INTRODUCTION
This chapter will focus on the treatment of HSP nephritis in adults and children.
The cost implications for global application of this guideline are addressed in Chapter
2.
11.1:
Treatment of HSP nephritis in children
11.1.1: We suggest that children with HSP nephritis and persistent proteinuria, >0.5-1 g/d
per 1.73 m2, are treated with ACE-I or ARBs. (2D)
11.1.2: We suggest that children with persistent proteinuria, >1 g/d per 1.73 m2,
after a trial of ACE-I or ARBs, and GFR >50 ml/min per 1.73 m2, be treated the same
as for IgAN with a 6-month course of corticosteroid therapy (see Chapter 10). (2D)
11.2:
Treatment of crescentic HSP nephritis in children
11.2.1: We suggest that children with crescentic HSP with nephrotic syndrome and/or
deteriorating kidney function are treated the same as for crescentic IgAN (see Recommendation
10.6.3). (2D)
BACKGROUND
HSP is an acute small-vessel vasculitis, characterized clinically by a nonthrombocytopenic
purpuric rash, nondeforming arthritis, gastrointestinal involvement, and nephritis.
554
The incidence of HSP is about 10 cases per 100,000 per year. It affects all ages,
but 90% of cases are found in those less than 10 years of age, with the median age
at presentation being 6 years.
554
Kidney involvement occurs in 30-50% patients.
554, 555, 556
Microscopic hematuria is the most common finding. In a systematic review of 12 studies
of 1133 unselected children with HSP, abnormal urinalysis occurred in 34% with the
majority (79%) having isolated hematuria with or without proteinuria.
555
Only 21% of those with kidney involvement (or 7.2% of all cases) developed a nephritic
and/or nephrotic syndrome. Ninety percent of children had developed kidney involvement
by 8 weeks after acute presentation, while 97% developed kidney involvement by 6 months.
Recurrence of rash and other symptoms occur in one-third of patients.
556
Nephritis is associated with older age at presentation, persistent rash, and recurrence
of HSP, while proteinuria >20 mg/m2/h was associated with recurrence and severe abdominal
pain.
557
Only 1-3% of patients progress to ESRD.
554
Long-term prognosis correlates with kidney presentation at onset. Compared to 1.6%
of children with isolated hematuria with/without proteinuria, 19.5% of children with
nephritic or nephrotic syndromes at initial presentation have nephrotic-range proteinuria,
hypertension, and/or reduced GFR at long-term follow up.
555
Among 78 patients managed in specialized pediatric kidney units, 44% of those with
a nephritic or nephrotic presentation had hypertension and/or impaired kidney function
at a mean follow-up of 23.4 years, while 82% of those presenting with hematuria with
or without proteinuria had normal urinalysis, kidney function, and blood pressure.
558
A recent study of 103 children found that, at final follow up, GFR correlated with
GFR and proteinuria at onset and 1 year, with ISKDC pathology grade and interstitial
fibrosis. Multivariate analysis identified that proteinuria at 1 year and ISKDC grade
were most useful in identifying patients with a poor prognosis.
559
However, one long-term study found that severity of findings on first kidney biopsy
did not correlate with the risk of a poor outcome (hypertension, persistent proteinuria,
ESRD).
560
RATIONALE
There is no evidence for the use of RAS blockade in HSP nephritis in children, but
an RCT in children and young adults with IgAN demonstrated the benefit of this therapy
in reducing proteinuria and maintaining GFR.
There is no evidence for the use of oral corticosteroids in HSP nephritis, but data
from RCTs in adults with IgAN have demonstrated a benefit in reducing proteinuria
and maintaining GFR.
There is very low–quality evidence for the benefit of high-dose corticosteroids and
immunosuppressive agents in HSP nephritis with deteriorating kidney function.
There is no evidence available for the use of RAS blockade in HSP nephritis. However,
an RCT in 66 children and young adults with IgAN with moderate proteinuria (>1 to
<3.5 g/d per 1.73 m2) and GFR >50 ml/min per 1.73 m2 demonstrated the benefit of ACE-I
in reducing proteinuria and maintaining GFR.478 There are very limited data to support
the use of corticosteroids in children with established nephritis of any severity,
561
though corticosteroids are widely used in children presenting with nephrotic-range
proteinuria or acute nephritis. In a post-hoc analysis of one placebo-controlled RCT,
562
nephritis resolved more rapidly in children treated with prednisone compared to placebo.
Seven of 36 children (19%) in the prednisone group still had kidney involvement at
6 months compared to 15 of 35 (43%) in the placebo group. The trial only provided
outcome data to 6 months after randomization, so it is unclear whether prednisone
treatment reduced the number of patients with persistent HSP nephritis overall, or
promoted more rapid resolution of kidney disease compared to placebo.
A prospective but uncontrolled study of 38 consecutive children with mean follow-up
period of 5 years and 7 months showed resolution of severe nephritis (nephrotic syndrome
and/or >50% crescents on biopsy) in 27 of 38 children treated with three pulses of
methylprednisolone followed by oral prednisone for 4 months.
563
Seven children had residual abnormalities and four progressed to ESRD. Two recent
RCTs in adults with IgAN, proteinuria ≥1 g/d, and GFR ≥30-50 ml/min per 1.73 m2 have
demonstrated the benefit of 6-8 months of prednisone and ACE-I, compared to ACE-I
alone, on reducing the rate of kidney functional deterioration and reducing proteinuria
during follow-up periods of up to 48 months511 or 96 months.510
In the absence of sufficient long-term data in HSP nephritis, we suggest that persistent
HSP nephritis can be treated as isolated IgAN (see Recommendation 10.3.1). However,
there are no data to determine when prednisone should be commenced in children with
HSP nephritis, and for how long ACE-I or ARB therapy should be administered before
commencing prednisone. Foster et al.
564
noted that the chronicity score (interstitial fibrosis, tubular atrophy, fibrosed
crescents) on initial kidney biopsy increased with increasing delay between onset
of kidney involvement and time of biopsy. Most children in their series of 20 patients
were biopsied within 3 months, with a median of 30 days. Treatment with prednisone
and azathioprine resulted in improvement in acuity score but not chronicity score.
Therefore, in HSP nephritis, it may be appropriate to commence prednisone therapy
earlier than in IgAN.
There are limited data on immunosuppressive agents, so it remains unclear whether
these have any role in HSP nephritis. In a single RCT of 56 children with significant
HSP nephritis (nephrotic range proteinuria, reduced kidney function, ISKDC* grades
III–V on kidney biopsy [crescents <50% to >75%]) treated within 3 months of onset
of HSP and followed for 5-6 years, there was no significant difference in the risk
for persistent kidney involvement of any severity between cyclophosphamide and supportive
treatment (RR 1.07; 95% CI 0.65-1.78).
565
Corticosteroids were not administered to these children. A nonrandomized comparative
study of 37 children with HSP nephritis and >50% crescents (ISKDC grades IV-V) on
kidney biopsy found that none of 17 treated with cyclophosphamide plus corticosteroids,
compared to four of 20 treated with corticosteroids alone, had persistent nephropathy
(proteinuria >20 mg/m2/h with/without GFR <40 ml/min per 1.73 m2) at 6-8 years of
follow-up.
566
A small RCT, in children with nephrotic-range proteinuria and/or ISKDC grades III-V
on kidney biopsy, found that all of 10 children treated with cyclosporin achieved
remission compared to five of nine children treated with methylprednisolone.
567
However, at the 2-year follow-up of 23 children, seven of 11 children treated with
cyclosporin and seven of 12 treated with methylprednisolone had persistent proteinuria
with/without decreased GFR.
568
One nonrandomized comparative study involving 20 children with nephrotic-range proteinuria
and ISKDC grades II-III on kidney biopsy reported that none of 10 children treated
with azathioprine and prednisone, compared to four of 10 treated with prednisone alone,
had nephrotic-range proteinuria and/or GFR <60 ml/min per 1.73 m2 after 4-5 years
of follow-up.
569
Observational studies have reported good outcomes with corticosteroids combined with
azathioprine,
564
cyclophosphamide,
570
cyclosporine,
571, 572
and plasma exchange.
573, 574
There are no data, other than small observational studies, examining the treatment
of crescentic HSP nephritis with rapidly progressive kidney failure. In the absence
of data, we suggest treating such patients similarly to patients with ANCA vasculitis.
A single small RCT
575
comparing 1 year of treatment with MMF to azathioprine has enrolled 17 children (ISKDC
grade II and III) to date. Proteinuria resolved in all of 10 children treated with
MMF, and six of eight treated with azathioprine. Seven patients treated with MMF and
five treated with azathioprine showed regression of histological changes at 1 year.
Children received prednisone for 6 months, but were not treated with ACE-I. These
data are insufficient to draw any conclusions on the value of MMF in HSP nephritis
in children.
11.3:
Prevention of HSP nephritis in children
11.3.1: We recommend not using corticosteroids to prevent HSP nephritis. (1B)
BACKGROUND
At first presentation with HSP, nephritis may be clinically mild or even absent. Therefore,
treatment strategies at the time of presentation have been developed with the goal
of preventing nephritis, or reducing the risk of severe persistent nephritis.
RATIONALE
There is moderate-quality evidence to recommend that corticosteroids not be given
at presentation of HSP, since they do not appear to influence the development of persistent
kidney involvement.
A meta-analysis
576, 577
of five RCTs (789 children) found no significant difference in the number of children
with evidence of persistent kidney disease (microscopic hematuria, proteinuria, hypertension,
reduced kidney function) during follow-up between those treated with prednisone for
2-4 weeks and those not treated (RR 0.73; 95% CI 0.43-1.24). There were no significant
differences in the risk of persistent kidney disease at 6 months (379 children; RR
0.54; 95% CI 0.25-1.18) and 12 months (498 children; RR 1.02; 95% CI 0.40-2.62). Three
of the five trials (568 patients) were well designed, placebo-controlled trials; exclusion
of poor-quality studies from the meta-analysis removed heterogeneity without altering
the findings. Two RCTs
562, 578
found no significant difference in the risk of severe nephritis (nephrotic-range proteinuria,
hypertension with/without reduced kidney function) between children treated with prednisone
or placebo at presentation, though the number of events was small, resulting in imprecision
(261 children; RR 1.92; 95% CI 0.57-6.50). There are no data on prevention strategies
for HSP nephritis in adults.
11.4:
HSP nephritis in adults
11.4.1: We suggest that HSP nephritis in adults be treated the same as in children.
(2D)
RATIONALE
Outcome data from HSP nephritis in adults are from retrospective series. A Spanish
retrospective study of HSP in adults suggested a higher frequency of kidney involvement
than children, but the final outcome of HSP is equally good in patients of both age
groups.
579
In an Italian cohort, the risk for progression of HSP nephritis was found greater
in adults and was associated with increasing proteinuria during follow-up.
580
In a UK series, the risk factors for ESRD were: proteinuria ≥1 g/d during follow-up,
hypertension at presentation and during follow-up, kidney impairment at presentation—very
similar to the prognostic indicators in IgAN in adults.
581
In a Finnish series, kidney survival 10 years after biopsy was 91%.
582
A recent cohort of HSP nephritis in Chinese adults showed a higher risk of progression
to kidney impairment compared to children.
583
The biggest retrospective cohort of 250 adults with HSP was from France.
584
After a median follow-up of 14.8 y, 32% of the patients showed kidney impairment (CrCl
<50 ml/min), usually associated with proteinuria and/or hematuria.
There are very few RCTs investigating the treatment of HSP nephritis in adults. A
recent 12-month, multicenter, prospective, open-label trial (CESAR study) was performed
using steroid therapy without or with cyclophosphamide in 54 adults with severe HSP
including proliferative GN and severe visceral manifestations.
585
The study did not include patients with rapidly progressive GN. All patients received
steroids while 25 were randomized to also receive cyclophosphamide. There was no additional
benefit of cyclophosphamide compared to steroids alone. The investigators commented
that the small population size did not permit definitive conclusions.
We suggest that treatment for HSP nephritis in adults should use the approach proposed
for HSP in children (see Sections 11.1 and 11.2). Current evidence does not suggest
using additional immunosuppressive agents other than steroids in HSP nephritis in
adults.
RESEARCH RECOMMENDATIONS
An RCT comparing a 6- to 12-month course of corticosteroids to shorter-duration corticosteroids
(28 days) should be performed in children with moderately severe HSP nephritis (acute
nephritic syndrome or nephrotic syndrome with normal kidney function and <50% crescents
or sclerosing lesions on biopsy).
RCTs are required to determine whether immunosuppressive agents (cyclosporine, azathioprine,
MMF) and corticosteroids are effective in treating children with severe HSP nephritis
(acute nephritic syndrome, nephrotic syndrome with or without reduced kidney function
with >50% crescents or sclerosing lesions on biopsy).
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