Canadian Diabetes Association
Clinical Practice Guidelines
Chronic Kidney Disease in Diabetes
Chapter 29
Phil McFarlane, Richard E. Gilbert,
Lori MacCallum, Peter Senior
Chronic Kidney Disease (CKD) Checklist
2013
 SCREEN regularly with random urine albumin
creatinine ratio (ACR) and serum creatinine for
estimated glomerular filtration rate (eGFR)
 DIAGNOSE with repeat confirmed
ACR ≥2.0 mg/mmol and/or eGFR <60 mL/min
 DELAY onset and/or progression with glycemic and
blood pressure control and ACE-inhibitor or Angiotensin
Receptor Blocker (ARB)
 PREVENT complications with “sick day management”
counselling and referral when appropriate
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Patients with DM 6-12X more likely to be hospitalized for
CKD or End-stage renal disease (ESRD)
Public Health Agency of Canada (August 2011); using 2008/09 data from the Canadian Chronic Disease Surveillance System (Public Health Agency of Canada).
Diabetes is #1 Cause of New Cases of ESRD
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Public Health Agency of Canada (August 2011); using 2008/09 data from the Canadian Chronic Disease Surveillance System (Public Health Agency of Canada).
2013
ACR ≥2.0 mg/mmol
CKD
in Diabetes
and / or
eGFR <60 mL/min
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Diabetic Nephropathy
“ Progressive increase in proteinuria in people
with longstanding diabetes, followed by
declining function which can eventually lead to
End-Stage Renal Disease (ESRD)”
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Stages of Diabetic Nephropathy
Note: change in definition of microalbuminuria
ACR ≥2.0 mg/mmol
2013
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Screening and
Diagnosis of CKD in
Diabetes
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Beware of Transient Albuminuria
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2013
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2
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Beware
of Other
Causes
of CKD
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When to Consider Other Causes of CKD
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2
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Care Gap Still Exists for Screening
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Canadian Institute of Health Information – Diabetes Care Gap 2009
Prevention of Diabetic Nephropathy
•
Optimal glycemic control in type 1 and type 2
diabetes has been shown to reduce the development
and progression of nephropathy
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DCCT: Reduction in Albuminuria
Primary Prevention
Secondary Intervention
34% RRR
43% RRR
(p<0.04)
(p=0.001)
56% RRR
(p=0.01)
RRR = relative risk reduction
Solid line = risk of developing microalbuminuria
Dashed line = risk of developing macroalbuminuria CI = confidence interval
The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986.
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EDIC: Continued Reduction in Albuminuria
Return to normoalbuminuria
Macroalbuminuria
HR 1.92
HR 0.64
(p<0.05)
(95% CI 0.40-1.02)
HR = hazard ratio
CI = confidence interval
deBoer IH et al. Arch Intern Med 2011;171(5):412-420.
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EDIC: Early Glycemic Control Reduces
Long-term Risk of Impaired GFR
Risk reduction with intensive therapy
50%
(95% CI 18-69; p=0.006)
DCCT/EDIC Research Group. N Engl J Med 2011;365:2366-76.
UKPDS: Post-trial Monitoring “Legacy Effect”
After median 8.5 years post-trial follow-up
Aggregate Endpoint
Any diabetes related endpoint
RRR:
P:
1997
12%
0.029
2007
9%
0.040
Microvascular disease
RRR:
25%
P: 0.0099
Myocardial infarction
RRR:
P:
16%
0.052
15%
0.014
All-cause mortality
RRR:
P:
6%
0.44
13%
0.007
Holman R, et al. N Engl J Med 2008;359.
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24%
0.001
ADVANCE: Primary Microvascular
Outcomes
New/worsening nephropathy, retinopathy
25
20
HR 0.86 (0.77-0.97)
p = 0.01
15
Cumulative
incidence (%)
Standard
control
10
Intensive
control
5
0
0
6
12
18
24
30
36
42
48
54
60
66
Follow-up (months)
Intensive
Standard
HR
p
Nephropathy/retinopathy (%)
9.4
10.9
0.86
0.01
Nephropathy (%)
4.1
5.2
0.79
0.006
Retinopathy (%)
6.0
6.3
0.95
NS
Adapted from:
ADVANCE
Collaborative
Group.
N Engl J Med
ADVANCE
Collaborative
Group. N Engl
J Med 2008;358:2560-72.
2008;358:24.
Reducing Progression of Diabetic Nephropathy
•
Optimal glycemic control (as shown)
•
Optimal blood pressure control
•
ACE-inhibitor (ACEi) or Angiotensin Receptor
Blocker (ARB)
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Proportion with Event
ACE-inhibitor in T1DM with MAU Reduces
Progression to Clinical Proteinuria
Months of Therapy
Laffel LM et al. Am J Med 1995;99(5):497-504.
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ACE-inhibitor in T1DM with
Macroalbuminuria Reduces Renal Outcomes
Lewis EJ et al. N Engl J Med 1993;329:1456-62.
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ARB in T2DM with MAU reduces
progression
Incidence of diabetic nephropathy (%)
Primary endpoint: Time to onset of diabetic nephropathy* (n=590)
20
Placebo
15
Irbesartan
150mg
10
Irbesartan
300mg
5
0
0
3
6
9
12
15
18
Follow-up (months)
*defined by persistent albuminuria in overnight specimens,
with urinary albumin excretion rate <200 μg/min and ≥30% higher than baseline level
Parving et al. N Engl J Med 2001;345:870-8
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21
24
ARB in T2DM with Macroalbuminuria
Reduces Renal Outcomes
Cumulative % of
patients with event
Primary endpoint: Time to doubling of serum creatinine,
ESRD, or death (n=1513)
50
Placebo
Risk reduction = 16%
40
p=0.02
30
20
Losartan
10
0
0
12
Brenner et al. N Engl J Med 2001;345:861-9
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24
Months
36
48
ARB in T2DM with Macroalbuminuria
Reduces Renal Outcomes
Primary endpoint: Time to doubling of serum creatinine,
ESRD, or death (n=1,715)
70
Irbesartan
60
Amlodipine
RRR 20%
p=0.02
p=NS
50
Patients (%)
RRR 23%
p=0.006
Placebo
40
30
20
10
0
0
6
12
Lewis et al. N Engl J Med 2001;345:851-60
18
24
30
36
Follow-up (mo)
42
48
54
60
Safe use of treatments in kidney
disease…..
Practical Tips: Potassium (K+) and
Creatinine (Cr)
•
Check serum K+ and Cr
–
–
–
Baseline
Within 1-2 weeks of initiation or titration
During acute illness
If K+ becomes elevated or Cr >30% increase
Review therapy
Recheck serum K+ and Cr
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Practical Tips: Potassium (K+) and
Creatinine (Cr)
•
•
Mild to moderate stable hyperkalemia
–
Counsel on a low potassium diet
–
If persistent, consider adding non-potassium sparing
diuretics and/or oral sodium bicarbonate (in those with
metabolic acidosis)
–
Consider temporarily holding or discontinuing ACEi, ARB or
Direct Renin Inhibitor (DRI)
Severe hyperkalemia
–
Hold or discontinue ACEi, ARB or DRI
–
Emergency management strategies
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Counsel all
Patients
About
Sick Day
Medication
List
2013
See
CPG Appendix 6
for therapeutic
considerations
for renal
impairment
2013
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When to Refer…..
•
Chronic, progressive loss of kidney function
•
ACR persistently >60 mg/mmol
•
eGFR <30 mL/min
•
Unable to remain on renal-protective therapies due to
adverse effects such as hyperkalemia or a >30%
increase in serum Cr within 3 months of starting ACEi
or ARB
•
Unable to achieve target BP (could be referred to any
specialist in hypertension)
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Recommendation 1: Screening
1. In adults, screening for CKD in diabetes should be
conducted using a random urine ACR and a
serum creatinine converted into an eGFR [Grade D,
Consensus].
Screening should commence at diagnosis of
diabetes in individuals with type 2 diabetes and 5
years after diagnosis in adults with type 1
diabetes and repeated yearly thereafter.
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2013
Recommendation 1: Screening (continued)
A diagnosis of chronic kidney disease should be made
in patients with a random urine ACR ≥2.0 mg/mmol
and/or an eGFR<60 mL/min on at least two out of
three samples over a three month period [Grade D,
Consensus].
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Recommendation 2: Vascular Protection
2. All patients with diabetes and chronic kidney
disease should receive a comprehensive,
multifaceted approach to reduce cardiovascular
risk (see Vascular Protection, CPG Chapter 22)
[Grade A, Level 1A].
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Recommendation 3: Treatment
3. Adults with diabetes and CKD with either
hypertension or albuminuria should receive an
ACE inhibitor or an ARB to delay progression of
CKD
[Grade A, Level 1A for ACE-inhibitor use in type 1 and type 2
diabetes, and for ARB use in type 2 diabetes; Grade D, Consensus, for ARB
use in type 1 diabetes].
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Recommendation 4 and 5
4. People with diabetes on an ACE inhibitor or an ARB
should have their serum creatinine and potassium
levels checked at baseline and within 1 to 2 weeks
of initiation or titration of therapy and during times
of acute illness [Grade D, Consensus].
5. Adults with diabetes and CKD should be given a
“sick day” medication list that outlines which
2013
medications should be held during times of acute
illness (see CPG Appendix) [Grade D, Consensus].
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Recommendation 6
2013
6. Combination of agents that block the reninangiotensin-aldosterone system (ACE-inhibitor,
ARB, DRI) should not be routinely used in the
management of diabetes and CKD [Grade A, Level 1].
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Recommendation 7: When to Refer
7. People with diabetes should be referred to a
nephrologist or internist with an expertise in chronic
kidney disease in the following situations:
–
Chronic, progressive loss of kidney function
–
ACR persistently >60 mg/mmol
–
eGFR<30 mL/min
–
Unable to remain on renal-protective therapies due to adverse
effects such as hyperkalemia or a >30% increase in serum
creatinine within 3 months of starting an ACE-inhibitor or ARB
–
Unable to achieve target BP (could be referred to any
specialist in hypertension) [Grade D, Consensus]
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CDA Clinical Practice Guidelines
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www.diabetes.ca – for patients