Brief Historical Perspective On Organ Preservation

It was apparent from the experiments of Medawar in the 1940s that allografted tissues and organs would be vigorously attacked by the recipient's immune system and destroyed in a short time. Early attempts at kidney transplantation failed in animals due to rejection of the allograft. There was little concern about preserving organs at this time because of the immunological hurdles that needed to be overcome. In the 1950s and 1960s, studies to understand the nature of allograft rejection as well as the discovery of agents (beta-mercaptopurine) to block rejection Organ Procurement and Preservation, edited by Goran B. Klintmalm and Marlon F. Levy. © 1999 Landes Bioscience were critical components in making organ preservation a clinical reality. Clinicians and basic scientists recognized that the availability of drugs to constrain rejection made it possible to use immunologically mismatched tissues obtained from cadaveric organ donors. Using cadaveric organs as the major source of organs for transplantation would be the only way to make transplantation therapy widespread.

In the 1960s, after Murray demonstrated successful kidney transplantation in a set of twins, several laboratories became active in pursuing organ preservation. Many laboratories made contributions, especially those of Pegg and Calne in Cambridge, UK, Belzer at the University of California (San Francisco), Collins at UCLA, Starzl in Denver and Pittsburgh, Marshall in Melbourne, and Halasz in San Diego. At this time, these labs' primary interest was in kidney preservation.

The concept of metabolic inhibition by hypothermia as a cornerstone of organ preservation was quickly accepted. Pegg and his colleagues1 attempted to preserve kidneys by simple cooling in cold saline or blood. They achieved successful results, viable as tested by transplantation, with preservation times of about 12 hours. Belzer et al2 reasoned that continuous hypothermic perfusion with a biologically based fluid (plasma) would be superior to simple cold storage of the kidney because the organ would be continuously supplied with metabolic-stimulating substrates, removing end products of metabolism. This would not only stimulate and support hypothermic metabolism but also allow tissues injured during the agonal period and harvest to be repaired. This was demonstrated successfully by transplanting dog kidneys after preservation for three days using low perfusion pressure (50-60 mm Hg), low flow (about 0.6-1.0 mL/min/g) and oxygenated cryoprecipitated plasma (CPP). CPP was prepared by freezing and thawing autologous dog plasma to remove cold-sensitive lipoproteins (by millipore filtration). These lipoproteins, which were found to aggregate in the kidney glom-erular vessels,3 cause an increase in renal vascular resistance, endothelial cell injury, and possibly occlusion and ischemia in portions of the kidney.

This method of machine perfusion using CPP as the perfusate became the standard method of human kidney preservation in the early 1970s4 and helped to increase dramatically the number of renal transplants performed nationally. At this time there was no clear definition or acceptance of brain death as a criterion for organ removal. Therefore, most organs were obtained from donors that were allowed to undergo death as judged by cessation of heart function. This resulted in kidneys that were not well-perfused for varying lengths of time, while death by cessation of heart function was awaited. Machine perfusion allowed successful preservation of these 'less than ideal' kidneys damaged by hypotension or ischemia. It has since been shown5-6 that machine perfusion for "less than ideal" kidneys is superior to other methods such as simple cold storage.

In the late 1970s Collins et al7 showed that dog kidneys could be safely preserved for 30 hours by simple cold storage. This method relied on refrigerated storage after flushout with a solution composed primarily of glucose, potassium, and phosphate. The Collins solution contained a high concentration of K+, used to suppress the loss of intracellular K+ that occurred in metabolically depressed

cells in exchange for extracellular cations, principally Na+.8 This so-called "extracellular-type solution" became the standard method for human kidney preservation over the next 8 to 10 years, primarily because of its simplicity. At this time, brain death also had become a criterion for organ donation; thus, organs could be retrieved from heart-beating cadavers. No machine was required, the solution was simple to prepare and shelf-stable, and the time of safe preservation (about 24 hours) was sufficient for use of most cadaveric kidneys.

Since these two landmark developments in organ preservation, many modified preservation solutions have been tested, but only a few have been found to be significantly better. Table 5.1 lists the various preservation solutions used either experimentally or clinically and the reference that describes the composition and method of use. Two solutions developed in the late 1980s at the University of Wisconsin have had much success in advancing organ preservation. The composition of these solutions is given in Table 5.2 and Table 5.3. The UW solution (ViaSpan, DuPont) is a cold-storage solution that extended preservation times for the liver9 and pancreas10 from about 4 hours (with Collins solution) to between 30 and 72 hours. The UW solution appears to give better and longer-term preservation of kidneys11 than the Collins-type solutions, and is safe for 6 to 12 hours' preservation of the heart and lung.12,13 Also, the UW gluconate solution (Belzer machine perfusion solutions, MPS) has found widespread use in the few centers that continue to use machine perfusion of kidneys.14 This solution is similar to the UW cold-storage solution, except that lactobionate has been replaced with gluconate, and the Na+/K+ ratio is higher. The UW gluconate solution has been used to obtain successful dog kidney preservation for 5 and 7 days.15,16 A modification of this solution is also capable of preserving the dog liver by machine perfusion for 3 days.17

Table 5.1. Some preservation solutions used clinically

Solution Name

Active Components

Reference

Collins (1967) Euro-Collins (1980)

Hypertonic Citrate (1976)

PBS (1989)

HTK (Date 1970s)

Silica-gel Plasma (1974)

PO4 buffered glucose solution

Same as Collins (no Mg2+)

Citrate, mannitol

PO buffered sucrose

Histidine

Perfusion solution Plasma defatted with silica gel

Euro Surg Res 12 (Suppl 1):22, 1980 Transplantation 21:498, 1976 Clinical use =

Transplantation 48:1067, 1989 Discovery =

Transplantation 35:136, 1983 Trans Proc 22:2212, 1990 Surg Gyn Obstet 138:901 (1974)

Table 5.2. UW cold storage solution'

Substance

Amount

K+-lactobionate (mM) KH2PO4 (mM) MgSO4 (mM) Raffinose (mM) Adenosine (mM) Glutathione (mM) Insulin (U/L) Bactrin

Dexamethasone (mg/L) Allopurinol (mM) Hydroxyethyl starch (g/L)

"This solution is brought to pH 7.4 at room temperature with NaOH. The final concentrations are: Na+ = 30 ± 5 mM; K+ = 120 ± 5 mM; mOsm/L = 320 ± 5. Bactrim = trimethoprim (16 mg/ml) and sulfamethoxazole (80 mg/ml).

Table 5.3. Composition of the UUWHydroxyethyl starch/K-Gluconate Solution*

Substance Concentration

Table 5.3. Composition of the UUWHydroxyethyl starch/K-Gluconate Solution*

Substance Concentration

K-gluconate

100 mmol/L

Raffinose

35 mmol/L

Ribose

1 mmol/L

NaH2PO4

25 mmol/L

Mg-gluconate

5 mmol/L

Adenine

1 mmol/L

Adenosine

5 mmol/L

Hydroxyethyl starch

50 g/L

Gutathione

3 mmol/L

Glucose

5 mmol/L

HEPES

10 mmol/L

Insulin

100 U/L

Dexamethasone

16 mg/L

Cotrimoxazole

2 ml/L

CaCl2+

1.5 mmol/L

*The pH is adjusted by the addition of NaOH/KOH (1:3) to pH = 7.7 (at room temperature).

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