ABO BLOOD GROUP INCOMPATIBILITY IN HUMAN RENAL HOMOTRANSPLANTATION

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1 THE AMERICAN JOURNAL OP CLINICAL PATHOLOGY Copyright 969 by The Williams & Wilkins Co. Vol. 5, No. Printed in U.S.A. ABO BLOOD GROUP INCOMPATIBILITY IN HUMAN RENAL HOMOTRANSPLANTATION RUPERT WILBRANDT, M.D., KENNETH S. K. TUNG, M.B., B.S., SHARAD D. DEODHAR, M.D., PH.D., SATORU NAKAMOTO, M.D., AND WILLEM J. KOLFF, M.D., PH.D. Department of Artificial Organs, the Division of Pathology, and the Department of Hemodialysis, The Cleveland Clinic Foundation, Cleveland, Ohio 446 The undesirability of homotransplantation of tissues in the presence of ABO incompatibility has been emphasized in the past, 2 ' 4> 6 ' 2 but the warning was ignored during the early period of renal homotransplantation in man. Now it is agreed that major ABO compatibility is essential in selecting donors for renal homografts. This consensus came about largely because of the studies of Starzl and associates. 8 The small number of recipients with ABO incompatible renal homografts available for study has limited the clarification of certain clinicopathologic observations in regard to these patients. Specifically, the questions concerning the ABO incompatible renal homografts are: () What is the probable cause of the early failure of these homografts? (2) What are the variations in the clinicopathologic patterns? () What are the patterns of changes in the isohemoagglutinin titers? Among the early renal homotransplantations performed at the Cleveland Clinic, there were 24 patients who received ABO incompatible renal homografts. In this report, we present results of a retrospective study of these patients in an attempt to provide answers to the above-mentioned questions. MATERIALS AND METHODS Clinical study. There were 2 patients with major ABO incompatibility (Table, Received May 9, 968. This study was supported by a grant from the John A. Hartford Foundation to the Cleveland Clinic Foundation, with Dr. W. J. KolfT as the principal investigator. Requests for reprints should be addressed to Dr. Sharad D. Deodhar, The Cleveland Clinic Foundation, 22 East 9rd St., Cleveland, Ohio 446. Dr. Tung's present address is Division of Experimental Pathology, Scripps Clinic, La Jolla, Calif. Downloaded from on 4 February 28 Patients through 2) and 2 patients with minor ABO incompatibility (Table, Patients through 24). The ABO blood group patterns among the donors and the recipients are summarized in Table 2. ic kidneys were used in all but four patients (Patients, 7, 9, and 22). The selection and the preparation both of cadaveric and of living donors, and the operative technic of renal transplantation have been reported in detail. 9, To assess renal function after transplantation, the fluid balance, body temperature, and blood pressure of the patient were recorded daily. The blood urea, urine urea, serum electrolytes, total leukocyte count, and creatinine clearance were studied once each week. The seven clinical criteria for rejection of the renal homograft were: () elevation of diastolic blood pressure, (2) elevation of blood urea nitrogen, () elevation of peripheral leukocyte count, (4) increasing proteinuria, (5) the presence of fever, (6) a decrease in urinary sodium, and (7) a decrease in creatinine clearance. It is an exception when these criteria are all present in a given rejection episode; the more common changes were increased blood urea nitrogen and a decrease in creatinine clearance. The administration of the immunosuppressive drugs, including azathioprine and prednisone, was started at the time of transplantation, and the dosages were individualized according to the clinical behavior and the drug tolerance of the patient. When there was clinical evidence of rejection, local irradiation (cobalt 6 teletherapy) to the site of the homograft, with or without the concurrent administration of actinomycin C, was given. The isohemapglutinin titers to A or B blood groups, or both. The isohemagglutinin (IHA) titers in six patients were studied by the indirect Coombs' method. This included 5

2 TABLE SUMMARY OF THE THE CLINICAL AND PATHOLOGIC DATA IN 24 PATIENTS WHO HAD ABO Bi,ooi) GROUP INCOMPATIBLE KIDNEY HOMOTRANSPLANTATION Patient No. Age, Sex Blood Group Donor Primary Renal Disease* Recipient Donor Duration until Nephrectomy or Autopsyt Rejection Crisis (Crises) No. Time from transplantation Immunosuppression Therapy, the Maintenance Dose in Living Subjects, or Preceding Homograft Removal Function of Renal Homograft, Recent! (Values just Before Removal of Graft) Pathologic Findings Vascular changes, type in the Homografts Comments Ischemic Time at Transplantation Renal artery thrombosis Total renal necrosis Cellular response, including pyroninophilic cells y- 27, F, F. F 48, F 4, M 47, F 25, M 2, F 58, M A + A- A + A min days (N; D) days (N; D) 5 days (D) 9 mo. (D) wk. (N; D) 2 mo. (N; D) 7 days (N) 7 days (N; D) mo. (N; D) 2 Within 5 days mo. days; 2 mo. Mild Arterial Hypertension, Posttransplantation (Unrelated to Rejection) Severe Mild Severe Severe mg./kg./day Azathioprine,.5 Prednisone, 2.7 Azathioprine,. Prednisone,. Azathioprine,. Prednisone,. Azathioprine,.2 Prednisone,. Azathioprine,. Prednisone,.4 Azathioprine,.9 Prednisone,.5 Azathioprine,. Prednisone,. Azathioprine, 2. Prednisone, 2. Azathioprine,. Prednisone,.2 Good (Cr. C 4) Poor (BU 225, Cr C 22) ff- (acute) -f-f- (acute) (acute) (acute) ~~ ~ + Nonspecific arterial thrombosis; no viable tissue for assessment of rejection Acute rejection Acute rejection Nonspecific arterial thrombosis; no viable tissue for assessment of rejection Significant rejection Nonspecific arterial thrombosis; no viable tissue for assessment of rejection Nonspecific arterial thrombosis; no viable tissue for assessment of rejection Acute significant rejection Downloaded from on 4 February 28

3 TABLE CONTINUED 5, M 9 mo. (D) 2 days; mo.;9 mo. Severe Azathioprine,. Prednisone,.5 46, F 2, F 4, F, M 4, F, F 5, M 28, M PK PK B B+ B+ + + Sister (living) Mother (living) mo. (D) days (N; D) 8 days (D) mo. (N) 22 days (N) 9 mo. (D) 2 mo.; 5 mo. 9 mo. 7 mo. Mild Azathioprine,.4 Prednisone,. Azathioprine,. Prednisone, 2. Azathioprine, (5 days) Prednisone,.2 Azathioprine, 2. Prednisone,.2 Azathioprine,.8 Prednisone,. Azathioprine,.9 Prednisone,.9 Azathioprine,.6 Prednisone,.9 Azathioprine, 2.5 Prednisone,.7 6, F 48, M 9, F 9, M 9, F 27, M PK PK A- A- Father (living) Unrelated person (living) mo. (D) Graft still in situ 2 mo. (D) 5 mo. 2 mo.; 4 mo.; mo. 2 mo. Azathioprine, 2. Prednisone,.2 Azathioprine,.4 Prednisone,.7 Azathioprine,. Prednisone,. Azathioprine,.6 Prednisone,. Azathioprine,.6 Prednisone,. Azathioprine, 2. Prednisone, 4.2 *, chronic pyelonephritis;, chronic glomerulonephritis; PK, polycystic kidneys. f N, nephrectomy; D, subsequent death. X BU, blood urea, mg./loo ml.; Cr C, creatinine clearance, ml./min., Cr, serum creatinine, mg./loo ml. +, Mild; -f-f, moderate; -f-f -f, severe;, none. Poor (required dialysis) Poor (BU 22, CrC 7) Excellent (BU 5, Cr.) Fair (Cr C 2, Cr 2.6) Excellent (BU 9, Cr C 62) Poor (required hemodialysis) (required hemodialysis) Fair with deterioration (BU 28) Excellent (BU 25, CrC 9) Good (Cr C 4) Excellent (Cr C 8, Cr.8) Fair (Cr C 5, BU 94) Excellent ( U 2, CrC 9) Fair (Cr.4) ~~ ~ -Jf-+ (acute and chronic) (acute) ~ Acute significant rejection; immunofluorescence demonstrated immunoglobulins IgM and IgG in vessel wall Acute severe rejection No significant rejection No significant rejection Rejection present Acute significant rejection Apparently normal kidney Acute significant rejection Downloaded from on 4 February 28

4 IS WILBRANDT ET AL. Vol. 5 TABLE 2 PATTERNS OF ABO BLOOD GROUP INCOMPATI BILITY IN 24 RENAL HOMOTRANSPLANTATIONS AB ISOAGGLUTININ (IHA) TITERS FOLLOWING KIDNEY TRANSPLANTATIONS Incompatibility Grouping Blood Groups Donor Recipient Major Minor A AB AB B A A A B only the IHA titers made on serial dilutions of patients' sera that corresponded to the ABO antigens of the donor that were lacking in the recipient. (Examples: AB donor to recipient, both anti-a and anti-b were studied; for A donor to B recipient, only anti-a was studied.) The IHA titers of these patients were not evaluated before renal transplantation. Direct titration of patients' sera with A 2 cells were not performed. In four patients (Table, Patients7, 9,, and 2), initial values were obtained within the first 5 days after transplantation; subsequent titers were then obtained within from to 9 days later. The second titers of Patients 7 and 2 were measured after removal of the renal homografts. The initial titers of the other two patients (Table, Patients 4 and ) were obtained and 5 days, respectively, after transplantation, and the second titers were obtained several months afterward. As a comparative control group, similar measurements were made of the IHA titers in four patients (all in blood Group A) who received ABO compatible renal homografts (Fig., CI, CII, CIII, and CIV). In these control patients, IHA titers were measured both before and after transplantations; and in one of them (CIII) it was measured after removal of the homograft. Pathologic study. Eleven kidneys from the major ABO incompatible group and six from the minor ABO incompatible group were available for study. The renal artery of each kidney was carefully examined. A minimum of six tissue sections, including two of each i I DAYS O 5 IOO 5 CONTROL SUBJECTS PATIENTS (4,7,9,,,2) (,,5,2) WITH MAJOR ABO INCOMPATABILITY ( t NEPHRECTOMY OF GRAFT) FIG.. AB isoagglutinin (IHA) titers after kidney transplantations. of the upper, the middle, and the lower portions of the kidney, was taken. After fixation in Zenker's solution, the sections were stained with hematoxylin and eosin, periodic acid-schiff, Masson trichrome, and Verhoeff elastic stains. In some cases, pyronin-methyl-green stain was used on tissues previously fixed in absolute alcohol. RESULTS CLINICOPATHOLOGIC FINDINGS I. The Major ABO Incompatible Group All 2 patients have lost their homografts, nine patients within months and three patients between and 9 months. They are classified into three groups according to their renal pathology. PATIENTS WITH THROMBOSIS OF THE RENAL ARTERY AND TOTAL NECROSIS OF THE KID NEY. (Table, Patients, 5, 7, and 8.) Clinical data. After transplantation, there was no urinary output by Patients, 7, and 8. Their homografts were removed in, 7 and 7 days, respectively. The homograft in Patient 5 functioned promptly, and excreted 7 ml. of urine during the 2nd day. On the rd day, clinical signs of rejection became evident. The homograft was removed 6 weeks after transplantation. Downloaded from on 4 February 28

5 Jan. 969 BLOOD GROUP AND KIDNEY TRANSPLANTATION 9 Pathologic changes. Occluding thrombosis of the renal artery, accompanied by reactive neutrophilic infiltrates and fibrin deposition at the intima, occurred in all of the homografts. The presence of fibrin deposition in the intrarenal blood vessels extending into the glomerular tufts indicated that the renal artery thrombosis took place after the establishment of renal circulation. Total necrosis of the renal parenchyma was observed, but usually there was little inflammatory cellular infiltrate. Comment. Total necrosis of these homografts prevented pathologic evaluation of rejection in these kidneys. The thrombus in the renal artery per se was not indicative of rejection. Clinical evidence of rejection was, however, observed in Patient 5. PATIENTS WITH THROMBOSIS OF THE RENAL ARTERY AND PARTIAL NECROSIS OF THE RENAL PARENCHYMA. (Table, Patients 2,, 6, 9, and 2.) Clinical data. The homografts of Patients 2,, and 2 excreted no urine, and Patients 2 and 2 underwent nephrectomy on the th day. In Patient malignant hypertension suddenly developed 4 hr. after transplantation; death occurred 5 days later, with signs of brain stem damage. In Patient 6, a rejection crisis occurred weeks after transplantation. Subsequent severe neutropenia necessitated lowering the dosage of azathioprine. This partial withdrawal of drug administration precipitated further rejection, and nephrectomy was performed 2 months after transplantation. Patient 9 experienced three episodes of rejection crisis, the first being evident month after transplantation. Nephrectomy was performed months after transplantation. Pathologic changes. The kidneys of these five patients had similar histopathologic patterns. The thrombosis in the renal artery was occlusive in Patients 2,, and 2, and stenotic in Patients 6 and 9. In areas of viable renal tissue, there was fibrinoid necrosis in the interlobar, the arcuate, the interlobular arteries, and the glomerular arterioles. Glomerulitis with focal necrosis was also present. In kidneys of Patients 2 and 2, there were additional vascular changes consistent with rejection reaction: loose interstitial fibroplasia, focal intimal hyperplasia, and reduplication of the internal elastic lamina in the arcuate arteries. Focal cellular infiltrates, including lymphocytes, plasma cells, and the large blastoid pyroninophilic cells, were distributed in capillary lumen, the perivenous zone, and in intertubular spaces. Comment. The pathologic findings in these patients are similar to those described for the acute and subacute rejection both in human and canine renal homografts. 7 The changes in this group of patients are particularly significant because, together with the clinical observations, they indicate that rejection had been an important factor in precipitating failure of the renal homografts. PATIENTS WITH NO RENAL ARTERY THROMBOSIS. (Table, Patients,, and 4.) Clinical data. The renal function of Patient was mildly decreased (creatinine clearance, 56 ml. per min.; blood urea, 56 nig. per ml.) for the first months after transplantation. During this period three rejection crises developed, but they were easily reversed. Three months of hypertension and a gradual decline in renal function preceded the patient's death in the 4th month. Patient died months after transplantation. During this time her renal function remained poor (creatinine clearance, ml. or less per ruin.). Neutropenia developed, as did hei'petic infection of the skin, and a renal biopsy demonstrated cytomegalic inclusion viral bodies in the tubular cells. Bacterial septicemia preceded death. Patient 4 lived for 9 months. During this time, she maintained good renal function, and showed no clinical rejection of the homograft. She died after massive hemorrhage from acute gastric ulceration. Pathologic changes. In both kidneys of Patients and, chronic rejection reaction, including intimal sclerosis, resulted in stenosis of the interlobar and the arcuate arteries. In addition, there were focal fibrinoid changes in the interlobular arteries and in the preglomerular arterioles. Cellular Downloaded from on 4 February 28

6 2 WILBRANDT ET AL. Vol. 5 infiltrates were sparse and were composed of lymphocytes and occasional clusters of plasma cells. There were fibrosis of the intertubular space and ischemic senescence in some glomeruli. In the kidney of Patient 4, the only abnormality consisted of focal membranous changes in some glomeruli. Comment. There was evidence of chronic as well as of acute rejection in the kidneys of Patients and. The nature of the membranous changes in the kidney of Patient 4 is uncertain and may either be related to rejection or to the recurrence of glomerulonephritis in the homograft. II. The Minor ABO Incompatible Group PATIENTS WITH FUNCTIONING HOMO- GRAFTS. (Table I, Patients 4, 5, 9, 2, 22, and 2.) All of the patients in this group have maintained good renal function up to the present time. Patients 5, 9, 2, and 2 had no rejection crises, and it is at the time of writing 22, 28, 2, and 22 months, respectively, after they underwent transplantation. Patient 4 had one rejection crisis and Patient 22 had three rejection crises, which were easily reversed. They now have functioning homografts and 24 months, respectively, after transplantation. PATIENTS WHOSE HOMOGRAFTS WERE REMOVED.. Homografts with no changes of rejection. (Table, Patients, 6, and 2.) Clinical data. In Patient a ureteral leakage developed which was corrected surgically. This was complicated by wound infection which, despite the cessation of administration of azathioprine, led to septicemia and death. The homograft showed no evidence of rejection even though the patient received no azathioprine for 5 days before death. Ureteral leakage, not accompanied by clinical signs of rejection, likewise developed in Patient 6, for which nephrectomy was performed. In Patient 2 fulminant hepatitis developed 9 months after transplantation and, although renal function remained satisfactory, he died days later. Pathologic changes. No morphologic evidence of acute rejection was noted either in the kidneys or the corresponding ureters. 2. Homografts showing changes of rejection. (Table, Patients 7, 8, and 24.) Clinical data. A biopsy of the homograft of Patient 7 was performed days after transplantation because of persistent anuria. He died 9 days later. The kidney of Patient 8 functioned well up to the 7th month after transplantation. At that time the dosage of azathioprine was gradually decreased, and slow rejection followed. The patient's death 2 months later was a result of bronchopneumonia. In Patient 24 rejection crisis developed 2 months after transplantation. His daily dosage of prednisone was increased to 4.2 mg. per kg. of body weight. This resulted in fatal gastric bleeding. Pathologic changes. The biopsy of the homograft of Patient 7 showed acute necrotizing vasculitis and thrombosis of the interlobular arteries. Nephrectomy 9 days later showed total necrosis of the kidney, with occluding thrombosis of the renal artery. Acute rejection with both vascular and cellular components was noted in the homografts of Patients 8 and 24. The renal arteries of these two kidneys were normal. ISOHEMAGGLUTININ TITERS The IHA titers of the patients in the control group ranged between /64 and /256 before transplantation (Fig. ). With the exception of Patient CII, the titer remained within this range after transplantation. It is important to note that the titer in Patient CHI did not rise after removal of the renal homograft. In patients with major ABO incompatibility there were several changes in the IHA titers that differed from those of the control group. The IHA titers of the early posttransplantation period of Patients 4,, and were lower than those of the control group. With the exception of the IHA titer of Patient, all titers showed a tendency to rise with time. In Patients 7 and 2, whose homografts were removed, the rise in subsequent IHA titers was precipitous. DISCUSSION Our results (Table 2) showed that when there is major ABO incompatibility between the donor and the recipient in renal homo- Downloaded from on 4 February 28

7 Jan. 969 BLOOD GROUP AND KIDNEY TRANSPLANTATION 2 transplantation, early failure of the homograft can be expected. In contrast, patients with minor ABO incompatibility have results similar to those in patients with ABO compatible homografts. Although the homografts failed acutely in most of the patients with major ABO incompatibility, the homografts in three patients (Table, Patients,, 4) nevertheless survived for as long as, 6, and 9 months, respectively. In the patients in the "acute group," thrombosis of the renal artery developed and total or partial necrosis of the homografts occurred within several hours to several days after the establishment of the renal blood flow. Urinary output was absent or poor from the beginning and, generally, early nephrectomy of the homograft had to be performed. In contrast, two of the three "long survivors" had good renal function for many months after transplantation, and repeated acute rejections developed only toward the end. The third "long survivor" never had clinical evidence of rejection. In regard to the pathogenetic relationship of the acute failure of renal homografts and the presence of major ABO incompatibility, Starzl and co-workers 8 stressed the significance of inadequate perfusion of the homograft before it was transplanted. They suggested that thrombosis of the renal artery was a result of intravascular clotting of the donor's erythrocytes by the IHA of the recipient, which in turn caused total necrosis of the renal homograft. The possibility of this occurrence cannot be confirmed or disproved in our series of patients. However, our data indicate that the major cause of failure of these homografts was primarily acute immunologic rejection that preceded thrombosis of the renal artery and parenchymal necrosis. Of the 2 patients, clinical or pathologic evidence of rejection, or both, was apparent in nine. In the other three patients, evidence of rejection was only presumptive because the homografts never excreted urine and, pathologically, total necrosis of the kidneys was found. However, the following reasons indicate that acute rejection may have been present. First, in five other homografts with major TABLE OUTCOME OF PATIENTS WITH ABO INCOMPATIBLE RENAL HOMOTRANSPLANTATIONS Findings Patients, total Patients alive to date Homografts removed at operation or autopsy Homografts with good function at time of removal Clinical or pathologic rejections, or both Patients with hypertension not related to rejection ABO Incompatibility Major 2 2 G Minor 2 7 (over 22 months) 6 ABO incompatibility, focal viable tissue with typical acute rejection reactions was discerned, and these reactions were associated with renal artery thrombosis. Second, we have seen renal artery thrombosis in homografts of compatible blood groups that were undergoing acute rejection. Repeated histologic studies of the kidney of Patient 7 showed that total necrosis of the kidney with renal artery thrombosis was actually preceded by acute rejection. Finally, there was clinical evidence of rejection in Patient 5, which preceded the finding of a totally necrotic homograft. To underline further the high incidence of rejection of the homografts in the major ABO incompatible group, our results (Table ) show that, in contrast, of seven of the kidneys of the minor ABO incompatible group only three gave evidence of rejection. ABO blood group antigens have been demonstrated in the arterial wall and in the renal tubular cells. In renal homotransplantation with major ABO incompatibility, these antigens may be significant in stimulating the production of the corresponding immunologic blood group antibodies. This consideration is supported in the present study by the rise in the IHA titers in five patients. If the IHA values of the control patients are considered comparable to the pretransplantation IHA titers of the patients in our series, then significance could be 7 Downloaded from on 4 February 28

8 22 WILBEANDT ET AL. Vol. 5 attached to the low IHA titers that were found during the early period after transplantation in four of the patients. We believe that these initially low IHA titers were not related to immunosuppressive therapy, since in three of four control patients the IHA titers that were measured before and after immunosuppressive therapy were of similar magnitude. One possible explanation for this initially low IHA titer after transplantation is the fixation of the IHA to the renal homograft that carries the blood group antigens. The fact that a sharp rise in the IHA titers after the removal of the homografts occurred in two of the patients, but not in a control subject, would support this explanation. It is difficult to account fully for the long survivals of homografts and the lack of early acute rejection in three of the patients with major ABO incompatibility. One explanation may be that the pattern of ABO incompatibility in these patients was relatively weak in comparison with that of other patients in the group. Two of the three patients (Patients ang ) were the only ones in the series having the blood group pattern of AB donor to A recipient. This pattern represents the weakest antigen-antibody combination in major ABO incompatibility, inasmuch as it is known 5 that the avidity of B antigen in an AB blood group is weaker than that in an A blood group, and that the anti-b antibody of patients with Group A blood is less avid than that in Group patients. This explanation would not, however, apply to Patient 4, because her blood group pattern was donor A to recipient, a strong antigenantibody combination. Whether or not this donor belongs to a subgroup of A other than Ai was unfortunately not evaluated, and the possibility of its being another subgroup cannot be excluded from consideration. It is interesting that the rises in the IHA titers for these three patients were gradual, in comparison with those of patients with early acute homograft rejection. Although the significance of IHA as an antibody related to rejection of the renal homograft was not conclusive from the results of our study, Dausset and Rapaport have recently shown that the AB blood group IHA are significant in the rejection of skin homografts in the presence of ABO blood group incompatibility in man. The key experiment that led to this conclusion was the finding of a second-set rejection in a skin graft of a recipient who was previously sensitized by blood group antigens that corresponded to the donors' ABO blood groups. SUMMARY Our data support the finding that poor results will be obtained in renal homotransplantation when major ABO incompatibility exists between the donor and the recipient. In contrast, the results of transplantation between persons having ABO minor incompatibility are similar to those between persons who are ABO compatible. The patients in the major ABO incompatible group can be classed into two categories: acute group (majority), and chronic group. In the acute group, renal artery thrombosis was common, often accompanied by various degrees of renal necrosis. In this group of patients, pathologic evidence suggests that the necrosis was the result of acute rejection. The resultant slowing down of renal blood flow may precipitate thrombosis of the renal artery. In the chronic group there was a gradual decline in renal function and a pathologic picture of chronic rejection in the homografts. In five patients with major ABO incompatibility, the ABO isohemoagglutinin measured after transplantation showed initially low and subsequently high values. The possible significance of these findings is discussed. REFERENCES. Barnes, B. A.: Survival data of renal transplantations in patients. New England J. Med., 272: , Brent, L.: In Wolstenholme, G. E. W., and Cameron, M. P.: Ciba Foundation Symposium on Transplantation. Boston: Little Brown and Company, 962, p Dausset, J., and Rapaport, F. T.: Role of ABO erythrocyte groups in human histocompatibility reactions. Nature, London, 29: 29-2, Hamburger, J., Vaysse, J., Crosnier, J., Auvert, J., and Dormont, J.: Kidney homotransplantation in man. Ann. New York Acad. Sc, 99: 88-82, Mollison, P. L.: In Blood Transfusion in Downloaded from on 4 February 28

9 Jan. 969 BLOOD GROUP AND KIDNEY TRANSPLANTATION 2 Clinical Medicine, Ed. 4. Philadelphia: F. A. Davis Company, 967, p Murray, J. E., and Harrison, J. H.: Surgical management of fifty patients with kidney transplants including eighteen pairs of twins. Am. J. Surg., 5: 25-28, 96." 7. Porter, K. A., and Starzl, T. E.: Pathological changes in transplanted kidneys. In Experience in Renal Transplantation. Philadelphia: W. B. Saunders Company, 964, p Starzl, T. E., Marchioro, T. L., Holmes, J. H., Hermann, G., Brittain, R. S., Stonington,. H., Talmage, D. W., and Waddell, W. R. : Renal homografts in patients with major donor-recipient blood group incompatibilities. Surgery, 55: 95-2, Stewart, B. H., Straffon, R. A., Hewitt, C. B., Kiser, W. S., Nakamoto, S., and Kolff, W. J.: Renal homotransplantation utilizing cadaver donors. Urol. Digest, 4-' 2, Straffon, R. A., Nakamoto, S., and Kolff, W. J.: Clinical experience with renal transplantation. Brit. J. Urol., 7: 7-79, Szulman, A. E.: The histological distribution of blood group substances A and B in man. J. Exper. Med., Ill: 785-8, Woodruff, M. F. A.: The transplantation of tissues and organs. Springfield,.: Charles C Thomas Publisher, 96, pp Downloaded from on 4 February 28