Immunoglobulin A Nephropathy and Immunoglobulin A Vasculitis
Immunoglobulin A Nephropathy and Immunoglobulin A Vasculitis
Manish K. Saha
IMMUNOGLOBULIN A NEPHROPATHY IN ADULTS
Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis (GN) in the world and is a leading cause of end-stage kidney disease (ESKD). The annual incidence worldwide is at least 2.5 cases/100,000 per year in adults, with a significant proportion being undiagnosed because of the subclinical nature of early-phase disease.1 The variability in prevalence estimates is multifactorial, including biopsy practice differences, environmental risk factors, and genetics.2,3,4,5 Studies have shown that males are more frequently affected than are females in the Western world compared to Asia, where the male-to-female ratio is about 1:1.6,7 IgAN can occur at any age but is most common in the second and third decades of life. Disease heterogeneity is significant, but about 15% to 25% of patients progress to ESKD within 10 years of diagnosis.8
The IgA1 molecule is made up of two identical heavy chains and light chains. Circulating immunoglobulin (Ig) A is mainly monomeric—90% IgA1 and 10% IgA2. IgA deposited in the mesangium is exclusively of the IgA1 subclass. Secretory IgA that is present in tears, colostrum, and mucosal surfaces is dimeric/polymeric. The heavy chain of IgA1 but not IgA2 contains a hinge region rich in proline/serine/threonine residues between the CH1 and CH2 domains. These amino acids are decorated with 3 to 5 O-linked oligosaccharides, namely, galactose, sialic acid, and N-acetylgalactosamine (GalNAc).9
The key autoantigen in IgAN is galactose-deficient IgA1(GdA1), that is, the amino acid residues in the hinge region of the IgA1 molecule that normally terminate with galactose are instead composed of GalNAc or sialylated GalNAc. Circulatory GdA1, an inheritable trait of a dominant pattern, is increased when compared to healthy controls. IgG or IgA1 glycan-specific autoantibodies generated against GdA1 may result in immune complex formation in circulation or in situ in the mesangium. Molecular mimicry has been speculated to play a role in the formation of glycan-specific antibodies based on clinical observations of synpharyngitic hematuria and the fact that certain viruses and bacteria express GalNAc moieties (Visual Abstract 11.1).10,11
Four hits have been postulated as necessary to the pathogenesis of IgAN: (i) genetically determined increased levels of circulatory GdA1; (ii) generation of autoantibodies against GdA1; (iii) formation of immune complexes IgG-GdA1 that deposit in the glomerular mesangium; and (iv) downstream immune activation by the immune complexes resulting in kidney injury.10 Lectin-based and lectin-independent assays have been developed to measure both circulating and tissue-bound GdA1, but these assays are not currently in use clinically for diagnostic or disease monitoring purposes.
IgAN is usually a sporadic form of disease, whereas a small percentage (2%-17%) of patients may have familial aggregation, suggesting that genetic factors may contribute to disease pathogenesis.12 Pedigree- and population-based studies have been performed. In a large Lebanese kindred, multigenerational inheritance suggested an autosomal dominant inheritance, but linkage analyses have not yielded genetic localization.13 Recent Genome-Wide Association Studies (GWAS) have found significant loci associated with the complement pathway (ITGAM, ITGAX, and complement factor 3 and related genes), adaptive immune system, innate mucosal immunity, and mucosal IgA production. CFH, CFHR3, and CFHR 1-5 encode factor H-related peptides involved in the alternate complement pathway, whereas ITGAM (Integrin Subunit Alpha M) encodes for inactivated C3b receptor.14 With future functional, clinical, and other association studies, we hope to have an improved understanding of IgAN immunopathogenesis14,15,16 (Visual Abstract 11.2).
IgA nephropathy is defined on the basis of immunohistology—IgA-dominant or codominant immune complex deposits in the glomeruli. The histologic changes evident on light microscopy vary from minimal mesangial expansion to crescentic GN (Figure 11.1).17 Notably, lupus nephritis, IgA membranous nephropathy, and IgA-dominant postinfectious GN may have immunohistologic changes similar to that of IgAN. Moreover, the pathologic features on kidney biopsy specimens from patients with primary IgAN are not distinguishable from secondary IgAN or immunoglobulin A vasculitis (IgAV).18 Among other immunoreactants, IgG is present in about 15% to 80% of cases, C3 deposits in more than 90% cases, and variable rates of IgM deposits.19 IgA deposits are mainly located in the mesangium, but capillary wall deposits are present in one-third of cases and are associated with increased mesangial and endocapillary hypercellularity.19 Both alternate and lectin complement pathways are involved in disease activity and progression. The classical pathway is not involved and C1q deposits are rare. IgA1 can activate both the alternate and lectin pathways in vitro, and components of both pathways have been detected in glomerular immune deposits; namely, factor H and properdin from the alternate pathway, and mannan-binding lectin and mannan-binding lectin-associated serine proteases 1 and 2 from the lectin pathway.20
The Oxford Classification
In a clinicopathologic study of 206 adults and 59 pediatric patients from multiple countries, four histologic variables were independently associated with the clinical outcome: mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental sclerosis (S), interstitial fibrosis/tubular atrophy (T), referred to as the MEST score. M, S, and T scores were independent predictors of the rate of loss of kidney function or kidney survival.21 In another study of 237 patients with IgAN, the scores of the patients with endocapillary proliferation who did not receive immunosuppression were independent predictors of loss of kidney function.22 In an updated 2016 classification, crescents were added to the classification: C0, no crescent; C1, 1% to 24% of the glomeruli; and C2, 25% or more of glomeruli. Importantly, the Oxford classification has not been validated in IgAV, and the MEST-C score cannot be used to determine the impact of any specific treatment23 (Visual Abstract 11.3).
FIGURE 11.1: A, Photomicrographs of a kidney biopsy specimen from a patient with immunoglobulin A nephropathy showing segmental fibrinoid necrosis (small arrow, Masson trichrome stain). B, This photomicrograph shows focal mesangial hypercellularity and increased mesangial matrix (smaller arrow) along with segmental cellular crescent (large arrow, Masson trichrome stain). C, Immunofluorescence image of a glomerulus shows prominent immunoglobulin A deposits in the mesangium and focally in the capillary walls. D, Electron photomicrograph demonstrates electron-dense mesangial deposits (small arrow).
Painless microscopic hematuria is the most common presenting sign of IgAN. Proteinuria is variable but is usually subnephrotic. Infection-related gross hematuria is present in three-fourths of children and young adults.7 Loin pain is uncommon but has been reported.8 Unlike in IgAV, extrarenal manifestations are not seen. Older patients may present with acute kidney injury (AKI), proteinuria, and hypertension.7 Nephrotic syndrome (NS) is an unusual presentation. Extensive diffuse foot process effacement (median of 90%) is the only single pathologic finding that correlates with clinical expression of NS.24,25 Crescentic IgAN (defined by the presence of crescents in >50% of glomeruli) is a rare presentation of rapidly progressive GN.26 Patients may present with AKI that can result from (i) presence of crescents; (ii) acute tubular necrosis with tubular red blood cell cast; (iii) acute tubular necrosis without cast; and (iv) interstitial nephritis.27
Kidney biopsy is the gold standard for the diagnosis of IgAN. Various serum and urine biomarkers have been studied (GdA1, IgG-GdA1, micro-RNA biomarker, let-7ba, and mir-148b), but currently there are no validated biomarkers that can be clinically used for diagnosis or prognosis.28,29,30 Biopsy practices vary among nephrologists around the globe, but common indications include proteinuria greater than 0.5 g/d and impaired kidney function; also, a kidney biopsy may be performed in a patient with microscopic hematuria if alternative diagnoses are suspected, such as Alport syndrome.
Secondary Immunoglobulin A Nephropathy
IgAN has been diagnosed in patients with various disorders, commonly liver diseases, inflammatory bowel diseases (IBDs), autoimmune diseases (eg, ankylosing spondylitis, rheumatoid arthritis, psoriasis), and infections (eg, hepatitis B, hepatitis C, HIV). Although IgAN is differentiated into primary and secondary forms, there are no specific clinical or distinguishing histologic characteristics. Whether the association of IgAN and associated comorbidities is coincidental or has a common immunopathogenesis remains to be defined. Liver disease is probably the most common secondary cause. The current hypothesis is that alterations in the size of endothelial fenestration, loss of hepatocytes, and portal hypertension may result in decreased clearance of IgA-containing immune complexes, thus facilitating its deposition in the mesangium.31,32,33
IgAN has been frequently reported in patients with IBD. In a retrospective review of 83 biopsies from patients with IBD, IgAN was the most frequent biopsy diagnosis (24%).34 A causal relationship has been speculated on the basis of the anecdotal report of biopsy-proven clearance of mesangial IgA deposits following treatment of IBD.34,35
A recently recognized entity, IgA-dominant infection-associated GN, has been described in adults with diabetes. Patients usually present with proteinuria, hematuria, and kidney injury a few weeks after skin or deep-seated Staphylococcus infection.36,37 There are no characteristic histologic features differentiating it from primary IgAN, but a stronger C3 staining and subepithelial humps on electron microscopy can be evident in some cases. Antibiotics and supportive therapy are the mainstays of treatment. The use of immunosuppression is generally not recommended.31
Based on a multiethnic international cohort, two models (with and without race/ethnicity as a factor) have been developed to estimate the risk of disease progression in adult patients with primary IgAN for up to 5 years after kidney biopsy. Demographics and clinical and histologic data (except crescents) were incorporated to study the primary outcome of either ESKD or permanent reduction in estimated glomerular filtration rate (eGFR) to below 50% of the value at biopsy. The tool is available at https://qxcalc.app.link/igarisk. Although the model provides risk stratification and is valuable for clinical trial design, it is not meant to predict the likelihood or extent of response to immunosuppression on disease progression.38
The three primary modalities of treatment for primary IgAN are lifestyle changes, renin-angiotensin-aldosterone system inhibition (RAASi), and immunotherapy. Patients with IgAN having features of minimal change disease (MCD) and AKI and those with rapidly progressive GN may require immediate evaluation and treatment. Once IgAN is confirmed on kidney biopsy, secondary causes including infection-related IgAN should be ruled out, because the approach and treatment differ widely. Before starting therapy, risk stratification using degree of proteinuria, MEST-C scoring, and IgAN prediction tool are essential. According to current guidelines, the high risk of progression of the disease is defined as proteinuria greater than 0.75 to 1 g/d despite 90 days or more of supportive therapy29 (Visual Abstract 11.4).
IgA Nephropathy With Normal Kidney Function and Urine Protein:Creatinine Ratio Greater Than 0.5 g/d
In patients with stable kidney function and more than 0.5 g/d of proteinuria, RAASi either with angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) should be considered as the initial treatment. The dose of ACEi/ARB should be titrated to a maximal tolerable dose to achieve a goal of urine protein:creatinine ratio (UPCR) of greater than 0.5 g/d.39 This recommendation is based on the consistent finding that worse proteinuria is associated with worse kidney outcomes. In a landmark study in 2007 by Reich et al, proteinuria was found to be the most important predictor of the glomerular filtration rate decline. The hazard ratio for ESKD was 3.5 for patients with 1 to 2 g/d of proteinuria, and 10 in those with nephrotic-range proteinuria.39,40,41,42
Noncrescentic IgA Nephropathy With Greater Than 1 g/d Proteinuria, Stable Kidney Function After 3 Months or More of Conservative Therapy, and Appropriate Blood Pressure Control
There is significant controversy over the best initial approach to the treatment of IgAN, particularly regarding the efficacy of systemic glucocorticoids. Although early randomized clinical trials (RCTs) showed that the use of glucocorticoids might result in clinical benefit in patients at high risk for disease progression, the STOP-IgAN (supportive vs immunosuppressive therapy for the treatment of progressive IgA nephropathy) and TESTING (therapeutic effects of steroids in IgA nephropathy global) trials have prompted concern over the true utility of steroids in IgAN.
In the STOP-IgAN trial, following initial maximal supportive therapy including RAASi, patients (N = 162) with >0.75 g/d proteinuria and eGFR >60 mL/min/1.73 m2 were randomized to receive pulse and oral glucocorticoids for total of 6 month or continued supportive measures. While those with an eGFR of ≥30 and ≤59 mL/min/1.73 m2 (N = 27) received combined immunosuppression (prednisone + oral cyclophosphamide/azathioprine maintenance). Although there was higher rate of remission of proteinuria in the immunosuppressive group, there was no significant difference in annual loss of eGFR between supportive groups and immunosuppressive group at end of 3 years and during a longer 7-year follow-up. More patients in the immunosuppressive (IS) group experienced adverse effects including weight gain, severe infections, and impaired glucose tolerance43,44 (Visual Abstract 11.5).
The TESTING trial, the largest in IgAN, evaluated the benefits and risks of glucocorticoid therapy on the outcomes of patients deemed at risk of progressive loss of kidney function (with proteinuria ≥1 g/d). The initial trial was interrupted by the safety monitoring board after 262 patients were enrolled because of increased severe adverse events in the treatment group.45 The protocol was subsequently modified with a reduction in the dose of methylprednisolone and the addition of prophylactic trimethoprim-sulfamethoxazole. The primary endpoint was the combination of 40% reduction in eGFR or ESKD. Overall, 503 participants were randomized; including 262 based on the original full-dose protocol, and 241 to the reduced-dose protocol (methylprednisolone 0.4 mg/kg/d [maximum 32 mg/d] for 2 months followed by a reduction by 4 mg/d each month for a total of 6-9 months).46 Over a mean follow up of 4.2 years, treatment with methylprednisolone was associated with a statistically significant reduction in the primary endpoint (HR, 0.53 [95% CI, 0.39-0.72]; P < .001), and a similar reduction in the risk of ESKD. Importantly, the beneficial effect of therapy showed no significant difference between the full dose and the reduced dose. The excess in adverse events was primarily observed among patients treated with the full-dose protocol compared to placebo.
Given the results of the TESTING trial, treatment with reduced dose methylprednisolone should be considered after shared decision-making in patients without crescentic IgAN and persistent proteinuria >1 g/d despite maximum tolerated RAS blockade, with careful monitoring for glucocorticoid-associated adverse events and antibiotic prophylaxis. For patients who are intolerant of or at high risk of glucocorticoid-induced adverse effects, referral to a clinical trial in IgAN should be considered. Before starting treatment, one may consider confirming a spot UPCR with a 24-hour urine study to avoid inaccurate estimation, especially in patients in whom urine creatinine excretion is expected to be above or under 1 g/d (lean body mass, muscle wasting, vegetarian diet, others). In patients with advanced chronic kidney disease (CKD; eGFR <30 mL/min), the risks of glucocorticoid therapy probably outweigh the benefits.39 Patient education about the short- and long-term adverse effects, risks of disease progression, and available clinical data is essential. One may choose either the Pozzi et al or Manno et al glucocorticoid protocols (Table 11.1), but most importantly, the dosage should be adjusted depending on tolerance and adverse effects. Pneumocystis jirovecii pneumonia (PJP) prophylaxis, bone health, and gastrointestinal protection should be strongly considered in appropriate cases. The U.S. Food and Drug Administration recently approved, under the accelerated approval pathway, the delayed-release oral budesonide for IgAN, which has relatively mild adverse effects according to the phase 2b study. The accelerated approval is based on the use of proteinuria reduction as a reasonably likely surrogate end point and requires a postmarketing study to confirm the benefit of the therapeutic agent. We await results from the phase 3 study; however, delayed-release oral budesonide may become a treatment option for patients for whom we would have otherwise considered glucocorticoids.47,48
TABLE 11.1 Glucocorticoid Protocols Used in Various Clinical Trials in Immunoglobulin A Nephropathy
CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate in mL/min/1.73 m2; IS, Immunosupressive therapy; IV, intravenous; UPCR, urine protein:creatinine ratio in g/d.
a Only 13% of subjects were on angiotensin-converting enzyme inhibitor at randomization.
b Before randomization (prednisone + ramipril vs ramipril), angiotensin-converting enzyme inhibitor (ACEi) therapy was withdrawn (only 5% were on ACEi).
c All subjects were in run-in phase and were on renin-angiotensin-aldosterone system inhibition.
d ClinicalTrials: NCT01560052: lower dose compared to origin TESTING trial and patients to received PJP prophylaxis.
e All subjects were in run-in phase with renin-angiotensin-aldosterone system inhibition. Among patients randomized (those with urine protein:creatinine ratio >0.75 g) after run-in phase who received glucocorticoid therapy for 6 months, those with estimated glomerular filtration rate (eGFR) greater than 60; eGFR between 30 and 59, received cyclophosphamide + corticosteroids, followed by azathioprine; total duration 36 months. Kidney parameters are mentioned as mean (± SD).
In patients with IgAN and both clinical and histologic evidence of MCD, treatment guidelines should follow that of primary MCD. Other causes of nephrotic-range proteinuria without NS in patients with IgAN include those with secondary focal segmental glomerulosclerosis, glomerulosclerosis and tubulointerstitial fibrosis39 (Table 11.2).
TABLE 11.2 KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases
All patients with IgAN at diagnosis and follow-up should have the following:
Blood pressure control
Cardiovascular risk minimization
Avoid or use extreme caution with the use of glucocorticoid in patients with IgAN at high risk for disease progression after maximal supportive therapy and concomitant following comorbidities:
<eGFR 30 mL/min/1.73 m2
Latent infections (tuberculosis, viral hepatitis)
BMI >30 kg/m2
Active peptic ulcer disease
Uncontrolled psychiatric illness
Mycophenolate mofetil could be considered a steroid-sparing agent in Chinese patients in whom glucocorticoids are being considered.
Hydroxychloroquine can be considered in Chinese patients at high risk for disease progression after maximal supportive management.
Tonsillectomy is not recommended as part of treatment for Caucasian patients.
Medications Without Proven Benefit
Cyclophosphamide (other than in rapidly progressive kidney disease)
IgAN with nephrotic-range proteinuria and kidney biopsy is consistent with MCD/IgAN overlap: Consider treating patients similar to those with MCD.
BMI, body mass index; CNI, calcineurin inhibitor; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; KDIGO, Kidney Disease: Improving Global Outcomes; MCD, minimal change disease; IgAN, immunoglobulin A nephropathy.
Adapted from KI: Rovin BH, Adler SG, Barratt J, et al. KDIGO 2021 clinical practice guideline for the management of glomerular diseases. Kidney Int. 2021;100(4S):S1-S276. doi:10.1016/j.kint.2021.05.021
IgA Nephropathy With Rapidly Progressive Crescentic Glomerulonephritis
Individuals with crescentic disease should be considered for IS therapy if there is a progressive decline in kidney function. In the setting of stable kidney parameters, patients can be followed closely, with the initiation of immunosuppression if eGFR starts to fall. Although no large prospective RCTs in patients with progressive decline in kidney function have been reported, it is possible that induction treatment may consist of glucocorticoid and monthly intravenous (IV) CYC infusions, followed by maintenance therapy with azathioprine or mycophenolate. The usual starting dose for monthly IV CYC is 0.5 g/m2, adjusted for age and kidney function.