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clinical investigation

& 2014 International Society of Nephrology

Enhanced posttransplant management of patients with diabetes improves patient outcomes Mira T. Keddis1, Mireille El Ters1, Emilio Rodrigo1, Patrick Dean2,3, Mariana Wohlfahrtova1, Yogish C. Kudva3,4, Elizabeth C. Lorenz1 and Fernando G. Cosio1,3 1

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA; 2Division of Transplantation Surgery, Mayo Clinic, Rochester, Minnesota, USA; 3William von Liebig Transplant Center, Mayo Clinic, Rochester, Minnesota, USA and 4Division of Endocrinology, Mayo Clinic, Rochester, Minnesota, USA

The survival of patients with diabetes mellitus in the general population has improved in recent years. Here we assessed whether similar trends have occurred in 1688 kidney recipients, including 413 with diabetes prior to transplant between 1996 and 2007. Compared to patients without diabetes, the 5-year mortality was significantly increased (hazard ratio (HR) 2.68 (1.95–3.69)) due to higher cardiovascular-, infection-, and malignancy-related deaths in those with diabetes. However, 5-year mortality in patients with diabetes significantly declined over time (HR 0.883 (0.817–0.954)), narrowing the mortality difference between patients with and those without diabetes and in more recent years largely eliminating it. Post transplant, patients with diabetes experienced a significant decline in major fatal/ nonfatal cardiac events (HR 0.853 (0.782–0.930)) and infectious deaths over time. In contrast, neither cardiac events nor overall mortality declined in recipients without diabetes. The decline in mortality due to diabetes did not relate to a reduced pretransplant risk profile and was independent of posttransplant variables. The use of cardioprotective medications and glycemic control improved over time post transplant. Furthermore, graft function and serum albumin significantly improved over time and these parameters related to better survival (albumin, HR 0.365 (0.223–0.599); eGFR, HR 0.803 (0.756–0.852)). Thus, survival of kidney recipients with diabetes mellitus has improved markedly since 1996 likely reflecting, at least in part, enhanced posttransplant management and outcomes. Kidney International advance online publication, 2 April 2014; doi:10.1038/ki.2014.70 KEYWORDS: cardiovascular morbidity; cardiovascular mortality; diabetes mellitus; patient survival

Correspondence: Fernando G. Cosio, Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA. E-mail: [email protected] Received 14 August 2013; revised 11 January 2014; accepted 16 January 2014 Kidney International

Diabetes mellitus (DM) has become one of the most prevalent diseases in the United States with dire health and economic consequences. Over the last decade, there have been improvements in the management of DM and cardiovascular disease. Likely reflecting these trends, recent studies have shown that since the mid-1990s there have been significant improvements in DM patient survival in the general population.1,2 The survival of patients with DM is in part compromised by an increase in cardiovascular (CV) risk. However, other variables contribute to the survival disadvantage of these patients.3 For this reason, it has been difficult to pinpoint specific parameters that may explain the improving survival of patients with DM.2 Diabetic nephropathy accounts for a large proportion of patients with end-stage renal disease.4 Unfortunately, the outcomes of patients with DM treated with dialysis or kidney transplantation remain inferior to those of patients without DM (no-DM).5,6 As in the general population, differences in posttransplant survival between recipients with and without DM are primarily due to higher CV- and infection-related deaths.3,6 Previous studies suggested that the survival of patients with DM after transplantation can be largely attributable to pretransplant variables.6,7 If that is the case one would expect that improvements in DM patient survival in the general population would translate into improvements in survival after transplant. Consistent with this hypothesis, the survival of patients with DM on dialysis who are waiting for a transplant has improved over time (http://www.srtr.org/ publications/Default.aspx; SRTR&OPTN annual report, 2011, slide KI 1.14). In addition, improvements in the practice and outcomes of kidney transplantation over time might have benefited patient survival. Those changes include increasing use of living donors, more preemptive transplants, and improved graft function.8–12 The goals of this study were to assess trends in the survival of kidney transplant recipients with and without DM who underwent transplantation from 1996 to 2007 and to investigate the variables that may relate to these trends. These analyses focused on the first 5 years post transplant to equalize the period at risk in patients transplanted during different time periods. 1

clinical investigation

MT Keddis et al.: Survival after kidney transplant in diabetes

RESULTS Patient characteristics

Patient and graft survival

This patient cohort included a high percentage of Caucasians (92.4%), living donor recipients (75.7%), and preemptive transplant recipients (38.8%) (Table 1). DM was diagnosed before transplant in 413 of the 1688 patients (24.5%); 74.8% had type 2 DM, 79.5% were diagnosed with DM as adults, and 74.8% required insulin before transplant. Compared with no-DM recipients, those with DM (Table 1) were older and had a significantly higher incidence of CV events before transplant. Patients with DM were also more likely to have undergone coronary artery bypass surgery (no-DM, 3.1%; DM, 15.5%, Po0.0001) and/or percutaneous coronary revascularization (no-DM, 3.8%; DM, 12.3%, Po0.0001). The follow-up time was shorter in patients with DM than in no-DM patients, likely because of the higher mortality of the former (Table 1).

During the first 5 years post transplant, 153 patients died with a functioning graft (9.1%), 221 grafts (13.1%) were lost not due to patient death, and 39 (2.3%) patients were lost to follow-up. Death-censored graft survival over the first 5 years post transplant was comparable between no-DM and DM patients (P ¼ 0.259). In contrast, compared with no-DM, 5-year mortality was significantly higher in patients with DM (hazard ratio (HR) ¼ 2.681 (1.951–3.685), Po0.0001). However, the mortality of recipients with DM declined progressively from 1996 to 2007 (HR ¼ 0.883 (0.817–0.954), P ¼ 0.002; Figure 1a and b). In those figures, the patient cohort was divided into four approximately equal groups according to the transplant year. Of interest, the reduction in DM mortality was similar between DM patients without pretransplant CV events (N ¼ 215, HR ¼ 0.815 (0.669–0.993), P ¼ 0.042) and those with pretransplant CV events (N ¼ 193,

Table 1 | Recipient characteristics Variables

All patients (N ¼ 1688)

No-DM (N ¼ 1275)

DM (N ¼ 413)

52.3±13.8 983 (58.2) 1531 (92.4) 413 (24.5) 648 (38.8) 4.33 (0, 376)b 1277 (75.7) 434 (25.9) 366 (21.9) 94 (5.6) 76 (4.6) 74.4±39.8

48.8±14.4 742 (58.2) 1152 (92.5) — 498 (39.4) 4.03 (0, 376) 962 (75.5) 241 (19.1) 206 (16.3) 39 (3.1) 35 (2.8) 78.2±40.1

55.7±11.1a 241 (58.4) 379 (92.2) 413 (100) 143 (35.0) 5.38 (0, 230) 315 (76.3) 193 (46.7)c 163 (39.5)c 55 (13.3)c 41 (9.9)c 68.9±35.9a

Recipient age (years) Recipient gender (N, % male) Recipient race (N, % Caucasian) Diabetes (N, %) Preemptive transplant (N, %) Pretransplant dialysis time (months) Donor type (N, % living) Pretransplant CV events (N, %) Cardiac Peripheral vascular disease Cerebrovascular disease Follow-up months Abbreviation: CV, cardiovascular. a Po0.0001 Student’s t-test. b Values represent median, minimum, and maximum values. c Po0.0001 by w2.

a

b 1.0

100

Patient survival at 5 years (%)

95

Patient survival

0.9

0.8

0.7

0.6

90 85 80 75 70 65 60 55 50

0.5

1996–2000 0

12

24 36 48 Months post-transplant

60

72

2001–2002 2003–2004 Transplant year

2005–2007

Figure 1 | Trends in patient survival over time in patients with or without diabetes. (a) Kaplan–Meier plots of patient survival during the first 5 years post transplant in patients without diabetes mellitus (DM) ( þ — þ ) and in patients with DM transplanted between 1996 and 2000 (N ¼ 91, þ — — þ ), between 2001 and 2002 (N ¼ 79, DyD), between 2003 and 2004 (N ¼ 104, J—J), and between 2005 and 2007 (N ¼ 138, .—.). (Log rank Po0.0001). (b) Five-year cumulative patient survival in patients without DM (hatched bars) and in patients with DM (black bars). 2

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MT Keddis et al.: Survival after kidney transplant in diabetes

Causes of death post transplant

The causes of death during the first 5 years post transplant differed between DM and no-DM recipients. Considering first the entire period of observation, compared with no-DM, DM patients had a higher risk for CV deaths (HR ¼ 3.776 (2.155–6.618), Po0.0001; 1.9% CV deaths in no-DM and 7.0% in DM patients), higher risk for death due to malignancies (HR ¼ 4.056 (1.756–9.410), Po0.0001; 0.8% of no-DM and 3.4% of DM patients), and higher risk for death from unknown causes (HR ¼ 3.348 (1.742–6.435), Po0.0001; 1.5% of no-DM and 5.0% of DM patients). In contrast, there were no significant differences in the risk of death from infections (no-DM, 0.7%; DM, 1.7%; P ¼ 0.067) or deaths from other causes (no-DM, 2.0%; DM, 2.3%; P ¼ 0.721). Of interest, the specific causes of death changed over time in patients with DM but not in patients without DM (Table 2). In these studies, because of the relatively limited number of events, we compared causes of death in patients who underwent transplantation in two time periods with approximately equal numbers of patients: 1996–2002 (N ¼ 803, 47.6%) and 2003–2007 (N ¼ 885, 52.4%). Compared with the 1996–2002 period, during 2003–2007 the total number of deaths among DM patients declined significantly (24.1% vs. 11.9%, P ¼ 0.001; Table 2) because of significant reductions in CV, infectious, and other causes of death. During the same time period, in DM patients there were no significant changes in the proportion of deaths due to malignancies or unknown cause. In contrast, in no-DM patients there were no significant changes in the total number of deaths or in the distribution of causes of death between the two time periods (Table 2). Compared with no-DM, during

the 1996–2002 period patients with DM had significantly higher risk for CV deaths (HR ¼ 6.408 (2.974–13.810), Po0.0001), deaths related to infections (HR ¼ 7.610 (1.89–31.846), P ¼ 0.005), and deaths due to malignancies (HR ¼ 3.837 (1.171–12.572), P ¼ 0.026; see Table 2). During the 2003–2007 period, overall mortality continued to be higher in DM (11.9%) than in no-DM (5.9%) patients. However, compared with the earlier period, differences in overall or cause-specific mortality between DM and non-DM patients declined (Table 2). Thus, compared with no-DM patients, during the 2003–2007 period in DM patients the risk for CV death (HR ¼ 2.265 (0.978–5.241), P ¼ 0.056) and for death from malignancies (HR ¼ 4.741 (1.380–16.103), P ¼ 0.013) was significantly lower than that in the previous period. Furthermore, during the 2003–2007 period the risk of death from infections was not significantly different between no-DM and DM patients (P ¼ 0.591). Among DM recipients, there was a progressive decline in the incidence of fatal and nonfatal major adverse cardiac events (MACEs) from 1996 to 2007 (HR ¼ 0.853 (0.782– 0.930), Po0.0001; Figure 2). It is important to note that the risk reduction occurred after the first year post transplant, particularly in patients who underwent transplantation after 2004 (HR ¼ 0.833, P ¼ 0.001). In contrast, during the first year the risk for MACE did not change over time (P ¼ 0.678, Cox) and remained higher in DM than in non-DM patients (Po0.0001, Cox). In no-DM patients, the incidence of MACE, fatal or nonfatal, did not change significantly from 1996 to 2007, either during the first year or beyond (P ¼ 0.554). 1.0

0.9 Event-free survival

HR ¼ 0.835 (0.746–0.936), P ¼ 0.002). In contrast to DM patients, no-DM recipients did not experience a decline in 5-year mortality over time (Figure 1b) (Cox, P ¼ 0.738). Consequently, the survival disadvantage associated with DM decreased over time (Figure 1b), and after 2004 there was no statistical difference in 5-year mortality between patients with and those without DM (HR ¼ 1.455 (0.737–2.873), P ¼ 0.279).

0.8

0.7

0.6

Table 2 | Five-year mortality and analyses of specific causes of death in kidney recipients with or without DM Cause of death Transplant year Number of patients All causes Cardiovascular Infection Malignancy Other Unknown

No-DM

DM

1996–2002

2003–2007

1996–2002

633 45 (7.1) 11 (1.8)a 3 (0.5) 6 (1.0) 14 (2.3) 11 (1.8)

642 38 (5.9) 12 (1.9) 5 (0.8) 4 (0.7) 10 (0.7) 7 (1.1)

170 41 (24.1)1 16 (11.0)1 5 (3.7)3 5 (3.7)4 6 (4.4) 9 (6.5)1

0

29 10 1 7 2 9

243 (11.9)b,1 (4.5)c,2 (0.5)d (3.2)1 (0.9)e,1 (4.0)1

12

24

36

48

60

72

Months post-transplant

2003–2007

Abbreviation: DM, diabetes mellitus. a Values represent number of patients (percentage of all patients in the group). b P ¼ 0.001; cP ¼ 0.016; dP ¼ 0.020; eP ¼ 0.032; w2 comparing DM transplanted during 1996–2002 vs. 2003–2007. 1 P ¼ 0.002, 2Po0.0001; 3P ¼ 0.001, 4P ¼ 0.020; w2 comparing DM vs. non-DM transplanted during the same time period.

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Group No DM DM 1996–2000 DM 2001–2003 DM 2004–2004 DM 2005–2007

12 Months 1130 79 71 95 129

36 Months 1018 67 62 87 121

60 Months 775 52 51 72 101

Figure 2 | Incidence of fatal or nonfatal major adverse cardiac events (MACEs) during the first 5 years after kidney transplant in patients without diabetes mellitus (DM) ( þ — þ ) and in patients with DM transplanted in the following periods of time: 1996–2000 (N ¼ 91, þ — þ ), 2001–2002 (N ¼ 79, D—D), 2003–2004 (N ¼ 104, J—J), and 2005–2007 (N ¼ 138, .—.). (Log rank Po0.0001). 3

clinical investigation

MT Keddis et al.: Survival after kidney transplant in diabetes

Pretransplant variables related to posttransplant mortality in DM recipients, changes over time

Posttransplant variables related to posttransplant mortality in DM recipients, changes over time

The percentage of recipients with DM increased progressively in our program over time (for example, 1996–2000, 10.1%; and 2005–2007, 27.6%; P ¼ 0.022). Analyses of pretransplant factors in DM recipients transplanted at different time periods revealed significant differences (Table 3). However, with the exception of minor improvements in pretransplant hemoglobin levels, none of these differences paralleled the time-related reduction in mortality noted in these recipients. The proportion of patients with a history of coronary bypass surgery was similar throughout the periods (for example, 1996–2000, 15.4%; vs. 2005–2007, 14.4%; P ¼ 0.408) but the proportion of patients with pretransplant percutaneous coronary interventions increased progressively (for example, 1996–2000, 4.4% vs. 2005–2007, 17.3%; P ¼ 0.017). The following pretransplant variables did not differ among DM recipients transplanted at different periods: recipient demographics (age, sex, and race), body mass index, results of cardiac evaluation (left ventricular hypertrophy, percentage with stress-induced ischemia, and left ventricular ejection fraction), proportion with preemptive transplants, time on dialysis, duration of DM, and pretransplant serum albumin and lipid levels. Data on pretransplant use of cardioprotective medications were incomplete and were not analyzed.

Analyses of posttransplant variables in DM patients (Table 3) showed an increased use of thymoglobulin induction and tacrolimus-based maintenance immunosuppression over time. Interestingly, progressive improvement in graft function (measured at 3 weeks and 1 year post transplant; Figure 3a) and 1-year serum albumin (Figure 4a) and hemoglobin levels were observed. Also notable is the decline in glycosylated hemoglobin over time (Table 3). Data on the use of cardioprotective medications were available in 77% of patients for aspirin, in 77% for beta blockers, and in 88.5% for statins. The proportion of patients treated with beta blockers and/or statins increased over time. The data on aspirin use varied (Table 3). The following posttransplant variables were not significantly different in DM patients transplanted over time: donor type, incidence of delayed graft function, incidence of first-year acute rejection, and body mass index, systolic or diastolic blood pressure, and uric acid levels at 1 year. Pre- and posttransplant variables related to mortality in DM recipients

We next sought to determine the factors related to the mortality of DM recipients from 1–5 years post transplant (Table 4). This time period was selected to allow an analysis

Table 3 | Variables related to recipient survival in patients with DM before transplant Transplant period (years) 1996–2000

2001–2002

2003–2004

2005–2007

91

79

104

138

P-value

Pretransplant Recipient age DM type (% type 2) Insulin use Smoking Pretransplant CV events: Cardiac Vascular Cerebrovascular Hemoglobin

56.4±11 85.6 88.0 30.3 56.0 51.6 16.5 6.6 11.1±1.0

54.2±12 67.4 70.6 9.2 24.1 17.7 7.6 7.6 11.3±1.2

56.8±10 75.0 73.1 13.1 49.0 39.4 7.7 18.3 11.5±1.2

55.1±11 71.1 67.4 28.0 51.8 43.9 18.7 7.3 11.9±1.4

0.369a 0.014b 0.012b 0.001b o0.0001b o0.0001b 0.012b 0.025b o0.0001a

Posttransplant Thymoglobulin (%) Tacrolimus use eGFR3 weeks eGFR1 year Serum creatinine1 year (mg/dl) Serum albumin1 year (g/dl) Hemoglobin1 year (g/dl) Glycosylated hemoglobin1 year Use of aspirin1 year Use of beta blockers1 year Use of statins1 year

48.8 53.9 42.3±15 47.0±18 1.64±0.61 3.83±0.34 12.6±1.7 9.5±2.5 48.6% 58.3% 41.9%

76.9 77.2 38.2±14 47.5±15 1.55±0.50 3.70±0.51 12.1±1.4 8.5±2.2 68.4% 63.6% 63.3%

90.4 93.3 41.2±12 51.7±15 1.44±0.47 4.00±0.38 13.0±1.6 7.2±1.7 57.1% 72.9% 61.9%

87.8 95.7 46.6±15 55.5±19 1.36±0.42 4.06±0.42 13.1±1.6 7.2±1.5 36.8% 77.6% 60.4%

o0.0001b o0.0001b 0.001a 0.001a o0.0001c o0.0001a o0.0001a o0.0001a 0.009b 0.031b 0.033b

Variables Number of recipients (DM)

Abbreviations: ANOVA, analysis of variance; CV, cardiovascular; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate. a ANOVA. b 2 w. c Mann–Whitney.

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MT Keddis et al.: Survival after kidney transplant in diabetes

a

b 31–60

eGFR: 60

100% 0.9 Patient survival

80%

60%

40%

0.8 0.7 0.6 0.5

20%

0.4 0

7

4

12

00

00

eGFR at 1 year

20

20

05

03

–2

–2

–2 20

19

01

96

–2

00

00

2

0

0%

Transplant period (years)

24 36 48 Months post-transplant

60

72

12 Months

36 Months

60

103

97

76

Figure 3 | Trends in post-transplant estimated glomerular filtration rate (eGFR) in kidney recipients with diabetes. (a) Changes over time in the proportion of patients with diabetes mellitus (DM) eGFR: o30 ml/min per 1.73 m2 (black bars); between 31 and 60 (hatched bars); or 460 (white bars). (b) Five-year mortality among recipients with DM and eGFR o30 (D—D), between 31 and 60 (J—J), or 460 (——). (Log rank Po0.0001).

a

3.9–4.1

Albumin: 4.1

b 1.0

100% 90%

0.9 Patient survival

80% 70% 60% 50% 40% 30%

0.8

0.7

0.6

20% 10%

0.5

0% 00 7

12

–2 20 05

20

03 –

20

04

00 2 01 –2 20

19 96

–2

00 0

0

Transplant period (years)

Serum albumin

24 36 48 Months post-transplant

60

72

12 Months

36 Months

4.1

147

139

120

Figure 4 | Trends in post-transplant serum albumin levels in kidney recipients with diabetes. (a) Changes over time in the proportion of patients with diabetes mellitus (DM) with serum albumin levels at 1 year: o3.8 g/dl (black bars), between 3.9 and 4.1 g/dl (hatched bars), or 44.1 g/dl (white bars). (b) Five-year mortality among recipients with DM and serum albumin o3.8 (K—K), 3.9–4.1 ( þ — — þ ), or 44.1 g/dl (D—D). (Log-rank Po0.0001).

of variables collected at 1 year post transplant and to equalize follow-up time periods. By univariate analyses, the following variables related to higher mortality: older age (HR ¼ 1.507 (1.385–1.639) per every 10 years, P ¼ 0.004), history of major CV events before transplant (HR ¼ 2.776 (1.676–4.599), Po0.0001), dialysis before transplant (HR ¼ 2.329 (1.201– 4.517), P ¼ 0.012), deceased donor transplant (HR ¼ 1.466 Kidney International

(1.114–1.930), P ¼ 0.006), delayed graft function (HR ¼ 2.899 (1.594–5.273), Po0.0001), and higher serum creatinine at 1 year (HR ¼ 2.289 (1.477–3.549) per 1 mg/dl increase, Po0.0001). In contrast, mortality was lower in more recent transplant years (HR ¼ 0.883 (0.817–0.954), P ¼ 0.002), in DM recipients with improved graft function at 1 year (HR ¼ 0.803 (0.756–0.852) per 10 ml/min per 1.73 m2 5

clinical investigation

MT Keddis et al.: Survival after kidney transplant in diabetes

Table 4 | Multivariate analyses of variables related to 5-year mortality in kidney recipients with DM Variables (N) Transplant year Recipient age (10 years) Pretransplant CV events Dialysis pretransplant Donor (deceased vs. living) Delayed graft function Creatinine1 year (change per 1 mg/dl) eGFR1 year (10 ml/min per 1.73 m2) Serum albumin1 year (change per 1 g/dl)

Model 1 (N ¼ 356)

Model 2 (N ¼ 357)

Model 3 (N ¼ 324)

0.858 (0.781–0.941) P ¼ 0.001 1.492 (1.363–1.633) P ¼ 0.010 2.100 (1.171–3.764) P ¼ 0.013 P ¼ 0.187 P ¼ 0.989 3.075 (1.674–5.648) Po0.001 Not included Not included Not included

0.856 (0.781–0.939) P ¼ 0.001 1.419 (1.297–1.553) P ¼ 0.019 2.198 (1.229–3.932) P ¼ 0.008 P ¼ 0.196 P ¼ 0.979 3.017 (1.646–5.528) Po0.0001 1.744 (1.084–2.808) P ¼ 0.022 P ¼ 0.403a Not included

0.892 (0.806–0.987) P ¼ 0.026 1.419 (1.289–1.562) P ¼ 0.058 2.213 (1.177–4.161) P ¼ 0.014 P ¼ 0.323 P ¼ 0.953 2.981(1.587–5.597) P ¼ 0.001 1.785 (1.159–2.750) P ¼ 0.009 P ¼ 0.100a 0.397 (0.219–0.720) P ¼ 0.002

Abbreviations: CV, cardiovascular; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate. a Serum creatinine and eGFR were analyzed in separate multivariate analyses.

increase, P ¼ 0.021; Figure 3b), and in those with higher serum albumin at 1 year (HR ¼ 0.365 (0.223–0.599) per 1 g/dl increase, Po0.0001; Figure 4b). Other variables not statistically related to mortality in univariate analyses included recipient and donor demographics (race and sex), DM type, age at diagnosis of DM, use of insulin before transplant, pretransplant biochemical parameters (hemoglobin, albumin, and lipids), hemoglobin A1c concentration at 1 year, type of immunosuppression, graft function at 3 weeks, acute rejection during the first year, or the use of aspirin, beta blockers, or statins at 1 year. Multivariate analyses (Table 4) showed that the relationship between patient mortality from 1 to 5 years and transplant year was statistically independent of pretransplant variables including recipient age, CV events before transplant, delayed graft function, dialysis, and donor type (Table 4, model 1). Furthermore, the relationship between transplant year and patient survival was independent of allograft estimated glomerular filtration rate (eGFR) and serum creatinine (model 2). Still, over time there was an increased proportion of recipients with eGFR 460 ml/min per 1.73 m2 at 1 year (who have the lowest mortality) and a reduction in the proportion of patients with eGFR o30 ml/min per 1.73 m2 who have high mortality (Figure 3a and b). In the final model (Table 4, model 3), it is noted that the reduction in DM recipient mortality over time was statistically independent of the parallel improvements in mean serum albumin (Figure 4a and b). Interestingly, the impact of transplant year on DM mortality was slightly attenuated by the increase in serum albumin at 1 year (model 3), suggesting that the improvement in serum albumin explains some of the improvement in survival observed over time. DISCUSSION

It is indeed encouraging to note that the mortality of kidney transplant recipients with DM has declined over time, particularly considering that the incidence of DM is increasing and that these patients historically have poor outcomes.6,7,13,14 These results suggest that the improvement in DM patient survival is likely reflective of changes in both pretransplant and posttransplant variables. Regarding the former, the improvement in posttransplant survival has 6

been progressive and parallels the improvement in survival reported in patients with DM in the general population.1,2 In fact, the improved survival of DM transplant recipients is likely to be at least in part a reflection of improvements in the health of patients with DM referred for dialysis and/or transplantation. Consistent with this postulate, the survival of DM dialysis patients waiting for a transplant has also improved in the United States over time (http:// www.srtr.org/publications/Default.aspx; SRTR&OPTN annual report, 2011, slide KI 1.14). Dialysis treatment has been shown to have major implications for posttransplant survival.15,16 Thus, advances in dialysis care likely portend a favorable impact on posttransplant survival. Consistent with this hypothesis, recent studies suggested that better dialysis care could explain the superior survival of transplant recipients in Spain compared with the United States.17 It could be argued that the improvement in DM patient survival might be explained by the selection of patients with lower risk in recent years. However, these analyses do not support this postulate. Admittedly, CV disease assessment and prediction of risk of CV events in kidney transplant recipients remain poor.18,19 These conclusions were emphasized in recent studies showing that posttransplant cardiac risk is better quantified by the biomarker cardiac troponin T than by results of traditional cardiac tests used to assess the presence of cardiac disease.19–21 It is important to note that our selection criteria did not change over the period of this study and that the transplant period analyzed in this study preceded that of our studies on cardiac troponin T and the incorporation of this biomarker into the selection of candidates for kidney transplantation. Additional evidence supports the conclusion that the improved survival of DM recipients is not due to selection of lower risk candidates: first, the reduction in mortality over time was similar in DM recipients with or without pretransplant CV events; second, cardiac risk during the first year post transplant remained increased in DM recipients and unchanged over time. Finally, we did not observe improvements in MACE or survival in recipients without DM. Despite these considerations, these analyses pertain specifically to those patients selected for transplantation who represent only a proportion of all Kidney International

MT Keddis et al.: Survival after kidney transplant in diabetes

candidates evaluated for transplant. Whether the improvement in survival of DM patients after transplantation should encourage expansion of the selection criteria for transplant candidates is a consideration. The analyses of pretransplant variables related to survival were limited by lack of pretransplant information on C-peptide levels, DM control, and the use of cardioprotective medications. Our findings support the hypothesis that changes in posttransplant management and outcomes also contributed to the improvement in DM patient survival. For example, over time the proportion of recipients receiving cardioprotective medications increased, glycemia control improved, serum albumin levels increased, and graft function improved. However, the relationship between transplant year and survival was statistically independent of these posttransplant variables. This may not be surprising as it is likely that the positive survival trends reflect multiple changes in the management of these patients that are difficult to quantitate. For example, the lack of relationship between use of cardioprotective medications and mortality cannot be interpreted as lack of beneficial effects because these medications were likely used preferentially for patients with the highest risk profile. The changes observed in posttransplant serum albumin over time are of particular interest because this parameter relates strongly to transplant patient survival22–25 as well as to the survival of dialysis patients.26–28 Over time there was a striking increase in the proportion of recipients with the highest concentration of serum albumin who also had the lowest mortality. However, the reasons behind the improvement in serum albumin could not be evaluated in this study. Serum albumin concentration is an indicator of nutritional status, proteinuria, and inflammation. However, the relationship between serum albumin and posttransplant mortality could not be explained by proteinuria or inflammation as measured by CRP levels.24 It is reasonable to postulate that improvement in serum albumin reflects an overall improvement in the health of DM recipients, a reduction in the incidence of acute insults, particularly acute rejection,29 and improvement in graft function,8 which also correlates with lower mortality.12,30,31 With regard to the latter, it is interesting to note that in our analyses serum creatinine had a stronger relationship with survival than did eGFR. This likely indicates that serum creatinine reflects other measures of health, such as muscle mass. Similar observations have been made with other parameters closely related to kidney function, such as cystatin C, which also relates better with survival compared with GFR.32 Consistent with data from the general DM population,3 the higher mortality of DM transplant recipients, compared with patients with no-DM, is due to increased risk of CV deaths as well as increased deaths from infections, malignancies, and ‘other’ causes. Of interest, the reduction in CV risk among DM recipients occurred beyond the first year, suggesting that posttransplant variables, rather than pretransplant variables, contributed to the reduced CV risk. This hypothesis Kidney International

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is consistent with the rapid reduction in CV risk that occurs following kidney transplantation regardless of pretransplant characteristics.21,33 The reduction in risk of infection-related death over time was also remarkable as it occurred while more intense immunosuppression was implemented in our program. The relatively small number of deaths due to infection did not permit an in-depth assessment of this interesting outcome. Deaths related to malignancies were higher in patients with DM, compared with no-DM, at all time periods. The increased risk for malignancies among DM patients has been reported in the general population3 and in kidney recipients34 but not in all series.35,36 It is important to note that these studies focused on outcomes during the first 5 years post transplant. Thus, additional studies are needed to determine whether these results are sustained over longer periods of follow-up.37 It should also be noted that the cohort of patients in this study is likely not reflective of the transplant population at large and is more representative of the region of the country and our transplant program (high proportion of Caucasians, living donor, and preemptive transplants). As such, these results may not be generalizable to other transplant populations worldwide. However, in the United States, there appears to be a consistent trend in improvement of survival in DM patients in both the general and the dialysis population, suggesting potential generalizability of these findings at least within the United States. These analyses showed no reduction in the mortality of patients without DM or in the risk for MACE or other causes of death. This finding remains puzzling as improvement in posttransplant parameters related to mortality, namely serum albumin and eGFR, were noted in no-DM recipients as well as in DM patients (data not shown). Perhaps the lack of evidence of improved survival in no-DM recipients is due to the fact that this cohort of patients had excellent survival throughout the study period. It could also be argued that the occurrence of new-onset DM after transplantation may have increased in no-DM patients over time, negatively impacting survival.38,39 However, the incidence of new-onset DM after transplantation in this patient cohort did not increase over time (data not shown). It is evident to clinicians that over the last 2–3 decades the health of patients with DM and advanced renal disease has improved considerably. This clinical impression is confirmed by studies reporting improvements in DM patient survival in the general population1,2 and in those on dialysis. It is likely that these gains translate into benefits in survival post transplant. However, these results also suggest that, despite the high burden of disease, the survival of patients with DM may be modified positively by transplantation and by improvements in posttransplant care.21,33,40 MATERIALS AND METHODS Patient population The cohort included 1688 adult recipients of kidney transplants performed at Mayo Clinic, Rochester, MN, from 1996 to October 7

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2007. Patients with non-renal transplants, including bone marrow transplants, before, at the time of, or after the index kidney transplant were excluded. Specifically, recipients of pancreas transplants were not included in the analysis. The institutional review board approved this study and the collection of data. Clinical and laboratory information was collected from the institution’s electronic databases. Patients with DM before kidney transplantation were identified by searching for the diagnosis of DM in the medical records and/or the use of anti-hyperglycemic drugs. The classification of DM type (1 vs. 2) was limited by the fact that C-peptide concentrations were not available for transplants performed in earlier transplant years. All no-DM patients had fasting glucose measured at least twice before transplant. CV disease assessment before transplant The protocol used to evaluate for the presence of CV disease before transplant was described previously20 and is based on the identification of patients at high CV risk using clinical parameters, including the presence of DM, age 459 years, history of major CV events before transplant, and/or dialysis for 42 years. Patients meeting one or more of these criteria undergo a dobutamine stress echocardiogram, and, if stress-induced ischemia is noted, patients are referred for cardiology consultation, consideration of coronary angiography, and possible intervention. Major CV events before and after transplant were classified as cardiac, vascular, and cerebrovascular. MACEs included acute myocardial infarction and/or surgical or angiographic coronary intervention; vascular events included surgical or percutaneous lower extremity revascularization for peripheral vascular disease or limb amputation and central vascular events including abdominal aortic aneurysm, carotid artery, and/or renal artery stenosis requiring surgical or percutaneous intervention; cerebrovascular events included ischemic or hemorrhagic cerebrovascular accidents. The use of cardioprotective medications (aspirin, beta blockers, or statins) was recorded at 1 year post transplant.

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patient death, graft failure, non-renal transplant, or the time of study completion. Causes of death were obtained by review of medical records and death certificates when available and classified as CV, infectious, malignancy, other, or unknown.6,41 DISCLOSURE

All the authors declared no competing interests.

ACKNOWLEDGMENTS

We thank the Mayo Clinic transplant coordinators for their tireless efforts in patient follow-up and data collection. These studies were supported by grants from the Mayo Clinic Division of Nephrology and Hypertension.

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