Effect of nifedipine on renal allograft function and survival beyond one year.

We previously reported that a calcium channel blocker supplemented immunosuppression produced excellent patient and graft survival rates in cadaveric kidney transplantation. We report here the long term outcome of patients treated with nifedipine-supplemented triple immunosuppression as compared with those of historical controls who were treated similarly without nifedipine. Study subjects included 111 patients transplanted in 1990-1994, treated with nifedipine and triple immunosuppression and with functioning grafts for more than one year (Nifedipine group). The results of cyclosporine (CyA) dose, blood pressure (BP), serum creatinine (Cr), and actuarial graft survival rate (GSR) up to 5 years posttransplant in these patients were compared with those of 52 patients transplanted in 1985-1990, treated similarly without calcium channel blockers (Control group). Donor sources, gender ratio, age distribution, causes of end stage renal disease, incidence of hypertension prior to transplantation and incidence of rejection in the first year between the groups were comparable. Throughout the study period the Nifedipine group had significantly lower serum Cr (1.5 +/- 0.7 vs. 1.8 +/- 0.7 mg/dl) and higher GSR (93.8% vs. 88% at 5 years) than the Control group. BP was comparable despite higher CyA doses in the Nifedipine group (4.3 +/- 1.1 vs. 3.3 +/- 1.1 mg/kg/day). We conclude that nifedipine is beneficial in improving long-term graft function and survival in kidney transplant recipients by mitigating CyA associated renal injury.

Regulation of transforming growth factor-beta 1 (TGF-beta 1) expression with a novel TGF-beta 1 complementary DNA.

We describe here a novel TGF-beta 1 complementary DNA (antisense oligomer) that is specific for TGF-beta 1 genomic DNA. The TGF-beta 1 antisense oligomer, complementary to the nucleotides flanking the first transcription start site of the human TGF-beta 1 gene and phosphorothioate modified, was efficacious in: a) constraining TGF-beta 1 promoter activity; b) reducing TGF-beta 1 secretion; and c) preventing TGF-beta 1 dependent inhibition of DNA synthesis in TGF-beta sensitive A-549 human adenocarcinoma cells. The biologic activities of the TGF-beta 1 antisense oligomer were sequence specific since neither the TGF-beta 1 sense oligomer nor the TGF-beta 1 missense oligomer prevented TGF-beta 1 expression. Our findings, in addition to demonstrating the efficacy and specificity of the TGF-beta 1 antisense oligomer, suggest that the oligomer might be of value for the treatment of diseases in which TGF-beta 1 overexpression might play a pathogenetic role (e.g., diabetic renal disease, AIDS).

Excellent outcome with a calcium channel blocker-supplemented immunosuppressive regimen in cadaveric renal transplantation. A potential strategy to avoid antibody induction protocols.

Many transplant centers routinely utilize monoclonal antibody or polyclonal antibody based induction protocols in recipients of cadaver renal allografts. Given the potential complications associated with antibody-based immunosuppression regimens (e.g., CMV disease), we tested the hypothesis that a combination of a calcium antagonist and a triple drug protocol (cyclosporine + prednisone + azathioprine) would be an effective substitute for antibody-based induction protocols in ensuring excellent patient and graft survival rates. Our postulate was tested in a prospective study of 52 consecutive recipients of cadaver renal allografts (44 first, 5 second, and 3 third grafts) utilizing nifedipine as the first line calcium antagonist. Nifedipine was selected over verapamil or diltiazem due to its lack of interference with the metabolism of CsA. Some of the significant outcomes of our prospective trial were (A) a cumulative patient survival rate of 98.1% for the 52 recipients at 18 months posttransplantation; (B) a cumulative allograft survival rate of 92.1% for the 52 consecutive cadaver renal allografts at 18 months; (C) a cumulative allograft survival rate of 100% at 18 months for the 24 of 52 renal allografts without delayed graft function following transplantation; and (D) a cumulative allograft survival rate of 86% at 18 months for the 28 of 52 renal allografts with delayed graft function. Of the 4 of 52 who lost their grafts, 2 grafts were removed following discontinuation of immunosuppressive therapy while the remaining 2 had primary nonfunction; and (E) the lack of a requirement for monoclonal or polyclonal antibodies for the treatment of acute rejection episodes in this patient population. These gratifying results compare very favorably with (A) recent reports of the effects of long-term diltiazem therapy and of verapamil used in conjunction with an induction protocol that included Minnesota antilymphocyte globulin in recipients of cadaver renal allografts, and (B) the clinical outcome in many institutions with OKT3/ATG/ALG induction protocols. Whereas the mechanisms involved in the excellent clinical outcome found with the calcium antagonist remain undefined, our results strongly argue for a prospective, randomized and controlled study in which a calcium antagonist-supplemented immunosuppressive regimen is compared with antibody-based induction protocols.

Immune stimulatory properties of metalloporphyrins.

A possible approach to the immunotherapy of tumors is to stimulate either specific or nonspecific immune responses in vivo. We recently found that provision of a mitogenic signal to PBMC, by incubation with the oxidizing mitogens, enhanced the effect of IL-2 in generating cytolytic activity. We therefore searched for a mitogen that might safely be administered to patients. The present study is an investigation of the mitogenic properties of iron and tin (Sn)-protoporphyrin and their capacity to induce cytotoxicity in human PBMC. These agents have been administered to humans with little toxicity. Both iron- (hemin) and Sn-protoporphyrin induce mitogenicity in peripheral T cells. This effect is markedly enhanced by low concentrations of IL-2. Hemin and Sn-protoporphyrin, in combination with IL-2, increase IL-2R on PBMC. Hemin alone, and to a greater extent in combination with IL-2, induces cytotoxicity for NK-sensitive and NK-resistant cell lines. Sn-protoporphyrin, a more potent mitogen than hemin, fails to induce cytotoxicity, and has a marked inhibitory effect on cytotoxicity induced by IL-2. Hemin and Sn-protoporphyrin stimulate TNF-alpha and IFN-gamma production by PBMC. IL-2 is synergistic with the metalloporphyrins in eliciting this effect. Metalloporphyrin-induced mitogenesis has a stringent requirement for macrophages. Scavengers of oxygen-free radicals and inhibitors of peroxidase inhibit mitogenicity induced by hemin but not that induced by Sn-protoporphyrin. Hence, an oxidative event may mediate the mitogenic effect of hemin. Our results indicate that hemin is an immunostimulatory agent in vitro and the data warrant further evaluation of its in vivo immunostimulatory and antitumor effect.