RENAL HETEROTRANSPLANTATION FROM BABOON TO MAN: EXPERIENCE WITH 6 CASES

Abstract

Six patients with terminal uremia due to glomerulonephritis or pyelonephritis were treated with heterografts from East African baboons. Immunosuppressive therapy was provided both before and after operation with azathioprine and prednisone and postoperatively local transplant irradiation and actinomycin C were administered intermittently. The individual rejection episodes in the post-transplant period could be reversed relatively easily but these reemred vigorously and repetitively, making it impossible to relax the stringent requirements of antirejectmion therapy. The continued need for high-dose immunosuppressive therapy precipitated lethal infections in the majority of cases.

The patients lived for 19 to 98 days after heterotransplantation. Four died with the baboon kidneys still in placc after 19, 23, 35, and 49 days. In the other two cases the heterografts were removed after 60 and 49 days respectively, at a time when urine excretion was still present, and homografts from volunteer convict donors were placed on the opposite side. Both the latter recipients died of septic complications following the second operation, after 39 and 44 days. Complete cessation of heterograft urine excrelion appeared only in two cases, although rend function was failing in the remainder prior to death or before removal of the heterografts. The relation of renal function to changes in heteroagglutinin and hemagglutinin titers is described.

After residence in the host for 19 to 60 days, all the heterotransplants were heavily infiltrated with plasma cells and large lymphoid cells with pyroninophilic cytoplasm. There was also disruption of peritubular capillaries, interstitial edema, widespread tubular damage, swelling of endothelial cells lining arterioles, fibrinoid necrosis of the walls of arterioles and interlobular arteries, and narrowing and obstruction of interlobular arteries by fibrin and platelet deposits on the intima. The pre-glomerular vascular lesions were accompanied by focal infarcts and extensive interstitial hemorrhages. All the pathologic changes were more severe than those seen by Reemtsma in a comparable series of chimpanzee-to-man heterotransplants, where cellular infiltration was slight and vascular lesions uncommon in the presence of major blood group incompatibility between donor and recipient.

Figure 1

Insertion of heterografts after technique of Reemtsma. E. Anastomosis of distal aorta and vena cava to external iliac vessels. F. Parallel ureteroneocystostomies. G. Folding back of kidneys in order to occupy less space.

Figure 2

Case 3. Recipient was AB+ blood group, and donor was B. The patient was anuric preoperatively. The difference in quality of function with the heterografts, compared to the secondarily placed homograft, is evident. Heterotransplant rejection crises occurred after 5 and 50 days. Urine function continued until heterografts were removed.

Figure 3

Case 4. Course after heterotransplantation (left) and subsequent homotransplantation (right). The patient was B+ blood type and received donations from a B baboon and an O human volunteer. The cause of death was pneumonia. Note sharp falls in urine sodium concentration with heterograft rejection episodes, as well as with the rejection that occurred after subsequent homotransplantation.

Figure 4

Case 6. Patient was O+ blood type and received AB baboon heterografts. Rejections occurred at 4, 18, and 48 days. Direct cause of death was pneumonia. Note gradual falls of creatinine clearance and slow progression of azotemia between partially reversible rejection crises.

Figure 5

Urine constituents in Case 2, during massive postoperative diuresis which totaled 24,290 cc in first 24 hours, initially being 1,500 cc per hour. Note low urine osmolality and limited free water clearance. The urine electrolyte composition is similar to that usually seen after homotransplantation.

Figure 6

Titers of human anti-B isoagglutinin and heteroagglutinin for baboon erythrocytes observed after transfer of a renal heterograft from a type A baboon to a type A+ patient. The levels of anti-B isoagglutinin remained unaltered. In contrast, there was a progressive fall in heteroagglutinin activity throughout the entire course.

Figure 7

Levels of human anti-A and anti-B isoagglutinins and heteroagglutinins in Case 2. Transfer was from a type B donor to an O– recipient. Note the slightly delayed fall in anti-A titer. There was a prompt fall in anti-B levels, followed by transient elevations. Heteroagglutinin activity roughly paralleled the anti-B isoagglutinin curve. The fluctuations in antibody tlter do not correlate well with the rejection episodes; however, a marked rise in titer was observed during the period of anuria.

Figure 8

Heteroagglutinin levels in Case 3. The titer fell only after reversal of the first rejection crisis. Increased activity was again demonstrated during the second episode of rejection. Removal of the heterograft was followed by total disappearance of heteroagglutinin activity. The recipient patient was AB+ and therefore had no isoagglutinins. The baboon was B.

Figure 9

Changes in human anti-A isoagglutinin and heteroagglutinin titers observed after transfer of B heterograft to a B+ recipient. There was a gradual decline in anti-A levels after 10 days. Heteroagglutinin activity fell initially, then increased and decreased with the onset and reversal of rejection crises.

Figure 10

Pattern of anti-A and anti-B isoagglutinin and heteroagglutinin activity of Case 5. The heteroagglutinin titer fell following operation and subsequently rose during the terminal, irreversible rejection episode. Similar changes were observed in both isoagglutinin titers. The donor was AB and the recipient O–.

Figure 11

Alterations in anti-A and anti-B isoagglutinins and heteroagglutinins in Case 6. An AB heterograft was placed into an O+ recipient. Note the slow decline in anti-A activity. In contrast, bath anti-B levels and titers of heteroagglutinin fluctuated throughout the course, tending to rise with rejection episodes and to recede with reversal.

Figure 12

Heterografts recovered at autopsy in Case 6. Each kidney weighed 80 grams. Note swollen hemorrhagic appearance of both heterografts The lighter wedge-shaped areas (far left) are small infarcts of the cortex.

Figure 13

Case 3. Baboon renal heterotransplant from patient who was in rejection for the second time when the specimen was removed at 60 days. Many tubules had been destroyed. Those surviving are dilated and lined by flattened epithelium. The interstitium is edematous and heavily infiltrated with cells. H & E (× 150).

Figure 14

Higher power view of baboon heterotransplant from patient 3. Dilated damaged tubules are lined by flattened epithelium. The interstitium is edematous and infiltrated with plasma cells, other pyroninophilic cells, some lymphocytes and a few eosinophils. Many peritubular capillaries have been destroyed. H & E (× 350).

Figure 15

Case 6. Baboon renal heterotransplant from patient who was in rejection for the third time when he died at 49 days. Hemorrhagic infarction (H) is shown. The glomerulus indicated with an arrow is necrotic. H & E (× 150).

Figure 16

Case 4. Baboon renal heterotransplant from patient who was in rejection for the second time when the specimen was removed at 49 days. There is marked fibrinoid necrosis (arrows) of the whole wall of an interlobular artery. An arteriole showing swelling of its lining endothelial cells, but no fibrinoid necrosis, is seen at a. There is also tubular atrophy and cellular infiltration of the interstitium. H & E (× 350).