Renal transplantation has become an accepted treatment for end-stage renal failure in cats. However, renal transplantation in cats has unique challenges with respect to the inherent difficulty of the surgical techniques and perioperative management required to maximize the potential for survival of both the graft and patient. Protocols and techniques used for renal transplantation in veterinary species have continued to evolve, particularly in the last decade, as more institutions have gained experience with the procedure.
In human medicine, donated kidneys (grafts) are frequently obtained from brain-dead patients who are located some distance from a regional transplant center1; therefore, the grafts routinely undergo ex vivo CS to maintain their viability during the time required for tissue typing and extensive donor-recipient matching analyses and transport to the facility where the transplantation into the recipient will occur. Hypothermic machine perfusion of ex vivo kidneys is also used in human medicine to help minimize delayed graft function and increase graft survival.2 Ex vivo CS of donated kidneys was not performed when renal transplantation was first developed in cats because the grafts were generally obtained from unrelated but allogeneic living donors and all donor-recipient matching analyses were performed prior to graft harvest.3 Furthermore, donor and recipient operations were frequently performed simultaneously at the same facility and prolonged ex vivo storage of the graft was not necessary.
The approach to transplantation in which the donor and recipient undergo simultaneous surgeries (IT) results in the graft being exposed to warm ischemia for a finite period from clamping of the renal vasculature and removal of the kidney from the donor to completion of vascular anastomoses in the recipient and removal of the vascular clamps. Some degree of renal injury, including the potential for acute or chronic dysfunction, is expected to result from that period of ischemia. Ischemic injury is minimized by limiting the time between clamping the renal vasculature in the donor and removing the clamps following vascular anastomoses in the recipient to preferably < 1 hour, a goal that pressures surgeons to hasten an already demanding technical procedure. Currently, it is unclear to what extent that ischemia contributes to slow or delayed graft function in recipient cats. Results of studies4,5 involving cats that underwent experimental renal transplantation by use of IT without CS indicate that the procedure results in some extent of acute graft dysfunction, which is typically characterized by abnormally increased serum creatinine concentrations after surgery. However, the complexity of the transplantation procedure makes it difficult to determine whether the impaired graft function is a direct result of ischemic injury or associated with technical problems inherent to the procedure. Clinical descriptions of CS methods for feline kidneys are limited, although results of some studies4–6 suggest that flushing ex vivo kidneys with a sucrose phosphate solution followed by CS resulted in peak posttransplantation serum creatine concentrations in recipient cats that were equivalent to or substantially less than those in cats that received a kidney by use of the IT procedure (ie, no CS) even when CS lasted up to 3 hours, which is substantially longer than the period of warm ischemia during the IT procedure.
In human medicine, CS of grafts has been routinely used to suppress warm ischemic injury for nearly 40 years.7 Most mechanisms of warm ischemic injury are mediated by enzymatic processes, and consequently, the rate of activity for those mechanisms is temperature-dependent. Cold temperatures have been used to slow the rate of cumulative ischemic cell damage and extend the period of time that grafts can be feasibly stored ex vivo with minimal injury. Cold storage is an effective ex vivo storage method for a wide variety of solid organs from various species.8–11 However, the tolerance of feline kidneys to CS is unknown, although in 1 case series,12 postoperative graft function was described as excellent for kidneys that had been preserved by CS for up to 7 hours prior to transplantation. In dogs under ideal conditions, successful graft function has been achieved following transplantation of kidneys stored for up to 6 days in simple static CS and up to 7 days with the use of continuous perfusion methods.13–15
In current clinical practice and most experimental studies, long-term storage of feline kidneys intended for transplantation is not necessary because the ex vivo period for most grafts is measured in minutes rather than hours or days. Therefore, the magnitude of any potential advantage provided by CS on the immediate function of a graft following transplantation is unknown. The sensitivity of feline kidneys to CS has not been established. Additionally, in cats, the effect of short-term warm ischemia on graft function, compared with the effects of confounders associated with the surgical procedure such as ureteral spasm and transient ureteral obstruction, is likewise unknown. Ultrasonographic evaluation of renal grafts is a rapid and sensitive method that can be used to facilitate assessment of those confounding factors on graft function following transplantation.
The RI is a unitless measure that describes the pulsatility of the intrarenal arterial time-velocity waveform and is independent of both insonation angle and Doppler frequency.16 Sonography and measurement of the RI have been evaluated in healthy cats,17 cats with renal disease,18 and cats following renal autotransplantation19 and clinical renal transplantation.20 The RI is most useful for the identification of azotemic cats with nonobstructive renal disease and dogs with acute tubular necrosis,18 and is considered a useful adjunct diagnostic modality for assessing renal function in human patients following kidney transplantation21 and those with chronic nephropathies.22 In cats that underwent kidney transplantation, graft size but not RI increased significantly after autotransplantation16,19 and for allografts in recipients with clinical signs of graft rejection or ureteral obstruction.20 Because both RI and kidney size are correlated with renal disease in cats, those may be 2 additional useful measurements for prediction of short-term outcomes for cats that receive grafts by the IT procedure or following CS.
The purpose of the study reported here was to describe the use of simple CS methods for short periods on immediate posttransplantation function of renal autografts in cats. We hypothesized that graft function would be significantly better in cats receiving kidneys that underwent CS in a sucrose phosphate preservation solution for periods that mimicked most clinical or experimental scenarios than in cats receiving kidneys during an IT procedure.
Supported by the University of Wisconsin Companion Animal Fund.
The authors declare that there were no conflicts of interest. Presented as a poster presentation at the American College of Veterinary Surgeons Symposium, Denver, October 2004.
Torbugesic, Fort Dodge Animal Health, Fort Dodge, Iowa.
Vicryl, Ethicon Inc, Somerville, NJ.
GE Logiq 400, General Electric Co, Piscataway, NJ.
C721, General Electric Co, Piscataway, NJ.
LA39, General Electric Co, Piscataway, NJ.
1. Fahner PJ, Idu MM, van Gulik TM, et al. Systematic review of preservation methods and clinical outcome of infrainguinal vascular allografts. J Vasc Surg 2006; 44:518–524.
2. Jiao B, Liu S, Liu H, et al. Hypothermic machine perfusion reduces delayed graft function and improves one-year graft survival of kidneys from expanded criteria donors: a meta-analysis. PLoS One 2013; 8:e81826.
3. Gregory CR, Bersteen L. Organ transplantation in clinical veterinary practice. In: Douglas SA, ed. Textbook of small animal surgery. 3rd ed. Philadelphia: WB Saunders Co, 2003;122–136.
4. Mehl ML, Kyles AE, Reimer SB, et al. Evaluation of the effects of ischemic injury and ureteral obstruction on delayed graft function in cats after renal autotransplantation. Vet Surg 2006; 35:341–346.
5. Bernsteen L, Gregory CR, Pollard RE, et al. Comparison of two surgical techniques for renal transplantation in cats. Vet Surg 1999; 28:417–420.
6. Schmiedt CW, Mercurio AD, Glassman MM, et al. Effects of renal autograft ischemia and reperfusion associated with renal transplantation on arterial blood pressure variables in clinically normal cats. Am J Vet Res 2009; 70:1426–1432.
8. Bartels-Stringer M, Kramers C, Wetzels JF, et al. Hypothermia causes a marked injury to rat proximal tubular cells that is aggravated by all currently used preservation solutions. Cryobiology 2003; 47:82–91.
9. Ambiru S, Uryuhara K, Talpe S, et al. Improved survival of orthotopic liver allograft in swine by addition of trophic factors to University of Wisconsin solution. Transplantation 2004; 77:302–319.
10. Amemiya H, Suzuki S, Niiya S, et al. Viability estimation of preserved dog kidneys based on the LDH activity in the preservation perfusate. Nihon Jinzo Gakkai Shi 1989; 31:643–649.
11. Belzer FO, Southard JH. Organ preservation and transplantation. In: Meryman HT, ed. Transplantation: approaches to graft rejection. New York: Alan R. Liss Inc, 1986;291–303.
12. McAnulty JF. Hypothermic storage of feline kidneys for transplantation: successful ex vivo storage up to 7 hours. Vet Surg 1998; 27:312–320.
13. McAnulty JF, Reid TW, Waller KR, et al. Successful six-day kidney preservation using trophic factor supplemented media and simple cold storage. Am J Transplant 2002; 2:712–718.
14. McAnulty JF, Vreugdenhil PK, Lindell S, et al. Successful 7-day perfusion preservation of the canine kidney. Transplant Proc 1993; 25:1642–1644.
15. Schilling M, Saunder A, Southard JH, et al. Five-to-seven-day kidney preservation with aspirin and furegrelate. Transplantation 1993; 55:955–958.
16. Pollard R, Nyland TG, Bernsteen L, et al. Ultrasonographic evaluation of renal autografts in normal cats. Vet Radiol Ultrasound 1999; 40:380–385.
17. Rivers BJ, Walter PA, O'Brien TD, et al. Duplex Doppler estimation of Pourcelot resistive index in arcuate arteries of sedated normal cats. J Vet Intern Med 1996; 10:28–33.
18. Rivers BJ, Walter PA, Polzin DJ, et al. Duplex Doppler estimation of intrarenal Pourcelot resistive index in dogs and cats with renal disease. J Vet Intern Med 1997; 11:250–260.
19. Newell SM, Ellison GW, Graham JP, et al. Scintigraphic, sonographic, and histologic evaluation of renal autotransplantation in cats. Am J Vet Res 1999; 60:775–779.
20. Schmiedt CW, Delaney FA, McAnulty JF. Ultrasonographic determination of resistive index and graft size for evaluating clinical feline renal allografts. Vet Radiol Ultrasound 2008; 49:73–80.
21. McArthur C, Geddes CC, Baxter GM. Early measurement of pulsatility and resistive indexes: correlation with long-term renal transplant function. Radiology 2011; 259:278–285.
22. Parolini C, Noce A, Staffolani E, et al. Renal resistive index and long-term outcome in chronic nephropathies. Radiology 2009; 252:888–896.
23. Lam FT, Mavor AI, Potts DJ, et al. Improved 72-hour renal preservation with phosphate-buffered sucrose. Transplantation 1989; 47:767–771.
25. Sutherland BJ, McAnulty JM, Hardie RJ. Ureteral papilla implantation as a technique for neoureterocystostomy in cats undergoing renal transplantation: 30 cases. Vet Surg 2016; 45:443–449.
26. Halling KB, Graham JP, Newell SP, et al. Sonographic and scintigraphic evaluation of acute renal allograft rejection in cats. Vet Radiol Ultrasound 2003; 44:707–713.
27. Kyles AE, Gregory CR, Wooldridge JD, et al. Management of hypertension controls postoperative neurologic disorders after renal transplantation in cats. Vet Surg 1999; 28:436–441.
29. Veres G, Hegedüs P, Barnucz E, et al. Graft preservation with heparinized blood/saline solution induces severe graft dysfunction. Interact Cardiovasc Thorac Surg 2015; 20:594–600.
30. Southard JH, Belzer FO. Control of canine kidney cortex slice volume and ion distribution at hypothermia by impermeable anions. Cryobiology 1980; 17:540–548.
31. Amersi F, Shen XD, Anselmo D, et al. Ex vivo exposure to carbon monoxide prevents hepatic ischemia/reperfusion injury through p38 MAP kinase pathway. Hepatology 2002; 35:815–823.
33. Southard JH, Lutz MF, Ametani MS, et al. Stimulation of ATP synthesis in hypothermically perfused dog kidneys by adenosine and PO4. Cryobiology 1984; 21:13–19.
34. McAnulty JF, Southard JH, Belzer FO. Comparison of the effects of adenine-ribose with adenosine for maintenance of ATP concentrations in 5-day hypothermically perfused dog kidneys. Cryobiology 1988; 25:409–416.
35. McAnulty JF, Ploeg RJ, Southard JH, et al. Successful five-day perfusion preservation of the canine kidney. Transplantation 1989; 47:37–41.
36. Kim JS, Southard JH. Alteration in cellular calcium and mitochondrial functions in the rat liver during cold preservation. Transplantation 1998; 65:369–375.
37. Southard JH, den Butter B, Marsh DC, et al. The role of oxygen free radicals in organ preservation. Klin Wochenschr 1991; 69:1073–1076.
39. Stringham JC, Southard JH, Hegge J, et al. Limitations of heart preservation by cold storage. Transplantation 1992; 53:287–294.
40. Southard JH, Marsh DC, McAnulty JF, et al. Oxygenderived free radical damage in organ preservation: activity of superoxide dismutase and xanthine oxidase. Surgery 1987; 101:566–570.
41. Tullius SG, Heemann UW, Azuma H, et al. Alloantigen-independent factors lead to signs of chronic rejection in long-term kidney isografts. Transpl Int 1994; 7(suppl 1):S306–S307.
43. Matas AJ, Humar A, Gillingham KJ, et al. Five preventable causes of kidney graft loss in the 1990s: a single-center analysis. Kidney Int 2002; 62:704–714.
45. Heemann UW, Tullius SG, Azuma H, et al. The relationship between reduced functioning kidney mass and chronic rejection in rats. Transpl Int 1994; 7(suppl 1):S328–S330.
Composition of the preservation solution that was used to flush feline renal autografts immediately after harvest and in which the autografts were immersed during CS.
|NaH2PO4 (monobasic)||15.5 mmol/L|
|Na2HPO4 (dibasic)||53.6 mmol/L|
— = Not applicable.
Compounds were mixed and allowed to equilibrate for a short period. The volume prepared was 500 mL/preparation. The pH was adjusted to 7.2 as necessary by the addition of NaOH or HCl in a dropwise manner. Then, the solution was sterilized by filtration (filter pore size, 0.22 μm) into a sterile plastic IV bag and stored refrigerated at 5°C. A separate bag of preservation solution was prepared for each cat in the CS group.