Graft irradiation in the treatment of acute rejection of renal transplants: a randomized study.

A randomized study of graft irradiation in the treatment of acute rejection of renal transplants was conducted from 1978 to 1981. Patients developing clinical signs of an acute graft rejection received customary antirejection treatment in the form of intravenous administration of high-dose (1 gm per day) of methylprednisolone. They were at the same time randomized to either receive therapeutic irradiation (175 rad every other day to a total of 525 rad) or sham irradiation. Neither the patient nor the Transplant Service surgeons knew at any time whether the radiation treatment had been given. Eight-three rejection episodes occurring in 64 grafts were entered into the study. Acute rejection was reversed in 84.5% of grafts in the control and 75% in the treated group. The incidence of recurrent rejection was higher in the treated group (66 vs. 46%) and graft survival was lower (22% vs. 54%). The study failed to demonstrate a beneficial effect of graft irradiation in the treatment of acute renal allograft rejection, when used in conjunction with high dose steroids.

The beneficial effect of pretransplant blood transfusions in cyclosporine-treated cadaver renal allograft recipients.

212 cyclosporine-treated recipients of mismatched first cadaveric renal allografts are evaluated with respect to the effect of pretransplant random blood transfusions. It is determined that transfusions do not effect patient survival or morbidity. Pretransplant random blood transfusions correlate with significantly improved allograft success. There is also a trend, although not statistically significant, for further improvement of allograft survival with increasing numbers of transfusions. The transfusion effect is not related to the time at which the transfusions are given up to 2 years prior to transplantation. Transfused patients have a higher percent reactive antibody (PRA) than untransfused patients, but this does not cause them to wait for a cadaveric allograft significantly longer than the untransfused patients. Rejections are less severe in transfused patients. It is concluded that cyclosporine-treated recipients of first cadaveric renal allografts benefit from pretransplant blood transfusions.

Randomized, prospective trial of mycophenolate mofetil versus azathioprine for prevention of acute renal allograft rejection after simultaneous kidney-pancreas transplantation.

BACKGROUND: In simultaneous kidney-pancreas (SPK) transplantation, manifestations of renal allograft rejection typically become evident before those of pancreatic rejection. This study compared mycophenolate mofetil (MMF) and azathioprine (AZA) in prevention of renal rejection after primary SPK transplantation. METHODS: In an open-label, randomized, multicenter study, patients received MMF 1.5 g twice daily (n=74) or AZA 1-3 mg/kg daily (n=76) for 1 year after transplantation. The incidence of rejection was assessed at 6 months. Adverse events were tracked through 1 year. Survival data are reported through 2 years. RESULTS: At 6 months, efficacy results for MMF vs. AZA patients, respectively, were the following: rejection (27% vs. 39%); rejection or death (34% vs. 42%); rejection, graft loss, death, or premature withdrawal (i.e., treatment failure; 41% vs. 55%). Six-month efficacy trends favored MMF, and time to rejection or treatment failure was significantly longer when compared with AZA (P=0.049). One-year efficacy results for MMF vs. AZA patients, respectively, were the following: treatment of renal rejection (35% vs. 47%); renal allograft loss or death (9% vs. 12%); pancreas allograft loss or death (15% vs. 14%). Five MMF patients (7%) and four (5%) in the AZA group died. More MMF than AZA patients developed opportunistic infections (54% vs. 38%), but the pathogens did not differ. CONCLUSIONS: Trends for most efficacy parameters favored MMF over AZA, and time to renal allograft rejection or treatment failure was statistically significantly longer for MMF. The use of MMF in the treatment of SPK recipients is a useful advance.

The risk of transmission of hepatitis B from HBsAg(-), HBcAb(+), HBIgM(-) organ donors.

Liver allografts from HBcAb(+), IgM(-), HBsAg(-) donors can transmit HBV to uninfected recipients. We currently no longer accept these livers for transplantation while continuing to accept the kidneys. The purpose of this study is to determine the risk of donor-transmitted HBV infections from HBcAb(+), HBIgM(-), HBsAg(-) organ donors and determine if the risk of donor-transmitted HBV infections and their severity is dependent on the organ being transplanted. This study consists of a retrospective review of the posttransplant course of recipients of HBcAb(+), HBIgM(-), HBsAg(-) donors accepted at UCSF from 6/85 to 12/93. Transmitted HBV infection was defined as one in which the recipient changed from HBsAg(-) prior to transplantation to HBsAg(+) posttransplant, with no other source. There were 25 of 1190 donors who were HBcAb(+), HBIgM(-), HBsAg(-); 1/42 kidney, 3/6 liver, and 0/7 heart HBsAg(-) transplant recipients of organs from these donors became HBsAg(+) after transplantation. This difference in infection rate (liver vs. kidney and heart) is statistically significant. The clinical course of the liver recipients was also more severe. All of the patients who became infected were HBsAb(-) and HBcAb(-) prior to transplant. We conclude that (1) HBV can be transmitted from HBcAb(+), HBIgM(-), HBsAg(-) organ donors, (2) the rate of transmission is highest and severity of infection is worst in the liver recipients; and (3) we will continue to transplant kidneys from these donors, preferably into immunized recipients.

"Anti-idiotypic" antibodies to HLA in transiently sensitized DST patients.

To test the hypothesis whether "anti-idiotypic" antibodies (Ab2) were involved in the loss of sensitization following donor-specific blood transfusions (DST), we investigated nine potential kidney graft recipients who became transiently sensitized after DST. Inhibiting "anti-idiotypic" activity of post-DST sera was determined using a complement-dependent cytotoxicity inhibition assay. The follow-up after DST ranged from 9 to 66 months. The nine patients developed 12 different anti-HLA antibodies (Ab1). Inhibiting post-DST serum activity was found in relation to four of them, while enhancement of cell killing caused by post-DST sera was observed in relation to six anti-HLA antibodies. In two patients presenting with more than one anti-HLA antibody inhibition was found with only one of the antibodies, indicating that the blocking of Ab1 was specific for the respective antibody. Enhancement was associated with a significantly prolonged sensitization of the patients. On the average, 5.7 +/- 5.0 months were necessary before "anti-idiotypic" activity was developed after the loss of sensitization, whereas enhancement was found immediately thereafter. Testing by flow cytometry indicated that enhancing sera still contained subthreshold levels of Ab1. Our results indicate that DST can induce the development of "anti-idiotypic" antibodies following a short period of sensitization. This finding provides further evidence that anti-idiotypic antibodies might be relevant factors in the eventual disappearance of sensitization to HLA antigens.

Successful revascularization of early posttransplant renal arterial occlusion.

A case involving immediate postoperative prolonged warm ischemia in a transplanted kidney from a living related donor is presented. Repair of the renal artery after 3 hours 15 minutes of complete occlusion resulted in an 18-day course of acute tubular necrosis followed by full return of normal renal function. Significant collateral circulation has been present in all previously salvageable cases of transplant renal artery obstruction. This case demonstrates that a kidney from an optimally prepared donor can withstand more than 3 hours of posttransplant warm ischemia despite the absence of collateral circulation. An aggressive surgical approach to restoring circulation is indicated.

Histamine stimulation and inhibition of human cryopreserved parathyroid tissue.

To elucidate the mechanism by which cimetidine, an H2 antagonist, inhibits parathormone secretion, immunoreactive cyclic AMP (cAMP) production was measured at low (0.5 mM) and normal (1.0 mM) calcium concentrations, with histamine stimulation and histamine inhibition by cimetidine, in a cell dispersion preparation from cryopreserved glands of 12 hyperparathyroid patients. At low calcium, histamine-mediated cAMP production increased from a basal level of 382 +/- 44 femtomoles/10(5) cells to 514 +/- 74 femtomoles/10(5) cells (P less than 0.05). Cimetidine inhibition of histamine-stimulated parathyroid cells at low calcium resulted in a decrease in cAMP production from 514 +/- 74 femtomoles/10(5) cells to 410 +/- 62 femtomoles/10(5) cells (P less than 0.01). At normal calcium the cAMP production in the histamine-stimulated experiment increased from a basal level of 293 +/- 66 femtomoles/10(5) cells to 477 +/- 100 femtomoles/10(5) cells (P less than 0.01) and decreased to 321 +/- 69 femtomoles/10(5) cells (P less than 0.01) in the histamine and cimetidine experiment. Stimulation by isoproterenol, a beta-adrenergic agonist, at low calcium in the histamine-primed group showed an increase in cAMP production from 514 +/- 74 femtomoles/10(5) cells to 639 +/- 71 femtomoles/10(5) cells (P less than 0.005). These results suggest that histamine plays an important role in cAMP production in hyperparathyroid cells and that cimetidine inhibition of histamine-stimulated cAMP production may explain the decrease of immunoreactive parathormone by this H2 antagonist reported in patients with hyperparathyroidism.

Tertiary hyperparathyroidism after renal transplantation: operative indications.

A retrospective analysis of our renal transplant population between 1981 and 1987 was undertaken to study the natural history of posttransplant hypercalcemia and to review indications and recommendations regarding the timing of parathyroidectomy. During this period, 1158 renal transplant procedures were performed in 1025 patients, with 819 allografts (71%) functioning currently. Posttransplant hypercalcemia greater than 10.5 mg/dl was associated with a longer duration of dialysis and developed in 227 patients, with onset of hypercalcemia occurring in 90% of these patients by 1 year. In 69% of these patients, spontaneous resolution of the hypercalcemia occurred between 6 months and 7 years after transplantation. A total of 42 patients with asymptomatic hypercalcemia are currently being followed up, with a mean serum calcium level of 11.0 +/- 0.41 mg/dl and a mean follow-up interval of 3.3 +/- 1.6 years since transplantation. Nine symptom-free patients with moderate hypercalcemia (12.0 to 12.4 mg/dl) more than 1 year after transplantation were identified. Five of these patients had spontaneous resolution of the hypercalcemia between 2 and 7 years. Fifteen patients with posttransplant hyperparathyroidism (6.6%) required parathyroidectomy--11 for symptomatic and four for asymptomatic hyperparathyroidism. One patient had symptomatic hyperparathyroidism despite the presence of normocalcemia. One symptom-free patient with significant hypercalcemia (serum calcium level, 14.7 mg/dl) underwent parathyroidectomy 3 months after transplantation. The remaining three symptom-free patients had serum calcium determinations of greater than or equal to 12.5 mg/dl more than 1 year after renal transplantation. Patients with pretransplant and posttransplant hypercalcemia required parathyroidectomy more frequently than did patients with only posttransplant hypercalcemia (18% versus 3.0%; p less than 0.001). An unusual finding was the occurrence of a single adenoma in two patients, which represents sporadic primary hyperparathyroidism in the patient undergoing renal transplantation rather than tertiary hyperparathyroidism. We recommend a conservative approach to posttransplant hypercalcemia, with surgery reserved for patients with symptomatic disease and patients with asymptomatic persistent hypercalcemia greater than or equal to 12.5 mg/dl more than 1 year after transplantation.

Peptic ulcer disease in kidney transplant recipients.

The occurrence of peptic ulcer in kidney transplant recipients treated with corticosteroids for immunosuppression is a problem of considerable magnitude and threatens both patient and graft survival. The fact that peptic ulcer usually occurs in the early months after transplantation, and that there are known risk factors including treatment for rejection, sepsis, and hepatitis, demand a high level of clinical suspicion, early and accurate diagnosis, and prompt treatment. Aggressive medical prophylaxis is important, but if it should fail prompt reduction of the dose of corticosteroids is imperative so that continued patient survival is emphasized rather than the continued survival of the transplant. Surgical intervention, when indicated, should also be prompt, and the more definitive operations such as vagotomy with pyloroplasty or gastric resection are preferred because of a lesser occurrence of reoperation among such patients. Prophylactic operations in patients with an antecedent history of peptic ulcer may provide considerable protection against the development of corticosteroid-related ulcers after transplantation.