A randomized prospective trial of anti-Tac monoclonal antibody in human renal transplantation.

Patient entry is now complete in a prospective trial of anti-Tac, a murine IgG2a monoclonal antibody directed against the p55 chain of the human IL-2 receptor, for the prevention of renal allograft rejection. Recipients of primary cadaver allografts were randomized to receive either anti-Tac (20 mg q.d. x 10 days beginning POD 1) plus low-dose CsA (4 mg/kg/day), azathioprine (2 mg/kg/day), and prednisone (30 mg q.d.), or conventional triple therapy with CsA (8 mg/kg/day), azathioprine, and prednisone. Forty patients were entered in each group, with current followup from 6 to 26 months. The results show a significant reduction in early rejection episodes in the anti-Tac-treated patients. During the 10-day treatment, 5 of 40 anti-Tac patients had rejection episodes, compared with 21 of 40 control patients (P less than 0.001). Anti-Tac significantly delayed the time to the first rejection (12.5 +/- 6.3 vs. 7.6 +/- 6.7 days) (P less than 0.05). Despite these effects, there were no differences in either actual or actuarial graft or patient survival between the two groups. Pneumonia, primarily CMV, developed in 5 treated and 4 control patients. In patients with functioning grafts mean serum creatinine at 3 months was 1.8 +/- 0.7 in the anti-Tac group and 2.0 +/- 0.8 in the control group (P = NS); at 12 months the values were 2.3 +/- 1.5 and 1.8 +/- 0.5, respectively (P = NS). The peak expression of IL-2 receptors on circulating T-cells was significantly lower in anti-Tac patients (15.1 +/- 3.6%) than in controls (21.9 +/- 4.5%) (P less than 0.05). Seven of 10 patients tested to date developed antimouse immunoglobulin antibodies, with antiidiotype shown in 6. These antibodies do not preclude subsequent treatment with OKT3. Five patients in this and previous anti-Tac protocols have received OKT3 for acute rejection despite known pretreatment antimouse antibodies, with resolution of rejection in all cases.     

Renal artery stenosis in transplant patients

Although hypertension appears not infrequently among recipients of kidney transplants, renal artery stenosis is relatively rare as a causative factor. A 23-year experience of patients receiving kidney grafts at the Brigham and Women's Hospital was reviewed to ascertain the incidence of renal artery stenosis and its surgical management. Risk factors leading to the condition and selection of patients for operation are emphasized. The incidence of arterial stenosis severe enough to require operation was 2.7% of 914 kidney transplants; the overall incidence in these patients is unknown, although operated patients comprise about one-half of those undergoing arteriography to diagnose hypertension. The mean time for development of the condition was 21.4 months from date of engraftment. A successful outcome as measured by fall in blood pressure and/or serum creatinine was achieved in 14 of 21 patients (67%) in whom surgical repair of the effected artery was undertaken. Reparative surgery was unsuccessful in seven patients, although hypertension was improved in one of these individuals following transplant nephrectomy. Surgery was never undertaken in four patients because of chronic rejection noted on biopsy. There was no mortality. Operative repair should be offered to patients with renal artery stenosis leading to unmanageable hypertension or renal dysfunction, but withheld from those with documented chronic rejection regardless of major arterial compromise.     

Experimental Arterial Thromboembolism in Baboons: MECHANISM, QUANTITATION, AND PHARMACOLOGIC PREVENTION

A quantitative primate model of arterial thromboembolism has been characterized with respect to mechanism and usefulness in evaluating modifying variables. The model involved the kinetic measurements of (51)Cr-platelets and (125)I-fibrinogen consumption by femoral arteriovenous cannulae in chaired baboons.Cannula platelet consumption correlated directly with exposed cannular area for irradiated Silastic and polyurethane (correlation coefficients of 0.940 and 0.901, respectively; P < 0.001) and remained steady state for months. Nonirradiated Silastic was only minimally reactive with platelets. Despite increased rates of platelet consumption circulating fibrinogen was not measurably destroyed by any of the cannulae tested. Cannula platelet consumption was independent of cannula flow rate, platelet count, heparin anti-coagulation, and ancrod defibrinogenation.(111)In-platelet imaging of irradiated Silastic cannulae demonstrated luminal accumulation and subsequent embolization of irregular platelet masses. When irradiated Silastic cannulae were inserted as extension segments in the renal arteries of four animals the glomerular vessels became progressively occluded with nonfibrin-containing platelet thromboemboli. Nonirradiated Silastic cannulae in control arteries produced no significant vascular occlusion. Because the survival of platelets from animals with consumptive cannulae was not shortened in normal recipient animals we concluded that platelets were either irreversibly removed through thromboembolic consumption or unaffected in their viability.Oral administration of dipyridamole and sulfinpyrazone decreased cannula platelet consumption in a dose-dependent manner with complete interruption at 20 and 250 mumol/kg body wt per d (in three divided doses), respectively, whereas oral acetylsalicylic acid (10-330 mumol/kg per d) had no measurable effect on cannula platelet consumption.We conclude that this primate model simulates arterial thrombotic processes in man and that this model is suitable for the in vivo evaluation of biomaterials and of drugs that modify platelet behavior.     

Biotransformation of the immunomodulator, 3-(p-chlorophenyl)-2,3-dihydro-3-hydroxythiazolo[3,2a]benzimidazole-2-acetic acid,and its relationship to tyroid toxicity

Wy-13,876, 3-(p-chlorophenyl)-2,3-dihydro-3-hydroxythiazolo[3,2a]benzimidazole-2-acetic acid, causes enlargement of the thyroids of rats and dogs. Radioactivity was accumulated in the thyroids, but not in other tissues of dogs given the ¹⁴C-labeled drug. Uptake of ¹⁴C by the thyroid of the rat was time dependent; there was little or no accumulation until 8 hr after drug administration. Biotransformation of Wy-13,876 is extensive. Two metabolites, benzimidazolethiol and benzimidazole, account for most of the radioactivity in the thyroid but almost no unchanged drug was detected. The two metabolites were also detected in liver, plasma, and urine, however, they represented little of the drug-related substances. Recovery of radiolabel in theexcreta of rats given [¹⁴C]Wy-13,876 was 79 ± 7.9% ± SD and was about evenly divided between feces and urine. Radioactivity, primarily benzimidazolethiol and benzimidazole, also accumulated in the thyroids of rats given labeled benzimidazolethiol. Chronic treatment with either the thiol metabolite or the parent compound reduced the plasma concentration of thyroid hormone and caused enlargement of the thyroid. Thus, the biotransformation of Wy-13,876 to benzimidazolethiol followed by accumulation of this metabolite in the thyroid initiates a sequence of events which begins with the inhibition of thyroid hormone synthesis. Reduced concentrations of circulating thyroid hormones stimulate the release of TSH which in turn increases thyroid activity leading to the hyperplasia and enlargement. Treatment of rats with l-thyroxine prior to administration of [¹⁴C]Wy-13,876 partially prevented the accumulation of radioactivity by the thyroid. Wy-18,251, an analog of Wy-13,876, was not metabolized to benzimidazolethiol and was not thyrotoxic.     

Thinking of something to say: public and private narratives of infertility

Autobiographical narratives of infertility are situated in both the private and public domains, particularly since the advent of assisted reproductive technology. Narratives of infertility told by 31 Australian women reveal that the tension between the public and the private is an uncomfortable one for the narrators. Infertile women must deal not only with the blow inflicted by infertility to their sense of self, but also with the difficulties of presenting a simple and coherent life story in the social world. The women expressed resentment at the public expectation that they should justify their desire to become mothers. Infertility support groups play a role in the construction and dissemination of a public narrative of infertility that is not pathological.     

Multimodal intracranial monitoring: implications for clinical practice

This article presents an overview of intracranial monitoring techniques during the perioperative and intensive care management of neurologic patients. Various regional and global brain monitors are available; some modalities are well established whereas others are new to the clinical arena and their indications are still being evaluated. Indications for monitoring are reviewed, modalities critically evaluated, and future directions identified.