Introduction
The Physiology of Altered Vitamin D and Bone Metabolism with CKD
Clinical Trials of Vitamin D in CKD Patients and Gaps in the Evidence-Base
Systematic Review and Meta-analyses of Randomised Controlled Trials
Methods
Search Strategy
Inclusion Criteria
Quality Assessment
Meta-analyses
Results
RCTs with Vitamin D Supplementation
Authors | Country | Study population | Intervention | Outcomes |
---|---|---|---|---|
Vitamin D* | ||||
Dogan et al. [41] | Slovakia | 40 predialysis CKD patients (stage 3 and 4), PTH < 200 pg/mL. No use of phosphate binders | 300,000 IU D3/month for 1 month or placebo Route: oral | Treatment group: ↑ 25(OH)D, ↓ iPTH, ↔ serum calcium, ↔ serum phosphorus, ↔ ALP |
Oksa et al. [42] | UK | 87 CKD patients (stage 2–4) (including hypertensive, diabetic and vitamin D insufficient/ deficient CKD patients). Use of phosphate binders (calcium-based). No calcimimetics use | 5000 or 20,000 IU/week D3 for 12 months Route: oral | ↑ 25(OH)D, ↓ iPTH in both treatment groups, ↔ serum calcium, ↔ serum phosphate, ↔ urinary calcium, ↔ urinary phosphate |
Petchey et al. [25] | USA | 28 CKD patients (stage 3–4), 25(OH)D < 150 nmol/L | 2000 IU/day D3 or placebo for 6 months Route: oral | ↑ 25(OH)D, ↑ 1,25(OH)2D, ↔ PTH, ↔ serum calcium, ↔ serum phosphate, ↔ insulin sensitivity |
Dreyer et al., [29] | USA | 38 CKD patients (stage3-4), non-diabetic, 25(OH)D < 40 nmol/L | 50,000 IU/week D2 for 1 month followed by 50,000 IU/month D2 for 5 months or placebo for 6 months Route: oral | ↑25(OH)D, ↔ PTH, ↔ calcium, ↔ phosphate, ↔ blood pressure, ↔ left ventricular mass index. Improvement in endothelium dependent microcirculatory vasodilation |
Chandra et al. [44] | Turkey | 34 CKD patients (stage 3 and 4), 25(OH)D < 75 nmol/L and SPTH (PTH > 70 pg/mL). No calcimimetic use | 50,000 IU/week D3 or placebo for 12 weeks Route: oral | ↑ 25(OH)D, ↔ 1,25(OH)2D, ↔ PTH, ↔ serum calcium, ↔ BAP, ↔ TRAP5b, ↔ CTX |
Westerberg et al. [45] | Sweden | 95 CKD patients (stage 3–4), 25(OH)D < 75 nmol/L, PTH > 64.1 pg/mL. No calcimimetic use | 8000 IU/day D3 or placebo for 12 weeks Route: oral | ↑25(OH)D, ↑1,25(OH)2D, ↔ PTH but it was significantly lower than the mean value of the placebo group. ↑ calcium, ↔ phosphate and ↔ FGF23 |
25 (OH) Vitamin D—calcifediol | ||||
Sprague et al. [22] | USA | 78 CKD patients (stage 2–4), 25(OH)D < 75 nmol/L, iPTH > 70 pg/mL | ER calcifediol (30, 60 or 90 µg/day) or placebo for 6 weeks Route: oral | Dose dependent ↑ 25(OH)D and ↓ iPTH, serum ↔ calcium, ↔ serum phosphorus ↔ FGF23 |
Petkovich et al. [48] | USA | 29 CKD patients (stage 3–4), 25(OH)D < 75 nmol/L, SHPT | Single oral dose of ER calcifediol (450 mg or 900 mg) or a single bolus IV injection of calcifediol (448 mg) and monitoring for 42 days Route: oral and iv | ER calcifediol (450 mg or 900 mg): ↔ 25(OH)D and ↔ 1,25(OH)2D, ↔ PTH compared to IV group ER calcifediol (900 mg): ↔ 25(OH)D and ↔ 1,25(OH)2D, ↔ 24,25(OH)2D, ↓iPTH after 72 h compared to IV group IV injection group: ↑25(OH)D, ↑1,25(OH)2D, ↑24,25(OH)2D, ↔ iPTH ↔ calcium in all treatment groups |
Sprague et al. [49] | USA | 429 CKD patients (stage 3–4), 25(OH)D 25–75 nmol/L, SHPT (≥ 85 and < 500 pg/mL) | ER calcifediol (30 or 60 μg/day) or placebo for 26 weeks Route: oral | ↑25(OH)D, ↓PTH in both treatment groups compared to placebo, ↔ serum calcium, ↔ serum phosphorus, ↔ FGF23 |
1,25(OH)2 vitamin D or Vitamin D analogues** | ||||
Coyne et al. [57] | USA | 220 CKD patients (stages 3 and 4) with PTH (> 70 pg/mL) | Paricalcitol capsules (Dosing was based on serum iPTH, calcium, and phosphorus levels) 3/week or 1/day or placebo for 24 weeks Route: oral | ↓ iPTH compared to placebo, ↔ urinary calcium,, ↔ urinary phosphorus, ↓ BAP, ↓ osteocalcin, ↓ urinary pyridinoline compared to baseline |
de Zeeuw et al. [53] | USA | 281 patients with type 2 diabetes, nephropathy (stages 1–4) and PTH 35–500 pg/mL | 1 μg paricalcitol/day, 2 μg paricalcitol/day or placebo for 24 weeks Route: oral | ↑25(OH)D, ↓iPTH in both treatment groups |
de Boer et al. [26] | USA, Poland | 22 non-diabetic CKD patients (stage 3–4). No phosphate binders use | Cross-overs study with paricalcitol or placebo for 8 weeks (washout 8 weeks between arms) Route: oral | ↓ 25(OH)D, ↓ 1,25(OH)2D, ↑ 24,25(OH)D, ↓ PTH, ↑ serum calcium, ↔ serum phosphorus, ↑ FGF23, ↔ insulin sensitivity |
Coyne et al. [58] | Germany, Greece, Italy, Netherlands, Poland, Portugal, Spain, USA, Taiwan | 110 CKD patients (stage 3–4), PTH > 120 pg/mL. Use of phosphate binders | 0.25 μg/d 1,25(OH)2D or 1 μg/day of paricalcitol for 24 weeks Route: oral | ↓ iPTH, ↔ serum calcium, ↔ serum phosphorus, ↓ALP compared to baseline |
Larsen et al. [28] | Sweden | 26 CKD patients (stage 3–4), non-diabetic, albuminuria (urine albumin > 30 mg/L) | paricalcitol (2 µg/day) or placebo for 6 weeks (crossover design) with a 2 week washout period Route: oral | ↔ 25(OH)D, ↓ iPTH, ↑ plasma calcium, ↑ plasma phosphate, ↑ urinary calcium (24 h), ↑ FGF23, ↓ ALP, ↓ albumin excretion rate, ↓ creatinine clearance, ↔ renin, ↔ angiotensin II, ↔ aldosterone |
Lundwall et al. [19] | Denmark | 36 non-diabetic CKD patients (stage 3–4), PTH 35–500 pg/mL | Paricalcitol (1 µg or 2 µg/day) or placebo for 3 months Route: oral | ↔ 25(OH)D, ↓ PTH, ↔ calcium, ↔ phosphate in both treatment groups ↔ albuminuria, ↔ pulse wave velocity, ↔ muscle sympathetic nerve activity, ↓ endothelial function at the placebo and 1 µg treatment group, ↑ blood velocity in both treatment groups |
Thadhani et al. [30] | USA | 227 CKD patients (stage 3–4), iPTH 50–300 pg/mL and mild- moderate left ventricular hypertrophy | Paricalcitol (2 µg/day) or placebo for 48 weeks Route: oral | ↓ PTH,↑ calcium, ↔ phosphate, ↔ left ventricular mass index |
Riccio et al. [56] | Italy | 60 CKD patients (stage 3b-5), PTH 20–300 pg/mL and anaemia (Hb levels: 10–12.5 g/dL), including use of calcium supplements and phosphate binders | Paricalcitol (1 μg/ day) or 1,25(OH)2D (0.5 μg/ every other day) for 6 months Route: oral | ↔ PTH, ↔ calcium, ↔ phosphate compared to baseline, ↓GFR in the paricalcitol group. The paricalcitol group had a significant ↑Hb where in 1,25(OH)2D group was significantly decrease |
Zoccali et al. [55] | Italy | 88 CKD patients (stage 3 to 4), PTH > 65 pg/mL. Use of phosphate binders | Paricalcitol (2 μg/ day) or placebo for 12 weeks Route: oral | ↑25(OH)D, ↓1,25(OH)2D, ↓ PTH, ↑ serum calcium, ↑ serum phosphate,↑ FGF23, ↓ GFR |
Kovesdy et al. [46] | USA | 80 CKD patients (stage 3–4), 25(OH)D < 75 nmol/L and SHPT. Use of phosphate binders | 50,000 IU/week D2 titrated to achieve serum 25(OH)D 75 nmol/L or paricalcitol (1 µg/day) for 16 weeks Route: oral | ↑25(OH)D in both groups compared to baseline, ↓PTH in paricalcitol group, ↔ serum calcium, ↔ serum phosphorus |
Moe et al. [43] | Australia | 47 CKD stages 3 and 4 with 25(OH)D < 50 nmol/L and SPTH (> 100 to 150 pg/mL for stage 3 and > 150 to < 400 pg/mL for stage 4). No calcimimetic use | 4000 IU/day D3 for 1 month, then 2000 IU/day D3 for 2 months or doxercalciferol (1 μg/day) for 3 months Route: oral | ↑ 25(OH)D in both treatment groups, ↓ PTH in doxercalciferol group, ↔ serum calcium, ↔ serum phosphorus, ↔ urinary calcium |
Levin et al. [50] | USA | 87 CKD patients (stage 3b-4). Use of phosphate binders (calcium-based) | Calcifediol (5000 IU) or 1,25(OH)2D (0.5 μg) or placebo, thrice weekly for 6 months Route: oral | ↑25(OH)D in the calcifediol group ↔ 1,25(OH)2D, ↓ PTH, ↔ serum calcium, ↔ serum phosphate, ↔ FGF23 in calcifediol and 1,25(OH)2D group |
Combination treatment | ||||
Susantitaphong et al. [21] | Thailand | 68 CKD patients (stage 3–4), 25(OH)D < 75 nmol/L with proteinuria | 40,000 IU/week D2 plus placebo or 40,000 IU/week D2 plus 1,25(OH)2D (5 µg two times/ week) for 12 weeks Route: oral | ↑ 25(OH)D in both treatment groups (higher in the combined group), ↔ iPTH in D2 group, ↓ iPTH levels in the combined treatment group, ↔ serum calcium ↔ serum phosphate. ↓ urine protein-creatinine ratio in both treatment groups |
RCTs with Calcifediol Supplementation
RCTs: with Calcitriol and Vitamin D Analogues
Discussion of Clinical Trials of Vitamin D in CKD Patients
Methods for Estimating Renal Function
Medication Use and Vitamin D
Summary of Published Guidelines
Guidelines for Dietary Vitamin D Intakes and Supplementation for Population Health and Patient Management
General Population Requirements and Recommendations
Country/organization | Adults IU/d (μg/day) | Older than 65 years IU/d (μg/day) | Deficiency of 25(OH)D [78] |
---|---|---|---|
Nordic countries [95] | 400 (10) | 400-800 (10–20) | 25–30 nmol/L |
UK [96] | 400 (10) | 400 (10) | 25 nmol/L |
Ireland [97] | 0-400 (0–10) | 400 (10) | 30 nmol/L |
Netherlands [98] | 0-400 (0–10) | 800 (20) | 25–30 nmol/L |
Belgium [98] | 400-600 (10–15) | 600 (15) | |
France [98] | 200 (5) | 400-600 (10–15) | |
DACH [98] | 800 (20) | 800 (20) | 25–30 nmol/L |
Spain [98] | 600 (15) | 600 (15) | |
Australia and New Zealand [86] | 600 (15) | 600-800 (15–20) | 25–30 nmol/L |
EFSA 2017 [81]* | 600 (15) | 600 (15) | 50 nmol/L* |
Institute of Medicine [82] | 600 (15) | 800 (20) | 30 nmol/L |
WHO/FAO | 200 (5) | 200 (5) | 25 nmol/L |
Guidance for Patient Management and CKD Patients
Endocrine society [9] | NICE [67] | ROS [85] |
---|---|---|
Dosage schemes for the correction of vitamin D deficiency | ||
Sufficient: > 75 nmol/L Insufficient: 50–75 nmol/L Deficiency: < 50 nmol/L | Sufficient: > 50 nmol/L Insufficient: 25–50 nmol/L Deficiency: < 25 nmol/L | Sufficient: > 50 nmol/L Insufficient: 25–50 nmol/L Deficiency: < 25 nmol/L |
Dietary intake for patients at risk: 19–70 year 600 IU/day; > 70y 800 IU/day Treating vitamin D deficiency in adults: 50,000 IU/week for 8 weeks or 6000 IU/day Followed by maintenance therapy of 1500–2000 IU/day | Vitamin D3 is the preferred form of supplementation to treat vitamin D deficiency Vitamin D deficiency treatment: Fixed loading dose of vitamin D up to total of 300,000 IU, split dose either weekly or daily Followed by lifelong maintenance treatment of 800 IU/day | Vitamin D3 is recommended for treating vitamin D deficiency Vitamin D deficiency treatment: fixed loading up to a total of 300,000 IU given either as weekly or daily split doses Maintenance therapy: started one month after loading with doses equivalent to 800–2000 IU/day (maximum 4000 IU/day) given either daily or intermittently |
G1 | G2 | G3 | G4 | G5 | |
---|---|---|---|---|---|
≥ 90 mL/min | 60–89 mL/min | 30–59 mL/min | 15–29 mL/min | < 15 mL/min | |
Follow guidelines for general population Target thresholds as general population | If plasma/serum 25(OH)D concentration is < 75 nmol/L D2 supplementation should be given with dosages dependent on baseline values (Table 4) with monitoring of 25(OH)D and calcium and phosphate homeostasis† (Fig. 1) Maintenance: continue supplementation with a vitamin-D containing multi-vitamin and an annual reassessment of 25(OH)D† ER calcifediol can be used with vitamin D deficiency and SHPT | Vitamin D analogue therapy should be given when SHPT is progressive and persistent higher from the upper limit of the assay used | |||
Follow guidelines for general population Target thresholds for 25(OH)D as for general population Monitor plasma/serum 25(OH)D concentrations once a year. If normal no treatment is required. If deficient, treat per general population‡ | Monitoring of plasma/serum 25(OH)D concentrations at intervals dependent on CKD stage, baseline values and therapeutic interventions*, with monitoring of calcium and phosphate homeostasis* Vitamin D deficiency and insufficiency be corrected using treatment strategies recommended for the general population In non-dialysis patients with progressively rising PTH concentrations above the upper limit of normal for the assay, despite correction of modifiable factors the use 1,25(OH)2D or vitamin D analogues is recommended With severe and progressive SHPT and CKD-MBD in G4-5 1,25(OH)2D or vitamin D analogues is recommended | ||||
Vitamin D deficiency (< 37.5 nmol/L) and insufficiency (37.5–75 nmol/L) should be corrected using treatment strategies recommended for the general population Vitamin D therapy for early CKD patients with SHPT is recommended with monitoring of markers of calcium and phosphate homeostasis and bone metabolism§ 25(OH)D and PTH levels should be monitored regularly whilst on vitamin D therapy§ |
Serum 25(OH)D nmol/L [ng/mL] | Definition | Vitamin D2 dose | Duration (months) | Comment |
---|---|---|---|---|
< 12 [< 5] | Severe vitamin D deficiency | 50,000 IU/w orally × 12 weeks; then monthly | 6 months | Measure 25(OH)D levels after 6 months |
500,000 IU as a single I.M. dose | n/a | Assure patient adherence; measure 25(OH)D at 6 months | ||
12–37 [5–15] | Mild vitamin D deficiency | 50,000 IU/w × 4 weeks; then 50 000 IU/m orally | 6 months | Measure 25(OH)D levels after 6 months |
40–75 [16–29] | Vitamin D insufficiency | 50,000 IU/m orally | 6 months | n/a |