Early Severe Thomas V. Berne, MD; L. Ake
Renal
Gustafsson, MD; Satya
N.
Allograft Rejection Chatterjee,
\s=b\An early, severe form of renal allograft rejection, occurring after an initial day or more of good function and within the first week after transplantation, is an increasingly recognized phenomenon. This type of rejection occurred in 17 of 187 (9%) postmortem-donor renal transplants. It could only be reversed in four grafts, and two of these failed because of recurrent rejection within four months. No clinical observations were helpful in determining which cases were likely to respond to antirejection therapy. Of the 17 patients, four died. Because of the poor graft survival and the high mortality, attempts to treat early severe rejection may not be warranted. (Arch Surg 111:758-760, 1976)
The coining
of the term "accelerated rejection" by Lucas seems to mark the recognition in the literature of a distinct form of rejection that does not fit the classical descriptions of hyperacute or acute renal allograft rejection. Kountz7' again used the term in 1973, and supported Lucas's belief that it was due to a humoral type of rejection in patients who, although negative on standard cross-match tests, were subliminally sensitized against histocompatibility (HL-A) antigens. More recently, Moore et al7 have reported that accelerated rejection occurred in 36 of 246 (15%) of cadaver renal allografts in the Southern California area that were preserved on a Beizer unit. This type of rejection could only be correlated with long periods of hemodialysis. More recently, Myburgh et al' have reported that 24 of 119 (20%) renal allografts have undergone accelerated rejection, and that two thirds of these cases had significant anti-HL-A presensitization prior to transplantation. Anderson and Newton7' have et al1 in 1970
Accepted
for publication Feb 12, 1976. From the Department of Surgery, University of Southern California School of Medicine and the Los Angeles County-USC Medical Center, Los
Angeles.
Read before the annual meeting of the Southern California Chapter of the American College of Surgeons, Newport Beach, Calif, Jan 17, 1976. Reprint requests to Department of Surgery, Los Angeles County-USC Medical Center, 1200 N State St, Los Angeles, CA 90033 (Dr Berne).
MB
BS, FRCS
recently reported on 12 of 67 (18%) renal grafts with accelerated rejection. Fifty-eight percent of their cases were reversible. Two of their patients died, and three other grafts were lost. No relationship to presensitization due to lymphocytotoxic or heterophil antibodies could be found. Although reported under different names, what are probably similar phenomena have been reported by other authors. Pillay et al" have reported two cases as a delayed form of hyperacute rejection with a characteristic selective thrombocytopenia. Baltzman et al7 have reported a syndrome termed "early acute rejection," which they believe is due to venous congestion. It is attractive to use the term "accelerated rejection" for such cases of rejection occurring in the first week, after a period of immediate postoperative function. Although the term seems to have gained wide acceptance in the literature, we have chosen to avoid its use because of the slightly different meanings given by different authors. There seems to be an almost assumed humoral or delayed hyperacute rejection connotation to the term since the original description and concurrence of several subsequent authors. We are not convinced that such rejection has a single cause, and we believe that until there is a better understanding of this phenomenon the term "accelerated rejection" should be avoided. Instead, we have used the descriptive term "early severe rejection." This report is a review of those renal allografts at the Los Angeles County-University of Southern California (USC) Medical Center that underwent early severe rejec¬ tion. Little is known regarding the optimal course of therapy for rejection occurring during this period. If certain early clinical characteristics could identify which grafts are likely to be saved and which should be aban¬ doned, considerable morbidity and mortality could be avoided. This review was carried out in the hope that we could learn the answers to some of these questions and help clarify the treatment of patients with early severe rejec¬ tion.
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/06/2015
SUBJECTS AND METHODS
There
There have been a total of 187 postmortem-donor renal allo¬ grafts done at the Los Angeles County-USC Medical Center. The cases selected for study in this report include only those patients with postmortem grafts that functioned for at least the first day after surgery, and in whom a falling serum creatinine level without any hemodialysis was documented. Additionally, all patients included here experienced an abrupt and sustained deterioration of renal function sometime within the first seven postoperative days. All patients were followed up by serial gamma camera studies, and routine laboratory tests, and frequent clinical observations. Patients with vascular occlusion and urinary tract complications were excluded. Seventeen grafts (9%) fulfilled these criteria for early severe rejection. Of these 17 patients, 11 were male and six were female. All were given 5 mg/kg of azathioprine before transplantation, once again after transplantation, and then a daily dose of 2.5/mg/ kg. Prednisone was given prior to surgery and for the first few days thereafter, at doses of approximately 2 mg/kg/day and then tapered. Episodes of rejection were treated by intravenous doses of 1 to 2 gm of methylprednisolone sodium succinate, which were repeated daily for up to three doses. Recycling of prednisone dosage back to the original 2 mg/kg/day was done if the rejection occurred after tapering had started. Some patients received intravenous heparin sodium therapy. The serum of all patients was evaluated on several occasions prior to transplantation for the presence of circulating lympho¬ cytotoxic antibodies. Also, immediately before all transplants, fresh serum from the potential recipient and lymphocytes from the donor were cross matched, using four-hour incubations. All cross matches were negative. Kidneys were preserved by a Beizer preservation machine, using cryoprecipitated plasma. All grafts were compatible for A, B, and O blood groups, and only two grafts were not also ABO-identical.
RESULTS
The earliest onset of rejection in this group of 17 kidneys was on the third day after transplantation, and the mean was 4.1 days. Fifteen kidneys (78%) had irreversible rejec¬ tion with essentially no response to antirejection therapy, and all were removed within the first month after graft¬ ing. In only four grafts (24%) could the rejection process be reversed so that graft function was maintained for more than two months. Because of this small number of rever¬ sible rejections, statistical comparison of these two groups is not possible. However, it was hoped that such a compar¬ ison would demonstrate some helpful clinical observa¬ tions.
Early Severe Rejection No.
(%) of Graft Rejections
r_
Clinical Observations Oliguria, 38.3C White blood cell count Increase Decrease Platelet count decrease More than twice normal lactic dehydrogenase
_
Irreversible
Reversible
(N 13) 10/13(77) 4/13(33)
(N 4) 2/4(50) 1/3(33)
7/13(54) 1/13(8) 3/10(30)
1/4(25) 2/4(50) 2/4(50)
=
=
level_0/4 (0)_0/3 (0)
essentially no difference in the mean time of rejection: 4.7 days for the reversible rejections, and 3.9 days for the irreversible rejections. As all patients received high-dose methylprednisolone intravenously for rejection, the only difference in therapy was that heparin was given intravenously to some patients. In those patients receiving heparin, five grafts failed without the patients having derived apparent benefit from the drug. Of the four who had early severe rejections that were successfully treated, three received heparin therapy. This apparent success must be balanced against several bleeding episodes and one death probably due to heparin. The patient who died had massive bleeding into the transplant wound, with subsequent sepsis. Another aspect of these cases was investigated, namely, HL-A and presensitization. Among the 13 reversible cases, there was a mean of 2.3 known HL-A antigens known to be present in the donor and not in the recipient. In the reversible rejections there was a mean of only one incom¬ patibility, and no case had more than two. There were only three patients with reactivity against more than 5% of the donor panel cases in the reversible early severe rejection group, and the same number in the nonreversible early severe rejection group. was
onset of
Several clinical observations are shown in the Table. These observations were all made for the period of the first three days following the onset of rejection. Oliguria was inconsistent because most of these patients had their own native kidneys in situ. As can be seen, none of these observations were consistent. Even serum lactic dehydrogenase values, which have been reported to be valuable in predicting graft recovery,7'"'' were not helpful. No consis¬ tent combination of findings was detected. The ultimate outlook for the group was bad. Of the 13 irreversible rejections, three patients (23%) died. Even among those four grafts that initially responded to treat¬ ment, two subsequently underwent later episodes of rejec¬ tion, and were lost at two and four months after transplan¬ tation. One of these patients died, making a mortality of 25% for the reversible early severe rejection group. COMMENT We were unable to detect any factors, such as the time of onset of rejection, levels of cytotoxic antibody presensiti¬
zation, or a laboratory finding, that would indicate which grafts undergoing early severe rejection would respond to therapy. The small numbers of grafts in which rejection could be reversed makes meaningful statistical analysis impossible, but in itself attests to the grave prognostic importance of early severe rejection. Considering that of 17 grafts only four recovered from the initial rejection
episode, and that two of those went on to fail within a few months, attempts to treat this kind of rejection may not be warranted. This view is in opposition to the report of Anderson and Newton7' in which the majority of the patients recovered graft function. In addition, we were
unable to make any clear statement as to the value of heparin therapy, as suggested by Williams et al." There is some suggestion that it may have been helpful in that
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/06/2015
three of the four
early
severe
patients whose grafts recovered from rejection were treated with heparin, but the
small number of cases does not allow such a conclusion. The one patient who died with an apparent complication from heparinization was treated with intermittent intravenous therapy. More recently, continuous intravenous heparin therapy has given much better control and minimal trouble with bleeding. The role of heparin therapy will have to await further evaluation. The early severe form of allograft rejection reviewed in this article remains an enigma. It appears to be an
increasingly recognized phenomenon. Our attempts to clarify the clinical picture have been unsuccessful, short of pointing out the grave prognosis for the grafts in this series if rejection occurs within the first week. Paul I. Terasaki, PhD,
performed
the
histocompatibility testing.
Nonproprietary Name and Trademark of Drug Azathioprine—Imuran.
References 1. Lucas ZJ, Coplon N, Kempson R, Transplantation 10:522-529, 1970. 2. Kountz SL: Clinical transplantation:
et al:
Early
renal
transplant.
An overview. Transplant Proc 5:59-65, 1973. 3. Moore TC, Berne TV, English TS: Accelerated rejection of 36 immediate post-transplant functioning machine-preserved human cadaveric kidneys. Surgery 75:357-367, 1974. 4. Myburgh JA, Majer G, Smit JA, et al: Presensitization and clinical kidney transplantation. Transplantation 18:206-212, 1974. 5. Anderson CB, Newton WT: Accelerated human renal allograft rejection. Arch Surg 110:1230-1232, 1975.
6. Pillay VKG, Kurtzman NA, Manaligod JR, et al: Selective thrombocytopenia due to localized microangiopathy of renal allografts. Lancet 2:988\x=req-\
991, 1973.
7. Baltzman MA, Baltzman RB, Pastershank S, et al: Early acute of renal allografts: A characteristic clinical syndrome. Can Med Assoc J 109:101-104, 1973. 8. Anderson CB, Codd JE, Graff RJ, et al: Serum lactic dehydrogenase and human allograft rejection. Surgery 77:674-679, 1975. 9. Williams M, Sterioff S, Bias W: Hyperacute and acute fulminating rejection of human renal allografts. Transplant Proc 4:665-667, 1972.
rejection
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/06/2015
Renal
Gustafsson, MD; Satya
N.
Allograft Rejection Chatterjee,
\s=b\An early, severe form of renal allograft rejection, occurring after an initial day or more of good function and within the first week after transplantation, is an increasingly recognized phenomenon. This type of rejection occurred in 17 of 187 (9%) postmortem-donor renal transplants. It could only be reversed in four grafts, and two of these failed because of recurrent rejection within four months. No clinical observations were helpful in determining which cases were likely to respond to antirejection therapy. Of the 17 patients, four died. Because of the poor graft survival and the high mortality, attempts to treat early severe rejection may not be warranted. (Arch Surg 111:758-760, 1976)
The coining
of the term "accelerated rejection" by Lucas seems to mark the recognition in the literature of a distinct form of rejection that does not fit the classical descriptions of hyperacute or acute renal allograft rejection. Kountz7' again used the term in 1973, and supported Lucas's belief that it was due to a humoral type of rejection in patients who, although negative on standard cross-match tests, were subliminally sensitized against histocompatibility (HL-A) antigens. More recently, Moore et al7 have reported that accelerated rejection occurred in 36 of 246 (15%) of cadaver renal allografts in the Southern California area that were preserved on a Beizer unit. This type of rejection could only be correlated with long periods of hemodialysis. More recently, Myburgh et al' have reported that 24 of 119 (20%) renal allografts have undergone accelerated rejection, and that two thirds of these cases had significant anti-HL-A presensitization prior to transplantation. Anderson and Newton7' have et al1 in 1970
Accepted
for publication Feb 12, 1976. From the Department of Surgery, University of Southern California School of Medicine and the Los Angeles County-USC Medical Center, Los
Angeles.
Read before the annual meeting of the Southern California Chapter of the American College of Surgeons, Newport Beach, Calif, Jan 17, 1976. Reprint requests to Department of Surgery, Los Angeles County-USC Medical Center, 1200 N State St, Los Angeles, CA 90033 (Dr Berne).
MB
BS, FRCS
recently reported on 12 of 67 (18%) renal grafts with accelerated rejection. Fifty-eight percent of their cases were reversible. Two of their patients died, and three other grafts were lost. No relationship to presensitization due to lymphocytotoxic or heterophil antibodies could be found. Although reported under different names, what are probably similar phenomena have been reported by other authors. Pillay et al" have reported two cases as a delayed form of hyperacute rejection with a characteristic selective thrombocytopenia. Baltzman et al7 have reported a syndrome termed "early acute rejection," which they believe is due to venous congestion. It is attractive to use the term "accelerated rejection" for such cases of rejection occurring in the first week, after a period of immediate postoperative function. Although the term seems to have gained wide acceptance in the literature, we have chosen to avoid its use because of the slightly different meanings given by different authors. There seems to be an almost assumed humoral or delayed hyperacute rejection connotation to the term since the original description and concurrence of several subsequent authors. We are not convinced that such rejection has a single cause, and we believe that until there is a better understanding of this phenomenon the term "accelerated rejection" should be avoided. Instead, we have used the descriptive term "early severe rejection." This report is a review of those renal allografts at the Los Angeles County-University of Southern California (USC) Medical Center that underwent early severe rejec¬ tion. Little is known regarding the optimal course of therapy for rejection occurring during this period. If certain early clinical characteristics could identify which grafts are likely to be saved and which should be aban¬ doned, considerable morbidity and mortality could be avoided. This review was carried out in the hope that we could learn the answers to some of these questions and help clarify the treatment of patients with early severe rejec¬ tion.
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/06/2015
SUBJECTS AND METHODS
There
There have been a total of 187 postmortem-donor renal allo¬ grafts done at the Los Angeles County-USC Medical Center. The cases selected for study in this report include only those patients with postmortem grafts that functioned for at least the first day after surgery, and in whom a falling serum creatinine level without any hemodialysis was documented. Additionally, all patients included here experienced an abrupt and sustained deterioration of renal function sometime within the first seven postoperative days. All patients were followed up by serial gamma camera studies, and routine laboratory tests, and frequent clinical observations. Patients with vascular occlusion and urinary tract complications were excluded. Seventeen grafts (9%) fulfilled these criteria for early severe rejection. Of these 17 patients, 11 were male and six were female. All were given 5 mg/kg of azathioprine before transplantation, once again after transplantation, and then a daily dose of 2.5/mg/ kg. Prednisone was given prior to surgery and for the first few days thereafter, at doses of approximately 2 mg/kg/day and then tapered. Episodes of rejection were treated by intravenous doses of 1 to 2 gm of methylprednisolone sodium succinate, which were repeated daily for up to three doses. Recycling of prednisone dosage back to the original 2 mg/kg/day was done if the rejection occurred after tapering had started. Some patients received intravenous heparin sodium therapy. The serum of all patients was evaluated on several occasions prior to transplantation for the presence of circulating lympho¬ cytotoxic antibodies. Also, immediately before all transplants, fresh serum from the potential recipient and lymphocytes from the donor were cross matched, using four-hour incubations. All cross matches were negative. Kidneys were preserved by a Beizer preservation machine, using cryoprecipitated plasma. All grafts were compatible for A, B, and O blood groups, and only two grafts were not also ABO-identical.
RESULTS
The earliest onset of rejection in this group of 17 kidneys was on the third day after transplantation, and the mean was 4.1 days. Fifteen kidneys (78%) had irreversible rejec¬ tion with essentially no response to antirejection therapy, and all were removed within the first month after graft¬ ing. In only four grafts (24%) could the rejection process be reversed so that graft function was maintained for more than two months. Because of this small number of rever¬ sible rejections, statistical comparison of these two groups is not possible. However, it was hoped that such a compar¬ ison would demonstrate some helpful clinical observa¬ tions.
Early Severe Rejection No.
(%) of Graft Rejections
r_
Clinical Observations Oliguria, 38.3C White blood cell count Increase Decrease Platelet count decrease More than twice normal lactic dehydrogenase
_
Irreversible
Reversible
(N 13) 10/13(77) 4/13(33)
(N 4) 2/4(50) 1/3(33)
7/13(54) 1/13(8) 3/10(30)
1/4(25) 2/4(50) 2/4(50)
=
=
level_0/4 (0)_0/3 (0)
essentially no difference in the mean time of rejection: 4.7 days for the reversible rejections, and 3.9 days for the irreversible rejections. As all patients received high-dose methylprednisolone intravenously for rejection, the only difference in therapy was that heparin was given intravenously to some patients. In those patients receiving heparin, five grafts failed without the patients having derived apparent benefit from the drug. Of the four who had early severe rejections that were successfully treated, three received heparin therapy. This apparent success must be balanced against several bleeding episodes and one death probably due to heparin. The patient who died had massive bleeding into the transplant wound, with subsequent sepsis. Another aspect of these cases was investigated, namely, HL-A and presensitization. Among the 13 reversible cases, there was a mean of 2.3 known HL-A antigens known to be present in the donor and not in the recipient. In the reversible rejections there was a mean of only one incom¬ patibility, and no case had more than two. There were only three patients with reactivity against more than 5% of the donor panel cases in the reversible early severe rejection group, and the same number in the nonreversible early severe rejection group. was
onset of
Several clinical observations are shown in the Table. These observations were all made for the period of the first three days following the onset of rejection. Oliguria was inconsistent because most of these patients had their own native kidneys in situ. As can be seen, none of these observations were consistent. Even serum lactic dehydrogenase values, which have been reported to be valuable in predicting graft recovery,7'"'' were not helpful. No consis¬ tent combination of findings was detected. The ultimate outlook for the group was bad. Of the 13 irreversible rejections, three patients (23%) died. Even among those four grafts that initially responded to treat¬ ment, two subsequently underwent later episodes of rejec¬ tion, and were lost at two and four months after transplan¬ tation. One of these patients died, making a mortality of 25% for the reversible early severe rejection group. COMMENT We were unable to detect any factors, such as the time of onset of rejection, levels of cytotoxic antibody presensiti¬
zation, or a laboratory finding, that would indicate which grafts undergoing early severe rejection would respond to therapy. The small numbers of grafts in which rejection could be reversed makes meaningful statistical analysis impossible, but in itself attests to the grave prognostic importance of early severe rejection. Considering that of 17 grafts only four recovered from the initial rejection
episode, and that two of those went on to fail within a few months, attempts to treat this kind of rejection may not be warranted. This view is in opposition to the report of Anderson and Newton7' in which the majority of the patients recovered graft function. In addition, we were
unable to make any clear statement as to the value of heparin therapy, as suggested by Williams et al." There is some suggestion that it may have been helpful in that
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/06/2015
three of the four
early
severe
patients whose grafts recovered from rejection were treated with heparin, but the
small number of cases does not allow such a conclusion. The one patient who died with an apparent complication from heparinization was treated with intermittent intravenous therapy. More recently, continuous intravenous heparin therapy has given much better control and minimal trouble with bleeding. The role of heparin therapy will have to await further evaluation. The early severe form of allograft rejection reviewed in this article remains an enigma. It appears to be an
increasingly recognized phenomenon. Our attempts to clarify the clinical picture have been unsuccessful, short of pointing out the grave prognosis for the grafts in this series if rejection occurs within the first week. Paul I. Terasaki, PhD,
performed
the
histocompatibility testing.
Nonproprietary Name and Trademark of Drug Azathioprine—Imuran.
References 1. Lucas ZJ, Coplon N, Kempson R, Transplantation 10:522-529, 1970. 2. Kountz SL: Clinical transplantation:
et al:
Early
renal
transplant.
An overview. Transplant Proc 5:59-65, 1973. 3. Moore TC, Berne TV, English TS: Accelerated rejection of 36 immediate post-transplant functioning machine-preserved human cadaveric kidneys. Surgery 75:357-367, 1974. 4. Myburgh JA, Majer G, Smit JA, et al: Presensitization and clinical kidney transplantation. Transplantation 18:206-212, 1974. 5. Anderson CB, Newton WT: Accelerated human renal allograft rejection. Arch Surg 110:1230-1232, 1975.
6. Pillay VKG, Kurtzman NA, Manaligod JR, et al: Selective thrombocytopenia due to localized microangiopathy of renal allografts. Lancet 2:988\x=req-\
991, 1973.
7. Baltzman MA, Baltzman RB, Pastershank S, et al: Early acute of renal allografts: A characteristic clinical syndrome. Can Med Assoc J 109:101-104, 1973. 8. Anderson CB, Codd JE, Graff RJ, et al: Serum lactic dehydrogenase and human allograft rejection. Surgery 77:674-679, 1975. 9. Williams M, Sterioff S, Bias W: Hyperacute and acute fulminating rejection of human renal allografts. Transplant Proc 4:665-667, 1972.
rejection
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