Understanding Mineral Bone Disease in Chronic Kidney Disease

• Renal osteodystrophy: dystrophy of bone in kidney disease. 
• CKD-MBD: Clinical, biochemical, imaging is needed as evidence.

Spectrum

• Extends from adynamic bone disease (low bone turnover) to osteitis fibrosa (highest bone turnover).
  • Turnover: level of decalcification, volume formation, and then ossification. 
• Osteomalacia: defective mineralization.
  • It is seen in conditions with aluminum deposition. 
• Osteopenia/Osteoporosis 
• Mixed renal osteodystrophy—osteitis fibrosa+ osteomalacia. 
• Other conditions
  • Beta 2 microglobulin amyloidosis 
  • Chronic acidosis 

Epidemiology

• In hemodialysis patients,
  • Change of osteitis fibrosa = ABD. 
• In Peritoneal dialysis patients,
  • ABD > OF 
• Starts when GFR falls less than 50 ml/min/1.73 m2, i.e., in CKD stage 3. 

Also read: Anti-GBM Disease & Goodpasture Syndrome: Overview & Treatment

Pathogenesis

Osteitis Fibrosa

• Abnormalities of
  • Calcium metabolism 
  • Phosphate metabolism 
  • Vitamin D 
  • I PTH
• Calcium metabolism 
  • 3 body pools
    • Bone 
    • Intracellular 
    • Extracellular 
  • 2 hormones
    • PTH 
    • Vitamin D

Pathogenesis of Calcium

Low Vitamin D 

Phosphate Retention 

Decreased calcium absorption 

Skeletal resistance to PTH

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Reduction of Total serum Calcium, Stimulation of PTH

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Levels of free calcium are maintained to normal

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Compensatory hyperparathyroidism

Also read: Chronic Allograft Injury : Factors Contribution, Pathogenesis

Pathogenesis of Phosphorus Metabolism 

• Hyperphosphatemia is seen either due to increased phosphate retention or decreased phosphate excretion. 
• Reduced calcium and increased phosphorus are stimulants for PTH. 
• Phosphate levels are made normal till stage 4 of CKD 
• Then phosphate levels will be increased after stage 4 
• Two mechanisms will be activated
  • Parathyroid hormone
    • Increases calcium and reduces phosphorus 
  • Fibroblast Growth Factor 23 (FGF 23)
    • Produced by the osteocytes or osteoblasts 
    • It reduces the serum phosphate levels (phosphaturic hormone) 
    • It also reduces vitamin D levels to reduce the phosphorus 
• Effects on Vitamin D
  • It directly reduces vitamin D. 
  • By activating (reduces 1 alpha-hydroxylase) FGF 23 
  • 1 alpha-hydroxylase is produced to synthesize vitamin D3
• Vitamin D acts on the parathyroid gland and inhibits the parathyroid hormone

Mechanism of Parathyroid Hormone

It brings calcium from the bone and stops the absorption of phosphorus 

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Increases the excretion of the phosphorus 

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Such that vitamin D acts on the parathyroid hormone and inhibits its mechanism

Also read: Membranous Nephropathy : Types, Epidemiology and Investigation

Pathogenesis of Vitamin D

• Reduced conversion of 25-OH Vitamin D to 1,25-dihydroxy vitamin D
  • Reduced production of 1-alpha-hydroxylase 
  • Reduced GFR hence reduced delivery of 25-hydroxyvitamin D to proximal tubule.
  • FGF-23 reduces 1 alpha-hydroxylase 
  • FGF-23 and PTH inhibit vitamin D.

Direct Effects of Calcidiol

• Vitamin D inhibits the PTH gene 
• Vitamin D present in the parathyroid gland will inhibit the production of PTH 
• Vitamin D receptors are showing resistance to PTH 
• Calcium sensing receptor decreases the secretions of the PTH 
• Hence the threshold will be increased 
• Due to all the above conditions, PTH levels will be increased and cause hyperparathyroidism 

Pathogenesis of Parathyroid Gland

• Parathyroid gland hyperplasia: Diffuse, nodular 
• Decreased expression of vitamin D receptors. 
• Decreased expression of Calcium receptors 
• Increased of calcium-regulated parathormone

Also read: Tuberculosis Of Urinary Tract

Types of Hyperparathyroidism

Primary hyperparathyroidism

• Parathyroid adenoma 
• Parathyroid gland itself produces the parathyroid hormone 

Secondary hyperparathyroidism

• Secretions of the PTH will be increased due to other causes like CKD

Tertiary hyperparathyroidism

• Parathyroid gland will become autonomous 
• It secretes the parathyroid hormone 
• It occurs as a continuation of the secondary 
• Surgery is only the way to solve this problem

Investigations

• X-ray
  • Subperiosteal erosion 
  • Resorption of terminal digits 
  • Brown tumor
    • Fractures 
  • Rachitic features of Vitamin D deficiency 
  • Growth retardation 
  • Extraskeletal calcification: blood vessels, heart, lungs, valves. 
• Bone biopsy: Gold standard 
• Serum calcium: Reduces in stage 4 
• Stage 2 or 3: Increase in PTH and FGF 23 (Phosphorus is normal) 
• Serum phosphorus: Increases in stage 4 (Decrease in calcium) 
• i PTH is broken down into different products. 
• When investigated, both PTH and PTH fragments are detected (Falsely Elevated values)
• Second-level testing will now detect only I PTH.
  • Detects large fragments, biontact PTH 
  • Normal-60pg/ml, 
  • In dialysis patients: > 600 pg/ml (Hyperparathyroidism)
• Vitamin D is assessed for nutritional status 
• DEXA: False positive with vascular and soft tissue calcification
  • It detects the bone density 
  • It is not useful to diagnose

Also read: Mastering Kidney Transplantation Surgery

Bone Formation Markers—Osteoblastic Marker 

1. Alkaline phosphatase 
2. Osteocalcin 
3. PINP (Procollagen Type l N-terminal propeptide)

Bone Destruction Markers: Osteoclastic Activity

1. Tartarate-resistant acid phosphatase 
2. Collagen degradation products (CTX)

X-Ray Manifestations Of Hyperparathyroidism

• Subperiosteal erosions 
• Pepper pot skull: Focal radiolucencies and ground glass appearance 
• Rugger jersey spine: Osteosclerosis of vertebrae
  • Increased density in the vertebral column; lucency is present in the center 
• Brown tumor: Focal collection of giant cells, seen in long bones, digits
  • More prone to fractures 
• Loosers zone/pseudofractures: Osteomalacia

Bone Biopsy

• TMV classification
  • Turnover
  • Mineralisation
  • Volume
• Mineralization: Tetracycline labeling

Also read: Alport Syndrome and Familial Glomerular Disorders

Treatment

• Start in stage 3 CKD 
• Hypocalcemia: It stimulates PTH secretion 
• To stop this
  • Calcium carbonate supplementation 
  • Vitamin D supplementation (Increases calcium through absorption)

First, estimate 25 hydroxy vitamin D 

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If the level is less than 30 ng/mL (KDO guidelines), 

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Supplement with vitamin D 

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If there is persistent hypocalcemia 

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Active vitamin D sterols are recommended (1,25-dihydroxy vitamin D)

Vitamin D Metabolites 

• Active Vitamin D: Calcitriol 
• Metabolites of vitamin D
  • Alfacalcidol (1-alpha-hydroxyvitamin D3) 
  • Doxercalciferol (1-alpha-hydroxyvitamin D2) 
  • Paricalcitol (1-alpha-25-dihydroxyvitamin D2) 
  • Advantages
    • Less calcemic activity 
    • Retain the ability to suppress PTH

Prerequisites

• Hyperparathyroidism 
• Correction of 25-hydroxy vitamin D deficiency 
• Prior control of serum phosphate 
• After supplementation with vitamin D, phosphorus levels decrease, and there can be calcium phosphate deposition. 
• Indication: To start early before tertiary hyperparathyroidism

Also read: Diuretics And Its Action

Side Effects 

• Hypercalcemia can worsen renal function 
• Hypercalcemia reduces the GFR by two mechanisms
  • Direct vasoconstriction 
  • Deposits as nephrocalcinosis and worsen the renal functions 
• Increased phosphate absorption from the intestine
  • Increased calcium phosphate products can cause metastatic calcification.

Control of Phosphorus

• Normal levels are maintained till stage 4, and then elevated. 
• Normal levels are maintained till stage 4 by action of 2 phosphaturic hormone 
• PTH 
• FGF 23 

Dietary Phosphate Restriction

• Stage 2 or 3 
• Protein restriction or dairy or processed foods 

Phosphate Binders 

• Binds ingested phosphate in the intestinal lumen 
• It is given along with food, and it reduces the absorption.
• Phosphorus binder with highest efficacy 
• Lanthanum 
• Aluminum hydroxide is avoided as it causes the neurological manifestations
  • Dialysis dementia syndrome 
  • Osteomalacia

Also read: Rapid Acquisition Of Key Nephrology Concepts

Calcimimetics

• Cinacalcet/ Etelcalcetide 
• Targets calcium-sensing receptors and increases sensitivity to calcium
  • It in turn reduces the PTH 
  • Recommended in Dialysis patients 
• Use
  • Marginal Frank hypercalcemia with hyperphosphatemia 
• Adverse effects
  • Hypocalcemia 
  • Nausea 
  • Vomiting 
• CKD patients not on dialysis: Can cause phosphate retention
  • Hence it is contraindicated 

Low Turnover Bone Disease

• Rigorous suppression of adaptive response. 
• Causes
  • CV calcification 
  • Fracture 
  • Mortality

Osteoporosis in Chronic Disease

• Bone: Thin and disconnected trabeculae 
• Classic risk factors
  • Hypoestrogenemia 
  • Immobilisation 
  • Steroid use 
• Significant overlap and difficulty in diagnosis 
• DEXA: Unable to differentiate. 
• Treatment
  • Antiresorptive (Bisphosphonates, Denosumab) 
• Antiresorptive therapy: Aggravate osteoclast paralysis and worsen adynamic bone disease (advanced stages)

ALso read: Immunosuppression In Transplantation

Pathogenesis 

• Non-variable light chain of HLA Class I complex 
• Renal retention of beta 2 microglobulin (11.8 kDa) 
• There are some amylogenicity factors and local factors.

Epidemiology 

• Dialysis patients: 13-15 years 
• Most amyloid: No clinical problems 
• Main risk factors
  • Age of onset of renal replacement therapy. 
  • Duration of renal replacement therapy.

Treatment and Prevention 

• Surgery 
• Renal transplant
  • Prevents progression 
• High-flux hemodialysis and online haemodiafiltration or adsorption column

High Yield Points

• bone manifestation of is increased turnover, reduced mineralization and increased volume 
• Stages of CKD in which beta 2 microglobulin amyloidosis occurs is Stage 5 D (Dialysis patients). 
• Most important risk factor: age of RRT. 
• X-ray of beta 2 microglobulin amyloidosis shows juxta articular position. 
• 5mm in wrist and 10mm in shoulder. 
• Increase by 30% per year. 
• Rule out any other subchondral cyst. 
• Type of dialysis benefiting beta 2 microglobulin amyloidosis: hemodiafiltration. 
• Maximum phosphate binding capacity-Lanthanum 

Also read: Diuretics - Classification And Adverse Effects

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