NEW TRENDS IN THE TREATMENT OF NEPHROTIC SYNDROME Fernando Fervenza - Mayo Clinic Rochester Discussant: Leonardo Cagnoli - Rimini Cagliari 2 Maggio 2011
RITUXIMAB THERAPY FOR MEMBRANOUS NEPHROPATHY; A SYSTEMATIC REVIEW Bomback AS et al CJASN 2009;4:734-744 12 Single Case Reports 9 Case Series (2 to 50 pts) Idiopathic MN 10 publ. Secondary MN 11 publ.
PUBLICATIONS ON PATIENTS WITH IDIOPATHIC MEMBRANOUS NEPHROPATY Bomback AS et al CJASN 2009;4:734-744 � 4 SINGLE CASE REPORTS � 6 UNCONTROLLED CASE SERIES (5 from a single center) REMUZZI � s GROUP FERVENZA 50 pts 15 pts
PUBLICATIONS ON PATIENTS WITH IMN Bomback AS et al CJASN 2009;4:734-744 � Small sample sizes with the bulk of published experiences coming from a single center in Italy � Patients with severe proteinuria and preserved renal function � Possible publication bias � Patients selection, prior therapy and RTX treatment protocols varying significantly � Previous immunosuppression (more frequently, including Fervenza et al, 2008) or not (Fervenza et al, 2008, Remuzzi et al, 2002, Ruggenenti et al, 2003 and 2006, Cravedi et al 2007, Ruggenenti et al 2008). � Selection on the basis of the histological absence of severe tubolointerstitial scarring (Ruggenenti et al, 2006) � RTX treatment dose: RTX 375mg/m 2 once weekly x 4 wk RTX 375mg/m 2 repeated 1 week later if circulating B cell ≥ 5 mmc (Cravedi et al 2007) RTX 1g on days 1 and 15 repeated at 6 mo if proteinuria >3g/24h and CD 19+ B cell ≥ 15 / µ l (Fervenza 2008, Pixley 2008)
PUBLICATIONS ON PATIENTS WITH IMN Bomback AS et al CJASN 2009;4:734-744 � Time to complete or partial remission not consistently reported � Short follow-up � Primary end point: proteinuria
CLINICAL OUTCOME OF IMN PATIENTS TREATED WITH RITUXIMAB CR PR n° % n° % IDIOPATHIC MN Ruggenenti 2008 (50pts) 10/50 20 36-50 65 pts Fervenza 2008 (15pts) 2/15 13 6/15 40
SERIOUS ADVERSE EVENTS Laryngospasm (Remuzzi et al, 2002) Lung Neoplasm (Fervenza et al, 2008)
HOWEVER, IN THE LONG-TERM ADVERSE EVENTS CAN OCCURR ... - Progressive multifocal leukoencephalopathy (JC poliomavirus) - Allergic reactions - Development of Human anti-chimeric antibodies 35 33 30 28 25 20 % HACA positive 15 10 7 5 0 0 0 0 3 6 9 12
SOME IMPORTANT QUESTIONS � NOTING THAT HIGH-GRADE PROTEINURIA MAY LEAD TO LOSSES OF RTX IN THE URINE, WHAT IS THE OPTIMAL DOSE IN Pts WITH NEPHROTIC SYNDROME ? � ARE RTX LEVELS CORRELATED WITH THE DEGREE OF B CELL DEPLETION AND IS THERE A RELATIONSHIP TO THE CLINICAL RESPONSE? � COULD A HIGH-DOSE REGIMEN OF RTX RESULTS IN A HIGHER REMISSION RATE MANTAINING A GOOD SAFETY PROFILE ? � WHAT ARE THE LONG-TERM RISKS AND BENEFITS IN PATIENTS WITH IMN ? � IS THERE ANY CORRELATION BETWEEN RTX DOSES AND DEVELOPMENT OF HACAs ?
SOME ANSWERS � PROTEINURIA APPEARED TO HAVE A SIGNIFICANT EFFECT ON THE PK AND PHARMACODYNAMICS OF RTX BUT THE EFFECTS ON THE EFFICACY COULD NOT BE DETERMINED � NO CORRELATION WAS OBSERVED BETWEEN RTX LEVELS AND THE DEGREE OF B CELL DEPLETION AND EVEN HERE THERE WAS NO RELATIONSHIP TO THE CLINICAL RESPONSE � NO SIGNIFICANT DIFFERENCES IN THE RESPONSE RATE AT 12 MONTHS WERE OBSERVED BETWEEN PATIENTS TREATED WITH TWO-DOSE REGIMEN VS PATIENTS TREATED WITH FOUR-DOSE REGIMEN � BY THE END OF 24 MONTHS THE PERCENTAGE OF PATIENTS WHO ACHIEVED REMISSION WAS HIGH (80%) BUT COMPLETE REMISSION WAS RARE (20%) � THE AUTHORS DID NOT REPORT SERIOUS ADVERSE EVENTS. IT IS POSSIBLE THAT Pts TREATED WITH HIGHER RTX DOSES ARE LESS LIKELY TO DEVELOP HACAs Fervenza F et al, Clin Jasn 2010;5: 2188-98
BUT TWO MAIN QUESTIONS HAVE STILL TO BE ANSWERED � SHOULD RITUXIMAB BE A FIRST LINE THERAPY FOR IDIOPATHIC MEMBRANOUS NEPHROPATHY ? � WHAT ARE THE MECHANISMS INVOLVED IN THE RESPONSE TO THERAPY ?
IMN: COMPLETE OR PARTIAL REMISSION WITH THREE DIFFERENT TREATMENTS DRUG AUTHORS AUTHORS RESPONSE Steroids/cytotoxic Passerini 2003 Jha 2007 Tot 81% Complete Remision 72/174 (41%) 15/47 (32%) 87/221 (40%) Partial Remission 72/174 (41%) 19/47 (40%) 91/221 (41%) Ponticelli 2006 Arnadottir 2006 Synthetic ACTH Tot 94% Complete Remision 5/16 (31%) 11/15 (73%) 16/31 (52%) Partial Remission 10/16 (62%) 3/15 (20%) 13/31 (42%) Fervenza 2008,2010 Tot 69% Cravedi 2007 Rituximab Complete Remision 4/36 (11%) 6/33 (18%) 10/69 (14%) Partial Remission 20/36 (55%) 18/33 (54%) 30/69 (55%)
CsA IN MEMBRANOUS NEPHROPATHY German CsA in NS Study Group Fritsche L. et al NDT 14, 1036, 1999 41 adult nephrotic pts treated in median for 353 days (3.3 ± 1.1 mg/Kg/day) plus steroids in 63% of pts (27.5 ± 21.2 mg/day) : CR (proteinuria<0.5 g/day) 14/41 (34%)
REMISSION NO IMPROVEMENT 100% 1 00 1 00 CONTROL TREATED 87 78 75 53 5 0 5 0 46 25 22 13 0 0 0 1° Tr . m i 2 ° Tr m i . 1° Tr m i . 2 ° Tr m i . 26 52 26 52 c o n t r o l r e a t t e d c o n t o l r e a t t r e d Time weeks Cattran D.C. et al, 2001
IMN at 10 yr f-u, MP 1g/diex3+P0.5 mg/Kg Jha V et al. JASN 2007;18:1899-1904 CPA 2 mg/Kg; alternate monthly course for 6 mo Survival without reaching doubling of serum creatinine Dialysis-free survival 89% 65% Complete or partial Complete remission remission
OPEN QUESTIONS B CELLS COULD FUNCTION AS ANTIGEN PRESENTING CELLS OF TUBULAR PROTEINS. BIOPSIES FROM SEVERAL PATIENTS WITH IMN SHOW A SIGNIFICANTLY HIGH CD20 mRNA EXPRESSION AND CD20+ CELLS IN THE TUBULO-INTERSTITIUM (Coen 2005). CAN THE BENEFICIAL EFFECT OF RTX BE ATTRIBUTED TO THE DEPLETION OF B CELLS AND TO ALTERATION OF B CELL FUNCTION AS ANTIGEN PRESENTING CELLS IN THE INTERSTITIUM ? CAN RTX REDUCE THE PRODUCTION OF ANTI-PHOSPHOLIPASE A2 RECEPTOR (HUMAN GLOMERULAR ANTIGEN SPECIFICALLY FOUND IN PATIENTS WITH IMN) ANTIBODIES ? WHAT IS THE RELATIONSHIP BETWEEN RTX TREATMENT AND RESORPTION OF ELECTRONDENSE IMMUNE DEPOSITS OBSERVED BY SOME AUTHORS AFTER THERAPY BOTH IN IMN OCCURING IN NATIVE KIDNEY AND IN KIDNEYS OF PATIENTS WITH RECURRENT POSTTRANSPLANT MEMBRANOUS NEPHROPATHY (Ruggenenti 2008, El Zogby 2009) ?
� In conclusion, great steps forward are being made in IMN treatment but ����
� adelante, Pedro, si puedes, con juicio. � A. Manzoni Cap. XIII � Promessi Sposi �
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