Surgery – Diagnostic testing
Reexamination Certificate
1999-11-05
2002-04-23
Winakur, Eric F. (Department: 3736)
Surgery
Diagnostic testing
C600S309000
Reexamination Certificate
active
06375613
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a method of prospectively evaluating organ function while the organ, which is intended for transplantation, is being maintained at a near normal rate of metabolism. More particularly, the method involves measuring one or more indicia of organ function, as a means of assessing functional capabilities of the organ which can then be correlated with its posttransplantation course.
BACKGROUND OF THE INVENTION
Transplantation is the therapy of choice for people with end-stage organ failure. In the case of end-stage heart, liver and lung disease, transplantation is the only life-saving therapy. The major limiting factor today in clinical transplantation is the persistent shortage of organs. For example, of the 265,000 patients with end-stage kidney disease in the U.S., only 5-6% will ever receive a transplant. World-wide there are more than 460,000 patients with end-stage kidney disease alone. Recent estimates indicate that approximately 30% of the End Stage Renal Disease (ESRD) population could benefit from a transplant if kidneys were available.
The patients who are considered for organ donation are primarily heart-beating cadaver donors (HBD), patients with head trauma who are maintained on a respirator in an intensive care unit prior to declaring death by brain criteria. Since these brain dead patients are maintained on a respirator until the time of organ donation, the organs rarely experience substantial warm ischemic (WI) damage. Unfortunately, HBD represent a very small perecentage of the patient population that expire each year from a traumatic injury. The HBD represents a limited supply of organs for transplantation that has remained constant for the past ten years.
There have been recent attempts to expand the organ donor pool for transplantation by using marginal organs, i.e. organs procured from elderly donors or those that have been hypothermically preserved for extended periods of time (>24 hrs). But these sources of marginal donors represent a modest expansion of the donor pool at best. Organs from non-heartbeating donors (NHB) are not commonly used in organ transplantation because the time period between cardiac arrest and intervention represents a threshold of damage from WI injury (<1 hour) that makes the posttransplantation outcomes uncertain. The major reason why the organ donor pool cannot be expanded into this substantially larger pool of non-heartbeating donors is that currently there is no ex vivo test available to measure the extent of the WI damage and/or predict which organs will function and which will not after they are transplanted. In kidneys from NHB the immediate non-function rate is >80%. This significantly decreases the cost effectiveness of the transplant when prolonged postoperative dialysis must be applied. In the case of hearts and livers, where immediate function is necessary, organs procured from marginal and NHB donors are not considered.
A much larger, untapped pool of patients consists of the non-retrievable donor (NRD), i.e. the patient in whom circulatory arrest has existed for >1 hour postmortem without any intervention and which represents the vast majority of patients dying each year from a traumatic injury. These NRD are never considered for organ donation.
Current organ preservation technology depends upon the use of hypothermia by either continuous hypothermic perfusion or simple hypothermic storage (see, for example, Collins et al., 1969, Lancet 2:1219). While a variety of perfusates have been utilized clinically, these two methods of organ storage have remained substantially unchanged for the past 20 years. The current perfusate solution that represents the state-of-the-art in hypothermic organ preservation, and that provides for optimized organ preservation under hypothermic conditions, contains components that prevent hypothermia-induced tissue edema; metabolites that facilitate organ function upon transplantation; antioxidants; membrane stabilizers; colloids; ions; and salts (Southard et al., 1990, Transpl. Proc., 21:1195). The formulation of this perfusate is designed to preserve the organs by hypothermia-induced depression of metabolism. While it minimizes the edema and vasospasm normally encountered during hypothermic storage, it does not provide for a substantially expanded donor pool because, at the temperatures used in hypothermic organ preservation (4°-8° C.), metabolism is suppressed by more than 95%. With virtually no metabolism, it is not possible to prospectively evaluate which organs will function once transplanted.
Recent efforts are in progress utilizing materials and techniques to resuscitate and repair ischemically damaged tissues and organs (U.S. Pat. No. 5,843,024). These techniques support organ resuscitation and preservation by supporting ongoing metabolism. Metabolism by the organ is sufficiently supported so that the organ continues to function during the period of ex vivo preservation. Because organ metabolism and function are ongoing, the potential exists for establishing parameters based on the function of the organ during ex vivo perfusion that can be applied to predict how the organ will function when it has been transplanted. Developing the ability to predict if an organ will function upon transplantation would provide a basis for expanding the donor pool.
The ability to expand the organ donor pool using this technology will be dependent upon the ability to differentiate those organs that represent reversible injury, commonly referred to as delayed graft function (DGF), or, in the case of kidneys, acute tubular necrosis (ATN), from those with irreversible injury, referred to as primary nonfunction (PNF). Currently, in clinical transplantation, there is no validated methodology to evaluate organ function prospectively. The result of having to transplant an organ without knowledge of its functional status is a very narrow definition of donor suitability that contributes to the continuing organ shortage.
One of skill in the transplantation art will recognize, therefore, that an important goal in any attempt to expand the existing organ donor pool is the development of a successful diagnostic tool having the ability to differentiate reversible damage (DGF or ATN) from irreversible damage (PNF) in an allograft. A successful prognostic test would have to prospectively evaluate the functional capacity of an allograft with a high degree of confidence.
SUMMARY OF THE INVENTION
In one aspect, the invention relates to a method for prospectively determining the functional potential an organ to be transplanted. According to the method, one obtains a value by measuring a parameter related to organ function of a fluid derived from an explanted organ selected from organ product, circulated perfusate, and a combination thereof, comparing the value obtained with a range of reference values indicative of normal organ function; and determining whether or not the value obtained falls within the range of reference values indicative of normal organ function.
In another aspect, the invention relates to a method for prospectively determining the functional potential of an organ to be transplanted, while the organ is being perfused in a warm preservation system, which allows for near normal levels of metabolism by the organ. According to the method, one evaluates one or more of the following parameters alone or in combination: normalization of perfusion characteristics for the organ, the extent of damage to the vascular endothelium of the organ, the level of oxidative capacity of the organ, and the metabolic capacity of the organ.
In a related aspect, the invention relates to a method for prospectively determining the functional potential of a kidney to be transplanted, by additionally evaluating one or more of the following parameters: the extent of leakage of a perfusate protein into urine produced by the kidney, the ability of the kidney to reabsorb ions, the ability of the kidney to secrete ions, and the ability of the kidney to retain a tracer molecule, such a
Breonics Inc.
Heslin Rothenberg Farley & & Mesiti P.C.
Winakur Eric F.
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