R. Y. Calne

CYCLOSPORIN A IN PATIENTS RECEIVING RENAL ALLOGRAFTS FROM CADAVER DONORS

Seven patients on dialysis with renal failure received transplants from mismatched cadaver donors and were treated with cyclosporin A (CyA), initially as the sole immunosuppressive agent. CyA was effective in inhibiting rejection but there was clear evidence of both nephrotoxicity and hepatotoxicity. A cyclophosphamide analogue was added to the CyA treatment in six of the patients. Five patients are out of hospital with functioning allografts, and two of these have received no steroids. One patient required an allograft nephrectomy because of pyelonephritis in the graft. Another died of systemic aspergillus and candida infection. Further careful study of this potentially valuable drug will by required before it can be recommended in clinical practice.

Liver transplantation for malignant disease. Results in 93 consecutive patients.

Ninety-three patients with malignant disease underwent or-thotopic liver transplantation between May 1968 and April 1987 in the Cambridge/Kings College Hospital program. Of 50 patients with primary hepatocellular carcinoma (HCC) (19 with cirrhosis, 31 without cirrhosis, including 7 with fibrolamellar variant), 37 (74%) survived for more than 3 months, and in this group evidence of tumor recurrence was obtained in 24 (64.9%), the longest survivor being 11.8 years post-transplant, and three survived for more than 5 years. Although there is no correlation between the frequency of tumor recurrence and underlying cirrhosis, or histologie type (except fibrolamellar variant), it was observed earlier in those with moderate/poorly differentiated tumors and also when prcdnisolone and azathioprine was used for immunosupprcssion. Tumor recurred in all but two of those with peripheral or central cholangiocarcinoma (one alive at 6.1 years) with median survival times of 34 weeks and 56 weeks for the central and peripheral types, respectively. Among the unusual primary tumors, one with epithelioid haemangioendothelioma developed tumor recurrence at 2 years, one of two patients with apudoma is tumor-free at 2.2 years, and the one patient with bile-duct papillary cystadenocarcinoma is alive at 1.7 years. For the secondary hepatic malignancy group, survival times were shorter with little palliation except for two patients with carcinoid syndrome who were free of associated symptoms at 6 and 10 months. Despite the overall high frequency of tumor recurrence in most categories of hepatic malignancy, liver transplantation gave worthwhile survival with a number of patients cured and in the others considerable palliation of symptoms.

Campath IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients.

BACKGROUND Campath 1H is a depleting, humanized anti-CD52 monoclonal antibody that has now been used in 31 renal allograft recipients. The results have been very encouraging and are presented herein. METHODS Campath 1H was administered, intravenously, in a dose of 20 mg, on day 0 and day 1 after renal transplant. Low-dose cyclosporine (Neoral) was then initiated at 72 hr after transplant. These patients were maintained on low-dose monotherapy with cyclosporine. RESULTS At present, the mean follow-up is 21 months (range: 15-28 months). All but one patient are alive and 29 have intact functioning grafts. There have been six separate episodes of steroid-responsive rejection. One patient has had a recurrence of her original disease. Two patients have suffered from opportunistic infections, which responded to therapy. One patient has died secondary to ischemic cardiac failure. CONCLUSIONS Campath 1H has resulted in acceptable outcomes in this group of renal allograft recipients. This novel therapy is of equal efficacy compared to conventional triple therapy, but allows the patient to be steroid-free and to be maintained on very-low-dose immunosuppressive monotherapy.

Liver Transplantation in Man—I, Observations on Technique and Organization in Five Cases

In view of the extreme sensitivity of the human liver to ischaemic damage, the organization of clinical transplantation is of necessity complicated. From our preliminary experience of five human liver allografts we feel that active collaboration between hospitals is essential in order to practise human liver transplantation. It is unnecessary and undesirable to interfere in any way with potential liver donors. Nevertheless, the nature of the surgical technique requires that the liver is cooled within 15 minutes of death if satisfactory function is to result in the grafted organ. This report describes technical difficulties that were encountered which can limit successful liver transplantation. The first patient was in severe liver failure and had an accessory liver graft in the splenic fossa after splenectomy. This liver suffered irreversible ischaemic damage, which led to an uncontrollable haemorrhagic state with exsanguination that resulted in death the day after operation. The second patient, a 10-month-old infant with biliary atresia and liver failure, died from cardiac arrest shortly after the operation. The remaining three transplants developed good initial function. One patient survived 11 weeks, and one has returned to work.

CYTOMEGALOVIRUS INFECTION AND DONOR/RECIPIENT HLA ANTIGENS: INTERDEPENDENT CO-FACTORS IN PATHOGENESIS OF VANISHING BILEDUCT SYNDROME AFTER LIVER TRANSPLANTATION

The contribution of cytomegalovirus (CMV) infection and its interrelation with HLA antigens in the development of chronic rejection (vanishing bile-duct syndrome--VBDS) was investigated in 101 patients surviving for at least 3 months after liver transplantation. A 1-2 antigen match for HLA DR antigens (30.9% vs 4.5% for zero DR match; p less than 0.002), a zero match for HLA A/B antigens (27.5% vs 10.9% for 1 or more A/B match; p less than 0.05), and active CMV infection (26.3% vs 4.4% for no CMV infection; p less than 0.005) were independently associated with an increased risk of VBDS. The coexistence of a 1-2 HLA DR match and CMV infection carried the highest relative risk (10.1) of VBDS; these two variables were probably interdependent since either alone was associated with a low relative risk (0.45 and 0.5). The association between VBDS and active CMV infection was not a consequence of alterations in immunosuppressive therapy. The findings would be consistent with precipitation of chronic rejection by CMV-induced HLA antigen expression in patients rendered susceptible by the donor/recipient HLA antigen match.

Prolonged survival of pig orthotopic heart grafts treated with cyclosporin A.

Cyclosporin A was given to pigs receiving orthotopic cardiac allografts from donors mismatched at the major locus. Median survival in 20 control pigs was only 6 days; in 5 pigs given cyclosporin A at 15 mg/kg on 3 days median survival was 22 days; and when 6 animals were given 25 mg/kg intramuscularly for 2 days and then orally median survival is greater than 68 days, with 4 animals still alive.

Liver transplantation for primary hepatocellular carcinoma: tumor size and number determine outcome

Liver transplantation for primary hepatocellular carcinoma (HCC) has in general been complicated by high recurrence rates. In the present study results from experience of 87 patients were analyzed [56 cirrhotic, 31 non-cirrhotic, 6 with the fibrolamellar (FL) variant] in relation to curative potential. Sixty-two survived > 90 days and form the study cohort. Fifty-six had non-fibrolamellar HCC and, of these, 39 had discrete lesions, measuring 0.8-21 cm (median 5.0 cm) including 4 in whom the diagnosis was made after examination of the explanted liver; 23 had multifocal lesions (> 2 tumor masses). There was no tumor recurrence in the group of 14 cases with single dominant lesions measuring < 4 cm, whereas in the 15 cases with lesions of 4-8 cm the recurrence rate was 40%, and 78% in those > 8 cm and the multifocal lesions (n = 27, P = 0.0001). Five-year actuarial survival figures were 57.1%, 44.4% and 11.1% (P < 0.003) respectively. The mean survival times in patients who died of recurrence were: 4-8 cm, 3.3 years (range 10 months to 6.3 years); > 8 cm or multifocal, 13 months (3-25 months). Reduction of serum alpha-fetoprotein (AFP) to normal levels does not exclude a later recurrence (7 of 17 cases) and this was documented after maintenance of normal AFP levels for up to 29 months.(ABSTRACT TRUNCATED AT 250 WORDS)

EVIDENCE FOR AN IMMUNE RESPONSE TO HLA CLASS I ANTIGENS IN THE VANISHING-BILEDUCT SYNDROME AFTER LIVER TRANSPLANTATION

The relation between donor and recipient status for HLA class I and II antigens in 62 patients undergoing liver transplantation was examined with particular reference to a well-defined variant of chronic rejection, the vanishing-bileduct (VBD) syndrome. A complete mismatch for class I antigens was more common in those with the VBD syndrome than in those with normal graft function or chronic graft malfunction unrelated to the syndrome (p less than 0.025). In contrast, a complete mismatch for class II antigens was considerably less common in those with the VBD syndrome than in those without (p less than 0.02). The association of a complete mismatch for class I and a partial or complete match for class II antigens with the VBD syndrome was highly significant (p less than 0.0005). These findings support the hypothesis that in the VBD syndrome both class I antigen expression on bileduct epithelium and immunological interaction at the level of class II antigens are required for the rejection process to occur. In addition, high-titre donor-specific antibodies to class I antigen, which were present in 6 of 14 of those with the VBD syndrome but in none of those without (p less than 0.0005), may be involved in the pathogenesis of bileduct damage.

Hypercalcemia and increased parathyroid-hormone activity in a primary hepatoma. Studies before and after hepatic transplantation.

Abstract A patient with hypercalcemia associated with a carcinoma of the intrahepatic bile ducts showed some decrease in serum calcium after a course of prednisone. Orthotopic liver transplantation...

GASTROINTESTINAL COMPLICATIONS AFTER RENAL TRANSPLANTATION

Abstract 32 patients out of 139 who received Summary renal allografts developed 38 gastrointestinal complications. Early surgical treatment is shown to be important in cases of upper gastrointestinal haemorrhage and bleeding. Thorough preoperative gastrointestinal investigations are recommended in all cases, and corrective surgery should be done before transplantation whenever possible. Perforation of the lower intestine with the high risk of severe gram-negative septicaemia carries a high mortality-rate. Reduction in the dose of immunosuppressive drugs and, if necessary, abandoning the graft may be important lifesaving procedures in such cases.