1. What is chronic kidney disease–mineral and bone disorder (CKD-MBD)?

CKD-MBD is a systemic disorder of mineral and bone metabolism resulting from CKD that may be manifested by either one or a combination of the following:

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  Laboratory abnormalities associated with disturbed mineral metabolism, including abnormalities of:

  
  
  
  
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    Calcium

    
    
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    Phosphorus,

    
    
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    Parathyroid hormone (PTH)

    
    
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    Vitamin D metabolites

  
  
  
  
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  Bone disease defined as renal osteodystrophy (ROD) including abnormalities in:

  
  
  
  
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    Bone turnover

    
    
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    Bone mineralization

    
    
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    Bone volume

    
    
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    Bone strength

    
    
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    Linear growth

  
  
  
  
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  Calcification of extraskeletal tissue, which would include the vasculature and other soft tissues

2. How do we define ROD?

ROD is the term used to describe the bone lesions associated with CKD-MBD. ROD is an alteration of bone morphology in patients with CKD. It represents the skeletal component of the systemic disorder CKD-MBD. It is assessed by bone histomorphometry. There are three key histologic descriptors:

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  Bone turnover: normal, increased, or decreased

  
  
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  Bone mineralization: normal or abnormal

  
  
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  Bone volume: normal, increased, or decreased

This is referred to as the TMV (turnover, mineralization, and volume) system—with any combination of each of the descriptors possible in each specimen. The TMV classification scheme provides a clinically relevant description of the underlying bone pathology.

3. Name the factors contributing to secondary hyperparathyroidism and high-turnover bone disease.

The factors responsible for secondary hyperparathyroidism associated with CKD include:

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  Hyperphosphatemia from diminished kidney phosphorus excretion

  
  
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  Hypocalcemia, impaired kidney production of active 1,25-dihydroxyvitamin D (calcitriol)

  
  
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  Alterations in the control of PTH gene transcription

  
  
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  Skeletal resistance to the calcemic action of PTH

  
  
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  Fibroblastic growth factor 23 (FGF23), which may indirectly promote hyperparathyroidism by inhibiting production of 1,25-dihydroxyvitamin D

4. Describe the bone lesion associated with hyperparathyroidism.

The primary histologic bone lesion associated with moderate to severe hyperparathyroidism is a high-turnover lesion, sometimes called osteitis fibrosa cystica . Clinically it is associated with nonspecific bone pain, proximal myopathy. The serum-intact PTH level is usually higher than 350 to 500 pg/mL. Radiologic features are subperiosteal resorption, Brown tumors, and a mottled and granular salt-and-pepper appearance to the skull. The histologic features include:

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  Increased turnover (T) as indicated by increased bone resorption and formation with increased numbers of osteoclasts and osteoblasts, and increased tetracycline uptake

  
  
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  Abnormal mineralization (M), as indicated by increase of woven bone, peritrabecular fibrosis and there may or may not be increased osteoid

  
  
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  Generally increased volume (V)

5. How is high-turnover bone disease treated?

Treatment of this disorder entails prevention and correction of the factors leading to secondary hyperparathyroidism:

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  Phosphorus control: dietary restriction, phosphate binders, adequate dialysis

  
  
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  Prevention of hypocalcemia: oral calcium supplements, correction of vitamin D deficiency, dialysis

  
  
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  Suppression of PTH production and secretion: vitamin D receptor activators (VDRA), including calcitriol, paricalcitol, and doxercalciferol, and/or the use of calcimimetics (cinacalcet, elecalcetide; Table 20.1 )

  
  
  
  

  Table 20.1.

  
  

  Impact and Challenges With Vitamin D to Treat Secondary Hyperparathyroidism in Patients With Chronic Kidney Disease

  
  

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  VITAMIN D COMPOUND	BIOLOGIC AND CLINICAL IMPACT	CHALLENGES
  Ergocalciferol (D 2 ) Cholecalciferol (D 3 )	Effective in repleting 25-D and 1,25-D in patients with early-stage CKD and adequate kidney function	Requires activation in the liver to generate 25-D Requires activation in the kidney to generate active 1,25-D Provides only partial suppression of PTH in patients with later-stage CKD
  ER Calcifediol	Effective in repleting 25-D and 1,25-D in patients with CKD 3 and 4 Effectively suppresses SHPT	No data in CKD stage 5
  Calcitriol	Biologically active VDR agonist Effectively suppresses SHPT Reduces abnormal high bone turnover	Hypercalcemia, hypercalciuria, and hyperphosphatemia evident at high doses
  Doxercalciferol	Suppresses SHPT similar to or better than calcitriol Noted reduction in serum bone-specific alkaline phosphatase and osteocalcin	Requires activation in liver to generate active 1,25-D Induces significant elevation of serum P, elevating need for phosphate binder use
  Alphacalcidol	Suppresses SHPT similar to or better than calcitriol	Requires activation in kidney to generate active 1,25-D Induces significant elevation of serum P, elevating need for phosphate binder use
  Paricalcitol	Biologically active VDR agonist Effectively suppresses SHPT Noted reduction in serum bone-specific alkaline phosphatase and osteocalcin	Minimal elevation in Ca, P, and Ca × P product, requiring Ca and P monitoring

   
  

  1,25-D , 1,25-Dihydroxyvitamin D; 25-D , 25-hydroxyvitamin; Ca , calcium; CKD , chronic kidney disease; ER , extended release; P , phosphorus; PTH , parathyroid hormone; SHPT , Secondary hyperparathyroidism; VDR , vitamin D receptor.
  
  
  
  
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  Surgical parathyroidectomy: in severe cases, parathyroidectomy may be required; however, bone biopsy should be considered prior to surgery

6. What disorders are associated with low-turnover bone disease?

Low-turnover or adynamic bone disease is defined by the presence of low or absent bone formation as determined by decreased tetracycline uptake into bone, in conjunction with a paucity of bone-forming osteoblasts and bone-resorbing osteoclasts (decreased T). It may also be associated with a defect in mineralization (abnormal M), resulting in the histologic lesion referred to as osteomalacia. Bone volume (V) is variable. Clinically it may manifest with nonspecific bone pain and fractures. PTH concentrations are relatively low (less than 100 to 200 pg/mL), and hypercalcemia is a common feature. There may be a tendency for increased extraskeletal calcification. Low turnover is characterized histologically by absence of cellular (osteoblast and osteoclast) activity, osteoid formation, and endosteal fibrosis. This is a disorder of decreased bone formation, accompanied by a secondary decrease in bone mineralization. Low turnover disease was initially described as a result of aluminum toxicity. Aluminum bone disease is diagnosed by special staining, which demonstrates the presence of aluminum deposits at the mineralization front. Outside of aluminum, the major risk factors for low turnover bone disease include diabetes, aging, and malnutrition. The other causes of low bone formation in CKD are multifactorial and include:

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  Vitamin D deficiency

  
  
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  High serum phosphate

  
  
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  Metabolic acidosis

  
  
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  Elevated circulating cytokine levels (interleukin [IL]-I, tumor necrosis factor [TNF])

  
  
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  Low estrogen and testosterone levels

Normal or mildly elevated serum PTH concentrations have been associated with adynamic bone disease, as there is a resistance to the bone stimulatory effect of PTH in CKD. PTH receptor downregulation is one potential mechanism to explain the bone resistance effect to PTH resulting, in part, from persistently elevated PTH.

7. What is osteomalacia?

Osteomalacia is an abnormality of mineralization (M) that is characterized by an excess of unmineralized osteoid, manifested as wide osteoid seams and a markedly decreased mineralization rate. The presence of increased unmineralized osteoid per se does not necessarily indicate a mineralizing defect, because increased quantities of osteoid appear in conditions associated with high rates of bone formation when mineralization lags behind the increased synthesis of matrix. Other features of osteomalacia include the absence of cell activity and the absence of endosteal fibrosis; there is normal or decreased osteoid volume and decreased mineralization. Frequently, aluminum disease is associated with osteomalacia. Serum PTH is, in general, normal or low, and hypercalcemia is common. Looser zones or pseudofractures are radiologic characteristics.

8. What is mixed uremic osteodystrophy (MUO)?

MUO is the term that has been used to describe bone biopsies that have features of secondary hyperparathyroidism together with evidence of a mineralization defect. There is extensive osteoclastic and osteoblastic activity and increased endosteal peritrabecular fibrosis, coupled with more osteoid than expected, and tetracycline labeling uncovers a concomitant mineralization defect. Unfortunately, MUO, in particular, and high- and low-turnover bone disease have been inconsistent and poorly defined. Thus it is best to describe bone histology or ROD according to the TMV system, as defined as part of CKD-MBD.

9. What is calcific uremic arteriolopathy (CUA)?

CUA, or calciphylaxis is a rare but life-threatening syndrome characteristically occurring in individuals with ESRD, but has been described in patients with normal kidney function and calcium/phosphate metabolism. CUA generally presents as excruciatingly painful eschars on the lower limbs but may affect other sites, including the abdominal wall, breasts, and penis, and only rarely the face or upper extremities. The syndrome typically begins with dysesthesia, followed by the development of erythema resembling livedo reticularis, and progression to frank ulceration. There may be palpable deposits of calcium subcutaneously. The lesions are intensely painful, and the surrounding tissue may be pruritic. The lesions have been proposed to occur at sites of adipose tissue where diminished blood flow contributes to hypoxia. Major risk factors for CUA include:

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  Female gender

  
  
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  Diabetes mellitus

  
  
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  Obesity

  
  
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  Malnutrition

  
  
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  Elevated serum phosphate

  
  
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  Warfarin

The underlying pathology is vascular calcification. The calcification was historically assumed to be a passive event caused by deranged calcium and phosphate metabolism; however, this calcification is an actively regulated process. Elevated phosphate levels has been regarded as one of the most important factors in initiating CUA, with persistent hyperphosphatemia and hypercalcemia promoting vascular mineralization. Defects in a number of inhibitors of calcification, including matrix GLA protein and fetuin, play a causative role. Most patients with CUA die from complications of wound infections. Therapy should be focused on wound management and controlling serum phosphate levels. Parathyroidectomy is controversial and is generally not recommended unless PTH levels are markedly elevated (>900 ng/mL). Aggressive dialysis, nutrition, and non-calcium-containing phosphate binders are the mainstay of therapy. Some studies have demonstrated anecdotal response to sodium thiosulfate. It is unclear if calcimimetics or bisphosphonates are beneficial.