Cheshire and Merseyside Renal Units Guidelines on the Management of Chronic Kidney Disease - Mineral Bone Disorder (adapted from Greater Manchester) Authors Name: Christopher Wong: Consultant Nephrologist Anne Waddington: Renal Pharmacist Eimear Fegan : Renal Dietitian Contact Name: Dr Chris Wong Contact Phone : 01515293356 Departments/Groups This Document Applies to: Patients under the care of the renal team Scope: Regional Renal Units Keywords: BONE, CALCIUM, PHOSPHATE, VITAMIN D, PARATHYROID HORMONE, PTH, CKD Classification: Replaces: Contents Page Policy Statement & Executive Summary 2 Introduction 2 Prescribing Guidelines 4 Guideline: CKD stage 3-4 5 Guideline: CKD stage 5 non-dialysis 6 Guideline: CKD stage 5 dialysis 7 Algorithm 1: Initial management for all renal patients 9 Algorithm 2: Phosphate management 10 Algorithm 3: PTH increasing or above target 11 Algorithm 4: PTH decreasing or below target 12 Algorithm 5: Low corrected calcium 13 Renal bone disease medicines - prescribing information 14 Rationale: Overall management and Phosphate management 16 Rationale: PTH management - increasing 16 Rationale: PTH management - decreasing 16 Rationale: 25(OH) vitamin D deficiency 16 Rationale: Low calcium 17 Rationale: Transplant patients 17 References 17 Page 1
Page 2 Policy Statement This policy is applicable to all nursing, medical, pharmacy and dietetic staff involved in the prescription, dispensing and administration of medications utilised to aid bone chemistry management within the renal department. Executive Summary These guidelines are designed to provide members of the multi-disciplinary team with a summary of evidence based clinical practice guidelines related to the management of CKD-MBD. It supports a uniform approach to the management of this condition while allowing individualisation as required. Treatment should take into account patients needs and preferences and should be culturally appropriate. Our medication choices are opinion based but should be followed within the Trusts. The departments will follow the Renal Association guidelines and each algorithm can be used separately or in conjunction with each other. Introduction rmal calcium and phosphate metabolism In patients with normal kidney function, the parathyroid gland regulates the serum calcium level in a number of ways. If the serum calcium level drops, calcium sensing receptors on the surface of the parathyroid gland detect this and the parathyroid gland consequently releases more parathyroid hormone (PTH). PTH acts to return the serum calcium level to normal in the following ways: and phosphate release from bone Increased tubular reabsorption of calcium and reduced phosphate reabsorption Increased 1-alpha-hydroxylase activity with subsequent increased calcitriol production and increased calcium and phosphate absorption from the gastrointestinal tract. and Phosphate metabolism in CKD: Phosphate As the kidney function deteriorates the ability of the kidney to excrete phosphate diminishes. In early kidney disease (CKD stages 1-3) high serum phosphate may not be seen due to compensatory mechanisms such as increased uptake in bone or reduced tubular reabsorption. In later stages of kidney disease (CKD stage 4-5) hyperphosphataemia is an inevitable occurrence. Hyperphosphataemia can have serious consequences and has been associated with an increased mortality amongst dialysis patients. Hyperphosphataemia is also implicated in the development of secondary hyperparathyroidism, cardiovascular and soft tissue calcification and calciphylaxis.
In patients with kidney disease the ability of the kidney to synthesize 1- alphahydroxylase is diminished, tubular reabsorption of calcium and phosphate is impaired as is the skeletal buffer. These effects culminate in a low serum calcium level which stimulates PTH secretion from the parathyroid gland. Parathyroid hormone (PTH) PTH is not able to completely correct serum calcium due to impaired compensatory mechanisms so PTH secretion increases again which leads to secondary hyperparathyroidism. If secondary hyperparathyroidism is not treated effectively the parathyroid gland may develop hyperplastic nodules which secrete PTH irrespective of any negative feedback, this is termed tertiary hyperparathyroidism and requires parathyroidectomy. and phosphate targets Standards for serum calcium, phosphate and PTH referred to in this protocol are based on the current Renal Association and KDIGO guidelines (1, 2). Doses of phosphate binders and alfacalcidol should be adjusted to maintain serum levels within the standards shown below. Consider trends (e.g. 3 consecutive serum levels) rather than one off results. Rapidly rising PTH levels, even if within normal range, warrant more aggressive monitoring and management. Roles and Responsibilities of the Multi-professional Team Take a proactive approach in order to identify people with CKD-MBD and follow this guideline. Establish baseline biochemistry and monitor according to test schedule. Provide evidence based, best practice advice taking into account clinical circumstances, peoples needs and preferences. Use this to optimise understanding and compliance with diet modification, phosphate binders and relevant medications associated with the management of CKD-MBD. Initiate and review prescription of phosphate binders, vitamin D, calcimimetics and titrate dose accordingly. Liaise with the patient and the GP regarding the prescription and administration of phosphate binders, vitamin D and calcimimetics and facilitate patient education, understanding and adherence to diet and medications. Maintain effective communication between patients and healthcare professionals. Ensure distribution of information to local teams. Aim to meet 1-3 monthly for review depending on modality. Page 3
Prescribing of medicines for the management of chronic kidney disease mineral bone disorder. The Pan Mersey Medicines Management Group, Interface prescribing subgroup issues an approved formulary for medicines across Mersey and issues a Red-Amber-Green list of medicines. This framework defines where clinical and prescribing responsibility lie by categorising individual drugs. te this is not a rigid guideline and is an advisory list. Most medicines used in the management of CKD MBD are appropriate for prescribing in primary care, following specialist initiation. The responsible commissioner is the relevant CCG Drug Status Additional information Alfacalcidol Green Vitamin D analogue Aluminium Amber Second line phosphate-binding hydroxide acetate Amber First line phosphate-binding agent Carbonate Amber First line phosphate-binding agent available as Adcal, Calcichew or -500 acetate and magnesium Amber Second line phosphate-binding agent available as Osvaren carbonate Cinacalcet Red NHS England commissioned drug indicated for hyperparathyroidism Lanthanum Amber Second line phosphate-binding agent Red if newly initiated in a dialysis patient, Amber in non-dialysis patients Paricalcitol Amber Vitamin D analogue Sevelamer Carbonate Sevelamer Hydrochloride Sucroferric oxyhydroxide Amber Amber Red Second line phosphate-binding agent Red if newly initiated in a dialysis patient te this salt form is only licensed for patients receiving dialysis Second line phosphate-binding agent Red if newly initiated in a dialysis patient, Amber in non-dialysis patients Available as Velphoro NHS England commissioned drug Page 4
GUIDELINE FOR THE MANAGEMENT OF CHRONIC KIDNEY DISEASE, MINERAL AND BONE DISORDER (CKD-MBD) CKD STAGE 3-4 egfr 15 59ml/min/1.73m 2 Biochemistry reference range Routine test schedule Phosphate Suggest within normal range (E) 2 a 3 6 months or on attendance if less frequent Corrected Maintain within normal reference range 1,2 (E) 2 a 3 6 months or on attendance if less frequent PTH Optimal range unknown 1 Suggest within normal range (GP) 2 a 6 12 months or on attendance if less frequent 25-OH Vit D * (D2 + D3) Maintain as per general population (E) 2 Obtain baseline sample 2 b If PTH elevated Bicarbonate rmal reference range 2 Monthly or on attendance if less frequent Alkaline Phosphatase rmal range c 12 months E = Evidence GP = Good Practice O = Opinion a Frequency is determined by presence and magnitude of abnormalities and rate of CKD progression, therefore frequency may be increased at discretion of medical team 2 b Serum 25- hydroxyl vitamin D should be measured in all patients with elevated PTH 1 (E), <20ng/ml indicates vitamin D insufficiency (O) 2. Frequency determined by baseline value and therapeutic interventions 1. c More frequently in presence of elevated PTH, at discretion of medical team. Page 5
GUIDELINE FOR THE MANAGEMENT OF CHRONIC KIDNEY DISEASE, MINERAL AND BONE DISRDER (CKD-MBD) CKD STAGE 5 non dialysis egfr <15 ml/min/1.73m 2 Biochemistry reference range Routine test schedule Suggest within normal range (E) 2 a 1-3months CCa Maintain within normal reference range 1,2 (E) a 1-3 months PTH Optimal range unknown 1 (GP) 2 a 3-6 months If marked change in either direction within target range then this should prompt change in therapy to avoid progression outside of range 25-OH Vit D * Maintain as per general population (E) 2 using activated vitamin D analogues, usually alfacalcidol or calcitriol Bicarbonate rmal reference range 2 b If PTH elevated Monthly or on Attendance if less frequent ALP rmal range c 12 months E = Evidence GP = Good Practice O = Opinion a Frequency is determined by presence and magnitude of abnormalities and rate of CKD progression, therefore frequency may be increased at discretion of medical team 2 b Serum 25- hydroxyl vitamin D should be measured in all patients with elevated PTH 1 (E), <20ngl/ml indicates vitamin D insufficiency (O) 2. Frequency determined by baseline value therapeutic interventions 1. c More frequently in presence of elevated PTH, at discretion of medical team. Page 6
GUIDELINE FOR THE MANAGEMENT OF CHRONIC KIDNEY DISEASE, MINERAL AND BONE DISRDER (CKD-MBD) CKD STAGE 5 dialysis egfr <15 ml/min/1.73m2 Biochemistry reference range Routine test schedule Phosphate Within normal reference range for the unit 1-3months Corrected Within normal reference range for the unit 1-3months PTH Optimal range unknown Suggest 2-7 x upper end of normal range Marked change in either direction within reference range should prompt change in therapy to avoid progression outside range. Every three months Bicarbonate Within normal reference range for the unit 1-3months Alkaline Phosphatase Within normal reference range for the unit Every three months E = Evidence GP = Good Practice O = Opinion * Low levels < 1.13mmol/l are associated with increased risk of death 1. Ensure sample has not been taken within 1 hour of dialysis. Low levels may indicate malnutrition. Consider stopping phosphate binders and referral to dietetics. Some patients may require phosphate supplementation. a Frequency is determined by presence and magnitude of abnormalities, therefore frequency may be increased at discretion of medical team. b Frequency is determined by presence and magnitude of abnormalities, post parathyroidectomy, dose titration of vitamin D and/or calcimimetic, therefore frequency may be increased at discretion of medical team or according to departmental guideline. Dialysis adequacy and compliance Phosphate is not easily removed by dialysis as it is largely an intracellular ion though if dialysis adequacy is consistently poor this may contribute to hyperphosphataemia. Optimising dialysis adequacy or converting to daily dialysis or to haemodiafiltration may improve phosphate removal. Compliance with phosphate binders is often poor due to the high tablet burden, side effects and large tablet size. Phosphate binders must be taken at meal times but may reduce the appeal of food. The pharmacist may be able to help with providing information on different formulations available, counselling patients and providing reminder charts / compliance aids where appropriate. Page 7
Dietetic referral The main dietary sources of phosphate are: Dairy produce Foods that contain protein such as milk, cheese, yoghurt and eggs are the richest source of phosphate. Achieving a low dietary phosphate intake should not compromise overall nutritional status. Phosphate additives Manufacturers are increasingly adding phosphate in the form of phosphate additives to lots of different foods. Nearly half of our daily phosphate intake comes from phosphate additives and almost all of this is absorbed by the body. Phosphate additives therefore can have more effect on the levels in blood than that from natural sources. A referral to the Renal Dietitian is recommended to ensure that a reduced dietary phosphate intake is achieved whilst still maintaining overall nutritional adequacy of the diet and advice can be given in relation to checking labels for phosphate additives. The Renal Dietitian can provide patients with written information to advise them on how to reduce the overall phosphate content of their diet. Page 8
ALGORITHM 1: OVERVIEW OF MANAGEMENT: all renal patients If phosphate or PTH increasing Dietary restriction of phosphate Phosphate >1.5mmol/l After dietary restriction Start binders see Algorithm 2 PTH in target action required Start PTH suppressant See algorithm 3 Page 9
ALGORITHM 2: PHOSPHATE MANAGEMENT All patients with an increasing or high phosphate need to be reviewed by a dietitian Review efficacy no sooner than 1 month First Line: Acetate Consider using an alternative such as calcium carbonate if calcium acetate is not tolerated Tolerated? Do not give 2 calcium based binders at one time Consider second line agent such as calcium acetate with magnesium carbonate (Osvaren ) if other calcium salts not tolerated Controlled : no action Second Line If calcium high change to 2 nd line non-calcium binder If phosphate not controlled add 2 nd line non-calcium binder Second Line non-calcium binder: Lanthanum, Sevelamer, sucroferric oxyhydroxide (Velphoro ) If second line not tolerated consider changing to alternative 2 nd line agent Third Line If still not controlled/ tolerated consider replacement or addition of Aluminium Hydroxide (Alu-Caps ) Do not use Alu-Caps in conjunction with Lanthanum If Alu-Caps are used Aluminium levels must be checked every 2 months Maximum 6 months treatment with Alu-Caps Page 10
ALGORITHM 3: MANAGEMENT OF A HIGH OR INCREASING PTH ABOVE TARGET IN ALL RENAL PATIENTS Review PTH 3 monthly or at review if seen less frequently IF taking cinacalcet titrate monthly IF PTH increasing or above target Ensure phosphate controlled and patient adherent with current meds Check serum 25-hydroxyvitamin D (25(OH)D) level - if D2+D3 < 20 ng/ml (< 50 nmol/l) consider addition of calcitriol Corrected [CCa] over normal range, despite low calcium dialysate and non-calcium containing phosphate binders Uncontrolled PTH > 80 pmol/l > 3 months First line: oral alfacalcidol consider parathyroidectomy Contra-indicated? PO or IV Paricalcitol starting at 2mcg twice a week. Titrate to maximum dose 4 mcg three times a week If not controlled on oral for oral directly observed or pulsed IV therapy Max dose 18mcg/week (Haemodialysis patients only) Start Cinacalcet a Refer for parathyroidectomy PTH >50 pmol/l and increasing consider Cinacalcet ab If not controlled, trial with PO or IV Paricalcitol starting at 2mcg twice a week. Titrate to maximum dose 4 mcg three times a week a te: cinacalcet NOT licensed in CKD or Transplant b te: outside of NICE guidance PTH assays taken from different hospitals are NOT interchangeable For further details see rationale on page 16 Page 11
ALGORITHM 4: MANAGEMENT OF DECREASING PTH OR PTH BELOW TARGET IN ALL RENAL PATIENTS If PTH is decreasing or is below target Is the patient on cinacalcet? Is Corrected high? Reduce alfacalcidol or paricalcitol by 50%. Does CCa drop to < 2.00? Review phosphate binders Reduce alfacalcidol or paricalcitol dose by 50% Monitor CCa monthly and PTH 1-3 monthly to monitor therapy Reduce cinacalcet dose Consider calcium supplements Monitor CCa monthly and PTH 1-3 monthly to monitor therapy Page 12
ALGORITHM 5: LOW CORRECTED CALCIUM (CCa) LOW CORRECTED CALCIUM < 2.1MMOL/L Remember to check serum magnesium Check the trend in calcium results CCa <1.6mmol/l CCa 1.6-1.8mmol/l CCa 1.8-2.1mmol/l High risk or signs of tetany? IV calcium infusion a Use central line if available OR new large cannula 50ml of 10% calcium gluconate in 500ml 0.9%NaCl over 12 hours (111mmol of calcium) Raised phosphate? Start calcium binder - see phosphate binder algorithm 2 Raised PTH Alfacalcidol Add 0.5mcg daily or increase by 25% Oral calcium supplements e.g. Sandocal 1000 x1 tds a gluconate is highly irritant and should only be used with caution. If peripheral administration, use a large gauge cannula in a large vein and check the infusion site every 15 minutes Page 13
Renal bone disease medicines - prescribing information Cost Brand name Generic name Presentation content How taken Starting dose Max daily dose Monitoring Restricted use/ Comments Approx. 10 per 100 Approx. 20 per 180 Approx. 10 per 100 Approx. 9 per 100 Approx 14 for 200 Calcichew Phosex 500 Adcal PhosLo carbonate acetate carbonate carbonate acetate 1.25g tablet 500mg Chewable 1 per meal 1000mg tablet 250mg 1.25g f/c tablet 500mg Swallowed whole Swallowed whole 1 per meal 1 per meal 1.5g tablet 600mg Chewable 1 per meal 667mg capsules 169mg calcium Swallowed whole licensed maximum however avoid more than 6 tablets daily 2 per meal 12 caps CCa & CCa & CCa & CCa & CCa & te higher calcium content than calcichew Approx 24 per 180 Osvaren acetate/ Heavy Magnesium carbonate Tablet 110mg calcium & 235mg Mg Swallowed whole 1 per meal 12 tabs CCa & Other medicines must be taken 2 hours before or 3 hours after to avoid interference with absorption 125 per 90 500mg tablet none 182 per 90 Fosrenol Lanthanum 750mg tablet none 195 per 90 1000mg tablet none Chewable 2.25g daily 3g daily (3 x 1g) Licensed for dialysis patients only Concomitant therapy with sevelamer not recommended 170 per 180 Renagel Sevelamer hydrochloride 800mg tablets none Swallowed whole 6 tablets daily 12 tabs Renagel licensed for dialysis patients only 135 per 180 Renvela 14 per 120 Alu-Cap Approx. 180 per 90 Velphoro Sevelamer carbonate Aluminium hydroxide Sucroferric Oxyhydroxide 800mg tablets 475mg ne ne Swallowed whole Swallowed whole or can be opened and mixed with food 6 tablets daily 4 daily Usual dose 7-8 tabs Up to 20 in divided doses, Aluminium 500mg ne Chewable 3 daily 6 tabs daily Renvela licensed for dialysis and CKD patients Alu-Caps Licensed for dialysis and CKD patients Velphoro Licensed for dialysis patients only Page 14
Cost Brand name Generic name Presentation content How taken Starting dose Max daily dose Monitoring Restricted use Comments 3.37 per 30 0.25 mcg n/a Caps 6.27 per 30 0.5 mcg n/a Caps 8.75 per 30 1 mcg n/a Caps One- alfa Alfacalcidol 0.2mcgs/ml 21.30 per 1drop = n/a Drops 10mls 0.1mcg 1mcg amp 2 mcgs/ml n/a Injection approx. 2 0.25mcg three times a week 10mcg s daily CCa & PTH te: iv route is 3x more potent than oral. Dose adjustment required 69.44 per 28 138.88 per 28 5mcg amp 62 per 5 Zemplar Paricalcitol 1 mcg 2 mcg 4 mcg 5 mcg/ ml n/a Caps Caps Caps Injection 2 mcg twice a week 4 mcg three times a week CCa & PTH 125.75 per 30mg 28 231.97 per 60mg 28 Mimpara Cinacalcet 347.96 per 28 90mg none none none Whole 30mg daily 180mg daily 4/52 PTH & 2/52 CCa then 4/52 CCa & in maintenance phase Must meet NICE criteria Contact renal pharmacist if patient suitable to start therapy. Page 15
Rationale: Overall management - Phosphate should always be controlled first prior to PTH suppressant medications - Renal Association guidelines suggest 25(OH) vitamin D levels should be checked in all non-dialysis patients whose PTH is increasing - There is only association data to suggest it would be beneficial to offer D3 replacement in dialysis patients who are 25(OH) deficient Rationale: Phosphate Management - 1 st line phosphate binder is Acetate 11 - Second line agents should be added to first line where possible to enable a lower dose can be given. This will improve cost and potentially improve tolerability by avoiding high doses. - Ensure that patients take phosphate binders before food except lanthanum which is taken after food. - If using Aluminium Hydroxide, measure aluminium levels every 2 months and treatment should not last longer than 6 months. Rationale: PTH suppressant medication - There is no evidence to suggest increased efficacy with I.V. versus oral alfacalcidol, however there is a substantial increase in cost. - Where alfacalcidol proves ineffective or doses that reduce PTH are associated with corrected calcium levels above normal range, paricalcitol can be used instead and dose titrated. - NOTE: cinacalcet is not licensed in CKD or transplant patients and can cause severe hypocalcaemia. Close monitoring of calcium is essential - All patients on cinacalcet need to have PTH reviewed 1 3 monthly and medications adjusted accordingly. - All patients on cinacalcet need to have efficacy reviewed at 6 months. Medication to be stopped if has not led to a reduction of 30% in PTH by 6 months. a Rationale: PTH decreasing or below target - A low PTH is associated with an increased risk of adynamic bone disorder. This has been associated with an increased risk of vascular calcification. In such situations, the agents used for PTH suppression should be reduced. - Alfacalcidol and paricalcitol can increase calcium, whereas cinacalcet can reduce serum calcium levels, so it is important to monitor calcium levels if doses are reduced. Rationale: 25(OH) vitamin D replacement and maintenance - Low 25(OH) vitamin D levels have been associated with an increased risk of infection, malignancy, hypertension and diabetes - It occurs due to a deficiency of D3 and D2, not due to liver impairment - 85% of 25(OH) vitamin D is used intracellular for autocrine and paracrine functions these functions are not affected by 1 alfacalcidol Page 16
- 25(OH) vitamin D deficiency needs replacement even if taking alfacalcidol - Please ensure patient only takes replacement dose for a maximum of 10 days to prevent hypercalcaemia Rationale: Low calcium replacement - Hypocalcaemia can be life threatening - If giving intravenous calcium ensure a large vein is used as severe skin necrosis can occur - Avoid using phosphate binders as calcium supplements to ensure clarity for patients and enable tablets to be taken correctly - Sandocal or calcium 500 should be first-line calcium supplements and should be taken 2 hours before or after food Rationale: Transplant patients - Transplant patients should follow CKD 5 protocol and guidance - te cinacalcet is not licensed in transplant patients as can cause severe hypocalcaemia. If used close monitoring of calcium is essential - There is little evidence for targets in transplant patients and this is purely opinion. a NICE recommends review of cinacalcet efficacy at 3 months. KDIGO guidelines recommend monitoring trends in biochemical parameters to guide truant of CKD-MBD. We therefore recommend review of cinacalcet at 6 months. References 1) KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney International, Vol 76; Suppl 113. August 2009 2) The Renal Association. Clinical Practice guidelines CKD- mineral and Bone disorders 5 th edition (2015). www.renal.org/guidelines 3) National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease in chronic kidney disease. Am J Kidney disease 2002: 39 (sups 2) S1-246 www.kidney.org 4) NICE. Chronic kidney disease. Early identification and management of chronic kidney disease in adults in primary and secondary care. Clinical guideline no 73, 2008 www.nice.org 5) Cinacalcet for the truant of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy. NICE technology appraisal guideline no 117, 2007 www.nice.org 6) Block GA, Lessen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral Metabolism, Mortality, and Morbidity in Maintenance Haemodialysis. J Am Soc Nephrology 15: 2208-2218, 2004 7) Block GA, Port FK. Re-evaluation of risks associated with hyperphosphataemia and hyperparathyroidism in dialysis patients: recommendations for a change in management. Am J Kid Dies 2000 35 1226-37 8) Goodman WG. The consequences of uncontrolled secondary hyperparathyroidism and its truant in chronic kidney disease. Seminars in Dialysis 2004 17 09-216 9) Management of Mineral and Bone Disorders in Chronic Kidney Disease. Journal of Renal Care; 35. Suppl 1, March 2009 10) British National formulary BNF. September 2015 11) NICE. Chronic kidney disease (Stage 4 or 5): management of hyperphosphatemia. Clinical guideline no 15, 2013 www.nice.org Page 17
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