In-Depth Review

Henoch-Schonlein Purpura Nephritis: Pathophysiology,

Treatment, and Future Strategy
Jean-Claude Davin

Summary
Henoch-Schonlein purpura nephritis is a rare kidney disease leading to chronic kidney disease in a non-negligible percentage of patients. Although retrospective studies suggest beneficial effects of some therapies, prospective randomized clinical trials proving treatment efficacy are still lacking. The dilemma of spontaneous
recovery even in patients with severe clinical and histologic presentation and of late evolution to chronic kidney disease in patients with mild initial symptoms renders it difficult for clinicians to expose patients to treatment protocols that are not evidence-based. A better understanding of the pathophysiology of progression to
chronic kidney disease in Henoch-Schonlein purpura patients could be achieved by designing prospective international multicenter studies looking at determinants of clinical and histopathological evolution as well as
possible circulating and urinary markers of progression. Such studies should be supported by a database available on the web and a new histologic classification of kidney lesions. This paper reports clinical, pathologic,
and experimental data to be used for this strategy and to assist clinicians and clinical trial designers to reach
therapeutic decisions.
Clin J Am Soc Nephrol 6: 679 689, 2011. doi: 10.2215/CJN.06710810

Introduction
Henoch-Schonlein purpura nephritis (HSPN) and IgA
nephropathy (IgAN) are currently considered related
diseases. Indeed, in a set of identical twins, one can
present with IgAN and the other one with HSPN (1).
Furthermore, both diseases display similar histologic
features and IgA abnormalities (2). The common clinical pattern of IgAN is an indolent progressive disease
with slowly increasing proteinuria and loss of renal
function with flair-ups of macroscopic hematuria in
half of the patients. HSPN, in contrast, presents most
often with an initial acute episode followed by complete healing in the majority of patients. Persisting
proteinuria and progressive chronic renal failure occur in a minority of patients (2). Nephritic and/or
nephrotic syndromes are more often seen at presentation in HSPN (2). End-stage renal failure (ESRF)
caused by HSPN is infrequent in adults (3), but it
reached 5.1% in a large series of children from
Necker-Enfants Malades Hospital (4). The prevalence
of HSP is difficult to assess from the literature (5).
Using the controversial American College of Rheumatology criteria for vasculitis classification (6,7), which
may result in overdiagnosis, the yearly incidence varies between 6.1/100,000 children in The Netherlands
to 20.4/100,000 children in UK (8 11). It is generally
agreed that the incidence of HSP decreases with age
(3). The proportion of children presenting with renal
involvement reported in studies varies from 20 to
100% (for a review, see reference 12). In one study
using a cohort of adult patients in whom the diagnosis was based on the findings of the characteristic
leucocytoclastic skin vasculitis accompanied by IgA
www.cjasn.org Vol 6 March, 2011

deposits (13), 49% of patients presented with abnormal urinary signs. In selected series, HSPN leads to
chronic kidney disease (CKD) 20 years after the diagnosis in up to 20% of children (14), whereas this
percentage falls to less than 5% in unselected series
(15). The risk of CKD in adults is higher. It varies from
35 to 69% in 388 patients followed up at least 5 years
in four published series (16 19). Furthermore, adults
have more often joint symptoms at presentation (20).
Our knowledge on treatment of HSPN is quite limited. Randomized clinical trials (RCTs) are scarce and
often inconclusive. Spontaneous complete recovery in
patients with severe initial presentation and/or extended histologic lesions and the late evolution to
CKD of patients with mild initial symptoms makes
the interpretation of treatment efficacy difficult
(12,14,21). The main goal of the present paper is to
propose a strategy aimed to better define patients at
risk, using renal symptoms, histologic lesions, and
possible new markers of progression to assist clinicians and clinical-trial designers to reach therapeutic
decisions.

Department of Pediatric
Nephrology, Emma
Childrens HospitalAcademic Medical
Center, Amsterdam,
The Netherlands and
Department of Pediatric
Nephrology, Hopital
Universitaire des
Enfants Reine Fabiola,
Brussels, Belgium
Correspondence: Dr.
J. C. Davin, Pediatric
Nephrology
Department, Emma
Childrens HospitalAcademic Medical
Center, Meibergdreef 9,
1105 AZ Amsterdam
Z-O, The Netherlands.
Tel: 31205669111; Fax:
31206917735; E-mail:
j.c.davin@amc.nl

Experimental Data and Pathophysiological

Hypothesis
The pathophysiology of HSPN has been extensively
described elsewhere (2,22). Endocapillary and extracapillary inflammation as well as glomerular fibrin
deposits are more frequent in HSPN than in IgAN. No
major biologic differences have been found between
the two illnesses excepted for the IgG content and
bigger size of the circulating IgA-containing complexes (IgA-CC) and the higher incidence of increased
Copyright 2011 by the American Society of Nephrology

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Clinical Journal of the American Society of Nephrology

IgE plasma levels in HSPN (2325). Our own study on the

possible role of immunoallergic mechanism (25) was initiated on the basis of reports of HSP associated with allergy
and high IgE plasma levels and on the observation of a
7-year-old boy with HSPN that started 1 day after he fell
into stinging nettles (Jean-Claude Davin, personal communication). This information led us to postulate that stimulation of IgE-sensitized mast cells (present in skin, intestine, and lungs) by specific antigens in the presence of
IgA-CC might lead to the release of vasoactive substances,
increasing capillary permeability and perivascular deposition of IgA-CC. Although mast cells are not usually found
in the mesangium, circulating vasoactive substances released by other organs might account for increasing the
deposition of large IgA-CC in glomeruli.
IgA Abnormalities
HSPN and IgAN might result primarily from an abnormal IgA1 glycosylation. The lack of terminal 1-galactosyl
residues in the hinge region of IgA1 observed in both
diseases might be due to a reduced activity of the 1,3galactosyltransferase in peripheral B cells (26 28). This
abnormality is present only in HSP complicated by nephritis, which suggests a pathophysiological role (26).
N-Acetylgalactosamine (GalNac) residues exposed on
IgA1 because of the lack of terminal 1 galactosylation
constitute a novel antigen inducing a humoral auto-immune response (29). The possible impaired resistance to
antigen penetration at mucosal levels suggested in HSPN
by an increased intestinal permeability (30) and in IgAN by
a reduced mucosal immune reaction to novel antigen (31)
might contribute to the production of large amounts of
GalNac-IgA1 that cannot be cleared by the asialoglycoprotein receptor of hepatocytes binding specifically to 1,3galactosyl-IgA1. Accumulating GalNaC-IgA1 in polymeric
forms (pIgA) in circulating blood favors the formation of
large IgA1-CC that deposit in different tissues and induce
local inflammation. IgA1 binding to leukocyte FcRI receptors is followed by cleavage of the FcRI extracellular
domain, resulting in a release of IgA1/FcRI receptor complexes that amplifies the molecular size of IgA-CC (32). In
glomeruli, IgA1 complexes localize in a mesangial or in a
subendothelial pattern (33) according to their physicochemical properties. CD71 mRNA coding for the transferrin receptor, which preferentially binds GalNac-IgA1, is
expressed on mesangial cells (32,34). In vitro studies have
shown binding of pIgA to mesangial cells to enhance cell
proliferation, cytokine release, and production of extracellular matrix (ECM) (3537).
Complement Activation
Activation of the complement pathway is probably an
important effecter event in the pathophysiology of glomerular lesions. C3 deposits are seen in a vast majority of
patients with HSPN (38). Alternative pathway components, such as FB in contrast to C1 and C4, and the membrane attack complex C5b9 are regularly present, accompanying predominant IgA deposits in a mixed mesangial
and capillary pattern (33). The glomerular deposition of
MBL, L-ficolin, MASP, C4d, but not C1q shown to be
associated with a higher grade of proteinuria and hema-

turia and more severe histologial lesions in HSPN (39)

strongly suggests, as seen in IgAN (40), a predominant
pathophysiological role of the activation of the complement system by the lectin pathway. This emphasizes the
need of studies examining the value of blood and urinary
complement splits product and of the membrane attack
complex to evaluate the disease activity.
Mesangial Cell Activation, Proliferation,
and Glomerulosclerosis
The deposition of IgA-CC in glomeruli is favored by
their high plasma concentration and their biochemical features in HSPN (23,24). Once in the mesangium, different
components of IgA-CC (for example, Fc and Fc fragments, fibronectin, C3b, etc.) can bind to their specific
receptors on the surface of mesangial cells (MCs) (2,41) and
trigger cell proliferation, ECM production, and synthesis of
chemokines monocyte chemoattractant protein-1 and IL-8
(34 37) that might account for the attraction of polymorphonuclear leukocytes and monocytes found in patient
biopsies. MCs can also be stimulated by cytokines of the
acute phase (IL-1, TNF-, and IL-6) and of the chronic
phase (PDGF and TGF-) produced by themselves (for a
review, see references 41 46) and/or by infiltrating cells.
Chemokines generated by IgA1-stimulated MCs can interact with their receptors on podocytes and in this way
may influence their metabolism, local migration, and adherence to the basement membrane and control of proteinuria (47,48). The urinary excretion of podocytes (u-podo
excretion) seems to be a good parameter for predicting
glomerulosclerosis in HSPN and IgAN because chronic
histology scores and glomerulosclerosis both correlate well
with cumulative u-podo excretion (49). Patients with severe histologic progression of disease also had persistent
u-podo excretion (49).
Crescent Formation
Because the presence of crescents is a prominent histologic feature of HSPN that represents an important prognostic factor and constitutes the basis for the International
Study Group of Kidney Disease in Childhood (ISKDC)
pathology classification (38), the study of crescent pathophysiology might provide useful information for therapeutic strategy (50 52). As already mentioned, crescents are
much more often seen in HSPN than in IgAN, and their
number is related to the severity of clinical signs and to the
prognosis of HSPN in most series (16,17,53 60). They are
frequently seen in association with capillary wall destruction and endocapillary cell proliferation (33). The presence
and extension of crescents are related to the finding of
subendothelial immune deposits of IgA and complement
using immunofluorescence microscopy and with the presence of subendothelial electron dense deposits (33).
Histology of patient biopsies combined with studies on
experimental crescentic glomerulonephritis (6175) suggest that the following succession of events is involved in
the crescent formation in HSPN (2): (1) subendothelial and
mesangial deposition of IgA-CC; (2) local complement activation; (3) IL-8 production by mesangial and endothelial
cells inducing neutrophil attraction; (4) stimulation of endothelial cells to express von Willebrand factor and tissue

Clin J Am Soc Nephrol 6: 679 689, March, 2011

factor that initiate the coagulation cascade, leading to glomerular-fibrin deposition; (5) destruction of the basement
membrane; (6) macrophages attraction and cytokine-induced epithelial cells proliferation in the Bowmans space;
and (7) disruption of the capsular integrity and infiltration
of the Bowmans space by interstitial fibroblasts resulting
in fibrosis formation. Importantly, genetically-determined differences in both glomerular and bone-marrow derived cells influence individual susceptibility to
crescent formation (76).

Prognostic Value of Renal 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. The interpretation of data from reported series is complicated by the
possible influence of treatment, which is most often heterogeneous and not precisely reported (dosage, duration of
administration). Moreover, the latter has varied through
the years. Until the 1980s, HSPN was considered to be
mostly an illness with spontaneous recovery (77). This
concept began to change after the publication of long-term
follow-up studies (5355). Parallel to this change and despite the lack of evidence-based data, recommended treatments in text books changed from supportive measures
(7779) to the use of steroids and immunosuppressive
drugs (80,81) even in the absence of a picture of rapidly
progressive glomerulonephritis (80). Another difficulty resides in the development of CKD up to 20 years after
disease initiation, especially during pregnancy, even after
complete apparent resolution (14,21). This implies that
only series with sufficient follow-up might be informative.
Finally, most series of long-term follow-up relate outcome
to initial symptoms and biopsy without intermediate observational moments, discarding the potential role of relapses and of a progressive active process. This lack of
information does not allow for the differentiation of different patterns of pathologic events leading to CKD: (1) one
unique episode with apparent complete recovery but leading to an important nephronic reduction and CKD at long
term by hyperfiltration; (2) recurrence of acute episodes;

Henoch-Schonlein Purpura Nephritis: Future Strategy, Davin

681

c/progressive indolent process as in IgAN. The latter is

suggested by several reports of HSPN observed in patients
known to have had IgAN for many years (82 85). In general, there is a good relationship between the severity of
initial clinical presentation and the risk of CKD at long
term (14,21) (Table 1), but it is far from being a constant
rule.
According to the study of Goldstein et al. (14), CKD is
encountered at long term in less than 5% of patients when
clinical signs at presentation are hematuria and/or minimal proteinuria, 15% when proteinuria is heavy but not
nephrotic or in the case of nephritic syndrome, 40% with
nephrotic syndrome, and in more than 50% when nephritic
and nephrotic syndromes are associated. It is remarkable
that some (rare) patients presenting with mild initial symptoms are seen with CKD at long term (14,86). A particular
example is CKD observed after repeated episodes of isolated macroscopic hematuria (87,88). Even patients with no
urinary abnormalities at all have been reported to present
with hypertension later on (89).
Bias in the interpretation of initial symptoms for prognostic purposes has resulted in the consideration of other
clinical parameters. Failure to reach a creatinine clearance
of 70 ml/min per 1.73 m2 at 3 years and increasing
proteinuria levels during follow-up correlate better with
the risk of progression to CKD than decreased renal function, severe proteinuria, hypertension, or crescents present
at onset of disease (88,90) (Table 1). On the other hand,
although there is no specific report of late follow-up of
patients with untreated initial severe renal symptoms at
presentation (nephrotic proteinuria, nephrotic syndrome
combined or not with nephritic syndrome), it is commonly
accepted that HSPN might heal completely when presenting with severe renal symptoms even when no treatment
has been used (77,86,90,91).

Prognostic Value of Histologic Lesions

Histologic lesions have been classified by the ISKDC in
five categories (I, II, III, IV, and V) according to the presence and number of crescents. Grade VI is used for a
membranoproliferative aspect (38). A rough appreciation

Table 1. Clinical prognostic factors for chronic kidney disease at long term in Henoch-Schnlein purpura

Symptoms

Patients (%)

Initial renal symptoms

nephrotic-nephritic syndrome
nephrotic syndrome
nephritic syndrome
heavy non-nephrotic proteinuria
hematuria and/or minimal proteinuria
Renal symptoms during follow-upb
GFR 70 ml/1.73 m2 per min at 3 years
Initial symptoms vs. increasing proteinuria during follow-upc
Mean follow-up proteinuria (g/d)
Severely impaired vs. normal GFR (onset)
Nephrotic vs. minimal proteinuria (onset)

CKD
50
40
15
15
5
ESRD
100
Progression (significance)
RR 1.77 (P 0.001)d
RR 3.83 (P 0.20)
RR 4.74 (P 0.17)

From reference 14.

From reference 88.
c
From reference 91. Univariate analysis of predictors related to renal survival by using dialysis therapy as end point.
d
Relative risk 1.77 for each 1-g/d increase for doubling of creatinine level. GFR has been calculated using the Schwartz formula.
b

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Clinical Journal of the American Society of Nephrology

of mesangial hypercellularity is also considered in this

classification.
As for clinical symptoms, it is generally accepted that the
risk for the development of CKD increases with the severity of the histologic lesions at presentation. 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. Only four (18,19,21,92) from 15 series
(eight in children and seven in adults) (14,16 19,21,53
60,92) reporting on the relation between outcome and the
histology of the first renal biopsy do not mention a predictive value of crescents for CKD and ESRF. In contrast, the
latter studies also show that low grade histologic lesions
can also lead to CKD and that high grade lesions can heal
definitively. The reasons for those discrepancies can be
multiple: (1) A renal biopsy is only a small fragment of
renal tissue; it is therefore possible that lesions observed
are either over-represented or on the contrary under-represented, giving a biased image of the reality in its totality.
(2) Reversibility with minimal or no scarring can be expected when crescents are not yet fibrotic and still remain
predominantly cellular without a significant fibroblast or
collagen component; this spontaneous resolution can be
expected with a triggering event of short duration such as
episodes of macroscopic hematuria accompanying respiratory infections in HSPN (53). (3) The ISKDC classification
does not consider some other important well-accepted
prognostic factors such as tubular lesions, interstitial fibrosis, interstitial and glomerular inflammation, crescent features (localized or completely surrounding the glomerulus,
fibrotic or not), segmental sclerosis, and arteriosclerosis;
this classification neither takes electron microscopy nor
immunofluorescence features into consideration; and the
importance of this issue is illustrated in a recently reported
large series of French patients (93) in whom interstitial
fibrosis and the percentage of sclerotic glomeruli, but not
crescents, were associated with a poor renal prognosis. (4)
Another possible explanation for this discrepancy is the
prompt use of aggressive immunosuppressive treatments
suggested by Ronkainen et al. (21) to explain the worse
outcome of ISKDC grades IIIII than grades IVV in their
series. This has led the latter authors to advise repeated
kidney biopsies when severe symptoms do not improve
and to rely more on symptoms than on histology for therapeutic decisions. It is remarkable that the four studies that
did not show a relationship between crescents at first biopsy and outcome report data from the last 15 years, when
the use of prednisone and immunosuppressive drugs had
become the rule. This suggests indirectly that treatment
might prevent cellular crescents to progress to fibrosis and
to contribute to CKD. (5) Finally, delaying the kidney
biopsy could play a role because crescentic glomeruli can
rapidly lead to complete glomerulosclerosis if not treated
(53,94).
In conclusion, those observations suggest that histologic
documentation should consider all factors that may provide prognostic information using a new detailed histo-

logic classification similar to that recently published for

IgAN (95). The latter should take into account the mesangial cellular score, the presence and extension of glomerulosclerosis, endocapillary hypercellularity, inflammatory
cells infiltration, the integrity of the Bowmans capsules,
cellular versus fibrotic crescents, and interstitial fibrosis/
tubular atrophy. The difficulty in predicting outcome underlines the necessity to develop markers of activity that
can be repeated easily with blood or urine samples (for
example circulating GalNac-IgA1 and anti-GalNac-IgA1
antibodies, various cytokines and products of the activation of the complement system, and urinary podocyte excretion) to avoid unnecessary renal biopsies.

Treatment Strategies According to Pathophysiology

The strategy to treat HSPN should take into account the
different steps of the pathophysiological process leading to
HSPN.
Antigen Penetration at a Mucosal Level
Because acute HSPN episodes are often triggered by an
upper respiratory tract infection (11), the removal of any
source of chronic bacterial infection should be theoretically
beneficial. That is the reason why some authors have performed tonsillectomy in patients with IgAN and HSPN.
Unfortunately, not a single report mentioned in recent
reviews on that topic (96 98) gives a level of evidence
sufficient to recommend this treatment, because it is often
associated with other therapies.
Reduction of IgA1 Production
All types of immunosuppressive drugs (steroids, cyclophosphamide, azathioprin, and calcineurin inhibitors)
have been used to prevent CKD in HSPN. No study has
been designed up to now to show drug efficacy on the
production of IgA1, pIgA1, or GalNac-IgA1. Interestingly,
efficacy of rituximab (RTX) therapy in chronic HSP has
been suggested in three pediatric patients treated with RTX
for severe refractory chronic HSP characterized mainly by
neurologic and gastroenterological symptoms resistant to
steroids and cyclophosphamide (CPH). All three patients
responded to one or two courses of RTX without serious
adverse events. The response was related to the suppression of the CD19 expression on mononuclear cells (99).
Removal of IgA1 and IgA1 Complexes
Several case reports relate the dramatic improvement of
extra renal symptoms (gastrointestinal, pulmonary, or cerebral) after plasma exchange (PE) (100 110). Interestingly,
Hattori et al. (109) and later on Shenoy et al. (110) reported
encouraging results on the use of PE as the only treatment
in patients with severe initial acute HSPN. In both series,
patients presented with acute renal impairment, heavy
proteinuria, or nephrotic syndrome and a histologic class
equal to or higher than III (110) or equal to V (109). At last
review after 4 (110) and 10 years (109), 13 of 14 and 6 of 9
patients, respectively, had a normal GFR and complete or
almost complete resolution of renal symptoms. The three
patients having reached ESRF were treated at least 1 month
after the start of symptoms. Apart from removing circulating complexes, the favorable role of PE might also be due

Clin J Am Soc Nephrol 6: 679 689, March, 2011

to the removal of inflammatory and procoagulatory substances.

Complement Activation
As stated above, activation of the lectin pathway of
complement in HSPN is associated with more severe renal
damage (39). It can be hypothesized than the latter might
be prevented by impeding the formation of some end
products of the complement activation playing a role in the
inflammatory response such as C5a and the membrane
attack complex C5b9. Eculizumab is a high affinity humanized monoclonal antibody that binds to and blocks the
cleavage of C5, leaving the upstream components of complement, most notably C3b, intact. Eculizumab has been
shown to be very efficacious in preventing acute episodes
of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome, two diseases resulting from defective inhibition of the complement system at different
levels (111115). This suggests that eculizumab might also
be of value in other kidney illnesses in which complement
activation plays a role.
Fibrin Formation
The possible role of fibrin in the pathogenesis of crescents has been strongly suggested by clinical and experimental observation. That is the reason why warfarin,
dipyridamol, and acetylsalicilic acid have been used along
with immunosuppressive agents by several authors (for a
review, see references 96 98). Difficulty of interpretation
results from the following cause of bias: retrospective studies, no controls, and heterogeneity of histology and clinical
symptoms as well as of heterogeneity of treatment. Aside
from the lack of reliable data, the possible bleeding complications in the case of gastroenterological complications
often seen in those patients might discourage clinicians
from using anti-coagulation.
Mesangial Proliferation, Glomerulosclerosis,
and Proteinuria
HSPN might possibly progress by continuous deposition of IgA-CC inducing mesangial proliferation, ECM
accumulation, and gomerulosclerosis such as IgAN (82
85). Proteinuria persisting after the acute phase might be
due to two different mechanisms: either hyperfiltration
due to nephronic mass reduction during the acute phase or
the effect of chemokines produced by persistently stimulated MCs on podocytes (47,48,116,117). Theoretically, both
mechanisms could be counteracted by ACE inhibitors,
whereas corticosteroids might prevent MC proliferation
and metabolic stimulation. Although prolonged administration of both classes of drugs has been shown to be
valuable in reducing proteinuria and preventing progression in IgAN (118 120), no similar studies have been done
in HSP. Despite the report of proteinuria reduction by
cyclosporine in some patients with HSPN not having responded to steroids and immunosuppressive drugs (121),
this treatment should not be recommended before the publication of the results of a RCT comparing cyclosporine to
high dosage methylprenisolone (MPNS) followed by prednisone (122), because of the potential nephrotoxicity of
cyclosporine.

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Crescent Formation
Because renal prognosis is related to crescent progression
to sclerosis, it is important to detect histologic signs predicting such an evolution (e.g. disruption of the Bowman capsule
and presence of fibroblasts in the Bowmans space) to initiate
anti-sclerosis strategies. Because genetically-determined
differences in both glomerular and bone marrow-derived
cells influence individual susceptibility to crescent formation in rats (76), studies directed to the latter will be initiated in humans. Known susceptibilities should indicate
more aggressive treatments.
Treatment has to be initiated early to prevent fibrotic
transformation (53). As mentioned above, prevention of
the development and resolution of crescents might be obtained by the removal of IgA-CC by plasmapheresis
(109,110). The use of pulses of high doses of MPNS instead
of the usual oral dosage of prednisone is sustained by
experimental results. In a rat model of crescentic glomerulonephritis, the maximal therapeutic effect is obtained
with 30 mg/kg IV MPNS (123). In a prospective noncontrolled study, Niaudet and Habib (124) suggested improved outcome of severe HSPN (nephrotic syndrome or
association of nephrotic and nephritic syndrome) when
MPNS pulses were used initially. In the latter series, only
11% progressed to end-stage renal failure in comparison
with 38 and 27% of patients in two historical series of the
same center receiving, respectively, a supportive treatment
or various immunosuppressive drugs but not MPNS.
Overall, these observations suggest that MPNS pulses
should be used preferentially at the initiation of the steroid
treatment. A favorable role of initial high dosage of steroids is suggested by other noncontrolled studies (125
128).
More specific treatment might be considered for clinical
trials to prevent the influx of monocytes in the Bowmans
space. Indeed selective blockade of IL-1 with IL-1 receptor
antagonists and of TNF with soluble TNF receptors markedly reduces crescent formation (68,70) by reducing the
expression of adhesion molecules and the recruitment of
macrophages in experimental models of glomerulonephritis.

Actual Choice for the Clinician

As usual, the clinician has to balance the risk of CKD
versus the risk and the cost of the proposed treatment. The
effect of treatment is particularly difficult to evaluate considering possible spontaneous complete recovery or apparent restoration of renal function masking a nephronic mass
reduction that could be sufficient to lead to CKD after
prolonged hyperfiltration.
The lack of benefit of steroids and immunosuppressive treatment reported in old series (14,54) and the lack
of data allowing a high level of evidence-based recommendations make the choice of therapy more difficult,
and one may wonder if treatment is really useful. However, pediatric nephrologists with expertise in this field
(21,80,81,98,124) are actually convinced of this necessity.
This opinion is based on the impression of a reduction of
CKD caused by HSPN parallel to treatment intensification and on several reports mentioning a worse evolution when treatment is delayed (21,109,110,124,126). Re-

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Clinical Journal of the American Society of Nephrology

cent papers have reviewed studies on HSPN therapy

(96 98). Several types of treatments have been claimed
to be efficacious in severe forms of HSPN in noncontrolled studies: MPNS followed by prednisone (124,126),
plasma exchange alone (109,110), or corticosteroids
(prednisone with or without initial MPNS) combined
with urokinase (125) or with immunosuppressive drugs
such as cyclophosphamide, azathioprin, and mizoribin
(124,127130). The value of the latter series might be
controversial because spontaneous recovery is not excluded when patients are compared with themselves.
Another pitfall is the short follow-up duration. However, two of the studies reported above merit special
attention: the first one showing the benefit of MPNS
compared with prednisone alone in two historical series
of the same hospital as a control (124) and the second
one showing the prevention of chronic renal failure development at long term (10 years) by PE as sole therapy
in patients with the most severe clinical (nephritic and
nephrotic syndrome) and histologic (class V) presentations where treatment was initiated early (109).
In the few RCTs performed until now, it has only been
shown that an initial short course of prednisone does not
prevent the development of renal symptoms in children
with HSP and does not affect the evolution of mild renal
symptoms (for a review, see references 96 98) and that
CPH is not effective. Indeed, 90 mg of CPH/m2 per day
for 42 days is not more effective than supportive treatment in patients with severe HSPN (proteinuria 40
mg/h per m2) (91) after 14 years of follow-up. A recent
paper (93) confirms the lack of efficacy of CPH in a
placebo-controlled prospective study comparing CPH
prednisone to prednisone alone in a cohort of adults
with HSPN.
In the case of minimal renal symptoms such as microhematuria, short duration macroscopic hematuria, or
mild proteinuria, one may choose not to start treatment
because of the low CKD risk (14). However, patients
should be followed to detect any change that could
eventually lead to a kidney biopsy and a decision to
treat.

In the case of nephritic syndrome or nephrotic proteinuria, even without clinical nephrotic syndrome, treatment
might be recommended (80) considering a risk of 15% to
develop CKD at long term (14). A course of steroids initiated as intravenous high dosage MPNS given without
delay might be proposed because oral prednisone alone
has been claimed to be of no benefit (14,54,81,124 128). The
addition of immunosuppressive drugs might be considered when improvement is delayed or in situations of
higher risks. However, considering negative RCTs and
side effects, CPH should probably not be recommended
anymore. Although PE might be seen as an aggressive
treatment, the risk of complications with modern devices is
minimal in expert hands in comparison with the risk of
CKD in patients with a severe clinical presentation especially in association with ISKDC pathology classification
class IV or V. The encouraging results cited above suggest
that PE should be considered promptly in patients where
steroids and immunosuppressive drugs are not effective or
even initially when nephritic and nephrotic syndromes are
associated with a high percentage of crescents. Reports of
long term follow-up of previous studies on the use of PE as
sole treatment will help to further determine the latter
indication (109,110). ACE inhibitors may be added at any
level of proteinuria and may be used alone in the case of
persisting proteinuria with a high chronicity index at biopsy. As mentioned above, early treatment initiation might
be a major factor for preventing the progression to CKD
(21,109,110,124,126).

Future Strategy
The future strategy will consist of better definition of
patients at risk of CKD to adapting treatment and clinical trials to groups of patients according to their risk
profiles (Table 2). The poor documentation of patient
history constitutes a major pitfall in the interpretation of
the prognostic role of the initial clinical signs and histologic data. The relationship of the latter to outcome has
been shown to be variable, and parameters of variability
can be multiple. Adequate assessment must consider all
features of the therapy (moment of administration re-

Table 2. Proposed strategy to improve Henoch-Schnlein purpura nephritis prognosis

Determination of risk factors

commercialization of kits for detecting specific markers of the disease as GalNac IgA1 and anti-GalNac IgG
setting up a new histological classification taking into account all suspected risk factors for developing CKD
blood and/or urinary measurements of markers possibly involved at different stages of the pathophysiological process
(i.e. Il-1, Il-6, Il-8, TNF-, TGF-, C5b-9, etc.)
development of a registry available on the web
multicenter studies recording prospectively and parallel clinical symptoms, biological markers values, histological data,
and treatment features
determining from registry data different grades of risk.
Clinical trials features
no placebo-controlled RCT allowed except for low grade risk
treatment started as soon as possible after disease initiation
tonsillectomy tested adequately
study treatment adapted according to risk grade and treatment toxicity
for highest risk, steroid treatment preferably with initial methylprednisolone bolus
for highest risk, plasma exchanges alone compared with other treatments
biological treatments considered (rituximab, antibodies anti-cytokines involved in inflammation and fibrosis processes, etc.).

Clin J Am Soc Nephrol 6: 679 689, March, 2011

lated to illness initiation, type of drugs used, dosage,

and duration of drug administration). Instead of relating
initial clinical and histologic data only to outcome, multiple intermediate moments should also be reported considering renal function, proteinuria, and relapses of purpura and of macroscopic hematuria. The report of the
delay between initial symptoms and biopsy is of major
importance because crescents can lead rapidly to glomerulosclerosis and tubular atrophy (53,94). It is now
obvious that the ISKDC classification that grades the
severity according to the amount of crescents only has
become obsolete and should be replaced by a new detailed histologic classification similar to that recently
published for IgAN (95), taking into account some or all
of the following parameters that are shown to be independent predictors of renal functional decline and/or
response to therapy: mesangial hypercellularity, endocapillary hypercellularity, crescents, segmental and global glomerulosclerosis, arterio- and arteriolosclerosis, interstitial inflammation, and tubular atrophy/interstitial fibrosis.
The high diversity of pathophysiological steps possibly
involved between the hypothesized initial event (GalNacIgA1 formation) and the final glomerular lesions enables
different types of evolution according to the specificity of
the markers participating in each step (i.e. size and composition of IgA1-CC, ability of the latter to localize in the
mesangium or under endothelial cells and to induce inflammation, capacity of glomerular cells to produce cytokines and matrix after stimulation, fibroblast ability to
invade the Bowmans space and to generate fibrosis, etc.).
A better understanding of HSPN pathophysiology,
defining the pattern of progression to CKD (scars from
acute limited episodes or a slowly progressive active
process as in IgAN) and the detection of patients at risk
are sine qua non conditions to improving treatment strategies. This could be reached by prospective multicenter
international studies initiated from disease presentation
and pursued at long term in large cohorts of patients
including also those presenting with minimal symptoms
and resulting in apparent complete healing. The latter
studies should be designed to look at regular intervals
for correlations between clinical signs, histologic findings, treatments, and modifications of circulating and/or
urinary markers (circulating GalNac-IgA1 and anti-GalNacIgA1 antibodies, various cytokines, products of the complement system activation, and urinary excretion of podocytes)
(26 29,34 37,43 47,131132). This process should be supported by an electronic database available on the web.
Clinical trials might be coupled to this electronic registry. They should be designed by experts in the field
who will decide on treatments according to risk profiles
and on puzzling issues such as primary end points and
follow-up duration. The results of studies looking for
early clinical prognostic indications for long term outcome should help with the design (88,90). If placebocontrolled studies could be considered to study the
value of treatments preventing the development of severe renal symptoms in patients with no or only minimal
initial urinary abnormalities, as has been previously
done (for a review, see references 96 98), it does not

Henoch-Schonlein Purpura Nephritis: Future Strategy, Davin

685

seem ethical to do this for all of the other presentations

because of their association with a significant CKD risk.
Trials should be designed to determine the efficacy of
immunosuppressive drugs, anticoagulation agents, and
PE. The dramatic improvement after RTX therapy in three
severe extrarenal cases of HSP resistant to steroids and
immunosuppressive treatment supports this drug as a candidate for RCTs (99). However, its potential severe and
sometimes fatal side effects (133) might limit its indication
to a RCT devoted to cases resistant to PEs. Other biologic
treatments such as eculizumab, for example, might also be
considered. Finally, the efficacy of tonsillectomy should be
tested adequately.
Acknowledgments
Jean-Claude Davin would like to thank Prof. Jan Weening for
his useful comments and Dr. Sally-Ann Clur for the revision of the
text.
Disclosures
None.

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