REVIEW ARTICLE

Educational Intervention for Metabolic Bone Disease in Patients With Chronic Kidney Disease: A Systematic Review and Meta-Analysis Yuexian Shi, MD,*,† Yinning Zhao, MB,‡ Junduo Liu, MD,§ Yahong Hou, MD,† and Yue Zhao, PhD* Metabolic bone disease (MBD) is a common complication of chronic kidney disease (CKD). The currently accepted international guidelines for treatment of CKD-MBD has been published, unfortunately adequate control of serum markers of disorder, especially hyperphosphatemia, is poorly achieved. Whether educational intervention is an effective way for improving CKD-MBD remains controversial. A systematic review of educational intervention versus routine care to improve patients with CKD-MBD was conducted. All randomized controlled trials (RCTs) and quasi-RCTs examining the efficacy of educational intervention to improve patients with CKD-MBD were included. We performed a comprehensive search of several databases and sources to identify eligible trials. In addition, we searched unpublished studies by tracking the SIGLE (System for Information on Grey Literature) database. Finally, 8 RCTs and 2 quasi-RCTs containing 775 participants were included in our systematic review. The result of our study revealed that the educational intervention to patients with CKD-MBD led to an improvement of the serum phosphorus and calcium by phosphate product. Educational intervention is a beneficial supplement method in improving CKD-MBD and putting off deterioration of the disease. Ó 2014 by the National Kidney Foundation, Inc. All rights reserved.

Introduction

C

HRONIC KIDNEY DISEASE (CKD), a major public health concern in terms of mortality, hospitalizations, and health spending, is characterized by progressive deterioration of kidney function.1 At present, CKD affects approximately 5% to 10% of the world population.2,3 Progression of CKD is associated with a number of serious complications. Metabolic bone disease (MBD) is a common complication of CKD and is caused by imbalance of the mineral metabolism.4,5 CKD–mineral and bone disorder(MBD) was proposed by Kidney Disease Improving Global Outcomes (KDIGO) working group in 2009.6,7 CKD-MBD is used to describe a systemic disorder characterized by laboratory abnormalities (e.g., serum calcium, phosphorus, parathyroid hormone [PTH]); abnormalities of bone turnover, mineralization, volume, linear growth, and strength; and vascular or soft tissue calcification.8 Alteration of mineral metabolism

*

School of Nursing, Tianjin Medical University, Tianjin, China. Nursing Department, Medical College Affiliated Hospital of Chinese People’s Armed Police Force, Tianjin, China. ‡ Haematology Department, the First Peoples’ Hospital of Yinchuan, Ningxia Hui Autonomous Region, China. § Hemodialysis Center, First Center Hospital of Tianjin, Tianjin, China. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Yue Zhao, PhD, School of Nursing, Tianjin Medical University, Qixiangtai Road, Heping district, Tianjin, China. †

E-mail: [email protected] Ó

2014 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 http://dx.doi.org/10.1053/j.jrn.2014.06.007

Journal of Renal Nutrition, Vol 24, No 6 (November), 2014: pp 371-384

occurs in the early stage of CKD and progressively deteriorates with the decline of kidney function.9,10 It is now recognized that bone and mineral abnormalities in CKD can impact many areas of the body and are identified as strong, independent risk factors for cardiovascular disease. Cardiovascular disease is the leading cause of death in patients suffering from CKD.11,12 It was reported that almost 25% of hemodialysis patients affected by either vascular or valvular calcifications.13 Hence, the management of MBD has become a pivotal element in the treatment of CKD. Nowadays, the management of CKD-MBD includes dietary phosphate restriction, dialysis, phosphate binders (both calcium based and calcium free), vitamin D, and cinacalcet7,8; however, the control of CKD-MBD remains a cornerstone in the treatment of patients with CKD. Patients with CKD always have a complex regimen of treatment, various medications, fluids, and diet management.14 The patients’ education is a vital part of the long-term management of CKD-MBD.6 Although there are some systematic reviews evaluating the different medicines in the treatment of MBD,15-17 there is no evidence as to whether the patient education is really beneficial. At present, several randomized controlled trials (RCTs), quasi-RCTs have assessed the efficacy of patient education in the management of MBD.18-20 The results were diverse across these studies, and by now, no systematic review has been produced to evaluate the efficacy of educational intervention on the MBD among patients with CKD. It has not been assessed, either, what the most effective educational strategies have in common. Therefore, we will attempt to summarize all this information to provide the best clinical evidence. 371

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SHI ET AL

Methods Search Methods for Identification of Studies All publications describing RCTs or quasi-RCTs of effects of educational intervention in patients with CKD–MBD were sought out using the search strategies developed by 2 experienced authors. Studies were obtained from searches of multiple electronic bibliographic databases supplemented with hand searches of references. We searched for articles combining terms related to intervention (e.g., health education, patient education, health knowledge, practice, patient compliance, comply, teach, and teaching), CKD (e.g., renal replacement therapy, dialysis, hemodialysis, hemofiltration, renal insufficiency, kidney diseases, end stage renal, chronic kidney, chronic renal, CKD, chronic kidney failure, chronic renal failure, chronic renal disease, end stage renal disease, and end stage kidney disease), and MBD (e.g., bone diseases, bone diseases metabolic, bone demineralization, renal osteodystrophy, hyperparathyroidism, secondary hyperparathyroidism, hyperphosphatemia, calcinosis, vascular calcification, soft tissue calcification, phosphorus, phosphate, and calcium) in the database of PubMed, EMBASE, and Cochrane Library from the beginning of the database to September 12, 2013. We handsearched relevant journals and article reference lists to identify additional eligible studies. We tried to identify unpublished studies by contacting experts who may have know about additional trials and retrieved http://opensigle.inist.fr/ System for Information on Grey Literature database to reduce publication bias.

educational intervention program (dietitian, nephrology nurse, or multidisciplinary led, etc) aiming to improve symptom of any 1 or a combination of CKD–MBD; (2) educational interventions directing to the disease-related knowledge of patients with CKD–MBD were included; and (3) educational interventions directing to therapy compliance among patients with CKD–MBD will be included. The participants in the control group just received routine care.

Outcome Measures Primary outcome measures were biochemistry marks (serum phosphorus, calcium, calcium by phosphate product, and PTH), the incidence of vascular calcification, other soft tissue or valvular calcification, and bone fractures, bone turnover, and mineralization. Secondary outcome measures were patient compliance with therapy, disease-related knowledge of patients with CKD–MBD, and all cause of mortality if these were reported in the original articles. Selection of Literature After excluding duplicates, literatures were independently selected by 2 authors according to the inclusion criteria. The title and abstract were first reviewed, and the studies that did not meet the inclusion criteria were excluded. A full text of any published article that potentially met the inclusion criteria was obtained to confirm. Any disagreements during the selection course were resolved by discussion with the third reviewer.

Types of Studies All RCTs and quasi-RCTs, which examined the efficacy of educational intervention to improve patients with CKD-MBD were included in this systematic review. No restrictions were made regarding the language or nationality of publication.

Data Extraction All relevant information about the included studies was extracted onto standardized data collection forms: basic information of included studies (author, year of publication, and country of origin) sample size, outcome measure, educator, follow-up time, tools of education, interventional strategies, and methodological quality of the included studies. We e-mailed the original authors to inquire about the deficient information in these studies. Two reviewers independently reviewed eligible studies. We used consensus and a third reviewer, if necessary, to resolve the differences of opinion.

Types of Participants Trials enrolling predialysis patients and patients with dialysis treatment were included. The patients with CKD–MBD were considered as any 1 or a combination of the following: abnormalities of calcium, phosphorus, PTH, and vitamin D metabolism; abnormalities of bone turnover, mineralization, volume, linear growth, and strength; and vascular or soft tissue calcification. Studies of patients with acute uremia or studies with children (aged ,18 years) were excluded.

Methodological Quality Assessment The methodological quality assessment was completed by 2 independent reviewers. We followed the criterion developed by the Cochrane Collaboration to assess the risk of bias.21 The quality items to be assessed were random sequence generation, allocation concealment, blinding (of participants, personnel, and outcome assessors), intention-to-treat analysis, and completeness of follow-up. Based on these criteria, studies were broadly subdivided into the following 3 categories.

Types of Interventions Interventions were aimed at improving CKD–MBD and were classified as (1) we will include studies assessed any

A. All quality criteria met: low risk of bias. B. One or more of the quality criteria only partly met: moderate risk of bias.

Inclusion Criteria We selected all publications and screened studies if they met the following criteria:

A SYSTEMATIC REVIEW AND META-ANALYSIS

C. One or more criteria not met: high risk of bias. In addition, we assessed the comparability of the baseline of the included studies.

Data Synthesis and Analysis Review Manager 5.2.6 (provided by Cochrane Collaboration) was used to conduct data synthesis and analysis. All the included studies in this systematic review used the continuous outcomes, so the mean difference (MD) and 95% confidence interval (CI) were used to assess the effects of treatment. Heterogeneity among the studies was evaluated by using the chi-squared test and the I2 test with a P value less than .10 indicating statistical significance. I2 values of 25, 50, and 75% correspond to low, medium, and high levels of heterogeneity. We analyzed the source of heterogeneity and conducted a sensitivity analysis if heterogeneity existed among the studies. Sensitivity analysis was performed to explore the influence of the following factors on effect size: study quality; duration of intervention, and sample size of trials. Meanwhile, relevant subgroup analyses were executed, which included related treatment strategies, the education practitioners (e.g., dietitian-led, and nurses-led), and the length of followup. If a sufficient number of studies are identified for a particular treatment, a funnel plot will be used to assess publication bias. We calculated the unreported standard difference if the P value or 95% CI is available in the original studies. Serum phosphorus, calcium, and calcium by phosphate product were converted to milligram per deciliter or square milligram per square deciliter: for serum phosphorus, 1 mmol/L 5 3.2 mg/dL; for serum calcium, 1 mmol/L 5 2.5 mg/dL, and for calcium by phosphate product, 1 mmol2/L2 5 12.35 mg2/dL2.17

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routine care group. Table 1 shows the characteristics of included studies.

Educational Intervention Strategies The educational interventions in 5 trials20,34-36,40 were mainly directed by dietician, whereas 2 were administrated by coordinators/multidisciplinary.38,39 One was led by nurse,42 1 by nephrologist,41 and 1 did not mention about the educator.37 Educational tools of the interventional group in 7 studies covered booklet, dietary or medication record chart, food list, refrigerator magnet, and specific protocol made by educators and so on.34-39,42 ‘‘Medication event monitoring system’’ and ‘‘Phosphorus Point System’’ were used respectively in 2 studies34,41 and 1 study was not clear.20 Strategies used in the interventions were variable, but mainly contained diet, medication, and disease-related knowledge by counseling, face-to-face discussion, education session, and so on (Table 3). Methodological Quality Table 2 presented the results of the risk of bias assessment. Among 8 RCTs, 5 trials were assigned in B level,35,38,39,41,42 whereas 3 studies had a high rate of withdrawal, and control group was higher than the interventional group, so we rated them in C level (Table 3).20,34,40 Outcomes Educational Intervention Versus Routine Care—Effect on Serum Phosphorus The results of the effectiveness of educational intervention versus routine care for the serum phosphorus are shown in Figures 2-4. The serum phosphorus was based on 9 trials with 663 participants.20,34-40,42 From Figure 2

Results Our search strategies identified 1,637 publications. Of these, 23 full-text articles were retrieved for more detailed assessment and 13 were excluded: 7 articles were not RCT study18,19,22-26; 2 articles included unsuitable interventional program27,28; 1 article included transplantation participants29; 2 articles were study protocols,30,31 and 1 article compared historical control data with intervention group.32 Two studies were related to our study after searching the reference lists of the full-text articles,33,34 but 1 of them was not available from the databases.33 We sent an e-mail to the author but no reply was received. Finally, 10 studies were included in our systematic review (Fig. 1).20,34-42

Characteristics of the Included Studies Our systematic review identified 8 RCTs,20,34,35,38-42 and 2 quasi- RCTs36,37 containing 775 participants, of whom 392 were in the education group and 383 in the

Figure 1. Selection of studies. RCT, randomized controlled trials.

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Table 1. Characteristics of Included Studies Studies: Authors Year, Country

Age (y)

No. of Patients (E/R)

Inclusion Criteria

Outcome Measures

HD, phosphate binders

Serum phosphate . 1.8 mmol/L, age . 18 y

Serum phosphorus, calcium, calcium phosphate product Serum phosphorus, calcium, calcium phosphate product, PTH; knowledge test Serum phosphorus; questionnaire test about knowledge, compliance, and belief Serum phosphorus, calcium, calcium phosphate product, PTH; serum calcium; compliance Serum phosphorus, calcium, calcium phosphate product, PTH Serum phosphorus; nutritional knowledge

Ashurst ID 2003, UK35

E: 53 (2388)*, I: 54 (2277)*

Ford 2004, USA36

74% aged .50 y

63 (32/31)

HD, phosphate binders, Vit D analog

HD, serum phosphate . 6.0 mg/dL

Karamanidou 2008, UK37

E: 57.7 6 14.86, I: 59.2 6 16.92

39 (19/20)

HD, phosphate binders

MHD $ 6-mo taking phosphate binders

Morey 2008, UK20

E: 60.50 6 15.60, R: 54.90 6 15.90

67 (34/33)

HD, phosphate binders, Vit D analog

Yokum 2008, UK38

E: 51.10 6 12.70, I: 47.60 6 14.40

34 (17/17)

HD, phosphate binders Vit D analog

Sullivan 2009, USA39

E: 54.00 6 13.00, I: 52.00 6 13.00

279 (145/134)

HD, phosphate binders Vit D analog

Degen 2009, Canada34

E: 56.00 6 10.00 I: 53.00 6 13.00

24 (11/13)

Phosphate binders

Karavetian 2013, USA40

E: 56.36 6 11.86, I: 63.00 6 2.89

81 (41/40)

HD, phosphate binders

MHD $ 6-mo, serum phosphate $ 1.8 mmol/ L, urea reduction rate $ 65%, BMI .20, age .18 y HD, 3 times/wk, serum phosphate . 1.8 mmol/ L, age .18 y MHD $ 6-mo, serum phosphate . 5.5 mg/dL, age $ 18 y Predialysis outpatient clinic or nephrologists’ private clinic; serum phosphate . 1.35 mmol/L, age .18 y MHD $ 3-mo taking phosphate binders, age $18 y

Forni Ogna 2013, Switzerland41

E: 59.1 6 15.6, I: 61.3 6 9.8

50 (24/26)

HD, Vit D analog

Shi 2013, China42

E: 54.75 6 11.86, I: 51.85 6 13.51

80 (40/40)

HD, phosphate binders

582 (9/29)

MHD $ 3-mo, high level of PTH and treated with cinacalcet MHD $ 6-mo, serum phosphate . 1.78 mmol/ L and taking phosphate binders, age .18 y

E, education group; HD, hemodiasysis; MHD, maintenance hemodiasysis; PTH, parathyroid hormone; R, routine care group; Vit D, vitamin D. Values are mean 6 standard deviation, unless stated otherwise. *Mean (range).

Serum phosphate, calcium, PTH, calcium phosphate product; knowledge of disease Serum phosphorus, calcium, calcium phosphate product, PTH; knowledge and compliance test PTH; compliance

Serum phosphorus, serum calcium, calcium phosphate product, PTH; knowledge and compliance test

SHI ET AL

Relevant Treatment

B B

B — — C B C B C

Low Low Forni Ogna 201341 Shi 201342

Low Low

Unclear Low

Low Unclear

Low Unclear

Unclear Low

Low Low

Low Low

Yes Yes Yes Yes Yes Yes Yes Yes but questionnaire test and serum phosphorus level Yes but paricalcitol dose Yes Low — — Low Low Low Low Low Low — — Low Low Low Low Low Low — — High Low High Low High Unclear — — Unclear Unclear Unclear Unclear Unclear 35

Ashurst ID 2003 Ford 200436 Karamanidou 200837 Morey 200820 Yokum 200838 Degen 200934 Sullivan 200939 Karavetian 201340

Low Quasi-RCT Quasi-RCT Low Low Low Low Unclear

Unclear — — Unclear Unclear Low Unclear Unclear

Low — — Low Unclear Low Unclear Unclear

Unclear — — Unclear Unclear Unclear Unclear Unclear

Withdrawal Assessors Participants Allocation Concealment Sequence Generation Studies: Author Year

Table 2. Methodological Quality of Included Studies

Personnel

Blinding

Incomplete Outcome Data

Selective Outcome Reporting

Baseline

Rank

A SYSTEMATIC REVIEW AND META-ANALYSIS

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we can see, at 3-month follow-up point, the participants in education group had a significant reduction in serum phosphorus compared with those in the usual care group, MD of 20.73, 95% CI (21.01, 20.44), similarly at 6-month follow-up point, MD of 21.15, 95% CI (21.62, 20.67). When we used the final point result of reported studies, there was a significant difference in the reduction of serum phosphorus, MD of 274, 95% CI (20.98, 20.50) in favor of the education group (Fig. 2). In our subgroup analysis of differences in serum phosphorus by educational practitioners, 5 studies20,34-36,40 with 246 participants and 2 studies38,39 with 310 were directed by the renal dietitian and multidisciplinary, respectively, and there were statistically significant decreases in serum phosphorus among participants directed by dietitian, MD of 20.98, 95% CI (21.34, 20.63)] and multidisciplinary, MD of 20.55, 95% CI (20.94, 20.16)]. A subgroup analysis based on nurse-led was not possible because of only a study (Fig. 3). In our analysis of differences in serum phosphorus stratified by relevant treatment (hemodiasysis and predialysis, taking vitamin D analog or not), the positive results were also shown in the education group among all of subgroups analysis but a subgroup of predialysis because of only a study (Fig. 4).34 Educational Intervention Versus Routine Care—Effect on Calcium by Phosphate Product The results of the effectiveness of educational intervention versus routine care for the calcium by phosphate product are shown in Figures 5-7. Changes in calcium by phosphate product were pooled for 7 studies with 357 participants.20,34-36,38,40,42 From the Figure 5, we can see that the participants in education group had a significant reduction in calcium by phosphate product at 6-month (MD of 28.19, 95% CI [213.67, 22.71])20,36,42 and at the final point (MD of 25.92, 95% CI [29.03, 22.81])20,34-36,38,40,42 comparing with those in the usual care group. But at the 3-month follow-up time, there was no significant difference between the groups in calcium by phosphate product with MD of 25.33, 95% CI (210.88, 0.22).34,35,42 Subgroup analysis of differences in calcium by phosphate product based on educational practitioner and treatment method also showed the participants in education group had a significant reduction in calcium by phosphate product comparing with those in the usual care group, if there were enough trial data available (Figs. 6 and 7). Educational Intervention Versus Routine Care—Effect on Serum Calcium Changes in serum calcium were pooled for 5 studies with 250 participants.20,34,36,38,42 A fixed-effects model was used (P 5.27, I2 5 22%). In pooled analysis, the serum calcium level in the control group was lower than that in the

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Table 3. Interventional Strategies of Included Studies Studies: Author Year 35

G

Director

Follow-Up Time

Tools of Education Booklet; medication record chart and refrigerator magnet Medication record chart Posters; handouts; puzzles; individualized phosphorus tracking tool

E

Trained dietitian

3-mo

Ford 200436

R E

Dietitian Registered dietitian

3-mo 6-mo

R

Registered dietitian

6-mo

Education materials were not available

Morey 200820

E

Dietician

12-mo

Not mentioned

Karamanidou 200837

R E

Dietician Not mentioned

12-mo 4-mo

Not mentioned Leaflet; demonstration

Yokum 200838

R E

4-mo 4-mo

No Specially designed phosphate management protocol

Renal consultant; dietitian; pharmacists

R

Senior doctor; dietitian

4-mo

A detailed low-phosphate diet booklet, a simplified handwritten diet action plan

Sullivan 200939

E

Study coordinator

3-mo

High-phosphorus foods from a list of 20 foods. Handout

Degen 200934

R E

Dietitians and nephrologists Dietitian

3-mo 12-wk

Phosphorus point system tool; booklet

R

Registered dietitian

12-wk

A one-page double-sided handout

One-to-one teaching session Normal management on the dialysis unit 2030 min of diet education monthly focusing on the importance of all aspects of diet phosphorus control Routine care, including a review of the monthly laboratory report by the dietitian Written and verbal education including motivational counseling, negotiation, behavior modification therapy, reminders, reinforcement, supportive care Standard care Encouraged patients to share their thoughts; the investigator talked with patients; demonstration Standard care Individual dietary advice. The protocol comprised 2 algorithms aiming to change patients’ medications as specified within the protocol Individual dietary advice. A senior doctor reviewed the monthly blood results, the dose and type of phosphate binder, and alfacalcidol during dialysis ward rounds or at an outpatient clinic Regular nutritional care. A study coordinator met in person with each intervention participant during a dialysis treatment and provided 30 min of education regarding phosphorus containing additives and their effect on the phosphorus content of foods Regular nutritional care Instructed participants to restrict phosphorus consuming. Discussion with the participants to ensure adequate protein consumption. Explained phosphorus metabolism, the risks of hyperphosphatemia, and the use of phosphate binders to the participants. Received the standard choose/avoid (C/A) phosphorus education

SHI ET AL

Ashurst ID 2003

Interventional Strategies

A SYSTEMATIC REVIEW AND META-ANALYSIS

educational group, MD of 20.17, 95% CI (0.04, 0.31), P 5 .002 (Fig. 8).

No 6-mo Nephrology nurse R

Educational Intervention Versus Usual Care—Effect on PTH Seven studies reported the changes of PTH.20,34,36,38,40-42 The results could not be combined because median and range were used to describe the data among these studies. However, the results from these studies showed no significant difference between the 2 groups after the intervention. Educational Intervention Versus Routine Care—Effect on Vascular or Soft Tissue Calcification, Abnormalities of Bone Turnover and All Cause of Mortality These were not addressed by any of the included trials. Educational Intervention Versus Routine Care—Effect on Compliance and Knowledge Patient compliance with therapy was detected in 5 trials.20,37,40-42 Diet, medication, fluid, or therapy compliance was measured in these studies using patient dietary nonadherence or self-developed questionnaires, etc. The results were various among these original studies. Researchers from 4 of them thought educational intervention could have a good effect on the compliance of participants about diet and medication.37,40-42 A research from Morey et al.20 showed that there was no significant difference in self-reported compliance between the 2 study groups after intervention.

E, education group; R, routine care group.

No Booklet, PowerPoint 6-mo 6-mo Nephrologist Trained and experienced nephrology nurse Shi 201342

R E

No Medication event monitoring system Dietitian Trained nephrologist Forni Ogna 201341

R E

2-mo 6-mo

Self-management dietary counseling. 20 min session each week; 10 min discussion and relevant nutritional counseling Routine nutritional education Nephrologist interviewed the participants and discussed with them about strategies and plans to overcome nonadherence Usual care Individual education, 2030 min, 23 times a week, adopting dialog form. Educational session Routine guideline Educational materials 2-mo Dietitian E Karavetian 201340

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Educational Intervention Versus Routine Care—Effect on Related Knowledge of Patients With CKD–MBD Patients’ knowledge related on disease, diet, medication, or other treatment methods was detected from 6 studies.34,36,37,39,40,42 Self-developed questionnaires were adopted to evaluate the related knowledge of participants, so the results could not be pooled. All but a single study confirmed that educational invention could efficiently improve the related knowledge. In Degens’ study,34 the significant difference was only existed in the domain of medication for 2 comparison groups, but there were no significant differences noted in the domains of diet and disease-related knowledge between the groups.

Sensitivity Analysis Sensitivity analyses were executed by excluding 2 quasi-RCTs,36,37 studies with a relative small sample size,34 long follow-up time,20 high risk of bias, and incomparability of baseline characteristics40,41 to explore the robustness of the result.20,34,40 No other sensitivity analysis changed our results.

378

SHI ET AL Education group Routine care group Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Fixed, 95% CI Year 1.1.1 3 months 4.4% -0.99 [-1.80, -0.18] 2003 Ashurst ID 2003 29 5.12 1.57 29 6.11 1.57 Sullivan 2009 134 16.1% -0.50 [-0.92, -0.08] 2009 6.2 1.7 145 6.7 1.9 Degen 2009 5.5% -0.54 [-1.27, 0.19] 2009 9 4.48 0.54 7 5.02 0.93 8.9% -1.12 [-1.69, -0.55] 2013 Shi 2013 40 5.73 1.22 40 6.85 1.38 Subtotal (95% CI) 212 35.0% -0.73 [-1.01, -0.44] 221 Heterogeneity: Chi² = 3.58, df = 3 (P = 0.31); I² = 16% Test for overall effect: Z = 4.94 (P < 0.00001) 1.1.2 6 months Ford 2004 5.2 1.2 32 6.7 Shi 2013 5.7 1.25 40 6.59 Subtotal (95% CI) 72 Heterogeneity: Chi² = 1.56, df = 1 (P = 0.21); I² = 36% Test for overall effect: Z = 4.75 (P < 0.00001) 1.1.3 Final results Ashurst ID 2003 5.12 1.57 29 6.11 Ford 2004 5.2 1.2 6.7 32 Karamanidou 2008 5.12 1.28 16 4.48 Morey 2008 5.25 1.34 27 5.95 Yokum 2008 5.79 1.73 14 6.62 Sullivan 2009 6.2 1.7 145 6.7 Degen 2009 4.48 0.54 7 5.02 Karavetian 2012 5.39 1.97 37 6.51 Shi 2013 5.7 1.25 40 6.59 Subtotal (95% CI) 347 Heterogeneity: Chi² = 12.81, df = 8 (P = 0.12); I² = 38% Test for overall effect: Z = 6.14 (P < 0.00001)

1.7 1.57

31 40 71

1.57 1.7 1.6 1.73 0.8 1.9 0.93 1.36 1.57

29 31 11 21 17 134 9 24 40 316

Mean Difference IV, Fixed, 95% CI

5.5% -1.50 [-2.23, -0.77] 2004 7.5% -0.89 [-1.51, -0.27] 2013 13.0% -1.15 [-1.62, -0.67]

4.4% 5.5% 2.3% 3.6% 3.0% 16.1% 5.5% 4.2% 7.5% 52.1%

-0.99 [-1.80, -0.18] -1.50 [-2.23, -0.77] 0.64 [-0.49, 1.77] -0.70 [-1.60, 0.20] -0.83 [-1.81, 0.15] -0.50 [-0.92, -0.08] -0.54 [-1.27, 0.19] -1.12 [-1.96, -0.28] -0.89 [-1.51, -0.27] -0.74 [-0.98, -0.50]

599 100.0% -0.79 [-0.96, -0.62] Total (95% CI) 640 Heterogeneity: Chi² = 20.49, df = 14 (P = 0.12); I² = 32% Test for overall effect: Z = 9.07 (P < 0.00001) Test for subgroup differences: Chi² = 2.54, df = 2 (P = 0.28), I² = 21.4%

2003 2004 2008 2008 2008 2009 2009 2012 2013

-2

-1 0 1 Favours experimental Favours control

2

Figure 2. Forest plot of serum phosphorus, stratified by follow-up time. Mean difference (MD) with 95% confidence interval (CI). IV, inverse variance; SD, standard difference.

Publication Bias The funnel plot, adopted to assess publication bias, was somewhat asymmetric (Fig. 9). This shows that our findings might exist publication bias.

Discussion We identified 8 RCTs and 2 quasi-RCTs that compared educational intervention with routine care for improving CKD–MBD. This systematic review provided a moderate evidence of all overall benefit that educational intervention is more efficient than routine care on CKD–MBD. Educational intervention led to a lower serum phosphorus level and calcium by phosphate products, which are the trigger factors for any other CKD–MBD symptoms, such as accidence of cardiovascular event, vascular or soft tissue calcification, etc. Lack of relevant knowledge is a common phenomenon among patients with CKD–MBD. The CKD-MBD is always of insidious onset and slow progression. Some symptoms induced by CKD–MBD are not acute, nor seriously uncomfortable in patients, so they neglect them. It was reported that the dialysis nonadherence rate was as high as 86%.14,43,44 Medication nonadherence in hemodialysis range from 9.7% to 49.5% and diet nonadherence in patients undergoing hemodialysis range from 9% to 21%.14,43 The Dialysis Outcomes and Practice Patterns Study indicated that nonadherence, no matter on dialysis treatment, medication, or fluid and diet could increase the risk of hospitalization and mortality.43This may be caused by insidious symptom and complicated treatment methods. Studies

have demonstrated that there is a close relationship between nonadherence and shortage of knowledge, whereas both of them have the adverse influence on the deterioration of disease and complication.37,45 In our included trials, educational intervention on patients mainly focused on improving compliance and promoting the patientsrelevant knowledge with the purpose of postponing the progress of CKD, reducing the morbidity and mortality risk. Form the guideline of KDIGO working group in 2009,6,7 we know dietary management is an important element in patients with CKD; therefore, the renal dietitian plays a pivotal role in guiding patient. Actually, in some developed countries and areas, patients with CKD can gain the help, diet guidance, and monitoring from renal dietitian. The educational practitioners in our selected studies were the dietitian, nurse, nephrologist, and a multidisciplinary team. We divided subgroup analysis by educators in our meta-analysis. The effect of dietitian-led management for patients with CKD was confirmed by our research. From the Figure 3, we can see 5 studies were conducted by dietitian and a positive result was shown after combining the data. However, dietitian-performed educational program is still difficult to obtain in some remote areas. Some studies42,46 have reported that nephrologist and nurse could play an important role for the extension of knowledge among patients with CKD. This systematic review included only a study led by nurse, so the effect of nurse-led education was not determined by subgroup analysis. Studies have indicated that the educational intervention was effective in the short term, but it was unsustainable in

379

A SYSTEMATIC REVIEW AND META-ANALYSIS Education group Routine care group Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Fixed, 95% CI Year 1.2.2 Dietitian Ashurst ID 2003 5.12 1.57 29 6.11 1.57 29 8.5% -0.99 [-1.80, -0.18] 2003 Ford 2004 5.2 1.2 32 6.7 1.7 31 10.5% -1.50 [-2.23, -0.77] 2004 Morey 2008 5.25 1.34 27 5.95 1.73 21 6.9% -0.70 [-1.60, 0.20] 2008 Degen 2009 4.48 0.54 7 5.02 0.93 9 10.5% -0.54 [-1.27, 0.19] 2009 Karavetian 2012 5.39 1.97 37 6.51 1.36 24 8.0% -1.12 [-1.96, -0.28] 2012 Subtotal (95% CI) 132 114 44.5% -0.98 [-1.34, -0.63] Heterogeneity: Chi² = 3.84, df = 4 (P = 0.43); I² = 0% Test for overall effect: Z = 5.44 (P < 0.00001) 1.2.3 Multidisciplinary collaboration Yokum 2008 5.79 1.73 14 6.62 Sullivan 2009 6.2 1.7 145 6.7 Subtotal (95% CI) 159 Heterogeneity: Chi² = 0.37, df = 1 (P = 0.55); I² = 0% Test for overall effect: Z = 2.78 (P = 0.005) 1.2.4 Nurse Shi 2013 5.7 1.25 40 Subtotal (95% CI) 40 Heterogeneity: Not applicable Test for overall effect: Z = 2.80 (P = 0.005) 1.2.5 Unclear Karamanidou 2008 5.12 1.28 16 Subtotal (95% CI) 16 Heterogeneity: Not applicable Test for overall effect: Z = 1.11 (P = 0.27)

0.8 1.9

17 134 151

5.8% -0.83 [-1.81, 0.15] 2008 31.0% -0.50 [-0.92, -0.08] 2009 36.7% -0.55 [-0.94, -0.16]

6.59

1.57

40 40

14.4% -0.89 [-1.51, -0.27] 2013 14.4% -0.89 [-1.51, -0.27]

4.48

1.6

11 11

4.3% 4.3%

Mean Difference IV, Fixed, 95% CI

0.64 [-0.49, 1.77] 2008 0.64 [-0.49, 1.77]

Total (95% CI) 347 316 100.0% -0.74 [-0.98, -0.50] Heterogeneity: Chi² = 12.81, df = 8 (P = 0.12); I² = 38% Test for overall effect: Z = 6.14 (P < 0.00001) Test for subgroup differences: Chi² = 8.60, df = 3 (P = 0.04), I² = 65.1%

-4

-2 0 2 Favours experimental Favours control

4

Figure 3. Forest plot of serum phosphorus, stratified by educational practitioners. Mean difference (MD) with 95% confidence interval (CI). IV, inverse variance; SD, standard difference.

the long term.20,36 In most of our selected studies, the period of study was 2 to 6 months. Subgroup analysis by the follow-up time at 3 and 6 months in our

meta-analysis showed a significant difference between the groups, but the follow-up periods in these studies were short, and we could not get the conclusion of its extended

Education group Routine care group Mean Difference Study or Subgroup Mean SD Total Weight IV, Fixed, 95% CI Year SD Total Mean 1.3.1 HD 4.3% -0.99 [-1.80, -0.18] 2003 Ashurst ID 2003 1.57 29 6.11 5.12 1.57 29 5.3% -1.50 [-2.23, -0.77] 2004 Ford 2004 1.7 1.2 32 6.7 5.2 31 2.2% 0.64 [-0.49, 1.77] 2008 Karamanidou 2008 16 4.48 5.12 1.28 1.6 11 3.5% -0.70 [-1.60, 0.20] 2008 Morey 2008 27 5.95 5.25 1.34 1.73 21 2.9% -0.83 [-1.81, 0.15] 2008 Yokum 2008 14 6.62 5.79 1.73 0.8 17 Sullivan 2009 6.7 1.7 145 6.2 1.9 134 15.5% -0.50 [-0.92, -0.08] 2009 4.0% -1.12 [-1.96, -0.28] 2012 Karavetian 2012 6.51 5.39 1.97 37 1.36 24 40 7.2% -0.89 [-1.51, -0.27] 2013 Shi 2013 6.59 5.7 1.25 40 1.57 307 44.7% -0.76 [-1.01, -0.51] Subtotal (95% CI) 340 Heterogeneity: Chi² = 12.48, df = 7 (P = 0.09); I² = 44% Test for overall effect: Z = 6.00 (P < 0.00001) 1.3.2 Vit D Ford 2004 6.7 5.2 1.2 32 Morey 2008 5.25 1.34 5.95 27 Yokum 2008 5.79 1.73 6.62 14 Sullivan 2009 6.2 1.7 145 6.7 Subtotal (95% CI) 218 Heterogeneity: Chi² = 5.44, df = 3 (P = 0.14); I² = 45% Test for overall effect: Z = 4.61 (P < 0.00001) 1.3.3 Pre-dialysis 4.48 0.54 Degen 2009 Subtotal (95% CI) Heterogeneity: Not applicable Test for overall effect: Z = 1.45 (P = 0.15)

7 7

5.02

1.3.4 Non-Vit D 5.12 1.57 6.11 29 Ashurst ID 2003 5.12 1.28 Karamanidou 2008 4.48 16 5.02 4.48 0.54 Degen 2009 7 5.39 1.97 Karavetian 2012 37 6.51 5.7 1.25 6.59 Shi 2013 40 Subtotal (95% CI) 129 Heterogeneity: Chi² = 7.35, df = 4 (P = 0.12); I² = 46% Test for overall effect: Z = 4.06 (P < 0.0001)

1.7 1.73 0.8 1.9

31 21 17 134 203

0.93

9 9

1.57 1.6 0.93 1.36 1.57

29 11 9 24 40 113

5.3% 3.5% 2.9% 15.5% 27.1%

-1.50 [-2.23, -0.77] -0.70 [-1.60, 0.20] -0.83 [-1.81, 0.15] -0.50 [-0.92, -0.08] -0.75 [-1.08, -0.43]

Mean Difference IV, Fixed, 95% CI

2004 2008 2008 2009

5.3% -0.54 [-1.27, 0.19] 2009 5.3% -0.54 [-1.27, 0.19]

4.3% 2.2% 5.3% 4.0% 7.2% 22.9%

-0.99 [-1.80, -0.18] 0.64 [-0.49, 1.77] -0.54 [-1.27, 0.19] -1.12 [-1.96, -0.28] -0.89 [-1.51, -0.27] -0.72 [-1.07, -0.37]

632 100.0% -0.74 [-0.91, -0.57] 694 Total (95% CI) Heterogeneity: Chi² = 25.61, df = 17 (P = 0.08); I² = 34% Test for overall effect: Z = 8.69 (P < 0.00001) Test for subgroup differences: Chi² = 0.34, df = 3 (P = 0.95), I² = 0%

2003 2008 2009 2012 2013

-2 -1 0 1 Favours experimental Favours control

2

Figure 4. Forest plot of serum phosphorus, stratified by treatment strategies. Mean difference (MD) with 95% confidence interval (CI). IV, inverse variance; SD, standard difference.

380

SHI ET AL Mean Difference Education group Routine care group SD Total Weight IV, Random, 95% CI Study or Subgroup Mean SD Total Mean 2.1.1 3 months 29 6.9% -1.65 [-8.81, 5.51] 29 60.25 12.96 Ashurst ID 2003 58.6 14.8 7.9 9 8.0% -3.08 [-9.52, 3.36] 7 44.58 Degen 2009 41.5 5.19 40 8.8% -10.50 [-16.40, -4.60] 40 61.26 14.57 Shi 2013 50.76 12.23 78 23.7% -5.33 [-10.88, 0.22] 76 Subtotal (95% CI) Heterogeneity: Tau² = 13.16; Chi² = 4.41, df = 2 (P = 0.11); I² = 55% Test for overall effect: Z = 1.88 (P = 0.06) 2.1.2 6 months 60 14.3 31 32 11 Ford 2004 47 30 56.19 12.97 30 Morey 2008 53.11 11.61 40 59.28 14.57 40 Shi 2013 50.76 11.73 102 Subtotal (95% CI) 101 Heterogeneity: Tau² = 13.73; Chi² = 4.83, df = 2 (P = 0.09); I² = 59% Test for overall effect: Z = 2.93 (P = 0.003) 2.1.3 Final results 29 60.25 12.96 Ashurst ID 2003 58.6 14.8 60 14.3 32 11 Ford 2004 47 6.3 14 59.28 Yokum 2008 54.71 14.82 27 52.61 15.68 Morey 2008 46.68 13.83 7.9 7 44.58 Degen 2009 41.5 5.19 37 52.5 13.59 Karavetian 2012 49.46 11.63 40 59.28 14.57 Shi 2013 50.76 11.73 186 Subtotal (95% CI) Heterogeneity: Tau² = 5.21; Chi² = 8.54, df = 6 (P = 0.20); I² = 30% Test for overall effect: Z = 3.73 (P = 0.0002)

29 31 17 21 9 24 40 171

Mean Difference IV, Random, 95% CI

Year 2003 2009 2013

8.1% -13.00 [-19.31, -6.69] 2004 -3.08 [-9.31, 3.15] 2008 8.3% 9.0% -8.52 [-14.32, -2.72] 2013 25.5% -8.19 [-13.67, -2.71]

6.9% -1.65 [-8.81, 5.51] 2003 8.1% -13.00 [-19.31, -6.69] 2004 5.6% -4.57 [-12.89, 3.75] 2008 5.4% -5.93 [-14.43, 2.57] 2008 -3.08 [-9.52, 3.36] 2009 8.0% 7.7% -3.04 [-9.64, 3.56] 2012 9.0% -8.52 [-14.32, -2.72] 2013 50.8% -5.92 [-9.03, -2.81]

364 350 100.0% Total (95% CI) Heterogeneity: Tau² = 6.52; Chi² = 18.98, df = 12 (P = 0.09); I² = 37% Test for overall effect: Z = 5.43 (P < 0.00001)

-6.37 [-8.67, -4.07] -20 -10 0 10 20 Favours experimental Favours control

Figure 5. Forest plot evaluating calcium by phosphate product, stratified by follow-up time. Mean difference (MD) with 95% confidence interval (CI). IV, inverse variance; SD, standard difference.

period effect. All of our included studies just focused on the effect of educational intervention on hyperphosphatemia but not on the combination of CKD–MBD. In these studies, the education tools, such as booklet, medication record chart, handbook, food list, PowerPoint, Phosphorus Point System were used and one-to-one teaching session, discussion, relevant nutritional counseling, etc. were

adopted as the educational strategies. But, from the available data, we could not be sure which was the optimal 1 among them. The study from Sullivan et al39 concentrated on education of participants to avoid consuming additivecontaining processed food and demonstrated a significantly decreased serum phosphorus in the intervention group.

Education group Routine care group Mean Difference SD Total Weight IV, Random, 95% CI Year Study or Subgroup Mean SD Total Mean 2.2.1 Nurse 40 59.28 14.57 50.76 11.73 40 18.0% -8.52 [-14.32, -2.72] 2013 Shi 2013 40 40 18.0% -8.52 [-14.32, -2.72] Subtotal (95% CI) Heterogeneity: Not applicable Test for overall effect: Z = 2.88 (P = 0.004) 2.2.2 Multidisciplinary collaboration 54.71 14.82 14 59.28 Yokum 2008 14 Subtotal (95% CI) Heterogeneity: Not applicable Test for overall effect: Z = 1.08 (P = 0.28)

6.3

Mean Difference IV, Random, 95% CI

17 10.8% -4.57 [-12.89, 3.75] 2008 17 10.8% -4.57 [-12.89, 3.75]

2.2.3 Dietitian 58.6 14.8 Ashurst ID 2003 29 60.25 12.96 29 47 11 Ford 2004 32 60 14.3 31 Morey 2008 46.68 13.83 27 52.61 15.68 21 41.5 5.19 7 44.58 7.9 Degen 2009 9 49.46 11.63 37 52.5 13.59 24 Karavetian 2012 132 Subtotal (95% CI) 114 Heterogeneity: Tau² = 11.26; Chi² = 7.62, df = 4 (P = 0.11); I² = 47% Test for overall effect: Z = 2.49 (P = 0.01)

13.6% -1.65 [-8.81, 5.51] 2003 16.1% -13.00 [-19.31, -6.69] 2004 10.5% -5.93 [-14.43, 2.57] 2008 15.7% -3.08 [-9.52, 3.36] 2009 15.2% -3.04 [-9.64, 3.56] 2012 71.1% -5.43 [-9.71, -1.15]

Total (95% CI) 186 171 100.0% Heterogeneity: Tau² = 5.21; Chi² = 8.54, df = 6 (P = 0.20); I² = 30% Test for overall effect: Z = 3.73 (P = 0.0002)

-5.92 [-9.03, -2.81] -50

-25 0 25 Favours experimental Favours control

50

Figure 6. Forest plot evaluating calcium by phosphate product, stratified by educational practitioners. Mean difference (MD) with 95% confidence interval (CI). IV, inverse variance; SD, standard difference.

381

A SYSTEMATIC REVIEW AND META-ANALYSIS Mean Difference IV, Fixed, 95% CI

Education group Routine care group Mean Difference SD Total Mean IV, Fixed, 95% CI Year Study or Subgroup Mean SD Total Weight 2.3.1 HD 29 60.25 12.96 58.6 14.8 -1.65 [-8.81, 5.51] 2003 6.5% Ashurst ID 2003 29 11 32 60 47 8.4% -13.00 [-19.31, -6.69] 2004 Ford 2004 14.3 31 27 52.61 15.68 46.68 13.83 4.6% -5.93 [-14.43, 2.57] 2008 Morey 2008 21 14 59.28 54.71 14.82 4.8% -4.57 [-12.89, 3.75] 2008 Yokum 2008 6.3 17 37 52.5 13.59 7.7% -3.04 [-9.64, 3.56] 2012 49.46 11.63 Karavetian 2012 24 40 59.28 14.57 9.9% -8.52 [-14.32, -2.72] 2013 50.76 11.73 40 Shi 2013 179 Subtotal (95% CI) 162 41.9% -6.61 [-9.43, -3.79] Heterogeneity: Chi² = 7.57, df = 5 (P = 0.18); I² = 34% Test for overall effect: Z = 4.59 (P < 0.00001) 2.3.2 Pre-dialysis 41.5 5.19 Degen 2009 Subtotal (95% CI) Heterogeneity: Not applicable Test for overall effect: Z = 0.94 (P = 0.35)

7 7

44.58

2.3.3 Vit D 11 32 60 Ford 2004 47 27 52.61 Morey 2008 46.68 13.83 14 59.28 Yokum 2008 54.71 14.82 73 Subtotal (95% CI) Heterogeneity: Chi² = 3.13, df = 2 (P = 0.21); I² = 36% Test for overall effect: Z = 4.02 (P < 0.0001) 2.3.4 Non-Vit D Ashurst ID 2003 58.6 14.8 29 60.25 Degen 2009 41.5 5.19 7 44.58 49.46 11.63 37 52.5 Karavetian 2012 Shi 2013 50.76 11.73 40 59.28 Subtotal (95% CI) 113 Heterogeneity: Chi² = 2.83, df = 3 (P = 0.42); I² = 0% Test for overall effect: Z = 2.71 (P = 0.007)

7.9

9 9

14.3 15.68 6.3

31 21 17 69

12.96 7.9 13.59 14.57

29 9 24 40 102

8.1% 8.1%

-3.08 [-9.52, 3.36] 2009 -3.08 [-9.52, 3.36]

8.4% -13.00 [-19.31, -6.69] 2004 4.6% -5.93 [-14.43, 2.57] 2008 4.8% -4.57 [-12.89, 3.75] 2008 17.8% -8.88 [-13.21, -4.56]

6.5% 8.1% 7.7% 9.9% 32.2%

-1.65 [-8.81, 5.51] -3.08 [-9.52, 3.36] -3.04 [-9.64, 3.56] -8.52 [-14.32, -2.72] -4.46 [-7.68, -1.24]

372 Total (95% CI) 342 100.0% Heterogeneity: Chi² = 17.08, df = 13 (P = 0.20); I² = 24% Test for overall effect: Z = 6.48 (P < 0.00001) Test for subgroup differences: Chi² = 3.55, df = 3 (P = 0.31), I² = 15.5%

-6.04 [-7.87, -4.21]

2003 2009 2012 2013

-20 -10 0 10 20 Favours experimental Favours control

Figure 7. Forest plot evaluating calcium by phosphate product, stratified by treatment strategies. Mean difference (MD) with 95% confidence interval (CI). IV, inverse variance; SD, standard difference; Vit D, vitamin D.

Phosphate-based food addictive contributes to a large source of diet phosphate. It has been revealed that phosphorus from additives may amount 1,000 mg/day47,48; however, this kind of knowledge is often scant in patients with CKD. Furthermore, the phosphate-based food addictive is not shown on the nutrition facts labels and ingredient lists or manufacturers are not required to quantify their amount in product labels, so the patients might puzzle because they can not be sure if the food contains it or not.47,49 However, several of our other selected trials have also confirmed that the education of patients in cutting down the processed food was an effective way to control the serum phosphorus levels.39,40,42 It is said that lack of relevant knowledge and complex treatment strategies make a poor compliance, which is a head-scratching puzzlement among patients with chronic Education group Routine care group Study or Subgroup Mean SD Total Mean SD Total 31 9.2 0.78 32 8.9 0.67 Ford 2004 17 6.18 0.38 14 5.85 0.65 Yokum 2008 30 6 0.5 30 5.75 0.5 Morey 2008 9 6 0.33 7 5.78 0.43 Degen 2009 40 5.75 0.55 40 5.83 0.65 Shi 2013 123 Total (95% CI) Heterogeneity: Chi² = 5.13, df = 4 (P = 0.27); I² = 22% Test for overall effect: Z = 2.47 (P = 0.01)

Weight 14.8% 14.1% 29.8% 13.8% 27.4%

condition, but there is no uniform method to estimate the compliance.18,42 A variety of questionnaires developed by researchers were used in our included studies, so the combination results were not available. Figure 8 showed that the serum calcium was higher in the education group than that in the routine care group. This might be the good adherence of phosphate binder among participants. As we all known, the calcium binders are widely used in treatment of CKD patients.42 In the study of Forni Ogna et al.,41 medication event monitoring system was used to monitor patient adherence to medication intake, they thought that education and interaction between patients and physicians integrating with medication event monitoring system were benefit for medicine adherence. Some researchers devoted to change patients behaviors, such as self-efficacy and health belief

Mean Difference IV, Fixed, 95% CI Year 0.30 [-0.06, 0.66] 2004 0.33 [-0.04, 0.70] 2008 0.25 [-0.00, 0.50] 2008 0.22 [-0.15, 0.59] 2009 -0.08 [-0.34, 0.18] 2013

Mean Difference IV, Fixed, 95% CI

127 100.0% 0.17 [0.04, 0.31] -1

-0.5 0 0.5 Favours experimental Favours control

1

Figure 8. Forest plot of Serum calcium. Mean difference (MD) with 95% confidence interval (CI). IV, inverse variance; SD, standard difference.

382

SHI ET AL 0

SE(MD)

0.2

0.4

0.6

0.8

1

MD -2

-1

0

1

2

Figure 9. Funnel plot for final result of serum phosphorus in 9 included studies. Vertical dotted line shows the average risk ratio across all trials reporting an outcome of serum phosphorus. MD, mean difference; SE, standard error.

to enhance adherence and knowledge of patients. They demonstrated that a patient with a positive healthy behavior led to a good adherence.18,40 No included study evaluated the cost of educational intervention. Compared with hemodialysis and drug therapies, educational intervention for patients with CKD–MBD seems to be simple, inexpensive, and feasible. Guideline form KDIGO working group in 2009 suggested that dietary counseling could help keep phosphorus level normal and this could be served as an adjunct to dialysis and drug therapies.

Study Strengths and Limitations This is the first systematic review for detecting the effectiveness of educational intervention on the CKD–MBD. We performed a comprehensive search of several databases and sources to identify eligible trials, with no language restriction. In addition, we searched unpublished studies by tracking the System for Information on Grey Literature database. Furthermore, 2 reviewers independently scanned through the search output, extract data, classify interventions, and assess the methodological quality of each trial to reduce the potential bias. However, several caveats with this systematic review affected the conclusion drawing. 1. Limited number of trials in this systematic review, small sample size within each trail, and the short follow-up period made our conclusion with caution. All these affected the strength of evidence. 2. Some outcomes were described using chart or language, and some of others were assessed adopting different measured method, which led us not to synthesize data or conduct subgroup analysis. 3. Our systematic review aimed to explore the effectiveness of educational intervention on the CKD–MBD. Unfortunately, included trials only reported some surrogate end points (biochemical outcomes: serum phosphorus, phosphorus by calcium

product, and calcium). We were unable to confirm whether the educational intervention is effective on end points, such as incidence of vascular or other soft tissue calcification, mortality, because these findings were not reported in any of the selected studies. It may be because these outcomes need a long term to determine, whereas existing researches were in a short period of follow-up. 4. In many included studies, the method quality was unclear; especially in the domain of ‘‘allocation concealment and blinding’’, which affect the overall methodological quality of included studies. Meanwhile, the high rate of withdrawal at the end of the studies existed in 3 RCTs, especially the control group was higher than interventional group, so we thought it with high risk and rated it in a C level. 5. The publication bias from funnel plot analysis showed a potential publication bias for serum phosphorus (Fig. 8). This might because of small amount of studies in our meta-analysis, and also 1 study was actually known that was not available.

Conclusions This systematic review confirmed that compared with routine care, the educational intervention to patients with CKD–MBD led to an improvement of some main biochemistry outcomes. Based on this meta-analysis, we could say that the educational intervention is a beneficial supplement method in improving CKD–MBD and putting off deterioration of the disease. Results were limited by short follow-up times and based on a small number of studies and individuals. The evidence for long-time effectiveness and some other outcomes (incidence of vascular or other soft tissue calcification, bone turnover, mortality etc.) remains unclear and calls for further research on the topic.

Practical Application This systematic review devotes to determine the effect of educational intervention to patients with CKD–MBD. Although the included studies could not covers outcome measures as we planned, the results of meta-analysis indicated that educational intervention was effective on control of serum phosphorus and calcium by phosphorus product. Educational intervention for patient with CKD–MBD can be simple, inexpensive, and feasible, and this approach should be valued and supported by clinical practitioners.

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