Effect of induction therapy on kinetic of procalcitonin following uncomplicated heart transplantation

BACKGROUND: The aim of the study was to determine the early postoperative kinetics of serum procalcitonin (PCT) levels in uncomplicated heart transplant patients under induction therapy using antithymocyte globulin (ATG). METHODS: PCT serum concentrations were measured for 7 days in 30 adult patients (26 males, 4 females, mean age 54.5 +/- 7.7 years) undergoing uncomplicated orthotopic heart transplantation. Of the 30 patients, 28 received ATG and 2 with the same immunosuppression regimen had no induction therapy. The induction therapy consisted of 100 mg/day ATG and was started 6 hours postoperatively. RESULTS: Mean PCT levels immediately before HTX were <0.3 ng/mL in both groups. After the first ATG infusion patients developed a significant (p < 0.05) elevation in PCT plasma levels without any incidence of infectious disease with peak levels up to 11.7 +/- 19.7 ng/mL on postoperative day (POD) 1. Thereafter values continuously decreased independently of further ATG administration in all patients (6.7 +/- 10.5 ng/mL on POD 3, 3.2 +/- 7.4 ng/mL on POD 5 and 1.2 +/- 3.0 ng/mL on POD 7). In the non-ATG group a mild postoperative rise in the serum PCT was observed. The values peaked on POD 2 with 2.0 +/- 1.6 ng/mL and normalized within four days. CONCLUSIONS: Perioperative administration of ATG is associated with significantly increased PCT levels even in uncomplicated heart transplant recipients. This phenomenon should not be misinterpreted as systemic infection, as systemic inflammatory reaction that seems to be induced by ATG therapy is responsible for increased PCT production.     

The quality of initial function following renal transplantation determined by creatinine elimination kinetics. Comparison of Minnesota antilymphocyte globulin and cyclosporine induction immunosuppression.

To compare the effect of type of induction immunosuppression on the quality of initial renal allograft function, we identified 35 cadaver donor kidney pairs in which one recipient of a kidney from a given pair received induction immunosuppression with Minnesota antilymphocyte globulin (MALG group) while the recipient of the contra-lateral kidney received cyclosporine from day zero (CsA group). In the absence of an existing quantitative measure to assess and compare the status of those grafts that function primarily, we defined the half-life of creatinine elimination (t1/2SCr) as such an outcome measure based on a review of creatinine elimination kinetics. All organs were procured with in-situ perfusion and en-bloc removal. Total cold storage times, rewarm times, and perioperative management were comparable for the two groups. In the MALG group, the mean t1/2SCr) was not different from that in the CsA group (1.38 +/- 0.96 days vs 1.35 +/- 1.2 days P = NS). Multiple regression analysis performed on the differences in recipient age, number of DR-B locus matches, total cold ischemia time, rewarm time, and central venous pressure at reperfusion of a given donor pair demonstrated no significant impact of any of these differences on the difference in t1/2SCr for the same pair set in this sample. The nadir of serum creatinine achieved in the first five days posttransplant was somewhat higher in the CsA group (234 +/- 131 mumol/L) as compared with the MALG group (200 +/- 132 mumol/L) but the difference was not significant. A similar nonsignificant trend was observed in the comparison of mean serum creatinine values at 30 days posttransplant (MALG group: 158 +/- 62 mumol/L vs. CsA group: 200 +/- 141 mumol/L). Only one of seventy recipients (CsA group) was dialyzed within the first 5 days posttransplant for an overall incidence of ATN of less than 2%. Fourteen of 35 (40%) recipients in both groups received treatment for acute rejection. The mean time to first treatment for acute rejection episode was shorter in the CsA group than the MALG group (10 +/- 8 days vs 23 +/- 24 days, P = 0.055). Graft survival at one year was not different for the two groups (92% vs. 87% for the MALG and CsA groups respectively, P = NS).(ABSTRACT TRUNCATED AT 400 WORDS)     

A prospective comparison of murine monoclonal CD-3 (OKT3) antibody-based and equine antithymocyte globulin-based rejection prophylaxis in cardiac transplantation. Decreased rejection and less corticosteroid use with OKT3

To test the efficacy of murine monoclonal CD-3 antibody (OKT3) in early prophylaxis for cardiac allograft rejection, we conducted a 6-month trial, prospectively assigning 51 patients to receive either equine antithymocyte globulin-based (n = 25) or OKT3-based (n = 26) early prophylaxis. ATG patients received 8 days of ATG (10 mg/kg), with the first dose given preoperatively. OKT3 patients received 14 days of OKT3 (5 mg) beginning on the second postoperative day. Corticosteroid and azathioprine administration were similar during early prophylaxis. Cyclosporine was begun preoperatively in ATG patients and on the fourth postoperative day in OKT3 patients. In addition, patients in both groups were randomized to receive or not receive eight weekly administrations of vincristine (0.025 mg/kg). While infection rate (0.8 +/- 0.2 infections/patient in both groups [mean +/- SEM]) and mortality (1 patient in each group) did not differ, OKT3-based early prophylaxis delayed the first rejection episode (76 +/- 11 days vs. 36 +/- 8 days, P = 0.005) and decreased the risk of rejection during the 6-month follow-up (P less than 0.001, product-limit analysis). Overall, the OKT3 group manifested 1.5 +/- 0.2 episodes of rejection/patient compared with 2.2 +/- 0.2 episodes/patient in the ATG group (P = 0.036). Despite similar 6-month cumulative cyclosporine and azathioprine dosages, six month average corticosteroid administration was less in the OKT3 group (12.2 +/- 1.5 mg prednisone equivalent/m2/day versus 19.3 +/- 2.1 mg prednisone equivalent/m2/day, P = 0.008), fewer OKT3 patients subsequently required additional cytolytic therapy for rejection (2 [8%] versus 12 [48%], P = 0.001), and more patients in the OKT3 group were successfully weaned off maintenance corticosteroids (22 [88%] versus 11 [46%], P = 0.002). We conclude that, relative to an equine ATG-based protocol, OKT3-based early prophylaxis results in less rejection, permitting less chronic corticosteroid administration.     

Prevention of acute rejection with antithymocyte globulin, avoiding corticosteroids, and delaying cyclosporin after renal transplantation.

BACKGROUND: Despite their well-known side-effects, corticosteroids (Cs) are currently used after kidney transplantation. Avoidance of Cs may improve patient quality of life and eventual long-term survival. We report on a regimen using antithymocyte globulin (ATG) and mycophenolate mofetil (MMF) for induction, and cyclosporin (CsA) plus MMF for maintenance treatment of recipients of primary kidney transplantation. METHODS: We studied 11 consecutive, non-sensitized renal transplant patients (nine cadaver and two living donors). Initial immunosuppression consisted of ATG (1.5 mg/kg/day, i.v.) given for 10 days and MMF (1.0 g/b.i.d.). CsA (8 mg/kg, in two divided doses) was started on post-operative day 11. Cs were only allowed in the case of MMF discontinuation, for the treatment of acute rejection, and in the event of recurrence of the primary glomerulonephritis. RESULTS: All patients completed the entire 10-day ATG course. Main side-effects included fever (>38 degrees C) and serum sickness, observed in 73 and 27% of the patients respectively. The incidence of acute rejection was 27% (three of 11 patients). In two patients with acute rejection, serum sickness was concomitantly diagnosed and renal histology was partially compatible with immune-complex disease. The remaining patient had two episodes of low-grade rejection. All rejection episodes were rapidly reversed. Two patients (18%) were treated with ganciclovir for cytomegalovirus (CMV) infection. Two patients (18%) are currently receiving Cs for recurrence of the native glomerulonephritis and two rejection episodes respectively. All patients are currently alive with functioning kidneys (average follow-up of 8.4 months; average creatinine level of 128 micromol/l). CONCLUSION: This pilot study suggests that ATG induction in combination with MMF and delayed introduction of CsA, in the absence of Cs, is not well tolerated in recipients of kidney transplants. An earlier introduction of calcineurin inhibitors and/or a shorter course of ATG may reduce the incidence of fever and serum sickness secondary to ATG.     

Evidence that addition of azathioprine improves renal function in cyclosporine-treated patients with allograft dysfunction

Several approaches have been attempted to manage renal allograft dysfunction in cyclosporine-prednisone (CsA-Pred)-treated patients. Conversion to conventional therapy and perioperative triple drug have been associated with high rates of acute rejection episodes, infections, or neoplasms. We report our experience in delayed addition of azathioprine (1-2 mg/kg/day) to CsA/Pred protocol in three groups of patients. Group I (n = 9) had chronic renal function deterioration due to chronic rejection; group II (n = 10) had repeated or severe acute rejection episodes despite adequate CsA levels; and group III (n = 8) had CsA toxicity despite drug tapering. In group I, serum creatinine (SCr) had risen from 2.2 +/- 0.9 to 2.9 +/- 0.7 mg/dl over the 6 months prior to Aza addition (P less than 0.05), renal function declining at a rate of -0.14 +/- 0.12 Cr-1/year. In the 6-month post-Aza, renal function improved at a rate of 0.06 +/- 0.06 Cr-1/year and during the entire follow-up at a rate of 0.04 +/- 0.12 Cr-1/year (P less than 0.05) with stable CsA levels (288 +/- 167 vs. 251 +/- 172 ng/dl, NS). In group II response was worse, though the rate of declining renal function prior to Aza (-0.10 +/- 0.10 Cr-1/year) was almost stopped after Aza. In group III there was very good response to Aza addition, as 7 out of 8 patients improved graft function (baseline SCr 2.5 +/- 0.7 mg/dl vs. 1.9 +/- 0.6 mg/dl at last follow-up, P less than 0.05), with significantly decreased CsA levels (480 +/- 97 vs. 268 +/- 120, P less than 0.05). One patient from group II died from pneumonia, and 6 patients (1 from group I and 5 from group II) lost their grafts. Fifteen patients improved graft function, and 9 worsened after addition of Aza. The bad-responders had significantly higher SCr at baseline compared with the good-responders (3.8 +/- 1.8 vs. 2.7 +/- 0.6 mg/dl, P less than 0.01). Amelioration of chronic graft dysfunction can be achieved by delayed addition of Aza to CsA-Pred in patients with chronic rejection or CsA toxicity. This is accompanied by low rate of acute rejection, good patient and graft survival, and low rate of infections. A worse outcome can be seen in patients with high-baseline SCr levels, suggesting the need for addition of Aza in the initial chronic graft dysfunction.     

The incidence and impact of early rejection episodes on graft outcome in recipients of first cadaver kidney transplants.

The objective of this study was to define the incidence and significance of acute rejection occurring in the first year following transplantation. The influence of contemporary induction immunosuppression on rejection, as well as the effect of rejection on graft and patient loss, renal function, and maintenance immunosuppression during the first year in 110 recipients of first cadaver renal transplants were analyzed. All patients received CsA, Aza, and prednisone for 30 days with withdrawal of Aza at 30 days and then prednisone at 105 days; 57 patients were prospectively randomized to receive ALG (Merieux) until serum creatinine was less than 300 mumol/L. Short-term ALG administration did not influence the incidence, severity, nature, or outcome of rejection episodes. Fifty-five (50%) patients had at least 1 rejection in the first 90 days. All patients with delayed graft function and 7/8 (88%) sensitized patients (current PRA greater than 50%) had at least 1 rejection episode; 71% (n = 35) of all rejection episodes occurred in the first 30 days posttransplant. Patients rejection free at 90 days remained rejection free the entire first year. Graft loss was 18% for rejections in the first month, 13% for rejections occurring later (P = NS); 20% (n = 11) of patients had a second rejection and 1% (n = 2) had a third rejection. The risk of graft loss was 9% with a first rejection, 38% with a second rejection, and 50% with a third rejection. Of 12 (22%) rejections that were steroid resistant, 10 (83%) were reversed with OKT3. One-year graft survival for patients without rejection, with steroid-sensitive rejection, and with steroid-resistant rejection was 96%, 88% (P = ns), and 58% (P less than 0.001), respectively; 1 year SCr was 168 +/- 93, 196 +/- 77 (P = ns), and 268 +/- 96 microMol/L (P less than 0.05), respectively. Patients free of rejection and with stable renal function continued to do well on maintenance CsA monotherapy, and they were more likely to be on CsA monotherapy than those with rejection episodes (P less than 0.01).     

Primary immunosuppression with mycophenolate mofetil and antithymocyte globulin for kidney transplant recipients of a suboptimal graft

Background. In renal transplantation the beneficial immunosuppressive effects of cyclosporin (CsA) may be curtailed by its nephrotoxicity, specially in patients receiving a cadaveric allograft from suboptimal donors or at risk of delayed graft function. Mycophenolate mofetil (MMF) and antithymocyte globulin (ATG) have each demonstrated to be potent immunosuppressants in renal transplantation. In a prospective analysis we have studied the results at 6 months of the combination of MMF, ATG and low-dose steroids in patients with low immunological risk receiving a first cadaveric renal allograft from a suboptimal donor or at risk of delayed graft function. Methods. Patients with preformed reactive antibodies <50% receiving a first graft from a suboptimal donor (age ⩾40years, non-heart-beating, acute renal failure, arterial hypertension) or at risk of delayed graft function (cold ischaemia time ⩾24 h) were eligible for this open single-arm pilot trial. From September 1996 to March 1997 we recruited 17 patients. They were treated with MMF 2 g p.o. preoperatively, and after transplantation at 3 g/day; rabbit ATG i.v. at 2 mg/kg preoperatively, and 1.5 mg/kg/day the first day after transplantation, followed by four doses of 1 mg/kg on alternate days; prednisone was given at 0.25 mg/kg/day and reduced progressively to 0.1 mg/kg/day at 3 months. Primary outcomes were incidence of biopsy-proven acute rejection, delayed graft function, opportunistic infections, graft and patient survival, and the need for introduction of CsA treatment. Results. Delayed graft function occurred in two cases (12%). Four of 17 patients (27%) had a biopsy-proven acute rejection (2 grade I and 2 grade II) within the first 3 months after transplantation. CsA was added in two cases with grade II biopsy-proven acute rejection, and in one with grade I biopsy-proven acute rejection. In one patient MMF was replaced by CsA because of gastrointestinal intolerance. Mean serum creatinine 6 months after transplantation was 159±59 &mgr;mol/l. Cytomegalovirus tissue invasive disease occurred in one patient (6%). At 6 months follow-up all patients are alive with functioning allografts. Conclusions. These preliminary results suggest that in low-immunological-risk patients who receive a suboptimal renal allograft or at risk of delayed graft function, the combination of MMF, ATG, and steroids is an efficient immunosuppressive regime that may avoid the use of CsA in 70% of the recipients.     

How common is delayed cyclosporine absorption following liver transplantation?

The mean time to peak absorption of cyclosporine (CsA) in liver transplant patients is approximately 2 hours, but in some patients the peak occurs later. The goal of this study was, therefore, to investigate the incidence of delayed absorption in 27 de novo liver transplant recipients receiving CsA > or =10 mg/kg/day (C(2) monitoring) and in 15 maintenance patients. Patients were categorized as 'normal' absorbers (C(2) exceeding C(4) and C(6)) or 'delayed' absorbers (C(4) or C(6) exceeding C(2)), and as 'good' (>800 ng/mL at C(0), C(2), C(4), or C(6)) or 'poor' absorbers (C(0), C(2), C(4) and C(6) <800 ng/mL) on the day of study. Among de novo patients, 15 (56%) had 'normal' CsA absorption and 12 (44%) 'delayed' absorption. Good CsA absorption occurred in 16 patients (59%) and poor absorption in 11 (41%). The proportion of poor absorbers was similar in patients with normal (6/15, 40%) or delayed (5/12, 42%) absorption. Among the 12 delayed absorbers, 11 had peak CsA concentration at C(4). Mean C(0) level was significantly higher in delayed absorbers (282 +/- 96 ng/mL) than in normal absorbers (185 +/- 88 ng/mL; P = .01). Delayed absorbers reverted to normal absorption (C(2) > C(4)) after a median of 6 days from the day of study, and no cases of delayed absorption were found among maintenance patients. In conclusion, almost 50% of the patients had delayed CsA absorption early posttransplant; around half of these exhibited normal CsA exposure. Measurement of C(4) in addition to C(2) differentiates effectively between delayed and poor absorbers of CsA such that over- or underimmunosuppression can be avoided.     

Improved results using OKT3 as induction immunosuppression in renal allograft recipients with delayed graft function

Delayed graft function remains a major problem in cadaveric renal allograft transplantation. We have used 2 different immunosuppressive induction regimens in patients with delayed graft function. The first regimen, used in 40 patients from January 1985 to December 1986, consisted of CsA (8 mg/kg/day, orally within 48 hr of cadaveric renal transplantation regardless of graft function), azathioprine (1.5-2.5 mg/kg/day), and steroids (methylprednisolone 375 mg on day 0, then prednisone tapered to 30 mg/day by day 10 with slow tapering to 7.5-10 mg/day over the first 6 months after transplantation). A second regimen, used from January 1987 to March 1989, employed the same doses of azathioprine and steroids; however, OKT3 (5 mg i.v./day for 7-21 days) was administered in the 34 patients who had delayed graft function. CsA was withheld until ATN resolved. The use of OKT3 as induction immunosuppression in patients with ATN led to a significant increase in 1-year graft survival (80% vs. 55%) while markedly decreasing the incidence of rejection episodes (44% vs. 82%) and the duration of nonfunction (9.4 vs. 14.9 days). There were 5 CMV infections in patients treated with OKT3. Antibodies to OKT3 developed in only 1 of 34 patients treated with OKT3. Five of 7 patients who received a second course of OKT3 successfully reversed the rejection episode. Patient survival (89%) was the same in the 2 groups. The benefit of OKT3 on long-term graft survival appears to stem from elimination of early rejection episodes that may be difficult to diagnose in a poorly functioning allograft. We conclude that OKT3 induction provides superior results over CsA induction at doses given in renal allograft recipients with delayed graft function without a significant increase in morbidity or mortality and permits the reuse of OKT3 for treatment of rejection in most cases.     

Use of Anti-Thymocyte Globulin for Induction Therapy in Cardiac Transplantation: A Review

The most common causes of death after heart transplantation (HTx) include acute rejection and multi-organ failure in the early period and malignancy and cardiac allograft vasculopathy (CAV) in the late period. Polyclonal antibody preparations such as rabbit anti-thymocyte globulin (ATG) may reduce early acute rejection and the later occurrence of CAV after HTx. ATG therapy depletes T cells, modulates adhesion and cell-signaling molecules, interferes with dendritic cell function, and induces B-cell apoptosis and regulatory and natural killer T-cell expansion. Evidence from animal studies and from retrospective clinical studies in humans indicates that ATG can be used to delay calcineurin inhibitor (CNI) exposure after HTx, thus benefiting renal function, and to reduce the incidence of CAV and ischemia-reperfusion injury in the transplanted heart. ATG may reduce de novo antibody production after HTx. ATG does not appear to increase cytomegalovirus infection rates with longer prophylaxis (6–12 months). In addition, ATG may reduce the risk of lymphoproliferative disease and does not appear to confer an additive effect on acquiring lymphoma after HTx. Randomized, controlled trials may provide stronger evidence of ATG association with patient survival, graft rejection, renal protection through delayed CNI initiation, as well as other benefits. It can also help establish optimal dosing and patient criteria to maximize treatment benefits.     

FTY720, an immunosuppressant that alters lymphocyte trafficking,abrogates chronic rejection in combination with cyclosporine A

BACKGROUND: Chronic rejection remains the leading cause of failure after transplantation (Tx). FTY720, a new immunosuppressant altering lymphocyte trafficking, is effective against acute rejection, but its activity against chronic rejection is not known. METHODS: A valid model of chronic rejection was produced. Heart transplantation (HTx) was performed using fully mismatched RA (RT1p) and PVG (RT1c) rats. Administration of donor-specific blood transfusion 12 days before HTx prolongs graft survival, but features of chronic rejection including intimal hyperplasia and vascular obliteration (VO) develop with time only in allogeneic Tx. This is therefore a valid model of chronic rejection. VO was assessed on post-Tx day 90 in six groups differing according to the maintenance immunosuppressive regimen administered. group 1, donor-specific blood transfusion only and no other treatment; group 2, FTY720 (0.3 mg/kg/day orally) for 90 days; group 3, cyclosporine A (CsA) (1 mg/kg/day orally) for 90 days; group 4, combined administration of FTY720 and CsA for 90 days; group 5, transient administration of combined FTY720 and CsA for 7 days; and group 6, syngeneic HTx (RA to RA). Graft infiltrate, endothelial immunoglobulin (Ig) G deposition, and complement binding were also examined on post-Tx day 90. RESULTS: In control group 1, severe VO was observed, compared with syngeneic HTx (group 6). Monotherapy with FTY720 (group 2) or with CsA (group 3) significantly but partially reduced VO. On the contrary, combined administration of FTY720 and CsA (group 4) abrogated VO. A 1-week treatment with combined FTY720 and CsA (group 5) reduced VO but only partially. In group 1, arteriosclerosis was accompanied by graft infiltrate, endothelial IgG deposition, and complement binding. In groups 2, 3, and 5, graft infiltrating scores were partially decreased compared with group 1 but remained higher than in syngeneic controls; endothelial IgG deposition and complement binding were still present. In group 4, continuous administration of combined FTY720 and CsA reduced graft infiltrate to the level of syngeneic control and abrogated both endothelial IgG deposition and complement binding. CONCLUSIONS: Maintenance treatment with either FTY720 or CsA monotherapy partially prevents chronic rejection; short-term treatment with combined FTY720 and CsA reduces chronic rejection only partially; and continuous treatment with combined FTY720 and CsA abrogates chronic rejection, and this is accompanied by dramatic reduction of graft infiltrating cells, endothelial IgG deposition, and complement binding. Prevention of chronic rejection by maintenance treatment with FTY720 and CsA represents indirect evidence that normal lymphocyte trafficking and function are mandatory for development of chronic rejection.     

Prevention of acute cyclosporine-induced renal blood flow inhibition and improved immunosuppression with verapamil

Pretreatment with calcium antagonists such as verapamil (VP) and isradipine prevents CsA-induced decrease in renal microcirculation in mice. Recently, in posttransplant cadaver renal transplant (CRT) recipients, we demonstrated a CsA-induced 70% reduction in renal parenchymal diastolic blood flow velocity (PDBFV). Using duplex Doppler scanning, this randomized study of forty CRT patients examines the effect of pretreatment with VP on renal blood flow velocity and posttransplant function. Patients with initially low PDBFV (less than 8.0 cm/sec) who received VP therapy prior to administration of CsA experienced prompt restoration of flow, and continued to improve during CsA administration. With CsA alone, PDBFV diminished from 8.9 +/- 2.4 (SD) to 5.3 +/- 2.7 cm/sec (P less than 0.002). Although blood CsA levels were significantly higher at 1, 4, and 7 days (68, 184, and 235 ng/ml, respectively), after CsA induction, during VP treatment than in control patients (39, 105, and 156 ng/ml, respectively) (P less than 0.001), with the same daily doses of CsA, serum creatinines at day 7 were lower during VP treatment (1.28 +/- 0.44 vs. 1.66 +/- 0.44 mg%) than in controls (P less than 0.01). When the glomerular filtration rate was less than 45 ml/min on day 1. VP-treated patients showed greater improvement in GFR at day 7 by 34.1 +/- 10.9 ml/min compared with the 18 +/- 13 ml/min in controls (P less than 0.02). Only 3 of the 22 VP patients had rejection episodes within 4 weeks, versus 10 of the 18 recipients randomized to no drug (P less than 0.005). We conclude that VP is beneficial in CRT because it improves renal blood flow characteristics and prevents CsA-induced inhibition of blood flow. VP also ameliorates CsA-induced acute nephrotoxicity, and is associated with improved immunosuppression and fewer early rejections.     

Long-term prolongation of cardiac allografts by subtherapeutic levels of cyclosporine in rats conditioned with pretransplant blood transfusions and cyclosporine

This study was aimed at ascertaining whether long-term graft survival was achievable with short term cyclosporine (CsA) therapy or with subtherapeutic doses of CsA in rats conditioned with blood transfusions (BT) combined with CsA. Previous studies had shown that donor-specific transfusions combined with a short course of CsA interacted synergistically, resulting in considerable prolongations of ACI and BUF grafts in LEW hosts receiving no postoperative treatment. The donor-specific depression of alloreactivity was confirmed in the present study by showing a depression of mixed-lymphocyte reaction (MLR) reactivity as well as of humoral antidonor responses in BT-CsA conditioned rats. The effects of postoperative CsA were then studied in recipients conditioned with BT-CsA or BT alone. ACI and BUF cardiac graft survival in LEW hosts conditioned with BT and treated with a five-day postoperative course of CsA (20 mg/kg/day) were indistinguishable from graft survival in untransfused hosts (ACI: 35.6 +/- 15.5 vs. 38.8 +/- 7.4; BUF: 58.4 +/- 39.8 vs. 48.0 +/- 21.7) indicating no interaction between BT and CsA under these conditions. In contrast, the effect of a post-operative five-day course of CsA (10 mg/kg/day) was extended by conditioning the recipients with donor-specific BT and CsA (ACI:41.7 +/- 7.0 vs. 27.4 +/- 11.6; P less than 0.05). More remarkably, a thirty-day course of subtherapeutic doses of CsA (2.5 mg/kg/day) resulted in long-term prolongation (greater than 100 days) of ACI grafts in a large proportion of hosts conditioned with donor-specific BT and CsA, while the majority of controls conditioned with nonspecific BT and CsA or CsA alone rejected their grafts within three weeks (P less than 0.01). The possible mechanisms of this phenomenon are discussed.     

Analysis of renal function in the immediate postoperative period after partial liver transplantation.

Although renal dysfunction is common after liver transplantation, postoperative renal function after split liver transplantation (SLT) has not been well studied. Renal function immediately after surgery was analyzed retrospectively in 16 patients that received a SLT (SLT group). The results were compared with corresponding data from 31 matched patients that received a full-size liver transplant (FSLT group) during the same period. Serum creatinine (SCr) was measured before surgery, and, after transplantation, daily during the first week and at days 14, 21, and 28. Renal dysfunction (RD) was defined as the requirement for renal replacement therapy (RRT) or a 100% increase in SCr if the basal value had been <1.0 mg/dL or a 50% increase in SCr if the basal value had been >1.0 mg/dL. SCr had to be at least 1.5 mg/dL for a diagnosis of RD to be considered. The classification of RD was: mild, SCr 1.5-2.4 mg/dL; moderate, SCr 2.5-4.0 mg/dL; or severe, SCr >4.0 mg/dL (the requirement for RRT). Both donor and recipient age and cold ischemia time were lower in the SLT group than in the FSLT group (P < 0.05). Length of surgery was longer in the SLT group (P < 0.05). There were no significant differences between groups with respect to Model for End-Stage Liver Disease scores, the need for transfusions, the length of admission to the intensive care unit (ICU), survival rate, individual severity index, or sepsis-related organ failure assessment scores at the time of diagnosing RD. Immunosuppression regimens were similar in both groups. RD developed in 82% of SLT patients, but in only 58% of FSLT patients (P = not significant [NS]). Among SLT patients, RD (23.0% mild, 15.5% moderate, and 61.5% severe) was more severe (P = 0.007) than in FSLT patients (63.1% mild, 15.8% moderate, and 24.1% severe). The requirement for RRT in the SLT group (43.7%) was significantly greater (P < 0.05) than that in the FSLT group (12.9%). This finding may be due to the different incidence of sepsis in the 2 groups (SLT 37.5% vs. FSLT 9.7%; P < 0.05). In conclusion, although the number of patients studied was small, our data suggest a higher incidence of RD and a greater requirement for RRT in patients that receive a split liver graft than in those that receive a full size liver graft.     

Significant prolongation of animal survival by combined therapy of FR167653 and cyclosporine A in rat renal allografts

BACKGROUND: Cyclosporine A (CsA) has improved short-term results in renal transplantation. However, its toxicities have been serious problems in clinical patients undergoing long-term administration. It is necessary to develop a nonnephrotoxic immunosuppressant that allows reducing doses of CsA. The authors tested the effect of a new pyrazolotriazin compound, FR167653 (FR), that inhibits the production of proinflammatory cytokines, using a rat renal acute-rejection model (Wistar-Lewis). METHODS: The authors first examined the adverse reactions of FR in naive rats. The effect of FR monotherapy was evaluated by treating allograft recipients at a dosage of 32 or 64 mg/kg/day intraperitoneally. The synergistic effect of FR and CsA at a minimum dose was examined by treating the recipients daily with 64 mg/kg of FR and 0.1, 0.5, or 1.0 mg/kg of CsA. RESULTS: Long-term administration of FR caused no severe adverse reactions in naive rats at less than 96 mg/kg/day, and FR is a nonnephrotoxic but liver-toxic agent at higher doses. Monotherapy of FR (8.7+/-1.3 days) or CsA (8.7+/-1.7 days) did not influence graft survival (vs. 8.2+/-0.8 in controls, n=10). However, the combined treatment of FR and CsA significantly prolonged animal survival (>50% of animals survived a 42-day follow-up period; P<0.01 vs. all other groups, n=15/group). Immunologic analysis demonstrated the significantly decreased production of major inflammatory mediators and adhesion molecules in the allografts as compared with those of all other groups. CONCLUSIONS: A nonnephrotoxic agent, FR may be a promising candidate for a new combined immunosuppressive regimen that potentially reduces the amount of CsA.     

Pharmacodynamic monitoring of the conversion of cyclosporine to tacrolimus in heart and lung transplant recipients

OBJECTIVE: Conversion from cyclosporine (CsA) to tacrolimus (TRL) remains challenging in the daily routine due to individual variations in blood concentrations (pharmacokinetics, PK), pharmacodynamics (PD) and in interactions on plasma mycophenolic acid (MPA) concentrations. Therefore, we used our PD assays of lymphocyte function to monitor the conversion of CsA to TRL in heart (HTx) and lung (LTx) transplant recipients. METHODS: Patients (six HTx, two LTx) were converted from CsA to TRL because of gingival hyperplasia. All patients were treated with 6 mg BID TRL 24 hours after the last CsA dose and received mycophenolate mofetil BID cotherapy. PK measurements of CsA, TRL, and MPA were done by EMIT. Expression of cytokine production (IL-2, TNF-alpha), lymphocyte proliferation (PCNA), and activation (CD25) was assessed by FACS. RESULTS: TRL concentrations increased from day 1 to 3, but did not alter MPA concentrations, which were comparably high to MPA concentrations in combination with CsA (day 0). Compared to CsA therapy, increased TRL concentrations did not further inhibit PCNA expression, inhibited CD25 expression less on days 1 and 2 and equally high on day 3, but inhibited expression of IL-2 and TNF-alpha significantly higher on days 2 and 3 (P < .05). CONCLUSION: This study shows that monitoring PD of lymphocyte functions after conversion from CsA to TRL in HTx and LTx recipients revealed differences of inhibition of lymphocyte functions. Monitoring PD of lymphocyte function may provide insights in drug interactions of immunosuppressive combination therapy and may help to tailor immunosuppression to avoid toxicity and to enhance efficacy.     

Diminished acetylcholine-induced vasodilation in renal microvessels of cyclosporine-treated rats.

The mechanisms mediating cyclosporin A (CsA)-induced nephrotoxicity have not been established, but damage to endothelial cells by CsA has been proposed as an important factor. In the study presented here, whether endothelial cell function is impaired in the renal vasculature of CsA-treated rats is investigated. The vasodilatory effects of acetylcholine (ACH) on norepinephrine (NE)-induced microvascular constriction in isolated perfused hydronephrotic rat kidneys pretreated with CsA were therefore examined. Hydronephrosis was established to permit direct visualization of renal microvessels. Nephrotoxicity was induced by s.c. injection of CsA (60 mg/kg/day for 5 days). NE (0.3 microM)-induced afferent arteriolar (AA) constriction was exaggerated in CsA rats as compared with that in vehicle (olive oil)-treated control rats. (reduction in diameter of -34 +/- 3 (SE) versus -26 +/- 2%; P less than 0.05). Similarly, efferent arteriolar (EA) constriction by NE in CsA rats exceeded that of controls (-34 +/- 2 versus -22 +/- 3%; P less than 0.01). The vasodilatory responses evoked by ACH were blunted in CsA rats. The AA response to ACH in CsA rats was significantly decreased (P less than 0.005) at ACH concentrations from 1 nM to 1 microM. Similarly, ACH (1 nM to 100 nM) induced less EA vasodilation in CsA rats (P less than 0.025). In control and CsA rats, the addition of nitro-L-arginine abolished AA and EA vasodilation induced by ACH, suggesting that the sustained vasodilatory responses of AA and EA to ACH are mainly dependent on nitric oxide synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Single bolus antithymocyte globulin versus basiliximab induction in kidney transplantation with cyclosporine triple immunosuppression: efficacy and safety

BACKGROUND: The aim of this prospective randomized study was to examine the effect of induction immunosuppression and low initial cyclosporine (CsA) on the onset of graft function and its long-term consequences. METHODS: During 1999-2001, 155 patients were randomized to single 9 mg/kg dose antithymocyte globulin (ATG)-Fresenius (group A) or two 20-mg doses of basiliximab (group B) with reduced dose CsA or conventional CsA triple therapy without induction (group C). RESULTS: Delayed function (DGF) was lower in group A than in groups B or C (5.7% vs. 24.1% and 15.9%, P<0.025) and need of dialysis was less in groups A and B compared to C (10.3 and 10.4 vs. 20.0 days, P<0.05). Acute rejections occurred in 11.3%, 12.1% and 20.5%, and the mean (median) time to rejection was 16 (13), 97 (46) and 101 (35) days in groups A, B, and C, respectively (P<0.005). One-and 5-year graft survivals (GS) were 98.1% and 90.6% (group A), 96.6% and 96.6% (group B), and 93.2% and 84.1% (group C). Five-year GS was significantly better in group B than in group C (P<0.05). The death censored 5-year GS in groups A, B, and C were 94.3%, 96.6%, and 90.0% (P=NS). Single high-dose ATG induction was associated with hemodynamic and pulmonary disturbances without, however, serious or long-term consequences. CONCLUSIONS: ATG induction significantly reduced DGF. Both induction regimens together with low initial CsA led to significantly less posttransplant dialysis and excellent survival. The high dose ATG was associated with significant hemodynamic and pulmonary side effects during drug infusion.     

Effectivity of a T-cell-adapted induction therapy with anti-thymocyte globulin (Sangstat).

BACKGROUND: Cytolytic induction therapy with anti-thymocyte globulin (ATG) should induce effective immunosuppression, with a low rate of rejection in the initial phase after heart transplantation. Induction therapy with ATG allows post-operative renal recovery without the negative effects of highly nephrotoxic cyclosporine levels. An increased rate of infection is a common problem, however, and has been associated with "over-immunosuppression" early after transplantation. Therefore, we investigated whether reduced T-cell-adapted ATG induction therapy could be performed without increasing the risk of graft loss by rejection and whether reductions in infection rates and costs are possible. METHODS: Between March 1999 and December 2002, T-cell-adapted ATG induction therapy with ATG (Sangstat) (1.5 mg/kg) was given to 62 heart transplant recipients (study group) starting on post-operative Days 1 to 6. T-lymphocyte sub-populations were screened daily using flow cytometry. If total lymphocytes were <100/microl (reference 1,300 to 2,300/microl), T-helper lymphocytes (CD4+) <50/microl (reference >500/microl) and T-suppressor cells (CD8+) <50/microl (reference >300/microl), then no ATG was given. Further immunosuppression was continued with triple therapy consisting of methylprednisolone, azathioprine and cyclosporine. An historic group of heart transplant recipients given a full-dose ATG regimen for 8 days served as controls. These recipients were treated with ATG (Merieux 1.5 mg/kg) until reaching monoclonal cyclosporine levels of >300 mg/dl. Additional immunosuppressive treatment did not differ. Patients in both groups received systemic antibiotics (Imipenem) peri-operatively. Results of routine endomyocardial biopsies and rates of infections were examined. RESULTS: Study group patients were older (52 +/- 10 vs 49 +/- 14 years). In the study group, mean cumulative ATG dose was reduced significantly to 596 +/- 220 mg (p < 0.05) for 3.9 +/- 1.6 days compared with 1,159 +/- 376 mg for 6.9 +/- 1.1 days in the control group. The rate of cytomegalovirus (CMV) seroconversion was 23% in the study group compared with 13% in the control group. Rate of deep sternal infections was lower in the study group (1.6% vs 3.2%). The mean rejection rate in the first 3 months was 0.4 +/- 0.7 for the study patients (185 biopsies) vs 1.1 +/- 1.7 for controls (237 biopsies). All biopsies with ISHLT Grade >2 were treated successfully with 1,000 mg of methylprednisolone intravenously for 3 days. Both groups showed a similar 1-year survival rate (study 88%, control 89%). CONCLUSIONS: T-cell-adapted ATG induction therapy can be a helpful tool for individualized immunosuppression. It is not associated with an increased rate of rejection. Lower doses of immunosuppression help to minimize the rates of infection. In addition, cytolytic induction therapy combined with reduced ATG results in significant cost reduction.     

Low dose antithymocyte globulins in renal transplantation: daily versus intermittent administration based on T-cell monitoring

BACKGROUND: Despite the long history of use of antithymocyte globulins (ATG) in renal transplantation, ideal doses and duration of ATG administration based on the monitoring of T lymphocytes have yet to be defined. METHODS: Two immunosuppressive regimens based on low-dose rabbit ATG (Thymoglobuline; Imtix-Sang-stat, Lyon, France) were assessed during the first year after transplantation: daily ATG (DATG; n=23) where 50 mg of ATG was given every day and intermittent ATG (IATG; n=16) where similar doses of ATG were given for the first 3 days and then intermittently only if CD3+ T lymphocytes (measured by flow cytometry) were > 10/mm3. Both groups received steroids, azathioprine, and cyclosporine. RESULTS: ATG-induced depletion was similar for peripheral blood lymphocytes and T cells in both groups: it began at day 1 after transplantation, was submaximal at day 3, and reached maximum intensity between days 6 and 8, from which time cell counts progressively increased. However, T-cell depletion was still present at day 20. The total ATG dose per patient (381.5+/-121 vs. 564+/-135 mg/patient) and the mean cumulative daily dose of ATG (0.60+/-0.17 vs. 0.80+/-0.14 mg/kg/day) were significantly lower in the IATG group (P=0.0001 and 0.0006, respectively). The overlap of ATG and cyclosporine treatment was 6.7+/-3 vs. 7.4+/-4.3 days (P=NS), and the mean duration of ATG therapy was 11.3+/-3.2 vs. 11.6+/-2.7 days in the IATG and DATG groups, respectively (P=NS). ATG was given in an average of one dose every 1.6 days in the IATG group compared with one dose daily in the DATG group (P=7 x 10(-7)). There was no significant difference in renal graft function, the number of acute graft rejections, or ATG-related side effects and complications. Despite the daily immunological follow-up, there was a net saving of $760/patient in the cost of treatment in the IATG group. CONCLUSION: IATG had the advantage of a reduction in the dose of ATG and in the cost of treatment, while offering similar T-cell depletion and effective immunosuppression. This approach could be proposed as an induction protocol, particularly for patients with poor graft function in whom cyclosporine introduction has to be delayed or those with increased risk of cytomegalovirus infections or secondary malignancies.