1. Calcium & phosphor disturbance CKD- MBD Dr. Atapour

2. Phosphor Parathyroid hormone (PTH) 1,25(OH)2D (calcitriol) Phosphatonins, (fibroblast growth factor 23 (FGF23) Target organs: – Bone – Kidney – Intestine

3. 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.

4. 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)

6. 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

8. Factors that increase Pi excretion are – Increased plasma Pi concentration – PTH – FGF23

9. Phosphorous Abnormalities in CKD GFR

10. 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

11. 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

12. 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

13. 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.

14. 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

15. KDIGO: Diagnosis of CKD-MBD Biochemical Abnormalities

16. Diagnosis of CKD-MBD: Biochemical Abnormalities In the initial CKD stage a, the recommendation is to monitor serum levels of: – Phosphorus, Calcium, PTH, Alkaline phosphatase In CKD stages 3-5D b, 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 children c, the suggestion is to begin monitoring in CKD stage 2 KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130

17. Diagnosis of CKD-MBD: Biochemical Abnormalities In patients with CKD stages 3-5D, the suggestions a 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

18. Evaluation of CKD-MBD: Biochemical Abnormalities CKD StageKDIGO 3Every 6–12 months 4Every 3–6 months 5 or DEvery 1–3 months Phosphate and Calcium

19. Evaluation of CKD-MBD: Biochemical Abnormalities CKD StageKDIGO 3Based on baseline level and CKD stage 4Every 6–12 months 5 or DEvery 3–6 months PTH

20. Treatment of CKD-MBD: Phosphorus and Calcium

21. Definition of “Normal” values “Normal” means within the above ranges. These are normal ranges for healthy individuals. Phosphorus2.5– 4.5 mg/dl Calcium8.5 – 10 (or 10.5) mg/dl iPTH (varies with the assay used) 10 - 65 pg/ml [Centers for Disease Control recommendations]

22. 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

23. 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

24. Treatment of CKD-MBD: Phosphorus and Calcium In patients with CKD stages 3-5D and hyperphosphatemia, the recommendation a 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 suggested b, in the presence of: Persistent or recurrent hypercalcemia KDIGO. Kidney Int. 2009; 76 (Suppl 113):S1-S130

25. 51% - 83% 57%16% - 54% Calcification Persistently Low PTH ABDHypercalcemia 1,2,3 2 2,3,4 Patients In Whom it is Recommended Calcium Be Restricted 1 Russo D, et al. Am J Neph 2007;27:152-158 2 Chertow GM, et al. Kidney Int. 2002;62:245-252 3 Block GA, et al. Kidney Int. 2005;68:1815-1824 4 Qunibi W, et al. AJKD. 2008 5 Andress D. Kidney Int. 2008;73:1345-1354 6 KDIGO. KI 2009; 76 (Suppl 113):S1-S130 Calcium Restriction 5 – 40% CKD 3,4,6 20 – 50 % HD 6 40 – 70% PD 5

26. Phosphate Binding Compounds KDIGO. Kid Int. 2009; 76 (Suppl 113):S1-S130

27. KDOQI / KDIGO - treatment recommendations in 5D: Laboratory values KDOQI Recommend. Grading KDIGO Recommend. Grading iPTH (pg/mL)150 to 300Evidence Suggested range 2 to 9 x ULN 2C Corrected Ca (mg/dL) 8.4 to 9.5Opinion Suggested to maintain in the normal range 2D P (mg/dL)3.5 to 5.5Evidence Suggested to lower toward the normal range 2C CaxP (mg 2 /dL 2 )<55Evidence Not suggested to direct clinical practice N/A KDIGO Clinical Practice Guideline for CKD-MBD. Kidney Int 2009;76 (Suppl 113)

28. PTH Levels

29. 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 suggestion a is to, first evaluate for: – Hyperphosphatemia – Hypocalcemia – Vitamin D deficiency It is reasonable to correct these abnormalities with any or all of the following b : – Reducing dietary phosphate intake and administering phosphate binders, calcium supplements, and/or native vitamin D The suggestion c 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

30. 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 335 - 70OpinionNot known 2C 470 - 110OpinionNot known2C 5 ND150 - 300EvidenceNot known 2C 5D150 - 300Evidence2 to 9 x ULN2C

31. KDIGO: Diagnosis of CKD-MBD Vascular Calcification

32. Diagnosis of CKD-MBD: Vascular Calcification In CKD stages 3-5D, the suggestions a 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

33. Diagnosis of CKD-MBD: Vascular Calcification In CKD stages 3-5D, the suggestions a 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-S130 a. 3.3.1 (2C)

34. In Summary … Phosphorus Goal = Normal Calcium Calcification represents the highest risk Detect with x-ray/ultrasound Restrict Calcium in 1.Hypercalcemia 2.Calcification 3.Low PTH 4.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