http://informahealthcare.com/rnf ISSN: 0886-022X (print), 1525-6049 (electronic) Ren Fail, 2014; 36(4): 526–533 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/0886022X.2013.876348

CLINICAL STUDY

Kidney transplantation outcomes from expanded criteria donors, standard criteria donors or living donors older than 60 years Sophia Lionaki1, Helen Kapsia1*, Ilias Makropoulos1*, Argyro Metsini1, Chrysanthi Skalioti1, Hara Gakiopoulou2, George Zavos1, and John N. Boletis1 Nephrology and Transplantation Department, Laiko Hospital, Athens, Greece and 2Pathology Department, University of Athens, Athens, Greece

Abstract

Keywords

Objectives: To evaluate outcomes in kidney allograft recipients from donors with expanded criteria (ECD) versus standard criteria (SCD) or living donors (LD)460 years. Methods: We studied all patients who received a kidney between 2005 and 2011, focusing in recipients of kidneys from deceased ECD, SCD and LD 460 years. ECD was any deceased donor 460 years or 450 years with two of the following: hypertension (HTN), stroke as the cause of death, or serum creatinine 41.5 mg/dL. We recorded characteristics of the transplant procedure, patient, graft survival and renal function 1 year after transplantation and at the end of follow-up. Results: Sixhundred and five patients were transplanted between 2005 and 2011 in our department. There were 142 (25.1%) transplantations from ECD, 192 (33.98%) from SCD and 96 (16.99%) from LDs older than 60 years. In a mean follow-up time of 36.4 months, graft survival rates were similar for all groups. Calculated GFR was found statistically different between the ECD and SCD groups, but still satisfactory at first year, and at end of follow-up time. Comparison of the patients, who received transplants from ECD, even older than 70 years, and those from LD 460 years revealed equivalent renal function in short and long term. Conclusions: Utilization of marginal kidneys effectively doubled our deceased transplant volume in the period 2005–2011. Patients’ and graft survival were shown similar at the end of follow-up for all groups. Renal outcomes were shown equivalent between the ECD and LD 460 years groups, and although significantly lower between the ECD and the SCD group, were still very satisfactory.

Donor, kidney transplantation, risk factors

Introduction Patients with end stage renal disease (ESRD)1 seeking kidney transplantation (KTX) face excessive waiting times, as a result of the increasing disparity between organ supply and demand.1 The use of kidneys from ECDs is generally accepted, but the challenge remains significant, as longterm maintenance of allograft function is further threatened by donors’ age and co morbidities.2–6 However, clear differences in morbidity and quality of life among dialyzed and transplanted patients7,8 is remarkable, and hence, any chance that permit more patients to benefit from KTX should be examined thoroughly. On the other hand, using kidneys from ECD is still being questioned, and hesitation remains, often circulated, among physicians and patients, because of concerns over diminished survival.2–6 For instance, although in the last decade, the proportion of deceased donors older than 50 years has increased from 21% to 30%,9,10 and the brain death resulting from cerebrovascular causes has *Helen Kapsia and Ilias Makropoulos contributed equally to this manuscript. Address correspondence to Sophia Lionaki, MD, PhD, Nephrology and Transplantation Department, Laiko Hospital, 17 Ag. Thoma Street, 11527 Athens, Greece. E-mail: [email protected]

History Received 10 September 2013 Revised 28 November 2013 Accepted 4 December 2013 Published online 20 January 2014

increased from 26% to 41% among organ donors, the median waiting times have doubled and the kidney waiting list has increased by 260%,1,9,10 while the number of deceased donor kidney transplants has increased by only 16%. Under these circumstances, with the patients in chronic dialysis facing the pivotal problem of accelerated atherosclerosis and advanced mortality, the question to be answered is how realistic is expecting the ‘‘pristine’’ donor.11 We studied all KTXs performed in our center between 2005 and 2011. The purpose of this study was to identify the differences, if any, in terms of outcomes, between KTX from SCD, ECD and older LD and comprehend the clinical impact of the donor quality in graft and patient survival in long term.

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1

Patients and methods Study design and definitions We retrospectively studied 568 patients who underwent KTX in our center between 1 January 2005 and 31 December 2011 (Figure 1). We compiled retrospective databases by thorough medical chart review. The observation period started at the time of KTX, and ended at the time of the most recent followup visit, or the date of patient death (with functioning graft), or the date of graft loss (initiation of permanent dialysis).

DOI: 10.3109/0886022X.2013.876348

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perfusion solution after kidney procurement surgery, and the time when the renal tissue reached physiological temperature during implantation. Preemptive KTX from living donors were excluded from the analysis regarding older LD.

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Donor evaluation

Figure 1. Study design.

We excluded simultaneous kidney-pancreas or liver-kidney cases, patients with ABO incompatible KTX, cases with dual transplants, patients who died or lost the graft due to major surgical complications within the first month, cases with unavailable information in long term and those with noncompliance issues. Kidneys form non-heart beating donors are not used in our practice. We recorded demographics and other characteristics of donors and recipients. The main variable of interest in this study was renal function at first post-transplant anniversary and at end of follow-up, as quantified by serum creatinine and eGFR. The MDRD formula was employed to estimate donor GFR.12 Primary outcomes of interest were patient and graft survival, assessed at the end of the observation period. Delayed graft function (DGF) was defined as the need for dialysis in the first week after KTX, with the duration reflected in the number of required sessions. A diagnosis of acute rejection was suggested by an increase in serum creatinine of 25% or more, from the baseline level, and confirmed by ultrasoundguided percutaneous biopsy. All biopsy proven acute rejection episodes (ARE) were treated on the basis of the histological type, by either intravenous methylprednisolone (3–5 pulses, 500–1000 mg each) with subsequent oral tapering or rATG, or both. Mortality was defined as death from any cause. All cause graft loss was defined as the combination of mortality and death censored graft failure leading to recommence of ongoing dialysis. HLA mismatch was assessed by comparing the HLA types of the donor and the recipient on the basis of six antigens at A, B, and DR loci. We recorded the percentage of panel reactive antibodies (PRA) at the time of KTX, categorizing the patients as having a titer above 30% or a titer above 70%. Pre-transplant dialysis time was considered the length of dialysis before KTX. Cold ischemia time (CIT) was defined as the time after the appliance of the cold

As ECD, was defined any deceased donor older than 60 years, or older than 50 years, also satisfying two of the following criteria: past history of HTN, cerebrovascular cause of brain death, or history of pre-retrieval serum creatinine above 1.5 mg/dL. For the purposes of our study, any deceased donor not meeting the above criteria, i.e., non-expanded criteria donor was defined as SCD. No specific deceased upper age limit was excluded from consideration, although the oldest deceased donor in this series was 81 years old. A history of diabetes was not contraindication to use an ECD kidney, unless the donor had documented proteinuria, or a significant decline in GFR. Selection of ECD kidneys was made on the basis of clinical information, or by combined clinical and histopathological data, when a biopsy was obtained. If the estimated GFR was 470 mL/min then a single-kidney transplant was performed with no further investigation, i.e., histological evaluation. If the estimated GFR was 550 mL/ min, then the kidney(s) were not used. If the estimated GFR was between 50 and 70 mL/min, then a donor kidney biopsy was performed to assist in the evaluation of preexisting and terminal renal parenchymal injury. Generally, if the biopsy showed moderate to severe vascular changes, (necrosis, edema, or atrophy), or moderate to severe interstitial changes (infiltrates or fibrosis), then the kidney was not accepted for KTX. In addition, 450% glomerulosclerosis was an absolute contraindication, while 35–50% glomerulosclerosis was a relative contraindication for kidney utilization. In general, ECDs with other risk factors, such as active infection or malignancy were excluded from consideration. Immunosuppression Immunosuppressive regimens, at the time of KTX were recorded for all patients. We usually administer induction treatment, namely basiliximab or daclizumab, in all patients who undergo KTX. Recipients of kidneys from ECDs with a CIT significantly longer than the mean CIT of our center (i.e., longer than 16 h), or in the occasion of DGF, received subsequent treatment with rabbit Antithymocyte Globulin (rATG) at a dose of 1.5 mg/kg, based on the actual body weight. It was administered through a central line for 10–14 consecutive days and was discontinued earlier if the patient experienced immediate graft function. Pre-medication included bolus hydrocortisone, acetaminophen, and diphenhydramine. The rATG dose was adjusted if the total white blood count was 53000/mm3 or if the platelet count was 580,000/mm3. All patients received treatment with corticosteroids at the time of KTX. They were administered as 500–1000 mg of methylprednisolone during surgery, followed by 20–40 mg/d (depending on the immunological risk) orally, and a gradual steroid taper in the absence of rejection. Maintenance immunosuppression consisted of a calcineurin inhibitor (CIN), namely cyclosporine or tacrolimus, with MPA formulations (mycophenolate mofetil or mycophenolic

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acid in equivalent doses) and methylprednisolone. We maintain our patients on C2 levels of cyclosporine of 700– 900 mg/dL for the first year post-transplant, tending to lower to 500–700 mg/dL afterwards. Goal of tacrolimus trough level was between 6 and 8 ng/mL during the first year and 5 and 7 ng/mL afterwards. However, for patients with kidneys from ECDs the goal level for both CNIs was about 25% lower. Also, CINs were discontinued in case of treatment with rATG, and were reinstituted 1–2 d before its cessation. Patients in high immunological risk were preferentially treated with tacrolimus and an MPA formulation in full dose, and those with a history of cancer were treated with an inhibitor of the Mammalian Target of Rapamycin (mTOR), namely rapamycin or everolimus, aiming at a goal of 6–8 ng/mL, if combined with MPA, and 4–6 ng/mL, if combined with a CNI. Oral MPA was begun immediately postoperatively at 1000 (760) mg twice daily. The MPA dose was adjusted in patients with gastrointestinal intolerance, or if the total white blood count was 53000/mm3. MPA formulations were discontinued temporarily in patients with a life threatening infection, or septicemia, or when the total white blood count was 52000/mm3 and was restarted later at a lower dose. However, long-term interventions included occasional switch from one immunosuppressive agent to the other, such as discontinuation of the CNI and replacement by an mTOR, typically in the light of a biopsy showing chronic allograft nephropathy. Furthermore, such interventions included switch due to unmanageable side effects of an immunosuppressant, i.e., MPA-related colitis, which has been documented by endoscopy and histology. In addition to recording all different types and combinations of immunosuppressants at entry, we recorded alterations of the agents used, i.e., switch from one agent to the other during the follow-up time. Statistical methods Mean values and standard deviations were calculated for continuous variables and categorical variables were presented as percentages. Student t-test procedure was used to examine the potential differences between the groups of this study, namely the ECD, SCD and LD 460 years regarding continuous variables of interest. Chi-square test was applied to check if there is any association between the aforementioned groups with respect to certain categorical variables. Patients were studied from the date of KTX until death, or initiation of permanent dialysis, or the date of last follow-up. The Kaplan–Meier methodology log-rank test was used to compare survival rates. Logistic regression was used to identify any difference in the risk of experience of ARE between groups. The statistical package for the social sciences (SPSS) version 18 was used throughout. p Values of 50.05 were considered statistically significant.

Results Description of the kidney transplant cohort There were 605 KTXs performed between 2005 and 2011 in our hospital. Thirty seven cases were excluded from this study using the exclusion criteria mentioned above (Figure 1).

Ren Fail, 2014; 36(4): 526–533

Hence, the study cohort was consisted of 568 kidney transplant recipients with a mean age of 45.42 years. There were 366 (64.4%) men and the mean pre-transplant dialysis time was 53.42 months. Causes of ESRD included diabetes mellitus (DM), HTN, glomerular diseases, obstructive uropathy and other less frequent causes. The mean HLA mismatch was 3.08 and the mean CIT was 19.5 h. There were 96 (17.5%) patients with a PRA titer more than 30%, and 42 (7.7%) patients with a PRA titer more than 70% detected before the KTX. Immunosuppressive regimens at KTX were recorded as following: a CNI plus an MPA plus corticosteroids was used in 424 (82.9%) patients, a CNI plus mTOR plus corticosteroids were used in 75 (14.64%), and a MPA plus an mTOR plus corticosteroids was used in only 3 cases (0.5%). Related data were missing in seven patients (1.5%) (Table 1).

Table 1. Description of the kidney transplant cohort and the donor pool.

Characteristics of recipients, N ¼ 568 Age (years), N ¼ 559 Gender (Male), N ¼ 568 Pre-transplant hemodialysis time (months), N ¼ 543 HLA mismatches, N ¼ 559 Cold ischemia time (hours), N ¼ 244 Panel reactive antibody 430%, N ¼ 549 Panel reactive antibody 470%, N ¼ 549 Delayed graft function (DGF), N ¼ 554 Hemodialysis sessions, N ¼ 200 Immunosuppression – induction Monoclonal antibodies (basiliximab or daclizumab) Immunosuppression – maintenance Calcineurin Inhibitor (CNI), N ¼ 512 Mycophenolic Acid (MPA), N ¼ 512 mTOR, N ¼ 512 Corticosteroids, N ¼ 511 CNI + MPA + Steroids, N ¼ 512 CNI + mTOR + Steroids, N ¼ 512 MPA + mTOR + Steroids, N ¼ 512 Patients with acute rejection episode (ARE), N ¼ 504 Absolute number of ARE, N ¼ 504 Incidence rate of ARE (per patient per year), N ¼ 504 Follow-up time (months), N ¼ 560 Characteristics of the donor pool Donor source, N ¼ 565 Living donor Deceased donor Age (years), N ¼ 557 Gender (male), N ¼ 568 History of hypertension (HTN), N ¼ 520 History of diabetes mellitus (DM), N ¼ 521 Cerebrovascular event as cause of death (CVE), N ¼ 326 Pre-retrieval serum creatinine 41.5 mg/dL, N ¼ 533 Deceased donor, N ¼ 334 Expanded criteria donor (ECD), N ¼ 331 Non-expanded criteria donor (SCD), N ¼ 331 Living donor, N ¼ 231 Living donor (LD) 460 yrs, N ¼ 225

Frequency N (%) or mean(±SD) 45.4 (±14.08) 366 (64.4%) 53.4 (±41.7) 3.1 19.5 96 42 203 5.7

(±1.2) (±6.2) (17.5%) (7.7%) (36.6%) (3.85)

100%

508 428 78 511 424 75 3 45

(99.2%) (83.6%) (15.2%) (100%) (82.8%) (14.6%) (0.5%) (10.3%)

48 0.03 39.14 (±24.6)

231 334 52.9 366 141 23 185

(40.9%) (59.1%) (±15.7) (64.4%) (27.1%) (4.4%) (56.7%)

146 (27.4%) 142 (42.5%) 192 (57.5%) 96 (42.7%)

Kidney transplantation from marginal donors

DOI: 10.3109/0886022X.2013.876348

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Donor pool characteristics There were 231 kidneys from LD (40.9%) and 334 (59.1%) from deceased donors, while information regarding donor source was missing from medical records in three cases. The mean age of the total donor pool was 52.9 ± 15.7 years. One hundred and ninety two of the deceased donors (57.5%) were older than 60 years, and 161 (48.20%) were between 50 and 60 years. Among the LD, there were 96 (41.55%) older than 60 years. The mean age of the deceased donors was 49.5 years (max: 81 years) and the mean age of the LD donors was 57.98 years (max: 78 years). There were 366 (64.4%) men in the total donor pool. One hundred forty-one (27.1%) donors in general, had a history of HTN, 23 (4.4%) had a history of DM and 146 (27.4%) cases had a pre-retrieval serum creatinine above 1.5 mg/dL. In 185 (56.7%) of the deceased donors, a cerebrovascular event (CVE) was the cause of death. Taken all information together, we identified 142 (42.5%) deceased donors with ECD and 192 (57.5%) donors with non-expanded criteria (SCD). We identified no difference between the two groups regarding recipient age, gender, cause of ESRD, pretransplant dialysis time, mean number of mismatches, and the CIT. The two groups were also similar in terms of the PRA titers (Table 2). We also compared the group of patients, who were transplanted from ECD versus those who received grafts from LD older than 60 years (N ¼ 96). As expected, these groups differed in the recipient age, the pre-transplant dialysis time, the mean number of HLA mismatch, and the percentage of patients with PRA430% or PRA470% (Table 3). The mean percentage of global glomerulosclerosis in the used ECD kidneys was 15%, the mean percentage of interstitial fibrosis was 11.7%, and the mean percentage of tubular atrophy was 11.2%. Kidney transplantation outcomes DGF was recorded in 203 cases (36.6%) in general, requiring a mean number of 5.7 hemodialysis sessions until renal function recovering. In the ECD group, 87/140 patients Table 2. Comparison of characteristics and outcomes between the ECD and SCD groups (all deceased donors).

Characteristic, Mean ± SD Recipient age (years) Recipient gender (F/M) Pre-transplant dialysis time (months) HLA mismatches Cold ischemia time (hours) Panel reactive antibody430% Panel reactive antibody470% Delayed graft function Sessions of dialysis Serum creatinine at first year (mg/dL) eGFR at first year (mL/min) Serum creatinine at end of follow-up (mg/dL) eGFR at end of follow-up (mL/min) Incidence rate of ARE (per patient per year) Follow-up time (months)

experienced DGF versus 96/187 in the SCD group (p ¼ 0.051) requiring a mean number of 6.2 and 5.6 dialysis sessions, respectively (p ¼ 0.293). Of the group of patients, who were transplanted from LD 460 years, 12/94 experienced DGF and were treated with hemodialysis (mean number of 5.5 sessions). Renal function: Serum creatinine at end of first year was 1.65 mg/dL for kidney recipients from ECD versus 1.23 mg/dL for those from SCD (p50.001). Accordingly, eGFR was 49.9 mL/min and 64.6 mL/min, respectively (50.001). Comparison of renal function at end of follow-up time revealed a serum creatinine of 2.07 mg/dL and 1.31 mg/dL for these groups of patients, while eGFR was 49.5 mL/min and 67.9 mL/min, respectively (p50.001, Table 2). Acute rejection: In a mean follow-up time of 39.1 months, 45 patients experienced at least one ARE while related information was missing in 64 cases. We recorded a total of 48 AREs accounting for an incidence rate of 0.03 episodes per patient per year (Table 1). Comparison of incidence of ARE between the ECD and SCD groups revealed different rates, accounting for 0.05 episodes per patient per year for the ECD group, versus 0.01 episodes per patient per year for the SCD group (p ¼ 0.013, OR: 3.204) recorded in a similar time (p ¼ 0.08) (Table 2). On the contrary, incidence rate of ARE was not different between the group from ECDs and LDs (p ¼ 0.521) (Table 3). Patient and graft survival: There were 164 (96.5%) alive patients with functioning graft in the group of patients transplanted from SCD, and 120 (93.8%) in the group of patients transplanted from ECD during the first 5 years post-KTX. For the same groups and during the same time line, there were eight and six alive patients with non-functioning graft, respectively. Hence, cumulative graft survival was found not different between these groups (p ¼ 0.224) (Figure 2). As for the groups of kidney transplant recipients from LD 460 years and ECD, there were 76 (98.7%), and 120 (93.8%) alive patients with functioning graft, respectively, with one and eight additional alive patients with non-functioning graft. Cumulative graft Table 3. Comparison of outcomes between the ECD and LD460 years groups.

Characteristic

ECD N ¼ 142

SCD N ¼ 192

51.7 ± 11.9 58/84 75.6 ± 34.8

50.0 ± 13.1 72/120 78.3 ± 36.7

3.1 ± 1.095 19.6 ± 7.03 37/139 19/139 87/140 6.2 ± 4.1 1.65 ± 0.75

3.07 ± 1.2 19.5 ± 5.6 43/187 15/187 96/187 5.6 ± 3.8 1.2 ± 0.4

0.945 0.904 0.452 0.099 0.051 0.293 50.001

49.9 ± 17.3 2.1 ± 1.9

64.6 ± 18.7 1.3 ± 0.9

50.001 50.001

49.5 ± 22.3

68.0 ± 24.4

50.001

0.05

0.01

0.013

36.4 ± 24.6

41.2 ± 24.8

0.08

p Value 0.230 0.530 0.512

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Recipient age (years) Recipient gender (F/M) Pre-transplant dialysis time (months) HLA mismatches Panel reactive antibody430% Panel reactive antibody470% Delayed graft function Sessions of dialysis Serum creatinine at first year (mg/dL) eGFR at first year (mL/min) Serum creatinine at end of follow-up (mg/dL) eGFR at end of follow-up (mL/min) Patients with at least one ARE, N(%) Incidence rate of ARE (per patient per year) Follow-up time (months)

ECD N ¼ 142 51.7 ± 11.865 58/84 75.6 ± 34.8 3.1 ± 1.095 37/139 19/139 87/140 6.2 ± 4.1 1.65 ± 0.75

LD460 yrs N ¼ 96

p Value

41.9 ± 10.8 50.001 33/63 0.314 18.9 ± 21.35 50.001 2.3 ± 0.9 9/94 6/94 12/94 5.5 ± 2.2 1.6 ± 0.45

50.001 0.001 0.078 50.001 0.597 0.537

49.9 ± 17.3 2.1 ± 1.9

51.765 ± 15.85 1.61 ± 0.5

0.470 0.008

49.5 ± 22.3

49.8 ± 16.15

0.907

16

11

0.05

0.05

0.521

40.0 ± 23.9

0.267

36.4 ± 24.6

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Table 4. Comparison of characteristics and outcomes between the ECD 470 years and SCD groups (all deceased donors).

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Characteristic, Mean ± SD

Figure 2. Cumulative graft survival for the ECD and SCD (non-ECD) groups.

Recipient age (years) Recipient gender (F/M) Pre-transplant dialysis time (months) HLA mismatches Cold ischemia time (hours) Panel reactive antibody430% Panel reactive antibody470% Delayed graft function Sessions of dialysis Serum creatinine at first year (mg/dL) eGFR at first year (mL/min) Serum creatinine at end of follow-up (mg/dL) eGFR at end of follow-up (mL/min) Patients with at least one ARE, N (%) Incidence rate of ARE (per patient per year) Follow-up time (months)

ECD470 yrs N ¼ 30

SCD N ¼ 192

p Value

59.1 ± 9.7 11/19 73.0 ± 27.2

50.04 ± 13.1 72/120 78.3 ± 36.7

50.001 0.931 0.454

3.4 ± 1.1 19.3 ± 5.3 6/29 3/29 22/30 6.2 ± 4.6 1.7 ± 0.75

3.07 ± 1.2 19.5 ± 5.6 43/187 15/187 96/187 5.6 ± 3.8 1.2 ± 0.4

47.5 ± 16.7 2.3 ± 2.2

64.6 ± 18.7 1.3 ± 0.9

50.001 0.031

46.25 ± 21.7

67.96 ± 24.4

50.001

6

7

0.08

0.01

0.01

41.4 ± 23.04

41.2 ± 24.8

0.970

0.116 0.873 0.783 0.716 0.025 0.523 0.004

Table 5. Comparison of characteristics and outcomes between the ECD 470 years and LD460 years groups.

Characteristic

ECD470 yrs N ¼ 30

LD460 yrs N ¼ 96

p Value 50.001 0.818

Figure 3. Cumulative graft survival for the ECD and LD460 years groups.

Recipient age (years) 59.1 ± 9.7 41.9 ± 10.8 Recipient gender (F/M) 11/19 33/63 Cause of ESRD Pre-transplant dialysis 73.0 ± 27.2 18.9 ± 21.35 time (months) HLA mismatches 3.4 ± 1.1 2.3 ± 0.91 Panel reactive antibody430% 6/29 9/94 Panel reactive antibody470% 3/29 6/94 Delayed graft function 22/30 12/94 Sessions of dialysis 6.2 ± 4.6 5.5 ± 2.2 Serum creatinine at 1.72 ± 0.76 1.59 ± 0.45 first year (mg/dL) eGFR at first year (mL/min) 47.48 ± 16.7 51.77 ± 15.85 Serum creatinine at end of 2.3 ± 2.2 1.6 ± 0.5 follow-up (mg/dL) eGFR at end of 46.25 ± 21.70 49.8 ± 16.15 follow-up (mL/min) Patients with at least 6 11 one ARE, N(%) Incidence rate of ARE 0.08 0.05 (per patient per year) Follow-up time (months) 41.4 ± 23.04 39.99 ± 23.9

survival was not different (p ¼ 0.083) (Figure 3). Finally, we compared outcomes of kidneys from ECD donors older than 70 years with and the ones from SCD donors. The related data is presented in Tables 4, 5, and Figure 4. Interestingly, although older than 70 years in this occasion, kidneys from ECD resulted in GFR around 47 mL/min at first year and also were able to preserve this level of renal function until the end of follow-up time, i.e., 41 months later (Table 4). Accordingly, comparison of outcomes between the ECD 470 years group and the LD 460 years group showed no difference (Table 5).

Multivariate analysis for other variables, including age and gender of patients and donors, HLA and immunosuppressive regimens revealed no one them was a predictor of graft survival. Specifically, the p value for age was 0.482, for gender was 0.832 for donor source was 0.174 and for the HLA mismatch was 0.272. Regarding the immunosuppressive regimens we compared the two most frequent regimens, i.e., MPA + CNI + MD versus MPA + mTOR + MD, since the regimen with AZA + CNI + MD accounted for only two patients and thus could not be included in the analysis. The other two regimens accounted for

50.001 50.001 0.110 0.474 50.001 0.597 0.338 0.260 0.130 0.369

0.456 0.774

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DOI: 10.3109/0886022X.2013.876348

Figure 4. Cumulative graft survival for the ECD 470 years and SCD (non-ECD) groups.

N ¼ 372 patients (MPA + CNI + steroids) and N ¼ 45 (MPA + mTOR + steroids) patients respectively. During the follow-up time, there were 22 patients who experienced graft loss. Of these, nine ended up in dialysis due to chronic allograft nephropathy, seven due to thrombosis or bleeding or other vascular complication of the renal vessels, four due to non-compliance, and two due to acute rejection.

Discussion The burgeoning crisis in organ supply challenges the transplant community to the most optimal use of organs from all potential donors. In the period 2005–2011, we almost doubled our deceased donor pool (42.5%) by utilization, after selection, of donors with risk factors, such as age, hypertension or decreased GFR. Graft function at first year was shown statistically different between transplants recipients from ECD and SCD (eGFR; 49.9 mL/min/m vs. 64 mL/min/m, p50.001), but we consider this level of renal function clinically satisfactory, and clearly better than being in a chronic dialysis status. Stratta et al., in an early study in 2004,13 found that calculated creatinine clearance was significantly lower in the ECD population. By definition, ECD kidneys are associated with a greater risk of graft failure when compared with a reference group of non-hypertensive donors who are 10 to 39 years old whose cause of death was not related to a CVE and serum creatinine was below 1.5 mg/dL.1 Later studies showed that using certain criteria to match the donor and the recipient, including histological preimplantation assessment of the graft, may improve outcomes significantly.14 For instance, it was shown15 that by matching donor and recipient using the estimated renal functional mass to recipient size (body mass index525 kg/m2), age440 years and assessment of immunological risk outcomes may be comparable with those from SCD. A very popular concept is

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the one of age-matching to optimize the usage of kidneys from elderly donors in analogues recipients.16–27 However, it seems that giving older kidneys to older recipients, although a common practice, does not improve overall graft survival.16 We follow an evaluation protocol for each ECD donor including a pre-KTX kidney biopsy, when indicated, to avoid the occasion of preexisting, terminal renal parenchymal injury or any other ongoing process that would be an obstacle for KTX. In addition, we generally try to follow the contention that ECD kidneys should not be placed in patients with a high medical or increased immunologic risk condition.13 It is our practice to use a number of maneuvers to minimize CIT, when feasible, front-loaded immunosuppression with rATG to minimize preservation injury and moreover accomplish the state of DGF due to acute tubular necrosis. We target lower tacrolimus levels long term to diminish the drug toxicity effect in allograft function, and when felt comfortable and safe we switch to a CIN sparing regimen using an mTOR inhibitor. These modifications in immunosuppression, including its type and intensity are crucial for the long term maintenance of allograft function, especially for patients, who accept a kidney with additional risk factors related to the donor quality. Nevertheless, the incidence rate of AREs was shown higher in patients who received an ECD kidney (0.05 episodes/patient-year vs. 0.01 episodes/patient-year, p ¼ 0.013). It is possible that using less intensive immunosuppression in these patients may be the reason. However, one should always weigh the cost benefit between the nephrotoxic effect of CNI therapy and the possibility of acute rejection. This question points to the use of mTOR instead of a CNI, for these cases with a diminished nephron mass reservoir. Patients, transplanted from ECD kidneys, who subsequently experienced an ARE, were treated with a CIN plus MPA in 10 cases, and a CIN plus an mTOR inhibitor in 6 cases at the time of rejection. Importantly, none of the 16 patients with ARE had been switched to a different regimen prior to the episode, and none of these patients experienced graft loss afterwards. Several suggestions have been made on the optimal combination of immunosuppressants to preserve renal function following KTX from ECD kidneys. Aull et al.28 recently showed that an early corticosteroid withdrawal regimen of rATG induction, tacrolimus, and mycophenolate mofetil is associated with excellent patient and kidney graft survival in a population consisted of 55% deceased donor kidney transplants, 46% of whom were ECD.28 Another study introduced the idea of a CNI-free regimen in patients receiving ECD kidneys with excellent 2-year patient and graft survival and good renal allograft function although longer follow-up in larger randomized controlled trials are necessary to establish these findings.29 We then compared allograft outcomes between kidney transplant recipients from ECD and LD older than 60 years. Although recipients from LD were significantly younger (mean age at KTX, 41.9 years vs. 51.7 years), their pre-KTX dialysis time was shorter, and had fewer HLA mismatches as expected in living donation, allograft function was equivalent between them, and the patients, who received kidneys from ECD at first year, and at end of a follow-up time (Table 3). This is particularly important for candidates with no possibility for getting a kidney through living donation. Lim et al.30

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studying a large cohort of 6317 renal transplant recipients identified that 5.5% of them had received kidneys from older LD. Older LD in that study were also associated with an inferior 5-year graft function (eGFR of 45 mL/min), when compared with younger LD and SCD.30 In actuality, we performed this analysis because we have repeatedly been in the difficult situation of not acceptance of a deceased ECD organ, by the matched candidate. This is often driven by the nephrologists, who provide dialysis to this certain patient. The dialysis team although absent from the allocation process, often plays a role, by encouraging or not the patient to proceed or not to a KTX from a certain deceased donor. The argument, in such occasions, is the older age of the donor, which creates an environment of uncertainty using only this type of circumscribed information. Undoubtedly, the risk of chronic kidney disease increases disproportionally with age. This is well understood, that, especially looking at the ESRD population, which is markedly influenced by age-related morbidity. Donor age is a surrogate for nephron mass, as older or ECD kidneys have decreased renal blood flow and intrinsic GFR, lose the ability to undergo compensatory hypertrophy and are more susceptible to nephrotoxicity, hypertension, and immune-mediated damage.30 However, in Greece, the vast majority of transplanted kidneys are coming from living donors. According to the current law in our country, are from biologic relatives, i.e., parents and grandparents, and thus typically are older than 60 years. The ECD kidneys on the other hand are by definition from older donors. The vast majority of donors in our study in the ECD group were older than 60 years, while the mean age of the LDs was 57.98 years. This is the main reason why eGFR and graft survival were shown similar between the ECD and older than 60 years LD groups. Additionally, when we compared the outcomes of recipients from LD older than 60 years with the ones from ECD older than 70 years we found that there was no difference between them in term of renal function at first year and at the end of the follow-up period (Table 4). Graft survival was shown similar between groups (Figure 4) with 98.7% and 96.2% of the patients, respectively, being alive with functioning graft. It is realistic to consider that minimization of the CIT and careful selection of organs may lead to equivalent results between ECD kidneys and kidneys from older LD. Therefore, the age motivation not to accept a graft from an older deceased donor is vanishing. In accordance, with our results, Lim et al. found that kidneys from older LD were associated with inferior graft outcomes compared to those from SCD.30 Graft and patient survival from older LD were shown no better than those from ECD kidneys. Yet, Gill et al. observed lower 1- and 5-year eGFR with kidneys from older LD and ECD.32 More importantly, it has been proved that KTX from marginal donors is associated with a significant survival benefit, when compared with maintenance dialysis.2 Considering that the waiting list is a ‘‘waiting to die list’’, since 5% of these patients die every year15 as well as the disparity between organ supply and demand, we think that a more careful look at the questions surrounding the ECD kidney is required. If the longevity of an ECD kidney is 4–6 years compared to 8–12 years of the SCD kidney, as has been estimated,1,2,13 then, appropriate selection

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of organs and educational information on the related statistics to patients in the waiting list should be the goal. The main limitation of this study refers to its retrospective design. Yet, it is probable that future interventions in clinical practice may change the outcomes regarding renal function at the end of first year.31 Another limitation pertains to the use of calculated GFR as a surrogate for measured renal function. However, measured GFR is not commonly used in the clinical practice of KTX, as it is more difficult to acquire, expensive and requires high accuracy in collecting the urine. In conclusion, careful selection of the ECD kidneys, on the basis of placement into low medical risk recipients, along with watchful monitoring of immunosuppression afterwards, makes KTX from such donors safe, and satisfactory in terms of allograft GFR in short and long term. Interestingly, patients’ and graft survival are equivalent with those from older living donors, if certain criteria of evaluation are applied.32 Maybe, another key element in KTX with ECD kidneys, pertains to strategies that will manage to slow the long-term decline in allograft function, with immunosuppressive protocols, which will maximize the functioning time of kidneys33–35 with reduced nephron mass. Finally, continuing comprehensive informational training for kidney transplant candidates, and dialysis teams is essential indeed. It will facilitate the allocation process by retaining patients’ autonomy and exploiting the maximum advantage of all offers.34,36

Declaration of interest The authors declare no conflicts of interests. The authors alone are responsible for the content and writing of this article.

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DOI: 10.3109/0886022X.2013.876348

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