Holley, JL

Johnson, JP

Jordan, M

Magnone, M

McCauley, J

Scantlebury, V

Shapiro, R

Starzl, T

Vivas, C

English

Name not available

Alpha-interferon induced acute renal allograft rejection

D-Scholarship@Pitt

Reprinted from Transplantation Volume 59, Number 7, April 1995 Copyright © 1995 by Williams & Wilkins INTERFERON-a-INDUCED ACUTE RENAL ALLOGRAFT REJECTION MARIO MAGNONE/ JEAN L. HOLLEY,! RON SHAPIRO,2 VELMA pCAkqib~royIO JERRY MCCArib~:~ MARK JORDAN,2 CARLOS VNAS,2 THOMAS STARZL, AND JOHN P. JOHNSON Renal-Electrolyte Division and the Division of Transplant Surgery, University. of Pittsburgh Medical Center3, Pittsburgh, Pennsylvama 1521 The immunomodulating effects of interferons have led to their use in the treatment of a variety of illnesses, including cancer (1), and virally mediated infections, such as hepatitis (2). In addition, IFN has been given to immunosuppressed patients in an attempt to reconstitute the immune re~ponse to prevent viral infections such as CMV and herpes SImplex (3). Since CMV and viral hepatitis are potentially serious complications of renal transplantation (3, 4), the use of IFN for prophylaxis or treatment has been advocated in this set-ting. However, the potential effects of giving an immuno-modulator such as IFN to immunosuppressed transplant pa-tients raises theoretical concerns about activation of immune responses and an increased risk of allograft rejection. Current immunosuppressive regimes for renal transplan-tation include CsA or FK506 in combination with steroids and sometimes AZA. While the mechanisms of action of CsA and FK506 are not completely understood, these agents ap-pear to inhibit T cell activation through binding to specific binding cellular proteins (immunophilins), thereby altering intracellular signaling pathways and ultimately inhibiting expression of IL-2 and other cytokines (5). Both CsA (6) and FK506 (7) may inhibit IFN production, and low levels of circulating IFN-a have been described in renal transplant recipients (8). Although IFN modulate the immune response-both at the level of T cell activation (9) and antigen expres-sion (10), the exact roles ofthese compounds in the immuno-suppressive action of CsA and FK506 are not known. A number of studies have claimed efficacy of IFN-a prep-arations in the treatment of chronic persistent hepatitis (2) and trials of IFN preparations for viral prophylaxis in renal transplant recipients have been reported (3, 11, 12). The results of such trials suggested a benefit of prophylaxis for viral infections (3, 11), but, at times, at the expense of in-creased rejection (12). The complex issues involved in using IFN to treat hepatitis in a transplanted, immunosuppressed population prompted us to review our experience with IFN-a treatment in renal transplant patients. 1 Renal-Electrolyte Division. 2 Division of Transplant Surgery. 3 Address correspondence to: John P. Johnson, MD, Renal-Elec-trolyte Division, F1159 Presbyterian University Hospital, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213. CASE STUDIES Between June 1990 and April 1994, 11 renal transplant patients were treated with recombinant IFN-a at our center. Seven patients had undergone renal transplantation alone (group 1) and 4 patients had received renal transplants fol-lowing orthotopic liver transplantation (group 2). The mean age of all patients was 38±3.8 years; there were 6 men and 5 women. Renal transplantation had been performed 25±6 months previously (range, 4-67 months). Seven patients had experienced early rejection during the first month after transplantation, but no patient had experienced more than one episode of rejection. The mean rejection-free interval before starting interferon was 28.4±5.7 months, and the baseline serum creatinine was 1.8±0.2 (range, 1.0-3.8) mg! 100 ml. Patients received immunosuppression with either FK506 (6 patients) or CsA (4 patients) and prednisone. Five patients (1, 2, 4, 5, and 8) were also receiving AZA. One patient was on FK506 alone (patient 6). No patient had immunosuppression reduced at the initiation of IFN therapy. The indications for IFN therapy were persistently elevated liver function tests with seropositivity for hepatitis C in 10 patients and surface antigenemia for hepatitis B in 1 patient (patient 2), with liver biopsy evidence of chronic hepatic inflammation. Kidney allograft function following induction of IFN-a therapy is shown in Table 1. The IFN dosage varied from 1.5 to 5 X 106 U of rIFN -a given subcutaneously 3 times weekly and was planned as a 6-month course. Only 4 patients com-pleted the entire course of therapy (mean treatment time, 4.1±1.1 months). Six of 7 patients in group 1 and 1 of 4 patients in group 2 experienced acute rejection at periods varying from 11 days to 8 months after initiation of IFN therapy (mean 2.9±0.8 months). Patient 2, who had persis-tent hepatitis B, received 6 months of 5 x 106 U 3 times weekly and experienced rejection 6 weeks after completing the course of IFN-a. Renal function stabilized after a course of intravenous methylprednisone. Two months later he was retreated with IFN at 10x106 U 3 times weekly because of continuing deterioration of liver function. Within 2 weeks of restarting IFN therapy, the serum creatinine doubled (2.5 mg/100 ml to 5 mg/100 ml) and did not fall despite discon-tinuation of IFN and a steroid recycle. Two weeks later, dialysis was started and IFN therapy was reinstituted. The April 15, 1995 BRIEF COMMUNICATIONS 1069 TABLE 1. Patients, interferon treatment, and outcome Interval to Cr at -----Patient Age Baseline Cr Rejection-free INF dose (mg/100 ml) interval (rna) (3Xweekly) Mas Rx rejection rejEdion Therapy and outcome (rna) (mg/IOO ml) Group 1 ---------1 51 1.8 19 2X106 1.5 1.5 li8 Steroid recycle,a hemodialysis 2 39 1.3 9 (a) 5X106 6 8 5.1 Steroid recycle, Cr stabilized (b) lOX106 0.5 0.5 7.5 Steroid recycle, hemodialysis 3 33 3.8 56 3xI06 3 3 8.0 Steroid recycle, hemodialysis 4 25 1.7 14 5X106 6 5 2.3 Steroid recycle, t INF to 3x106 Cr 5 38 1.0 3X106 stabilized X 1 mo, then hemodialysis 66 2.5 2 3.0 Steroid recycle, i esA, hemodialysis 6 34 1.2 21 5X106 0.3 0.3 3.7 Steroid recycle, IV FK, Cr required intermittent hemodialysis, stabilized at Cr 2.5 7 25 2.4 36 (a)5X106 5 Stable renal function (Cr 2.0) at 36-mo follow-up (b) 3X106 5 (c)5X106 3 Group2 8 37 1.8 9 3X106 2.5 2.5 6.1 Steroid recycle, IV FK, hemodialysis 9 24 1.7 25 1.5X106 1.5 Discontinued for systemic side effects, renal function stable 10 67 1.6 18 3X106 2.5 Still on Rx 11 46 1.8 40 5XI06 6 Stable renal function 2-yr follow-up a An 8-day tapering course of prednisone was started at 200 mg daily. patient remained dialysis dependent until his death 6 months later. Patient 4 was diagnosed with acute allograft rejection by renal biopsy following an increase in serum creatinine 5 months into a course of 5xl06 U 3 times per week. He was treated with a steroid recycle and lowering of the IFN dosage to 3 x 106 U 3 times per week for the final month of his course. The serum creatinine level initially stabilized but subse-quently rose, and dialysis was required 1 month after com-pleting the course of IFN-a therapy. Patients 1, 3, 5, 6, and 8 had IFN discontinued at the time of allograft rejection; all but patient 5 returned to dialysis within 1 month of the rejection episode. Patient 7 received 3 different courses of rIFN over a course of 24 months for persistent hepatitis C-related liver function abnormalities without ever experi-encing rejection. This patient has stable allograft function 36 months after treatment. The allograft histopathology of all 7 patients who experi-enced graft dysfunction showed evidence of acute cellular rejection with interstitial cell infiltrates, hemorrhage, and tubulitis. Three patients (3, 4, and 8) had evidence of in-creased endothelial reactivity and 2 others (patients 1 and 6) had focal necrosis of glomeruli, features that suggests vascu-lar rejection. Of interest, 4 patients had new-onset protein-uria varying from 1 to 5 g/day with minimal glomerular changes by light microscopy. DISCUSSION Six of 7 renal transplant recipients and 1 of 4 recipients of combined liver-renal transplants experienced acute deterio-ration of allograft function associated with rIFN-a therapy. Although nephrotoxicity has been reported with IFN therapy (13), it is rare. Biopsy of our patients demonstrated cellular rejection, with some components of vascular rejection that occurred after long periods of graft stability. Rejection was not reversed by standard therapy and 6 ofthe 7 patients have returned to dialysis. Early reports of the use ofIFN-a for immunoprophylaxis of CMV infection used dosages similar to those used in our patients and were given over 3 months early after transplan·· tation. There was no associated increased graft loss or rejec-tion episodes (3). These studies were carried out before rou-tine use of CsA or FK506, but this experience has been essentially duplicated (11) in patients immunosuppressed with CsA. In contrast to these reports, high dose IFN therapy (36Xl06 U 3 times weekly) given to CsA-treated renal trans-plant patients caused a marked increase in the occurrence of steroid-resistant acute rejections with vascular components (12). Although this experience suggested that the toxicity of IFN might be dose related, a recent placebo-controlled trial of IFN prophylaxis using doses similar to those used in our patients also demonstrated a significant increase in irrevers-ible rejection in the IFN-treated patients (14). Thus, the relationship between IFN-a and allograft rejection can be seen irrespective of the dosage. Differences exist between the studies reviewed above and our experience. In all previous reports, IFN was given pro-phylactically early after transplantation to patients with nor-mal liver function. In our patients, a significant period of stable allograft function was followed by IFN-a therapy. However, recent experience shows that IFN-a may be quite safe when given to liver transplant recipients with active hepatocellular disease (15). Moreover, our own experience suggests that renal transplant patients with prior liver al-lografts (patients 8, 9, and 10) may be more tolerant ofIFN-a treatment. More experience with IFN-a therapy in patients with different organ transplants is needed to determine whether this speculation is correct. Another possible factor involved in the precipitation of acute allograft rejection after IFN administration may be the ----- ... -.------------------- - -_ .. _---_._-_ ... _ ... _---_._----1070 TRANSPLANTATION Vol. 59, No.7 preparation of IFN used. All reports of renal transplant dys-function associated with IFN therapy involved the use of rIFN-a (12,14). Conversely, all reports of successful therapy with IFN have used preparations derived from leukocyte- or lymphocyte-stimulated cultures (3, 11). This raises the pos-sibility that the purified recombinant preparation may actu-ally have greater toxicity for allografts than preparations derived from stimulated cells. Alternatively, the latter prep-arations may contain some protective factors. The mechanism of IFN-induced rejection in renal trans-plants is not known, but the observed clinical cases suggest that suppression of IFN production may be a factor in avoid-ing rejection in renal transplants. IFN-alJ3 has been shown to accelerate rejection in a model of heart transplantation (16), and it was suggested that this may be due to enhanced expression of class I antigens. IFN have been noted to en-hance the expression of both class I and class II antigens (3). Our patients who experienced rejection had a mean 2.4±0.49 class I mismatches (range 0-4) and 1.1±0.24 class II mis-matches (range 0-2). Whatever the mechanism, our experi-ence, and that of others, suggests that rIFN-a is associated with the development of resistant rejection in renal trans-plant patients. REFERENCES 1. Krawn SE. Interferons and interferon inducers in cancer treat-ment. Semin Oncol 1986; 13: 207. 2. Di Bisceglie AM, Martin P, Kassianides C, et aL Recombinant interferon alpha therapy for chronic hepatitis C: a randomized, double-blind, placebo-controlled triaL N Engl J Med 1989; 321 (No. 22): 1506. 3. Cheeseman SH, Rubin RR, Stewart JA, et aL Controlled clinical trial of prophylactic human-leukocyte interferon in renal transplantation: effects on cytomegalovirus and herpes sim-plex virus infections. N Engl J Med 1979; 300 (No. 24): 1345. 4. Rao KY, Anderson WR, Kasiske BL, Dahl DC. Value of liver biopsy in the evaluation and management of chronic liver disease in renal transplant recipients. Am J Med 1993; 94: 241. 5. Furman DA, BurakoffSJ, Bierer BE. Immunophillins in protein folding and immunosuppression. FASEB J 1994; 8: 391. 6. Reem GR, Cook LA. Gamma interferon synthesis by human thymocytes and T lymphocytes inhibited by cyclosporine A. Science 1983; 221: 63. 7. Yoshimura N, Matsui S, Hamashima T, Oka T. Effect of a new immunosuppressive agent, FK506, on human lymphocyte re-sponses in vitro. II. Inhibition of the production of IL-2 and -IFN, but not B cell-stimulating factor 2. Transplantation 1984; 47: 36. 8. Ambrus JL, Chadha KC, Anthone S, Athone R, Sayyid S. The alpha-interferon system in patients undergoing renal trans-plantation and treated with cyclosporine and prednisone. Surg Gynecol Obstet 1993; 176: 588. 9. Trinchieri D, Santoli D. Anti-viral activity induced by culturing lymphocytes with tumor-derived or virus transformed cells. Enhancement of human natural killer cell activity by culturing lymphocytes with turom-derived or virus-transformed cells: enhancement of human natural killer cell activity by inter-feron and antagonistic inhibition or susceptibility of target cells to lysis. J Exp Med 1978; 147: 1314. 10. DeMaeyer-Guignard J. Effects of interferon on cell mediated immunity as manifested by delayed hypersensitivity and al-lograft rejection. In: Vilcek J, DeMaeyer E, eds. Interferon 2. Interferons and the immune system. Amsterdam: Elsevier Sci-ence Publications, 1984: 133. 11. Lui SF, Ali AA, Grund.y JE, Fernando ON, Griffiths PD, Sweny P. Double-blind, placebo-controlled trial of human lymphoblas-toid interferon prophylaxis of cytomegalovirus infection in re-nal transplant recipients. Nephrol Dial Transplant 1992; 7: 1230. 12. Kramer P, Kate FWJ, Bijnen AB, Jeekel J, Weimar W. Recom-binant leucocyte interferon-a induces steroid-resistant acute vascular rejection episodes in renal transplant recipients. Lan-cet 1984; 1: 989. 13. Averbuch SD, Austin HA, Sherwin SA, Antonovych T, Bunn PA, Longo DL. Acute interstitial nephritis with the nephrotic syn-drome following recombinant leukocyte a interferon therapy for mycosis fungoides. N Engl J Med 1984; 310 (No. 1): 32. 14. Kovarik J, Mayer G, Pohanka E, et a1. Adverse effect oflow-dose prophylactic human recombinant leukocyte interferon-alpha treatment in renal transplant recipients: cytomegalovirus in-fection prophylaxis leading to an increased. incidence of irre-versible rejections. Transplantation 1988; 45 (No.2): 402. 15. Gurakar A, Fagiuoli S, Hassanein T, et aL Role of early initiation of alpha-interferon (lFN) in the prevention of liver allograft reinfection with either HBV or HCV hepatitis. Gastroenterol-ogy 1993; 104: 711A. 16. Slater AD, Klein JB, Sonnenfeld G, Ogden LL, Gray LA. The effects of interferon-alphalbeta in a model of rat heart trans-plantation. J Heart Lung Transplant 1992; 11: 975. Received 8 August 1994. Accepted 29 September 1994. 

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Alpha-interferon induced acute renal allograft rejection

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