SIMPLIFIED Background and Rationale Thomas Hiemstra

7-dihydrocholesterol Vitamin D3 (cholecalciferol) UV / heat Circulation Diet Vitamin D3 (cholecalciferol) Vitamin D2 (ergocalciferol) Hepatic 25-hydroxylation 25-hydroxyvitamin D (calcifediol) 1,25-dihydroxyvitamin D (calcitriol) 1α-hydroxylase circulation DBP 1α-hydroxylase extrarenal Calcitroic acid (biliary excretion) CYP24A1

KDIGOK/DOQIRA CKD3-5dMeasure and replaceMeasure. Repeat annually if normal Treat with ergocalciferol if <75 nmol/l Measure and replace (if not receiving active vitamin D) RegimenNSSevere: 50,000IU/w x 12w, then 1x/m Moderate: 50,000IU/w x 4w, then 1x/m Mild: 50,000IU/m x 6m, then repeat NS

Assessing Status Vitamin D status Life stage BMIEthnicity Liver function Renal functionDiet Environment SUPPLYFUNCTIONOUTCOME 25(OH)DPTHBone Disease

Defining Adequacy DeficiencyInsufficiency SACN Rickets Osteomalacia Decreased AMP synthesis Increased fractures and falls Increased colon cancer risk Decreased calcium absorption Maximal PTH suppression Decreased fallsToxicity 25-Hydroxyvitamin D (nmol/l) Hiemstra TF, Br J Ren Med 2012

+/+ +/- -/- Hair loss Rickets  Ca 2+  PTH  Calcitriol  Fertility  Survival  renin, angiotensin  Sodium retention  LVH  Anxiety  auto-immunity  Skeletal Muscle function  Hearing loss  Tumorigenesis  Glucose tolerance  infection Consequences of Deficiency Yoshizawa T, Nature Gen 1997 Li YC, PNAS 1997 O’Kelly. J Clin Invest 2002 Bouillon et al, Endocr Rev 2008

Control Myocyte VDR (-/-) Isoprenalin Myocyte VDR (-/-) Isoprenalin LV-section Cardiac section Collagen Chen S et al. Circulation 2011 LVH

25(OH)D and CV disease Wang L et al, Circ Cardiovasc Qual Outcomes 2012

AuthorPopulationFollow-upNumberFindings Normal population Dobnig 2008 Single centre, referred for coronary angiography 7.7y3258 Higher mortality (Lower two quartiles) Giovannucci 2008 Health professionals, Follow-up study, men 40-70y Up to 10y18,255 Myocardial infarction (compared to 25(OH)D>75 nmol/L) Pilz 2008 Single centre, referred for coronary angiography 7.7y3316 Fatal / non fatal strokes (low vitamin D levels) Wang 2008 Framingham offspring study5.4y1739 Increased CV events (compared to 25(OH)D>37 nmol/Ll) Melamed 2008 Third National Health and Nutrition Examination Survey 8.713,311 All cause mortality (lowest compared to highest quartile) Chronic kidney disease Wolf 2007 ESRD on HD90d825 All cause mortality ( 75 nmol/L) Wang 2008 ESRD on CAPDUp to 3y230 Higher fatal / nonfatal CV events (when <45 nmol/Ll) Ravani 2009 CKD stage 2-54y168 Independent inverse predictor for ESRD and mortality Low 25D and CV events / mortality Artaza N et al. cJASN 2009

Krause et al, Anticancer Res 2012 All-cause mortality

25(OH)D and early mortality in HD Wolf M et al, Kidney Int 2007

Afzal S et al. BMJ 2014 Mendelian Randomisation

Afzal S et al. BMJ 2014 Deficiency and Health Outcomes Theodoratou et al, BMJ 2014

Malignancy Theodoratou et al, BMJ 2014 Deficiency and Health Outcomes

Theodoratou et al, BMJ 2014 Cardiovascular events

Deficiency and Health Outcomes Theodoratou et al, BMJ 2014 Infection

Deficiency and Health Outcomes Theodoratou et al, BMJ 2014 Fractures

Deficiency and Health Outcomes Theodoratou et al, BMJ 2014 Mortality in CKD

Deficiency and Survival Chowdhury et al, BMJ 2014

Replacement and Survival Chowdhury et al, BMJ 2014

Uremia and CYP2R1 Oh et al, Nephrol Dial Transplant 2012 Gutierrez O, J Am Soc Nephrol 2005

Hiemstra, unpublished

Uremia and CYP2R1

Nephrotic Syndrome Barragry J et al, Lancet 1977

Plasma Exchange Hiemstra et al, QJM 2014

Dietary Restriction Hiemstra TF, Br J Ren Med 2012

FGF23 PTH Klotho Bone Kidney Parathyroid 25(OH)D 1,25(OH)2D Serum Levels Normal CKD Stage Klotho FGF23 PTH Phosphate 25(OH)D Endocrine Vitamin D Regulation

Deficiency and Outcome in PD n = 230 Wang A Y et al. Am J Clin Nutr 2008

Deficiency and Outcome in HD n=1108 Drechsler C et al, Eur Heart J 2010

Supplementation and Outcomes Lishmanov et al, Eur J Ther 2011 Ergocalciferol 50,000U/w for 6 months: fewer CV events (OR 0.37 [0.14 – 1.0] p = 0.05)

Current Practice

SIMPLIFIED Protocol Caroline O’Leary / Thomas Hiemstra

Consent Trial participation UKRR data HSCIC data Baseline Demographics Comorbidity Prescriptions QoL 6 monthly F/U QoL Adherence AE Randomise 1:1 Standard Care Colecalciferol 60,000IU UK Dialysis Patients LTFU Trial End (2,200 events)

Target Population: All adult UK incident and prevalent haemo- and peritoneal dialysis patients InclusionsExclusions Aged ≥ 18 yearsHypercalcaemia (> 3 values > 2.6 mmol/L despite appropriate action) Able to consentLife expectancy < 6 months Life expectancy ≥ 6 months UK resident Current high dose colecalciferol or ergocalciferol (>1,000IU/day)* Have dialysis-requiring ESRDNot contributing UKRR data Pregnancy Population *May be included after a 30 day run-in off treatment

Intervention Colecalciferol 60,000 IU fortnightly by mouth Open label Generic Continued until primary endpoint reached (median 5.5 years)

Standard Care Active vitamin D permitted Alfalcalcidol Calcitriol Paricalcitol Ergocalciferol/colecalciferol contra-indicated Control

1.Recruitment: 887 after 12 months 2.Vitamin D – Separation >= 20nmol/l after 4 months (n=300) Outcomes: Feasibility

Primary efficacy endpoint All cause mortality Secondary efficacy parameters Health-Related Quality of life by EQ5D Hospital admission-requiring composite cardiovascular events defined as CV death acute coronary syndrome (ACS), heart failure or arrhythmia admissions, and stroke Hospitalisation for infection Incidence of Malignancy Incidence of hospitalisation-requiring fractures Cost-effectiveness of colecalciferol from the perspective of the NHS Outcomes

Schedule of Assessments BASELINE Face-to-Face visit:  Demographics  Medical History  Concomitant medications  Corrected calcium levels  Pregnancy test if applicable  Baseline HRQoL questionnaire FOLLOW-UP Plasma Vitamin D after 4 months: first 300 subjects 6-Monthly questionnaires: HRQoL Medication RRT modality

CCTU Database Baseline CRFs UKRDC HES ONS UKIACR ISDPEDW HSNI Monthly downloads Renal Units Follow-up Schedule of Assessments

Patient Information & Consent One combined Participant Information Sheet and Informed Consent Form (PIS/ICF) Consent to: Trial participation Release of UKRR data Capture and storage of PID Linkage

Safety Hypercalcaemia Common in RRT patients No evidence of hypercalcamia with high doses 1 (exceeding SIMPLIFIED regimen). Follow local treatment guidelines 1 Jean G et al, Nephrol Dial Transplant 2008

Safety

Vitamin D toxicity > 354nmol/L Very rare All reported cases – hypercalcaemia reversed with stopping active vitamin D 1 Jean G et al, Nephrol Dial Transplant 2008

Vitamin D Toxicity Algorithm