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Bone Disease in Renal Failure
Dr Anne Kleinitz and Dr Cherelle Fitzclarence
Overview
• Pathogenesis• Normal Bone Remodeling• Hyperparathyroidism• Classifications of bone disease• Diagnosis of bone disease• Treatment of bone disease in CKD• Case Studies
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
↓GFR
↑PO4
↓1,25 DHCC
↓Ca
↑PTHCalcitriol
• Although bone disease and abnormal PTH are a major feature, CVD and excess calcification (extra-skeletal) are important causes of morbidity and mortality
• Pathogenesis• Normal Bone Remodeling
Resorptionosteoclasts
Formationosteoblasts →matrix
MineralisationQuiescence
Normal Bone Normal Bone Remodelling CycleRemodelling Cycle
• Pathogenesis• Normal Bone Remodeling• Hyperparathyroidism
Hyperparathyroidism
• Increase PTH is hallmark of secondary hyperparathyroidism
• The major factors leading to it’s increase are; – Decreased production of Vit D3 (calcitriol)– Decreased serum calcium– Increased serum phosphorous
↓GFR
↑PO4
↓1,25 DHCC
↓Ca
↑PTHCalcitriol
• 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
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
• 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.
Uraemic Secondary Uraemic Secondary HyperparathyroidismHyperparathyroidism
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)
Secondary hyperparathyroidism
• In renal failure driven by– Hypocalcaemia– Decreased vitamin D– hyperphosphataemia
↓GFR
↑PO4
↓1,25 DHCC
↓Ca
↑PTHCalcitriol
hyperPTH in CKD
• In CKD is a progressive disorder.• Involves both increased secretion PTH &
hyperplasia• Can occur once eGFR < 60• PTH levels increase progressively as renal
function declines and by CKD stage 5(<15) most pt’s 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
Overview
• Pathogenesis• Normal Bone Remodeling• Hyperparathyroidism• Classifications of bone disease in CKD
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
Types of Renal Bone DiseaseTypes 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 amyloidosisOsteoporosis
– Post-menopausal - Post-transplant
Resorptionosteoclasts
Formationosteoblasts →matrix
Accelerates:High PO4 or
Low Ca2+, Vit D3,
Retards: Vit D3, Age, Diabetes, Al3+, PTHx
MineralisationQuiescence
Uraemic Bone Uraemic Bone RemodellingRemodellingCycleCycle
Resorptionosteoclasts
Formationosteoblasts →matrix
Accelerates:High PO4 or
Low Ca2+, calcitriol, HCO3, oestrogen
Retards: Calcitriol*, Age, Diabetes, Al3+, PTHx
Mineralisation
*Acts via osteoblasts
Quiescence
Uraemic Bone Uraemic Bone RemodellingRemodellingCycleCycle
Via PTH*, IL-1,6 & TNF
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.
Mixed uraemic bone disease
• Mixture of high turn over bone disease and osteomalacia
Osteomalacia
• Formally linked to aluminium toxicity– From aluminium based phosphate binders– From contamination of water in diasylate
solutions
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
Clinical manifestations of bone disease
• Most with CKD and mildly elevated PTH are asymptomatic
• When present classified as either– Musculoskeletal– Extra-skeletal
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.
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)
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 “Monckeberg’s sclerosis”• Increases blood vessel stiffness and reduces vascular
compliance• Results in widened pulse pressure• Increased afterload• LVH
• Contributing to CVD morbidity
• As per Cherelle “If we X-Ray most of our patients, they’ve got “tram tracks” – we hardly need an angiogram!”
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
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)
Angulated black eschar with surrounding livedo. Note the bullous change at the inferior edge of the eschar.
(courtesy Up To Date)
Amyloidosis
• Pts on dialysis for 7- 10 years can develop osteoarticular amyloid deposits.
• May present with carpel tunnel syndrome and arthritis
Overview
• Pathogenesis• Normal Bone Remodeling• Hyperparathyroidism• Classifications of bone disease• Diagnosis of bone disease
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
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.
Overview
• Pathogenesis• Normal Bone Remodeling• Hyperparathyroidism• Classifications of bone disease• Diagnosis of bone disease• Treatment of bone disease in CKD
Treatment of CKD bone disease
• Directed towards normalising serum calcium, phosphate and PTH, while minimizing the risks associated with Rx
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
↓GFR
↑PO4
↓1,25 DHCC
↓Ca
↑PTH
↓Coke & dairy food
CaCO3 with meals
Calcitriol
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
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.
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
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.
Calcitriol
• 1,25-(OH)2 Vitamin D3 or other analogues bind to receptor on PT tissue and suppress PTH production
↓GFR
↑PO4
↓1,25 DHCC
↓Ca
↑PTHCalcitriol
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
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
↓GFR
↑PO4
↓1,25 DHCC
↓Ca
↑PTHCalcitriol
Parathyroidectomy
• Last option• Considered when other methods fail to ↓
PTH• Either total or sub-total
– Used to re-implant in forearm.
Summary of Rx
• Dietary phosphate restriction• Phosphate binders• Calcitriol or other Vit D analogues • Calcium supplementation/calcimimetics• Parathyroidectomy
Prevention of osteodystrophyPrevention of osteodystrophy
↓GFR
↑PO4
↓1,25 DHCC
↓Ca
↑PTH
↓Coke & dairy food
CaCO3 with meals
Calcitriol
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.
Case Studies
Case 1
MC• Diabetic nephropathy – Haemodialysis• Hypothyroidism• Pancreatic pseudocyst• Epilepsy• Anaemia• Hypertension
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
Case 1
• What do we do?• Thoughts?
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
Case 2
RJ• Diabetes• Anaemia• Dementia• Alcoholism• End stage kidney disease – CAPD• IHD/cardiomyopathy – recent massive AMI• Syphilis
Case 2
• PO4 3.77• Ca 1.82• Product 6.86• PTH 166
• Thoughts?
Case 2
• Again non compliance• Recent finding of around 20 webster packs
in his room
Case 3
DB• Diabetes• End stage kidney disease – HD• Hypothyroidism• Hypertension• Anaemia• Recurrent laryngeal palsy• IHD• Constipation• Depression• Cerebrovasvcular disease
Case 3
• Ca 2.72• PO4 1.39• PTH 20.1• Product 3.7
• Thoughts?
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
Case 4
ID• Usual litany of problems• HD
• Po4 1.0• Ca 2.6• PTH 3.1
• Thoughts?
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
Calcium and Phosphorus Homeostasis
•
References
• Dr Mark Thomas, Nephrologist, Royal Perth Hospital
• Primer on Kidney Diseases, 5th Edition. Greenberg, National Kidney Foundation. 2009