IgA Nephropathy (IgAN)

 Idiopathic and Sporadic IgAN

• Most cases of IgAN are idiopathic, accounting for over 90% of presentations.
• Disease exacerbation often follows mucosal infections, especially of the upper respiratory or gastrointestinal tracts.
• No specific infectious agent has been conclusively identified as causative.
• Abnormal immune processing—specifically defective O-glycosylation of IgA1—leads to the formation of nephritogenic immune complexes that deposit in the glomerular mesangium.

Familial and Genetic Predisposition

• Fewer than 10% of cases are familial.
• Autosomal dominant inheritance has been observed in some kindreds; loci include 6q22-23 and 2q36, the latter containing COL4A3 and COL4A4.
• GWAS studies have identified associations with multiple HLA alleles and non-HLA loci (e.g., TGFBI, CCR6, STAT3, GABBR1, CFB).
• Additional genes implicated include DEFA1A3 and ENAH, both associated with disease susceptibility and severity in children.
• Mutations in C1GALT1 and C1GALT1C1 may impair IgA1 glycosylation and promote mesangial deposition.

Secondary IgA Nephropathy

 Liver Disease

• Chronic liver disease, particularly cirrhosis, is the most frequent cause of secondary IgAN.
• Mechanism involves impaired hepatic clearance of IgA-containing immune complexes by Kupffer cells.
• IgA deposition in glomeruli is a common histological finding in cirrhosis, although often clinically silent.
• Resolution of urinary abnormalities has been observed post-liver transplantation.

Gastrointestinal Disorders

• Coeliac disease:
  • Up to one-third of patients with gluten enteropathy exhibit glomerular IgA deposits.
  • Gluten withdrawal has led to clinical improvement in some patients.
  • IgA1 deposition may be mediated by transglutaminase 2 binding to transferrin receptor-1.
• Inflammatory Bowel Disease (IBD):
  • Crohn's disease and ulcerative colitis have been linked to increased mortality in IgAN.
  • Mechanisms include mucosal immune dysregulation and aberrant IgA production.
• Abnormal gut microbiota:
  • IgAN is associated with reduced diversity of Clostridium, Enterococcus, and Lactobacillus species.
  • Altered mucosal immunity and leaky gut may promote systemic immune activation.

Infectious Triggers

• Episodes of macroscopic haematuria often follow infections, particularly upper respiratory tract infections (synpharyngitic haematuria).
• Tonsillar inflammation involving organisms such as Haemophilus parainfluenzae, Fusobacterium, and Treponema species is implicated.
• Viral infections including HIV, hepatitis B, and SARS-CoV-2 have been linked to IgAN pathogenesis.
• Circulating IgA antibodies against viral proteins have been identified in affected individuals.

Autoimmune and Dermatological Disorders

• Autoimmune diseases like systemic lupus erythematosus, Sjögren syndrome, spondyloarthritis, and Behçet disease are associated with IgAN.
• Psoriasis is the most common skin disorder linked to IgAN; other associated conditions include juvenile dermatomyositis and leukocytoclastic vasculitis.
• Leukocytoclastic vasculitis may cause renal IgA deposition secondary to dermal immune complex vasculitis.

IgA Vasculitis (Henoch-Schönlein Purpura)

• IgAN shares histopathological features with IgA vasculitis, which also involves IgA deposition in small vessels.
• While IgAN is typically confined to the kidney, IgA vasculitis presents systemically with rash, arthritis, and gastrointestinal symptoms.

Drug-Induced IgAN

• TNF-α inhibitors (e.g., infliximab, adalimumab) may precipitate IgAN through antiglycan antibody formation or binding of aberrant IgA1.
• Other implicated agents include:
  • IL-12/IL-23 inhibitors
  • Immune checkpoint inhibitors
  • Direct oral anticoagulants (e.g., rivaroxaban)
  • Warfarin
  • Antithyroid drugs (e.g., thioureylenes)

Other Associations

• Pulmonary disorders: Sarcoidosis, idiopathic pulmonary fibrosis, and diffuse alveolar haemorrhage may be linked with secondary IgAN.
• Malignancies: IgA deposition has been reported in patients with gastric, pulmonary, and renal cell carcinomas, as well as myeloproliferative neoplasms.
• Mucosal-Associated Lymphoid Tissue (MALT):
  • A key source of IgA, especially in the gut and tonsils, contributing to the immunological basis of IgAN.
  • Pathological activation of MALT contributes to abnormal IgA synthesis and immune complex formation.

The Multi-Hit Model

Hit 1: Production of Galactose-Deficient IgA1 (Gd-IgA1)

• Individuals with genetic predisposition exhibit increased levels of IgA1 molecules lacking galactose residues in the hinge region.
• This O-glycosylation defect is heritable and seen in approximately 25% of first-degree relatives of patients with IgAN, although not all develop clinical disease.
• IgA1 is mainly produced in mucosal-associated lymphoid tissue (MALT), particularly in the respiratory and gastrointestinal tracts, implicating mucosal immunity as the site of pathogenesis initiation.
• Infections, particularly of the upper respiratory or gastrointestinal tracts, may trigger the overproduction of this aberrant IgA1.

Hit 2: Autoantibody Formation

• Galactose-deficient IgA1 behaves as an autoantigen, stimulating the production of glycan-specific IgG and IgA autoantibodies.
• These antibodies form circulating immune complexes with Gd-IgA1, which are poorly cleared from the bloodstream.

Hit 3: Immune Complex Deposition

• The immune complexes predominantly composed of polymeric IgA1 accumulate in the mesangium of glomeruli.
• Mesangial deposition is facilitated by the low-affinity nature of these complexes and their tendency to self-aggregate.
• Their presence incites mesangial cell activation, leading to release of pro-inflammatory cytokines and extracellular matrix proteins.

Hit 4: Inflammatory Cascade and Complement Activation

• The deposited complexes stimulate mesangial cells to release chemokines and cytokines, attracting inflammatory cells, especially macrophages and dendritic cells.
• Activation of the complement system—particularly the alternative and lectin pathways—is central to tissue damage.
  • Mannose-binding lectin (MBL) and other components such as factor H and properdin have been detected in glomerular deposits.
  • C3 deposition is seen in approximately 90% of biopsies and mirrors the distribution of IgA.
• Complement activation contributes to podocyte injury, glomerular basement membrane damage, increased glomerular permeability, and ultimately tubular injury and interstitial fibrosis.

Mucosal Immunity and Environmental Triggers

• Gd-IgA1 is primarily derived from the mucosal immune system. Environmental exposures such as infections and altered microbial handling can stimulate aberrant immune responses.
• Abnormal mucosal responses may be influenced by:
  • Chronic tonsillitis
  • Altered intestinal microbiota (e.g., reduced Clostridium and Lactobacillus diversity)
  • Gluten sensitivity and coeliac disease
• This supports the observation of synpharyngitic haematuria and the co-occurrence of gastrointestinal disorders such as coeliac disease and inflammatory bowel disease (IBD).

Systemic and Non-Immune Contributions

• Although immune mechanisms dominate, several non-immune factors modulate disease progression:
  • Hypertension and smoking promote microvascular injury and glomerulosclerosis.
  • Obesity contributes via glomerulomegaly and hyperfiltration-related injury.
• Coexistent liver disease impairs hepatic clearance of immune complexes, exacerbating deposition.

Heterogeneity of Clinical Expression

• While complement activation and immune complex deposition are nearly universal, their clinical manifestations vary:
  • Some individuals present with asymptomatic haematuria.
  • Others develop rapidly progressive glomerulonephritis and eventual end-stage renal failure.
• The reasons for this variation are not fully understood but may include differences in host immune response, complement regulatory protein expression, and genetic background.

 Asymptomatic Presentation

• Many patients, particularly adults, are asymptomatic and diagnosed through incidental findings:
  • Microscopic haematuria (with or without proteinuria)
  • Mild hypertension (often coexisting with subclinical kidney dysfunction)
  • Proteinuria usually less than 2–3 g/day
• These patients may have long-standing undiagnosed disease and typically follow a more indolent course. Spontaneous remission is rare.

Symptomatic Presentations

Macroscopic (Gross) Haematuria

• Occurs in 40–50% of cases.
• Commonly triggered by mucosal infections, particularly upper respiratory tract infections or gastroenteritis.
• Termed synpharyngitic haematuria, with episodes beginning within 48–72 hours of pharyngotonsillitis and resolving within a few days.
• Often associated with loin pain due to capsular swelling and low-grade fever, mimicking urinary tract infection or urolithiasis.
• Recurrence over several years is typical, especially in children and young adults.

Microscopic Haematuria

• Seen in approximately one-third of cases.
• Frequently identified during routine health checks or evaluations for chronic kidney disease.
• May progress to macroscopic haematuria in 20–25% of these patients.

Proteinuria

• Common but typically non-nephrotic range (<3 g/day).
• Nephrotic syndrome (proteinuria >3.5 g/day, hypoalbuminaemia, oedema, hyperlipidaemia) is less common.

Rapidly Progressive Glomerulonephritis (RPGN)

• Occurs in fewer than 10% of cases.
• Presents with haematuria, oedema, hypertension, and acute kidney injury.
• May lead to renal replacement therapy if not promptly treated.

Acute Kidney Injury

• Occasionally presents as the first manifestation, sometimes related to intratubular obstruction by red blood cells.
• More severe forms associated with crescentic IgAN.

Differences Between Adults and Children

• Children more frequently present with gross haematuria and acute nephritic syndrome.
• Biopsies in children often show more prominent mesangial/endocapillary hypercellularity.
• Children may have an initial increase in eGFR followed by a gradual decline, contrasting with the linear decline in adults.
• Higher remission rates are observed in paediatric populations.

Associated Risk Factors

Demographics

• Most commonly diagnosed in individuals aged 16–35 years.
• Strong male predominance (2:1 in Western populations); more balanced sex distribution in East Asia.
• Increased incidence in those of Asian, White, and Native American (particularly Zuni tribe) ancestry.

Genetic predisposition

• Family history in <10% of cases.
• Familial cases have diverse genetic linkages; GWAS studies implicate multiple risk loci.

Lifestyle factors

• Smoking, alcohol use, and physical inactivity increase risk of progression to ESRD.
• Regular exercise has a protective effect, especially in males.

Associated Conditions

IgA Vasculitis

• Clinically overlaps with IgAN but includes systemic features (rash, arthralgia, abdominal pain).
• Kidney histology indistinguishable from primary IgAN.

Chronic Liver Disease

• Especially alcoholic cirrhosis and hepatitis B/C.
• Associated with impaired IgA clearance by Kupffer cells.
• Often asymptomatic in adults; children may show microscopic haematuria that resolves post-liver transplantation.

Coeliac Disease

• Up to one-third show IgA deposition.
• Often asymptomatic renal involvement; mild proteinuria/haematuria may respond transiently to a gluten-free diet.

HIV Infection

• Polyclonal IgA elevation contributes to glomerular deposition.
• Usually mild proteinuria and haematuria; overt IgAN is rare.

Monoclonal Gammopathy of Renal Significance (MGRS)

• Must be differentiated from IgAN due to monoclonal nature of deposits.
• Responds to clone-directed therapy.

Other Glomerular Diseases

• Co-occurrence with minimal change disease, membranous nephropathy, or lupus nephritis is reported.
• Often incidental and may reflect the commonality of IgA deposition.

Systemic and Malignant Associations

• Infrequently linked to conditions such as IBD, granulomatosis with polyangiitis, lymphoma, tuberculosis, and autoimmune skin disorders.
• Most associations likely represent coincidental findings due to the prevalence of IgA deposition in the general population.

Normal Physical Findings

• The majority of patients with microscopic haematuria or low-grade proteinuria without renal impairment have no abnormal findings on physical examination.
• In asymptomatic individuals diagnosed incidentally (e.g., through screening), examination may be entirely normal.

Haematuria-Associated Findings

Gross (visible) haematuria episodes

• Typically painless and may be accompanied by loin (flank) pain, reflecting renal capsular distension.
• Low-grade fever may be present during acute episodes.
• Symptoms often mimic urinary tract infection or urolithiasis.
• On examination during active episodes, findings may be limited to mild costovertebral angle tenderness.

Nephrotic Syndrome Findings

Peripheral oedema

• Especially in the lower limbs; may also involve periorbital regions.

Hypertension

• May be present, particularly in patients with concurrent chronic kidney disease.

Other features

• Ascites and pleural effusion are rare but possible in severe hypoalbuminaemia.
• Hyperlipidaemia may not be clinically evident but contributes to cardiovascular risk.

Rapidly Progressive Glomerulonephritis (RPGN)

• Found in a minority of patients (<10%), characterised by:
  • Oedema
  • Hypertension (occasionally severe)
  • Signs of acute kidney injury, such as:
    • Pallor (due to anaemia)
    • Fatigue
    • Reduced urine output (may present with oliguria)
    • Signs of fluid overload (e.g., basal lung crackles, elevated jugular venous pressure)

Malignant hypertension

• Very rare but may present with:
  • Fundoscopic changes (e.g., flame haemorrhages, papilloedema)
  • Encephalopathy or seizure
  • Signs of cardiac strain

Acute Kidney Injury (AKI)

• May result from:
  • Crescentic glomerulonephritis
  • Glomerular haematuria leading to tubular red cell obstruction
• Clinical signs may include:
  • Volume overload (peripheral oedema, pulmonary crackles)
  • Uraemic signs (e.g., pruritus, confusion in late stages)
  • Hypertension and reduced urine output

Differential and Associated Systemic Conditions

IgA Vasculitis (Henoch–Schönlein purpura)

• Distinguished by extra-renal features:
  • Palpable purpuric rash, typically on the lower limbs
  • Arthralgia
  • Abdominal pai
• Renal findings may mirror IgAN with haematuria and proteinuria.

Associated Systemic Disorders (on exam)

• Chronic liver disease: Spider naevi, palmar erythema, hepatomegaly, splenomegaly
• HIV infection: Generalised lymphadenopathy, oral thrush, cachexia
• Coeliac disease: Often no clinical signs, but may have signs of malabsorption (weight loss, pallor, glossitis)
• Inflammatory bowel disease: Abdominal tenderness, perianal disease in Crohn’s
• Dermatitis herpetiformis (coeliac association): Clusters of intensely pruritic papulovesicular lesions on extensor surfaces
• Systemic malignancies or autoimmune conditions: May show lymphadenopathy, hepatosplenomegaly, or other systemic features depending on the underlying condition

 When to Suspect IgAN

• Clinicians should suspect IgAN in patients presenting with
  • Episodes of macroscopic haematuria, particularly following an upper respiratory or gastrointestinal infection.
  • Persistent microscopic haematuria, with or without proteinuria.
  • Progressive decline in renal function, especially when accompanied by proteinuria or hypertension.
• Although less common, presentations with nephrotic syndrome, acute kidney injury, or rapidly progressive glomerulonephritis may also warrant suspicion.

Initial Investigations

Urinalysis and Urine Microscopy

• Microscopic haematuria with dysmorphic red blood cells suggests glomerular origin.
• Red cell casts may occasionally be seen.
• Proteinuria, typically <2–3 g/day, is common but may reach nephrotic levels in a minority.

Urine Culture

• Used to rule out urinary tract infection as a cause of haematuria or proteinuria.
• Findings: No bacterial growth; presence of dysmorphic erythrocytes.

Serum Biochemistry

• Includes creatinine and estimated glomerular filtration rate (eGFR).
• Renal function is often preserved in early disease.
• Decline in eGFR correlates with severity of proteinuria and disease progression.

Complement Levels (C3 and C4)

• Usually normal in IgAN.
• Helps exclude other immune complex-mediated nephritides (e.g., lupus nephritis, membranoproliferative GN).

Renal Imaging

• Ultrasound or CT-KUB: Performed to exclude structural abnormalities in the presence of persistent haematuria or proteinuria.
• Typically shows normal renal size and echogenicity in IgAN.

Definitive Diagnosis: Kidney Biopsy

• Essential to confirm IgAN, especially when:
  • Persistent proteinuria ≥500 mg/day
  • Abnormal renal function
  • Suspicion of progressive or atypical disease
• Histological Assessment:
  • Light Microscopy: Shows mesangial proliferation, matrix expansion, and possible segmental sclerosis or crescents.
  • Immunofluorescence: Pathognomonic mesangial IgA deposition, often with C3; IgG and IgM may also be present.
  • Electron Microscopy: Reveals electron-dense deposits predominantly in the mesangium; subendothelial or subepithelial deposits indicate severe disease.

Oxford Classification (MEST-C Score)

• Applied to biopsy findings to predict progression risk:
  • Mesangial hypercellularity
  • Endocapillary hypercellularity
  • Segmental glomerulosclerosis
  • Tubular atrophy/interstitial fibrosis
  • Crescent formation

Further Investigations (Selective Use)

Flexible Cystoscopy

• Recommended for patients >40 years with persistent haematuria to exclude urological malignancy (e.g., transitional cell carcinoma).

Skin Biopsy

• Considered only when IgA vasculitis is suspected.
• Demonstrates capillary wall deposits of IgA, C3, and fibrin in dermal vessels.

Emerging Biomarkers (Research Use Only)

• Galactose-deficient IgA1 and corresponding autoantibodies.
• microRNAs influencing O-glycosylation of IgA1.
• These are not yet validated for routine clinical diagnosis.

Geographic Considerations in Biopsy Practices

• In countries like Japan, where routine screening and low biopsy thresholds exist, IgAN is diagnosed at earlier stages.
• In contrast, delayed biopsy in Western countries often results in diagnosis at more advanced stages of chronic kidney disease.

IgA Vasculitis (Henoch–Schönlein Purpura)

• Overlap: Identical renal histology to IgAN.
• Distinguishing Features:
  • Systemic symptoms: palpable purpura (especially on lower limbs), abdominal pain, arthralgia, and gastrointestinal bleeding.
  • More common in children under 15.
  • Skin or gastrointestinal biopsy may show IgA deposition in small vessels.
  • No diagnostic serology; differentiation based on presence of extra-renal manifestations.

Poststreptococcal Glomerulonephritis (PSGN)

• Overlap: Gross haematuria following an upper respiratory infection.
• Distinguishing Features:
  • Latency period: PSGN presents 1–3 weeks after infection; IgAN presents within 72 hours.
  • PSGN is typically non-recurrent; IgAN often recurs.
  • Serological markers: Elevated anti-streptolysin O and anti-DNase B titres.
  • Low C3 complement levels in early infection.
  • Histology: PSGN shows hypercellularity with C3-dominant deposition and subepithelial "humps".

Lupus Nephritis

• Overlap: May have prominent mesangial IgA deposition.
• Distinguishing Features:
  • Systemic lupus erythematosus features (malar rash, arthritis, photosensitivity).
  • Serology: Positive ANA, anti-dsDNA; low C3 and C4.
  • Immunofluorescence: “Full-house” pattern (IgA, IgG, IgM, C3, C1q, kappa, and lambda light chains).
  • Histology: Diffuse proliferative lesions more severe than typical IgAN.

Thin Basement Membrane Nephropathy (TBMN)

• Overlap: Persistent microscopic haematuria.
• Distinguishing Features:
  • Family history of isolated haematuria.
  • Proteinuria is rare and progression to ESRD is unusual.
  • Electron microscopy: Uniform thinning of the glomerular basement membrane.
  • Immunofluorescence: No IgA deposition.

Alport Syndrome

• Overlap: Microscopic haematuria with a family history.
• Distinguishing Features:
  • X-linked inheritance pattern, often affecting males more severely.
  • Associated with sensorineural hearing loss and ocular abnormalities.
  • Electron microscopy: Lamina densa thickening and splitting.
  • Immunohistochemistry: Loss of collagen IV alpha-3, -4, or -5 chains.

IgA-Dominant Staphylococcus-Associated Glomerulonephritis

• Overlap: IgA-dominant mesangial and capillary wall deposition.
• Distinguishing Features:
  • Seen in older adults or diabetics.
  • Occurs during active Staphylococcus aureus infection.
  • Histology: Diffuse proliferative GN with neutrophilic infiltration; subepithelial and subendothelial deposits on EM.
  • Differentiated from IgAN by concurrent infection and systemic inflammatory signs.

Membranoproliferative Glomerulonephritis (MPGN)

• Overlap: Can present with haematuria and proteinuria.
• Distinguishing Features:
  • Histology: Double-contour appearance of glomerular basement membrane.
  • May involve immune complex or complement-mediated mechanisms.
  • Often associated with hepatitis C or monoclonal gammopathies.

Monoclonal Gammopathy of Renal Significance (MGRS)

• Overlap: IgA-PGNMID may mimic IgAN histologically.
• Distinguishing Features:
  • Presence of monoclonal IgA rather than polyclonal.
  • Light chain restriction on biopsy (kappa or lambda dominance).
  • Serum or urine electrophoresis may reveal a monoclonal spike.
  • Requires clone-directed therapy rather than immunosuppression.

Fabry Disease

• Overlap: Coincidental findings of IgA deposits.
• Distinguishing Features:
  • Presents with angiokeratomas, neuropathic pain, corneal verticillata.
  • Renal biopsy: Lamellar inclusions (zebra bodies) on electron microscopy.
  • α-galactosidase A deficiency confirms diagnosis.

Urological Malignancy or Stones (in Adults >40)

• Overlap: Visible haematuria.
• Distinguishing Features:
  • Urolithiasis presents with colicky flank pain and imaging abnormalities.
  • Transitional cell carcinoma considered with painless haematuria; ruled out via cystoscopy and imaging.
  • Not associated with glomerular pathology or proteinuria.

Risk Stratification and Indications for Treatment

• Before initiating treatment, assess for risk factors predictive of progressive kidney disease:
• Clinical factors: sustained proteinuria >1 g/day, hypertension, reduced estimated glomerular filtration rate (eGFR).
• Histopathological features (Oxford MEST-C classification):
  • M1: mesangial hypercellularity
  • E1: endocapillary hypercellularity
  • S1: segmental sclerosis
  • T2: tubular atrophy/interstitial fibrosis >50%
  • C1/C2: crescents in <25% or ≥25% of glomeruli, respectively
• These features help estimate progression risk but are not used in isolation to guide immunosuppressive therapy decisions.

Supportive (Non-Immunosuppressive) Therapy

• Supportive care is the cornerstone of management for all patients except those with very low-risk profiles (e.g., isolated haematuria with normal GFR and <0.5 g/day proteinuria).
• Routine monitoring of renal function, proteinuria, and blood pressure is essential to ensure optimal disease control.

Key components include

• Renin-Angiotensin System (RAS) Inhibition:
  • First-line for proteinuria >0.5 g/day or any degree of hypertension.
  • Use ACE inhibitors or ARBs (not in combination).
  • Target urine protein <1 g/day and blood pressure <130/80 mmHg.
  • Discontinue before pregnancy and transition to safer alternatives.
• Lifestyle Modifications:
  • Low-salt diet
  • Smoking cessation
  • Weight management
  • Regular exercise

Immunomodulatory Therapy

Indicated for

• Persistent proteinuria >1 g/day despite ≥3 months of optimised supportive therapy.

Corticosteroids

• KDIGO recommends a 6-month tapering course of corticosteroids, typically oral prednisolone.
• Demonstrated reduction in proteinuria and progression risk in earlier studies, but associated with high adverse event rates (TESTING trial).
• Avoid in patients with:
  • eGFR <30 mL/min/1.73 m²
  • Diabetes, obesity, active infections, cirrhosis, peptic ulcer disease, psychiatric illness, or osteoporosis.

Special cases

• Minimal Change Disease with IgA deposits:
  • Sudden-onset nephrotic syndrome with podocyte effacement on biopsy.
  • Treat with corticosteroids as in minimal change disease.

Other immunosuppressants

• Cyclophosphamide, azathioprine, or mycophenolate may be considered only in rapidly progressive glomerulonephritis (RPGN)
• Mycophenolate has shown some promise as a steroid-sparing agent in Chinese cohorts, but not routinely recommended globally.

STOP-IgAN Trial

• No additional benefit of immunosuppression over optimised supportive therapy alone.
• Reinforces need for aggressive supportive management before escalating to immunosuppression.

Acute Kidney Injury (AKI) in IgAN

AKI can occur due to

• Haematuria-induced tubular injury: from RBC casts; usually reversible.
• Crescentic IgAN: a severe immune-mediated injury resembling ANCA-associated vasculitis.

Management

• Supportive care for haematuria-induced AKI.
• In crescentic forms, initiate aggressive immunosuppression:
  • Cyclophosphamide + corticosteroids for 6 months.
  • Maintenance with azathioprine.
• Kidney biopsy is warranted if there is no renal recovery within 48 hours or if RPGN is suspected.

Tonsillectomy and Other Therapies

• Tonsillectomy: popular in Japan (often combined with corticosteroid pulses), but no clear evidence of benefit in white populations.
• Omega-3 Fish Oils: inconsistent data; not recommended by KDIGO due to lack of robust evidence.
• Experimental Biomarkers (e.g., galactose-deficient IgA1, anti-glycan antibodies, microRNAs) lack validated diagnostic utility and are not yet used in routine clinical practice.

Long-Term Risk of Progression

• Approximately 15–20% of patients progress to ESKD within 10 years, with 25–30% progressing by 20 years.
• The trajectory of disease is often slow, but insidious.
• One-third of patients will experience progressive kidney function decline, while up to half may remain in remission or experience a benign course.
• Those of East Asian ancestry are disproportionately at higher risk of progression to ESKD.

Prognostic Indicators

Clinical Predictors

• Proteinuria: Strongest clinical predictor.
  • Proteinuria >1 g/day correlates with significantly worse outcomes.
  • Patients with proteinuria >3.5 g/day have <10% renal survival at 10 years.
• Hypertension: Systolic or diastolic elevation, or the requirement for antihypertensive therapy, significantly worsens prognosis.
• eGFR: A reduced glomerular filtration rate at presentation (<60 mL/min/1.73 m²) is associated with more rapid progression.
• Serum Creatinine >120 µmol/L: Associated with worse outcomes at the time of diagnosis.
• C4d staining: Indicates complement pathway activation and is associated with adverse outcomes.

Histopathological Predictors – MEST-C Score

• Developed as part of the Oxford Classification and refined in 2016 with the addition of crescents.
• Each component predicts different aspects of disease progression:
  • M1 (Mesangial hypercellularity ≥50%) – worse outcome.
  • E1 (Endocapillary hypercellularity) – worse outcome without immunosuppression; may improve with treatment.
  • S1 (Segmental sclerosis) – indicates irreversible damage.
  • T1/T2 (Tubular atrophy/interstitial fibrosis) – strongest predictor of ESKD.
  • C1/C2 (Crescents in <25% or ≥25% of glomeruli) – predictive of poor outcome; C1 may improve with immunosuppression, C2 often does not.

Prognostic Tools

International IgAN Prediction Tool

• MEST-C score
• Baseline eGFR
• Blood pressure
• Proteinuria
• Age
• Use of RAS blockade
• Provides 5-year risk estimates for a 50% eGFR decline or ESKD
• Available in adult and paediatric versions, both at and post-biopsy

Xie Risk Model (China)

• eGFR
• Systolic blood pressure
• Haemoglobin
• Serum albumin
• Not yet validated in non-Asian populations

Implications for Kidney Transplantation

• Patients reaching ESKD may benefit from renal transplantation.
• However, recurrence of IgAN post-transplant occurs in 25–50% of cases.
• While recurrence is often histological, it may also lead to clinical graft dysfunction and eventual failure in a minority of patients.

Factors Suggesting Benign Course

• Isolated microscopic haematuria with minimal or no proteinuria.
• Normal blood pressure and preserved eGFR.
• Absence of MEST-C features, particularly T1/T2 and C2.
• These patients often require conservative management and have a favourable long-term prognosis.

 Chronic Kidney Disease (CKD)

• High likelihood, particularly in patients with persistent proteinuria and hypertension.
• CKD in IgAN is typically associated with:
  • Normocytic anaemia of chronic disease
  • Volume overload
  • Hyperkalaemia
  • Metabolic acidosis
  • Hyperphosphataemia and renal osteodystrophy
  • Hypertension
  • Dyslipidaemia and sexual dysfunction
• Management is aimed at slowing progression (e.g., RAS blockade), correcting metabolic derangements, and cardiovascular risk reduction.

End-Stage Kidney Disease (ESKD)

• Occurs in approximately 1–2% of patients per year, culminating in long-term dialysis or transplantation needs.
• Risk factors accelerating progression:
  • Sustained hypertension
  • Proteinuria >1 g/day
  • Impaired baseline kidney function
  • Adverse Oxford classification biopsy features (M1, E1, S1, T2)
• In patients with multiple high-risk features, up to 60% progress to ESKD within 7 years.
• Requires ongoing renal replacement therapy and management of ESKD-associated complications (e.g., secondary hyperparathyroidism, anaemia, vascular calcification).

Acute Kidney Injury (AKI)

• Uncommon, affecting <5% of patients with IgAN.
• AKI may result from:
  • Crescentic glomerulonephritis (rapidly progressive form)
  • Glomerular haematuria-induced tubular obstruction, often self-limiting
• In cases with tubular occlusion, renal function typically returns to baseline with supportive care (fluid management and avoidance of nephrotoxins).

Therapy-Related Complications

Corticosteroids

• Frequently used in moderate to severe IgAN, but associated with:
  • Hypertension, weight gain, hyperglycaemia/diabetes mellitus
  • Osteoporosis and iatrogenic Cushing’s syndrome
  • Fluid retention and mood disturbances
  • Increased susceptibility to infections

Steroid-sparing immunosuppressants 

• e.g., cyclophosphamide, mycophenolate, azathioprine
• Potential complications include:
  • Hepatotoxicity and nephrotoxicity
  • Cytopenias, bone marrow suppression
  • Anaphylaxis and infusion reactions
  • Opportunistic infections (e.g., tuberculosis, viral reactivation)
• Given the potential risks, immunosuppression must be reserved for select patients with high risk of progression, and careful patient selection, monitoring, and risk-benefit assessment are critical.

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