Glomerular Disease Subspecialty · KIMS Secunderabad
IgG4 Nephropathy — When IgG4-Related Disease Attacks the Kidneys
IgG4-related disease (IgG4-RD) is a systemic immune-mediated fibroinflammatory condition characterised by dense infiltration of IgG4-secreting plasma cells into organs, storiform fibrosis, and obliterative phlebitis. It can affect virtually any organ — the pancreas (autoimmune pancreatitis), bile ducts, salivary glands, orbits, aorta, lungs, and kidneys. IgG4-related kidney disease (IgG4-RKD) is the renal manifestation — occurring in approximately 15 to 25% of patients with systemic IgG4-RD.
IgG4-RKD is important to diagnose because: it is highly steroid-responsive (most patients achieve complete or near-complete remission with prednisolone), it causes progressive CKD if untreated (the dense fibrosis permanently destroys tubular function), and it can mimic other conditions — lymphoma, sarcoidosis, Sjögren's syndrome, and other tubulointerstitial nephritides. Kidney biopsy with specific IgG4 immunostaining is the definitive diagnostic test. At KIMS, IgG4 immunostaining is performed in-house on the kidney biopsy specimen alongside the standard LM, IF, and EM panel.
Two patterns of kidney involvement
IgG4-related tubulointerstitial nephritis (IgG4-TIN)
The most common pattern (70–80% of IgG4-RKD). The kidney interstitium is densely infiltrated by IgG4-positive plasma cells, lymphocytes, and eosinophils, with storiform fibrosis — a specific 'cartwheel' pattern of fibrosis that is characteristic of IgG4-RD. The tubular basement membranes may be thickened by immune complex deposits. Clinical presentation: declining eGFR (often subacute — over weeks to months), with mild or absent proteinuria. Hypocomplementaemia (low C3 and C4) is common. CT imaging may show characteristic hypo-attenuating lesions within the kidney parenchyma — multiple bilateral low-density areas corresponding to areas of plasma cell infiltration.
IgG4-related membranous nephropathy (IgG4-MN)
Less common (15–20% of IgG4-RKD). IgG4 immune complexes deposit in the subepithelial space of the glomerular basement membrane — producing a membranous nephropathy pattern on biopsy. Clinically: nephrotic syndrome (heavy proteinuria, oedema, hypoalbuminaemia). The IgG subclass staining on IF distinguishes IgG4-MN (dominant IgG4 staining) from primary membranous nephropathy (dominant IgG4 but also anti-PLA2R positivity) and secondary membranous nephropathy (dominant IgG1/IgG2 with no IgG4 predominance). Anti-PLA2R antibody may be positive — its presence suggests primary membranous nephropathy rather than IgG4-MN.
Systemic features suggesting IgG4-RD
Autoimmune pancreatitis — pancreatic mass or diffuse pancreatic enlargement, often mistaken for pancreatic cancer. The key differentiator: IgG4-related pancreatitis responds dramatically to steroids; pancreatic cancer does not.
Submandibular gland swelling (Mikulicz's disease) — bilateral painless firm swelling of the salivary and lacrimal glands, mimicking Sjögren's syndrome.
Retroperitoneal fibrosis — periaortic fibrosis causing ureteric obstruction and hydronephrosis.
Orbital pseudotumour — proptosis from orbital plasma cell infiltration.
Aortitis — inflammatory thickening of the aortic wall.
Elevated serum IgG4 level — above 135 mg/dL (the upper limit of normal) in approximately 60 to 70% of patients with active IgG4-RD. A normal serum IgG4 does not exclude IgG4-RKD — tissue diagnosis is required.
Diagnosis at KIMS
Serum IgG4 level
Elevated (above 135 mg/dL) in 60 to 70% of active cases. Useful for monitoring response to treatment — falls with steroid therapy. Normal serum IgG4 does not exclude the diagnosis.
Kidney biopsy with IgG4 immunostaining
The definitive test. Light microscopy (LM) shows tubulointerstitial nephritis with plasma cell infiltration and storiform fibrosis. Immunofluorescence (IF) shows the IgG subclass staining — IgG4-positive plasma cells confirmed by specific anti-IgG4 antibody staining. The diagnostic threshold: more than 10 IgG4-positive plasma cells per high-power field in the kidney biopsy, with IgG4/total IgG ratio above 40%. EM confirms the tubular basement membrane immune complex deposits in IgG4-TIN. At KIMS, IgG4 immunostaining is performed in-house alongside the standard biopsy panel.
CT of the abdomen (including pancreas and kidneys)
Characteristic findings: multiple bilateral hypo-attenuating renal cortical lesions (round or wedge-shaped, corresponding to areas of plasma cell infiltration), pancreatic enlargement, retroperitoneal fibrosis, and salivary gland involvement.
Treatment — the steroid response
IgG4-RKD is highly steroid-responsive — the majority of patients achieve significant improvement in eGFR and proteinuria within weeks of starting prednisolone. Standard treatment:
Prednisolone induction
0.6 to 1.0 mg/kg/day (maximum 40 to 60mg/day) for 4 weeks — induction phase. A dramatic improvement in eGFR within 2 to 4 weeks confirms the diagnosis (the 'steroid test').
Gradual taper
Gradual taper over 3 to 6 months — typical CKD and autoimmune steroid tapering schedule.
Maintenance low-dose prednisolone
Maintenance low-dose prednisolone (5 to 10mg/day) for 12 to 36 months — reduces relapse rate (IgG4-RD relapses in 30 to 40% of patients after steroid cessation).
Rituximab
Anti-CD20 B-cell depleting agent for steroid-dependent or steroid-refractory IgG4-RKD. Depletes the B-cell source of IgG4-secreting plasma cells. At KIMS, rituximab is used for relapsing or refractory cases.
The established fibrosis in IgG4-TIN does not reverse with steroids — early treatment before fibrosis is extensive gives the best recovery of eGFR. A patient treated promptly (within weeks of symptom onset) may recover most of their kidney function; one treated after months of untreated progressive CKD will have less recovery because the fibrosis is already established. Time matters.
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Frequently Asked Questions — IgG4 Nephropathy
IgG4 is the rarest of the four IgG antibody subclasses — making up only 3 to 6% of total IgG in healthy individuals. In IgG4-related disease, a pathological immune process drives the overproduction of IgG4 from plasma cells, which infiltrate organs and deposit immune complexes. In the kidney, IgG4-secreting plasma cells accumulate in the interstitium, causing inflammation and the characteristic storiform (cartwheel) fibrosis that defines IgG4-RD histologically. The precise trigger for IgG4-RD is not understood — genetic, environmental, and autoimmune mechanisms have been proposed, but no single unifying cause has been identified.
Both can cause interstitial nephritis and glomerular pathology, but they differ in mechanism, systemic features, and treatment. Lupus nephritis is driven by anti-dsDNA antibodies and complement consumption — it shows low C3 and C4, positive ANA and anti-dsDNA, and affects women predominantly in the reproductive years. IgG4-RKD is driven by IgG4 plasma cell infiltration — it shows elevated serum IgG4, affects middle-aged to elderly men more commonly, and is associated with systemic IgG4-RD features (pancreatitis, salivary gland swelling) rather than systemic lupus features (rash, arthritis, serositis). Both respond to steroids, but lupus requires more complex immunosuppression for severe nephritis. Kidney biopsy with IgG4 immunostaining and lupus serology together distinguish the two.
Yes — in two ways. First, IgG4-related pancreatic disease (autoimmune pancreatitis) can closely mimic pancreatic cancer on CT imaging — a pancreatic mass with biliary obstruction and weight loss. The key distinction: autoimmune pancreatitis shows elevated serum IgG4, responds to steroids, and does not show the vascular invasion or metastases of pancreatic cancer. Unnecessary pancreatic surgery has been performed on IgG4-RD patients misdiagnosed with cancer — a high-stakes diagnostic error. Second, IgG4-related renal lesions on CT can mimic renal cell carcinoma. Kidney biopsy distinguishes IgG4-TIN from RCC definitively.
It can — particularly if treatment is delayed. The storiform fibrosis of IgG4-TIN is irreversible once established — steroids reduce the inflammation and plasma cell infiltration but cannot dissolve the fibrosis that has already replaced functional tubular tissue. Patients treated early (when inflammation predominates and fibrosis is minimal) show the best eGFR recovery. Patients treated late (after extensive fibrosis) show less recovery. Relapse (30 to 40% of cases after steroid cessation) also adds fibrosis with each episode — which is why low-dose maintenance steroids or rituximab is used to prevent relapse.
KIMS Secunderabad — Dr. Aswini Dutt T (glomerular disease subspecialty), kidney biopsy with IgG4 immunostaining in-house (not outsourced), serum IgG4 measurement, CT abdomen for systemic IgG4-RD assessment, prednisolone induction and taper protocol, rituximab for refractory cases, long-term follow-up with eGFR and serum IgG4 monitoring. NABH and NABL accredited. Call 040-4488-5000.