K. A. Porter

EFFECTS OF INSULIN, GLUCAGON, AND INSULIN/GLUCAGON INFUSIONS ON LIVER MORPHOLOGY AND CELL DIVISION AFTER COMPLETE PORTACAVAL SHUNT IN DOGS

Insulin, glucagon, and insulin/glucagon mixtures have been infused for four days into the left portal vein of dogs after portacaval shunt. In the left but not in the right liver lobes, insulin alone reduced atrophy, preserved hepatocyte ultrastructure, and trebled cell renewal. Glucagon alone had no effect. In small doses, glucagon did not potentiate the action of insulin and in large doses it may have reduced the insulin benefit. These studies explain the development of the previously mysterious Eck fistula syndrome, provide clues about in-vivo cell growth control by hormones, and suggests new lines of inquiry about the pathogenesis and/or treatment of several human disease processes.

Long-term survival after renal transplantation in humans: With special reference to histocompatibility matching, thymectomy, homograft glomerulonephritis, heterologous ALG, and recipient malignancy

AT the University of Colorado Medical Center, 189 patients have been given kidney homografts at a remote enough time to permit relatively long follow-up in the event of continued survival. On the basis of this experience, a reassessment will be attempted of the practical value of renal transplantation. In addition, the effect of various factors upon short and long-term survival will be examined including the organ source, the quality of HL-A antigen matching, thymectomy before or after transplantation, the addition of heterologous antilymphocyte globulin (ALG) to the immunosuppressive regimen, the development of glomerulonephritis in the transplants, and the occurrence of a significantly increased incidence of de novo malignancies in the recipients.

GROWTH-STIMULATING FACTOR IN REGENERATING CANINE LIVER

Extracts from dog livers which had been regenerating for 24, 48, and 72 h after hepatectomy were infused for 6 h into the left portal vein of animals which had fresh portacaval shunts (Eck fistula) and which were killed 2 and 3 days later. The brief exposure to the 48-h and especially the 72-h regenerating liver extracts induced a delayed proliferative response predominantly in the left liver lobes, with a slight spillover effect to the right liver lobes but none to the kidney. The response reached its peak 3 days later. In the left but not the right liver lobes, both the 48-h and the 72-h regenerating liver extract reversed the atrophy ordinarily caused by Eck fistula in 3 days and partly prevented the ultrastructural hepatocyte deterioration characteristic of Eck fistula. The active liver extracts apparently contained a growth-control factor or factors which is (are) not insulin or glucagon.

INTRAPORTAL INSULIN PROTECTS FROM THE LIVER INJURY OF PORTACAVAL SHUNT IN DOGS

4 days after portacaval shunt, the livers of normal dogs had pronounced atrophy and other structural abnormalities. These changes were greatly reduced in the left liver lobes, but not in the right, by a constant infusion to the left portal vein of insulin in non-hypoglycaemic doses. These experimental findings should have implications in clinical medicine.

Acute neurological complications after liver transplantation with particular reference to intraoperative cerebral air embolus.

Nine of 48 adult patients who underwent orthotopic liver transplantation developed significant clinical neurological abnormalities recognized shortly after operation. Decrease in consciousness occurred with resultant coma, focal and generalized seizures and the occasional appearance of a state of akinetic mutism. Neuropathological abnormalities consisted of multifocal areas of infarction in cerebral cortex and basal ganglia in five patients, central pontine myelinolysis in five (often more extensive than usually reported), Wernickes encephalopathy in three, glial nodules in two, and fungal abscesses in one. Alzheimer II astrocytosis was found in all brains available for retrospective study. There was direct evidence in two of the patients that air embolization from the homografts had occurred. Correlation of this with the brain infarcts in these and other cases seems reasonable. The ease with which air passed to the systemic circulation is explicable by the right to left venous-arterial shunts that are common in chronic liver disease. With the delineation of this cause for the neurologic complications, measures to prevent it in future cases have been described.

The clinical use of antilymphocyte globulin in renal homotransplantation

Twenty patients were treated with antilymphocyte globulin (ALG) which was prepared from the serum of immunized horses. The ALG was used as an adjuvant to azathioprine and prednisone and its use limited to 4 months. The surviving patients are now 1 to 7 months postoperative. There was 1 death, the consequence of a technical accident. The function in the remaining 19 patients is excellent, despite reduced doses of azathioprine and especially prednisone. Biopsies were obtained in the first 8 consecutive cases from 108 to 145 days after operation. There was no evidence in the specimens of either Masugi-like or serum sickness nephritis.

Portacaval shunt in patients with familial hypercholesterolemia.

Portacaval shunt was performed in ten patients with homozygous and two with heterozygous familial hypercholesterolemia (FH). Total serum cholesterol was lowered by 20% to 55.4% during follow-up periods of 14 months to almost 9 years, with commensurate decreases in LDL cholesterol. The effect on HDL cholesterol and triglyceride levels was variable. Tendinocutaneous xanthomas diminished or disappeared. Growth and development in children proceeded or accelerated. There was no detectable emotional or intellectual deterioration. Hepatic failure did not occur, although blood ammonia concentrations and serum alkaline phosphatase levels increased relative to preoperative values. Cardiac symptoms were often improved, but evidence of reversal of cardiovascular lesions was inconclusive. Three patients with pre-existing heart disease died of cardiac complications after 4 months, 18 1/2 months, and 30 months. Portacaval shunt has been effective therapy for patients with FH who were refractory or intolerant to medical treatment; it should be performed before the development of irreversible cardiovascular damage.

DETECTION OF CIRCULATING IMMUNE COMPLEXES IN PATHOLOGICAL HUMAN SERA

The results of attempts to detect circulating immune complexes in sera by two methods are described. Both rely on the binding of the first complement component (C1) to the complex for its detection. The results, using these methods, of attempts to show which patients have complexes which contain nucleic acid and hence possibly viral antigens in the complexes are discussed. The anti-complementary complexes found in some patients seem to be associated with immune-complex vascular disease.

Renal Homotransplantation: Late Function and Complications

Fifty-one patients were treated with homografts obtained from both related and nonrelated volunteer donors in the interval from November 24, 1962, to February 10, 1964. Thirty-three of the 51 patients lived for 4 or more months postoperatively, and 30 of these are still living on June 10, 1964. The three deaths which occurred after 4 months were due to a combination of gastrointestinal hemorrhage and sepsis in one; to a cerebrovascular accident of undetermined etiology in the second; and to uncontrolled late rejection in the third, which was first diagnosed 229 days after operation, 66 days before death. The two homografts examined at autopsy after 207 and 295 days were both enlarged and showed glomerular hypertrophy, tubular atrophy, mild cellular infiltrations, marked interstitial fibrosis, and destruction of peritubular capillaries. The case that died in uncontrolled rejection also showed interstitial edema and a spectrum of vascular lesions. Late nonfatal rejection was observed in five other cases 112 to 300 days postoperatively. In all these cases, and in the unsuccessfully treated one as well, certain consistent features were present. There had always been a preceding alteration in steroid dose, prednisone having been discontinued in five of the six patients from 16 to 154 days previously. Progress of the rejection was slow, and the proper diagnosis depended most strongly upon demonstration of a gradual fall in creatinine clearance. Elevations in blood pressure, transplant wound tenderness, fluid accumulation, alopecia, polyarthritis, fever, malaise, and anorexia were all observed. Azotemia was a late finding. The diagnosis of late rejection is one of exclusion. Pyelonephritis, vascular anastomotic failure, and ureteral obstruction are first ruled out. The last possibility is a particularly important one since 4 of the 33 patients who lived for 4 months or longer have been shown to have partial ureteral obstruction which required secondary repair. In one case, there was strong evidence that the stricture resulted from healing of an earlier ureteral rejection. If diagnosed promptly, late homograft rejection can be reversed. The crucial step in the treatment of rejection is the resumption or increase of steroid dosage. In addition, local irradiation to the graft and intravenous actinomycin C are both of use as emergency therapy. The chronic administration of azathioprine has thus far appeared to be very well-tolerated by those patients who are receiving only this drug, although its ultimate toxicity will take years to determine. The superimposition of steroid therapy, in those patients whose homograft function cannot be otherwise maintained, adds a serious risk. Gastrointestinal hemorrhages, infections, aseptic bone necrosis, potentiation of hypertension, and severe obesity have all been observed. The course of five patients who received preliminary thymectomy and who survived more than 4 months is compared to that of the other recipients who did not receive this additional operation. One of the patients who had thymic excision died after 207 days of nonrenal complications. The other four had steroids discontinued in 9 months or less, and none have had any evidence of delayed rejection 14 to 18 months after operation. The 6 examples of late rejection all occurred in the other 28 long-surviving patients who did not have removal of the thymus gland. The possible role of thymectomy in influencing these late events remains to be determined. Renal function ranged from adequate to essentially normal levels in all patients who survived longer than 4 months, except the one who died of uncontrolled late rejection. In four cases, in which late renal function was tested at a time when rejection was not present, the results in paired donors and recipients were almost identical, suggesting hypertrophy in the homograft as well as in the donor’s residual kidney. These results indicate that considerably more than half the patients who are treated with renal homotransplantation can be brought into a chronic stage, even when the statistics are unfavorably altered by the use of a substantial number of nonrelated donors as was the case in the present series. The data also indicate that overoptimism must be avoided in assessing the future role of this form of therapy since it is quite evident that many adverse factors still exist in the residual group of living patients, and that life-threatening late complications are going to be common. These include toxicity from drugs, especially if indefinite steroid therapy is required; late rejection; urologic complications; and subtle subclinical progression of pathologic alterations in the homograft.

HOMOTRANSPLANTATION OF THE LIVER

The feasibility of hepatic homotransplantation has been clearly established in principle inasmuch as several animals are still alive almost 3 years after complete hepatectomy and liver replacement. Both orthotopic and auxiliary operations are complicated surgical techniques. Nevertheless, the results in dogs are comparable to those which can be obtained with homotransplantation of the kidney. In man the problem is more difficult. In patients who have a need for such operations, there is invariably a metabolic disorder more complex than that caused by renal failure. In addition, the new organ must function efficiently from the beginning since its complete functional failure leads to death within a few hours. There is no recourse to an artificial liver to maintain life until the reversal of an injury which is caused by either ischemia or rejection. Nevertheless, research of several kinds may soon make possible the successful use of hepatic transplantation procedures for the definitive treatment of human liver disease as exemplified by the reports in this symposium concerning new techniques of organ preservation, histocompatibility analysis, and immunosuppression.