Bone Disease in Renal Failure

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Bone Disease in Renal Failure

• Dr Anne Kleinitz and
• Dr Cherelle Fitzclarence
• renalgp_at_kamsc.org.au

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Overview

• Pathogenesis
• Normal Bone Remodeling
• Hyperparathyroidism
• Classifications of bone disease
• Diagnosis of bone disease
• Treatment of bone disease in CKD
• Case Studies

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Pathogenesis

• Kidney failure disrupts systemic calcium and
  phosphate homeostasis and affects the bone, GIT
  and parathyroid glands.
• In kidney failure there is decreased renal
  excretion of phosphate and diminished production
  of calcitriol (1,25-dihydroxyvitamin D)
• Calitriol increases serum calcium levels
• The increased phosphate and reduced calcium,
  feedback and lead to secondary hyperparathyroidism
  , metabolic bone disease, soft tissue
  calcifications and other metabolic abnormalities

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?PO4
?Ca
?GFR
?1,25 DHCC
?PTH
Calcitriol
5

• Although bone disease and abnormal PTH are a
  major feature, CVD and excess calcification
  (extra-skeletal) are important causes of
  morbidity and mortality

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• Pathogenesis
• Normal Bone Remodeling

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Normal Bone Remodelling Cycle
Resorption osteoclasts
Formation osteoblasts ? matrix
Quiescence
Mineralisation
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• Pathogenesis
• Normal Bone Remodeling
• Hyperparathyroidism

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Hyperparathyroidism

• Increase PTH is hallmark of secondary
  hyperparathyroidism
• The major factors leading to its increase are
• Decreased production of Vit D3 (calcitriol)
• Decreased serum calcium
• Increased serum phosphorous

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?PO4
?Ca
?GFR
?1,25 DHCC
?PTH
Calcitriol
11

• 4 or more small glands on the posterior surface
  of the thyroid gland.
• Can function without neural control so can
  transplant to another part of the body
• 2 types of cells
• Chief cells produce parathyroid hormone
• Oxyntic cells function unknown

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Role of PTH

• Responsible for maintaining serum calcium in a
  narrow range (2.15-2.6)
• Does this by
• acting directly on the distal tubule of the
  kidney to increase calcium reabsorption
• Increases calcitriol production (D3)
• D3 increases GIT absorption of Ca and Phos and
  promotes osteoclast formation.
• Acting on bone to increase calcium and phosphate
  efflux

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• The net effect of PTH is to create positive
  calcium balance necessary to maintain
  homeostasis.
• To balance out the increased phos from skeletal
  effects, and GIT effects of calcitriol, PTH acts
  secondarily to increase renal phos excretion
• By decreasing activity of sodium phosphate
  co-transporter in prox renal tubule.

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Uraemic Secondary Hyperparathyroidism

• Cause PO4 retention
• Low 1,25 Vit D synthesis
• Effects Proximal weakness, Bone pain (late)
• ?Alk Phos, bone erosions
• Rx Diet, PO4 binders
• Calcitriol, PTHx (usually for 3o)

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Secondary hyperparathyroidism

• In renal failure driven by
• Hypocalcaemia
• Decreased vitamin D
• hyperphosphataemia

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?PO4
?Ca
?GFR
?1,25 DHCC
?PTH
Calcitriol
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hyperPTH in CKD

• In CKD is a progressive disorder.
• Involves both increased secretion PTH
  hyperplasia
• Can occur once eGFR lt 60
• PTH levels increase progressively as renal
  function declines and by CKD stage 5(lt15) most
  pts expected to have this.
• Usually the 1st sign and occurs before lab tests
  pick up ? phosphatemia, ? Vit D3 and ? calcium
• Presumably as PTH is maintaining homeostasis.
• Unless treated, progresses and frequency of
  parathyroidectomy proportional to yrs on dialysis

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Overview

• Pathogenesis
• Normal Bone Remodeling
• Hyperparathyroidism
• Classifications of bone disease in CKD

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Classification of Bone Disease in CKD

• The circulating level of PTH is primary
  determinant of bone turnover in CKD
• Type of bone disease depends upon
• Age of pt
• Duration of kidney failure
• Severity of hyperPTH
• Type of dialysis
• PTH Vit D receptors, as well as calcium sensors
  are present on osteoblasts

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Types of Renal Bone Disease

• Traditionally classified according to degree of
  abnormal bone turnover
• High Turnover (osteitis fibrosa)
• Hyperparathyroidism
• Low turnover
• Adynamic - Osteomalacia
• Beta 2 MG amyloidosis
• Osteoporosis
• Post-menopausal - Post-transplant

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Uraemic Bone Remodelling Cycle
Accelerates High PO4 or Low Ca2, Vit D3,
Resorption osteoclasts
Formation osteoblasts ? matrix
Mineralisation
Quiescence
Retards Vit D3, Age, Diabetes, Al3, PTHx
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Uraemic Bone Remodelling Cycle
Accelerates High PO4 or Low Ca2, calcitriol,
HCO3, oestrogen
Via PTH, IL-1,6 TNF
Resorption osteoclasts
Formation osteoblasts ? matrix
Mineralisation
Quiescence
Retards Calcitriol, Age, Diabetes, Al3, PTHx
Acts via osteoblasts
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High turn over bone disease

• Due to excess PTH
• Increased bone turnover activity (greater number
  of osteoclasts and osteoblasts) and defective
  mineralization.
• Associated with bone pain and increased risk of
  fractures.
• Severe symptomatic disease is currently uncommon
  with modern therapy.

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Mixed uraemic bone disease

• Mixture of high turn over bone disease and
  osteomalacia

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Osteomalacia

• Formally linked to aluminium toxicity
• From aluminium based phosphate binders
• From contamination of water in diasylate solutions

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Adynamic bone disease

• Characterized by low osteoblastic activity and
  bone formation rates
• Seen in up to 40 HD and 50 PD
• May be due to excess suppression of the
  parathyroid gland with therapies, particularly
  calcium-containing phosphate binders and vitamin
  D analogues.
• Typically maintain a low serum intact PTH
  concentration, which is frequently accompanied by
  an elevated serum calcium level.
• Felt to represent a state of relative
  hypoparathyroidism

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Clinical manifestations of bone disease

• Most with CKD and mildly elevated PTH are
  asymptomatic
• When present classified as either
• Musculoskeletal
• Extra-skeletal

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Musculoskeletal

• Fractures, tendon rupture and bone pain from
  metabolic bone disease, muscular pain and
  weakness.
• Most clinically significant is hip fracture, seen
  in CKD 5 (and is associated with increase risk of
  death)
• NB. In dialysis pts there is already a 4.4 x
  increase risk of hip fracture.

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Extra-skeletal

• Important to recognise disordered bone and
  mineral metabolism is a systemic disorder
  affecting soft tissues, particularly vessels,
  heart valves and skin.
• CVD accounts for around half of all deaths of
  dialysis patients.
• Coronary artery and vascular calcifications occur
  frequently in CKD 5 (and increase each year on
  dialysis)

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Types of calcification

• Focal calcification associated with lipid laden
  atherosclerotic plaques
• Increases fragility and risk of plaque rupture
• Diffuse calcification
• not in atherosclerotic plaques and occurs in
  media of vessels
• Called Monckebergs sclerosis
• Increases blood vessel stiffness and reduces
  vascular compliance
• Results in widened pulse pressure
• Increased afterload
• LVH
• Contributing to CVD morbidity

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• As per Cherelle If we X-Ray most of our
  patients, theyve got tram tracks we hardly
  need an angiogram!

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Types of calcification

• Calciphylaxis or calcemic uremic arteriopathy
• Seen primarily in CKD 5
• Occurs in 1-4 of dialysis patients
• Presents with extensive calcification of the
  skin, muscles and SC tissues.
• Extensive medial calcification of small arteries,
  arterioles, capillaries and venules.
• Clinically they may have skin nodules, skin
  firmness, eschars, livedo reticularis and painful
  hyperaesthesia of the skin.
• May lead to non healing ulcers and gangrene

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calciphylaxis

• A, Confluent calf plaques (borders shown with
  arrows). Parts of the skin are erythematous,
  which is easily confused with simple cellulitis.
  B, Gross ulceration in the same patient 3 months
  later. The black eschar has been surgically
  débrided. C, Calciphylactic plaques, a few of
  which are beginning to ulcerate. (Photographs
  courtesy of Dr. Adrian Fine. Up To Date)

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Angulated black eschar with surrounding livedo.
Note the bullous change at the inferior edge of
the eschar. (courtesy Up To Date)
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Amyloidosis

• Pts on dialysis for 7- 10 years can develop
  osteoarticular amyloid deposits.
• May present with carpel tunnel syndrome and
  arthritis

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Overview

• Pathogenesis
• Normal Bone Remodeling
• Hyperparathyroidism
• Classifications of bone disease
• Diagnosis of bone disease

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Diagnosis of CKD bone disease

• Blood
• PTH
• Random circulating PTH (1/2 life 2-4 mins)
• Excreted renally so present for longer in RF
• Calcium
• Phosphate
• Bone biopsy
• no longer frequently performed
• Imaging
• In general not indicated

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PTH levels

• Normal (Pathwest) 0.7 7.0 pmol/L
• In CKD there is end-organ resistance
• Hence, recommended levels are 2 3 x normal.

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Overview

• Pathogenesis
• Normal Bone Remodeling
• Hyperparathyroidism
• Classifications of bone disease
• Diagnosis of bone disease
• Treatment of bone disease in CKD

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Treatment of CKD bone disease

• Directed towards normalising serum calcium,
  phosphate and PTH, while minimizing the risks
  associated with Rx

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Treatment of CKD bone disease

• Various Rx for secondary hyperPTH and
  hyperphosphataemia include
• Dietary phosphorous restriction
• Calcium and non-Ca phosphate binders
• Calcitriol or other Vit D analogues
• Calcimimetics
• Parathyroidectomy

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?Coke dairy food
CaCO3 with meals
?PO4
?Ca
?GFR
?1,25 DHCC
?PTH
Calcitriol
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Phosphorus (oxidized form is phosphate)

• 80 in the bone
• Food products include nuts, beer, chocolate,
  coca-cola
• Normal level 0.8 1.5mmol/L (Pathwest)
• Passes into glomerular filtrate and 90
  reabsorbed
• Reabsorption decreased by PTH and by calcitonin
  and increased if PTH is absent
• Low levels if hyperparathyroidism with excessive
  losses in urine
• High levels in hypoparathyroidism or renal failure

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Phosphate binders

• Calcium-based phosphate binders
• Calcium carbonate (Cal-Sup/Caltrate)
• Only Cal-Sup i PBS/S100
• Varies, eg. 1 BD, 1-4 TDS
• Must be chewed with food to maximize binding of
  ingested phosphorous.

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Phosphate binders

• Non-calcium phos binder
• Sevelamer (available for 12 months)
• Often used in conjunction with Cal-sup
• Used when phos still high despite max Cal-Sup (2
  TDS)
• More costly

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Phosphate binders

• Aluminium-containing phos binders
• Alu-tabs/aluminium hydroxide
• Most effective, but ceaesd use around 12 months
  ago when sevelamer and cinacalcet available.
• Systemic absorption with subsequent neurological,
  haematological and bone toxicity.

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Calcitriol

• 1,25-(OH)2 Vitamin D3 or other analogues bind to
  receptor on PT tissue and suppress PTH production

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?PO4
?Ca
?GFR
?1,25 DHCC
?PTH
Calcitriol
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Calcitonin

• Produced by parafollicular or C cells of the
  thyroid gland
• Secreted when plasma calcium level rises
• Main action is the lowering of plasma calcium by
  limiting bone resorption and it increases
  phosphate excretion in the urine

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Calcimimetics

• Calcium receptor-sensing agonists
• Act on PT gland and increase sensitivity of
  receptor to calcium
• Cinacalcet (Sensipar)
• Significant decrease PTH, w/o ? Ca or phos
• Avoids calcification

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?PO4
?Ca
?GFR
?1,25 DHCC
?PTH
Calcitriol
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Parathyroidectomy

• Last option
• Considered when other methods fail to ? PTH
• Either total or sub-total
• Used to re-implant in forearm.

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Summary of Rx

• Dietary phosphate restriction
• Phosphate binders
• Calcitriol or other Vit D analogues
• Calcium supplementation/calcimimetics
• Parathyroidectomy

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Prevention of osteodystrophy
?Coke dairy food
CaCO3 with meals
?PO4
?Ca
?GFR
?1,25 DHCC
?PTH
Calcitriol
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Transplant

• Bony changes improve post Tx, but if severe
  increased PTH, levels can persist for up top 10
  years.
• Although Tx corrects many conditions leading to
  disordered mineral metabolism,
• Steroids may lead to bone fragility, osteoporosis
  and increased fractures.

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Case Studies
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Case 1

• MC
• Diabetic nephropathy Haemodialysis
• Hypothyroidism
• Pancreatic pseudocyst
• Epilepsy
• Anaemia
• Hypertension

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Case 1

• Currently PTH 104
• Ca corrected 2.04
• Po4 1.77
• Medications
• Calcium carbonate 2 three times with meals
• Calcitriol 1mic 3 times a week

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Case 1

• What do we do?
• Thoughts?

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Case 1

• This lady is non compliant!
• No point changing her regime if she is not taking
  what you have written up
• Encourage compliance
• Explain the essential nature of compliance with
  this therapy

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Case 2

• RJ
• Diabetes
• Anaemia
• Dementia
• Alcoholism
• End stage kidney disease CAPD
• IHD/cardiomyopathy recent massive AMI
• Syphilis

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Case 2

• PO4 3.77
• Ca 1.82
• Product 6.86
• PTH 166
• Thoughts?

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Case 2

• Again non compliance
• Recent finding of around 20 webster packs in his
  room

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Case 3

• DB
• Diabetes
• End stage kidney disease HD
• Hypothyroidism
• Hypertension
• Anaemia
• Recurrent laryngeal palsy
• IHD
• Constipation
• Depression
• Cerebrovasvcular disease

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Case 3

• Ca 2.72
• PO4 1.39
• PTH 20.1
• Product 3.7
• Thoughts?

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Case 3

• Has had parathyroidectomy (hence the recurrent
  laryngeal palsy) and parameters are exactly where
  we want them
• Meds
• Calsup 2 tds with food
• Calcitriol 6 (1.5mics) twice a week at dialysis

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Case 4

• ID
• Usual litany of problems
• HD
• Po4 1.0
• Ca 2.6
• PTH 3.1
• Thoughts?

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Case 4

• Oversuppressed
• Need the PTH to be 2-3 times normal or patient
  will likely get adynamic bone disease
• Back off Vit D and Calcium
• In this case pt was on Calsup 2 tds and
  Calcitriol 6 (1.5mics) twice a week. Decrease
  Calcitriol eg 1.5mics once a week and decrease
  Calsup to 1 tds
• Monitor

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Thank you!

• renalgp_at_kamsc.org.au

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Calcium and Phosphorus Homeostasis

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References

• Dr Mark Thomas, Nephrologist, Royal Perth
  Hospital
• Primer on Kidney Diseases, 5th Edition.
  Greenberg, National Kidney Foundation. 2009