T. Besse

Induction versus noninduction in renal transplant recipients with tacrolimus-based immunosuppression

Background. The aim of this study was to compare the efficacy and safety of induction treatment with antithymocyte globulins (ATG) followed by tacrolimus therapy with immediate tacrolimus therapy in renal transplant recipients. Methods. This 12-month, open, prospective study was conducted in 15 centers in France and 1 center in Belgium; 309 patients were randomized to receive either induction therapy with ATG (n=151) followed by initiation of tacrolimus on day 9 or immediate tacrolimus-based triple therapy (n=158). In both study arms, the initial daily tacrolimus dose was 0.2 mg/kg. Steroid boluses were given in the first 2 days and tapered thereafter from 20 mg/day to 5 mg/day. Azathioprine was administered at 1–2 mg/kg per day. Results. At month 12, biopsy-confirmed acute rejections were reported for 15.2% (induction) and 30.4% (noninduction) of patients (P =0.001). The incidence of steroid-sensitive acute rejections was 7.9% (induction) and 22.2% (noninduction)(P =0.001). Steroid-resistant acute rejections were reported for 8.6% (induction) and 8.9% (noninduction) of patients. A total of nine patients died. Patient survival and graft survival at month 12 was similar in both treatment groups (97.4% vs. 96.8% and 92.1% vs. 91.1%, respectively). Statistically significant differences in the incidence of adverse events were found for cytomegalovirus (CMV) infection (induction, 32.5% vs. noninduction, 19.0%, P =0.009), leukopenia (37.3% vs. 9.5%, P <0.001), fever (25.2% vs. 10.1%, P =0.001), herpes simplex (17.9% vs. 5.7%, P =0.001), and thrombocytopenia (11.3% vs. 3.2%, P =0.007). In the induction group, serum sickness was observed in 10.6% of patients. The incidence of new onset diabetes mellitus was 3.4% (induction) and 4.5% (noninduction). Conclusion. Low incidences of acute rejection were found in both treatment arms. Induction treatment with ATG has the advantage of a lower incidence of acute rejection, but it significantly increases adverse events, particularly CMV infection.

Measurement of the vasoconstrictive substances endothelin, angiotensin II, and thromboxane B2 in cold storage solution can reveal previous renal ischemic insults.

Abstract In a rat model, the left kid ney was subjected to 60 min of normothermic ischemia followed by 15 min of reperfusion, whereas the right kidney, serving as a paired control, was not rendered ischemic. Both kidneys were then perfused in situ with either Euro‐Collins (EC) solution (n=12) or University of Wisconsin (UW) solution (n=6) for 10 min. Each kidney was then harvested and stored at 4°C in its respective solution. After 24 and 48 h of cold storage, the following vasoactive substances were measured in the preservation media: endothelin (ET), angiotensin II (A‐II), thromboxane (B2) (TxB2), and prostaglan‐din I2 (PGI2). After 24 h in EC solution, left kidneys uniformly produced significantly higher concentrations of each vasoactive substance than right kidneys: ET 1.64 ± 0.3 pg/ml vs 0.82 ± 0.1 pg/ml (P 0.009); A‐II 20.8 ± 6.2 pg/ml vs 7.75 + 2.3 pg/ml (P 0.007); TxB2, 100.8 ± 17.7 pg/ml vs 40.1 f 11.7 pg/ml (P 0.04); PGI2, 638.3 ± 41.1 pg/ml vs 318.3 ± 36.4 pg/ml (P 0.001), respectively. At 48 h, a similar pattern of results was obtained as the kidney continued to produce TxB2 and prostacyclins during the 24–48 h period. In the UW solution, basal levels of ET and A‐II were lower than those in EC solution, but similarly increased after initial ischemia. At 24 h, the concentrations produced by the left and right kidneys were as follows: ET 0.66 ± 0.1 pg/ml vs 0.48 ± 0.1 pg/ml (P 0.14); A‐II 10.36 f 3.7 pg/ml vs 2.14 ± 0.7 pg/ml (P 0.006); TxB2 178 ± 53 pg/ml vs 52 ± 23.1 pg/ml (P 0.001); and PGI2 448.3 ± 49 pg/ml vs 323 ± 44.3 pg/ml (P 0.01), respectively. After 48 h, the range of concentrations of each substance was similar to that obtained after 24 h. In further studies, the concentrations of ET and A‐II were measured in solution previously used to preserve human kidneys (n=7). The mean concentration of ET and A‐II in these samples was 3.82 ± 1.14 pg/ml and 21.3 ± 9.2 pg/ml, respectively, whereas in control media both substances were below the limits of detection. These results demonstrate that vaso‐constrictive substances can be measured in the preservation media after a kidney has been stored cold and that higher concentrations are found when the organ has been subjected to prior normothermic ischemia. The measurement of these vasoactive substances before transplantation may reveal that the kidney has been subjected to previous ischemic events. Moreover, these vasoactive substances could be involved in the early recovery of renal function after kidney transplantation.

Successful conversion from cyclosporine to tacrolimus for gastric motor dysfunction in a lung transplant recipient.

BACKGROUND Conversion after transplantation from cyclosporine to tacrolimus is often performed because of recurrent acute/chronic rejection or unacceptable side effects such as nephrotoxicity, arterial hypertension, and cosmetic disorders. Although gastrointestinal discomfort is often reported after transplantation, it is usually not considered a sufficient reason for conversion, although tacrolimus seems beneficial with regards to gastric motor activity in renal transplant patients. METHODS A lung transplantation was performed in a 41-year-old woman with alpha-1 antitrypsin deficiency emphysema. Because the patient presented severe symptoms of nausea, vomiting, and dyspepsia, without obvious endoscopic explanation, that resulted in highly variable cyclosporine trough levels, she was converted from cyclosporine to tacrolimus. RESULTS After conversion, dyspepsia, nausea, and vomiting resolved. Neurological complications caused by a transient high trough level of tacrolimus resolved completely upon dose reduction with tacrolimus trough levels remaining very stable afterwards. CONCLUSION Tacrolimus may be the immunosuppressant of choice after solid organ transplantation in patients with problems related to gastric motor dysfunction.

The experimental (in vitro) and clinical (in vivo) immunosuppressive effects of a rat IgG2b anti-human CD2 mAb, LO-CD2a/BTI-322.

BACKGROUND CD2 is a cell surface glycoprotein expressed on most human T cells and natural killer (NK) cells, working as a cell adhesion and costimulatory molecule. The aim of this paper is to analyze the mechanism of action of a rat IgG2b anti-human CD2 monoclonal antibody (mAb) (LO-CD2a/BTI-322 mAb), which is a potent immunosuppressive agent and inducer of cell death. In vivo, this mAb is able to prevent or treat kidney allograft rejection. METHODS The mechanisms by which the LO-CD2a/BTI-322 mAb is able to induce inhibition of cell activation and cell death were analyzed by mixed lymphocyte reactions and by flow cytometry. After in vivo treatment, levels of circulating mAb were measured by ELISA as well as anti-rat immunization and cytokine release. RESULTS We show that the inhibition of cell activation induced by LO-CD2a/BTI-322 mAb after allogeneic or OKT3 stimulation is due to an Fcgamma receptor-dependent CD2 down-modulation and to T-cell depletion through an antibody-dependent cell-mediated cytotoxicity mechanism mediated by NK cells or activated monocytes. Peripheral T- and NK-cell depletion was observed after in vivo treatment with LO-CD2a/BTI322. Cytokine release (TNFalpha) was correlated with some side effects, but only after the first injection, and the effects were never severe or life threatening. CONCLUSION The correlation between the in vitro and in vivo data suggests that T-cell depletion, especially of activated cells, and inhibition of cell activation after CD2 down-modulation are the main mechanisms of action of the LO-CD2a/BTI-322 mAb.

BTI-322 for acute rejection after renal transplantation.

Abstract BTI-322/LO-CD2a, a rat IgG2b, anti-CD2 monoclonal antibody which binds to all human T and natural killer (NK) cells, was first produced at our Institution1 and was first administered to patients on a compassionate-use basis in 1992. Four patients (three with renal allograft rejection and one with graft-versus-host-disease [GVHD]) resistant to standard therapies received treatment with LO-CD2a 10 mg/d intravenously (IV) for up to 12 days, plus steroids. In all cases, the drug was well tolerated, with no evidence of undesirable side effects; significant clinical benefit was demonstrated in each case. In 1993, LO-CD2a was successfully produced in vitro and became known as BTI-322. A study was initiated to evaluate the safety and determine the minimally effective dose of BTI-322 for treatment of either the first episode of acute renal allograft rejection (group AR) or uncontrolled rejection (rescue therapy; group RT).

Effect of PGI2 and thromboxane antagonist on liver ischemic injury.

Thromboxane, prostacyclin and their ratio could play an important role in the ischemic liver injury. To study this hypothesis, thromboxane and prostacyclin were measured by RIA after incubation of liver tissues removed during and after an ischemia of 90 min in male Wistar rats. The thromboxane to prostacyclin ratio increases during this period. In order to examine if this change could influence the survival rate of animals submitted to the same period of ischemia, drugs able to reduce the relative predominance of thromboxane were infused. The survival rate was not modified by administration of Iloprost or Daltroban, the antagonist of the thromboxane receptors. By contrast, imidazole, an inhibitor of thromboxane synthetase, significantly increased the survival rate. The same result was obtained with the administration of Daltroban plus Iloprost, suggesting that the reduction of thromboxane action associated with the increase of PGI2 level reduces the ischemic injury.

Atrial natriuretic factor, arachidonic acid metabolites and acute renal ischemia: experimental protocol in the rat.

The effects of an atrial natriuretic factor (ANF) infusion upon the production of the arachidonic acid metabolites (thromboxane B2, TxB2; 6-keto-prostaglandin F1 alpha, 6-keto-PGF1 alpha, PGI2, or prostaglandins E2, PGE2) were investigated after acute renal ischemia in the rat. This experimental protocol included a right nephrectomy and a 45-min left renal artery occlusion. Fifteen minutes after declamping, blood samples were collected from the left renal venous effluent for the assay of plasmatic prostanoid concentrations. Three experimental groups were studied: group I (n = 9) sham, no ischemia-group II (n = 9) control group, 45 min of left renal ischemia, followed by a 15-min revascularization, and group III (n = 10) ANF group, a similar ischemic protocol to that in group II was used but, after declamping, synthetic Atriopeptin III was infused (0.5 micrograms/kg/min) during the 15-min of vascular reflow. Fifteen minutes after declamping, TxB2 secretion significantly increased after ischemia in the control and ANF groups: TxB2: 210 +/- 22.4 pg/ml (control group) and 234.8 +/- 25.1 pg/ml (ANF group) versus 135.8 +/- 17.8 pg/ml (sham group) (p less than 0.05 and 0.01, respectively). On the other hand, the 6-keto-PGF1 alpha plasma levels were significantly higher after ischemia in the ANF group (221 +/- 34 pg/ml) in comparison with the sham (124 +/- 24.1 pg/ml) or with the control group (116.7 +/- 12.5 pg/ml). The calculated TxB2/6-keto-PGF1 alpha ratio was therefore higher in the control group, 1.93 +/- 0.27, than in physiological conditions (sham group), 1.2 +/- 0.17.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention of rejection with BTI-322 after renal transplantation (results at 9 months).

Abstract BTI-322, a rat IgG2b, anti-CD2 monoclonal antibody that binds to all human T and natural killer (NK) cells,1 was first administered to renal allograft recipients either on a compassionate-use basis or for treatment of the first episode of acute renal allograft rejection.2 In all cases, the drug was well tolerated, with no evidence of undesirable side effects; significant clinical benefit was shown in each case with a minimally effective dose of 5 mg/d. Moreover, in vitro data showed that BTI-322 can induce antigen-specific hyporesponsiveness. Therefore, we conducted a randomized study to evaluate the efficacy of BTI-322 in preventing first renal allograft rejection.

Technetium-99m L,L-ethylenedicysteine clearance and correlation with iodine-125 orthoiodohippurate for the determination of effective renal plasma flow

Technetium-99mL,l-ethylenedicysteine (99mTcL,l-EC) is a new renal tubular tracer that allows the determination of the effective renal plasma flow (ERPF). The aim of this study was to derive simplified methods for the estimation of99mTc-L,l-EC clearance using one or two plasma samples after bolus injection. Fifty-nine multiple plasma dual-tracer samples (nine samples from 5 to 120 min after injection) were obtained after injection of kit-formulated99mTc-L,l-EC and iodine-125 orthoiodohippurate (01H). The studies were performed in 25 stable and 24 unstable transplant recipients, in five patients with renal insufficiency (four on chronic haemodialysis) and in five normal volunteers. This allowed a wide range of renal function values to be covered, with ERPF (estimated by 01H clearance) ranging from 25.4 to 604.0 ml/min. The reference99mTc-L,l-EC clearance, as calculated from the multisample model, could be estimated from two samples at 15 and 90 min with an error of 11.3 ml/min and from one sample at 90 min with an error of 17.8 ml/min. Using appropriate linear regression analysis, ERPF could be estimated by the two- and one sample99mTc-L,l-EC clearance with an error of 24.2 and 22.8 ml/min, respectively. In conclusion,99mTc-L,l-EC clearance can be accurately estimated by simplified one or two-sample methods. Moreover, these methods can be used to estimate ERPF with an error that remains acceptable for clinical purposes.

Use of Anti-μ Monoclonal Antibodies in Xenotransplantation: A Potential Approach To Overcome Vascular Rejection

In 1982, Alexandre and colleagues demonstrated that hyperacute rejection (HAR) of ABO-incompatible kidney allografts could be overcome if the recipient’s circulating preformed natural antibodies were depleted prior to transplantation. Although anti-ABO natural antibodies regain normal serum levels in the few days following transplantation, HAR usually does not occur [1, 3, 4, 36]. As first hypothesized by RH. Bach [8], the acceptance of an ABO-incompatible allograft could result from modification of endothelial cells (EC) physiological response, characteristics leading to “accommodation,” i.e., allowing the survival of the transplant in the presence of high levels of circulating IgM natural antibodies and complement, after a period of depletion.