Calcium-Phosphate Homeostasis System
Interactive diagram showing phosphate regulation via FGF23-Klotho axis, PTH, and calcitriol pathways
🔑 Key Concept: Phosphate homeostasis involves the critical FGF23-Klotho axis (primarily from kidneys) working with PTH and calcitriol. Note the inverse Ca-PO₄ relationship and the central role of kidneys in both excretion and hormone production.
🎯 Phosphorus Quick Reference
Normal Range: 2.5-4.5 mg/dL (0.81-1.45 mmol/L)
Critical for: ATP synthesis, bone mineralization, cellular signaling
📊 Phosphorus Distribution & Physiology
Total Body Phosphorus
~700g
Adult human body
Skeletal System
85%
As hydroxyapatite
Soft Tissues
14%
Intracellular (ATP, DNA)
Extracellular
1%
Measured serum level
Key Physiologic Roles
- Energy Metabolism: ATP, ADP, AMP, creatine phosphate
- Cellular Signaling: Protein phosphorylation, second messengers
- Structural: DNA, RNA, phospholipid membranes
- Bone Mineralization: Hydroxyapatite Ca₁₀(PO₄)₆(OH)₂
- Acid-Base Buffer: HPO₄²⁻/H₂PO₄⁻ system
- Oxygen Delivery: 2,3-DPG in RBCs
🔄 Phosphate Regulation System
Primary Regulators
| Regulator | Stimulus | Kidney Effect | GI Effect | Net Result |
|---|---|---|---|---|
| PTH | ↑ PO₄, ↓ Ca²⁺ | ↓ PO₄ reabsorption (phosphaturia) ↑ Calcitriol synthesis |
Indirect (via calcitriol) | ↓ Serum PO₄ |
| FGF23 | ↑ PO₄, ↑ Calcitriol | ↓ PO₄ reabsorption ↓ Calcitriol synthesis |
↓ PO₄ absorption | ↓ Serum PO₄ |
| Calcitriol | ↓ PO₄, ↑ PTH | ↑ PO₄ reabsorption | ↑ PO₄ absorption | ↑ Serum PO₄ |
| Klotho | Co-receptor for FGF23 | Enables FGF23 signaling | - | ↓ Serum PO₄ |
Phosphate Reabsorption Sites
Proximal Tubule: 80-90% (via NaPi-2a, NaPi-2c)
Distal Tubule: 10-20%
PTH & FGF23 → ↓ NaPi transporters → phosphaturia
📉 Hypophosphatemia Overview
PO₄ < 2.5 mg/dL
Severity Classification
- Mild: 2.0-2.5 mg/dL
- Moderate: 1.0-2.0 mg/dL
- Severe: <1.0 mg/dL (life-threatening)
Key Causes
- Redistribution: Refeeding syndrome (!), insulin, respiratory alkalosis
- ↓ GI Absorption: Malabsorption, antacids, vitamin D deficiency
- ↑ Renal Loss: Hyperparathyroidism, Fanconi syndrome
- Other: CRRT, hungry bone syndrome, DKA treatment
Clinical Manifestations
- Muscular: Weakness, rhabdomyolysis
- Neurologic: Altered mental status, seizures
- Hematologic: Hemolysis, impaired WBC function
- Respiratory: Failure (diaphragm weakness)
- Cardiac: Cardiomyopathy
📈 Hyperphosphatemia Overview
PO₄ > 4.5 mg/dL
Key Causes
- ↓ Renal Excretion: CKD (most common), AKI
- ↑ Cellular Release: Tumor lysis, rhabdomyolysis
- ↑ Intake/Absorption: Phosphate enemas, vitamin D excess
- Endocrine: Hypoparathyroidism, acromegaly
- Pseudohyperphosphatemia: Paraproteinemia, hyperlipidemia
Clinical Consequences
- Acute: Hypocalcemia (precipitation)
- Chronic (CKD-MBD):
- Vascular calcification
- Secondary hyperparathyroidism
- Renal osteodystrophy
- Calciphylaxis
⚠️ REFEEDING SYNDROME - Critical Alert
Life-threatening phosphate depletion with refeeding after starvation
High-Risk Patients:
- BMI <16 kg/m²
- Unintentional weight loss >15% in 3-6 months
- Little/no nutrition for >10 days
- Low baseline K⁺, PO₄, or Mg²⁺
- Chronic alcoholism, anorexia nervosa
Prevention Protocol:
1. Check baseline: PO₄, K⁺, Mg²⁺ before feeding
2. Start low: 10-20 kcal/kg/day initially
3. Supplement: Thiamine 100mg IV before feeding, then electrolytes
4. Monitor: Daily electrolytes × 3-5 days
5. Advance slowly: Increase calories by 20% q2-3 days
🦴 CKD-Mineral Bone Disease (CKD-MBD)
The central role of phosphate retention in CKD complications
Pathophysiology Cascade:
- ↓ GFR → Phosphate retention
- ↑ FGF23 (earliest change)
- ↓ Calcitriol synthesis
- ↓ Calcium absorption → hypocalcemia
- ↑ PTH (secondary hyperparathyroidism)
- Bone disease + vascular calcification
Calcium-Phosphate Product
Ca × PO₄ < 55 mg²/dL²
Higher values → metastatic calcification risk
💊 Phosphate Binder Comparison
| Binder Type | Examples | Advantages | Disadvantages | Clinical Use |
|---|---|---|---|---|
| Calcium-based | Calcium carbonate Calcium acetate |
• Inexpensive • Effective • Treats hypocalcemia |
• Hypercalcemia risk • ↑ Ca×PO₄ product • Vascular calcification |
First-line if Ca not elevated |
| Non-calcium | Sevelamer Lanthanum |
• No Ca load • ↓ LDL (sevelamer) • Less calcification |
• Expensive • GI side effects • Lanthanum accumulation? |
Hypercalcemia or high Ca×PO₄ |
| Iron-based | Ferric citrate Sucroferric oxyhydroxide |
• Treats anemia • Potent binding • No Ca load |
• GI side effects • Iron overload risk • Dark stools |
CKD with anemia |
| Aluminum | Aluminum hydroxide | • Very effective • Short-term use |
• Aluminum toxicity • Dementia, bone disease |
Acute severe hyperPO₄ only |
Clinical Pearl: Take binders WITH meals (bind dietary phosphate). Separate from other medications by ≥1 hour.
📋 Phosphate Replacement Protocols
IV Phosphate Replacement (for PO₄ <2.0 mg/dL)
| Serum PO₄ | IV Dose | Rate |
|---|---|---|
| 1.5-2.0 mg/dL | 0.16-0.32 mmol/kg | Over 4-6 hours |
| 1.0-1.5 mg/dL | 0.32-0.64 mmol/kg | Over 6-8 hours |
| <1.0 mg/dL | 0.64-1.0 mmol/kg | Over 8-12 hours |
⚠️ Maximum rate: 7 mmol/hour to avoid hypocalcemia/tetany
Preparations: K-Phos (K⁺ 4.4 mEq/mmol PO₄) or Na-Phos (Na⁺ 4.0 mEq/mmol PO₄)
Oral Replacement (for PO₄ >2.0 mg/dL)
- Mild deficiency: 30-60 mmol/day divided TID-QID
- Options: K-Phos, Neutra-Phos, milk (1 mmol/30 mL)
- Side effect: Diarrhea (osmotic)
💡 High-Yield Clinical Pearls
- ✓ Refeeding syndrome - Most dangerous cause of hypophosphatemia
- ✓ Respiratory alkalosis - Causes acute intracellular shift of PO₄
- ✓ CKD is #1 cause of chronic hyperphosphatemia
- ✓ FGF23 rises first in CKD, before PTH or phosphate
- ✓ Ca × PO₄ product >55 = Metastatic calcification risk
- ✓ Phosphate binders WITH meals - Bind dietary phosphate
- ✓ IV phosphate can cause hypocalcemia, give slowly
- ✓ Tumor lysis syndrome - Massive PO₄ release, treat with rasburicase
- ✓ Vitamin D increases both Ca AND PO₄ absorption
- ✓ PTH paradox - ↑PTH but ↑PO₄ in CKD (kidney can't excrete)
- ✓ Hidden phosphate - Processed foods, dark sodas (phosphoric acid)
- ✓ Hungry bone syndrome - Post-parathyroidectomy PO₄ drops
📋 Quick Reference Values
| Parameter | Normal Range | Critical Values |
|---|---|---|
| Serum Phosphate | 2.5-4.5 mg/dL | <1.0 or >7.0 mg/dL |
| 24hr Urine PO₄ | 400-1300 mg/day | Varies with diet |
| FGF23 | <50 RU/mL | ↑↑ in CKD |
| PTH (with PO₄) | 15-65 pg/mL | ↑ with hyperPO₄ in CKD |
| Ca × PO₄ Product | <55 mg²/dL² | >70 high calcification risk |
| Dietary PO₄ | 1000-1500 mg/day | Restrict to 800-1000 in CKD |
🔗 Calcium-Phosphate Interactions
Inverse Relationship
- PTH effect: ↑ Ca reabsorption but ↓ PO₄ reabsorption
- Precipitation: High Ca × PO₄ → tissue deposition
- Vitamin D: ↑ BOTH Ca and PO₄ absorption
- FGF23: ↓ PO₄ and ↓ calcitriol (indirect ↓ Ca)
Clinical Implications
- Acute hyperPO₄ → Hypocalcemia (precipitation)
- CKD: ↑ PO₄ drives secondary hyperparathyroidism
- Post-parathyroidectomy: Both Ca and PO₄ drop (hungry bone)
- Vitamin D therapy: Monitor BOTH Ca and PO₄