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					  Henoch-Schönlein Purpura
Evidence based management ?


         Ian Ramage
       Renal Unit, RHSC.
    Epidemiology
    Incidence of 13.5 to 18/100000 children
     (Stewart M et al Eur J Pediatr 1988:147:113-115,Neilsen HE Acta Paediatr Scand 1988;75:125-131)




    Peaks in Winter and Spring
     (Meadow SR Q J Med 1972;41:241-258)




    Commoner in Boys (2:1)
     (Robson WLM Advances in Pediatrics 1994;41:163-194, Levy M Advances Nephrol Necker Hosp 1976;6:183-228)




    Commonly follows URTI
     (Coppo R Ann Med Interne 1999;150:143-150)



    50% < 5 years & 75% < 10 years
     (Robson WLM Advances in Pediatrics 1994;41:163-194, Levy M Advances Nephrol Necker Hosp 1976;6:183-228)




    Rare in Afro/caribbeans
     (Galla JH Lancet 1984;2:522)




    11/05/2010
    Extrarenal Manifestations
    Dermal

    Lower limb and buttocks
    Extensor surfaces, symmetrical
       – Erythematous Macules
       – Purple, non-blanching, urticarial
         non-pruritic, purpuric papules
       – Confluent
    Associated hand/feet oedema
    Swellling of scalp, ears or
     periorbitally
    Haemorrhagic vesicles & bullae
     desquamation
     (Cream JJ Q J Med 1970;39:461-484, Levy M Adv Nephrol Necker Hosp
     1976;6:183-228, Balmelli C Schweiz Med Wochenschr 1996;126:293-298)




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Clinical Manifestations
Dermal

             Skin Biopsy

   Leukocytoclastic Vasculitis

   IgA deposition in vessel
    walls




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    Extrarenal manifestations
    Gastrointestinal
      Abdo pain in ~65%
      Precedes rash in 14-36%
       –      Vomiting
       –      Diorrhoea
       –      Periumbilical pain
       –      Bloody stools/Malaena
      Major GI complications ~ 5%
       –      Intussusception (90%)
               •      Ischaemia & Infarction
               •      Necrosis, perforation, fistula
               •      Late ileal stricture, appendicitis
               •      Upper GI haemorrhage
               •      Pancreatitis
               •      Gall bladder hydrops
               •      Pseudomembranous colitis
      (Balmelli C Schweiz Med Wochenschr 1996;126:293-298, Choong CK J
       Paediatr Child Health 1998;34:405-409, Lin SJ 1998)



    11/05/2010
Extrarenal Manifestations
Joints
   Arthralgia and periarticular
    oedema ~66%
   May precede rash & joint
    pain
   Self limiting
   No synovial effusions
      –    Knees
      –    Ankles
      –    Elbows
      –    Wrists

    (Cream JJ Q J Med 1970;39:461-484, Levy M Adv Nephrol
    Necker Hosp 1976;6:183-228)



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Extrarenal Manifestations
Rare
                                          Neurological
      Gastrointestinal              Encephalopathy
   Oesophageal stenosis            Cortical blindness
   Haemorrhagic pancreatitis       Intracerebral haemorrhage
   Protein-losing enteropathy      Cerebral vasculitis
             Respiratory            Behavioural changes
   Pulmonary and Pleural                   Urological
    haemorrhage                     Ureteric obstruction
   Pulmonary function              Scrotal swelling
    abnormalities                   Cord haematoma
   Interstitial lung disease       Testicular necrosis
                                    Ecchymotic scrotal induration
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                                    Haemorrhagic ascites/cystitis
    Renal Involvement
   Variable 41-61%
    (Kobayashi O Contrib Nephrol 1977;4:48-71, Koskimies O Acta Pediatr Scand 1974;63:357-363)




   Haematuria
               • Macroscopic
               • Microscopic
   Proteinuria
   Hypertension
   Azotaemia


    11/05/2010
    Glomeruli
   Mesangial Hypercellularity
     – Focal
     – Diffuse
   Leukocyte infiltration
   Increased mesangial matrix
   Mesangial interposition
   Synechiae
   Crescent formation
     – Cellular
     – Fibrous
   Pseudotubule formation
   Double Contours

    11/05/2010
Classification of Henoch-Schönlein purpura glomerulonephritis International
Study of Kidney Disease in Childhood.
(Heaton JM Histopathology 1977;1:93-104)




I Minimal changes (2%)
II Pure mesangial proliferation without crescents
    (a) Focal
    (b) Diffuse
III Mesangial proliferative glomerulonephritis with less than 50% crescents
    (a) Focal
    (b) Diffuse
IV Mesangial proliferative glomerulonephritis with 50–75% crescents
    (a) Focal
    (b) Diffuse
V Mesangial proliferative glomerulonephritis with more than 75% crescents
    (a) Focal
    (b) Diffuse
VI Membranoproliferative (mesangiocapillary) glomerulonephritis (2%)

(Meadow SR Q J Med 1972;41:241-258)




   11/05/2010
                Light Microscopy
            Grade I



            Grade 3



            Grade 5


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Investigations

   U & E’s, Protein & Albumin
   Urinalysis
             • Weekly until systemic symptoms resolve
             • EMU Protein/Creatinine ratio
             • Microscopy
   Blood Pressure
   FOB

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Clinical Course
   Average initial duration ~ 1 month
   Relapsing course
   Recurrent purpura common in first
    month, but rare after 3rd month
   Relapses
             •   Associated with URTI
             •   Duration 1 week
             •   Recurrence of symptoms e.g. Abdo pain
             •   Recurrence of renal signs
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Treatment - Extrarenal
   Skin
        • Steroids
        • Dapsone    (Albrecht J Hautartz 1999;50:308-311)




   Joints
        • No documented treatment
        • Limited bed rest               (Meadow SR Q J Med 1972;41:241-258)




   Cerebral Vasculitis
        • Plasma exchange                     (Gianviti A Arch Dis Child 1996;75:186-190)




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Treatment – Extrarenal
Gastrointestinal
   Allen DM Am J Dis Child 1960;99:147-168
    – 70 children with HSP & abdominal pain
         • 23% Abdo pain alone
         • 56% Abdo pain & malaena
         • 21% Abdo pain & guaiac-positive stools
    – 37 received steroids
         • In 50% pain resolved in 72 hours
         • No data on the clinical course of non-treated patients
    – On the basis of this study all children with HSP presenting to Boston
      Children’s Hospital received oral steroids

   Glasier CM AJR 1981;136:1081-1085
    – 22 patients with HSP & abdominal pain
    – Abdo pain self limiting
    – Resolved in 3- 7 days

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Treatment – Extrarenal
Gastrointestinal
   Rosenblum ND Paediatrics 1987;79:1081-1021
      – Retrospective case note review
      – 43 patients (1974-1985)
           • Abdo Pain – 75% (all bar one in first 30 days)
           • 49% Periumbilical, 60% intermittent
           • 60% vomiting, 19% melaena, 7% haematemesis
      –   25 had steroids 1-2mg/kg/day (75% within 4 days, 96% within 12 days)
      –   Non-randomised
      –   Similar IV fluids, fasting
      –   Mention IV antibiotics and continuous NG suction

    11/05/2010
    Results
    Rosenblum ND 1987;6:1018-1021




    Steroid group
                • 44% in 24 hours
                • 65% in 48 hours
                • 75% in 72 hours


    Non –Steroid group
                • 14% in 24 hours
                • 45% in 48 hours
                • 75% in 72 hours




“It is difficult to justify treatment with steroids”
    11/05/2010
Treatment – Extrarenal
Gastrointestinal
   Lin SJ 1998;39:186-190 Chung Hua Min Kuo Hsiao
    Erh Ko I Hseuh Hui Tsa Chih
     –   Retrospective study
     –   27 children
     –   Abdo pain 78%, Vomiting 52%, diarrhoea 30%
     –   All received steroids
     –   Abdominal pain relieved within 2.4±0.2 days




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Treatment – Extrarenal
Gastrointestinal – Protein losing enteropathy

   Reif S Acta Pediatr Scand 1991;80:482-485
     –   Case Report
     –   IV Prednisolone 20mg bd for 2 weeks
     –   Oral Prednisoslone 40mg tapered
     –   Increase in Albumin
     –   Faecal alpha 1 antitrypsin normalised




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Outcome
   Mortality <1%, Renal Morbidity 1-5%
    (Stewart M et al Eur J Pediatr 1988;147:113-115, Koskimies O Arch Dis Child 1981;56:482-484, Kobayashi Contrib Nephrol 1977;4:48-
    71)



   23.4 year follow-up; 78/88 patients
    (Goldstein et al Lancet 1992;339:280-282)


      –    39 Nephritic/Nephrotic
      –    17 hypertension or CRF
      –    7 completely normal at 10 years
      –    5 died and 6 had 11 transplants
      –    Proteinuria 82% normal, 2 CRF
      –    16/44 pregnancies associated with gestational
           proteinuria ± hypertension

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Outcome
Goldstein AR et al Lancet 1992;339:280-282

   A Normal
   Normal physical examination, no urinary
   abnormality,normal renal function

   B Minor urinary abnormality
   Normal physical examination, haematuria
   (microscopic±intermittent macroscopic)
   and/or proteinuria <1 g/24 h, normal renal
   function

   C Active renal disease
   Proteinuria >1 g/24 h and/or
   hypertension,
   normal renal function

   D Renal insufficiency
   Glomerular filtration rate <60 ml/min/1.73
   m2, death or renal replacement therapy
      11/05/2010
Outcome
Goldstein AR et al Lancet 1992;339:280-282

         Clinical Presentation               Biopsy Grades       Risk of Renal
                                                                    Failure
Macro/microhaematuria, minimal or              1-2 rarely 3          <5%
          no proteinuria
Haematuria+proteinuria (persistent)                 1-4              15%
         Acute Nephritis                            2-4              15%
      Nephrotic syndrome                     2-4 rarely 1 or 5       40%
  Nephritic-nephrotic syndrome                 2-5 mostly 5         >50%




Goldstein AR et al Lancet 1992;339:280-282


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Treatment – Renal
Prevention
   Buchanec J Int J Urol                   Saulsbury FT Pediatr Nephrol
    1988;20:409-412                          1993;7:69-71
     – Prospective non-randomised             – Retrospective non-randomised
       concurrent cohort comparison
                                                concurrent cohort comparison
     – 33 patients (23 received
       steroids)                              – 50 patients (20 received
                                                steroids)
     – 1 - 2.5mg/kg/day for average of
       21 days                                – 1.7±0.4mg for 5-10 days
     – 1/23 treated and 5/10 non-               beginning at 1-19 days
       treated developed HSP                  – 4/20 treated developed
       nephropathy (p=0.0054 Fisher’s           nephritis
       exact test)
                                              – 6/30 non-treated developed
     – No long term follow-up data              nephritis

     – Questionable patient selection
                                              – Marked selection bias


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Treatment – Renal Prevention
    Kaku Y Kidney Int                         Mollica F Eur J Pediatr
     1998;53:17551759                           1992;151:140-144
       – Prospective non-randomised              – Randomised controlled trial
         concurrent cohort comparison            – 221 children with HSP, 168 no
       – 194 patients with HSP & normal            nephritis at presentation.
         urinalysis                              – 84 received Prednisolone
       – 79 received steroids                      1mg/kg/day for 2 weeks
       – Prednisolone 1-2mg/kg/day for 1-        – No nephropathy in treated group
         2 weeks                                 – 10 untreated developed
       – Methylprednisolone 5mg/kg 4-              nephropathy within 10 weeks
         6/day for 3-5 days then                 – 2 more developed nephropathy at
         Prednisolone 1-2mg/kg/day for 1-          24 and 72 weeks
         2 weeks                                 – 2 only had microscopic
       – Hazard ratio of 0.36 (p=0.037)            haematuria
       – Steroids 32.9%                          – Selection Bias
       – No steroids 33.9%                       – Surrogate markers for ESRF
       – Severe abdo pain HR 3.26                – Definition of Nephritis
         (p=0.034)

    11/05/2010
Treatment- Renal
Moderate nephritis




        There are no definitive studies on the
        use of steroids ± immunosuppressive
        agents in HSP
11/05/2010
Treatment – Renal
Cresentic/ Rapidly progressive nephritis




   Absence of published evidence
   Any study would be fraught with problems
             • Multicenter, multinational
             • Identification of surrogate markers for ESRF
             • Duration of follow-up
11/05/2010
Treatment
   Azathioprine
    1998;49:9-14)
                                                       (Foster BJ et al 200;136:370-375, White RHR Br Med J 1966;2:853-860, Bergstein et al Clin Nephrol




   Cyclophosphamide                                                             (Meadow SR et al. Q J Med 1972;41:241-258, Ayoub EM et al Adv Nephrol
    1976;6:183-224, Counahan R et al.Br Med J 1977;2:11-14, White RHR Br Med J 1966;2:853-860, Oner A et al 1995;9:6-10, Niaudet P et al 1998;12:238-243,
    Iijima K et al 1998;12:244-248)



   Chlorambucil                                         (Ayoub EM et al Adv Nephrol 1976;6:183-224)




   Dipyridamole                                         (Oner A et al 1995;9:6-10, Iijima K et al 1998;12:244-248)




   Heparin/Warfarin                                                    (Iijima K et al 1998;12:244-248)



   Plasmapheresis
    1999;13:816-823)
                                                                    ( Hattori M et al. Am J Kid Dis 1999;33:427-433, Scharer K et al. Pediatr Nephrol




   IVIg               (Rostoker G et al. Ann Intern Med 1994;120:476-484, Rostoker G et al. Nephron 1995;69:327-334)




   Rifampacin                                    (Kim PK et al. Child Nephrol Urol 1988;9:50-56)




       11/05/2010
Renal Transplantation
   Meulders Q Transplantation 1994;58:1179-1186
         • Review of 10 patients
         • 5yr recurrence 35%, 5yr graft survival 11%
   Kessler M Am J Kid Dis 1996;28:99-104
         • Review of 84 patients with IgA and HSP (13 patients)
         • No difference of graft survival from controls
   Ramos EL J Am Soc Nephrol 1991;2:109-121
         • Increased incidence of HSP from LRD grafts
         • Shorter duration of initial disease
         • NOT confirmed in other studies of IgA nephropathy                  (Frohnert PP Clin Transplant
             1997;11:127-133, Donadio JV J Am Soc Nephrol 1997;8:1324-1332)




11/05/2010
Guidelines
         Investigation                        Who to refer
   U & E’s, Protein &                   Nephritic
    Albumin                              Nephrotic
   Urinalysis                           Persistent Proteinuria
             • Weekly until systemic      (>100mg/mmol creatinine)
               symptoms resolve           ± haematuria
             • EMU Protein/Creatinine
               ratio                     Hypertension
             • Microscopy                Haematuria
   Blood Pressure                           • Microscopic
                                             • Macroscopic
   FOB
                                             • ± Minimal proteinuria

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                                                   I Minimal changes (2%)




Management –
                                                   II Pure mesangial proliferation without crescents
                                                       (a) Focal
                                                       (b) Diffuse
                                                   III Mesangial proliferative glomerulonephritis with less than 50% crescents
                                                       (a) Focal
                                                       (b) Diffuse
                                                   IV Mesangial proliferative glomerulonephritis with 50–75% crescents

Renal Biopsy Result                                    (a) Focal
                                                       (b) Diffuse
                                                   V Mesangial proliferative glomerulonephritis with more than 75% crescents
                                                       (a) Focal

    Favourable                                        (b) Diffuse
                                                   VI Membranoproliferative (mesangiocapillary) glomerulonephritis (2%)


       – Grades I, IIa & IIb
       – No treatment
       – ACE inhibitor if persistent proteinuria

    Worrying
       – Grades IIIa & IIIb
       – Pulsed Methylprednisolone 600mg/m2 for 3 days
       – Oral Prednisolone 2mg/kg/day (max 50mg) for 1 month & then taper
    Poor
       – Grades IVa, IVb, Va, Vb & VI
       – Steroids as above
       – Cyclophosphamide 2.5mg/kg/day for 8 weeks


    11/05/2010