Nottingham Renal and Transplant Unit

Transcription

1 Nottingham Renal and Transplant Unit Full Title of Guideline: Author (include and role): Division & Speciality: Scope (Target audience, state if Trust wide): Review date (when this version goes out of date): Explicit definition of patient group to which it applies (e.g. inclusion and exclusion criteria, diagnosis): Changes from previous version (not applicable if this is a new guideline, enter below if extensive): Summary of evidence base this guideline has been created from: Guidelines for the Management of Chronic Kidney Disease Mineral Bone Disease in Adults Dr S.D. Roe, Consultant Nephrologist. simon.roe@nuh.nhs.uk Cancer and Associated Specialities (CAS) / Renal and Transplant Speciality specific guideline September 2020 Applies to: All patients under the care of Nottingham Renal and Transplant Unit (including patients dialysing at Kings Mill Hospital, Ilkeston Community Hospital and Diaverum Clinic at Lings Bar Hospital) Exclusion: Patients without Chronic Kidney Disease Addition of sucroferric oxyhydroxide (Velphoro ) as an additional second line phosphate binder option. Switch from sevelamer hydrochloride (Renagel ) to generic sevelamer carbonate, to reflect Nottinghamshire Area Prescribing Committee recommendations. Addition of etelcalcetide for treatment of severe hyperparathyroidism in haemodialysis patients. Updated to reflect KDIGO 2017 guidelines. Removal of IV paricalcitol. Unlicensed preparation of sodium thiosulfate replaced with a licensed preparation (sodium thiosulfate solution for infusion). See evidence base section below This guideline has been registered with the trust. However, clinical guidelines are guidelines only. The interpretation and application of clinical guidelines will remain the responsibility of the individual clinician. If in doubt contact a senior colleague or expert. Caution is advised when using guidelines after the review date or outside of the Trust. Guidelines for the management of CKD Mineral Bone Disease/ September 2017/ Review September

2 Evidence base of policy: These guidelines have been derived using the following evidence base. 1. KDIGO 2017 Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD- MBD). Kidney International, Kidney International Supplements Volume 7, Issue 1, Pages A1-A4, 1-60 (July 2017) 2. The Renal Association. Clinical Practice guidelines CKD- mineral and Bone disorders. 5 th edition (reviewed March 2015). 3. NICE. Chronic kidney disease. Early identification and management of chronic kidney disease in adults in primary and secondary care. Clinical guideline no 73, Cinacalcet for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy. NICE technology appraisal guideline no 117, British National formulary August Chronic kidney disease (stage 4 or 5): management of hyperphosphataemia. NICE Clinical guideline 157. Published March Etelcalcetide for treating secondary hyperparathyroidism (TA448). NICE Technology appraisal guidance Published June Audit Plans: The following items are suggested for audit: 1. Serum calcium in dialysis patients (pre-dialysis for haemodialysis patients) 2. Serum phosphate in dialysis patients (pre-dialysis for haemodialysis patients) 3. Proportion of PTH values within range 0/4, 1/4, 2/4, 3/4, and 4/4 of the 4 annual measurements of PTH in CKD stage 5D patients 4. Percentage of patients with all parameters (calcium/phosphate/pth) within target range 5. Proportion of patients taking calcium containing binders, non-calcium containing binders or no binders 6. Proportion and frequency of dietetic reviews for patients with CKD stage 4 or 5 7. Adherence to NICE guidelines for use of cinacalcet and etelcalcetide. Training and implementation: The guidelines are available on the Trust intranet and via the NUH clinical guidelines app. New members of staff will be made aware of the guidelines as part of their induction programme. Limitations of evidence base: There is a limited evidence base to support recommendations regarding the correction of 25 (OH) vitamin D deficiency, in patients with advanced CKD or those on dialysis. Background Progressive chronic kidney disease leads to reduced phosphate excretion in the urine, decreased production of endogenous 1,25 (OH) 2 vitamin D 3 by the kidneys, and reduced dietary calcium absorption. These abnormalities lead to an increased production of parathyroid hormone. The resulting secondary hyperparathyroidism leads to a state of high bone turnover. Adynamic (or low Guidelines for the management of CKD Mineral Bone Disease/ September 2017/ Review September

3 turnover) bone disease has been increasingly recognised in patients with established kidney disease, particularly in diabetics and patients treated with vitamin D derivatives. Epidemiological studies have shown a direct correlation between serum phosphate and mortality in haemodialysis patients. High serum phosphate levels can directly and indirectly increase parathyroid hormone secretion, leading to the development of secondary hyperparathyroidism. If left untreated, secondary hyperparathyroidism increases morbidity and mortality and may lead to renal bone disease, with people experiencing bone and muscular pain, increased incidence of fracture, abnormalities of bone and joint morphology, and vascular and soft tissue calcification. Aims of management are to maintain healthy skeletal architecture by controlling phosphate, maintaining normocalcaemia, and controlling PTH. These guidelines are meant as a logical way of managing mineral and bone disorders in patients with CKD. Patients are individuals and may need treatment that is different to the general approach suggested here. In particular, consideration needs to be given to treatment goals based on a patient s prognosis, therapy plans, and their wishes around therapy; for example, in a patient with limited life expectancy who has elected for conservative care, management of phosphate levels would be geared towards controlling symptomatic hyperphosphataemia. Difficult cases should always be discussed at a senior level. NUH Laboratory Normal Ranges Parameter Phosphate Calcium (corrected) PTH Alkaline phosphatase Normal Range mmol/l mmol/l ng/l U/l Target Biochemical Parameters The following targets are based on the Renal Association Guidelines and the K-DIGO bone guidelines. CKD Stage Biochemical Parameter 3-4 GFR ml/min/1.73m 2 5 non dialysis GFR <15 ml/min/1.73m 2 5 dialysis GFR <15 ml/min/1.73m 2 Calcium Within normal range mmol/l Within normal range mmol/l Within normal range (Aim mmol/l) 1 Phosphate mmol/l Aim towards normal range mmol/l Aim towards normal range mmol/l Aim towards normal range PTH Optimal levels not known Optimal levels not known ng/l 2 25-OH Vitamin D >50 nmol/l > 50 nmol/l > 50 nmol/l (by extrapolation from general population) 1 Audit standard is mmol/l Guidelines for the management of CKD Mineral Bone Disease/ September 2017/ Review September

4 Biochemical Parameter Bicarbonate 3-4 GFR ml/min/1.73m 2 Normal reference range mmol/l Alkaline phosphatase Normal range u/l 5 non dialysis GFR <15 ml/min/1.73m 2 Normal reference range mmol/l Normal range u/l 5 dialysis GFR <15 ml/min/1.73m 2 Normal reference range mmol/l Normal range u/l 2 If marked change in either direction within target range this should prompt review of therapy to avoid progression out of the target range. Patient Screening The origins of renal bone disease lie early in progressive renal failure when the GFR is as high as 60ml/min/1.73m 2. Who should be screened? Chronic kidney disease patients (including failing transplants) with a calculated GRF <45 mls/min/1.73m 2 (CKD Stages 3b-5) Established renal failure (ERF) patients on haemodialysis or peritoneal dialysis 1. Baseline Evaluation Serum calcium / phosphate / alkaline phosphatase and bicarbonate. In haemodialysis patients serum values should be obtained before a short gap dialysis session. Serum intact PTH. Serum 25-OH vitamin D. 2. Measurement of PTH PTH should not be measured routinely in CKD Stages 1 and 2, or in non-progressive CKD stage 3A, unless there is a clinical indication to do so (including calcium < 2.2 mmol/l, phosphate > 1.5 mmol/l, evidence of osteoporosis including a fragility fracture). PTH should be measured in progressive stage 3B, Stage 4 and 5 CKD and in patients receiving renal replacement therapy. 3. Measurement of 25-OH vitamin D levels 25-OH vitamin D levels should be checked at baseline in patients with progressive Stage 3B, 4 and 5 CKD Suggested frequency of testing is described in the table below. CKD Stage Calcium Phosphate PTH Alk phos 25-OH Vitamin D 3b Progressive Every 6-12 months Every 6-12 months Baseline Every 6-12 months Baseline 4 Every 3-6 months Every 3-6 months Every 6-12 months Every 3-6 months Baseline 5 Every 1-3 months Every 1-3 months Every 3-6 months Every 3-6 months Baseline 5D Every 1-3 months Every 1-3 months Every 3-6 months Every 3-6 months Baseline Guidelines for the management of CKD Mineral Bone Disease/ September 2017/ Review September

5 Management of Hyperphosphataemia Treatment of CKD-MBD should be based on serial assessments of phosphate, calcium and PTH levels, considered together. Treatment should be targeted at patients with overt hyperphosphataemia, aiming to lower phosphate levels towards the normal range. 1. Dietary Management Patients with CKD stages 3 to 5 should be reviewed by a renal dietitian to obtain a baseline dietary history and to evaluate phosphate intake. Phosphate restriction can lead to control of hyperparathyroidism. In dialysis patients, the amount of dietary phosphate restriction that is necessary to achieve target values without the use of phosphate binders is likely to cause protein energy wasting. If phosphate levels are elevated dietary phosphate restriction should be individualised. In general, intake should be restricted to 800 to 1000mg/day when the serum phosphate is elevated above the upper limit of normal (1.5 mmol/l), by giving information about controlling intake of phosphate rich food (foods with a high phosphate content per gram of protein, as well as food and drinks with high levels of phosphate additives) to control serum phosphate, while avoiding malnutrition by maintaining a protein intake at the minimum recommended level. As GFR falls, the risk of malnutrition increases and hyperphosphataemia may be a sign of the need to start dialysis rather than poor concordance with diet/binders. All patients prescribed a phosphate binder should be referred to a renal dietitian. The dietary management of hyperphosphatemia should include the following as per NICE 2013: A specialist renal dietitian will need to carry out a dietary assessment and give individualised information and advice on dietary phosphate management. Advice on dietary phosphate management should be tailored to individual learning needs and preferences, rather than being provided through a generalised or complex multicomponent programme of delivery. Information about controlling intake of phosphate-rich foods (in particular, foods with a high phosphate content per gram of protein, as well as food and drinks with high levels of phosphate additives) to control serum phosphate, while avoiding malnutrition by maintaining a protein intake at or above the minimum recommended level. For people on dialysis, this should take into account possible dialysate protein losses. If a nutritional supplement is needed to maintain protein intake in people with hyperphosphatemia, offer a supplement with a lower phosphate content, taking into account patient preference and other nutritional requirements Regular dietary monitoring of patients with hyperphosphatemia is required. 2. Calcium based Phosphate Binders (1 st line therapy) Decisions to use phosphate binders and vitamin D therapy should be based on corrected calcium and phosphate results. If phosphate levels are progressively or persistently elevated (above CKD stage specific range see table above), despite dietary phosphate restriction, pharmacological treatment should usually be initiated with a calcium based phosphate binder. Calcium acetate should be used first line. Preparations available for use at NUH include Phosex (available in 1g tablets) and Renacet (available in 475mg and 950mg tablets). Both tablets should be swallowed whole. Renacet 475mg tablets are smaller than Phosex and Renacet 950mg tablets, and may be a useful option for patients that struggle to swallow larger preparations of calcium acetate (although they have a lower elemental calcium content, so patients will need to take more tablets to achieve an equivalent level of phosphate binding). Guidelines for the management of CKD Mineral Bone Disease/ September 2017/ Review September

6 Calcium carbonate (Calcichew ) is generally not recommended as a phosphate binder. It is less effective than calcium acetate and has a higher elemental calcium content which limits the maximum daily dose. Calcichew tablets should be chewed. Further information about formulation, starting doses, timing of binders and cost is contained in Appendix 1. Calcium acetate containing binders should be taken just before or with a meal. Calcium acetate may cause dyspepsia if taken without food. Calcium carbonate binders should be taken 10 to 15 minutes before meals on an empty stomach, because it is ph dependent. Phosphate binders should be prescribed in accordance with meal size and each patient s dietary habits. It is illogical to use a blanket prescription of 2 tablets tds for patients. Ranitidine, PPIs (protein pump inhibitors) and other drugs that increase gastric ph, may reduce phosphate binding by calcium carbonate. Dissociation of phosphate binders may differ between manufactures and formulations. It may be useful to try a different formulation, if phosphate control is poor despite patient concordance. There is increasing evidence that excess exposure to calcium through diet, medications or dialysis may be harmful across all categories of CKD. The revised KDIGO guidelines recommend restricting the dose of calcium-containing binders, although no specific advice is given on the maximum daily dose. NICE guidelines recommend the use of calcium acetate as a first line phosphate binder in addition to dietary management. Calcium based phosphate binders should be avoided in patients who are hypercalcaemic or at high risk of hypercalcaemia (Ca>2.5mmol/l), if PTH levels are low, or where there is evidence of established vascular calcification. The total daily dose of elemental calcium provided by calcium based phosphate binders should not exceed 1500mg, and the total daily intake of elemental calcium (including dietary) should not exceed 2000mg. 3. Non-Calcium Based Phosphate Binders (2 nd and 3 rd line agents) The commonest cause of continuing poor phosphate control is poor concordance with or timing of phosphate binders and diet. DO NOT increase the dose and/or add in newer and more expensive phosphate binders without checking concordance first. Refer and/or discuss with dietitians who are best at assessing concordance with phosphate binders as well as diet. Use sevelamer carbonate (generic) as a 2 nd line agent (more cost-effective). Lanthanum carbonate and sucroferric oxyhydroxide are available as 3 rd line agents, if sevelamer carbonate is not tolerated or is ineffective. Sevelamer carbonate (generic), lanthanum carbonate and sucroferric oxyhydroxide All 3 binders have been shown to be effective alternatives to calcium based phosphate binders. Their main advantage is a significantly reduced incidence of hypercalcaemia. The choice between them is often made based on patient preferences regarding the different formulations which are described in the table below. Sucroferric oxyhydroxide is only licensed for use in patients receiving peritoneal dialysis or haemodialysis. Lanthanum carbonate and sevelamer carbonate are both licensed in patients receiving peritoneal dialysis or haemodialysis and patients with CKD that are not receiving renal replacement therapy. Generic sevelamer carbonate is significantly more cost-effective to use than lanthanum carbonate or sucroferric oxyhydroxide. Guidelines for the management of CKD Mineral Bone Disease/ September 2017/ Review September

7 Sevelamer Carbonate (generic) Available as film coated tablets (that should be swallowed whole) and a sachet (containing powder for reconstitution). Reduces total and LDL cholesterol levels in ERF patients. Sevelamer may bind coadministered drugs and reduce absorption (e.g. warfarin). Lanthanum Carbonate (Fosrenol ) Available as chewable tablets and a sachet (the sachet contains powder that should be sprinkled on soft food; the powder is insoluble, so must not be mixed with liquid). Significantly higher cost than generic sevelamer carbonate Sucroferric oxyhydroxide (Velphoro ) Available as a chewable tablet that has a wild berry flavour. Most patients will require 3 to 4 tablets per day (maximum daily dose of 3g per day). Only licensed for use in peritoneal and haemodialysis patients. Significantly higher cost than generic sevelamer carbonate Further information about formulation, starting doses, timing of binders and cost is contained in Appendix 1. Criteria for the use of Sevelamer Carbonate, Lanthanum Carbonate and Sucroferric Oxyhydroxide Use of second and third line phosphate binders should be considered where: There is persistently elevated phosphate levels, despite dietary phosphate restriction and adherence to calcium based phosphate binders Intolerance (e.g. unmanageable side effects) to a calcium based phosphate binder Calcium levels above target on conventional treatment with calcium based phosphate binder therapy, despite adjustment of active vitamin D therapy to lowest effective dose Low intact PTH with high normal or elevated serum calcium Clinical evidence of established vascular calcification Prior to starting these binders, patients should be reviewed to ensure compliance with dietary phosphate restriction and their current prescription of binders. 4. Aluminium hydroxide (4 th line therapy) Long-term use may contribute to intellectual deterioration and to other features of aluminium toxicity. Aluminium hydroxide should be considered for short term use in situations where prompt reduction in hyperphosphataemia is required and other binders are not felt to be appropriate. Aluminium levels should be monitored every 3 months in all patients receiving aluminium hydroxide. When used for longer than 3 months, the dose of Alu-Cap Capsules should not exceed 2 tablets tds. Ideally maximum duration should not exceed 6 months. Aluminium hydroxide should not be used in combination with lanthanum carbonate. Aluminium hydroxide can significantly reduce the absorption of doxycycline when taken together, so Aluminium hydroxide should be withheld for the duration of the doxycycline course. 5. Possible drug interactions Phosphate binders may decrease absorption of antibiotics (notably quinolones and tetracyclines) considerably, if taken concurrently. Either administer antibiotics 2 hours before or at least 2 hours after the dose of these agents, or omit binders for the duration of antibiotic course. Guidelines for the management of CKD Mineral Bone Disease/ September 2017/ Review September

8 Phosphate binders may reduce absorption of levothyroxine. If patient is prescribed levothyroxine and is started on a phosphate binder, which after assessment by a dietitian needs to be taken with breakfast, the patient s GP should be asked to repeat TFT s in 4 to 6 weeks to assess thyroid function. Significant changes to phosphate binder regime in patients taking levothyroxine should prompt follow-up TFT s. Phosphate binders can significantly reduce the absorption of the integrase inhibitors raltegravir, dolutegravir and elvitegravir (note that these drugs are used in the management of HIV infection). Patients taking any of these drugs should be discussed with a renal dietitian, pharmacist or consultant nephrologist to decide upon the most appropriate regime of phosphate binders/dietary restriction for the patient. In general, patients taking anti-retrovirals for HIV infection should be discussed with a pharmacist prior to starting therapy with phosphate binders or cinacalcet. 6. Role of dialysis in phosphate control Phosphate control is generally easier on peritoneal dialysis compared to haemodialysis. Intensification of dialysis leads to better control of hyperphosphataemia. As a result of the slow equilibration of phosphate between body compartments, longer haemodialysis time (as would be achieved with nocturnal haemodialysis) or more frequent haemodialysis sessions are more efficient at phosphate removal than increased blood flow or dialyser clearance. In haemodialysis patients with hyperphosphataemia the minimum dialysis regime should be 4 hours 3 times per week. Also consider improving blood pump speed and increasing the dialyser surface area. Management of vitamin D deficiency in patients with CKD Low 25(OH) vitamin D levels have been associated with an increased risk of infection, malignancy, hypertension and diabetes. Justification for the identification and treatment of vitamin D substrate deficiency assumes independent benefits for non-activated vitamin D (ergocalciferol, colecalciferol) through tissue conversion of 25-hydroxyvitamin D (calcidiol) to 1,25-dihydroxyvitamin D (calcitriol). Vitamin D insufficiency appears to be common in the CKD population, perhaps the consequence of co-morbidity limiting access to sunlight, and may be a cause of early increases in PTH concentration. In addition, numerous observational studies show an association between low vitamin D levels and adverse clinical outcomes, although randomised trial evidence remains inconclusive. Although the benefits are unconfirmed, a reasonable case exists for the measurement of vitamin D in CKD. There is insufficient evidence to routinely recommend measurement or repletion in those patients who are already taking an active vitamin D sterol. Pending further data from ongoing studies it is not recommended that 25(OH) vitamin D is measured in patients on dialysis, unless there are specific indications such as falls or clinical evidence of a proximal myopathy. Serum 25(OH)D Concentration <25 nmol/l Vitamin D deficiency nmol/l Vitamin D insufficiency nmol/l Vitamin D Status Manifestation Management Borderline Insufficient - Adequate Risk of Rickets, Osteomalacia Associated with disease risk Healthy See below See below No supplementation required Lifestyle advice only >75 nmol/l Optimal Healthy None >125 nmol/l Potential for adverse effects Stop vitamin D supplements Guidelines for the management of CKD Mineral Bone Disease/ September 2017/ Review September

9 Symptoms of vitamin D deficiency Symptoms are generally of gradual onset but may show a seasonal variation (i.e. worse over winter months). Symptoms include: Limb girdle and back pain Muscle pain Proximal myopathy (difficulty climbing stairs, waddling gait) Low trauma fracture More rarely: seizures, tetany and hypocalcaemia. Symptomatic vitamin D deficiency (Vitamin D level < 25nmol/L AND symptoms) Patients meeting the above criteria should be managed as follows: For both primary and secondary care prescribing, use Invita D3 25,000 units/ml oral solution; prescribe 50,000 UNITS, once a week, for 6 weeks. Invita D3 does not contain peanut oil or soya and is therefore suitable for use in patients with peanut or soya allergies. Oral therapy is more effective than IM injections, except where there is malabsorption. Where poor compliance is suspected, give supervised stat oral doses of 100,000 UNITS at weekly intervals, for a total of 3 to 6 weeks. Most patients only require a single course of high dose therapy and can then be managed on long term maintenance colecalciferol 800 to 1600 units once a day. Colecalciferol can be purchased over the counter (see appendix 4) or prescribed as Desunin (licensed Vitamin D preparation containing colecalciferol 800 units per tablet). Desunin does not contain peanut oil or soya and can therefore be used in individuals with peanut and/or soya allergies. Maintenance therapy should be commenced immediately after completion of high dose therapy. Serum calcium should be checked 3 to 4 weeks after initiation of high dose vitamin D therapy. Calcium, phosphate, alkaline phosphatase and PTH should be checked 12 weeks after starting therapy. Routine repeat of vitamin D levels is not needed if symptoms of vitamin D deficiency resolve. If symptoms do not resolve, despite adequate vitamin D repletion, then the symptoms are not due to vitamin D deficiency. If significant hypercalcaemia develops, vitamin D supplements should be discontinued. Asymptomatic vitamin D deficiency (Vitamin D level <25nmol/L AND no symptoms, Vitamin D level 25 to 50nmol/l) Patients should be treated with colecalciferol 800 to 1600 units once a day. Colecalciferol may be purchased over the counter (see appendix 4 for a list of suitable preparations) or prescribed as Desunin 800 to 1600 units once a day. Suppression of elevated PTH in CKD Stages 3, 4 and 5 (not on dialysis) In patients with CKD not yet on dialysis, the optimal PTH level is not known. Patients with PTH levels, that are progressively rising or persistently above the upper end of the normal range, should be evaluated for modifiable factors, including high dietary phosphate intake, hyperphosphataemia, hypocalcaemia and vitamin D deficiency. Patients should be referred to a renal dietitian to assess dietary phosphate intake (refer to management of hyperphosphatemia section). Ensure 25 (OH) vitamin D levels are optimal (>50nmol/l). If 25 (OH) vitamin D levels are suboptimal, treat as outlined above. It is reasonable to repeat 25 (OH) vitamin D levels after 3 to 6 months treatment, to ensure patients are on an adequate maintenance dose of colecalciferol, but multiple repeat 25 (OH) vitamin D assays are expensive and rarely helpful. Guidelines for the management of CKD Mineral Bone Disease/ September 2017/ Review September

10 PTH suppression therapy with active vitamin D or vitamin D analogues should not be routinely used. Recent RCTs of vitamin D analogues failed to demonstrate improvements in clinically relevant outcomes, but demonstrated increased risk of hypercalcemia. Active vitamin D therapy should be reserved for patients with severe and progressive hyperparathyroidism. Hypercalcaemia should be avoided. Suppression of High or Increasing PTH in Established Renal Failure (CKD Stage 5D) 1. Dietary Management Dietary phosphate should be restricted to 800 to 1000mg/day when levels of PTH are elevated above target range; patients should be referred to a renal dietician (refer to the Management of hyperphosphatemia section). 2. Criteria for Initiation of Active Vitamin D therapy All of the following criteria should be met before initiating vitamin D therapy: PTH increasing progressively and above target Corrected Calcium <2.5 mmol/l Serum phosphate <2.0 mmol/l Other considerations prior to initiating vitamin D therapy Treatment decisions should be made after considering trends in PTH (i.e. not based on a single result) and should take into account calcium and phosphate levels. Control phosphate first; vitamin D therapy increases calcium and phosphate absorption from the gut, and will exacerbate hyperphosphataemia. Assess patient adherence to prescribed dietary modifications and phosphate binder therapy. Reinforce patient education. If the patient has a history of hypercalcaemia, or serum Calcium >2.4 mmol/l, consider using a low calcium dialysate to reduce the likelihood of hypercalcaemia. Active vitamin D therapy should not be used in patients with sarcoidosis due to the risk of hypercalcaemia. Vitamin D therapy should be started with alfacalcidol. Oral calcitriol is an alternative; it is as effective and equipotent as alfacalcidol, but more expensive. Initial starting dose of alfacalcidol is 0.25 micrograms ONCE daily, at night. 3. Monitoring Vitamin D therapy Calcium, albumin, phosphate and alkaline phosphatase should be monitored monthly in dialysis patients. Corrected calcium and phosphate should be checked 2 weeks after any change in calcaemic therapy. 4. Evaluation of Vitamin D therapy Hypercalcaemia Vitamin D therapy should be withheld if serum Ca >2.6 mmol/l. Serum calcium should be monitored at least weekly, until the patient becomes normocalcaemic. Vitamin D therapy should then be restarted at 50% of the previous dose. Other measures to prevent hypercalcaemia include:- o Withdrawal or reduction of calcium containing phosphate binders, o Change to a non-calcium containing phosphate binder, o Change to low calcium dialysate, Guidelines for the management of CKD Mineral Bone Disease/ September 2017/ Review September

11 o Ensure patient is taking binders with meals and that vitamin D therapy is taken at night. o Ensure no over the counter Vitamin D and or calcium preparations are being taken. Always bear in mind rarer causes of hypercalcaemia; these include granulomatous disease, malignancy, immobilisation, hyperthyroidism, hypervitaminosis D and A, and Addison s disease. Elevated phosphate Consider temporarily holding vitamin D therapy if phosphate persistently >2.0. Vitamin D therapy can be restarted once adequate phosphate control is achieved. 5. Titration of Vitamin D dose PTH should be repeated after 8 to 12 weeks of therapy and the dose of vitamin D titrated appropriately (see flow sheet). Maximum doses rarely exceed 8 micrograms per dialysis session or 4 micrograms per day. 6. Oversuppression of PTH Optimal PTH is between 144 and 648 ng/l. If PTH <144 ng/l, vitamin D therapy should be withheld until PTH >200 ng/l, and then restarted at a reduced dose. Patients should be observed for symptoms of hypercalcaemia, as this is often associated with oversuppression of PTH. Serum calcium and phosphate should be monitored at least monthly. 7. Non-response Potential causes of hyporesponsiveness to vitamin D include inadequate dietary phosphate restriction and lack of adherence to prescribed vitamin D treatment. Pulsed oral alfacalcidol or calcitriol, or IV alfacalcidol therapy can be supervised on the dialysis unit for haemodialysis patients if necessary. After evaluating these factors, increase the dose of vitamin D up to the maximal dose tolerated. Non-responsive patients with severe hyperparathyroidism should be evaluated for parathyroidectomy or treatment with cinacalcet or etelcalcetide. 8. Use of Intravenous alfacalcidol If there are concerns about concordance with oral alfacalcidol or calcitriol then directly observed pulsed oral alfacalcidol or calcitriol therapy should be considered first, when patients attend for haemodialysis. In rare cases where the oral route isn t tolerated or appropriate, IV dosing can be used. IV alfacalcidol should be administered as a bolus over 30 seconds into the venous return line at the end of each dialysis session. The initial starting dose should be 1 microgram per HD session. The dose can be titrated up to a maximum of 6 micrograms per haemodialysis session, and not more than a total of 12 micrograms per week (in divided doses). Paricalcitol therapy for management of hyperparathyroidism in patients with CKD Paricalcitol is indicated for the prevention and treatment of secondary hyperparathyroidism associated with CKD Stages 3, 4 and 5 and for patients on haemodialysis or peritoneal dialysis. Paricalcitol is a synthetic, biologically active vitamin D analogue of calcitriol, which selectively activates the vitamin D receptor (VDR) in the parathyroid glands. The term selective means that the molecule acts mostly on the parathyroid gland, more so than on intestine and bone. Paricalcitol also up-regulates the calcium sensing receptor in the parathyroid glands. As a result, paricalcitol Guidelines for the management of CKD Mineral Bone Disease/ September 2017/ Review September

12 reduces parathyroid hormone (PTH) levels by inhibiting parathyroid proliferation and decreasing PTH synthesis. Head to head studies comparing calcitriol and paracalcitol are limited but show a similar reduction in PTH levels and a low incidence of hypercalcaemia (which was not different between the two agents). Recent clinical studies have not shown any impact of paracalcitol therapy on left ventricular mass. Paricalcitol is significantly more expensive than alfacalcidol and calcitriol. Paracalcitol is available as an oral tablet. Criteria for use of paricalcitol Paricalcitol should be considered in the following groups of patients: 1. Peritoneal dialysis patients who meet the criteria for use of cinacalcet but who are intolerant of cinacalcet. Etelcalcetide should be used in haemodialysis patients who are intolerant of cinacalcet. 2. Patients with CKD Stages 3 to 5D with refractory hyperparathyroidism, who are intolerant of alfacalcidol and calcitriol and are not hypercalcaemic. Oral Paricalcitol Use Starting dose Initial dose should be based on baseline PTH as described in the table below. Baseline ipth Level Daily Dose Three Times a Week Dose* 500 ng/l 1 microgram 2 micrograms > 500 ng/l 2 micrograms 4 micrograms * To be administered no more frequently than every other day Dose Titration PTH Level Relative to Baseline The same or increased Decreased by < 30% Dose Adjustment at 2 to 4 Week Intervals Daily Dose Increase 1 microgram Three Times a Week Dose 1 Increase 2 micrograms Decreased by 30%, 60% Maintain Maintain Decreased > 60% Decrease 2 PTH < 60 ng/l 1 microgram Decrease 2 2 micrograms 1 To be administered no more frequently than every other day. 2 If a patient is taking the lowest dose on the daily or three times a week regimen, and a dose reduction is needed, dosing frequency can be decreased. Monitoring Initiation or dose titration PTH baseline, then monthly. Corrected calcium within 1 week of initiation, then weekly until maintenance dose established. Maintenance dose PTH 1-3 months. Corrected calcium monthly. Guidelines for the management of CKD Mineral Bone Disease/ September 2017/ Review September

13 Paricalcitol should only be prescribed after agreement by a Consultant Nephrologist. Response to treatment should be monitored regularly and treatment should only be continued if a reduction in the plasma level of intact parathyroid hormone of 30% or more is seen within 6 months of treatment, including dose escalation as appropriate. Side effects CKD 3 and 4 common side effects include stomach discomfort, rash, pruritus. CKD 5 common side effects include dizziness, diarrhoea, GI reflux, acne, hypercalcaemia, hypocalcaemia, hyperphosphataemia, taste perversion, headache, decreased appetite and breast tenderness. Cinacalcet therapy for management of severe hyperparathyroidism in patients with Established Renal Failure Cinacalcet hydrochloride (Mimpara ) is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to extracellular calcium ions, thereby inhibiting the release of PTH. It is licensed for treatment of secondary hyperparathyroidism in patients with ERF on maintenance dialysis therapy. It may be used as part of a therapeutic regimen including phosphate binders and or vitamin D sterols, as appropriate. Cinacalcet is not licensed for use in transplant patients or patients that are not receiving dialysis. An appraisal of the use of cinacalcet for the treatment of secondary hyperparathyroidism in patients with established renal failure on dialysis was completed by NICE in Criteria for the use of cinacalcet in a restricted group of patients is detailed below. Indications for the prescription of cinacalcet Cinacalcet hydrochloride is not recommended for the routine treatment of secondary hyperparathyroidism in patients with established renal failure on maintenance dialysis therapy. Cinacalcet hydrochloride is recommended only in those patients with refractory secondary hyperparathyroidism (including those with calciphylaxis): who have very uncontrolled plasma levels of intact parathyroid hormone (defined as greater than 800 ng/l) that are refractory to standard therapy*, and a normal or high adjusted calcium level, and in whom surgical parathyroidectomy is contraindicated, in that the risks of surgery are considered to outweigh the benefits. *Standard therapy includes diet, adequate dialysis, the use of maximal tolerated doses of phosphate binders and vitamin D. Response to treatment should be monitored regularly and treatment should only be continued if a reduction in the plasma level of intact parathyroid hormone of 30% or more is seen within 6 months of treatment, including dose escalation as appropriate. Cinacalcet should only be prescribed after agreement by a Consultant Nephrologist. Before prescribing seriously consider whether the long-term benefits will be realised in patients with multiple co-morbid conditions and limited life expectancy. Dosing and administration Cinacalcet tablets are for oral use and should be taken with food or shortly after a meal. Cinacalcet is available as 30mg, 60mg and 90mg tablets. Guidelines for the management of CKD Mineral Bone Disease/ September 2017/ Review September

14 The recommended starting dose for adults is 30 mg once per day. The dose of cinacalcet should be titrated every 2 to 4 weeks up to a maximum dose of 180 mg once daily to achieve a target PTH level of between ng/l. PTH levels should be assessed at least 12 hours after dosing with cinacalcet. Unless serum Ca >2.6mmol/l cinacalcet should be co-prescribed with low dose alfacalcidol (0.25 microg) to prevent hypocalcaemia. If the PTH remains above target, the dose of cinacalcet should be increased unless the serum calcium is < 2.1 mmol/l, the patient is receiving 180mg of cinacalcet, or the patient is experiencing an adverse event that precludes dose escalation. If PTH falls to <144 ng/l, reduce cinacalcet to next lowest dose. If at 30mg day, reduce to 30mg 3 x week. If PTH < 72 ng/l stop cinacalcet. Monitoring cinacalcet therapy Hypocalcemia is common when using cinacalcet and careful monitoring is required. Calcium and phosphate levels should initially be checked weekly for the first 2 weeks following initiation. If stable, reduce frequency to every 2 weeks for a total of 4 weeks, then return to monthly measurements. PTH should be checked monthly for all patients on cinacalcet. If Ca < 2.1 mmol/l consider: o Increasing dialysate calcium concentration o Changing to a calcium containing phosphate binder if taking sevelamer carbonate, lanthanum carbonate or sucroferric oxyhydroxide. o Increasing dose of/or reintroducing alfacalcidol o Adding calcium supplementation If hypocalcaemia persists, reduce the dose or stop cinacalcet Intensive monitoring should be reinstituted after a dose increase. Adverse effect profile The most commonly reported adverse events are nausea and vomiting, occurring in around a third of patients. Nausea and vomiting were mild to moderate in severity and transient in nature. Other adverse reactions are listed below: Very common: nausea, vomiting. Common: anorexia, dizziness, paraesthesia, rash, myalgia, asthenia, hypocalcaemia, reduced testosterone levels. Uncommon: seizures, dyspepsia. Drug interactions Cinacalcet is metabolised by the enzymes CYP3A4 and CYPA12. Dose adjustment of cinacalcet may be required if a patient receiving cinacalcet initiates or discontinues therapy with a strong inhibitor (e.g. ketoconazole, itraconazole, ciprofloxacin) or inducer (e.g. rifampicin) of these enzymes. Cinacalcet is a strong inhibitor of CYP2D6; doses of drugs metabolised by this enzyme (e.g. amitriptyline, metoprolol, flecainide, propafenone) may need to be reduced, if taken concurrently with cinacalcet. Multiple oral doses of cinacalcet did not affect the pharmacokinetics or pharmacodynamics of warfarin. Guidelines for the management of CKD Mineral Bone Disease/ September 2017/ Review September

15 Etelcalcetide therapy for management of severe hyperparathyroidism in Haemodialysis Patients Cinacalcet directly lowers PTH levels by increasing the sensitivity of the calcium sensing receptor to extracellular calcium. Etelcalcetide (Parsabiv ) is a synthetic peptide that reduces PTH levels by binding to and activating the calcium sensing receptor. It is administered intravenously at the end of haemodialysis, three times per week. Prescribing/Funding of Etelcalcetide Etelcalcetide should only be used on the advice of a consultant nephrologist. NHS England will only commission etelcalcetide for patients that have been registered (before treatment is started) via the Blueteq system (available at: Prescribers will have to complete an online declaration to confirm that each patient meets the following criteria: The patient has secondary hyperparathyroidism The patient has CKD and is on haemodialysis A calcimimetic is indicated, but cinacalcet is not suitable The patient will receive the licensed dose and frequency of etelcalcetide Etelcalcetide will not be funded by NHS England, for patients that do not meet the criteria listed above, or who are not registered via the Blueteq system. Indications for the prescription of Etelcalcetide Etelcalcetide is indicated for haemodialysis patients who meet the criteria for the use of cinacalcet, but cinacalcet is either contra-indicated or patients are unable to tolerate an appropriate therapeutic dose due to side effects. Dosing and administration Etelcalcetide is available in 3 different IV preparations: 2.5mg in 0.5ml of solution 5mg in 1ml of solution 10mg in 2ml of solution Patients taking cinacalcet should discontinue cinacalcet at least 7 days before starting etelcalcetide. The recommended initial dose of etelcalcetide is 5mg, administered by IV bolus, 3 times per week. Etelcalcetide is administered by bolus injection into the venous line of the dialysis circuit at the end of the haemodialysis treatment, during wash-back or intravenously after wash-back. When given during wash-back at least 150 ml of wash-back volume should be administered after injection. If wash-back is completed and etelcalcetide was not administered, then it may be administered intravenously followed by at least 10 ml flush with 0.9% sodium chloride. Corrected serum calcium should be 2.2 mmol/l prior to administration of the first dose of etelcalcetide. Etelcalcetide should not be administered more than 3 times a week. If a patient misses a regularly scheduled haemodialysis session, the missed dose of etelcalcetide should not be administered. Etelcalcetide should be administered at the next haemodialysis session, at the same dose. If doses are missed for more than 2 weeks, Guidelines for the management of CKD Mineral Bone Disease/ September 2017/ Review September

16 etelcalcetide should be restarted at a dose of 5mg (or 2.5mg if that was the last prescribed dose). Monitoring etelcalcetide therapy Hypocalcaemia is common when using etelcalcetide and careful monitoring is required. Calcium and phosphate levels should be checked 1 week after initiation of etelcalcetide and after any dose change. Once the maintenance dose of etelcalcetide has been established, corrected serum calcium should be measured approximately every 4 weeks. PTH should be checked monthly for all patients who receive etelcalcetide. Etelcalcetide dose should be adjusted in 2.5mg or 5mg increments when PTH is above the target range (provided serum calcium is 2.2 mmol/l). The maximum dose of etelcalcetide is 15mg 3 times per week. Doses should not be increased more frequently than monthly. Reduce or temporarily discontinue etelcalcetide therapy if PTH is below target range (<144 ng/l). Ordering Supplies of Etelcalcetide Etelcalcetide should be ordered as a named-patient supply from TRUST Pharmacy at NCH. It is the responsibility of the prescriber to write a prescription, complete a Blueteq registration form, and to notify the renal pharmacy team of any new patients that are initiated on etelcalcetide (so that a supply can be organised). Satellite dialysis units must notify the renal pharmacy team, at least 2 weeks before existing supplies of etelcalcetide are exhausted for patients, so that a new supply can be organised in a timely manner. Dose titration based on serum Calcium levels Corrected serum calcium value or clinical symptoms of hypocalcaemia <2.08 mmol/l and 1.88 mmol/l Recommendations If clinically indicated: Start or increase calcium supplements, calcium containing phosphate binders, and or, alfacalcidol/calcitriol. Increase dialysate calcium concentration. Consider reducing Etelcalcetide dose. <1.88 mmol/l or symptoms of hypocalcaemia Stop Etelcalcetide until corrected serum calcium levels are 2.08mmol/L and symptoms of hypocalcaemia (if present) have resolved. If clinically indicated: Start or increase calcium supplements, calcium containing phosphate binders, and/or alfacalcidol/calcitriol. Increase dialysate calcium concentration. Reinitiate Etelcalcetide at a dose 5 mg lower than the last administered dose. If patient s last administered dose was 2.5 mg or 5 mg, reinitiate at 2.5 mg once corrected serum calcium levels are 2.08 mmol/l and symptoms of hypocalcaemia (if present) have resolved. Guidelines for the management of CKD Mineral Bone Disease/ September 2017/ Review September

17 Parathyroidectomy Indications 1. Therapy resistant hypercalcaemia and hyperphosphataemia in the presence of elevated PTH levels (usually >800 ng/l). 2. Biomechanical problems caused by hyperparathyroidism e.g. fractures, severe bone / muscle pain (exclude osteomalacia and other bone diseases). 3. Calciphylaxis. 4. Metastatic soft tissue calcification. 5. Severe intractable pruritus. All potential patients should be discussed with a Consultant Nephrologist. Referrals should be made to Mr Rigg (until 30th April 2018) or Mr Dutta. Aluminium bone disease should be excluded. Patients exposed to aluminium hydroxide for more than 3 months should have a serum aluminium level sent. Particularly complex patients may benefit from a bone biopsy to evaluate bone turnover and confirm hyperparathyroid bone disease prior to surgery. In general patients will undergo a sub-total parathyroidectomy. Patients requiring redo parathyroid surgery will undergo a completion (total) parathyroidectomy. Pre-operative management Routine parathyroid imaging is not necessary unless the patient has had previous parathyroid surgery. Start alfacalcidol 2 micrograms bd for 48 hours pre-op. Stop cinacalcet on day of admission. Post-operative Monitoring The target range for serum calcium post operatively is mmol/l. Minimum monitoring for Calcium / Phosphate /PTH Day of surgery Four hours and ten hours post-op and then six hourly until calcium has stopped falling. Start Sandocal to 2 tablets bd immediately postoperatively. Day 1 post op Calcium, phosphate and PTH Rest of stay Daily until discharge unless calcium <2.0mmol/l when more frequent monitoring should be initiated. (In case of supply issues with Sandocal 1000, Calcichew Forte is an alternative and contains the same amount of elemental calcium per tablet as Sandocal 1000 ) Routine review of medication (day of operation) Change to 1.5 mmol calcium dialysate (if on haemodialysis) or 1.75 mmol calcium PD fluid. Review phosphate binders. Stop sevelamer carbonate, lanthanum carbonate or sucroferric oxyhydroxide. Start calcium acetate as a phosphate binder if necessary. Management of mild symptoms and calcium >1.8 mmol/l Continue alfacalcidol 1-6 microgram/day according to serum calcium Guidelines for the management of CKD Mineral Bone Disease/ September 2017/ Review September

18 Start oral calcium supplementation usually with Sandocal tablets bd, but increase if calcium continues to fall/fails to rise. Each Sandocal 1000 tablet provides 25 mmol of elemental calcium. Medication should be taken between meals to maximise calcium absorption (and not before food). Management of severe symptoms and/ or corrected calcium <1.8 mmol/l Calcium gluconate 10%: 10mls = 2.2 mmol calcium Intravenous calcium is indicated if the patient develops rapid and progressive falls in serum calcium or develops symptoms related to hypocalcaemia, or plasma calcium below 1.8 mmol/l. In emergency give slow IV bolus of 10mls of 10% calcium gluconate via a patent, non-tissued cannula over at least 5 minutes. Extravasation of IV calcium can lead to extensive skin necrosis. Otherwise administer 10 to 20mls of 10% calcium gluconate, diluted in 100mls of 5% glucose, over 10 to 20 minutes. An infusion is often required initially; dilute 10 ampoules of 10% calcium gluconate in 250mls of 5% glucose and infuse at 20 to 30 mls/hour ( mmol/kg/hour) in an attempt to maintain the serum calcium above 2 mmol/l. Monitor calcium closely (2 to 8 hourly). If Ca <2.0 mmol/l double rate of infusion. Calcium gluconate can also be administered during haemodialysis. One to three ampoules of calcium gluconate can also be added to each bag of PD fluid. Check Mg intermittently in patients who are hypocalcaemic. Follow up following discharge Inform dialysis unit, PD team or transplant clinic on discharge. Monitor biochemistry regularly. Frequency Corrected Calcium 2 to 3 times per week When stable reduce to weekly If remains stable Phosphate and Alk Phos Weekly Duration (minimum) 2 weeks 4 weeks Monthly 2 weeks The activity of alkaline phosphatase increases initially. When alkaline phosphatase starts to fall the ability of the skeleton to trap calcium decreases and the risks of hypercalcaemia increase considerably. The dose of alfacalcidol or calcitriol should be reduced as the alkaline phosphatase approaches normal to avoid over-shooting the serum calcium (see table below). Following total parathyroidectomy, the majority of patients will need to remain on long-term low dose alfacalcidol or calcitriol. A rapid fall in serum calcium may occur if alfacalcidol or calcitriol therapy is discontinued. Corrected calcium (mmol/l) Alfacalcidol/Calcitriol dose Calcium dose <1.8 Double Admit for IV calcium >1.8 and <2.0 Double Double >2.0 and <2.6 and stable No change No change >2.0 and <2.6 but trend Reduce total dose by 25% - Guidelines for the management of CKD Mineral Bone Disease/ September 2017/ Review September