Henoch–Schönlein purpura nephritis in children · Henoch–Schönlein purpura (HSP) is the most fre-quently detected form of vasculitis in children. The incidence of HSP decreases

NATURE REVIEWS | NEPHROLOGY VOLUME 10 | OCTOBER 2014 | 563

Emma Children’s Hospital and Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, Netherlands (J.‑C.D.). Nephrology, Dialysis and Transplantation Unit, Città della Salute e della Scienza di Torino, Regina Margherita University Hospital, Piazza Polonia 94, Turin 1016, Italy (R.C.).

Correspondence to: J.‑C.D. [email protected]

Henoch–Schönlein purpura nephritis in childrenJean-Claude Davin and Rosanna Coppo

Abstract | Henoch–Schönlein purpura (HSP) is the most common vasculitis in children, in whom prognosis is mostly dependent upon the severity of renal involvement. Nephritis is observed in about 30% of children with HSP. Renal damage eventually leads to chronic kidney disease in up to 20% of children with HSP nephritis in tertiary care centres, but in less than 5% of unselected patients with HSP, by 20 years after diagnosis. HSP nephritis and IgA nephropathy are related diseases resulting from glomerular deposition of aberrantly glycosylated IgA1. Although both nephritides present with similar histological findings and IgA abnormalities, they display pathophysiological differences with important therapeutic implications. HSP nephritis is mainly characterized by acute episodes of glomerular inflammation with endocapillary and mesangial proliferation, fibrin deposits and epithelial crescents that can heal spontaneously or lead to chronic lesions. By contrast, IgA nephropathy normally presents with slowly progressive mesangial lesions resulting from continuous low‑grade deposition of macromolecular IgA1. This Review highlights the variable evolution of similar clinical and histological presentations among paediatric patients with HSP nephritis, which constitutes a challenge for their management, and discusses the treatment of these patients in light of current guidelines based on clinical evidence from adults with IgA nephropathy.

Davin, J.‑C. & Coppo, R. Nat. Rev. Nephrol. 10, 563–573 (2014); published online 29 July 2014; doi:10.1038/nrneph.2014.126

IntroductionHenoch–Schönlein purpura (HSP) is the most fre-quently detected form of vasculitis in children. The incidence of HSP decreases with age,1 but the preva-lence of the disease is not well established.2 In a Dutch study,3 the yearly incidence of HSP was 6.1 per 100,000 children in a cohort of children aged 0–18 years versus 14.9 per 100,000 in children aged between 3–6 years. The reported annual incidence of HSP varies from 6.1 cases per 100,000 children in the Netherlands to 20.4 cases per 100,000 children in the UK.3–6 However, these figures might be overestimated, as they were based on the contro versial 1990 American College of Rheumatology criteria for classification of vasculitis.7 Diagnosis of HSP required the presence of two or more of the fol-lowing criteria: age ≤20 years at disease onset; palpa-ble purpura; acute abdominal pain; and biopsy samples showing granulo cytes in the walls of small arterioles or venules.7 These criteria risk confusion with various forms of hypersensitivity vasculitis and may result in overdiagnosis of HSP in children.8

In 1994, HSP was defined by the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis as “a vasculitis with IgA-dominant immune deposits, affecting small vessels (that is, capillaries, venules or arterioles) typically involving skin, gut and glomeruli, and associated with arthralgias or arthri-tis.”8 The European League Against Rheumatism and

the Paediatric Rheumatology European Society (PRES) published modified criteria in 2006— palpable purpura (mandatory criterion) in the presence of at least one of the following: diffuse abdominal pain; any biopsy sample showing predominant IgA deposition; arthritis or acute arthralgia in any joint; and renal involvement (any haema turia and/or proteinuria).9 After a formal statistical validation of these criteria, performed by the Paediatric Rheumatology International Trials Organization and PRES, the 2008 Ankara Consensus Conference updated the 2006 PRES classification by adding the criterion that IgA deposition in a biopsy sample is required in patients who have an atypical distribution of purpura.10

Although complications resulting from lesions in organs other than the kidney (lung, intestine, brain and testis) are sometimes severe, the prognosis of HSP is mainly dependent on the renal component of the disease. Moreover, for decades HSP nephritis and primary IgA nephropathy have been considered related diseases because of their similar renal histologic features and IgA abnormalities.11,12 This relationship is exemplified by the occurrence of HSP nephritis and IgA nephropathy in identical twins.13 The proportion of children with HSP who present with renal involvement varies from 20% to 100% according to the level of nephrology care.14 In a 20 year follow-up series from a tertiary care centre, HSP nephritis led to chronic kidney disease (CKD) in up to 20% of children.15 By contrast, in unselected patients, the corresponding percentage is less than 5%.16,17 HSP nephritis is an infrequent cause of end-stage renal disease

Competing interestsThe authors declare no competing interests.

REVIEWS

© 2014 Macmillan Publishers Limited. All rights reserved

mailto:[email protected]

http://www.nature.com/doifinder/10.1038/nrneph.2014.126

564 | OCTOBER 2014 | VOLUME 10 www.nature.com/nrneph

(ESRD) in adults,1 but in historical series of children with HSP nephritis, the incidence of CKD can reach 5%.18 Thanks to improvements in the care and short-term outcomes of these children, only a few require dialysis nowadays, although whether the long-term outcomes of patients with HSP have also substantially improved remains unclear.

This Review summarizes advances in our understand-ing of the clinical symptoms, prognosis, pathology, pathophysiology and treatment of HSP nephritis in chil-dren. We also present contemporary perspectives on the typical clinical presentation and course of HSP nephri-tis. Similarities and differences with IgA nephropathy, as well as the consequences of the latter for treatment of HSP nephritis, are also discussed.

Clinical symptomsA recent or simultaneous infection is reported in 33–66% of patients with HSP.1 Although any of the four major components of the syndrome (rash, joint pain, abdominal symptoms and renal disease) might precede the others, the renal symptoms are rarely first to develop.1 In a

Key points

■ Henoch–Schönlein purpura (HSP)—the most common vasculitis in children—is complicated by nephritis in about 30% of patients

■ Long‑term prognosis of HSP nephritis depends mainly on the development of chronic kidney disease (CKD); often CKD risk cannot be predicted from the initial clinical and histological presentation

■ CKD can be observed at long‑term follow‑up even after apparent complete recovery from HSP nephritis

■ HSP nephritis and IgA nephropathy both result from glomerular deposition of aberrantly glycosylated IgA1 but have different histological features and clinical courses

■ Typically IgA nephropathy presents as slowly progressive mesangial lesions, whereas HSP nephritis presents as acute episodes characterized by inflammatory glomerular lesions that require prompt resolution to avoid chronic progression

■ Use of guidelines based on evidence obtained in adults with IgA nephropathy to select treatment for children with HSP nephritis risks delaying the provision of adequate therapies

Finnish series of 223 paediatric patients with HSP, the risk factors for development of nephritis were age >8 years at onset, abdominal pain and recurrence of vasculitis.19 The natural history of HSP in children has changed over time; late diagnosis and late referral of patients with renal involvement were common in early reports, but diagnosis is now easily performed and the risk of progression is the most important factor to be considered.

The frequency of renal involvement in HSP is variable. In a population-based survey in the Netherlands, which included 232 patients aged 0–18 years (average 6 years) with HSP, 60% of participants were male (a higher per-centage of males than females also have IgA nephritis) and 29% presented with renal symptoms within 1 month of onset (although the majority of these patients had only mild renal signs, such as haematuria and/or minimal proteinuria).3 Proteinuria >1 g/l was detected in 3% of patients, nephrotic syndrome in 2%, hypertension in 3% and renal insufficiency in 1%.9 These figures are consistent with the contemporary experience of neph-rologists and large published series, rather than with the extremely broad range of 20–100% of patients present-ing with renal involvement described in the early litera-ture.14 In some reviews, up to 97% of patients with HSP nephritis developed renal symptoms within 6 months after presentation,20 and 35% developed clinical signs of renal impairment after 1 year, with a continuous increase in frequency thereafter.21 By contrast, a review published in 2009 concluded that 1–2% of all unselected patients with HSP nephritis will develop CKD in the long term.17 This proportion is much higher in patients from tertiary medical centres; up to 20–30% of such patients have CKD or ESRD by 20 years after diagno-sis of HSP.15,22–24 As expected, patients with severe initial symptoms are at higher risk of CKD than are those with mild symptoms (Table 1).15,23

PrognosisA major difficulty in the identification of prognostic factors in HSP nephritis resides in the fact that CKD can develop up to 20 years after disease initiation, even after apparently complete resolution of symptoms.15,23 The possibility of clinically silent progression towards CKD was initially raised in 1992.15 Progression towards CKD is particularly likely to occur during pregnancy.15,23 Approximately 20 years after initial presentation, CKD develops in 15% of patients who present with heavy proteinuria without nephrotic syndrome, in 40% of those who present with nephrotic syndrome, and in >50% of those who present with both nephritic and nephrotic syndromes.15 However some (rare) patients who present with mild initial symptoms also eventually develop CKD,15,23,25 sometimes after repeated episodes of macroscopic haematuria.26,27 Even patients without urinary abnormalities can later present with hyper-tension28 and ESRD can occasionally result from rapidly progressive glomerulonephritis.29,30

These reports show that any initial clinical renal presentation can result either in CKD or in complete healing.15,23,25–27 The unpredictability of the prognosis of

Table 1 | Predictors of long‑term renal outcome in Henoch–Schönlein purpura

Factor Symptoms Outcome

Initial renal symptoms15,32

Nephrotic and nephritic syndromeNephrotic syndromeNephritic syndromeHeavy non‑nephrotic proteinuriaHaematuria and/or minimal proteinuriaNephrotic syndrome persisting <3 monthsNephrotic syndrome persisting >3 months

CKD >50%15

CKD 40%15

CKD 15%15

CKD 15%15

CKD <5%15

ESRD 0%32

ESRD 41%32

Renal symptoms during follow‑up

GFR <70 ml/min/1.73 m2 at 3 years* ESRD 100%26

Initial symptoms versus increasing proteinuria during follow‑up

Mean follow‑up proteinuria (g per day)

Severely impaired versus normal GFR at onset

Nephrotic versus minimal proteinuria at onset

ESRD RR 1.78, P <0.0131

ESRD RR 3.83, P = 0.2031

ESRD RR 4.74, P = 0.1731

*Univariate analysis of predictors related to renal survival that used dialysis therapy as an end point; GFR was calculated using the Schwartz formula. Abbreviations: CKD, chronic kidney disease; ESRD, end‑stage renal disease; GFR, glomerular filtration rate; RR, relative risk. Reproduced and modified with permission from the American Society of Nephrology © Davin, J. C. Clin. J. Am. Soc. Nephrol. 6, 687–689 (2011). http://cjasn.asnjournals.org/.

REVIEWS


http://cjasn.asnjournals.org/

http://cjasn.asnjournals.org/


HSP nephritis probably results from the varied patho-genetic pathways involved and the response to treat-ment. HSP nephritis is typically an acute disease, but even severe inflammatory glomerular lesions can resolve completely in patients who receive early adequate treat-ment, or when the causal event has been of short dura-tion. On the contrary, when the cause of active lesions persists or when adequate treatment is delayed, a fibrotic process leads to chronic damage. The reduction in func-tional glomeruli can be insufficient to induce substan-tial proteinuria or impair filtration function in the short term, a clinical picture that can initially be confused with apparent healing but could result in hyperfiltration and relentless progression to CKD. These clinical fea-tures imply that two important conditions would render further studies more informative: they should have long follow-up periods, and instead of only looking for cor-relations between initial clinical and histological param-eters and outcome at last follow-up, patients’ data should be analysed at intervals throughout the study to investi-gate the possible role of relapses or of persistently active disease processes.

Difficulty in the interpretation of initial symptoms for prognostic purposes has resulted in the considera-tion of other clinical parameters related to the status of patients at subsequent stages of the illness (Table 1). Unfortunately, assessment of those parameters might not improve the outcomes of patients with HSP nephritis because all imply a period of observation, which could potentially delay the initiation of treatment to prevent the development of chronic lesions (Table 1).26,31,32 Pooled data from three studies that investigated the outcomes of children with HSP nephritis, classified according to International Study for Kidney Diseases in Children (ISKDC) criteria, showed that about 25% of patients progressed to various stages of CKD during a median follow-up of 6 years.24,25,30,33 Although more common in patients with class IV and class V features of HSP nephritis, such as moderate to severe extracapillary proliferation and crescent formation (37% and 70% of such patients progressed to CKD, respectively), than in those with milder disease, progression to CKD was eventually also observed in 15% of patients with class II or III features.

The predictive value of crescents has been addressed in several retrospective studies. This feature was often associ ated with outcome in univariate but not in multi-variate analyses.15,24,25,31,33–42 The latest research sup-ports the idea that even extensive crescentic lesions can undergo regression and healing, and that progression to CKD can occur in individuals with relatively mild disease.22,23,26,40 Several factors might influence the effect of crescents on final outcome, including the possibility that renal biopsy sampling might miss areas with focal crescentic glomeruli, the healing of limited segmental crescents (which can appear and disappear within a few weeks) and changes in the percentage of glomeruli involved.42 Moreover, the ISKDC classification does not consider the concomitant presence of tubulointerstitial fibrosis, endocapillary hypercellularity, arteriolar damage

or segmental sclerosis, which might also predict CKD according to their extension.43

Another factor that is likely to modify the outcome of patients with crescents is the prompt institution of aggressive immunosuppressive treatment, which can blunt the risk of progression. This observation might explain the apparent paradox that patients with ISKDC grades II–III disease tend to have worse outcomes than those with grades IV–V disease in published series.23 Notably, an adverse effect of crescentic HSP nephritis on outcome was reported in early published series,15 although this association has not been detected in series published after use of prednisone and immunosuppres-sive drugs had become the rule.40 This observation sug-gests that prompt immunosuppressive treatment might prevent cellular crescents from progressing to fibrosis and thereby contributing to CKD. Conversely, delaying kidney biopsy and the initiation of immunosuppressive treatment might enable crescentic lesions to progress to complete glomerulosclerosis.42,44,45

Because considering only the approximate extent of mes angial proliferation (focal or diffuse) and the per-centage of crescentic glomeruli (ISKDC classification) has limited prognostic utility, it is necessary to improve prognostic predictions by introducing other param-eters. These could potentially include a precise evalu-ation of mesangial hypercellularity (by calculating the mesangial cell score), endocapillary hypercellularity, inflammatory cell infiltration, Bowman capsule integ-rity, extent and type of crescents (cellular versus fibrotic), glomerulo sclero sis and interstitial fibrosis or tubular atrophy, following the example of the new histological classification of IgA nephropathy.43

Recurrence of glomerular IgA deposits after kidney transplantation is very frequent in patients with HSP nephritis, but does not significantly affect the rate of graft loss during the first 5 years of follow-up.46 By 10 years post-transplantation, however, the risk of graft loss owing to recurrence of IgA deposits was 7.5% in one study.47 The same pattern is observed for IgA nephropathy.48,49

IgA nephropathy versus HSP nephritisPresentation and clinical course HSP nephritis frequently presents as acute nephritic and/or nephrotic syndrome, reflecting a rapidly developing pathophysiological mechanism.12 In patients with HSP nephritis, repeated or prolonged episodes of acute glo-merular inflammation lead to fibrous scars and hyper-filtration in the remaining areas, which finally result in CKD and ESRD. Hence, the number and severity of acute episodes of HSP nephritis have a crucial role in the sub-sequent progression and loss of renal function (Box 1). However, HSP nephritis is more benign in children than in adults, as children mostly enter stable remission, which enables healing, whereas HSP nephritis in adults tends to show a chronic and relentless course similar to that of primary IgA nephropathy.16,17,34 By contrast, IgA nephropathy is often discovered as an incidental finding of asymptomatic haematuria, or as short- lasting episodes of gross haematuria that generally do not

REVIEWS



affect chronic progression. As a consequence, in IgA nephropathy, initi ation and progression of CKD occurs slowly and often goes unnoticed, eventually leading to glomerulosclerosis and tubulointerstitial fibrosis.

Histological findingsThe histologic lesions of HSP nephritis are categorized as ISKDC grades I, II, III, IV and V according to the presence and percentage of glomeruli with crescents. Grade VI is used for lesions with a membranoprolifer-ative aspect.30 Extent of mesangial proliferation (focal or diffuse) further characterizes the different classes of ISKDC (Box 2).30

The glomerular lesions found in patients with HSP nephritis, particularly those in children, are charac-terized in early stages after clinical onset by acute inflammation with leucocyte influx and endocapillary hypercellularity.29,30,42 Tuft necrosis is frequently found in crescentic glomeruli, and this feature is, therefore, thought to favour crescent formation.29,30,50 However, these acute-phase inflammatory changes can also be found in patients with IgA nephropathy, albeit mostly in those with macroscopic haematuria or in the rare patients with rapidly progressive disease. By contrast, acute-phase inflammatory changes are uncommon in patients with stable clinical conditions.29 Endocapillary proliferation and inflammatory cell infiltration by poly-nuclear neutrophils is another histological feature that is more frequently observed in HSP nephritis than in IgA nephropathy.29

The lesions observed in kidney biopsy samples from patients with HSP nephritis are strongly dependent on the timing of renal biopsy in relation to the onset of clini-cal symptoms and detection of urinary abnormalities. Early acute clinical phases of HSP nephritis are charac-terized by mesangial and endocapillary hyper cellularity, often with fibrinoid necrosis and small cellular crescents, whereas advanced stages present with segmental dis-organized sclerosis, mostly coincident with fibrous cres-cents. The presence of crescents is a prominent histologic feature of HSP nephritis, and has also been considered a pivotal feature for the ISKDC pathology classification,

owing to its prognostic relevance (Box 2).30 Crescents in patients with HSP nephritis rarely involve more than 50% of glomeruli.29 A pathophysiological role of inflam-matory cells and fibrin in the formation of crescents is suggested by the predominance of glomerular leucocyte infiltration, glomerular necrosis and fibrin deposition in glomeruli with crescents.42,50–53 The role of fibrin is also supported by the observation that crescent formation can be prevented by the anti coagulant warfarin in experi-mental models of crescentic nephritis.54 Degenerative tubular changes and lesions of the interstitium (oedema, infiltration of lymphocytes, macrophages and plasma cells) are consistent with the severity and duration of glomerular injury.29 Unlike in HSP nephritis, crescents are uncommon in IgA nephropathy (detected only in 5–10% of renal biopsy samples) and generally occupy only part of the capsule parietal wall.29

The most characteristic immunohistochemical finding consists of predominant glomerular deposits of IgA, mostly represented by the subclass IgA1.

29 The typical immunofluorescence pattern is diffuse, granular mes-angial staining with associated capillary wall staining in patients with endocapillary proliferation. The associ-ation between an increased severity of diffuse endocapil-lary proliferation (and/or extensive crescent formation) and extensive capillary deposits of IgA and complement strongly suggests the crucial pathophysiological role of the latter.29 Differences in the extent and distribution of crescent formation between the two disorders might reflect the increased intensity of subendothelial depo-sition of IgA circulating immune complexes (CIC) in HSP nephritis.29,30 IgG and/or IgM and fibrin-related antigen are also detected in 65–75% of biopsy samples.29 Complement factors B, C3 and C5b–9 complex are frequently found in biopsy samples from patients with HSP nephritis.29,30,55 Components of the lectin pathway (mannose-binding protein C, ficolin-2, mannan-binding lectin serum protease [MASP-1] and C4d) are present in 50% of patients,55 whereas C1q is rarely found.29

PathophysiologyBoth diseases result from the glomerular deposition of IgA-CIC; however, the pathophysiological mecha-nisms activated in HSP nephritis (Figure 1) and IgA nephro pathy are complex and divergently modulated, leading to relevant histological and clinical differences that might result in disparate responses to the same

Box 1 | Factors linked to adverse renal outcome in HSP

Several observations support the role of the initial acute episode in developing irreversible scarring and loss of renal function at long term follow‑up: ■ Relationship between the severity of initial

clinical and histological signs and the long‑term prognosis15,24,25,30,33

■ Correlation between the chronicity score and the time elapsed between clinical onset of renal signs and the kidney biopsy45

■ Rapid evolution of florid crescents to global glomerular sclerosis44

■ Relationship between delayed treatment and worse evolution23,115,116

■ Development of impaired renal function in the long term after apparently complete resolution15

Abbreviation: HSP, Henoch–Schönlein purpura.

Box 2 | ISKDC histologic classification of HSP nephritis30

■ I: Minimal histologic alterations ■ II: Pure mesangial proliferation ■ III: Focal (IIIa) or diffuse (IIIb) mesangial proliferation

with <50% crescentic glomeruli ■ IV: Focal (IVa) or diffuse (IVb) mesangial proliferation

with 50–75% crescentic glomeruli ■ V: Focal (Va) or diffuse (Vb) mesangial proliferation

with >75% crescentic glomeruli ■ VI: Membranoproliferative‑like glomerulonephritis

Abbreviations: HSP, Henoch–Schönlein purpura; ISKDC, International Study of Kidney Disease in Children.

REVIEWS



1Mucosalantigen

Mucosalvillous

Intestinalmicrovillus

MALT2

Increased antigenpenetration due todefective mucosal

immunity DC

CD4+

3Synthesis of galactose-de�cientIgA1 exposing GalNAc residues

and IgG anti-GalNAc IgA1

6

Activation of circulatingleucocytes

7Activation of resident

endothelial cellsand mesangial cells

8

4

GalNAc

IgA IgG

GalNAc IgA1–mucosal antigen

immune complexesGalNAc IgA1–IgG

immune complexes

Formation of immune complexesand autoaggregates

GalNAc IgA1autoaggregates

Podocyte

Mesangial cell

Attraction ofin�ammatory cells

and activationof podocytes

Genetic factorsEpigenetic factors

Glomerular capillaryIn�amed glomerular capillary

Damagedpodocyte

Leakymembrane

Podocytefoot process

Endothelialcell

Glomerularbasementmembrane

C3

Deadendothelial cell

9

Lumen

Cytokines

Neutrophil

Lymphocyte

Macrophage

Monocyte

Crescent formation

Immune complexesand autoaggregates

Activation of complementin the circulation and at the

mesangial and endothelial level

5

CytokineIgA

Figure 1 | Pathogenesis of Henoch–Schönlein purpura nephritis. Genetic and epigenetic factors contribute to activation of the mucosal immune system after antigen exposure (1), favoured by increased antigen penetration owing to defective mucosal immunity (2). Antigens reach the MALT and activate DCs and CD4+ lymphocytes, leading to synthesis of GalNAc‑IgA1 (3) and anti‑GalNAc‑IgA1 IgG autoantibodies. Several circulating macromolecular forms of IgA1: GalNAc‑IgA1, IgA‑CIC (formed by binding of GalNAc‑IgA1 to mucosal antigens or anti‑GalNAc‑IgA1 IgG) and galactose‑deficient IgA1 autoaggregates, (4) activate the complement system, mostly through the alternative and lectin pathways (5). Collectively, these factors favour the activation and influx of PBMCs and neutrophils (6) and the activation of resident endothelial and mesangial cells (7). Podocytes are activated via chemokines produced by mesangial cells (8). Subendothelial and mesangial deposition of IgA‑CIC leads to fibrin deposition, destruction of the glomerular basement membrane, attraction of macrophages and inflammatory cells, and cytokine‑induced proliferation of epithelial cells in the Bowman space. Eventually, capsular destruction and fibrous crescent formation result from infiltration of the Bowman space by interstitial fibroblasts (9). Abbreviations: C3, activated complement component 3 protein; CIC, circulating immune complex; DC, dendritic cell; GalNAc‑IgA1, galactose‑deficient IgA1; MALT, mucosa‑associated lymphoid tissue; PBMC, peripheral blood mononuclear cell.

REVIEWS



treatment (Table 2). The glomerular deposition of IgA-CIC initiates a cascade of cross-talk between resi-dent cells resulting in their mutual stimulation and the attraction of inflammatory cells. These processes lead to mes angial expansion and both endocapillary and extracapillary proliferation. The variability of patients’ symptoms might be explained by differences in the duration of production, amount, composition and local-isation of IgA-CIC, as well as by the intensity of reaction of the different cells involved.

HSP nephritis and IgA nephropathy are characterized by an abnormal IgA1 glycosylation pattern with reduced galactosylation (Figure 2). The lack of terminal β1,3-galactosyl residues in the hinge region of IgA1 might be due to reduced activity of β1,3-galactosyltransferase in IgA1-producing peripheral B cells,56,57 which might be regulated by miRNAs58 or the result of type 2 T-helper cell prevalence.59–62 This reduced galactosylation results in exposure of N-acetylgalactosamine (GalNAc) residues at the IgA1 surface, forming a novel antigen and inducing a humoral IgG autoimmune response.63 Circulating com-plexes of mixed IgG and galactose-deficient IgA1 have been detected in both HSP nephritis and IgA nephro-pathy.64 The characteristic feature of IgA nephropathy is an increased proportion of circulating mucosal-type IgA1 antibodies.65 However, this ‘hypogalactosylated’ form of IgA1 is not restricted to patients with IgA nephro-pathy but is also observed in the serum of individuals in response to mucosal infection.65 The pathophysiological role of galactose-deficient IgA1 molecules in renal lesions is suggested by the observation that they are only found in the serum of patients with HSP when they are having an episode of nephritis.57

Since HSP nephritis and IgA nephropathy are both characterized by predominant glomerular IgA depos-its and mesangial proliferative changes, they have been suggested to be determined by the same pathophysio-logical mechanisms. A relationship between these two diseases was further confirmed by the detection of familial clustering of individuals with HSP nephritis and IgA nephropathy, who have similar circulating IgA abnormalities.12,13 However, the two diseases also have important differences that should be considered in therapeutic decision-making.

The increased intestinal permeability reported in patients with HSP nephritis,66 and the reduced mucosal immune reaction to novel antigens in those with IgA nephropathy,67 suggest that resistance to mucosal antigen penetration is impaired in both diseases. A high antigen load stimulates the immune system to produce large amounts of galactose-deficient IgA1, forming circulating IgA-CIC that cannot be cleared by asialoglycoprotein receptor 1 on hepatocytes. The size of macro molecular IgA1 further increases after binding to IgA Fc receptors (FcαRI, also known as CD89) on leuco-cytes, and IgA1–FcαRI complexes are released after cleav-age of the FcαRI extracellular domain.68,69 Why IgA-CICs provoke multi-organ inflammation only in patients with HSP nephritis is not known. However, some data suggest that IgE-associated mechanisms (such as an increased

Table 2 | Comparison of primary IgA nephropathy and HSP nephritis

Clinical and histological features

Detection method IgA nephropathy HSP nephritis

Renal histology

CrescentsGlomerular tuft necrosisNeutrophil infiltration

Light microscopy +/–+/–+/–

++++++

Mesangial IgA deposits IgA deposits along capillary walls

Immunofluorescence +++–

+++++

Subendothelial deposits Electron microscopy +/– ++

Clinical presentation

Extrarenal symptoms NA +/– +++

Age at onset NA Mostly >15 years Mostly <15 years

Nephritic syndrome NA +/– ++

Nephrotic syndrome NA +/– ++

Disease course NA Continuous moderate activity with exacerbations

Repeated acute episodes

Renal outcomes

Clinical remission NA 30–50% 98%

CKD long after apparent complete remission

NA – +

ESRD NA 20–40% after 20 years

1–3% in children, 30% in adults

Transplantation outcomes

IgA deposit recurrence Immunofluorescence Frequent Frequent

Graft loss at 5 years post‑transplantation

NA Rare Rare

Graft loss at 10 years post‑transplantation

NA 9.7% 7.5%

–, +/–, +, ++ and +++ indicate the relative likelihood of each clinical or histological feature occurring in a direct comparison of IgA nephropathy and HSP nephritis. Abbreviations: CKD, chronic kidney disease; ESRD, end‑stage renal disease; HSP, Henoch–Schönlein purpura; NA, not applicable.

CH1

CH2

CH3

Hingeregion

CH1ProSerThr*ProProThr*ProSer*ProSer*ProThrProThr*ProSerProSerCH2

I

GalNAcα1-0

III

GalNAc

Gal

α1-0

β1-3

II

GalNAc α2,6Neu5Acα1-0

V


Galβ1-3

IV

GalNAc

Gal

α1-0

β1-3

Neu5Acα2-3

VI


Galβ1-3

Neu5Acα2-3

Figure 2 | Human IgA1 O‑glycosylation sites and galactosylation patterns. The hinge region of IgA1 contains up to six major glycosylation sites at serine and threonine residues. The O‑glycans include a core GalNAc, usually extended with Gal to form Galβ1,3GalNAc, which can bind to Neu5Ac. Thus, each IgA1 O‑glycan can have one of four short carbohydrate structures (types III, IV, V and VI), leading to a mixture of IgA1 forms with varying degrees of galactosylation. Patients with Henoch–Schönlein purpura nephritis or primary IgA nephropathy have a high prevalence of galactose‑deficient (types I and II) IgA1. Abbreviations: Gal, galactosamine; NAc, N‑acetyl; Neu5Ac, α2,6 sialic acid and/or α2,3 sialic acid.

REVIEWS



abundance of mast cells in skin, gut and joints, peri-vascular IgE dermal deposits, high IgE plasma levels and high concentration of eosinophil cationic protein) have a role in increasing vascular permeability and favour IgA-CIC deposition in various organs.70–72

Mesangial cellsAfter penetration into the mesangium, which is driven by the intraglomerular filtration pressure, macromolecules containing galactose-deficient IgA1 can bind to resident mesangial cells. Mesangial proliferation is an invari-able histological finding in patients with HSP nephritis.29 Binding of IgA-CICs to mesangial cells, and subsequent activation of these cells, depends on the constituents of IgA-CICs, and particularly their galactose-deficient IgA1 content.68,69,73–76 As circulating galactose-deficient IgA1 is also found in healthy relatives of patients with HSP nephritis and IgA nephropathy, the involvement of some additional factors is likely to be necessary to render galactose- deficient IgA1 pathogenic.76 This ‘second hit’ might be related to the degree of self-aggregation of galactose- deficient IgA1,

77 the presence and amount of molecules other than IgA1 in IgA-CIC, for which mes-angial cells also display membrane receptors (including IgG autoanti bodies and complement breakdown products; Table 3)73,75–79 or the presence of oxidative stress.80

Stimulation of mesangial cells by aberrantly glyco-sylated macromolecules triggers their proliferation and matrix production, along with the release of many factors (Table 3): prostaglandins, angiotensin II, nitric oxide synthase,56 chemokines that attract polymorphonuclear leuco cytes and monocytes,56,73,74,78 cytokines and medi-ators that affect key functions of podocytes (including local migration, adherence to the basement membrane and control of proteinuria).81,82 Cytokines involved in acute and chronic inflammatory responses stimulate mes-angial cells,78 and can be produced by the mesangial cells themselves (in an autocrine process) or by inflammatory cells that have migrated into glomeruli (Table 3).74,78,83–90 Tumour necrosis factor seems to have a key role as a direct or indirect effector of podocyte damage and altered nephrin expression.82,89,90

In summary, the stimulation of mesangial cells by glo-merular deposition of IgA-CIC can result in mesangial hypercellularity, extracellular matrix expansion, oxi-dative stress, attraction of inflammatory cells and altered podocyte function. These factors lead to glomerulo-sclerosis and tubulointerstitial damage, owing to feed-back mechanisms involving the glomeruli and tubules, which have the clinical consequences of proteinuria, hypertension and renal insufficiency.

Complement activationIn patients with HSP nephritis, extensive crescents are often associated with capillary wall destruction and endocapillary hypercellularity,30 along with the pres-ence of subendothelial immune deposits of IgA and complement.29 These observations, combined with data on experimental crescentic glomerulonephritis,50,91–102 suggest that the mechanism of crescent formation involves local complement activation.

Glomerular C3 deposits are seen in the vast majority of patients with HSP nephritis.30 Although no relation-ship between serum levels of C3 and C4 and the presence of nephritis has been demonstrated,103 in situ activation of the complement system is probably an important event in

Table 3 | Immune system reactants involved in the pathogenesis of HSP nephritis

Reactant* Details Reference(s)

Circulating IgA molecules

Galactose‑deficient IgA1

Autoaggregated galactose‑deficient IgA1

IgG antibodies to galactose‑deficient IgA1

IgG–IgA1 circulating immune complexesIgA1–soluble CD89 complexes

34,3577637669

Receptors for IgA1 Myeloid FcαRI (also known as CD89)Transferrin receptor (also known as CD71) on mesangial cells

68129

Cytokines‡ IL‑17 (increased ratio of IL‑17:TREG cells), TNF, IL‑1β, IL‑2, IL‑6, IL‑8, TGF‑β, VEGF, TWEAK, low IFN‑γ and IL‑12, increased IL‑4 (imbalance of TH1:TH2)

130

Mesangial cell receptors§

C3, FcγRI, TNF, TGF‑β, PDGF‑RB, IL‑1, IL‑6, IFN‑γ, fibronectin receptor, integrins, angiotensin II receptor, CD71, EGF, TLR‑3, TLR‑4, chemokines

78,79

Products of mesangial cells

Cytokines: TNF, IL‑1β, IL‑6, TGF‑βChemokines: IL‑8, RANTES, MCP‑1Prostanoids, angiotensin II, nitric oxide, reactive oxygen species

78

*This list is not exhaustive; the most relevant reactants are shown. ‡Produced by endothelial cells and/or infiltrating blood mononuclear cells. §Activated by specific ligands released in the mesangium. Abbreviations: C3, complement protein C3; EGF, epidermal growth factor; FcαRI, IgA fragment crystallizable receptor; FcγRI, IgG fragment crystallizable receptor; HSP, Henoch–Schönlein purpura; IFN, interferon; MCP‑1, monocyte chemotactic protein 1; PDGF‑RB, platelet‑derived growth factor‑receptor β polypeptide; RANTES, regulated upon activation normal T cell expressed and secreted; TGF‑β, transforming growth factor‑β; TH, T‑helper; TLR, Toll‑like receptor; TNF, tumour necrosis factor; TREG, T regulatory; TWEAK, TNF‑like weak inducer of apoptosis; VEGF, vascular endothelial growth factor.

Table 4 | Treatment of HSP nephritis

Type of treatment Evidence

Randomized clinical trials Nonrandomized studies

Oral steroids Oral prednisone does not prevent the development of nephritis17

No effect of prednisone alone on existing nephritis (retrospective studies)25,36,122,123

Other immunosuppressive drugs or combination

In children, no advantage of cyclophosphamide (used without prednisone) over placebo109

In adults, no advantage of cyclophosphamide plus methylprednisolone pulses followed by oral prednisone versus the steroid schema alone111

In patients with nephrotic‑range proteinuria, 1 year of treatment with ciclosporin is not inferior to methylprednisolone pulses followed by 4 months prednisone110

Advantage of methylprednisolone pulses followed by prednisone versus prednisone alone (prospective study with historical controls)116

Favourable effect of immunosuppressive drugs in patients receiving several agents (retrospective studies and one prospective study)45,118–121

ACE inhibitors NA Efficacy of ACE inhibitors in moderately severe proteinuria (retrospective study)131

Plasma exchange NA Favourable effects of plasma exchange in patients with very severe clinical and histological features (retrospective study)114,115

Abbreviations: ACE, angiotensin‑converting enzyme HSP, Henoch–Schönlein purpura; NA, not available.

REVIEWS



the pathophysiology of glomerular lesions. Complement activation might be initiated by subendothelial and mesangial deposition of IgA-CIC, leading to fibrin depo-sition, destruction of the glomerular basement membrane and attraction of inflammatory cells and macrophages as well as cytokine-induced proliferation of epithelial cells in the Bowman capsule space. Ultimately, IgA-CIC deposition results in destruction of capsular integrity and formation of fibrous crescents due to infiltration of the Bowman space by interstitial fibroblasts (Figure 1).

Immunofluorescence studies, as mentioned above, suggest a role of both the alternative and lectin path-ways in activation of the complement system. However, mannose-binding protein C, MASP-1 and C4d depos-its are associated with severe glomerular inflammation and clinical signs in both patients with HSP nephri-tis55 and IgA nephropathy,104,105 which suggests that the pathogenetic role of the lectin pathway is predominant.

TreatmentHSP nephritis in children was initially considered to be a rather benign disease for which only supportive treat-ment was necessary, as affected children mostly undergo spontaneous recovery.106 However, after the publica-tion of long-term follow-up studies showing delayed

development of CKD in this population,33,36,42 the treat-ment policy changed and the use of steroids and immuno-suppressive treatments was recommended even in the absence of rapidly progressive glomerulonephritis.107,108

Randomized controlled trials in HSP nephritis are scarce and have provided little clinically useful informa-tion109–111 (Table 4). In the absence of strong therapeutic evidence, principles of treatment should take into account existing knowledge of pathophysiological mechanisms and important clinical observations (Box 3).

Updated Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for the treatment of HSP nephri-tis were published in 2012.112 In light of the similarities between HSP nephritis and primary IgA nephritis, the KDIGO guidelines include similar indications for the two diseases when their clinical features are similar (Box 4).112 However, these guidelines conflict with generally used clinical protocols, which include the use of methyl-predniso lone pulses, other immunosuppressive drugs and plasma exchange in patients at a lower threshold of long-term CKD risk (Box 4).113–121 Moreover, although these two diseases can present with clinical and histological similarities, HSP nephritis differs from IgA nephropathy in pathophysiology, the predictability of its prognosis and the effects that delayed treatment can have on patients’ long-term outcomes. Following the KDIGO guidelines might, therefore, delay the initiation of effective treatment and increase the risk of CKD in the long-term.23,115,116 For example, in patients with nephrotic syndrome and ISKDC grade III disease who have extensive inflamma-tory lesions, the KDIGO guidelines recommend initial treatment with angiotensin-converting- enzyme (ACE) inhibitors, and only suggest adding oral prednisone if improvement does not occur (Box 4). However, treat-ment with ACE inhibitors is unlikely to improve the acute glomerular inflammatory changes in these patients, and a delay of 3–6 months before initi ation of a possibly effective treatment might not prevent the development of sclerotic changes. Although some retrospective case series reported a lack of effect of oral prednisone,25,36,122,123 a possible beneficial effect of methyl prednisolone pulses followed by prednisone was suggested in a prospective case series (in which parti cipants were compared to a cohort of historical controls treated at the same centre),116 as well as in the control arm of a randomized controlled trial.111 The beneficial effect of methylprednisolone pulses is also suggested in patients receiving combinations of multiple immuno suppressive drugs (Table 4),119–121 and is supported by experimental models showing maximal therapeutic benefits of steroids with 30 mg/kg intra-venous methylprednisolone pulses in experimental crescentic glomerulonephritis.124

Children with similar presentations of HSP nephritis can experience either complete disappearance of urinary signs or an unexpected late progression to CKD— sometimes in spite of an apparent long-term remission of symptoms—hence, prolonged observation is necessary. Repetition of renal biopsy is mandatory for individuals with symptom aggravation or lack of improvement with therapy, as useful information for choosing a therapeutic

Box 3 | Treatment of HSP nephritis in children

Principles of treatment based on pathophysiology ■ Reduce endocapillary hypercellularity owing to inflammatory cell infiltration ■ Reduce endothelial cell activation ■ Reduce mesangial cell activation and proliferation ■ Reverse podocyte activation and crescent formation ■ Reduce the production of aberrantly glycosylated IgA1 and anti‑GalNAC IgG ■ Enhance the removal of circulating IgA1‑containing immune complexes

Important clinical observations and resulting principles of treatment ■ Initial clinical and histological symptoms do not predict outcome accurately

except when very mild or very severe ■ Renal lesions can rapidly change owing to dynamic pathogenetic events and

histology can deteriorate rapidly ■ Renal biopsy samples might not be representative of the whole kidney ■ Worsening of clinical features can follow detection of moderate lesions (in renal

biopsy samples) by only a few days ■ Delaying adequate treatment can be harmful ■ Owing to the unpredictability of disease evolution, prolonged follow‑up is

mandatory ■ In case of no response or deterioration under treatment, a repeated renal biopsy

is useful to adapt therapyAbbreviation: HSP, Henoch–Schönlein purpura.

Box 4 | 2012 KDIGO guidelines for treatment of HSP nephritis112

■ Only when proteinuria is >0.5g/1.73 m2 daily, treat children (including those with nephrotic syndrome) with angiotensin‑converting‑enzyme inhibitors or angiotensin II‑receptor antagonists for 3–6 months

■ In patients who fail to respond to the above treatment, administer corticosteroid therapy

■ More aggressive treatment, including methylprednisolone pulses plus cyclophosphamide, is reserved for patients with >50% crescentic glomeruli and rapidly progressive renal deterioration with or without nephrotic syndrome. Plasma exchange sessions can be added when plasma creatinine is >500 μmol/l

Abbreviations: HSP, Henoch–Schönlein purpura; KDIGO, Kidney Disease: Improving Global Outcomes.

REVIEWS



strategy can result from the analysis of crescent patho-physiology.51,92,93 The timing and frequency of biopsy is dependent upon the severity of the symptoms and his-tology, on the evolution of the disease and on response to treatment.45

ConclusionsIt seems obvious that the clinical, histological and patho-physiological differences between IgA nephropathy and HSP nephritis need different therapeutic approaches. In our opinion, this renders the 2012 KDIGO guidelines, which are mostly based on evidence obtained in adults with IgA nephropathy, at risk of being inappropriate for children with HSP nephritis.

A 2013 study has shown that even small acute changes in kidney function, particularly in pre-existing kidney disease, can be complicated later on by CKD.125 Improved treatment strategies are necessary to detect patients at risk of CKD at an early stage. This goal should be achieved by advances in understanding of HSP nephritis patho-physiology, the availability of new biomarkers of disease activity, and improved knowledge of the pattern of pro-gression to CKD (either scarring resulting from acute but self-limited episodic disease, or a slowly progressive but chronically active process, as occurs in IgA nephro-pathy). A serious need remains for multicentre, inter-national studies that prospectively enrol patients at their initial presentation with the disease (including individu-als with mild initial symptoms), and include continued monitoring for long periods of time, even after apparent

complete healing. To modulate each patient’s treatment according to the specific pathophysiological pathways activated, the researchers will need to evaluate at regular intervals the relationships between clinical signs, histo-logic findings, treatments and levels of immune reactants in plasma and/or urine that reflect an active process (Table 3). Further research into the pathogenetic impor-tance of circulating galactose-deficient IgA1, CIC consist-ing of galactose-deficient IgA1 bound to anti-GalNac-IgA1 IgG, cleavage products of C3 and C5b-9 resulting from activation of the complement system, urinary podo-cyte markers and expression of CD71 (the latter result-ing from the high proliferation activity of mesangial cells11,56,57,75,126–130), is highly recommended. This research should be supported by online registry data coupled to all prospective clinical trials in patients with HSP nephritis. In the meantime, panels of paediatric experts should be created by international societies to amend the KDIGO guidelines in accordance with clinical practice, to propose prospective studies on new biomarkers of disease activity, and to design randomized controlled trials.

Review criteria

The PubMed online database was searched for full‑text, English language articles published in major medical journals during 2010–2014. The search terms used were “IgA nephropathy” and “Henoch–Schönlein purpura”. The authors also utilized their personal libraries of original papers and review articles on the same topic. Reference lists of identified papers were reviewed for further leads.

1. Haycock, G. B. In Oxford Textbook of Clinical Nephrology 1st edn, Ch. 4 (eds Cameron, S. et al.) 595–612 (Oxford University Press, 1992).

2. Eleftheriou, D. & Brogan, P. A. Vasculitis in children. Best Pract. Res. Clin. Rheumatol. 23, 309–323 (2009).

3. Aalberse, J., Dolman, K., Ramnath, G., Pereira, R. R. & Davin, J. C. Henoch Schönlein purpura in children: an epidemiological study among Dutch paediatricians on incidence and diagnostic criteria. Ann. Rheum. Dis. 66, 1648–1650 (2007).

4. Dolezalova, P., Telekesova, P., Nemcova, D. & Hoza, J. Incidence of vasculitis in children in the Czech Republic: 2‑year prospective epidemiology survey. J. Rheumatol. 31, 2295–2299 (2004).

5. Gardner‑Medwin, J. M., Dolezalova, P., Cummins, C. & Southwood, T. R. Incidence of Henoch–Schönlein purpura, Kawasaki disease, and rare vasculitides in children of different ethnic origins. Lancet 360, 1197–1202 (2002).

6. Yang, Y. H. et al. A nationwide survey on epidemiological characteristics of childhood Henoch–Schönlein purpura in Taiwan. Rheumatology 44, 618–622 (2005).

7. Mills, J. A. et al. The American College of Rheumatology 1990 criteria for the classification of Henoch–Schönlein purpura. Arthritis Rheum. 33, 1114–1121 (1990).

8. Jennette, J. C. et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum. 37, 187–192 (1994).

9. Ozen, S. et al. EULAR/PRES endorsed consensus criteria for the classification of childhood vasculitides. Ann. Rheum. Dis. 65, 936–941 (2006).

10. Ozen, S. et al. EULAR/PRINTO/PRES criteria for Henoch–Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Ann. Rheum. Dis. 69, 798–806 (2010).

11. Lau, K. K. et al. Serum levels of galactose‑deficient IgA in children with IgA nephropathy and Henoch–Schönlein purpura. Pediatr. Nephrol. 22, 2067–2072 (2007).

12. Davin, J. C., Ten Berge, I. J. & Weening, J. J. What is the difference between IgA nephropathy and Henoch–Schönlein purpura nephritis? Kidney Int. 59, 823–834 (2001).

13. Meadow, S. R. & Scott, D. G. Berger disease: Henoch–Schönlein without the rash. J. Pediatr. 106, 27–32 (1985).

14. White, R. H. R., Yoshikawa, N. & Feehally, J. In Pediatric Nephrology 4th edn, Ch. 41 (eds Barratt, T. M., Avner, E. D. & Harmon, W. E.) 691–706 (Williams & Wilkins, 1999).

15. Goldstein, A. R., White, R. H. R., Akuse, R. & Chantler, C. Long‑term follow‑up of childhood Henoch–Schönlein nephritis. Lancet 339, 280–282 (1992).

16. Koskimies, O., Mir, S., Rapola, J. & Vilska, J. Henoch–Schönlein nephritis: long‑term prognosis of unselected patients. Arch. Intern. Med. 56, 482–484 (1981).

17. Bogdanovic, R. Henoch–Schönlein purpura nephritis in children: risk factors, prevention and treatment. Acta Paediatr. 98, 1882–1889 (2009).

18. Broyer, M. In Néphrologie Pédiatrique [French] 3rd edn, Ch. 2 (eds Royer, P. et al.) 75–98 (Flammarion Médecine‑Sciences, 1983).

19. Jauhola, O. et al. Renal manifestations of Henoch–Schönlein purpura in a 6‑month

prospective study of 223 children. Arch. Dis. Child. 95, 877–882 (2010).

20. Narchi, H. 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. Arch. Dis. Child. 90, 916–920 (2005).

21. Kaku, Y., Nohara, K. & Honda, S. Renal involvement in Henoch–Schönlein purpura: a multivariate analysis of prognostic factors. Kidney Int. 53, 1755–1759 (1998).

22. Coppo, R., Mazzucco, G., Cagnoli, L., Lupo, A. & Schena, F. P. Long‑term prognosis of Henoch–Schönlein nephritis in adults and children. Italian Group of Renal Immunopathology Collaborative Study on Henoch–Schönlein purpura. Nephrol. Dial. Transplant. 12, 2277–2283 (1997).

23. Ronkainen, J., Nuutinen, M. & Koskimies, O. The adult kidney 24 years after childhood Henoch–Schönlein purpura: a retrospective cohort study. Lancet 360, 666–670 (2002).

24. Scharer, K. et al. Clinical outcome of Schönlein–Henoch purpura nephritis in children. Pediatr. Nephrol. 13, 816–823 (1999).

25. Counahan, R. et al. Prognosis of Henoch–Schönlein nephritis in children. Br. Med. J. 2, 11–14 (1977).

26. Bunchman, T. E., Mauer, S. M., Sibley, R. K. & Vernier, R. L. Anaphylactoid purpura: Characteristics of 16 patients who progressed to renal failure. Pediatr. Nephrol. 2, 393–397 (1988).

27. Niaudet, P., Murcia, I., Beaufils, H., Broyer, M. & Habib, R. Primary IgA nephropathies in children: prognosis and Treatment. Adv. Nephrol. Necker Hospital 22, 121–140 (1993).

REVIEWS



28. Nussinovitch, N., Elishkevitz, K., Volovitz, B. & Nussinovitch, M. Hypertension as a late sequela of Henoch–Schönlein purpura. Clin. Pediatr. 44, 543–547 (2005).

29. Emancipator, S. N. In Pathology of the Kidney 4th edn, Ch. 6 (ed. Heptinstall, R. H.) 389–476 (Little Brown, 1993).

30. Haas, M. In Pathology of the Kidney 6th edn, Ch. 10 (eds Jennette, J. C. et al.) 423–486 (Lippincott, Williams & Wilkins, 2007).

31. Coppo, R. et al. Predictors of outcome in Henoch–Schönlein nephritis in children and adults. Am. J. Kidney Dis. 47, 993–1003 (2006).

32. Wakaki, H. et al. Henoch–Schönlein purpura nephritis with nephrotic state in children: predictors of poor outcomes. Pediatr. Nephrol. 26, 921–925 (2011).

33. Yoshikawa, N., White, R. H. & Cameron, A. H. Prognostic significance of the glomerular changes in Henoch–Schönlein nephritis. Clin. Nephrol. 16, 223–229 (1981).

34. Pillebout, E. et al. Henoch–Schönlein purpura in adults: outcome and prognostic factors. J. Am. Soc. Nephrol. 13, 1271–1278 (2002).

35. Fogazzi, G. B. et al. Long‑term outcome of Schönlein–Henoch nephritis in the adult. Clin. Nephrol. 31, 60–66 (1989).

36. Meadow, S. R. et al. Schönlein–Henoch nephritis. Q. J. Med. 41, 241–258 (1972).

37. Heaton, J. M., Turner, D. R. & Cameron, J. S. Localization of glomerular “deposits” in Henoch–Schönlein nephritis. Histopathology 1, 93–104 (1977).

38. Schillinger, F. et al. Severe Schönlein–Henoch nephritis in adults: a report of twenty cases [French]. Nephrologie 21, 247–252 (2000).

39. Shenoy, M., Bradbury, M. G., Lewis, M. A. & Webb, N. J. Outcome of Henoch–Schönlein purpura nephritis treated with long‑term immunosuppression. Pediatr. Nephrol. 22, 1717–1722 (2007).

40. Soylemezoglu, O. et al. Henoch–Schönlein nephritis: a nationwide study. Nephron Clin. Pract. 112, 199–204 (2009).

41. Shrestha, S. et al. Henoch Schönlein purpura with nephritis in adults: adverse prognostic indicators in a UK population. Q. J. Med. 99, 253–265 (2006).

42. Habib, R. In Néphrologie Pédiatrique 3rd edn, Ch. 11 (eds. Royer, P. et al.) 342–350 (Flammarion Médecine‑Sciences, 1983).

43. Working Group of the International IgA Nephropathy Network and the Renal Pathology Society et al. The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Int. 76, 534–545 (2009).

44. Bennett, W. M. & Kincaid‑Smith, P. Macroscopic hematuria in mesangial nephropathy: correlation with glomerular crescents and renal dysfunction. Kidney Int. 23, 392–400 (1983).

45. Foster, B. J., Bernard, C., Drummond, K. N. & Sharma, A. K. Effective therapy for severe Henoch–Schönlein purpura nephritis with prednisone and azathioprine: a clinical and histopathologic study. J. Pediatr. 136, 370–375 (2000).

46. Kanaan, N. et al. Recurrence and graft loss after kidney transplantation for Henoch–Schönlein purpura nephritis: a multicenter analysis. Clin. J. Am. Soc. Nephrol. 6, 1768–1772 (2011).

47. Thervet, E. et al. Histologic recurrence of Henoch–Schönlein purpura nephropathy after renal transplantation on routine allograft biopsy. Transplantation 92, 907–912 (2011).

48. Ponticelli, C. et al. Kidney transplantation in patients with IgA mesangial glomerulonephritis. Kidney Int. 60, 1948–1954 (2001).

49. Briganti, E. M., Russ, G. R., McNeil, J. J., Atkins, R. C. & Chadban, S. J. Risk of renal allograft loss from recurrent glomerulonephritis. N. Engl. J. Med. 347, 103–109 (2002).

50. Kincaid‑Smith, P., Nicholls, K. & Birchall, I. Polymorphs infiltrate glomeruli in mesangial IgA glomerulonephritis. Kidney Int. 36, 1108–1111 (1989).

51. Cunningham, M. A., Kitching, A. R., Tipping, P. G. & Holdsworth, S. R. Fibrin independent proinflammatory effects of tissue factor in experimental crescentic glomerulonephritis. Kidney Int. 66, 647–654 (2004).

52. Kamitsuji, H. et al. Urinary cross‑linked fibrin degradation products in glomerular disease with crescents. Clin. Nephrol. 29, 124–128 (1988).

53. Szeto, C. C. et al. Grading of acute and chronic renal lesions in Henoch–Schönlein purpura. Mol. Pathol. 14, 635–640 (2001).

54. Vassalli, P. & McCluskey, R. T. The pathogenetic role of the coagulation process in rabbit Masugi nephritis. Am. J. Pathol. 45, 653–677 (1964).

55. Hisano, S., Matsushita, M., Fujita, T. & Iwasaki, H. Activation of the lectin complement pathway in Henoch–Schönlein purpura nephritis. Am. J. Kidney. Dis. 45, 295–302 (2005).

56. Novak, J., Julian, B. A., Mestecky, J. & Renfrow, M. B. Glycosylation of IgA1 and pathogenesis of IgA nephropathy. Semin. Immunopathol. 34, 365–382 (2012).

57. Allen, A. C., Willis, F. R., Beattie, T. J. & Feehally, J. Abnormal IgA glycosylation in Henoch–Schönlein purpura restricted to patients with clinical nephritis. Nephrol. Dial. Transplant. 13, 930–934 (1998).

58. Serino, G., Sallustio, F., Cox, S. N., Pesce, F. & Schena, F. P. Abnormal miR‑148b expression promotes aberrant glycosylation of IgA1 in IgA nephropathy. J. Am. Soc. Nephrol. 23, 814–824 (2012).

59. Chintalacharuvu, S. R. et al. T cell cytokines determine the severity of experimental IgA nephropathy by regulating IgA glycosylation. Clin. Exp. Immunol. 126, 326–333 (2001).

60. Chintalacharuvu, S. R. et al. T cell cytokine polarity as a determinant of immunoglobulin A (IgA) glycosylation and the severity of experimental IgA nephropathy. Clin. Exp. Immunol. 153, 456–462 (2008).

61. Inoshita, H. et al. Disruption of SMAD4 expression in T cells leads to IgA nephropathy‑like manifestations. PLoS ONE 8, e78736 (2013).

62. Yamada, K. et al. Down‑regulation of core 1 β1, 3‑galactosyltransferase and Cosmc by TH2 cytokine alters O‑glycosylation of IgA1. Nephrol. Dial. Transplant. 25, 3890–3897 (2010).

63. Suzuki, H. et al. Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. J. Clin. Invest. 119, 1668–1677 (2009).

64. Wyatt, R. J. & Julian, B. A. IgA nephropathy. N. Engl. J. Med. 368, 2402–2414 (2013).

65. Smith, A. C., Molyneux, K., Feehally, J. & Barratt, J. O‑glycosylation of serum IgA1 antibodies against mucosal and systemic antigens in IgA nephropathy. J. Am. Soc. Nephrol. 17, 3520–3528 (2006).

66. Davin, J. C., Forget, P. & Mahieu, P. R. Increased intestinal permeability to 51Cr EDTA is correlated with IgA immune complex‑plasma levels in children with IgA‑associated nephropathies. Acta Paediatr. Scand. 77, 118–124 (1988).

67. de Fijter, J. W. et al. Deficient IgA1 immune response to nasal cholera toxin subunit B in primary IgA nephropathy. Kidney Int. 50, 952–961 (1996).

68. Monteiro, R. C. The role of IgA and IgA Fc receptors in inflammation. J. Clin. Immunol. 30, 1–9 (2010).

69. Vuong, M. T. et al. Association of soluble CD89 levels with disease progression but not susceptibility in IgA nephropathy. Kidney Int.78, 1281–1287 (2010).

70. Davin, J. C. et al. Possible pathogenic role of IgE in Henoch–Schönlein purpura. Pediatr. Nephrol. 8, 169–171 (1994).

71. Kawasaki, Y., Hosoya, M. & Suzuki, H. Possible pathologenic role of interleukin‑5 and eosino cationic protein in Henoch–Schönlein purpura nephritis. Pediatr. Int. 47, 512–517 (2005).

72. Namgoong, M. K., Lim, B. K. & Kim, J. S. Eosinophil cationic protein in Henoch–Schönlein purpura and in IgA nephropathy. Pediatr. Nephrol. 11, 703–706 (1997).

73. Chen, A., Chen, W. P., Sheu, L. F. & Lin, C. Y. Pathogenesis of IgA nephropathy: in vitro activation of human mesangial cells by IgA. J. Pathol. 173, 119–126 (1994).

74. Gomez‑Guerrero, C., Lopez‑Armada, M. J., Gonzalez, E. & Egido, J. Soluble IgA and IgG aggregates are catabolized by cultured rat mesangial cells and induce production of TNF‑α and IL‑6, and proliferation. J. Immunol. 153, 5247–5255 (1994).

75. Oortwijn, B. D. et al. Differential glycosylation of polymeric and monomeric IgA: a possible role in glomerular inflammation in IgA nephropathy. J. Am. Soc. Nephrol. 17, 3529–3539 (2006).

76. Suzuki, H. et al. The pathophysiology of IgA nephropathy. J. Am. Soc. Nephrol. 22, 1795–1803 (2011).

77. Yan, Y., Xu, L. X., Zhang, J. J., Zhang, Y. & Zhao, M. H. Self‑aggregated deglycosylated IgA1 with or without IgG were associated with the development of IgA nephropathy. Clin. Exp. Immunol. 144, 17–24 (2006).

78. Schlöndorff, D. & Banas, B. The mesangial cell revisited: no cell is an island. J. Am. Soc. Nephrol. 20, 1179–1187 (2009).

79. Wan, J. X. et al. Complement 3 is involved in changing the phenotype of human glomerular mesangial cells. J. Cell Physiol. 213, 495–501 (2007).

80. Camilla, R. et al. Oxidative stress and galactose‑deficient IgA1 as markers of progression in IgA nephropathy. Clin. J. Am. Soc. Nephrol. 6, 1903–1911 (2011).

81. Wang, C. et al. Mesangial cells stimulated by immunoglobin A1 from IgA nephropathy upregulate transforming growth factor β1 synthesis in podocytes via renin–angiotensin system activation. Arch. Med. Res. 41, 255–260 (2010).

82. Coppo, R. et al. Aberrantly glycosylated IgA1 induces mesangial cells to produce platelet‑activating factor that mediates nephrin loss in cultured podocytes. Kidney Int. 77, 417–427 (2010).

83. Horii, Y. et al. Involvement of IL‑6 in mesangial proliferative glomerulonephritis. J. Immunol. 143, 3949–3955 (1989).

84. Kashem, A. et al. Glomerular FcαR expression and disease activity in IgA nephropathy. Am. J. Kidney Dis. 30, 389–396 (1997).

85. Niemir, Z. I. et al. PDGF and TGF‑β contribute to the natural course of human IgA glomerulonephritis. Kidney Int. 48, 1530–1541 (1995).

86. Lopez‑Armada, M. J., Gomez‑Guerrero, C. & Egido, J. Receptors for immune complexes activate gene expression and synthesis of matrix proteins in cultured rat and human mesangial cells: role of TGF‑β. J. Immunol. 157, 2136–2142 (1996).

REVIEWS



87. Terada, Y. et al. Expression of PDGF and PDGF receptor mRNA in IgA nephropathy. J. Am. Soc. Nephrol. 8, 817–819 (1997).

88. Yokoyama, H. et al. Urinary levels of chemokines (MCAF/MCP‑1, IL‑8) reflect distinct disease activities and phases of human IgA nephropathy. J. Leukocyte Biol. 63, 493–499 (1998).

89. Camussi, G. et al. Tumor necrosis factor induces contraction of mesangial cells and alters their cytoskeletons. Kidney Int. 38, 795–802 (1990).

90. Ha, T. S. The role of tumor necrosis factor‑α in Henoch–Schönlein purpura. Pediatr. Nephrol. 20, 149–153 (2005).

91. Couser, W. G. Glomerulonephritis. Lancet 353, 1509–1515 (1999).

92. Jennette, J. C. Rapidly progressive crescentic glomerulonephritis. Kidney Int. 63, 1164–1177 (2003).

93. Bonsib, S. Glomerular basement membrane discontinuities: scanning electron microscopic study of acellular glomeruli. Am. J. Pathol. 119, 357–360 (1985).

94. Atkins, R. C., Nikolic‑Paterson, D. J., Song, Q. & Lan, H. Y. Modulators of crescentic glomerulonephritis. J. Am. Soc. Nephrol. 7, 2271–2278 (1996).

95. Lan, H. Y., Nikolic‑Paterson, D. J. & Atkins, R. C. Involvement of activated periglomerular leukocytes in the rupture of Bowman’s capsule and crescent progression in experimental glomerulonephritis. Lab. Invest. 67, 743–751 (1992).

96. Lan, H. Y., Nikolic‑Paterson, D. J., Mu, W., Vannice, J. L. & Atkins, R. C. Interleukin‑1 receptor antagonist halts the progression of established crescentic glomerulonephritis in the rat. Kidney Int. 47, 1303–1309 (1995).

97. Isaka, Y. et al. Gene therapy by transforming growth factor‑β receptor–IgG Fc chimera suppressed extracellular matrix accumulation in experimental glomerulonephritis. Kidney Int. 55, 465–475 (1999).

98. Adler, S. & Brady, H. R. Cell adhesion molecules and the glomerulopathies. Am. J. Med. 107, 371–386 (1999).

99. Morel‑Maroger Striker, L., Killen, P. D., Chi, E. & Striker, G. E. The composition of glomerulosclerosis. I. Studies in focal sclerosis, crescentic glomerulonephritis, and membranoproliferative glomerulonephritis. Lab. Invest. 51, 181–192 (1984).

100. Mathieson, P. W. The ins and outs of glomerular crescent formation. Clin. Exp. Immunol. 110, 155–157 (1997).

101. Emancipator, S. N. IgA nephropathy: morphologic expression and pathogenesis. Am. J. Kidney. Dis. 23, 451–462 (1994).

102. Border, W. A. & Noble, N. A. Transforming growth factor in tissue fibrosis. N. Engl. J. Med. 331, 1286–1292 (1994).

103. Lin, Q. et al. Henoch–Schönlein purpura with hypocomplementemia. Pediatr. Nephrol. 27, 801–806 (2012).

104. Roos, A. et al. Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease. J. Am. Soc. Nephrol. 17, 1724–1734 (2006).

105. Espinosa, M. et al. Mesangial C4d deposition: a new prognostic factor in IgA nephropathy. Nephrol. Dial. Transplant. 24, 886–891 (2009).

106. McLean, R. H., Michael, A. F., Fish, A. J. & Vernier, R. L. In Pediatric Nephrology 1st edn, Ch. 25 (eds Rubin, M. I. & Barratt, T. M.) 584–588 (Williams & Wilkins, 1975).

107. Coppo, R. & Amore, A. In Pediatric Nephrology 5th edn, Ch. 25 (eds Avner, E. D. et al.) 851–864 (Lippincott Williams & Wilkins, 2004).

108. Rees, L., Webb, N. J. A. & Brogan, P. A. In Paediatric Nephrology 2nd edn, Ch. 20 (eds Rees, L. et al.) 312–313 (Oxford University Press, 2007).

109. Tarshish, P., Bernstein, J. & Edelmann, C. M. Jr. Henoch–Schönlein purpura nephritis: course of disease and efficacy of cyclophosphamide. Pediatr. Nephrol. 19, 51–56 (2004).

110. Jauhola, O. et al. Cyclosporine A vs. methylprednisolone for Henoch–Schönlein nephritis: a randomized trial. Pediatr. Nephrol. 26, 2159–2166 (2011).

111. Pillebout, E. et al. Addition of cyclophosphamide to steroids provides no benefit compared with steroids alone in treating adult patients with severe Henoch Schönlein purpura. Kidney Int. 78, 495–502 (2010).

112. Kidney Disease: Improving Global Outcomes. Chapter 11: Henoch–Schönlein purpura nephritis. Kidney Int. Suppl. 2, 218–220 (2012).

113. Davin, J. C. Henoch–Schönlein purpura nephritis: pathophysiology, treatment, and future strategy. Clin. J. Am. Soc. Nephrol. 6, 679–689 (2011).

114. Hattori, M. et al. Plasmapheresis as the sole therapy for rapidly progressive Henoch–Schönlein purpura nephritis in children. Am. J. Kidney Dis. 33, 427–433 (1999).

115. Shenoy, M., Ognjanovic, M. V. & Coulthard, M. G. Treating severe Henoch–Schönlein and IgA nephritis with plasmapheresis alone. Pediatr. Nephrol. 22, 1167–1171 (2007).

116. Niaudet, P. & Habib, R. Methylprednisolone pulse therapy in the treatment of severe forms of Schönlein–Henoch purpura nephritis. Pediatr. Nephrol. 12, 238–243 (1998).

117. Andersen, R. F., Rubak, S., Jespersen, B. & Rittig, S. Early high dose immunosuppression in Henoch–Schönlein nephrotic syndrome may improve outcome. Scand. J. Urol. Nephrol. 43, 409–415 (2009).

118. Flynn, J. T., Smoyer, W. E., Bunchman, T. E., Kershaw, D. B. & Sedman, A. B. Treatment of Henoch–Schönlein purpura glomerulonephritis in children with high‑dose corticosteroids plus

oral cyclophosphamide. Am. J. Nephrol. 21, 128–133 (2001).

119. Kawasaki, Y., Suyama, K., Hashimoto, K. & Hosoya, M. Methylprednisolone pulse plus mizoribine in children with Henoch–Schönlein purpura nephritis. Clin. Rheumatol. 30, 529–535 (2011).

120. Kawasaki, Y., Suzuki, J. & Suzuki, H. Efficacy of methylprednisolone and urokinase pulse therapy combined with or without cyclophosphamide in severe Henoch–Schönlein nephritis: a clinical and histopathological study. Nephrol. Dial. Transplant. 19, 858–864 (2004).

121. Kawasaki, Y., Suzuki, J., Nozawa, R., Suzuki, S. & Suzuki, H. Efficacy of methylprednisolone and urokinase pulse therapy for severe Henoch–Schönlein nephritis. Pediatrics 111, 785–789 (2003).

122. Ashton, H., Frenk, E. & Stevenson, C. J. Therapeutics. XV. The management of Henoch–Schönlein purpura. Br. J. Dermatol. 85, 199–203 (1971).

123. Borges, W. H. Anaphylactoid purpura. Med. Clin. North Am. 56, 201–206 (1972).

124. Ou, Z. L. et al. Effective methylprednisolone dose in experimental crescentic glomerulonephritis. Am. J. Kidney Dis. 37, 411–417 (2001).

125. Lameire, N. H. et al. Acute kidney injury: an increasing global concern. Lancet 382, 170–179 (2013).

126. Branten, A. J., Kock‑Jansen, M., Klasen, I. S. & Wetzels, J. F. Urinary excretion of complement C3d in patients with renal diseases. Eur. J. Clin. Invest. 33, 449–456 (2003).

127. Wickman, L. et al. Urine podocyte mRNAs, proteinuria, and progression in human glomerular diseases. J. Am. Soc. Nephrol. 24, 2081–2095 (2013).

128. Delanghe, S. E. et al. Soluble transferrin receptor in urine, a new biomarker for IgA nephropathy and Henoch–Schönlein purpura nephritis. Clin. Biochem. 46, 591–597 (2013).

129. Moura, I. C. et al. Identification of the transferrin receptor as a novel immunoglobulin (Ig)A1 receptor and its enhanced expression on mesangial cells in IgA nephropathy. J. Exp. Med. 194, 417–425 (2001).

130. Park, S. J. et al. Advances in our understanding of the pathogenesis of Henoch–Schönlein purpura and the implications for improving its diagnosis. Expert Rev. Clin. Immunol. 9, 1223–1238 (2013).

131. Ninchoji, T. et al. Treatment strategies for Henoch–Schönlein purpura nephritis by histological and clinical severity. Pediatr. Nephrol. 26, 563–569 (2011).

Author contributionsThe authors contributed equally to researching the data for the article, discussions of its content, writing the article and review and/or editing of the manuscript before submission.

REVIEWS


Documents

Henoch–Schönlein purpura nephritis in children · Henoch–Schönlein purpura (HSP) is the most fre-quently detected form of vasculitis in children. The incidence of HSP decreases