Chronic Kidney Disease-Mineral Bone Disorders Kamal Mohamed Okasha MD.

Prof of Nephrology, Tanta UinversityISN Sistership Renal Program with Sheffield instite.

Definition of CKD-Mineral and Bone Disorder

A systemic disorder of mineral and bone metabolism due to

CKD manifested by either one or a combination of the

following:

Abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism

Abnormalities in bone turnover, mineralization, volume, linear

growth, or strength

Vascular or other soft tissue calcification

Moe S, et al. Kidney Int 69: 1945, 2006

Definition of Renal Osteodystrophy

Renal osteodystrophy is an alteration of bone

morphology in patients with CKD.

It is one measure of the skeletal component of the

systemic disorder of CKD-MBD that is quantifiable

by histomorphometry of bone biopsy.

Moe S, et al. Kidney Int 69: 1945, 2006

Chronic Kidney Disease-Related Mineral and Bone Disorder: Public Health Problem. Kerry Willis PhD

National Kidney Foundation

Secondary hyperparathyroidism encompasses most of the

biochemical abnormalities that characterize CKD-MBD.

Causes of secondary hyperparathyroidism:

Phosphate retention.

Decreased free calcium concentration.

Decreased 1,25-dihydroxyvitamin D (calcitriol) concentration.

Reduced expression of vitamin D receptors (VDRs).

Calcium-sensing receptors (CaSR).

Fibroblast growth factor receptors (FGFRs), and klotho in the

parathyroid glands.

Characteristics of the major CKD-related bone

diseases:

Osteitis fibrosa cystica

Adynamic bone disease

Osteomalacia

Mixed uremic osteodystrophy

Case 1• Mr SM is a 53-year-old man with end-stage renal disease

(ESRD) secondary to type 2 diabetes. • He also has hypertension and hypercholesterolemia. His

medications include insulin, an antihypertensive, and a cholesterol-lowering agent.

• He has recently begun hemodialysis. He quit smoking cigarettes 1 year ago; he had a 30-year pack/day history.

• He is a retired high school teacher. • His physical activity is limited to indoor.

• Which of the following is most likely to be true regarding Mr SM serum calcium and phosphorus levels?

1. Both his serum phosphorus and serum calcium levels will be above the normal laboratory range

2. Both his serum phosphorus and serum calcium levels will be below the normal laboratory range

3. His serum phosphorus level will be above the normal laboratory range and his serum calcium level will be below the normal laboratory range

4. His serum phosphorus level will be above the normal laboratory range and his serum calcium level will be within the normal laboratory range

• Available data demonstrate that among individuals with stage 5D CKD (stage 5 CKD on dialysis) serum calcium levels remain in the normal range and serum phosphorus levels are elevated.

• Results were found when examining cross-sectional data from the international Dialysis Outcomes and Practice Pattern Study (DOPPS)

• Therefore: the correct answer is: 4. His serum phosphorus level will be above the normal laboratory range and his serum calcium level will be within the normal laboratory range

Patient Case 1 (cont)• His calcium and phosphorus levels every 3 months and have

noted based on several measures that while his serum calcium level is normal, his serum phosphorus level remains persistently above the normal laboratory range.

• Which of the following would be the first step in trying to lower Mr Smith's serum phosphorus level?

1. Increase the frequency of dialysis from 3 times to 5 times a week

2. Increase the dialytic phosphate removal3. Reduce phosphate intake through dietary modifications4. Start a phosphate binder

• Adequate control of serum phosphorus is a cornerstone in the clinical management of patients with CKD because hyperphosphatemia contributes to the pathogenesis of hyperparathyroidism, vascular calcification, and increased cardiovascular mortality.

• Interventions include dietary phosphate restriction (first-line), dialysis, and phosphate binders.

• So the correct answer is: 3. Reduce phosphate intake through dietary modificationsso dietary restriction of phosphorus – restricting the intake of colas, legumes, and dairy products -- is the cornerstone of management.

Patient Case 1 (cont)

• Despite dietary modifications aimed to decrease phosphate intake, serum phosphorus level remains elevated. He now requires an intestinal phosphorus binder.

• Which of the following statements concerning use of a phosphate binder in this patient is true?

1. Non-calcium-based binders are associated with a decrease in mortality

2. Aluminum hydroxide is safe to use3. Calcium salts have not been associated with any harm4. Non-calcium-based binders have no advantage with respect

to hard clinical outcomes compared with calcium-based binders

• Aluminum hydroxide is a potent phosphate binder but is associated with skeletal, neurological, and hematological toxicity.

• Calcium salts, specifically calcium carbonate and calcium acetate, are effective in lowering serum phosphorus levels but may cause harm.

• It appears that non-calcium-based phosphate binders are associated with less progression of coronary artery calcification and a decrease in mortality, likely due to a decrease in CV deaths.

• Therefore the correct answer is:1. Non-calcium-based binders are associated with a decrease

in mortality

Patient case 1• Mr SM has now been on dialysis for 1 year. • He is poorly compliant to low phosphorus diet and calcium

carbonate, he often skips doses. • His laboratory testing consistently demonstrates a mild elevation

in his phosphorus level, a normal serum calcium level, and an elevated serum intact parathyroid hormone (PTH) level.

• He is at risk for Vascular complication.• Which of the following interventions would be inappropriate

for Mr SM?1. Refer to a renal dietitian2. Change from a calcium-based to a non-calcium-based binder3. Obtain a lateral abdominal radiograph to assess for the

presence or absence of vascular calcification4. Prescribe vitamin K to prevent calcification

• The prevalence of vascular calcification increases as kidney function declines.

• Vitamin K (through its effects on matrix Gla protein) may inhibit the progression of vascular calcification.

• Individuals with ESRD commonly have a vitamin K deficiency.• Of note, while there are 3 randomized controlled trials

currently recruiting individuals with CKD to evaluate the effects vitamin K on vascular calcification.

• To date there are no data showing that correcting a vitamin K deficiency prevents or improves vascular health in CKD.

• As a result, clinical practice guidelines such as those from KDIGO do not recommend routine vitamin K supplementation in individuals with kidney disease.

• Therefore the correct answer is :4. Prescribe vitamin K to prevent calcification would be inappropriate for Mr SM?

Case 2• Ms L S is a 29-year-old woman with recently diagnosed lupus

nephritis. • She is referred to you for management of her stage 3 CKD

(estimated glomerular filtration rate [eGFR]= 35 mL/min). • She is asymptomatic with regard to her lupus. • She does not smoke and attends excercise twice each week.• She is married with a 7-year-old child.

Case 2• Which of the following is most likely to be TRUE regarding Ms

LS serum phosphorus level?• Her serum phosphorus level will be above the normal

laboratory range• There are no data showing that elevated serum phosphorus

levels are associated with any adverse events• Her serum phosphorus level will be below the normal

laboratory range• The lower you can get her serum phosphorus level, the lower

the prevalence of adverse events in this patient

The prevalence of abnormalities in serum phosphorus has been described using cross-sectional data in 1800 individuals with stages 3 to 5 CKD. once eGFR declines to less than 40 mL/min –her eGFR is 35 mL/min -- then serum phosphorus rises.

• Hyperphosphatemia is an inevitable consequence of decreasing renal function.

• Therefore the correct answer is:1. Her serum phosphorus level will be above the normal

laboratory range

• Which of the following statements about Ms West's serum calcium is most likely correct?

1. Her serum calcium level will be below the normal laboratory range

2. Her serum calcium level will be within the normal laboratory range

3. There are no clinical consequences associated with an elevated serum calcium level

4. Her serum calcium level will be above the normal laboratory range

• The same cross-sectional study also described the prevalence of abnormalities in serum calcium according to stage of CKD

• Note that the prevalence of hypocalcemia that increases with declining renal function is exceedingly low -- at most 15% with an EGFR lower than 20 mL/min.

• The presence of an abnormal calcium level is unlikely at this stage of kidney disease

• So the correct answer is :2. Her serum calcium level will be within the normal laboratory range

Case 2Laboratory testing demonstrates a serum calcium level of 2.50 mmol/L (within normal laboratory range), a serum phosphorus level of 1.8 mmol/L (above the normal laboratory range), and a PTH of 10.3 pmol/L (above the normal laboratory range).• Based on these laboratory results, which of the following

statements is FALSE regarding the next appropriate step for Ms West?

1. Dietary restriction of serum phosphorus would be beneficial2. In the early stages of CKD dietary restriction of phosphorus may

be all that is required3. Phosphate binders (calcium-based and/or non-calcium-based)

have no role in the management of hyperphosphatemia in predialysis CKD

4. Calcium salts are effective phosphate binders

• phosphate binders and a phosphorus-restricted diet can be considered in patients with CKD to help keep serum phosphorus levels within the normal range.

All-cause mortality for each type of phosphate binder

• So the correct answer is: 3. Phosphate binders (calcium-based and/or non-calcium-based) have no role in the management of hyperphosphatemia in predialysis CKD

Case 3• 42-year-old man who has advanced focal segmental glomerulosclerosis

and an estimated glomerular filtration rate (eGFR) of 18 ml/min/1.73m2. • His past medical history includes hypertension and osteoarthritis. He

does not smoke or drink alcohol excessively. • Current medications include lisinopril 20 mg daily, amlodipine 10 mg

daily, and fish oil. • A previous 6-month trial of high-dose corticosteroids failed to impact the

course of his disease and was discontinued. • He plans to receive a living donor kidney from his sister when he reaches

end-stage renal disease.• He denies uremic symptoms, including dyspnea, fatigue, anorexia,

nausea, pruritus, or swelling. • His exam reveals a body mass index of 27 kg/m2, blood pressure of

147/85 mm Hg, and trace pedal edema. • His serum albumin level is 3.6 g/dL

Serum calcium 7.8 mg/dL(normal range 8.4 to

10.2 mg/dL)

Serum phosphate 4.0 mg/dL(normal range 2.5 to 4.5

mg/dL)Serum parathyroid

hormone 241 pg/mL(normal range 8 to 65

pg/mL)Serum 25-

hydroxyvitamin D 32 ng/mL

• Which of the following is most likely to be responsible for the patient's hypocalcemia and hyperparathyroidism?

1. Phosphate retention2. Substrate vitamin D deficiency3. Calcitriol deficiency4. Parathyroid hormone related peptide5. Osteoarthritis

• Chronic kidney disease leads to impaired phosphate excretion and reduced synthesis of 1,25(OH)2D (calcitriol).

• Calcitriol deficiency causes reduced absorption of dietary calcium with a fall in serum calcium concentrations and secondary hyperparathyroidism.

• So the correct answer is : 3. Calcitriol deficiency

• Which of the following treatments for mineral metabolism disorders would be most appropriate in this case?

• Oral calcitriol 0.25 μg daily• Cholecalciferol 2,000 IU daily• Ergocalciferol 50,000 IU weekly• Calcium carbonate 1200 mg daily• Diltiazem 360 mg daily

• Calcitriol, the hormonally active form of vitamin D3 will most effectively affect this patient's reduced synthesis of 1,25(OH)2D and thereby correct his low calcium levels and secondary hyperparathyroidism.

• Serum 25-hydroxyvitamin D is 32 ng/mL within normal.• So the correct answer is: • Oral calcitriol 0.25 μg daily

• You initiate treatment with oral calcitriol 0.25 μg per day. Which of the following should be checked within the next 3 months?

1. Serum 25-hydroxyvitamin D2. Serum magnesium3. Serum parathyroid hormone4. Urine fractional excretion of phosphate5. Serum calcium and phosphate

• Calcitriol increases gastrointestinal absorption of calcium and phosphate through different receptors. Increased levels of these minerals can be noted hours to days after treatment initiation.

• The correct answer: 5. Serum calcium and phosphate

Thank You