1. HSP Nephritis
David A Hughes

2. Epidemiology and diagnosis
Disease course and monitoring
Disease outcome
Intervention and treatment
Future directions

3. Diagnosis of HSP (EULAR/PReS consensus criteria)
Palpable purpura (essential) in the presence of one of the following:
Diffuse abdominal pain
Any biopsy showing predominant IgA
Acute arthritis/arthralgia
Renal involvement defined as any haematuria or proteinuria.

4. How many patients should we expect to see in a year in Scotland?
HSP
20.4 per 100,000 cp
highest between years 70.3 per
Gardner-Medwin et al. Lancet 2002
How many HSP patients should develop renal involvement in a year in Scotland?

5. Health Board Area GGC 39 Lothian 27 Lanarkshire 20 Fife 12 A&A Borders
Estimated HSP cases per Health Board population (0-14 years) at 20.4 per 100,000 cp Registrar General for Scotland’s Mid-2010 Population Estimates Scotland by Health Board
Health Board Area
GGC 39
Lothian 27
Lanarkshire 20
Fife 12
A&A
Borders 4
D&G
Tayside 13 FV 10
Grampian 18
Western Isles 1
Highland
Orkney & Shetland 2
TOTAL
172

6. How many patients should we expect to see in a year in Scotland?
HSP
20.4 per 100,000 cp
highest between years 70.3 per
Gardner-Medwin et al. Lancet 2002
How many HSP patients should develop renal involvement in a year in Scotland?

7. What constitutes renal involvement?
Isolated Haematuria
Isolated Proteinuria
Nephrotic syndrome
Nephritic syndrome
Renal impairment
Hypertension
Risk of long term renal impairment and duration of follow up recommended for Henoch-Schönlein purpura with normal or minimal urinary findings: a systematic review. Narchi H. Arch Dis Child 2005

8. What constitutes ‘severe’ renal involvement?
Nephrotic syndrome
Nephrotic range proteinuria
Suspect for urine ‘stix’ testing > ++.
Quantify as urine protein:creatinine (P:CR) >200mg/mmol.
Hypoalbuminaemia
serum albumin <25 g/l
Generalised oedema
Nephritic syndrome
Renal impairment
Hypertension

9. How many with renal disease?
Any renal involvement
% in unselected series of HSP
Systematic review of 12 studies with 1133 cases
34.2% of unselected patients
‘Severe’ renal disease
5 - 7% of all HSP presentations
21% of patients with any renal involvement
Narchi H. Arch Dis Child 2005
HSP ‘nephritis’
3-6 pa in DGH population with 30k children and 5000 deliveries
Improving the standard of care of children with kidney disease through paediatric nephrology networks. RCPCH August 2011

10. ‘Severe’ renal disease (21% of ‘any’) ~11
Estimated HSP cases with any renal involvement per Health Board population (0-14 years) at rate of 34% Registrar General for Scotland’s Mid-2010 Population Estimates Scotland by Health Board
Health Board Area
GGC 13
Lothian 9
Lanarkshire 7
Fife 4
A&A
Borders 1
D&G
Tayside FV 2
Grampian 6
Western Isles
<1
Highland 3
Orkney & Shetland
TOTAL 55
‘Severe’ renal disease (21% of ‘any’)
~11

11. So... who should follow up HSP patients?
HSP – initial presentation
Community based
Primary care
Community Children’s Nurse
Hospital based
Nurse specialist led service
General paediatrician

12. When will renal disease be apparent?
Within 4 weeks in %
Within 3 months in 97 – 100%
Time of onset of urinary abnormalities after the diagnosis of HSP: cumulative percentage of abnormalities and 95% confidence intervals
Weeks after HSP diagnosis 1 2 4 6 8 24
Cumulative percentage 37 54 84 91 90 97
95% CI
Risk of long term renal impairment and duration of follow up recommended for Henoch-Schönlein purpura with normal or minimal urinary findings: a systematic review
Risk of long term renal impairment and duration of follow up recommended for Henoch-Schönlein purpura with normal or minimal urinary findings: a systematic review. Narchi H. Arch Dis Child 2005

13. What should I check... and how often?
Dipstix urinalysis for blood and protein
Blood pressure
Clinical assessment
If no proteinuria
No consensus – ‘expert’ opinion
Week 1, 2, 4, 8, 12, 26, 52

14. How do other centres follow HSP patients?
Week 1 2 3 4 6 8 10 12 26 52
Bristol BP
EMU
SPRUN old
SPRUN new ?
AHCH old
AHCH new
Ø protein
protein

15. Detection and referral of patients with Henoch–Schönlein purpura nephritis (adapted from local guidelines developed by Dr D Hothi and Bristol Paediatric Nephrologists).
Detection and referral of patients with Henoch–Schönlein purpura nephritis (adapted from local guidelines developed by Dr D Hothi and Bristol Paediatric Nephrologists).
Tizard E J , Hamilton-Ayres M J J Arch Dis Child Educ Pract Ed 2008;93:1-8
Copyright © BMJ Publishing Group Ltd & Royal College of Paediatrics and Child Health. All rights reserved.

16. SPRUN current HSP pathway
Based on Alder Hey care pathway.
Green path for ‘low risk’ outcome and exit strategy.
Amber path for closer ‘general paediatric’ review and exit back to ‘low risk’ or onward referral for nephrology review.
Red box for more urgent assessment/admission and nephrology referral.

17. What should I consider if renal involvement?
Haematuria
Is it isolated?
What degree of haematuria?
Does it persist?
Proteinuria
What degree of proteinuria?

18. What investigations if renal involvement?
Primary Investigations
U&E, HCO3, creatinine
Albumin
urine Protein:Creatinine
urine dipstix and microscopy
FBC
Clotting screen
Secondary Investigations
Anti-streptococcal titre (ASOT)
Antinuclear antibody (ANA) + dsDNA
Antinuclear cytoplasmic antibody (ANCA)
Complement – C3, C4
ESR
CRP
Renal ultrasound

19. When should I worry at presentation?
Nephrotic syndrome
uP:CR >250mg/mmol
Albumin <25g/L
Oedema
Nephritic syndrome
Renal impairment
Raised creatinine; oliguria
Hypertension
Macroscopic haematuria > 5-7 days

20. ‘Red flags’ for less favourable HSP
Age at onset above 8 years
More severe abdominal involvement
Persistent purpura
Henoch-Schönlein purpura nephritis in children: risk factors, prevention and treatment. Bogdanović. Acta Paediatrica, 2009.

21. HSP care pathway follow up
Alder Hey Children’s Hospital
Nurse led care pathway
Henoch Schonlein Purpura – A 5-Year Review and Proposed Pathway. Watson L, et al. PLoS ONE 7(1). (2012).
Original model for SPRUN pathway
Audit of 5 year data
Primary outcome of renal referral
Hypertension
Proteinuria
‘severe’ nephritis
We are the first group to clinically assess, critically analyse and subsequently revise a nurse led monitoring pathway for HSP. A cohort of 102 children presenting with HSP to a
secondary/tertiary level UK paediatric hospital over a five year period, were monitored using a nurse led care pathway.
Using this cohort, the incidence (6.21 cases per 100,000 children per year) and natural disease course of HSP nephritis (46% initial renal inflammation; 9% subsequent renal referral; 1% renal biopsy and immunosuppression) was determined. Older patients were at higher risk of requiring a renal referral (renal referral 12.3 (8.4–13.5) years vs. normal outcome 6.0 (3.7–8.5)
years; p,0.01). A normal urinalysis on day 7 had a 97% (confidence interval 90 to 99%) negative predictive value in predicting a normal renal outcome. Using this data and existing literature base, The Alder Hey Henoch Schonlein Purpura Pathway was developed, a revised pathway for the screening of poor renal outcome in HSP. This is based on a six-month monitoring period for all patients presenting with HSP, which importantly prioritises patients according to the urine findings on day 7 and thus intensively monitors those at higher risk of developing nephritis. The pathway could be easily adapted for use in different settings and resources. The introduction of a standardised pathway for the monitoring of HSP will facilitate the implementation of disease registries to further our understanding of the condition and permit future clinical trials

22. HSP care pathway 5 year review
Watson L, et al. PLoS ONE 7(1). (2012).

23. When should I worry during follow up?
Hypertension
BP >95th centile on 3 separate occasions
At presentation/diagnosis 14% hypertensive (10% BP >99th centile)
64% - normal urinalysis,
28% - proteinuria (>1+)
1 patient (7%) - proteinuria 1+ and haematuria 3+
No hypertension after day 7
Watson L, et al. (2012) Henoch Schonlein Purpura – A 5-Year Review and Proposed Pathway. PLoS ONE 7(1)

24. When should I worry during follow up?
The finding of an abnormal urine (day 7) and the occurrence of a renal referral
Abnormal urine
Normal urine
Totals
Clinician referral 7
(True positive) 2
(False negative) 9
Discharged 15
(False positive) 76
(True negative) 91 22 78
100
Watson L, et al. PLoS ONE 7(1). (2012).
Proteinuria
uP:CR > 200mg/mmol for 4 weeks
uP:CR mg/mmol with increasing trend in first 4 weeks
uP:CR >100mg/mmol for 3 months
uP:CR >50mg/mmol for 6 months
Serum albumin declining
Nine patients from the study group met the primary outcome of a medical referral, two of these had an early rise in UACR and were referred within 3 months from diagnosis for nephrology review (one of which started on the standard pathway described above); the other seven patients had persistent proteinuria or haematuria at 12 months.
Positive and negative predictive values
Using the urine dipstick results from the urine samples obtained on day 7, the positive and negative predictive values of these urinalyses in predicting the need for a renal referral were calculated. The calculated positive predictive value of an initial abnormal urinalysis indicating the need for a subsequent renal referral during follow up is 32% and the negative predictive value of a normal urinalysis indicating a normal outcome is 97%.

25. When can I stop worrying?
At 6 months if
Urine clear of blood and protein
BP normal
No nephrotic syndrome or nephritic syndrome during presentation
97% of children develop renal involvement of HSP within 3 months of presentation
Narchi, Arch Dis Child, 2005
Most common outcome is complete resolution
Recurrence of HSP within the first year is not uncommon, affecting about 30–40%

26. Presentation on diagnosis of HSP and long term renal impairment
Children
Long term renal impairment No %
% (95% CI)
RR (95% CI)
Total
1133 21
1.8 (1.1 – 2.8) NA
With normal urine
746
65.8
0 (0 – 0.5)
With abnormal urinalysis
387
34.2
5.4 (3.3 – 8.3)
Isolated haematuria ± proteinuria
305
78.8 5
1.6 (0.5 – 3.8)
Baseline
Nephritic or nephrotic syndrome 82
21.2 16
19.5 (11/1 – 31.7)
11.9 (4.1–41.5)
Narchi H. Arch Dis Child 2005

27. Presentation on diagnosis of HSP and long term renal impairment
Children
Long term renal impairment No %
% (95% CI)
RR (95% CI)
Total
1133 21
1.8 (1.1 – 2.8) NA
With normal urine
746
65.8
0 (0 – 0.5)
With abnormal urinalysis
387
34.2
5.4 (3.3 – 8.3)
Isolated haematuria ± proteinuria
305
78.8 5
1.6 (0.5 – 3.8)
Baseline
Nephritic or nephrotic syndrome 82
21.2 16
19.5 (11/1 – 31.7)
11.9 (4.1–41.5)
Narchi H. Arch Dis Child 2005

28. Prognostic Value of Renal Symptoms
Data interpretation of reported series difficult
influence of treatment
heterogeneous
not precisely reported
varied through the years
Before 1980s - HSPN an illness with spontaneous recovery
1980s - steroids and immunosuppressive drugs even when no RPGN
Late development of CKD
Limitations of long-term follow-up relating outcome to initial symptoms
The use of the severity of initial renal symptoms to adapt the treatment should be justified by the correlation between the latter and the prognosis at long term.
influence of treatment
Heterogeneous (dosage, duration of administration)
not precisely reported
varied through the years
Before 1980s - HSPN an illness with spontaneous recovery
1980s on - steroids and immunosuppressive drugs even in the absence of RPGN

29. Prognostic Value of Renal Symptoms
Data interpretation of reported series difficult
influence of treatment
Late development of CKD
20 years (and more) after disease
during pregnancy
Limitations of long-term follow-up relating outcome to initial symptoms
The use of the severity of initial renal symptoms to adapt the treatment should be justified by the correlation between the latter and the prognosis at long term.
influence of treatment
Heterogeneous (dosage, duration of administration)
not precisely reported
varied through the years
Before 1980s - HSPN an illness with spontaneous recovery
1980s on - steroids and immunosuppressive drugs even in the absence of RPGN

30. Prognostic Value of Renal Symptoms
Data interpretation of reported series difficult
influence of treatment
Late development of CKD
Limitations of long-term follow-up relating outcome to initial symptoms
Few intermediate observations
role of further relapses
role of progressive active process
The use of the severity of initial renal symptoms to adapt the treatment should be justified by the correlation between the latter and the prognosis at long term.
influence of treatment
Heterogeneous (dosage, duration of administration)
not precisely reported
varied through the years
Before 1980s - HSPN an illness with spontaneous recovery
1980s on - steroids and immunosuppressive drugs even in the absence of RPGN

31. Patterns of events leading to CKD
Single acute episode
apparent complete recovery
but reduction in nephron number
hyperfiltration causing CKD at long term
Recurrent of acute episodes
Progressive indolent process as in IgAN

32. Indications for renal biopsy
Acute renal impairment/nephritic syndrome at presentation
Nephrotic syndrome with normal renal function persisting at 4 weeks
Nephrotic range proteinuria (urine protein/creatinine ratio, >250 mg/mmol) at 4–6 weeks (if not improving spontaneously)
Persistent proteinuria
urine protein/creatinine ratio >100 mg/mmol at >3 months particularly if diagnosis is not clear.
Clinical practice: Diagnosis and management of Henoch–Schönlein purpura. Hugh J. McCarthy & E. Jane Tizard
Eur J Pediatr (2010) 169:643–650
Clinical practice: Diagnosis and management of Henoch–Schönlein purpura.
McCarthy H & Tizard EJ. Eur J Pediatr (2010)

33. Histology and the normal glomerulus

34. Moderate mesangial expansion – class 2 – ‘mild’.
Normal glomerulus
Moderate mesangial expansion – class 2 – ‘mild’.
Normal glom
IgA nephropathy with moderate mesangial expansion with increased matrix and cells ([A] periodic acid-Schiff; [B] Jones' silver stain; original magnification for each x200).
Henoch-Schönlein purpura (HSP) also has mesangial IgA deposits, and thus it appears morphologically like IgA nephropathy. Clinicopathological correlation is required to distinguish HSP from IgA nephropathy, but crescents, shown here, are more frequent in biopsied HSP than in IgA nephropathy (Jones's silver stain, original magnification x100).
The diagnosis of HSP/IgA nephropathy rests on the finding of dominant or codominant IgA mesangial deposits, as shown here. Staining may also be present for IgG and IgM, but not in greater intensity than for IgA. C3 is also often present in the mesangial areas, usually equal to or less than IgA staining (anti-IgA immunofluorescence, original magnification x200).
Mesangial proliferation and crescent formation
IgA deposits in the mesangium on immunofluorescence

35. Henoch- Schönlein Nephritis histological classification – ISKDC
Mesangial change
Crescents
Frequency %
(n = 355) * I
Minimal changes 8 II
Pure mesangial proliferation 29
III a b
focal
diffuse
mesangial proliferation
<50% 43 IV
50 – 75% 12 V
>75% 6 VI
Membranoproliferative like glomerulonephritis 3
In: Pathology of the Kidney, 6th Edition, edited by Jennette
JC, Olson JL, Schwartz MM, Silva FG, Philadelphia, Lippincott
Williams & Wilkins, 2007,
* Pooled data from Pathology of the Kidney, 6th Edition, Jennette et al. Philadelphia, Lippincott Williams & Wilkins, 2007.

36. Numbers of patients with poor outcome, by severity of renal symptoms at onset of HSP
Series
Patient numbers
FU (yrs)
No symptoms
Mild symptoms
Severe symptoms
Ronkainen
Lancet 2002 47
24·1 (mean)
0/9
2/18 (11%)
7/20 (35%)
Stewart et al
Eur J Ped 1988 55
8·3 (mean) -
0/37
3/18 (17%)
Goldstein
Lancet 1992 78
23·4 (mean)
5/39 (13%)
17/39 (44%)
Niaudet
Adv Nephrol 1993
151
>1
50/133 (38%)
Schärer et al Ped Nephrol 1999 63
6·1 (mean)
2/25 (8%)
18/38 (47%)
Total
394
12/137 (9%)
95/248 (38%)
We analysed 394 patients with Henoch-Schönlein purpura, here and in four other studies, (1-4 below) by classification into three categories, in accordance with symptoms at onset :, no, mild, and severe renal symptoms (table). Severity of symptoms at onset of Henoch-Schönlein purpura proved a prognostic factor.
Patients with severe renal symptoms at onset more often had poor outcome after 1–24 years of follow up (38%, range 17–47) than did those with mild or no renal symptoms (9%, 0–17; p<0·0001).
1 Stewart and colleagues
2 Goldstein and colleagues
3 Niaudet and colleagues
4 Schärer and colleagues
The adult kidney 24 years after childhood Henoch-Schönlein purpura: a retrospective cohort study. Ronkainen et al. Lancet, 2002

37. Clinical presentation at onset of Henoch - Schönlein purpura
The adult kidney 24 years after childhood HSP: a retrospective cohort study.
Clinical presentation at onset of Henoch - Schönlein purpura I
no renal symptoms II
proteinuria + haematuria, and no biopsy specimen or ISKDC biopsy grade I - II
III
renal symptoms > 1 month, nephritis or nephrosis, and ISKDC biopsy grade III or more
Nephritis:
haematuria and 2/3 symptoms: increase in serum creatinine, oliguria, hypertension.
Nephrosis:
proteinuria > 40 mg/m2/hr.
Clinical outcome A
healthy B
minor urinary abnormalities (intermittent hypertension, proteinuria, haematuria) C
active renal disease (hypertension, constant proteinuria) D
end-stage renal disease (dialysis treatment or renal transplantation)
The adult kidney 24 years after childhood Henoch-Schönlein purpura: a retrospective cohort study
Ronkainen J, Nuutinen M, Koskimies O Lancet 360: 666–670, 2002
We studied a cohort of 26 boys and 26 girls who were treated for Henoch-Schönlein purpura at Helsinki University Hospital during 1964—83. Mean follow-up was 24·1 years (SD 6·0; 16·4—36·5). All participants were asked about their state of health in a questionnaire, and 47 (90%) were examined by a doctor.
Seven (35%) of 20 adults who had severe Henoch-Schönlein purpura and glomerulonephritis at onset had renal impairment as adults, compared with two (7%) of 27 with mild or no renal symptoms at onset (relative risk 4·7, 95% CI 1·3—18·7). Relative risk for a poor outcome was 5·0 in women (1·1—32·5) and 2·0 in men (0·2—17·5). All patients with no renal symptoms at onset had a good outcome after 24 years of follow-up. Severity of first kidney biopsy finding did not correlate with risk of a poor outcome. 16 (70%) of 23 pregnancies had been complicated by hypertension, proteinuria, or both. Five (56%) of the nine women with complicated pregnancies had a poor renal outcome.
Interpretation
Long-term follow-up of all patients who had Henoch-Schönlein purpura with severe renal symptoms at onset is needed during adulthood. All women who had even mild renal symptoms at onset of Henoch-Schönlein purpura should be carefully observed during and after pregnancy
Ronkainen et al. Lancet, 2002

38. The adult kidney 24 years after childhood HSP: a retrospective cohort study.
Onset Grade
Number of patients
Good outcome
A + B
Poor Outcome
C + D I 9
9 (100%) II 18
16 (89%)
2 (11%)
III 20
13 (65%)
7 (35%)
The adult kidney 24 years after childhood Henoch-Schönlein purpura: a retrospective cohort study
Ronkainen J, Nuutinen M, Koskimies O Lancet 360: 666–670, 2002
We studied a cohort of 26 boys and 26 girls who were treated for Henoch-Schönlein purpura at Helsinki University Hospital during 1964—83. Mean follow-up was 24·1 years (SD 6·0; 16·4—36·5). All participants were asked about their state of health in a questionnaire, and 47 (90%) were examined by a doctor.
Seven (35%) of 20 adults who had severe Henoch-Schönlein purpura and glomerulonephritis at onset had renal impairment as adults, compared with two (7%) of 27 with mild or no renal symptoms at onset (relative risk 4·7, 95% CI 1·3—18·7). Relative risk for a poor outcome was 5·0 in women (1·1—32·5) and 2·0 in men (0·2—17·5). All patients with no renal symptoms at onset had a good outcome after 24 years of follow-up. Severity of first kidney biopsy finding did not correlate with risk of a poor outcome. 16 (70%) of 23 pregnancies had been complicated by hypertension, proteinuria, or both. Five (56%) of the nine women with complicated pregnancies had a poor renal outcome.
Interpretation
Long-term follow-up of all patients who had Henoch-Schönlein purpura with severe renal symptoms at onset is needed during adulthood. All women who had even mild renal symptoms at onset of Henoch-Schönlein purpura should be carefully observed during and after pregnancy
Clinical outcome after mean follow-up of 24·1 years, by symptoms at onset
Ronkainen et al. Lancet, 2002

39. Long-term follow-up of childhood Henoch-Schönlein nephritis.
Renal outcome at mean 23·4 yrs after onset in 78 subjects
If nephritic, nephrotic, or nephritic/nephrotic syndromes at onset
44% - hypertension or impaired renal function
If haematuria (with or without proteinuria) at onset
82% - normal renal function
Initial renal biopsy
correlates well with outcome
but poor predictive value in individuals
Goldstein et al. Lancet 1992
A study of long-term outcome of 78 subjects who had had Henoch-Schönlein nephritis during childhood (at a mean of 23·4 years after onset) shows that severity of clinical presentation and initial findings on renal biopsy correlate well with outcome but have poor predictive value in individuals. 44% of patients who had nephritic, nephrotic, or nephritic/ nephrotic syndromes at onset have hypertension or impaired renal function, whereas 82% of those who presented with haematuria (with or without proteinuria) are normal.
AR Goldstein, RH White, R Akuse, C Chantler
Long-term follow-up of childhood Henoch-Schönlein nephritis.
Lancet, 339 (1992)

40. Prognostic value of renal biopsy
3 studies report risk of CKD increases with the severity of the histological lesions at presentation
Other studies show that low grade histological lesions can also lead to CKD and that high grade lesions can heal definitively
Henoch-Schönlein Purpura Nephritis: Pathophysiology, Treatment, and Future Strategy. Davin. CJASN, 2011.
Combining three studies (55,57,86) with a follow-up of about 6 years (38), all ISKDC grades combined result in 25% of severe complications (active renal disease and/or CKD and/or ESRF): 15, 15, 35, 70, and 66% for classes II, III, IV, V, and VI, respectively. Class I, which includes minimal glomerular abnormalities, is the only class without long term complications.

41. Why the discrepancies? Renal biopsy ISKDC classification
sample bias; lesions observed over-represented or under-represented
delay to kidney biopsy: crescentic glomeruli rapidly progress to complete glomerulosclerosis
ISKDC classification
Reversibility with no scarring: if crescents cellular are not fibrotic
Series from different eras
Renal biopsy
sample bias; lesions observed over-represented or under-represented
delay to kidney biopsy: crescentic glomeruli rapidly progress to complete glomerulosclerosis
ISKDC classification
limited recognition of important prognostic factors
tubular lesions
interstitial fibrosis
interstitial and glomerular inflammation
crescent features (localized or completely surrounding the glomerulus, fibrotic or not)
segmental sclerosis
arteriosclerosis
electron microscopy and immunofluorescence features not considered;
Reversibility with no scarring: if crescents cellular are not fibrotic
Series from different eras
Recent large French series
renal prognosis association
not with crescents
Better with interstitial fibrosis and percentage of sclerotic glomeruli
Ronkainen et al. series worse outcome of ISKDC grades II–III than grades IV–V
prompt use of aggressive immunosuppressive treatments in latter group.
4 studies in last 15 years
no relationship between crescents at first biopsy and outcome for CKD and ESRF
when the use of prednisone and immunosuppressive drugs had become the rule

42. Why the discrepancies? Renal biopsy ISKDC classification
limited recognition of important prognostic factors
tubular lesions
interstitial fibrosis
interstitial and glomerular inflammation
crescent features (localized or completely surrounding the glomerulus, fibrotic or not)
segmental sclerosis
arteriosclerosis
electron microscopy and immunofluorescence features not considered
Reversibility with no scarring: if crescents cellular are not fibrotic
Series from different eras
Renal biopsy
sample bias; lesions observed may be over-represented or under-represented
Delay to kidney biopsy: crescentic glomeruli can rapidly lead to complete glomerulosclerosis
ISKDC classification limited recognition of important well-accepted prognostic factors
tubular lesions
interstitial fibrosis
interstitial and glomerular inflammation
crescent features (localized or completely surrounding the glomerulus, fibrotic or not)
segmental sclerosis
arteriosclerosis
electron microscopy and immunofluorescence features not considered;
Reversibility with no scarring: if crescents cellular are not fibrotic
Series from different eras
Recent large French series
renal prognosis association
not with crescents
Better with interstitial fibrosis and percentage of sclerotic glomeruli
Ronkainen et al. series worse outcome of ISKDC grades II–III than grades IV–V
prompt use of aggressive immunosuppressive treatments in latter group.
4 studies in last 15 years
no relationship between crescents at first biopsy and outcome for CKD and ESRF
when the use of prednisone and immunosuppressive drugs had become the rule

43. Why the discrepancies? Renal biopsy ISKDC classification
Reversibility with no scarring: if crescents cellular are not fibrotic
Series from different eras
Recent large French series
renal prognosis association
not with crescents
Better with interstitial fibrosis and percentage of sclerotic glomeruli
Ronkainen et al. series
worse outcome of ISKDC grades II–III than grades IV–V
prompt use of aggressive immunosuppressive treatments in latter group.
4 studies in last 15 years
no relationship between crescents at first biopsy and outcome for CKD and ESRF
use of prednisone and immunosuppressive drugs had become the rule
Renal biopsy
sample bias; lesions observed may be over-represented or under-represented
Delay to kidney biopsy: crescentic glomeruli can rapidly lead to complete glomerulosclerosis
ISKDC classification limited recognition of important well-accepted prognostic factors
tubular lesions
interstitial fibrosis
interstitial and glomerular inflammation
crescent features (localized or completely surrounding the glomerulus, fibrotic or not)
segmental sclerosis
arteriosclerosis
electron microscopy and immunofluorescence features not considered;
Reversibility with no scarring: if crescents cellular are not fibrotic
Series from different eras
Recent large French series
renal prognosis association
not with crescents
Better with interstitial fibrosis and percentage of sclerotic glomeruli
Ronkainen et al. series worse outcome of ISKDC grades II–III than grades IV–V
prompt use of aggressive immunosuppressive treatments in latter group.
4 studies in last 15 years
no relationship between crescents at first biopsy and outcome for CKD and ESRF
when the use of prednisone and immunosuppressive drugs had become the rule

44. Will steroids prevent renal disease in HSP?
No!
Figure 3. Forest plot of comparison: 1 Prevention of persistent kidney disease - prednisone compared with placebo/supportive treatment, outcome: 1.3 Continuing kidney disease at different time points - study with high risk of bias excluded.
Interventions for preventing and treating kidney disease in Henoch-Schönlein Purpura (HSP) (Review)
Chartapisak W, Opastirakul S, Hodson EM, Willis NS, Craig JC
Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2010, Issue 4
Chartapisak W, Opastirakul S, Willis NS, Craig JC, Hodson EM. ADC, 2008 and Cochrane review updated, 2010.

45. Will steroids improve outcome for acute mild renal symptoms?
RCT early steroid in HSP
Sub group analysis
71 with renal symptoms in first month
More rapid resolution with steroids at 6 months
Ronkainen et al. J Ped 2006.
Renal involvement after treatment in HSP patients with mild renal symptoms in the acute phase, by treatment group (36 in the prednisone group and 35 in the placebo group). P values, differences for proportions, and their 95% CIs in the resolution of renal symptoms are given above the columns for each control visit (1, 3, and 6 months). Grey bar, placebo; white bar, prednisone.
Ronkainen et al. J Ped 2006.

46. What treatments can be used for ‘severe’ HSP Nephritis?
Immunosuppressants
Steroids
IVMP
po Prednisolone
Cyclophosphamide (CyP)
Ciclosporin
Plasma exchange
Rituximab?
ACEi

47. Current RHSC(G) guideline
HSP Class
Management
I & II
No immunosuppressant treatment routinely
ACEi if persistent proteinuria
III
Pulse IV methylprednisolone 600mg/m2 for 3 days
Oral prednisolone 60mg/m2 (max 60mg) for 1 month and taper
Consider Cyclophosphamide 2.5mg/kg/day for 56 days
IV & V (VI)
Cyclophosphamide 2.5mg/kg/day for 56 days
Consider Plasma exchange

48. What is the evidence for treatment when HSP nephritis develops?
No adequate evidence
No RCTs for treatment of HSP nephritis
Treatment-based literature of Henoch–Schönlein purpura nephritis in childhood
Zafanello and Fanos. Ped Neph, 2009.

49. Treatment of moderately severe HSPN
Small case series or retrospective studies only
Moderately severe proteinuria
Prednisone
IVIG
Tonsillectomy
...and degree of severity of renal histology
pulse IVMP
CyP
Evidence not supportive of any particular treatment
Zafanello and Fanos. Ped Neph, 2009.

50. Treatment of rapidly progressive or crescentic HSPN
Case series, retrospective and prospective studies (controlled and uncontrolled), cohort studies
Single RCT of 42 days cyclophosphamide (CyP)
No difference in end stage renal failure up to 14 years
did not recommend the use of CyP in treating severe HSPN
non-trial patients analyzed together with trial-patients
Tarshish et al. Ped Neph 2004
Insufficient data to support any particular treatment
Zafanello and Fanos. Ped Neph, 2009.
Evidence   Current protocols include the prescription of a single specific immunosuppressive treatment with steroids [27, 28], cyclosporine A (CSA) [29] and CYCP [30]. Other protocols were performed with double immunosuppressant therapy, including steroid–CYCP [5, 31–35], steroid–azathioprine (AZA) [36–39], and steroid–CSA or steroid–ACEI–CSA [40–42]. Triple immun
osuppressant therapy was carried out using steroid–CYCP–AZA [43] and steroid–AZA–mycophenolate mofetil (MM) [8].
Grade B, for which sound scientific evidence
suggests that the benefits afforded by clinical treatment
outweigh potential risks

51. Plasma exchange Plasma exchange in HSPN
either alone or in combination with immunosuppressant
Not currently recommended due to paucity of data available
Reserve for most severe HSPN?
Grade V histology
Zafanello and Fanos. Ped Neph, 2009.

52. ACE inhibitors in IgA nephropathy
Survival without the combined end point of 30% reduction of baseline CrCl and/or increase in proteinuria up to >3.5 g/d/ 1.73 m2 in IgAN patients receiving ACE-I or placebo (Kaplan-Meier estimates, log rank, P = 0.034).
IgACE: A Placebo-Controlled, Randomized Trial of Angiotensin-Converting Enzyme Inhibitors in Children and Young People with IgA Nephropathy and Moderate Proteinuria Coppo et al CJASN 2007.
Coppo R et al. JASN 2007
IgAN patients receiving ACE-I or placebo.
Survival without 30% reduction of baseline CrCl and/or increase in proteinuria (>3.5 g/d/ 1.73 m2)
©2007 by American Society of Nephrology

53. Future directions – risk markers at diagnosis
Abnormal IgA glycosylation in Henoch-Schönlein purpura restricted to patients with clinical nephritis.
Allen et al. NDT 1998
CONCLUSIONS:
These data indicate that the abnormality of IgA1 O-glycosylation seen in IgA nephropathy is also found in Henoch-Schönlein purpura, but only in those subjects with renal involvement, while IgA1 O-glycosylation is normal in patients with other forms of renal disease. These findings lend strong support to a role for altered IgA1 O-glycosylation in the pathogenesis of IgA-associated glomerular disease.

54. Summary HSP is the commonest vasculitis of childhood
Renal involvement is frequent
Significant renal disease is less common but can develop up to 3 months from presentation
Early steroid therapy in HSP does not prevent nephritis
Treatment interventions for HSP nephritis are not well evidence based
Variations in long term outcomes may reflect changes in clinical practice over time
Prompt intervention in more severe nephritis with immunosuppression is still used
ACEi for persistent ‘chronic’ proteinuric nephropathy is recommended

55. Future directions Review current HSP care pathway
Capture diagnosis all cases of HSP with renal involvement on clinical database
Clinical audit system (MCNs) for any renal HSP
SERPR for all HSP nephritis with nephrology referral, especially biopsy.
Participation in multi-centre studies?