Complement Alternative Pathway Dysregulation → Thrombotic Microangiopathy → Multi-Organ Damage
Atypical Hemolytic Uremic Syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy (TMA) driven by chronic, uncontrolled activation of the complement alternative pathway (AP). Unlike typical HUS (caused by Shiga toxin-producing E. coli), aHUS is caused by:
- Germline mutations in complement regulatory genes: CFH (~25%), CD46 (~12%), CFI (~8%), C3 (~8%), CFB (~2%), THBD (~3%)
- Anti-CFH autoantibodies (~10% of cases)
- Incomplete penetrance (~50% in CFH carriers) — environmental triggers required
AP Dysregulation (CFH/CFI mutation)
↓
C3 Tickover → C3b accumulation (uncontrolled)
↓
C5 Convertase (C3b₂Bb) → C5 cleavage
↓
C5a (anaphylatoxin) + C5b → MAC (C5b-9)
↓
Endothelial injury → TMA
↓
Thrombocytopenia + MAHA + Acute Kidney Injury
- Incidence: ~0.5–2 per million/year
- Median age at onset: 2.5 years (children) / 33 years (adults)
- ESRD risk: 50% within first year if untreated
- Mortality: 25% in first acute episode
- Relapse rate: 40–80% with CFH mutations
| File | Description |
|---|---|
ahus_qsp_model.dot |
Graphviz source (13 clusters, 130+ nodes) |
ahus_qsp_model.svg |
Scalable vector diagram |
ahus_qsp_model.png |
High-resolution raster (150 dpi) |
Clusters included:
- Genetic & Acquired Risk Factors
- Complement Alternative Pathway (AP)
- Classical & Lectin Pathways (CP/LP)
- Complement Regulatory Proteins (CFH, CFI, CD46, CD59...)
- Terminal Complement (C5–C9 → MAC)
- Endothelial Injury & TMA
- Platelet & Hematological Compartment
- Renal Pathophysiology
- Extrarenal Manifestations
- Inflammatory & Coagulation Amplification
- Drug Mechanisms (PK/PD)
- Clinical Endpoints & Biomarkers
- Clinical Monitoring & Management
| # | Compartment | Variable | Unit | Notes |
|---|---|---|---|---|
| 1 | Drug central | Drug_C |
mg | Eculizumab PK (IV) |
| 2 | Drug peripheral | Drug_P |
mg | 2-comp PK |
| 3 | Drug-C5 complex | Drug_C5 |
mg | TMDD complex |
| 4 | C3 pool | C3pool |
nM | Plasma C3 (~8000 nM) |
| 5 | AP C3b | C3b_AP |
nM | Active C3b accumulation |
| 6 | Free C5 | C5free |
nM | Key drug target (~395 nM) |
| 7 | C5 convertase | C5conv |
AU | C3b₂Bb activity |
| 8 | MAC flux | MACflux |
AU | C5b-9 formation rate |
| 9 | Endothelial injury | Endo_inj |
0–10 | TMA driver score |
| 10 | Platelet count | PLT |
×10⁹/L | Thrombocytopenia marker |
| 11 | Hemoglobin | Hgb |
g/dL | MAHA marker |
| 12 | LDH | LDH |
U/L | Hemolysis marker |
| 13 | Haptoglobin | Hpg |
g/L | Free Hgb scavenger |
| 14 | eGFR | GFR |
mL/min/1.73m² | Renal function |
| 15 | Schistocytes | Schist |
% | Blood smear |
| 16 | CRP | CRP |
mg/L | Inflammatory marker |
| 17 | sC5b-9 | sC5b9 |
ng/mL | Complement activation biomarker |
| 18 | CH50 | CH50pct |
% | Functional complement activity |
| Parameter | Value | Unit | Reference |
|---|---|---|---|
| CL | 0.31 | L/day | Menne 2015 |
| V1 | 5.30 | L | Menne 2015 |
| Q | 0.54 | L/day | Menne 2015 |
| V2 | 4.10 | L | Menne 2015 |
| t½ | ~11 | days | Calculated |
| C5 Kd | ~10 | pM | Thomas 1996 |
| MW | 148 | kDa | Product info |
| Scenario | Treatment | Dosing | Route |
|---|---|---|---|
| 1 | Natural history | — | — |
| 2 | Eculizumab (standard) | 900 mg/wk×4 → 1200 mg/q2w | IV |
| 3 | Ravulizumab | 2400/3000 mg → 3300 mg/q8w | IV |
| 4 | Eculizumab + Danicopan (fDi) | Standard + 150 mg TID oral add-on | IV+PO |
| 5 | Iptacopan (oral fBi) | 200 mg BID | PO |
dC3b/dt = kAP × C3/C3_ss + kAP_amp × (C3b/C3_ss) × C3/C3_ss
- kC3b_deg × CFH_factor × CFI_factor × C3b
dC5free/dt = kC5syn - kC5deg × C5free - kC5conv × C5conv × C5free
- (kon × Cc_nM × C5free - koff × [Drug-C5])
dEI/dt = kEI_MAC × MACflux - kEI_rep × EI
dGFR/dt = kGFR_rep × (GFR_ss - GFR) × (1 - EI/EI_max)
- kGFR_loss × GFR × (EI/6)
| Tab | Content |
|---|---|
| Overview | Disease overview, mechanistic cascade, KPI value boxes |
| Patient Profile | Complement regulatory radar, presentation values, cascade dynamics |
| PK Analysis | Eculizumab concentration-time, TMDD (C5 free vs bound), blockade % |
| Complement PD | C3 pool, C3b AP, C5 convertase, MAC flux |
| TMA & Hematology | Platelets, Hgb, LDH, haptoglobin, schistocytes |
| Renal Outcomes | eGFR trajectory, endothelial injury, dialysis risk, CKD staging |
| Scenario Compare | All 5 treatment arms overlaid, efficacy summary table |
| Biomarkers | sC5b-9, CH50, CRP, biomarker correlation dashboard |
# Install required packages
install.packages(c("mrgsolve","dplyr","ggplot2","tidyr","patchwork",
"shiny","shinydashboard","plotly","DT"))source("ahus_mrgsolve_model.R")
# → runs 5 treatment scenarios × 365 days
# → generates multi-panel comparison plot
# → prints efficacy summary table at days 28, 84, 180, 365shiny::runApp("ahus_shiny_app.R")
# → Interactive 8-tab dashboard
# → Parameter sliders: CFH/CFI/CD46 function, AP activation rate, kEI_MAC
# → Scenario selector: 5 treatment arms
# → All plots in plotly (interactive, zoom, download)- Day 7: CH50 → <10% (complement blockade confirmed)
- Day 28: PLT >150 ×10⁹/L in ~80% of patients
- Day 84: eGFR improvement of 25–35 mL/min
- Day 365: Dialysis-free rate ~85% vs ~30% untreated
- Progressive TMA → ESRD within 3–6 months
- 25% mortality in first acute episode
- Persistent dialysis requirement in >50%
- Proximal complement inhibition → also addresses C3-mediated hemolysis
- Oral bioavailability eliminates IV infusion burden
- Covers C3 fragment deposition (missed by anti-C5 agents)
| Biomarker | Normal | Active aHUS | On Eculizumab |
|---|---|---|---|
| CH50 | 60–144 U/mL (75–100%) | ↓↓ (consumed) | <10% |
| sC5b-9 | <244 ng/mL | >2000 ng/mL | <244 ng/mL |
| C3 | 1.0–1.8 g/L | ↓ (consumed) | Normalizes |
| C4 | 0.2–0.4 g/L | Normal (AP) | Normal |
| PLT | 150–400 ×10⁹/L | <150 | Recovers |
| LDH | <ULN (200 U/L) | >500 U/L | Normalizes |
| Haptoglobin | 0.3–2.0 g/L | <0.1 g/L | Normalizes |
atypical-hemolytic-uremic-syndrome/
├── ahus_qsp_model.dot ← Graphviz mechanistic map source
├── ahus_qsp_model.svg ← Scalable diagram (13 clusters, 130+ nodes)
├── ahus_qsp_model.png ← High-res PNG thumbnail (150 dpi)
├── ahus_mrgsolve_model.R ← 18-ODE mrgsolve model, 5 scenarios
├── ahus_shiny_app.R ← Interactive Shiny dashboard (8 tabs)
├── ahus_references.md ← 55 PubMed references (13 sections)
└── README.md ← This file
- Fakhouri F et al. Lancet 2017;390:1847–1860. PMID: 28499565
- Legendre CM et al. NEJM 2013;368:2169–2181. PMID: 23738544
- Jokiranta TS. Blood 2017;129:2847–2856. PMID: 28416507
- Rother RP et al. Nat Biotechnol 2007;25:1256–1264. PMID: 17989688
- Goodship TH et al. (KDIGO). Kidney Int 2017;91:539–551. PMID: 28131400
See ahus_references.md for all 55 references.
Built by Claude Code Routine | 2026-06-27 | QSP Disease Model Library