Objectives: In 2011, a pilot program of organ donation after cardiac death was begun at the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, where we hosted one of the largest donation after cardiac death organ transplant programs in the country. We report our initial single-center experiences of kidney transplant from donation after cardiac deaths.

Materials and Methods: From January 2011 to July 2013 at our center, 101 kidney transplants from donation after cardiac death donors were performed. The results of kidney transplants from donation after cardiac death donors were compared with those of 50 kidney transplants from donation after brain death performed during the same time.

Results: Delayed graft function occurred more frequently in donation after cardiac death than donation after brain death kidneys (16.8% vs 4.0%; P = .035). There was no difference in the incidence of acute rejection between donation after cardiac death and donation after brain death kidneys (10.9% vs 6.0%). Actual 1-year graft survival rate was similar (donation after cardiac death 94.4% vs donation after brain death 96.2%). Estimated glomerular filtration rate at 12 months was similar between donation after cardiac death and donation after brain death kidneys (73.8 ± 20.0 vs 77.8 ± 22.7 mL/min/1.73m2).

Conclusions: Kidney transplants from donation after cardiac death donors have comparable short-term outcomes to kidney transplants from donation after brain death donors. Donation after cardiac death can play a crucial role in overcoming the organ shortage in China.

Key words : Kidney transplant, Donation after cardiac death, Delayed graft function

Introduction

In March 2011, at the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, the Chinese Ministry of Health and the Red Cross Society jointly hosted one of the largest donation after cardiac death organ transplant programs in the country.¹ In response to this program, our center began using DCD organs to meet the demand for organs. However, many transplant surgeons in China remain reluctant to use the kidneys from DCD concerned about the quality of DCD organs. Here, we report our initial experience of kidney transplant from DCD donors.

Materials and Methods

Study design
This is a single-center retrospective review of all kidney transplants from DCD performed at our center between January 2011 and July 2013. Our study comprised only controlled DCD kidney transplants. During the same time, 50 kidney transplants from donation after brain death (DBD) donors were performed at our center. All organ donation procedures and kidney transplant opera-tions were approved by our local institutional ethics committee. All protocols conformed with the ethical guidelines of the 1975 Helsinki Declaration and the Declaration of Istanbul which prohibits the use of organs from convicts.

Donation process
In 2011, China developed its own National Protocol for Donation after Cardiac Death.² In this protocol, 3 categories were described: China category I: Organ donation after brain death. China category II: Organ donation after circulatory death (Maastricht category I, II, III and V). China category III: Organ donation after brain death followed by circulatory death (Maastricht category IV). The organ donation and procurement of this study were conducted according to the Chinese protocol for DCD.² Briefly, severely brain-damaged patients or brain-dead patients (diagnosed according to the criteria of Ministry of Health),³ were referred to the personnel from the Guangdong branch of the Red Cross Society of China, who discussed the possibility of organ donation with the family, coordinated between the organ procurement team and transplant team, and witnessed the entire organ procurement process. After detailed consents for organ donation were obtained from all direct relatives (including the donors’ spouses, parents, and children), potential donors were referred to our program.

In brain-dead potential donors, if the relatives of the donor accepted the concept of brain death (with informed consent), we proceeded with the National Protocol for China category I.⁴ Otherwise, we proceeded with the National protocol for China category III. In severely brain-damaged potential donors without definite diagnosis of brain death, we proceeded with the National Protocol for China category II. The decision to withdraw mechanical assistance was made by the patient’s direct relatives. The declaration of cardiac death was made by 2 physicians from the intensive care unit. The blood pressure and oxygen saturation were recorded continually. If death did not occur within 1 hour after withdrawing life support, organ donation would not proceed, and end-of-life care would be continued by the intensive care unit physicians. There were 93 successful deceased donors, including China category I (DBD, n = 31), China category II (Maastricht category III, n = 37) and China category III (Maastricht category IV, n = 25).

Surgical technique of organ procurement
In DCD donors (China category II and III), after declaring death, a further 2 to 5 minutes observation was performed as described in the Chinese guidelines of DCD (2). After the legal 2 or 5 minutes time, the donor was immediately underwent a “super-rapid” procurement technique. In brief, this involves a rapid abdominal incision, rapid cannulation of the abdominal aorta and superior mesenteric or portal vein for perfusion with the University of Wisconsin solution. The intra-abdominal organs were removed en bloc and placed in University of Wisconsin solution at 4°C for storage. In DBD donors (China category I), the super-rapid technique also was adopted.

Definitions
Expanded criteria donor (ECD) were defined by United Network for Organ Sharing criteria as all deceased donors aged ≥ 60 years or donors aged 50 to 59 years with any 2 of the following 3 specific comorbid conditions: brain death from cerebro-vascular accident, history of hypertension, or a serum creatinine level > 133 μmol/L.⁵ Primary graft nonfunction was defined as the requirement for an early posttransplant nephrectomy and/or early, permanent dialysis. Delayed graft function (DGF) was defined by the need for dialysis in the first week after transplant, while slow graft function (SGF) was defined by serum creatinine > 265 μmol/L on postoperative day 5 but no need for dialysis, and immediate graft function defined by as a serum creatinine level < 265 μmol/L on postoperative day 5.⁶

Organ preservation
The kidneys were preserved by pulsatile perfusion preservation using a standardized system (LifePort, Organ Recovery Systems, Chicago, IL, USA) or by static cold storage with University of Wisconsin solution. We had a tendency to pump kidneys with a warm ischemia time > 20 minutes from either ECD or DCD donors. In machine perfusion, kidneys were perfused with Belzer’s hypothermic machine preservation solution (KPS-1, Organ Recovery Systems, Chicago, IL, USA ) at 4°C to 8°C at a systolic pressure of 30 mm Hg, and prostaglandin E1 10 μg in liposome formulation (Beijing Tide Pharmaceutical, Beijing, China) was routinely added to the KPS-1.

Donor selection
Selection criteria were modified from previous report.⁷ Absolute contraindications for use of DCD kidneys included initial donor estimated creatinine clearance < 1 mL/s (using the Cockcroft-Gault formula), malignancy, human immunodeficiency virus serology; warm ischemia time > 90 minutes in an non-ECD and > 60 minutes in an ECD, machine perfusion flow ≤ 1 mL/S or resistance > 0.4 mm Hg/mL/min, and biopsy findings such as > 15% glomerulosclerosis or a Remuzzi sum score ≥ 7.⁸

Immunosuppression
All patients received induction therapy with three methylprednisolone pulses (3 × 500 mg). The majority of the recipients received rabbit antithymocyte globulin (ATG, Thymoglobulin, Genzyme Corp, Cambridge, MA, USA) 1.5 mg/kg/day up to 7 days (range, 3-7 d). The first dose of ATG was given intraoperatively. Subsequent maintenance immuno-suppression consisted of prednisone 20 mg/day with a taper to 5 mg/day by 3 months posttransplant, mycophenolate mofetil 1000 mg twice daily with a taper to 500 mg twice daily by 3 months, and tacrolimus to maintain a target 12 hours’ trough level of 8 to 10 ng/mL for the first 3 months, 6 to 8 ng/mL for months 3 to 6, and 5 to 7 ng/mL after 6 months. Administration of tacrolimus was delayed until the patient had exhibited a brisk diuresis.

Statistical analyses
Results are expressed as numerical values and percentages for categorical variables and as mean ± standard deviation for continuous variables. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 16.0, IBM Corporation, Armonk, NY, USA). Comparisons were based on the chi-square test for categorical data and the t test for normally distributed continuous data. Results were considered significant when P was less than .05.

Results

Donation after cardiac death donors
There were 101 kidney transplants from 62 DCD donors. Mean donor age was 28.4 ± 13.3 years (range, 6-65 y; Table 1), and causes of death included trauma in 56 (55.4%), cerebrovascular diseases in 33 (32.7%), brain tumor in 8 (7.9%), drowning in 2 (2.0%), carbon monoxide poisoning in 1 (1.0%) and suffocation in 1 (1.0%). Twelve donors (11.9%) were ECDs. Mean initial and terminal serum creatinine (SCr) levels were 66.5 ± 13.4 μmol/L and 120.9 ± 86.0 μmol/L (P < .001); mean initial and terminal calculated creatinine clearances (Cockcroft-Gault formula) were 119.9 ± 34.4 and 96.0 ± 50.7 mL/min (P < .001).

Donation after brain death donors
There were 50 kidney transplants from 31 DBD donors. Mean donor age was 29.5 ± 14.5 years (range, 9-58 y), and causes of brain death included trauma in 24 (48.0%), cerebrovascular diseases in 19 (38.0%), brain tumor in 3 (6.0%) and anoxia in 4 (8.0%). Seven donors (14.0%) were ECDs. Mean initial and terminal SCr levels were 66.0 ± 15.0 μmol/L and 120.4 ± 93.6 μmol/L (P < .001); mean initial and terminal calculated creatinine clearances were 122.8 ± 28.3 and 98.0 ± 45.6 mL/min (P < .001).

Donation after cardiac death recipients
The DCD recipient included 64 men and 37 women with a mean age of 45 years (range, 14-70 y), a mean body mass index of 21.7 kg/m², and a mean waiting time of 17.8 months (range, 1-122 mo; Table 2). Causes of end-stage renal disease included glomerulo-nephritis (n = 63, 62.4%), hypertension (n = 13, 12.9%), diabetes mellitus (n = 12, 11.9%), polycystic kidney disease (n = 6, 5.9%), lupus (n = 3, 3.0%), and 4 (4.0%) single other causes. A total of 11 patients (10.9%) were sensitized (panel reactive antibody > 10%), 8 (7.9%) were retransplant patients. Mean human leukocyte antigen (HLA) mismatch was 2.7 (range, 1-6; Table 3). Ninety-eight recipients (97.0%) received ATG induction, compared with 47 (94.0%) in the DBD control group (P = NS).

Donation after brain death recipients
The DBD and DCD recipients were almost similar. Donation after brain death recipients were similar to DCD recipients with respect to age (45.6 ± 12.1 vs 45.0 ± 12.3 y), male sex (66.0% vs 63.4%), retransplant (10.0% vs 7.9%), sensitization (14.0% vs 10.9%), presence of diabetes (12.0% vs 11.9%), body mass index (BMI) (22.0 ± 3.6 vs 21.7 ± 3.7 kg/m²), and mean waiting time (19.8 ± 16.1 vs 17.8 ± 17.2 mo; Table 2).

Transplant characteristics and outcomes
Donation after cardiac death recipients were similar to DBD recipients with respect to HLA mismatch (2.7 ± 1.4 vs 2.5 ± 1.3 months), ATG induction (97.0% vs 94.0%), 1 month estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease equation (58.5 ± 15.5 vs 59.4 ± 15.2 mL/min), 6-month eGFR (67.8 ± 18.3 vs 70.7 ± 17.0 mL/min) and 12-month eGFR (73.8 ± 20.0 vs 77.8 ± 22.7 mL/min). Donation after cardiac death recipients showed shorter cold ischemia time (CIT) (7.5 ± 2.5 vs 12.6 ± 3.4 h; P < .001) and worse perfusion parameters (flow 98.7 ± 24.8 vs 144.2 ± 24.6 mL/min; P < .001; resistance 0.29 ± 0.11 vs 0.18 ± 0.03 mm Hg/mL/min; P = .025) than did DBD recipients (Table 3). More kidneys were pumped in DCD kidneys than in DBD kidneys (34.7% vs 12.0%; P = .003).

After transplant, DCD kidneys showed a lower incidence of immediate graft function (66.3% vs 90.0%; P = .002) and higher rate of DGF (16.8% vs 4.0%; P = .035) and SGF (15.8% vs 6.0%; P = .086). There was no difference in the incidence of acute rejection between DCD and DBD kidney transplants (10.9% vs 6.0%; P = .39; Table 3). All 12 episodes of acute cellular rejection were reversed by ATG therapy. There were 2 episodes of acute humoral rejection, 1 case from DCD kidney transplant was reversed by ATG and plasmapheresis plus low-dose intravenous immuno-globulin as reported by our group,⁹ the other case from DBD kidney transplant was not reversed.

With a mean follow-up of 13 months (range, 1-25 mo), actual patient and graft survival rates for DCD kidney recipients were 99.0% and 97.0%, which were similar to those of the control group of 50 concurrent kidney transplants from DBD (100% and 98.0%; P = NS). Actual 1-year patient and graft survival rates were comparable between DCD and DBD kidney transplants (98.1% vs 100%, 94.4 vs 96.2%; P = NS). There was 1 episode of primary nonfunction (primary graft nonfunction, 1.0%; Table 3) and 1 death in the DCD recipients, 1 patient died of cancer with a functioning graft at 6 months’ posttransplant. There were 2 case of graft failure in DCD group: 1 case of renal graft vein thrombosis occurred at 8 days’ posttransplant and 1 case of renal graft aneurysm occurred at 3 months’ posttransplant. In the DBD recipients, there was no primary graft nonfunction, no patient death, and only 1 case of graft loss owing to acute humoral rejection occurred at 14 days' posttransplant.

Discussion

In this single-center cohort study of controlled DCD kidney transplants, we found that with shorter CIT (7.2 ± 3.4 h), the incidence of DGF of kidney transplants from DCD donors was low (16.8%). The 1-year graft survival rate and graft function of DCD kidney transplants are comparable to those of DBD kidney transplants.

From January 2011 to July 2013, one hundred fifty-one kidney transplants were performed from deceased donors in our center, about two thirds were from DCD kidneys. As showed in Table 3, DCD group showed a higher incidence of SGF (15.8% vs 6.0%; P = .086) and DGF (16.8% vs 4.0%; P = .035), although the difference in SGF was not statistically significant. Actually, SGF is a similar state to DGF, only to a lesser degree. The DGF rate of our DCD kidney transplants (16.8%) was lower than the DGF rate of DCD kidney transplants from United Network for Organ Sharing Standard Transplant Analysis and Research Files (38.7%).¹⁰ Fewer DGF of our group may ascribe to the short CIT (7.2 ± 3.4 h). Locke and associates reported limiting cold ischemia to < 12 hours can decrease the rate of DGF to 15% among DCD kidney transplants from donors < 50 years.¹⁰ The association of increased incidence of DGF and extended CIT in kidney transplants from DCD also has been demonstrated by Pine and colleagues.¹¹ The short CIT of our DCD kidney transplants benefited from the current organ sharing policy in China–the DCD organs are first shared locally. To minimize the CIT, recipients are admitted and prepared before donor surgery. Effective communication between the donor team and the recipient transplant team is mandatory.

Following the still widely accepted traditional recommendations, that kidneys with low flow and high resistance (> 0.4 mm Hg/mL/min) are at risk for primary nonfunction,¹² we discarded kidneys with insufficient perfusion parameters (flow ≤ 60 mL/min or resistance > 0.4 mm Hg/mL/min). We found that kidneys from DBD donors showed higher flow and lower resistance in pump than do kidneys from DCD donors. In DCD kidney transplants, renovascular resistance in machine perfusion was significantly and independently associated with primary graft nonfunction and DGF.13 Hypothermic machine perfusion may improve outcomes after transplant of kidneys from DCD donors. Jochmans and associates showed that machine perfusion preservation reduced the incidence of DGF from 69.5% to 53.7% (adjusted odds ratio: 0.43) in kidney transplants from DCD compared with static cold storage. But 1-year graft and patient survival was similar in both groups.¹⁴ In contrast to the aforesaid study, Watson and associates found that there was no difference in the incidence of DGF preserved by machine perfusion or cold storage in kidney transplants from DCD.¹⁵

The presence of DGF is an early surrogate marker of organ quality and preservation. It represents a combined response to a series of ischemic, reperfusion, inflammatory, and immunologic injuries. Delayed graft function is a form of acute renal necrosis, which results in posttransplant oliguria, increased allograft immunogenicity, risk of acute rejection episodes, and decreased long-term survival.¹⁶ It seems that DGF of kidneys transplant from DCD donors does not affect short-term renal graft survival. Nagaraja and associates reported that neither DGF nor acute rejection affected the 1-year graft survival rate in DCD recipients, whereas in DBD recipients, the 1-year graft survival rate was worse in the presence of DGF and 4-year death-censored graft survival was worse in the presence of acute rejection.¹⁷ Singh and colleagues showed similar results, despite higher rates of DGF and acute rejection in DCD donor kidney transplants, patient and graft survival were similar to DBD donor kidney transplants. Donation after cardiac death donor kidney transplants with DGF had lower 2-year mean serum creatinine level than DBD kidney transplants experiencing DGF.¹⁸ There may be different pathogenesis of DGF in kidney transplants from DCD or DBD donor, which results in the different effect of DGF on the graft survival of kidney transplants from DCD or DBD.

In summary, kidneys from DCD donors have excellent short-term clinical outcomes in terms of graft survival and function. Donation after cardiac death can play a critical role in overcoming the extreme organ shortage in China.

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