This invention relates to monitoring organ function. One function of some organs, such as for example the kidney or the liver, is removal of substances from body fluids. The performance of such a clearance organ can be determined by assaying for accumulation in body fluids of a substance that is expected to remain constant or to deplete, or by monitoring the clearance by the organ of a labelled substance from the body fluids, for example.
The kidney is one such clearance organ that removes substances from body fluids. Acute renal failure ("ARF") as a complication of medical, obstetrical and multiple surgical conditions represents an important health problem. Currently patients suffering from ARF have a survival rate of about 50%. The pathogenesis of renal failure remains undefined, and there are no clear approaches for its prevention and treatment. In the early stages of renal failure patients show no symptoms and feel no discomfort. Diagnosis can be made by analyzing the body fluids to determine whether the kidneys are maintaining the expected levels of one or more substances.
Because of the abruptness of the renal impairment in patients having ARF, their clinical status following the onset of renal failure is determined largely by their prior state of health and the nature of the insult that led to the renal failure. Hypoperfusion of the kidney is a frequently recognized insult leading to ARF in the setting of trauma, surgery, hemorrhage or dehydration. Continuous and precise monitoring of the cardiopulmonary function in such settings has long been available and has helped in restoring the normal circulatory status of the acute patient, but estimation of the renal function conventionally is carried out by such relatively crude means as measurement of urine output and determination of plasma creatinine level. Such standard methods are inadequate for monitoring renal function in the acute patient.
Although the kidney is capable of virtually complete recovery after an episode of hypoperfusion, transient ischemia or toxin-induced cellular destruction can suppress urine formation for days or even weeks. Current methods of measuring renal function have poor time resolution, and undetected or late-detected renal failure accounts for substantial mortality. There is at present no reliable method for continuous and near real-time monitoring of renal function.
Renal function is conventionally determined by measuring the levels of substances in the urine or the serum, or both. Either technique can be made quantitative, but they have not become widely used for monitoring because, among other reasons, they require taking multiple samples from the patient and the sample analysis is time-consuming and costly.
Renal function is commonly assayed by determining creatinine levels in the urine or serum (Carrie et al., 1980, Am. Jour. Med., Vol. 69, pp. 177 ff.; Shemesh et al., 1985, Kidney Int., Vol. 28, pp. 839 ff.; Walser et al., 1988, Kidney Int., Vol. 34, pp. 412 ff.; Price et al., 1972, Urology, Vol. 107, pp. 339 ff.). However, measurement of serum creatinine or of creatinine clearance may not provide an accurate measure of glomerular filtration rate.
In one accurate but technically difficult approach to determining clearance rate, a substance is introduced to the patient by continuous intravenous infusion until an equilibrium is reached at which the plasma level of the substance (as determined by analysis of plasma samples) is steady, at which point the infusion rate is equal to the rate of loss in the urine (Earle et al., 1946, Proc. Soc. Exp. Biol. Med., Vol. 62, pp. 262 ff.)
In another approach, the glomerular filtration rate is calculated from an analysis of the rate of disappearance of a labelled substance from the plasma after a single intravenous injection. Following an equilibration period, the clearance of the labelled substance is determined by measuring the level of the label remaining in a series of blood samples taken over a period of several hours; the injected substance can be radiolabelled and the amount of the radiolabel detected in the samples (Sapirstein et al., 1955, Am. Jour. Physiol., Vol. 181, pp. 330 ff.; Chantler et al., 1972, Arch. Dis. Child., Vol. 47, pp. 613 ff.) or the quantity of the substance remaining in each of the series of blood samples can be determined by gas chromatography after extraction of the substance from the serum (H. -U. Schulz, 1990, U.S. Pat. No. 4,908,202). The non-endogenously produced substance inulin may be an ideal filtration marker for GFR determination, and it has remained the "gold standard". Because inulin is in limited supply and difficult to measure, alternative substances have become the choice for routine use, particularly .sup.51 Cr-EDTA, .sup.99m Tc-DTPA and .sup.125 I-sodium iothalamate.
External monitors for measuring renal function have been suggested, but have not come into wide use for a variety of reasons. In the suggested approaches, a radiolabelled substance is administered to the patient, and then a radiation detector is positioned so that it is exposed to radiation from the labelled substance in the blood or urine. External monitors have been positioned adjacent the head, and on the chest of the patient to be monitored, to bring the detector near the blood stream; or adjacent the kidney or urinary bladder, to bring the detector near the urine. The proposed apparatus can be expensive, patient movement can be restricted during monitoring, the patient can be uncomfortable during monitoring, and background noise generally limits the accuracy and reliability of the measurements.
In one such approach, Blaufox et al., 1967, Jour. Nucl. Med., Vol. 8, pp. 77-85, describes measuring clearance of .sup.125 I-hippurate using an external counter aimed at the zygomatic arch of the skull, and requires two blood samples for monitor calibration. This approach has the disadvantage that the patient must be immobilized while the apparatus is in use, and development of a helmet containing the monitor and recorder is suggested as a means for providing some patient mobility during monitoring.
Rossing et al., 1978, Scand. Jour. Clin. Lab. Invest., Vol. 38, pp. 23-28; and Casey et al., 1986, Nucl. Med. Comm., Vol. 7, pp. 811-818, describe using external detectors placed upon the patient's chest to determine the clearance of .sup.99m Tc-DTPA from the blood as a measure of renal function. In these approaches, one plasma sample is taken in order to convert the external rate constant to plasma clearance. Because the background noise to signal ratio is fairly high, and renal function, as expressed by GFR, can be determined by taking the slope of the data values at intervals longer than about 30 to 60 minutes.
Bak et al., 1982, Proc. III World Congress of Nuclear Medicine and Biology, Paris: 1982, pp. 609-13, describes positioning a CdTe detector at the back of the leg 10 cm below the knee for analyzing .sup.99m DTPA clearance as a measure of renal function.
In another approach, Junges German Patent No. 3,245,778 describes using a gamma camera with three detectors, one focused on each kidney and the third on the urinary bladder, to measure quantity of a radiolabelled substance removed by the kidneys.