Renal osteodystrophy: Difference between revisions

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{{SI}}
{{SI}}


{{CMG}}; {{AE}} {{N.F}}
{{CMG}}; {{AE}} {{N.F}} , [[User:Parnian Jabbari|Parnian Jabbari]]


{{SK}}Chronic kidney disease- mineral bone disorder
{{SK}}Chronic kidney disease- mineral bone disorder
==Overview==
==Overview==
Renal osteodystrophy is<nowiki/> defined as the complex metabolic bone disorders which are present in [[Chronic kidney disease|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. [[Aluminium|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 [[Calcification|calcifications]] that have been associated with increased [[cardiovascular]] mortality. Classification of renal osteodystrophy describes a wider clinical syndrome based on bone turnover, bone [[Mineralization of 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<nowiki/> if the results of biochemical markers are not consistent, there is unexplained bone pain, or presence of unexplained bone fractures. However, bone [[Biopsy|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]], c[[Congestive heart failure|ongestive heart failure]], h[[Heart murmur|eart murmur]], increase pulse pressure (due to [[aortic calcification]]) and skin [[Ischemia]] and [[necrosis]]. In laboratory findings serum [[calcium]] levels are typically low. Serum [[Phosphorous acid|phosphorous]] is elevated depending on the stage of [[Chronic renal failure|chronic kidney disease]], dietary [[Phosphorous acid|phosphorous]], and use of [[phosphate binders]][[Alkaline phosphatase|. 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 cystica|osteitis fibrosa]].[[Electrocardiogram|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 of the hand|phalanges]], distal ends of the [[Clavicle|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
Renal osteodystrophy (ROD) is within the broad spectrum of Chronic Kidney Disease (CKD)- Mineral Bone Disease (MBD). The disease occurs as a natural complication of the CKD and is characterized by abnormal levels and metabolism of [[calcium]] (Ca), [[phosphorus]] (Ph), [[parathyroid hormone|parathyroid Hormone]] (PTH), and [[vitamin D]], as well as calcification of soft tissues and bone turn over and mineralization abnormalities. Secondary [[hyperparathyroidism]] and 1,25-dihydroxycholecalciferol (vitamin D3) deficiency play a major role in ROD. Any factor leading to CKD is potentially a risk factor for ROD. [[Hypocalcemia]], [[hyperphosphatemia]], vitamin D deficiency, [[parathyroid gland]] [[hyperplasia]] and [[acidosis]] are the other contributors of ROD. [[Aluminium|Aluminum]] related ROD is mostly seen in patients who undergo [[dialysis]]. ROD is an important cause of [[morbidity]], decreased quality of life, and extravascular [[Calcification|calcifications]] that have been associated with increased [[cardiovascular]] mortality. Primary investigation of ROD includes measurement of blood levels of [[parathyroid hormone]] (PTH), [[calcium]], [[phosphorus]], [[alkaline phosphatase]] and [[bicarbonate]]. Imaging studies should focus on finding [[calcification]] in soft tissues. A bone [[biopsy]] is indicated if the results of biochemical markers are not consistent or when there is unexplained bone pain, or in case of presence of unexplained bone fractures. However, bone [[Biopsy|biopsies]] are infrequently used in clinical practice due to invasiveness and low cost-effectiveness. Common complications of ROD include bone fractures and vascular calcifications leading to [[atherosclerosis]], coronary artery calcification, [[hypertension]], [[left ventricular hypertrophy]], and [[congestive heart failure|congestive heart failure (CHD)]]. Extra-skeletal 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|ongestive heart failure]], [[Heart murmur|heart murmur]], increased pulse pressure (due to [[aortic calcification]]) and skin [[ischemia]] and [[necrosis]]. In laboratory findings, serum [[calcium]] levels are typically low. Serum [[Phosphorous acid|phosphorous]] is elevated depending on the stage of [[Chronic renal failure|chronic kidney disease]], dietary [[Phosphorous acid|phosphorous]], and use of [[phosphate binders]][[Alkaline phosphatase|. 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 cystica|osteitis fibrosa]]. [[Electrocardiogram|Elecrocardiographic]] findings in patients with renal osteodystrophy include [[heart block]] and non-ST-elevation [[myocardial infarction]]. Radiographic findings are less sensitive for diagnosis compared to 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 of the hand|phalanges]], distal ends of the [[Clavicle|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 its treatment if present.
 


==Historical Perspective==
==Historical Perspective==
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* Renal osteodystrophy can be classified according to histology into the following subtypes:<ref name="HruskaEpstein19952" /><ref name="MoeDrüeke20062">{{cite journal|last1=Moe|first1=S.|last2=Drüeke|first2=T.|last3=Cunningham|first3=J.|last4=Goodman|first4=W.|last5=Martin|first5=K.|last6=Olgaard|first6=K.|last7=Ott|first7=S.|last8=Sprague|first8=S.|last9=Lameire|first9=N.|last10=Eknoyan|first10=G.|title=Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO)|journal=Kidney International|volume=69|issue=11|year=2006|pages=1945–1953|issn=00852538|doi=10.1038/sj.ki.5000414}}</ref>
* Renal osteodystrophy can be classified according to histology into the following subtypes:<ref name="HruskaEpstein19952" /><ref name="MoeDrüeke20062">{{cite journal|last1=Moe|first1=S.|last2=Drüeke|first2=T.|last3=Cunningham|first3=J.|last4=Goodman|first4=W.|last5=Martin|first5=K.|last6=Olgaard|first6=K.|last7=Ott|first7=S.|last8=Sprague|first8=S.|last9=Lameire|first9=N.|last10=Eknoyan|first10=G.|title=Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO)|journal=Kidney International|volume=69|issue=11|year=2006|pages=1945–1953|issn=00852538|doi=10.1038/sj.ki.5000414}}</ref>
{| class="wikitable"
{| class="wikitable"
| Increased osteoid, defective
! colspan="4" |Histologic Classification of Renal Osteodystrophy
[[mineralization]]! colspan="4" |Histologic Classification of Renal Osteodystrophy
|-
|-
!Disorder
!Disorder
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|-
|-
|[[Osteitis fibrosa]]
|[[Osteitis fibrosa]]
| [[Peritrabecular fibrosis]], increased  
| [[Peritrabecular fibrosis]], increased  
remodeling — resorption and
remodeling — resorption and
formation.
formation.
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|-
|-
|[[Osteomalacia]]
|[[Osteomalacia]]
| Increased osteoid, defective
[[mineralization]]
|Aluminum deposition, plus
|Aluminum deposition, plus
unknown factors
unknown factors
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|Mixed disease
|Mixed disease
| Features of both [[osteitis fibrosa]]  
| Features of both [[osteitis fibrosa]]  
and osteomalacia
and [[osteomalacia]]
|Secondary hyperparathyroidism
|[[Secondary hyperparathyroidism]]
and aluminum deposition,
and aluminum deposition,


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|Mild disease
|Mild disease
| Slightly increased remodeling
| Slightly increased remodeling
|Early or treated secondary  
|Early or treated [[Secondaryhyperparathyroidism|secondary]]
hyperparathyroidism
[[Secondaryhyperparathyroidism|hyperparathyroidism]]
|3
|3
|-
|-
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|Hypocellular bone surfaces,  
|Hypocellular bone surfaces,  
no remodeling
no remodeling
|Aluminum deposition, parathyroid hormone
|[[Aluminum]] deposition, [[parathyroid hormone]]
suppression, and other factors  
suppression, and other factors  


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|27
|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), [[Mineralization (biology)|bone mineralization]](M) and bone volume(V).


* After the bone pathology is assessed by histomorphometry,renal osteodystrophy can be subdivided according to TMV classification
* It helps to define the [[pathophysiology]] and to choose the right therapy.<ref name="MoeDrüeke20062" />
* TMV uses three descriptions- [[bone turnover]](T), [[Mineralization (biology)|bone mineralization]](M)
and bone volume(V).
* it helps to define the [[pathophysiology]] and to choose the right therapy.<ref name="MoeDrüeke20062" />


== Pathophysiology  ==
== Pathophysiology  ==


The following factors in chronic kidney disease are considered to be the main contributors to renal osteodystrophy:<ref name="GonzalezMartin19952">{{cite journal|last1=Gonzalez|first1=E. A.|last2=Martin|first2=K. J.|title=Renal osteodystrophy: pathogenesis and management|journal=Nephrology Dialysis Transplantation|volume=10|issue=supp3|year=1995|pages=13–21|issn=0931-0509|doi=10.1093/ndt/10.supp3.13}}</ref><ref name="MoeDrüeke20064">{{cite journal|last1=Moe|first1=S.|last2=Drüeke|first2=T.|last3=Cunningham|first3=J.|last4=Goodman|first4=W.|last5=Martin|first5=K.|last6=Olgaard|first6=K.|last7=Ott|first7=S.|last8=Sprague|first8=S.|last9=Lameire|first9=N.|last10=Eknoyan|first10=G.|title=Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO)|journal=Kidney International|volume=69|issue=11|year=2006|pages=1945–1953|issn=00852538|doi=10.1038/sj.ki.5000414}}</ref><ref name="MoeDrüeke20062" />
'''Overview of pathophysiology'''<ref name=":0" /><ref name="GonzalezMartin19952" /><ref name="MoeDrüeke20062" />''':'''
* [[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.
In CKD, serum Ca levels decrease and serum Ph levels increase. Initially in the course of renal disease, compensatory mechanisms try to increase serum Ca and decrease serum Ph. These mechanisms include increased levels of [[fibroblast growth factor 23]] (FGF23) which in turn increases urinary Ph excretion. On the other hand, increased PTH levels further increase urinary excretion of Ph. However, as the renal disease becomes chronic, these compensatory mechanisms do not respond any more and the characteristic features of ROD become evident <ref name=":1">{{Cite web|url=https://onlinelibrary.wiley.com/doi/full/10.1111/nep.13457|title=Mineral bone disorders in chronic kidney disease|last=Yi-Chou Hou, Chien-Lin Lu, Kuo-Cheng Lu|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>. Once an abnormality in serum levels of these minerals is established (decreased Ca and increased Ph), PTH levels increase and change bone metabolism via alterations in osteoblast and osteoclast activity. Early in CKD, due to increased FGF23, 1,25 (OH) vitamin D decreases which further leads to hyperparathyroidism (HPTH). However, some contributors to CKD-MBD alter before PTH levels are increased, an example of these contributors are sclerostin and FGF23 which are increased even before HPTH. HPTH can also insert its effects via the reduction of β-catenin which inhibits maturation of osteoblasts. 
* Low activated [[Vitamin D3|vitamin D<sub>3</sub>]] levels happen because the damaged kidneys are unable to convert [[Vitamin D3|vitamin D<sub>3</sub>]] into its active form, [[calcitriol]], which results in further [[hypocalcemia]].
* PTH receptors are found on preosteoblasts, [[Osteoblast|osteoblasts]] and [[Osteocyte|osteocytes]] and increases their proliferation. ([[Osteoclast|Osteoclasts]] do not have PTH receptors and are activated by preosteoblasts and osteoblasts.)
* [[Hyperphosphatemia]] combined with [[hypocalcemia]] results in [[hyperparathyroidism]]
* Increased levels of PTH lead to increased bone resorption by osteoclasts <ref>{{Cite web|url=https://academic.oup.com/endo/article/140/8/3552/2990646|title=Parathyroid hormone stimulates TRANCE and inhibits osteoprotegerin messenger ribonucleic acid expression in murine bone marrow cultures: correlation with osteoclast-like cell formation.|last=Lee SK, Lorenzo JA.|first=|date=|website=https://academic.oup.com/endo/article/140/8/3552/2990646|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and [[Osteitis fibrosa cystica|osteitis fibrosa]].
* Elevated level of [[hyperparathyroid]] leads to [[Osteitis fibrosa cystica|osteitis fibrosa]].
As a result, HPTH leads to high-turnover bone disease.
* High levels of [[fibroblast growth factor 23]] are found in [[chronic kidney disease]].
 
* [[Aluminium|Aluminum]] levels in body raises in patients with [[chronic renal failure]].
Many factors can contribute to low levels of PTH, such as increased dietary intake of Ca and Vit D, using Ph binders containing Ca dialysate. Low levels of PTH lead to low-turnover bone disease, also known as adynamic bone disease. Low PTH levels lead to excess circulating Ca (since Ca is not deposited in the bone). This excess Ca may lead to calcification of soft tissues.
* High levels of [[Aluminium|aluminum]] cause renal osteodystrophy, specially [[osteomalacia]] and an aplastic lesion.
 
* Since the composition of [[dialysis]] fluids was changed and [[calcium carbonate]] was substituted for [[Aluminium|aluminum s]]<nowiki/>alts,  bone disease due to deposition of [[aluminium|aluminum]] is decreasing.
[[Aluminium|Aluminum]]-based [[chelation]] of Ph during dialysis was among the common factors contributing to osteomalacia. However since replacement of aluminum with other chelators this factor is less prominent. <ref name="GonzalezMartin19952">{{cite journal|last1=Gonzalez|first1=E. A.|last2=Martin|first2=K. J.|title=Renal osteodystrophy: pathogenesis and management|journal=Nephrology Dialysis Transplantation|volume=10|issue=supp3|year=1995|pages=13–21|issn=0931-0509|doi=10.1093/ndt/10.supp3.13}}</ref><ref name="MoeDrüeke20064">{{cite journal|last1=Moe|first1=S.|last2=Drüeke|first2=T.|last3=Cunningham|first3=J.|last4=Goodman|first4=W.|last5=Martin|first5=K.|last6=Olgaard|first6=K.|last7=Ott|first7=S.|last8=Sprague|first8=S.|last9=Lameire|first9=N.|last10=Eknoyan|first10=G.|title=Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO)|journal=Kidney International|volume=69|issue=11|year=2006|pages=1945–1953|issn=00852538|doi=10.1038/sj.ki.5000414}}</ref><ref name="MoeDrüeke20062" />
 
CKD leads to uremia and hyperphosphatemia which change the pluripotent smooth muscle cells to osteoblasts. This coupled with increased Ca levels leads to calcification of soft tissues <ref>{{Cite journal|last=Jorge B, Cannata-Andνa, Minerva Rodrνguez-Garcνa, et al|first=|date=2006|title=ascular calcifications: Pathogenesis, management and impact on clinical outcomes|url=|journal=J Am Soc Nephrol|volume=17|pages=267-73|via=}}</ref>.
 
Overall, following factors contribute to vascular calcification <ref name=":1" />:
* Hypocalcemia and hyperphosphatemia
* Hyperparathyroidemia
* Matrix degradation and alteration of matrix proteins
* Apoptosis of smooth muscle cells
* Systemic inflammation
 
{| class="wikitable"
{| class="wikitable"
! colspan="7" | Factors in the pathogenesis of hyperparathyroidism in chronic renal disease
! colspan="6" | Factors in the pathogenesis of hyperparathyroidism in chronic renal disease
|-
|-
|
|
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resistance
resistance
|Altered
|Altered
[[parathyroid]]
[[parathyroid]] function
function
|-
|-
|↓Renal mass
|↓Renal mass
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| +
| +
| +
| +
|unknown
|Unknown
|-
|-
|↓[[Calcium]]
|↓[[Calcium]]
Line 165: Line 174:
** [[Hypocalcemia]]
** [[Hypocalcemia]]
** [[Hyperphosphatemia]]
** [[Hyperphosphatemia]]
** Increased FGF23 and sclerostin
** Vit D deficiency
** Vit D deficiency
** [[Parathyroid gland]] [[hyperplasia]]
** [[Parathyroid gland]] [[hyperplasia]] and hyperparathyroidism (HPTH is the most important factor in CKD-MBD)
** [[Acidosis]]
** [[Acidosis]]
** [[Aluminum]] retention (in [[dialysis]] patients)  
** [[Aluminum]] retention (in [[dialysis]] patients)  
** Accumulation of β2M(beta-2 microglobulin) in [[bone]] and [[joints]]
** Accumulation of β2M (beta-2 microglobulin) in [[bone]] and [[joints]]


==Differentiating Renal Osteodystrophy from Other Diseases==
==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:<ref name=":0" />
* Renal osteodystrophy must be differentiated from the diseases that cause abnormal bone mineralization, unexplained [[bone fractures]] and bone pain:<ref name=":0" />
*
{| class="wikitable"
{| class="wikitable"
! colspan="4" |Differential diagnosis of renal osteodystrophy
|-
!
!
!
![[Calcium]]
!
![[Phosphate]]
!
![[Renal function]]
!
|-
!Renal osteodystrophy
|↓
|↑
|Markedly declined
|-
![[Primary hyperparathyroidism]]
|↑
|Low to normal
|Normal or slightly
reduced
|-
!Tertiary [[hyperparathyroidism]]
|↑
|Slightly elevated
|Normal or slightly reduced
|-
|-
|
![[Osteoporosis]]
|
|Normal
|
|Normal
|
|Normal
|
|-
|-
|
![[Vitamin D]] deficiency
|
|
|
|
|
|Normal
|
|-
|-
|
!Osteomalacia
|
|
|
|
|
|Normal
|
|}
|}
** Primary [[hyperparathyroidism]] will cause [[hypercalcemia]], [[hyperparathyroidism]], and normal-to-low [[phosphate]] in patients with either normal or slightly reduced renal function.
* 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 renal failure|chronic kidney disease]] and [[mineral]] bone disorder (CKD-MBD).
* Tertiary [[hyperparathyroidism]] causes [[hypercalcemia]], [[hyperparathyroidism]], and normal or slightly elevated [[phosphate]] in patients with long-term [[Chronic renal failure|chronic kidney disease]] and [[mineral]] bone disorder (CKD-MBD).
** [[Osteoporosis]], patients will have normal [[renal function]].
* [[Osteoporosis]], patients will have normal [[renal function]].
** [[Vitamin D]] deficiency will cause normal or slight reduction in [[renal function]].
* [[Vitamin D]] deficiency will cause normal or slight [[reduction]] in [[renal function]].


==Epidemiology and Demographics==
==Epidemiology and Demographics==
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* [[Prevalence]] in developing countries:
* [[Prevalence]] in developing countries:
**The [[prevalence]] of renal osteodystrophy in developing countries is 24.4% to 63%.
**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.
** [[Aluminium|Aluminum]], increased [[strontium]] levels and high levels of iron in the blood play a major role in the development of renal osteodystrophy in patients who undergo [[dialysis]] in developing countries.
** Extraskeletal manifestations of CKD-MBD (calcification of soft tissues) is observed in 1000 per 100,000 of CKD patients on dialysis.


==Risk Factors==
==Risk Factors==
*The major risk factors in the development of renal osteodystrophy are:<ref name=":0" />
Any factor leading to CKD, indirectly leads to renal osteodystrophy. These factors include:
** [[Chronic renal disease]]
* [[Diabetes mellitus|Diabetes Mellitus]]
**[[Dialysis]]
* Nephrotoxins such as [[alcohol]] and recreational drugs
** [[Diabetes mellitus|Diabetes mellitus]]
* Acute kidney injury
* Hypertension
Some factors can enhance the effects of these risk factors such as Vitamin D deficiency and high-phosphate, low-calcium diet.


The major risk factors in the development of renal osteodystrophy are:<ref name=":0" />
* [[Chronic renal disease]]
*[[Dialysis]] (specifically with aluminum-based dialysate)
==Natural History, Complications, and Prognosis==
==Natural History, Complications, and Prognosis==
CKD leads to:
* hypocalcemia
* hyperphosphatemia (a predictor of cardiovascular and all-cause mortality)
* decreased Vit D levels
* hyperparathyroidism
* either increased bone turnover (due to HPTH and uremia) or adynamic bone disease
* calcification of soft tissues and vessels.
* [[Hypertension|HTN]] due to lessening [[ARB]] efficacy by increased levels of FGF23.
* cardiovascular disorders (uremic cardiomyopathy) (most important cause of mortality and morbidity in CKD).
* CKD can lead to [[Chronic renal failure|ESRD]] and subsequent dialysis.
If left untreated, high-turnover bone disease leads to [[osteopenia]] and extraskeletal complications.
Common complications of renal osteodystrophy include:<ref name=":0" />
Common complications of renal osteodystrophy include:<ref name=":0" />
* [[Bone fractures]]
* [[Bone fractures]]
Line 231: Line 272:
===Diagnostic Study of Choice===
===Diagnostic Study of Choice===
====Bone biopsy====
====Bone biopsy====
* A definitive tool for diagnosis of renal osteodystrophy is bone [[biopsy]] according to KIDGO 2017 guidelines.<ref name=":0" />  
[[File:Renal osteodystrophy microscopic pathology.jpg|alt=https://www.flickr.com/photos/bc_the_path/537039421/in/photolist-Pst7n|thumb|Microscopic pathology of bone marrow biopsy in a patient with chronic kidney disease. Increased areas of bone absorption are seen due to increased osteoclastic activity. Courtesy of image from <nowiki>https://www.flickr.c</nowiki><ref>{{Cite web|url=https://www.flickr.com/photos/bc_the_path/537039421/in/photolist-Pst7n|title=renal psteodystrophy microscopic pathology|last=|first=|date=|website=https://www.flickr.com/photos/bc_the_path/537039421/in/photolist-Pst7n|archive-url=|archive-date=|dead-url=|access-date=}}</ref>om/photos/bc_the_path/537039421/in/photolist-Pst7n.]]A definitive tool for diagnosis of renal osteodystrophy is bone [[biopsy]] according to KIDGO 2017 guidelines.<ref name=":0" />
* However, bone biopsies are infrequently performed because it is an [[invasive]] and expensive procedure.
* However, bone [[Biopsy|biopsies]] are infrequently performed because it is an [[invasive]] and expensive procedure.
* Bone [[biopsy]] results can be summerized in following pathologic categories.<ref name="HruskaEpstein19952" />
* In [[Osteitis fibrosa cystica|osteitis fibrosa]] there is increase amount of peritrabecular [[fibrosis]], and increased amount of [[Osteoclast|osteoclasts]] and [[Osteoblast|osteoblasts]].
* [[Osteomalacia]] demonstrate increased unmineralized [[bone matrix]] and decrease number of [[Osteoclast|osteoclasts]].
* Mixed uremic renal osteodystrophy shows areas of [[fibrosis]] and increased remodeling activity with poor [[Mineralization (biology)|mineralization]] and remodeling.
* Adynamic bone disease, shows absence of remodeling activity. The number of bone cells ([[Osteoblast|osteoblasts]] and [[Osteoclast|osteoclasts]]) is decreased.
'''Serum biomarkers''': 


'''Serum biomarkers''': 
The following biomarkers are used in the diagnosis of renal osteodystrophy:
* The following biomarkers are used in the diagnosis of renal osteodystrophy:
* Serum [[calcium]]
* Serum [[Phosphorous acid|phosphorous]]
* [[Alkaline phosphatase]] (total or bone-specific)
* [[Parathyroid hormone]] (PTH)
* Osteocalcin
* Tartrate-resistant acid phosphatase (TRAP)*
* Collagen degradation  products  (CDP)
** However, these products tend to accumulate in CKD regardless of MBD status*
* Pyrodinoline  (PYD)*
* Dihydro-pyrodinoline (DPD)*


** Serum [[calcium]]
** Serum [[Phosphorous acid|phosphorous]]
** [[Alkaline phosphatase]] (total or bone-specific)
** [[Parathyroid hormone]](PTH)
*'''PTH''' levels are considered to be the best [[Non-invasive (medical)|noninvasive]] option to assess bone turnover.<ref name="GonzalezMartin19952" />
*'''PTH''' levels are considered to be the best [[Non-invasive (medical)|noninvasive]] option to assess bone turnover.<ref name="GonzalezMartin19952" />
*The following framework is used to describe the risk for different subtypes of renal osteodystrophy:<ref name="HruskaEpstein19952" />  
The following levels of PTH is used to describe the risk for different subtypes of renal osteodystrophy:<ref name="HruskaEpstein19952" />  
**[[PTH]] <100 pg/mL  means adynamic bone disease and a decreased risk of [[osteitis fibrosa cystica ]]
*[[PTH]] <100 pg/mL means adynamic bone disease.
**[[PTH]] >450 pg/mL means [[osteitis fibrosa cystica]] and/or MUO(mixed uremic osteodystrophy)
*Decreased risk of [[osteitis fibrosa cystica |osteitis fibrosa cystica.]]
**Intermediate [[PTH]] levels between 100 and 450 pg/mL  Intermediate values may be due to normal or increased turnover or even reduced [[bone turnover]].   
*[[PTH]] >500 pg/mL means [[osteitis fibrosa cystica]] and/or MUO (mixed uremic osteodystrophy).
*Intermediate [[PTH]] levels between 100 and 500 pg/mL  Intermediate values may be due to normal or increased turnover or even reduced [[bone turnover]].   
<nowiki>*</nowiki> Still under investigation


===History and Symptoms===
===History and Symptoms===
*Patients with renal osteodystrophy are usually asymptomatic.
[[File:Renal osteodystrophy.png|thumb|Protrusio of the right hip can be seen in renal osteodystrophy. Courtesy of image to https://www.flickr.com/photos/radiology_cases/2214862332/in/photolist-Pst7n-4nHKpA-JhaC1-2eccibt.]]
*When symptomatic, they usually present with:<ref name="MoeDrüeke20062" />
* Patients with renal osteodystrophy are usually asymptomatic.
* When symptomatic, they usually present with:<ref name="MoeDrüeke20062" />
** Bone pain
** Bone pain
** [[Arthralgia]]
** [[Arthralgia]]
** [[Chest pain]]  
** [[Chest pain]]  
** [[Dyspnea]]
** [[Dyspnea]]
** [[Palpitation]] or slow pulse
** [[Palpitation]]


===Physical Examination===
===Physical Examination===
*Patients with renal osteodystrophy usually appear sick.  
* Patients with renal osteodystrophy usually appear sick.  
*Physical examination of patients with renal osteodystrophy may include:<ref name=":0" />
* Physical examination of patients with renal osteodystrophy may include:<ref name=":0" />
** Bone [[deformity]]
** Bone [[deformity]]
** Bone fracture
** Bone fracture
Line 268: Line 323:


=== Laboratory Findings ===
=== 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.
* 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 [[calcium]] levels are typically low.
Line 275: Line 330:
'''PTH('''parathyroid hrmone) levels are the best noninvasive option for assessment of bone turnover.<ref name="MoeDrüeke20062" />
'''PTH('''parathyroid hrmone) levels are the best noninvasive option for assessment of bone turnover.<ref name="MoeDrüeke20062" />


*The following parameters are used to define the risk for specific subtypes of renal osteodystrophy.<ref name="MoeDrüeke20062" />
* The following parameters are used to define the risk for specific subtypes of renal osteodystrophy.<ref name="MoeDrüeke20062" />
**PTH <100 pg/mL suggests adynamic bone disease and a decreased risk of [[osteitis fibrosa cystica]] and or MUO(mixed uremic osteodystrophy)
** PTH <100 pg/mL is seen in adynamic bone disease and shows 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).
** PTH >450 pg/mL is present in [[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.<ref name=":0" />
** Intermediate PTH levels between 100 and 450 pg/mL.  Intermediate values may be associated with normal or increased bone turnover or even reduced turnover.<ref name=":0" />


=== Electrocardiogram ===
=== Electrocardiogram ===
*[[Electrocardiogram|Electrocardiographic]] findings in patients with renal osteodystrophy may include:<ref name=":0" />  
* [[Electrocardiogram|Electrocardiographic]] findings in patients with renal osteodystrophy may include:<ref name=":0" />  
** [[Heart block]]
** [[Heart block]]
** [[Non ST elevation MI]]
** [[Non ST elevation MI]]
Line 289: Line 344:
* Radiographic findings are less sensitive for diagnosis than PTH levels.
* Radiographic findings are less sensitive for diagnosis than PTH levels.
* Imaging is usually performed for patients with unexplained bone pain or [[Bone fracture|fractures]].  
* Imaging is usually performed for patients with unexplained bone pain or [[Bone fracture|fractures]].  
Radiographic changes in ROD can be classified into four groups:
* Osteitis  fibrosa
* Osteomalacia
* Osteosclerosis
* Soft-tissue calcification
* Radiographic findings of [[osteitis fibrosa cystica]] include:
* Radiographic findings of [[osteitis fibrosa cystica]] include:
**[[Subperiosteal]] resorption and
**[[Subperiosteal]] resorption
**New bone formation especially at the radial aspect of the middle [[Phalanx bones|phalanges]].
** New bone formation especially at the radial aspect of the middle [[Phalanx bones|phalanges]].
** Focal accumulation of giant cells (brown tumor) in facial bones, long bones, clavicle and phalanges.
** Varying density in skull bone ("salt and pepper" appearance)
* Radiographic findings of osteomalacia include:
** Psuedofractures in [[Ischium (bone)|ischium]] and pubic rami
* Osteosclerosis is usually seen in spine, ribs and pelvis
* Extraeskeletal calcification is usually seen in [[cornea]] and [[Conjunctiva|conjuctiva]] and is directly associated with HPTH.
* Radiographs will show soft tissue [[calcification]] that involves the [[vasculature]].<ref name="GonzalezMartin19952" />
* [[Resorptive]] loss of bone may be seen at the terminal phalanges, distal ends of the [[Clavicle|clavicles]], and in the [[skull]].
* [[Resorptive]] loss of bone may be seen at the terminal phalanges, distal ends of the [[Clavicle|clavicles]], and in the [[skull]].
* Radiographs will show soft tissue [[calcification]] that involves the [[vasculature]].<ref name="GonzalezMartin19952" />


===Echocardiography or Ultrasound===
===Echocardiography or Ultrasound===
Line 302: Line 369:


===CT scan===
===CT scan===
*CT scan findings associated with renal osteodystrophy are the same that are related to [[chronic kidney disease]].
* CT scan findings associated with renal osteodystrophy are the same that are related to [[chronic kidney disease]].


===MRI===
===MRI===
*There are no [[MRI]] findings associated with renal osteodystrophy.
* There are no specific [[MRI]] findings associated with renal osteodystrophy since associated changes are usually within the skeletal and bony tissue.
 
===Other Imaging Findings===
*There are no other imaging findings associated with renal osteodystrophy.


===Other Diagnostic Studies===
===Other Diagnostic Studies===
* [[DEXA scan|DEXA]] bone densitometry will show low [[bone density]].<ref name="MoeDrüeke20062" />
* [[DEXA scan|DEXA]] bone densitometry will show low [[bone density]].<ref name="MoeDrüeke20062" />
* Deferoxamine Challenge Test (DFO) can be used to rule out aluminum-related bone disease.
==Treatment==
==Treatment==
===Medical Therapy:===
===Medical Therapy:===
Line 318: Line 384:
* [[Calcium]] malabsorption is seen in end-stage renal disease because of deficient 1,25-dihydroxycholecalciferol.<ref name="GonzalezMartin19952" />  
* [[Calcium]] malabsorption is seen in end-stage renal disease because of deficient 1,25-dihydroxycholecalciferol.<ref name="GonzalezMartin19952" />  
* To prevent or suppress oversecretion of [[parathyroid hormone]], [[calcium]] concentrations should be maintained at the high end of the normal range.
* 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.  
* In patients with [[calcium]] intakes of 800–1000 mg/day, additional [[calcium]] supplements or [][][,gcontaining medications should be avoided.  
* Patients with total calcium intakes (>approx. 1000 mg/day) should be advised to decrease calcium intake.
* Patients with total [[calcium]] intakes (>approx. 1000 mg/day) should be advised to decrease calcium intake.
* Patients with lower [[Calcium|calcium i]]<nowiki/>ntakes should be advised to increase [[calcium]] intake in foods,or take calcium supplements.
* Patients with lower [[Calcium|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.]]  
* Calcium-rich foods include da<nowiki/>iry, 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.
* 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 '''
'''Control of Serum Phosphate '''
Line 328: Line 394:
** Preferred regimen(1): [[Calcium carbonate (medication)|Calcium carbonate]], 500 mg PO q8h to be taken with each meal.
** Preferred regimen(1): [[Calcium carbonate (medication)|Calcium carbonate]], 500 mg PO q8h to be taken with each meal.
** Preferred regimen (2): [[Sevelamer]] carbonate 800 mg PO q8h with 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]].
* Total dose of elemental [[calcium]] (including dietary sources and [[calcium]]-based [[phosphate binders]]) should not exceed 2000 mg daily in [[chronic kidney disease]].
* [[Aluminium|Aluminum]]-containing [[phosphate]] binders should be avoided.
* [[Aluminium|Aluminum]]-containing [[phosphate]] binders should be avoided.
* Lanthanum carbonate is a non-calcium, non-aluminum phosphate binder proven to be effective when taken 1350 to 2250 mg/day.<ref>{{Cite journal|last=Abdullah M.W. El-Kishawi*, A.M. El-Nahas|first=|date=2006|title=Renal Osteodystrophy: Review of the Disease and its Treatment|url=|journal=Saudi J Kidney Dis Transplant|volume=17 (3)|pages=373-382|via=}}</ref>
'''Use of Vit D analogue'''
'''Use of Vit D analogue'''
* [[Calcitriol]] [[alfacalcidol]], [[Doxercalciferol]], and [[calcifediol]]  
* [[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(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(2): [[Alfacalcidol]], 0.25 mcg PO daily for 2 months.
** Preferred regimen(3): [[Doxercalciferol]] 10 mcg PO 3 times/week at [[dialysis]],may increase the dose by 2.5 mcg.
** 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
* [[Dialysis]] patients recieve 1 mcg [[intravenously]] during each [[dialysis]] session, 2-3 times weekly.
* Make sure [[Calcium|serum calcium]] in <9.8 mg/dL before initiating [[vitamin D]] analogues.
* Make sure [[Calcium|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 [[Calcium|serum calcium]] concentrations and inhibiting [[parathyroid hormone]] gene [[transcription]]<ref name="GonzalezMartin19952" /><ref name=":0" />
* They decrease bone pain, improve bone [[histologic]] characteristics, and suppress [[parathyroid hormone]] secretion by increasing [[Calcium|serum calcium]] concentrations and inhibiting [[parathyroid hormone]] gene [[transcription]].<ref name="GonzalezMartin19952" /><ref name=":0" />


===Surgery===
===Surgery===
* Subtotal [[parathyroidectomy]]
The treatment for renal osteodystrophy is medical therapy. Surgery is considered under the following circumstances:
* The treatment for renal osteodystrophy is medical therapy.
* Subtotal [[parathyroidectomy]] (if PTH > 800 pg/ml).
* Surgery is usually reserved for patients with [[hyperparathyroid]] bone disease
* [[Renal transplant]] as final treatment approach.<ref name=":0" />
* [[Renal transplant]]<ref name=":0" />


=== Primary Prevention ===
=== Primary Prevention ===
* Early diagnosis and treatment of [[Hyperparathyroidism|hyperparathyroid]] patients.
* Early diagnosis and treatment of [[Hyperparathyroidism|hyperparathyroid]] patients.
* Reducing exacerbating factors such as smoking, uncontrolled diabetes, high-phosphate, low-calcium diet and sedentary life style.
* Early diagnosis and treatment of renal diseases to prevent [[chronic renal failure]] and consequently renal osteodystrophy.<ref name="GonzalezMartin19952" />
* Early diagnosis and treatment of renal diseases to prevent [[chronic renal failure]] and consequently renal osteodystrophy.<ref name="GonzalezMartin19952" />


===Secondary Prevention===
===Secondary Prevention===
* Vitamin D administration with every session of [[dialysis]]
* Vitamin D administration with every session of [[dialysis]].
* Use of [[aluminium|aluminum]]-free [[phosphate binders]].<ref name=":0" />
* Use of [[aluminium|aluminum]]-free [[phosphate binders]].<ref name=":0" />


Line 363: Line 430:
*[[hyperparathyroidism]]
*[[hyperparathyroidism]]
*[[multiple myeloma]]
*[[multiple myeloma]]
*soft tissue calcification including [[collagen vascular disease]]
*Soft tissue calcification including [[collagen vascular disease]]
*[[Calcium pyrophosphate deposition disease|hydroxyapatite crystal deposition disease]]
*[[Calcium pyrophosphate deposition disease|Hydroxyapatite crystal deposition disease]]
*hypervitaminosis
*Hypervitaminosis


==External links==
==External links==

Latest revision as of 20:57, 15 March 2019

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

Synonyms and keywords:Chronic kidney disease- mineral bone disorder

Overview

Renal osteodystrophy (ROD) is within the broad spectrum of Chronic Kidney Disease (CKD)- Mineral Bone Disease (MBD). The disease occurs as a natural complication of the CKD and is characterized by abnormal levels and metabolism of calcium (Ca), phosphorus (Ph), parathyroid Hormone (PTH), and vitamin D, as well as calcification of soft tissues and bone turn over and mineralization abnormalities. Secondary hyperparathyroidism and 1,25-dihydroxycholecalciferol (vitamin D3) deficiency play a major role in ROD. Any factor leading to CKD is potentially a risk factor for ROD. Hypocalcemia, hyperphosphatemia, vitamin D deficiency, parathyroid gland hyperplasia and acidosis are the other contributors of ROD. Aluminum related ROD is mostly seen in patients who undergo dialysis. ROD is an important cause of morbidity, decreased quality of life, and extravascular calcifications that have been associated with increased cardiovascular mortality. Primary investigation of ROD includes measurement of blood levels of parathyroid hormone (PTH), calcium, phosphorus, alkaline phosphatase and bicarbonate. Imaging studies should focus on finding calcification in soft tissues. A bone biopsy is indicated if the results of biochemical markers are not consistent or when there is unexplained bone pain, or in case of presence of unexplained bone fractures. However, bone biopsies are infrequently used in clinical practice due to invasiveness and low cost-effectiveness. Common complications of ROD include bone fractures and vascular calcifications leading to atherosclerosis, coronary artery calcification, hypertension, left ventricular hypertrophy, and congestive heart failure (CHD). Extra-skeletal 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, ongestive heart failure, heart murmur, increased 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 and non-ST-elevation myocardial infarction. Radiographic findings are less sensitive for diagnosis compared to 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 its treatment if present.


Historical Perspective

Classification

  • Renal osteodystrophy can be classified according to histology into the following subtypes:[1][2]
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).

Pathophysiology

Overview of pathophysiology[3][4][2]:

In CKD, serum Ca levels decrease and serum Ph levels increase. Initially in the course of renal disease, compensatory mechanisms try to increase serum Ca and decrease serum Ph. These mechanisms include increased levels of fibroblast growth factor 23 (FGF23) which in turn increases urinary Ph excretion. On the other hand, increased PTH levels further increase urinary excretion of Ph. However, as the renal disease becomes chronic, these compensatory mechanisms do not respond any more and the characteristic features of ROD become evident [5]. Once an abnormality in serum levels of these minerals is established (decreased Ca and increased Ph), PTH levels increase and change bone metabolism via alterations in osteoblast and osteoclast activity. Early in CKD, due to increased FGF23, 1,25 (OH) vitamin D decreases which further leads to hyperparathyroidism (HPTH). However, some contributors to CKD-MBD alter before PTH levels are increased, an example of these contributors are sclerostin and FGF23 which are increased even before HPTH. HPTH can also insert its effects via the reduction of β-catenin which inhibits maturation of osteoblasts.

  • PTH receptors are found on preosteoblasts, osteoblasts and osteocytes and increases their proliferation. (Osteoclasts do not have PTH receptors and are activated by preosteoblasts and osteoblasts.)
  • Increased levels of PTH lead to increased bone resorption by osteoclasts [6] and osteitis fibrosa.

As a result, HPTH leads to high-turnover bone disease.

Many factors can contribute to low levels of PTH, such as increased dietary intake of Ca and Vit D, using Ph binders containing Ca dialysate. Low levels of PTH lead to low-turnover bone disease, also known as adynamic bone disease. Low PTH levels lead to excess circulating Ca (since Ca is not deposited in the bone). This excess Ca may lead to calcification of soft tissues.

Aluminum-based chelation of Ph during dialysis was among the common factors contributing to osteomalacia. However since replacement of aluminum with other chelators this factor is less prominent. [4][7][2]

CKD leads to uremia and hyperphosphatemia which change the pluripotent smooth muscle cells to osteoblasts. This coupled with increased Ca levels leads to calcification of soft tissues [8].

Overall, following factors contribute to vascular calcification [5]:

  • Hypocalcemia and hyperphosphatemia
  • Hyperparathyroidemia
  • Matrix degradation and alteration of matrix proteins
  • Apoptosis of smooth muscle cells
  • Systemic inflammation
 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

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:[3]
Differential diagnosis of renal osteodystrophy
Calcium Phosphate Renal function
Renal osteodystrophy Markedly declined
Primary hyperparathyroidism Low to normal Normal or slightly

reduced

Tertiary hyperparathyroidism Slightly elevated Normal or slightly reduced
Osteoporosis Normal Normal Normal
Vitamin D deficiency Normal
Osteomalacia Normal

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.[3]
  • Prevalence in developing countries:
    • The prevalence of renal osteodystrophy in developing countries is 24.4% to 63%.
    • Aluminum, increased strontium levels and high levels of iron in the blood play a major role in the development of renal osteodystrophy in patients who undergo dialysis in developing countries.
    • Extraskeletal manifestations of CKD-MBD (calcification of soft tissues) is observed in 1000 per 100,000 of CKD patients on dialysis.

Risk Factors

Any factor leading to CKD, indirectly leads to renal osteodystrophy. These factors include:

Some factors can enhance the effects of these risk factors such as Vitamin D deficiency and high-phosphate, low-calcium diet.

The major risk factors in the development of renal osteodystrophy are:[3]

Natural History, Complications, and Prognosis

CKD leads to:

  • hypocalcemia
  • hyperphosphatemia (a predictor of cardiovascular and all-cause mortality)
  • decreased Vit D levels
  • hyperparathyroidism
  • either increased bone turnover (due to HPTH and uremia) or adynamic bone disease
  • calcification of soft tissues and vessels.
  • HTN due to lessening ARB efficacy by increased levels of FGF23.
  • cardiovascular disorders (uremic cardiomyopathy) (most important cause of mortality and morbidity in CKD).
  • CKD can lead to ESRD and subsequent dialysis.

If left untreated, high-turnover bone disease leads to osteopenia and extraskeletal complications.

Common complications of renal osteodystrophy include:[3]

Prognosis

Diagnosis

Diagnostic Study of Choice

Bone biopsy

https://www.flickr.com/photos/bc_the_path/537039421/in/photolist-Pst7n
Microscopic pathology of bone marrow biopsy in a patient with chronic kidney disease. Increased areas of bone absorption are seen due to increased osteoclastic activity. Courtesy of image from https://www.flickr.c[10]om/photos/bc_the_path/537039421/in/photolist-Pst7n.

A definitive tool for diagnosis of renal osteodystrophy is bone biopsy according to KIDGO 2017 guidelines.[3]

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)
  • Osteocalcin
  • Tartrate-resistant acid phosphatase (TRAP)*
  • Collagen degradation products (CDP)
    • However, these products tend to accumulate in CKD regardless of MBD status*
  • Pyrodinoline (PYD)*
  • Dihydro-pyrodinoline (DPD)*
  • PTH levels are considered to be the best noninvasive option to assess bone turnover.[4]

The following levels of PTH is used to describe the risk for different subtypes of renal osteodystrophy:[1]

* Still under investigation

History and Symptoms

Protrusio of the right hip can be seen in renal osteodystrophy. Courtesy of image to https://www.flickr.com/photos/radiology_cases/2214862332/in/photolist-Pst7n-4nHKpA-JhaC1-2eccibt.

Physical Examination

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.

PTH(parathyroid hrmone) levels are the best noninvasive option for assessment of bone turnover.[2]

  • The following parameters are used to define the risk for specific subtypes of renal osteodystrophy.[2]
    • PTH <100 pg/mL is seen in adynamic bone disease and shows a decreased risk of osteitis fibrosa cystica and or MUO(mixed uremic osteodystrophy).
    • PTH >450 pg/mL is present in 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.[3]

Electrocardiogram

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 changes in ROD can be classified into four groups:

  • Osteitis fibrosa
  • Osteomalacia
  • Osteosclerosis
  • Soft-tissue calcification
  • Radiographic findings of osteitis fibrosa cystica include:
    • Subperiosteal resorption
    • New bone formation especially at the radial aspect of the middle phalanges.
    • Focal accumulation of giant cells (brown tumor) in facial bones, long bones, clavicle and phalanges.
    • Varying density in skull bone ("salt and pepper" appearance)
  • Radiographic findings of osteomalacia include:
    • Psuedofractures in ischium and pubic rami
  • Osteosclerosis is usually seen in spine, ribs and pelvis
  • Extraeskeletal calcification is usually seen in cornea and conjuctiva and is directly associated with HPTH.
  • Radiographs will show soft tissue calcification that involves the vasculature.[4]
  • Resorptive loss of bone may be seen at the terminal phalanges, distal ends of the clavicles, and in the skull.

Echocardiography or Ultrasound

CT scan

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

MRI

  • There are no specific MRI findings associated with renal osteodystrophy since associated changes are usually within the skeletal and bony tissue.

Other Diagnostic Studies

  •  DEXA bone densitometry will show low bone density.[2]
  • Deferoxamine Challenge Test (DFO) can be used to rule out aluminum-related bone disease.

Treatment

Medical Therapy:

Control of Serum Calcium

  • Calcium malabsorption is seen in end-stage renal disease because of deficient 1,25-dihydroxycholecalciferol.[4]
  • 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 [][][,gcontaining 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

Use of Vit D analogue

Surgery

The treatment for renal osteodystrophy is medical therapy. Surgery is considered under the following circumstances:

Primary Prevention

  • Early diagnosis and treatment of hyperparathyroid patients.
  • Reducing exacerbating factors such as smoking, uncontrolled diabetes, high-phosphate, low-calcium diet and sedentary life style.
  • Early diagnosis and treatment of renal diseases to prevent chronic renal failure and consequently renal osteodystrophy.[4]

Secondary Prevention

References

  1. 1.0 1.1 1.2 1.3 Hruska, Keith A.; Epstein, Franklin H.; Teitelbaum, Steven L. (1995). "Renal Osteodystrophy". New England Journal of Medicine. 333 (3): 166–175. doi:10.1056/NEJM199507203330307. ISSN 0028-4793.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Moe, S.; Drüeke, T.; Cunningham, J.; Goodman, W.; Martin, K.; Olgaard, K.; Ott, S.; Sprague, S.; Lameire, N.; Eknoyan, G. (2006). "Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO)". Kidney International. 69 (11): 1945–1953. doi:10.1038/sj.ki.5000414. ISSN 0085-2538.
  3. 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 https://www.orthopaedicsone.com/display/MSKMed/Renal+osteodystrophy
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 Gonzalez, E. A.; Martin, K. J. (1995). "Renal osteodystrophy: pathogenesis and management". Nephrology Dialysis Transplantation. 10 (supp3): 13–21. doi:10.1093/ndt/10.supp3.13. ISSN 0931-0509.
  5. 5.0 5.1 Yi-Chou Hou, Chien-Lin Lu, Kuo-Cheng Lu. "Mineral bone disorders in chronic kidney disease".
  6. Lee SK, Lorenzo JA. "Parathyroid hormone stimulates TRANCE and inhibits osteoprotegerin messenger ribonucleic acid expression in murine bone marrow cultures: correlation with osteoclast-like cell formation". https://academic.oup.com/endo/article/140/8/3552/2990646. External link in |website= (help)
  7. Moe, S.; Drüeke, T.; Cunningham, J.; Goodman, W.; Martin, K.; Olgaard, K.; Ott, S.; Sprague, S.; Lameire, N.; Eknoyan, G. (2006). "Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO)". Kidney International. 69 (11): 1945–1953. doi:10.1038/sj.ki.5000414. ISSN 0085-2538.
  8. Jorge B, Cannata-Andνa, Minerva Rodrνguez-Garcνa; et al. (2006). "ascular calcifications: Pathogenesis, management and impact on clinical outcomes". J Am Soc Nephrol. 17: 267–73.
  9. Nissenson, Allen (2009). Current diagnosis & treatment. New York: McGraw-Hill Medical. ISBN 978-0-07-144787-4.
  10. "renal psteodystrophy microscopic pathology". https://www.flickr.com/photos/bc_the_path/537039421/in/photolist-Pst7n. External link in |website= (help)
  11. Abdullah M.W. El-Kishawi*, A.M. El-Nahas (2006). "Renal Osteodystrophy: Review of the Disease and its Treatment". Saudi J Kidney Dis Transplant. 17 (3): 373–382.

Related Chapters

External links

Renal Osteodystrophy

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