IgA Nephropathy (Berger Disease)

• Aberrant IgA1 glycosylation and production: The primary defect involves dysregulation of the O-linked glycosylation of the IgA1 hinge region in Peyer's patches and bone marrow, resulting in increased production of Gd-IgA1 (IgA1 with reduced galactose content). This hypogalactosylated form is more prone to polymerization and has reduced clearance from circulation. Genetic polymorphisms (particularly in C1GALT1C1, COSMC, and TNFSF13B genes) predispose to this abnormality, explaining the familial clustering observed in 5-10% of cases. Mucosal infections (particularly respiratory infections with IgA-inducing antigens like Streptococcus pneumoniae) and potentially aberrant epithelial cell signaling trigger increased Gd-IgA1 synthesis.

• Immune complex formation and glomerular deposition: Circulating Gd-IgA1-containing immune complexes form when anti-IgA antibodies (IgG or IgA class) recognize the abnormal IgA1, creating large pathogenic complexes. These complexes deposit preferentially in the glomerular mesangium due to the mesangium's specialized receptors (transferrin receptor-1 and other pathogen recognition receptors) and its highly permeable architecture that allows direct exposure to circulating immune complexes. The mesangial location explains why IgAN rarely causes subendothelial or subepithelial deposits, distinguishing it pathologically from other IgA-mediated diseases. In situ immune complex formation also occurs when anti-IgA antibodies bind to trapped IgA1 directly within the glomerulus.

• Mesangial proliferation and inflammatory amplification: Deposition of IgA1-containing immune complexes activates the classical complement pathway (particularly via C1q and mannose-binding lectin pathways) and directly engages mesangial cell receptors (CD89 for the Fc receptor for IgA). Complement activation generates C3a and C5a anaphylatoxins, recruiting neutrophils and monocytes; direct receptor engagement activates intracellular signaling cascades involving mitogen-activated protein kinases (MAPK) and nuclear factor-κB (NF-κB). This leads to mesangial cell proliferation and production of pro-inflammatory cytokines (TNF-α, IL-6, IL-8) and pro-fibrotic mediators (transforming growth factor-β, platelet-derived growth factor). Persistent mesangial inflammation drives glomerular injury visible on light microscopy as mesangial proliferation, and progressive fibrosis leads to glomerulosclerosis.

• Progressive glomerular damage and proteinuria: The inflammatory milieu damages the glomerular filtration barrier through multiple mechanisms: oxidative stress from activated inflammatory cells, production of reactive oxygen species, and endothelial cell injury. This results in loss of charge selectivity and size selectivity of the glomerular basement membrane (GBM), allowing proteinuria that ranges from microscopic hematuria to nephrotic-range proteinuria. Proteinuria itself becomes pathogenic (proteinuria-induced tubular toxicity) and drives further tubular atrophy and interstitial fibrosis, creating a vicious cycle of progressive renal disease. The degree of proteinuria at presentation and its reduction with treatment are the strongest predictors of renal outcomes.

• Crescentic transformation and rapidly progressive disease: In approximately 5-10% of cases, IgAN progresses to crescentic IgAN, where necrotizing vasculitis of afferent arterioles occurs, often with superimposed pauci-immune necrotizing glomerulonephritis (ANCA-negative). This transition involves rupture of the GBM and infiltration of fibrin and cellular crescents (fibrin deposition and proliferation of parietal epithelial cells, fibroblasts, and macrophages), rapidly destroying remaining glomerular function. This transformation dramatically accelerates renal disease progression and is a medical emergency.

• Primary IgAN (>90% of cases): Results from dysregulation of the mucosal immune system without an identifiable systemic disease. The pathogenesis is multifactorial, involving genetic susceptibility (identified risk loci include IGAN1-IGAN13, with significant loci at 6q31.3, 12q24, 22q13, and others) and environmental triggers. Genetic polymorphisms affect complement components, cytokine production, and immunoglobulin handling. Environmental triggers include mucosal infections (particularly nasopharyngeal and respiratory tract infections), dietary antigens, and intestinal dysbiosis. Twin studies and familial clustering support genetic contribution, though environmental factors determine clinical expression.

• Secondary IgAN (rare, <5%): Occurs in association with systemic diseases including IgA vasculitis (formerly Henoch-Schönlein purpura) where IgAN-like deposits occur but with systemic small-vessel vasculitis, lupus nephritis (occasionally), celiac disease, inflammatory bowel disease, HIV infection, and chronic liver disease. Secondary IgAN associated with IgA vasculitis occurs in >50% of patients with this systemic disease and is distinguished by the presence of systemic manifestations (palpable purpura, abdominal pain, arthralgia). Hepatitis B and C may trigger secondary IgAN, though this is rare in developed countries.

• Modifying risk factors: Once IgAN develops, disease severity and progression are modified by several factors. Proteinuria is the strongest independent predictor—patients with >1 g/day at diagnosis have significantly worse outcomes. Hypertension accelerates glomerular injury through mechanical injury and promotes proteinuria. Male gender predicts worse outcomes (male-to-female ratio of disease severity approximately 2:1), suggesting sex hormone influences. Age at presentation <30 years typically confers better prognosis, while presentation >40 years suggests more aggressive disease. Smoking is an independent risk factor for progression to ESRD. Genetic variants (particularly in complement-related genes) and ethnicity (Asians may have more aggressive disease) influence outcomes.

• Asymptomatic hematuria and proteinuria (30-40% at discovery): Many patients are identified incidentally on routine screening or evaluation for other reasons, presenting with isolated microscopic hematuria or low-grade proteinuria without systemic symptoms. This group has the best long-term prognosis, with 10-year renal survival >90% if proteinuria remains <0.5 g/day. The absence of symptoms does not indicate benign disease, however, as progressive renal injury can occur silently over years.

• Episodic gross hematuria (40-50% present this way): The classic presentation involves synpharyngitic gross hematuria, where macroscopic hematuria occurs 1-2 days after an upper respiratory tract infection (often concurrent with URI symptoms, distinguishing it from post-infectious GN where hematuria appears 1-2 weeks after URI resolution). Episodes typically last several days to weeks and may recur with subsequent infections. The hematuria is accompanied by dysuria, flank pain, or gross hematuria visible to the patient. This presentation reflects IgA1 overproduction triggered by mucosal infection with subsequent immune complex precipitation. Each episode is associated with transient proteinuria and may cause acute kidney injury if severe, though creatinine typically normalizes between episodes in the absence of underlying progressive disease.

• Progressive renal insufficiency (20-30% present this way): Some patients present with slowly rising creatinine, hypertension, and progressive proteinuria, often recognized when an acute intercurrent illness prompts laboratory evaluation. This group may have had silent disease for years before clinical recognition. The degree of proteinuria at presentation (<0.5, 0.5-1, 1-3, >3 g/day) strongly predicts 5-year renal outcomes and should be quantified at diagnosis.

• Rapidly progressive glomerulonephritis (5-10% present this way): Patients with crescentic transformation present with acute rise in creatinine, often with constitutional symptoms (malaise, fatigue), gross hematuria, and hypertension. This represents a medical emergency and may present with symptoms of acute kidney injury including oliguria and fluid overload. Elevated creatinine, active urinary casts, and systemic inflammation (elevated ESR, normal complement levels distinguishing from lupus or post-infectious GN) are characteristic.

• Nephrotic syndrome (10-15%): While less common as initial presentation than in other glomerulonephritides, IgAN can present with nephrotic-range proteinuria (>3.5 g/day) with edema, hypoalbuminemia, hyperlipidemia, and lipiduria. This predicts aggressive disease course and higher likelihood of progression to ESRD.

• Physical examination findings: Most patients have no specific physical findings. Hypertension is present in 20-50% at diagnosis and increases with disease progression. Peripheral edema may be present if significant proteinuria and hypoalbuminemia have developed. Absence of systemic features helps distinguish primary IgAN from IgA vasculitis (which would show palpable purpura on lower extremities and buttocks, arthralgia, and abdominal pain). Absence of rash and normal complement levels further exclude post-infectious GN.

• Kidney biopsy with immunofluorescence (definitive diagnostic test): Light microscopy shows mesangial proliferation (proliferation of mesangial cells and matrix) as the hallmark finding, ranging from mild to focal global proliferation. Associated findings include segmental sclerosis, crescents (cellular, fibrocellular, or fibrous), and varying degrees of interstitial fibrosis and tubular atrophy reflecting chronicity. Immunofluorescence microscopy is absolutely required for diagnosis and reveals predominant IgA staining in the mesangium, which is the defining diagnostic criterion. IgA staining intensity is typically 2-3+ on a 0-3+ scale and exceeds IgG or IgM staining (in contrast to other IgA-mediated diseases where other immunoglobulins may equal IgA intensity). C3 complement staining is present in 90% of cases and is often more intense than IgA staining. Electron microscopy shows electron-dense deposits in the mesangium, often with subendothelial involvement in proliferative disease. The combination of IgA predominance on immunofluorescence + mesangial proliferation on light microscopy is required for diagnosis.

• Urinalysis and urine sediment: Hematuria (dysmorphic RBCs and RBC casts indicating glomerular origin) is found in nearly all patients at some point; RBC casts are particularly characteristic of IgAN and distinguish it from non-glomerular hematuria. Proteinuria quantification by 24-hour urine protein or spot urine protein-to-creatinine ratio (UPCR) is essential for prognosis and guides treatment intensity. Proteinuria <0.5 g/day predicts stable renal function, while >1 g/day predicts progression in most patients without intervention.

• Serum creatinine and eGFR: At diagnosis, baseline renal function is measured; most patients have normal to near-normal creatinine at initial diagnosis, though eGFR varies widely. Serum creatinine alone is insensitive early in disease and may be normal despite significant glomerular injury. Subsequent serial creatinine measurements document progressive renal dysfunction. Rapid increase in creatinine (doubling within 3-6 months) indicates crescentic disease or rapid progression requiring urgent intervention.

• Serum IgA level measurement: Elevated serum IgA1 (particularly Gd-IgA1-specific assays) supports the diagnosis but is not required and has limited clinical utility for diagnosis or prognosis. The test is not routinely performed clinically. Total serum IgA is elevated in 50-60% of IgAN patients but has limited sensitivity and specificity for diagnosis. Serum IgA does not predict disease outcomes reliably.

• Complement studies: Serum C3 and C4 levels are normal in primary IgAN, which is an important diagnostic feature distinguishing it from post-infectious GN (low C3), lupus (low C3 and C4), or IgA vasculitis with systemic features. Normal complement levels with hematuria, proteinuria, and renal biopsy showing IgA-predominant staining support primary IgAN diagnosis.

• ANCA and anti-GBM serology: ANCA is negative in typical IgAN (present in <5% of cases); positive ANCA would suggest overlap with pauci-immune vasculitis. Anti-GBM antibodies are negative, excluding Goodpasture syndrome. These tests help exclude alternative diagnoses.

• Oxford Classification and scoring systems for prognosis: The Oxford MEST-C score is validated for risk stratification: M (mesangial hypercellularity: 0-1), E (endocapillary hypercellularity: 0-1), S (segmental sclerosis: 0-1), T (tubular atrophy/interstitial fibrosis: 0-2), C (crescent score: 0-2). Each component is scored, and higher scores predict worse renal outcomes independent of proteinuria and creatinine at diagnosis. This provides pathology-based prognostic stratification.

• Diagnostic approach summary: Diagnosis is suspected with presentation of hematuria ± proteinuria and confirmed by renal biopsy showing IgA-predominant mesangial immune complex deposition. Clinical context supports the diagnosis if presentation includes synpharyngitic gross hematuria (hematuria synchronous with URI) or asymptomatic hematuria detected on screening, combined with normal complement levels and negative ANCA/anti-GBM serology.

• Supportive care and blood pressure control (foundational for all patients): Angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) are first-line agents for all IgAN patients with any degree of proteinuria, given their proven ability to reduce proteinuria and slow GFR decline. Lisinopril or enalapril (typical dosing 10-20 mg daily) or losartan or valsartan (typical dosing 80-160 mg daily) are used to achieve target blood pressure <120 mmHg systolic (per recent guidelines, previously <130/80 recommended). The antiproteinuric effect of ACEi/ARB is independent of blood pressure reduction and reflects decreased intraglomerular hypertension. These agents reduce proteinuria by 20-50% on average. Dual therapy with both ACEi and ARB is generally avoided due to hyperkalemia risk. For patients intolerant to ACEi/ARB (cough, hyperkalemia), calcium channel blockers (amlodipine or diltiazem) provide blood pressure control though with less antiproteinuric benefit. Loop diuretics are used if fluid overload develops. NSAIDs are generally avoided due to worsening renal function, hyperkalemia, and lack of proven benefit.

• Immunosuppression for high-risk disease: Patients with

Disease-related complications

• Progressive CKD and ESRD: sustained proteinuria drives tubulointerstitial protein overload, tubular atrophy, and nephron dropout. Signaled by a falling eGFR slope with persistent proteinuria above roughly 1 g/day; the Oxford T score (tubular atrophy/interstitial fibrosis) already present on biopsy predicts this trajectory. KDIGO's 2021 glomerular diseases guideline frames all therapy around this endpoint.
• Crescentic (rapidly progressive) IgAN: GBM rupture with parietal epithelial cell proliferation. Signaled by creatinine doubling over weeks, oliguria, and an active sediment with RBC casts. This is an emergency — urgent repeat biopsy and immunosuppression, since fibrous crescents are irreversible.
• AKI with macroscopic hematuria episodes: heme pigment tubular toxicity plus intratubular RBC cast obstruction during a synpharyngitic episode. Signaled by a creatinine rise that tracks the gross hematuria and usually recovers; failure to recover suggests underlying crescents.
• Malignant/accelerated hypertension: intraglomerular and systemic RAAS activation. Signaled by severe hypertension with retinal hemorrhages, papilledema, or a thrombotic microangiopathy picture — an emergency requiring controlled IV antihypertensive reduction.
• Nephrotic-range proteinuria complications: urinary loss of antithrombin III and other regulators produces a hypercoagulable state. Signaled by flank pain with worsening hematuria (renal vein thrombosis) or pleuritic chest pain and hypoxemia (pulmonary embolism) — an emergency. Hyperlipidemia and infection risk from immunoglobulin loss also accrue.
• Recurrence in the renal allograft: the systemic Gd-IgA1 defect persists after transplantation, so mesangial IgA redeposits in a substantial minority of grafts. Signaled by recurrent hematuria/proteinuria post-transplant.

Treatment-related complications

• RAAS blockade: efferent arteriolar dilation causes an expected modest creatinine rise; a steep rise suggests volume depletion or bilateral renal artery stenosis. Hyperkalemia is the other signal. ACE inhibitors and ARBs are teratogenic and contraindicated in pregnancy.
• Systemic corticosteroids: the TESTING trial demonstrated excess serious infection, including fatal infection, with full-dose regimens — the reason KDIGO restricts steroids to high-risk patients with preserved eGFR. Consider Pneumocystis prophylaxis. Hyperglycemia, osteoporosis, and avascular necrosis follow.
• Cyclophosphamide (crescentic disease): marrow suppression, hemorrhagic cystitis, infertility, later bladder malignancy.

• **"*Synpharyngitic* gross hematuria"**: cola-colored urine within 1–2 days of a URI in a young adult is the single most tested stem. Contrast with post-streptococcal GN, where hematuria follows the infection by 1–3 weeks (or 3–6 weeks after skin infection) — the latency, not the urine, is the discriminator.
• Normal C3 and C4 is the association examiners love: complement is consumed in post-infectious GN (low C3), lupus nephritis (low C3 and C4), and membranoproliferative GN, but is normal in IgA nephropathy despite local mesangial complement activation. Normal complement + hematuria after a URI = IgAN until biopsy says otherwise.
• Best next step depends on the stem: quantify proteinuria (spot UPCR) and check creatinine and blood pressure first; kidney biopsy is the definitive step and is required whenever proteinuria is significant or renal function is declining. Isolated microscopic hematuria with normal eGFR and minimal proteinuria is often observed rather than biopsied.
• Immunofluorescence is the answer choice: IgA-dominant mesangial deposits, usually with C3, and mesangial electron-dense deposits on EM. Light microscopy alone (mesangial hypercellularity) is nonspecific.
• IgA vasculitis (Henoch–Schönlein purpura) is the systemic twin: identical renal histology, but with palpable purpura on buttocks and lower extremities, arthralgias, and colicky abdominal pain (intussusception risk in children). Same disease, different compartment.
• Distractors to avoid: thin basement membrane nephropathy gives persistent painless microhematuria with a family history and benign course; Alport syndrome adds sensorineural hearing loss, lenticonus, and basket-weave GBM lamellation. Neither shows mesangial IgA.
• Do not treat the pharyngitis: antibiotics do not alter IgAN, and tonsillectomy is not recommended in North American practice by KDIGO despite Japanese data.
• RAAS blockade is foundational, and SGLT2 inhibitors are now standard add-on therapy for proteinuric CKD including IgAN; steroids are reserved for high-risk patients per KDIGO because of infection risk.
• In a patient over 40 with gross hematuria, glomerular disease does not excuse skipping urologic malignancy evaluation (AUA hematuria guideline).