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Urinary Excretion of Interferon, Albumin, and /?2-Microglobulin During Interferon Treatment1

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Urinary Excretion of Interferon, Albumin, and /?2-Microglobulin During Interferon Treatment1 [CANCER RESEARCH 44, 3599-3603, August 1984) Urinary Excretion of Interferon, Albumin, and /?2-Microglobulin during Interferon Treatment1 Bauer E. Sumpio,2 Marc S. Ernstoff, and John M. Kirkwood Departments of Surgery [B. E. S.J and Medicine [M. S. E., J. M. K.¡,Yale University School of Medicine, New Haven, Connecticut 06510 ABSTRACT The aim of this study was to attempt to characterize the Serum and urinary levels of albumin, ß2-microglobulin, and proteinuria which occurs during IFN treatment and to attempt to correlate these findings with the serum and urine levels of IFN in Interferon were determined in ten patients undergoing Interferon the patient group. therapy. The pharmacokinetics during a phase I trial of interferon administration intramuscularly is presented. Only trace amounts of interferon activity are found in the urine, even during peak MATERIALS AND METHODS serum interferon activity. Serum ft>-microglobulin levels in creased after interferon treatment, especially at the higher dosing Patient Selection. Ten patients with histologically verified metastatic levels. Urinary excretion of 02-microglobulin increased due to the carcinoma (6 with melanoma, 3 with colorectal adenocarcinoma, and 1 with osteogenic sarcoma) were enrolled in this study (Table 1). All relatively low affinity of the transport system. Saturation, com petition, or inhibition of the absorption process for 02-microglob- patients had measurable or évaluablemetastatic cancer and a perform ance status <2 on the Eastern Cooperative Oncology Group scale, had ulin was not attained. Measurement of the urinary albumin/ been off of all therapy for 4 weeks or more than 6 weeks for nitrosourea urinary 02-microglobulin ratio reveals no glomerular or tubular and mitomycin C treatment prior to this study with no residual toxicity lesion, and we conclude that interferon therapy does not result from previous therapy, and had no serious secondary effects of their in a clinically significant nephrotoxicity. cancer (e.g., paraneoplastic, hormonal, or metabolic syndromes). Exclu sion criteria included pregnancy, central nervous system metastasis, previous ¡nterferon exposure, and abnormal laboratory studies (WBC INTRODUCTION <4000/ml; granulocytes <1500/ml; platelets <100,uOO/ml; hemoglobin The IFNs3 are a group of glycoproteins first discovered be <10 g/dl; serum calcium >11 mg/dl; serum creatinine >2 mg/dl; and aspartate aminotransferase, alanine aminotransferase, or alkaline phos- cause of their potent antiviral activity (11). Subsequent obser phatase greater than twice the upper limits of normal). vations have suggested that IFN may, in addition, have significant IFN Treatment Protocol. Recombinant IFN a-2, prepared, purified, immunological, antiproliferative, and antitumor activity against and assayed as reported by Goeddel et al. (B), was supplied by Schering- virally and chemically induced tumors, as well as spontaneously Plough Corporation (Bloomfield, NJ). In brief, nucleic acids obtained from occurring tumors (2, 12). A range of toxicities was encountered virally challenged human lymphocytes were spliced into Escherichia coli during the initial clinical studies of IFN in humans, but the majority DNA by means of plasmid vectors. The product was assayed for IFN have been tolerable and virtually all reversible on withholding of activity and found to contain 1.0 to 2.4 x 108 units of antiviral activity the drug (14). Dose-limiting toxicity included leukopenia, eleva per mg of protein. Limulus assay testing for endotoxin (5) revealed less tion in transaminases, changes in central nervous system func than 5 ng of lipopolysaccharide/1.0 x 106 units. Cultures for bacteria tion, and fatigue. Recently, the appearance of protein in the urine and Mycoplasma were negative. of patients treated with increasing doses of recombinant IFN a- IFN «-2was administered i.m. at doses of 3, 30, 50, and 100 x 106 units per day for 28 days or to tolerance (Table 1). Patients were seen 2 has been found during a phase I trial (6). In addition, the for administration of each dose, and each patient had serum and timed administration of high doses of exogenous and endogenous IFN urine collections on the day prior to initiation of IFN therapy and on the to newborn mice has been demonstrated to cause a progres day after the end of their treatment protocol. Urine was checked for pH, sively fatal glomerulonephritis which can be ameliorated by anti- and an aliquot was stored at -70° with a simultaneous serum specimen. IFN globulin treatment (9, 10). These observations suggested Analysis. Serum and urine creatinine and albumin levels were mea that IFN administration, in relatively high doses over long periods sured in duplicate by the clinical laboratory, the latter by a nephalometric of time, might lead to a clinically important nephrotoxicity. technique. The serum samples were assayed for IFN by the Department i82-Microglobulin is a small protein with a molecular weight of of Microbiology, Schering Corporation. A radioimmunoassay procedure 11,700 and is normally found in low concentrations in serum and was used.The analysts did not have access to the random treatment in all biological fluids (7). In the kidneys, albumin and /32-micro- code until all assays were completed. The radioimmunoassay for the globulin are filtered at the glomerulus and subsequently reab determination of IFN levels in serum at 0 hr and following administration of IFN «-2was a modification of the Celltech Interferon Immunoradio- sorbed in the proximal tubules (19, 20). An increased urinary metric Assay. Following treatment of the serum to remove interfering excretion of /32-microglobulin associated with unchanged or only substances, appropriate dilutions of the sample are mixed with an 125I- slightly increased albumin excretion has been demonstrated to anti-a IFN monoclonal antibody and a polystyrene bead coated with a occur primarily in tubular lesions; on the other hand, increased sheep polyclonal anti-a IFN antibody. This mixture is then incubated at albumin excretion with unchanged 02-microglobulin excretion ambient temperature for 3 to 4 hr, followed by overnight storage at 4- suggests a glomerular lesion (16). 6°.During this period, IFN in the serum sample reacts with both antibod ies, thereby linking the labeled monoclonal antibody to the bead. The 1Supported in part by NIH Grants CA 09200 and CA 08341. 2To whom requests for reprints should be addressed, at Department of Surgery, amount of radioactivity bound to the bead is then determined. The level Yale University School of Medicine, 333 Cedar St., New Haven, CT 06510. of IFN is determined by comparing this amount of radioactivity to that 3The abbreviations used are: IFN, interferon; GFR, glomerular filtration rate. on a standard curve. This standard curve is determined using serum Received January 30,1984; accepted April 30,1984. samples spiked with known amounts of IFN a-2 treated and assayed at AUGUST 1984 3599 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1984 American Association for Cancer Research. S. E. Sumpio et al. the same time as the study samples under the same conditions. Controls Serum fo-microglobulin levels rose after IFN treatment in all of of IFN tt-2 at low concentrations are treated in the same manner as the the patients, but only in 6 of these were the values above the samples and must have a standard deviation equal to or less than 10% reported upper limits of the normal population. for the assay to be considered valid. The level of IFN is expressed as ID/ Although there was no detectable rise in serum albumin after ml. The above procedure can detect IFN at a level as low as 5 ID/ml with IFN treatment, 3 of the 10 patients excreted significant amounts a precision of >90%. ,c?2-microglobulin was quantitated in duplicate by of albumin in the urine. One of the patients, G. T., however, radioimmunoassay using a commercial kit (Phadebas Pharmacia, Upps ala, Sweden). already had an increased urine albumin level prior to initiation of therapy. Serum creatinine levels remained unaffected by the IFN treatment. The urinary albumin/fe-microglobulin ratio is given in RESULTS Table 2 and is plotted in Chart 1. The levels of /tf2-microglobulin, albumin, and creatinine mea The clearance values for the proteins, calculated from the sured from the serum and urine of the patients in the study are product of the urine/plasma ratio of the protein and the urine presented in Table 2. The "pre"-treatment values reflect serum flow rate, is given in Table 3. GFR is determined from the and urine levels of the proteins obtained just prior to initiation of creatinine clearance. The fractional clearance of the proteins, IFN therapy. The "posf'-treatment values were from samples clearance/GFR, is also given in Table 3 and is a more accurate taken close to or at the end of the treatment protocol. Pretreat assessment of the renal handling of the proteins independent of ment serum and urine levels of 02-microglobulin, albumin, and the GFR. As seen in Table 3, the fractional clearance of 02- creatinine were within normal limits for all patients except in 3 microglobulin and albumin in these patients remained at very low instances. Patient J. M. had an elevated serum j32-microglobulin levels, despite IFN therapy. level, R. P. had a slightly increased urinary excretion of ß2- The relationship between the filtered load of ft>-microglobulin microglobulin, and G. T. had a slightly elevated albumin excretion and its urinary excretion rate and tubular absorption rate in these in the urine. IFN treatment led to an increased urinary excretion patients was assessed. Filtered load is a product of the glomer- of 02-microglobulin in 9 of the 10 patients. In 8 of these patients, ular filtration rate, plasma protein concentration, and glomerular the values were above the reported range of normal values. sieving coefficient of the particular protein.
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