Chronic Kidney Disease-Mineral Bone Disease

Agenda

Overview.

Pathogenesis.

Clinical Features.

KDIGO Diagnosis Guidelines of CKD-MBD.

Laboratory Target Levels.

Treatment of CKD-MBD.

Treatment Failure and Surgical Intervention.

KDIGO Treatment Guidelines.

Conclusion. Waleed El-Refaey CKD-MBD 21/2/2016

Agenda

Overview.

Pathogenesis.

Clinical Features.







Overview

Waleed El-Refaey CKD-MBD 21/2/2016

• As kidney function declines in chronic kidney disease (CKD), there is a progressive deterioration in mineral homeostasis, with a disruption of normal serum and tissue concentrations of phosphorus and calcium, and changes in circulating levels of hormones.

• These include parathyroid hormone (PTH), 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), fibroblast growth factor-23 (FGF-23), and growth hormone.

Introduction and definition of CKD-MBD and the development of the guideline

statements. Kidney Int 2009; 76:S3.

Overview


• Beginning in CKD stage 3, the ability of the kidneys to appropriately excrete a phosphate load is diminished, leading to hyperphosphatemia, elevated PTH, and decreased 1,25(OH)2D with associated elevations in the levels of FGF-23.

• The kidney fails to respond adequately to PTH, which normally promotes phosphaturia and calcium reabsorption, or to FGF-23, which also enhances phosphate excretion.



Overview


• The mineral and endocrine functions disrupted in CKD are critically important in the regulation of both initial bone formation during growth (bone modeling) and bone structure and function during adulthood (bone remodeling).

• Numerous cohort studies have shown associations between disorders of mineral metabolism, fractures and cardiovascular disease (the leading cause of death in patients at all stages of CKD).



Overview


KDIGO defined CKD-MBD as a systemic disorder of mineral and bone metabolism due to CKD, manifested by either one or a combination of the following three components:

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

●Abnormalities in bone turnover, mineralization, volume linear growth, or strength.

●Extraskeletal calcification.



Agenda

Overview.

Pathogenesis.

Clinical Features.







Pathogenesis


• The pathophysiology of this disorder is complex and involves a number of feedback loops between the kidney, bone, intestine, parathyroid glands and the vasculature.

• The main goal of this system is maintenance of calcium and phosphorus balance, often at the expense of abnormalities in other components of the system.

Fang Y, Ginsberg C, Sugatani T, et al. Early chronic kidney disease-mineral bone

disorder stimulates vascular calcification. Kidney Int 2014; 85:142.

.

Pathogenesis


1. ABNORMALITIES OF CALCIUM, PHOSPHORUS, PTH, AND VITAMIN D METABOLISM.

2. ABNORMALITIES IN BONE TURNOVER, MINERALIZATION, VOLUME LINEAR GROWTH, OR STRENGTH.

3. EXTRASKELETAL CALCIFICATION.

Extraskeletal Calcification

Pathogenesis


PLAYERS

CKD-MBD is A State of Target Organs Resistance In The Face of Positive and Negative Feedback Loops.

PTH

FGF-23

Pathogenesis


Pathogenesis


1-Elevated PTH: • Secondary hyperparathyroidism (SHPT) begins early in

the course of CKD, and the prevalence increases as kidney function declines (eGFR <60 mL/min per 1.73 m2).

• The main abnormalities that contribute to the pathogenesis of SHPT are:

- PO4 retention - Decreased iCa. - Decreased calcitriol. - Increased FGF-23. - The reduced expression of vitamin D receptors (VDRs), calcium-sensing receptors (CaSRs), fibroblast growth factor receptors, and klotho in the parathyroid glands.

Cunningham J, Locatelli F, Rodriguez M. Secondary hyperparathyroidism: pathogenesis, disease

progression, and therapeutic options. Clin J Am Soc Nephrol 2011; 6:913.

Pathogenesis


• Skeletal resistance to the calcemic action of PTH is primarily due to downregulation of PTH receptors induced by the high circulating PTH concentrations.

• Although both calcitriol deficiency and hyperphosphatemia may play a contributory role.

• Tertiary hyperparathyroidism reflects severe parathyroid hyperplasia, with autonomous secretion of PTH that is no longer adequately responsive to the plasma calcium concentration.

Rodriguez M, Felsenfeld AJ, Llach F. Calcemic response to parathyroid hormone in renal

failure: role of calcitriol and the effect of parathyroidectomy. Kidney Int 1991; 40:1063.

Pathogenesis


• In patients with tertiary hyperparathyroidism, decreased expression of CaSR and VDRs results in a lack of suppression of PTH by increasing calcium or vitamin D analogs.

• Nodular parathyroid glands do not undergo involution, despite resolution of some of the triggering mechanisms.

• This is best illustrated by the high PTH concentrations and hypercalcemia that may persist in CKD patients after receiving renal transplant.

Grzela T, Chudzinski W, Lasiecka Z, et al. The calcium-sensing receptor and vitamin D

receptor expression in tertiary hyperparathyroidism. Int J Mol Med 2006; 17:779.

Pathogenesis


2-Hyperphosphatemia: • Three major theories have been proposed to explain how

phosphate retention initially promotes PTH release: The induction of hypocalcemia. Decreased formation or activity of calcitriol. Increased PTH gene expression. • The initial elevation in PTH secretion is appropriate since

the ensuing increase in phosphate excretion lowers the plasma phosphate concentration toward normal.

Llach F. Secondary hyperparathyroidism in renal failure: the trade-off hypothesis

revisited. Am J Kidney Dis 1995; 25:663.

Pathogenesis


2-Hyperphosphatemia: • In ESRD patients, PTH inhibits proximal tubule phosphate

reabsorption from the normal 80 to 95% to as low as 15% of the filtered phosphate.

• Continued PTH-induced release of phosphate from bone can actually exacerbate the hyperphosphatemia.

• Hyperparathyroidism also tends to correct both the hypocalcemia (by increasing bone resorption) and the calcitriol deficiency (by stimulating the 1-hydroxylation of calcidiol [25-hydroxyvitamin D] in the proximal tubule).

Cunningham J, Locatelli F, Rodriguez M. Secondary hyperparathyroidism: pathogenesis,

disease progression, and therapeutic options. Clin J Am Soc Nephrol 2011; 6:913.

Pathogenesis


3-Decreased calcitriol activity: • Plasma calcitriol concentrations generally fall below

normal when the GFR is <60 mL/min per 1.73 m2.

• Initially, the decline in calcitriol concentration is likely to be due to the increase in FGF-23 concentration (inhibiting 1-

alpha-hydroxylase activity) rather than the loss of functioning renal mass.

• However, in advanced CKD, hyperphosphatemia and loss of renal mass may also contribute to the decline in calcitriol synthesis.

Gutierrez O, Isakova T, Rhee E, et al. Fibroblast growth factor-23 mitigates hyperphosphatemia but

accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 2005; 16:2205.

Pathogenesis


3-Decreased calcitriol activity: • Low calcitriol concentrations increase PTH secretion by

indirect and direct mechanisms.

• Indirect: effects on PTH are achieved through decreased intestinal absorption of calcium and calcium release from bone, both of which promote the development of hypocalcemia, which stimulates PTH secretion.

Denda M, Finch J, Brown AJ, et al. 1,25-dihydroxyvitamin D3 and 22-oxacalcitriol prevent the

decrease in vitamin D receptor content in the parathyroid glands of uremic rats.

Kidney Int 1996; 50:34.

Pathogenesis


3-Decreased calcitriol activity: • Direct: Calcitriol normally acts on the VDR in the

parathyroid gland to suppress PTH transcription, but not PTH secretion.

• A decrease in calcitriol concentrations also lowers the number of VDRs in the parathyroid cells, both promote parathyroid chief cell hyperplasia and nodule formation.

Denda M, Finch J, Brown AJ, et al. 1,25-dihydroxyvitamin D3 and 22-oxacalcitriol prevent the

decrease in vitamin D receptor content in the parathyroid glands of uremic rats.

Kidney Int 1996; 50:34.

Pathogenesis


4-Hypocalcemia and calcium-sensing receptor:

• Calcium is a major regulator of PTH secretion.

• Minute changes in the serum ionized calcium are sensed by a specific membrane receptor, the CaSR, which is highly expressed on the surface of the chief cells of the parathyroid glands, tightly regulating PTH secretion.

Rodriguez M, Nemeth E, Martin D. The calcium-sensing receptor: a key factor in the

pathogenesis of secondary hyperparathyroidism. Am J Physiol Renal Physiol 2005; 288:F253.

Pathogenesis


4-Hypocalcemia and calcium-sensing receptor:

• Total serum calcium concentration decreases during the course of CKD due to:

1. phosphate retention, 2. decreased calcitriol concentration, and 3. resistance to the calcemic actions of PTH on bone.

Pathogenesis


4-Hypocalcemia and calcium-sensing receptor: • In CKD, the number of CaSRs may be reduced in

hypertrophied parathyroid glands, particularly in areas of nodular hypertrophy.

• The change in receptor number can lead to inadequate suppression of PTH secretion by calcium, resulting in inappropriately high PTH concentrations in the setting of normal or high calcium concentrations.

Yano S, Sugimoto T, Tsukamoto T, et al. Association of decreased calcium-sensing receptor expression

with proliferation of parathyroid cells in secondary hyperparathyroidism. Kidney Int 2000; 58:1980.

Pathogenesis


Pathogenesis


5-Fibroblast growth factor-23: • FGF-23 is a circulating peptide that plays a key role in the

control of serum phosphate concentrations.

• FGF-23 is secreted by bone osteocytes and osteoblasts in response to calcitriol, increased dietary phosphate load, PTH, and calcium.

• Klotho, a transmembrane protein produced by osteocytes, is required for FGF-23 receptor activation.

Liu S, Quarles LD. How fibroblast growth factor 23 works. J Am Soc Nephrol 2007; 18:1637.

Pathogenesis


5-Fibroblast growth factor-23: • FGF-23's primary function is to maintain normal serum

phosphate concentration by reducing renal phosphate reabsorption and by reducing intestinal phosphate absorption through decreased calcitriol production.

• In renal proximal tubular cells, FGF-23 binds to the FGF receptor (FGFR) and its coreceptor, klotho, causing inhibition of the expression of the Na/Pi IIa cotransporter .

Miyamoto K, Ito M, Tatsumi S, et al. New aspect of renal phosphate reabsorption: the type IIc

sodium-dependent phosphate transporter. Am J Nephrol 2007; 27:503.

Pathogenesis


5-Fibroblast growth factor-23: • FGF-23 also suppresses PTH secretion by the parathyroid

gland.

• However, among CKD patients, the presence of high PTH concentrations, despite high FGF-23 concentrations, suggests that the parathyroid is relatively resistant to the elevated concentrations of FGF-23 in uremia.

• This may be related to the markedly decreased expression of FGFR 1 and klotho protein in the hyperplastic parathyroid gland.

Komaba H, Goto S, Fujii H, et al. Depressed expression of Klotho and FGF receptor 1 in

hyperplastic parathyroid glands from uremic patients. Kidney Int 2010; 77:232.

Pathogenesis


Pathogenesis


Pathogenesis


Pathogenesis


• 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. • Kidney Disease: Improving Global Outcomes (KDIGO)

recommended that three parameters be used to assess bone pathology. These parameters include bone turnover, mineralization, and volume (TMV system).

Introduction and definition of CKD-MBD and the development of the guideline statements.

Kidney Int 2009; 76:S3.

Pathogenesis


TMV characteristics of the major CKD-related bone diseases are as follows: • Osteitis fibrosa cystica is characterized by high bone

turnover due to secondary hyperparathyroidism.

• Adynamic bone disease is characterized by low bone turnover. Most current cases result from excessive suppression of the parathyroid glands due to increased and earlier use of vitamin D analogs and calcium-containing phosphate binders. This represents the major bone lesion in peritoneal dialysis and hemodialysis patients.

Pathogenesis


• Osteomalacia is characterized by low bone turnover in combination with abnormal mineralization.

The incidence of osteomalacia has decreased with the abandonment of aluminum-based phosphate binders and the introduction of more efficient techniques for treatment of water used in preparing the dialysate.

Moe SM, Drüeke TB. A bridge to improving healthcare outcomes and quality of life. Am J

Kidney Dis 2004; 43:552..

Pathogenesis


• Mixed uremic osteodystrophy is characterized by either high or low bone turnover and by abnormal mineralization.

• A fifth, but different, type of uremic bone disease, with a unique pathogenesis, occurs in patients on long-term dialysis and presents as bone cysts, which result from beta2-microglobulin-associated amyloid deposits.

Pathogenesis


• The prevalence of high-turnover bone disease (osteitis fibrosa cystica) among dialysis patients has markedly decreased, while non-aluminum-induced low-turnover bone disease (adynamic bone disease) has increased, with variations based in part upon geographic region evaluated.

Martin KJ, Olgaard K, Coburn JW, et al. Diagnosis, assessment, and treatment of bone turnover

abnormalities in renal osteodystrophy. Am J Kidney Dis 2004; 43:558.

Pathogenesis


• 56 dialysis patients from Thailand followed between 1996 and 1998, bone biopsy in combination with other analyses revealed that low-turnover (adynamic) bone disease was present in 41%, and high-turnover (osteitis fibrosa cystica) disease was present in 29% of patients.

Pathogenesis


• In this study, bone biopsies revealed low-turnover disease in 59% of 119 hemodialysis patients.

• This high prevalence was observed despite treating most patients in accordance with K/DOQI guidelines and having serum mineral parameters within recommended ranges.

Pathogenesis


• Extraskeletal calcification is common in patients with CKD, particularly those on dialysis, and it contributes to cardiovascular mortality.

• VC results from both passive and active processes implicating a variety of mediator and effector proteins.

London GM, Guérin AP, Marchais SJ, et al. Arterial media calcification in end-stage renal disease:

impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 2003; 18:1731.

.


Pathogenesis


• Calciphylaxis (Calcific uremic arteriolopathy) is a rare and serious disorder characterized by systemic medial calcification of the arterioles that leads to ischemia and subcutaneous necrosis.

• Calciphylaxis most commonly occurs in patients with ESRD who are on hemodialysis or who have recently received a renal transplant, but may also occur in non-ESRD patients

Fine A, Zacharias J. Calciphylaxis is usually non-ulcerating: risk factors, outcome and therapy.

Kidney Int 2002; 61:2210.

.




calcific uremic arteriolopathy

calcific Aortic valve

Pathogenesis

Pathogenesis




Extraskeletal Calcification Pathogenesis

Agenda

Overview.

Pathogenesis.

Clinical Features.







Clinical Features


Piraino B, Chen T, Cooperstein L, et al. Fractures and vertebral bone mineral density in patients

with renal osteodystrophy. Clin Nephrol 1988; 30:57.

.

.

Bone Disease • Although frequently asymptomatic, this disorder can

result in weakness, fractures, bone and muscle pain, and avascular necrosis (especially in dialysis).

• Bone pain is the predominant symptom among patients with adynamic bone disease. Pain results from low bone turnover, which in turn leads to an impaired ability to repair microdamage.

Clinical Features


Raggi P, Boulay A, Chasan-Taber S, et al. Cardiac calcification in adult hemodialysis patients. A link

between end-stage renal disease and cardiovascular disease? J Am Coll Cardiol 2002; 39:695.

Vascular Calcifications • Both intimal and medial calcification have been closely

associated with increased mortality.

• Intimal calcification is a marker for an advanced atherosclerotic plaque and has been used for screening for coronary disease.

• Medial calcification is strongly associated with loss of arterial distensibility and thereby systolic hypertension, left ventricular hypertrophy, and impaired coronary artery perfusion.

Agenda

Overview.

Pathogenesis.

Clinical Features.







Diagnosis of CKD-MBD




Diagnosis of CKD–MBD: biochemical abnormalities












Diagnosis of CKD–MBD: bone



Diagnosis of CKD–MBD: bone



Diagnosis of CKD–MBD: vascular calcification



Cardiovascular calcification

Aortic Calcifications

Digital Arteries

Calcification

Agenda

Overview.

Pathogenesis.

Clinical Features.







Laboratory Target levels


Calcium and phosphorus levels For those with stage 3 & 4 CKD, the following treatment goals were recommended: ●Serum level of phosphorus should be maintained between 2.7 mg/dL - 4.6 mg/dL. ●The serum levels of corrected total calcium should be maintained within the "normal" range for the laboratory used ●The serum calcium-phosphorus product should be maintained at <55 mg2/dL2



Calcium and phosphate levels For those with stage 5 & 5D CKD, the following are recommended: ●Serum levels of phosphate should be maintained between 3.5 and 5.5 mg/dL ●Serum levels of corrected total calcium should be maintained between 8.4 and 9.5 mg/dL ●The serum calcium-phosphate product should be maintained at <55 mg2/dL2



Parathyroid hormone levels • Stage 3 CKD: 35 to 70 pg/mL. • Stage 4 CKD: 70 to 110 pg/mL. • Stage 5 & 5D CKD: 150 to 300 pg/mL



• Calcium and phosphorus levels For patients with stage 3 to 5D CKD, the KDIGO working group suggest: ● Maintaining serum calcium and phosphorus in the normal range. ● Evaluating individual values of serum calcium and phosphorus together, rather than the calcium-phosphorus product.

• Parathyroid hormone levels In CKD 5D it is recommended to maintain PTH level in the range of approximately 2-9 times the upper limit of normal for the assay.

Agenda

Overview.

Pathogenesis.

Clinical Features.







Treatment


The treatment of patients with CKD-MBD varies depending upon the prevailing metabolic abnormality, the characteristic bone disease, and the severity of underlying kidney dysfunction.

Treatment


1) Dietary phosphate restriction and phosphate binders: Dietary restriction • Limiting phosphate intake is difficult to achieve unless

protein intake is limited, which could contribute to protein malnutrition without resulting in a decreased rate of progression of renal dysfunction.

• Among patients with PTH or serum phosphate levels greater than target levels, it is suggested to restrict dietary phosphate intake to 900 mg/day.

Llach F, Massry SG. On the mechanism of secondary hyperparathyroidism in moderate

renal insufficiency. J Clin Endocrinol Metab 1985; 61:601.

.

Treatment


1) Dietary phosphate restriction and phosphate binders: Dietary restriction • Dietary phosphorus should be derived from sources of high

biologic value, such as meats and eggs. Phosphorus from food additives should also be estimated and restricted.

• A decrease in serum PTH levels plus improvements in bone histology with dietary phosphate restriction among patients with mild CKD was noted.

Llach F, Massry SG. On the mechanism of secondary hyperparathyroidism in moderate

renal insufficiency. J Clin Endocrinol Metab 1985; 61:601.

.

Treatment


BMC Nephrology

2015, 16:9

Treatment


1) Dietary phosphate restriction and phosphate binders: Phosphate binders • However, hyperparathyroidism and hyperphosphatemia are

unlikely to be prevented by dietary phosphorus restriction alone in the setting of progressive renal insufficiency.

• Thus, most patients will require the addition of a phosphate binder (calcium- or non-calcium-based).



Treatment


Phosphate binders Sucroferric oxyhydroxide (Velphoro) is a chewable phosphate binder that has received approval from the US Food and Drug Administration (FDA) and is now available in the United States for treatment of hyperphosphatemia in patients with estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2.

http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Dr

ugDetails (Accessed on February 28, 2014

Treatment


• Various doses of sucroferric oxyhydroxide were compared with sevelamer in a randomized, multicenter, open-label study that included 154 hemodialysis patients.

Treatment


• At six weeks, sucroferric oxyhydroxide at doses of 5, 7.5, 10, and 12.5 g/day (which provided 1.0, 1.5, 2.0, and 2.5 g/day elemental iron), but not 1.25 g/day (which provided 250 mg elemental iron), decreased the serum phosphorus.

• Doses of 5 and 7.5 g/day produced decreases in serum phosphorus similar to sevelamer dosed at 4.8 g/day. There was no difference between sucroferric oxyhydroxide and sevelamer in the rate of adverse events (61 versus 58 percent, respectively).

Treatment


• In a phase-III study of dialysis patients, sucroferric oxyhydroxide was noninferior to sevelamer in reducing serum phosphate and was associated with a lower pill burden (three tablets versus eight of sevelamer).

• Although adherence was better for sucroferric oxyhydroxide, more patients stopped taking sucroferric oxyhydroxide because of adverse effects (15.7 versus 6.6 percent for sevelamer).

Treatment


• The most common adverse effects were gastrointestinal (diarrhea, nausea, abnormal product taste, constipation, and vomiting).

• The starting dose of sucroferric oxyhydroxide is 2.5 g (500 mg elemental iron) three times daily with meals.

Treatment


Phosphate binders Dosing and administration • For all phosphate buffers, the lowest dose that is

effective should be used with meals.

• If calcium-containing buffers are selected, the amount of elemental calcium contained in the phosphate binder should not exceed 1500 mg per day.

Treatment


Phosphate binders Choice of agent: ● Hypocalcemic patients: we generally use calcium-containing phosphate binders. Hypocalcemic patients are less likely to become hypercalcemic with calcium-containing binders. ● Normocalcemic patients: we generally use calcium-containing phosphate binders for normocalcemic patients who have no evidence of vascular calcification or adynamic bone disease.

Treatment


Phosphate binders Choice of agent: ● Hypercalcemic patients: we generally use noncalcium-containing phosphate binders for hypercalcemic patients. ● Patients with adynamic bone disease or vascular calcification: we generally use noncalcium-containing phosphate binders for these patients.

Treatment


2) Vitamin D, calcitriol, and vitamin D analogs: Terminology • Vitamin D includes both vitamin D2 (ergocalciferol) and

vitamin D3 (cholecalciferol).

• Vitamin D derivatives include: 1. the naturally occurring vitamin D metabolite, calcitriol

(1,25-dihydroxycholecalciferol [1,25(OH)2D]), and

2. synthetic vitamin D analogs such as doxercalciferol, paricalcitol, alfacalcidol, falecalcitriol, and 22-oxacalcitriol (or maxacalcitol [1,25 dihydroxy-22-oxavitamin D3]).

Treatment


2) Vitamin D, calcitriol, and vitamin D analogs: Vitamin D supplementation (ergocalciferol and cholecalciferol) are not usually given to dialysis patients, despite a high prevalence of nutritional vitamin D deficiency, as defined by 25(OH)D levels <30 ng/mL.

Treatment


2) Vitamin D, calcitriol, and vitamin D analogs: Vitamin D supplementation

• The effect of cholecalciferol 25,000 international units per week was compared with placebo among 55 25(OH)D-deficient hemodialysis patients in a double-blind, randomized trial.

Treatment



• At 13 weeks, compared with placebo, more cholecalciferol-treated patients had normal levels of 25(OH)D (7.4 versus 61.5 percent, respectively); 1,25(OH)2D (12 versus 54 percent, respectively); and calcium (44 versus 77 percent, respectively).

Treatment



• In a placebo-controlled, multicenter trial, 105 hemodialysis patients with 25(OH)D concentrations ≤32 ng/mL were randomly assigned to receive oral ergocalciferol 50,000 international units either weekly or monthly, or receive placebo.

Treatment



• At 12 weeks, vitamin D sufficiency (defined as 25(OH)D concentration >32 ng/mL) was achieved in 91, 66, and 35 percent of patients administered weekly ergocalciferol, monthly ergocalciferol, or placebo, respectively. There was no difference among groups in serum ca, PO4, or PTH.

Treatment


2) Vitamin D, calcitriol, and vitamin D analogs: Calcitriol and synthetic vitamin D analogs • Most dialysis patients with increased plasma iPTH levels

(>300 pg/mL) require treatment with calcitriol or vitamin D analogs.

• Because calcitriol increases gastrointestinal absorption of calcium and phosphate, more selective vitamin D analogs have been developed that may reduce the risk of hypercalcemia and hyperphosphatemia.

Treatment


2) Vitamin D, calcitriol, and vitamin D analogs: Choice of agent • There are six active (ie, 1-hydroxylated) vitamin D

derivatives currently available. These include calcitriol and five synthetic vitamin D analogs including paricalcitol, doxercalciferol, alfacalcidol (not available in the United States), falecalcitriol (not available in the United States), and 22-oxacalcitriol (not available in the United States).

• Paricalcitol and doxercalciferol are predominantly used in the United States,

• whereas calcitriol and alfacalcidol are more frequently used in other countries.

Treatment


2) Vitamin D, calcitriol, and vitamin D analogs: Choice of agent

• This prospective, randomized trial has directly compared

calcitriol with a synthetic vitamin D analog (paricalcitol).

• No significant difference was observed in the primary endpoint (lowering of PTH values) and secondary endpoints (the single incidence of hypercalcemia or elevated Ca x P product).

Treatment


2) Vitamin D, calcitriol, and vitamin D analogs: There is no convincing evidence, including the result from the one large, prospective, randomized comparative trial, supporting the use of a specific derivative of the six analogs currently available over another.

Treatment


2) Vitamin D, calcitriol, and vitamin D analogs: Dose • The optimal dose of calcitriol or synthetic vitamin D analogs

has not been established and depends upon the concurrent use of calcimimetics, the dose of concomitant calcium-based phosphate binders, and the potency/selectivity of the vitamin D analog.

• The current approach has been empiric, with the goal of administering increasing doses of vitamin D analogs, along with phosphate binders, to achieve target plasma levels of Ca, PO4 and PTH.

Treatment


2) Vitamin D, calcitriol, and vitamin D analogs: Dose • The continued up-titration with active vitamin D to

supraphysiologic levels, if necessary to suppress PTH, is often successful in lowering PTH, but frequently achieves this one goal at the expense of hypercalcemia and hyperphosphatemia.

Treatment


2) Vitamin D, calcitriol, and vitamin D analogs: Dose

Treatment



Treatment



Treatment



Treatment


2) Vitamin D, calcitriol, and vitamin D analogs: Dose • Patients who are responsive to calcitriol supplementation

typically show significant reductions in plasma PTH concentrations during the first three to six months of therapy.

• In general, the dose of calcitriol or synthetic vitamin D analogs should be reduced by 50% or stopped with plasma calcium levels at the upper normal range or with mild hypercalcemia (between 9.5 and 10.2 mg/dL).

• Calcitriol or the synthetic analog should be discontinued for frank hypercalcemia (>10.2 mg/dL).

Treatment


2) Vitamin D, calcitriol, and vitamin D analogs: Contraindications 1- Calcitriol or synthetic vitamin D analogs should not be given until the serum phosphorus concentration has been controlled (<5.5 mg/dL) and the serum calcium is <9.5 mg/dL. 2- Low plasma PTH concentration, possibly <150 pg/mL, because of the association with adynamic bone disease. • Empiric observations suggest that somewhat higher than

normal PTH levels are required for normal bone formation rates in patients with kidney disease, presumably due to the end-organ resistance to PTH observed in uremia.

Treatment


2) Vitamin D, calcitriol, and vitamin D analogs: Resistance Up to one-half of patients with severe hyperparathyroidism show little or no decline in plasma PTH levels with calcitriol therapy. Limiting factors include: 1. large functioning gland mass with nodular hyperplasia

(marked reduction in calcitriol receptors ), 2. altered calcium sensitivity of parathyroid cells, and 3. failure of high-dose vitamin D derivatives because of

hypercalcemia and/or hyperphosphatemia.

Katoh N, Nakayama M, Shigematsu T, et al. Presence of sonographically detectable parathyroid glands can predict resistance to oral pulsed-dose calcitriol treatment of

secondary hyperparathyroidism. Am J Kidney Dis 2000; 35:465.

Treatment


3) Calcimimetics:

• Calcimimetics are agents that increase the sensitivity of the calcium-sensing receptor (CaSR) in the parathyroid gland to calcium, regulating PTH secretion and the gland hyperplasia.

• Studies have found that the addition of cinacalcet to current treatment regimens increases the percentage of patients who are able to attain PTH, calcium, and phosphate target levels.

Nemeth EF, Bennett SA. Tricking the parathyroid gland with novel calcimimetic agents.

Nephrol Dial Transplant 1998; 13:1923.

Treatment


3) Calcimimetics:

Treatment


3) Calcimimetics:

• The administration of a calcimimetic agent increases the sensitivity of the receptor to extracellular calcium and can lower PTH secretion from the parathyroid gland indirectly.

• Calcimimetic agents also mediate reductions in serum PTH

concentrations by directly decreasing PTH gene expression and by increasing the VDR expression in the parathyroid glands.

Treatment


3) Calcimimetics:

• In this large trial (which was the combination of three phase-III studies), 1136 dialysis patients with iPTH levels of >300 pg/mL were randomly assigned to traditional therapy plus cinacalcet HCl or placebo for 26 weeks.

• To achieve the target iPTH levels of between 100 to 250 pg/mL, the dose was adjusted from 30 to 180 mg/day.

Treatment


3) Calcimimetics: Compared with placebo, the following benefits with cinacalcet in terms of achieving K/DOQI target levels were reported:

● A significant increase in the likelihood of achieving a mean iPTH level of <300 pg/mL (56 versus 10%). ● Significantly more likely to achieve serum calcium levels between 8.4 to 9.5 mg/dL (42 versus 24%); serum phosphorus levels between 3.5 to 5.5 mg/dL (46 versus 33%); and a Ca x P product <55 mg2/dL2 (65 versus 36%). ● Compared with placebo, cinacalcet lowered the risk of parathyroidectomy, fracture, and cardiovascular hospitalization.

Treatment


3) Calcimimetics: Evaluation of Cinacalcet Hydrochloride Therapy to

Lower Cardiovascular Events [EVOLVE]

• In this trial, 3883 patients were randomly assigned to receive cinacalcet or placebo in addition to conventional therapy including phosphate binders and/or vitamin D.

Treatment


3) Calcimimetics: Evaluation of Cinacalcet Hydrochloride Therapy to

Lower Cardiovascular Events [EVOLVE]

• At a median follow-up of less than two years, there was no difference between groups in the primary composite endpoint that included time until death or the first nonfatal cardiovascular event (myocardial infarction, hospitalization for

unstable angina, heart failure, or a peripheral vascular event).

• Cinacalcet reduced the rate of parathyroidectomy by approximately half.

Treatment


3) Calcimimetics:

Treatment


3) Calcimimetics:

Treatment


3) Calcimimetics:

Treatment


3) Calcimimetics: • Indications: may be indicated in dialysis patients with PTH

levels >300 pg/mL who have serum calcium levels >8.4 mg/dL.

• Dose: Cinacalcet is initiated at a dose of 30 mg/day, with stepwise increments to 60, 90, and 180 mg/day. The dose can be increased every four weeks until goals are achieved.

• Contraindications: Cinacalcet should not be started if serum calcium is <8.4 mg/dL. Frequent monitoring of plasma calcium and PTH levels is needed.

Amgen Sensipar label prepares for off-label use in pre-dialysis population.

Pharmaceutical Approvals Monthly 2004; 9:28.

Treatment


Treatment of Adynamic Bone Disease (ABD):

• The initial approach to treatment of adynamic bone disease is to allow PTH secretion to rise.

• This can be achieved by: 1. decreasing the doses of calcium-based phosphate

binders, 2. using non-calcium-based phosphate binders; 3. decreasing or stopping active vitamin D analogs; and, 4. for patients on dialysis, possibly by using a low-

dialysate calcium concentration.

Treatment


Dialysate Calcium:

Treatment


Dialysate Calcium:

Treatment


Dialysate Calcium:

Treatment


Dialysate Calcium:

Treatment


Dialysate Calcium:

Agenda

Overview.

Pathogenesis.

Clinical Features.







Treatment


Treatment failures include:

1. dialysis patients with tertiary hyperparathyroidism, which is defined as elevated PTH levels and spontaneous hypercalcemia or

2. patients with persistent and progressive elevations of serum PTH that cannot be lowered to levels <300 pg/mL despite treatment with vitamin D analogs and cinacalcet (180 mg/day).

Failure

Treatment


Treatment failure Several interrelated factors are thought to be involved in the pathogenesis of refractory hyperparathyroidism. These include:

1. Delayed or inadequate therapy.

2. Persistent hyperphosphatemia.

3. An increase in parathyroid gland mass.

Failure

Treatment


Indications for surgery

• ESRD patients who have markedly elevated, medical therapy-refractory PTH levels and related signs and symptoms are generally referred for parathyroidectomy.

• Parathyroidectomy should not be performed unless

high PTH levels (>800 pg/mL) have been documented.

Treatment


Indications for surgery

The following signs and symptoms warrant parathyroidectomy in the setting of elevated PTH values in the absence of another known etiology: 1. Severe hypercalcemia. 2. Progressive and debilitating hyperparathyroid bone

disease. 3. Refractory pruritus. 4. Progressive extraskeletal calcification or calciphylaxis. 5. Otherwise unexplained myopathy.

Agenda

Overview.

Pathogenesis.

Clinical Features.







Treatment


Treatment of CKD–MBD targeted at lowering high serum phosphorus and maintaining serum calcium

Treatment



Treatment



Treatment



Treatment


Treatment of abnormal PTH levels in CKD–MBD

Treatment



Treatment



Treatment



Treatment


Treatment of bone with bisphosphonates, other osteoporosis medications, and growth hormone

Treatment


Treatment of bone with bisphosphonates, other osteoporosis medications, and growth hormone

Treatment


Treatment options of Osteoprosis: 1. Bisphosphonates 2. Intermittent administration of 1–34 PTH

(teriparatide{Forteopen}): might be useful in patients with surgical hypoparathyroidism and adynamic bone disease.

3. Raloxifene {Ralox} is a selective estrogen receptor modulator.

Agenda

Overview.

Pathogenesis.

Clinical Features.







Conclusion


• Disorders of mineral and bone metabolism are common sequelae of CKD, with Secondary hyperparathyroidism encompassing most of the biochemical abnormalities.

• There is an increased risk of all-cause and cardiovascular mortality in patients with disorders of mineral metabolism.

• Among dialysis patients with elevated PTH levels, a stepped approach to the management of hyperparathyroidism and bone mineral abnormalities is recommended.

Conclusion


• This approach requires a complex balance of four medications, namely calcium-containing binders, non-calcium-containing binders, calcimimetics, and either calcitriol or synthetic vitamin D analogs.

• Most current ABD cases result from excessive suppression of the parathyroid glands due to increased and earlier use of vitamin D analogs and calcium-containing phosphate binders.

• Among patients with refractory hyperparathyroidism, prompt parathyroidectomy is suggested.

Health & Medicine

Chronic Kidney Disease-Mineral Bone Disease