NEW TRENDS IN THE TREATMENT OF NEPHROTIC SYNDROME Fernando Fervenza - - PowerPoint PPT Presentation

Cagliari 2 Maggio 2011

NEW TRENDS IN THE TREATMENT OF NEPHROTIC SYNDROME

Fernando Fervenza - Mayo Clinic Rochester

Discussant: Leonardo Cagnoli - Rimini

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

• 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/m2 once weekly x 4 wk

RTX 375mg/m2 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 /µl (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 PUBLICATIONS ON PATIENTS WITH IMN

Bomback AS et al CJASN 2009;4:734-744

CLINICAL OUTCOME OF IMN PATIENTS TREATED WITH RITUXIMAB

n° % n° % Ruggenenti 2008 (50pts) 10/50 20 36-50 Fervenza 2008 (15pts) 2/15 13 6/15 40 CR PR IDIOPATHIC MN 65 pts

SERIOUS ADVERSE EVENTS

Laryngospasm (Remuzzi et al, 2002) Lung Neoplasm (Fervenza et al, 2008)

• Progressive multifocal leukoencephalopathy (JC poliomavirus)
• Allergic reactions
• Development of Human anti-chimeric antibodies

7 28 33 5 10 15 20 25 30 35 % HACA positive 3 6 9 12

HOWEVER, IN THE LONG-TERM ADVERSE EVENTS CAN OCCURR ...

• 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 IMPORTANT QUESTIONS

• 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

SOME ANSWERS

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%)

Synthetic ACTH

Ponticelli 2006 Arnadottir 2006

Tot 94%

Complete Remision 5/16 (31%) 11/15 (73%) 16/31 (52%) Partial Remission 10/16 (62%) 3/15 (20%) 13/31 (42%)

Rituximab

Cravedi 2007 Fervenza 2008,2010 Tot 69% 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%)

• l

• l

100%

REMISSION NO IMPROVEMENT

CONTROL TREATED

Time weeks

26 52 26 52

Cattran D.C. et al, 2001

22 13 78 87 75 46 25 53

Dialysis-free survival Survival without reaching doubling of serum creatinine Complete remission Complete or partial remission IMN at 10 yr f-u, MP 1g/diex3+P0.5 mg/Kg CPA 2 mg/Kg; alternate monthly course for 6 mo 89% 65%

Jha V et al. JASN 2007;18:1899-1904

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 ?

OPEN QUESTIONS

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