Philippe Lang

Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine.

BACKGROUND Sirolimus (rapamycin) is a potent immunosuppressant with a mechanism of action different from cyclosporine (CsA) or tacrolimus. METHODS In 11 European centers, first cadaveric renal allograft recipients were randomized to CsA (n=42) or sirolimus (n=41). Dosing of these agents was concentration-controlled and open-labeled. All patients received corticosteroids and azathioprine. RESULTS At 12 months, graft survival (98% sirolimus vs. 90% CsA), patient survival (100% vs. 98%), and incidence of biopsy-confirmed acute rejection (41% vs. 38%) were similar. Serum creatinine was lower with sirolimus, significantly (P< or =0.05) so at 3 and 4 months, and serum uric acid and magnesium were normal. Laboratory abnormalities reported significantly more often with sirolimus included hypertriglyceridemia (51% vs. 12%), hypercholesterolemia (44% vs. 14%), thrombocytopenia (37% vs. 0%), leukopenia (39% vs. 14%), and, of lesser importance, increased liver enzymes and hypokalemia. These abnormalities improved 2 months after transplantation when the sirolimus target trough level was lowered from 30 to 15 ng/ml. Occurrence of cytomegalovirus was comparable (14% vs. 12%); incidences of herpes simplex (24% vs. 10%, P=0.08) and pneumonia (17% vs. 2%, P=0.03) were higher with sirolimus. No gingival hyperplasia was seen with sirolimus, tremor was rare, and hypertension was less frequent (17% vs. 33%). Two malignancies were observed with CsA and none with sirolimus. CONCLUSIONS Results at 12 months suggest that sirolimus can be used as base therapy in the prophylaxis of acute renal transplant rejection, and has a safety profile that differs from CsA.

Repair of the lower and middle parts of the face by composite tissue allotransplantation in a patient with massive plexiform neurofibroma: a 1-year follow-up study

BACKGROUND The risk to benefit ratio of face transplantation with a composite tissue allograft remains debatable, although this procedure is technically feasible. We report here a 1-year follow-up of a patient who underwent face transplantation with a composite tissue allograft. METHODS On Jan 21, 2007, a 29-year-old man with neurofibromatosis type 1 underwent resection of a massive plexiform neurofibroma diffusely infiltrating the middle and lower part of his face. The main goal was to restore both the cutaneous appearance and function of the face, including, in particular, control of orbicularis oculi and oris muscle contraction. The issues of immunosuppressive therapy, psychological outcome, and social reintergration were addressed, together with the monitoring of graft rejection by biopsies of the skin and mucosa. FINDINGS The initial postoperative course was uncomplicated. Two episodes of clinical rejection occurred on days 28 and 64. The second episode was associated with cytomegalovirus infection. Both episodes resolved favourably, with no further clinical signs of rejection, making the reduction of immunosuppressive treatment possible. A year after surgery, the functional outcome was very good, with successful sensory and motor reinnervation in the transplanted territory. Psychological recovery was excellent, with complete social reintegration. INTERPRETATION This case demonstrates the feasibility of surgically removing a large part of the face and replacing it with a composite tissue allograft. This facial repair procedure, which seems to have a satisfactory risk to benefit ratio, could be offered in rare and selected cases.

Three-Year Outcomes from BENEFIT, a Randomized, Active-Controlled, Parallel-Group Study in Adult Kidney Transplant Recipients

The clinical profile of belatacept in kidney transplant recipients was evaluated to determine if earlier results in the BENEFIT study were sustained at 3 years. BENEFIT is a randomized 3 year, phase III study in adults receiving a kidney transplant from a living or standard criteria deceased donor. Patients were randomized to a more (MI) or less intensive (LI) regimen of belatacept, or cyclosporine. 471/666 patients completed ≥3 years of therapy. A total of 92% (MI), 92% (LI), and 89% (cyclosporine) of patients survived with a functioning graft. The mean calculated GFR (cGFR) was ∼21 mL/min/1.73 m2 higher in the belatacept groups versus cyclosporine at year 3. From month 3 to month 36, the mean cGFR increased in the belatacept groups by +1.0 mL/min/1.73 m2/year (MI) and +1.2 mL/min/1.73 m2/year (LI) versus a decline of −2.0 mL/min/1.73 m2/year (cyclosporine). One cyclosporine‐treated patient experienced acute rejection between year 2 and year 3. There were no new safety signals and no new posttransplant lymphoproliferative disorder (PTLD) cases after month 18. Belatacept‐treated patients maintained a high rate of patient and graft survival that was comparable to cyclosporine‐treated patients, despite an early increased occurrence of acute rejection and PTLD.

Three-year outcomes from BENEFIT-EXT: a phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys.

Recipients of extended‐criteria donor (ECD) kidneys have poorer long‐term outcomes compared to standard‐criteria donor kidney recipients. We report 3‐year outcomes from a randomized, phase III study in recipients of de novo ECD kidneys (n = 543) assigned (1:1:1) to either a more intensive (MI) or less intensive (LI) belatacept regimen, or cyclosporine. Three hundred twenty‐three patients completed treatment by year 3. Patient survival with a functioning graft was comparable between groups (80% in MI, 82% in LI, 80% in cyclosporine). Mean calculated GFR (cGFR) was 11 mL/min higher in belatacept‐treated versus cyclosporine‐treated patients (42.7 in MI, 42.2 in LI, 31.5 mL/min in cyclosporine). More cyclosporine‐treated patients (44%) progressed to GFR <30 mL/min (chronic kidney disease [CKD] stage 4/5) than belatacept‐treated patients (27–30%). Acute rejection rates were similar between groups. Posttransplant lymphoproliferative disorder (PTLD) occurrence was higher in belatacept‐treated patients (two in MI, three in LI), most of which occurred during the first 18 months; four additional cases (3 in LI, 1 in cyclosporine) occurred after 3 years. Tuberculosis was reported in two MI, four LI and no cyclosporine patients. In conclusion, at 3 years after transplantation, immunosuppression with belatacept resulted in similar patient survival, graft survival and acute rejection, with better renal function compared with cyclosporine. As previously reported, PTLD and tuberculosis were the principal safety findings associated with belatacept in this study population.

Feasibility, reproducibility, risks and benefits of face transplantation: a prospective study of outcomes.

Composite tissue allotransplantations can be indicated when autologous transfers fail to restore human appearance. We report the reproducibility, difficulties, serious adverse events and outcomes of our patients. Five patients were included in a registered clinical research protocol after thorough screenings assessed by an independent expert committee systematically discussing the alternative options. One patient suffered from plexiform neurofibromas, two from third degree burns and two from gunshot injuries. They were included on a national waiting list with a dedicated face procurement procedure. Transplants were harvested from heart beating brain‐dead donors before other tissues and organs. Induction immunosuppressive therapy included antithymocyte globulins, steroids, mycophenolate mophetil and tacrolimus. Maintenance therapy included the last three ones associated with extracorporeal‐photopheresis. Four patients were transplanted with 7‐ to 38‐month follow‐up. One could not due to multiple panel reactive antibodies after 18 months on waiting list. Acute cellular rejections were controlled by conventional treatment. Opportunistic infections affected all patients and lead one patient to die two month after the transplantation. Voluntary facial activity appeared from 3 to 5 month. Face transplantation has been reproducible under conventional immunosuppression. Major improvements in facial aesthetic and function allowed patients to recover social relations and improved their quality of life.

Five-Year Safety and Efficacy of Belatacept in Renal Transplantation

Belatacept is a first-in-class co-stimulation blocker in development for primary maintenance immunosuppression. A Phase II study comparing belatacept with cyclosporine (CsA) for prevention of acute rejection and protection of renal function in kidney transplant recipients demonstrated similar efficacy and significantly higher measured GFR at 1 year for belatacept, but the incidence of posttransplantation lymphoproliferative disorder was higher. Here, we present the results for the extension of this trial, which aimed to assess long-term safety and efficacy of belatacept. Seventy-eight of 102 patients who were receiving belatacept and the 16 of 26 who were receiving CsA completed the long-term extension period. GFR remained stable in patients who were receiving belatacept for 5 years, and the incidences of death/graft loss or acute rejection were low. The frequencies of serious infections were 16% for belatacept and 27% for CsA, and neoplasms occurred in 12% of each group. No patients who were treated with belatacept and one patient who was treated with CsA developed posttransplantation lymphoproliferative disorder during the follow-up period. Serious gastrointestinal disorders occurred more frequently with belatacept (12% belatacept versus 8% CsA), and serious cardiac disorders occurred more frequently with CsA (2% belatacept versus 12% CsA). Pharmacokinetic analyses showed consistent exposure to belatacept over time. CD86 receptor saturation was higher in patients who were receiving belatacept every 4 weeks (74%) compared with every 8 weeks (56%). In conclusion, this study demonstrated high patient persistence with intravenous belatacept, stable renal function, predictable pharmacokinetics, and good safety with belatacept over 5 years.

Diabetes mellitus after renal transplantation: characteristics, outcome, and risk factors.

The incidence and risk factors of posttransplant diabetes mellitus were evaluated in 1325 consecutive renal transplant recipients. Thirty-three (2.5%) patients developed diabetes mellitus requiring insulin therapy. Onset occurred a mean of 5.7 +/- 1.5 months following transplantation. The patients were compared with 33 paired-control kidney recipients. The patients were significantly older than the controls (46.8 +/- 1.9 vs. 40.6 +/- 2.1 years) (P<0.05), and chronic renal failure was more often related to interstitial nephritis (P<0.05). A family history of diabetes mellitus, the body mass index, ethnic origin, HLA phenotype, and the total doses of steroids and cyclosporine were similar in the two groups. The number of patients with at least one rejection episode was significantly higher among the diabetic patients (21 versus 9) but the number of episodes was similar. Diabetes occurred a mean of 1.1 +/- 0.3 months following rejection treatment. Intravenous pulsed prednisolone was always used for anti-rejection therapy. Insulin was withdrawn in 16 cases after a mean of 4 +/- 1 months, independently of steroid dosage reductions. Actuarial patient and graft survival rates were not significantly different, although 6-year outcome tended to be better in the controls (86% versus 93% for patient survival and 67% versus 93% for graft survival). This study suggests that pulsed steroid therapy might be the critical factor in the onset of posttransplant diabetes and that the risk is increased in older patients with chronic interstitial nephrititis.

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.

Daclizumab versus Antithymocyte Globulin in High-Immunological-Risk Renal Transplant Recipients

Nondepleting anti-CD25 monoclonal antibodies (daclizumab) and depleting polyclonal antithymocyte globulin (Thymoglobulin) both prevent acute rejection, but these therapies have not been directly compared in a high-risk, HLA-sensitized renal transplant population. We randomly assigned 227 patients, who were about to receive a kidney graft from a deceased donor, to either Thymoglobulin or daclizumab if they met one of the following risk factors: current panel reactive antibodies (PRA) >30%; peak PRA >50%; loss of a first kidney graft from rejection within 2 yr of transplantation; or two or three previous grafts. Maintenance immunosuppression comprised tacrolimus, mycophenolate mofetil, and steroids. Compared with the daclizumab group, patients treated with Thymoglobulin had a lower incidence of both biopsy-proven acute rejection (15.0% versus 27.2%; P = 0.016) and steroid-resistant rejection (2.7% versus 14.9%; P = 0.002) at one year. One-year graft and patient survival rates were similar between the two groups. In a comparison of rejectors and nonrejectors, overall graft survival was significantly higher in the rejection-free group (87.2% versus 75.0%; P = 0.037). In conclusion, among high-immunological-risk renal transplant recipients, Thymoglobulin is superior to daclizumab for the prevention of biopsy-proven acute rejection, but there is no significant benefit to one-year graft or patient survival.

High-Dose Immunoglobulin Therapy for Severe IgA Nephropathy and Henoch-Schonlein Purpura

IgA nephropathy (IgAN) is characterized by IgA and C3 deposits in the mesangium [1] and is the most common form of primary glomerulonephritis [2]. Chronic renal failure occurs in approximately 25% of patients 10 years after diagnosis and in as many as 40% to 50% after 20 years [2-4]. Idiopathic Henoch-Schonlein purpura (HSP) is a more severe and systemic form of IgAN [4]. The causes of IgAN are still poorly understood. Glomerular damage might be related to deposits of IgA-containing immune complexes [4, 5], resulting from an uncontrolled mucosal immune response to chronic exposure to environmental antigens or from an anomaly of the medullary IgA system, which is thought to be a second line of defense against foreign antigens [6]. Studies have identified factors associated with poor outcome, such as heavy proteinuria, hypertension, altered renal function, and high histologic grade [2, 4, 7, 8]. Although renal insufficiency develops slowly in most patients, a subset of patients experiences a more severe disease course that requires dialysis within 1 to 5 years [2-4, 7, 9]. Unfortunately, despite the fact that glomerular injury is immunologically mediated, IgAN and HSP do not respond to steroids and immunosuppressive drugs [3]. We previously reported a partial IgG subclass deficiency (mainly involving IgG1) in proteinuric IgAN and HSP [10]. We postulated that such an IgG imbalance might favor viral and bacterial infections [11, 12], a known trigger of flare-ups in these diseases, or activate noxious isotypic compensatory mechanisms [13]. Because high-dose intravenous immunoglobulins are effective in some human immune-mediated diseases [14], we began a prospective trial of high-dose intravenous immunoglobulins in patients with severe IgAN and HSP who had indicators of poor prognosis. Methods Patients Ten men and one woman were enrolled in the study. The criteria for eligibility were idiopathic IgAN or HSP at histologic stage II/III, III, III/IV, or IV; proteinuria level greater than 2 g/d; and glomerular filtration rate greater than 35 mL/min per 1.73 m2. The local ethics committee approved the trial and all patients gave informed consent. Nine had IgAN and two had HSP. Five patients with IgAN were referred by their general practitioner for heavy proteinuria, whereas the remaining four were referred for severe IgA nephropathy by the nephrology units of two general hospitals. One patient with HSP was found to have nephritis while being treated in the dermatology unit of our institution, and the second was referred to our nephrology unit by his general practitioner for HSP with renal involvement. The median age was 24 years (range, 18 to 36 years). The median time between diagnosis and therapy was 5 months (range, 1 to 18 months) (Table 1). All patients had been treated for focal infections and had tonsillectomy for chronic tonsillitis or for reasons of immunity [15]. Two patients were treated unsuccessfully with high-dose steroids at least 3 months earlier. No patient received nonsteroidal anti-inflammatory drugs in the year before the trial. Nine of the 11 patients were treated for hypertension before entry into the trial, and their blood pressure levels rapidly returned to normal during therapy with -blockers alone (atenolol or betaxolol) or combined with prazosin; these drugs were pursued during the trial. None of the patients had severe hypertension: Results of the fondus oculi, hemogram, and heart ultrasound examinations were normal. Treatment of hypertension did not reverse the decline in renal function, despite prolonged follow-up before immunoglobulin therapy. Nine of the 11 patients had altered renal function (median glomerular filtration rate of the group, 57.5 mL/min per 1.73 m2; range, 39 to 134 mL/min per 1.73 m2). The median monthly rate of renal function decline before therapy was 3.78 mL/min (range, 13.80 to 0 mL/min) (Table 1), with a median total decline in renal function before therapy of 27.5 mL/min (range, 55 to 0 mL/min). All patients had heavy proteinuria (median protein level, 5.20 g/d; range, 2.37 to 10.70 g/d) (Table 1), a high histologic grade (1 with stage II/III; 4 with stage III; 3 with stage III/IV; 3 with stage IV), a high histologic index of activity (median, 5; range, 2 to 10), and a moderate histologic index of sclerosis (median, 4; range, 0 to 9) (Table 1). All had dense IgA and C3 mesangial deposits; four patients also had IgA deposits along the glomerular capillary wall. Immunoglobulin G deposits were absent, whereas mild IgM deposits were found in 5 of the 11 patients. The two patients with HSP also had articular effusion, extensive cutaneous purpura, abdominal pain, and diarrhea. Table 1. Changes in Renal Function and Urinary Variables with Immunoglobulin Therapy* Intervention The patients received 1 g/kg of body weight per day (in a 12-hour infusion) of pepsin-pH 4 intravenous immunoglobulins (Biotransfusion, Roissy, France) on 2 successive days each month for 3 successive months, followed by intramuscular immunoglobulins (Polygamma, 16.5%; Association Nationale pour la Distribution des Fractions Plasmatiques Humaines, Paris, France) at a dose of 0.35 mL/kg of body weight twice each month for another 6 months. To avoid serum sickness related to formation of immune complexes between free circulating environmental antigens and infused IgG, a complication previously reported with IgG deficiency [16], the first intravenous immunoglobulin infusion was preceded by single 3-L plasmapheresis with albumin replacement. We examined patients monthly during their hospital stay for the first 3 months, as outpatients from the third to the eighth month, and in the hospital at the end of the study (ninth month). After the 9-month trial, patients received the same maintenance therapy (0.35 mL/kg of intramuscular immunoglobulins twice each month) and were examined every 3 months as outpatients. Angiotensin-converting-enzyme inhibitors, calcium channel blockers, corticosteroids, and nonsteroidal anti-inflammatory drugs were not allowed during the trial. The patients ate a normal protein diet (1.5 to 2 g/kg per day of protein). Follow-up We assessed clinical, renal, viral, and immunologic tolerance at each visit during the 9-month study period and then every 3 months thereafter. Measurements Renal Histologic Findings Global Histologic Grading: We used the grading system of Lee and associates [7], which requires that at least nine glomeruli be scored. Biopsy specimens were blindly scored in five grades of increasing severity [7], accounting for both cellular proliferation and sclerosis. Stage I corresponded to normal glomeruli or occasional segmental mesangial thickening with or without cellularity. In stage II, fewer than one half of the glomeruli showed localized mesangial proliferation and sclerosis. Stage III was characterized by diffuse mesangial proliferation and thickening with focal and segmental variation, and focal interstitial edema and infiltrates may be present as small crescents and adhesions. In stage IV, marked diffuse mesangial proliferation and sclerosis were evident, with crescents in as many as 45% of the glomeruli. Partial or total glomerulosclerosis was frequently seen as tubular atrophy and interstitial infiltrates. Lesions classified as stage V were the same as in stage IV but more severe. Some biopsy specimens were given intermediate scores. Histologic Activity Index: We noted proliferation of mesangial and epithelial cells blindly using a final scale of 14 points; we required that at least nine glomeruli be examined. In evaluating mesangial cell proliferation, we accounted for the intensity (absent = 0; mild = 1; moderate = 2; severe = 3) and extent of the lesions (no glomeruli affected = 0; <25% of glomeruli = 1; >25% but <50% = 2; >50% but <75% = 3; >75% = 4). We noted epithelial cell proliferation in the same way. Histologic Sclerosis Index: We evaluated two parameters blindly (mesangial plus glomerular sclerosis, and interstitial sclerosis) and required that at least nine glomeruli be scored. Mesangial sclerosis accounted for both the intensity (absent = 0; moderate = 1; severe = 2) and extent of the lesions (no glomeruli affected = 0; <25% of the glomeruli = 1; >25% but <50% = 2; >50% but <75 % = 3; >75% = 4). With regard to interstitial sclerosis, we evaluated interstitial fibrosis on a 2-point scale (absent = 0; moderate = 1; severe = 2) and tubular atrophy in the same way (absent = 0; moderate = 1; severe = 2). Immunofluorescence Studies: We used a direct immunofluorescence technique with fluorescein-labeled goat antisera derived from the same batches (Institut Pasteur, Marnes la coquette, France, and Behring Institut, Marburg, Germany) directed against IgA, IgG, IgM, C1q, C3, and C4. The fluorescence intensity was scored blindly from 0 to 3. Biochemical Measurements of Renal Disease Activity We assayed protein levels at 24 hours using a dye-based method derived from Bradfords technique. We determined the proteinuria selectivity index by studying the IgG:albumin clearance ratio, which we measured using a nephelometer and specific polyclonal antisera (Behring Institut). We measured urinary erythrocyte and leukocyte counts during a 3-hour morning rest period and assayed urinary fibrin-fibrinogen degradation products according to the method of Merskey and Kleiner [17]. Using a specific enzymatic method, we measured plasma creatinine. We assessed global renal function through measurements of creatinine clearance (according to Cockroft and Gault [18]) and an inulin analog clearance (polyfructosan). Because evaluation of renal function decline with both the 1/creatinine ratio and the slope of the glomerular clearance curve was recently criticized (because the decline in renal function is not always linear [19, 20]), we evaluated the rate of renal function decline as follows: loss in glomerular filtration rate during the period studied (mL/min per 1.73 m2) divided by