Ex vivo normothermic perfusion for quality assessment of marginal donor kidney transplants

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1 Original article Ex vivo normothermic perfusion for quality assessment of marginal donor kidney transplants S. A. Hosgood 1,2,A.D.Barlow 1,2, J. P. Hunter 1 and M. L. Nicholson 1,2 1 Department of Infection, Immunity and Inflammation, Transplant Group, University of Leicester, Leicester General Hospital, Leicester, and 2 Department of Surgery, University of Cambridge. Addenbrooke s Hospital, Cambridge, UK Correspondence to: Dr S. A. Hosgood, Department of Surgery, University of Cambridge, Addenbrooke s Hospital, Cambridge CB2 0QQ, UK ( sarahhosgood@hotmail.com) Background: A significant proportion of kidneys procured for transplantation are discarded because of concerns about their suitability. In this study ex vivo normothermic perfusion (EVNP) was used as a quality assessment device before renal transplantation. Methods: Seventy-four human kidneys deemed unsuitable for transplantation following retrieval underwent 60 min of EVNP with an oxygenated red cell-based solution at 36 C. Receiver operating characteristic (ROC) curves were used to identify thresholds of renal blood flow and urine output. These thresholds and a grading of macroscopic appearance were incorporated into an EVNP assessment score (highest quality, 1; lowest, 5). This was applied to a series of 36 kidneys transplanted after EVNP. Results: In the discarded kidney series, 60 (81 per cent) scored 1 4 and 14 (19 per cent) scored 5. Although none of these kidneys was transplanted, those with a score from 1 to 4 were considered suitable for transplantation. In the 36 transplanted kidneys, the score ranged between 1 and 3 (score 1, 17; score 2, 11; score 3, 8). All of these kidneys were transplanted without any complications or primary non-function. The delayed graft function rate was 6 per cent (1 of 17) in kidneys scoring 1, 0 per cent (0 of 11) in those scoring 2 and 38 per cent (3 of 8) in those scoring 3 (P = 0 024). The mean(s.d.) estimated glomerular filtration rate at 12 months was 51(16), 63(15) and 38(21) ml in kidneys scoring 1, 2 and 3 respectively (P = 0 015). Conclusion: EVNP combined with a simple scoring system is an innovative technology for pretransplant assessment of kidney quality and acceptability for transplantation. This study suggests that a high percentage of retrieved kidneys are being discarded unnecessarily. Presented to the Society of Academic and Surgical Research, Durham, UK, January 2015, and winner of the Surgical Innovations Prize; published in abstract form as Br J Surg 2015; 102(Suppl 5): 1 2 Paper accepted 10 June 2015 Published online 27 August 2015 in Wiley Online Library ( DOI: /bjs.9894 Introduction The proportion of donation after circulatory death (DCD) and extended criteria donor kidneys used for transplantation has increased significantly in the last 5 years 1. Owing to concerns regarding primary non-function or suboptimal renal function after transplant, many retrieved kidneys are subsequently deemed unsuitable for transplantation 2. Particular caution is often needed in DCD kidneys, or older donors, especially when other co-morbidities such as hypertension, diabetes and obesity are also present 3.In the UK in 2012, 6 per cent of donation after brain death (DBD) kidneys and 17 per cent of DCD kidneys were retrieved but not transplanted because of concerns about their suitability 1. At present this decision is based primarily on a subjective evaluation of donor characteristics and macroscopic assessment of the kidney. Objective techniques to assess the quality and viability of an individual kidney would be valuable in this decision process. Re-establishing renal function ex vivo is likely to be an informative measure of organ quality and acceptability for transplantation. Ex vivo normothermic perfusion (EVNP) is a new technique of preservation that restores kidney function by recirculating an oxygenated packed red blood cell-based solution through the kidney at normal body temperature. Preliminary evidence suggests that this improves the condition of a kidney and protects against 2015 BJS Society Ltd BJS 2015; 102:

2 1434 S. A. Hosgood, A. D. Barlow, J. P. Hunter and M. L. Nicholson ischaemia reperfusion injury to reduce rates of delayed graft function (DGF) 4 6. EVNP may also be used as a device to assess the quality of a kidney, and to aid in the decision regarding its suitability for transplantation. The first aim of this study was to develop a pretransplant EVNP assessment scoring system using discarded human kidneys. This second aim was to use EVNP to correlate the EVNP assessment score with post-transplant outcome in a separate series of kidneys transplanted following conditioning with EVNP. Methods Table 1 Ex vivo normothermic perfusion assessment score Score Macroscopic assessment Grade I: excellent perfusion (global pink appearance) 1 Grade II: moderate perfusion (patchy appearance) 2 Grade III: poor perfusion (global mottled and 3 purple/black appearance) Renal blood flow (ml per min per 100 g) Threshold 50 0 Threshold < 50 1 Total urine output Threshold 43 0 Threshold < 43 1 Discarded human kidney series From October 2012 to May 2014, 92 kidneys offered for research after being deemed unsuitable for transplantation by the national organ allocation scheme were used for this project 2. Discarded kidneys with an absolute contraindication to transplantation, such as malignancy, were excluded. Consent for the use of the organs for research was obtained from the donor family by the specialist nurses in organ donation before organ retrieval. Ethical approval was granted for the study by the National Research Ethics Committee in the UK. All kidneys were retrieved by one of the National Organ Retrieval teams. Following in situ flushing of the abdominal organs with University of Wisconsin solution (53 organs) or hyperosmolar citrate (21), the kidneys were removed and stored on ice. Eight kidneys in the series underwent hypothermic machine perfusion. Ex vivo normothermic perfusion After transport to the study centre, kidneys were prepared for EVNP. In brief, the ex vivo kidney perfusion circuit was designed using paediatric cardiopulmonary bypass technology (Medtronic, Watford, UK) and consisted of a centrifugal blood pump (Bio-pump 560), a heat exchanger (Chalice Medical, Worksop, UK), a venous reservoir (Medtronic), 1 4 -inch PVC tubing and an Affinity membrane oxygenator (Medtronic). The hardware included a speed controller, a TX50P flow transducer and a temperature probe (Cole-Parmer, London, UK). Two Alaris infusion pumps (Carefusion, Basingstoke, UK) were also incorporated into the system 5,6. The circuit was primed with a perfusate solution (Ringer s solution; Baxter Healthcare, Borehamwood, UK) and supplements were added to provide a physiological environment. One unit of O-positive blood group packed red cells from the local blood bank was added to the priming solution. Kidneys were perfused at a set mean arterial pressure (70 75 mmhg). The plasma-free red cell-based perfusate was circulated from the venous reservoir through the centrifugal pump into the membrane oxygenator, where it was oxygenated and also warmed to 36 C. It then flowed through the arterial limb of the circuit to the renal artery. Venous return from the renal vein was fed back into the reservoir. Renal blood flow was monitored continuously during EVNP and the total urine output was recorded. Ex vivo normothermic perfusion assessment parameters For macroscopic assessment, each kidney was categorized into one of three groups according to its macroscopic appearance during EVNP as follows: grade I, excellent perfusion (global pink appearance); grade II, moderate perfusion (patchy pink/purple appearance which either remained or improved during EVNP); or grade III, poor perfusion (global mottling and purple/black appearance which remained throughout EVNP). Kidney function was assessed by mean renal blood flow and total urine output during 60 min of EVNP. Derivation of normothermic perfusion assessment score A combination of the macroscopic and functional parameters was used to create an index of organ quality. Receiver operating characteristic (ROC) curves were used to determine thresholds of renal blood flow and urine output to differentiate between macroscopic grades I and II versus grade III. These thresholds were combined with the macroscopic grade to give an overall EVNP assessment score of 1 to 5. Macroscopic grades I, II and III were assigned scores of 1, 2 and 3 respectively. Kidneys with a mean renal blood flow below the threshold were given an additional score of 1. Kidneys producing less than the threshold volume of urine were also given an additional score of 1. Therefore, overall EVNP assessment scores ranged from 1, indicating the least injury, to 5, the most severe (Table 1).

3 Ex vivo normothermic perfusion for quality assessment of donor kidneys 1435 Clinical transplant series The EVNP assessment score derived from the discarded series was then applied to a separate clinical series of 36 kidneys transplanted after EVNP between December 2010 and October Inclusion criteria were: recipient aged 18 years or above; and patient undergoing a renal transplant from a deceased donor. Exclusion criteria were: kidneys that were deemed unsuitable for transplantation owing to absolute or relative medical contraindications, defined as donors known as being human immunodeficiency virus-positive, known or suspected to have Creutzfeldt Jakob disease, active untreated tuberculosis, any malignancy within the past 12 months (excluding brain tumour) or multiple organ failure; and kidneys with irreparable vascular damage. The University Hospitals of Leicester NHS Trust Clinical Ethics Committee, and New Interventional Procedures Advisory Group approved the implementation of EVNP into clinical practice for kidneys from marginal donors. Approval was also granted from the Kidney Advisory Group, and National Health Service (NHS) Blood and Transplant. Written informed consent was obtained from the recipients before the transplant procedure. Ex vivo normothermic perfusion Kidneys were perfused exactly as described for the discarded series, except that 1 unit of blood group-compatible packed red cells was used rather than O-positive blood. Renal blood flow was monitored continuously during EVNP and the amount of urine produced was recorded. After EVNP, kidneys were flushed with approximately 500 ml hyperosmolar citrate (Baxter Healthcare) at 4 Cto remove the red cell-based perfusate and were then placed back in ice until transplantation. Before transplantation, the arterial Carrel patch was excised along with a short segment of vein in order to remove the cannula ligature sites. Transplantation Kidneys were transplanted into the right iliac fossa with anastomosis of the artery and vein to the external iliac vessels, and the ureter to the bladder as an extravesical onlay over a double J stent. Immunosuppression All patients were immunosuppressed with the standard unit regimen of basiliximab (20 mg on days 0 and 4), tacrolimus (0 1 mg per kg per day to maintain trough levels of 6 10 ng/ml), mycophenolate mofetil (500 mg twice daily) and prednisolone (20 mg daily). The regimen in one patient was converted to rapamycin 2 months after transplant because of the onset of diabetes. Outcome measures Primary non-function was defined as failure of a graft ever to function, irrespective of cause. DGF was defined as the need for dialysis within the first week following transplantation (excluding a single dialysis for postoperative hyperkalaemia). Slow graft function was defined as a less than 10 per cent fall in serum creatinine levels on 3 consecutive days in the first 7 days after transplant. The creatinine reduction ratio on day 2 after transplant (CRR2) was calculated. Graft failure was defined as the need for graft nephrectomy or return to renal replacement therapy. Renal allograft rejection was biopsy-proven and classified by the Banff criteria. Statistical analysis Continuous data are presented as mean(s.d.), or median (range) where appropriate. ANOVA was used for analysis of normally distributed data, and Kruskal Wallis test for variables with a non-normal distribution. ROC curves for renal blood flow and urine output were constructed by plotting sensitivity on the ordinate axis and 100 minus specificity on the abscissa. The highest level of sensitivity and specificity was selected for each. Categorical variables were analysed by Fisher s exact test. P < was considered statistically significant. GraphPad Prism 6 (GraphPad Software, La Jolla, California, USA) was used for statistical analysis. Results Discarded kidney series Eighteen kidneys were excluded from the discarded series owing to suspected malignancy, leaving 74 for analysis. Thirty-two kidneys were from DBD and 42 from DCD donors; the study included 17 pairs of kidneys. The most common reasons for decline were inadequate in situ perfusion, past medical history and older donor age (Table 2). Eight kidneys were declined based on perfusion parameters during hypothermic machine perfusion. Six kidneys were discarded because histology showed chronic damage, but this was not formally assessed using a scoring system. The mean warm ischaemia time was 13 3(3 3) (range 6 20) min in the DCD kidneys. The mean cold ischaemia time was 28 7(13 8) (range ) h. Ex vivo normothermic perfusion assessment score Based on the macroscopic appearance, 27 kidneys were graded as I, 31 were graded II and 16 graded III. Two independent observers assessed macroscopic appearance and there was no discordance between their gradings. Renal blood flow was significantly higher in grade I kidneys compared with grade II and III organs (P < 0 001).

4 1436 S. A. Hosgood, A. D. Barlow, J. P. Hunter and M. L. Nicholson Table 2 Reasons for decline of organs 100 No. of kidneys (n = 74) Inadequate in situ perfusion 21 (28) Technical/damage 12 (16) Past medical history 11 (14) Donor age 10 (13) HMP parameters 8 (11) Histology 6 (8) Prolonged ischaemia 5 (7) No suitable recipient 1 (1) Sensitivity (%) 50 HMP, hypothermic machine perfusion. Renal blood flow (ml per min per 100 g) Grade I a Renal blood flow Grade II Grade III 0 a Renal blood flow 100 Sensitivity (%) specificity (%) Total urine output (ml) Grade I b Total urine output Grade II Grade III Fig. 1 a Mean renal blood flow and b total urine output of kidneys graded I, II and III by visual assessment during ex vivo normothermic perfusion for 60 min in the discarded kidney series. Values are mean(s.d.). P < (Student s t test) Grade II kidneys had a significantly higher blood flow than grade III kidneys (P < 0 001) (Fig. 1a). Urine output was similar in grade I and II kidneys, and both produced significantly more urine than grade III kidneys (P < 0 001) (Fig. 1b). Using ROC analysis (Fig. 2), selecting the highest level of sensitivity and specificity, a mean renal blood flow below 50 ml per min per 100 g and urine output of less than 43 ml were chosen as the threshold values for inclusion in the scoring system (Table 3). The overall EVNP assessment scores were 1 (22 kidneys), 2 (18), 3 (15), 4 (5) and 5 (14). 0 b Total urine output specificity (%) Fig. 2 Receiver operating characteristic (ROC) analysis of a mean renal blood flow and b total urine output of discarded kidneys undergoing ex vivo normothermic perfusion for 60 min Table 3 Results of receiver operating characteristic (ROC) curve analysis to determine thresholds of renal blood flow and total urine output differentiating between macroscopic grade I and II versus grade III kidneys Threshold Sensitivity (%) Specificity (%) AUC Mean renal blood flow 88 (62, 99) 72 (59, 83) < 50 ml per min per 100 g Total urine output < 43 ml 94 (68, 100) 81 (69, 90) Values in parentheses are 95 per cent c.i. Mean renal blood flow and total urine output were measured in discarded human kidneys undergoing ex vivo normothermic perfusion for 60 min. AUC, area under the curve. Clinical ex vivo normothermic perfusion assessment series Donor characteristics Twenty-three kidneys were from extended criteria donors, eight from DCD donors and five from standard criteria

5 Ex vivo normothermic perfusion for quality assessment of donor kidneys 1437 Table 4 Donor and recipient characteristics in clinical transplant ex vivo normothermic perfusion series Score 1 (n = 17) Score 2 (n = 11) Score 3 (n = 8) P Donor characteristics Age (years)* 57 2(9 4) 52 2(17 0) 59 8(16 1) Sex ratio (M : F) 6 : 11 3 : 8 5 : Donor type Extended criteria donor Donation after cardiac death Standard criteria donor Hypertension Diabetes Terminal serum creatinine (μmol/l) 78 (58 132) 65 (45 350) 76 (31 282) Recipient demographics Age (years)* 57(12) 54(13) 61(13) Sex ratio (M : F) 12 : 5 7 : 4 5 : Dialysis Predialysis Haemodialysis Peritoneal dialysis Total HLA-A, -B, -DR mismatches Warm ischaemia time (min)* 16(1) 11(1) 11(3) First cold ischaemia time (h)* 10 3(5 3) 11 0(4 3) 13 2(3 3) Duration of EVNP (min)* 67(11) 59(9) 53(14) Second cold ischaemia time (min) 33 (5 300) 35 (15 60) 34 (15 59) Time taken for anastomosis (min)* 28(8) 3(5) 27(8) Total ischaemia time (h)* 12 5(5 8) 13 1(4 6) 15 3(3 2) Hospital stay (days)* 9(3) 10(7) 12(5) Primary non-function Delayed graft function Slow graft function CRR2 < 20% Acute rejection Serum creatinine at 12 months (μmol/l) 128 (76 228) 109 (82 162) 160 ( ) egfr at 12 months* 51(16) 63(15) 38(21) Values are *mean(s.d.) and median (range). EVNP, ex vivo normothermic perfusion; CRR2, creatinine reduction ratio on day 2 after transplantation; egfr, estimated glomerular filtration rate. Fisher s exact test, except ANOVA and Kruskal Wallis test. donors, who were regarded as higher risk. The additional risks were: death from hypoxic brain injury after a cardiac arrest (2), death after a drug overdose (1), carbon monoxide poisoning (1) and intracranial haemorrhage with an 88-min cardiac arrest (1). Four DCD donors also had acute kidney injury with raised serum creatinine levels (over 132 μmol/l) at the time of retrieval. One of these donors also had liver failure. Ex vivo normothermic perfusion assessment score The macroscopic grades of kidneys were grade I (26) and grade II (10); none had a macroscopic grade of III. Nine kidneys had a renal blood below the threshold of 50 ml per min per 100 g and six had a total urine output of less than 43 ml. The overall EVNP assessment scores in the clinical series were 1 (17 kidneys), 2 (11) and 3 (8). None of the kidneys in the clinical series scored 4 or 5. Outcome Table 4 details the donor and recipient demographics and outcome. The three groups were well matched in terms of donor and recipient demographics. EVNP was carried out for approximately 60 min; however, the duration was significantly longer in kidneys with a score of 1 than in those with a score of 2 or 3 (P = 0 012). The duration of the second interval of cold ischaemia was significantly longer in the kidneys that scored 2 (P = 0 004). There was no primary non-function in the clinical series. The overall rate of DGF was 4 of 36 (11 per cent). It was three of eight (38 per cent) in kidneys with a total score of 3 compared with one of 17 (6 per cent) in kidneys with a score of 1 (P = 0 024). There was no significant difference in the rates of slow graft function (P = 0 617) or CRR2 below 20 per cent (P = 0 679) between the groups. The duration of

6 1438 S. A. Hosgood, A. D. Barlow, J. P. Hunter and M. L. Nicholson hospital stay and incidence of acute rejection were similar among the groups (P = and P = respectively). Recipients of kidneys with a total score of 3 had a higher serum creatinine level (P = 0 030) and lower estimated glomerular filtration rate (egfr) (P = 0 015)at12months. There was one graft loss in group scoring 1 owing to withdrawal of immunosuppression after diagnosis of an in situ bladder carcinoma 212 days after transplantation. The overall graft survival rate in the series was 97 per cent (35 of 36) and the patient survival rate was 100 per cent at 12 months. Discussion In this study, EVNP of discarded human kidneys was used to develop a novel scoring system for the pretransplant assessment of marginal kidneys. The scoring system was straightforward, involving a qualitative assessment of the macroscopic appearance combined with measurement of renal blood flow and urine output. In the clinical series of kidneys transplanted after EVNP, a higher overall EVNP assessment score reflected a greater degree of pretransplant injury, and was associated with reduced early graft function and lower egfr at 12 months. Normothermic techniques in solid organ transplantation are increasingly used to expand the marginal donor programme 7,8. Normothermic perfusion can protect against ischaemic damage, to improve graft function. In the heart, lung and liver, recent focus has been on using normothermic techniques to assess organ quality and viability before transplantation. These techniques rely on restoring function ex vivo to provide a full assessment. The level of injury can be determined and, most importantly, a measure of the organ s ability to recover is also examined. In the heart, aortic pressure, coronary flow and differential lactate profiles are used to determine quality 7,9. A lactate level below 5 mmol/l at the end of the perfusion period is considered to be the key criterion for organ transplantation. Gas exchange is a fundamental indicator in lung EVNP 10,11, and in the liver the production of bile is the important parameter 12,13. Reliable and rapid techniques to assess the quality and suitability of a kidney are also essential to ensure the safe expansion of the marginal kidney donor programme. This would safeguard against primary non-function and suboptimal function. During EVNP, kidneys were reconditioned for 60 min with an oxygenated red cell-based solution. Cellular metabolism was restored immediately, allowing measures of renal function to be assessed. The red cell-based solution allowed any abnormalities or areas of inadequate perfusion to be visualized easily. The scoring system in the kidney was based on a combination of the macroscopic appearance and thresholds of renal blood flow and urine output. The scores ranged from 1, indicating the least injured and therefore the highest quality, to 5, the most injured and lowest-quality kidneys. Renal blood flow was used as an index of vascular integrity. The perfusion pressure in the EVNP system was fixed, which allowed the kidney to autoregulate blood flow according to intrarenal resistance. A low renal blood flow indicated a high intrarenal resistance and therefore increased vascular injury or interstitial oedema. An adequate blood supply to the kidney is essential to ensure optimal oxygen delivery to prevent the risk of further ischaemic injury. Urine production was used as a simple index of glomerular filtration and tubular function. The production of urine after transplantation indicates a functioning organ. Production ceases as a result of acute tubular injury caused by ischaemic damage. However, this can be recoverable and urine output per se is likely to be an unreliable marker. The combination of the perfusion parameters (renal blood flow), urine output and macroscopic assessment provides an overall measure of kidney quality. This series of discarded kidneys highlighted the significant variation in the quality of kidneys offered and then declined for transplantation. The most common reason for decline was poor in situ perfusion during organ retrieval. Older donor age and co-morbidities, such as hypertension and diabetes, are also regarded as high risk with the likelihood of suboptimal function Prolonged ischaemia is an important risk factor for early and long-term graft function. The warm ischaemia interval in DCD kidneys is associated with a higher risk of DGF, but at present this does not appear to affect long-term graft survival 17. An important question is how many of these discarded kidneys would have been viable if transplanted. Based on the EVNP assessment scores from the clinical series, it is clear that kidneys with a score of 1 to 3 can be transplanted successfully. The authors also believe that kidneys with a score of 4 would be suitable for transplantation because anuria per se does not mean that a kidney is not usable. Sixty (81 per cent) of 74 kidneys in the present series of discarded kidneys had a score of 1 to 4. Kidneys with an EVNP assessment score of 5 would be very high risk and unlikely to be suitable for transplantation. In the clinical series, 17 kidneys had a total score of 1, 11 a score of 2 and eight a score of 3; none of the kidneys had a total score of 4 or 5. Kidneys with an EVNP assessment score of 3 had a significantly higher incidence of DGF (3 of 8) than those with a score of 1 (one of 17) or 2 (0 of 11). Post-transplant renal function was also significantly worse in these kidneys, with higher serum creatinine levels and a lower egfr at 12 months. Long-term graft survival has yet to be determined in this

7 Ex vivo normothermic perfusion for quality assessment of donor kidneys 1439 series; however, reduced function at 12 months is likely to be predictive of reduced long-term graft survival. The overall rate of DGF in this series of patients was lower than expected at 11 per cent (4 of 36). DGF is common in extended criteria donor and DCD kidneys, and affects approximately 50 per cent of recipients The low rate in this series may be explained by the beneficial effects of EVNP. However, this question can be answered only by adequately powered controlled clinical trials. A larger number of kidneys is also needed to validate the EVNP scoring system. None of the transplanted kidneys had an EVNP score above 3, and so the outcome of kidneys that score 4 or 5 is unknown. Nonetheless, this series suggests that EVNP could be a useful adjunct in the pretransplant assessment of marginal kidneys. There is also scope for EVNP to provide a more detailed assessment. The addition of histological evaluation or the use of biomarkers to determine the severity of renal injury may be advantageous in kidneys with higher EVNP assessment scores to aid the decision process. The clinical decision to decline a number of kidneys in this series can be questioned; however, all of the kidneys were declined by at least five UK centres before being offered for research. This is therefore a reflection of national practice. The clinicians involved clearly did not have enough confidence to accept the kidneys for transplantation. EVNP is a technology in development that may prove helpful in increasing the pool of marginal kidneys that are accepted for transplantation by providing objective measures of kidney quality. A reduction in DGF rates would shorten hospital stay and the technique may prove to be cost-effective, as each perfusion costs approximately In the financial year a total of 262 human kidneys retrieved in the UK were not transplanted because of concerns about quality or viability 21. Assuming the same discard level because of potential malignancy found in the present series, 211 of 262 kidneys could be considered for transplantation. A crude estimate of the influence of EVNP on discard rates can be made on the assumption that kidneys with a score from 1 to 4 could be transplanted successfully. These comprised 81 per cent of the present series and, if this is scaled up to a national level, a total of 171 additional kidneys transplants could have been performed, an annual increase of approximately 10 per cent. Acknowledgements This study was funded by Kidney Research UK, and was also supported by the National Institute for Health Research Cambridge Biomedical Research Centre. 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