Roberto Maffeis

A prospective randomized trial on azathioprine addition to cyclosporine versus cyclosporine monotherapy at steroid withdrawal, 6 months after renal transplantation

BACKGROUND Many attempts have been made to withdraw steroid therapy in renal transplant patients in order to avoid its many side effects. Results have been, so far, controversial. In this randomized prospective study, we compare the efficacy of azathioprine adjuncts to cyclosporine at the time of steroid withdrawal, 6 months after transplantation, versus Cyclosporine monotherapy, in preventing acute rejection. METHODS One hundred and sixteen kidney transplant patients with good and stable renal function (creatininemia <2 mg/dl) received, in the first 6 months, cyclosporine + steroid. They were then randomized into two groups (A and B), and steroid therapy was withdrawn over 2 months. Group A (58 patients) continued on cyclosporine monotherapy, whereas group B (58 patients) added azathioprine (1 mg/kg/day) at the beginning of randomization and continued on cyclosporine + azathioprine. In both groups, patients resumed steroid therapy at the first episode of acute rejection. Follow-up after randomization was 5.3+/-1.6 years. RESULTS After 5 years, the incidence of steroid resumption was 57% in group A and 29% in group B (P<0.02); of those, 68% and 88% of them were within 6 months from randomization. Anti-rejection therapy was always successful. Five-year patient and graft survival rates were 90% and 88% in group A and 100% and 91% in group B. Creatininemia did not differ, at follow-up. Side effects differed only for mild and reversible leukopenia caused by azathioprine in group B. CONCLUSION Cyclosporine plus azathioprine is more effective than cyclosporine monotherapy in reducing the incidence of acute rejection after steroid withdrawal. Graft loss as a result of chronic rejection, mild in both groups, did not differ. Steroid withdrawal is feasible and advantageous, and the addition of azathioprine allowed 71% of our selected patients to remain steroid-free.

Steroid withdrawal five days after renal transplantation allows for the prevention of wound-healing complications associated with sirolimus therapy

Abstract:  Background:  Sirolimus (SRL) can increase the risk of wound complications. In this study, we investigated the impact of steroids when added to SRL, in this side effect.

Tacrolimus versus cyclosporine for early steroid withdrawal after renal transplantation.

INTRODUCTION This study compares cyclosporine (CsA) with tacrolimus (Tac) in preventing acute rejection (AR) after steroid withdrawal (SW) 5 days after renal transplantation (Tx). METHODS The data were collected from 2 prospective sequential studies carried out from February 2002 to May 2006. Forty-nine patients received CsA, 56 patients Tac. Rapamycin (Rapa) was added to both calcineurin inhibitors (CNIs). The studies were homogeneous regarding both clinical procedures and patient demographics. RESULTS Three years after SW, Tac was more effective than CsA in reducing the risk both of AR (35% vs. 53%; p<0.06) and mainly of relapses (9% vs. 33%; p<0.007). In addition, Tac enabled more patients to go onto a steroid-free regime (88% vs. 65%; p<0.01). No difference arose concerning the timing of AR, graft function, CNI withdrawal, incidence of side effects or patient and graft survival rates. In both groups, rejection after SW was associated with a worse graft function. CONCLUSIONS Tac was more effective than CsA in preventing AR after early SW, and increased significantly patient probability of maintaining a steroid-free regime. In this setting, Tac and CsA had the same safety profile. However, a follow-up longer than 3 years might be needed to estimate the consequences of the higher rate of AR encountered under CsA therapy.

Steroid-free immunosuppression regime reduces both long-term cardiovascular morbidity and patient mortality in renal transplant recipients.

Abstract:  The aim of this retrospective study was to assess the impact of steroid therapy on cardiovascular disease (CVD) and patient mortality, in 486 on‐CsA renal transplant recipients, with a follow‐up of 9.5 ± 4.3 yr. Two hundred and one patients had their steroids permanently withdrawn at sixth month after transplantation (G1); 285 patients did not (G2) as they were unable (acute rejection after suspension) or unsuitable (because of clinical criteria or immunosuppressive protocols). The CVD considered were coronary artery disease diagnosed by angiography and myocardial infarction. G1 and G2 patients were well‐matched regarding CVD risk factors, except for age (G1: 44 ± 14 yr; G2: 40 ± 12 yr; p < 0.003), incidence of male (G1: 62%; G2: 72%, p < 0.02) incidence of acute rejection (G1: 39%; G2: 83%, p < 0.0001). Both CVD and deaths occurring during the first year of transplantation were excluded from the analysis. At 20 yr, the cumulative probability of developing a CVD, was 3.8% in G1; 23.8% in G2 (p < 0.0005). Patient survival rate was 95% in G1; 62% in G2 (p < 0.003). Mortality caused by CVD was higher in G2 (4.2% vs. 0.5%; p < 0.03). The Cox analysis identified in steroid therapy the main independent risk factors for both CVD (hazard ratio 9.56 p < 0.0001) and patient mortality (hazard ratio 5.99, p < 0.0001). At 10th and 15th year after transplantation, the mean‐daily dose of steroids was 4.2 mg.

Early (fifth day) vs. late (sixth month) steroid withdrawal in renal transplant recipients treated with Neoral® plus Rapamune®: four-yr results of a randomized monocenter study

Sandrini S, Setti G, Bossini N, Chiappini R, Valerio F, Mazzola G, Maffeis R, Nodari F, Cancarini G. Early (fifth day) vs. late (sixth month) steroid withdrawal in renal transplant recipients treated with Neoral® plus Rapamune®: four‐yr results of a randomized monocenter study. 
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01171.x.
© 2009 John Wiley & Sons A/S.

Study of Peripheral Flow During Successful Aortoiliac and Aortofemoral Prosthetic Reconstructions by Intraoperative Above-Ankle Pressure Index Monitoring

Doppler above-ankle pressure index (API) was monitored during 368 consec utive bilateral aortoiliac or aortofemoral graft reconstructions performed for aneurysmal or occlusive disease. The aim of this study was to investigate the variations of peripheral pressure, during and just after completion of the proce dure, either when followed by immediate and definitive success or when an intraoperative correction or an early postoperative reoperation was necessary owing to postreconstructive ischemia. For this purpose the API courses were subdivided into three groups: A (705 limbs), which underwent immediately suc cessful reconstructions; B (22 limbs), which needed intraoperative correction; C (9 limbs), which required early reoperation. All 736 limbs were studied individ ually as monolateral reconstructions and classified into six subgroups: 1, pervi ous iliac, pervious femoral artery; 2, occluded iliac, pervious femoral; 3, pervi ous iliac, stenotic femoral (i.e, stenosis > 75% of the superficial femoral artery); 4, occluded iliac, stenotic femoral; 5, pervious iliac, occluded femoral; 6, oc cluded iliac, occluded femoral. APIs were monitored before the operation (PRE), at the completion of the distal anastomosis (DEC), and five, fifteen, thirty, and forty-five minutes after. Data were statistically analyzed by multivariate analysis in regards to 705 immediately successful limbs (group A) and by comparison of all corrected or reoperated cases (groups B and C) with the lower bound of the fifth centiles of group A. The results in group A show that: API-PRE is different in the six subgroups (p < 0.001); API-DEC is lower than API-PRE in the patent iliac artery sub groups (1,3, and 5) and higher than API-PRE in the occluded iliac artery sub groups (2,4, and 6) (p always < 0.001). From declamping time to the forty-five- minutes observation, the mean courses turn out parallel and rising but on dif ferent levels (p < 0.001): pervious femoral, stenotic femoral, occluded femoral. API-forty-five minutes is higher than API-PRE in occluded iliac artery subgroups (2, 4, and 6) (p < 0.001), whereas in the patent iliac artery subgroups only the fifth subgroups reveals a slight but significant rise (p < 0.01), probably owing to the high rate of profunda femoral endarterectomy or angioplasty asso ciated with aortofemoral reconstructions. APIs values of 31 cases in groups B and C, compared with the lower bound of the fifth centile of group A, show that 8/31 cases (26%) remain above that bound, while 23/31 cases (74%) fall below it.

Immediate detection of postreconstructive ischaemia by intra-operative Doppler ankle pressure index monitoring during aortic reconstructions

From March 1980 to February 1988, 368 aorto-iliac or aorto-femoral bilateral reconstructions were performed for aneurysmal or occlusive disease. In order to demonstrate early postreconstructive ischaemic complications, the intra-operative Doppler Ankle Pressure Index (API) was measured immediately before reconstruction (PRE), just after declamping (DEC) and 5, 15, 30 and 45 min thereafter. Each limb of the reconstruction (736) was considered individually and subdivided as follows: Group (A) 705 immediately successful (96% of limbs and 92% of patients); Group (B) 22 (3% of limbs and 5% of patients) in which, on the grounds of API data, an ischaemic complication was regarded as imminent and treated by graft revision or a peripheral thromboembolectomy (intra-operative corrections); Group (C) 9 (1% of limbs and 2% of patients) in which the diagnosis of ischaemic complications was made postoperatively when the patients underwent successful reoperation. All 736 reconstructions were patent and functional at discharge of the patient. By a retrospective analysis the intra-operative APIs were studied and the features (single or associated) suggesting an ischaemic complication examined. These were: (1) no flow at the time of declamping or its disappearance during the operation (10 cases, 1.25% of limbs) all detected and successfully corrected intra-operatively.(ABSTRACT TRUNCATED AT 250 WORDS)

Kidney transplantation in HIV‐positive patients treated with a steroid‐free immunosuppressive regimen

One of the main concerns associated with renal transplantation in HIV‐infected patients is the high risk of acute rejection, which makes physicians reluctant to use steroid‐free immunosuppressive therapy in this subset of patients. However, steroid therapy increases cardiovascular morbidity and mortality. The aim of this study was to define the efficacy of a steroid‐sparing regimen in HIV‐infected renal transplant recipients. Thirteen HIV‐infected patients were consecutively transplanted. The induction therapy consisted of basiliximab and methylprednisolone for 5 days followed by a calcineurin inhibitor plus mycophenolate acid. The mean follow‐up was 50 ± 22 months. Eight patients (61.5%) experienced acute rejection, and 75% of the first episodes occurred within 2 months after transplantation. The probability of first acute rejection was 58% after 1 year and 69% after 4 years. Seven of eight patients recovered or maintained their kidney function after antirejection therapy and steroid resumption. At the last follow‐up, seven of 13 patients (54%) had resumed steroid therapy. The 4‐year patient and graft survivals were 100% and 88.9%, respectively. The benefits of this steroid‐free regimen in HIV‐infected renal recipients must be reconsidered because of the high rate of acute rejection. New immunosuppressive steroid‐free strategies should be identi‐fied in this set of patients.

Upper limb artery segmental occlusions due to chronic use of ergotamine combined with itraconazole, treated by thrombolysis

BackgroundThe ergotamine tartrate associated with certain categories of drugs can lead to critical ischemia of the extremities. Discontinuation of taking ergotamine is usually sufficient for the total regression of ischemia, but in some cases it could be necessary thrombolytic and anticoagulant therapy to avoid amputation.Case reportA woman of 62 years presented with a severe pain left forearm appeared 10 days ago, with a worsening trend. The same symptoms appeared after 5 days also in the right forearm. Physical examination showed the right arm slightly hypothermic, with radial reduced pulse in presence of reduced sensitivity. The left arm was frankly hypothermic, pulse less on radial and with an ulnar humeral reduced pulse, associated to a decreased sensitivity and motility.Clinical history shows a chronic headache for which the patient took a daily basis for years Cafergot suppository (equivalent to 3.2 mg of ergotamine).From about ten days had begun therapy with itraconazole for vaginal candidiasis. The Color-Doppler ultrasound shown arterial thrombosis of the upper limbs (humeral and radial bilateral), with minimal residual flow to the right and no signal on the humeral and radial left artery.ResultsAngiography revealed progressive reduction in size of the axillary artery and right humeral artery stenosis with right segmental occlusions and multiple hypertrophic collateral circulations at the elbow joint. At the level of the right forearm was recognizable only the radial artery, decreased in size. Does not recognize the ulnar, interosseous artery was thin. To the left showed progressive reduction in size of the distal subclavian and humeral artery, determined by multiple segmental steno-occlusion with collateral vessels serving only a thin hypotrophic interosseous artery.Arteriographic findings were compatible with systemic drug-induced disease. The immediate implementation of thrombolysis, continued for 26 hours, with heparin in continuous intravenous infusion and subsequent anticoagulant therapy allowed the gradual disappearance of the symptoms with the reappearance of peripheral pulses.ConclusionAngiography showed regression of vasospasm and the resumption of flow in distal vessels. The patient had regained sensitivity and motility in the upper limbs and bilaterally radial and ulnar were present.

Neoral reduces the incidence of acute rejection after renal transplantation.

A NEW oral formulation of cyclosporine A based on microemulsion technology, Neoral, is available. Studies on healthy volunteers and stable renal transplant patients indicated that interand intrapatient variability of all the pharmacokinetic parameters are significantly reduced when compared with Sandimmune. Initially these advantages were considered to be an improvement only for the management of patients, but as time went on, Neoral turned out to be an improvement in immunosuppression since reduced the incidence of acute rejection. To clarify the immunosuppressive efficacy of Neoral, we retrospectively analysed the incidence of acute and steroidresistant rejections observed during the first 3 months in a group of patients who underwent first renal transplantation and were treated with Neoral. As comparison, we considered a matched group of patients transplanted in the same centre during the months immediately preceding the use of Neoral.