The First Clinical Case of Intermediate Ex Vivo Normothermic Perfusion in Renal Transplantation

Authors

  • S. A. Hosgood,

    Corresponding author
    1. Department of Infection, Immunity and Inflammation, Transplant Group, Leicester General Hospital, University of Leicester, Leicester, UK
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  • M. L. Nicholson

    1. Department of Infection, Immunity and Inflammation, Transplant Group, Leicester General Hospital, University of Leicester, Leicester, UK
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Abstract

A short period of ex vivo normothermic perfusion (EVNP) immediately before transplantation can revive the kidney and reduce the effects of cold ischemic (CI) injury. Herein, we report a clinical case of EVNP carried out at an intermediate period of the preservation interval. The kidney was retrieved from a 63-year-old extended criteria donor. After 10 h 29 min of CI the kidney underwent EVNP with 1 unit of compatible packed red blood cells mixed with a priming solution at 35.0°C while the recipient was being prepared for surgery. The mean renal blood flow was 93.6 mL/min/100 g and the kidney produced 60 mL of urine. Shortly after the start of surgery the first intended recipient became unfit for transplantation. After 60 min EVNP the kidney was flushed with cold preservation solution and re-packed in ice. The second period of CI was 5 h and 21 min. The kidney was transplanted without any complications into a 54-year-old predialysis patient. The recipient had immediate graft function with serum creatinine levels falling from 315 to 105 µmol/L by day 7. This is the first report of an intermediate period of EVNP in clinical renal transplantation. This case demonstrates the feasibility and safety of the technique.

Abbreviations
CI

cold ischemia

CMV

cytomegalovirus

ECD

extended criteria donor

eGFR

estimated GFR

EVNP

ex vivo normothermic perfusion

IRI

ischemia reperfusion injury

Introduction

Transplanting kidneys from extended criteria donors (ECDs) offer an added survival benefit to patients compared to remaining on the transplant waiting list [1]. Nonetheless, ECD kidneys have the distinct disadvantage of high rates of early graft dysfunction and shorter graft survival compared to kidneys from standard criteria donors [1].

A short interval of ex vivo normothermic perfusion (EVNP) after hypothermic preservation is a new technique of preservation that is designed to revive the kidney and reverse some of the detrimental effects of ischemic injury to improve early graft function [2]. Kidneys are perfused under “ideal conditions” with a red cell based solution to support oxygen delivery and renal metabolism [3]. Experimental evidence has also shown that during EVNP, protective mechanisms are up-regulated which help to reduce the severity of ischemia reperfusion injury (IRI) [4].

After EVNP, it is necessary for the kidney to undergo a second period of hypothermic preservation to remove the red cell based solution and cool the kidney in preparation for transplantation. In practice, this is limited to approximately 30 min. Nonetheless, EVNP may also be beneficial if carried out at an earlier stage. Evidence from several historical, experimental studies suggests that a short period of EVNP in the middle of the preservation interval may protect the kidney against additional cold ischemic (CI) injury [5-7]. Herein, we report a case of intermediate EVNP in clinical kidney transplantation.

Methods

The kidney was from a 63-year-old female ECD who died of an intracranial hemorrhage and had a past medical history of Guillain–Barré syndrome. The terminal serum creatinine was 57 µmol/L and the donor was cytomegalovirus (CMV) positive. The kidneys were retrieved after in situ flushing and cooling with University of Wisconsin solution by the National Organ Retrieval Service. The kidneys were packed in ice and transported to the recipient centers. On arrival, after 10 h 29 min of CI, the right kidney was prepared and underwent EVNP for 60 min as previously described (Figure 1) [3].

Figure 1.

Ex vivo normothermic perfusion system. The renal artery vein and ureter were cannulated and the kidney was perfused with 1 unit of compatible packed red blood cells mixed with a priming solution. The kidney was perfused at a mean arterial pressure of 60 mmHg and temperature of 35.0°C for 60 min.

The mean renal blood flow was 93.6 mL/min/100 g and intra-renal resistance 0.16 mmHg/mL/min/100 g during EVNP. The kidney produced 60 mL of urine and appeared pink and evenly perfused throughout perfusion. After the 60 min of EVNP, the kidney was flushed with 1 L of hyperosmolar citrate (Soltran®; Baxter Healthcare, Thetford, UK) before being re-packed in ice. Prior to transplantation the arterial Carrel patch was excised along with a short segment of vein in order to remove the cannula ligature sites. The preperfusion biopsy showed mild intimal fibrosis and elastic reduplication but no significant histological abnormalities.

The intended recipient was a 56-year-old male with end-stage renal failure. However, the patient had an anaphylactic reaction to penicillin shortly after the start of surgery and while the kidney was undergoing EVNP. The patient was resuscitated in theater then transferred to the intensive care unit.

A second suitable recipient was identified. She was a 54-year-old female predialysis patient with end-stage renal failure with an estimated GFR (eGFR) of 12 mL/min. The HLA mismatch was 2–1–2 and the recipient was CMV negative. The second period of CI was 5 h and 21 min. The kidney was transplanted without any complications. The renal vein was anastomosed end to side to the external iliac vein and the renal artery was anastomosed end to side to the external iliac artery. The anastomosis time was 30 min.

The patient was immunosuppressed with the standard unit regimen of basiliximab (20 mg on days 0 and 4), tacrolimus (0.1 mg/kg/day to maintain trough levels of 6–10 ng/mL), mycophenolate mofetil (500 mg twice daily) and prednisolone (20 mg daily).

The recipient had immediate graft function and serum creatinine levels fell from 315 µmol/L preoperatively to 105 µmol/L by day 7 posttransplant (Figure 2). The mean urine output over the first 5 days posttransplant was 4115 mL/day. She was discharged from hospital 7 days posttransplant. Her renal function remained stable and at 1 and 2 years the serum creatinine and eGFR were 117, 107 µmol/L and 44, 49 mL/min, respectively. The recipient did not have any other complications or incidences of rejection.

Figure 2.

Serum creatinine (Cr) levels pretransplant and up to 7 days posttransplant.

Discussion

Optimizing kidney grafts using EVNP offers immense potential to improve marginal donor transplantation. Foremost, this first reported case of intermediate EVNP in man has shown that there were no untoward effects of the additional CI insult. This implies that this technique of renal preservation is feasible and safe.

The combination of older donor age and CI injury increases the likelihood of early graft dysfunction and reduces graft survival [8]. Strategies to reduce the length of preservation have proved successful in improving the outcome of these kidneys [9]. A reduction in the CI time from 19 to 12 h in a series of ECD kidneys improved graft survival from 79% to 86% at 12 months [9]. However, reducing the preservation time is not always practical. EVNP can be used to improve graft quality by reversing some of the detrimental effects of CI injury. In our reported series of EVNP in ECD kidneys, the delayed function rate was 5.6% compared to 36.2% in a similarly matched cohort of patients whose kidney underwent static cold storage alone [2]. In this present case, the recipient had initial graft function despite nearly 17 h of preservation.

Although further evidence is needed, EVNP at an intermediate interval may also be an effective way to reduce the effects of CI injury or perhaps extend the length of preservation. Canine studies have shown that viability can be enhanced and the preservation interval increased twofold by a period of intermediate normothermic perfusion [5, 7]. The exact mechanisms of protection remain speculative. However, the benefits are thought to include restoring energy metabolites and circulation to protect the endothelium and cellular membranes. This may enhance tolerance to CI and IRI.

Significant developments have been made in the optimization and assessment of lungs with ex vivo lung perfusion. A recent case reported by Wigfield et al [10], demonstrated the successful re-conditioning of a pair of marginal lungs after a period of hypothermic preservation at an organ repair center. After assessment the lungs were cooled and transported on ice to the recipient center [10]. This concept could be applied to the kidneys to optimize their condition before transferral to the transplanting center.

In conclusion, EVNP applied at an intermediate stage of the preservation interval is feasible and safe. Furthermore, it may be an effective way to reduce the effects of CI injury or perhaps extend the length of preservation.

Acknowledgments

Kidney Research UK for their financial support.

Disclosure

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

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