Renal osteodystrophy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nazia Fuad M.D.

Synonyms and keywords:Chronic kidney disease- mineral bone disorder

Overview

Renal osteodystrophy is defined as the complex metabolic bone disorders which are present in chronic renal insufficiency. Secondary hyperparathyroidism and 1,25-dihydroxycholecalciferol (Vitamin D3) deficiency play a major role in renal osteodystrophy. Renal osteodystrophy is defined as an alteration of bone morphology in patients with chronic kidney disease and is considered to be a component of chronic kidney disease - mineral bone disorder (CKD-MBD). Chronic kidney disease is the major cause of renal osteodystrophy so all those conditions that cause chronic kidney disease are the risk factors for renal osteodystrophy. Hypocalcemia, hyperphosphatemia, vit D deficiency, parathyroid gland hyperplasia, acidosis are the other contributors of renal osteodystrophy. Aluminum related renal osteodystrophy is mostly seen in patients who undergo dialysis. Renal osteodystrophy is an important cause of morbidity, decreased quality of life, and extravascular calcifications that have been associated with increased cardiovascular mortality. Classification of renal osteodystrophy describes a wider clinical syndrome based on bone turnover, bone mineralization, and bone volume. Renal osteodystrophy should be differentiated from primary hyperparathyroidism, hypocalcemia and osteoporosis. To investigate renal osteodystrophy, blood levels of parathyroid hormone (PTH), calcium, phosphorus, alkaline phosphatase, bicarbonate should initially be ordered. Imaging studies should focus on finding calcification in soft tissues. A bone biopsy is indicated if the results of biochemical markers are not consistent, there is unexplained bone pain, or presence of unexplained bone fractures. However, bone biopsies are infrequently used in clinical practice due to invasiveness and lower cost effectiveness.Common complications of renal osteodystrophy include bone fractures vascular calcifications leading to atherosclerosis, coronary artery calcification, hypertension, left ventricular hypertrophy, and congestive heart failure. Extraskeletal calcification can also affect the heart valves and the cardiac conduction system.Calcification of skin arterioles may lead to a condition of ischemia and necrosis of the skin known as calciphylaxis. Patients with renal osteodystrophy usually present with bone pain, Arthralgia, Chest pain, Dyspnea, and Palpitation. Physical examination of patients with renal osteodystrophy may include bone deformity, bone fracture, Hypertension, congestive heart failure, heart murmur, increase pulse pressure (due to aortic calcification) and skin Ischemia and necrosis. In laboratory findings serum calcium levels are typically low. Serum phosphorous is elevated depending on the stage of chronic kidney disease, dietary phosphorous, and use of phosphate binders. Alkaline phosphatase levels (total or bone-specific) are elevated and show increased osteoblastic activity. High levels of alkaline phosphatase are seen in severe osteitis fibrosa.Elecrocardiographic findings in patients with renal osteodystrophy include heart block, non st elevation myocardial infarction. Radiographic findings are less sensitive for diagnosis than parathyroid hormone levels. Imaging is usually performed for patients with unexplained bone pain or fractures.Radiographic findings of osteitis fibrosa cystica include Subperiosteal resorption.Resorptive loss of bone may be seen at the terminal phalanges, distal ends of the clavicles, and in the skull. Radiographs will show soft tissue calcification that involves the vasculature. Phosphate binders and supplemental calcium are mainly used for prevention and treatment of renal osteodystrophy.The major objective in the prevention and management of renal osteodystrophy is either prevention of hyperparathyroidism or treatment if present already.g

Historical Perspective

• Renal osteodystrophy was first defined by Kidney Disease: Improving Global Outcomes (KDIGO) in 2006.
• It was discovered in the 1970s and 1980s, that aluminum in water that is used for dialysis and aluminum salts that are used as phosphate binders caused osteomalacia and an adynamic bone disease.
• The identification of these disorders led to define renal osteodystrophy.

Classification

• Renal osteodystrophy can be classified according to histology into the following subtypes:

Histologic Classification of Renal Osteodystrophy
Disorder	Description	Pathogenesis	Frequency (%)
Osteitis fibrosa	Peritrabecular fibrosis, increased remodeling — resorption and formation.	Secondary hyperparathyroidism, secondary role of cytokines and growth factors	50
Osteomalacia	Increased osteoid, defective mineralization	Aluminum deposition, plus unknown factors	7
Mixed disease	Features of both osteitis fibrosa and osteomalacia	Secondary hyperparathyroidism and aluminum deposition, plus unknown factors	13
Mild disease	Slightly increased remodeling	Early or treated secondary hyperparathyroidism	3
Adynamic renal bone disease	Hypocellular bone surfaces, no remodeling	Aluminum deposition, parathyroid hormone suppression, and other factors (deficiency of bone growth factors or increased suppressors of bone remodeling)	27

• After the bone pathology is assessed by histomorphometry,renal osteodystrophy can be subdivided according to TMV classification
• TMV uses three descriptions- bone turnover(T), bone mineralization(M)

and bone volume(V).

• it helps to define the pathophysiology and to choose the right therapy.

Pathophysiology

The following factors in chronic kidney disease are considered to be the main contributors to renal osteodystrophy:

• Hyperphosphatemia: when GFR falls below 60 ml/min in chronic kidney disease there is impaired renal phosphorus excretion resulting in hyperphosphatemia.
• Hypocalcemia, because of decreased excretion of phosphate by the damaged kidneys.
• Low activated vitamin D₃ levels happen because the damaged kidneys are unable to convert vitamin D₃ into its active form, calcitriol, which results in further hypocalcemia.
• Hyperphosphatemia combined with hypocalcemia results in hyperparathyroidism
• Elevated level of hyperparathyroid leads to osteitis fibrosa.
• High levels of fibroblast growth factor 23 are found in chronic kidney disease.
• Aluminum levels in body raises in patients with chronic renal failure.
• High levels of aluminum cause renal osteodystrophy, specially osteomalacia and an aplastic lesion.
• Since the composition of dialysis fluids was changed and calcium carbonate was substituted for aluminum salts, bone disease due to deposition of aluminum is decreasing.

Factors in the pathogenesis of hyperparathyroidism in chronic renal disease
	Phosphorus retention	Hypocalcemia	Low calcitriol	Skeletal resistance	Altered parathyroid function
↓Renal mass	+		+
↑Phosphorus		+	+	+	unknown
↓Calcium					+
↓Calciterol		+		+	+
Skeletal resistance	+
Desensitization to PTH		+
↓Vit D receptors					+
Altered cell growth					+
Acidosis			+

Causes

• The common causes of renal osteodystrophy are:
  • Chronic renal disease
  • Hypocalcemia
  • Hyperphosphatemia
  • Vit D deficiency
  • Parathyroid gland hyperplasia
  • Acidosis
  • Aluminum retention (in dialysis patients)
  • Accumulation of β2M(beta-2 microglobulin) in bone and joints

Differentiating Renal Osteodystrophy from Other Diseases

• Renal osteodystrophy must be differentiated from the diseases that cause abnormal bone mineralization, unexplained bone fractures and bone pain:

• • Primary hyperparathyroidism will cause hypercalcemia, hyperparathyroidism, and normal-to-low phosphate in patients with either normal or slightly reduced renal function.
  • Tertiary hyperparathyroidism causes hypercalcemia, hyperparathyroidism, and normal or slightly elevated phosphate in patients with longterm chronic kidney disease and mineral bone disorder (CKD-MBD).
  • Osteoporosis, patients will have normal renal function.
  • Vitamin D deficiency will cause normal or slight reduction in renal function.

Epidemiology and Demographics

• The prevelence of renal osteodystrophy is 8,000 per 100,000 in the adult population in US. Incidence of renal osteodystrophy increases in patients with chronic kidney disease who have glomerular filtration rate (GFR) less than 60 mL/min.
• Prevalence in developing countries:
  • The prevalence of renal osteodystrophy in developing countries is 24.4% to 63%.
  • Aluminum, high strontium levels and iron overload play a major role in the development of renal osteodystrophy in patients who undergo dialysis in developing countries.

Risk Factors

• The major risk factors in the development of renal osteodystrophy are:
  • Chronic renal disease
  • Dialysis
  • Diabetes mellitus

Natural History, Complications, and Prognosis

Common complications of renal osteodystrophy include:

• Bone fractures
• Vascular calcification leading to atherosclerosis, coronary artery calcification, hypertension, left ventricular hypertrophy, and congestive heart failure.
• Extraskeletal calcification can also affect the heart valves and the cardiac conduction system.
• Calcification of skin arterioles may lead to a condition of ischemia and necrosis of the skin known as calciphylaxis.

Prognosis

• Renal osteodystrophy is associated with an increased risk of bone fractures, cardiovascular calcification, poor quality of life and increased morbidity and mortality in patients with chronic kidney disease.
• However, prognosis is generally good after a renal transplant.

Diagnosis

Diagnostic Study of Choice

Bone biopsy

• A definitive tool for diagnosis of renal osteodystrophy is bone biopsy according to KIDGO 2017 guidelines.
• However, bone biopsies are infrequently performed because it is an invasive and expensive procedure.

Serum biomarkers: 

• The following biomarkers are used in the diagnosis of renal osteodystrophy:

• • Serum calcium
  • Serum phosphorous
  • Alkaline phosphatase (total or bone-specific)
  • Parathyroid hormone(PTH)
• PTH levels are considered to be the best noninvasive option to assess bone turnover.
• The following framework is used to describe the risk for different subtypes of renal osteodystrophy:
  • PTH <100 pg/mL  means adynamic bone disease and a decreased risk of osteitis fibrosa cystica
  • PTH >450 pg/mL means osteitis fibrosa cystica and/or MUO(mixed uremic osteodystrophy)
  • Intermediate PTH levels between 100 and 450 pg/mL  Intermediate values may be due to normal or increased turnover or even reduced bone turnover.   

History and Symptoms

• Patients with renal osteodystrophy are usually asymptomatic.
• When symptomatic, they usually present with:
  • Bone pain
  • Arthralgia
  • Chest pain
  • Dyspnea
  • Palpitation or slow pulse

Physical Examination

• Patients with renal osteodystrophy usually appear sick.
• Physical examination of patients with renal osteodystrophy may include:
  • Bone deformity
  • Bone fracture
  • Hypertension
  • Congestive heart failure
  • Heart murmur
  • Increase pulse pressure (due to aortic calcification)
  • Skin Ischemia and necrosis ( calciphylaxis)

Laboratory Findings

•  Measurement of bone turnover on a bone biopsy is determined by labeling the bone with tetracycline. The procedure is done at two separate times approximately 2 weeks apart. The distance between the two areas of tetracycline deposition is measured and can be used to calculate bone growth.

• Serum calcium levels are typically low.
• Serum phosphorous is elevated depending on the stage of chronic kidney disease, dietary phosphorous, and use of phosphate binders.
• Alkaline phosphatase levels (total or bone-specific) are elevated and show increased osteoblastic activity. High levels are seen in severe osteitis fibrosa.

PTH(parathyroid hrmone) levels are the best noninvasive option for assessment of bone turnover.

• The following parameters are used to define the risk for specific subtypes of renal osteodystrophy.
  • PTH <100 pg/mL suggests adynamic bone disease and a decreased risk of osteitis fibrosa cystica and or MUO(mixed uremic osteodystrophy)
  • PTH >450 pg/mL suggests osteitis fibrosa cystica and/or MUO (mixed uremic osteodystrophy).
  • Intermediate PTH levels between 100 and 450 pg/mL.  Intermediate values may be associated with normal or increased bone turnover or even reduced turnover.

Electrocardiogram

• Electrocardiographic findings in patients with renal osteodystrophy may include:
  • Heart block
  • Non ST elevation MI

X-ray

• Routine radiographic screenings are not done for bone disease in patients with end-stage renal disease (ESRD).
• Radiographic findings are less sensitive for diagnosis than PTH levels.
• Imaging is usually performed for patients with unexplained bone pain or fractures.
• Radiographic findings of osteitis fibrosa cystica include:
  • Subperiosteal resorption and
  • New bone formation especially at the radial aspect of the middle phalanges.
• Resorptive loss of bone may be seen at the terminal phalanges, distal ends of the clavicles, and in the skull.
• Radiographs will show soft tissue calcification that involves the vasculature.

Echocardiography or Ultrasound

• Echocardiography will show:
  • Diastolic dysfunction
  • Left ventricular hypertrophy
  • Valvular calcifications

CT scan

• CT scan findings associated with renal osteodystrophy are the same that are related to chronic kidney disease.

MRI

• There are no MRI findings associated with renal osteodystrophy.

Other Imaging Findings

• There are no other imaging findings associated with renal osteodystrophy.

Other Diagnostic Studies

•  DEXA bone densitometry will show low bone density.

Treatment

Medical Therapy:

• Phosphate binders and supplemental calcium are mainly used for prevention and treatment of renal osteodystrophy.

Control of Serum Calcium

• Calcium malabsorption is seen in end-stage renal disease because of deficient 1,25-dihydroxycholecalciferol.
• To prevent or suppress oversecretion of parathyroid hormone, calcium concentrations should be maintained at the high end of the normal range.
• In patients with calcium intakes of 800–1000 mg/day, additional calcium supplements or calcium-containing medications should be avoided.
• Patients with total calcium intakes (>approx. 1000 mg/day) should be advised to decrease calcium intake.
• Patients with lower calcium intakes should be advised to increase calcium intake in foods,or take calcium supplements.
• . Calcium-rich foods include dairy, dark green leafy vegetables, calcium-set tofu, and calcium-fortified orange juice.
• The timing of taking oral calcium is crucial as calcium taken between meals is more like a calcium supplement than a phosphate binder.

Control of Serum Phosphate

• A low-phosphate diet is crucial in the end-stage renal disease, to keep serum phosphate concentration within the normal limits.
• Phosphate binder:
  • Preferred regimen(1): Calcium carbonate, 500 mg PO q8h to be taken with each meal.
  • Preferred regimen (2): Sevelamer carbonate 800 mg PO q8h with meal.
• Total dose of elemental calcium (including dietary sources and calcium-based phosphate binders) should not exceed 2000 mg daily in chronic kidney disease.
• Aluminum-containing phosphate binders should be avoided.

Use of Vit D analogue

• Calcitriol alfacalcidol, Doxercalciferol, and calcifediol
  • Preferred regimen(1):Calcifediol , 30 mcg PO qHS for 3 months then increase the dose to 60mcg PO qHS is preferred regimen.
  • Preferred regimen(2): Alfacalcidol, 0.25 mcg PO qdaily for 2 months.
  • Preferred regimen(3): Doxercalciferol 10 mcg PO 3 times/week at dialysis,may increase the dose by 2.5 mcg.

• Dialysis patients recieve 1 mcg intravenously during each dialysis session, 2-3 times weekly
• Make sure serum calcium in <9.8 mg/dL before initiating vitamin D analogues.
• They decrease bone pain, improve bone histologic characteristics, and suppress parathyroid hormone secretion by increasing serum calcium concentrations and inhibiting parathyroid hormone gene transcription

Surgery

• Subtotal parathyroidectomy
• The treatment for renal osteodystrophy is medical therapy.
• Surgery is usually reserved for patients with hyperparathyroid bone disease
• Renal transplant

Primary Prevention

• Early diagnosis and treatment of hyperparathyroid patients.
• Early diagnosis and treatment of renal diseases to prevent chronic renal failure and consequently renal osteodystrophy.

Secondary Prevention

• Vitamin D administration with every session of dialysis
• Use of aluminum-free phosphate binders.

Related Chapters

• osteoporosis
• osteopenia
• osteomalacia
• hyperparathyroidism
• multiple myeloma
• soft tissue calcification including collagen vascular disease
• hydroxyapatite crystal deposition disease
• hypervitaminosis

External links

Renal Osteodystrophy

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