Dual Transplantation of Marginal Kidneys From Nonheart Beating Donors Selected Using Machine Perfusion Viability Criteria

Transplantation/Vascular Surgery Dual Transplantation of Marginal Kidneys From Nonheart Beating Donors Selected Using Machine Perfusion Viability Criteria Alex Patricio Navarro,* Soroush Sohrabi, Mettu Reddy, Noel Carter, Ahmed Ahmed and David Talbot From the Liver and Renal Transplant Unit, Freeman Hospital, Newcastle-upon-Tyne and University of Sunderland (NC), Sunderland, United Kingdom

Purpose: Viability testing can be used to avoid the transplantation of nonheart beating donor organs that are likely to have primary nonfunction. Such testing also identifies a second group of kidneys which, although unsuitable for solitary transplantation, may be considered for dual transplantation. In kidneys in this group solitary transplants would be unlikely to produce a sufficient glomerular filtration rate to support the recipient. However, if used together as a dual transplant, they have the potential to produce sufficient renal function in 1 patient. Materials and Methods: The group at our unit has performed 23 dual nonheart beating donor renal transplants from 2003 to date. Using 3 and 12-month post-transplantation recipient glomerular filtration rates as primary end points we compared our dual transplant group with our series of 115 single nonheart beating donor transplants from 1998 to 2006. Results: At 3 and 12 months mean glomerular filtration rates in the dual group were 46.2 and 45.5 ml per minute per 1.73 m2, respectively. These values were not significantly different from the mean glomerular filtration rates of 40.7 and 43.0 ml per minute per 1.73 m2, respectively, in the single transplant group. Conclusions: We have observed that a subset of nonheart beating donor kidneys that do not satisfy the viability criteria for single organ transplantation may become successful dual organ grafts, thus, avoiding unnecessary organ nonuse and maximizing organ resources. Key Words: kidney, kidney transplantation, tissue donors, warm ischemia, tissue survival

idneys transplanted from NHBDs are generally regarded as marginal grafts due to their association with warm ischemic injury. The degree of warm ischemia sustained by NHBD grafts is related to the Maastricht criteria with the most prolonged periods occurring in category II (uncontrolled) donors (see Appendix). Prolonged warm ischemia results at best in DGF and at worst in PNF. In the United Kingdom the demand for kidneys continues unabated, prompting interest in the use of marginal organs to increase the donor pool.1– 4 Concerns exist regarding the outcomes of such grafts with several groups reporting increased rates of DGF and PNF.5–7 However, many series have shown encouraging short-term and medium term functional and graft survival outcomes using organs from these donors.1– 4 In addition, it has been shown that marginal kidney transplantation is associated with a significant survival benefit over that of maintenance on dialysis.8 Kidneys from NHBDs have often sustained a significant degree of ischemic injury. As a result, it is necessary to assess the extent of this injury before transplantation to determine whether viability thresholds have been

K

Submitted for publication October 10, 2007. Supported by Newcastle-upon-Tyne Hospitals National Health Service Foundation Trust and Northern Counties Kidney Research Fund. * Correspondence: Liver and Renal Transplant Unit, Freeman Hospital, High Heaton, Newcastle-upon-Tyne, NE7 7DN, United Kingdom (telephone: ⫹44 1661854956; FAX: ⫹44 7939549887; e-mail: [email protected]).

0022-5347/08/1796-2305/0 THE JOURNAL OF UROLOGY® Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION

breached.9,10,11 Our group has reported that viability testing can be used to avoid transplanting organs that are likely to have PNF.1 Such testing also identifies a second group of kidneys which, although unsuitable for single transplantation, may be considered for dual transplantation. In kidneys in this group solitary transplants would be unlikely to produce a sufficient GFR to support the recipient. However, when used together as a dual transplant, they could potentially produce sufficient renal function in 1 patient.

MATERIALS AND METHODS At our center NHBD renal transplantation relies on a rapid response retrieval team, which allows the establishment of early organ preservation interventions in controlled and uncontrolled donor situations. Following organ retrieval all NHBD kidneys undergo hypothermic machine perfusion, which allows viability assessment. This involves the calculation of PFI, defined as the flow per 100 gm renal mass divided by systolic pressure,1,9,10,12 and the measurement of perfusate GST, an enzymatic marker of ischemic injury.10 –12 The Newcastle viability protocol for single NHBD renal transplants requires a PFI of 0.4 ml per minute per 100 gm/mm Hg or greater and a GST of less than 100 IU/l/100 gm renal mass.1 All organs with a PFI of less than 0.4 are discarded. However, if GST measurements are above the threshold for single organ transplantation (or occasionally due to other factors, such as donor comorbidity or cold ischemia time), our surgeons may choose a dual transplant.

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Vol. 179, 2305-2309, June 2008 Printed in U.S.A. DOI:10.1016/j.juro.2008.01.113

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DUAL TRANSPLANTATION OF MARGINAL KIDNEYS FROM NONHEART BEATING DONORS

Most dual transplant organs in this study were selected based on viability assessment. Therefore, they had invariably breached the viability criteria deemed safe for single organ transplantation at our center. This precluded the randomization of such organs to single transplantation in the context of a randomized, control trial. Subsequently to determine whether our dual transplants achieved appropriate early functional outcomes a retrospective study was performed. Dual renal transplantation is performed as an ipsilateral procedure at our center, allowing the preservation of 1 iliac fossa for future use as required. In an ipsilateral dual transplant the 2 kidneys from a single donor are implanted into the right iliac fossa with anastomoses to the common (right kidney) and external iliac (left kidney) arterial circulation. The result is a double-deck configuration with the left kidney overlying the right kidney. The ureters are implanted separately as 2 ureteroneocystostomies. Therefore, the procedure necessitates a longer ureter for the cephalad kidney because this ureter must exceed the length of the caudal kidney and allow tensionfree ureteroneocystostomy. The second WIT for dual transplants is reported as the mean of the second WITs of the 2 organs. The group at our unit has performed 23 dual NHBD renal transplants to date. Using post-transplantation recipient GFRs at 3 and 12 months as the primary end points we compared the dual transplant group with our series of 115 single NHBD transplants. GFR in ml per minute per 1.73 m2 was estimated from patient age, sex, ethnicity, serum creatinine, urea and albumin using the extended Modification of Diet in Renal Disease formula.13 Secondary end points were the DGF, PNF and organ discard rates. DGF was defined as insufficient initial graft function requiring dialysis.14 PNF was defined as permanent graft loss without evidence of function at any point. Statistical analysis was performed using Prism®, version 4.0 for Windows®. Data are expressed as the mean ⫾ SD. Distribution normality was confirmed using the D’Agostino and Pearson omnibus normality test before unpaired t test comparison. Nonparametric analysis of continuous data were performed using the Mann-Whitney U test. Categorical variables were compared using Fisher’s exact test. Statistical significance was considered at p ⫽ ⬍0.05. RESULTS From December 2003 to date our group has performed 23 dual renal transplants, of which 17 were category II and 6 were category III. Of the cases 18 were selected using viable PFI (0.4 ml per minute per 100 gm/mm Hg or greater) with high GST (greater than 100 IU/100 gm) in the 2 organs. The remaining transplants were selected using viable PFIs with high GST plus evidence of poor in situ perfusion in 1, poor in situ perfusion alone in 1, donor comorbidity alone in 2 and long cold ischemia time alone in 1. A total of 115 single NHBD transplants from 1998 to 2006, of which 48 were category II and 67 were category III, were identified for comparison. The dual group contained a greater proportion of category II donors compared to the single group according to the NHBD category II:III ratio (17:6 in 23 cases vs 48:67 in 115, p ⫽ 0.009). Otherwise the dual and single groups were well

matched with no significant differences with respect to donor and recipient age, ischemic time, HLA mismatch, cytomegalovirus mismatch and recipient cardiovascular risk score (table 1). One dual transplant recipient died 8 months after transplantation with a functioning graft. There was no significant difference in the rates of PNF between the groups. Two dual transplants resulted in PNF compared with 11 single transplants (8.7% vs 9.6%, table 2). The incidence of DGF in the dual transplant group was 81.0%, significantly higher than in the single group, in which the incidence of DGF was 59.2% (p ⫽ 0.049). However, no difference was found between the dual group and the single category II donor transplants, in which the DGF incidence was 88.9%. In the 21 functioning dual transplants mean GFR after 3 months was 46.2 ⫾ 17.3 ml per minute per 1.73 m2. In the single transplant group of 104 cases mean 3-month GFR was 40.7 ⫾ 13.7 ml per minute per 1.73 m2. In the dual group 16 recipients have attained 12 months after transplantation. Mean GFR at this point was 44.6 ⫾ 17.2 vs 43.0 ⫾ 15.7 ml per minute per 1.73 m2 in the single group in 81 cases. No significant differences in graft function were observed 3 or 12 months after transplantation (p ⫽ 0.21 and 0.72, respectively, table 3 and fig. 1). Table 4 lists the organ discard rate for each year of the Newcastle NHBD program. When examining these data, it is useful to consider our NHBD program in 3 eras, including 1998 to 2001 (basic protocol) 2001 to 2003 (introduction of streptokinase flush during in situ perfusion) and 2004 to 2006 (establishment of dual transplantation). As previously reported, the introduction of streptokinase produced a significant decrease in the nonuse rate from 49.4% ⫾ 10.0% to 28.8%% ⫾ 2.9% between eras 1 and 2, respectively (p ⫽ 0.0125).15 Introduction of the dual renal transplantation option has also resulted in a decrease in the nonuse rate to 19.1% ⫾ 4.3%, although this did not attain statistical significance (fig. 2). DISCUSSION The concept of nephron dosing suggests that for successful transplantation a critical mass of renal tissue is required to satisfy the metabolic demands of the recipient.16 It could be argued that organs that have sustained acute or chronic injury may, if transplanted, produce less function per unit mass than might otherwise be expected. As the severity of injury increases, a point is achieved at which a single organ graft would result in the transplantation of

TABLE 1. Dual and single group matching for potential confounding factors

Mean ⫾ SD age: Donor Recipient Mean ⫾ SD ischemia time: WIT 1 (mins) WIT 2 (mins) Cold (hrs) No. Maastricht category II/III No. cytomegalovirus mismatch (%) Median recipient cardiovascular score

Dual

Single

p Value

49.9 ⫾ 11.6 52.8 ⫾ 11.4

42.3 ⫾ 15.3 49.9 ⫾ 13.1

NS NS

26.5 ⫾ 6.7 33.1 ⫾ 6.1 21.7 ⫾ 1.8 15/8 4 (23.5) 7

21.5 ⫾ 7.3 38.5 ⫾ 8.0 23.7 ⫾ 4.7 48/67 13 (11.3) 6

NS NS NS 0.009 NS NS

Median HLA mismatch for A, B and DR was 1 (p NS).

DUAL TRANSPLANTATION OF MARGINAL KIDNEYS FROM NONHEART BEATING DONORS 100

TABLE 2. Complications in dual transplant group No. Cases (%)

PNF DGF Acute rejection Ureteral complications/urine leakage Wound dehiscense

2 (8.7) 17 (81.0) 6 (28.6) 2 (9.52) 1 (4.76)

Single

b

c

a

75

eGFR

Complication

2307

d

Dual

a-b p= 0.12 c-d p= 0.72

50

25

There were no cases of vascular thrombosis.

0

insufficient renal mass to support the recipient. The only option available to increase the mass of renal tissue received from such a donor is to transplant the 2 kidneys into a single recipient, effectively doubling the nephron dose. The concept of nephron dosing increases in importance when considering the uncontrolled NHBD situation. The pathophysiological difference between controlled (categories III and IV) and uncontrolled (category II) NHBD organs is warm ischemia exposure. In the controlled NHBD situation organs can be cooled relatively effectively through the combination of peritoneal ice slush introduction after rapid laparotomy and cold in situ perfusion. In the uncontrolled donor intervention during the period between failed resuscitation, cardiac arrest and arrival of the retrieval team is currently impossible. However, even after cold in situ perfusion is established through femoral cannulation the intra-abdominal temperature does not decrease immediately to the temperatures necessary for effective ischemia protection. This is currently only achieved at laparotomy which, after family consent and legal permission are obtained, can be up to 2 hours after death. In 2 typical examples at our center the area under a cooling curve from death to packing of the kidneys was 1,576C minutes in a category III donor compared to 5,869C minutes in the uncontrolled category II NHBD. Dual renal transplantation has been previously reported for ECDs with excellent functional recipient outcomes.17,18 Alfrey et al retrospectively reviewed the outcomes of 52

3 months

3 months

1 year

1 year

Period Post-Transplant

FIG. 1. Median functional GFR outcomes with IQR and data spread in dual and single NHBD grafts 3 and 12 months after transplantation. Significance was determined with unpaired t test.

transplants from ECD donors that had been refused by groups at other centers.17 These organs included 15 dual transplants. In the dual transplants, of which most were from donors 59 years or older with a GFR of less than 90 ml per minute per 1.73 m2, mean sCr at 1 year was 1.6 ⫾ 1.5 mg/dl (141 ␮mol/l) compared to 2.8 ⫾1.5 mg/dl (248 ␮mol/l) in single organ transplants. Therefore, the investigators suggested that organs retrieved from ECDs 59 years or older with a GFR of less than 90 ml per minute per 1.73 m2 would be best used as dual grafts. Using different criteria for age (54 years or older vs younger than 54) later outcome data were reported that confirmed the encouraging performance of 121 dual ECD grafts.18 At 1 year mean sCr in dual graft recipients was 1.7 ⫾ 0.7 mg/dl (150 ⫾ 62 ␮mol/l) compared with that in the single organ group, in which sCr was 2.2 ⫾ 1.0 mg/dl (194 ⫾ 88 ␮mol/l). In a 50-year-old white male these sCr values would represent GFRs of approximately 46 and 34 ml per minute per 1.73 m2 in the dual and single groups, respectively. This suggests that the dual and single ECD transplant groups reported by Alfrey17 and Lu18 et al provided approximately appropriate levels of recipient renal function.

TABLE 3. NHBD dual transplant early outcomes GFR (ml/min/1.73 m2)

Recipient No.

Maastricht Category

Dual Transplant Reason

PNF

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

II II III II II II II II III II II II II III III II II III II III III II III

Long CIT High GST Poor in situ perfusion High GST Diabetes, renal impairment High GST High GST High GST Diabetes, renal impairment High GST High GST Poor in situ perfusion, high GST High GST High GST High GST High GST High GST High GST High GST High GST High GST High GST High GST

No No No No No Yes No No No No No No No No No No No No No No Yes No No

DGF

Mo 3

Mo 12

— Yes Not available Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Not available No No

45 73 24 30 20 — 87 52 40 56 49 28 47 27 58 53 40 50 56 41 — 67 25

67 84 33 39 20 — 22 48 49 52 52 41 Death 20 62 41 43 39 — — — — —

Yes Yes Yes

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DUAL TRANSPLANTATION OF MARGINAL KIDNEYS FROM NONHEART BEATING DONORS TABLE 4. NHBD kidney discard rates in 1998 to 2006

NHBD Program Era (yr) Basic: 1998 1999 2000 Streptokinase: 2001 2002 2003 Dual transplant: 2004 2005 2006

No. Category Discards/Total No. (%) II–IV

II

TABLE 5. Functional outcome at 12 months in dual and single groups by ECD and SCD criteria donor status ECD

No. Dual Transplants

7/16 (43.8) 13/32 (40.6) 19/30 (63.3)

4/10 (66.7) 9/20 (45.0) 16/24 (66.7)

0 0 0

16/32 (50.0) 8/26 (30.8) 8/30 (26.7)

12/18 (66.7) 7/14 (50.0) 5/12 (41.7)

0 0 1

9/34 (26.5) 5/26 (19.2) 3/26 (11.5)

6/16 (37.5) 2/12 (16.7) 2/14 (14.3)

4 5 7

ECDs might generally be expected to perform inferiorly to SCDs on viability assessment because they have had greater exposure to chronic disease processes. Indeed, when the dual and single transplant groups were assessed according to United Network for Organ Sharing ECD/SCD status, ECD donors made up approximately half of the dual group compared to less than 20% of the single group. However, early functional graft performance was unaffected by ECD/SCD status with no significant differences observed between the groups (table 5). Transplanting 2 kidneys into 1 recipient, which then produce an excellent GFR, is a waste of resources. In this situation patients on the waiting list would have been better served by 2 single organ transplants producing 2 significantly lower but sufficient and appropriate recipient GFRs. Equally a dual transplant that produces insufficient function or results in PNF is extremely unwelcome. However, consideration must be given to any transplant procedure that has the potential to provide an appropriate level of recipient renal function and may prevent unnecessary organ nonuse following retrieval. Thus, the decision to use the dual transplant option is a crucial one. In this series kidneys suitable for dual transplantation were identified by several factors, including prolonged cold ischemia time after nonheart beating donation and suboptimal donor stable renal function. However, most kidneys were selected based on viability tests, namely a viable PFI combined with high perfusate GST. Currently PFI is used purely to decide when an organ must be discarded. We are currently examining the possibility of

No. cases (% study group) Mean ⫾ SD GFR (ml/min/1.73 m2)

SCD

Dual

Single

Dual

Single

11 (47.8)

20 (17.4)

12 (52.2)

95 (82.6)

41.7 ⫾ 14.0

42.2 ⫾ 11.0

48.3 ⫾ 21.2

43.2 ⫾ 16.7

Unpaired t test p NS.

using different PFI thresholds for single and dual organ transplantation. In retrospect 2 pairs of kidneys in recipients 2 and 7, respectively, probably had an insufficient flush before machine perfusion, producing an artificially high GST. Therefore, they could have been transplanted singly. After excellent initial progress problems developed with immunosuppressant medication concordance in patient 7, resulting in graft function deterioration. Outcomes in the single group were broadly in line with previous publications from this group1 and the GFRs resulting from our dual transplants from marginal NHBDs correlated well with these outcomes. We have noted that pairs of NHBD kidneys with an individually viable PFI but high GST may be transplanted together successfully as dual grafts. Such kidneys, which do not satisfy the criteria for single organ transplantation, can then go on to produce early recipient renal function that is statistically comparable to that of their single organ counterparts. CONCLUSIONS Using the factors outlined to identify NHBD kidneys suitable for dual transplantation unnecessary organ nonuse is avoided and organ resources are maximized. Early functional outcomes suggest that dual NHBD renal transplants can reliably generate appropriate graft function for recipients. APPENDIX The Maastricht Criteria for NHBDs I II III IV

Dead on arrival Unsuccessful resuscitation Awaiting cardiac death Cardiac death in a brain dead donor

Uncontrolled Uncontrolled Controlled Controlled

Abbreviations and Acronyms Program Evolution

a

Basic Protocol Streptokinase flush Dual Transplant

Discard Rate %

50 40

b

30

c 20 10

a-b p = 0.0125 a-c p = <0.0001 b-c NS

DGF ECD GFR GST NHBD PFI PNF SCD sCr WIT

⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽ ⫽

delayed graft function expanded criteria donor glomerular filtration rate glutathione-S-transferase nonheart beating donor pressure flow index primary nonfunction standard criteria donor serum creatinine warm ischemia time

0 1998-2001

2002-2003

2004-2006

Newcastle NHBD Program Era

FIG. 2. Kidney discard rate according to NHBD program evolution.

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DUAL TRANSPLANTATION OF MARGINAL KIDNEYS FROM NONHEART BEATING DONORS

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donors: single centre experience. Transplant Int 2005; 18: 299. 16. Nicholson ML, Windmill DC, Horsburgh T and Harris KP: Influence of allograft size to recipient body-weight ratio on the long-term outcome of renal transplantation. Br J Surg 2000; 87: 314. 17. Alfrey EJ, Lee CM, Scandling JD, Pavlakis M, Markevich AJ and Dafoe DC: When should expanded criteria donor kidneys be used for single versus dual kidney transplants? Transplantation 1997; 64: 1142. 18. Lu A, Carter JT, Weinstein RJ, Stratta RJ, Taylor RJ and Bowers VD: Outcome in recipients of dual kidney transplants: an analysis of the dual registry patients. Transplantation 2000; 69: 281.

EDITORIAL COMMENT The Newcastle group is at the forefront of extended criteria kidney transplantation and viability testing in the United Kingdom.1 This study shows that it is still possible to stretch the boundaries of what a transplantable kidney is. Those used in this study would normally have been rejected for single transplantation because of high enzyme levels in the machine perfusate. Using dual transplantation the resulting recipient GFR was equivalent to that of a single NHBD kidney that had normal enzyme measurements. The drawbacks of dual transplantation are a longer and more complex operation, a higher rate of ureteral complications since there are 2 ureters, and a higher DGF rate, mainly because the dual transplants were from uncontrolled donors. These problems must be considered in the context of the other option, which is discarding the kidneys and continuing the patient on dialysis. Running a NHBD program is demanding of time and resources, and decreasing the nonuse rate with dual transplants is cost-effective and laudable. These authors used hypothermic perfusion with artificial solutions. Recently normothermic perfusion with blood has been tried in animals.2 Although it is some way from clinical studies, it offers the possibilities of a more physiological viability assessment since the kidney is perfused near body temperature and of resuscitation or biochemical manipulation of the organ. Nicholas R. Brook Department of Urology University of Leicester Nottingham, United Kingdom 1.

2.

Gok MA, Asher JF, Shenton BK, Rix D, Soomro NA, Jaques BC et al: Graft function after kidney transplantation from nonheartbeating donors according to Maastricht category. J Urol 2004; 172: 2331. Bagul A, Hosgood SA, Kaushik M, Kay MD, Waller HL and Nicholson ML: Experimental renal preservation by normothermic resuscitation perfusion with autologous blood. Br J Surg 2008; 95: 111.