Peritoneal dialysis guidelines 2019 Part 2: Appendix

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Peritoneal dialysis guidelines 2019 Part 2: Appendix

1. About this CPG 2. Funding

3. About our clinical questions (CQs) / systematic reviews (SRs) 3.1. Analytical framework

3.2. Clinical questions (CQ)

3.3. The relationship between CQs and SRs 4. About our outcomes

4.1. Outcomes At-a-Glance

4.2. Detailed definitions of each outcome 5. Queries and analytical methods

5.1. About the treatment (Peritoneal dialysis) 5.2. About the study design

5.3. Databases

5.4. Data extraction and analysis:

5.4.1. Study selection 5.4.2. Data extraction 5.5. Bias risk evaluation

5.6. Evaluation of treatment effects

6. Evidence-to-decision frameworks (EtD Table) and related systematic reviews (SRs)

6.1. CQ1: Is the use of renin-angiotensin system inhibitors (RAS inhibitors), such as angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB), effective in peritoneal dialysis patients?

SR1: SR1.1. Comparison of ACEI and ARB with other drugs SR1.2. Comparison of ACEI with ARB (Effect of ARB to ACEI) 6.2. CQ2: Icodextrin or glucose solution: which is more useful

as a dialysate among patients with peritoneal dialysis?

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SR2: Comparison of icodextrin and glucose dialysis solution monotherapy

6.3. CQ3: Is it better to apply or not apply mupirocin/gentamicin ointment to the exit site?

SR3: SR3.1. Comparison of mupirocin ointment with a control treatment

SR3.2. Comparison of mupirocin and gentamicin ointments 6.4. CQ4: Which surgical approach is more desirable when a

PD catheter is placed, open surgery or laparoscopic surgery?

SR4: Comparison of open surgery with laparoscopic surgery

6.5. CQ5:Which administration route of antibiotics is better in peritoneal dialysis patients with peritonitis, intravenous or

intraperitoneal?

SR5: SR5.1. Comparison of the administration route of antibiotics between intravenous and intraperitoneal

SR5.2. Comparison of the intraperitoneal administration manner of antibiotics between continuous and intermittent

6.6. CQ6: Is peritoneal dialysis or hemodialysis better as the first renal replacement therapy in diabetic patients?

SR6: Comparison of peritoneal dialysis with hemodialysis as the first renal replacement therapy in diabetic patients

6.7. CQ7 (Withdrawn: progress report): In peritoneal dialysis patients who have developed peritonitis, is first-time peritoneal lavage an effective treatment?

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1．About these clinical practice guidelines

These clinical practice guidelines (CPG) were created primarily by the Working Group on Revision of Peritoneal Dialysis Guidelines of the Japanese Society for Dialysis (JSDT) Therapy. Our clinical questions (CQs) were derived from important clinical issues raised by our working members and systematic review (SR) committee members. SRs were carried out for each of these CQs. We also considered the levels of our recommendations and their phrasing, and the final version of these guidelines after discussion of the results among the panel members of each CQ team.

2．Funding

Literature surveys, conference expenses, transportation expenses, etc. were paid via the financial support from the JSDT.

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Dialysis methods

3．About clinical questions / systematic reviews 3.1. Analytic framework

3.2. Clinical question

Initially, we had planned on including CQ7, However, after conducting a systematic search as part of our SR, we determined that the only existing publication that pertained to CQ7 was a case report that lacked experimental controls. We concluded that it would be difficult to carry out a sufficiently valid investigation to formulate a recommendation; hence, we withdrew the CQ7. Furthermore, we have annotated in the text accompanying each CQ if the associated SRs were conducted on the basis of observational research, not of randomized controlled trials (RCTs). Hereafter, we will refer to the operation for placement of a perfusion catheter for continuous ambulatory peritoneal dialysis (PD) as catheter insertion in this CPG.

Table 3.1: Clinical Questions (CQ) At-a-Glance

CQ1: Is the use of renin-angiotensin system inhibitors (RAS inhibitors), such as angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB), effective in PD patients?

CQ2: Icodextrin or glucose solution: which is more useful as a dialysate among patients with peritoneal dialysis?

Risks: diabetic non-diabetic

Peritoneal dialysis

Hemodialysis Harms

Dialy- sis pa-

tients

Indirect outcomes, e.g.

urine peritoneal dial-

ysis proce-

dures, etc. Death

Cardiovascu- lar event Technical

suvival

Harms

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CQ3: Is it better to apply or not apply mupirocin/gentamicin ointment to the exit site?

CQ4: When a peritoneal dialysis catheter is placed, which surgical approach is desirable, open surgery or laparoscopic surgery?

CQ5: Which administration route of antibiotics is better in peritoneal dialysis patients with peritonitis, intravenous or intraperitoneal?

CQ6: Is PD or hemodialysis (HD) better as the first renal replacement therapy in diabetic patients?

Figure 1: Conceptual diagram of clinical questions (CQs)

3.3. The relationship between CQs and SRs

CQ1: Is the use of renin-angiotensin system inhibitors (RAS inhibitors), such as angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB), effective in PD patients?

SR1.1. Comparison of ACEI and ARB with other drugs

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SR1.2. Comparison of ACEI with ARB (Effect of ARB to ACEI)

CQ2: Icodextrin or glucose solution: which is more useful as a dialysate among patients with peritoneal dialysis?

SR2.Comparison of icodextrin and glucose dialysis solution monotherapy

CQ3: Is it better to apply or not apply mupirocin/gentamicin ointment to the exit site?

SR3.1. Comparison of mupirocin ointment with a control treatment SR3.2. Comparison of mupirocin and gentamicin ointments

CQ4：Which surgical approach is more desirable when a PD catheter is placed, open surgery or laparoscopic surgery?

SR4. Comparison of open surgery with laparoscopic surgery

CQ5: Which administration route of antibiotics is better in PD patients with peritonitis, intravenous or intraperitoneal?

SR5.1. Comparison of the administration route of antibiotics between intravenous and intraperitoneal

SR5.2. Comparison of the intraperitoneal administration manner of antibiotics between continuous and intermittent

CQ6: Is PD or HD better as the first renal replacement therapy in diabetic patients?

SR6.1. Comparison of PD with HD as first renal replacement therapy in diabetic patients

4. About our outcomes 4.1. Outcomes at-a-glance

Table 4.1: The Relationships Between Outcomes and CQs

CQ1 CQ2 CQ3 CQ4 CQ5 CQ6

Overall survival rate 8 9 9

Technical survival (PD continuation period/PD withdrawal)

7.5 9 8

Urine volume/residual renal function 8 8 8

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Complications (including drug adverse effects/safety issues/hospital stay period)

7 7 7

Peritoneal function (creatinine level, etc.) 8 6 Occurrence rate of abnormal glucose

tolerance

7 Peritoneal clearance (episodes of

uncontrolled fluid overload)

9

Peritonitis (CQ3) 9

Exit site tunnel infection 8

Catheter survival (PD catheter patency rate) 9

Complications (CQ4) 8

QOL (including postoperative pain) 7.5

PD catheter functional abnormalities that require reoperation (abnormal placement or drainage)

8

Hospitalization period 7

PD withdrawal 9

Complications (drug adverse events/safety) (CQ5)

6

Complete cure of peritonitis 9

Time till complete cure of peritonitis 8

Peritonitis reoccurrence 8

Complications (cardiovascular/infectious illness) (CQ6)

8

Glycemic control 7

Cardiovascular events 8

Notes:

CQ1: For technical survival, we selected peritonitis (and decided to lower indirectness by one level)

CQ2: The definitions for the purpose of data extraction have been listed below in 6.2.3.3,

“Other Materials,” of SR2 Complications have been categorized into complications (peritonitis) and complications (rash)

CQ3: For this CQ, peritonitis is an important outcome; we have therefore considered it separately from other complications

CQ4: Complications: To consider the following three subgroups, we have defined them separately from other complications

Early complications following PD catheter placement (leakage) Late complications following PD catheter placement (hernia)

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PD catheter-related infection (exit site infection and tunnel infection) within 2 weeks of operation

CQ5: Complications: Because drug adverse events and safety are of critical importance, we have defined them separately.

CQ6: Complications: Cardiovascular/infectious illnesses have been divided into different subgroups in some instances

*With regards to complications, whenever we determined that complications were more easily understood when separated, these were defined separately during the study formulation.

* In light of the potential for competing risks between outcomes and to prevent “double counting,” we took great care in our explanations at CPG panel meetings. For example, if catheter insertion was associated with complications such as sustained pain and catheter migration, ultimately leading to hospitalization, we might have counted the same outcome multiple times, under different complications’ names.

4.2. Detailed definitions of each outcome (definitions may vary slightly due to specific studies)

Table 4.2: Outcome definitions at-a-glance

Outcome Definition

Overall survival rate

Overall survival: Overall survival rate/mortality Quality of life

(QOL)

QOL/Health-related quality of life: Improvement of health-related QOL.

Satisfaction: Satisfaction with care at the clinic Peritoneal

dialysis (PD) continuation period

Technical survival (number of patients remaining on PD at study completion):

Based on the study by Xu et al (2010), “Technical survival was defined as inadequate dialysis, ultrafiltration insufficiency, exit-site or tunnel

infection, conversion to hemodialysis (HD) because of peritonitis, and the presence of any mechanical problems; patient and peritonitis-free survival corresponded to death as the outcome event and the first episode of peritonitis respectively.”

PD withdrawal Technical failure/technical: Based from CANUSA 1996”, technical

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failure was defined as transfer to HD or to conventional intermittent HD.

Death, transplantation, recovery of renal function, and loss to follow-up were censored observations for the technical survival analysis.

Residual renal function

Loss of residual renal function/deterioration of residual renal function PD-associated

illness

Peritonitis rate: (episodes/year, episode/total patient-months on PD) and incidence (number of events/follow-up period) peritonitis/refractory exit site infection: Illnesses that do not occur during HD alone but do occur in PD, such as refractory exit site infection, etc. If PD-associated illness caused technical failure, the outcome was the same as that of technical failure occurred. However, if treatment resolved the illness and PD continued, it was classified as a separate outcome.

Major

complications

Major morbid events (acute myocardial infarction, stroke, amputation, loss of vision, electrolyte imbalance (hyperkalemia and other potentially severe occurrences), pure red cell aplasia rate, etc.): Major pathological events

Minor

complications

Minor morbid events (hypoglycemia, delayed wound healing, infection, visual disturbances, pain, etc.): Minor pathological events

Safety Safety: Safety of treatment (e.g., the functioning of HD machine or other instruments, sterility of dialysis solution).

Hospitalization period

Hospital stays: Reduction of hospital stay / Hospital admission. Because reduction of frequency in hospital visits is the greatest advantage of PD compared to HD. If the hospitalization stay was increased, this benefit of PD will be lost.

Catheter insertion complications

Early complications (perforation [of intestine or bladder], bleeding, postoperative infection [peritonitis, exit site or tunnel infection], leakage) / Late complications (poor drainage, catheter migration, blockage, hernia, reinsertion or removal)

Cure of peritonitis

Complete cure of peritonitis (clinical or microbiological improvement or both with no subsequent relapse)

Peritonitis recurrence

Peritonitis relapse (recurrence of peritonitis due to the same organism with the same antibiotic sensitivities within 28 days of completing treatment)

Other Reoperation rate / Antibiotic adverse effects / Occurrence rate of abnormal glucose tolerance / Electrolyte imbalance (hyponatremia) and hyperamylasemia, etc.

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References

Terms for complications, etc. http://pj.ninjal.ac.jp/byoin/teian/ruikeibetu/teiango/teiango- ruikei-b/gappeisyo.html. Accessed Dec. 31, 2017.

Xu R, Zhuo M, Yang Z, Dong J. Experience with Assisted Peritoneal Dialysis in China. Perit Dial Int. 2012;32:94-101

Canada-USA (CANUSA) Peritoneal Dialysis Study Group. Adequacy of dialysis and nutrition in continuous peritoneal dialysis: association with clinical outcomes. J Am Soc Nephrol. 1996;7:198-207.

Janssen IM, Gerhardus A, von Gersdorff GD, Baldamus CA, Schaller M, Barth C, Scheibler F. Preferences of patients undergoing hemodialysis? Results from a questionnaire-based study with 4,518 patients. Patient Prefer Adherence. 2015;9:847-55.

5．Queries and analytical methods:

The details of this process relied on the studies used for each SR. Here, we have listed only representative PubMed search terms.

5.1. Regarding the disease and PD

("Peritoneal Dialysis"[MH]) OR (periton*[TW] AND dialy*[TW]) OR (CAPD[TIAB] OR CCPD[TIAB] OR APD[TIAB] OR TPD[TIAB] OR (PD[TIAB] AND (periton*[TW] OR dialy*[TW]))

5.2. Regarding the study design

5.2.1. Existing systematic reviews/existing clinical practice guidelines

("Meta-Analysis"[PT] or "meta-analysis"[TIAB]) OR ("Cochrane Database Syst Rev"[TA] or "systematic review"[TIAB]) OR ("Practice Guideline"[PT] or "Practice Guidelines as Topic"[MH] or (guideline*[TIAB] not medline[SB]))

5.2.2. Randomized clinical trials

We used the following search strategy from the Cochrane handbook (Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [up- dated March 2011]. The Cochrane Collaboration, 2011.), Box 6.4.a: Cochrane Highly Sensi- tive Search Strategy for identifying randomized trials in MEDLINE: sensitivity-maximizing version (2008 revision); PubMed format, or Box 6.4.b: Cochrane Highly Sensitive Search

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Strategy for identifying randomized trials in MEDLINE: sensitivity- and precision-maximizing version (2008 revision); PubMed format.

Example: ((randomized controlled trial[pt] OR controlled clinical trial[pt] OR

randomized[tiab] OR placebo[tiab] OR drug therapy[sh] OR randomly[tiab] OR trial[tiab]

OR groups[tiab]) NOT (animals[mh] NOT humans[mh]))

5.3. Databases

Generally, we performed searches in two databases. Searches on Medline (via PubMed) were required. Other databases included Embase, Cochrane Library (CENTRAL), and Ichushi.

Searches were entrusted to the consignment project of the CPGs Creation Support Service (Literature Search) of the Japan Medical Library Association, and were carried out by an expert librarian.

5.4. Data extraction and analysis

5.4.1. Study selection

For existing SRs and CPGs, two independent reviewers used titles and abstracts to screen papers. Papers that passed the initial screening were evaluated on the basis of their full text, and those with high-quality reviews were selected. Checking the search dates and strategies of the selected reviews, after these dates, literature searches were repeated in same strategies.

Again, two independent reviewers used titles and abstracts to screen the results of these searches. Studies that passed the initial screening were evaluated together with any RCTs included in the selected reviews on the bases of their full texts. Lastly, the studies to be included were finalized.

5.4.2. Data extraction

Data extraction was carried out independently by two reviewers who used the same data collection form. Discrepancies between reviewers were resolved through discussion, and when issues remained unresolved, a third reviewer was consulted.

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5.5. Bias risk evaluation

Two independent reviewers evaluated the bias risk using the Cochrane Handbook bias risk tool. Discrepancies between reviewers were resolved through discussion, and when issues remained unresolved, a third reviewer was consulted. Three designations were used to define risk: high risk, low risk, and unclear risk.

5.6. Evaluation of treatment effects

Relative risk and 95% confidence intervals (CI) were used for binary outcomes, whereas, standardized mean difference (SMD) or mean difference (MD) and 95% CIs were used for continuous outcomes to conduct meta-analysis corresponding to the continuous variables outlined below. For studies that had numerous adverse effects or other event-zero

phenomena, risk differences were used instead. For meta-analyses, the Review Manager Software (Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.) was used. Because we assumed clinical heterogeneity, we performed our meta-analysis using the random-effects model.

6．Evidence-to-decision Frameworks (EtD Table)¹ and the relative Systematic Reviews

6.1. CQ1: Is the use of RAS inhibitors, such as ACEI and ARB, effective in PD patients?

SR1: SR1.1. Comparison of ACEI and ARB with other drugs

SR1.2. Comparison of ACEI with ARB (Effect of ARB to ACEI) 6.1.1. Literature Search

Using “Peritoneal Dialysis”, “Angiotensin-Converting Enzyme Inhibitors”, and “Angiotensin II Type 1 Receptor Blockers” as keywords, we searched existing SRs and CPGs in PubMed

1 With regards to the items in the EtD table: In the EtD framework, different templates have been prepared in accordance with different types of recommendations and decisions based on differing perspectives (e.g., individual and population). However, we adopted the individual template. Because “cost” does not occur as an item in the individual template, we appended the cost item in accordance with the four factors of recommendation decision of the GRADE approach. Additionally, we include them as factors in our discussion of recommendations while items for acceptability and feasibility do not exist. “Values and Preferences” refer to the set of goals, ex- pectations, dispositions, and beliefs that each individual hold towards a specific decision or to the outcomes associated with it. “Cost” describes the direct costs that patients pay. However, drugs that have caused social issues are discussed from a social perspective, as well.

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(up to April 10, 2017), Cochrane CENTRAL (up to April 10, 2017), and Ichushi (up to April 10, 2017). We found 12 items published between 1988 and 2017. Among these, two SRs matched our selection criteria (Akbari 2009 [Perit Dial Int], and Zhang 2014 [Cochrane Database Syst Rev]).

The RCTs used in the study Akbari 2009 were also used in the study by Zhang 2014. The Zhang 2014 SR was based on the following six papers: Li 2003, Phakdeekitcharoen 2004, Suzuki 2004, Wang 2007, Zhong 2007, and Reyes-Marin 2012. Upon searching once more for RCTs between 1988 and 2017 with the SR committee, we found three additional studies:

Suzuki 2003, Shigenaga 2009, and Atabak 2013. The Zhang 2014 SR excluded the studies by Suzuki 2003 and Shigenaga 2009 that did not include data on residual renal function (GFR);

however, these two studies mentioned the outcomes to be analyzed in our CQ; thus, both were included. The study by Atabak 2013 had a testing period of only 1 week, which we considered too short; thus, this study was excluded.

As outlined above, the following 8 references were selected for this SR: Li 2003,

Phakdeekitcharoen 2004, Suzuki 2004, Wang 2007, Zhong 2007, Reyes-Marin 2012, Suzuki 2003, and Shigenaga 2009. Furthermore, the following six references were used for SR1.1. to compare ACEI or ARB and other drugs: Li 2003, Suzuki 2004, Wang 2007, Zhong 2007, Suzuki 2003, and Shigenaga 2009. For SR1.2., studies by Phakdeekitcharoen, 2004, and Reyes-Marin, 2012, were used to compare ACEI and ARB.

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6.1.2．Included studies

Study Study Design

Subjects Intervention Control Outcomes Exclusion Criteria Comments

Li 2003 ・Open-

label RCT

・F/U period 12- months

・Used CAPD for 3 or more months

・China, single- facility

・residual renal GFR

≧2 mL/min/1.73 m²

・Men/women 38/22

・No use of ARB or ACEI for at least 6 months

・30 patients

・Mean age 58.0

± 14.0 years

・Ramipril 5 mg/day

・30 patients

・mean age 59.1 ± 9.8 years

・No ramipril

・Residual renal GFR (3，6，9，12 months)

・Time to anuria, anuria

・Proteinuria

・All deaths

・Peritonitis

・Hospitalization period / frequency

・CVD events

・Use history of ACEI or ARB

・History of

cardiovascular events

・Bilateral renal vascular stenosis

・ACEI allergy, intolerance, etc.

・Intervention: 3 deaths and 1 conversion to transplantation , 5 patients withdraw

・Control: 2 death, 1 conversion to transplantation, 2 began ACE therapy Phakdeekitcharoen

2004

・Open- label crossover RCT

・F/U period: 4 months

・Used CAPD for 3 or more months

・Thailand, single- center

・Residual renal GFR

<10 mL/min/1.73 m²

・15-65 years

・Normal potassium

Group 1

•ACEI: enalapril 10 mg/day Group 2

•ARB:

candesartan 8 mg/day

Group 1

•ARB:

candesartan 8 mg/day Group 2

•ACEI:

enalapril 10 mg/day

•Residual renal function

•Plasma electrolytes

•Blood pressure

•Adverse events

•Appropriate dialysis evaluation

・Symptomatic ischemic heart disease

・Recent stroke

・Cirrhosis

・ACEI allergy, intolerance

・Peritonitis within the last month, etc.

2 patients no longer wished to continue, 2 patients developed ischemic heart disease 2 patients lost

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values

・Mean age: 44.8 ± 10.1 years

・Men/Women 14/7

•Hyperkalemia appetite,

2 patients had ulcers and sepsis.

However, unclear in which drug dosing period they withdrew.

Reyes-Marín FA, 2012

・Parallel RCT

・F/U period 12- months

・Mexico, single- center

•Receiving APD for one year or more as initial renal

replacement therapy.

•Residual renal GFR

≥ 2 mL/min/1.73 m²

•Men/Women 36/24

Group 1: 30 patients

•ACEI: enalapril 10 mg/day

・mean age 42.5

± 18.5 years

Group 2: 30 patients

•ARB: losartan 50 mg/day

・mean age　 49.2 ± 19 years

・eGFR (3, 6, 9, 12 months)

•Peritonitis

・Time to anuria

•Cardiovascular events

・Number of hospitalizations

•Adverse events etc.

・Systemic infection

・Peritonitis

・Severe malnutrition

・Intolerance of ACEI, ARB

・ Cardiac failure, myocardial infarction

・Cerebral infarction within 6 months, malignant hypertension etc.

No withdrawals.

Suzuki 2003 ・Double-

blind RCT

・F/U period 12 months

・Japan

・CAPD patient with left ventricular hypertrophy

・14 patients

・ARB: valsartan 40-80 mg/day

・Mean age: 56 ± 3 years

・Dialysis history 9.4 ± 2.2 months

・10 patients

・placebo

・mean age 57

± 2 years

・Dialysis history 8.9 ± 3.2 months

・Blood pressure

・Urine volume (3, 6, 12 months)

・Cardiothoracic ratio

・Echocardiogram findings

・PWV

・Diabetes

・Cardiac failure

・Myocardial infarction within the last 6 months, cerebrovascular event

・Pregnant

・Illnesses requiring hospitalization

No withdrawals.

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・Peritonitis

・Immune disease etc.

Suzuki 2004 ・Open-

label RCT

•F/U period: 24 months

・Japan

•Over 3 months since beginning CAPD

・18 patients

・ARB: valsartan 40 to 80 mg/day

・mean age 63.5

± 3.7 years

・Men/women 11/9?

・16 patients

・Did not use ACEI or ARB

・Mean age 63.5 ± 3.3 years

・Men/women 11/7?

・Urine volume (6, 9, 12, 18, 24 months)

・Residual renal function: kidney CCR

・Blood pressure

・Plasma Cr

・Total CCR, total Kt/V

・Peritoneal CCR

・Proteinuria

・Cardiac failure requiring treatment with ACEI or ARB

・Myocardial infarction within the last 6 months, severe valve disease

・Malignant hypertension

・Hypertensive encephalopathy or cerebrovascular event within the last 6 months

・ARB

allergy/intolerance etc.

・No withdrawals.

・Number of subjects and male/female ratio mismatched?

Intervention: 3 cases of peritonitis Control: 4 cases of peritonitis

Shigenaga 2009 ・Open- label RCT

・F/U period: 6 months

・Japan, single-center

•CAPD patients

ARB Group 1

・15 patients

・Candesartan 4 mg/day

・mean age 52.9±2.8 years

・Dialysis history 39±9 months

・15 patients

・No ACEI or ARB

・Mean age　 53.3±3.1 years

・dialysis history　 38±12 months

・Blood pressure (6 months)

・Pulse pressure

・Pulse rate

・Weight

・Cardiothoracic ratio

・APD

・Diabetic nephropathy

・Cardiac failure

・Acute illness

・Use history of ACEI or ARB in the last 4 months

No withdrawals.

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ARB Group 2

・15 patients

・Valsartan 40~

mg/day

・Mean age 53.1±3.0 years

・Dialysis history 41±11 months

・Urine volume

・CAPD drainage volume

・Echocardiogram findings

・ANP, BNP

・PWV

ZHONG 2007 ・Open-

label RCT

•Research period:

2004- 2007

•F/U period: 12 months

・China, single- center

・1 or more months since beginning CAPD

•Mean age 44.0 ± 14.6 years

•Men/Women 31/17

・24 patients

・ARB: irbesartan 300 mg/day

・20 patients

・No ACEI or ARB

・Residual renal eGFR (3, 6, 9, 12 months)

・Urine volume (12 months)

・Blood pressure

・Total Kt/V

・total CCｒ

・potassium

・Bilateral renal artery stenosis

・Hypertensive encephalopathy

・Cardiovascular complications

・Peritonitis

・Cardiac failure

・Use history of ACEI or ARB in the last 3 months

・ARB allergy etc.

・Intervention: 1 patient stopped receiving checkups, 1 had a transplant

・Control: 1 patient stopped receiving checkups, one converted to HD

WANG 2005 ・Open-

label RCT

・Within 3 months of beginning CAPD

・19 patients

・ARB: valsartan

・13 patients

・No ACEI or

・Residual renal function

・Bilateral renal artery stenosis

・Intervention: 2 patients stopped

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•Research period 2004-2007

•F/U period: 28

± 13 months

・China, single- center

・GFR ≥ 2 mL/min/1.73 m²

•Mean age 42 (17-65) years

•Men/Women 22/12

80 mg/day ARB •Urine volume

•Proteinuria

•Total Kt/V per week

•Total CCr per week

・History of hypertensive encephalopathy or cerebrovascular events

・Severe cardiac failure

・Peritonitis

・ACEI allergy, intolerance etc.

receiving checkups

・Controls: no withdrawals

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6.1.3. Data extraction and integration with studies 6.1.3.1. Risk of bias table

(Note: SR1.1 and SR1.2 are shown in the study by Reyes-Marin 2012) 6.1.3.1.1 SR1.1

(1) Overall survival rate (number of deaths due to events)

(2) Technical survival (PD continuation period/PD withdrawal) (PD withdrawal)

(3) Technical survival (PD continuation period/PD withdrawal) (peritonitis)

(4) Urine volume/residual renal function (urine volume)

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(5) Urine volume/residual renal function (anuria)

(6) urine volume/residual renal function (GFR)

(7) Peritoneal function (creatinine level, etc.) (total Kt/V)

(8) Complications (including drug adverse effects・safety issues・hospital stay period) (hyperkalemia)

(9) Complications (including drug adverse effects・safety issues・hospital stay period) (hospitalization)

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(10) Other outcomes considered important by the CQ team (cardiovascular events)

6.1.3.1.2 SR1.2

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(6) Urine volume/residual renal function (GFR)

(8) Complications (including drug adverse effects・safety issues・hospital stay period) (hyperkalemia)

(9) Complications (including drug adverse effects・safety issues・hospital stay period) (hospitalization)

(10) Other outcomes considered important by the CQ team (cardiovascular events)

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6.1.3.2. Forest plots

6.1.3.2.1. SR1.1. Comparison of ACEI and ARB with other drugs (1) Overall survival rate (number of deaths due to events)

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(8) Complications (including drug adverse effects, safety issues, hospital stay period) (hyperkalemia)

(9) Complications (including drug adverse effects, safety issues, hospital stay period) (hospitalization)

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(10) Cardiovascular events

6.1.3.2.2. SR1.2. Comparison of ACEI with ARB

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(8) Complications (including drug adverse effects, safety issues, hospital stay period) (hyperkalemia)

(9) Complications (including drug adverse effects, safety issues, hospital stay period) (hospitalization)

(10) Cardiovascular events

6.1.3.3. Other factors

6.1.3.3.1. SR1.1. Comparison of ACEI and ARB with other drugs

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6.1.4. Evidence to Decision (EtD) table

EtD table summarizing CQ1: SR1.1. Comparison of ACEI or ARB and other drugs, and SR1.2.

Comparison of ACEI and ARB

Certainty of evidence

What is the overall level of evidential certainty regarding observed effects?

JUDGMENT RESEARCH EVIDENCE NOTES

○ Very low

● Low

○ Moderate

○ High

○ No corresponding research

Our judgments for evidence certainty in all critical outcomes were “Low.” (SR1.1.) (SR1.2.)

Values and preferences

Are there any important uncertainties regarding the weight patients place on the primary outcome?

○ Important uncertainty or variance present

○ Important uncertainty or variance may be present

● Important uncertainty or variance likely not present

○ Important uncertainty or variance not present

RAS inhibitors are widely used, and the majority of patients use them if they believe there is some sort of benefit. Consequently, it is likely that no variance is present here.

Urine volume allows us to judge whether the patient is able to ingest enough water. Furthermore, the larger the patient’s urine volume, the greater their satisfaction. Thus, we have judged urine volume to be critical outcome

(SR1.1.) (SR1.2.)

Effect balance

Does the balance between desirable and undesirable effects support either the intervention or control?

○ Control is superior

○ Control is likely superior

○ Neither is superior to the other

● Intervention is likely superior

○ Intervention is superior

○ Varies

○ Unknown

It was impossible to estimate the superiority of RAS inhibitors for the overall survival and technical survival as no events occurred in the two outcomes (SR1.1., SR1.2.).

Additionally, it was impossible to estimate cardiovascular events. For cardiovascular events in SR1.2, ACEI had a RR of 1.3, indicating a benefit, but the studies were all small-scale, with only 30 patients per study. There was only a difference of

(31)

1 as the number of events, so we judged that a difference in effect balance was not present.

For this reason, we determined that urine volume, which reflects patient QOL, was the most critical outcome for clinical judgments. Similarly, an average increase in urine volume of 142.5 mL was observed, and the lower limit of the 95% CI showed an increase of 25.42 mL. Despite the absence of a statistically significant difference in anuria occurrence rates, the RR of 0.70 for the intervention allowed us to conclude that the intervention is likely superior (SR1.1.). However, we did not include ACEI data in the comparison of urine volume. In an analysis where GFR was considered as an outcome of residual renal function, both ARB and ACEI significantly maintained GFR. The MD showed an increase of 0.97 mL/min/1.73 m², and the lower limit of the 95% CI was 0.49 mL/min/1.73 m². From these, we assessed that both ARB and ACEI were significant and meaningful interventions.

In SR1.2, ARB was superior for both urine volume and anuria occurrence rates. However, the average urine volume for both drugs was above 500 mL, which made it difficult to determine whether this increase is clinically significant. The difference in anuria occurrences was observed in only 1 case. After 6-12 months of intervention, no difference was observed in GFR.

Thus, we evaluated that a difference in effect balance does not exist between ACEI and ARB as our result from SR1.2.

Resource use

How high is the cost?

○ High cost

○ Moderate cost

● Negligible cost or savings

○ Moderate savings

○ Large savings

○ Varies

○ Unknown

Under the social insurance treatment program in Japan, dialysis patients do not have to pay any additional cost for the treatment of RASIs by presenting a certificate from the “Grant-in-Aid Program for Specific Diseases”.

(32)

References

Akbari A, Knoll G, Ferguson D, McCormick B, Davis A, Biyani M. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in peritoneal dialysis: systematic review and meta-analysis of randomized controlled trials. Perit Dial Int 2009;29:554-61.

Atabak S, Taziki O, Argani H, Abolghasemi R. Effects of oral enalapril and verapamil on dialysis adequacy and solute clearance in chronic ambulatory peritoneal dialysis. Saudi J Kidney Dis Transplant.

2013;24:1170–4.

Li PK, Chow K, Wong TY, Leung C, Szeto CC. Effects of an angiotensin-converting enzyme inhibitor on residual renal function in patients receiving peritoneal dialysis. A randomized, controlled study. Ann Intern Med. 2003;139:105–12.

Phakdeekitcharoen B, Leelasa-nguan P. Effects of an ACE inhibitor or angiotensin receptor blocker on potassium in CAPD patients. Am J Kidney Dis. 2004;44:738–46.

Reyes-Marin FA, Calzada C, Ballesteros A, Amato D. Comparative study of enalapril vs. losartan on residual renal function preservation in automated peritoneal dialysis. A randomized controlled study.

Revista de Investigacion Clinica 2012;64:315–21.

Suzuki H, Nakamoto H, Okada H, Sugahara S, Kanno Y. A selective angiotensin receptor antagonist, valsartan, produced regression of left ventricular hypertrophy associated with a reduction of arterial stiffness. Adv Perit Dial. 2003;19:59–66.

Strong recommendation against the above

intervention

Weak recommendation against the above

intervention

Conditional recommendation of either the intervention or

the control

Weak recommendation in favor of the above

intervention

Strong recommendation in favor of the above

intervention

○ ○ ○ ● ○

(33)

Suzuki H, Kanno Y, Sugahara S, Okada H, Nakamoto H. Effects of an angiotensin II receptor blocker, valsartan, on residual renal function in patients on CAPD. Am J Kidney Dis. 2004;43:1056–64.

Shigenaga A, Tamura K, Dejima T, Ozawa M, Wakui H, Masuda S, et al. Effects of angiotensin II type 1 receptor blocker on blood pressure variability and cardiovascular remodeling in hypertensive patients on chronic peritoneal dialysis. Nephron Clin Prac. 2009;112:c31-c40.

Zhong H, Sha Z-H, Cui T-L, Qiu H-Y, Liu F, Qin W, Fu P. Effects of irbesartan on residual renal function in peritoneal dialysis patients. Chinese Journal of Nephrology 2007;23:413–6.

Wang J, Xiao MY. Protective effects of valsartan on residual renal function in patients on CAPD.

Chinese Journal of Blood Purification 2005;4:605–6.

6.2. CQ2: Icodextrin or glucose solution: which is more useful as a dialysate among patients with peritoneal dialysis?

SR2. Comparison of icodextrin and glucose dialysis solution monotherapy 6.2.1. Literature search

Using “peritoneal dialysis” and “dialysis solutions” as keywords, we searched PubMed (up to April 10, 2017) for existing SRs and CPGs. We identified 106 papers between 1968 and 2017. From these, 17 individual studies had matching patients (P) and interventions (I), and a total of five—four SRs and one CPG—of these satisfied our selection criteria (Cho 2014，Cho 2013，He 2011, Qi 2011，Hall 2007).

Among these, the most recent SR was a Cochrane Review by Cho et al. in 2014, which we considered as an existing SR. From the 11 RCTs that compared icodextrin dialysis solution (ICO) and glucose dialysis solution (Glu) monotherapy, we excluded one crossover trial (Bredie 2001) and extracted the rest.

Furthermore, from the 260 RCTs published after the study by Cho et al—that is, between 2013 and 2017

—we extracted 11 studies whose P and I matched. We ultimately extracted only the three studies whose P, I, and comparison (C) matched, which is in addition to the 10 RCTs extracted from the Cochrane Review, a total of 13 RCTs for this CQ. The list of RCT papers that were the targets of this CQ are as

(34)

follows: Lin 2009, Takatori 2011, Finkelstein 2005, de Davies 2003, Konings 2003, Posthuma 1997, Paniagua 2008, MIDAS study, Plum 2002, Wolfson 2002, Yoon 2014, Moraes 2015, and Chang 2016.

6.2.2. Included studies

Author Publicatio

n Year

Study Design (Follow -up periods

)

Subject Participant

s

Interventio

n Control Outcome Comments

Chang TI

2016 RCT

(12 months)

100 patients aged 20 or older using PD

Concomitant use of 7.5%

ICO

Use of only Glu

Overall survival rate, technical survival, complications (peritonitis/rash), peritoneal function, peritoneal ultrafiltration.

In the ICO group, the rate of urine volume decrease was low (-32.02 vs -11.88 mL/month), but in all other outcomes, there was no difference.

de Moraes

TP 2015 RCT

(90 days)

60 adult patients using APD, except those with DM as an

underlying illness

ICO

Use of only Glu

Overall survival rate, complications (peritonitis), peritoneal ultrafiltration, episodes of uncontrolled fluid overload.

In the ICO group, the amount of daily peritoneal ultrafiltration was

significantly higher (800 vs 586 mL/day).

(35)

Yoon HE

2014 RCT

(12 months)

80 adult patients using CAPD

ICO

Use of only Glu

Overall survival rate, technical survival, residual renal function (urine

volume/GFR/CCr) , complications (peritonitis), peritoneal ultrafiltration.

In the Glu group, the decrease in urine volume after 12 months was significant (-363.0 mL/day), but in the ICO group, no significant decrease was observed (- 108.6 mL/day).

Takatori Y

2011 RCT

(24 months)

41 adult patients using CAPD/

APD for DM

ICO

Use of only Glu

Overall survival rate, technical survival, residual renal function (urine

volume/GFR/CCr) , peritoneal function, peritoneal ultrafiltration, episodes of uncontrolled fluid overload.

After 24 months, technical survival was 71.4% for the ICO group and 41.5% for the Glu group, with uncontrolled volume overload as the main cause. The ICO group had significantly higher daily peritoneal ultrafiltration (947.6 vs 588.7 mL/day).

Lin A.

2009 RCT (4

weeks)

201 patients 18 or older using CAPD

ICO

Use of only Glu

Overall survival rate, complications (peritonitis/rash),

In the ICO group, as PET category rose, peritoneal ultrafiltration increased (LA< HA< H). No difference in terms of the complication occurrence rate was observed.

Paniagua

R. 2008 RCT

(12 months)

ICO

Use of only

Glu Complications

(peritonitis).

Throughout the

observation period, daily peritoneal ultrafiltration volume for the ICO group was consistently higher than that of the Glu group (mean: 197 mL/day). No difference in peritonitis occurrence rates was

(36)

observed.

Finkelstein

F. 2005 RCT (2 weeks)

92 patients 18 or older using APD

ICO

Use of only

Glu Complications

(rash).

ICO group: rashes occurred in 11 patients of 47. Conversely, no rashes were observed in the 45 patients in the Glu group.

Konings

CJ. 2003 RCT (4 months)

50 adult patients using CAPD or APD

ICO

Use of only Glu

Overall survival rate, technical survival, residual renal function (urine volume), peritoneal ultrafiltration.

The ICO group tended to have higher peritoneal ultrafiltration, and ECW and LV mass decreased significantly. No clear difference was observed in other outcomes.

Davies SJ.

2003 RCT (6

months)

50 patients 18 or older using CAPD or APD

ICO

Use of only Glu

Overall survival rate, episodes of uncontrolled fluid overload.

In the ICO group, indices for clearance volume, body weight, and extracellular fluid all improved. No patient presented with uncontrolled volume overload. (1 patient of 22 in the Glu group did).

Wolfson

M. 2002 RCT

(safety:

52 weeks/

efficacy : 4 weeks)

safety: 287 patients using CAPD or APD, efficacy:

ICO

Use of only Glu

Overall survival rate, complications (peritonitis/rash).

Across both the safety trial (52 weeks) and the efficacy trial (4 weeks), rashes occurred in 44 patients of 265 in the ICO group and in 14 patients of 197 in the Glu group.

Plum J.

2002 RCT

(14 weeks)

39 patients using APD

ICO

Use of only Glu

residual renal function (GFR/CCr).

No difference in residual renal function (average of creatinine and urea clearance) observed at the end of the observation period (ICO group:

2.9±3.3, Glu group:

1.7±2.4 mL/min/1.73 m²).

Posthuma

N. 1997 RCT 38 patients using CCPD

Use of only Glu

Overall survival rate, residual renal

For peritoneal ultrafiltration, up till 6

(37)

(24 months)

ICO function (urine

volume/GFR/CCr) , complications (peritonitis), peritoneal ultrafiltration.

months, the ICO group had a significantly higher value, but after the 9^th month, no significant difference was observed between the groups.

MIDAS Study Group, 1994

RCT (6 months)

209 patients 18 or older using CAPD

ICO

Use of only Glu

Overall survival rate, peritoneal ultrafiltration, technical survival.

Upon comparing

peritoneal ultrafiltration in the ICO group with that with 1.36% glucose solution, the former showed a significant increase, but when compared with 3.86%

glucose solution, no significant difference was observed. No clear differences were observed for any other outcomes.

6.2.3. Data extraction and integration 6.2.3.1. Risk of bias tables

The included papers were evaluated using risk of bias tables from the Cochrane Handbook. Evaluation items were as follows: A: random sequence generation, B: allocation concealment, C: blinding of

participants and personnel, D: blinding of outcome assessment, E: incomplete outcome data, F: selective reporting, and G: others bias. For each outcome, the risk of bias was evaluated as: high risk, low risk, and unclear risk.

(1) All-cause mortality (number of deaths due to events)

(38)

(2) Technical survival (PD continuation period/PD withdrawal)

(3) Episodes of uncontrolled fluid overload

(4) Peritoneal ultrafiltration (total daily ultrafiltration volume)

(5) Urine volume

(6) Residual renal function (GFR/CCr)

(39)

(7) Peritoneal function (creatinine level, etc.) (D/P Cr value)

(8) Complications (peritonitis)

(9) Complications (rash)

(10) Complications (exit site tunnel infection) None

(11) Occurrence rate of abnormal glucose tolerance None

6.2.3.2. Forest plots

(1) All-cause mortality (number of deaths due to events)

(40)

(2) Technical survival (PD continuation period/PD withdrawal)

(3) Episodes of uncontrolled fluid overload

(4) Peritoneal ultrafiltration (total daily ultrafiltration volume)

(41)

(5) Urine volume

(6) Residual renal function (GFR/CCr)

(7) Peritoneal function (D/P Cr value)

(8) Complications (peritonitis)

(42)

(9) Complications (rash)

(10) Complications (Exit site tunnel infection) None.

(11) Occurrence rate of abnormal glucose tolerance None.

6.2.3.3. Other factors

Table 6.2: Rules for Data Extraction in SR2

1. All-cause mortality (number of deaths due to events)

Binary variable indicating the occurrence of death during the observation period of each study 2. Technical survival (PD continuation period/PD withdrawal)

Binary variable indicating percentage of patients who completed PD by the end of the

(43)

observation period of each study (PD withdrawal due to death or transplant were treated as discontinuations and not counted)

※ If completion of PD was not reported and the outcome of catheter removal was reported, we counted them as completed.

3. Peritoneal ultrafiltration (episodes of uncontrolled fluid overload) 3-1. Episodes of uncontrolled fluid overload

Binary variable indicating whether or not a patient was seen at the hospital for uncontrolled fluid overload during the observation period of each study

3-2. Total daily peritoneal ultrafiltration volume

※ If the episode of fluid overload was not reported, continuous variable of total daily ultrafiltration was used at the end of the observation period

4. Urine volume/residual renal function 4.1. Urine volume

Continuous variable of daily urine volume at the end of the observation period of each study

※ If urine volume was not reported, continuous variable of renal CCR was used at the end of the observation period

※ If neither urine volume nor CCR were reported, continuous variable of renal Kt/V was used at the end of the observation period

4.2. Residual renal function (GFR/CCr)

5. Peritoneal function (D/PCr) (important outcome)

Continuous variable of D/P Cr value at four hours during the PET test at the end of the observation period in each study

6. Complications (including drug adverse effects/safety issues/hospital stay period) 6-1. Peritonitis

Binary variable indicating whether or not peritonitis (definitions given in each RCT) occurred at least once in the observation period of each study

6-2. Rash

6-3. Exit site tunnel infection

(44)

Binary variable indicating whether or not exit site infection or tunnel infection (definitions given in each RCT) occurred during the observation period of each study

7. Occurrence rate of abnormal glucose tolerance

Binary variable indicating if diabetes (diagnosis up to author’s definition) occurred in patients who did not originally have the condition during each study’s observation period.

6.2.4. Evidence to Decision (EtD) table

Certainty of evidence

What is the overall level of evidential certainty regarding the observed effects?

○ Very low

● Low

○ Moderate

○ High

○ No corresponding research

Peritoneal function (creatinine level, etc.) (D/P Cr value) is an important outcome. We also assessed evidence to be low given the other critical outcomes.

Values and preferences

Are there any important uncertainties regarding the weight patients place on the primary outcome?

○ Important uncertainty or variance present

○ Important uncertainty or variance may be present

○ Important uncertainty or variance likely not present

● Important uncertainty or variance

Because this question simply involves changing the dialysis solution, it does not present any burden on the patient.

Hence, we believe that no variability is present.

(45)

not present

Effect balance

Does the balance between desirable and undesirable effects support either the intervention or control?

○ Control is superior

○ Control is likely superior

○ Neither is superior to the other

● Intervention is likely superior

○ Intervention is superior

○ Varies

○ Unknown

Although the difference in survival rates, a decrease by 7 patients per 1000 patients (for 18 patients decreased – 19 patients increased), was not significant, point estimates for the intervention were superior. Furthermore, the clinically useful measures of poor body fluid management and peritoneal clearance were present, and these are known to contribute greatly to patient QOL. Additionally, technical survival improved these results, and our assessment was made carefully to avoid double counting.

With regards to harms, we did observe higher reports of common occurrence of rashes. This was primarily because of the high rate of occurrence in Wolfson 2002. Specifically, 5 patients in the intervention group developed a rash and withdrew from the study (it was unclear whether they converted to Glu monotherapy or simply stopped PD), but none of the patients in the control group developed a rash.

However, specialists in this field have postulated that this incidence rate of rashes is higher than that seen in Japan. In previous studies, an inconsistency between 2002-2005 and 2009-2016 was observed (95% CI overlap and differences in decades were thought to be the reasons; thus, we did not lower the grade). Consequently, in the modern usage of ICO, rashes appear to occur rarely, and we judged the harms to be slight.

Thus, the intervention is likely superior for effect balance.

Resource use

How high is the cost?