Metabolic Determinants of Autoimmune Kidney Diseases

1. Immunometabolic Reprogramming: The Central Framework

2. Lupus Nephritis - The Best-Characterized Immunometabolic Disease

mTOR Overactivation

• Enhanced TCR signaling (CaMK4-dependent)
• Mitochondrial hyperpolarization and increased reactive oxygen species (ROS)
• Reduced AMPK activity

Glycolysis and Oxidative Phosphorylation

Glutaminolysis and Th17 Cells

B Cell Metabolism

Mitochondrial Dysfunction and Interferon Signaling

• Mitochondria are platforms for nucleic acid sensing via MAVS
• In SLE, enhanced type I interferon signaling drives αKG accumulation, altering histone demethylation and sustaining inflammatory gene expression (a form of "metabolic-inflammatory memory")
• Glycolysis-derived lactate repurposes MAVS away from IFN signaling, creating a feedback loop where metabolic state gates the interferon response

Complement as a Metabolic Sensor

• Firestein & Kelley's Textbook of Rheumatology, 2-Volume Set, p. 533-534

3. IgA Nephropathy - Glycosylation as the Primary Metabolic Defect

The Four-Hit Hypothesis (Glycosylation-Centered)

1. Hit 1 - Galactose-deficient IgA1 (Gd-IgA1): B cells secreting IgA1 fail to properly galactosylate the O-glycans in the hinge region of IgA1. Instead of terminating with galactose, the glycans are truncated, exposing N-acetylgalactosamine. This is determined by defects in two enzymes: core 1β-galactosyltransferase (C1GALT1) and its molecular chaperone COSMC (C1GALTC1). Genetic polymorphisms in these genes associate with higher serum Gd-IgA1 levels.
2. Hit 2 - Autoantibody formation: IgG and IgA autoantibodies form against the exposed N-acetylgalactosamine neoepitopes on Gd-IgA1.
3. Hit 3 - Immune complex formation: These autoantibodies bind Gd-IgA1 to form circulating immune complexes.
4. Hit 4 - Mesangial deposition and complement activation: The Gd-IgA1-containing immune complexes deposit in the mesangium, where they activate the lectin complement pathway (via mannose-binding lectin recognizing aberrant glycans) and the alternative pathway, causing mesangial cell proliferation and glomerular inflammation.

Key textbook source: Brenner and Rector's The Kidney, 2-Volume Set, pp. 1383-1384 - "The prevailing hypothesis regarding the pathogenesis of IgA nephropathy focuses on defects in protein glycosylation, particularly in B cells secreting IgA1... polymorphisms of C1GALT1 and COSMC genes may be associated with increased susceptibility."

4. Membranous Nephropathy - Lipid-Podocyte-Immune Metabolic Crosstalk

T Cell Metabolic Drivers

• Pro-inflammatory Th1 and Th2 cells driving the initial autoimmune response rely on glycolysis and glutaminolysis
• Tfh cells, which provide B cell help for IgG4 class-switching, use mixed metabolism (lower glycolysis than Th1/Th2, with mTORC1-driven lipogenesis via ICOS stimulation)
• mTOR integrates T cell activation and metabolic outputs - mTORC1 in early Tfh expansion and mTORC2 in later stages

B Cell Metabolic Reprogramming in MN

• mTORC1 and mTORC2 enhance glycolytic targets in MN B cells, leading to primitive B cell expansion
• Glutaminolysis contributes to primitive B cell differentiation
• FAO and OXPHOS drive plasma cell expansion and immunoglobulin secretion
• Rapamycin, targeting mTOR, disrupts these B cell metabolic programs
• Source: Duan et al., Commun Biol 2025 (PMID: 40065158)

The Lipid-Podocyte Axis

5. ANCA-Associated Vasculitis - Neutrophil Immunometabolism

Neutrophil Metabolic Activation by ANCA

• ANCA (particularly MPO-ANCA) primes neutrophils for a respiratory burst
• ANCA binding to primed neutrophils triggers degranulation and NET (neutrophil extracellular trap) formation
• NETs release MPO and PR3 into the circulation, amplifying autoantigen exposure and perpetuating the autoantibody response
• The respiratory burst is metabolically intense, consuming glucose via the hexose monophosphate shunt to generate NADPH for NOX2-mediated superoxide production

Metabolic Epigenetic Reprogramming

6. Anti-GBM Disease - Oxidative Metabolic Injury

7. Cross-Cutting Metabolic Determinants

Vitamin D - the Immunometabolic Modulator

• Suppresses Th1/Th17 differentiation
• Promotes Treg expansion
• Inhibits B cell activation and immunoglobulin synthesis
• Downregulates NF-κB signaling in mesangial cells CKD itself impairs renal 1α-hydroxylation, creating a vicious cycle where kidney damage reduces the metabolic capacity to produce immunomodulatory vitamin D.

Microbiome-Gut-Kidney Metabolic Axis

Epigenetic-Metabolic Memory

• Acetyl-CoA → histone acetylation (promotes inflammatory gene transcription)
• αKG → histone/DNA demethylation (accumulates in SLE via type I IFN)
• Succinate, fumarate → inhibit α-KG-dependent demethylases → hypermethylation
• Lactate → histone lactylation (H4K12la, H3K18la) → profibrotic programs in renal fibrosis
• NAD+/SIRT1 axis → deacetylation of NF-κB and FOXP3 → regulates Treg function

mTOR as a Convergence Hub

• Integrates TCR/BCR signals with metabolic nutrient status
• Drives glycolysis, protein synthesis, and lipid synthesis in activated lymphocytes
• Overactivated in SLE T cells and MN B cells
• Inhibition by rapamycin reduces autoimmune kidney damage across multiple models
• SGLT2 inhibitors (dapagliflozin, empagliflozin) inhibit CD4+ T cell mTORC1 through AMPK activation, reducing glutamine anaplerosis, glycolysis, and OXPHOS - a newly recognized renoimmune mechanism beyond glycosuria

8. Therapeutic Implications

Summary

• Duan X et al. Commun Biol 2025 - immune cell metabolism in membranous nephropathy (PMID: 40065158)
• Novak J et al. Glycobiology 2024 - O-glycosylation and IgA nephropathy (PMID: 39095059)
• Liu et al. Front Immunol 2024 - T cell metabolism in kidney immune homeostasis (PMID: not assigned at search time)
• Zeng Q et al. Front Immunol 2023 - Gd-IgA1 systematic review (PMID: 37671165)
• Zhang P et al. Front Immunol 2025 - complement in anti-GBM GN (PMID: 40469278)
• Casal Moura M et al. Nat Rev Rheumatol 2025 - ANCA-associated vasculitis (PMID: 41102379)
• Brenner and Rector's The Kidney, 2-Volume Set, Chapter 31 (IgA Nephropathy)
• Firestein & Kelley's Textbook of Rheumatology, pp. 533-534 (SLE complement)

Treatment Protocols for Autoimmune Kidney Diseases

I. LUPUS NEPHRITIS (LN)

Prerequisite: Always add in all classes

• Hydroxychloroquine (HCQ) 5 mg/kg/day (max 400 mg/day) - continues indefinitely unless contraindicated; reduces flares, cardiovascular risk, and thrombosis
• ACE inhibitor or ARB for proteinuria control
• Blood pressure target: <130/80 mmHg
• Statin if dyslipidemia; calcium/vitamin D supplementation with steroids
• PCP prophylaxis (trimethoprim-sulfamethoxazole) while on immunosuppression
• Monitor CBC, LFTs, urinalysis, creatinine, complement (C3/C4), anti-dsDNA every 3 months

Class I & II LN (Minimal Mesangial / Mesangial Proliferative)

• No specific immunosuppression for kidney disease
• Treat underlying SLE as clinically indicated
• Follow-up: urinalysis + creatinine every 6-12 months

Class III & IV LN (Focal / Diffuse Proliferative) - Core Protocol

INDUCTION (3-6 months) - Choose one regimen:

Glucocorticoids + Mycophenolate mofetil (MMF)

• Methylprednisolone IV pulse: 500-1000 mg/day x 3 days, then
• Oral prednisolone: 0.5-1 mg/kg/day (max 60 mg/day), taper to ≤10 mg/day by week 12-24
• MMF: 2-3 g/day (or mycophenolate sodium 1440-2160 mg/day)

• IV cyclophosphamide 500 mg every 2 weeks x 6 doses
• • Methylprednisolone IV pulse then oral prednisolone as above

Glucocorticoids + MMF + Belimumab (anti-BAFF) OR Voclosporin (CNI)

• Belimumab 10 mg/kg IV monthly x 3, then every 4 weeks; or 200 mg SC weekly
• OR Voclosporin 23.7 mg twice daily (requires eGFR >45 mL/min)
• Both approved as first-line additions per KDIGO 2024 and ACR 2025

• IV cyclophosphamide 0.5-1.0 g/m² monthly x 6 doses
• Reserved for severe proliferative LN with deteriorating kidney function

MAINTENANCE (minimum 3 years after complete response):

• MMF 1-2 g/day (first choice, KDIGO 2024 Grade 1B)
• Azathioprine 1.5-2 mg/kg/day (preferred if pregnancy planned)
• Continue HCQ
• Taper steroids to lowest effective dose; aim to discontinue by 12-18 months
• Those on belimumab or voclosporin during induction: continue for 2-3 years

Response targets (KDIGO 2024):

• Complete renal response: uPCR <500 mg/g (0.5 g/g) + stable creatinine (within 10% of baseline)
• Partial response: >50% reduction in proteinuria, creatinine stabilized
• Assess response at 3 months; if <25% improvement, reconsider regimen

Class V LN (Membranous)

• EULAR: Rituximab preferred for class V refractory
• KDIGO 2024: MMF ± CNI (voclosporin/tacrolimus); rituximab for refractory cases
• Induction: MMF 2-3 g/day + low-dose prednisolone, OR CNI + MMF, OR rituximab
• Maintenance: MMF 1-2 g/day

Refractory / Relapsing LN

• Switch induction agent (MMF → CYC or vice versa)
• Add belimumab if not already used
• Rituximab 1000 mg IV x 2 doses, 14 days apart (cyclophosphamide-sparing, especially in CNI-experienced patients)
• Voclosporin if not already incorporated
• Consider repeat kidney biopsy to reclassify

II. IgA NEPHROPATHY (IgAN)

Step 1: Proteinuria risk stratification

• Target: <0.5 g/day, ideally <0.3 g/day (lowered from prior <1 g/day target)
• Patients with ≥0.5 g/day despite optimized supportive care are candidates for disease-modifying therapy

Step 2: Universal Supportive Therapy (ALL patients)

• RASi (ACEi or ARB) - maximize to highest tolerated dose
  • Do NOT combine ACEi + ARB simultaneously (safety concerns)
• SGLT2 inhibitor - recommended class-wide (dapagliflozin or empagliflozin): independently reduces proteinuria, slows eGFR decline, and provides immune-metabolic benefits (AMPK activation, T cell suppression)
• Blood pressure target: <130/80 mmHg
• Salt restriction, smoking cessation, weight management

Step 3: Disease-Modifying Therapies (approved agents, layer as needed)

A. Targeted-release budesonide (Nefecon / Tarpeyo)

• Mechanism: Delivers budesonide to Peyer's patches in the ileum → suppresses mucosal B cells → reduces Gd-IgA1 production (targeting the primary metabolic defect)
• Dose: 16 mg/day orally for 9 months
• Indication: Persistent proteinuria ≥0.5 g/day despite optimized RASi ± SGLT2i; eGFR ≥35 mL/min
• Evidence: NEFIGAN and PROTECT trials; significant proteinuria reduction vs. placebo
• KDIGO 2025 recommendation: 2B (suggested)

B. Sparsentan (Filspari) - DEARA (dual endothelin-angiotensin receptor antagonist)

• Dose: 400 mg/day orally
• Replaces RASi (do NOT combine with ACEi/ARB - sparsentan already incorporates RASi activity)
• Evidence (PROTECT trial): -49.8% proteinuria reduction vs. -15% with irbesartan; slower eGFR decline (-6.1 vs. -9.9 mL/min/1.73m²) at 2 years
• FDA accelerated approval 2023; EMA conditional authorization 2024
• KDIGO 2025: Grade 2B
• Monitor: liver function monthly for first year, then quarterly; pregnancy test (teratogenic - REMS program); BP

C. Iptacopan (Fabhalta) - complement factor B inhibitor

• Mechanism: Blocks alternative complement pathway at Factor B → prevents Gd-IgA1-triggered glomerular C3 deposition
• Dose: 200 mg twice daily orally
• Evidence (APPLAUSE-IgAN, NEJM 2025): Significant proteinuria reduction in patients with persistent proteinuria ≥1 g/day
• FDA accelerated approval; KDIGO 2026 commentary endorses use
• Update meningococcal vaccination before initiating

D. Atrasentan (Vanrafia) - selective endothelin A receptor antagonist

• Dose: 0.75 mg/day orally
• Evidence (ALIGN trial, NEJM 2024): Significant proteinuria reduction; can be combined WITH RASi (unlike sparsentan)
• FDA approved 2024
• Monitor: fluid retention, BNP; avoid in heart failure

E. Sibeprenlimab (Voyxact) - anti-APRIL antibody

• Mechanism: Blocks APRIL (a proliferation-inducing ligand) → reduces B cell activation and Gd-IgA1 production
• Evidence (VISIONARY trial): Significant proteinuria reduction; FDA accelerated approval 2025
• SC monthly injection

Step 4: Systemic Corticosteroids (conditional use)

• KDIGO 2025: When targeted-release budesonide is unavailable AND proteinuria persists ≥0.5 g/day despite RASi + SGLT2i
• Reduced-dose regimen: prednisolone 0.5 mg/kg/day tapered over 6 months (NOT high-dose - TESTING trial showed excess deaths from infection with high-dose oral steroids)
• Combine with antimicrobial prophylaxis (PCP prophylaxis)
• Avoid in eGFR <30 mL/min

IgAN with Rapidly Progressive GN (crescentic IgAN)

• Treat as RPGN: IV methylprednisolone pulse → oral prednisolone + cyclophosphamide
• Prognosis poor (kidney survival ~50% at 1 year, ~20% at 5 years)

III. MEMBRANOUS NEPHROPATHY (Primary MN - PLA2R-positive)

Risk Stratification (guides timing and choice of therapy):

Universal Supportive Therapy (all patients):

• ACEi or ARB maximized
• SGLT2 inhibitor (emerging benefit in nephrotic syndrome)
• Statins (nephrotic hyperlipidemia)
• Anticoagulation if albumin <2.5 g/dL (high VTE risk in MN) - consider prophylactic LMWH or warfarin
• Low-salt, moderate-protein diet
• Diuretics for edema

Immunosuppression:

First-line: Rituximab (preferred for high-risk stable eGFR)

• MENTOR trial (NEJM 2019): Rituximab superior to cyclosporine at maintaining complete/partial remission at 24 months in patients with proteinuria >10 g/day
• Regimen: 1000 mg IV x 2 doses, 14 days apart (repeat cycle at 6 months if anti-PLA2R antibody titer remains elevated or no response)
• Monitor: CD19 count (B cell depletion marker), anti-PLA2R titer (serological remission often precedes clinical remission by 3-6 months)
• RI-CYCLO trial: rituximab comparable to alternating steroid-cyclophosphamide; preferred in fertility-concerned patients

Second-line/Deteriorating eGFR: Alkylating agent regimens

• Month 1, 3, 5: IV methylprednisolone 1 g/day x 3 days → oral methylprednisolone 0.5 mg/kg/day x 27 days
• Month 2, 4, 6: Oral chlorambucil 0.2 mg/kg/day OR cyclophosphamide 2.5 mg/kg/day x 30 days
• UK Membranous Trial: this regimen superior to cyclosporine and supportive therapy for preventing ESKD when eGFR is declining

Calcineurin Inhibitors (CNIs): Cyclosporine or tacrolimus

• Option when rituximab or alkylating agents are contraindicated or declined
• Tacrolimus 0.05-0.075 mg/kg/day (target trough 4-8 ng/mL) x 18 months, then taper
• High relapse rate (>70% by 3 years after discontinuation) - combine with MMF (STARMEN trial: alternating steroid-CYC superior to sequential tacrolimus→rituximab)
• Cyclosporine 3-5 mg/kg/day

Rituximab-refractory MN:

• Obinutuzumab (anti-CD20, type II) - more complete B cell depletion; emerging evidence (PMID: 40104551)
• Off-label: belimumab (anti-BAFF), mycophenolate mofetil

Monitoring response:

• Anti-PLA2R antibody: serological remission (antibody negative) typically precedes proteinuria remission by 3-6 months; negative antibody with ongoing proteinuria = "immunological remission" - continue to observe for proteinuria response before retreating

IV. ANCA-ASSOCIATED VASCULITIS (AAV)

Classification-Guided Decision:

• Severe AAV: eGFR <50 mL/min/1.73m², dialysis-dependent, or pulmonary hemorrhage → aggressive induction
• Non-severe AAV: No organ-threatening features → less intensive approach
• PR3-ANCA (c-ANCA) vs. MPO-ANCA (p-ANCA) affects relapse risk and rituximab preference

INDUCTION THERAPY (3-6 months)

Standard: Glucocorticoids + Rituximab OR Cyclophosphamide

• 375 mg/m² IV weekly x 4 doses, OR 1000 mg IV x 2 doses (14 days apart)
• RAVE trial: rituximab non-inferior to cyclophosphamide overall; superior in PR3-ANCA and relapsing disease
• RITUXVAS trial: rituximab ± 2 doses cyclophosphamide, comparable to cyclophosphamide alone
• FDA/EMA-approved for AAV induction

• IV: 15 mg/kg (max 1.2 g) every 2-3 weeks x 3-6 pulses (CYCLOPS regimen - preferred: lower total dose vs. oral, equal efficacy)
• Oral: 2 mg/kg/day (reduce by 25 mg if age >60 years); max 3-6 months then switch to maintenance
• Target leukocyte nadir ≥3000/mm³

• 2 doses of rituximab 375 mg/m² + 2 doses IV cyclophosphamide → rapid steroid taper
• Reduces mortality, relapses, and ESKD vs. cyclophosphamide alone (propensity-matched data)

• IV methylprednisolone pulse 500-1000 mg/day x 1-3 days (severe disease/pulmonary hemorrhage)
• Then oral prednisolone 1 mg/kg/day (max 60-80 mg); taper to <10 mg/day by week 12-16
• PEXIVAS regimen (non-inferior, 60% less steroid): preferred to reduce cumulative GC exposure

• 30 mg twice daily orally
• Used as a glucocorticoid-sparing strategy - replaces prednisone taper after initial pulse
• Remission rate 72.3% (avacopan) vs. 70.1% (prednisone) at week 26; superior sustained remission at week 52
• FDA/EMA approved 2021 for AAV
• Especially valuable: diabetes, osteoporosis, infections (to minimize steroid burden)
• Monitor: liver enzymes, meningococcal vaccination

Plasma Exchange (PLEX) - Selective Use Only:

• Use for: Pulmonary hemorrhage requiring oxygen/mechanical ventilation, dialysis-dependent AKI without significant chronic fibrosis (eGFR <30 mL/min/1.73m²)
• Do NOT use routinely: PEXIVAS trial (n=704) showed no reduction in mortality or ESKD with PLEX in severe AAV

MAINTENANCE THERAPY (minimum 24 months, often longer)

• 500 mg IV every 6 months x 2 years (MAINRITSAN regimen)
• OR 1000 mg IV at months 0 and 6

• Switch after 3-6 months of CYC induction (CYCAZAREM trial)
• Non-inferior to MMF for maintenance (IMPROVE trial)

• PR3-ANCA positive: higher relapse risk → minimum 48 months maintenance; some guidelines suggest indefinite low-dose rituximab
• MPO-ANCA: lower relapse risk → 24-36 months; consider stopping after sustained remission
• Monitor: ANCA titers (rising titer signals relapse risk, but not always), urinalysis, creatinine every 3 months

Relapsing AAV:

• Reinduction with rituximab (preferred over re-treatment with cyclophosphamide to minimize cumulative alkylating agent toxicity)
• Consider avacopan addition if not already used
• Extend maintenance duration

V. Summary Comparison Table

• KDIGO 2024 Lupus Nephritis guideline - Kidney Int. 2024;105(1S):S1-S69
• KDIGO 2025 IgAN/IgAV guideline
• ACR 2025 SLE Guideline (published May 2025)
• EULAR 2023 SLE recommendations - Ann Rheum Dis. 2024;83(1):15-29
• PEXIVAS (NEJM 2020), ADVOCATE (NEJM 2021), MENTOR (NEJM 2019), PROTECT (Lancet 2023), APPLAUSE-IgAN (NEJM 2025), ALIGN (NEJM 2024)
• Comprehensive Clinical Nephrology 7e, pp. 362-370 (AAV); NKF Primer on Kidney Diseases 8e, pp. 265-280 (MN, IgAN)
• Casal Moura M et al. Nat Rev Rheumatol 2025 (PMID: 41102379) - AAV management update
• De Vriese AS et al. Kidney Int 2025 (PMID: 39521057) - Lupus nephritis treatment goals