2017 Kidney Disease: Improving Global Outcomes (KDIGO) Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Upda

MEETING REPORT

2017 Kidney Disease: Improving Global Outcomes (KDIGO) Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD) Guideline Update Implementation: Asia Summit Conference Report

Angela Yee-Moon Wang1, Tadao Akizawa2, Sunita Bavanandan3, Takayuki Hamano4, Adrian Liew5, Kuo-Cheng Lu6, Dusit Lumlertgul7, Kook-Hwan Oh8, Ming-Hui Zhao9,10, Samuel Ka-Shun Fung11, Yoshitsugu Obi12, Keiichi Sumida13, Lina Hui Lin Choong14, Bak Leong Goh15, Chuan-Ming Hao16, Young-Joo Kwon17, Der-Cherng Tarng18, Li Zuo19, David C. Wheeler20, Yusuke Tsukamoto21 and Masafumi Fukagawa22 1Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong SAR, China; 2Department of Medicine, Showa University School of Medicine, Tokyo, Japan; 3Department of Nephrology, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia; 4Department of Comprehensive Kidney Disease Research, Osaka University Graduate School of Medicine, Osaka, Japan; 5Department of Renal Medicine, Tan Tock Seng Hospital, Singapore; 6Department of Internal Medicine, Cardinal Tien Hospital, School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan; 7Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; 8Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea; 9Renal Division, Department of Medicine, Peking University First Hospital, China; 10Peking-Tsinghua Center for Life Sciences, Beijing, PR, China; 11Department of Medicine and Geriatrics, Jockey Club Nephrology and Urology Centre, Princess Margaret Hospital, Kowloon, Hong Kong SAR, China; 12Department of Medicine, University of California Irvine Medical Center, Orange, California, USA; 13Nephrology Center, Toranomon Hospital, Kawasaki, Kanagawa, Japan; 14Department of Renal Medicine, Singapore General Hospital, Singapore; 15Department of Nephrology, Serdang Hospital, Jalan Puchong, Kajang, Selangor, Malaysia; 16Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China; 17Department of Internal Medicine, Korea University College of Medicine, Guro Hospital, Seoul, South Korea; 18Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; 19Department of Nephrology, Peking University People’s Hospital, Beijing, China; 20Department of Renal Medicine, University College London, London, UK; 21Department of Nephrology, Itabashi Chuo Medical Center, Tokyo, Japan; and 22Division of Nephrology, Endocrinology, and Metabolism, Tokai University School of Medicine, Isehara, Japan

The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on Chronic Kidney Disease–Mineral and Bone Disorder (CKD–MBD) 2009 provided recommendations on the detection, evaluation, and treatment of CKD-MBD in patients CKD who are and are not undergoing dialysis. Because of the accumulation of evidence since this initial publication, the CKD-MBD Guideline underwent a selective update in 2017. In April 2018, KDIGO convened a CKD-MBD Guideline Implementation Summit in Japan with the key objective to discuss various barriers to the uptake and implementation of the CKD-MBD Guideline in 8 Asian countries/regions. These countries/regions were comparable according to their high-to-middle economic ranking assigned by the World Bank. The discussion took into account the availability of CKD-MBD medication therapies and government health policies that may inﬂuence reimbursement and practice patterns in the region. Most importantly, Summit participants developed a framework of multifaceted strategies aimed at overcoming barriers to guideline implementation. The Summit attendees suggested a shared decision-making approach between clinicians and patients in CKD-MBD management, as well as individualized care based on the treatment risk-beneﬁt ratio. The Summit participants also discussed how KDIGO, as a guideline development organization, may work in partnership with local and national nephrology societies to provide education and facilitate implementation of the guideline by clinicians. The conclusions drawn from this Summit in Asia may serve as an important guide for other regions to follow. Kidney Int Rep (2019) 4, 1523–1537; https://doi.org/10.1016/j.ekir.2019.09.007 KEYWORDS: bone mineral density; calcium; CKD; dialysis; hyperparathyroidism; hyperphosphatemia; KDIGO CKD- MBD Guideline ª 2019 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BY- NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Correspondence: Angela Yee-Moon Wang, Department of Medi- KD-MBD is one of the key complications in patients cine, Queen Mary Hospital, The University of Hong Kong, 102 Pok- fulam Road, Pokfulam, Hong Kong. E-mail: [email protected] C with CKD. Disturbances in various biochemical pa- – Received 3 July 2019; revised 9 September 2019; accepted 9 rameters, as well as CKD-MBD related complications, are September 2019; published online 23 September 2019 highly prevalent and cause signiﬁcant morbidity and

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1,2 mortality in this population. KDIGO developed the INCIDENCE AND PREVALENCE OF first clinical practice guideline (CPG) on the diagnosis, END-STAGE KIDNEY DISEASE IN ASIA evaluation, prevention, and treatment of CKD-MBD in Data from the United States Renal Data System 2017 2009.3 In October 2013, KDIGO held a Controversies showed that 7 of the 8 Asian countries/regions repre- Conference entitled “CKD-MBD: Back to the Future” in sented at the Summit, with the exception of China, are Madrid, Spain. During the conference, recommendation among the top 25 in the world with respect to incidence statements from the 2009 CPG were selected for revisit- and prevalence of end-stage kidney disease (ESKD)5 ing based on a newly accumulated body of evidence. A (Figure 1). Of the represented countries/regions, KDIGO Guideline Work Group was later convened, and a Taiwan leads this list with an annual ESKD incidence subsequent CKD-MBD CPG Update was published in rate of 476 per million population (pmp), followed by July 2017.4 KDIGO decided to explore how different Thailand (338 pmp), Singapore (319 pmp), Japan (290 parts of the world, and specifically Asia, have imple- pmp), South Korea (286 pmp), Malaysia (261 pmp), and mented KDIGO’s CPG on the diagnosis, evaluation, pre- Hong Kong (160 pmp). Similarly, Taiwan leads in the vention, and treatment of CKD-MBD through a Guideline annual ESKD prevalence rate (3317 pmp), followed by Implementation Summit. Japan (2529 pmp), Singapore (1972 pmp), South Korea Recognizing that a country’s government health and (1689 pmp), Thailand (1482 pmp), Malaysia (1295 pmp), reimbursement policies, economic position, and regula- and Hong Kong (1284 pmp). Thailand, Singapore, tory issues all impact local practice patterns and potential Malaysia, and South Korea are among the top 10 coun- implementation of the KDIGO CPG in CKD-MBD man- tries with the highest percentage increase in their ESKD agement, KDIGO organized a CKD-MBD Guideline incidence rate from 2002–2003 to 2014–2015.5 The Implementation Summit in April 2018 in Japan with recent annual data report from the China Kidney Disease several key meeting objectives. The first aim was to Network estimated that the age-adjusted incidence rate understand the availability and reimbursement of drugs for dialysis was 122 pmp with an estimated prevalence recommended by the KDIGO CKD-MBD CPG in 8 Eastern of hemodialysis and peritoneal dialysis of 402 pmp and and Southern Asian countries/regions with a comparable 40 pmp, respectively.6 high-to-middle economic ranking by the World Bank. Given such high incidence and prevalence of ESKD The second goal was to understand variations in gov- in Eastern and Southern Asia, a significant burden of ernment health policies that may influence CKD-MBD CKD-MBD and related complications also can be ex- practice patterns in the region. The third objective was pected. Thus there is a clinical need to drive better to understand the current implementation status of the implementation of the KDIGO CKD-MBD CPG and to CKD-MBD CPG and address specific barriers to its optimize CKD-MBD care to reduce mortality and implementation in the region. Lastly, the Summit aimed morbidity and improve patient outcomes. to develop a framework of practical, multifaceted stra- Race also may influence treatment effects and tegies to overcome recognized barriers and improve treatment targets. For example, the target para- KDIGO CKD-MBD CPG implementation and quality of thyroid hormone (PTH) level was lower for Japanese care for patients with CKD-MBD in the region. With CKD G5D patients (60–240 pg/ml) than other Asian these aims in mind, the Summit attendees discussed both populations that generally adopted KDIGO- the need for individualized implementation strategies recommended 2- to 9-fold upper laboratory refer- and suggestions for what KDIGO could do to further ence as the PTH target. A recent analysis from the facilitate CPG implementation in the region. Dialysis Outcomes and Practice Patterns Study The Summit was attended by nephrologists from China, showed that Japanese patients undergoing dialysis Hong Kong, Japan, Malaysia, Singapore, South Korea, maintained a more steady PTH level over a 9-month Taiwan, and Thailand. The conference participants spe- period in contrast to the European, Australian, New cifically identified 7 recommendation statements from the Zealand, and North American counterparts, which 2017 CKD-MBD CPG Update as the basis for focused dis- were more likely to show an increase in PTH level.7 cussions. The selection of these recommendations took into consideration the strength of the recommendation statement, the quality of the evidence supporting the AVAILABILITY AND REIMBURSEMENT recommendation, current practice patterns, and the need POLICIES OF MEDICATIONS USED TO TREAT for better implementation. To highlight the similarities CKD-MBD IN ASIA and important differences among the countries in the re- The 8 Asian countries/regions represented at the gion, the Summit participants discussed specific barriers Summit have notable variations in the availability of and challenges to implementing these 7 recommendations. CKD-MBD–related drugs and their reimbursement

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Incidence rate* Prevalence rate* Taiwan 3,317 Japan 2,529 Taiwan 476 United States 2,138 Jalisco (Mexico) 411 Singapore 1,972 Brunei 393 Portugal 1,824 United States 378 Rep. of Korea 1,689 Thailand 338 Brunei 1,673 Singapore 319 Jalisco (Mexico) 1,558 Japan 290 Thailand 1,485 Rep. of Korea 286 Chile 1,337 Malaysia 261 Canada 1,314 Greece 227 Malaysia 1,295 Portugal 227 Hong Kong 1,284 Czech Republic 227 Belgium, French-sp. 1,279 Hungary 223 Belgium, Dutch-sp. 1,258 Canada 197 France 1,237 Brazil 194 Greece 1,235 Israel 194 Spain 1,209 Belgium, French-sp. 188 Israel 1,183 Philippines 182 Austria 1,079 Chile 180 Uruguay 1,078 Belgium, Dutch-sp. 179 Czech Republic 1,068 France 165 Italy 1,050 Poland 162 Netherlands 990 Hong Kong 160 Hungary 968 Argentina 159 Australia 968 Romania 158 Sweden 961 Uruguay 156 Romania 958 Indonesia 154 United Kingdom^ 953 Bulgaria 153 New Zealand 950 Macedonia 152 Tur key 936 Tur key 147 Switzerland 932 Saudi Arabia 144 Norway 932 Morocco 144 Scotland 916 Country Austria 140 Denmark 904 Spain 135 Argentina 865 Italy 131 Finland 854 Kuwait 125 Brazil 833 Qatar 121 Poland 806 United Kingdom^ 121 Serbia 800 Sweden 119 Macedonia 790 Iran 119 Lithuania 754 Netherlands 118 Saudi Arabia 751 Serbia 115 Bosnia and Herzegovina 751 Scotland 115 Kuwait 750 New Zealand 115 Qatar 720 Bosnia and Herzegovina 114 Oman 670 Colombia 112 Estonia 661 Australia 112 Iceland 659 Denmark 108 Iran 635 Lithuania 105 Egypt 624 Switzerland 103 Colombia 624 Norway 99 Bulgaria 593 Finland 95 Morocco 541 Estonia 87 Latvia 512 Albania 80 Albania 422 Latvia 77 Philippines 319 Iceland 73 Russia 300 Russia 57 Kazakhstan 211 Egypt 56 Indonesia 206 Bangladesh 47 South Africa 189 South Africa 28 Ukraine 178 Ukraine 26 Bangladesh 119 0 100 200 300 400 500 0 100 200 300 400 500 ESRD incidence per million population/year ESRD prevalence per million population *Unknown for China where data are available only for HD *Unknown for China where data are available only for HD Figure 1. International comparisons of incidence and prevalence of end-stage renal disease (ESRD). Red bars indicate countries/regions from which participants attended the implementation summit. Reprinted with permission from the United States Renal Data System.5 Ûnited Kingdom: England, Wales, Northern Ireland (Scotland data reported separately). policies (Figure 2a and b). Calcium-based phosphate Taiwan and Hong Kong. Oral calcimimetic agents are binders (CPBs) are most commonly used and reim- available in all countries/regions;however,reimburse- bursed in all the 8 countries/regions. Sevelamer car- ment of calcimimetics requires the fulfilmentofspecific bonate/hydrochloride, although available, requires indications in many countries/regions. Intravenous cal- specific criteria for reimbursement in some countries/ cimimetics are available only in Japan and Taiwan, yet regions such as China, Hong Kong, Korea, Malaysia, and neither oral nor intravenous calcimimetics are reim- Singapore (Figure 2a and b). Lanthanum carbonate also bursed in Taiwan. requires specific criteria for reimbursement in Korea Although calcimimetics are available, para- and Malaysia (Figure 2a and b). In Taiwan, neither thyroidectomy is still considered the first-line treat- sevelamer- nor lanthanum-based phosphate binders ment for severe secondary hyperparathyroidism are reimbursed. Aluminum-based phosphate binders are refractory to locally available medical therapies in all still prescribed in China, Taiwan, Hong Kong, and countries/regions except Japan. Different PTH Thailand. Other newer classes of phosphate binders, thresholds were used as an indication for para- such as bixalomer and iron-based phosphate binders, are thyroidectomy across all 8 countries/regions available in very few countries. (Supplementary Table S1A), with or without consid- Figure 3a and b summarize the availability and ering other local indications for parathyroidectomy reimbursement policies of various vitamin D analogs and (Supplementary Table S1B). Supplementary Table S2 calcimimetics in the region. Second-generation oral provides the different PTH levels treatment targets vitamin D analogs are reimbursed in all countries except adoptedintheregion.

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a Japan Korea China Taiwan Hong Kong Singapore Malaysia Thailand

FR (D) Calcium-based FR FR FR FR PR † FR PR (ND)

FR but not FR but not Aluminum-based FR FR FR recommended recommended

FR if serum P level > 5.5 mg/dl at initiation NR except for of NCPB; Need fulfill Sevelamer Need fulfill NR (PR from those with Civil FR if serum P level > criteria (D) NR † carbonate criteria Nov 2018)* Service Welfare 4.0 mg/dl during NR (D) Medical Benefit maintenance phase Schemes of NCPB treatment Need fulfill Sevelamer Need fulfill NR (PR from FR (D) criteria (D) NR hydrochloride criteria Nov 2018)* NR (D) FR (D) Bixalomer PR (ND)

FR if serum P level > 5.5 mg/dl at initiation NR except for those with Civil Lanthanum- FR(D) of NCPB; PR NR NR NR † Service Welfare based PR (ND) FR if serum P level > 4.0 mg/dl during Medical Benefit maintenance phase Schemes of NCPB treatment

FR (D) Iron-based NR PR (ND)

*† Detailed in part (b). Note: drugs are fully/partially reimbursed unless otherwise specified. Available Not available b

*Singapore †Malaysia

CPBs are used as first-line Calcium-based standard drug listings, which are heavily Partial – pay $1.28 per prescription (irrespective of number or type of meds) if meds are obtained subsidized by the government. from specialist hospital but pay only $0.26 if from government health clinics – no criteria for reimbursement. NCPBs are only reimbursed when contraindications to CPBs, and therefore Aluminum-based serve mainly as a salvage therapy. No longer available.

The philosophy of health care in Singapore Sevelamer carbonate is that patients have individual responsibility Partial but it is heavily subsidized – only pay $1.28 at specialist hospital, subject to quota in for their health care costs, and will co-pay a number of patients supported by department budget. If no more quota in public hospital, certain amount. available by self-purchase. Government pensioner or their dependent dialyzing in private/ nongovernment organization center can apply for reimbursement but would require Financial constraints pose an important endorsement by government nephrologist. This mechanism is in the process of changing and will barrier for nephrologists to prescribe likely make logistics more difficult for some patients. NCPBs. Lanthanum-based Similar to sevelamer carbonate.

Figure 2. (a) Availability and (b) reimbursement policy of various phosphate binders in the 8 Asian countries/regions. CPB, calcium-based phosphate binder; D, dialysis; FR, full reimbursement; NCPB, non–calcium-based phosphate binder; ND, nondialysis; NR, not reimbursed; P, phosphate; PR, partial reimbursement.

GOVERNMENT HEALTH AND guideline recommendations. Taiwan and Malaysia are REIMBURSEMENT POLICIES mixed in their reimbursement policies. Thailand, South Korea, and Japan have their own local government policies for the reimbursement of sevelamer- CURRENT UPTAKE OF KDIGO CKD-MBD based or lanthanum-based phosphate binders, second- GUIDELINE generation activated vitamin D, and cinacalcet. Most countries follow the KDIGO CKD-MBD CPG, Singapore, Hong Kong, and China have reimbursement but some countries continue to refer to the Kidney policies for these drugs that are not linked to any Disease Outcomes Quality Initiative (KDOQI) 2003

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a Vitamin D analogs Japan Korea China Taiwan Hong Kong Singapore Malaysia Thailand

FR (D) FR if eGFR < 40 1st generation (oral) FR FR FR PR ‡ FR PR (ND) ml/min per 1.73 m2

FR if iPTH > 200 1st generation (injection) FR (D) pg/ml PR FR FR PR ‡ FR

FR (D) 2nd generation (oral) PR NR NR NR† ‡ FR NR (ND)

FR if iPTH > 300 pg/ml with SHPT FR (D) treatment initiation; 2nd generation (injection) PR NR NR NR†‡ FR NR (ND) FR if iPTH > 150 pg/ml in maintenance phase of SHPT treatment Ca > 9.0 mg/dl and iPTH > 300 pg/ml with SHPT treatment FR (D) Need **Depending Calcimimetics (oral) initiation; FR if iPTH PR NR NR† ‡ NR (ND) fulfill criteria* on coverage >150 pg/ml in maintenance phase of SHPT treatment

FR (D) Calcimimetics (injection) NR NR (ND)

*†‡ Detailed in part (b). Available Not available **Two out of 3 fund providers support payment. b

Korea *Hong Kong †Singapore ‡Malaysia

Cinacalcet Cinacalcet 1st generation oral 1st generation vitamin D analog (oral) reimbursement reimbursement vitamin D analogs in Partial – pay $1.28 per prescription (irrespective of number criteria criteria standard drug or type of drugs) if drugs obtained from specialist hospital; listings, which are pay only $0.26 if from government health clinics – no criteria 1. Dialysis patients, Dialysis patients with heavily subsidized for reimbursement either hemodialysis iPTH over 9 times of by the government. or peritoneal dialysis upper normal The remaining can 1st generation vitamin D analog (injections) laboratory reference be reimbursed In nongovernment units, covered by cost of hemodialysis 2. FR for iPTH > 300 unresponsive to based on financial in some centers; otherwise, extra charge to patients. In pg/ml in initial SHPT conventional means testing government facilities, it is provided free of charge treatment and serum therapies and/or with: performed by social Ca > 9 mg/dl; FR for workers. 2nd generation vitamin D analog (oral or intravenous) iPTH > 150 pg/ml in 1. Hypercalcemia Patients who require 1. For patients receiving chronic dialysis in public hospitals or maintenance SHPT unsuitable for financial assistance government pensioners/dependents, partial reimbursement – treatment vitamin D analogs may receive full would pay $1.28 per prescription but need approval by the 3. funding. The Director General of Health; no set criteria for reimbursement but serum Ca > 10.2 2. Not feasible for philosophy of need to provide justification mg/dL (in this case, parathyroidectomy health care in 3-month use of Singapore is that 2. Need self-finance for patients not belonging to the above activated vitamin D 3. Calciphylaxis patients have categories is not needed) or individual responsibility for Calcimimetic (oral) Reimbursement is 4. Develop recurrent their health care 1. For patients receiving chronic dialysis in public hospitals or given if 1+2 or if 1+3 SHPT post- costs, and will government pensioners/dependents, partial reimbursement – parathyroidectomy co-pay a certain would pay $1.28 per prescription; however, in the former it is amount. subject to available quota space due to budget restrictions

2. For patients not belonging to the above categories, will need to self-pay

Figure 3. (a) Availability and (b) reimbursement policy of various vitamin D analogs and calcimimetics in the 8 Asian countries/regions. Ca, serum calcium; D, dialysis; eGFR, estimated glomerular ﬁltration rate; FR, full reimbursement; iPTH, intact parathyroid hormone; ND, nondialysis; NR, not reimbursed; PR, partial reimbursement; SHPT, secondary hyperparathyroidism. guideline. Japan has developed its own national collaboration with the Ministry of Health, recently Japanese Society for Dialysis Therapy CPG for CKD- has developed a speciﬁc national CKD-MBD and MBD, and the Malaysian Society of Nephrology, in parathyroidectomy CPG and standard of practice.

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KDIGO CKD-MBD 2017 GUIDELINE In Singapore, PTH testing is variably performed in – RECOMMENDATIONS IDENTIFIED FOR patients with CKD G3a G5. Family physicians or non- BETTER IMPLEMENTATION nephrologists would rarely order PTH testing in CKD G3a–G5 patients and timing of referral to nephrologists The Summit participants assessed 7 KDIGO CKD-MBD therefore is variable. As such, many patients with CKD CPG statements for better implementation in the re- – 4 G3a G3b may not have their case managed by ne- gion (Table 1). phrologists. Recently, Singapore set up the National CKD Program by which all patients with CKD G3b are KDIGO CKD-MBD Guideline Recommendation referred to nephrologists. Raising the awareness among 3.1.1 primary care physicians or other clinicians of early Monitoring Biochemical Parameters of CKD-MBD in referral of patients with CKD to nephrologists starting the Region at CKD G3b may help promote earlier PTH testing and The Summit participants recognized wide variations in standardize monitoring frequency in persons with the frequency of monitoring of CKD-MBD biochemical CKD. parameters in the region. Taiwan’s national structured On the other hand, some hospitals in Hong Kong pre-ESKD education program supported by the gov- set restrictions on the frequency of PTH testing in ernment requires referral of patients with CKD to ne- persons with CKD because of resource limitations. For phrologists starting at CKD G3a when routine, regular example, testing cannot be done more than once per monitoring of CKD-MBD parameters is initiated. The year in nondialysis CKD G3a–G5 patients. In China, it government of Taiwan reimburses all biochemical tests is common to have late presentations and referrals of for CKD-MBD including calcium, phosphorus, alkaline patients with CKD to nephrologists; thus many pa- phosphatase performed every 3 months, and PTH tients may have missed PTH, calcium, and phos- testing every 6 to 12 months starting from CKD G4. The phorus monitoring in the nondialysis CKD stages. government provides incentives to physicians who Rural areas of China may also lack the required refer cases early to nephrologists for structured CKD nephrology expertise and biochemical tests for CKD- care. MBD monitoring. In Malaysia there is a gap in the availability of PTH tests in CKD G3a–G4, but not in CKD G5. In Thailand, the government does not fully Table 1. KDIGO CKD-MBD CPG recommendation statements iden- – tiﬁed for better implementation in the region reimburse all PTH testing in CKD G3a G5 patients. Guideline no. Recommendation statement Other countries, including South Korea and Japan, do

Monitoring of CKD-MBD not restrict biochemical testing of CKD-MBD in pa- – 3.1.1 We recommend monitoring serum levels of calcium, tients with CKD G3a G5 as long as it is reasonably phosphate, PTH, and alkaline phosphatase activity compatible with the diagnosis for health insurance; beginning in CKD G3a (1C ) however, there is no standardized monitoring fre- Calcium and phosphorus control 4.1.3 In adult patients with CKD G3a–G5D, we suggest avoiding quency for these parameters. hypercalcemia (2C ) 4.1.6 In adult patients with CKD G3a–G5D receiving phosphate- Barriers to the Implementation of KDIGO 2017 lowering treatment, we suggest restricting the dose of calcium-based phosphate binders (2B ) CKD-MBD Guideline Recommendation 3.1.1 in Asia 4.1.7 In patients with CKD G3a–G5D, we recommend avoiding the Across the 8 countries/regions participating in the long-term use of aluminum-containing phosphate binders Summit, some barriers at the governmental, hospital, and, in patients with CKD G5D, avoiding dialysate aluminum contamination to prevent aluminum intoxication (1C ) physician, and patient levels may make it difficult to PTH control implement Recommendation 3.1.1. Except for Taiwan, 4.2.4 In patients with CKD G5D requiring PTH-lowering therapy, most Asian countries do not have structured CKD care we suggest calcimimetics, calcitriol, or vitamin D analogs, or a combination of calcimimetics with calcitriol or vitamin D programs; therefore, there is generally late referral of analogs (2B ) patients with CKD to nephrologists and low awareness Osteoporosis management of the need to monitor PTH levels regularly. In China, a 4.3.1 In patients with CKD G1–G2 with osteoporosis and/or high risk of fracture, as identified by World Health Organization large discrepancy in health policy and reimbursement criteria, we recommend management as for the general coverage for CKD, bundled payment, and cost population (1A ) containment exists between urban and rural areas. 4.3.2 In patients with CKD G3a–G3b with PTH in the normal range and osteoporosis and/or high risk of fracture, as identified by Some basic biochemical tests such as PTH and alkaline World Health Organization criteria, we suggest treatment as phosphatase may not be available in rural areas. Pa- for the general population (2B ) tients may move between different nephrology centers CKD-MBD, chronic kidney disease–mineral bone disorder; CPG, clinical practice guidelines; KDIGO, Kidney Disease: Improving Global Outcomes; PTH, parathyroid for follow-up and lack continuity in CKD care. Some hormone. public hospitals in Hong Kong set restrictions on PTH

1528 Kidney International Reports (2019) 4, 1523–1537 AY-M Wang et al.: KDIGO 2017 CKD-MBD Guideline Implementation Asia Summit Report MEETING REPORT testing frequency in persons with CKD because of was believed that aluminum exposure is not a major resource limitation. issue for patients with CKD in the 8 Asian countries/ In Singapore a physician’s workload is generally regions. very high, and they often need reminders to order Calcium exposure and hypercalcemia appear to be biochemical tests of CKD-MBD. Furthermore, CKD G3b a highly prevalent problem in the region. Epidemi- patients may not be managed by nephrologists. In ologic studies demonstrated an important association some countries such as Malaysia, where a bundled between serum calcium level and mortality in pa- payment exists, physicians in the private sector have tients undergoing dialysis: the higher the serum – to absorb the costs of biochemical tests in patients’ calcium level, the greater the mortality risk.8 10 consultation fees and may skip ordering of these tests A calcium balance study showed that taking a daily to save costs. dose of 1500 mg calcium carbonate for only 3 weeks Patients’ noncompliance poses another important caused significant positive calcium balance in CKD barrier to adherence of monitoring. In Singapore, some G3a–G4 subjects.11 Another study by Spiegel and patients who are followed up in private dialysis centers Brady12 corroborated similar findings showing may refuse biochemical tests of CKD-MBD because of significantly more positive calcium balance in CKD high cost, as they need to pay out of pocket. PTH tests G3b and G4 subjects receiving a 2000-mg calcium are not fully reimbursed in Singapore, China, and diet (500 mg from their diet and 1500 mg from cal- Thailand (Table 2). cium carbonate) than those CKD patients taking an Consensus on Monitoring Frequency for Various 800-mg calcium diet or healthy individuals taking a 12 Biochemical Parameters of CKD-MBD in the Region 2000-mg calcium diet at least over 9 days of study. To improve implementation of the KDIGO CKD-MBD However, these calcium balance studies are not CPG, the Summit reached a consensus on the mini- without limitations in that they could not estimate mum monitoring frequency of various biochemical the rate of calcium deposition into extraskeletal tis- parameters of CKD-MBD in persons with CKD (Table 3). sues. The study time frame of 9 days to 3 weeks is The participants believed that more frequent, struc- also too short for the bone to achieve a steady state of 13 tured monitoring of these biochemical parameters is calcium balance. An early study suggested that the justified as the estimated glomerular filtration rate de- mean duration to achieve calcium balance was 90 14 creases below 30 ml/min per 1.73 m2. days. Thus, one needs to caution against over- interpreting these findings, and a more balanced view How Can We Improve Adherence to CKD-MBD Monitoring Recommendation 3.1.1 in Asia? of these studies is called for. The KDIGO 2017 guideline update suggested restricting the dose of Potential ways to improve adherence to Recommenda- CPBs in persons with CKD G3a–G5D, and the tion 3.1.1 include (i) establishing structured patient recommendation statement was given a grading of referral systems so that patients with CKD are referred 2B.4 It is noteworthy that there are significant early to nephrologists; (ii) setting up structured CKD regional variations in dietary calcium intake, with care programs with protocol-guided CKD management; countries including China, India, and Indonesia and (iii) incorporating regular monitoring of CKD-MBD having the world’s lowest average calcium intakes— biochemical tests starting at CKD G3b. Taiwan’s na- often less than 400 mg a day.15 These regional dif- tional, multidisciplinary CKD care program may serve ferences in dietary calcium intake will need to be as a good reference model for other Asian countries in taken into account when prescribing the dose of the region. Continuous education of health pro- CPBs. fessionals and patients on the need for regular moni- In all 8 countries/regions, non–calcium-based toring of biochemical parameters for CKD-MBD starting phosphate binders (NCPBs) such as sevelamer-based at CKD G3b is essential to raise awareness of the phosphate binders are not reimbursed in patients importance of CKD-MBD monitoring in the overall care with CKD who are not undergoing dialysis. In Japan, of patients with kidney disease. NCPBs are fully reimbursed in patients undergoing KDIGO CKD-MBD Guideline Recommendations dialysis, but CPBs are still prescribed and often used 4.1.3, 4.1.6, and 4.1.7 in combination with NCPBs so as to minimize the dose Barriers to the Implementation of KDIGO 2017 of NCPBs. According to the Japan CKD-MBD Guide- CKD-MBD Guideline Recommendations 4.1.3, 4.1.6, line, the daily prescribed dose of calcium carbonate is and 4.1.7 in Asia limited to a maximum of 3 g, which corresponds to Except in Japan, Malaysia, and Singapore, aluminum- 1.2 g of elemental calcium. In South Korea, sevelamer- based phosphate binders are currently still in use. All based phosphate binders are reimbursed as a first-line 8 countries/regions use aluminum-free dialysis fluid. It drug for phosphate control in patients undergoing

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Table 2. Barriers in implementation of KDIGO CPG on monitoring biochemical parameters of CKD-MBD Japan Korea Taiwan Singapore China Hong Kong Thailand Malaysia

Government/policy Nil Nil; in Korea, Not a barrier as there is No policy requirements for Diverse policies in different Lack of structured CKD Late referral of Lack of government level reimbursement on structured CKD program monitoring of biochemical parts of the country— program patients with CKD to policy on referral of monitoring covers with standardized parameters of CKD-MBD urban vs. rural nephrologists CKD3a and 3b patients, CKD from G3a monitoring frequency with hence patients with CKD incentive available for are cared for mostly by

referral of CKD G3b to primary care physicians Report Summit Asia Implementation Guideline CKD-MBD 2017 KDIGO al.: et Wang AY-M nephrologist Hospital level Nil Nil Nil Heavy workload in Many institutions in rural Cost of PTH testing high Nil Lag time in results nephrology unit, and areas do not have and restrictions on PTH reporting as tests are reminder needed on biochemical tests testing in hospitals processed in batches; timing of monitoring available results may not be acted upon until much later Physician level Low awareness Low awareness of the CKD guidelines require CKD G3a is mostly Low awareness of the A large proportion of CKD G3a–G4 are Non-nephrologists may of the need to need to institute referral of CKD G3b to managed by primary care need for regular predialysis patients may mostly managed by not be aware of the need monitor PTH frequent monitoring nephrologists physicians and PTH test monitoring; goals of be managed in the private family or general for regular monitoring may not be performed management is cost sector; lack of education physicians, thus PTH containment of general and primary and alkaline care physicians phosphatase testing not likely being done Patient level Nil Nil Nil Patients may refuse tests Out-of-pocket costs; Nil Out-of-pocket costs Nil in private settings because noncompliance of follow- they require out-of-pocket up, which will affect costs monitoring frequency Reimbursement Nil Nil Nil Tests not fully reimbursed, Reimbursement may not Nil PTH/alkaline Reimbursement may not inyItrainlRprs(2019) Reports International Kidney issues but may be offset by be available in some phosphatase testing be available for some certain schemes hospitals may not be institutions reimbursed, depending on the reimbursement policy

CKD-MBD, chronic kidney disease–mineral bone disorder; CPG, clinical practice guidelines; KDIGO, Kidney Disease: Improving Global Outcomes; PTH, parathyroid hormone. 4, 1523 – 1537 AY-M Wang et al.: KDIGO 2017 CKD-MBD Guideline Implementation Asia Summit Report MEETING REPORT

Table 3. Consensus on suggested monitoring frequency of KDIGO CKD-MBD Guideline Recommendation biochemical parameters of CKD-MBD according to CKD GFR 4.2.4 categories in the region Barriers to the Implementation of KDIGO 2017 CKD GFR Calcium Alkaline CKD-MBD Guideline Recommendation 4.2.4 in Asia category /phosphate Intact PTH 25-hydroxyvitamin D phosphatase Cinacalcet use is restricted across the region, except in G3a Yearly Yearly Nil Yearly Japan, because of high costs. Gastrointestinal side ef- G3b Yearly Yearly Nil Yearly G4 6 mo Yearly Nil 6 mo fects of cinacalcet may sometimes affect its prescription G5 3 mo 6 mo Nil 3 mo and compliance. As such, vitamin D analogs are more G5D 3 mo 6 mo Nil 3 mo widely used in the region. CKD-MBD, chronic kidney disease–mineral bone disorder; GFR, glomerular filtration In Japan, cinacalcet is reimbursed until PTH levels rate; PTH, parathyroid hormone. reach the Japanese CKD-MBD guideline target range. Both etelcalcetide and evocalcet are available and dialysis when serum phosphate levels exceed 5.5 mg/dl. reimbursed in patients undergoing dialysis. In patients In Taiwan and Singapore, NCPBs are not reimbursed not undergoing dialysis, cinacalcet can be used only in in patients undergoing dialysis, although in Taiwan patients with parathyroid cancer or noncontrollable patients undergoing dialysis with disability cards may primary hyperparathyroidism after surgery. receive subsidies with an NCPB prescription. In In South Korea, cinacalcet has been reimbursed as a Malaysia, reimbursement of NCPBs is restricted by in- first-line agent for treatment of secondary hyperpara- dividual hospital quotas in the public sector or only in thyroidism since 2018. In Singapore, cinacalcet is certain groups of patients. available but not reimbursed. Cost remains a significant In Singapore, financial constraints pose an important barrier for its prescription. In Hong Kong, cinacalcet is barrier for nephrologists to prescribe NCPBs, although reimbursed as a second-line drug in patients with ESKD subsidies are available to patients who require financial when parathyroidectomy is either not feasible or con- assistance. NCPBs often are used as second-line drug traindicated or in those who experience recurrent treatment for hyperphosphatemia when there are con- secondary hyperparathyroidism after surgery. Because traindications to the use of CPBs. In China, payment Recommendation 4.2.4 does not prioritize the use of policy is bundled and the prescription of NCPBs is cinacalcet over vitamin D analogs, the Summit at- highly restricted because of cost issues. NCPBs are not tendees did not perceive barriers to implementing this reimbursed in most parts of Mainland China and specific guideline recommendation. therefore incur out-of-pocket costs by patients. Thus their prescription remains highly restrictive. In KDIGO CKD-MBD Guideline Recommendations Thailand, only government officials, civil servants, and 4.3.1 and 4.3.2 their family members are entitled to reimbursement of Barriers to the Implementation of KDIGO 2017 CKD- NCPBs. In Hong Kong, the reimbursement policy only MBD Guideline Recommendations 4.3.1 and 4.3.2 in allows NCPB prescriptions as a second-line drug under Asia the fulfillment of certain criteria, including poor cal- These 2 recommendation statements are especially cium phosphorus control despite maximal dose of CPBs, relevant for patients with CKD who have a high risk of aluminium toxicity, or hypercalcemia with first-line fracture, such as those receiving glucocorticoid treat- CPBs. Furthermore, there are variations in practice ment. The implementation of these recommendations patterns among different public hospitals because some requires a concerted effort that entails working with may choose to restrict prescription of NCPBs further endocrinologists or orthopedic surgeons who usually due to budget constraints. manage osteoporosis. Major barriers to implementing Apart from financial issues and reimbursement these 2 recommendation statements may relate to the policies of NCPBs, there are other significant barriers lack of awareness among nephrologists of the impor- to implementation of Recommendations 4.1.3 and 4.1.6 tance of osteoporosis treatment in persons with CKD in China, Hong Kong, Malaysia, and Thailand. These because nephrologists mostly focus on CKD manage- include physicians’ low awareness of the importance of ment. Furthermore, a dual energy x-ray absorptiometry phosphorus control, the need to avoid hypercalcemia, (DEXA) scan is not reimbursed for patients with CKD in and the need to restrict the dose of CPB. Nephrologists this region, except in Japan and in the dialysis popu- may not place phosphorus control as a high priority in lation in South Korea. Thus there are financial barriers the management of patients with CKD. Patient factors to ordering DEXA scans in CKD G1–G3b patients who also may be potential barriers in CPG implementation are at high risk of the development of osteoporosis. because large pill burden could contribute to poor Patients with CKD G1 and G2 also are followed up adherence to phosphate binders (Table 4). mostly by primary care physicians who may lack

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Table 4. Barriers in implementing KDIGO CKD-MBD guidelines 4.1.3, 4.1.6, and 4.1.7 Japan Korea Taiwan Singapore China Hong Kong Thailand Malaysia

Government/ Nil Reimbursement policy for Nil Only CPBs are in the Bundled payment CRC sets limitations on Only CPBs are in the Nil policy level NCPBs and cinacalcet has national list of subsidized policy may restrict the the use of NCPBs national list of essential been broadened since drugs use of NCPBs drugs 2018 because of cost Hospital level Nil Nil Nil Some hospitals may Variability in practice Variability in practice Some hospitals are Nil preferentially stock only in rural and urban among hospitals; hospital allowed to stock only one one kind of NCPBs areas is free to restrict use of kind of NCPBs NCPB based on budget beyond restrictions by CRC Physician level Nil Nil Nil Physicians not Physicians not Physicians not Physicians not Physicians not Report Summit Asia Implementation Guideline CKD-MBD 2017 KDIGO al.: et Wang AY-M recognizing the recognizing the recognizing the recognizing the recognizing the importance to avoid importance to avoid importance to avoid importance to avoid importance to avoid hypercalcemia and need hypercalcemia and hypercalcemia and need hypercalcemia and need hypercalcemia and need to restrict CPBs need to restrict CPBs to restrict CPBs; to restrict CPBs to restrict CPBs physicians may not place phosphorus control as a high priority Patient level Low adherence of Nil Dietary calcium intake Drug adherence problem In early CKD, Failure to recognize the Failure to recognize the High dietary phosphorus phosphate binders is low in Taiwanese due to high pill burden; hypocalcemia and importance of phosphorus importance of phosphorus intake and low patients with CKD, so financial resistance to start vitamin D deficiency control and how dietary control and how dietary adherence to phosphate use of calcium-based NCPB because they need allows liberal use of control may facilitate intake may facilitate binders binders is not a to self-finance the drug CPBs phosphorus control; phosphorus control contraindication phosphorus control is also suboptimal with twice weekly hemodialysis Drug availability CPBs are often used Sevelamer and lanthanum Nil CPBs are heavily CPBs are heavily Nil CPBs are heavily Nil in combination with used as the first-line subsidized in standard used; NCPB is used subsidized in the national NCPBs so as to agents for dialysis drug list, promoting their as a second-line drug drug list, promoting their inyItrainlRprs(2019) Reports International Kidney reduce dose of patients since 2018; use; NCPB is used as a therapy in limited use; NCPB is used as a NCPBs to save cost aluminum is not second-line drug therapy institutions and only second-line drug therapy prescribed any more partially reimbursed Reimbursement Cost of NCPBs fully NCPBs are reimbursed in NCPBs are not NCPBs are not Bundled payment as NCPBs are reimbursed as NCPBs are not reimbursed NCPBs are reimbursed issues reimbursed in dialysis patients undergoing reimbursed in patients reimbursed, although above a second-line therapies under most health care under specific criteria in patients but not in dialysis but not in patients undergoing dialysis; assistance schemes may under specific criteria in schemes; they are only patients undergoing CKD with CKD disability cards for be available to some patients undergoing available to persons with dialysis and not dialysis patients may patients dialysis; NCPBs are not Civil Service Welfare reimbursed in CKD allow subsidies reimbursed in patients Medical Benefits with CKD

CKD-MBD, chronic kidney disease–mineral bone disorder; CPBs, calcium-based phosphate binders; CRC, Central Renal Committee; KDIGO, Kidney Disease: Improving Global Outcomes; NCPBs, non–calcium-based phosphate binders. 4, 1523 – 1537 AY-M Wang et al.: KDIGO 2017 CKD-MBD Guideline Implementation Asia Summit Report MEETING REPORT awareness of this complication in persons with CKD. Implementation of these recommendation statements Significance Stakeholders thus requires a concerted, multidisciplinary effort among primary care physicians, nephrologists, endocrinologists, Sharing implementation Systems and and orthopedic surgeons. Furthermore, there is insuffi- stories structure cient knowledge about the efficacy of anti-osteoporosis Keys to CPG drugs in persons with advanced CKD (i.e., subjects implementation – Seminar, with CKD G4 G5), and existing noninvasive in- Social factors education tools vestigations have limitations in differentiating osteoporosis from adynamic bone disease. Lastly, many patients Skills and Surveillance are unwilling to undergo an invasive bone biopsy. support Would the KDIGO 2017 CPG Change Your Practice Pattern Regarding Performing DEXA Scans in Your Figure 4. Eight key steps prior to clinical practice guideline (CPG) Patients With CKD? implementation. The Summit recognized that fracture is an important complication in patients with CKD and causes signifi- first approach is to identify and motivate key local cant morbidity. The Dialysis Outcomes and Practice physicians, particularly leaders of local nephrology Patterns Study reported a significantly higher inci- societies or key opinion leaders who could help to dence of fractures for patients receiving hemodialysis advocate and influence health policy change of pro- than in the general population, with a 3.7-fold increase vincial or local governments. The second approach is to in the unadjusted relative risk of death.16 Five pro- involve national and international nephrology organi- spective cohort studies demonstrated that DEXA- zations in engaging government and health ministries, derived bone mineral density predicted fractures making them aware of the importance and impact of – across CKD G3a–G5D.17 21 However, DEXA scans CKD-MBD so they may further advocate for policy currently are not reimbursed in the 8 Asian countries/ change and government reimbursement of drugs rec- regions for patients with CKD, except in Japan, and ommended by the KDIGO CPG, such as NCPBs. there is limited evidence to inform the best practice for Cost poses a key barrier for CPG implementation in osteoporosis treatment in this population. Uncertainties the region. This encompasses not only the costs of also exist about the safety and efficacy of anti- various biochemical tests of CKD-MBD but also the osteoporotic drugs such as bisphosphonates and costs of newer drug treatment such as NCPBs, second- – denosumab in patients with advanced CKD.22 24 Thus generation vitamin D analogs, and calcimimetics. The the Summit did not insist strongly on performing and group felt that a cost-effectiveness analysis of regular reimbursing a DEXA scan for patients with CKD G3a– biochemical testing and the use of newer, yet more G5D. However, the Summit participants unanimously costly drugs for CKD-MBD management could shed suggested on performing a DEXA scan and treating light on their use in CKD-MBD management in the osteoporosis in patients with CKD G1–G2 as in the region and could help facilitate discussions with local general population with osteoporosis and/or high risk health policy makers or health ministers for their po- of fracture. More evidence will be required to drive tential reimbursement. An alternative strategy to better implementation of this recommendation state- overcome cost or financial barriers for both the gov- ment in the region. ernment and patients may include sourcing for generic versions of more costly drugs such as NCPBs and cal- STRATEGIES TO IMPROVE IMPLEMENTATION cimimetics, if available. OF KDIGO CKD-MBD CPG Key performance indicators (KPIs) could be used to Figure 4 depicts the 8 key elements that facilitate CPG assess clinical performance and quality of CKD-MBD care implementation. The Summit participants discussed in individual health care institutions, as well as adher- potential strategies to improve implementation of the ence to treatment targets recommended by the KDIGO KDIGO CKD-MBD CPG. Figure 5 outlines a framework CPG. The achievement of various KPIs may correlate of multifaceted strategies that aim to improve CPG with government funding allocations to health care implementation. institutions or incentive payments such as pay-by- performance or pay-by-adherence to targets recom- Government and Policy Level mended by KDIGO. This may serve as a useful strategy Two approaches may help overcome barriers at the to motivate healthcare institutions or dialysis centers and government or health policy level, depending on the add incentives to drive for better CKD-MBD care and health care financing infrastructure of the country. The better adherence to the global CKD-MBD CPG.

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Government and policy level Institution or dialysis center level

• Identify and motivate local key opinion leaders to influence government • Set up regional support system connecting small hospitals/centers with big, policy change central and regional hospitals/dialysis centers so as to increase accessibility • Involve national and international nephrology societies in engaging of small hospitals or hospitals in rural areas to blood tests such as iPTH government and health ministries, making them aware of the importance testing and also accessibility to drug supply and provision and impact of CKD-MBD and advocating for policy change and • Adopt KPIs to assess clinical performance and quality of CKD-MBD care and government reimbursement of drug items recommended by CPGs adherence to treatment targets delivered by HPs • Sourcing for generic drugs, if available • Set up multidisciplinary CKD-MBD management team to facilitate • Tie in government funding allocations to the degree of achieving KPI implementation of CPGs in CKD-MBD • Provide training, credentialing, certification and recognition of these • Incentive payment to dialysis centers or hospitals, e.g., pay-by-performance CKD-MBD management teams for adherence to CPGs' recommended targets • Decision support system incorporated in hospital computerized medical • Provide economic evaluation of various monitoring tests and new drugs system may serve as reminders or prompts for HPs for CKD-MBD • Audit and feedback system

Transforming Clinical Practice and Improving CPG Implementation

Health care Professional (HP) level Patient level KDIGO level

• CME of HPs • Education and raising patients’ • Include health economics analysis and cost-effectiveness • National or local nephrology societies awareness of the importance of data as a supplement in KDIGO CPG publication to develop CME program that includes CKD-MBD through patient support • Develop web-based education and training materials on CPG education to its members or peer groups CPG and podcasts, as well as management tool kits • CME of clinical practice guidelines • Education during clinics consultation • Develop decision support aids to assist clinicians in for HPs who reside in geographically by HPs or multidisciplinary CKD-MBD providing structured CKD-MBD care according to KDIGO remote areas care team CPG or locally adapted CPG • Web-based education of CKD-MBD • Web-based education, seminars or • Work in partnerships with local professional organizations guidelines providing pamphlets as a reminder of or national nephrology societies in education, training and • Case scenarios discussions the importance of CKD-MBD implementation of KDIGO CPG • Local translation and adaptation of KDIGO • Inform patients of various available • Promote CPG through various social media, mobile apps guidelines and incorporation in national CPG treatment options for CKD-MBD and regular KDIGO newsletters

Figure 5. A framework of multi-level implementation strategies to overcome barriers for chronic kidney disease-mineral bone disease (CKD- MBD) Guideline implementation in the region. CME, continuing medical education; CPG, clinical practice guideline; HP, health professionals; iPTH, intact parathyroid hormone; KDIGO, Kidney Disease: Improving Global Outcomes; KPI, key performance indicator.

Institution Level physicians, and allied health professionals through The availability of biochemical tests of CKD-MBD, such developing continuing medical education programs. as PTH, is vital in ensuring adherence to CKD-MBD Continuing medical education of the KDIGO CPG also monitoring and achieving treatment targets recom- could be delivered to health professionals who reside in mended by KDIGO. However, some tests may not be geographically remote areas. Web-based education of the readily available in rural areas or small peripheral CKD-MBD CPG with patient-case discussions are an hospitals. Therefore, a regional support system should effective means of training health professionals and be established to connect small hospitals with large, facilitating continuing medical education. In addition, central, or regional hospitals whereby patient blood because some countries such as Japan and Malaysia have samples could be transported for testing. For the developed their own national CPG for CKD-MBD care, availability and supply of NCPBs and calcimimetics, a the KDIGO CPG may be translated or adapted and similar regional support and transport system could be incorporated into the national CPG by local professional set up, connecting small peripheral hospitals with large societies or guideline groups. central and regional hospitals for drug supply and A CKD-MBD management task force that involves a provision. multidisciplinary team of nephrologists, nurses, di- eticians, social workers, and pharmacists to coordinate Health Professional Level the monitoring and treatment of CKD-MBD may be Continuous education of health professionals is essential useful for the case management of patients with CKD in facilitating CPG implementation and changing practice and may facilitate better implementation of the KDIGO patterns. National or local nephrology societies may assist CPG in individual health care institutions and dialysis KDIGO guideline implementation by educating health centers. In addition, training, credentialing, and certi- professionals including nephrologists, non-nephrology ﬁcation of this CKD-MBD management task force may

1534 Kidney International Reports (2019) 4, 1523–1537 AY-M Wang et al.: KDIGO 2017 CKD-MBD Guideline Implementation Asia Summit Report MEETING REPORT provide recognition and more motivation to health may help bridge the gap between guideline recom- professionals, such that the implementation of the mendations and implementation. KDIGO CKD-MBD CPG would become a routine and KDIGO also may consider developing web-based standard part of the clinical practice. Decision support education and training materials on CPGs, such as systems incorporated in hospital electronic medical podcasts, regionally relevant management toolkits, record systems may serve as prompts and useful re- and decision support aids to assist clinicians in minders for health professionals in their daily clinical providing structured CKD-MBD care. KDIGO may practice. work in partnership with local professional organizations or national nephrology societies on education, ASSESSING THE EFFECTIVENESS OF KDIGO training, and implementation of a KDIGO CPG. CKD-MBD CPG IMPLEMENTATION KDIGO also may consider promoting their CPG Adopting KPIs may be an important strategy for through various social media, mobile apps, and reg- facilitating KDIGO CPG’s implementation and moni- ular newsletters. toring the degree of adherence at health institutions or dialysis centers in the region. Some suggested examples CONCLUSIONS of KPI in CKD-MBD management may include the Although the 8 Eastern and Southern Asian countries/ following: regions represented in this Summit have a similar (i) percentage of patients with CKD who have high-to-middle income ranking, clinical practices in frequent testing of serum calcium, phosphorus, CKD-MBD and related drugs reimbursement policies fi fi PTH and alkaline phosphatase presented according vary among them. This Summit identi ed speci c to severity of CKD; barriers in implementing CKD-MBD Guidelines in this fi (ii) percentage of patients with hypercalcemia who are region, among which nancial barriers and reim- undergoing dialysis (with a threshold to be defined bursement policies of NCPBs appear to be the most fi using the local laboratory reference values) in signi cant. The Summit also presented a framework dialysis centers; of strategies that target various facilitators, namely (iii) percentage of patients undergoing dialysis who are local government, health, and reimbursement policy; prescribed CPBs and NCPBs in dialysis centers; institution and dialysis centers; health professionals; (iv) percentage of patients by dose of CPBs prescribed patients; and KDIGO itself, with an aim to improve (e.g., patients with daily elemental calcium dose both the implementation of the CKD-MBD CPG and prescribed exceeding 1.5 g); and the translation of knowledge in CKD-MBD care in the (v) percentage of patients prescribed aluminium-based region. There is a need to recognize possible racial phosphate binders. differences in treatment effects; however, given the Because currently there is a lack of strong evidence paucity of published data on Asian patients, more supporting a specific treatment target for each studies are required from this region if local data are biochemical parameter of CKD-MBD and reimburse- to contribute to future KDIGO CPG development. It is fi ment policies also differ across the region, threshold hoped that this rst Asia Summit on KDIGO CKD- levels for various KPIs may be locally adapted to suit MBD Guideline Implementation will help facilitate local situations and needs for an individual country. knowledge translation on a local level and serve as an Installing an audit and feedback system will be useful important example for other regions of the world to in monitoring CPG implementation. follow.

WHAT KDIGO CAN DO TO ASSIST CKD-MBD DISCLOSURE CPG IMPLEMENTATION AY-MW declared having received research grants and Because cost and reimbursement policies are among the speaker honorarium from Sanoﬁ Renal. TA declared having key barriers to implementing the CKD-MBD CPG, received consultancy fees from Astellas, Bayer Healthcare KDIGO could consider incorporating health economics Pharmaceuticals, FUSO Pharmaceutical Industries, analysis and relevant data as a supplement to publi- GlaxoSmithKline, JT Pharmaceuticals, Kyowa Hakko Kirin, cation of a CPG. General formulas for calculating the Nipro Medical Corporation, Ono Pharmaceutical, Sanwa incremental cost-effectiveness ratio could be developed Chemical, and Torii Pharmaceutical; and speaker honoraria and calculations could be personalized based on the from Bayer HealthCare, Chugai Pharmaceutical, Kissei actual costs incurred in individual regions or countries. Pharmaceutical, Kyowa Hakko Kirin, Ono Pharmaceutical, and These data are of direct relevance and interest to health Torii Pharmaceutical. YT declared having received speaker policy makers and are important considerations that honoraria from Bayer HealthCare, Boehringer Ingelheim,

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Kyowa Kirin Pharmaceutical, Otsuka Pharmaceutical, and Disorder (CKD-MBD) Guideline Update: what’s changed and Torii Pharmaceutical; and consultancy fees from Kyowa why it matters. Kidney Int. 2017;92:26–36. Kirin Pharmaceutical. MF declared having received speaker 5. United States Renal Data System. 2017 USRDS annual data honoraria from Bayer HealthCare, Kissei Pharmaceutical, report: epidemiology of kidney disease in the United States. Kyowa Hakko Kirin, and Torii Pharmaceutical; and Chapter 11: international comparisons. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive consultancy fees from Kyowa Hakko Kirin, Ono and Kidney Diseases; 2017. Available at: https://www.usrds. Pharmaceutical, and Torii Pharmaceutical. All the other org/2017/view/v2_11.aspx. Accessed September 19, 2019. authors declared no competing interests. 6. Wang F, Yang C, Long J, et al. Executive summary for the 2015 Annual Data Report of the China Kidney Disease ACKNOWLEDGMENTS Network (CK-NET). Kidney Int. 2019;95:501–505. This Summit conference was sponsored by KDIGO and 7. Yamamoto S, Karaboyas A, Komaba H, et al. Mineral and supported in part by unrestricted educational grants from bone disorder management in hemodialysis patients: Bayer HealthCare, Boehringer Ingelheim, Chugai Pharma- comparing PTH control practices in Japan with Europe and North America: the Dialysis Outcomes and Practice Patterns ceutical, Fresenius Medical Care, Japan CKD-MBD Forum, Study (DOPPS). BMC Nephrol. 2018;19:253. Japanese Society of Nephrology (JSN), Kissei Pharma- 8. Tentori F, Blayney MJ, Albert JM, et al. Mortality risk for ceutical, Kyowa Kirin Pharmaceutical Development, Nik- dialysis patients with different levels of serum calcium, kiso, Ono Pharmaceutical, Suntop Healthcare, and Torii phosphorus, and PTH: the Dialysis Outcomes and Practice Pharmaceutical. We thank Dr. Sinee Disthabanchong for Patterns Study (DOPPS). AmJKidneyDis. 2008;52:519– valuable input into this manuscript. 530. Other conference participants are Ali K. Abu-Alfa, 9. Fernandez-Martin JL, Martinez-Camblor P, Dionisi MP, Lebanon; Hideki Fujii, Japan; Naohiko Fujii, Japan; et al. Improvement of mineral and bone metabolism markers is associated with better survival in haemodialysis Kunitoshi Iseki, Japan; Nobuhiko Joki, Japan; Tilakavati patients: the COSMOS study. NephrolDialTransplant. Karupaiah, Malaysia; Naoki Kashihara, Japan; Junichiro 2015;30:1542–1551. Kazama, Japan; Fumihiko Koiwa, Japan; Hirotaka 10. Fukagawa M, Kido R, Komaba H, et al. Abnormal mineral Komaba, Japan; Braden J. Manns, Canada; Masahide metabolism and mortality in hemodialysis patients with Mizobuchi, Japan; Yusuke Sakaguchi, Japan; Hiroko secondary hyperparathyroidism: evidence from marginal Segawa, Japan; Takashi Shigematsu, Japan; Tetsuo structural models used to adjust for time-dependent con- – Shoji, Japan; Motoko Tanaka, Japan; Masatomo Tani- founding. Am J Kidney Dis. 2014;63:979 987. guchi, Japan; Minako Wakasugi, Japan; and Suguru 11. Hill KM, Martin BR, Wastney ME, et al. Oral calcium carbonate Yamamoto, Japan. affects calcium but not phosphorus balance in stage 3-4 chronic kidney disease. Kidney Int. 2013;83:959–966. SUPPLEMENTARY MATERIAL 12. Spiegel DM, Brady K. Calcium balance in normal individuals and in patients with chronic kidney disease on low- and high- Supplementary File (Word) calcium diets. Kidney Int. 2012;81:1116–1122. Table S1A. Intact parathyroid hormone threshold for 13. Evenepoel P, Wolf M. 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