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CKD-MBD (Chronic Kidney Disease - Mineral and Bone Disorder)

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1. Definition (KDIGO, 2006)

Renal Osteodystrophy is the skeletal component only - an alteration of bone morphology in CKD patients, quantifiable by histomorphometry of bone biopsy. It is one measure of the broader CKD-MBD syndrome.

• Brenner & Rector's The Kidney, Table 53.1

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2. Pathophysiology

Normal Mineral Homeostasis

• PTH (parathyroid hormone)
• Calcitriol [1,25(OH)₂D₃] - active vitamin D
• FGF-23 (fibroblast growth factor 23)
• Klotho (co-receptor/circulating factor)

Sequence of Events in CKD

1. Reduced renal mass → decreased phosphate excretion → mild phosphate retention
2. Declining renal mass → reduced 1α-hydroxylase activity → decreased calcitriol synthesis
3. Low calcitriol + hyperphosphatemia → hypocalcemia (reduced intestinal Ca²⁺ absorption)
4. Bone secretes FGF-23 (earliest detectable change) → phosphaturia via downregulation of NaPi-IIa transporters; also inhibits calcitriol synthesis
5. PTH rises (secondary hyperparathyroidism) → increases phosphaturia + bone resorption
6. Together PTH and FGF-23 maintain near-normal serum phosphorus in stages 3-4

1. GFR <30 mL/min → compensatory mechanisms fail
2. Hyperphosphatemia develops; hypocalcemia worsens
3. Secondary hyperparathyroidism (2°HPT) becomes severe
4. Parathyroid glands develop nodular hyperplasia, decreased VDR expression, decreased CaSR expression, decreased klotho expression - making them resistant to calcitriol and calcimimetic therapies (tertiary hyperparathyroidism)
5. Vascular calcification and extraskeletal calcification ensue

The FGF-23/Klotho Axis (Key)

• Acts on kidney via the FGFR-Klotho co-receptor complex
• Inhibits Cyp27b1 (↓ calcitriol synthesis)
• Upregulates Cyp24 (↑ calcitriol catabolism)
• Suppresses PTH gene expression

• Brenner & Rector's The Kidney, p. 2395

Parathyroid Gland Abnormalities in CKD (Box 88.1)

• Parathyroid gland hyperplasia: diffuse, then nodular (monoclonal expansion)
• Decreased expression of vitamin D receptors (VDR)
• Decreased expression of calcium-sensing receptors (CaSR)
• Decreased expression of α-klotho
• Increased set-point of calcium-regulated PTH secretion
• Comprehensive Clinical Nephrology, 7th Ed, Box 88.1

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3. Biochemical Abnormalities

Serum calcium and phosphate levels are usually normal in mild-moderate CKD. Hypercalcemia may occur with excessive calcium binders or vitamin D analogues.

• Comprehensive Clinical Nephrology, 7th Ed, Chapter 88

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4. Renal Osteodystrophy: Histologic Classification

A. High-Turnover Bone Disease

• Caused by excess PTH (secondary hyperparathyroidism)
• Histology: Increased osteoclasts + osteoblasts; dissecting lacunae; peritrabecular fibrosis; woven (disorganized) collagen; "brown tumors" in severe disease
• Radiology: Subperiosteal erosions (radial aspect of middle phalanges - pathognomonic), "Rugger-jersey spine," "Pepper-pot skull," resorption of terminal digits, distal clavicle erosion
• Mechanism: Excess PTH → increased bone resorption → fibrous tissue replaces bone marrow

• Features of both osteitis fibrosa AND osteomalacia
• Increased osteoid with features of hyperparathyroidism
• May represent a normal response to increased turnover rather than a distinct entity

B. Low-Turnover Bone Disease

• Histology: Excessive unmineralized osteoid (wide osteoid seams); prolonged mineralization lag time; absent cellular activity
• Causes: Vitamin D deficiency (↓ calcitriol synthesis in CKD), aluminum toxicity (historically major cause - aluminum from dialysate or Al-containing antacids)
• Aluminum deposits at the mineralization front (detected by special staining)
• Aluminum disease is less common today due to improved dialysate purification

• Histology: Near-total absence of osteoblast and osteoclast activity; minimal osteoid; no fibrosis
• Essentially a disorder of decreased bone formation
• Osteoid is normal or low (distinguishes from osteomalacia)
• Causes: Calcium supplementation, excessive vitamin D, overtreatment of hyperparathyroidism (calcimimetics, calcitriol), diabetes, corticosteroids, advanced age, immobilization
• Epidemiology: More common in White vs. Black ESKD patients; may be a consequence of overtreatment of 2°HPT
• Risk: Fractures AND vascular calcification (adynamic bone cannot buffer calcium-phosphate load)
• Brenner & Rector's The Kidney, p. 2403; National Kidney Foundation Primer, 8th Ed, p. 557

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5. Clinical Manifestations

Musculoskeletal

• Bone pain: Lower back, hips, legs; aggravated by weight-bearing
• Fractures: 4.4-fold increased hip fracture risk in dialysis vs. general population; both high AND low PTH levels increase fracture risk
• Muscle weakness: Gradual onset; involves hyperparathyroidism + vitamin D deficiency
• Periarticular pain/acute arthritis: Due to calcium-phosphate crystal deposition; mimics gout/pseudogout
• Growth retardation: In children; slipped epiphysis
• Brown tumors: Localized, lytic bone lesions from osteoclast activity in severe osteitis fibrosa

Extraskeletal (Cardiovascular)

• Vascular calcification - Two patterns:
  1. Intimal (atherosclerotic): Focal calcification in plaques - increases plaque fragility
  2. Medial (Mönckeberg sclerosis): Diffuse, non-atherosclerotic; increases vascular stiffness, pulse pressure, cardiac afterload → LVH
• Cardiac valve calcification
• Calciphylaxis (Calcific Uremic Arteriolopathy): Rare but devastating; skin necrosis from small vessel calcification
• Pruritus: From skin calcium-phosphate deposition

CVD accounts for approximately half of all deaths in dialysis patients. Coronary artery calcification can be documented in dialysis patients before 30 years of age.

• National Kidney Foundation Primer, 8th Ed

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6. Vascular Calcification - Inhibitors and Promoters

• Brenner & Rector's The Kidney, p. 2403

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7. Diagnosis

Biochemical Monitoring (KDIGO)

• CKD Stages G3a-G5: Monitor Ca, Pi, PTH, and alkaline phosphatase
• Frequency increases with worsening CKD stage
• Use the same PTH assay serially; evaluate trends rather than absolute values

PTH Assay Generations

• 1st generation: Radioimmunoassays (unreliable, no longer used)
• 2nd generation (Intact PTH assay): Detects PTH(1-84) + large C-terminal fragments; most commonly used clinically
• 3rd generation (Whole/Bioactive PTH): Detects PTH(1-84) exclusively; uses N-terminal antibody (epitopes 1-4)
• C-terminal fragments represent ~80% of circulating PTH in healthy persons and ~95% in CKD → explains why "elevated PTH is normal in CKD"
• Brenner & Rector's The Kidney, p. 2399

Bone Biopsy (Gold Standard)

• Double tetracycline labeling required to assess dynamic bone formation rate
• Indicates quantitative histomorphometry: osteoid thickness, fibrosis, mineralization lag time
• TMV classification: Turnover (low/normal/high), Mineralization (normal/abnormal), Volume (low/normal/high)
• Required in clinical practice when: aluminum toxicity suspected; unexplained fractures; before bisphosphonate use in CKD

Radiology

• Subperiosteal erosions: radial aspect of middle phalanges (2°HPT)
• Rugger-jersey spine; pepper-pot skull
• Vascular calcification by CT or plain film
• DXA: Predicts fracture risk in CKD (as in general population)

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8. Management

A. Control Serum Phosphorus

• Target: 800-1000 mg phosphorus/day
• Avoid phosphate additives (up to 100% bioavailable vs. natural food phosphate)
• Protein-phosphorus balance is challenging (malnutrition in ~50% of dialysis patients)
• More frequent/prolonged dialysis lowers phosphorus

KDIGO cautions against excessive calcium intake from binders. Non-calcium binders preferred in patients with vascular calcification, hypercalcemia, or low PTH.

B. Vitamin D Therapy

• Nutritional vitamin D (cholecalciferol/ergocalciferol): Correct 25(OH)D deficiency first
• Active vitamin D analogues (for secondary HPT):
  • Calcitriol [1,25(OH)₂D₃]: Most potent; increases GI calcium + phosphate absorption
  • Paricalcitol (19-nor-1,25(OH)₂D₂): Selective VDR activator; less hypercalcemia/hyperphosphatemia risk; PRIMO study: 48 weeks did not alter cardiac mass index in CKD 3/4
  • Doxercalciferol, alfacalcidol
• Active vitamin D analogues suppress PTH gene transcription; increase Ca and Pi absorption from gut (worsens hyperphosphatemia - must balance with binders)

C. Calcimimetics

• Cinacalcet (Sensipar): Allosteric activator of CaSR on parathyroid chief cells; increases receptor sensitivity to extracellular calcium → ↓ PTH secretion
  • Approved for dialysis patients with secondary HPT
  • Not FDA-approved for CKD stages 3-4 (limited evidence)
  • Main side effects: nausea, vomiting, hypocalcemia
  • EVOLVE trial: Did not significantly reduce major cardiovascular events vs. placebo in dialysis patients (intention-to-treat analysis)
• Etelcalcetide (Parsabiv): IV calcimimetic for hemodialysis patients

D. Dialysis Modifications

• More frequent dialysis (daily/nocturnal) → lower phosphorus
• Hemodiafiltration associated with better mineral control

E. Parathyroidectomy

• Indicated for: Severe, refractory 2°HPT unresponsive to medical therapy; hypercalcemia; severe symptoms
• Indications: PTH persistently >800-1000 pg/mL (varies by guideline), hypercalcemia, symptomatic bone disease
• Types: Subtotal parathyroidectomy or total parathyroidectomy + autotransplantation
• Risk of post-op "hungry bone syndrome" (severe hypocalcemia as bone rapidly reabsorbs calcium)

F. Special Considerations

• Generally NOT recommended for CKD stages 4-5 (eGFR <30 mL/min)
• Inhibit bone turnover → can worsen or induce adynamic bone disease
• Accumulate in bones and may cause osteonecrosis of the jaw

• Bone loss common in first year (largely reversed with steroid minimization)
• DXA recommended at transplant and yearly
• Avascular necrosis (femoral head) is a complication, especially with corticosteroids

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9. KDIGO Targets (Summary)

No clinical trial data exist demonstrating that any current CKD-MBD treatment reduces mortality. Current guidelines are based largely on observational data linking elevated phosphorus/calcium to increased mortality.

• National Kidney Foundation Primer, 8th Ed, p. 562

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Key Summary Diagram

↓ GFR → ↓ Phosphate excretion → Phosphate retention
       → ↓ 1α-hydroxylase → ↓ Calcitriol
       → ↓ Calcium absorption → Hypocalcemia
                                    ↓
                         ↑ PTH (2° Hyperparathyroidism)
                                    ↓
                    High-turnover bone disease (Osteitis Fibrosa)
                    + FGF-23 ↑↑ (earliest marker)
                    + Vascular/Extraskeletal Calcification
                    + Cardiovascular Disease & ↑ Mortality

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• Brenner & Rector's The Kidney, 2-Volume Set - Chapter 53, pp. 2388-2410
• National Kidney Foundation Primer on Kidney Diseases, 8th Ed - Chapter 53, pp. 553-565
• Comprehensive Clinical Nephrology, 7th Ed - Chapter 88
• Tietz Textbook of Laboratory Medicine, 7th Ed - Chapter on CKD-MBD
• Goodman & Gilman's Pharmacological Basis of Therapeutics - Chapter 15

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Significant (Pathological) Lymph Nodes: All Criteria

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Overview

1. Clinical (palpation) criteria
2. Size criteria (general + site-specific)
3. Imaging criteria (US, CT, MRI, PET)
4. Architectural/morphologic criteria
5. Site-specific significance
6. Extranodal extension
7. RECIST criteria (oncologic follow-up)

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1. Clinical Examination Criteria

Size (on palpation)

• Harrison's Principles of Internal Medicine 22E, p. 2085

Consistency / Texture

Tenderness

• Tender nodes - usually inflammatory/reactive (capsule stretched by rapid enlargement)
• Can also occur in aggressive malignancies (rapid enlargement → hemorrhage/necrosis - e.g., acute leukemia)
• Nontender nodes - more suspicious for malignancy (metastatic cancer, lymphoma)

"A mass that is tender is more likely inflammatory, whereas a mass that is fixed and nontender is more likely malignant." - Cummings Otolaryngology

Mobility / Fixation

• Mobile - benign or lymphoma
• Fixed/non-movable - metastatic cancer (fixation to surrounding tissues); also TB (periadenitis)

Warmth

• Warm, erythematous overlying skin - acute inflammatory/infective adenitis
• Sabiston Textbook of Surgery, p. 1593

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2. Size Criteria by Imaging (CT/MRI)

General Rule

Site-Specific Size Thresholds (CT)

Important caveat: Up to 21% of nodes <1 cm are malignant and up to 40% of nodes >1 cm are benign in mediastinal staging - highlighting the limitations of size alone.

• Grainger & Allison's Diagnostic Radiology; Fishman's Pulmonary Diseases

RECIST 1.1 Criteria (Oncologic Response Assessment)

• Washington Manual of Medical Therapeutics

Lugano Classification (Lymphoma)

• Lymph node with longest diameter >1.5 cm = enlarged
• For FDG-avid lymphomas: a node is positive if there is abnormal FDG uptake regardless of size

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3. Ultrasound (US) Criteria

Normal vs. Pathological on Ultrasound

• Sabiston Textbook of Surgery; Grainger & Allison's

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4. CT / MRI Additional Features

"Abnormal lymph nodes on CT or MRI are virtually never normal from a pathologic standpoint, even if the diagnosis is not clinically significant." - Fishman's Pulmonary Diseases, p. 1887

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5. PET/CT Criteria

• Fishman's Pulmonary Diseases

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6. Extranodal Extension (ENE) / Extracapsular Spread (ECS)

• Defined as extension of nodal metastases beyond the lymph node capsule
• Can be diagnosed pathologically (histology) or clinically (imaging/palpation showing clear extension)
• AJCC 8th edition: ENE automatically classifies as N3b in head and neck cancers
• Each factor (ipsilateral node, contralateral node, extracapsular spread) decreases 5-year survival by 50%
• Imaging features: irregular/infiltrative margins, loss of fat planes, matting of adjacent nodes

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7. Site-Specific Significance

Supraclavicular / Scalene Nodes

• Enlargement is ALWAYS abnormal (Harrison's Principles)
• Drain: lung, retroperitoneal space, mediastinum
• Virchow's node: enlarged left supraclavicular node = metastatic GI malignancy (Troisier's sign)
• Also: lung, breast, testis, ovarian cancers; TB, sarcoidosis, toxoplasmosis

Cervical Nodes

• Most common site of lymphadenopathy; usually benign (URTI, dental, EBV)
• 7 levels (Levels I-VII) in head and neck cancer
• Level II (jugulodigastric): largest normal cervical node - upper limit 13 mm short axis

Axillary Nodes

• Benign: upper limb infections, cat-scratch disease
• Malignant: breast cancer (primary drainage), melanoma, lymphoma

Epitrochlear Nodes

• Normal: not usually palpable
• Any enlargement: sarcoidosis, secondary syphilis, lymphoma, infections of forearm/hand
• Bilateral epitrochlear adenopathy = strong indicator of systemic disease (sarcoidosis, EBV)

Inguinal Nodes

• Normal: can be palpable up to 1-2 cm (inguinal region has naturally larger normal nodes)
• Pathological: STIs (LGV, primary syphilis, genital herpes, chancroid), lymphoma, melanoma, GU/GI/GYN malignancy

Mediastinal Nodes

• Any mass-like conglomerate adenopathy is malignant until proven otherwise
• Distribution pattern aids diagnosis (lung → ipsilateral hilar/subcarinal; H&N SCC → supraclavicular; breast → axillary/internal thoracic; HCC → anterior cardiophrenic)

Intra-abdominal / Retroperitoneal Nodes

• Not normally visible on imaging
• If visible and >10 mm = pathological
• Porta hepatis/gastrohepatic: >8 mm
• Retrocrural: >6 mm

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8. Summary Table: Normal vs. Significant

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Key Clinical Pearl

Nodes <1.0 cm² should be observed (excluding EBV/toxoplasma). Nodes >2 cm or >2.25 cm² (1.5×1.5 cm) warrant biopsy. Supraclavicular/scalene adenopathy is ALWAYS abnormal. Hard, fixed, nontender nodes suggest metastatic carcinoma; large, rubbery, discrete, bilateral nodes suggest lymphoma.

• Harrison's Principles of Internal Medicine 22E