Guidelines for the Management of Chronic Kidney Disease Mineral Bone Disease in Adults

Nottingham Renal and Transplant Unit Guidelines for the Management of Chronic Kidney Disease Mineral Bone Disease in Adults Author: Contact Name and ...
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Nottingham Renal and Transplant Unit

Guidelines for the Management of Chronic Kidney Disease Mineral Bone Disease in Adults Author: Contact Name and Job Title

SD Roe, Consultant Nephrologist

Directorate & Speciality

Cancer and Associated Specialities (Renal/Transplant)

Date of submission

September 2015

Explicit definition of patient group to which it applies (e.g. inclusion and exclusion criteria, diagnosis)

Applies to: All patients under the care of the Nottingham Renal and Transplant Unit (including patients dialysing at Kings Mill Hospital and Ilkeston Community Hospital and Diaverum Clinic Lings Bar Hospital). Exclusion: Patients without Chronic Kidney Disease

Version

Revised September 2015

If this version supersedes another clinical guideline please be explicit about which guideline it replaces including version number.

Replaces previous version dated 2013

Statement of the evidence base of the guideline – has the guideline been peer reviewed by colleagues?

These guidelines were developed in conjunction with medical and nursing staff within the renal unit. Evidence level ranges from 3 – 5.

Evidence base: (1-6) 1

NICE Guidance, Royal College Guideline, SIGN (please state which source).

2a

meta analysis of randomised controlled trials

2b

at least one randomised controlled trial

3a

at least one well-designed controlled study without randomisation

3b

at least one other type of well-designed quasi-experimental study

4

well –designed non-experimental descriptive studies (ie comparative / correlation and case studies)

5

expert committee reports or opinions and / or clinical experiences of respected authorities

6

recommended best practise based on the clinical experience of the guideline

Guidelines for the management of CKD Mineral Bone Disease/ September 2015/ Review September 2018

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developer

Consultation Process

These guidelines were developed in conjunction with medical, pharmacy, nursing and dietetic staff within the renal unit.

Ratified by:

Renal Unit Senior Staff Meeting

Date:

September2015

Target audience

Renal unit medical and nursing staff

Review Date: (to be applied by the Integrated Governance Team)

September 2018

A review date of 5 years will be applied by the Trust. Directorates can choose to apply a shorter review date; however this must be managed through Directorate Governance processes. 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.

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Evidence base of policy: These guidelines have been derived using the following evidence base. 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. th 5 edition (reviewed March 2015). 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. 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. 5. Cinacalcet for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease on maintenance dialysis therapy. NICE technology appraisal guideline no 117, 2007. 6. British National formulary August 2015

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 ta rget range 5. Proportion of patients taking calcium containing binders, non-calcium containing binders or no binders 6. Adherence to NICE guidelines for use of cinacalcet.

Training and implementation: The guidelines will be available on both renal wards and on the dialysis units. The guidelines are also available on the renal unit network and the NUH clinical guidelines database. New members of staff will be made aware of the guidelines as part of their induction programme.

Limitations of evidence base: There is limited evidence base to support recommendations regarding the correction of 25 (OH) vitamin D deficiency in patients with advanced CKD or those on dialysis.

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Background Progressive chronic renal failure leads to reduced phosphate excretion in the urine, decreased production of endogenous 1,25 (OH) 2 vitamin D3 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 turnover) bone disease has been increasingly recognised in patients with established renal failure, 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. 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 calcific ation. Aims of management are the maintenance of healthy skeletal architecture by controlling phosphate, achieving normocalcaemia and by 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. Difficult cases should always be discussed at a senior level.

NUH Laboratory Normal Ranges Parameter

Normal Range

Phosphate

0.8-1.45 mmol/l

Calcium (corrected)

2.2-2.6 mmol/l

PTH

14-72 ng/l

Alkaline phosphatase

40-130 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 15-59

5 non dialysis GFR 50 nmol/l

> 50 nmol/l (by extrapolation from general population)

1

Audit standard is 2.2-2.5mmol/l

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3-4 GFR 15-59 Bicarbonate

Normal reference range 22-30 mmol/l

Alkaline phosphatase Normal range 40-130 u/l

5 non dialysis GFR 2.6 mmol/l) or whose plasma PTH levels are 125 nmol/l

Optimal Potential for adverse effects

Manifestation Risk of Rickets, Osteomalacia Associated with disease risk

Management See below See below

Healthy

No supplementation required Lifestyle advice only

Healthy

None Stop vitamin D supplements

Symptoms of vitamin D deficiency Symptoms are generally of gradual onset but may show a seasonal variation (ie worse over the 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 2.0. Vitamin D therapy can be restarted once phosphate control has been achieved.

6. Titration of Vitamin D dose PTH should be repeated after 8-12 weeks of therapy and the dose of vitamin D titrated appropriately (see flow sheet). Maximum doses rarely exceed 8g/ dialysis session or 4g/day. 7. Oversuppression of PTH Optimal PTH is between 144 and 648 ng/l. If 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. 8. 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/ 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 paracalcitrol/ cinacalcet therapy. 9. Use of Intravenous alfacalcidol Intravenous alfacalcidol can be used for haemodialysis patients. If there are concerns about concordance with oral alfacalcidol then directly observed pulsed oral alfacalcidol therapy should be considered first when patients attend for haemodialysis. In rare cases where the oral route isn’t tolerated/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. Initial dose should be 1 microgram per session. Dose can be titrated up (to a maximum of 6 micrograms per haemodialysis session and not more than 12 micrograms per week). Guidelines for the management of CKD Mineral Bone Disease/ September 2015/ Review September 2018

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Paricalcitol therapy for management of hyperparathyroidism in patients with CKD Paricalcitol is indicated for the prevention and treatment of secondary hyperparathyroidi sm associated with CKD Stages 3 and 4 patients and CKD Stage 5 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 therefore has an improved safety profile with regards to hypercalcaemia and hyperphosphataemia, which makes it more effective than alfacalcidol or calcitriol. Paricalcitol also up-regulates the calcium sensing receptor in the parathyroid glands. As a result, paricalcitol reduces parathyroid hormone (PTH) levels by inhibiting parathyroid proliferation and decreasing PTH synthesis, with minimal impact on calcium and phosphorus levels and can act directly on bone cells to maintain bone volume and improve mineralisation surfaces. Selective VDR-activation agents are reported to have anti-inflammatory and antithrombotic effects, and could inhibit vascular smooth muscle cell proliferation, the renin-angiotensin system, and vascular calcification and stiffening, and could regress left-ventricular hypertrophy. Paricalcitol is however significantly more expensive than alfacalcdiol and calcitriol. Criteria for use of paricalcitol Paricalcitol should be considered in the following groups of patients: 1. Dialysis patients who meet the criteria for use of cinacalcet but are intolerant to cinacalcet. 2. Patients with Stage 3-5 CKD with corrected calcium levels of >2.5 mmol/l and rising and PTH >500 ng/l (would not meet the criteria for cinacalcet use), despite stopping calcium containing binders and the use of alfacalcidol/ calcitriol. 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

Dose Adjustment at 2 to 4 Week Intervals Daily Dose Three Times a Week Dose 1

The same or increased Decreased by < 30%

Increase 1 microgram

Increase 2 micrograms

Decreased by ≥30%, ≤60% Decreased > 60%

Maintain Decrease2

Maintain Decrease2

PTH < 60 ng/L

1 microgram

2 micrograms

1

To be administered no more frequently than every other day. 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. 2

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IV Paricalcitol Use for patients on Haemodialysis Starting dose Initial dose should be based on baseline PTH and calculated according to the formula; baseline PTH in ng/l 80 and administered as an IV bolus up to a maximum of three times a week on dialysis. The maximum dose safely administered in clinical trials was as high as 40 micrograms. Appendix 5 gives more information on dosing for IV paricalcitol. Dose Titration PTH Level Relative to Baseline

Dose Adjustment at 2 to 4 Week Intervals Paricalcitol Dose Adjustment

Same or increased Decreased by < 30% Decreased by ≥30%, ≤60% Decreased > 60% PTH < 60 ng/L

Increase by 2 to 4 micrograms Maintain Decrease by 2 to 4 micrograms

Monitoring Initiation or dose titration PTH baseline, then monthly. Corrected calcium within 1 week of initiation, then weekly until maintenance dose esta blished. Maintenance dose PTH 1-3 months. Corrected Calcium monthly. Paricalcitol should only be prescribed after agreement by a Consultant Nephrologist. Response to treatment should be monitored regularly and treatment should be continued only 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 which 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 ESRD 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 transplan t patients or patients not yet on dialysis.

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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 2007. 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 end-stage renal disease 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 (d efined 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. Response to treatment should be monitored regularly and treatment should be continued only 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. *Standard therapy includes diet, adequate dialysis, the use of maximal tolerated doses of phosphate binders (including sevelamer and lanthanum carbonate) and vitamin D.

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 are recommended to be taken with foo d or shortly after a meal. Cinacalcet is available as 30mg, 60mg and 90mg tablets. The recommended starting dose for adults is 30 mg once per day. Cinacalcet should be titrated every 2 to 4 weeks to a maximum dose of 180 mg once daily to achieve a target PTH of between 144-648 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 mcg) to prevent hypocalcaemia.  

If the PTH remains above target, the dose of cinacalcet should be increased unless the serum calcium is 500 & increasing

1. Reduce dialysate Ca 2. Switch Ca based binders to non-Ca based binders 3. Check no over the counter Ca containing medication

Ca 2.2-2.5*

*2.6 in non-dialysis patients

Yes

No

Start alfacalcidol

Consider paricalcitol

Guidelines for the management of CKD Mineral Bone Disease/ September 2015/ Review September 2018 22

Algorithm 3: Management of falling PTH or PTH below target in all renal patients If PTH is decreasing or is below target

Is the patient on cinacalcet?

Yes

No Suspend or reduce alfacalcidol1/ paracalcitol dose

Is Calcium high?

Yes

No

Reduce alfacalcidol1 dose by 50%

Reduce cinacalcet dose

Continue to monitor bone profile & PTH monthly 1

Or calcitriol

Review Calcium

Low

In range

Consider calcium supplements

High

Consider changing Ca to non-Ca containing binder

Continue to monitor bone profile & PTH monthly

Guidelines for the management of CKD Mineral Bone Disease/ September 2015/ Review September 2018 23

Appendix 1: Phosphate Binders Name

Composition

Pharmaceutical Calcium form content per tablet

Administration

Starting dose

Maximum daily dose

Cost (approx., NHS list price)

Comments

Calcium acetate (Phosex®)

1000mg

250mg

Swallowed whole with a meal

1 per meal

6 tablets

£20 per 180

Inexpensive. First line binder. GI side effects.

Calcium acetate (Renacet)

475mg

Oval yellow tablet. Lemon meringue flavour. White, round, convex, filmcoated tablets

120mg

Swallowed whole with a meal

14 tablets (as per SPC)

£10 for 200 tablets

Alternative 1st line binder. May be better tolerated than Phosex®.

Calcium carbonate (Calcichew®)

1250mg

Rounded 500mg white, uncoated tablet. Orange flavour.

Chewed or sucked 10-15 mins before a meal

1 per meal for CKD 3-5 2 per meal for dialysis patients 1 per meal

3 tablets

£10 per 100

Calcium carbonate (Adcal®)

1500mg

600mg

Chewed or sucked 10-15 mins before a meal

1 per meal

3 tablets

£8 per 100

Sevelamer hydrochloride (Renagel®)

800mg

Rounded white, uncoated tablet. Fruit flavour. Oval, filmcoated tablet. No taste

None

Swallowed whole with a meal

2 per meal

12 tablets

£141 per 180

Not licensed as phosphate binder. Higher elemental calcium content than calcium acetate. Requires acid pH. Higher elemental calcium content than calcium acetate. Requires acid pH. Not licensed for CKD patients not on dialysis. Potential for reduced bicarbonate levels

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Name

Composition

Pharmaceutical Calcium form content per tablet

Administration

Starting dose

Maximum daily dose

Cost

Comments

Lanthanum carbonate (Fosrenol®)

500mg

White, round, bevelled-edge flat tablets. No taste

None

Taken with or immediately after meal. Must be chewed.

1 per meal

3750mg daily (usually 3000mg day)

Concomitant therapy with sevelamer not recommended

750mg 1000mg

Powder

None

Mix with small quantity of soft food

1 sachet with each meal

3750mg day (usually 3000mg day)

£124 per 90 £182 per 90 £193 per 90 £182 per 90 £193 per 90

475mg

Hard gelatin capsules (green/red). No taste

None

Swallowed whole with a meal

1 tab per meal

9 day

750mg 1000mg

Lanthanum carbonate powder (Fosrenol®) Aluminium hydroxide (Alucaps®)

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Very effective phosphate binder. Potential for aluminium toxicity.

Appendix 2: Cost comparison – PTH control Preparation Alfacalcidol capsules

Strength

Cost per pack (pack size)

0.25 micrograms

£2.35 (30) £3.26

0.5 micrograms

£4.80 (30) £6.18

1 microgram

£9.18 (30) £9.00

Alfacalcidol oral drops

2 micrograms in 1 ml

£25.50 (10ml) £21.33

Alfacalcidol injection (IV)

2 micrograms in 1 ml

£49.36 (10 x 1ml) £41.13

Calcitrol capsules

0.25 micrograms

£11.78 (100) £16.24

0.5 micrograms

£8.63 (30) £23.98

30mg

£151 (28) £126.21

60mg

£280 (28) £231.97

90mg

£419 (28) £394.44

120mg

£559 (28) £463.94

150mg

£699 (28) £626.41

180mg

£839 (28) £788.88

1 microgram

£83 (28) £69.44

2 microgram

£167 (28) £138.88

4 microgram

£333 (28) £277.76

Paracalcitrol injection (IV)

5 microgram in 1 ml

£74 (5 x 1ml) £62.00

Colecalciferol 25,000 units/ml oral solution

25,000 units/ml

£4.12 (3)

Cinacalcet

Paracalcitrol capsules

Prices based on current NUH costings including VAT August 2015

Guidelines for the management of CKD Mineral Bone Disease/ September 2015/ Review September 2018 26

Appendix 3 – Aluminium Overload The most important source of increased aluminium is contaminated dialysis water; the second is aluminium containing phosphate binders. Aluminium toxicity can occur in stages 4 & 5 CKD and dialysis patients. If clinically suspected aluminium levels should be determined. Care needs to be taken to avoid aluminium contamination of the blood sample. Serum aluminium levels should be measured every 3 months in all patients receiving aluminium hydroxide, but are not needed routinely in other dialysis patients.  

Ideally serum aluminium for dialysis patients should be 200 µg/L to avoid DFO-induced neurotoxicity.  Aluminium levels need to be interpreted in conjunction with the iron status. Patients with serum ferritin