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Immunoglobulin A nephropathy and Henoch–Schönlein purpura 

Immunoglobulin A nephropathy and Henoch–Schönlein purpura
Chapter:
Immunoglobulin A nephropathy and Henoch–Schönlein purpura
Author(s):

Jonathan Barratt

and John Feehally

DOI:
10.1093/med/9780199204854.003.210801_update_002

Update:

Updated information on the genetics of Immunoglobulin A nephropathy (IgAN)

New table showing RCTs examining the efficacy of a variety of novel therapies in IgAN

Updated further reading

Updated on 22 September 2016. The previous version of this content can be found here.
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Essentials

Immunoglobulin A nephropathy (IgAN) is the commonest pattern of glomerulonephritis identified in areas of the world where renal biopsy is widely practised. It is defined pathologically by IgA deposition in the glomerular mesangium accompanied by a mesangial proliferative glomerulonephritis which may vary greatly in severity. Aetiology is uncertain, but abnormalities of IgA1 hinge-region O-glycosylation are consistently found.

Clinical features—IgAN can present with: (1) visible haematuria, typically in children and young adults, developing within a day or two of upper respiratory tract infection (‘synpharyngitic’); (2) asymptomatic non-visible haematuria/proteinuria; (3) nephrotic syndrome (less than 5% of cases); (4) acute kidney injury (uncommon); and (5) chronic renal failure with up to 25% of patients reaching endstage renal failure within 20 years of diagnosis. Henoch–Schönlein purpura (HSP) is a small vessel systemic vasculitis characterized by small blood vessel deposition of IgA that predominantly affects the skin, joints, gut, and kidney, with nephritis that may be histologically indistinguishable from IgA nephropathy.

Management—there is no treatment known to modify mesangial deposition of IgA. Treatment options are mostly directed at controlling blood pressure and limiting proteinuria through blockade of the renin–angiotensin–aldosterone axis. In the rare patient presenting with acute kidney injury in whom biopsy shows crescentic IgA nephropathy, a regimen such as those used for renal vasculitis and other forms of crescentic glomerulonephritis should be considered, e.g. oral prednisolone in combination with cyclophosphamide.

Introduction

Immunoglobulin A nephropathy (IgAN) was first described by Berger in 1968 and at one time was known as Berger’s disease. It is defined by IgA deposition in the glomerular mesangium accompanied by a mesangial proliferative glomerulonephritis which may vary greatly in severity. Although recurrent visible haematuria is the hallmark of the disease, the old term ‘benign recurrent haematuria’ is a discredited misnomer since it is now clear that IgAN is associated with a significant risk of progression to endstage renal failure. Henoch–Schönlein purpura (HSP) is a somewhat misleading historical term: the purpuric rash is in fact a cutaneous vasculitis, and the renal lesion (HSP nephritis) is a mesangial proliferative glomerulonephritis usually indistinguishable from IgAN.

Aetiology

In most cases the aetiology of IgAN remains unclear. The provocation of visible haematuria by mucosal infection in IgAN and the presumption that the mesangial IgA represented deposited immune complexes led to the view that IgAN was a complication of infection. Cytomegalovirus and Haemophilus parainfluenzae have been most studied, but neither these nor any other viral or bacterial antigens have been consistently associated with development of the disease or identified in IgA immune complexes or mesangial deposits. Alternatively, it has been suggested that IgAN results from hypersensitivity to food antigens, in view of its association with gluten-sensitive enteropathy. There is some evidence that withdrawal of gluten from the diet of these specific patients may improve the renal disease, but there is little evidence for widespread hypersensitivity to food antigens in IgAN.

Genetics

Despite many studies of potential immunogenetic associations, the genetic basis for susceptibility to IgAN has not yet been identified. IgAN is familial in less than 10% of cases, but the true frequency of familial IgAN remains uncertain because there are no reliable serological markers for the disease. Four kindreds have been described in which IgAN appears to show Mendelian inheritance, in each case autosomal dominance with incomplete penetrance. The genetic linkage differs in each of the four kindreds, arguing strongly against any generalizability of these findings to sporadic IgAN. Furthermore, study of the three novel loci (designated IGAN1, IGAN2, IGAN3) has identified no likely candidate genes. Only the 2q36 locus identified in the Canadian pedigree is potentially informative since it contains COL4A3 and COL4A4 genes coding for basement membrane collagen, mutations of which are associated with thin membrane nephropathy (TMN; see Chapter 21.8.2). Three independent genome-wide association studies (GWAS) in different populations with IgAN have also been reported, and recently a fourth meta-analysis incorporating the populations from all three previous GWAS and including additional populations from both Europe and Asia. All have shown an enrichment of single nucleotide polymorphisms implicated in autoimmune or inflammatory traits (multiple alleles within the HLA region at chromosome 6p21 and chromosome 1q32 suggesting a role for complement-regulatory proteins), and furthermore most loci associated with IgAN encode proteins implicated in maintenance of the intestinal barrier and regulation of mucosal immune response to pathogens.

Pathogenesis

Mechanism of mesangial IgA deposition

Mesangial proliferative glomerulonephritis such as is seen in IgAN and HSP nephritis may be the consequence of immune complex deposition, either due to trapping of circulating IgA immune complexes or the formation of complexes in situ by reaction of IgA with antigen which has already been deposited. No exogenous antigen has been consistently identified in the mesangial deposits in IgAN, which may indicate that the IgA complexes are a common response to different antigens, or that the initiating antigen has disappeared by the time of the renal biopsy. Alternatively, the IgA may be deposited by some mechanism independent of classic antigen–antibody interactions, such as a physicochemical abnormality of the IgA.

The frequent recurrence of both IgAN and HSP nephritis after renal transplantation strongly suggests that the abnormality resides in the host IgA immune system. The mesangial IgA deposits are polymeric IgA1 (pIgA1). Most pIgA is synthesized in the mucosa and the clinical association of visible haematuria with mucosal infection originally led to the assumption that an exaggerated mucosal IgA response resulted in mesangial IgA deposition. But IgA production is in fact down-regulated in the mucosal immune system and up-regulated in the bone marrow, and exaggerated IgA1 responses to immunization in these patients are marrow-, rather than mucosally, derived.

There is increasing evidence of under-galactosylation of both serum and mesangial IgA1 in patients with IgAN and HSP nephritis. Changes in the O-glycan composition of circulating IgA1 may favour the development of immune complexes or may directly provoke mesangial deposition. New data suggests that poorly galactosylated IgA1 O-glycoforms might in fact act either as autoantigens driving the formation of glycan-specific autoantibodies, or antigens for cross-reactive anti-microbial antibodies. The resultant formation of IgA:IgG immune complexes appears pivotal to the pathogenesis of IgAN and there is strong in vitro data to support their role in activation of mesangial cells, induction of podocyte injury, and activation of proximal tubular epithelial cells.

Progression of IgA nephropathy

IgA deposition may occur in many patients with mild disease with little mesangial injury. What decides the prognosis in any individual is the extent to which the IgA deposition is followed by mesangial proliferation, inflammation, and scarring. There is nothing to suggest that these subsequent mechanisms of damage and scarring are unique to IgAN, rather they are generic to many forms of glomerulonephritis.

Relationship of IgAN and HSP

There is much indirect evidence to suggest a close relationship between IgAN and HSP. Monozygotic twins have been described, one who developed IgAN and the other HSP at the same time. HSP developing on a background of proven IgAN has been described in both adults and children. Many abnormalities of the IgA immune system, including abnormal IgA1 glycosylation, have been described in both IgAN and HSP. IgAN is increasingly thought of as ‘HSP without the rash’. Why some individuals get a renal-limited disease (IgAN) and others a systemic disease (HSP) is not known.

Pathology

Immune deposits

IgAN and HSP nephritis are defined by the presence of mesangial IgA detected by immunofluorescence or immunoperoxidase (Fig. 21.8.1.1). Complement C3 frequently accompanies IgA in the same mesangial distribution; IgG and IgM are less common. Electron microscopy identifies mesangial electron-dense deposits corresponding to mesangial IgA (Fig. 21.8.1.2).


Fig. 21.8.1.1 Immunofluorescence of a glomerulus in IgAN. Bright fluorescent staining is seen within the mesangium with labelled antibodies to IgA. In some cases similar staining is also seen along capillary walls. A similar distribution of staining for C3 is commonly present. Antihuman IgA, magnification ×375.

Fig. 21.8.1.1
Immunofluorescence of a glomerulus in IgAN. Bright fluorescent staining is seen within the mesangium with labelled antibodies to IgA. In some cases similar staining is also seen along capillary walls. A similar distribution of staining for C3 is commonly present. Antihuman IgA, magnification ×375.


Fig. 21.8.1.2 Electron micrograph of glomerular capillary loop in IgA nephropathy. Numerous electron-dense deposits representing deposits of IgA (large arrows) are seen within the expanded mesangium. BM, basement membrane; BS, Bowman’s space; C, capillary lumen; En, fenestrated endothelium; Ep, visceral epithelium; MC, mesangial cell nucleus. Magnification ×5200.

Fig. 21.8.1.2
Electron micrograph of glomerular capillary loop in IgA nephropathy. Numerous electron-dense deposits representing deposits of IgA (large arrows) are seen within the expanded mesangium. BM, basement membrane; BS, Bowman’s space; C, capillary lumen; En, fenestrated endothelium; Ep, visceral epithelium; MC, mesangial cell nucleus. Magnification ×5200.

Light microscopy

Mesangial proliferative glomerulonephritis is the characteristic appearance, although when haematuria is the only clinical finding abnormalities on light microscopy may be minimal despite florid IgA deposition. Mesangial hypercellularity and matrix expansion are usually global (Fig. 21.8.1.3a) but may be focal and segmental (Fig. 21.8.1.3b, c). The hypercellularity is followed by increasing mesangial matrix deposition and eventual sclerosis (Fig. 21.8.1.3b). In acute kidney injury there may be severe glomerular inflammation with crescent formation. In advanced cases there is glomerulosclerosis and corresponding tubular atrophy and interstitial fibrosis; these are entirely nonspecific changes of ‘endstage kidney’. A number of histological scoring systems have been devised to evaluate the renal biopsy appearances of IgAN. Of these the most extensively evaluated is the Oxford Classification of IgAN. In this classification four variables: (1) the mesangial hypercellularity score, (2) segmental glomerulosclerosis, (3) endocapillary hypercellularity, and (4) tubular atrophy/interstitial fibrosis were shown to have independent value in predicting renal outcome.


Fig. 21.8.1.3 Light microscopic appearances of IgA nephropathy. (a) Glomerulus showing global increase in mesangial matrix and cellularity. Alcian blue/PAS stain, magnification ×375. (b) Glomerulus showing segmental increase in mesangial matrix and hypercellularity with fibrinoid necrosis (solid arrow) and synechia formation (open arrow) between the segmental lesion and parietal epithelium of Bowman’s capsule. Alcian blue/PAS stain, magnification ×375. (c) Glomerulus showing segmental increase in mesangial matrix and segmental sclerosis with synechia formation (open arrows) overlying Bowman’s capsule. Masson’s trichrome stain, magnification ×375.

Fig. 21.8.1.3
Light microscopic appearances of IgA nephropathy. (a) Glomerulus showing global increase in mesangial matrix and cellularity. Alcian blue/PAS stain, magnification ×375. (b) Glomerulus showing segmental increase in mesangial matrix and hypercellularity with fibrinoid necrosis (solid arrow) and synechia formation (open arrow) between the segmental lesion and parietal epithelium of Bowman’s capsule. Alcian blue/PAS stain, magnification ×375. (c) Glomerulus showing segmental increase in mesangial matrix and segmental sclerosis with synechia formation (open arrows) overlying Bowman’s capsule. Masson’s trichrome stain, magnification ×375.

Epidemiology

IgAN is the commonest glomerulonephritis in countries where renal biopsy is widely used. It is typically found in 30% of biopsies with primary glomerular disease, but the apparent prevalence varies markedly around the world. It is commoner in the Pacific Rim and Mediterranean countries, and less so in North America and northern Europe. At least part of this apparent difference is explained by the varying use of urine testing in health screening and varying attitudes to the value of renal biopsy in individuals with isolated haematuria or other minor clinical evidence of renal disease. For example, in Japan there is routine urine testing of schoolchildren and employed adults, the threshold for renal biopsy is low, and the reported prevalence of IgAN is high. There are also important racial differences in susceptibility. IgAN is uncommon in Afro-Caribbean people and also less common in Polynesian people than white people in Australasia, a particularly striking finding given the exaggerated susceptibility of Polynesian people to most forms of renal disease.

Clinical features

IgAN

IgAN can occur at any age, but the peak age of onset is in the second and third decades of life (Fig. 21.8.1.4). In western Europe IgAN is three times more common in males than females, but this gender difference disappears in the Pacific Rim.


Fig. 21.8.1.4 Clinical presentations of IgA nephropathy and HSP in relation to age at diagnosis. HSP is commonest in childhood but may occur at any age. Visible haematuria is very rare over the age of 40 years. The importance of asymptomatic urine abnormality as the presentation of IgAN will depend on attitudes to routine urine testing and renal biopsy. It is uncertain whether those presenting with chronic kidney disease have a disease distinct from that of those presenting younger with visible haematuria.

Fig. 21.8.1.4
Clinical presentations of IgA nephropathy and HSP in relation to age at diagnosis. HSP is commonest in childhood but may occur at any age. Visible haematuria is very rare over the age of 40 years. The importance of asymptomatic urine abnormality as the presentation of IgAN will depend on attitudes to routine urine testing and renal biopsy. It is uncertain whether those presenting with chronic kidney disease have a disease distinct from that of those presenting younger with visible haematuria.

Visible haematuria

The characteristic clinical picture of recurrent macroscopic haematuria occurs in about 40 to 50% of cases. A child or young adult develops episodes of painless visible haematuria occurring within a day or so of the onset of an upper respiratory tract infection, or occasionally infections of other mucosal or IgA-secreting surfaces such as gastrointestinal tract, bladder, or breast. The urine may be frankly bloody, but more often is brown (like Coca-Cola or tea without milk), there are no clots passed, and it is usually painless although there may be dull loin ache. The episodes settle spontaneously after 1 to 5 days and may be recurrent, but rarely for more than a year or two. Serum IgA is moderately elevated in 30% of cases, but serum complement C3 and C4 are normal. Between episodes there will be persistent non-visible haematuria. This presentation does not occur beyond the age of 40 years (Fig. 21.8.1.4).

Asymptomatic haematuria/proteinuria

Thirty to 40% of cases of IgAN are identified by urine testing, when non-visible haematuria may be combined with proteinuria (usually <2 g/24 h). Since this is glomerular haematuria, dysmorphic red cells may be seen on phase contrast microscopy, but red cell casts are frequently absent in mild disease.

Nephrotic syndrome

Nephrotic syndrome is the presentation in only 5% of IgAN. Very occasionally in children or young adults this appears to be the consequence of coincidental minimal-change nephrotic disease; the proteinuria resolves completely with corticosteroid therapy, but haematuria and IgA deposits persist. More commonly nephrotic syndrome may develop in IgAN with overt mesangial proliferative glomerulonephritis, or may be a consequence of glomerular scarring in advanced IgAN.

Acute kidney injury

Acute kidney injury occurs for two reasons in IgAN. Episodes of macroscopic haematuria may produce acute tubular occlusion by red cells in the face of minor glomerular injury. Alternatively, there can be acute severe necrotizing glomerulonephritis with crescent formation, ‘crescentic IgA nephropathy’, which may be the presenting feature or occur on a background of known milder disease.

Chronic kidney disease

IgAN may also present with hypertension and established renal impairment, often in older patients (Fig. 21.8.1.4). Too little is yet known about the pathogenesis of IgAN to understand whether this is a distinct disease entity or the same disease presenting much later because there was never an episode of visible haematuria or a urine test to bring it to medical attention earlier.

Clinical associations with IgAN

The commonest secondary cause of IgAN is chronic liver disease, typically alcoholic liver disease, in which it is probable that IgA deposition is a consequence of impaired IgA clearance from the circulation via the liver. Most hepatic IgAN is asymptomatic, and progression to endstage renal failure is unusual. The other best established associations are with coeliac disease and dermatitis herpetiformis; with rheumatoid arthritis, ankylosing spondylitis, and Reiter’s disease; and with HIV infection. Many other conditions have been reported occasionally with IgAN, but since IgAN is so common it is difficult to know if these are more than chance associations.

HSP nephritis

HSP can occur at any age but is commonest in the first decade of life (Fig. 21.8.1.4). There is a slight male preponderance. A palpable purpuric rash caused by cutaneous vasculitis is the presenting feature. It has a characteristic extensor surface distribution with sparing of the trunk and face (Fig. 21.8.1.5). Crops of rash, often provoked by intercurrent infection, may continue for some time, but rarely beyond a year from first presentation. Polyarthralgia is common. Abdominal pain, due to gut vasculitis, is usually mild and transient, but severe pain and bloody diarrhoea may develop due to intussusception.


Fig. 21.8.1.5 Characteristic purpuric rash affecting the lower limbs in HSP.

Fig. 21.8.1.5
Characteristic purpuric rash affecting the lower limbs in HSP.

Apart from intussusception, the major sequelae of HSP come from renal involvement. Much of the renal disease in HSP is transient, with asymptomatic haematuria or proteinuria disappearing in a few weeks. Of those with persistent evidence of renal disease, asymptomatic haematuria/proteinuria is the commonest clinical state, but 20% will have nephrotic syndrome. Serum IgA is raised in 50%, but complement C3 and C4 are normal. Acute kidney injury due to crescentic HSP nephritis usually occurs early and is commoner than crescentic IgAN.

Differential diagnosis

Visible haematuria

Nonglomerular causes of haematuria, including renal stones and neoplasia, must always be considered and excluded where appropriate by urological investigation. While episodic visible haematuria coinciding with upper respiratory tract infection in children and young adults is the hallmark of IgAN, it is not pathognomonic. Similar episodes can occur with other glomerular diseases, most commonly hereditary nephropathies such as Alport’s syndrome and thin membrane nephropathy. The distinction of IgAN from postinfectious (usually poststreptococcal) glomerulonephritis is also important. In poststreptococcal glomerulonephritis there is a 10- to 14-day latency from the onset of infection and the development of symptomatic renal disease, contrasting with the immediacy of haematuria in IgAN, for which the term ‘synpharyngitic haematuria’ has been coined. The haematuria is usually less heavy in poststreptococcal glomerulonephritis so that the urine is typically smoky rather than frankly bloody; hypertension, oedema, and other features of the acute nephritic syndrome are usually present. Serological evidence of recent streptococcal infection (such as antibodies to endostreptosin) and low C3 are not found in IgAN.

Nephrotic syndrome

The differential diagnosis when IgAN presents with nephrotic syndrome includes the usual range of glomerular disease known to cause nephrotic syndrome given the age of the patient.

Chronic kidney disease

Advanced IgAN presenting with hypertension, proteinuria, and renal impairment is clinically indistinguishable from many other causes of chronic progressive renal disease. Renal biopsy can establish the diagnosis since mesangial IgA can often still be identified even when light microscopy shows ‘endstage kidney’, but should only be performed if there is a reasonable expectation that the result might benefit the particular patient.

HSP

In children HSP is the commonest form of vasculitis, and a clinical diagnosis is often made from the characteristic rash and abdominal pain. In adults the differential diagnosis is wider, including many other forms of small vessel vasculitis which must be distinguished on the basis of clinical, serological, and histopathological findings.

Clinical investigation

No accumulation of clinical and laboratory evidence has sufficient specificity and sensitivity to avoid the need for diagnostic biopsy in IgAN or HSP. IgA deposits are seen in blood vessels in affected skin, but this is not a universal feature. Raised serum IgA1 levels are found in 30 to 50% of all patients, but are less common in children and do not correlate with disease activity or severity. A high proportion of λ‎ light chain, rather than the normal predominance of the κ‎ isotype, is also a distinctive feature of serum IgA in IgAN, although the significance of this is unknown. Complement components C3 and C4, and CH50 in the serum, are usually normal, but there is some evidence of systemic complement activation with more specific testing. Circulating autoantibodies to the IgA1 hinge region glycans, IgA-rheumatoid factors, and IgA-containing circulating immune complexes have been reported by many different assay methods, but they are not currently diagnostically useful, nor can they be reliably correlated with disease activity.

Secondary causes of IgAN must be identified. A thorough history and physical examination, along with laboratory checks for liver function and hepatitis B status are sufficient to exclude the common secondary associations with IgAN.

Criteria for diagnosis

IgAN

By definition, the diagnosis of IgAN requires a renal biopsy; no serological or other laboratory indices provide diagnostic information reliable enough to avoid the need for biopsy.

HSP

While the distribution of the vasculitic rash may be highly suggestive in HSP, ultimate confirmation requires identification of tissue IgA deposition which can be found in the vessels of affected skin as well as the kidney.

Treatment

IgAN

The 2012 KDIGO treatment guidelines for IgA nephropathy are summarized in Table 21.8.1.1. Only in very few patients with IgAN is there any evidence that drug therapy alters the natural history of the disease. Despite being so common among renal diseases, there is still a dearth of well-conducted prospective randomized controlled trials in IgAN on which to base therapeutic decisions.

Table 21.8.1.1 Current recommendations for the treatment of IgAN

Clinical feature

Recommendation

Visible haematuria

No treatment

Non-visible haematuria

No treatment—no indication for prophylactic antibiotics or tonsillectomy

Acute kidney injury

Biopsy

Tubular occlusion

Supportive treatment only

Crescentic IgAN

  • Prednisolone 0.5 mg/kg per day, reducing to 5–10 mg daily by 3 months

  • Cyclophosphamide 2–3 mg/kg per day for 3 months, followed by azathioprine 2–3 mg/kg per day

Proteinuria <1 g/24 h

No treatment

Nephrotic syndrome with minimal change on biopsy

Prednisolone 0.5 mg/kg per day for 8–12 weeks

All other proteinuria >1 g/24 h

ACE inhibitor and ARB

Hypertension

Target BP 125/75 mmHg if proteinuria >1 g/24 h, otherwise target BP 130/80 mmHg, using regimen including ACE inhibitor and ARB

Proteinuria >1 g/24 h and GFR >50 ml/min despite maximal ACE inhibitor/ARB and BP control

Consider immunosuppression or enrolment in a RCT (see below)

ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BP, blood pressure; GFR, glomerular filtration rate; RCT, randomized controlled trial.

Specific treatment for IgAN would either restrict the formation of relevant pathogenic IgA molecules or prevent their deposition in the mesangium. However, so little is understood about the pathogenesis of the disease that the prospect for such treatment is still remote.

Haematuria

There is no specific treatment for the great majority of patients with IgAN who have isolated haematuria with or without low-grade proteinuria (<1 g/24 h). Non-visible haematuria should merely be observed. Recurrent visible haematuria settles without treatment; there is no role for prophylactic antibiotics as most precipitating infections are viral. Tonsillectomy will reduce the number of episodes of visible haematuria, but there is no evidence that it reduces the risk of progressive renal failure.

Proteinuria

Those with proteinuria above 1 g/24 h as well as haematuria have a worse prognosis. Immunosuppressive therapies have been tried, although the frequent recurrence of IgAN in transplanted kidneys when patients are receiving immunosuppressive therapy argues against their value. Short-term randomized controlled trials of corticosteroids have shown no benefit. A controlled trial of 6 months of treatment with corticosteroids (prednisolone 0.5 mg/kg per day) showed a significant reduction in proteinuria and reduced risk of developing renal impairment at 10 years follow-up. This requires further confirmation, and corticosteroid treatment is not presently recommended except in the rare circumstance where the biopsy suggests coincidental minimal-change nephrotic syndrome which may be fully steroid-responsive.

Other immune-modulating drugs have been tried in IgAN, including cyclophosphamide, mycophenolate mofetil, azathioprine, ciclosporin, and pooled human intravenous immunoglobulin, but there are few properly controlled studies and for none is there consistent evidence of benefit or an acceptable risk–benefit ratio in most patients who have indolent slowly progressive disease.

There are a number of well-designed placebo-controlled, double-blinded, randomized controlled trials examining the efficacy of a variety of novel therapies in IgAN under way or nearing formal reporting (Table 21.8.1.2).

Table 21.8.1.2 Randomized controlled trials examining the efficacy of a variety of novel therapies in IgAN

Trial name

ClinicalTrials.gov identifier

Inclusion proteinuria and GFR (once established on maximal ACE inhibitor/ARB for 90 days)

Treatment to be tested

Primary outcome measure

STOP-IgAN

NCT00554502 (https://clinicaltrials.gov/ct2/show/NCT00554502)

Proteinuria >0.75 g/day and GFR <90 ml/min

  • Traditional immunosuppressives:

  • Corticosteroids, cyclophosphamide, and azathioprine

  • Complete remission defined by proteinuria of <0.2 g/day with stable renal function (loss of GFR <5 ml/min from baseline)

  • GFR loss of 15 ml/min or higher, at the end of 3 years

TESTING

NCT01560052 (https://clinicaltrials.gov/ct2/show/NCT01560052)

Proteinuria >1 g/day, and GFR 20–90 ml/min

Corticosteroids

Composite of:

  1. 1. 50% decrease in GFR

  2. 2. Development of ESRD, and

  3. 3. Death due to kidney disease

NEFIGAN

NCT01738035 (https://clinicaltrials.gov/ct2/show/NCT01738035)

Proteinuria >0.75 g/day, and GFR >45 ml/min

Enteric budesonide

Change in proteinuria at 9 months

BRIGHT-SC

NCT02062684 (https://clinicaltrials.gov/ct2/show/NCT02062684)

Proteinuria 1–6 g/day and GFR >30 ml/min

Blisibimod

Change in proteinuria at 24 weeks

SIGN

NCT02112838 (https://clinicaltrials.gov/ct2/show/NCT02112838)

Proteinuria >0.5 g/day and GFR >30 ml/min

Fostamatinib

Change in proteinuria at 24 weeks

Rituximab in IgA nephropathy

NCT00498368 (https://clinicaltrials.gov/ct2/show/NCT00498368)

Proteinuria >1 g/day and GFR 30–90 ml/min

Rituximab

Change in proteinuria at 12 months

Velcade in IgA nephropathy

NCT01103778 (https://clinicaltrials.gov/ct2/show/NCT01103778)

Proteinuria >1 g/day

Bortezomib

Change in proteinuria at 12 months

ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; ESRD, endstage renal disease; GFR, glomerular filtration rate.

Acute kidney injury

Renal biopsy is mandatory when acute kidney injury develops in IgAN. If this shows mild glomerular disease but tubular occlusion with erythrocytes and accompanying acute tubular necrosis, supportive treatment only is required while recovery is awaited. If there is crescentic IgAN, a regimen such as those used for renal vasculitis and other forms of crescentic glomerulonephritis should be considered unless the histological appearances are thought to be advanced and irreversible, e.g. oral prednisolone 0.5 mg/kg per day (reducing to a maintenance dose of 5–10 mg daily by 3 months) in combination with oral cyclophosphamide 2 to 3 mg/kg per day (replaced by azathioprine 2–3 mg/kg per day after 3 months). Plasma exchange has also been used. There are no randomized controlled trials of these treatments in crescentic IgAN. Although initial response to treatment is excellent, the medium-term outlook is much less good; 50% will be on long-term dialysis after 12 months.

Progressive renal impairment

Slowly progressive renal impairment due to IgAN requires a management approach common to any form of chronic renal failure. Rigorous control of blood pressure is the one established method of delaying progressive renal failure. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers are widely used as first-line therapy for their special role in lessening proteinuria for the same degree of blood pressure control. Fish oil therapy (which provides a supplement of ω‎-3 fatty acids) has effects likely to impact favourably on mechanisms of progressive renal damage and has been used in randomized controlled trials in IgAN, but there is no reason to expect its effects are specific for IgAN rather than other progressive diseases. One randomized controlled trial has shown a substantial reduction in the risk of progression to endstage renal failure, but other studies have not shown comparable benefit and at present the use of fish oil is not recommended until confirmatory studies are available.

HSP nephritis

There is very little information to guide treatment of HSP nephritis. There are no published randomized controlled trials and most therapeutic studies in IgAN exclude those with HSP, hence it is unclear whether their conclusions can be extrapolated to HSP.

Transient early nephritis requires no specific treatment. There is no evidence that corticosteroids or other immunosuppressive regimens alter the natural history of nephrotic syndrome or slowly progressive glomerular damage in HSP. Crescentic HSP nephritis is more common than crescentic IgAN. Regimens used for renal vasculitis have also been applied to crescentic HSP nephritis with apparent benefit, although there are no controlled trials.

Prognosis

Thirty per cent of children will have a spontaneous clinical remission with complete disappearance of haematuria within 10 years of diagnosis. But IgAN, despite the apparently benign presentation in many cases, is an important cause of endstage renal failure, with up to 25% of patients reaching this within 20 years of diagnosis. Where a lower risk of endstage renal failure is reported the series will contain larger numbers of patients with mild disease, such as those with isolated non-visible haematuria.

Perhaps unexpectedly a history of episodic visible haematuria is a favourable prognostic feature. The prognosis for patients who present with microscopic haematuria and minimal proteinuria (<1 g/24 h) is very good, but not perfect; even in this group up to 5% of patients will develop worsening proteinuria and hypertension during follow-up and are at eventual risk of endstage renal failure. Consequently the long-term follow-up of any patient with biopsy-proven IgAN is mandatory. The risk of progressive renal failure can be predicted by clinical and pathological features at diagnosis (Table 21.8.1.3), but these predictive features are not specific to IgAN as they would identify the risk of progression in any glomerular disease.

Table 21.8.1.3 Prognostic markers at presentation in IgAN

Poor prognosisa

Good prognosis

No influence on prognosis

Clinical

Increasing age

Recurrent visible haematuria

Gender

Duration of preceding symptoms

Ethnicity

Severity of proteinuria

Serum IgA level

Hypertension

Renal impairment

Increased body mass index

Serum uric acid

Histopathological

Mesangial hypercellularity (M1)

M0

Intensity of IgA deposits

Endocapillary hypercellularity (E1)

E0

Codeposition of IgG, IgM, and C3

Segmental glomerulosclerosis (S1)

S0

Tubulointerstitial scarring (T2 > T1 > T0)

T0 > T1 > T2

Capillary loop IgA deposits (some reports only)

a M, E, S, T form the Oxford Classification of IgA nephropathy.

Both IgAN and HSP nephritis recur after renal transplantation. Mesangial IgA deposits appear within a few months in 60% of patients with IgAN. Initially this is benign, accompanied by little mesangial injury, but in the long term recurrent disease will contribute to progressive graft loss in a number of patients. However, overall transplant success and graft longevity do not differ in IgAN or HSP from other primary renal diseases. The changes in immunosuppressive regimens used to prevent rejection over the last two decades have not altered the recurrence rate or its prognosis.

Further reading

Clinical

D’Amico G (2004). Natural history of idiopathic IgA nephropathy and factors predictive of disease outcome. Semin Nephrol, 24, 179–96.Find this resource:

Davin JC, Ten Berge IJ, Weening JJ (2001). What is the difference between IgA nephropathy and Henoch–Schönlein purpura nephritis? Kidney Int, 59, 823–34.Find this resource:

Floege J (2004). Recurrent IgA nephropathy after renal transplantation. Semin Nephrol, 24, 287–91.Find this resource:

Pouria S, Feehally J (1999). Glomerular IgA deposition in liver disease. Nephrol Dial Transplant, 14, 2279–82.Find this resource:

Wyatt RJ, Julian BA (2013). IgA nephropathy. N Engl J Med, 368, 2402–14.Find this resource:

Pathogenesis and genetics

Barratt J, Feehally J (2011). Primary IgA nephropathy: new insights into pathogenesis. Semin Nephrol, 31, 349–60.Find this resource:

Coppo R, Amore A (2004). Aberrant glycosylation in IgA nephropathy (IgAN). Kidney Int, 65, 1544–7.Find this resource:

Gharavi AG, et al. (2000). IgA nephropathy, the most common cause of glomerulonephritis, is linked to 6q22-23. Nat Genet, 26, 354–7.Find this resource:

Gharavi AG, et al. (2008). Aberrant IgA1 glycosylation is inherited in familial and sporadic IgA nephropathy. J Am Soc Nephrol, 19, 1008–14.Find this resource:

Hastings MC, et al. (2010). Galactose-deficient IgA1 in african americans with IgA nephropathy: serum levels and heritability. Clin J Am Soc Nephrol, 5, 2069–74.Find this resource:

Hsu SI, et al. (2000). Evidence for genetic factors in the development and progression of IgA nephropathy. Kidney Int, 57, 1818–35.Find this resource:

Lin X, et al. (2009). Aberrant galactosylation of IgA1 is involved in the genetic susceptibility of Chinese patients with IgA nephropathy. Nephrol Dial Transplant, 24, 3372–55.Find this resource:

Suzuki H, et al. (2009). Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. J Clin Invest, 119, 1668–77.Find this resource:

Treatment

Appel GB, Waldman M (2006). The IgA nephropathy treatment dilemma. Kidney Int, 69, 1939–44.Find this resource:

Barratt J, Feehally J (2006). Treatment of IgA nephropathy. Kidney Int, 69, 1934–8.Find this resource:

Cattran DC, et al.; Working Group of the International IgA Nephropathy Network and the Renal Pathology Society (2009). The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Int, 76, 534–45.Find this resource:

Donadio JV Jr, et al. (1999). The long-term outcome of patients with IgA nephropathy treated with fish oil in a controlled trial. Mayo Nephrology Collaborative Group. J Am Soc Nephrol, 10, 1772–7.Find this resource:

Floege J (2006). Is mycophenolate mofetil an effective treatment for persistent proteinuria in patients with IgA nephropathy? Nat Clin Pract Nephrol, 2, 16–17.Find this resource:

Gharavi AG, et al. (2008). Aberrant IgA1 glycosylation is inherited in familial and sporadic IgA nephropathy. J Am Soc Nephrol, 19, 1008–14.Find this resource:

Hastings MC, et al. (2010). Galactose-deficient IgA1 in African Americans with IgA nephropathy: serum levels and heritability. Clin J Am Soc Nephrol, 5, 2069–74.Find this resource:

Lin X, et al. (2009). Aberrant galactosylation of IgA1 is involved in the genetic susceptibility of Chinese patients with IgA nephropathy. Nephrol Dial Transplant, 24, 3372–5.Find this resource:

Pozzi C, et al. (2004). Corticosteroid effectiveness in IgA nephropathy: long-term results of a randomized, controlled trial. J Am Soc Nephrol, 15, 157–63.Find this resource:

Samuels JA, et al. (2004). Immunosuppressive treatments for immunoglobulin A nephropathy: a meta-analysis of randomized controlled trials. Nephrology, 9, 177–85.Find this resource:

Suzuki H, et al. (2009). Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. J Clin Invest, 119, 1668–77.Find this resource:

Tumlin JA, Hennigar RA (2004). Clinical presentation, natural history, and treatment of crescentic proliferative IgA nephropathy. Semin Nephrol, 24, 256–68.Find this resource:

Yeo SC, Liew A, Barratt J (2015). Emerging therapies in immunoglobulin A nephropathy. Nephrology (Carlton), 20, 788–800.Find this resource: