Treatment of MGN A roundtable discussion based on best evidence Drs Cattran Expert Panel Dr Ruggenenti,Falk,Ponticelli,Fervenza,Remuzzi

Level 1 2 3 4 5 6 Definition of evidence Randomized, controlled trial (RCT) that demonstrated a statistically significant difference in at least one important outcome OR If the difference is not statistically significant, an RCT of adequate sample size to exclude a 25% difference in relative risk with 80% power, given the observed results RCT that does not meet level 1 criteria Non-randomized trial with contemporaneous controls selected by some systematic method (i.e. not selected by perceived suitability for one of the treatment options for individual patients) OR Subgroup analysis of a randomized trial Before-after study or case series (of 10 patients) with historical controls or controls drawn from other studies Case series (of 10 patients) without controls Case reports (of <10 patients) Levels of evidence for rating studies and grading system for treatment recommendations [Carruthers 1993 ]

Levels of evidence for rating studies and grading system for treatment recommendations [Carruthers 1993 ]

March 2,2007 Courtesy of Dr Ron Falk

Treatment of MGN More than one question A who to treat B when to treat C what to target D when to stop

WHO 1.persistent nephrotic syndrome?if unresponsive to conservative therapy alone 2.unresponsive (remains nephrotic) despite first- line specific immunosuppression 3.impaired and/or deteriorating renal function 4.unacceptable adverse events?can this be defined

When 1. How long should conservative or first-line therapy be tried? 2. Is there a degree of proteinuria that should dictate initiation? 3. Are there complications of the nephrotic syndrome that should dictate starting specific therapy(when and what)? 4. Are there surrogate markers that should be used?

What are the options?

What targets should be considered a success 1. Complete or partial remission? 2. Stable GFR (+/-20%)? 3. Acceptable risk profile

How long (if successful) 1.Complete remission-monitor only 2.Partial remission - continue for a minimum of one year? - add an additional agent? - except this results and continue Rx indefinitely?

How long (if not successful) 1. No complete remission in 3-6? 2. Alternate therapy if < 50% reduction in proteinuria by 3-6? 3. More than 30% reduction in renal function regardless of improved proteinuria?

A RETROSPECTIVE LONGITUDINAL STUDY TO EVALUATE THE PREDICTORS OF RESPONSE TO RITUXIMAB THERAPY IN IMN PATIENTS WITH PERSISTENT NEPHROTIC PROTEINURIA Study design 14 patients: - IMN (biopsy) - Proteinuria > 3.5 g/day despite ACEi therapy Treatment: - Rituximab (4 weekly infusions, 375 mg/sqm) Main outcome: - Proteinuria Ruggenenti et al., Clin J Am Soc Nephrol, 2006

Decline in Renal Function in Patients Treated With Prednisone for Idiopathic Membranous Nephropathy and in Controls Level 1Grade A Cattran DC et al. N Engl J Med 1989; 320(4):210-215

Level1Grade A Cameron JS et al. Q J Med 1999; 274:133-156

ACTH in Patients with Membranous Nephropathy 30 nephrotic patients with idiopathic MN randomized to ACTH or no specific treatment (control) for 9 months ACTH 1.0 mg once/week alternating with 0.75 mg twice/week for the first 8 months, then 0.5 mg once/week during month 9 Complete or partial remission in 15/15 ACTH group vs. 1/15 patients in controls (p<0.0001) Results were similar after further 12-month followup Level 1 Grade A Berg A-L et al. Kidney Int 1999; 56:1534-1543

CLINICAL STATUS AT 10 YEARS Ponticelli C et al Kidney Int 48,1600, 1995 Complete remission Partial remission Treated pts (%) 47 19 P=0.020 Untreated pts (%) 7 36 Nephrotic syndrome Renal insufficiency 16 9 18 Dialysis Death Level 1,Grade A 6 3 P=0.043 25 14