Henoch-Sch nlein Purpura Evidence based management

1. Henoch-Sch�nlein Purpura Evidence based management ? Ian Ramage Renal Unit, RHSC.

2. 11/05/2010 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) HSP seemed to follow an upper respiratory tract infection and in one of study of 219 � patients a potential eliciting factor mostly infectious was identified in 37% of cases HSP seemed to follow an upper respiratory tract infection and in one of study of 219 � patients a potential eliciting factor mostly infectious was identified in 37% of cases

3. 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)

4. 11/05/2010 Clinical ManifestationsDermal Skin Biopsy Leukocytoclastic Vasculitis IgA deposition in vessel walls The skin biopsy demonstrates the large white areas which are adipose cells and at 12 o�clock you can seen a capillary which is invaded by leucocytes and also if you look down below that at the bullseye position you can see there is another capillary which has been invaded by white cells. When you look at this with immunfluoresence you can see deposition of IgA in the vessel walls and that is shown quite nicely in the slide down below. � The skin biopsy demonstrates the large white areas which are adipose cells and at 12 o�clock you can seen a capillary which is invaded by leucocytes and also if you look down below that at the bullseye position you can see there is another capillary which has been invaded by white cells. When you look at this with immunfluoresence you can see deposition of IgA in the vessel walls and that is shown quite nicely in the slide down below. �

5. 11/05/2010 Extrarenal manifestationsGastrointestinal 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) The plain radiograph of the child�s abdomen shows very little gas in the left side of the abdomen which was in the region of the patients� clinically palpable mass. Soft tissues are slightly mottled over that area probably due to some bowel content and there is multiple moderately dilated distended bowel loops which are seen in the right abdomen in the mid pelvis but she might be able to convince yourself there is slight separation of the bowel loops suggesting bowel wall oedema and/or ascites and of course there is a nasogastric tube which terminates at the stomach. The ultrasound is an ultrasound of the left flank and this shows the sausage shape mass, the classical appearance of a pseudo kidney or a donut sign and you can see around the donut shaped mass there is a darker area which is ascites and again on the bottom right corner you can see the ascites in the right upper quadrant between the liver and the kidney. The plain radiograph of the child�s abdomen shows very little gas in the left side of the abdomen which was in the region of the patients� clinically palpable mass. Soft tissues are slightly mottled over that area probably due to some bowel content and there is multiple moderately dilated distended bowel loops which are seen in the right abdomen in the mid pelvis but she might be able to convince yourself there is slight separation of the bowel loops suggesting bowel wall oedema and/or ascites and of course there is a nasogastric tube which terminates at the stomach. The ultrasound is an ultrasound of the left flank and this shows the sausage shape mass, the classical appearance of a pseudo kidney or a donut sign and you can see around the donut shaped mass there is a darker area which is ascites and again on the bottom right corner you can see the ascites in the right upper quadrant between the liver and the kidney.

6. 11/05/2010 Extrarenal ManifestationsJoints 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)

7. 11/05/2010 Extrarenal ManifestationsRare Gastrointestinal Oesophageal stenosis Haemorrhagic pancreatitis Protein-losing enteropathy Respiratory Pulmonary and Pleural haemorrhage Pulmonary function abnormalities Interstitial lung disease Neurological Encephalopathy Cortical blindness Intracerebral haemorrhage Cerebral vasculitis Behavioural changes Urological Ureteric obstruction Scrotal swelling Cord haematoma Testicular necrosis Ecchymotic scrotal induration Haemorrhagic ascites/cystitis

8. 11/05/2010 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 Renal involvement in HSP varies depending on which study you look at and diagnostic criteria used, from as low 20% up to 100%. There are two studies in which routine analysis was carried out in all HSP hospital admissions. Renal involvement was reported in 41-61%. In 80% of those with renal involvement it was apparent in the first four weeks with the remainder occurring within the next two months although there are a few case reports of renal involvement occurring much further out. The classical clinical features is haematuria which is most commonly macroscopic. You may also notice microscopic haematuria and a variable degree of proteinuria which may even within patients themselves show a remarkable variability. There are several case reports of hypertension occurring independently of any abnormalities in urinalysis in patients with HSP but the finding of haematuria, proteinuria, hypertension and azotemia give a collectively termed HSP nephritis. If the proteinuria is severe > 200mg/mmol of creatinine in an early morning urine specimen in association with hypoalbuminaemia and oedema then this is a nephrotic presentation. We have largely moved away from using these descriptions but for HSP there are still applicable and allow us to prognosticate for collective clinical presentations. Renal involvement in HSP varies depending on which study you look at and diagnostic criteria used, from as low 20% up to 100%. There are two studies in which routine analysis was carried out in all HSP hospital admissions. Renal involvement was reported in 41-61%. In 80% of those with renal involvement it was apparent in the first four weeks with the remainder occurring within the next two months although there are a few case reports of renal involvement occurring much further out. The classical clinical features is haematuria which is most commonly macroscopic. You may also notice microscopic haematuria and a variable degree of proteinuria which may even within patients themselves show a remarkable variability. There are several case reports of hypertension occurring independently of any abnormalities in urinalysis in patients with HSP but the finding of haematuria, proteinuria, hypertension and azotemia give a collectively termed HSP nephritis. If the proteinuria is severe > 200mg/mmol of creatinine in an early morning urine specimen in association with hypoalbuminaemia and oedema then this is a nephrotic presentation. We have largely moved away from using these descriptions but for HSP there are still applicable and allow us to prognosticate for collective clinical presentations.

9. 11/05/2010 Glomeruli Mesangial Hypercellularity Focal Diffuse Leukocyte infiltration Increased mesangial matrix Mesangial interposition Synechiae Crescent formation Cellular Fibrous Pseudotubule formation Double Contours On biopsy you see mesangial hypercellularity which you can see in both the H and E section on the top and the silver section on the bottom which can either be focal or diffuse. There is generalised leukocyte infiltration and a corresponding increase in the mesangial matrix which is stained darker on the H and E section. Also noted is mesangial inter position which you see better in the EM and I will show you that later and the presence of synechiae which are just small areas of adhesion between Bowman�s capsule and the glomerular tuft. What we do not like to see is crescent formation because this is associated with a poor prognosis and you get two types of crescent. The cellular crescent which we believe to be reversible which we try to melt away with IV steroids and fibrous crescents which are commonly held to be irreversible and you can see the crescent formation on the three glomeruli shown on the top slide. Within the crescents , which I do not know if you can see, you get presence of pseudo tubules but mesangial inter position you can get a mebrano-priliferative picture which is demonstrated by a double contour which is shown in the silver stain at the bottom, very nicely in the 11 o�clock position. In the tubules you see evidence of tubular atrophy with loss of the cells in the tubules which may become vaculated and you can see here filled with some red cells and this tends to go along with the degree of the glomerular injury. On biopsy you see mesangial hypercellularity which you can see in both the H and E section on the top and the silver section on the bottom which can either be focal or diffuse. There is generalised leukocyte infiltration and a corresponding increase in the mesangial matrix which is stained darker on the H and E section. Also noted is mesangial inter position which you see better in the EM and I will show you that later and the presence of synechiae which are just small areas of adhesion between Bowman�s capsule and the glomerular tuft. What we do not like to see is crescent formation because this is associated with a poor prognosis and you get two types of crescent. The cellular crescent which we believe to be reversible which we try to melt away with IV steroids and fibrous crescents which are commonly held to be irreversible and you can see the crescent formation on the three glomeruli shown on the top slide. Within the crescents , which I do not know if you can see, you get presence of pseudo tubules but mesangial inter position you can get a mebrano-priliferative picture which is demonstrated by a double contour which is shown in the silver stain at the bottom, very nicely in the 11 o�clock position. In the tubules you see evidence of tubular atrophy with loss of the cells in the tubules which may become vaculated and you can see here filled with some red cells and this tends to go along with the degree of the glomerular injury.

10. 11/05/2010 There has been two studies looking at this. The first one by Roy Meadow which has largely fallen by the way side and replaced by the ISKDC study published by Heaton but the figures for the prevalence of each published in red at number 1 and 6 relate to Roy Meadows paper and as you can see at the extremes there is very little and indeed I do not know whether Neil spoke about HSP on Friday but his patient with clinical evidence of nephrotic syndrome had a type 2B pattern with diffuse mesangial proliferation but no crescent formation. � There has been two studies looking at this. The first one by Roy Meadow which has largely fallen by the way side and replaced by the ISKDC study published by Heaton but the figures for the prevalence of each published in red at number 1 and 6 relate to Roy Meadows paper and as you can see at the extremes there is very little and indeed I do not know whether Neil spoke about HSP on Friday but his patient with clinical evidence of nephrotic syndrome had a type 2B pattern with diffuse mesangial proliferation but no crescent formation. �

11. 11/05/2010 Light Microscopy Grade I Grade 3 Grade 5

12. 11/05/2010 Investigations U & E�s, Protein & Albumin Urinalysis Weekly until systemic symptoms resolve EMU Protein/Creatinine ratio Microscopy Blood Pressure FOB

13. 11/05/2010 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

14. 11/05/2010 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)

15. 11/05/2010 Treatment � ExtrarenalGastrointestinal 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

16. 11/05/2010 Treatment � ExtrarenalGastrointestinal 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

17. 11/05/2010 ResultsRosenblum 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

18. 11/05/2010 Treatment � ExtrarenalGastrointestinal 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

19. 11/05/2010 Treatment � ExtrarenalGastrointestinal � 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

20. 11/05/2010 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 The long term morbidity and mortality of HSP is related to its renal involvement with follow-up studies showing that patients with renal involvement so that the overall incidence but the overall renal morbidity but only in those with renal involvement up to 12% were found to have established chronic renal failure with a further 7% having ongoing active disease. But this is a selective patient group and in all patients there is an incidence of end stage renal failure has been reported in up to 5%. The long term morbidity and mortality of HSP is related to its renal involvement with follow-up studies showing that patients with renal involvement so that the overall incidence but the overall renal morbidity but only in those with renal involvement up to 12% were found to have established chronic renal failure with a further 7% having ongoing active disease. But this is a selective patient group and in all patients there is an incidence of end stage renal failure has been reported in up to 5%.

21. 11/05/2010 Outcome Goldstein AR et al Lancet 1992;339:280-282

22. 11/05/2010 OutcomeGoldstein AR et al Lancet 1992;339:280-282

23. 11/05/2010 Treatment � RenalPrevention Buchanec J Int J Urol 1988;20:409-412 Prospective non-randomised concurrent cohort comparison 33 patients (23 received steroids) 1 - 2.5mg/kg/day for average of 21 days 1/23 treated and 5/10 non-treated developed HSP nephropathy (p=0.0054 Fisher�s exact test) No long term follow-up data Questionable patient selection Saulsbury FT Pediatr Nephrol 1993;7:69-71 Retrospective non-randomised concurrent cohort comparison 50 patients (20 received steroids) 1.7�0.4mg for 5-10 days beginning at 1-19 days 4/20 treated developed nephritis 6/30 non-treated developed nephritis Marked selection bias

24. 11/05/2010 Treatment � Renal Prevention Kaku Y Kidney Int 1998;53:17551759 Prospective non-randomised concurrent cohort comparison 194 patients with HSP & normal urinalysis 79 received steroids Prednisolone 1-2mg/kg/day for 1-2 weeks Methylprednisolone 5mg/kg 4-6/day for 3-5 days then Prednisolone 1-2mg/kg/day for 1-2 weeks Hazard ratio of 0.36 (p=0.037) Steroids 32.9% No steroids 33.9% Severe abdo pain HR 3.26 (p=0.034) Mollica F Eur J Pediatr 1992;151:140-144 Randomised controlled trial 221 children with HSP, 168 no nephritis at presentation. 84 received Prednisolone 1mg/kg/day for 2 weeks No nephropathy in treated group 10 untreated developed nephropathy within 10 weeks 2 more developed nephropathy at 24 and 72 weeks 2 only had microscopic haematuria Selection Bias Surrogate markers for ESRF Definition of Nephritis

25. 11/05/2010 Treatment- RenalModerate nephritis There are no definitive studies on the use of steroids � immunosuppressive agents in HSP

26. 11/05/2010 Treatment � RenalCresentic/ 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

27. 11/05/2010 Treatment Azathioprine (Foster BJ et al 200;136:370-375, White RHR Br Med J 1966;2:853-860, Bergstein et al Clin Nephrol 1998;49:9-14) 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 ( Hattori M et al. Am J Kid Dis 1999;33:427-433, Scharer K et al. Pediatr Nephrol 1999;13:816-823) 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)

28. 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)

29. 11/05/2010 Guidelines Investigation U & E�s, Protein & Albumin Urinalysis Weekly until systemic symptoms resolve EMU Protein/Creatinine ratio Microscopy Blood Pressure FOB Who to refer Nephritic Nephrotic Persistent Proteinuria (>100mg/mmol creatinine) � haematuria Hypertension Haematuria Microscopic Macroscopic � Minimal proteinuria

30. 11/05/2010

31. 11/05/2010 Management �Renal Biopsy Result Favourable 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