9.5 Complications of Chronic Kidney Disease: Anemia, CKD-MBD & Acidosis
Key Takeaways
- Chronic kidney disease-mineral and bone disorder is enumerated under disorders of calcium metabolism and bone as well as under nephrology.
- Iron stores must be repleted before starting an erythropoiesis-stimulating agent, and hemoglobin is not normalized because higher targets increase stroke and death.
- Non-calcium-based phosphate binders are preferred when vascular calcification is present or calcium load is a concern.
- Sodium bicarbonate to correct metabolic acidosis slows progression and preserves muscle mass in advanced disease.
- Vein preservation in the non-dominant arm should begin well before dialysis is needed so that arteriovenous fistula creation remains possible.
1. Anemia of Chronic Kidney Disease
Anemia in CKD is typically normocytic, normochromic, and hypoproliferative, developing predictably once eGFR declines below 45–60 mL/min/1.73m2.
Pathophysiology
- Relative Erythropoietin (EPO) Deficiency: Interstitial peritubular fibroblasts in the renal cortex become fibrotic and unable to synthesize adequate erythropoietin in response to hypoxia.
- Functional Iron Deficiency (Hepcidin Excess): Chronic systemic inflammation in CKD upregulates hepatic Hepcidin production. Hepcidin binds to and degrades Ferroportin (the sole cellular iron exporter on enterocytes and macrophages), trapping iron in storage sites and preventing bone marrow utilization for erythropoiesis.
- Uremic Toxins: Shorten red blood cell lifespan from 120 days to 60–90 days.
Evaluation & Iron Repletion Targets
- Initial Workup: Complete Blood Count (CBC), absolute reticulocyte count, Serum Ferritin, Transferrin Saturation (TSAT = [Serum Iron / TIBC] x 100), Vitamin B12, Folate, and TSH.
- Iron Repletion Goals (KDIGO):
- Target Ferritin > 100 ng/mL in non-dialysis CKD (> 200 ng/mL in hemodialysis CKD).
- Target TSAT > 20% (optimally 20–30%).
- Route of Administration:
- Oral Iron (Ferrous sulfate, Ferrous gluconate, Ferric citrate): Trial in non-dialysis CKD; poorly absorbed due to elevated hepcidin and causes GI intolerance.
- Intravenous Iron (Ferric carboxymaltose, Iron sucrose, Ferumoxytol): Preferred when TSAT <=20% or ferritin <=100–200 ng/mL, if oral iron fails, or in all patients on maintenance hemodialysis.
Erythropoiesis-Stimulating Agents (ESAs) & Safety Limits
- Agents: Short-acting Epoetin alfa (Procrit, Epogen) or long-acting Darbepoetin alfa (Aranesp) or Methoxy polyethylene glycol-epoetin beta (Mircera).
- Initiation Threshold: Initiate ESA therapy only when Hemoglobin is < 10.0 g/dL, and only AFTER iron stores are fully repleted (TSAT >20%, Ferritin >100–200 ng/mL).
- Target Hemoglobin Range: 10.0 to 11.5 g/dL.
Black Box Warning & Landmark Trials (TREAT, CHOIR, CREATE): NEVER target a normal hemoglobin level (>11.5–12.0 g/dL or >13.0 g/dL). The TREAT and CHOIR randomized controlled trials demonstrated that aggressive ESA dosing to achieve normal hemoglobin levels resulted in a significant increase in fatal and non-fatal stroke (almost 2-fold in TREAT), venous and arterial thromboembolism, vascular access thrombosis, refractory hypertension, and all-cause mortality without improving survival.
2. CKD-Mineral and Bone Disorder (CKD-MBD)
CKD-MBD is a systemic disorder of mineral and bone metabolism characterized by biochemical abnormalities (calcium, phosphorus, PTH, FGF-23, vitamin D), bone alterations (osteodystrophy), and soft tissue / vascular calcification.
Pathophysiologic Sequence
Decreased GFR (<60 mL/min)
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Phosphate Retention (Hyperphosphatemia)
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Stimulates Osteocytes Directly Lowers Ionized Calcium
to Secrete FGF-23 (Calcium x Phosphate Binding)
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FGF-23 Suppresses Renal │
1-Alpha-Hydroxylase (CYP27B1) │
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Decreased 1,25-(OH)2 Vitamin D │
(Calcitriol Deficiency) │
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Decreased Gut Calcium Absorption │
│ │
└───────────┬──────────────┘
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Systemic Hypocalcemia
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Massive Stimulation of Parathyroid Glands
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SECONDARY HYPERPARATHYROIDISM (High PTH)
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High-Turnover Bone Disease Extensive Medial Vascular
(Osteitis Fibrosa Cystica) & Valvular Calcification
Management of CKD-MBD
| Therapeutic Target | Modality / Pharmacotherapy | Mechanism & Key Instructions |
|---|---|---|
| 1. Hyperphosphatemia | Dietary Phosphate Restriction (800–1000 mg/day) | Eliminate processed foods, sodas, and inorganic phosphate food preservatives (which have 90–100% intestinal absorption compared to 40–60% for organic plant/meat phosphates). |
| Non-Calcium-Based Phosphate Binders (Preferred):<br/>• Sevelamer Carbonate (800–1600 mg PO TID with meals)<br/>• Lanthanum Carbonate (500–1000 mg PO TID chewed with meals) | Bind dietary phosphate in gut lumen; preferred first-line to minimize exogenous calcium loading, slowing progressive vascular and valvular calcification. Also lowers LDL cholesterol. | |
| Calcium-Based Phosphate Binders:<br/>• Calcium Acetate (PhosLo)<br/>• Calcium Carbonate | Inexpensive; avoid if patient has hypercalcemia, arterial calcifications, or adynamic bone disease due to accelerated vascular calcification risk. | |
| 2. Active Vitamin D Deficiency & High PTH | Active Vitamin D Sterols:<br/>• Calcitriol (0.25–0.5 µg PO daily)<br/>• Paricalcitol (selective VDR activator) | Directly suppresses PTH transcription; monitor closely as active vitamin D increases intestinal absorption of both calcium and phosphate, triggering hypercalcemia and hyperphosphatemia. |
| 3. Secondary Hyperparathyroidism | Calcimimetics:<br/>• Cinacalcet (Sensipar, 30–90 mg PO daily)<br/>• Etelcalcetide (IV post-hemodialysis) | Allosteric modulators of the Calcium-Sensing Receptor (CaSR) on parathyroid cells. Increases receptor sensitivity to extracellular calcium, suppressing PTH secretion without increasing serum calcium or phosphate (causes hypocalcemia; monitor serum Ca2+). |
| 4. Tertiary Hyperparathyroidism | Subtotal Parathyroidectomy | Indicated when parathyroid hyperplasia becomes autonomous with refractory hypercalcemia, hyperphosphatemia, and PTH >800–1000 pg/mL despite maximal medical therapy. |
3. Metabolic Acidosis & Vascular Access Preparation
Chronic Metabolic Acidosis in CKD
- Mechanism: As functional nephron mass decreases below 25%, the kidney fails to synthesize adequate ammonia (NH3) and excrete daily dietary fixed hydrogen ions (titratable acid), producing a normal or high anion gap metabolic acidosis.
- Consequences: Chronic acidosis (serum bicarbonate <22 mEq/L) stimulates the ubiquitin-proteasome system causing muscle wasting (sarcopenia), accelerates osteoclastic bone resorption, and accelerates progressive GFR decline.
- Management: Treat with Oral Sodium Bicarbonate (650 mg PO BID to TID; 1 g = ~12 mEq HCO3-) or Sodium Citrate (Bicitra; note: avoid citrate if receiving aluminum binders) titrated to maintain serum bicarbonate between 22 and 26 mEq/L.
Vascular Access Planning & "Save the Vein"
Timely preparation for renal replacement therapy (RRT) prevents emergency hospital admissions with temporary tunneled catheters.
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Vascular Access Hierarchy:
- Native Arteriovenous Fistula (AVF) (Gold Standard): Surgical anastomosis connecting an artery directly to a vein (e.g., radial-cephalic [Brescia-Cimino] or brachial-cephalic). Lowest infection rate, lowest thrombosis rate, best secondary patency, and lowest mortality. Requires 3 to 6 months to mature.
- Arteriovenous Graft (AVG): Synthetic PTFE tube interposed between artery and vein. Matures faster (2–4 weeks), but significantly higher thrombosis and infection rates.
- Tunneled Cuffed Catheter (Permacath): Highest rates of catheter-related bloodstream infection, central venous stenosis, and all-cause mortality. Reserve as a bridge or last resort.
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Access Timing: Construct the AVF 6 to 12 months before anticipated maintenance dialysis (typically when eGFR is 15 to 20 mL/min/1.73m2, Stage G4/G5).
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"Save the Vein" Rule: In all patients with CKD Stage G4 or G5 (eGFR <30 mL/min/1.73m2), strictly protect the non-dominant upper extremity from all peripheral venipunctures, IV line placements, and especially Peripherally Inserted Central Catheters (PICCs). Subclavian vein catheterization is strictly contraindicated due to high rates of subclavian vein stenosis, which destroys the ipsilateral limb for future AVF/AVG creation.
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Pre-Emptive Kidney Transplantation:
- Transplantation provides superior long-term survival, lower cardiovascular mortality, and superior quality of life compared to maintenance dialysis.
- Referral Threshold: Refer for comprehensive transplant evaluation when eGFR falls below 20 mL/min/1.73m2 (Stage G4). A pre-emptive living donor transplant (performed prior to ever starting dialysis) yields the highest graft and patient survival rates.
A 64-year-old woman with CKD Stage G4 (eGFR 22 mL/min/1.73m2) presents with progressive fatigue and exertional dyspnea. Her hemoglobin is 8.6 g/dL, MCV is 88 fL, serum ferritin is 70 ng/mL, and transferrin saturation (TSAT) is 15%. Serum B12, folate, and TSH are normal, and stool occult blood tests are negative. What is the most appropriate next step in the management of her anemia?
A 60-year-old man with CKD Stage G4 (eGFR 18 mL/min/1.73m2) secondary to hypertensive nephrosclerosis presents for follow-up. Laboratory studies demonstrate: Serum Calcium 9.2 mg/dL, Serum Phosphorus 6.8 mg/dL (normal: 2.5–4.5 mg/dL), Intact PTH 380 pg/mL (target for stage G4: 70–110 pg/mL), and 25-hydroxyvitamin D 32 ng/mL. Plain abdominal radiography reveals extensive calcification of the abdominal aorta and iliac arteries. In addition to dietary phosphate restriction, which phosphate binder is most appropriate?