New NKF-K/DOQI guidelines Shahrzad Ossareh-M.D. Kidney Disease Outcome Quality Initiative

Definition of Chronic Kidney Disease Criteria 1. Kidney damage ≥ 3 months as defined by structural or functional abnormalities of the kidney, with or without decreased GFR, manifested by either: Pathologic abnormalities; or Pathologic abnormalities; or Markers of damage including abnormalities in blood or urine tests or imaging studies. Markers of damage including abnormalities in blood or urine tests or imaging studies. 2. GFR< 60 ml/min/1.73 m 2 for ≥ 3 months, with or without kidney damage

Estimated GFR (mL/min/1.73 m2) Estimated GFR (mL/min/1.73 m2) 1. Cockraft-Gault Formula 2. MDRD study formula: 186 x [SCr(-1.154)] x [Age(-0.203)] x (0.742 if female) x (1.21 if African American)

Stages of Chronic Kidney Disease StageDescription GFR (ml/min/1.73 m 2 ) (Prevalence) 1 Kidney damage with normal or ↑ GFR 90(3.3%) 2 Kidney damage with mild ↓ GFR (3%) (3%) 3 Moderate ↓ GFR (4.3%) (4.3%) 4 Severe ↓ GFR 15-29(0.2%) 5 Kidney failure <15 or on dialysis (0.1%)

Guidelines for Bone Metabolism in Chronic Kidney Disease

GUIDELINE 1. Evaluation of Ca and P metabolism

1.1- Serum levels of calcium, phosphorus, and intact PTH should be measured in all patients with CKD and GFR <60 ml/min/1.73 m 2. (EVIDENCE) 1.1- Serum levels of calcium, phosphorus, and intact PTH should be measured in all patients with CKD and GFR <60 ml/min/1.73 m 2. (EVIDENCE)

CKDstage GFR Range PTH measurement Ca/P measurement measurement Q 12 mo Q 3 mo 5 <15 or dialysis Q 3 mo Every month Frequency of measurement of PTH and Ca/P by stage of CKD *More frequently in patients receiving therapy for the abnormalities in Ca, P or PTH and in transplant recipients.

Target Range of plasma iPTH by CKD stage CKD stage GFR range Target iPTH (opinion) (opinion) 5 <15 or dialysis (evidence)

Relationship between serum I-PTH levels and CCR based on data extracted from Martinez et al (1997). Values on the y-axis are serum I-PTH levels (pg/ml). Values on the x-axis are CCR in ml/min. The lines fitted to the data set are based on 4 different mathematical functions (power, linear, exponential, and logarithmic), rather than on any assumptions about an underlying physiological mechanism. The horizontal line represents the upper limit of the normal range of serum I-PTH levels.

Newer assays specific for 1-84 PTH. Newer assays specific for 1-84 PTH. The normal range for the new assay for 1-84 PTH is 7 to 36 pg/ml compared to 16 to 65 pg/ml for iPTH. The normal range for the new assay for 1-84 PTH is 7 to 36 pg/ml compared to 16 to 65 pg/ml for iPTH. Thus the relationship between the 2 assays is about 1:2 (1-84 PTH to intact PTH). Thus the relationship between the 2 assays is about 1:2 (1-84 PTH to intact PTH). The differences in the levels between the 2 types of assays are a reflection of the levels of circulating PTH fragments that are detected by the intact PTH assay but not by the new 1-84 PTH assay. The differences in the levels between the 2 types of assays are a reflection of the levels of circulating PTH fragments that are detected by the intact PTH assay but not by the new 1-84 PTH assay.

GUIDELINE 2. ASSESSMENT OF BONE DISEASE ASSOCIATED WITH CKD

2.1- The most accurate diagnostic test for determining the type of bone disease in CKD is iliac crest bone biopsy with double tetracycline labeling and bone histomorphometric analysis. (EVIDENCE)

2.2- It is not necessary to perform bone biopsy for most 2.2- It is not necessary to perform bone biopsy for most situations in clinical practice. It should be considered in situations in clinical practice. It should be considered in patients with kidney failure (Stage 5) who have: patients with kidney failure (Stage 5) who have:

2.2- It is not necessary to perform bone biopsy for most 2.2- It is not necessary to perform bone biopsy for most situations in clinical practice. It should be considered in situations in clinical practice. It should be considered in patients with kidney failure (Stage 5) who have: patients with kidney failure (Stage 5) who have: 2.2a- Fractures with minimal or no trauma (pathological 2.2a- Fractures with minimal or no trauma (pathological fractures); (OPINION) fractures); (OPINION)

2.2- It is not necessary to perform bone biopsy for most 2.2- It is not necessary to perform bone biopsy for most situations in clinical practice. It should be considered in situations in clinical practice. It should be considered in patients with kidney failure (Stage 5) who have: patients with kidney failure (Stage 5) who have: 2.2a- Fractures with minimal or no trauma (pathological 2.2a- Fractures with minimal or no trauma (pathological fractures); (OPINION) fractures); (OPINION) 2.2b- Intact PTH levels between 100 and 500 pg/ml (in CKD 2.2b- Intact PTH levels between 100 and 500 pg/ml (in CKD Stage 5) with coexisting conditions such as unexplained Stage 5) with coexisting conditions such as unexplained hypercalcemia, severe bone pain, or unexplained increases in hypercalcemia, severe bone pain, or unexplained increases in bone alkaline phosphatase activity;(OPINION) bone alkaline phosphatase activity;(OPINION)

2.2- It is not necessary to perform bone biopsy for most 2.2- It is not necessary to perform bone biopsy for most situations in clinical practice. It should be considered in situations in clinical practice. It should be considered in patients with kidney failure (Stage 5) who have: patients with kidney failure (Stage 5) who have: 2.2a- Fractures with minimal or no trauma (pathological 2.2a- Fractures with minimal or no trauma (pathological fractures); (OPINION) fractures); (OPINION) 2.2b- Intact PTH levels between 100 and 500 pg/ml (in CKD 2.2b- Intact PTH levels between 100 and 500 pg/ml (in CKD Stage 5) with coexisting conditions such as unexplained Stage 5) with coexisting conditions such as unexplained hypercalcemia, severe bone pain, or unexplained increases in hypercalcemia, severe bone pain, or unexplained increases in bone alkaline phosphatase activity;(OPINION) bone alkaline phosphatase activity;(OPINION) 2.2c- Suspected aluminum bone disease, based upon 2.2c- Suspected aluminum bone disease, based upon clinical symptoms or history of aluminum exposure clinical symptoms or history of aluminum exposure (OPINION) (OPINION)

2.3- Bone radiographs are not indicated for the assessment of bone disease of CKD, (EVIDENCE) but they are useful in detecting severe peripheral vascular calcification (OPINION) and bone disease due to ß2-microglobulin amyloidosis. (EVIDENCE) 2.3- Bone radiographs are not indicated for the assessment of bone disease of CKD, (EVIDENCE) but they are useful in detecting severe peripheral vascular calcification (OPINION) and bone disease due to ß2-microglobulin amyloidosis. (EVIDENCE) 2.4- Bone mineral density (BMD) should be measured by dual energy X-ray absorptiometry (DEXA) in patients with fractures and in those with known risk factors for osteoporosis. (OPINION) 2.4- Bone mineral density (BMD) should be measured by dual energy X-ray absorptiometry (DEXA) in patients with fractures and in those with known risk factors for osteoporosis. (OPINION)

2.3- Bone radiographs are not indicated for the assessment of bone disease of CKD, (EVIDENCE) but they are useful in detecting severe peripheral vascular calcification (OPINION) and bone disease due to ß2-microglobulin amyloidosis. (EVIDENCE) 2.3- Bone radiographs are not indicated for the assessment of bone disease of CKD, (EVIDENCE) but they are useful in detecting severe peripheral vascular calcification (OPINION) and bone disease due to ß2-microglobulin amyloidosis. (EVIDENCE) 2.4- Bone mineral density (BMD) should be measured by dual energy X-ray absorptiometry (DEXA) in patients with fractures and in those with known risk factors for osteoporosis. (OPINION) 2.4- Bone mineral density (BMD) should be measured by dual energy X-ray absorptiometry (DEXA) in patients with fractures and in those with known risk factors for osteoporosis. (OPINION)

Beginning at Stage 3, patients with CKD almost always have secondary hyperparathyroidism and elevated PTH. Beginning at Stage 3, patients with CKD almost always have secondary hyperparathyroidism and elevated PTH. In these patients, the classical lesion seen in bone biopsy is osteitis fibrosa cystica althoug increasing prevalence of other bone lesions such as low-turnover bone disease has recently been shown. In these patients, the classical lesion seen in bone biopsy is osteitis fibrosa cystica althoug increasing prevalence of other bone lesions such as low-turnover bone disease has recently been shown.

Factors Prevalent in CKD patients Which May Influence the Type of Osteodystrophy Lesion Prolonged Al exposure Prolonged Al exposure G.C. therapy in patients with parenchymatous kidney disease & renal Tx recipients G.C. therapy in patients with parenchymatous kidney disease & renal Tx recipients Previous PTX Previous PTX Vitamin D Rx Vitamin D Rx Diabetes Mellitus* Diabetes Mellitus*  2 microglobulin amyloidosis  2 microglobulin amyloidosis Hypophosphatemia secondary to aggressive dietary phosphate restriction or excessive use of P binders Hypophosphatemia secondary to aggressive dietary phosphate restriction or excessive use of P binders *Responsible for 30-40% of ESRD cases

GUIDELINE 3. EVALUATION OF SERUM P

3.1- In CKD patients (Stages 3 and 4), 3.1- In CKD patients (Stages 3 and 4), the serum P should be maintained between the serum P should be maintained between 2.7 mg/dl (EVIDENCE) and 4.6 mg/dl. (OPINION) 2.7 mg/dl (EVIDENCE) and 4.6 mg/dl. (OPINION) 3.2- In CKD patients with kidney failure (Stage 5) and those treated with HD or PD, the serum P should be maintained between 3.5 and 5.5 mg/dl. (EVIDENCE) 3.2- In CKD patients with kidney failure (Stage 5) and those treated with HD or PD, the serum P should be maintained between 3.5 and 5.5 mg/dl. (EVIDENCE)

Prolonged hyperphosphatemia causes soft-tissue and vascular calcification due at least in part to an increase in Ca-P product and is associated with increased morbidity and mortality. Prolonged hyperphosphatemia causes soft-tissue and vascular calcification due at least in part to an increase in Ca-P product and is associated with increased morbidity and mortality.

Hyperphosphatemia exerts a direct calcifying effect on vascular smooth muscle cells. Hyperphosphatemia exerts a direct calcifying effect on vascular smooth muscle cells.

Prolonged hyperphosphatemia causes soft-tissue and vascular calcification due at least in part to an increase in Ca-P product and is associated with increased morbidity and mortality. Prolonged hyperphosphatemia causes soft-tissue and vascular calcification due at least in part to an increase in Ca-P product and is associated with increased morbidity and mortality. Hyperphosphatemia exerts a direct calcifying effect on vascular smooth muscle cells. Hyperphosphatemia exerts a direct calcifying effect on vascular smooth muscle cells. Calcification of coronary arteries, cardiac valves, and pulmonary tissues produces cardiac disease, the leading cause of death in patients with CKD. Calcification of coronary arteries, cardiac valves, and pulmonary tissues produces cardiac disease, the leading cause of death in patients with CKD.

Prolonged hyperphosphatemia causes soft-tissue and vascular calcification due at least in part to an increase in Ca-P product and is associated with increased morbidity and mortality. Prolonged hyperphosphatemia causes soft-tissue and vascular calcification due at least in part to an increase in Ca-P product and is associated with increased morbidity and mortality. Hyperphosphatemia exerts a direct calcifying effect on vascular smooth muscle cells. Hyperphosphatemia exerts a direct calcifying effect on vascular smooth muscle cells. Calcification of coronary arteries, cardiac valves, and pulmonary tissues produces cardiac disease, the leading cause of death in patients with CKD. Calcification of coronary arteries, cardiac valves, and pulmonary tissues produces cardiac disease, the leading cause of death in patients with CKD. It is therefore imperative to prevent hyperphosphatemia and maintain serum P levels within the normal range. It is therefore imperative to prevent hyperphosphatemia and maintain serum P levels within the normal range.

Most data indicate that < 30% of dialysis patients are able to maintain P in the suggested target range. Most data indicate that < 30% of dialysis patients are able to maintain P in the suggested target range. The goal should be to increase the percentage of patients in this target range. The goal should be to increase the percentage of patients in this target range. This needs: This needs: 1. An increased dietitian-to-patient ratio, 2. Educational tools to increase patient compliance, 3. Studies for dialytic techniques that are better able to control serum P (such as nocturnal or daily HD), 4. The widespread availability and affordability of different phosphate binders, regardless of patient insurance.

GUIDELINE 4. RESTRICTION OF DIETARY PHOSPHORUS IN PATIENTS WITH CKD

4.1- Dietary phosphorus should be restricted to 800 to 1,000 mg/day (adjusted for dietary protein needs): 4.1- Dietary phosphorus should be restricted to 800 to 1,000 mg/day (adjusted for dietary protein needs): 1. When the serum P >4.6 mg/dl at Stages 3 and 4 of CKD, (OPINION) and >5.5 mg/dl at stage 5 kidney failure (OPINION) and >5.5 mg/dl at stage 5 kidney failure (EVIDENCE). (EVIDENCE). 2. When the plasma iPTH are elevated. (EVIDENCE) The serum P should be monitored every month following the initiation of dietary phosphorus restriction. (OPINION) The serum P should be monitored every month following the initiation of dietary phosphorus restriction. (OPINION)

GUIDELINE 5. USE OF PHOSPHATE BINDERS

5.1- If P or intact PTH levels cannot be controlled despite dietary P restriction, phosphate binders should be prescribed. (OPINION) 5.1- If P or intact PTH levels cannot be controlled despite dietary P restriction, phosphate binders should be prescribed. (OPINION) Either calcium-based phosphate binders and other noncalcium-, nonaluminum-, nonmagnesium- phosphate binders (such as sevelamer HCl) may be used as the primary therapy. Either calcium-based phosphate binders and other noncalcium-, nonaluminum-, nonmagnesium- phosphate binders (such as sevelamer HCl) may be used as the primary therapy.

5.4- In dialysis patients who remain hyperphosphatemic (P >5.5 mg/dl) despite the use of either of phosphate binders, a combination of both should be used. (OPINION) 5.4- In dialysis patients who remain hyperphosphatemic (P >5.5 mg/dl) despite the use of either of phosphate binders, a combination of both should be used. (OPINION)

5.5- The total dose of elemental calcium provided by the calcium-based phosphate binders should not exceed 1,500 mg/day (OPINION), and the total intake of elemental calcium (including dietary calcium) should not exceed 2,000 mg/day. (OPINION) 5.5- The total dose of elemental calcium provided by the calcium-based phosphate binders should not exceed 1,500 mg/day (OPINION), and the total intake of elemental calcium (including dietary calcium) should not exceed 2,000 mg/day. (OPINION)

5.6- Calcium-based phosphate binders should not be used in dialysis patients who are hypercalcemic (corrected serum Ca >10.2 mg/dl, or have plasma PTH 10.2 mg/dl, or have plasma PTH <150 pg/ml on 2 consecutive measurements. (EVIDENCE)

5.7- Noncalcium-containing phosphate binders are preferred in dialysis patients with severe vascular and/or other soft tissue calcifications. (OPINION) 5.7- Noncalcium-containing phosphate binders are preferred in dialysis patients with severe vascular and/or other soft tissue calcifications. (OPINION)

5.8-In patients with serum P>7.0 mg/dl, aluminum-based phosphate binders may be used as a short-term therapy (4 weeks), and for one course only, to be replaced thereafter by other phosphate binders. (OPINION) In such patients, more frequent dialysis should also be considered. (EVIDENCE) 5.8-In patients with serum P>7.0 mg/dl, aluminum-based phosphate binders may be used as a short-term therapy (4 weeks), and for one course only, to be replaced thereafter by other phosphate binders. (OPINION) In such patients, more frequent dialysis should also be considered. (EVIDENCE)

GUIDELINE 6. SERUM Ca & Ca-P PRODUCT

In CKD Patients (Stages 3 and 4): In CKD Patients (Stages 3 and 4): 6.1- The serum levels of corrected total calcium should be maintained within the "normal" range for the laboratory used. (EVIDENCE) In CKD Patients With Kidney Failure (Stage 5): In CKD Patients With Kidney Failure (Stage 5): 6.2- Serum levels of corrected total calcium should be maintained within the normal range for the laboratory used, preferably toward the lower end (8.4 to 9.5 mg/dl). (OPINION)

6.3- In the event corrected total serum Ca >10.2 mg/dl, therapies that cause serum Ca to rise should be adjusted as follows: 6.3- In the event corrected total serum Ca >10.2 mg/dl, therapies that cause serum Ca to rise should be adjusted as follows:

6.3a- In patients taking calcium-based phosphate binders, the dose should be reduced or therapy switched to a noncalcium-, nonaluminum-, nonmagnesium-containing phosphate binder. (OPINION) 6.3a- In patients taking calcium-based phosphate binders, the dose should be reduced or therapy switched to a noncalcium-, nonaluminum-, nonmagnesium-containing phosphate binder. (OPINION)

6.3b- In patients taking active vitamin D sterols, the dose should be reduced or therapy discontinued until the serum levels of corrected total calcium return to the target range (8.4 to 9.5 mg/d). (OPINION) 6.3b- In patients taking active vitamin D sterols, the dose should be reduced or therapy discontinued until the serum levels of corrected total calcium return to the target range (8.4 to 9.5 mg/d). (OPINION)

6.3c- If hypercalcemia persists despite modification of therapy, dialysis using low dialysate calcium (1.5 to 2.0 mEq/L) may be used for 3 to 4 weeks. (OPINION) 6.3c- If hypercalcemia persists despite modification of therapy, dialysis using low dialysate calcium (1.5 to 2.0 mEq/L) may be used for 3 to 4 weeks. (OPINION)

In CKD Patients (Stages 3 to 5): In CKD Patients (Stages 3 to 5): 6.4-Total elemental calcium intake (dietary calcium+ calcium-based phosphate binders) should not exceed 2,000 mg/day. (OPINION) 6.5-The serum Ca-P product should be maintained at <55 mg 2 /dl 2. (EVIDENCE) This is best achieved by controlling serum levels of P within the target range. (OPINION)

6.6- Patients whose serum Ca level are below the lower limit (<8.4 mg/dl) should receive therapy to increase serum Ca if: 6.6- Patients whose serum Ca level are below the lower limit (<8.4 mg/dl) should receive therapy to increase serum Ca if:

6.6a-There are clinical symptoms of hypocalcemia such as paresthesia, Chvostek’s and Trousseau’s signs, bronchospasm, laryngospasm, tetany, and/or seizures (OPINION); or 6.6a-There are clinical symptoms of hypocalcemia such as paresthesia, Chvostek’s and Trousseau’s signs, bronchospasm, laryngospasm, tetany, and/or seizures (OPINION); or

6.6- Patients whose serum Ca level are below the lower limit (<8.4 mg/dl) should receive therapy to increase serum Ca if: 6.6- Patients whose serum Ca level are below the lower limit (<8.4 mg/dl) should receive therapy to increase serum Ca if: 6.6a-There are clinical symptoms of hypocalcemia such as paresthesia, Chvostek’s and Trousseau’s signs, bronchospasm, laryngospasm, tetany, and/or seizures (OPINION); or 6.6a-There are clinical symptoms of hypocalcemia such as paresthesia, Chvostek’s and Trousseau’s signs, bronchospasm, laryngospasm, tetany, and/or seizures (OPINION); or 6.6b-The plasma iPTH level is above the target. (OPINION) 6.6b-The plasma iPTH level is above the target. (OPINION)

6.7-Therapy for hypocalcemia should include calcium salts such as calcium carbonate (EVIDENCE) and/or oral vitamin D sterols. (EVIDENCE) 6.7-Therapy for hypocalcemia should include calcium salts such as calcium carbonate (EVIDENCE) and/or oral vitamin D sterols. (EVIDENCE)

GUIDELINE 7. PREVENTION AND TREATMENT OF VITAMIN D INSUFFICIENCY AND DEFICIENCY IN CKD PATIENTS

In CKD Patients (Stages 3 and 4): 7.1- If plasma intact PTH is above the target range serum 25-(OH)D should be measured at first encounter. If it is normal, repeat annually. (EVIDENCE) 7.1- If plasma intact PTH is above the target range serum 25-(OH)D should be measured at first encounter. If it is normal, repeat annually. (EVIDENCE) 7.2- If the serum level of 25-(OH)D is <30 ng/ml, supplementation with vitamin D 2 should be initiated.(OPINION) 7.2- If the serum level of 25-(OH)D is <30 ng/ml, supplementation with vitamin D 2 should be initiated.(OPINION)

7.3- Following initiation of vitamin D therapy: 7.3- Following initiation of vitamin D therapy: 7.3a- The use of ergocalciferol therapy should be integrated with the serum Ca & P. 7.3a- The use of ergocalciferol therapy should be integrated with the serum Ca & P. 7.3b- The serum Ca and P level should be measured at least every 3 months. (OPINION) 7.3b- The serum Ca and P level should be measured at least every 3 months. (OPINION)

7.3c- If the serum Ca >10.2 mg/dl discontinue ergocalciferol and all forms of vitamin D therapy. (OPINION) 7.3c- If the serum Ca >10.2 mg/dl discontinue ergocalciferol and all forms of vitamin D therapy. (OPINION) 7.3d- If the serum P >4.6 mg/dl, add or increase the dose of phosphate binder. If hyperphosphatemia persists, discontinue vitamin D therapy. (OPINION) 7.3d- If the serum P >4.6 mg/dl, add or increase the dose of phosphate binder. If hyperphosphatemia persists, discontinue vitamin D therapy. (OPINION)

7.3e- Once patients are replete with vitamin D, continued supplementation with a vitamin-D- containing multi-vitamin preparation should be used with annual reassessment of serum levels of 25- (OH)D, and the continued assessment of corrected total Ca and P every 3 months. (OPINION)

In CKD Patients With Kidney Failure (Stage 5): In CKD Patients With Kidney Failure (Stage 5): 7.4- Active vitamin D sterol (calcitriol, alfacalcidol, paricalcitol, or doxercalciferol) should be given if iPTH is >300 pg/ml (OPINION) 7.4- Active vitamin D sterol (calcitriol, alfacalcidol, paricalcitol, or doxercalciferol) should be given if iPTH is >300 pg/ml (OPINION)

In CKD patients with serum P<4.6 mg/dl, serum Ca<9.5 mg/dl, & serum PTH in the higher target range for CKD stage Measure serum 25(OH)D Is serum 25(OH)D <30 ng/ml? Oral vitamin D2 or D3 See guideline 8A Measure serum Ca & P Is serum Ca<10.2 mg/dl? Is serum P<4.6 mg/dl? Continue or resume vitamin D2 or D3 Initiate or increase P binder or restrict Dietary P Hold vitamin D dose No Yes No

Recommended Supplementation for vitamin D deficiency/insufficiency in CKD stages 3 & 4 Serum 25(OH)D (ng/ml) Definition Ergocalcifero l Dose Duration (months) Comment <5-15 Severe vitamin D deficiency 50,000 IU/wk PO  12 wk, then monthly 500,000 IU as single IM dose 6 months Measure 25 (OH)D after 6 months Assure patient adherence; measure 25(OH) at 6 months 5-15 Mild vitamin D deficiency 50,000 IU/wk  4 weeks then 50,000 IU/month PO Assure patient adherence; measure 25(OH) at 6 months Vitamin D insufficiency 50,000 IU/month PO

GUIDELINE 8.A-VITAMIN D THERAPY IN CKD STAGE 3 & 4

8A.1- In patients with CKD Stages 3 and 4, therapy with an active oral vitamin D sterol (calcitriol, alfacalcidol, or doxercalciferol) is indicated when serum levels of 25(OH)D are >30 ng/ml, and plasma iPTH above the target. (EVIDENCE) 8A.1- In patients with CKD Stages 3 and 4, therapy with an active oral vitamin D sterol (calcitriol, alfacalcidol, or doxercalciferol) is indicated when serum levels of 25(OH)D are >30 ng/ml, and plasma iPTH above the target. (EVIDENCE) 8A.1a- Treatment with an active vitamin D should be undertaken only in patients with serum Ca < 9.5 mg/dl and serum P < 4.6 mg/dl. (OPINION) 8A.1a- Treatment with an active vitamin D should be undertaken only in patients with serum Ca < 9.5 mg/dl and serum P < 4.6 mg/dl. (OPINION)

8A.1b- Vitamin D should not be prescribed for patients with rapidly worsening kidney function or those who are noncompliant with medications or follow-up. (OPINION) 8A.1b- Vitamin D should not be prescribed for patients with rapidly worsening kidney function or those who are noncompliant with medications or follow-up. (OPINION) 8A.2- During therapy with vitamin D sterols, serum levels of Ca and P should be monitored at least every month for the first 3 months, then every 3 months thereafter. Plasma PTH levels should be measured at least every 3 months for 6 months, and every 3 months thereafter. (OPINION) 8A.2- During therapy with vitamin D sterols, serum levels of Ca and P should be monitored at least every month for the first 3 months, then every 3 months thereafter. Plasma PTH levels should be measured at least every 3 months for 6 months, and every 3 months thereafter. (OPINION)

8A.3- Dosage adjustments: 8A.3- Dosage adjustments: 8A.3a- If plasma levels of intact PTH fall below the target, hold active vitamin D until plasma PTH rise to above the target, then resume treatment with half dose active vitamin D. -If the lowest daily dose of the active vitamin D is being used, reduce to alternate-day dosing. (OPINION) -If the lowest daily dose of the active vitamin D is being used, reduce to alternate-day dosing. (OPINION)

8A.3b If serum Ca >9.5 mg/dl, hold active vitamin D until serum calcium 9.5 mg/dl, hold active vitamin D until serum calcium <9.5 mg/dl, then resume treatment at half dose. If the lowest daily dose of the active vitamin D sterol is being used, reduce to alternate-day dosing. (OPINION) If the lowest daily dose of the active vitamin D sterol is being used, reduce to alternate-day dosing. (OPINION)

8A.3c- If serum P level rise to >4.6 mg/dl, hold active vitamin D, initiate or increase dose of phosphate binder until P 4.6 mg/dl, hold active vitamin D, initiate or increase dose of phosphate binder until P < 4.6 mg/dl; then resume the prior dose of active vitamin D. (OPINION) then resume the prior dose of active vitamin D. (OPINION)

In CKD patients stages 3 & 4 with stable renal function, compliant with medications, with serum P < 4.6 mg/dl, serum Ca < 9.5 mg/dl, & 25(OH)D  30 ng/ml: Measure serum PTH Is serum PTH >70 pg/ml (stage 3) or > 110 pg/ml (stage 4)? Begin vitamin D sterol Monitor according to guidline 1 Measure serum Ca & P Is serum Ca <9.5 mg/dl? Is serum P< 4.6 mg/dl? Measure serum PTH Initiate or increase P binder or restrict Dietary P Hold or reduce vitamin D dose No Yes No >70 pg/ml (stage 3) or >110 pg/ml (stage 4) Continue oral dose of vitamin D <35 pg/ml (stage 3) or <70 pg/ml (stage 4) Stop or reduce dose of Ca-based P-binder or reduce Ca supplement

Serum levels of PTH, Ca & P required for initiation of oral vitamin D sterol & recommended initial dose in stages 3 & 4 CKD Plasma PTH (pg/ml) Ca (mg/dl) P (mg/dl) Dose Oral Calcitriol Dose Oral Alfacacidiol Dose Oral Doxercalciferol >70 (stage 3) or > 110 (stage 4) < 9.5 <  g/day 0.25  g 3  wk

GUIDELINE 8B. VITAMIN D THERAPY IN PATIENTS ON DIALYSIS (CKD STAGE 5)

8B.1-Patients treated with HD or PD with serum iPTH >300 pg/ml should receive an active vitamin D sterol (such as calcitriol, alfacalcidol, paricalcitol, or doxercalciferol; to reduce the serum levels of PTH to a target range of 150 to 300 pg/ml. (EVIDENCE) 8B.1-Patients treated with HD or PD with serum iPTH >300 pg/ml should receive an active vitamin D sterol (such as calcitriol, alfacalcidol, paricalcitol, or doxercalciferol; to reduce the serum levels of PTH to a target range of 150 to 300 pg/ml. (EVIDENCE)

8B.1a-The intermittent, IV calcitriol is more effective than daily oral calcitriol in lowering serum PTH. (EVIDENCE) 8B.1a-The intermittent, IV calcitriol is more effective than daily oral calcitriol in lowering serum PTH. (EVIDENCE) 8B.1b-In patients with high serum Ca &/or P, a trial of alternative vitamin D analogs, such as paricalcitol or doxercalciferol may be warranted. (OPINION) 8B.1b-In patients with high serum Ca &/or P, a trial of alternative vitamin D analogs, such as paricalcitol or doxercalciferol may be warranted. (OPINION)

8B.2-When therapy with vitamin D sterols is initiated or the dose is increased, serum Ca & P should be monitored at least every 2 weeks for 1 month and then monthly thereafter. 8B.2-When therapy with vitamin D sterols is initiated or the dose is increased, serum Ca & P should be monitored at least every 2 weeks for 1 month and then monthly thereafter. The plasma PTH should be measured monthly for at least 3 months and then every 3 months once target levels of PTH are achieved. (OPINION) The plasma PTH should be measured monthly for at least 3 months and then every 3 months once target levels of PTH are achieved. (OPINION)

8B.3-For PD patients, oral doses of calcitriol (0.5 to 1.0 µg) or doxercalciferol (2.5 to 5.0 µg) can be given 2 or 3 times weekly. Alternatively, a lower dose of calcitriol (0.25 µg) can be administered daily. (OPINION) 8B.3-For PD patients, oral doses of calcitriol (0.5 to 1.0 µg) or doxercalciferol (2.5 to 5.0 µg) can be given 2 or 3 times weekly. Alternatively, a lower dose of calcitriol (0.25 µg) can be administered daily. (OPINION) 8B.4- When either HD or PD patients are treated with active vitamin D sterols, management should integrate the changes in serum Ca & P and plasma PTH. 8B.4- When either HD or PD patients are treated with active vitamin D sterols, management should integrate the changes in serum Ca & P and plasma PTH.

Algorithm 3. Managing Vitamin D sterols based on serum Ca levels Measure serum Ca Reduce dose of Ca containing P-binders & change to or ↑ dose of non-Ca containing P-binders Continue or modify vitamin D using Algorithm 4 & 5 Measure serum Ca Measure serum PTH Stop vitamin D Rx No Optional Dialysate Ca 2 meq/L for 2-3 HD Rx Ca= mg/dl Ca<9.5 mg/dl Ca>10.2 mg/dl Ca= mg/dl Is serum PTH>300 pg/ml? Continue or modify vitamin D using Algorithm 4 & 5 Yes Ca<9.5 mg/dlCa>10.2 mg/dl Optional Change to less calcemic vitamin D sterol

Algorithm 4. Managing Vitamin D sterols based on serum Pi levels Measure serum P Increase P-binders dose Continue or modify vitamin D using Algorithm 1 & 5 Measure serum P Hold vitamin D Rx No P= mg/dl Is serum P<5.5 mg/dl? If patient has been on vitamin D reduce dose by 25-50% If vitamin D has been held Resume at dose lowered by 25-50% Yes P <5.5 mg/dlP> 6.0 mg/dl

Measure serum PTH Reduce vitamin D dose by half for 2 months Maintain same vitamin D dose for 3 months Measure Serum PTH Hold vitamin D Rx for 1 month PTH= pg/ml PTH= pg/ml PTH< 150 pg/ml Raise vitamin D dose by 25-50% PTH>300 pg/ml P< 5.5 mg/dl Ca< 9.5 mg/dl PTH>300 pg/mlPTH<150 pg/ml Hold vitamin D Rx for 3 month If on Vitamin D, raise vitamin D dose by 25-50% If vitamin D has been held, resume 75% of initial dose for 3 mo Maintain same vitamin D dose for 3 months If on Vitamin D, raise vitamin D dose by 25-50% If vitamin D has been held, resume therapy with earlier dose PTH= pg/mlPTH= pg/ml

When intact PTH is between pg/ml and changes in 2 successive determinations are small (<25%), there is no need to change vitamin D dose, as far as Ca and P are within the desired limits. When intact PTH is between pg/ml and changes in 2 successive determinations are small (<25%), there is no need to change vitamin D dose, as far as Ca and P are within the desired limits. When intact PTH is persistently > pg/ml and P is mg/dl &/or Ca is mg/dl, a trial with a less calcemic analog may be warranted for 3-5 months. If such a patient fails to respond, parathyroidectomy may be required. When intact PTH is persistently > pg/ml and P is mg/dl &/or Ca is mg/dl, a trial with a less calcemic analog may be warranted for 3-5 months. If such a patient fails to respond, parathyroidectomy may be required.

MDRD study equation Estimated GFR (mL/min/1.73 m2) = Estimated GFR (mL/min/1.73 m2) = 186 x [SCr(-1.154)] x [Age(-0.203)] x (0.742 if female) x (1.21 if African American) 186 x [SCr(-1.154)] x [Age(-0.203)] x (0.742 if female) x (1.21 if African American) This equation is also equivalent to: This equation is also equivalent to: Estimated GFR (mL/min/1.73 m2) = exp( X ln (SCr) x ln (Age) - (0.299 if female) + (0.192 if African American) Estimated GFR (mL/min/1.73 m2) = exp( X ln (SCr) x ln (Age) - (0.299 if female) + (0.192 if African American)