IgA nephropathy (IgAN) in CKD

1. Presentation

• Asymptomatic microscopic hematuria, often detected on routine urinalysis, with or without proteinuria. This is the common adult presentation.
• Synpharyngitic gross hematuria: recurrent visible, cola-colored urine occurring during or within 1 to 2 days of an upper respiratory or gastrointestinal mucosal infection. This contrasts with post-streptococcal GN, where hematuria usually follows infection after a latent interval.
• Proteinuria: variable, usually subnephrotic but occasionally nephrotic-range.
• Hypertension, edema, and declining eGFR in progressive disease.
• Acute kidney injury, sometimes during severe macroscopic hematuria.
• Rapidly progressive GN: uncommon but serious, with a rapid eGFR fall, active sediment, and extensive crescents on biopsy.

• Persistent proteinuria, especially at or above 0.5 g/day
• Falling eGFR at presentation or over follow-up
• Hypertension
• Significant chronic scarring on biopsy, especially tubular atrophy/interstitial fibrosis
• Oxford MEST-C lesions, particularly segmental sclerosis, tubular atrophy/interstitial fibrosis, and crescents in the appropriate clinical setting

2. Etiology and pathogenesis

Four-hit model

1. Overproduction of galactose-deficient IgA1 at mucosal sites, especially the upper respiratory and gastrointestinal tract.
2. Formation of IgG or IgA autoantibodies directed against this abnormal IgA1.
3. Formation of circulating pathogenic immune complexes.
4. Mesangial deposition of complexes, with mesangial activation, complement activation, inflammation, glomerulosclerosis, and tubulointerstitial fibrosis.

Secondary IgA deposition or IgA-dominant disease to consider

• Cirrhosis or chronic liver disease
• HIV, hepatitis B, or hepatitis C
• Inflammatory bowel disease
• Autoimmune disease
• IgA vasculitis
• IgA-dominant infection-related GN, especially staphylococcal infection in older adults or people with diabetes

3. Evaluation

Initial clinical assessment

• BP, edema/volume status, cardiovascular risk factors
• History of gross hematuria related to infections
• Medication review, especially NSAIDs and other nephrotoxins
• Family history of kidney disease
• Features of systemic disease: purpura, arthralgia, abdominal pain, liver disease, chronic infection, autoimmune symptoms

Core tests

Kidney biopsy

• M: mesangial hypercellularity
• E: endocapillary hypercellularity
• S: segmental sclerosis
• T: tubular atrophy/interstitial fibrosis
• C: crescents

Risk stratification and follow-up

• BP
• eGFR and its slope
• Proteinuria trend
• Potassium and creatinine after renin-angiotensin system therapy
• CKD complications as eGFR declines

4. Management

A. Supportive CKD care for all patients

• Control BP, commonly targeting standardized systolic BP <120 mmHg if tolerated, individualized for symptoms, frailty, and comorbidities.
• ACE inhibitor or ARB at the maximally tolerated dose for proteinuria at or above 0.5 g/day, even if BP is not elevated, unless contraindicated.
• Do not combine ACE inhibitor plus ARB.
• Dietary sodium reduction, generally <2 g sodium/day.
• Avoid smoking, obesity, NSAIDs, and other nephrotoxins.
• Exercise and cardiovascular risk reduction.
• Manage diabetes, lipids, acidosis, anemia, mineral-bone disorder, and volume overload according to CKD stage.
• Vaccination and infection-risk review, especially before immunosuppressive therapy.

B. Disease-modifying treatment in patients at risk of progression

1. SGLT2 inhibitor
   Consider for eligible CKD patients, especially with persistent proteinuria and adequate eGFR, unless contraindicated. It offers kidney protection beyond glucose lowering.
2. Targeted-release budesonide, Nefecon
   KDIGO 2025 suggests a 9-month course for patients at risk of progressive loss of kidney function. It targets gut-associated mucosal immune activity and may reduce proteinuria and slow eGFR decline. Monitor for steroid-related effects.
3. Sparsentan
   A dual endothelin-angiotensin receptor antagonist that can reduce proteinuria and slow eGFR decline in eligible high-risk patients. It must not be combined with an ACE inhibitor or ARB, because it already has angiotensin receptor-blocking activity. Pregnancy prevention and monitoring requirements apply.
4. Systemic glucocorticoids
   Not routine first-line treatment. They may be considered in selected high-risk patients after careful shared decision-making, but infection, diabetes, osteoporosis, weight gain, gastrointestinal, and psychiatric risks are significant. The KDIGO approach favors newer targeted therapies where available.
5. Other immunosuppressants
   Mycophenolate, cyclophosphamide, rituximab, and hydroxychloroquine are not universal standard therapy for typical primary IgAN. Their role is selective and population-specific. Avoid treating biopsy findings alone without integrating proteinuria, eGFR trend, and clinical phenotype.

C. Special clinical situations

• Visible hematuria with AKI: usually treat conservatively with volume and BP management, avoidance of nephrotoxins, and close monitoring. Biopsy or escalation is needed if kidney function fails to recover or RPGN is suspected.
• True rapidly progressive IgAN: urgent nephrology assessment and biopsy. If eGFR declines by at least 50% within <3 months with extensive active crescentic GN, treatment is generally modeled on ANCA-associated vasculitis protocols, often glucocorticoids plus cyclophosphamide.
• Nephrotic syndrome with minimal-change-like lesion: manage as minimal change disease rather than as ordinary IgAN.
• Kidney failure: provide CKD education, preparation for dialysis or transplant when appropriate. IgAN can recur after transplant, but transplantation remains an effective treatment.

Practical summary

1. Suspect IgAN in recurrent infection-associated gross hematuria or persistent microscopic hematuria with proteinuria.
2. Quantify proteinuria and assess eGFR and BP.
3. Exclude secondary causes and other rapidly progressive glomerulonephritides.
4. Confirm with kidney biopsy and document MEST-C score.
5. Start optimized supportive CKD care, especially an ACE inhibitor or ARB when proteinuria is at least 0.5 g/day.
6. If proteinuria persists or eGFR declines, assess candidacy for SGLT2 inhibition, targeted-release budesonide, sparsentan, or carefully selected immunosuppression.
7. Monitor proteinuria, BP, eGFR slope, potassium, and CKD complications longitudinally.