IgA nephropathy: Update on pathogenesis and treatment

Seshma Ramsawak; Scott Cohen; Andrea Linares; Corey Cavanaugh

doi:10.3949/ccjm.92a.24105

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Figure 1
Pathogenesis of immunoglobulin (Ig) A nephropathy: the “4-hits” hypothesis.
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Figure 2
Our approach to immunoglobulin (Ig) A nephropathy.
^aWe monitor patients receiving immunosuppressive therapy with assessment of blood pressure and protein-creatinine ratio, renal function panel, and urinalysis every 3 months.
^bThose with proteinuria > 0.5 g/day.
GFR = glomerular filtration rate; MEST-C = mesangial hypercellularity, endocapillary proliferation, segmental glomerulosclerosis, tubulointerstitial fibrosis, crescents

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TABLE 1

Immunoglobulin (Ig) A nephropathy and its mimics

	IgA nephropathy^1,12	Systemic IgA vasculitis^1,12	IgA-dominant postinfectious glomerulonephritis¹³	Proliferative glomerulonephritis with monoclonal IgA deposits¹⁴
Clinical presentation	Varied, can present with a range of clinical syndromes: microscopic hematuria (more common than macroscopic), acute kidney injury, rapidly progressive glomerulonephritis, macroscopic hematuria with concurrent respiratory or gastrointestinal infection (ie, synpharyngitic hematuria) Involvement limited to kidneys	More common in children Extrarenal involvement (leukocytoclastic vasculitis; rash; joint pain; gastrointestinal, pulmonary, neurologic involvement)	Older adults, hypocomplementemia, acute kidney injury with hematuria and proteinuria	Rare; involvement limited to kidneys
Kidney biopsy	Dominant mesangial IgA staining on immunofluorescence microscopy with variable IgG staining and frequent C3 staining; chunky, irregular mesangial IgA staining on immunofluorescence Polyclonal light chain deposition with lambda more intense than kappa		Endocapillary hypercellularity, often with neutrophils, on light microscopy Dominant IgA staining with dominant or codominant C3 staining and absent or weak IgG staining; chunky, irregular mesangial IgA staining; lambda not dominant light chains on immunofluorescence microscopy Subepithelial hump-shaped immune deposits on electron microscopy	Membranoproliferative pattern on light microscopy Monotypic light chain deposition of IgA kappa more intense than lambda
Pathogenesis	4-hit model		Unclear: likely a host-pathogen interaction with superantigens stimulating host T-cell response	Unclear: rarely associated with malignancies despite monoclonal deposition of IgA
Associations	Primary and secondary^{^a} distinguished by presence of associated systemic disease	Upper respiratory or gastrointestinal infection	Staphylococcus aureus infection, diabetes	Myeloma (rarely)

↵a Common secondary: liver disease, celiac disease, inflammatory bowel disease, viral (human immunodeficiency virus, hepatitis B and C), ankylosing spondylitis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, Sjögren syndrome, tumors (lung, renal, lymphoma).
Based on information from references 1,12–14.

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TABLE 2

Oxford Classification of immunoglobulin A nephropathy: MEST-C score

Histologic feature	Definition^15,16	Prognosis
Mesangial hypercellularity	≥ 4 mesangial cells in any mesangial area of a glomerulus M0: < 50 glomeruli M1: ≥ 50 glomeruli	M1 is predictive of worse outcomes vs M0¹⁵	Mesangial hypercellularity and endocapillary proliferation (hematoxylin and eosin stain, magnification ×400)
Endocapillary proliferation	Increased number of cells in glomerular capillary lumen E0: absent E1: present	E1 is independently associated with worse renal survival in patients who receive no immunosuppression, and does not predict outcomes in studies where patients receive immunosuppression Patients with endocapillary proliferation (E1) are more likely to receive immunosuppression, which is associated with improved outcomes in these patients¹⁶
Segmental glomerulosclerosis	Adhesion or sclerosis that does not involve the entire glomerulus S0: absent S1: present	S1 is predictive of worse outcomes compared with S0¹⁵
Tubulointerstitial fibrosis	Percentage of tubular atrophy and interstitial fibrosis of cortical area T0: absent or ≤ 25% of tubules T1: 26%–50% of tubules T2: > 50% tubules	Presence of tubulointerstitial fibrosis (T1 or T2) is strongest predictor of adverse renal outcomes¹⁶	Crescent formation (periodic acid–Schiff stain, magnification ×400)
Crescents, cellular or fibrocellular	Extracapillary cell proliferation > 2 cell layers and < 50% of matrix C0: absent C1: 1%–24% of glomeruli C2: > 25% of glomeruli	C1 is not predictive if immunosuppression is used C2 is predictive of worse outcomes regardless of immunosuppression¹⁶

Images courtesy of Leal Herlitz, MD, Cleveland Clinic Anatomic Pathology.

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TABLE 3

Recently approved and future treatment options for immunoglobulin A nephropathy

	Drugs	Status
Recent approvals	Endothelin and angiotensin receptor antagonist: sparsentan²⁴ Endothelin receptor antagonist: atrasentan²⁵ Corticosteroid: targeted-release formulation budesonide³⁰ Complement inhibitor: iptacopan^32,38	Full approval Accelerated approval Full approval Accelerated
Future (not approved) treatment options	Complement inhibitors^{33–35,37,39,40}
	Avacopan, ravulizumab, cemdisiran, vemircopan, pegcetacoplan IONIS-Fb-LRx Narsoplimab RO7434656 ARO-C3	Phase 2 and 3 trials in progress Phase 3 trial in progress Phase 3 negative trial Phase 3 trial in progress Phase 1 trial in progress
	B-cell–depleting therapies^41–45
	Atacicept Sibeprenlimab, zigakibart, telitacicept	Phase 3 trial in progress Phase 2 and 3 trials in progress
	Plasma cell inhibitors^46,47
	Felzartamab, mezagitamab, bortezomib	Phase 2 trials in progress