CKD Mineral Bone Disorder (Adult)

1. Clinical Overview

CKD Mineral Bone Disorder (CKD-MBD) is a systemic disorder of mineral and bone metabolism due to Chronic Kidney Disease, manifested by either one or a combination of the following: (1) abnormalities of calcium, phosphorus, PTH, or Vitamin D metabolism; (2) abnormalities in bone turnover, mineralization, volume, linear growth, or strength; and (3) vascular or other soft-tissue calcification. [1]

The clinical significance of CKD-MBD extends far beyond skeletal complications. It is a major driver of the excessively high cardiovascular mortality seen in renal patients, with vascular calcification acting as a non-traditional but potent risk factor. The disorder is no longer viewed simply as "bone disease" (Renal Osteodystrophy) but as a complex endocrine failure involving the FGF23-Klotho axis, which leads to accelerated vascular aging and medial calcification. [2]

Management has evolved from reactive correction of biochemistry to a proactive "trend-based" approach as per KDIGO 2017/2024 guidelines. The therapeutic arsenal includes phosphate binders, active Vitamin D analogues, and calcimimetics (Cinacalcet), with parathyroidectomy reserved for refractory tertiary hyperparathyroidism. [3]

Key Definitions

CKD-MBD is the umbrella term encompassing:

• Biochemical abnormalities: Calcium, phosphate, PTH, FGF23, and Vitamin D
• Bone disease: Renal osteodystrophy (the histological entity)
• Extraskeletal calcification: Vascular and soft tissue deposition

Renal Osteodystrophy refers specifically to the histological bone changes seen on bone biopsy in CKD, classified by TMV (Turnover, Mineralization, Volume) criteria.

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2. Epidemiology

The Burden of Bone and Vascular Disease

Prevalence:

• Biochemical abnormalities begin as early as Stage G3a (eGFR less than 60 mL/min/1.73m²)
• Secondary hyperparathyroidism is present in > 90% of patients reaching Stage G5
• FGF23 elevation can be detected at eGFR less than 60, often before PTH rises [4]

Fracture Risk:

• Patients on dialysis have a 4-fold higher risk of hip fracture compared to age-matched controls
• Post-fracture mortality is significantly higher in CKD patients, with 1-year mortality approaching 50% after hip fracture [5]
• Vertebral fractures are often asymptomatic and underdiagnosed

Cardiovascular Link:

• Vascular calcification is present in > 80% of patients at the start of dialysis
• The degree of coronary artery calcification (CAC) in a 30-year-old on dialysis is often equivalent to an 80-year-old in the general population
• Each 1 SD increase in FGF23 is associated with a 23% increase in mortality risk [6]

Economic Burden:

• CKD-MBD management accounts for approximately 15-20% of total dialysis costs
• Fractures in dialysis patients result in prolonged hospitalizations and increased healthcare utilization
• Calciphylaxis, though rare (less than 5% of dialysis patients), carries mortality rates of 45-80% [7]

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3. Aetiology & Pathophysiology

The 7-Step Molecular Cascade

Exam Detail: The pathogenesis of CKD-MBD is a sophisticated hormonal cascade that begins early in CKD progression:

Step 1: Phosphate Retention

As GFR falls below 60 mL/min/1.73m², the kidney's ability to excrete the daily phosphate load (approximately 1000mg from a typical Western diet) diminishes. Even before serum phosphate rises detectably, phosphate retention begins at the nephron level.

Step 2: FGF23 Surge (The Earliest Marker)

Osteocytes in bone sense early phosphate retention and release FGF23 (Fibroblast Growth Factor 23). This phosphaturic hormone is the earliest biochemical abnormality in CKD-MBD, rising at CKD Stage 2-3, often years before PTH elevation. [4]

FGF23 levels can increase 100-1000 fold by the time dialysis is initiated. While initially adaptive (maintaining phosphate balance), chronically elevated FGF23 becomes maladaptive, causing direct cardiac toxicity, left ventricular hypertrophy, and increased mortality risk independent of phosphate levels. [8]

Step 3: The Klotho Coreceptor

FGF23 acts on the kidney via the Klotho-FGFR1 complex in the proximal tubule. Klotho is an anti-aging protein that serves as the obligate coreceptor for FGF23. In CKD, Klotho expression falls dramatically (Klotho deficiency), which:

• Reduces FGF23 sensitivity (creating FGF23 resistance)
• Promotes vascular calcification directly
• Contributes to accelerated aging phenotype in CKD [9]

FGF23's actions include:

• Phosphaturia: Inhibits sodium-phosphate cotransporters (NPT2a, NPT2c) in the proximal tubule
• Vitamin D suppression: Inhibits 1-α-hydroxylase (the enzyme that converts 25(OH)D to active 1,25(OH)2D)
• PTH modulation: Directly suppresses PTH secretion (though this effect is overwhelmed in advanced CKD)

Step 4: Calcitriol Deficiency

Reduced 1-α-hydroxylase activity, combined with increased expression of 24-hydroxylase (which degrades Vitamin D), leads to a progressive fall in 1,25(OH)2D (Calcitriol).

Calcitriol deficiency causes:

• Reduced intestinal calcium absorption (via decreased expression of TRPV6 channels and calbindin-D)
• Transient hypocalcaemia (though often masked by other compensatory mechanisms)
• Loss of negative feedback on parathyroid glands

Additionally, in advanced CKD, the kidneys lose their ability to hydroxylate Vitamin D, making supplementation with native Vitamin D (cholecalciferol) less effective.

Step 5: PTH Disinhibition and Secondary Hyperparathyroidism

The parathyroid glands sense:

• Low Calcitriol (loss of Vitamin D receptor-mediated suppression)
• Low serum calcium (via the Calcium-Sensing Receptor - CaSR)
• High serum phosphate (direct stimulation of PTH gene expression)

This triggers the release of PTH (Parathyroid Hormone), which attempts to restore calcium homeostasis by:

• Bone resorption: Stimulating osteoclasts to release calcium and phosphate from bone
• Renal calcium reabsorption: Increased tubular calcium retention (but effect limited by reduced nephron mass)
• Renal phosphate excretion: Phosphaturic effect (again, limited by CKD)
• Vitamin D activation: Stimulates 1-α-hydroxylase (but this is already suppressed by FGF23 and uremia)

Step 6: Parathyroid Gland Hyperplasia

Chronic stimulation leads to parathyroid gland hyperplasia:

• Diffuse hyperplasia (early): All parathyroid cells enlarge proportionally
• Nodular hyperplasia (late): Monoclonal proliferation of parathyroid cells that are less responsive to calcium and Vitamin D suppression

The glands also undergo:

• Decreased Vitamin D receptor (VDR) expression: Making them resistant to Vitamin D therapy
• Decreased Calcium-Sensing Receptor (CaSR) expression: Causing the "set-point" for calcium sensing to shift upward, requiring higher calcium levels to suppress PTH

This creates a vicious cycle where PTH continues to rise despite normalization or even elevation of serum calcium.

Step 7: Skeletal Resistance and Tertiary Hyperparathyroidism

In advanced CKD:

• Skeletal resistance to PTH develops (uremic toxins interfere with PTH receptor signaling)
• Tertiary hyperparathyroidism emerges when parathyroid glands become autonomous, secreting PTH despite hypercalcaemia
• High calcium-phosphate product leads to metastatic calcification

Ectopic Calcification occurs when the calcium × phosphate product (Ca × P) exceeds 4.4 mmol²/L² (55 mg²/dL²):

• Vascular calcification: Precipitation of hydroxyapatite in the tunica media of arteries (Mönckeberg's sclerosis), creating rigid, non-compliant vessels
• Soft tissue calcification: Deposition in periarticular tissues, cardiac valves, myocardium, and subcutaneous tissues
• Calciphylaxis: A devastating syndrome of calcific uremic arteriolopathy causing skin necrosis

The FGF23-Klotho-Vitamin D-PTH Axis

The normal axis is tightly regulated:

• Phosphate load → FGF23 secretion → Renal phosphate excretion + Vitamin D suppression → Reduced calcium absorption → PTH release → Calcium mobilization from bone

In CKD, this axis becomes profoundly dysregulated:

• Phosphate retention → Massive FGF23 elevation → Severe Vitamin D deficiency → Uncontrolled PTH secretion → High-turnover bone disease + Vascular calcification

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4. Histological Classification: The TMV System

Renal osteodystrophy is classified using bone biopsy with tetracycline labeling according to TMV criteria:

T = Turnover (Bone Formation Rate)

• High turnover: Osteitis fibrosa cystica (from high PTH)
• Low turnover: Adynamic bone disease (from over-suppression of PTH or diabetes)

M = Mineralization

• Normal: Appropriate mineralization of osteoid
• Abnormal: Osteomalacia (from Vitamin D deficiency or aluminum toxicity)

V = Volume

• Normal, increased, or decreased bone volume

The Four Major Histological Subtypes

1. Osteitis Fibrosa Cystica (High-turnover disease)

   • High PTH driving osteoclastic bone resorption
   • Peritrabecular fibrosis
   • Woven bone formation
   • Tunneling resorption and cyst formation

2. Adynamic Bone Disease (Low-turnover disease)

   • Suppressed bone formation and resorption
   • Associated with over-treatment with calcium, Vitamin D, or calcimimetics
   • More common in diabetics and older patients
   • Clinical concern: Inability to buffer calcium/phosphate loads, leading to increased vascular calcification

3. Osteomalacia

   • Defective mineralization with increased osteoid
   • Historically from aluminum toxicity (from dialysate or phosphate binders)
   • Now rare in developed countries
   • Can occur with severe Vitamin D deficiency or hypophosphatemia

4. Mixed Uremic Osteodystrophy

   • Features of both high turnover and abnormal mineralization
   • Intermediate PTH levels

Clinical Relevance: Bone biopsy is the gold standard for diagnosis but rarely performed in practice. PTH and bone-specific alkaline phosphatase are used as surrogate markers of bone turnover.

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5. Clinical Presentation

Symptoms: The Silent Progression

CKD-MBD is often asymptomatic until advanced stages. When symptoms occur:

Bone Pain:

• Typically dull, aching, and exacerbated by weight-bearing
• May involve the lower back, hips, knees, and long bones
• Can be severe in osteitis fibrosa cystica

Pruritus (The "Invisible Torment"):

• Severe, relentless itching described as "deep" or "internal"
• Often linked to high calcium-phosphate product and secondary hyperparathyroidism
• Can be debilitating, affecting sleep and quality of life
• Associated with elevated serum phosphate and histamine release

Proximal Myopathy:

• "Waddling gait" and difficulty climbing stairs or rising from a chair
• Due to both Vitamin D deficiency (affecting muscle Vitamin D receptors) and high PTH
• Can mimic polymyositis or muscular dystrophy

Fractures:

• Often low-trauma or pathological fractures
• Increased risk of vertebral compression fractures, hip fractures, and rib fractures
• Poor healing and high post-fracture mortality

Calciphylaxis (Medical Emergency):

• Agonizingly painful, non-healing necrotic skin ulcers
• Typically affects areas of high adiposity (abdomen, thighs, buttocks)
• Violaceous, reticulated, mottled skin progressing to necrosis
• Mortality rate 45-80% [7]

Physical Signs

Early Signs (Often Absent):

• None in early CKD-MBD

Late Signs:

1. Red Eye Syndrome: Band keratopathy or subconjunctival calcification (rare but pathognomonic)
2. Fragility Fractures: Evidence of previous low-trauma fractures
3. Ruptured Tendons: Spontaneous quadriceps or patellar tendon rupture (from tendon calcification) [10]
4. Tumoral Calcinosis: Large periarticular calcium deposits, typically around shoulders, hips, and elbows
5. Vascular Calcification: Palpable calcified arteries (e.g., radial artery feels like a "pipe")
6. Proximal Muscle Weakness: Difficulty with shoulder abduction or hip flexion

Calciphylaxis Examination Findings:

• Livedo reticularis progressing to purpura
• Painful, indurated plaques
• Central necrosis with black eschar
• Most commonly affects lower limbs, abdomen, and buttocks

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6. Investigations

The Biochemical Profile

Core CKD-MBD Biochemistry:

Phosphate:

• Target: Maintain in normal range for CKD G3-G5; trend toward normal for G5D
• Rising phosphate indicates progression and need for dietary counseling and binders
• Hyperphosphatemia is an independent predictor of mortality in dialysis patients [11]

Calcium:

• Secondary HPT: Often low or normal due to reduced intestinal absorption
• Tertiary HPT: High (> 2.6 mmol/L) indicating autonomous PTH secretion
• Corrected calcium must be calculated: Corrected Ca = Measured Ca + 0.02 × (40 - Albumin g/L)
• Ionized calcium is more accurate but less commonly measured

PTH (Parathyroid Hormone):

• The "Master Regulator" of bone turnover
• KDIGO targets for dialysis (G5D): 2-9× the upper limit of normal (approximately 130-585 pg/mL for most assays)
• Rationale for range: Too low PTH → adynamic bone disease; too high PTH → osteitis fibrosa cystica
• Trend is more important than single value: Serial measurements guide therapy
• Intact PTH vs. Whole PTH: Intact PTH measures both 1-84 PTH and 7-84 fragments; whole PTH is more specific but less widely available

Alkaline Phosphatase (ALP):

• Marker of bone turnover (bone-specific ALP preferred if available)
• High ALP suggests high-turnover bone disease (osteitis fibrosa cystica)
• Low ALP suggests adynamic bone disease
• Can be elevated in liver disease (check GGT to differentiate)

Vitamin D:

• 25(OH)D (Calcidiol): Reflects nutritional Vitamin D status; target > 30 ng/mL (> 75 nmol/L)
• 1,25(OH)2D (Calcitriol): Active form; low in CKD due to reduced 1-α-hydroxylase activity
• KDIGO recommends correcting 25(OH)D deficiency before starting active Vitamin D analogues

Novel Biomarkers (Research/Selected Centres):

• FGF23: Earliest marker of CKD-MBD; predicts mortality and cardiovascular events [6]
• Klotho: Anti-aging protein; deficiency correlates with CKD progression and vascular calcification [9]
• Sclerostin: Osteocyte-derived inhibitor of bone formation; elevated in CKD
• Bone-specific ALP: More specific marker of bone formation than total ALP

Advanced Biochemical Monitoring

Calcium-Phosphate Product (Ca × P):

• Calculated as: Serum Ca (mmol/L) × Serum P (mmol/L)
• Target: less than 4.4 mmol²/L² (less than 55 mg²/dL² in conventional units)
• Values > 4.4 mmol²/L² associated with increased risk of metastatic calcification and mortality
• Historical importance: Previously emphasized; now KDIGO focuses more on individual Ca and P control

Imaging

Plain Radiography:

1. Hands (PA view): Look for subperiosteal resorption along the radial side of middle phalanges (pathognomonic of hyperparathyroidism)
2. Skull: "Salt-and-pepper" appearance due to cortical bone resorption
3. Spine (Lateral): "Rugger jersey spine" (alternating sclerotic and lucent bands due to subchondral osteosclerosis)
4. Pelvis: Looser zones (pseudofractures) in osteomalacia
5. Lateral Abdominal X-ray: Quantify aortic calcification (Kauppila score)

Vascular Calcification Imaging:

• CT Calcium Score: Quantifies coronary artery calcification (CAC); strong predictor of cardiovascular events
• Lateral Abdominal X-ray: Simple, non-invasive method to assess abdominal aortic calcification
• Echocardiography: Assess for valvular calcification (especially aortic and mitral valves)

DEXA Scan (Bone Densitometry):

• Limited utility in CKD: T-scores are less predictive of fracture risk than in the general population
• Why?: Vascular calcification can falsely elevate bone mineral density readings
• KDIGO guidance: DEXA can be considered in CKD G3a-G3b but interpretation is complex in G4-G5 [3]

Bone Biopsy:

• Gold standard for diagnosing type of renal osteodystrophy (TMV classification)
• Requires tetracycline double-labeling (oral tetracycline given 2 days, then repeated 10 days later; biopsy 5 days after second dose)
• Indications (rare):
  • Unexplained fractures with atypical biochemistry
  • Suspected aluminum toxicity
  • Persistent hypercalcemia of unclear etiology
  • Research studies

Advanced Imaging (Research/Specialized Centres):

• High-resolution peripheral quantitative CT (HR-pQCT): Assesses bone microarchitecture
• MRI: Can detect bone marrow edema in fractures or osteonecrosis
• 18F-NaF PET/CT: Assesses bone turnover and vascular calcification activity

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7. Management: The Integrated Endocrine Strategy

Management of CKD-MBD has evolved from simple biochemical correction to a comprehensive, trend-based approach targeting both skeletal and cardiovascular complications.

KDIGO 2017 Paradigm Shift

From: "Treat to Target" (strict PTH/Ca/P thresholds)
To: "Trend-Based Therapy" (monitor trends, avoid fluctuations)

Rationale:

• No RCT has proven survival benefit from strict PTH targets
• Over-suppression of PTH leads to adynamic bone disease and potentially increased vascular calcification
• Individual patient variability necessitates personalized treatment

The 5-Pillar Management Framework

Pillar 1: Phosphate Control (The Foundation)

Dietary Phosphate Restriction:

• Target: 800-1000 mg/day (compared to typical Western diet of 1400-1800 mg/day)
• High-phosphate foods to limit:
  • Dairy products (milk, cheese, yogurt)
  • Processed meats and fish (phosphate additives)
  • Dark sodas (phosphoric acid)
  • Nuts and seeds
  • Beans and lentils (though nutritionally valuable)
• Challenges: Phosphate restriction can limit protein intake and worsen nutritional status
• Education: Patients need dietitian support; phosphate is "hidden" in many processed foods

Phosphate Binders:

Phosphate binders prevent intestinal phosphate absorption by forming insoluble complexes in the gut.

Key Principles:

• Start binders when phosphate consistently > 1.45 mmol/L (> 4.5 mg/dL) despite dietary restriction
• Titrate dose based on phosphate trends, not single values
• Take binders with meals to maximize phosphate binding
• Avoid calcium-based binders if:
  • Corrected calcium > 2.5 mmol/L
  • Evidence of vascular calcification
  • Ca × P product > 4.4 mmol²/L²
• Individualize choice: Consider patient preference, pill burden, cost, and comorbidities

Evidence:

• DCOR study: Sevelamer vs. calcium-based binders showed trend toward mortality benefit in sevelamer group (not statistically significant in primary analysis) [12]
• INDEPENDENT-CKD: Showed no cardiovascular benefit of lanthanum in CKD G3-4 [13]
• Conclusion: Phosphate binders improve biochemistry but mortality benefit remains unproven in RCTs

Pillar 2: Vitamin D Supplementation

Two-Step Approach:

Step 1: Correct Native Vitamin D Deficiency

• Measure 25(OH)D in all CKD patients
• Target: > 30 ng/mL (> 75 nmol/L)
• Supplementation: Cholecalciferol (Vitamin D3) 800-2000 IU daily or weekly bolus dosing
• Rationale: Repletes Vitamin D stores; may have pleiotropic benefits (immune function, muscle strength)

Step 2: Active Vitamin D Analogues (If Indicated)

• Used to suppress PTH in secondary hyperparathyroidism
• Indications:
  • PTH > 2× ULN in CKD G3-G5 (not on dialysis) if progressive rise
  • PTH > 2-9× ULN in dialysis patients (trend-based)
• Agents:
  • "Alfacalcidol (1-α-hydroxycholecalciferol): Requires renal 25-hydroxylation"
  • "Calcitriol (1,25-dihydroxycholecalciferol): Fully active; no further metabolism needed"
  • "Paricalcitol (Selective Vitamin D receptor activator): May cause less hypercalcemia/hyperphosphatemia (debated) [14]"

Dosing:

• Start low (e.g., Alfacalcidol 0.25 mcg three times weekly or Calcitriol 0.25 mcg daily)
• Titrate based on PTH trends
• Monitor calcium and phosphate closely (weekly initially, then monthly)

Risks:

• Hypercalcemia: Increased intestinal calcium absorption
• Hyperphosphatemia: Increased intestinal phosphate absorption
• Vascular calcification: High Ca × P product
• Adynamic bone disease: Over-suppression of PTH

KDIGO Guidance:

• Suggest NOT routinely using calcitriol or Vitamin D analogues in CKD G3a-G3b
• Suggest using in CKD G4-G5 if severe/progressive hyperparathyroidism
• Monitor trends; avoid PTH over-suppression

Evidence:

• No RCT has proven mortality benefit from Vitamin D analogues
• Observational data suggest survival benefit, but prone to confounding
• Benefits likely mediated through PTH suppression and pleiotropic effects on immunity and cardiovascular system

Pillar 3: Calcimimetics (The Game-Changer)

Cinacalcet (Sensipar/Mimpara):

• Mechanism: Allosteric modulator of the Calcium-Sensing Receptor (CaSR) on parathyroid glands
• Effect: "Fools" the parathyroid gland into sensing higher calcium than actual, thereby suppressing PTH secretion
• Unique advantage: Lowers PTH without raising serum calcium or phosphate (in fact, often lowers calcium)

Indications:

• Secondary hyperparathyroidism in dialysis patients (G5D) with PTH > 9× ULN despite Vitamin D therapy
• Tertiary hyperparathyroidism with hypercalcemia (off-label in some regions)
• Pre-transplant to reduce post-transplant hypercalcemia risk

Dosing:

• Start: 30 mg once daily with food
• Titrate: Increase by 30 mg increments every 2-4 weeks based on PTH and calcium
• Maximum: 180 mg once daily

Monitoring:

• Check calcium weekly for first month, then monthly
• Check PTH monthly
• Risk: Hypocalcemia (can be severe; monitor for symptoms)

Side Effects:

• GI upset: Nausea, vomiting, diarrhea (dose-dependent; taking with food helps)
• Hypocalcemia: Can cause paresthesias, muscle cramps, seizures
• QT prolongation: Theoretical risk; monitor in high-risk patients

Evidence:

• EVOLVE Trial (2012): Largest RCT of Cinacalcet in dialysis patients [15]
  • "Primary outcome: No significant reduction in all-cause mortality or cardiovascular events (ITT analysis)"
  • "Secondary analyses: Benefit in per-protocol and older subgroups"
  • "Interpretation: Difficult to prove mortality benefit but biochemical efficacy clear"
• ADVANCE Trial: Cinacalcet + low-dose Vitamin D reduced vascular and cardiac valve calcification progression [16]

KDIGO Guidance:

• Suggest using calcimimetics in G5D patients with severe hyperparathyroidism (PTH persistently > 9× ULN) despite Vitamin D therapy
• Consider earlier if progressive hypercalcemia or hyperphosphatemia limits Vitamin D use

Future:

• Etelcalcetide (IV calcimimetic): Administered thrice-weekly during dialysis; may improve adherence

Pillar 4: Parathyroidectomy (The Surgical Solution)

Indications:

1. Tertiary Hyperparathyroidism:

   • Autonomous PTH secretion with persistent hypercalcemia (Ca > 2.6 mmol/L)
   • Common in long-term dialysis patients
   • Consideration for pre-transplant (to avoid post-transplant hypercalcemia)

2. Refractory Secondary Hyperparathyroidism:

   • PTH > 800-1000 pg/mL despite maximal medical therapy (Vitamin D + calcimimetics)
   • Symptomatic: severe bone pain, fractures, calciphylaxis, pruritus

3. Calciphylaxis (Controversial):

   • Some centers perform emergency parathyroidectomy for calciphylaxis, but evidence is limited

Surgical Approaches:

1. Subtotal Parathyroidectomy: Remove 3.5 glands, leaving remnant in situ
2. Total Parathyroidectomy with Auto-transplantation: Remove all 4 glands, transplant ~50 mg of parathyroid tissue into forearm (easier to access if recurrence occurs)
3. Total Parathyroidectomy without Auto-transplantation: Rarely performed due to risk of permanent hypoparathyroidism

Outcomes:

• Highly effective: > 90% achieve biochemical cure (normalization of PTH and calcium)
• Risks:
  • "Hungry Bone Syndrome: Severe, prolonged hypocalcemia post-operatively due to rapid remineralization of skeleton; requires massive calcium and Vitamin D supplementation (IV calcium infusions may be needed)"
  • "Recurrent laryngeal nerve injury: Hoarseness"
  • "Permanent hypoparathyroidism: Requires lifelong calcium and Vitamin D"
  • "Recurrence: Can occur from supernumerary glands or remnant hyperplasia"

Post-Operative Management:

• Monitor calcium frequently (every 4-6 hours initially)
• Anticipate and aggressively treat hungry bone syndrome:
  • Oral calcium carbonate 3-6 g/day
  • Alfacalcidol 1-3 mcg/day
  • IV calcium infusions if symptomatic hypocalcemia

Pillar 5: Calciphylaxis Management (The Emergency)

Calciphylaxis (Calcific Uremic Arteriolopathy) is a devastating complication with mortality rates of 45-80%. [7]

Pathophysiology:

• Calcification of dermal and subcutaneous arterioles
• Resulting in ischemia, necrosis, and non-healing wounds
• High risk of secondary infection and sepsis

Risk Factors:

• Female gender, obesity, diabetes, warfarin use, high Ca × P product, iron therapy

Clinical Features:

• Painful, violaceous, reticulated skin lesions progressing to necrosis
• Typically affects areas of high adiposity (abdomen, thighs, buttocks)
• Two patterns: Proximal (worse prognosis) vs. distal (acral)

Diagnosis:

• Clinical diagnosis (biopsy can worsen lesions but may be needed for confirmation)
• Biopsy shows: Medial calcification of arterioles with intimal hyperplasia and thrombosis

Management (Multidisciplinary):

1. Aggressive wound care: Debridement, pain control, infection prevention
2. Discontinue warfarin: Switch to heparin or alternative anticoagulation
3. Optimize CKD-MBD biochemistry:
   • Reduce calcium and phosphate
   • Stop calcium-based binders
   • Consider Cinacalcet or parathyroidectomy
4. Sodium thiosulfate: IV infusions (25 g thrice-weekly during dialysis); antioxidant and calcium chelator [17]
5. Hyperbaric oxygen: Limited evidence but used in some centers
6. Intensify dialysis: Consider increasing dialysis frequency or duration

Prognosis:

• Mortality 45-80% despite treatment
• Sepsis is the leading cause of death

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8. Evidence Base: Landmark Trials and Guidelines

Key Randomized Controlled Trials

KDIGO 2017 Guidelines (Updated 2024) [3]

Philosophy:

• Move from "treat to target" to "trend-based therapy"
• Individualize treatment based on patient factors, biochemical trends, and tolerance
• Recognize uncertainty in optimal PTH targets

Key Recommendations:

CKD G3a-G3b:

• Measure calcium, phosphate, PTH, 25(OH)D
• Correct 25(OH)D deficiency
• Do NOT routinely use phosphate binders or Vitamin D analogues

CKD G4-G5 (not on dialysis):

• Monitor calcium, phosphate, PTH every 6-12 months (or more frequently if abnormal)
• Use phosphate binders if persistent hyperphosphatemia despite dietary restriction
• Consider Vitamin D analogues if severe/progressive hyperparathyroidism
• PTH target: No specific target; monitor trends

CKD G5D (dialysis):

• Monitor calcium, phosphate, PTH monthly
• PTH target: 2-9× ULN (approximately 130-585 pg/mL)
• Use phosphate binders to maintain phosphate toward normal
• Use Vitamin D analogues or calcimimetics if PTH above target range
• Avoid over-suppression of PTH (less than 2× ULN) due to adynamic bone disease risk

General Principles:

• Avoid calcium-based binders if persistent/recurrent hypercalcemia or vascular calcification
• Use calcimimetics if severe hyperparathyroidism despite Vitamin D therapy
• Consider parathyroidectomy if refractory tertiary hyperparathyroidism

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9. Complications and Prognosis

Skeletal Complications

Fractures:

• 4-fold increased risk of hip fracture in dialysis patients [5]
• 1-year mortality after hip fracture: ~50% (compared to ~20% in general population)
• Vertebral fractures often asymptomatic and underdiagnosed

Bone Pain and Disability:

• Chronic bone pain affects quality of life and mobility
• Proximal myopathy leads to functional impairment

Skeletal Deformities:

• Growth retardation in children with CKD-MBD
• Slipped capital femoral epiphysis in adolescents with renal osteodystrophy

Cardiovascular Complications

Vascular Calcification:

• Medial arterial calcification (Mönckeberg's sclerosis) → arterial stiffness → increased pulse wave velocity → left ventricular hypertrophy → heart failure
• Coronary artery calcification → myocardial ischemia → arrhythmias → sudden cardiac death
• Valvular calcification → aortic stenosis, mitral regurgitation

FGF23-Mediated Cardiac Toxicity:

• Direct effects on cardiomyocytes → left ventricular hypertrophy
• Independent predictor of mortality [6]

Calciphylaxis

• Mortality: 45-80% [7]
• Sepsis is the leading cause of death
• Requires aggressive multidisciplinary management

Prognosis

Mortality:

• Cardiovascular disease is the leading cause of death in CKD patients
• Vascular calcification and elevated FGF23 are independent predictors of mortality
• Post-fracture mortality is significantly higher in CKD patients

Quality of Life:

• Bone pain, pruritus, and fractures severely impact quality of life
• Skeletal disability affects mobility and independence
• Psychological burden of chronic illness and treatment burden

Transplant Outcomes:

• Successful kidney transplantation can partially reverse CKD-MBD
• Post-transplant hypercalcemia is common (from autonomous parathyroid function)
• Persistent hyperparathyroidism post-transplant may require parathyroidectomy

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10. Special Populations

Diabetic Patients

• Higher prevalence of adynamic bone disease
• Greater vascular calcification burden
• Consider lower PTH targets to avoid over-suppression

Elderly Patients

• Higher fracture risk
• Greater pill burden and polypharmacy challenges
• May tolerate lower PTH levels

Paediatric Patients

• Growth retardation is a major concern
• Rickets-like skeletal deformities
• More aggressive PTH suppression may be needed to optimize growth
• Specialized paediatric nephrology management essential

Post-Transplant Patients

• Tertiary hyperparathyroidism may persist post-transplant
• Hypercalcemia common (usually resolves within 1 year)
• Parathyroidectomy may be needed if persistent hypercalcemia or graft dysfunction

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11. Patient Education and Shared Decision-Making

Explaining CKD-MBD to Patients:

"CKD-MBD is a complication of kidney failure where your 'mineral thermostat' breaks. Because your kidneys can't clear phosphorus properly, your body releases a hormone called PTH that 'steals' calcium from your bones to balance the blood. This makes your bones weak and fragile.

At the same time, the calcium can get stuck in your blood vessels, making them hard like chalk. This increases your risk of heart attacks and strokes.

We manage this with several strategies:

• Diet: Limiting high-phosphorus foods
• Binders: Medications taken with meals to trap phosphorus in your gut
• Vitamin D: To help your body absorb calcium properly and keep PTH in check
• Calcimimetics: Special medications that tell your parathyroid glands to calm down without raising calcium or phosphorus
• Surgery: Rarely, if medications don't work, we may need to remove some of your parathyroid glands

The goal is to keep your bones strong and prevent calcium from building up in your heart and blood vessels."

Shared Decision-Making:

• Discuss treatment options, including risks and benefits
• Address pill burden and adherence challenges
• Involve dietitians for phosphate education
• Set realistic expectations (improvement in trends, not normalization)

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12. Future Directions and Research

Emerging Therapies

Anti-FGF23 Strategies:

• FGF23 antibodies (in development)
• Klotho replacement therapy

Novel Phosphate Binders:

• Tenapanor (NHE3 inhibitor): Reduces intestinal phosphate absorption by a different mechanism

Bone-Targeted Therapies:

• Denosumab (RANKL inhibitor): Used with caution in CKD due to severe hypocalcemia risk
• Teriparatide (PTH analogue): Anabolic bone therapy; limited data in CKD

Calciphylaxis Therapies:

• SNF472 (calcification inhibitor): In clinical trials for calciphylaxis prevention

Biomarker Research

• FGF23, Klotho, sclerostin as therapeutic targets and prognostic markers
• MicroRNAs and epigenetic markers of CKD-MBD progression

Precision Medicine

• Genetic markers predicting response to Vitamin D or calcimimetics
• Personalized PTH targets based on bone turnover markers

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13. Single Best Answer (SBA) Questions

Question 1

A 50-year-old male on haemodialysis has a PTH of 850 pg/mL (Upper limit 65 pg/mL). His corrected calcium is 2.72 mmol/L and phosphate is 1.9 mmol/L. He is currently taking Alfacalcidol 0.25 mcg three times weekly. What is the most appropriate management?

• A) Increase Alfacalcidol to 0.5 mcg three times weekly
• B) Start Sevelamer Carbonate
• C) Start Cinacalcet
• D) Refer for total parathyroidectomy
• E) Reduce dialysate calcium concentration

Answer: C.

The patient has severe secondary hyperparathyroidism with PTH > 9× ULN (850/65 = 13× ULN). However, his calcium is already high-normal (2.72 mmol/L). Increasing Alfacalcidol (option A) would further raise calcium and phosphate, worsening vascular calcification risk.

Cinacalcet is the ideal choice here because it suppresses PTH without raising serum calcium or phosphate. In fact, Cinacalcet often lowers calcium, making it perfect for this scenario.

Sevelamer (option B) addresses phosphate (which is normal here) but does not address PTH. Parathyroidectomy (option D) is premature before trialing calcimimetics. Reducing dialysate calcium (option E) may help calcium but does not address the primary problem of severe hyperparathyroidism.

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Question 2

What is the earliest biochemical abnormality detected in the pathogenesis of CKD-MBD?

• A) Hyperphosphataemia
• B) Hypocalcaemia
• C) Elevation of FGF23
• D) Elevation of PTH
• E) Suppression of 1-α-hydroxylase

Answer: C.

FGF23 rises very early in CKD (Stage 2/3) to maintain phosphate balance before any overt rise in serum phosphate is detectable. [4]

The sequence is:

1. FGF23 elevation (earliest, often at eGFR less than 60)
2. Suppression of 1-α-hydroxylase (due to FGF23)
3. Calcitriol deficiency
4. PTH elevation
5. Hyperphosphatemia (late)
6. Hypocalcemia (variable, often masked)

Understanding this cascade is critical for understanding CKD-MBD pathophysiology and is high-yield for MRCP.

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Question 3

A 62-year-old woman on peritoneal dialysis presents with excruciatingly painful, violaceous, reticulated skin lesions on her abdomen that have progressed to black necrotic ulcers. She has diabetes and is on warfarin for atrial fibrillation. Her PTH is 1200 pg/mL, calcium 2.8 mmol/L, phosphate 2.3 mmol/L. What is the most likely diagnosis and the most important immediate management step?

• A) Necrotizing fasciitis; urgent surgical debridement
• B) Calciphylaxis; discontinue warfarin
• C) Pyoderma gangrenosum; start high-dose corticosteroids
• D) Cholesterol embolization; start antiplatelet therapy
• E) Vasculitis; start cyclophosphamide

Answer: B.

This is classic calciphylaxis (calcific uremic arteriolopathy):

• Dialysis patient
• Painful violaceous/purpuric skin lesions progressing to necrosis
• High adiposity areas (abdomen)
• Risk factors: female, diabetes, warfarin, high Ca × P product (2.8 × 2.3 = 6.44 mmol²/L² → very high)

Immediate management priorities:

1. Discontinue warfarin (strong risk factor; switch to heparin if anticoagulation needed)
2. Aggressive wound care
3. Stop calcium-based binders
4. Start Cinacalcet or consider parathyroidectomy
5. Start sodium thiosulfate (IV infusions)
6. Pain management
7. Infection prevention/treatment

Mortality is 45-80%, so urgent multidisciplinary management is critical. [7]

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14. Viva Scenario: The "Tertiary" Transition

Examiner: "A patient with long-standing CKD who previously had low calcium and high PTH now presents with high calcium (3.1 mmol/L) and a PTH of 1200 pg/mL. What has happened and what is the treatment?"

Model Answer:

"This patient has transitioned from Secondary to Tertiary Hyperparathyroidism.

Pathophysiology: Chronic overstimulation of the parathyroid glands over many years has led to nodular hyperplasia. The parathyroid glands have undergone monoclonal proliferation and have become autonomous—they no longer respond to negative feedback from calcium or Vitamin D. The glands continue to secrete PTH despite hypercalcemia.

Key features of tertiary HPT:

• Hypercalcemia (> 2.6 mmol/L, often > 3.0 mmol/L)
• Very high PTH (often > 1000 pg/mL)
• Autonomous secretion (resistant to medical therapy)
• Decreased VDR and CaSR expression in parathyroid tissue

Clinical risks:

• Severe vascular and soft tissue calcification (high Ca × P product)
• Fragility fractures (high-turnover bone disease)
• Nephrocalcinosis (if transplanted)
• Calciphylaxis risk

Management approach:

1. Medical trial: Cinacalcet can be attempted, but often insufficient in true tertiary HPT
2. Definitive treatment: Parathyroidectomy (subtotal or total with auto-transplantation)
3. Pre-operative preparation:
   • Stop Vitamin D analogues and calcium-based binders
   • Optimize nutrition and dialysis adequacy
   • Counsel patient about hungry bone syndrome risk
4. Post-operative management:
   • Anticipate hungry bone syndrome (severe, prolonged hypocalcemia)
   • Aggressive calcium and Vitamin D supplementation (oral ± IV)
   • Monitor calcium frequently (every 4-6 hours initially)

Indications for parathyroidectomy:

• Persistent hypercalcemia (Ca > 2.6 mmol/L) with high PTH
• Refractory hyperparathyroidism (PTH > 800-1000 pg/mL despite maximal medical therapy)
• Symptomatic disease (bone pain, fractures, pruritus, calciphylaxis)
• Pre-transplant consideration (to prevent post-transplant hypercalcemia)

Surgical options:

• Subtotal parathyroidectomy (remove 3.5 glands)
• Total parathyroidectomy with auto-transplantation (remove all 4 glands, transplant ~50 mg into forearm)

Outcomes: > 90% achieve biochemical cure, but must manage hungry bone syndrome aggressively."

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15. Clinical Pearls for Examinations

High-Yield Facts:

1. FGF23 is the earliest marker of CKD-MBD (rises before PTH or phosphate)
2. Klotho deficiency is central to CKD-MBD pathogenesis and vascular aging
3. KDIGO PTH target for dialysis patients: 2-9× ULN (not normalization)
4. Cinacalcet unique advantage: Lowers PTH without raising calcium/phosphate
5. Calciphylaxis mortality: 45-80%; discontinue warfarin immediately
6. Hungry bone syndrome: Post-parathyroidectomy complication requiring massive calcium/Vitamin D
7. Adynamic bone disease: Low-turnover disease from PTH over-suppression; paradoxically increases vascular calcification risk
8. Rugger jersey spine, salt-and-pepper skull, subperiosteal resorption: Classic X-ray findings of renal osteodystrophy
9. EVOLVE trial: Cinacalcet showed neutral primary outcome for mortality (controversial)
10. Phosphate binders: No proven mortality benefit but biochemical efficacy clear

Differential Diagnosis Pitfalls:

• Not all bone pain in CKD is CKD-MBD (consider metastases, myeloma, osteomalacia)
• Hypercalcemia in CKD patient: Consider tertiary HPT, malignancy, sarcoidosis, or aluminum toxicity
• Adynamic bone disease can present with normal/low PTH but high fracture risk

Red Flag Recognition:

• Calciphylaxis: Painful skin lesions → medical emergency
• Tertiary HPT: Hypercalcemia + high PTH → consider parathyroidectomy
• Hungry bone syndrome: Post-parathyroidectomy hypocalcemia → aggressive replacement

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16. References

1. Moe S, et al. Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2006;69(11):1945-53. [PMID: 16641930]

2. Drueke TB, Massy ZA. Changing bone patterns with progression of chronic kidney disease. Kidney Int. 2016;89(2):289-302. [PMID: 26806833]

3. KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl. 2017;7(1):1-59. [PMID: 30675420]

4. Isakova T, et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA. 2011;305(23):2432-9. [PMID: 21673295]

5. Alem AM, et al. Increased risk of hip fracture among patients with end-stage renal disease. Kidney Int. 2000;58(1):396-9. [PMID: 10886587]

6. Gutierrez OM, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008;359(6):584-92. [PMID: 18687639]

7. Nigwekar SU, et al. Calciphylaxis: risk factors, diagnosis, and treatment. Am J Kidney Dis. 2015;66(1):133-46. [PMID: 25960299]

8. Faul C, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121(11):4393-408. [PMID: 21985788]

9. Hu MC, et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol. 2011;22(1):124-36. [PMID: 21115613]

10. Coco M, Rush H. Increased incidence of hip fractures in dialysis patients with low serum parathyroid hormone. Am J Kidney Dis. 2000;36(6):1115-21. [PMID: 11096034]

11. Block GA, et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol. 2004;15(8):2208-18. [PMID: 15284307]

12. Suki WN, et al. Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients. Kidney Int. 2007;72(9):1130-7. [PMID: 17728707]

13. Chertow GM, et al. Effect of lanthanum carbonate on cardiovascular outcomes in patients with stage 3 or 4 chronic kidney disease. Kidney Int Rep. 2022;7(8):1665-78. [PMID: 35967090]

14. Thadhani R, et al. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial. JAMA. 2012;307(7):674-84. [PMID: 22337679]

15. Chertow GM, et al. (EVOLVE Trial Investigators). Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med. 2012;367(26):2482-94. [PMID: 23121374]

16. Raggi P, et al. The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis. Nephrol Dial Transplant. 2011;26(4):1327-39. [PMID: 21148030]

17. Nigwekar SU, et al. Sodium thiosulfate therapy for calcific uremic arteriolopathy. Clin J Am Soc Nephrol. 2013;8(7):1162-70. [PMID: 23520041]

18. Ketteler M, et al. Executive summary of the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update: what's changed and why it matters. Kidney Int. 2017;92(1):26-36. [PMID: 28646995]

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Last Updated: 2026-01-06 | MedVellum Editorial Team
Evidence Level: High
Citations: 18 PubMed-indexed references