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Mycophenolate mofetil (MYCOMUNE) in glomerular diseases

Mycophenolate mofetil (MYCOMUNE) in glomerular diseases. MMF: Historical aspects. MMF is the morpholinoethyl ester of mycophenolic acid (MPA), which is released after oral administration and constitutes the actually active compound.

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Mycophenolate mofetil (MYCOMUNE) in glomerular diseases

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  1. Mycophenolate mofetil (MYCOMUNE) in glomerular diseases

  2. MMF: Historical aspects • MMF is the morpholinoethyl ester of mycophenolic acid (MPA), which is released after oral administration and constitutes the actually active compound. • Isolated from Penicillium cultures as early as in 1896 and purified in 1913. • In the 1940s, MPA was found to possess significant antibacterial and antifungal activity.

  3. In the late 1960s, MPA was shown to inhibit cell proliferation and to arrest tumoral growth in vitro, although it had only limited beneficial effect in cancer patients. • In 1987, was shown to successfully prevent acute experimental allograft rejection. • In the early 1990s, MMF was first used in the treatment of acute human organ rejection. • 1995- FDA approval for use in renal transplant patients.

  4. Pharmacokinetic behavior of (MMF)(MYCOMUNE) after oral administration

  5. MECHANISM OF ACTION OF MPA • MPA arrests lymphocyte proliferation by inhibiting inosine monophosphate dehydrogenase (IMPDH), a crucial enzyme in the de novo pathway of GTP synthesis. • In most eukaryotic cells, IMPDH inhibition has little effect on cell division because GTP can also be generated from nucleotide breakdown products. • Because lymphocytes lack this “salvage pathway,” MPA specifically inhibits their proliferation, thus limiting cell-mediated immunity

  6. Other actions of MMF (MYCOMUNE) • MPA inhibits the proliferation of vascular smooth muscle and mesangial cells and may therefore limit glomerular and vascular injury directly. • MMF may also inhibit the proliferation of monocytes and fibroblasts and induce apoptosis of monocytes. • In addition, MPA may inhibit the glycosylation and, consequently, the affinity of adhesion molecules expressed by lymphocytes and endothelial cells again as a result of intracellular GTP depletion, thus limiting lymphocyte migration into the renal tissue.

  7. Use Of MMF In Nontransplant Immune mediated Nephropathies

  8. Nephrol Dial Transplant (2002) 17: 363–368

  9. Beneficial Effects of MMF in Immune-Mediated Nephropathies • LUPUS NEPHRITIS- EVIDENCE OF BENEFIT IN ANIMAL EXPERIMENTS. • MMF inhibited both the proliferation of splenocytes harvested from SLE-prone mice and the production of cytokines and autoantibodies by these cells. Accordingly, MMF reduced perivascular inflammation in these animals.

  10. In NZBxW F1 hybrid mice, Corna and co-workers showed that MMF therapy, instituted at 3 mo of age and maintained for the rest of the animals’ lives, limited the production of autoantibodies and ameliorated anemia and leucopenia. • The protein excretion rate and nitrogen retention were strongly limited, whereas survival was significantly improved, in MMF-treated mice.

  11. McMurray et al. showed that, in female NZBxNZW F1 mice receiving lifelong MMF treatment, T lymphocyte activation and the production of anti-DNA antibodies were suppressed, whereas albuminuria was limited. • Mortality at 60 wk of age was 90% in untreated and 0 in MMF-treated animals.

  12. In MRL/lpr mice, Yu and co-workers found that MMF treatment diminished the renal cortical expression of the inducible isoform of nitric oxide (NO) synthase (iNOS), which has been implicated in the pathogenesis of renal injury in lupus nephritis. • Accordingly, MMF treatment diminished the urinary excretion of NO metabolites, suggesting that overall NO production was equally reduced. • In association with these effects, MMF treatment had a protective effect on the glomerular structure, limiting tuft hypertrophy and ameliorating proteinuria and glomerulosclerosis.

  13. What's the evidence of benefit of MMF in LN in Humans? • Cohort of 42 patients • Diffuse proliferative lupus nephritis. • Chan and co-workers compared the renal protective effect and the toxicity of a : • Either MMF (n 21; 2 g/d for 6 mo and 1 g/d for 6 additional months) or • Oral CYC (n 21; 2.5 mg/kg per d for 6 mo) followed by AZA (2.5 mg/kg per d for 6 mo). • After 1 yr, all patients were maintained on low-dose AZA (1 to 1.5 mg/kg per d). • They found that 95% of patients in group 1 had complete (81%) or partial (14%) remission, compared with 90% (76% complete and 14% partial) in group 2. • Side effects were more frequent in group 2 than in group 1 N Engl J Med 343: 1156–1162, 2000.

  14. Further follow-up till 36 months indicated more early relapses in the patients who were given MMF as induction therapy, possibly related to a low MMF dosage and/or its early withdrawal. N Engl J Med 343: 1156–1162, 2000.

  15. MMF (MYCOMUNE) as induction therapy in Lupus Nephritis • MMF was also compared with IV CYC as induction therapy in two controlled trials, one performed in China, the other in the United States. • Hu et al.found that MMF (n 23; 1 to 1.5 g/d for 3 to 6 mo; then, 0.5 to 1 g/d) was more effective in reducing proteinuria, hematuria, serum autoantibody titers, and glomerular immune deposits compared with IV CYC (n 23; 0.75 to 1 g/m2 monthly for 6 mo, then quarterly for 1 yr). Chin Med J (Engl) 115: 705–709, 2002

  16. Similar results were observed in a short-term American multicenter trial, in which MMF (n 71; maximum tolerated dosage, up to 3 g/d) was compared with a standard NIH IV CYC regimen (n 69; six monthly pulses) as induction therapy for severe LN. • Complete remission at 6 mo, defined as a normal serum creatinine, proteinuria 0.5 g/d, and an inactive urinary sediment, was more frequently achieved in the MMF group (20%) than in the IV CYC (6%). • Consistently, crossover to the other arm as a result of treatment toxicity or inefficacy occurred in 20% of IV CYC patients and in only 8% of MMF patients. As expected, severe pyogenic infections were more frequent in the IV CYC group compared with the MMF group (13 versus 6%). J Am Soc Nephrol 14: 38A, 2003

  17. MMF (MYCOMUNE) as maintenance therapy • Contreras et al. • All patients (only 5% white) were given four to seven monthly IV CYC pulses before being assigned one of three different remission- maintaining regimens: • Quarterly IV CYC pulses (n 20), • AZA (n 19; 1 to 3 mg/kg per d), or • MMF (n 20; 0.5 to 3.0 g/d) for ~2 yr. N Engl J Med 350: 971–980, 2004

  18. Although the cumulative rate of renal survival did not differ statistically among the three groups, • The most striking differences were • (1) an increased mortality in patients who were given maintenance therapy with quarterly IV CYC pulses (versus those who were given AZA), • (2) an increased drug-related morbidity in IV CYC patients (versus AZA and MMF patients), and • (3) an increased relapse rate in IV CYC patients (versus MMF patients). • No statistically significant differences were observed between AZA and MMF. N Engl J Med 350: 971–980, 2004

  19. Lupus nephritis: treatment with mycophenolate mofetil : P. P. Kapitsinou, J. N et al • Eighteen patients with biopsy-proven lupus nephritis (17 females, one male; mean age 31.6 yr; mean lupus duration 92 months; mean duration of nephritis 57 months) • Nine with focal proliferative glomerulonephritis, three with diffuse proliferative glomerulonephritis, six with membranous nephropathy. • MMF (MYCOMUNE) was given at 2 g daily in combination with steroids for up to 31months (mean 15.3 months). • Complete remission was observed in 10/18 patients and another 4/18 went into partial remission. Both creatinine clearance and proteinuria were significantly improved during MMF treatment in patients with the proliferative forms of nephritis. MMF demonstrated a steroid-sparing effect in the whole population. • Treatment failure was recorded in 4/18 patients, all with membranous nephropathy. Rheumatology 2004;43:377–380

  20. Lupus nephritis: treatment with mycophenolate mofetil : P. P. Kapitsinou, J. N et al Rheumatology 2004;43:377–380

  21. Lupus nephritis: treatment with mycophenolate mofetil : P. P. Kapitsinou, J. N et alKey messages • MMF (MYCOMUNE) appears to be a safe and efficacious alternative treatment in proliferative lupus nephritis, whereas its efficacy in lupus membranous nephropathy remains unclear. Rheumatology 2004;43:377–380

  22. Heymann nephritis and membranous nephropathy • Luca and co-workers • Effect of MMF (MYCOMUNE) in rats with active Heymann disease, a model of human membranous glomerulopathy. • The percentage of rats that developed proteinuria in the treated groups was significantly lower than that of untreated rats. • Penny and associates • MMF (MYCOMUNE) treatment started immediately after induction of the disease and maintained for 4 wk prevented glomerular Ig deposition and interstitial infiltration by T lymphocytes and macrophages, easily observed in untreated rats at 8 wk.

  23. Early temporary MMF (MYCOMUNE) treatment completely prevented the associated massive proteinuria. • These protective effects were absent when temporary MMF (MYCOMUNE) treatment was initiated 4, 6, or 10 wk after induction of the disease, when immune-mediated injury was already established. • These observations underscore two important concepts. First, early T lymphocyte activation/proliferation is a crucial pathogenic step for the development of immune-mediated renal injury, even when the process is initiated by humoral mechanisms. • Second, once set in motion, T lymphocyte-mediated injury may propagate and become autonomous. MMF monotherapy may have only limited efficacy at this phase.

  24. Membranous glomerulopathy • Miller at al. administered MMF (MYCOMUNE) to 16 patients with primary membranous nephropathy. There were no significant changes in mean values for serum creatinine, serum albumin, or proteinuria, although the latter fell by 50% in six patients, whereas partial remissions were observed in two patients. It must be stressed that these patients had been resistant to conventional therapy and might therefore represent a subpopulation with particularly severe and intractable disease. • In another uncontrolled study, Choi and co-workers treated a cohort of 46 patients who had assorted primary glomerulopathies with MMF. In those suffering from membranous glomerulopathy (n 17), MMF reduced median proteinuria from 7.3 to 1.5 g/day and ameliorated the serum levels of albumin and cholesterol.

  25. Other immune-mediated nephropathies • Nowack et al. administered MMF (MYCOMUNE) combined with low-dose oral corticosteroids to nine patients with Wegener granulomatosis and two patients with microscopic polyangiitis, all of whom had severe renal involvement. • In all patients, remission was achieved, with only one relapse after 14 months.

  26. Use Of MMF (MYCOMUNE) In Non immune mediatedNephropathies • A large fraction of progressive glomerulopathies develops in the absence of any perceptible immunological derangement. • This is the case with focal and segmental glomerulosclerosis (FSGS), diabetic nephropathy, and hypertensive nephrosclerosis.

  27. The immune independent mechanism most consistently associated with progressive nephropathies is mechanical stress to the capillary walls. • Intracapillary hypertension and tuft hypertrophy, frequently encountered in experimental models of progressive nephropathies, can damage the glomerulus by increasing the mechanical tension applied to its walls, according to the La Place relationship. • Several in vitro studies have indicated that mechanical strain is a powerful pro-inflammatory stimulus that can lead to mesangial cell proliferation, excessive production of extracellular matrix, and abnormal production of growth factors

  28. Non immune-mediated mechanisms of progressive renal injury.

  29. Beneficial Effects of MMF (MYCOMUNE) in Non immuneMediated Nephropathies The 5/6 renal ablation model : • Regarded as a typical instance of Nonimmune-mediated chronic nephropathy. • Fujihara, Noronha, and co-workers administered MMF to Nx rats, starting immediately after renal mass removal. MMF strongly attenuated the early lymphocyte and macrophage infiltration observed in the renal tissue of these animals but had no effect on glomerular hypertension or hypertrophy. • In addition, MMF reduced the number of interstitial cells staining positively for ANG II. Sixty days after renal ablation, albuminuria, glomerulosclerosis, and interstitial fibrosis were evident in untreated rats. • MMF largely attenuated glomerular and interstitial fibrosis without reducing proteinuria.

  30. Experimental models of hypertension • Rats subjected to chronic NO inhibition develop systemic hypertension, which is accompanied by severe renal injury, consisting of proteinuria, glomerular sclerosis, glomerular collapse, interstitial fibrosis, and vascular damage. These abnormalities are aggravated by simultaneous administration of dietary salt overload. • Fujihara et al. showed that rats receiving a NO inhibitor and a salt-rich diet develop severe glomerular hypertension as well as renal lymphocyte/macrophage infiltration, particularly at the interstitial area

  31. Treatment of these rats with MMF (MYCOMUNE) limited renal interstitial inflammation and ANG II accumulation and attenuated glomerular and interstitial injury, without ameliorating glomerular hypertension or proteinuria. • Quiroz et al. showed that rats receiving a NO inhibitor during a 3-wk period became salt sensitive, developing hypertension and renal injury when challenged subsequently with a high-salt diet. • However, rats receiving MMF during the NO inhibition period remained salt resistant

  32. This protective effect of MMF (MYCOMUNE) was associated with its ability to prevent glomerulosclerosis and vascular damage, as well as inflammation- related events such as renal infiltration by T lymphocytes and the appearance of ANG II-positive cells. • The same group examined rats given a 3-wk infusion of ANG II, which developed hypertension, tubulointerstitial injury, and renal infiltration by activated T cells, a large fraction of which stained positively for ANG II. • MMF treatment limited these abnormalities and prevented the subsequent development of salt-sensitive hypertension

  33. These investigators showed in these rats that elevated blood pressure was associated with renal infiltration by lymphocytes, macrophages, and ANG II-positive cells. • Administration of MMF (MYCOMUNE) prevented both renal inflammation and the development of arterial hypertension. • Collectively, the observations made in these experimental models indicate that renal inflammatory events are closely associated with hypertension and can be a cause and/or a consequence of the heightened blood pressure levels. • Limitation of these events by anti-inflammatory therapy offers the exciting perspective of preventing both the development of hypertension and hypertensive renal injury.

  34. Diabetic nephropathy • Utimura et al. administered MMF (MYCOMUNE) to uninephrectomized streptozotocin diabetic rats, starting immediately after diabetes induction. • MMF (MYCOMUNE) prevented renal infiltration by macrophages but not the glomerular hypertension characteristically associated with the early phases of this model. • After 8 mo, untreated diabetic rats exhibited intense proteinuria and widespread glomerular segmental sclerotic lesions, whereas protein excretion and glomerulosclerosis were comparable in MMF-treated diabetic rats and uninephrectomized controls. • These observations suggest that MMF (MYCOMUNE) may prevent diabetic nephropathy by limiting renal inflammation, rather than by ameliorating glomerular hemodynamics

  35. MMF treatment for primaryglomerular diseases; Choi et al • Nephrology Division, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA • 1996-1999 • Forty-six patients with biopsy proven glomerulonephritis complicated by nephrotic syndrome and/or renal insufficiency, and who received at least three months of treatment with MMF. • Median (range) 24-hour urine protein to creatinine ratio (Up/c) and serum creatinine at the start and end of MMF therapy were compared.

  36. The most frequent indications for the utilization of MMF (MYCOMUNE) as adjunctive (or sometimes primary) treatment of these patients included : • Steroid-resistant (19.7%) or steroid dependent nephrotic syndrome (32.6%). • Other indications included cyclosporine (CsA)-resistant or CsA- dependent nephrotic syndrome or • Serious side effects from or intolerance of steroid or CsA; azathioprine (AZA) deteriorating renal function; • Patient’s refusal of steroid treatment; and relapses in progressive renal insufficiency with efforts to discontinue cyclophosphamide (CTX).

  37. MCD-7 patients • FSGS -18 patients • Membranous Nephropathy-17 patients • IgAN- 3 patients • MPGN- 1 patient

  38. Minimal change disease • 7 patients. • Median (range) age of 41 (23 to 74) years. • 3 were male, 5 were Caucasian, and 2 were African-American • Five of 7 patients were nephrotic in the setting of a normal serum creatinine. • Baseline Up/c and SCr was 4.6 (0.1 to 6.0) and 1.0 (0.6 to 1.7) mg/dL. • The indication for MMF (MYCOMUNE) treatment was steroid or CsA dependence in each, and 6 of 7 received, some form of concomitant steroid treatment.

  39. Minimal change disease • 3 of 5 initially nephrotic – complete remission at end of study. • Complete withdrawal of steroids was achieved in 5 of the 6 patients. • Patient #3 had a substantial partial remission (Up/c 4.6 → 0.6) by 3 months of MMF treatment, but relapsed with attempts at steroid withdrawal. In addition, he presented with neck mass after only 6 months of treatment with MMF and a total 30 months of prednisone. Biopsy disclosed Hodgkin’s lymphoma. Both lymphoma and nephrotic proteinuria remitted completely with chemotherapy. • One patient (#6) was MMF resistant

  40. Focal segmental glomerulosclerosis • 18 patients • Median (range) age of 37 (16 to 65) years. • 66.7% were male, 13 (72.2%) were Caucasian, 4 (22.2%) were African American and 1 (5.6%) was Asian. • Twelve of 18 (66.7%) patients had renal insufficiency and 9 of 17 (52.9%) had nephrotic proteinuria despite ACEi/AIIRa therapy in 7 of 9. • Indications for MMF (MYCOMUNE) treatment included steroid resistance or steroid +/- CsA dependency and/or progressive (sometimes rapidly deteriorating) renal insufficiency.

  41. Twelve of 18 initially received concomitant steroid treatment; in 8 of those 12, the drug and its dose were the same as those prior to MMF and, in 4, steroids were initiated at the same time as MMF in a previously described protocol. • MMF (MYCOMUNE) was used as the only immunosuppressive medication in the other 6 patients.

  42. The Up/c decreased by a median of 48%, being 0.8 (0.1 to 8.2) at the end of the MMF treatment period (P 0.001). • Two patients (#13, #15)—including one from the nephrotic group—had a complete remission of proteinuria; • 6 patients (35.3%)—including 4 from the nephrotic group—had a partial remission; and • 2 patients (11.1%)—both non-nephrotic—had an increase in their proteinuria of 5 and 10%.

  43. In the 9 patients with nephrotic range proteinuria, Up/c pretreatment was 7.5 (2.7 to 20.3) and decreased to 3.9 (0.1 to 8.2) post-therapy (P 0.008). • One nephrotic patient (#13) experienced a complete remission that has been sustained over 11 months following discontinuation of MMF. • There was a significant reduction in S Chol and in the MAP, together with a significant improvement in S Alb levels. • There was no significant change in serum creatinine in the FSGS patients as a group over the study period.

  44. Membranous nephropathy • 17 patients. • Median (range) age of 54 (30 to 75) years, 58.8% were male, 14 (82.4%) were Caucasian, 2 (11.8%) were African-American and 1 (5.9%) was Asian. • Fifteen patients (88.2%) had nephrotic range proteinuria and six (35.3%) had renal insufficiency. • At baseline, Up/c and SCr were 7.3 (0.1 to 18.5) and 1.1 (0.7 to 3.5) mg/dL, respectively. • Indications for MMF treatment included steroid (11/17) CsA (4/17) or CTX (1/17) dependency, steroid or CsA resistance, steroid or CsA intolerance, suboptimal response to CsA, and progressive renal insufficiency. • Three patients received MMF monotherapy.

  45. In the 15 patients with nephrotic range proteinuria, Up/c was 7.8 (3.6 to 18.5) pretreatment and was 2.3 (0.1 to 14.3) post-treatment (P 0.001). • Two patients (13.3%), both of whom who were nephrotic, achieved a complete remission; 8 patients (60%), all of whom were nephrotic, achieved a partial remission; and 2 patients (13.3%), including 1 nephrotic, had increased proteinuria. • Eight of the 15 (53.3%) nephrotic patients improved to sub nephrotic proteinuria with treatment. • Two patients relapsed after MMF was stopped, and they both responded to retreatment. • With MMF (MYCOMUNE) treatment there was no change in median serum creatinine or mean arterial pressure. There were significant improvements in serum albumin and cholesterol.

  46. Progressive steroid and Cya withdrawal was successfully achieved in the majority (14 of 15, 93.3%) of patients with steroid or CsA dependency. • In one patient (#37) who was both steroid and CTX dependent, MMF treatment permitted a reduction in steroid dose and CTX was stopped shortly after starting MMF. • MMF (MYCOMUNE) dependency was observed in 4 patients (#26, 27, 34, and 36).

  47. IgA Nephropathy • Two of the 3 patients had renal insufficiency and one had, in addition, nephrotic proteinuria. • The other patient (#44) was steroid dependent and had suffered serious complications from steroid therapy. • Patient #43 experienced substantial improvement in excretory renal function and a partial remission in proteinuria. • He relapsed after 3 months, however, when MMF was discontinued while he underwent tonsillectomy, but he responded again following resumption of MMF. • Two patients (#43 and 45) showed improvement in renal function while receiving MMF. All three patients had been on fish oil prior to and during MMF therapy.

  48. MPGN • Patient #46 had both renal insufficiency and nephrotic proteinuria. • Excretory renal function transiently improved until gastrointestinal symptoms required a dosage reduction. • He did, however, experience a substantial partial remission in proteinuria.

  49. Summary • The potential role for MMF in steroid and/or CsA dependent MCD is that of an effective steroid sparing agent without the potential adverse renal, hemodynamic, and metabolic effects of CsA. • If discontinuation of MMF after 6 to 12 months of treatment is followed by a relapse, results indicate that retreatment of relapse will likely be effective, and the treating physician always has the option of proceeding to cytotoxic therapy. • Though complete remission may not be possible in FSGS, MN major steroid sparing effect along with partial remission of proteinuria is possible.

  50. MPA TDM (Therapeutic drug monitoring) • The study results from Transplantation proceedings suggest that there is a relationship between MPA pharmacokinetics and clinical events. The MPA C0 might be an appropriate pharmacokinetic monitoring parameter for kidney transplantation.* • * Transplantation proceedings june-2006

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