ckd mbd prof. babikir kaballo

BABIKIR KABALLOMBBS (U of K), MD, FRCP (London),

President of Sudan nephrology society

New trends for treatment of hyperphosphataemiaAn Increasingly Complex Problem

Outline

• Define the problem• Discuss basic parathyroid, vitamin D, Ca and PO4

,FGF-23 (fibroblast growth factor), and bone physiologyIn relation to hyperphosphataemia

• Discuss pathophysiologic changes that effectCKD/ESRD patients

• Therapeutic options for treatment ofhyperphosphataemia – what we can do to helpCKD and ESRD patients in terms of CKD-MBD

• Define the problem• Discuss basic parathyroid, vitamin D, Ca and PO4

,FGF-23 (fibroblast growth factor), and bone physiologyIn relation to hyperphosphataemia

• Discuss pathophysiologic changes that effectCKD/ESRD patients

• Therapeutic options for treatment ofhyperphosphataemia – what we can do to helpCKD and ESRD patients in terms of CKD-MBD

1. abnormalities of Ca, PO4, iPTH or Vitamin Dmetabolism

2. abnormality in bone turnover, mineralization,volume, linear growth or strength

3. vascular or soft tissue calcification

Chronic Kidney Disease – MetabolicBone Disorder: CKD-MBD

1. abnormalities of Ca, PO4, iPTH or Vitamin Dmetabolism

2. abnormality in bone turnover, mineralization,volume, linear growth or strength

3. vascular or soft tissue calcification

The Key regulators of divalent ion metabolism are:1. PTH 2. vitamin D 3. Klotho/FGF-23

Abnormalities of MBD in CKD

• Reduced calcium• Increased phosphorus• Increased PTH• Reduced calcitriol (1,25 vitamin D)• Increased FGF-23• Reduced Klotho

Normal Calcium BalanceDietary Intake

(1000mg)

IntestinalAbsorption

IntestinalSecretion

(400mg)

(200mg)

BloodPlasma

Efflux(300mg)

Influx (300mg)IntestinalSecretion

(200mg)Renal Excretion

1000mg Input = 800mg Fecal Loss + 200mg Renal ExcretionNet Balance = 0

(800mg)

Fecal Loss

What Happens with Loss of Renal Function?

• Decreased activation of vitamin D• Decreased absorption of calcium from GI tract• Diminished renal calcium and phosphorus

excretion as GFR declines• Reduction in serum calcium level as

phosphorus level increases and gut absorptionis reduced

• Increase in parathyroid hormone (PTH) levels

• Decreased activation of vitamin D• Decreased absorption of calcium from GI tract• Diminished renal calcium and phosphorus

excretion as GFR declines• Reduction in serum calcium level as

phosphorus level increases and gut absorptionis reduced

• Increase in parathyroid hormone (PTH) levels

Normal Calcium BalanceDietary Intake

(1000mg)

IntestinalAbsorption

IntestinalSecretion

(400mg)

(200mg)

BloodPlasma

Efflux(300mg)

Influx (300mg)

Increased phosphorus

IntestinalSecretion

(200mg)Renal Excretion

(800mg)

Fecal LossPTH

Overview of Ca++ Homeostasis

Decrease in serumcalcium level leads torelease of PTH fromvesicles in the gland

Vitamin D

1,25 Vit D rolesa) Increases Ca, Ph gut absorptionb) Increases bone turnoverc) Suppresses PTH

1-hydroxlase increased by:a) Reduced calciumb) Reduced phosphorusc) Increased PTH

1-hydroxylase reduced bya) increased FGF 23 levelsb) Increased phosphorus

1 hydroxlase

Effects of Paricalcitol and Calcitriol on Intestinal Absorption ofCalcium and Phosphorus in Normal Rats

††

10 ng 10 ng 50 ng 100 ng

† †

10 ng 10 ng 50 ng 100 ng

ControlCalcitriolParicalcitol

n = 5*Absorption measured by subtracting fecal Ca++ and P content from dietary Ca++ and P intake.†P < 0.05 vs control.Brown et al. J Lab Clin Med. 2002;139:279-284.

††

10 ng 10 ng 50 ng 100 ng

† †

10 ng 10 ng 50 ng 100 ng

Phosphorus: background• Total body content of phosphate is around 700

gms• 85% in bone and teeth, primarily as

hydroxyapetite• 14% in intracellular fluid– the majority of this is

complexed with proteins, lipids, carbohydrates• 1% in ECF: of this, 2/3 is in organic form mainly

as phospholipids and 1/3 in inorganic form (85%as free inorganic phosphate)

• Total body content of phosphate is around 700gms

• 85% in bone and teeth, primarily ashydroxyapetite

• 14% in intracellular fluid– the majority of this iscomplexed with proteins, lipids, carbohydrates

• 1% in ECF: of this, 2/3 is in organic form mainlyas phospholipids and 1/3 in inorganic form (85%as free inorganic phosphate)

increased

decreased

Increased phosphorusreduces calcium levels

FMC DATABASE: SERUM PHOSPHORUSAND RR OF DEATH

CORRECTED FOR CLINICAL FACTORS AND LAB DATA

<4 4-4.5 4.5--5 5-5.5 5.5-6 6.0-7.0 7.0-8.0 8-9.5 >9.50

<4 4-4.5 4.5--5 5-5.5 5.5-6 6.0-7.0 7.0-8.0 8-9.5 >9.5

FMC Distribution Of 3 Month AveragePhosphorus Value In ESRD Patients

41% > 5.5 mg%

Phos mg%

Serum Phosphate Levels and Mortality Risk Among6730 CKD Patients (creat > 1.2 mg% for women and >1.5 mg% for men)

Kestenbaum JASN 16:520, 2005

Phosphorus level: mg/dl*Adjustments: age, diabetes, CAD,

*CVA, CHF, Hgb, creat, calcium

Consequences of Increased Phosphorus

• Reduced 1,25 vitamin D• Increased PTH• Increased FGF-23 levels• Increased vascular calcification

PTH FGF23

CaPO4 + PTH increased PO4 excretion

calcitriol+ +

BoneResorption + renal

calcium reabsoption

calcitriol

increased GI Ca/PO4 absorption

Parathyroid HormoneCaPO4 + PTH increased PO4 excretion

calcitriol+ +

BoneResorption + renal

calcium reabsoption

calcitriol

increased GI Ca/PO4 absorption

Ca, Ph, and PTH levels with CKD

Progression of SHPT in CKD

Lewin E, et al. Semin Dial 2006;19:238-245.

What About FGF-23?

Effects of FGF-23• stimulates PO4 renal

excretion• decreases intestinal PO4

absorption• inhibits formation of 1,25

vitamin D3 by inhibiting1-alpha hydroxylase andstimulates 24 hydroxylase

• inhibits iPTH synthesisand secretion

• stimulates PO4 renalexcretion

• decreases intestinal PO4absorption

• inhibits formation of 1,25vitamin D3 by inhibiting1-alpha hydroxylase andstimulates 24 hydroxylase

• inhibits iPTH synthesisand secretion

PTH+ _

+FGF-23 _ 1,25 Vit D3

+ _24 Hydroxylase (degrades 1,25 and 25 Vit D)

FGF-23, PTH, Vit D - interactionsPTH+ _

+FGF-23 _ 1,25 Vit D3

+ _24 Hydroxylase (degrades 1,25 and 25 Vit D)

Klotho

• Co-receptor for FGF-23 (FGF-23 needs Klothoto bind at the cell surface to be effective)

• Mainly found in kidney, parathyroid• Membrane bound and free• Free mainly form kidney source• Klotho levels decrease with progressive renal

failure -- ? if reducd Klotho levels are responsible for earlyincrease in FGF 23 levels in CKd patients

• Co-receptor for FGF-23 (FGF-23 needs Klothoto bind at the cell surface to be effective)

• Mainly found in kidney, parathyroid• Membrane bound and free• Free mainly form kidney source• Klotho levels decrease with progressive renal

failure -- ? if reducd Klotho levels are responsible for earlyincrease in FGF 23 levels in CKd patients

Elevated FGF-23

• FGF-23 is associated with increased CVmortality

• FGF-23 is associated with left ventricularhypertrophy

• Unclear if FGF-23 is directly associated withvascular calcification – some studies yes andsome no

• FGF-23 is associated with increased CVmortality

• FGF-23 is associated with left ventricularhypertrophy

• Unclear if FGF-23 is directly associated withvascular calcification – some studies yes andsome no

• FGF-2 is expressed in many cell types includingcardiomyocytes and fibroblasts

• FGF receptors are also expressed in the heart• FGF-2 causes LVH by inducing changes in gene

expression that is similar to that caused by chronicpressure overload

• FGF23 exerted a direct hypertrophic effect on isolatedrat ventricular cardiomyocytes (NRVM) similar to FGF2via activation of FGFR but through a klotho-independentpathway

FGF23 Induces Left Ventricular HypertrophyFaul et al: J Clin Invest 2011; 121:4393-4408

• FGF-2 is expressed in many cell types includingcardiomyocytes and fibroblasts

• FGF receptors are also expressed in the heart• FGF-2 causes LVH by inducing changes in gene

expression that is similar to that caused by chronicpressure overload

• FGF23 exerted a direct hypertrophic effect on isolatedrat ventricular cardiomyocytes (NRVM) similar to FGF2via activation of FGFR but through a klotho-independentpathway

Intramyocardial Injection of FGF23 Induces LVH in Mice

Faul et al: J Clin Invest 2011; 121:4393-4408

• Reveals a klotho-independent,causal role for FGF23 in thepathogenesis of LVH

• Chronically elevated FGF23 levelsmay contribute directly to high ratesof LVH and mortality in individualswith CKD

FGF-23 and heart/LVH• Reveals a klotho-independent,

causal role for FGF23 in thepathogenesis of LVH

• Chronically elevated FGF23 levelsmay contribute directly to high ratesof LVH and mortality in individualswith CKD

Clinical Presentation

• Most with CKD and mildly elevated PTH areasymptomatic

• When present classified as either1. Musculoskeletal2. Extra-skeletal

• Most with CKD and mildly elevated PTH areasymptomatic

• When present classified as either1. Musculoskeletal2. Extra-skeletal

Musculoskeletal

• Fractures, tendon rupture and bone pain frommetabolic bone disease, muscular pain andweakness.

• Most clinically significant is hip fracture, seenin CKD 5.

• Fractures, tendon rupture and bone pain frommetabolic bone disease, muscular pain andweakness.

• Most clinically significant is hip fracture, seenin CKD 5.

Extra-skeletal

• disordered bone and mineral metabolism is asystemic disorder affecting soft tissues, particularlyvessels, heart valves and skin.

• May present with :LVH, cardiac fibrosis, extraskeletalcalcification, prepheral neuropathy, impotence

• CVD accounts for around half of all deaths of dialysispatients.

• disordered bone and mineral metabolism is asystemic disorder affecting soft tissues, particularlyvessels, heart valves and skin.

• May present with :LVH, cardiac fibrosis, extraskeletalcalcification, prepheral neuropathy, impotence

• CVD accounts for around half of all deaths of dialysispatients.

• Calciphylaxis or calcemic uremic arteriopathy– Seen primarily in CKD 5– Occurs in 1-4% of dialysis patients– Is small vessel vasculopathy involving mural

calcification with intimal proliferation, fibrosis andthrombosis

– Presents with extensive calcification of the skin,muscles and SC tissues.

• Clinically they may have skin nodules, skin firmness,eschars, and painful hyperaesthesia of the skin.

• May lead to non healing ulcers and gangrene

• Calciphylaxis or calcemic uremic arteriopathy– Seen primarily in CKD 5– Occurs in 1-4% of dialysis patients– Is small vessel vasculopathy involving mural

calcification with intimal proliferation, fibrosis andthrombosis

– Presents with extensive calcification of the skin,muscles and SC tissues.

• Clinically they may have skin nodules, skin firmness,eschars, and painful hyperaesthesia of the skin.

• May lead to non healing ulcers and gangrene

calciphylaxis

• A, Confluent calf plaques(borders shown with arrows).Parts of the skin areerythematous, which is easilyconfused with simple cellulitis.B, Gross ulceration in the samepatient 3 months later. The blackeschar has been surgicallydébrided. C, Calciphylacticplaques, a few of which arebeginning to ulcerate.(Photographs courtesy ofDr. Adrian Fine. Up ToDate)

Diagnosis of CKD bone disease

• Blood– PTH

• Random circulating PTH (1/2 life 2-4 mins)• Excreted renally so present for longer in RF

– Calcium– Phosphate ; raised early– Alkaline phosphatase ; increase in SHPT

• Bone biopsy– no longer frequently performed

• Imaging– In general not indicated

• Blood– PTH

• Random circulating PTH (1/2 life 2-4 mins)• Excreted renally so present for longer in RF

– Calcium– Phosphate ; raised early– Alkaline phosphatase ; increase in SHPT

• Bone biopsy– no longer frequently performed

• Imaging– In general not indicated

Treatment

• Goals :keep s.Ca s.Po4 within normal range .keep bone turnover and strength as near normal as possible .keep PTH aprpriate to these objective .

Treatment• Low PO4 Diet: early in CKD• PO4 Binders: early in CKD• Vitamin D repletion: calcitriol early in CKD• Efforts to prevent PTH elevation: control phosphorus,

calcium, 1,25 vitamin D levels• Oral Calcimimetics in advanced CKD or ESRD patients

with persistently high PTH levels• Parathyroidectomy: for persistent severe

hyperparathyroidism• Improve our understanding of FGF-23 and its role in

LVH and vascular calcification

• Low PO4 Diet: early in CKD• PO4 Binders: early in CKD• Vitamin D repletion: calcitriol early in CKD• Efforts to prevent PTH elevation: control phosphorus,

calcium, 1,25 vitamin D levels• Oral Calcimimetics in advanced CKD or ESRD patients

with persistently high PTH levels• Parathyroidectomy: for persistent severe

hyperparathyroidism• Improve our understanding of FGF-23 and its role in

LVH and vascular calcification

• Measures to s.Po4 :dietary restrictionoral phosphate bindersdialysis

• Measures to suppress PTH :vit D analogues (alfacaciferol).calcimimetic agent .

• Measures to normalize s.Ca :appropriate Ca intake +- supplementappropriate vit D treatment .apprpriate dialysate conc.

• Measures to s.Po4 :dietary restrictionoral phosphate bindersdialysis

• Measures to suppress PTH :vit D analogues (alfacaciferol).calcimimetic agent .

• Measures to normalize s.Ca :appropriate Ca intake +- supplementappropriate vit D treatment .apprpriate dialysate conc.

K/DOQI™ Clinical Practice Guidelineson Bone Metabolism Target Levels

CKDStage 3

CKDStage 4

CKDStage 5

(on dialysis)P

(mg/dL) 2.7 - 4.6 2.7 - 4.6 3.5 - 5.5*P(mg/dL)

Ca(mg/dL) “Normal” “Normal”

8.4 - 9.5;Hypercalcemia =

IntactPTH

(pg/mL)35 - 70 70 - 110 150 - 300*

*Evidence

SHPT• Check Ca ,PO4, PTH ,1.25(OH)2 D• If serum cacitriol is less 30ng/ml concider replacement• first control s.PO4• Start with low dose 0.25 ug/day alfacalcidol and

increased as nessesary over several weeks .• IV therapy 0.5_2.0 ug *3/week are altrnative to daily

regiment .• Calcimimetic agent (cincalcet)• If uncontrol; review diet and compliance.• Parathyriodectomy.

• Check Ca ,PO4, PTH ,1.25(OH)2 D• If serum cacitriol is less 30ng/ml concider replacement• first control s.PO4• Start with low dose 0.25 ug/day alfacalcidol and

increased as nessesary over several weeks .• IV therapy 0.5_2.0 ug *3/week are altrnative to daily

regiment .• Calcimimetic agent (cincalcet)• If uncontrol; review diet and compliance.• Parathyriodectomy.

• 4.3.3. In patients with CKD Stages 3a-5D withbiochemical abnormalities of CKD-MBD andlow BMD and/or fragility fractures, wesuggest that treatment choices take intoaccount the magnitude and reversibility ofthe biochemical abnormalities and theprogression of CKD, with consideration of abone biopsy (2D).

(KDOGI 2016) Vs (KDOGI 2009)

• 5.5. In patients with CKD Stages 1-5T withrisk factors for osteoporosis, we suggest thatBMD testing be used to assess fracture risk ifresults will alter therapy. (2C)

Calcimimetics

• Calcium sensing receptor agonists• Small molecule that bind to CaR and mimic

effect of increase extracellular Ca• Act on PT gland and increase sensitivity of

receptor to calcium• Cinacalcet (Sensipar)

– Significant decrease PTH, with Ca and phoshate .– Decrease risk of parathyriodectomy , CV

cacification .

• Calcium sensing receptor agonists• Small molecule that bind to CaR and mimic

effect of increase extracellular Ca• Act on PT gland and increase sensitivity of

receptor to calcium• Cinacalcet (Sensipar)

– Significant decrease PTH, with Ca and phoshate .– Decrease risk of parathyriodectomy , CV

cacification .

Transplant

• Bony changes improve post Tx, but if severeincreased PTH, levels can persist for up top 10years.

• Although Tx corrects many conditions leadingto disordered mineral metabolism, Steroidsmay lead to bone fragility, osteoporosis andincreased risk of fractures.

• Bony changes improve post Tx, but if severeincreased PTH, levels can persist for up top 10years.

• Although Tx corrects many conditions leadingto disordered mineral metabolism, Steroidsmay lead to bone fragility, osteoporosis andincreased risk of fractures.

Role Of Cinacalcet (sensipar)

• Several studies publishedover the last few yearsshowed the efficacy ofcinacalcet in themanagement of secondary PTH (e.g. Block et al, N EnglJ Med. 2004 350:1516-25)

• These reductions in PTHwere associated withimprovements inphosphate levels

Sensipar®

Binds tothe CaR

Activationof Second

Messengers

• Several studies publishedover the last few yearsshowed the efficacy ofcinacalcet in themanagement of secondary PTH (e.g. Block et al, N EnglJ Med. 2004 350:1516-25)

• These reductions in PTHwere associated withimprovements inphosphate levels

PTHPTH

PTHPTHPTH

PTHPTH

PTHPTHPTH

PTHPTH

DecreasedPTH

Secretion

Activationof Second

Messengers

Cinacalcet Significantly Reduces iPTH inPatients on Dialysis

Placebo Cinacalcet HCl

1/6/2017

BL 2 4 6 8 12 14 16 18 20 22 24 2610

354 338 333 315 297 298 293 280 276 266 257 257305n = 371Cinacalcet HCl

No. of Patients

Dose Titration Efficacy Assessment

Week354 342 344 328 323 315 312 308 291 287 291 289321n = 370Placebo

Mean ± SEP < 0.001

Adapted with permission from Block GA, et al. N Engl J Med. 2004;350:1516-1525.

Cinacalcet Significantly Reduces Serum Calciumin Patients on Dialysis

Control Sensipar®

1/6/2017Block GA, et al. J Am Soc Nephrol. 2003;14:461. Abstract SA-PO743 and poster.

BL 2 4 6 8 12 14 16 18 20 22 24 2610Week

Dose Titration Efficacy Assessment8.0

n = 166n = 175

n = 205n = 205

n = 147n = 157

Mean ± SEP < 0.001

Cinacalcet Significantly Reduces SerumPhosphorus in Patients on Dialysis

6.5Control Sensipar®

1/6/2017

Mean ± SEP < 0.013Block GA, et al. J Am Soc Nephrol. 2003;14:461. Abstract SA-PO743 and poster.

n = 166n = 175

n = 205n = 205

n = 147n = 157

WeekBL 2 4 6 8 12 14 16 18 20 22 24 2610

Dose Titration Efficacy Assessment5.0

Treatment with phosphate binders has been associatedwith a survival benefit.However, most phosphatebinders are associated with a high pill burden, posing amajor obstacle to adherence for patients attempting tomaintain optimal control of serum phosphorusconcentrations.Arenas MD, Malek T, Gil MT et al. Challenge of phosphorus control in hemodialysis patients: a problem of adherence? J

Nephrol 2010; 23: 525–534. 10.Chiu YW, et al. Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients.

Clin J Am Soc Nephrol 2009; 4: 1089–1096. 11.Wang S, et al. Pill burden and its Association with Medication Possession Ratio Among Hemodialysis Patients with

Hyperphosphatemia.European Dialysis and Transplantation Association Annual Meeting; 24–27 May 2012. Paris, France.

Treatment with phosphate binders has been associatedwith a survival benefit.However, most phosphatebinders are associated with a high pill burden, posing amajor obstacle to adherence for patients attempting tomaintain optimal control of serum phosphorusconcentrations.

A phase III study of the efficacy and safety of a noveliron-based phosphate binder in dialysis patientsJu ¨rgen Floege1, Adrian C. Covic2, Markus Ketteler3, Anjay Rastogi4, Edward M.F.Chong5, Sylvain Gaillard5, Laura J. Lisk5 and Stuart M. Sprague6, on behalf of the PA21Study Group

Kidney International (2014) 86, 638–647

A phase III study of the efficacy and safety of a noveliron-based phosphate binder in dialysis patientsJu ¨rgen Floege1, Adrian C. Covic2, Markus Ketteler3, Anjay Rastogi4, Edward M.F.Chong5, Sylvain Gaillard5, Laura J. Lisk5 and Stuart M. Sprague6, on behalf of the PA21Study Group

PA21 (sucroferric oxyhydroxide)phosphate binder with a low pill burden and goodtolerability may improve adherence and couldthereby help optimize serum phosphorus control inpatients on dialysis.PA21 (sucroferric oxyhydroxide)is a new calcium-free polynuclear iron(III)-oxyhydroxide phosphate binder with a highphosphate binding capacity over a wide pH range. Itis formulated as flavored, chewable tablets thatdisintegrate easily in the gastrointestinal (GI) tract,bind phosphate across the whole physiologicallyrelevant pH range, each contain 500mg of iron, andmay be taken without water.

phosphate binder with a low pill burden and goodtolerability may improve adherence and couldthereby help optimize serum phosphorus control inpatients on dialysis.PA21 (sucroferric oxyhydroxide)is a new calcium-free polynuclear iron(III)-oxyhydroxide phosphate binder with a highphosphate binding capacity over a wide pH range. Itis formulated as flavored, chewable tablets thatdisintegrate easily in the gastrointestinal (GI) tract,bind phosphate across the whole physiologicallyrelevant pH range, each contain 500mg of iron, andmay be taken without water.

In this phase III study, the efficacy and safety of PA21was compared with that of sevelamer carbonate (SEV)in treating hyperphosphatemia in patients undergoingdialysis

A phase III study of the efficacy and safety of a novel iron-based phosphate binder in dialysis patients

Ju ¨rgen Floege1, Adrian C. Covic2, Markus Ketteler3, Anjay Rastogi4, Edward M.F.Chong5, Sylvain Gaillard5, Laura J. Lisk5 and Stuart M. Sprague6, on behalf of the

PA21 Study Group

• 4.1.2. In patients with CKD Stages 3a-5D, we suggestlowering elevated phosphorus levels towards thenormal range. (2C) (KDOGI 2016)

• 4.1.1. In patients with CKD stages 3–5, we suggestmaintaining serum phosphorus in the normal range(2C). In patients with CKD stage 5D, we suggestlowering elevated phosphorus levels toward thenormal range (2C). (KDOGI 2009)

• There is an absence of data that efforts to maintainphosphorus in the normal range are of benefit to CKDStage 3a-4 patients, including some safety concerns.Treatment should aim at overt hyperphosphatemia

• 4.1.2. In patients with CKD Stages 3a-5D, we suggestlowering elevated phosphorus levels towards thenormal range. (2C) (KDOGI 2016)

• 4.1.1. In patients with CKD stages 3–5, we suggestmaintaining serum phosphorus in the normal range(2C). In patients with CKD stage 5D, we suggestlowering elevated phosphorus levels toward thenormal range (2C). (KDOGI 2009)

• There is an absence of data that efforts to maintainphosphorus in the normal range are of benefit to CKDStage 3a-4 patients, including some safety concerns.Treatment should aim at overt hyperphosphatemia

• 4.1.1. In patients with CKD Stages 3a-5D,treatments of CKD-MBD should be based onserial assessments of phosphorus, calcium andPTH levels, considered together. (Not Graded)

• This new recommendation was provided inorder to emphasize the complexity andinteraction of CKD-MBD laboratory parameters.

• 4.1.1. In patients with CKD Stages 3a-5D,treatments of CKD-MBD should be based onserial assessments of phosphorus, calcium andPTH levels, considered together. (Not Graded)

• This new recommendation was provided inorder to emphasize the complexity andinteraction of CKD-MBD laboratory parameters.

• 4.1.3. In adult patients with CKD Stages 3a-5D, wesuggest avoiding hypercalcemia (2C).

• In children with CKD Stages 3a-5D, we suggestmaintaining serum calcium in the age-appropriatenormal range. (2C)

• 4.1.2. In patients with CKD stages 3–5D, we suggestmaintaining serum calcium in the normal range (2D).

• Mild and asymptomatic hypocalcemia (e.g., in thecontext of calcimimetic treatment) can be tolerated inorder to avoid inappropriate calcium loading in adults.

• 4.1.3. In adult patients with CKD Stages 3a-5D, wesuggest avoiding hypercalcemia (2C).

• In children with CKD Stages 3a-5D, we suggestmaintaining serum calcium in the age-appropriatenormal range. (2C)

• 4.1.2. In patients with CKD stages 3–5D, we suggestmaintaining serum calcium in the normal range (2D).

• Mild and asymptomatic hypocalcemia (e.g., in thecontext of calcimimetic treatment) can be tolerated inorder to avoid inappropriate calcium loading in adults.

• 4.1.4. In patients with CKD Stage 5D, we suggest usinga dialysate calcium concentration between 1.25 and1.50 mmol/l (2.5 and 3.0 mEq/l). (2C)

• 4.1.3. In patients with CKD stage 5D, we suggest using adialysate calcium concentration between 1.25 and 1.50mmol/l (2.5 and 3.0 mEq/l) (2D).

• Additional studies of better quality are available;however, these do not allow discrimination ofbenefits and harms between calcium dialysateconcentrations of 1.25 and 1.50 mmol/l (2.5 and 3.0mEq/l); hence the wording is unchanged but evidencegrade is upgraded from 2D to 2C.

• 4.1.4. In patients with CKD Stage 5D, we suggest usinga dialysate calcium concentration between 1.25 and1.50 mmol/l (2.5 and 3.0 mEq/l). (2C)

• 4.1.3. In patients with CKD stage 5D, we suggest using adialysate calcium concentration between 1.25 and 1.50mmol/l (2.5 and 3.0 mEq/l) (2D).

• Additional studies of better quality are available;however, these do not allow discrimination ofbenefits and harms between calcium dialysateconcentrations of 1.25 and 1.50 mmol/l (2.5 and 3.0mEq/l); hence the wording is unchanged but evidencegrade is upgraded from 2D to 2C.

• 4.1.5. In patients with CKD Stages 3a-5D, decisions aboutphosphate-lowering treatment should be based onprogressively or persistently elevated serum phosphorus.(Not Graded)

• 4.1.4. In patients with CKD stages 3–5 (2D) and 5D (2B), wesuggest using phosphate-binding agents in the treatment ofhyperphosphatemia. It is reasonable that the choice ofphosphate binder takes into account CKD stage, presenceof other components of CKD–MBD, concomitant therapies,and side-effect profile (not graded).

• Emphasizes the perception that early “preventive”treatment of hyperphosphatemia is currently notsupported by data (see Recommendation 4.1.2).

• 4.1.5. In patients with CKD Stages 3a-5D, decisions aboutphosphate-lowering treatment should be based onprogressively or persistently elevated serum phosphorus.(Not Graded)

• 4.1.4. In patients with CKD stages 3–5 (2D) and 5D (2B), wesuggest using phosphate-binding agents in the treatment ofhyperphosphatemia. It is reasonable that the choice ofphosphate binder takes into account CKD stage, presenceof other components of CKD–MBD, concomitant therapies,and side-effect profile (not graded).

• Emphasizes the perception that early “preventive”treatment of hyperphosphatemia is currently notsupported by data (see Recommendation 4.1.2).

• 4.1.6. In adult patients with CKD Stages 3a-5Dreceiving phosphate-lowering treatment, wesuggest restricting the dose of calcium-basedphosphate binders. (2B)

• 4.1.5. In patients with CKD stages 3–5D and hyperphos-phatemia, we recommend restricting the dose of calcium-based phosphate binders and/or the dose of calcitriol orvitamin D analog in the presence of persistent or recurrenthypercalcemia (1B). In patients with CKD stages 3–5D andhyperphosphatemia, we suggest restricting the dose ofcalcium-based phosphate binders in the presence of arterialcalcification (2C) and/or adynamic bone disease (2C) and/orif serum PTH levels are persistently low (2C).

(KDOGI 2016) Vs (KDOGI 2009)• 4.1.6. In adult patients with CKD Stages 3a-5D

receiving phosphate-lowering treatment, wesuggest restricting the dose of calcium-basedphosphate binders. (2B)

• 4.1.5. In patients with CKD stages 3–5D and hyperphos-phatemia, we recommend restricting the dose of calcium-based phosphate binders and/or the dose of calcitriol orvitamin D analog in the presence of persistent or recurrenthypercalcemia (1B). In patients with CKD stages 3–5D andhyperphosphatemia, we suggest restricting the dose ofcalcium-based phosphate binders in the presence of arterialcalcification (2C) and/or adynamic bone disease (2C) and/orif serum PTH levels are persistently low (2C).

• 4.1.8. In patients with CKD Stages 3a-5D, we suggestlimiting dietary phosphate intake in the treatment ofhyperphosphatemia alone or in combination with othertreatments. (2D) It is reasonable to consider phosphatesource (e.g., animal, vegetable, additives) in making dietaryrecommendations. (Not Graded)

• 4.1.7. In patients with CKD stages 3–5D, we suggest limitingdietary phosphate intake in the treatment ofhyperphosphatemia alone or in combination with othertreatments (2D).

• New data on phosphate sources were felt to be included asan additional qualifier to the previous recommendation.

• 4.1.8. In patients with CKD Stages 3a-5D, we suggestlimiting dietary phosphate intake in the treatment ofhyperphosphatemia alone or in combination with othertreatments. (2D) It is reasonable to consider phosphatesource (e.g., animal, vegetable, additives) in making dietaryrecommendations. (Not Graded)

• 4.1.7. In patients with CKD stages 3–5D, we suggest limitingdietary phosphate intake in the treatment ofhyperphosphatemia alone or in combination with othertreatments (2D).

• New data on phosphate sources were felt to be included asan additional qualifier to the previous recommendation.

• 4.2.2. In adult patients with CKD Stages 3a-5 not ondialysis, we suggest calcitriol and vitamin D analogsnot be routinely used (2C). It is reasonable toreserve the use of calcitriol and vitamin D analogsfor patients with CKD Stages 4-5 with severe andprogressive hyperparathyroidism (Not Graded).

• Recent RCTs of vitamin D analogs failed todemonstrate improvements in clinically relevantoutcomes but did demonstrate increased risk ofhypercalcemia

• 4.2.2. In adult patients with CKD Stages 3a-5 not ondialysis, we suggest calcitriol and vitamin D analogsnot be routinely used (2C). It is reasonable toreserve the use of calcitriol and vitamin D analogsfor patients with CKD Stages 4-5 with severe andprogressive hyperparathyroidism (Not Graded).

• Recent RCTs of vitamin D analogs failed todemonstrate improvements in clinically relevantoutcomes but did demonstrate increased risk ofhypercalcemia

• 4.2.4. In patients with CKD Stage 5D requiringPTHlowering therapy, we suggestcalcimimetics, calcitriol, or vitamin D analogs,or a combination of calcimimetics andcalcitriol, or vitamin D analogs. (2B)

Summary of Rx

• Dietary phosphate restriction• Phosphate binders• Calcitriol or other Vit D analogues• Calcium supplementation/calcimimetics• Parathyroidectomy• Transplant

Thank you

ckd mbd prof. babikir kaballo

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