Henöch Schönlein Purpura nephritis and management. Licia Peruzzi

Transcription

1 IPNA-ESPN Junior Master Class Henöch Schönlein Purpura nephritis and management Licia Peruzzi Nephrology Dialysis and Transplantation Regina Margherita Children s Hospital Health and Science University Hospital Turin Italy

2 HSP:.the most common vasculitis in children Incidence: in th Netherlands from 6.1/ children 0-18 years old to 14.9/ children 3-6 years old Aalberse et al Ann Rheum Dis. 66, , 2007 In UK: 20.4/ children Dolezalova et al J Rheumatol 31, , 2004 Gardner-Medwin at al Lancet 360, , 2002 Yang et al Rheumathol 44, , 2005 overestimation? a matter of diagnostic criteria

3 HSP:.which diagnostic criteria? 1990 American College of Rheumatology: at least 2 of the following Age <20 years at onset Palplable purpura Acute abdominal pain Biopsy specimens with granulocytes in the walls of small arteries or venules 1990 Chapel Hill conference on the nomenclature of systemic vasculitis Vasculitis with IgA dominant immune deposits affecting small vessels tipically involving skin, gut and glomeruli and associated with arthralgias or arthritis 2006 EULAR- Pediatric Rheumathology European Society (PRES Classification) Palpable purpura mandatory + at least one of the following: Diffuse abdominal pain Any biopsy sample showing predominant IgA deposition Arthritis or acute arthralgia in any joint Renal involvement: any hematuria or proteinuria 2008 Ankara Consensus Conference updated PRES: IgA deposition in biopsy sample is required in atypical purpura

4 the renal involvement: how often? a b c d e f In children with HSP: from 20 to 54 % mean 33% when? giorni 1 mese 2 mesi 3 mesi 6 mesi 12 mesi 18 mesi from 3 days to 17 months from HSP onset Almost all within 6 months..someone after months or even years

5 which type of renal involvement? Isolatad persistant hematuria 28% urinary abnormalities persistant for 4 weeks : Hematuria and proteinuria Acute nephritic s Nephrotic s Evolution to CRF 5% 20% Long term progression 70-80% recover Cumulative series of children with renal involvement (666 patients) (Koskimes 1981, Niaudet 1986, Stewart 1988, Mollica 1992, Michel 1992, Blanco 1997) VARIABLE RENAL INVOLVEMENT : IN MOST CASES MILD with RAPID RESOLUTION BUT..

6 how to monitor renal involvement? REPEAT AND CONFIRM FOR 3 TIMES ONCE A WEEK FOR 1 MONTH ONCE A MONTH FOR 6 MONTHS THEN EVERY 6 MONTHS Hb Prot POSITIVE NEGATIVE PROTEINURIA/CREATININURIA RATIO ON SPOT URINE PEDIATRIC NEPHROLOGIST CONFIRM FOR 3 TIMES <0.5 mg/mg >0.5 mg/mg

7 is there anything to do to prevent renal involvement? precocious steroid treatment can prevent the development of renal involvement?

8 Relative Risk of nephritis after short term steroid treatment vs placebo 1m PREDNISONE mg/kg/day for 7-21 days 3m 6m 12m No evidences of benefit of prednisone compared to placebo in preventing nephritis within 6-12 mesi EBM: GRADE A RECOMMENDATION

9 Similar conclusions STEROIDS DO NOT PREVENT NEPHRITIS but can be useful to control extrarenal signs STANDARD DOSE 1 mg/kg/day for 1-2 weeks

10 No other strategies to prevent nephritis proved effective

11 Prednisone 2 mg/kg for 1 week 1 mg/kg for 1 week 7 days from onset of purpura Placebo 2 weeks PROTEINURIA at 12 months No evidence of benefit of steroids

12 if persistant urinary abnormalities? CONFIRMED AT LEAST 3 TIMES MACROSCOPIC (GROSS) HEMATURIA Hb Prot POSITIVE PROTEINURIA/CREATININURIA RATIO ON SPOT URINE PEDIATRIC NEPHROLOGIST >0.5 mg/mg

13 which type of nephritis? 219 patients (83 children), with HSP nephritis assessed by renal histology Enrolled from 1973 to 1993 and followed up until 2002 Class I Class II Class III Class IV Class V Class VI Children

14 renal biopsy is it necessary immediately? is it helpful for therapy? is it predictive of outcome? Renal biopsy at onset of disease can display more severe histology due to the characteristics of the disease acutely inflammatory but potentially reversible Timing for renal biopsy is guided by the clinical situation Can be delayed in a further time but should be performed in persistant urinary abnormalities particularly in scarcely responding cases It can be of help in difficult and severe cases

15 .a critical reading of KDIGO GUIDELINES HSP is an acute disease with more severe inflammatory lesion particularly when biopsy is performed early Histology : More severe Acute inflammation Glomerular cell proliferation Crescents : often more than 20-30% acute lesions can heal progression is due to several bursts of inflammation

16 ..different histological classifications ISKDC EMANCIPATOR Limits: exclusive attention to crescents, expression of acute damage. Not predictive for progression to CKD: more bound to sclerosis and tubulo-interstitial damage OXFORD Limits: crescents are not included not yet validated for children

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18 progression: impressive data from very long term followup of HSP cases with nephrits with onset in childhood Goldstein Lancet 1992 Ronkainen Lancet YEARS FOLLOW-UP 78 PATIENTS 47 PATIENTS 44% SEVERE NEPHRITIS AT ONSET 35% 13% MILD NEPHRTIS AT ONSET 11% REDUCED RENAL FUNCTION and/or HYPERTENSION 16/46 PREGNANCIES COMPLICATED BY HYPERTENSION and/or 16/23 PROTEINURIA WARNING: need for long term observation even in cases who went to remission (no urinary activity signs)

19 which factors are predictive of long term unfavourable outcome? Uncontrolled proteinuria during follow-up, in particular in girls is predictive of progression

20 APPLICATION: Licia Peruzzi on behalf of the board of the ESPN WG Immune mediated renal disorders GRANTED for TITLE: : A EUROPEAN REGISTRY OF CHILDREN WITH HENOCH SCHOENLEIN NEPHRITIS TO DETECT CLINICAL, GENETIC AND IMMUNOLOGICAL RISK FACTORS 1) GWAS: on all cases of HSP with or without renal involvement 2) HSP NEPHRITIS REGISTRY: cases so severe to deserve renal biopsy 3) PROSPECTIVE STUDY: (on a limited cohort of very active cases) focusing on selected mucosal immune systems disorders

21 which is the AIM of therapy in HSP nephritis? Induce remission of proteinuria which drugs are available? ACE inhibitors Steroids: iv MP pulses followed by oral prednisone Cyclophosphamide: associated to steroids Cyclosporin Azathioprine Mycophenolate Ig iv Antioxidants Plasma exchange which protocols?

22 same as IgAN

23 OPTIMIZED SUPPORTIVE THERAPY

24 .a critical reading of KDIGO GUIDELINES proteinuria and MC proliferation may be reduced, but the endocapillary inflammatory component and the crescents are not expected to improve. following this guideline may delay a potentially more effective treatment and increase the risk of CKD progression in patients with a relevant percentage of crescentic glomeruli and/or a massive inflammatory leucocyte infiltration and/or necrotic lesions. these lesions, if not healed, leave sclerotic irreversible scars. delaying a more effective anti-inflammatory treatment for months may be dangerous with respect to the final outcome.

25 .a critical reading of KDIGO GUIDELINES no placebo-controlled RCT on oral prednisone alone or methylprednisolone (MP) pulses associated with oral prednisone in established HSPN has been performed. no reports proving the benefit of oral prednisone alone in HSPN the use of prednisone alone has been abandoned in favour of MP pulses followed by oral prednisone MP pulses have a stronger anti-inflammatory effect

26 Niaudet 1998 Prospective no controlled study 38 patients treated with 3 pulses MP 1 g/1.73 m2 followed by oral prednisone for 3.5 months Follow-up 1-16 years Effective in severe cases at high risk of progression PREDNISONE IS EFFICACIOUS IN TREATING HSP NEPHRITS

27 .a critical reading of KDIGO GUIDELINES Immune suppressors are generally USEFUL in SEVERE HSP nephritis.. No controlled studies available demonstrating that steroids and immune suppressors are useful in moderatly severe HSP nephritis (crescents in <50% of glomeruli) to induce significant results on progression at distance but can be useful in proteinuria reduction the suggestion of the KDIGO guidelines not to add immunosuppressive drugs to steroids in patients with <50 % crescentic glomeruli even in presence of nephrotic syndrome and/or deterioration of GFR is in contrast with the expert opinion and at risk of not being followed

28 CRESCENTIC IgAN Rare cases Poor prognosis: 40 to 75% reached ESRF in 3-10 years No RCT 3 observational studies retrospective immunosuppression with steroids and cyclophosphamide Poor quality evidence for plasma exchange Due to high probability of rapid progression to ESRF aggressive treatment as for ANC A vasculitis is suggested

29 Crescents may regress or evolve into sclerotic lesions Crescents may disappear when detected during gross hematuria TIMING OF BIOPSY Crescents are found when biopsy is prompt In Oxford and Valiga crescents had no predictive value: but advanced cases were not included Role of therapy No trial conceivable

30 56 pts A: steroids B:steroids+ CFM 90 mg/m2/day for 42 days 48.2% complete remission 39.3% persistant urinary abnormalities 12.5 % ESRD Randomized controlled trial Outcome does not correlate with : Age, BP, total protein, serum albumin, proteinuria at onset, relapses, extrarenal signs 5/28 pts with NS at onset and severe GN have completely recovered Crescents 50% glomeruli: ESRD Persistant urinary abnormalities = poor outcome Effects not demonstrated on long distance outcome

31 Cyclosporin EFFECTIVE IN MAINTAINING REMISSION OF NEPHROTIC SYNDROME AT DISTANCE : stronger effect than MP

32 Cyclosporin 2 cases: 7 years old children Biopsy: ISKDC IIIb 14 months CyA for persistant nephrotic proteinuria 2 biopsy no nephrotoxicity EFFECTIVE IN INDUCING REMISSION OF NEPHROTIC RANGE PROTEINURIA: stronger effect than MP

33 Mycophenolate SMALL CASE SERIES UNCONTROLLED STUDIES NON INFERIORITY TO STEROIDS

34 Mycophenolate Results superimposable to steroids: useful as steroid sparing agent 3 severe pediatric cases: 1 RPGN 2 nephritic nephrotic syndrome resistant to steroids treated for 6 months Remission of proteinuria and renal function improvement

35 WHOM TO TREAT According to risk factors evaluation: PROTEINURIA, GFR, HISTOLOGY LOW RISK proteinuria<0.5 g/d microscopic hematuria GFR normal histology in case of persistancy: < grade III MODERATE-HIGH RISK: proteinuria > g/d reduced GFR hypertension histology: > grade III RAPIDLY PROGRESSIVE rapid GFR decline AKI Nephrotic proteinuria Histology: crescents> 50% FOLLOW-UP Monitor every 6 months for at least 3 years then annually OPTIMIZED SUPPORTIVE THERAPY for 3-6 months: NOT LONGER!!! and questionable Proteinuria >1 g/d GFR decline IMMUNESUPPRESSION CORTICOSTEROIDS

36 how about long distance follow-up? Arch Dis Child Nov;54(11): IT IS RECOMMENDED BASING ON DATA FORM LONG TERM FOLLOW-UP STUDIES TO MAINTAIN LONG TERM FOLLOW-UP IN CHILDREN WHO DEVELOPED HSP WITH RENAL INVOLVEMENT EVEN AFTER RESOLUTION OF URINARY ABNORMALITIES IN PARTICULAR IN GIRLS AND AT PREGNANCY IT IS USEFUL TO ADVISE IN THE MEDICAL HISTORY HSP EVEN WITHOU RENAL INVOLVEMENT In PARTICULAR IN GIRLS

37 Keep memory of HSP HSP HSP HSP + NEPHRITIS HSP PEDIATRICIAN HSP + NEPHRITIS CHRONIC NEPHRITIS GENERAL PRACTITIONER PEDIATRIC NEPHROLOGIST ADULT NEPHROLOGIST PEESONAL MEDICAL FILE

38 QUESTION TIME

39 GFR ml/min/1.73 m2 EMATURIA PROT/CREA mg/mg Cr 30 oct 2013 Arthritis Severe functional impairment MP MP 8 PULSES: 650 mg/kg= 1.2 g tot INTUSSUSCEPTION Ileum severe gi bleeding RENAL BIOPSY Palpable purpura, Worsening of arthralgias, Severe abdominal pain CYCLOPHOSPHAMIDE (12 weeks) Oral PREDNISONE tapering 1-nov 8-nov 15-nov 22-nov 29-nov 6-dic 13-dic 20-dic 27-dic 3-gen 10-gen 17-gen 24-gen 31-gen 7-feb 14-feb 21-feb 28-feb 7-mar HSP No crescents No mesangial proliferation Diffuse endocapillary proiliferation Deposits IgA C3 mes, subendoth, intramembranous TI normal Normal renal function ; normal blood pressure 0 1-nov 8-nov 15-nov 22-nov 29-nov 6-dic 13-dic 20-dic 27-dic 3-gen 10-gen 17-gen 24-gen 31-gen 7-feb 14-feb 21-feb 28-feb 7-mar

40 1) How would you treat severe joint and abdominal localization? 2) Apperance of renal involvement after heavy steroids treatment: how to continue? 3) Timing of biospy? 4) How to critically interpretate the histology finding? 5) Which therapeutical approach?

41 which therapy options are available? HEMATURIA PROTEINURIA other THERAPy Microscopic < 1mg/mg Mild extrarenal signs Prednisone 1 mg/kg for 3-4 weeks Macroscopic hematuria < 1mg/mg Prednisone up to 2 mg/kg or for longer Microscopicc Macroscopic hematuria > 1mg/mg NEPHRITIC SYNDROME NEPHROTIC SYNDROME Methylprednisolone 3 iv bolus 10 mg/kg followed by prednisone Microscopicac Persistant +++ NEPHROTIC PERSISTANT UNFAVOURABLE HISTOLOGY IMMUNO SUPRESSORS MACROSCOPIC HEMATURIA RECURRENT Microscopic Persistant +++ 1mg/mg NEPHROTIC PERSISTANT RAPIDLY PROGRESSIVE RENAL FAILURE PLASMA EXCHANGE IMMUNE- SUPPRESSORS STEROIDS