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Decreased function of a renal transplant after influenza virus infection
Decreased Function of a Renal Transplant after Influenza Virus Infection Robert T. Schweizer, MD, Hartford, Connecticut Stanley A. Bartus, MD, Hartford, Connecticut James H. Foster, MD, Hartford, Connecticut
Recent publications have reported the occurrence of probable rejection episodes in a few recipients of renal transplants after a viral infection [l-4]. Viruses of the herpesvirus group and the influenza virus are the most frequent types associated with rejection episodes. In these reports, the onset of viral infection and the decreased renal function usually coincided. The following is a case report of a probable influenza-induced rejection episode occurring one month after the viral infection. Case Report The patient, a sixteen year old white girl with chronic membranoproliferative hypocomplementemic glomerulonephritis, began hemodialysis therapy in October 1972. Antikidney antibodies were demonstrated in low titer. Bilateral nephrectomies were performed in November 1972, and four weeks later the antikidney antibody titer was negative. She received a kidney transplant from her forty-three year old father in December 1972, with azathioprine (Imuran@) and prednisone employed for immunosuppression. A slight rejection episode was diagnosed beginning on the seventh day post transplantation. This was quickly reversed with intravenous methylprednisolone (Solu-Medrol@) and irradiation of the graft. The highest serum creatinine level during the rejection episode was 1.3 mg/lOO ml. Immunosuppression was maintained with 125 mg of azathioprine and 15 mg of prednisone daily. The patient’s renal function was stable, with an average serum creatinine level of 1.2 mg/lOO ml, blood urea nitrogen level of 17 mg/lOO ml, and creatinine clearance of 65 ml/min. Moderate proteinuria was present. From the Departments of Surgery, Hartford Hospital, and the University of Connecticut School of Medicine, Hartford, Connecticut. Reprint requests should be addressed to Robert T. Schweizer. MD, Transplantation Service, Hartford Hospital, Hartford, Connecticut 06115.
The patient remained well until March 1974 when, during a New England flu epidemic, she experienced a chill followed by a fever. A few hours after the chill the temperature was 104.6’F. The physical examination was otherwise unremarkable. Laboratory data on admission revealed a white blood cell count of 15,400 per mm3, hematocrit of 31 per cent, blood urea nitrogen level of 10 mg/lOO ml, serum creatinine level of 1.5 mg/lOO ml, and creatinine clearance of 60 ml/min. Urinalysis proved normal and urine protein was 817 mg/24 hr. Blood sugar and liver function test results proved normal. Several blood and urine cultures were obtained. She was treated with intravenous cephalothin (Keflin”), 1 gm every six hours for five days, and intramuscular gentamycin (Garamycine), 120 mg per day, for a total dose of 510 mg. A nonproductive cough developed on the second hospital day. Chest x-ray films revealed no abnormalities. She became afebrile on the fourth hospital day, and since all cultures showed no growth, antibiotics were discontinued. Maintenance immunosuppression was moderately reduced while the patient was febrile. Leukopenia developed on the fifth hospital day. White blood cell count was 3,300 per mm3, with 73 per cent polymorphonuclear cells, 3 per cent band forms, 17 per cent lymphocytes, and 21 per cent monocytes. Platelet count was 225,000 per mm3. Renal function remained stable and the serum creatinine level decreased to 1.1 mg/lOO ml on .the second hospital day without antirejection therapy. She was discharged on March 11,1974, the ninth hospital day. Follow-up renal function test results were unchanged on March 15, 1974 and March 22, 1974. However, one month after the onset of the febrile illness, the serum creatinine level was 1.9 mg/lOO ml, blood urea nitrogen level was 23 mg/lOO ml, and creatinine clearance was 27 ml/min. She was admitted for further tests. Physical examination was unremarkable, except for a moderately enlarged transplanted kidney. Other laboratory tests
The American Journal of Surgery
Decreased Function of Renal Transplant
showed a white blood cell count of 7,800 per mm3, hematocrit of 32 per cent, urine protein of 649 mg/24 hr, and normal urine sediments. The serum electrolyte, blood sugar, liver enzyme, calcium, and phosphorus levels were within normal limits. An intravenous pyelogram compared with a study one year earlier showed a 2 cm increase in length of the transplant. There was no ureteral obstruction. She was treated with large doses of oral prednisone, pulse doses of methylprednisolone, and irradiation of the graft. On the third hospital day the serum creatinine level was 2.3 mg/lOO ml, blood urea nitrogen level was 37 mg/lOO ml, and creatinine clearance was 41 ml/min. Serum complement level (C 3) on admission was within normal limits. The prednisone dosage was tapered quickly, the kidney decreased in size, and the patient was discharged on the twelfth hospital day. The serum creatinine level at the time of discharge was 1.3 mg/lOO ml and the blood urea nitrogen level was 32 mg/lOO ml. Three months after discharge, the serum creatinine level is 1.5 mg/lOO ml, blood urea nitrogen level is 16 mg/lOO ml, and creatinine clearance is 44 ml/ min. Antibody titers for influenza virus type A (England), determiged by the hemagglutination inhibition technic, were measured in serum samples obtained at the time of the febrile episode and again one month later at the time of decreased renal function. A sixty-four-fold increase in titers was demonstrated. Antibody titers for influenza virus type B and type A (Hong Kong), as well as titers for cytomegalovirus, adenovirus, and herpesvirus group, were negative or unchanged.
ed by Lopez [I], Simmons [2], and co-workers. A nonspecific stimulation of an immunologic process, in this case a rejection episode, might have been initiated by the specific immune response to the virus. This could occur in a manner similar t.o the stimulation of immunologic processes by certain bacterial agents [8,9]. The swelling of the graft and the rapid improvement in renal function after antirejection therapy are typical of an acute rejection episode. Whatever the exact cause of the decline in renal function, this case serves to emphasize the need for continual monitoring of renal function after transplantation, especially after a viral infection. Furthermore, it is apparent from this case and from a case reported by Briggs et al [4] that renal function should be monitored carefully for at least one month after viral infection in transplant recipients, as there may be a delay in the onset of impaired function. Summary A sixteen year old female recipient of a renal transplant had decreased renal function one month after an influenza virus infection. An acute rejection episode induced by the viral infection was the probable cause. Renal function in transplant recipients should be carefully monitored for at least one month after viral infection.
Comments Other than an episode of acute rejection, there are three possibilities that could account for the decline in renal function. One is a recurrence of the original renal disease, membranoproliferative glomerulonephritis [5], a second is nephritis induced by virus [6], and a third is a nephrotoxic action of the antibiotics. The delayed onset of impaired function, the lack of increase in proteinuria, the normal urine sediment, and the normal serum complement level do not support the idea of recurrence of disease or a virally caused nephritis. Use of antibiotics also does not appear as a probable cause of decreased renal function, as the dosages administered were moderate and of brief duration. Although gentamycin is a known nephrotoxic agent, the delayed onset of decreased renal function is not typical of nephrotoxicity due to gentamycin [ 71. A more likely cause of the decline in renal function is an acute rejection episode induced by the influenza infection, a possible mechanism suggest-
Volume
129, June 1975
References 1. Lopez C, Simmons RL. Mauer SM, Najarian JS. Good RA: Association of renal allograft rejection with virus infections. Am JMed56: 280, 1974. 2. Simmons RL, Weil R, Tallent MB, Kjellstrand CM, Najarlan JS: Do mild infections trigger the rejection of renal allografts? Transplant Proc 2: 419, 1970. 3. David DS, Millian SJ, Whitsell JC, Schwartz GH, Riggio RR, Stenzel KH. Rubin AL: Viral syndromes and renal homograft rejection. Ann Surg 175: 257, 1972. 4. Briggs JD, Timbury MC, Paton AM, Bell PR: Viral infection and renal transplant rejection. Br Med J 4: 520. 1972. 5. Schurch W, Leski M, Hinglais N: Evolution of recurrent lobular glomerulonephritis in a human kidney allotransplant. Combined light immunofluorescent and electron microscopic studies of serial biopsies. Virchows Arch (PatholAnat) 355: 66, 1972. 6. Jensen MM: Viruses and kidney disease. Am J Med 43: 897, 1967. 7. Falco FG, Smith HM, Arcieri GM: Nephrotoxicity of aminoglycosides and gentamicin. J Infect Dis 119: 406, 1969. 8. Yashpke DJ: Immunological factors in nonspecific stimulation of host resistance to syngeneic tumors. fsr J Med Sci 7: 90, 1971. 9. Al-Askari S, Zweiman B, Lawrence HS. Thomas L: The effect of endotoxin on skin homografts in rabbits. J /mmuno/ 9: 742, 1964.
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Recent publications have reported the occurrence of probable rejection episodes in a few recipients of renal transplants after a viral infection [l-4]. Viruses of the herpesvirus group and the influenza virus are the most frequent types associated with rejection episodes. In these reports, the onset of viral infection and the decreased renal function usually coincided. The following is a case report of a probable influenza-induced rejection episode occurring one month after the viral infection. Case Report The patient, a sixteen year old white girl with chronic membranoproliferative hypocomplementemic glomerulonephritis, began hemodialysis therapy in October 1972. Antikidney antibodies were demonstrated in low titer. Bilateral nephrectomies were performed in November 1972, and four weeks later the antikidney antibody titer was negative. She received a kidney transplant from her forty-three year old father in December 1972, with azathioprine (Imuran@) and prednisone employed for immunosuppression. A slight rejection episode was diagnosed beginning on the seventh day post transplantation. This was quickly reversed with intravenous methylprednisolone (Solu-Medrol@) and irradiation of the graft. The highest serum creatinine level during the rejection episode was 1.3 mg/lOO ml. Immunosuppression was maintained with 125 mg of azathioprine and 15 mg of prednisone daily. The patient’s renal function was stable, with an average serum creatinine level of 1.2 mg/lOO ml, blood urea nitrogen level of 17 mg/lOO ml, and creatinine clearance of 65 ml/min. Moderate proteinuria was present. From the Departments of Surgery, Hartford Hospital, and the University of Connecticut School of Medicine, Hartford, Connecticut. Reprint requests should be addressed to Robert T. Schweizer. MD, Transplantation Service, Hartford Hospital, Hartford, Connecticut 06115.
The patient remained well until March 1974 when, during a New England flu epidemic, she experienced a chill followed by a fever. A few hours after the chill the temperature was 104.6’F. The physical examination was otherwise unremarkable. Laboratory data on admission revealed a white blood cell count of 15,400 per mm3, hematocrit of 31 per cent, blood urea nitrogen level of 10 mg/lOO ml, serum creatinine level of 1.5 mg/lOO ml, and creatinine clearance of 60 ml/min. Urinalysis proved normal and urine protein was 817 mg/24 hr. Blood sugar and liver function test results proved normal. Several blood and urine cultures were obtained. She was treated with intravenous cephalothin (Keflin”), 1 gm every six hours for five days, and intramuscular gentamycin (Garamycine), 120 mg per day, for a total dose of 510 mg. A nonproductive cough developed on the second hospital day. Chest x-ray films revealed no abnormalities. She became afebrile on the fourth hospital day, and since all cultures showed no growth, antibiotics were discontinued. Maintenance immunosuppression was moderately reduced while the patient was febrile. Leukopenia developed on the fifth hospital day. White blood cell count was 3,300 per mm3, with 73 per cent polymorphonuclear cells, 3 per cent band forms, 17 per cent lymphocytes, and 21 per cent monocytes. Platelet count was 225,000 per mm3. Renal function remained stable and the serum creatinine level decreased to 1.1 mg/lOO ml on .the second hospital day without antirejection therapy. She was discharged on March 11,1974, the ninth hospital day. Follow-up renal function test results were unchanged on March 15, 1974 and March 22, 1974. However, one month after the onset of the febrile illness, the serum creatinine level was 1.9 mg/lOO ml, blood urea nitrogen level was 23 mg/lOO ml, and creatinine clearance was 27 ml/min. She was admitted for further tests. Physical examination was unremarkable, except for a moderately enlarged transplanted kidney. Other laboratory tests
The American Journal of Surgery
Decreased Function of Renal Transplant
showed a white blood cell count of 7,800 per mm3, hematocrit of 32 per cent, urine protein of 649 mg/24 hr, and normal urine sediments. The serum electrolyte, blood sugar, liver enzyme, calcium, and phosphorus levels were within normal limits. An intravenous pyelogram compared with a study one year earlier showed a 2 cm increase in length of the transplant. There was no ureteral obstruction. She was treated with large doses of oral prednisone, pulse doses of methylprednisolone, and irradiation of the graft. On the third hospital day the serum creatinine level was 2.3 mg/lOO ml, blood urea nitrogen level was 37 mg/lOO ml, and creatinine clearance was 41 ml/min. Serum complement level (C 3) on admission was within normal limits. The prednisone dosage was tapered quickly, the kidney decreased in size, and the patient was discharged on the twelfth hospital day. The serum creatinine level at the time of discharge was 1.3 mg/lOO ml and the blood urea nitrogen level was 32 mg/lOO ml. Three months after discharge, the serum creatinine level is 1.5 mg/lOO ml, blood urea nitrogen level is 16 mg/lOO ml, and creatinine clearance is 44 ml/ min. Antibody titers for influenza virus type A (England), determiged by the hemagglutination inhibition technic, were measured in serum samples obtained at the time of the febrile episode and again one month later at the time of decreased renal function. A sixty-four-fold increase in titers was demonstrated. Antibody titers for influenza virus type B and type A (Hong Kong), as well as titers for cytomegalovirus, adenovirus, and herpesvirus group, were negative or unchanged.
ed by Lopez [I], Simmons [2], and co-workers. A nonspecific stimulation of an immunologic process, in this case a rejection episode, might have been initiated by the specific immune response to the virus. This could occur in a manner similar t.o the stimulation of immunologic processes by certain bacterial agents [8,9]. The swelling of the graft and the rapid improvement in renal function after antirejection therapy are typical of an acute rejection episode. Whatever the exact cause of the decline in renal function, this case serves to emphasize the need for continual monitoring of renal function after transplantation, especially after a viral infection. Furthermore, it is apparent from this case and from a case reported by Briggs et al [4] that renal function should be monitored carefully for at least one month after viral infection in transplant recipients, as there may be a delay in the onset of impaired function. Summary A sixteen year old female recipient of a renal transplant had decreased renal function one month after an influenza virus infection. An acute rejection episode induced by the viral infection was the probable cause. Renal function in transplant recipients should be carefully monitored for at least one month after viral infection.
Comments Other than an episode of acute rejection, there are three possibilities that could account for the decline in renal function. One is a recurrence of the original renal disease, membranoproliferative glomerulonephritis [5], a second is nephritis induced by virus [6], and a third is a nephrotoxic action of the antibiotics. The delayed onset of impaired function, the lack of increase in proteinuria, the normal urine sediment, and the normal serum complement level do not support the idea of recurrence of disease or a virally caused nephritis. Use of antibiotics also does not appear as a probable cause of decreased renal function, as the dosages administered were moderate and of brief duration. Although gentamycin is a known nephrotoxic agent, the delayed onset of decreased renal function is not typical of nephrotoxicity due to gentamycin [ 71. A more likely cause of the decline in renal function is an acute rejection episode induced by the influenza infection, a possible mechanism suggest-
Volume
129, June 1975
References 1. Lopez C, Simmons RL. Mauer SM, Najarian JS. Good RA: Association of renal allograft rejection with virus infections. Am JMed56: 280, 1974. 2. Simmons RL, Weil R, Tallent MB, Kjellstrand CM, Najarlan JS: Do mild infections trigger the rejection of renal allografts? Transplant Proc 2: 419, 1970. 3. David DS, Millian SJ, Whitsell JC, Schwartz GH, Riggio RR, Stenzel KH. Rubin AL: Viral syndromes and renal homograft rejection. Ann Surg 175: 257, 1972. 4. Briggs JD, Timbury MC, Paton AM, Bell PR: Viral infection and renal transplant rejection. Br Med J 4: 520. 1972. 5. Schurch W, Leski M, Hinglais N: Evolution of recurrent lobular glomerulonephritis in a human kidney allotransplant. Combined light immunofluorescent and electron microscopic studies of serial biopsies. Virchows Arch (PatholAnat) 355: 66, 1972. 6. Jensen MM: Viruses and kidney disease. Am J Med 43: 897, 1967. 7. Falco FG, Smith HM, Arcieri GM: Nephrotoxicity of aminoglycosides and gentamicin. J Infect Dis 119: 406, 1969. 8. Yashpke DJ: Immunological factors in nonspecific stimulation of host resistance to syngeneic tumors. fsr J Med Sci 7: 90, 1971. 9. Al-Askari S, Zweiman B, Lawrence HS. Thomas L: The effect of endotoxin on skin homografts in rabbits. J /mmuno/ 9: 742, 1964.
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