Calcium & phosphor disturbance

CKD- MBD

Dr. Atapour

Phosphor

• Parathyroid hormone (PTH)• 1,25(OH)2D (calcitriol)• Phosphatonins, (fibroblast growth factor 23

(FGF23)• Target organs:– Bone– Kidney– Intestine

• GFR levels below 60 mL/min

• GFR below 30 mL/min.

• Normal serum concentrations of calcium and

phosphorus

– Altered production of calcitriol, PTH, and FGF23.

Eventually

1. Altered serum levels of calcium, phosphorus, PTH, calcitriol, and FGF23

2. Disturbances in bone remodeling and mineralization or impaired linear growth in children (renal osteodystrophy)

3. Extraskeletal calcification in soft tissues and arteries.

increased risk of fractures, cardiovascular disease, and mortality in CKD stage 4 to 5D patients.

In 2006, the term chronic kidney disease–mineral bone disorder (CKD-MBD)

Phosphorous Homeostasis

• 60% and 70% of dietary Pi is absorbed by GI

– Passive transport related to the concentration

– Active transport stimulated by 1,25(OH)2D

• The kidneys are responsible for maintaining Pi

balance

• Factors that increase Pi excretion are

–Increased plasma Pi concentration

–PTH

–FGF23

Phosphorous Abnormalities in CKD

• GFR

Calcium

• Serum calcium concentrations 8.5 to 10.5 mg/dL

• The NKF K/DOQI guidelines recommend calcium-

containing phosphate binders to 1500 mg of

elemental calcium per day + 500 mg intake per

day from diet=total intake of 2000 mg/day

• approximately 18% to 20% of calcium is absorbed

the net intake is 400 mg/day from 2000 mg .

• The excretion of calcium in stool and sweat = 150 to

250 mg/day

• if patients have residual urine output, the excretion

rate may increase by 50 to 100 mg/day

• Thus, with 400 mg net absorbed calcium, most

patients will still be in positive calcium balance

It is important to emphasize three points:

• First, this 1500-mg maximum intake of elemental calcium from phosphate binders in the NKF K/DOQI guidelines is based on

opinion because no recent formal metabolic balance studies are available to inform these decisions.

• More recent international Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommended that total calcium intake be restricted

• Second, in patients taking vitamin D calcitriol or

its analogs, the intestinal absorption of calcium

will be increased, and thus the maximum amount

of calcium in the form of binders should probably

be decreased.

• Third, in patients with low turnover bone

disease, NKF K/DOQI and KDIGO guidelines do

not recommend calcium binders with low

turnover disease or very low PTH

KDIGO: Diagnosis of CKD-MBDBiochemical Abnormalities

Diagnosis of CKD-MBD: Biochemical Abnormalities

• In the initial CKD stagea, the recommendation is to monitor serum levels of:– Phosphorus, Calcium, PTH, Alkaline phosphatase

• In CKD stages 3-5Db, frequency of monitoring serum calcium, phosphorus, and PTH should be based:– On the presence and magnitude of abnormalities– The rate of progression of CKD

• In childrenc, the suggestion is to begin monitoring in CKD stage 2

KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130

Diagnosis of CKD-MBD: Biochemical Abnormalities

• In patients with CKD stages 3-5D, the suggestionsa are to:– Measure 25(OH)D (calcidiol) levels– Repeat testing on the basis of:• Baseline values• Therapeutic interventions

– Correct vitamin D deficiency and insufficiency in accordance to treatment strategies recommended for the general population

KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130

Evaluation of CKD-MBD: Biochemical Abnormalities

CKD Stage KDIGO

3 Every 6–12 months

4 Every 3–6 months

5 or D Every 1–3 months

Phosphate and Calcium

Evaluation of CKD-MBD: Biochemical Abnormalities

CKD Stage KDIGO

3 Based on baseline level and CKD stage

4 Every 6–12 months

5 or D Every 3–6 months

PTH

Treatment of CKD-MBD: Phosphorus and Calcium

Definition of “Normal” values

•“Normal” means within the above ranges. These are normal ranges for healthy individuals.

Phosphorus 2.5– 4.5 mg/dl

Calcium 8.5 – 10 (or 10.5) mg/dl

iPTH(varies with the assay used)

10 - 65 pg/ml[Centers for Disease Control

recommendations]

Treatment of CKD-MBD:Phosphorus and Calcium

• In patients with CKD stages 3-5, the suggestions are to:– Maintain serum P in the normal range a

– Maintain serum Ca in the normal range b

• Phosphate binders are suggested in the treatment of hyperphosphatemia c

• For choice of phosphate binder, it is reasonable to take into account c: – CKD stage– Presence of other components of CKD-MBD– Concomitant therapies– Side-effect profile

a. 4.1.1 (2C); b. 4.1.2 (2D); c. 4.1.4 (not graded) KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130

Treatment of CKD-MBD:Phosphorus and Calcium

• In patients with CKD stages 5D, the suggestion is to:– Lower elevated P levels toward normal range (2C)– Use a dialysate Ca concentration between 1.25 and 1.5 mmol/l

(2.5 and 3.0 meq/L) (2D) – Increase dialytic phosphate removal in the treatment of

persistent hyperphosphatemia (2C)

KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130

Treatment of CKD-MBD: Phosphorus and Calcium

• In patients with CKD stages 3-5D and hyperphosphatemia, the recommendationa is to:– Restrict calcium based phosphate binders in the presence of:• Arterial calcification• Adynamic bone disease • Persistently low serum PTH levels

– Restrict the dose of calcium based phosphate binders and/or restrict the dose of calcitriol or vitamin D analog are suggestedb, in the presence of:• Persistent or recurrent hypercalcemia

KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130

51% - 83% 57% 16% - 54%

Calcification Persistently Low PTH ABDHypercalcemia

1,2,32

2,3,4

Patients In Whom it is Recommended Calcium Be Restricted

1 Russo D, et al. Am J Neph 2007;27:152-1582 Chertow GM, et al. Kidney Int. 2002;62:245-2523 Block GA, et al. Kidney Int. 2005;68:1815-18244 Qunibi W, et al. AJKD. 20085 Andress D. Kidney Int. 2008;73:1345-13546 KDIGO. KI 2009; 76 (Suppl 113):S1-S130

Calcium Restriction

5 – 40% CKD 3,4,6

20 – 50 % HD 6

40 – 70% PD 5

Phosphate Binding Compounds

KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130

KDOQI / KDIGO - treatment recommendations in 5D:

Laboratory valuesKDOQIRecommend.

GradingKDIGORecommend.

Grading

iPTH (pg/mL) 150 to 300 Evidence Suggested range 2 to 9 x ULN 2C

Corrected Ca (mg/dL) 8.4 to 9.5 Opinion Suggested to maintain in

the normal range 2D

P (mg/dL) 3.5 to 5.5 Evidence Suggested to lower toward the normal range

2C

CaxP (mg2/dL2) <55 Evidence Not suggested to direct clinical practice

N/A

KDIGO Clinical Practice Guideline for CKD-MBD. Kidney Int 2009;76 (Suppl 113)

PTH Levels

Treatment of Abnormal PTH levels in CKD-MBD

• In patients with CKD stages 3-5 not on dialysis, the optimal PTH level is unknown

• In patients with levels of intact PTH (iPTH) above the upper normal limit of the assay, the suggestiona is to, first evaluate for: – Hyperphosphatemia– Hypocalcemia– Vitamin D deficiency

• It is reasonable to correct these abnormalities with any or all of the followingb: – Reducing dietary phosphate intake and administering phosphate binders, calcium

supplements, and/or native vitamin D• The suggestionc is to treat with calcitriol or vitamin D analogs if:

– Serum PTH is progressively rising and remains persistently above the upper limit of normal for the assay despite correction of modifiable factors

KDIGO. KI 2009; 76 (Suppl 113):S1-S130

KDOQI / KDIGO - PTH TARGETS

KDIGO Clinical Practice Guideline for CKD-MBD. Kidney Int 2009;76 (Suppl 113)

CKD Stage Target iPTH (pg/ml) KDOQI Grading Target iPTH

(pg/ml) KDIGO Grading

3 35 - 70 Opinion Not known2C

4 70 - 110 Opinion Not known 2C

5 ND 150 - 300 Evidence Not known2C

5D 150 - 300 Evidence 2 to 9 x ULN 2C

KDIGO: Diagnosis of CKD-MBDVascular Calcification

Diagnosis of CKD-MBD: Vascular Calcification

• In CKD stages 3-5D, the suggestionsa indicate that:– It is reasonable to use alternatives to CT-based

imaging to detect vascular calcifications, including: • Lateral abdominal radiograph• Echocardiogram

– Patients with known vascular/valvular calcifications can be considered at highest cardiovascular risk

– It is reasonable to use this information to guide the management of CKD–MBD

KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130

Diagnosis of CKD-MBD: Vascular Calcification

• In CKD stages 3-5D, the suggestionsa indicate that:– It is reasonable to use alternatives to computed

tomography-based imaging to detect the presence or absence of vascular calcification, including: • Lateral abdominal radiograph• Echocardiogram

– Patients with known vascular/valvular calcification can be considered at highest cardiovascular risk

– It is reasonable to use this information to guide the management of CKD–MBD

KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130a. 3.3.1 (2C)

In Summary …

Phosphorus

Goal = Normal

Calcium

Calcification represents the highest risk

Detect with x-ray/ultrasound

Restrict Calcium in1. Hypercalcemia2. Calcification3. Low PTH4. ADBD

PTH

Evaluate PTH in context of hyperP, hypoCa, vitamin D deficiency

Marked changes should trigger treatment changes

Decrease cinacalcet in event of hypocalcemia

KDIGO International Clinical Practice Guidelines

Treat the trends: Treat P and Ca to normal, PTH to Goal

KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130