Transplantation Biology: Cellular and Molecular Aspects. Lippincott-Raven, Philadelphia1996: 567Google Scholar, and the more neutral terms chronic allograft nephropathy or chronic allograft dysfunction have been coined. In this overview, the histopathology and risk factors of chronic allograft nephropathy are reviewed, and existing hypotheses regarding its pathophysiology are highlighted. The final section of this overview touches on the lack of effective treatment strategies to prevent or treat chronic allograft nephropathy clinically, despite the successes obtained with some treatment modalities in animal models. Chronic allograft nephropathy is characterized by a relatively slow but variable rate of decline in renal function after the initial three post-transplant months, often in combination with proteinuria and aggravation or de novo appearance of hypertension6.Paul L.C. Häyry P. Foegh M. Dennis M.J. Mihatsch M.J. Larsson E. Fellström B. Diagnostic criteria for chronic rejection/accelerated graft atherosclerosis in heart and kidney transplants: Joint proposal from the Fourth Alexis Carrel Conference on Chronic Rejection and Accelerated Arteriosclerosis in Transplanted Organs.Transplant Proc. 1993; 25: 2022-2023PubMed Google Scholar. Linear regression analysis of the reciprocal of the serum creatinine concentration over time shows progressive of loss of function in more than 80% of patients with histologically proven chronic allograft nephropathy7.Riggio R.R. Haschemeyer R. Suthanthiran M. Cheigh J. Tapia L. Stubenbord W. Miller I. Stenzel K.H. Predictability of renal allograft failure time in long-term survivors: A hypothesis.Transplant Proc. 1985; 17: 2311-2313Google Scholar,8.Kasiske B.L. Heim-Duthoy K.L. Tortorice K.L. Rao K.V. The variable nature of chronic declines in renal allograft function.Transplantation. 1991; 51: 330-334Crossref PubMed Scopus (72) Google Scholar. Twenty to 28% of patients with chronic allograft nephropathy have more than 0.5 g proteinuria per 24 hours compared with 6 to 8% of patients who do not have this condition9.Massy Z.A. Guijarro C. Wiederkehr M.R. Ma J.Z. Kasiske B.L. Chronic renal allograft rejection: Immunologic and nonimmunologic risk factors.Kidney Int. 1996; 49: 518-524Abstract Full Text PDF PubMed Scopus (300) Google Scholar. The diagnostic value of post-transplant hypertension is very limited because of its high prevalence10.Raine A.E.G. Does antihypertensive therapy modify chronic allograft failure?.Kidney Int. 1995; 48: S107-S111Google Scholar. None of these clinical manifestations are specific, and other causes of graft dysfunction such as acute rejection, drug toxicity, or glomerulonephritis need to be excluded to make the diagnosis of chronic allograft nephropathy. The histopathology of chronic allograft nephropathy is also not specific and consists of atherosclerosis, glomerular lesions and glomerular sclerosis, multilayering of the peritubular capillaries, interstitial fibrosis, and tubular atrophy. Graft atherosclerosis consists of mostly concentric intimal thickening that affects large parts of arteries and arterioles, often accompanied by a moderate degree of infiltration of the vessel wall with macrophages, lymphocytes, and, to a much lesser extent, foam cells. The intimal thickening is thought to result from the migration of (myo)fibroblasts from the media into the intima, followed by local proliferation and deposition of extracellular matrix proteins. It is difficult to predict to what extent the intimal thickening results in reduction in luminal area available for blood flow as vessels with intimal thickening undergo dilation unless there is concomitant adventitial fibrosis resulting in shrinking of the lumen11.Luo H. Nishioka T. Eigler N.L. Forrester J.S. Fishbein M.C. Berglund H. Siegel R.J. Coronary artery restenosis after balloon angioplasty in humans is associated with circumferential coronary constriction.Arterioscler Thromb Vasc Biol. 1996; 16: 1393-1398Crossref PubMed Scopus (50) Google Scholar. The glomerular lesions of chronic transplant nephropathy are variable and include wrinkling and collapse of the glomerular tuft, glomerular hypertrophy12.Barrientos A. Portoles J. Herrero J.A. Torralbo A. Prats D. Gutierrez-Millet V. Blanco J. Glomerular hyperfiltration as a nonimmunologic mechanism of progression of chronic renal rejection.Transplantation. 1994; 57: 753-756Crossref PubMed Scopus (48) Google Scholar, mesangial matrix expansion, and focal glomerulosclerosis13.Cheigh J.S. Mouradian J. Soliman M. Tapia L. Riggio R.R. Stenzel K.H. Rubin A.L. Focal segmental glomerulosclerosis in renal transplants.Am J Kidney Dis. 1983; 2: 449-455Abstract Full Text PDF PubMed Scopus (44) Google Scholar. In 1964, Hamburger, Crosnier, and Dormont described transplant glomerulopathy14.Hamburger J. Crosnier J. Dormont J.A. Observations in patients with a well tolerated homotransplanted kidney.Ann NY Acad Sci. 1964; 120: 558-577Crossref PubMed Scopus (5) Google Scholar as a lesion characterized by enlargement of the glomeruli, with swelling of the endothelial and mesangial cells, mesangiolysis, infiltration of the glomeruli with mononuclear cells, mesangial matrix expansion, and widening of the subendothelial zone with interposition of mesangial cells and matrix15.Olsen T.S. Pathology of allograft rejection.in: Burdick J.F. Racusen L.C. Solez K. Williams G.M. Kidney Transplant Rejection: Diagnosis and Treatment. Basel, Hong Kong, Marcel Dekker, New York1992: 333Google Scholar. Immunofluorescent studies of grafts with chronic allograft nephropathy show, in most cases, a nondiagnostic pattern of immunoglobulin deposition, although some cases show linear IgG deposits along the glomerular basement membrane or granular deposits of IgG or IgA in peripheral capillary loops16.Habib R. Antigua C. Hinglais N. Gagnadoux M.F. Broyer M. Glomerular lesions in the transplanted kidney in children.Am J Kidney Dis. 1987; 10: 198-207Abstract Full Text PDF PubMed Scopus (82) Google Scholar. On electron microscopic examination, circumferential multilamellation of the peritubular capillary basement membranes is found in 80% of grafts with chronic allograft nephropathy17.Monga G. Mazzucco G. Messina M. Motta M. Quaranta S. Novara R. Intertubular capillary changes in kidney allografts: A morphologic investigation on 61 renal specimens.Mod Pathol. 1992; 5: 125-130PubMed Google Scholar. Although this lesion is not specific, more than seven layers of basement membranes seem specific and are found in 38% of chronic allograft nephropathy specimens18B. Ivanyi. H. Fahmy. P. Szenohradszky. H. Hansen. S. Olsen. P. Halloran. K. Solez. Peritubular capillary basement membrane changes in chronic renal allograft rejection. Transplant Proc (in press)Google Scholar. Immunohistochemical studies have shown deposition of extracellular matrix proteins such as tenascin and the extradomain A (EDA) isoform of cellular fibronectin in the glomeruli, the vessel wall, and the interstitium19.Gould V.E. Martinez-Lacabe V. Virtanen I. Sahlin K.M. Schwartz M.M. Differential distribution of tenascin and cellular fibronectins in acute and chronic renal allograft rejection.Lab Invest. 1992; 67: 71-79PubMed Google Scholar,20.Habib R. Zurowska A. Hinglais N. Gubler M.-C. Antignac C. Niaudet P. Broyer M. Gagnadoux M.-F. A specific glomerular lesion of the graft: allograft glomerulopathy.Kidney Int. 1993; 44: S104-S111Google Scholar. These molecules are involved in tissue remodeling and are found in a variety of conditions such as acute rejection, lupus nephritis, and diabetic nephropathy21.Koukoulis G.K. Gould V.E. Bhattacharyya A. Gould J.E. Howeedy A.A. Virtanen I. Tenascin in normal, reactive, hyperplastic and neoplastic tissues: Biologic and pathologic implications.Hum Pathol. 1991; 22: 636-643Abstract Full Text PDF PubMed Scopus (200) Google Scholar. A comparison of chronic allograft nephropathy and native kidney diseases has shown that both forms of renal scarring exhibit similar extracellular matrix composition consisting of the normal basement membrane components collagen type IV, laminin, and heparan sulfate, as well as decorin and collagen type III, whereas the glomerular matrix accumulation is entirely due to increased deposition of normal glomerular extracellular matrix components22.Vleming L.-J. Baelde J.J. Westendorp R.G.J. Daha M.R. van Es L.A. Bruijn J.A. Progression of chronic renal disease in humans is associated with the deposition of basement membrane components and decorin in the interstitial extracellular matrix.Clin Nephrol. 1995; 44: 211-219PubMed Google Scholar. Thus, there seems no fundamental difference in the composition of the extracellular matrix in kidneys with native glomerular disease and chronic allograft nephropathy. However, a recent study compared kidneys with chronic allograft nephropathy and chronic cyclosporine (CsA) toxicity and found new expression of collagen type IV and laminin in the former condition and accumulation of collagens I and III in chronic CsA nephrotoxicity23.Abrass C.K. Berfield A.K. Stehman-Breen C. Alpers C.E. Davis C.L. Unique changes in interstitial extracellular matrix composition are associated with rejection and cyclosporine toxicity in human renal allograft biopsies.Am J Kidney Dis. 1999; 33: 11-20Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar. Since 1991, there have been four international meetings in Banff, Canada, to standardize renal transplant pathology interpretations and reporting to establish objective and reproducible end points for clinical trials of new antirejection agents and to guide therapy24.Solez K. Axelsen R.A. Benediktsson H. Burdick J.F. Cohen A.H. Colvin R.B. Crocker B.P. Droz D. Dunmill M.S. Halloran P.F. Häyry P. Jennette J.C. Keown P.A. Marcussen N. Mihatsch M.J. Morozami K. Myers B.D. Nast C.C. Olsen C.C. Racusen L.C. Ramos E.L. Rosen S. Sachs D.H. Salomon D.R. Sanfilippo F. Verani R. Von Willebrand E. Yamaguchi Y. International standardization of criteria for the histologic diagnosis of renal allograft rejection: The Banff 97 working classification of kidney transplant pathology.Kidney Int. 1993; 44: 411-422Abstract Full Text PDF PubMed Scopus (1228) Google Scholar, 25.Solez K. Benediktsson H. Cavallo T. Croker B. Demetris A.J. Drachenberg C. Emancipator S. Furness P.N. Gaber L.W. Gibson I.W. Gough J. Gupta R. Halloran P. Häyry P. Kashgarian M. Marcussen N. Massy Z.A. Mihatsch M.J. Morozumi K. Noronha I. Olsen S. Papadimitriou J. Paul L.C. Picken M. Report of the third Banff conference on allograft pathology (July 20-24, 1995) on classification and lesion scoring in renal allograft pathology.Transplant Proc. 1996; 28: 441-444PubMed Google Scholar, 26.Racusen L.C. Solez K. Colvin R.B. Bonsib S.M. Castro M.-C. Cavallo T. Croker B.P. Demetris A.J. Drachtenberg C.B. Fogo A.B. Furness P. Gaber L.W. Gibson I.W. Glotz D. Goldberg J.C. Grande J. Halloran P.F. Hansen H.E. Hartley B. Häyry P.J. Hill C.M. Hoffman E.O. Hunsicker L.G. Lindblad A. Marcussen N. Mihatsch M.J. Nadasdy T. Nickerson P. Olsen T.S. Papaditriou J.C. Randhawa P.S. Rayer D.C. Roberts I. Rose S. Rush D. Salinas-Madrigal L. Salomon D.R. Sund S. Taskinen E. Trpkov K. Yamaguchi Y. The Banff 97 working classification of renal allograft pathology.Kidney Int. 1999; 55: 713-723Abstract Full Text Full Text PDF PubMed Scopus (2665) Google Scholar. Although the Banff scheme has focused mainly on the classification of acute rejection based on routine light microscopy readings, the more recent versions of the scheme deal in more detail with chronic allograft nephropathy. Recognizing that tubulointerstitial changes are most accurately sampled and appear to have prognostic significance27.Nicholson M.L. Harper S.J. Wheatley T.J. McCulloch T.A. Feehally J. Furness P.N. 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The Banff 97 working classification of renal allograft pathology.Kidney Int. 1999; 55: 713-723Abstract Full Text Full Text PDF PubMed Scopus (2665) Google Scholar. An analysis of risk factors of chronic allograft nephropathy has mostly focused on postdonation events. However, donor age explains approximately 30% of the variance in graft outcome beyond one year28.Gjertson D.W. A multi-factor analysis of kidney graft outcomes at one and five years posttransplantation: 1996 UNOS update.in: Cecka J.M. Terasaki P.I. Clinical Transplants 1996. UCLA Tissue Typing Laboratory, Los Angeles1997: 343Google Scholar. An analysis by Terasaki et al using the UNOS Scientific Renal Transplant Registry data demonstrated a strong effect of donor age on long-term outcome and graft half-life29.Terasaki P.I. Gjertson D.W. Cecka J.M. Takemoto S. Cho Y.W. Significance of the donor age effect on kidney transplants.Clin Transpl. 1997; 11: 366-372PubMed Google Scholar. The authors attributed this effect to a relative deficiency in the number of nephrons vis-a-vis the recipient's metabolic demands. Transplants with prolonged ischemic exposure and delayed graft function also experience inferior long-term outcome30.Shoskes D. Cecka M. Deleterious effects of delayed graft function in cadaveric renal transplant recipients independent of acute rejection.Transplantation. 1998; 55: 1697-1701Crossref Scopus (345) Google Scholar, as do grafts that have been exposed to acute rejection episodes31.Almond P.S. Matas A. Gillingham K.J. Dunn D.L. Payne W.D. Gores P. Gruessner R. Najarian J.S. Risk factors for chronic rejection in renal allograft recipients.Transplantation. 1993; 55: 752-757Crossref PubMed Scopus (619) Google Scholar,32.Matas A.J. Gillingham K.J. Payne W.D. Najarian J.S. The impact of an acute rejection episode on long-term renal allograft survival (t1/2).Transplantation. 1994; 57: 857-859Crossref PubMed Scopus (394) Google Scholar. Repeated, severe, and prolonged acute rejection episodes32.Matas A.J. Gillingham K.J. Payne W.D. Najarian J.S. The impact of an acute rejection episode on long-term renal allograft survival (t1/2).Transplantation. 1994; 57: 857-859Crossref PubMed Scopus (394) Google Scholar, as well as rejection episodes that occur months or years after transplantation, are at a high risk of evolving into chronic allograft nephropathy9.Massy Z.A. Guijarro C. Wiederkehr M.R. Ma J.Z. Kasiske B.L. Chronic renal allograft rejection: Immunologic and nonimmunologic risk factors.Kidney Int. 1996; 49: 518-524Abstract Full Text PDF PubMed Scopus (300) Google Scholar. Approximately 50% of biopsies taken during an acute rejection episode show endarteritis, a histopathological characteristic that makes the rejection episode less responsive to steroids. Sticking of mononuclear cells to endothelial cells also correlates to steroid resistance, whereas rejection with fibrinoid necrosis does not respond to either steroids or antibodies. Therefore, acute vascular rejection and endarteritis are highly statistically adverse prognostic features compared with tubulointerstitial rejection33.Van Saase J.L.C.M. Van der Woude F.J. Thorogood J. Hollander A.A.M.J. van Es L.A. Weening J.J. van Bockel J.H. Bruijn J.A. The relation between acute vascular and interstitial renal allograft rejection and subsequent chronic rejection.Transplantation. 1995; 59: 1280-1285Crossref PubMed Scopus (172) Google Scholar,34.Nickeleit V. Vamvakas E.C. Pascual M. Poletti B.J. Colvin R.B. The prognostic significance of specific arterial lesions in acute renal allograft rejection.J Am Soc Nephrol. 1998; 9: 1301-1308PubMed Google Scholar. Other biopsy features that correlate with chronic allograft nephropathy are tissue infiltration with large numbers of monocytes or macrophages and large numbers of class II-positive tubular and interstitial cells35.Alexopoulos E. Leontsini M. Papadimitriou M. Macrophages and HLA-DR (+) cells in acutely rejecting kidney transplants predict subsequent graft survival, even after reversal of the acute episode.Nephrologie. 1998; 4: 113-117Crossref Google Scholar. Graft biopsies from patients with elevated cholesterol levels more often display more severe chronic damage than biopsies from patients with lower cholesterol levels, although not all studies have found this association36.Dimény E. Wahlberg J. Lithell H. Fellström B. Hyperlipidaemia in renal transplantation—Risk factor for long-term graft outcome.Eur J Clin Invest. 1995; 25: 574-583Crossref PubMed Scopus (84) Google Scholar,37.Brazy P.C. Pirsch J.D. Belzer F.O. Factors affecting renal allograft function in long-term recipients.Am J Kidney Dis. 1992; 19: 558-566Abstract Full Text PDF PubMed Scopus (52) Google Scholar. In multivariate analyses, hypertriglyceridemia is an independent risk factor of late graft loss9.Massy Z.A. Guijarro C. Wiederkehr M.R. Ma J.Z. Kasiske B.L. Chronic renal allograft rejection: Immunologic and nonimmunologic risk factors.Kidney Int. 1996; 49: 518-524Abstract Full Text PDF PubMed Scopus (300) Google Scholar. Recipient hypertension also portends a poorer outcome with a faster decline in function and a greater likelihood of return to dialysis compared with patients with a normal blood pressure38.Opelz G. Wujciak T. Ritz E. Collaborative Transplant Study Association of chronic kidney graft failure with recipient blood pressure.Kidney Int. 1998; 53: 217-222Abstract Full Text PDF PubMed Scopus (528) Google Scholar. Finally, impaired graft function at 6 or 12 months is also a risk factor for late graft loss39.Opelz G. Critical evaluation of the association of acute with chronic graft rejection in kidney and heart transplant recipients.Transplant Proc. 1997; 29: 73-76Abstract Full Text PDF PubMed Scopus (82) Google Scholar. Cytomegalovirus (CMV) infections enhance chronic vascular rejection in cardiac transplant patients and experimental animals; however, such a correlation has not been found in renal transplant patients9.Massy Z.A. Guijarro C. Wiederkehr M.R. Ma J.Z. Kasiske B.L. Chronic renal allograft rejection: Immunologic and nonimmunologic risk factors.Kidney Int. 1996; 49: 518-524Abstract Full Text PDF PubMed Scopus (300) Google Scholar, and studies of transplants with chronic allograft nephropathy have failed to show CMV mRNA or protein in such grafts. A multivariate analysis in our center of kidney transplants, which failed after the initial six months, identified several independent risk factors of chronic allograft nephropathy, including donor age, acute rejection history, graft function at six months, smoking, and proteinuria. In addition to these factors, it was found that sharing of broadly cross-reactive class I antigens (so-called CREGs) confers protection against late graft failure, whereas matching for human lymphocyte antigens (HLAs) had no effect (abstract; Sijpkens et al, J Am Soc Nephrol 9:699A, 1998). Another recent study separately analyzed the risk factors of tubulointerstitial fibrosis or transplant glomerulopathy and nephrotic proteinuria in patients with chronic allograft nephropathy40.Kupin W. Nakhleh R. Lee M. Venkat K.K. Goggins M. Mozes M. Escobar F. Abouljoud M. Separate risk factors for the development of transplant glomerulopathy vs chronic tubulointerstitial rejection.Transplant Proc. 1997; 29: 245-246Abstract Full Text PDF PubMed Scopus (9) Google Scholar. Significantly more black recipients, female donors, and preceding steroid sensitive-rejection episodes were found in the transplant glomerulopathy group, whereas the donor/recipient surface area ratio, a surrogate marker for donor/recipient size matching, was significantly lower compared with the patients with interstitial fibrosis, suggesting that glomerular hyperfiltration and hypertension play a role in transplant glomerulopathy40.Kupin W. Nakhleh R. Lee M. Venkat K.K. Goggins M. Mozes M. Escobar F. Abouljoud M. Separate risk factors for the development of transplant glomerulopathy vs chronic tubulointerstitial rejection.Transplant Proc. 1997; 29: 245-246Abstract Full Text PDF PubMed Scopus (9) Google Scholar. On the other hand, the degree of HLA mismatching was higher in patients with tubulointerstitial fibrosis but was not different between the transplant glomerulopathy group and control cases, supporting the supposition that immune mechanisms play a dominant role in the tubulointerstitial fibrosis of chronic allograft nephropathy. Prior to 1982, standard immunosuppression consisted of the combination of corticosteroids and azathioprine, complemented in some centers with the prophylactic use of antilymphocyte antisera in the first few post-transplant weeks. The addition of the calcineurin inhibitor CsA in the early 1980s resulted in a decreased incidence of acute rejection episodes and an improved one-year graft survival rate, but it did not seem to affect the rate of graft attrition after the first post-transplant year41.Terasaki P.I. Cecka J.M. Gjertson D.W. Cho Y. Takemoto S. Cohn M. A ten year prediction for kidney transplant survival.in: Terasaki P.I. Cecka J.M. Clinical Transplants 1992. UCLA Tissue Typing Laboratory, Los Angeles1992: 501Google Scholar. This raises the question as to whether its immunosuppressive efficacy is off-set by its nephrotoxic side-effects42.Myers B.D. Ross J. Newton L. Leutscher J. Perlroth M. Cyclosporine-associated chronic nephropathy.N Engl J Med. 1984; 311: 699-705Crossref PubMed Scopus (1045) Google Scholar, whether inadequate drug doses have been prescribed because of concerns of nephrotoxicity31.Almond P.S. Matas A. Gillingham K.J. Dunn D.L. Payne W.D. Gores P. Gruessner R. Najarian J.S. Risk factors for chronic rejection in renal allograft recipients.Transplantation. 1993; 55: 752-757Crossref PubMed Scopus (619) Google Scholar,43.Burke J.F. Pirsch J.D. Ramos E.L. Salomon D.R. Stablein D.M. Van Buren D.H. West J.C. Long-term efficacy and safety of cyclosporine in renal-transplant patients.N Engl J Med. 1994; 331: 358-363Crossref PubMed Scopus (241) Google Scholar, or whether the drug has no effect on chronic allograft nephropathy. Similar arguments can be made for the calcineurin inhibitor tacrolimus or FK-506; both CsA and tacrolimus can cause functional and histological renal impairments that are difficult to differentiate from chronic allograft nephropathy44.Randhawa P.S. Tsamandas A.C. Magnone M. Jordan M. Shapiro R. Starzl T.E. Demetris A.J. Microvascular changes in renal allografts associated with FK506 (Tacrolimus) therapy.Am J Surg Pathol. 1996; 20: 306-312Crossref PubMed Scopus (65) Google Scholar,45.Connolly J.O. Gane E. Higgins R.M. O'donnell P.J. Devlin J. Scoble J.E. Williams R. Renal arteriopathy associated with FK506 therapy following liver transplantation.Nephrol Dial Transplant. 1994; 9: 834-836PubMed Google Scholar. Glucocorticoids also accelerate the development of proteinuria and glomerulosclerosis in renal ablation models46.Garcia D.L. Rennke H.G. Brenner B.M. Anderson S. Chronic glucocorticoid therapy amplifies glomerular injury in rats with renal ablation.J Clin Invest. 1987; 80: 867-874Crossref PubMed Scopus (69) Google Scholar. Furthermore, CsA, corticosteroids, and tacrolimus aggravate hypertension, whereas the former two drugs also have detrimental effects on lipid metabolism. The lack of randomized trials with robust follow-up information makes it difficult to assess the impact of various immunosuppressive drug regimens on long-term outcome, although some information is available from registry data and mostly underpowered single-center studies. It is important to note that registry data on immunosuppressive drug therapies should be regarded with caution, as they are not derived from randomized trials and often reflect a treatment bias. In the Collaborative Transplant Study database, the five-year graft survival and projected graft half-life rates were significantly better in patients who had been switched from CsA, steroids, and azathioprine to steroid-free maintenance immunosuppression with CsA, with or without azathioprine47.Opelz G. Effect of maintenance immunosuppressive drug regimen on kidney transplant outcome.Transplantation. 1994; 58: 443-446Crossref PubMed Scopus (111) Google Scholar,48.Opelz G. Influence of treatment with cyclosporine, azathioprine and steroids on chronic allograft failure.Kidney Int. 1995; 48: S89-S92Google Scholar, suggesting that the detrimental effect of corticosteroids exceeds their potential benefit on long-term graft outcome. However, only 10% of patients reported were treated with steroid-free maintenance regimens, and it is likely that the group in whom steroids were withdrawn were mostly low-risk patients. A Canadian multicenter steroid-withdrawal study of patients treated with triple therapy found a better five-year graft survival (85%) in patients who continued on prednisone (0.3 mg/kg on alternate days) compared with 73% in patients who were treated with an “ultra-low” dose of prednisone (2 to 3 mg on alternate days) three months after transplantation. The graft survival curves of the two groups were dissociated 1.5 to 2 years after study enrollment and suggest a beneficial effect of steroids on
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