Monoclonal antibodies in renal transplantation: Preliminary results

Abstract

A 51-yearo1d man was referred to the Massachusetts General Hospital for evaluation of persistent proteinuria and azotemia. Five years ago he underwent an emergency right femoral artery embolectomy for symptomatic impairment ofthe circulation in his legs. Abnormal renal function first was discovered at that time. After an uneventful postoperative course, the patient was admitted to the Hospital of the University of Pennsylvania for further investigation. Mild hypertension and bilateral cataracts were noted. Laboratory findings disclosed a urine protein excretion of 2.2 g/day, a BUN of 40 nig/dI, and a serum creatinine concentration of 2.8 mg/dl. The serum cholesterol and triglyceride concentrations were 235 mg/dl. The serum calcium, phosphorus, and uric acid levels during allopurinol therapy for an episode of podagra were normal. An intravenous pyelogram revealed scarred kidneys, and retrograde pyelography suggested the possibility of papillary necrosis. Rena! arteriography, normal except for moderate attenualion of the smallest cortical arterial branches bilaterally, suggested moderate nephrosclerosis. Aortoiliac atherosclerotic disease was present. The patient had no history of diabetes niellitus, sickle cell disease, collagen vascular disease, or analgesic abuse. In addition, there was no family history of renal disease. The exact nature of his progressive renal failure remained unclear, and attempts to manage it by diet and pharmacologic control of the blood pressure were not wholly successful. The next 3 years witnessed progressive elevations of the serum creatinine and BUN to 6.4 mg/dI and 71 mg/dl, respectively. The patient complied poorly with various programs of antihypertensive medication. Two years ago, results of urinalysis revealed 4+ proteinuria and occasional hyaline and granular casts with 0 to rare red and white blood cells. The urinary protein excretion was 8.9 g/day, and the creatinine clearance was 24 L/day. Further studies included a negative LE prep, a negative ANA, and a negative test for Bence-Jones protein in the urine. An inferior vena cavagram and bilateral renal venograms showed no evidence of renal vein thrombosis. Renal ultrasonography demonstrated small kidneys, which were 8 cm in length. This finding, coupled with a prolonged bleeding time, precluded renal biopsy. The patient's medications included clonidine , chlorothiazide, clofibrate, allopurinol, and potassium chloride. One year ago, a left radial artery-cephalic vein fistula was constructed in anticipation of hemodialysis. Thrice-weekly hemodialysis was instituted 10 months ago because of progressive symptoms of uremia including incipient encephalopathy. Five months after hemodialysis was begun, the patient received a cadaver renal allograft in the right iliac fossa. None of the detectable HLA specificities of the donor matched those of the patient. Immunosuppressive therapy consisted of azathioprine and prednisone. On the 12th postoperative day, the patient developed left-sided sciatica and a temperature of 99° F. The serum creatinine climbed from a nadir of I .9 mg/dl to its zenith of 2.4 mg/dl over the next 3 days. A needle biopsy of the allograft performed on the 16th postoperative day demonstrated a dense interstitial infiltrate composed of lymphocytes and plasma cells that was consistent with an acute cellular allograft rejection. A 10-day course of treatment with a monoclonal antibody directed against all peripheral blood T cells (OKT-3), given intravenously at 2 mg/day, was started that day; the patient continued taking azathioprine and prednisone without changes in dosage. The patient developed a temperature of 101.6° F and shaking chills about one hour after receiving the initial dose of OKT-3 antibody; no other signs of toxicity were apparent and subsequent antibody injections were well tolerated. The BUN and serum creatinine levels peaked at 55 mg/dl and 4.8 mg/dl, respectively, on the third day of OKT-3 immunotherapy and fell to 32 mg/dl and 2.1 mg/dl, respectively, on the 10th and final day oftherapy. Another renal biopsy performed 2 days later showed a reduced cellular infiltrate. Therapy with azathioprine and prednisone was continued (see Fig. 1). Three months following transplantation. the patient continued to receive azathioprine and prednisone, the dose of both being gradually reduced; neither symptoms nor signs of further allograft dysfunction were apparent. The serum creatinine concentration declined slowly to 1.6 ing/dI.