Perit Dial Int 2011 Blake 218 39
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Perit Dial Int 2011 Blake 218 39
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doi:10.3747/pdi.2011.00026
Division of Nephrology,1 University of Western Ontario, London, Ontario; Division of Nephrology,2 University
of Toronto, Toronto, Ontario; Division of Nephrology,3 McMaster University, Hamilton, Ontario; Division
of Nephrology and Transplant Immunology,4 University of Alberta, Edmonton, Alberta; Division
of Nephrology,5 Dalhousie University, Halifax, Nova Scotia; Division of Nephrology,6
University of Ottawa, Ottawa, Ontario; Division of Nephrology,7 University of
British Columbia, Vancouver, British Columbia, Canada
Peter G. Blake,1 Joanne M. Bargman,2 K. Scott Brimble,3 Sara N. Davison,4 David Hirsch,5
Brendan B. McCormick,6 Rita S. Suri,1 Paul Taylor,7 Nadia Zalunardo,7 and
Marcello Tonelli4, the Canadian Society of Nephrology Work Group
on Adequacy of Peritoneal Dialysis
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financial or research relationships with companies manufacturing products relevant to the care of PD patients.
The work group was asked to apply both its content
expertise and an English-language-focused literature
search aimed at identifying randomized trials to identify
new evidence.
A search strategy was designed to identify all relevant
randomized controlled trials (RCTs) of PD in MEDLINE
(1950 to 10March 2010) and multiple Cochrane databases
(Cochrane Controlled Trials Register, Cochrane Database
of Systematic Reviews, Health Technology Assessments
to 10March 2010). All citations were reviewed in duplicate by 2 work group members, and potentially relevant
articles were retrieved for review and (if relevant) incorporation into the guidelines at the discretion of the work
group. Although this approach might be criticized for lack
of methodologic rigor, such an approach is pragmatic and
has been used and advocated by others (2).
The guidance that follows is intended to rely on evidence and, where possible, to avoid opinion-based statements. Other renal work groups have made a distinction
between clinical practice guidelines and clinical practice
recommendations, with guidelines being provided when
the work group felt that the evidence was sufficiently
strong to make definitive statements about the appropriateness of clinical practice (3). Alternatively, clinical
practice recommendations were provided for statements
based upon a lesser gradeof evidence. The main reason
for making this distinction is to highlight areas in which
adherence to a guideline would be particularly likely to
improve outcomes. Although this goal is reasonable,
distinguishing between guidelines and recommendations
is clearly inherently subjective.
The evidence in support of each guideline is graded using the scheme developed by the Canadian Hypertension
Education Program (4) and used by the CSN Guidelines
Committee (5) in the past (Figures1 3).
When there is a lack of agreement between studies or
when a lack of good-quality evidence made it difficult
to create clinical practice guidelines, the work group
provides an overview of existing evidence, which the
members hope will guide management by practitioners.
Where possible, specific research recommendations to
close relevant research gaps are also provided.
The entire work group reviewed and modified the first
draft of this document. The document underwent peer review by selected individuals (members and nonmembers
of the CSN). After peer review, the document was revised
by the work group in response to comments received and
then distributed to all members of the CSN and to relevant
stakeholders, including the Kidney Foundation of Canada
and provincial ministries of health.
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Figure 2 Algorithm for assigning evidence grades to therapy recommendations (continued from Figure1) for adequate randomized controlled trials (RCTs), systematic reviews, or subgroup analyses. (e)Adequate power in a negative study implies that 95%
confidence limits exclude a clinically important difference. (f)Effect estimates in each study included in the systematic review (SR)
are qualitatively similar (that is, in the same direction). (g)Hard endpoints such as death, stroke, myocardial infarction, hospitalization, and need for dialysis, or measures of quality of life. (h)Endpoints that have consistently been shown to be associated
with the clinical endpoint in multiple studies (observational or RCT), and RCTs have consistently demonstrated that improvement
in the surrogate translates into a consistent and predictable improvement in the clinical endpoint.
Figure 1 Algorithm for assigning evidence grades to therapy recommendations. (a) Randomized clinical trial (RTC) with
blinded assessment of outcomes (if applicable), intention-to-treat analysis, adequate follow-up (that is, at least 90%, or losses
to follow-up are too few to materially affect the results), and sufficient sample size to detect a clinically important difference
with power greater than 80%. (b)Subgroup analysis was a priori, done within an adequate RCT, one of only a few tested, and there
was sufficient sample size within the examine subgroup to detect a clinically important difference with power greater than 80%.
(c)Systematic review (SR, also called a meta-analysis) in which the comparison arms are derived from head-to-head comparisons
within the same RCT. (d)Systematic review in which the comparison arms are derived from different placebo-controlled RCTs, and
then extrapolations are made across RCTs.
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Maintenance of residual renal clearance has been associated with better BP control, and two randomized clinical
trials have suggested that ACEIs or ARBs preserve residual
renal clearance independent of their BP effects (1720).
A dose of 250mg daily of oral furosemide leads to better
preservation of urine volume and sodium excretion, but
has no effect on residual renal clearance (21). In the
same study, patients also received metolazone 5mg daily
if daily urine output was less than 500mL. No randomized
prospective trial has examined whether better BP control
results in better preservation of RRF in PD, and so recommendations concerning BP targets are extrapolated from
the literature on earlier stages of CKD and from general
Canadian guidelines on hypertension.
Substances known to be nephrotoxic in the non-dialysis population are generally avoided in PD patients with
preserved RRF. Short courses of aminoglycoside therapy
for peritonitis may not cause a long-term loss of RRF
(22,23). Use of intravenous contrast dye should be minimized, although observational data suggest that there
may be no long-term effects on residual renal clearances,
at least when low-osmolality contrast is used and when
coexistent nephrotoxic agents and volume depletion are
avoided (24). Volume depletion can lead to decreases in
urine output and residual renal clearance (17).
Observational data suggest that a run-in period of
HD before the start of PD may have detrimental effects
on RRF (25). Patients starting PD with a failing renal
transplant may lose renal function as immunosuppressive
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Figure 3 Algorithm for assigning evidence grades to therapy recommendations (continued from Figure1) for observational
studies. (e)Adequate power in a negative study implies that 95% confidence limits exclude a clinically important difference.
(f) Effect estimates in each study included in the systematic review are qualitatively similar (that is, in the same direction).
(g)Hard endpoints such as death, stroke, myocardial infarction, hospitalization, and need for dialysis, or measures of quality of
life. (h)Endpoints that have consistently been shown to be associated with the clinical endpoint in multiple studies (observational
or RCT), and RCTs have consistently demonstrated that improvement in the surrogate translates into a consistent and predictable
improvement in the clinical endpoint.
blake et al.
medication is tapered, but whether the benefits of prolonging the duration of immunosuppression outweigh
the risks is unknown (26). The effect of PD modality
on RRF is controversial. Some studies showed that
automated PD (APD) is associated with more rapid
loss of RRF; others did not (17,2730). Randomized controlled trials of biocompatible PD solutions
(with normal pH, low levels of glucose degradation products, and bicarbonate/lactate buffer) have
not consistently showed better maintenance of residual renal clearance over at least 1 year of follow-up
(3133).
1.3 RESEARCH
Recommendations:
1.3.1 A prospective clinical trial to examine usual compared with tight BP targets and their effect on
rate of loss of residual renal clearance among PD
patients is needed. Such a trial could also further
elucidate the interaction between suppression
of proteinuria and preservation of residual renal
clearance in this population.
1.3.2 A prospective clinical trial to examine rapid compared with slow tapering of immunosuppression
for patients with failing renal grafts who are
initiating PD is needed.
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events (97). Based on the aforementioned post hoc analysis (118), however, a TC:HDL ratio below 4.0 has been
suggested as a secondary target in those at high risk of a
future CV event when LDL-C is less than 2.0mmol/L. That
goal can usually be achieved by increasing the statin dose.
Treatment with simvastatin and ezetimibe in the SHARP
study was associated with an 11.7% reduction in TG levels.
Evidence supporting the use of lipid-lowering agents
other than statins and ezetimibe has been weak. In the
general population, fibrates may reduce CV events, but
not CV mortality or total mortality (120123), with an
increased risk of non-CV mortality (122). A subgroup
analysis of a large RCT evaluating the role of fibrates
in reducing CV events in patients with CKD (Cockcroft
Gault creatinine clearance< 75mL/min) demonstrated
a significant reduction in coronary death or nonfatal
myocardial infarction (124). Observational data on the
use of fibrates in dialysis patients indicate these agents
can be used at reduced dosages, but that such use is not
associated with improved outcomes (102). When used in
conjunction with statins, fibrates are associated with a
reversible increase in creatinine (especially fenofibrate)
(120) and with a markedly increased risk of rhabdomyolysis (especially gemfibrozil) (125,126). This risk appears to
be increased in the presence of CKD (125). Nicotinic acid
has not been studied in PD patients, and current evidence
does not demonstrate a reduction in CV events despite
this agents ability to lower TGs and LDL-C and to increase
HDL-C in the general population (122,123). Sevelamer
appears to reduce LDL-C and TGs while increasing HDL-C
in dialysis patients (127); however, a meta-analysis of
existing RCTs does not demonstrate any CV benefit for
sevelamer in the treatment of hyperphosphatemia (128).
Other bile-acid sequestrants, including cholestyramine,
have been shown to increase TG levels (129131), which
are often already high in PD patients. Based on the lack
of consistent data in the general population regarding
the use of agents other than statins or ezetimibe for
lipid-lowering therapy, the work group makes no recommendations regarding their use in PD patients for the
management of dyslipidemia. If fibrates are to be used
at all, given the concerns discussed here, they should
not be used in combination with a statin.
4.2
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events, defined as the combination of myocardial infarction, coronary death, ischemic stroke, or any revascularization procedure (p= 0.0022). A smaller, nonsignificant
difference in the primary outcome was observed in the
subgroup of 3023 dialysis patients (1.5% absolute risk
reduction). Notably, the primary outcome was changed
during the trialto major atherosclerotic events from
all major vascular eventsbased on findings from
other trials that suggested that non-atherosclerotic
vascular events (that is, hemorrhagic stroke and other
causes of cardiac death) were not responsive to therapy
lowering LDL-C.
Patients on PD tend to have a more atherogenic lipid
profile than do HD patients; the former have higher TC,
TGs, and lipoprotein(a) levels (108), which may worsen
over time. The lipid profile of PD patients is presumably
related to cumulative dialysate glucose exposure (109).
That hypothesis is supported by observations in small
studies of a beneficial impact on lipid profile with the
substitution of icodextrin or amino acidbased solutions
for glucose-based ones (75,110,111). The SHARP study
included 500 patients on PD; however, results have not
as yet been presented for that subgroup, which would
undoubtedly be underpowered to detect a statistically
significant difference in the primary outcome. It would
seem unlikely that there will ever be a sufficiently large
RCT in PD patients to assess the impact of LDL-C lowering
therapy on important clinical outcomes. Nevertheless,
statins and ezetimibe have been shown to be effective
in reducing cholesterol, including LDL-C and TGs, in PD
patients, and these agents are safe (112,113). Based on
the high baseline CV risk of patients on PD, their more
atherogenic lipid profile, and the body of evidence
available, the work group recommends that LDL-C lowering therapy with statins, with or without ezetimibe,
should be considered in all PD patients regardless of
baseline LDL-C.
Triglycerides are clearly associated with risk for CV
disease; however, whether TG levels are an independent
risk factor for CV disease is unclear; the observed risk is
substantially attenuated when adjusted for other known
risk factors, including HDL-C (114117). Nevertheless,
treatment with a statin appears to have the greatest
benefit in patients with an elevated LDL-C, low HDL-C,
and elevated TGs (that is, a high TC:HDL ratio) (118).
In the general population, treatment with a fibrate in
at-risk subjects with low HDL, high TGs, or both, did not
reduce CV events except in the subgroup of subjects with
TGs above 2.26mmol/L (119). Because of the inconclusive nature of this literature in the general population,
practice guidelines do not currently recommend the
achievement of specific TG targets to prevent future CV
blake et al.
4.3 RESEARCH
Recommendations:
4.3.1 There is a need for an updated systematic review
and meta-analysis of the impact of lipid-lowering
therapy in ESRD patients, including those on PD.
4.3.2 There is a need for RCTs evaluating the role of
various anticoagulant and revascularization
strategies in dialysis patients with acute coronary
syndrome, including those on PD.
SECTION 5: NUTRITION IN PD
5.1 NUTRITION
Recommendation:
5.1.1 Nutritional status should be monitored at routine clinical visits by the physician and by other
members of the health care team, including a
registered dietician (opinion).
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5.3
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5.5 RESEARCH
Recommendations:
5.5.1 Further studies to determine the optimum serum
bicarbonate level in PD patients are needed.
5.5.2 Further investigations into the initial promising
observations on the use of anabolic steroids in
malnourished PD patients would be helpful.
In both the foregoing areas, positive results in randomized trials do not appear to have convinced practicing
physicians to alter practice.
SECTION 6: MANAGEMENT OF HYPERGLYCEMIA
6.1 GLYCEMIC CONTROL
Guideline:
6.1.1 Patients using icodextrin exchanges must employ
a glucometer that uses the glucose oxidase or
hexokinase method (gradeA).
Recommendations:
6.1.2 Control of hyperglycemia in the PD population
should adhere to the recommendations of the
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231
their use in renal failure. If they are prescribed, the recipients must be closely monitored (175). In particular,
given recently published concerns about the possible CV
risks of thiazolidinediones, the work group suggests that
these agents not be considered the preferred agents in
this population. Many clinicians have experience with
gliclazide and repaglinide in this population, and those
agents are effective in some patients, but no comprehensive safety or efficacy data have been reported. Insulin
is probably the most effective agent, but may be difficult
to introduce for elderly patients already having difficulty
coping with the demands of PD.
Most Canadian centers use subcutaneous rather than
intraperitoneal insulin. Although no large trial has
been performed, there is observational evidence that
intraperitoneal insulin use is associated with a significantly increased rate of peritonitis (176,177). Because
peritonitis is a leading cause of technique failure in PD
(178), this disadvantage of intraperitoneal insulin is
believed by many nephrologists to outweigh its possible
benefits. Other described disadvantages of the intraperitoneal route of insulin administration compared with the
subcutaneous route include the development of hepatic
subcapsular steatosis (179), the need for larger doses
of insulin, and the development of a more atherogenic
lipid profile (177). Reported benefits of intraperitoneal
insulin include improved glucose control in some (but not
all) studies (44) and a more physiologic plasma insulin
profile (180).
For self-monitoring of glucose in patients using any
icodextrin exchanges, a glucometer using the glucose
oxidase or hexokinase methods is a must (181,182). Other
methods can yield falsely high glucose readings because
of maltose and other absorbed icodextrin metabolites
registering as glucose. The higher readings can encourage the use of additional insulin or oral agents, producing
hypoglycemia that may not be detected.
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TABLE 1
Conflict of Interest Statements for Members of the Canadian Society of Nephrology Peritoneal Dialysis (PD)
Guideline Work Groupa
Member
Type of potential
conflict of interest
Role
Period
Amgen
Baxter
Baxter
Baxter
Fresenius
Mitsubishi
The list is restricted to companies that make products relevant to the care of PD patients; last 3years only.
Collaborative Study Group. Effects of increased peritoneal clearances on mortality rates in peritoneal dialysis:
ADEMEX, a prospective, randomized, controlled trial. J Am
Soc Nephrol 2002; 13:130720.
8. Churchill DN, Taylor DW, Keshaviah PR, and the CANUSA
Peritoneal Dialysis Study Group. Adequacy of dialysis
and nutrition in continuous peritoneal dialysis: association with clinical outcomes. J Am Soc Nephrol 1996;
7:198207.
9. DiazBuxo JA, Lowrie EG, Lew NL, Zhang SM, Zhu X, Lazarus
JM. Associates of mortality among peritoneal dialysis patients with special reference to peritoneal transport rates
and solute clearance. Am J Kidney Dis 1999; 33:52334.
10. Rocco M, Soucie JM, Pastan S, McClellan WM. Peritoneal
dialysis adequacy and risk of death. Kidney Int 2000;
58:44657.
11. Menon MK, Naimark DM, Bargman JM, Vas SI, Oreopoulos DG. Long-term blood pressure control in a cohort
of peritoneal dialysis patients and its association with
residual renal function. Nephrol Dial Transplant 2001;
16:220713.
12. Konings CJ, Kooman JP, Schonck M, Struijk DG, Gladziwa
U, Hoorntje SJ, et al. Fluid status in CAPD patients is related to peritoneal transport and residual renal function:
evidence from a longitudinal study. Nephrol Dial Transplant
2003; 18:797803.
13. Bammens B, Evenepoel P, Verbeke K, Vanrenterghem Y.
Removal of middle molecules and protein-bound solutes
by peritoneal dialysis and relation with uremic symptoms.
Kidney Int 2003; 64:223843.
14. PecoitsFilho R, Heimbrger O, Brny P, Suliman M, FehrmanEkholm I, Lindholm B, et al. Associations between
232
circulating inflammatory markers and residual renal function in CRF patients. Am J Kidney Dis 2003; 41:121218.
15. Wang AY, Sea MM, Ip R, Law MC, Chow KM, Lui SF et al.
Independent effects of residual renal function and dialysis
adequacy on actual dietary protein, calorie, and other
nutrient intake in patients on continuous ambulatory
peritoneal dialysis. J Am Soc Nephrol 2001; 12:24507.
16. van Olden RW, Krediet RT, Struijk DG, Arisz L. Measurement
of residual renal function in patients treated with continuous ambulatory peritoneal dialysis. J Am Soc Nephrol 1996;
7:74550.
17. Jansen MA, Hart AA, Korevaar JC, Dekker FW, Boeschoten
EW, Krediet RT on behalf of the NECOSAD Study Group.
Predictors of the rate of decline of residual renal function in incident dialysis patients. Kidney Int 2002;
62:104653.
18. Ortega O, Gallar P, Carreo A, Gutierrez M, Rodriguez I,
Oliet A, et al. Peritoneal sodium mass removal in continuous ambulatory peritoneal dialysis and automated
peritoneal dialysis: influence on blood pressure control.
Am J Nephrol 2001; 21:18993.
19. Li PK, Chow KM, Wong TY, Leung CB, 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;
139:10512.
20. 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; 43:105664.
21. Medcalf JF, Harris KP, Walls J. Role of diuretics in the
preservation of residual renal function in patients on
Bargman
Honoraria
Speaker or writer
Honoraria
Speaker or writer
Blake
Honoraria
Speaker
12 times annually
during the past 5years
Brimble
None
Davison
None
Hirsch
None
McCormick
Honoraria
Speaker
12 times annually
during the past 5years
Suri
Grant funding
Grant funding
Taylor
None
Tonelli
None
Zalunardo
None
Sponsor
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237
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growth hormone therapy in malnourished dialysis patients: a randomized controlled study. Am J Kidney Dis
1998; 32:45463.
159. Fouque D, Peng SC, Shamir E, Kopple JD. Recombinant
human insulin-like growth factor-1 induces an anabolic
response in malnourished CAPD patients. Kidney Int 2000;
57:64654.
160. J ohansen KL, Mulligan K, Schambelan M. Anabolic
effects of nandrolone decanoate in patients receiving
dialysis: a randomized controlled trial. JAMA 1999;
281:127581.
161. Johansen KL, Painter PL, Sakkas GK, Gordon P, Doyle J,
Shubert T. Effects of resistance exercise training and
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162. Rammohan M, KalantarZadeh K, Liang A, Ghossein C.
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of malnutrition-inflammation complex in maintenance
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163. W ynne K, Giannitsopoulou K, Small CJ, Patterson M,
Frost G, Ghatei MA, et al. Subcutaneous ghrelin enhances
acute food intake in malnourished patients who receive
maintenance peritoneal dialysis: a randomized, placebocontrolled trial. J Am Soc Nephrol 2005; 16:211118.
164. Stein A, Moorhouse J, IlesSmith H, Baker F, Johnstone
J, James G, et al. Role of an improvement in acidbase
status and nutrition in CAPD patients. Kidney Int 1997;
52:108995.
165. Szeto CC, Wong TY, Chow KM, Leung CB, Li PK. Oral sodium
bicarbonate for the treatment of metabolic acidosis in
peritoneal dialysis patients: a randomized placebo-control
trial. J Am Soc Nephrol 2003; 14:211926.
166. Ross EA, Koo LC. Improved nutrition after the detection
and treatment of occult gastroparesis in nondiabetic
dialysis patients. Am J Kidney Dis 1998; 31:626.
167. Silang R, Regalado M, Cheng TH, Wesson DE. Prokinetic
agents increase plasma albumin in hypoalbuminemic
chronic dialysis patients with delayed gastric emptying.
Am J Kidney Dis 2001; 37:28793.
168. McMurray SD, Johnson G, Davis S, McDougall K. Diabetes
education and care management significantly improve
patient outcomes in the dialysis unit. Am J Kidney Dis
2002; 40:56675.
169. Canadian Diabetes Association (CDA). Canadian Diabetes
Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Toronto, ON:
CDA; 2003.
170. Williams ME, Lacson E Jr, Teng M, Ofsthun N, Lazarus
JM. Hemodialyzed typeI and typeII diabetic patients in
the U.S.: characteristics, glycemic control, and survival.
Kidney Int 2006; 70:15039.
171. Khan IH, Catto GR, MacLeod AM. Severe lactic acidosis
in patient receiving continuous ambulatory peritoneal
dialysis. BMJ 1993; 307:10567.
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