Efficacy and safety of 'rescue therapy' with mycophenolate mofetil in resistant primary glomerulonephritis--a multicenter study.

BACKGROUND: Studies of mycophenolate mofetil (MMF) in primary glomerulonephritis have varied in their inclusion criteria, regimen and follow-up compromising assessments of efficacy and optimal dose. METHOD: This multicentre study analysed the safety and efficacy of MMF monotherapy in a large cohort with primary glomerulonephritis that was resistant to other conventional therapies. A total of 98 patients with biopsy-proven primary glomerulonephritis resistant to other drugs received MMF monotherapy for 1 year. Primary outcome measures were urinary protein excretion and the number of patients with complete or partial remission of proteinuria. Secondary analyses were time to remission and changes in the slope of creatinine clearance. RESULTS: Fifty-four percent of the patients achieved either complete or partial remission of proteinuria with no significant differences between glomerulonephritis types. Median (range) dose of MMF was 2 g/day (1.5-2 g/day) Mean (SD) treatment time to remission was 141.5 (+/-61.1) days with no significant differences between glomerulonephritis types. Serum albumin increased (P<0.01), whereas proteinuria (P<0.01) serum LDL-cholesterol (P<0.01) and mean blood pressure (P<0.05) decreased post-treatment. No significant changes were observed in glomerular filtration rate (GFR), serum creatinine or slopes of GFR. The reduction of urinary protein excretion was significantly higher in patients with basal nephrotic proteinuria and preserved renal function; it did not arise from an increased dose of angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists, since, among responders, mean blood pressure significantly decreased and the number of anti-hypertensive drugs could be reduced. CONCLUSIONS: MMF monotherapy causes a moderate decrease in proteinuria in >50% of the patients who do not have other treatment options. The response to therapy is largely influenced by a preserved renal function and requires sustained MMF treatment.     

Clinical observations of mycophenolate mofetil therapy in refractory primary nephrotic syndrome

SUMMARY:   Mycophenolate mofetil (MMF) is an effective immunosuppressive agent in renal transplantation, and preliminary studies suggest that it may also be effective in the treatment of lupus nephritis. This study investigated the efficacy and safety of MMF therapy in patients with refractory primary nephrotic syndrome in a prospective multicentre clinical observation. Nineteen refractory nephrotic patients with minimal change disease or mesangial proliferative glomerulonephritis were enrolled in this study. Combined MMF and prednisone therapy was used for 6 months with an initial MMF dose of 1.0–2.0 g/day and a prednisone dose of 20–60 mg/day; both drugs were tapered gradually. It was found that all patients achieved clinical remission and 11 of 19 responded within 4 weeks, and 12 of 19 patients entered complete clinical remission. The prednisone dose in those patients who were previously steroid dependent could be successfully tapered. During follow up, three patients experienced transient increasing of proteinuria associated with infections and recovered without an adjustment of therapy. One patient was withdrawn from the study because of a fall in haemoglobin levels; other adverse effects did not necessitate withdrawal. Follow-up renal biopsies in two patients found no alteration in renal pathology. Mycophenolate mofetil is an effective and well-tolerated immunosuppressive agent for patients with refractory nephrotic syndrome.     

Efficacy of mycophenolate mofetil on recurrent glomerulonephritis after renal transplantation

Recurrent glomerulonephritis in transplanted kidneys is not rare despite classical immunosuppressive drugs and depends on the etiology of nephropathy. Treatment of recurrence of renal disease on graft remains controversial. We report 6 cases of patients with recurrent glomerulonephritis after renal transplantation treated with mycophenolate mofetil (MMF). The glomerular diseases were Wegener's granulomatosis (n = 1), membranoproliferative glomerulonephritis type I (n = 1), focal and segmental glomerular sclerosis (n = 1), membranous glomerulonephritis (idiopathic membranous nephropathy (n = 1) and systemic lupus erythematous) (n = 1)) and immunoglobulin A nephropathy (n = 1). MMF was introduced because of intolerance of classical immunosuppressive treatment in 2 cases and because of its inefficiency in the other cases. MMF was introduced between 3 months and 36 months (13.5 +/- 7 months) after recurrence of the primitive glomerulonephritis. During combined MMF/cyclosporine/prednisone therapy, only 3 patients responded to MMF. MMF was disrupted precociously in 1 out of 3 patients who stabilized renal function because of discovery of lung cancer and in 2 out of the 3 other patients because of gastrointestinal intolerance and severe anemia. We supposed that MMF could represent a new effective alternative therapy of recurrent glomerulonephritis on renal graft in some cases.     

Mycophenolate mofetil in the treatment of focal segmental glomerulosclerosis

AIMS: Primary focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage renal disease in both children and adults. Our current treatments are suboptimal, and a significant percentage of cases are resistant to current therapy. PATIENTS AND METHODS: We performed an open-label, 6-month trial of the new immunosuppressive agent mycophenolate mofetil (MMF) in 18 biopsy-proven patients resistant to a course of corticosteroids therapy. Seventy-five percent had also failed to respond to a cytotoxic agent and/or a calcineurin inhibitor. RESULTS: A substantial improvement in proteinuria was seen in 44% (8/18) of the patients by 6 months. This was sustained for up to 1 year post treatment in 50% (4/8) of this group. No patient had a complete remission. No deterioration in renal function was observed in any patient over the treatment period, but 3 progressed to chronic kidney failure during follow-up. Adverse effects were mild. Only 1 patient required a dose reduction due to an intercurrent infection. CONCLUSIONS: MMF appears safe to use in this group of patients and did lower proteinuria in 44% of this cohort resistant to other forms of treatment. Relapses were common, suggesting more prolonged or combination therapy may be required. More rigorous trials utilizing this medication should be considered to further assess the risk-benefit ratio of treatment with MMF in patients with FSGS.     

Place du mycophénolate mofétil dans la néphropathie lupique proliférative de l’enfant

The management of lupus nephritis remains a clinical problem in children as in adults. Corticosteroids, cyclophosphamide and azathioprine have been used with satisfactory response, but the most important problems are their potential toxicities. Therefore, we evaluate the use of mycophenolate mofetil (MMF) as a new agent for treatment of lupus nephritis in children. Five children with biopsy-proven proliferative glomerulonephritis with active lesions received MMF, combined with corticosteroids during the induction phase and alone during the maintenance phase. We retrospectively studied the efficacy and safety of this therapeutic regimen. All patients had proteinuria and renal failure. Four patients from five presented nephrotic syndrome. During the induction phase, three patients achieved complete remission of their nephrotic syndrome with normalization of renal function. One patient achieved partial remission and kept moderate renal failure. One patient died at 50 days by severe sepsis secondary to leucopenia. During the maintenance phase, three patients had complete remission. One patient was kept proteinuria with a creatinine clearance of 55 mL/min/1,73 m². The growth of these patients is not affected. In childhood lupus proliferative glomerulonephritis, MMF was well tolerated, and most of the patients achieved remission and improvement of their renal functions.     

Two-year experience with immunosuppressive treatment of chronic glomerular diseases

The authors describe their two-year experience in the treatment of chronic glomerular diseases with cytostatic immunosuppressive agents. Cyclophosphamide, imuran and chloraminophene were used in low doses for an average of 6 months. A total of 25 patients have been treated, including 17 with various anatomic-clinical forms of chronic glomerulonephritis and 7 with secondary glomerular lesions due to systemic diseases: SLE, polyarteritis nodosa, amyloidosis. Remission was observed in 8 patients, improvement in 14, no effect in 3. The best results were observed in the cases of membranous glomerulonephritis, intracapillary proliferative glomerulonephritis and lupus nephritis. In the cases with good response, the nephrotic syndrome, haematuria, renal function, hypertension and immunologic parameters were favourably influenced. The immunosuppressive agents have the value of a causal kind of treatment. They offer new possibilities in the management of more severe and progressive cases of chronic glomerular diseases resistant to classical methods of treatment and to corticosteroids.     

Effects of deoxyspergualin on proliferative glomerulonephritis

A clinical trial of the immunosuppressive drug, deoxyspergualin (DSG), was conducted in five patients with various forms of proliferative glomerulonephritis (GN), such as IgA nephropathy in 2 patients, purpura nephritis in 1, membranoproliferative GN(MPGN) in 1, and rapidly progressive GN (RPGN) in 1 patient, respectively. DSG was intravenously administered at a daily dose of 0.25 or 0.5 mg/kg for 4 weeks. A marked decrease in proteinuria (to less than 50% of baseline) was observed in four patients. The other patient showed 38% reduction of proteinuria. However, proteinuria exacerbated again after discontinuation of DSG in three patients during a four-week follow-up period. Marked decrease (3,000/microliter) in white blood cell (WBC) counts was observed in three patients during the course of DSG treatment. We concluded that DSG therapy is beneficial in reducing proteinuria in patients with various forms of proliferative GN. However, since proteinuria increased after the discontinuation of DSG and serious leukocytopenia was observed, indiscriminate use of DSG in proliferative GN should be discouraged.     

Treatment of Henoch-Schönlein Purpura glomerulonephritis in children with high-dose corticosteroids plus oral cyclophosphamide

BACKGROUND: Henoch-Sch?nlein Purpura (HSP) is a common childhood vasculitis with manifestations in numerous organ systems, including glomerulonephritis. Patients with more severe HSP-associated glomerulonephritis may develop chronic renal failure. Currently, no widely accepted treatment protocols exist for patients with significant renal involvement. METHODS: We retrospectively reviewed the clinical courses of 12 children (mean age 9 years) with HSP glomerulonephritis treated with high-dose corticosteroids plus oral cyclophosphamide. All patients had nephrotic-range proteinuria, and all had significant histopathologic changes on biopsy, including crescentic nephritis in 10 patients. Treatment consisted of either intravenous pulse methylprednisolone or oral prednisone followed by oral cyclophosphamide (2 mg/kg/day) for 12 weeks, along with either daily or alternate-day oral prednisone. Prednisone was tapered following completion of cyclophsophamide. RESULTS: Serum albumin rose significantly after treatment from 2.8 +/- (SD) 0.5 to 3.7 +/- 0.4 g/dl (p < 0.001), and there was a concurrent reduction in proteinuria, as reflected by decreasing serial protein-to-creatinine ratios: from 6.3 +/- 4.4 to 0.8 +/- 0.8 (p = 0.002). Renal function remained normal in all patients. Hypertension developed during treatment in 10 patients, all but 1 of whom were normotensive at last follow-up, 35 +/- 17 months following biopsy. CONCLUSIONS: We conclude that treatment of children with HSP nephritis with high-dose corticosteroids plus oral cyclophosphamide is safe and, as in nephrotic syndrome, appears to significantly reduce proteinuria which is a known risk factor for the development of renal insufficiency in HSP. Further studies with larger numbers of patients should be conducted to confirm this finding.     

Mycophenolate therapy of SLE membranous nephropathy

BACKGROUND: The immunosuppressant mycophenolic acid (MMF) has been used successfully to manage proliferative forms of systemic lupus erythematosus (SLE) glomerulonephritis (GN) World Health Organization (WHO) Classes III and IV. Less is known about MMF treatment of membranous SLE GN (WHO Class V, SLE MN). METHODS: We report our experience with MMF therapy in 13 consecutive SLE MN patients participating in a prospective study of risk factors for SLE flare. RESULTS: Baseline characteristics were: mean age 33 +/- 14 SD years, female/male ratio 11/2, Caucasians 7, African Americans 5, Oriental 1, serum creatinine 1.02 +/- 0.41, and mean 24-hour urine protein (P)/creatinine (C), ratio 5.1 +/- 4.1. Initial therapy was prednisone mean dose 31 +/- 17 mg/day, and MMF mean dose 1173 +/- 746 mg/day. Therapy also featured interventions to achieve renoprotection and proteinuria reduction. At 6 months of therapy, complete or partial remission was achieved in 10 of 13 patients. At most recent follow-up visit (mean follow-up 16 +/- 8 months), 9 of 13 patients were in complete remission, and in 11 of 13 patients, urine P/C ratio was < 0.8. During follow-up, serum creatinine either stabilized or was improved. The only serious complication during 208 patient months of follow-up was histoplasma pneumonia in 1 patient. CONCLUSION: These promising results suggest that moderate dose MMF in combination with renoprotective/antiproteinuria therapy warrants further study in the management of SLE MN.     

Urinary retinol-binding protein as a prognostic marker in the treatment of nephrotic syndrome

We studied the urinary levels of retinol-binding protein (urRBP), an index of proximal tubular dysfunction, in patients with nephrotic syndrome before and approximately 2 months after the beginning of steroid therapy as a predictor of response to therapy which included for some patients courses of immunosuppressive drugs. Those patients with minimal-change disease, mesangial proliferative glomerulonephritis, and focal-segmental glomerulosclerosis who had normal pretreatment urRBP levels were responsive to treatment; occasionally, responsive patients had an initially elevated urRBP level which normalized during treatment. Contrariwise, those patients with abnormally high levels of urRBP which did not normalize during treatment did not respond to treatment. The chance of a patient with minimal-change disease, mesangial proliferative glomerulonephritis, or focal-segmental glomerulosclerosis and a pretreatment urRBP level equal to or >1.0 mg/l being resistant to steroid treatment is 30 times that of a patient with a urRBP level <1.0 mg/l and even higher, if we consider the levels obtained during treatment.     

Mycophenolate mofetil treatment for therapy-resistant glomerulopathies

BACKGROUND: The management of steroid-resistant glomerulopathies remains a clinical problem. In this trial, we report a clinical observation of 43 patients treated with mycophenolate mofetil (MMF) for steroid-resistant glomerulopathies. METHODS: All patients underwent renal biopsies, and immunofluorescence and light microscopy examinations were conducted in all cases. All patients had been treated with prednisone at a dose of 1 mg/kg per day for at least 8 weeks. Of the 43 patients, 16 were treated with cyclophosphamide and five were treated with cyclosporine A before MMF started. The primary study outcomes were the change in the urinary protein excretion, serum creatinine, comparing the levels at the start of MMF treatment with those at the end of the MMF treatment period. Changes in renal function were also estimated with Modification of Diet in Renal Failure calculation. Wilcoxon signed-ranks test was used as appropriate to compare data from the start with data at the end of the treatment period. RESULTS: The primary glomerular diseases represented included membranoproliferative glomerulonephritis in 23.2%, membranous glomerulonephritis in 18.6%, IgA nephropathy in 13.9%, focal segmental glomerulosclerosis in 9.3%, lupus nephritis (systemic lupus erythematosus) in 25.6% and pauci-immune glomerulopathy in 9.3% of patients. The mean follow-up time was 28.9+/-12 months. Before MMF treatment, 16 patients (37%) had nephrotic range proteinuria and 11 (26%) had renal insufficiency. The urinary protein before MMF treatment was 3.3+/-2.6 g/dL (0.6-9.6) and decreased significantly to 0.87+/-1.1 g/dL (0-5.5) at the end of the MMF treatment period (P=0.02). During treatment, complete remission was seen in 27 patients, partial remission in 10 patients and MMF failure in six patients. The serum creatinine level decreased significantly from 1.29+/-0.55 mg/dL (0.6-3.0) to 1.14+/-0.38 mg/dL (0.5-2.4) post MMF therapy (P=0.046). Using the four-variable Modification of Diet in Renal Failure formula, the glomerular filtration rate increased from 71.5+/-28 mL/min per 1.73 m2 to 78.1+/-27 mL/min per 1.73 m2 (P=0.021). Renal insufficiency resolved in seven of the 11 (63.6%) patients with renal insufficiency initially, two with membranoproliferative glomerulonephritis, two with membranous glomerulonephritis, one with focal segmental glomerulosclerosis, four with pauci-immune glomerulopathy, two with systemic lupus erythematosus nephritis, and in two patients de novo renal insufficiency developed. CONCLUSION: In general, MMF was well tolerated, and most of the patients achieved remission and improvement of renal functions. MMF treatment appeared to offer benefits to problematic patients refractory to conventional therapies for glomerulopathies.     

Additive antiproteinuric effect of angiotensin II receptor antagonist and angiotensin-converting enzyme inhibitor in patients with chronic glomerulonephritis

Angiotensin II type-1 receptor blocker (ARB) and angiotensin-converting enzyme inhibitor (ACEI) have been thought to be effective for reducing proteinuria in patients with chronic glomerulonephritis. Recently, an additive effect of these two types of angiotensin blockers has been reported in patients with IgA nephropathy, but the mechanism responsible for the effect has not yet been determined. In this study, we examined additive effect of these two drugs in chronic glomerulonephritis patients. Ten patients with biopsy-proven primary glomerulonephritis (eight IgA nephropathy patients, two membranous nephropathy patients), non-nephrotic proteinuria (protein, 0.5 to 3.5 g/day) received candesartan cilexetil (2 or 4 mg) for 8 weeks. After the 8 weeks, a combination of perindopril erbumine (1 or 2 mg) and candesartan cilexetil was administered to the patients. Perindopril was stopped after the 8-week administration of the two drugs. Candesartan alone reduced proteinuria by 13%. Combination of these two drugs induced a more remarkable reduction of proteinuria (48%; p < 0.05 vs other periods). The decrease in mean blood pressure by the combination therapy was significantly correlated with the decrease in proteinuria. The combination of drugs also reduced the amount of urinary type-IV collagen excretion. An additive effect of ACEI and ARB on proteinuria and urinary type-IV collagen excretion was recognized in patients with chronic glomerulonephritis.     

Immunosuppressive effect of deoxyspergualin in proliferative glomerulonephritis.

A clinical trial of the immunosuppressive drug deoxyspergualin (DSG) was conducted in five patients with various forms of proliferative glomerulonephritis (immunoglobulin A nephropathy in two patients, purpura nephritis in one patient, membranoproliferative glomerulonephritis in one patient, and rapidly progressive glomerulonephritis in one patient). DSG was intravenously administered at 0.25 or 0.5 mg/kg/d for 4 weeks. A marked decrease in proteinuria (to <50% of baseline) was observed in four patients, and the other patient showed a 38% reduction in proteinuria, but the proteinuria was exacerbated again after discontinuation of DSG in three patients during a 4-week follow-up period. Proinflammatory CD16(+) (FcgammaRIII) monocytes disappeared from the peripheral blood during the administration of DSG but reappeared after DSG treatment was discontinued. A significant decrease in urinary macrophage counts that was far more marked than the decrease in peripheral blood monocyte counts was observed after administration of DSG. Interestingly, we also observed that the CD16 marker on the CD14(+) macrophage population in the urine disappeared in response to DSG treatment. These findings suggest that DSG may have a unique effect of suppression of FcgammaRIII expression on monocytes and/or macrophages that may result in amelioration of activated macrophage-mediated glomerulonephritis.     

The Combination of Mycophenolate Mofetil with Corticosteroids Induces Remission of Henoch-Schönlein Purpura Nephritis

Background: Henoch-Sch?nlein purpura (HSP) is a form of systemic vasculitis that can progress to Henoch-Sch?nlein purpura nephritis (HSPN), and the most effective treatment remains controversial. Our aim was to compare the effects of oral mycophenolate mofetil (MMF) with low-dose prednisone and the full-dose corticosteroids (CS; prednisone) for the induction therapy of HSPN with large proteinuria. Methods: Fifty-three patients with biopsy-proved HSPN with large proteinuria (>2.0 g/24 h) were divided into two groups: the MMF group (n = 27) who received oral MMF 1.0 g/day (1.5 g/day for patients with a body weight >70 kg) combined with low-dose prednisone (0.4-0.5 mg/kg/day), and the CS group (n = 26) who received the full-dose prednisone (0.8-1.0 mg/kg/day). We compared the effects of inducing remission at 6-month follow-up and the overall remission rate at the end of the follow-up between the two groups. Results: At 6 months, the estimated glomerular filtration rate level remained stable, while the urine protein decreased significantly in both groups, and the remission rate was 76.9% in the CS group and 55.5% in the MMF group (p = 0.101). With a median follow-up of 28.8 months in the CS group and 28.2 months in the MMF group, the overall remission rate was 80.8% in the CS group and 77.8% in the MMF group (p = 0.788). The MMF group had less side effects than the CS group (48.1 vs. 76.9%, p = 0.031). The relapse was 4/21 (19.0%) in the CS group and 0/21 in the MMF group (p = 0.115). Conclusion: MMF is useful for inducing remission and maintaining remission in Chinese HSPN, and may be used as a steroid-sparing agent in the treatment of HSPN.     

Primary glomerulonephritides with nephrotic syndrome. Limitations of therapy in adult patients

Thirty years of clinical studies have shown that a correct therapeutic approach to human glomerulonephritides with nephrotic syndrome requests the evaluation of three important parameters such as renal biopsy, long monitoring of daily proteinuria and renal function. In addition, age and clinical manifestations should be considered. Corticosteroids, alkylating agents (cyclophosphamide, chlorambucil) and purine analogues are currently used in the treatment of primary glomerulonephritis (minimal-change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous (MGN) and membranoproliferative glomerulonephritis (MPGN)), however results are different. Patients with nephrotic syndrome in MCD when treated with corticosteroids and/or cytotoxic drugs have complete or partial remission in a more than 90% of cases. On the contrary, nephrotic FSGS remits completely or partially only in 50% of treated cases when a more aggressive and prolonged immunosuppressive therapy is carried out. Data from clinical trials in MGN patients are controversial, however it is evident that a greater percentage of patients with stage 1 and stage 2 renal lesions benefit from corticosteroids in association with immunosuppressive drugs. Finally, no encouraging data have been obtained by clinically controlled trials in patients with MPGN. Future perspectives suggest the use of other drugs such as receptor blockade of cytokines and growth factors, administration of cytokine antagonists, intracellular signalling blockade and gene therapy with antisense oligonucleotides. Unfortunately, until specific therapies become available, we have to use unspecific or only symptomatic therapy.     

Mycophenolate mofetil ameliorates nephropathy in the obese Zucker rat

BACKGROUND: The obese Zucker rat has metabolic condition resembling type II diabetes, including hyperlipidemia, obesity, insulin resistance, and hyperglycemia. With advancing age, the obese Zucker rat develops glomerulosclerosis, proteinuria, and renal failure. Since immune cells play a central role in the development of chronic renal injury, we evaluated the potential benefit of mycophenolate mofetil (MMF), alone and in combination with angiotensin receptor type 1 blockade (ARB) in the obese Zucker rat. METHODS: Thirteen-week-old male obese Zucker rats (fa/fa) were randomly assigned to four experimental groups (five rats each) that received the following treatments for 3 months: (1) losartan (100 mg/L in the drinking water), (2) MMF (20 mg/kg/day), (3) MMF and losartan, and (4) placebo. Lean Zucker rats (N = 5) were included as normal controls. Renal function, biochemical parameters, renal histology, and immunohistology were evaluated. RESULTS: The placebo-treated obese Zucker rats exhibited proteinuria and significant glomerular and tubulointerstitial injury in association with renal immune cell infiltration. Proteinuria, histologic damage, and renal immune cell infiltration were all reduced by MMF treatment alone or in combination with ARB. The improvement of proteinuria and structural damage was more pronounced in the group that received the combination of MMF and losartan. CONCLUSION: MMF treatment alone, and especially in combination with ARB, improves nephropathy in the obese Zucker rat.     

C1Q nephropathy in children

C1q nephropathy (C1qNP) is a peculiar form of glomerulonephritis characterized by mesangial immunoglobulin and complement deposits, predominantly C1q, with no evidence of systemic lupus erythematosus. We describe the incidence, manifestation, histopathologic findings, follow-up, treatment and outcome of C1qNP. Twelve C1qNP patients were identified among 131 children who had undergone renal biopsy, accounting for a 9.16% incidence of C1qNP. Light microscopy examination showed focal segmental glomerulosclerosis (FSGS) with or without diffuse mesangial proliferation (n=6), minimal change disease (MCD) (n=4) or focal glomerulonephritis (n=2). C1q deposits were found in all, while electron microscopy revealed visible deposits in nine cases. Eight children presented with nephrotic syndrome, while one had nephrotic proteinuria and renal insufficiency that progressed to end-stage renal failure. The remaining three patients presented with nonnephrotic proteinuria associated with microhematuria, hypertension or renal insufficiency. Only one nephrotic syndrome patient responded excellently to corticosteroids, while four became corticosteroid dependent, and three were corticosteroid resistant, showing a very poor response to other immunosuppressive therapy as well. Patients with non-nephrotic proteinuria demonstrated fixed laboratory findings. Most C1qNP patients had FSGS or MCD, the majority of them presenting with corticosteroid-dependent or corticosteroid-resistant nephrotic syndrome. The latter showed a very poor response to any immunosuppressive therapy and high risk for progressive renal insufficiency.     

Everolimus (Certican) 12-month safety and efficacy versus mycophenolate mofetil in de novo renal transplant recipients

BACKGROUND: Everolimus is a proliferation inhibitor designed to target chronic rejection, including prevention of acute rejection. Everolimus blocks growth factor-mediated transduction signals, preventing organ rejection by a mechanism different than that of calcineurin inhibitors and of mycophenolate mofetil (MMF). METHODS.: Everolimus (1.5 mg or 3 mg daily) was compared with MMF (2 g daily) in a randomized, multicenter, multinational, 12-month double-blind, double-dummy and 2-year open-label, phase 3 trial in de novo renal allograft recipients (n = 588) who also received cyclosporine and corticosteroids as part of a triple immunosuppressive regimen. RESULTS: At 12 months, there were no statistically significant differences between doses of 1.5 and 3 mg/day everolimus and MMF (2 g/day) in incidence of biopsy-proven acute rejection (23.2%, 19.7%, and 24.0%, respectively), graft loss (4.6%, 10.6%, and 9.2%), or death (5.2%, 4.0%, and 2.6%), respectively. Everolimus 1.5 mg/day and MMF were generally equally well tolerated. Both were better tolerated than everolimus 3 mg/day. The incidence of cytomegalovirus infection was significantly lower in patients receiving either 1.5 or 3 mg/day everolimus than in those receiving MMF (5.2% and 7.6% vs. 19.4%, respectively) (P = .001). CONCLUSIONS: Everolimus is effective in preventing acute rejection and graft loss in de novo renal allograft recipients receiving a triple immunosuppressive regimen. Prevention of acute rejection, along with reduction in cytomegalovirus infection, addresses two factors known to contribute to chronic rejection in such patients.