The impact of early-diagnosed new-onset post-transplantation diabetes mellitus on survival and major cardiac events
2006; Elsevier BV; Volume: 69; Issue: 3 Linguagem: Inglês
10.1038/sj.ki.5000116
ISSN1523-1755
AutoresJøran Hjelmesæth, Anders Hartmann, T. Leivestad, Hallvard Holdaas, Solbjørg Sagedal, Marte Olstad, Trond Jenssen,
Tópico(s)Transplantation: Methods and Outcomes
ResumoThe impact of early-diagnosed new-onset post-transplantation diabetes mellitus (PTDM) on cardiovascular (CV) disease is not well described. The objectives of the present prospective single-center observational study were to assess the long-term effects of early-diagnosed new-onset PTDM on major cardiac events (MCE; cardiac death or nonfatal acute myocardial infarction) and patient survival. Diabetic status and CV risk factors were assessed in 201 consecutive renal allograft recipients 3 months after transplantation (baseline) during a period of 16 months (1995–96). Follow-up data until January 1, 2004 were obtained from the Norwegian Renal Registry. The 8-year (range 7–9 years) cumulative incidence of MCEs was 7% (nine out of 138) in recipients without diabetes, 20% (seven out of 35) in patients with new-onset PTDM and 21% (six out of 28) in patients with diabetes mellitus before transplantation (DM). Proportional hazards regression analyses (forward stepwise regression) revealed that patients with PTDM had an approximately three-fold increased risk of MCEs as compared with nondiabetic patients (hazard ratio (HR)=3.27, 95% confidence interval (CI)=1.22–8.80, P=0.019). A total of 61 patients (30%) died. Eight-year patient survival was 80% in the nondiabetic group, 63% in the PTDM group and 29% in the DM group, respectively. Pretransplant diabetes (HR=5.09, 95% CI=2.60–9.96, P<0.001), age (HR=1.03, 95% CI=1.01–1.05, P=0.016), cytomegalovirus (CMV) infection (HR=2.66, 95% CI=1.27–5.53, P=0.009), and creatinine clearance (HR=0.98, 95% CI=0.96–1.00, P=0.046), but not PTDM (HR=1.20, 95% CI=0.58–2.49, P=0.621), were independent predictors of death in the multiple Cox regression model. Early-diagnosed PTDM is a predictor of MCEs, but not of all-cause mortality, the first 8 years after renal transplantation. The impact of early-diagnosed new-onset post-transplantation diabetes mellitus (PTDM) on cardiovascular (CV) disease is not well described. The objectives of the present prospective single-center observational study were to assess the long-term effects of early-diagnosed new-onset PTDM on major cardiac events (MCE; cardiac death or nonfatal acute myocardial infarction) and patient survival. Diabetic status and CV risk factors were assessed in 201 consecutive renal allograft recipients 3 months after transplantation (baseline) during a period of 16 months (1995–96). Follow-up data until January 1, 2004 were obtained from the Norwegian Renal Registry. The 8-year (range 7–9 years) cumulative incidence of MCEs was 7% (nine out of 138) in recipients without diabetes, 20% (seven out of 35) in patients with new-onset PTDM and 21% (six out of 28) in patients with diabetes mellitus before transplantation (DM). Proportional hazards regression analyses (forward stepwise regression) revealed that patients with PTDM had an approximately three-fold increased risk of MCEs as compared with nondiabetic patients (hazard ratio (HR)=3.27, 95% confidence interval (CI)=1.22–8.80, P=0.019). A total of 61 patients (30%) died. Eight-year patient survival was 80% in the nondiabetic group, 63% in the PTDM group and 29% in the DM group, respectively. Pretransplant diabetes (HR=5.09, 95% CI=2.60–9.96, P<0.001), age (HR=1.03, 95% CI=1.01–1.05, P=0.016), cytomegalovirus (CMV) infection (HR=2.66, 95% CI=1.27–5.53, P=0.009), and creatinine clearance (HR=0.98, 95% CI=0.96–1.00, P=0.046), but not PTDM (HR=1.20, 95% CI=0.58–2.49, P=0.621), were independent predictors of death in the multiple Cox regression model. Early-diagnosed PTDM is a predictor of MCEs, but not of all-cause mortality, the first 8 years after renal transplantation. Diabetes mellitus (DM) is a heterogeneous group of metabolic disorders characterized by chronic hyperglycemia, and diabetes is associated with increased risk of micro- and macrovascular complications.1.American Diabetes Association Diagnosis and classification of diabetes mellitus.Diabetes Care. 2005; 28: S37-S42Crossref PubMed Scopus (938) Google Scholar The strong relation between diabetes and cardiovascular (CV) disease (CVD) has been explained by a variety of mechanisms, including the detrimental effects of high fasting or postprandial blood glucose levels,2.Brownlee M. Biochemistry and molecular cell biology of diabetic complications.Nature. 2001; 414: 813-820Crossref PubMed Scopus (6541) Google Scholar, 3.Ceriello A. Postprandial hyperglycemia and diabetes complications. Is it time to treat?.Diabetes. 2005; 54: 1-7Crossref PubMed Scopus (733) Google Scholar, 4.Hanefeld M. Fischer S. Julius U. et al.Risk factors for myocardial infarction and death in newly detected NIDDM: The diabetes intervention study, 11-year follow up.Diabetologia. 1996; 39: 1577-1583Crossref PubMed Scopus (905) Google Scholar, 5.Esposito K. Giugliano D. Nappo F. Marfella R. Regression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus.Circulation. 2004; 110: 214-219Crossref PubMed Scopus (356) Google Scholar, 6.The DECODE Study Group, the European Diabetes Epidemiology Group Glucose tolerance and mortality: comparison of WHO and American Diabetes association diagnostic criteria.Lancet. 1999; 354: 617-621Abstract Full Text Full Text PDF PubMed Scopus (1189) Google Scholar insulin resistance,7.Ginsberg H.N. Insulin resistance and cardiovascular disease.J Clin Invest. 2000; 106: 453-458Crossref PubMed Scopus (877) Google Scholar dyslipidemia, hypertension, or a combination of these risk factors (metabolic syndrome)8.Isomaa B. Almgren P. Tuomi T. et al.Cardiovascular morbidity and mortality associated with the metabolic syndrome.Diabetes Care. 2001; 24: 683-689Crossref PubMed Scopus (3692) Google Scholar on the vasculature. It is well known that renal transplant recipients are at high risk of ischemic heart disease (IHD),9.Lindholm A. Albrechtsen D. Frödin L. et al.Ischemic heart disease. Major cause of death and graft loss after renal transplantation in Scandinavia.Transplantation. 1995; 60: 451-457Crossref PubMed Scopus (316) Google Scholar, 10.Kasiske B.L. Guijarro C. Massy Z.A. et al.Cardiovascular disease after renal transplantation.J Am Soc Nephrol. 1996; 7: 158-165Abstract Full Text PDF PubMed Scopus (357) Google Scholar, 11.Aakhus S. Dahl K. Widerøe T.E. Cardiovascular disease in stable renal transplant patients in Norway: morbidity and mortality during a 5-yr follow-up.Clin Transplant. 2004; 18: 596-604Crossref PubMed Scopus (86) Google Scholar and patients with diabetes mellitus before renal transplantation (DM) carry an additionally two- to four-fold higher risk of CVD9.Lindholm A. Albrechtsen D. Frödin L. et al.Ischemic heart disease. Major cause of death and graft loss after renal transplantation in Scandinavia.Transplantation. 1995; 60: 451-457Crossref PubMed Scopus (316) Google Scholar, 10.Kasiske B.L. Guijarro C. Massy Z.A. et al.Cardiovascular disease after renal transplantation.J Am Soc Nephrol. 1996; 7: 158-165Abstract Full Text PDF PubMed Scopus (357) Google Scholar, 11.Aakhus S. Dahl K. Widerøe T.E. Cardiovascular disease in stable renal transplant patients in Norway: morbidity and mortality during a 5-yr follow-up.Clin Transplant. 2004; 18: 596-604Crossref PubMed Scopus (86) Google Scholar, 12.Aker S. Ivens K. Guo Z. et al.Cardiovascular complications after renal transplantation.Transplant Proc. 1998; 30: 2039-2042Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar and major cardiac events (MCEs)13.Jardine A.G. Holdaas H. Fellstrom B. et al.ALERT Study Investigators: Fluvastatin prevents cardiac death and myocardial infarction in renal transplant recipients: post-hoc subgroup analyses of the ALERT study.Am J Transplant. 2004; 4: 988-995Crossref PubMed Scopus (110) Google Scholar as compared with nondiabetic recipients. During the last decade, new-onset post-transplantation diabetes mellitus (PTDM) has been recognized as a serious complication after renal transplantation.14.Montori V.M. Basu A. Erwin P.J. et al.Posttransplantation diabetes. A systematic review of the literature.Diabetes Care. 2002; 25: 583-592Crossref PubMed Scopus (447) Google Scholar, 15.Markell M. New-onset diabetes mellitus in transplant patients: pathogenesis, complications and management.Am J Kidney Dis. 2004; 43: 953-965Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 16.Hjelmesæth J. Hartmann A. Kofstad J. et al.Glucose intolerance after renal transplantation depends upon prednisolone dose and recipient age.Transplantation. 1997; 64: 979-983Crossref PubMed Scopus (273) Google Scholar New-onset PTDM may be provoked by immunosuppressive drugs (glucocorticoids and calcineurin inhibitors), but also shares several features with type 2 diabetes, as both insulin resistance and relative insulin deficiency are involved in the pathogenesis.17.Ekstrand A.V. Eriksson J.G. Gronhagen-Riska C. et al.Insulin resistance and insulin deficiency in the pathogenesis of posttransplant diabetes in man.Transplantation. 1992; 53: 563-569Crossref PubMed Scopus (117) Google Scholar, 18.Hjelmesæth J. Hagen M. Hartmann A. et al.The impact of impaired insulin release and insulin resistance on glucose intolerance after renal transplantation.Clin Transplant. 2002; 16: 389-396Crossref PubMed Scopus (49) Google Scholar The question whether PTDM is associated with increased risk of CVD has been the subject of some debate. A number of studies indicate that PTDM is associated with reduced patient survival19.Cosio F.G. Pesavento T.E. Kim S. et al.Patient survival after renal transplantation: IV. Impact of post-transplant diabetes.Kidney Int. 2002; 62: 1440-1446Abstract Full Text Full Text PDF PubMed Google Scholar, 20.Kasiske B.L. Snyder J.J. Gilbertson D. Matas A.J. Diabetes mellitus after kidney transplantation in the United States.Am J Transplant. 2003; 3: 178-185Crossref PubMed Scopus (1000) Google Scholar, 21.Revanur V.K. Jardine A.G. Kingsmore D.B. et al.Influence of diabetes mellitus on patient and graft survival in recipients of kidney transplantation.Clin Transplant. 2001; 15: 89-94Crossref PubMed Scopus (165) Google Scholar or increased risk of CVD.10.Kasiske B.L. Guijarro C. Massy Z.A. et al.Cardiovascular disease after renal transplantation.J Am Soc Nephrol. 1996; 7: 158-165Abstract Full Text PDF PubMed Scopus (357) Google Scholar, 12.Aker S. Ivens K. Guo Z. et al.Cardiovascular complications after renal transplantation.Transplant Proc. 1998; 30: 2039-2042Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 22.Lentine K.L. Brennan D.C. Schnitzler A. Incidence and predictors of myocardial infarction after kidney transplantation.J Am Soc Nephrol. 2005; 16: 496-506Crossref PubMed Scopus (229) Google Scholar, 23.Ducloux D. Kazory A. Chalopin J.M. Posttransplant diabetes mellitus and atherosclerotic events in renal transplant recipients: a prospective study.Transplantation. 2005; 79: 438-443Crossref PubMed Scopus (76) Google Scholar In contrast, a large retrospective study including 1.811 renal transplant recipients followed for a mean of 8 years reported a similar proportion of CV deaths in patients with PTDM (54%) and nondiabetic controls (49%).19.Cosio F.G. Pesavento T.E. Kim S. et al.Patient survival after renal transplantation: IV. Impact of post-transplant diabetes.Kidney Int. 2002; 62: 1440-1446Abstract Full Text Full Text PDF PubMed Google Scholar A small case–control study reported similar long-term patient survival (mean 9 years) in PTDM patients and nondiabetic controls.24.Miles A.M. Sumrani N. Horowitz R. et al.Diabetes mellitus after renal transplantation: as deleterious as non-transplant-associated diabetes?.Transplantation. 1998; 65: 380-384Crossref PubMed Scopus (238) Google Scholar Further, although hyperglycemia improves after tapering of immunosuppressive therapy in a substantial number of patients with new-onset PTDM,25.Hjelmesæth J. Hartmann A. Kofstad J. et al.Tapering off prednisolone and cyclosporin the first year after transplantation: the effect on glucose tolerance.Nephrol Dial Transplant. 2001; 16: 829-835Crossref PubMed Scopus (112) Google Scholar it remains unknown whether resolution of PTDM is associated with reduced CV risk.26.Gaston R.S. Basadonna G. Cosio F.G. et al.Transplantation in the diabetic patient with advanced chronic kidney disease: a task force report.Am J Kidney Dis. 2004; 44: 529-542Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Previous studies addressing the effects of PTDM on CVD were hampered by retrospective designs.10.Kasiske B.L. Guijarro C. Massy Z.A. et al.Cardiovascular disease after renal transplantation.J Am Soc Nephrol. 1996; 7: 158-165Abstract Full Text PDF PubMed Scopus (357) Google Scholar, 12.Aker S. Ivens K. Guo Z. et al.Cardiovascular complications after renal transplantation.Transplant Proc. 1998; 30: 2039-2042Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 19.Cosio F.G. Pesavento T.E. Kim S. et al.Patient survival after renal transplantation: IV. Impact of post-transplant diabetes.Kidney Int. 2002; 62: 1440-1446Abstract Full Text Full Text PDF PubMed Google Scholar, 20.Kasiske B.L. Snyder J.J. Gilbertson D. Matas A.J. Diabetes mellitus after kidney transplantation in the United States.Am J Transplant. 2003; 3: 178-185Crossref PubMed Scopus (1000) Google Scholar, 21.Revanur V.K. Jardine A.G. Kingsmore D.B. et al.Influence of diabetes mellitus on patient and graft survival in recipients of kidney transplantation.Clin Transplant. 2001; 15: 89-94Crossref PubMed Scopus (165) Google Scholar, 22.Lentine K.L. Brennan D.C. Schnitzler A. Incidence and predictors of myocardial infarction after kidney transplantation.J Am Soc Nephrol. 2005; 16: 496-506Crossref PubMed Scopus (229) Google Scholar, 24.Miles A.M. Sumrani N. Horowitz R. et al.Diabetes mellitus after renal transplantation: as deleterious as non-transplant-associated diabetes?.Transplantation. 1998; 65: 380-384Crossref PubMed Scopus (238) Google Scholar In addition, the criteria for the diagnosis of PTDM have not been consistently defined. Most reports define PTDM to be present in recipients with no history of diabetes before transplantation, but who are subsequently treated with insulin or oral hypoglycemic agents after transplantation.14.Montori V.M. Basu A. Erwin P.J. et al.Posttransplantation diabetes. A systematic review of the literature.Diabetes Care. 2002; 25: 583-592Crossref PubMed Scopus (447) Google Scholar, 21.Revanur V.K. Jardine A.G. Kingsmore D.B. et al.Influence of diabetes mellitus on patient and graft survival in recipients of kidney transplantation.Clin Transplant. 2001; 15: 89-94Crossref PubMed Scopus (165) Google Scholar Others have used self-reported diabetes20.Kasiske B.L. Snyder J.J. Gilbertson D. Matas A.J. Diabetes mellitus after kidney transplantation in the United States.Am J Transplant. 2003; 3: 178-185Crossref PubMed Scopus (1000) Google Scholar, 22.Lentine K.L. Brennan D.C. Schnitzler A. Incidence and predictors of myocardial infarction after kidney transplantation.J Am Soc Nephrol. 2005; 16: 496-506Crossref PubMed Scopus (229) Google Scholar or random blood glucose values14.Montori V.M. Basu A. Erwin P.J. et al.Posttransplantation diabetes. A systematic review of the literature.Diabetes Care. 2002; 25: 583-592Crossref PubMed Scopus (447) Google Scholar, 21.Revanur V.K. Jardine A.G. Kingsmore D.B. et al.Influence of diabetes mellitus on patient and graft survival in recipients of kidney transplantation.Clin Transplant. 2001; 15: 89-94Crossref PubMed Scopus (165) Google Scholar to identify patients with PTDM. To our knowledge, no previous study has addressed the impact of early-diagnosed new-onset PTDM (World Health Organization/American Diabetes Association (ADA) criteria)27.Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.Diabetes Care. 1997; 20: 1183-1197Crossref PubMed Scopus (7218) Google Scholar, 28.World Health Organization Department of Noncommunicable Disease Surveillance Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus.Report of a WHO Consultation. WHO, Geneva1999Google Scholar on CVD. Thus, the objectives of the present 8-year prospective single-center observational study were to assess the long-term effects of early-diagnosed new-onset PTDM on the cumulative incidence of MCEs (cardiac death or nonfatal acute myocardial infarctions) and patient survival. Baseline traditional and transplantation-related CV risk factors in the three groups of patients are shown in Table 1. Diabetic (DM and PTDM) recipients were on average 7–8 years older than nondiabetic patients, and the prevalence of pretransplant CVD was significantly higher in the DM group than in the nondiabetic group (P=0.013). The proportion of patients with left ventricular hypertrophy was significantly higher in the DM group than in both the nondiabetic group (P=0.001) and the PTDM group (P=0.037). The PTDM patients had a significantly higher incidence of CMV infection than nondiabetic patients (P=0.001), whereas no significant difference was found between the two diabetic groups (P=0.096).Table 1Traditional and transplantation-related cardiovascular risk factors at baseline (3 months after transplantation) (n=201)No diabetes (n=138)New-onset PTDM (n=35)Pretransplant diabetes (n=28)PTraditional risk factors Age (years)46 (16)54 (15)53 (13)0.002 Male gender98 (71%)22 (63%)19 (68%)0.639 Pretransplant cardiovascular disease21 (15%)7 (20%)10 (36%)0.045 Weight (kg)69 (62–79)72 (58–86)71 (63–79)0.792 Smokers (yes)29 (21%)11 (31%)8 (35%)0.209 Hypertension after transplantation113 (83%)31 (89%)22 (82%)0.660 Left ventricular hypertrophy (yes)26 (19%)8 (24%)12 (50%)0.005Transplantation-related risk factors Cadaveric donor78 (57%)26 (74%)17 (61%)0.159 First transplant117 (85%)31 (89%)23 (82%)0.798 Acute rejection(s) (yes; ≥1)74 (54%)24 (69%)21 (75%)0.051 Prednisolone (mg/day)10 (10–20)15 (10–25)10 (10–15)0.092 Creatinine clearance (ml/min)55 (45–71)51 (41–67)48 (38–63)0.161 Creatinine (μmol/l)138 (118–160)131 (109–168)147 (117–171)0.673 Cytomegalovirus infection78 (57%)30 (88%)20 (71%)0.002Values are given as mean (standard deviation (s.d.)), median (interquartile range) or numbers of patients (%). Statistics: ANOVA, Kruskal–Wallis, χ2 or Fisher's exact test as appropriate. Open table in a new tab Values are given as mean (standard deviation (s.d.)), median (interquartile range) or numbers of patients (%). Statistics: ANOVA, Kruskal–Wallis, χ2 or Fisher's exact test as appropriate. Only eight patients received a statin at baseline (4%): five out of 138 nondiabetic patients, one out of 35 PTDM patients and two out of 28 DM patients (no significant differences between groups). Nine out of 35 patients (26%) with PTDM required hypoglycemic drug therapy; six patients were treated with insulin and three with oral hypoglycemic agents. A total of 14 PTDM patients had a normal fasting serum glucose (<5.6 mmol/l; n=7) or impaired fasting glucose (5.6–6.9 mmol/l; n=7). Thus, the diagnosis of PTDM in these patients was based on the oral glucose tolerance test (OGTT)-derived 2-h blood glucose concentration. The patients with PTDM were on average significantly more insulin resistant, and had lower high-density lipoprotein-cholesterol levels, higher triglyceride concentrations and a higher median glycosylated hemoglobin than nondiabetic controls (Table 2).Table 2Metabolic cardiovascular risk factors and hsCRP at baseline (3 months after transplantation) (n=173)No diabetes (n=138)New-onset PTDM (n=35)PInsulin sensitivity index7.88 (2.37)5.35 (2.01)<0.001Fasting blood glucose (mmol/l)5.4 (5.0–5.7)6.6 (5.9–7.9)<0.0012-h blood glucose (mmol/l)7.0 (6.0–8.1)13.4 (11.3–15.3)<0.001HbA1c (%)5.2 (4.8–5.6)5.5 (4.9–6.2)0.044Total cholesterol (mmol/l)6.5 (5.8–7.4)6.8 (5.7–7.5)0.789Triglycerides (mmol/l)1.8 (1.4–2.3)2.3 (1.7–3.6)0.017HDL-cholesterol (mmol/l)1.4 (1.2–1.7)1.3 (0.9–1.7)0.028LDL-cholesterol (mmol/l)4.1 (3.4–5.0)4.4 (3.5–5.1)0.623Apo-A1 (g/l)1.4 (1.3–1.6)1.4 (1.1–1.6)0.340Apo-B (g/l)1.2 (1.0–1.4)1.3 (1.1–1.4)0.166Apo-B/Apo-A ratio0.85 (0.68–1.00)0.91 (0.75–1.17)0.142Homocysteine (μmol/l)24 (19–33)30 (20–38)0.281Lp (a) (mg/l)94 (41–273)68 (26–201)0.190hsCRP (mg/l)0.72 (0.24–1.56)1.63 (0.45–3.91)0.008Values are given as mean (SD), median (interquartile range) or numbers of patients (%). Statistics: independent t-test, Mann–Whitney, χ2 or Fisher's exact test as appropriate. Open table in a new tab Values are given as mean (SD), median (interquartile range) or numbers of patients (%). Statistics: independent t-test, Mann–Whitney, χ2 or Fisher's exact test as appropriate. The 8-year cumulative incidence of MCEs was 11% (22 out of 201); 7% in recipients without diabetes (nine out of 138), 20% in patients with new-onset PTDM (seven out of 35) and 21% in patients with DM (six out of 28), respectively. The Kaplan–Meier estimates of recipients free of cardiac events in the three groups are shown in Figure 1. Univariate Cox regression analyses revealed that patients with PTDM and DM had a three- to five-fold increased risk of an MCE as compared with nondiabetic patients (HR=3.49, 95% CI=1.30–9.37, P=0.013 and HR=5.13, 95% CI=1.81–14.58, P=0.002, respectively). Other variables associated with increased risk of an MCE in the univariate analyses were pretransplant CVD (P<0.001), older age (P=0.003), male gender (P=0.038), rejection(s) (P=0.023), left ventricular hypertrophy (P=0.029), and CMV infection (P=0.041). Neither daily dose of prednisolone nor statin therapy was associated with MCEs (data not shown). Variables significantly associated (P<0.05) with MCEs in the univariate analyses were included in the forward stepwise regression analyses. After retaining pretransplant CVD in the forward regression model, only PTDM remained associated with a significant three-fold increased risk of an MCE (Table 3).Table 3HRs of MCE (cardiac death or nonfatal myocardial infarction) and death in patients with new-onset PTDM or pretransplant DM as compared with no-diabetic patients during the period 3 months to 8 years (98±8 months) after renal transplantationMajor cardiac eventsAll-cause mortalityHR95% CIPHR95% CIPPTDM3.271.22–8.800.0191.200.58–2.490.621Pretransplant diabetes2.550.80–8.140.1145.092.60–9.96<0.001Pretransplant CVD5.232.09–13.07<0.001NENENEAgeNENENE1.031.01–1.050.016CMV infectionNENENE2.661.27–5.530.009Creatinine clearanceNANANA0.980.96–1.000.046The results of proportional hazards regression analyses are shown. Variables associated with MCEs and death in the univariate analyses, diabetic status, pretransplant CVD, age, left ventricular hypertrophy and CMV infection, were included in the regression analyses for both models. In addition, rejection and gender were included in the analyses for the MCE model, and creatinine clearance in the all-cause mortality model. NA, not addressed; NE, not in the equation. Open table in a new tab The results of proportional hazards regression analyses are shown. Variables associated with MCEs and death in the univariate analyses, diabetic status, pretransplant CVD, age, left ventricular hypertrophy and CMV infection, were included in the regression analyses for both models. In addition, rejection and gender were included in the analyses for the MCE model, and creatinine clearance in the all-cause mortality model. NA, not addressed; NE, not in the equation. A total of 61 recipients (30%) died during the 8-year follow-up (Table 4). All-cause mortality rates were significantly higher in the patients with DM (71%) than in those with PTDM (37%) (P=0.007). Both diabetes groups had significantly higher mortality rates than the nondiabetic group (20%) (P<0.001 and 0.036, respectively). Kaplan–Meier estimates of patient survival comparing patients with either types of diabetes and nondiabetic patients are shown in Figure 2.Table 4All cause mortality beyond 3 months after transplantation according to diabetic statusTotal (n=201)No diabetes (n=138)New-onset PTDM (n=35)Pretransplant diabetes (n=28)PDeath total (% of patients)61 (30%)28 (20%)13 (37%)20 (71%)<0.001Cause of death (% of patients) Cardiovascular29 (14%)11 (8%)7 (20%)11 (39%)<0.001 Infection11 (5%)3 (2%)2 (6%)6 (21%)0.001 Malignancy16 (8%)11 (8%)4 (11%)1 (4%)0.562 Other/unknown5 (2%)3 (2%)0 (0%)2 (7%)0.241Pearson χ2 or Fisher's exact test as appropriate. Open table in a new tab Pearson χ2 or Fisher's exact test as appropriate. Univariate Cox regression analysis revealed that patients with PTDM and DM had a two- to five-fold increased risk of death as compared with nondiabetic patients (HR=2.11, 95% CI=1.09–4.09, P=0.026 and HR=5.48, 95% CI=3.06–9.82, P<0.001, respectively). Other variables significantly associated with increased mortality risk in univariate analyses were older age (P<0.001), lower creatinine clearance (P<0.001), pretransplant CVD (P=0.001), CMV infection (P=0.001) and left ventricular hypertrophy (P=0.015). Daily dose of prednisolone did not influence the all-cause mortality significantly (data not shown). After retaining age, CMV infection and creatinine clearance in the regression model, DM, but not PTDM, remained associated with a significant five-fold increased all-cause mortality risk (Table 3). The major causes of death were CVD (48% of total) and malignancy (26% of total) (Table 4). Patients with DM had a significantly higher cumulative incidence of both CV- and infection-related death, than the nondiabetic group (both P<0.001). On average, a trend towards a higher incidence of CV deaths was observed in the DM group as compared with the PTDM group (P=0.092), and in the PTDM group as compared with the nondiabetic group (P=0.058) (Table 4). Metabolic baseline risk factors were prospectively registered in all patients without DM (Table 2), and the potentially confounding effects of these parameters on survival and MCEs were addressed. Univariate analysis revealed that high-density lipoprotein-cholesterol was associated with lower risk (HR=0.15, 95% CI=0.04–0.56, P=0.004) and apolipoprotein B/apolipoprotein A ratio with higher risk (HR=4.32, 95% CI=1.20–15.54, P=0.025) of MCEs. Other metabolic risk factors were not significantly associated with MCEs (data not shown). Patients with high-sensitivity C-reactive protein (hsCRP) in the upper quartile had a significantly higher risk of death (HR=3.08, 95% CI=1.27–7.44, P=0.013), but not of MCEs (HR=3.10, 95% CI=0.80–12.07, P=0.102), as compared with the patients in the lower hsCRP quartile. However, the association between hsCRP and death lost significance in the multiple regression model (data not shown). PTDM and pretransplant CVD remained independent predictors of MCEs (HR=3.63, 95% CI=1.35–9.77, P=0.011, and HR=4.53, 95% CI=1.62–12.63 and P=0.004, respectively) after forward stepwise regression analysis. Univariate Cox regression analyses did not reveal any significant association between metabolic risk factors and all-cause mortality (data not shown). This 8-year prospective observational study indicates that new-onset PTDM (World Health Organization/American Diabetes Association criteria) diagnosed during the early post-transplant period (<3 months) is a predictor of future myocardial infarction and cardiac death. Previous reports have suggested that new-onset PTDM is associated with lower patient survival19.Cosio F.G. Pesavento T.E. Kim S. et al.Patient survival after renal transplantation: IV. Impact of post-transplant diabetes.Kidney Int. 2002; 62: 1440-1446Abstract Full Text Full Text PDF PubMed Google Scholar, 20.Kasiske B.L. Snyder J.J. Gilbertson D. Matas A.J. Diabetes mellitus after kidney transplantation in the United States.Am J Transplant. 2003; 3: 178-185Crossref PubMed Scopus (1000) Google Scholar, 21.Revanur V.K. Jardine A.G. Kingsmore D.B. et al.Influence of diabetes mellitus on patient and graft survival in recipients of kidney transplantation.Clin Transplant. 2001; 15: 89-94Crossref PubMed Scopus (165) Google Scholar and increased frequency of IHD.10.Kasiske B.L. Guijarro C. Massy Z.A. et al.Cardiovascular disease after renal transplantation.J Am Soc Nephrol. 1996; 7: 158-165Abstract Full Text PDF PubMed Scopus (357) Google Scholar, 22.Lentine K.L. Brennan D.C. Schnitzler A. Incidence and predictors of myocardial infarction after kidney transplantation.J Am Soc Nephrol. 2005; 16: 496-506Crossref PubMed Scopus (229) Google Scholar, 23.Ducloux D. Kazory A. Chalopin J.M. Posttransplant diabetes mellitus and atherosclerotic events in renal transplant recipients: a prospective study.Transplantation. 2005; 79: 438-443Crossref PubMed Scopus (76) Google Scholar These studies, however, were limited by retrospective designs, varying criteria for diagnosis of PTDM or inclusion of patients developing PTDM up till several years after transplantation. This study differs from others by its prospective inclusion of adult patients transplanted at a single national center during a relatively short period of time (16 months), a long-term follow-up period (8 years), and no included patients being lost to follow-up. Nonetheless, our results are in accordance with previous studies, suggesting that PTDM is associated with an up to three-fold increased risk of myocardial infarction, IHD or CVD, 3–7 years after renal transplantation.10.Kasiske B.L. Guijarro C. Massy Z.A. et al.Cardiovascular disease after renal transplantation.J Am Soc Nephrol. 1996; 7: 158-165Abstract Full Text PDF PubMed Scopus (357) Google Scholar, 12.Aker S. Ivens K. Guo Z. et al.Cardiovascular complications after renal transplantation.Transplant Proc. 1998; 30: 2039-2042Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 22.Lentine K.L. Brennan D.C. Schnitzler A. Incidence and predictors of myocardial infarction after kidney transplantation.J Am Soc Nephrol. 2005; 16: 496-506Crossref PubMed Scopus (229) Google Scholar, 23.Ducloux D. Kazory A. Chalopin J.M. Posttransplant diabetes mellitus and atherosclerotic events in renal transplant recipients: a prospective study.Transplantation. 2005; 79: 438-443Crossref PubMed Scopus (76) Google Scholar We were unable to confirm recently published studies suggesting that C-reactive protein is an independent risk factor of atherosclerotic events23.Ducloux D. Kazory A. Chalopin J.M. Posttransplant diabetes mellitus and atherosclerotic events in renal transplant recipients: a prospective study.Transplantation. 2005; 79: 438-443Crossref PubMed Scopus (76) Google Scholar and death29.Winkelmayer W.C. Lorenz M. Kramar R. et al.C-reactive protein and body mass index independently predict mortality in kidney transplant recipients.Am J Transplant. 2004; 4: 1148-1154Crossref PubMed Scopus (57) Google Scholar in renal transplant recipients. Although hsCRP was associated with increased all-cause mortality in the univariate analysis, this association lost significance in the multiple regression model in our study. Moreover, hsCRP was not significantly associated with MCEs. Importantly, the present study was neither designed nor powered to specifically address the potentially detrimental effects of hsCRP on outcomes. Although DM was not documented to be an independent predictor of MCEs in the present study, this may partly be explained by a significantly higher prevalence of pretransplant CVD in the DM group than in nondiabetic patients (Tables 1 and 3). The proportion of patients who suffered an MCE was similar in patients with DM and PTDM (21 and 20%, respectively), and the incidence of CV death tended to be higher in DM patients than in PTDM patients (39 and 20%, respectively). Thus, our data are not in conflict with the notion that the relative risk of CV events in patients with PTDM and DM may be comparable. This view is in line with a previous report showing that both patients with PTDM and DM had a three-fold increased risk of atherosclerotic CVD during the first 2 years after transplantation,12.Aker S. Ivens K. Guo Z. et al.Cardiovascular complications after renal transplantation.Transplant Proc. 1998; 30: 2039-2042Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar and a recent large-scale registry-based study suggesting that both PTDM and DM are independent predictors of post-transplant myocardial infarction.22.Lentine K.L. Brennan D.C. Schnitzler A. Incidence and predictors of myocardial infarction after kidney transplantation.J Am Soc Nephrol. 2005; 16: 496-506Crossref PubMed Scopus (229) Google Scholar In the latter study, the relative risk of myocardial infarction was actually higher in patients with PTDM (relative risk=1.6) than in patients with either pretransplant diabetes as a comorbidity (relative risk=1.1) or recipients with diabetic nephropathy (relative risk=1.4).22.Lentine K.L. Brennan D.C. Schnitzler A. Incidence and predictors of myocardial infarction after kidney transplantation.J Am Soc Nephrol. 2005; 16: 496-506Crossref PubMed Scopus (229) Google Scholar On the other hand, all-cause mortality was significantly higher in DM than in PTDM patients (71 vs 37%). This may be explained by a tendency towards higher frequencies of death related to CVD and infections in patients with DM (Table 4). The average annual mortality rate of 8.9% in DM patients seems high, but is comparable with the results from a previous 5-year follow-up study reporting a mortality rate of 7.2%/year in a group of patients with either PTDM or DM.11.Aakhus S. Dahl K. Widerøe T.E. Cardiovascular disease in stable renal transplant patients in Norway: morbidity and mortality during a 5-yr follow-up.Clin Transplant. 2004; 18: 596-604Crossref PubMed Scopus (86) Google Scholar Importantly, all diabetic patients in the present study were carefully examined for CV disease before transplant, including cycle ergometer exercise testing, and the majority also underwent coronary angiography pretransplant. Insulin resistance has been associated with CVD in the general population,7.Ginsberg H.N. Insulin resistance and cardiovascular disease.J Clin Invest. 2000; 106: 453-458Crossref PubMed Scopus (877) Google Scholar and a recent Japanese report suggests that insulin resistance may be an independent predictor of CV mortality in patients with end-stage renal disease.30.Shinohara K. Shoji T. Emoto M. et al.Insulin resistance is an independent risk factor of cardiovascular mortality in patients with end-stage renal disease.J Am Soc Nephrol. 2002; 13: 1894-1900Crossref PubMed Scopus (298) Google Scholar However, we did not confirm any significant relation between insulin resistance and MCEs in renal transplant recipients. Although it may be difficult to explain this apparent discrepancy, the study populations are clearly different (Asian vs Caucasian), and, importantly, patients in chronic dialysis seem to be more insulin resistant than transplanted patients with adequate renal function.31.Shimizu M. Iino Y. Terashi A. Improvement of insulin sensitivity after renal transplantation measured by a glucose clamp technique.Nippon Ika Daigaku Zasshi. 1998; 65: 50-54Crossref PubMed Scopus (11) Google Scholar, 32.Nam J.H. Mun J.I. Kim S.I. et al.β-cell dysfunction rather than insulin resistance is the main contributing factor for the development of postrenal transplantation diabetes mellitus.Transplantation. 2001; 71: 1417-1423Crossref PubMed Scopus (135) Google Scholar Increased low-density lipoprotein-cholesterol is an established risk factor for IHD in renal transplant recipients33.Holdaas H. Fellstrom B. Jardine A.G. et al.Assessment of LEscol in Renal Transplantation (ALERT) Study Investigators: effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomized, placebo-controlled trial.Lancet. 2003; 361: 2024-2031Abstract Full Text Full Text PDF PubMed Scopus (741) Google Scholar and it has also been suggested that dyslipidemia,22.Lentine K.L. Brennan D.C. Schnitzler A. Incidence and predictors of myocardial infarction after kidney transplantation.J Am Soc Nephrol. 2005; 16: 496-506Crossref PubMed Scopus (229) Google Scholar and more specifically low high-density lipoprotein-cholesterol,10.Kasiske B.L. Guijarro C. Massy Z.A. et al.Cardiovascular disease after renal transplantation.J Am Soc Nephrol. 1996; 7: 158-165Abstract Full Text PDF PubMed Scopus (357) Google Scholar, 11.Aakhus S. Dahl K. Widerøe T.E. Cardiovascular disease in stable renal transplant patients in Norway: morbidity and mortality during a 5-yr follow-up.Clin Transplant. 2004; 18: 596-604Crossref PubMed Scopus (86) Google Scholar, 13.Jardine A.G. Holdaas H. Fellstrom B. et al.ALERT Study Investigators: Fluvastatin prevents cardiac death and myocardial infarction in renal transplant recipients: post-hoc subgroup analyses of the ALERT study.Am J Transplant. 2004; 4: 988-995Crossref PubMed Scopus (110) Google Scholar predicts IHD in renal transplant recipients. Although high-density lipoprotein-cholesterol and apolipoprotein B/apolipoprotein A ratio were associated with MCEs in the univariate analyses, this relationship lost significance in the multiple regression model. Whether resolution of PTDM is associated with reduced risk of CVD is unclear.26.Gaston R.S. Basadonna G. Cosio F.G. et al.Transplantation in the diabetic patient with advanced chronic kidney disease: a task force report.Am J Kidney Dis. 2004; 44: 529-542Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar As previously reported from our cohort, 12 out of 23 patients with early new-onset PTDM had transient PTDM according to a repeated normalized OGTT 1 year later.25.Hjelmesæth J. Hartmann A. Kofstad J. et al.Tapering off prednisolone and cyclosporin the first year after transplantation: the effect on glucose tolerance.Nephrol Dial Transplant. 2001; 16: 829-835Crossref PubMed Scopus (112) Google Scholar Interestingly, a post hoc analysis of these data revealed that no MCE occurred in the group of 12 patients with transient PTDM, as compared to four MCEs in the group of 11 patients with persistent PTDM (P=0.037). Obviously, this finding needs verification, but it indicates that repeated OGTTs in patients with early-diagnosed PTDM may be of clinical importance. Our study has limitations. First, the unexpected relatively low number of events reduced the power of detecting the potential adverse effect of PTDM on predefined study end points. The average annual mortality rate was lower than reported in a previous Norwegian study (annual mortality 3.8 vs 4.3%),11.Aakhus S. Dahl K. Widerøe T.E. Cardiovascular disease in stable renal transplant patients in Norway: morbidity and mortality during a 5-yr follow-up.Clin Transplant. 2004; 18: 596-604Crossref PubMed Scopus (86) Google Scholar which may be explained by the generally observed improved survival in renal transplant recipients during the last two decades.34.van Dijk P.C. Jager K.J. de Charro F. et al.ERA-EDTA registry: renal replacement therapy in Europe: the results of a collaborative effort by the ERA-EDTA registry and six national or regional registries.Nephrol Dial Transplant. 2001; 16: 1120-1129Crossref PubMed Scopus (267) Google Scholar Second, the diagnosis of PTDM was made in the early post-transplant period of high corticosteroid exposure, and the results may not have relevance for transplant patients not receiving steroids or recipients on steroid-sparing immunosuppressive regimens. In addition, the majority of patients were Caucasian, and our results may not be generalized to non-Caucasian transplant populations. Finally, new-onset PTDM was associated with increased mortality in the univariate analysis, but did not predict death after adjustment for confounding factors. This is in contrast with findings from some previous studies,19.Cosio F.G. Pesavento T.E. Kim S. et al.Patient survival after renal transplantation: IV. Impact of post-transplant diabetes.Kidney Int. 2002; 62: 1440-1446Abstract Full Text Full Text PDF PubMed Google Scholar, 20.Kasiske B.L. Snyder J.J. Gilbertson D. Matas A.J. Diabetes mellitus after kidney transplantation in the United States.Am J Transplant. 2003; 3: 178-185Crossref PubMed Scopus (1000) Google Scholar, 21.Revanur V.K. Jardine A.G. Kingsmore D.B. et al.Influence of diabetes mellitus on patient and graft survival in recipients of kidney transplantation.Clin Transplant. 2001; 15: 89-94Crossref PubMed Scopus (165) Google Scholar but in agreement with others.24.Miles A.M. Sumrani N. Horowitz R. et al.Diabetes mellitus after renal transplantation: as deleterious as non-transplant-associated diabetes?.Transplantation. 1998; 65: 380-384Crossref PubMed Scopus (238) Google Scholar, 35.Vesco L. Busson M. Bedrossian J. et al.Diabetes mellitus after renal transplantation.Transplantation. 1996; 61: 1475-1478Crossref PubMed Scopus (127) Google Scholar Of note, the apparent lack of relationship between PTDM and mortality in the latter24.Miles A.M. Sumrani N. Horowitz R. et al.Diabetes mellitus after renal transplantation: as deleterious as non-transplant-associated diabetes?.Transplantation. 1998; 65: 380-384Crossref PubMed Scopus (238) Google Scholar, 35.Vesco L. Busson M. Bedrossian J. et al.Diabetes mellitus after renal transplantation.Transplantation. 1996; 61: 1475-1478Crossref PubMed Scopus (127) Google Scholar and present studies may be due to limited sample size (type II error). More specifically, the present study was not powered to detect a less than two-fold increased risk of all-cause death. A larger number of patients and/or a longer time of follow-up are probably necessary to establish any independent effect of early-diagnosed new-onset PTDM on patient survival. Some risk factors associated with cardiac events are irremediable: the most important of them are age and gender. The potential remediable risk factors for cardiac outcomes in transplant recipients are smoking, dyslipidemia, hypertension and obesity, among others. Only one CV intervention study has been performed in renal transplant recipients; demonstrating that lowering of low-density lipoprotein-cholesterol resulted in reduction of cardiac events.33.Holdaas H. Fellstrom B. Jardine A.G. et al.Assessment of LEscol in Renal Transplantation (ALERT) Study Investigators: effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomized, placebo-controlled trial.Lancet. 2003; 361: 2024-2031Abstract Full Text Full Text PDF PubMed Scopus (741) Google Scholar Our study indicates that strategies to limit the development of diabetes after renal transplantation may also have a beneficial effect on the incidence of future cardiac events. Clearly, this hypothesis needs further study. Early-diagnosed new-onset PTDM is a predictor of MCEs the first 8 years after renal transplantation. An OGTT in the early post-transplant period may represent a simple and valuable method to screen and detect renal allograft recipients developing this potentially serious post-transplant complication.
Referência(s)