Transcript Renal Replacement Therapies: Chronic Critical Care for

Managing Diabetes in Peritoneal Dialysis
Western PD Days
April 9, 2015
Presented by :
Sharon Kelly RN BN CDE
Pat Holmes RN BN BSc MSc CDE
Diabetes Nurse Clinicians
Southern Alberta Renal program
DISCLOSURES
Renal Replacement Therapies:
Chronic Critical Care for Years to
Decades.
Critical care medicine provides technologically
advanced support for failing organ systems ,
thereby preventing what previously was the
inevitable demise of the organism.
In doing so, man enters an unnatural state
supported by medications and machines.
Hollander et al; Nutrition in clinical Practice, 21:587
– 604, Dec./2006.
TEAMWORK- the power of a
multidisciplinary approach
Nephrologist
Nurse
Clinician
Patient and
family
Registered
Dietitian
Pharmacist
Diabetes
Educator
Social
Work
OUTLINE
Clinical Practice Guidelines and Recommendations
Diabetes characteristics in advanced CKD.
Glucose patterns.
Targets
Significance of Hgb A1C and home glucose testing
The role of Lifestyle assessment
How glycemia may affect the peritoneal membrane
Tailoring Diabetes Drugs to BG patterns and PD.
Cardiovascular risk in Diabetes and in CKD
Clinical Practice Guidelines
Canadian CPG 2013
KDIGO, 2012
KDOQI 2014
ADA: Standards of
Medical Care in Diabetes:
2015
Kidney Disease: A Report
from an ADA Consensus Conference/Oct.
2014
CPG and Recommendations on PD Adequacy
2011.
Canadian Clinical Practice Guidelines 2013
Focus on prevention, screening, therapies,
complications, DM1, DIP.
Targets 4-7 mmol fasting ; 5-8 mmol PC
HgbA1C < 7%
Little to no information on management in ESRD
Individualized A1C targets for people with:
• longer duration of diabetes
• established CV risk factors
• severe hypoglycemia episodes
• higher ac and pc meal target glucose ranges
Diabetes Drug use
KDIGO, 2012
Importance of glycemic control to
improve outcomes in patients
with diabetes and ckd due to
higher risk.
Integration with other chronic disease
management including diabetes,
hypertension and heart failure.
Diabetes Drug Use in CKD
KDOQI, 2012
Extensive discussion re : diabetes drug use in
Stage 4- 5 CKD
Interpretation of Hg A1C, similar to Canadian
CPG
Hypoglycemia risk:
Prolonged action of some diabetes drugs
Impaired gluconeogenesis
Optimize safety
ADA: Standards of Medical Care in Diabetes:
2015
Emphasize management of albuminuria and
hypertension
Glycemic control as CVD risk management
Referral to Nephrology when GFR is < 30 ml/min.
Discussion on factors that affect the A1C value ;
individualize goals
Similar ac/pc meal glucose goals (AC 4.4-7.2 mmol ;
Pc < 10.0 mm0l)
Use of real-time CGM
Use of Insulin Analogs – prev. of Hypoglycemia
Kidney Disease: A Report from an ADA
Consensus Conference/Oct. 2014
• Glycemic control and regression of
albuminuria – Hgb A1C < 8%.
• Increased incidence of CVD events
associated with CKD and Diabetes.
• Factors that affect the A1c value
• Hypoglycemia: longer duration of diabetes
drug effects, malnutrition, deficiency of
gluconeogenic precursors
• Hypoglycemia as a reason for higher
mortality
CPG’s and Recommendations on
Peritoneal Dialysis Adequacy – 2011
• Volume status as important parameter of “adequate
PD”
• Relationship of volume status to CVD risk factors
and risk reduction.
• Address Glycemic control and exposure to
hypertonic glucose solutions and contribution to UF
• Increased atherogenic profile of PD patients
• “Few data exist to guide the management of diabetes
in this population” (p 15).
• Adherence to CPG where possible; avoid
hypoglycemia
• Address some diabetic drugs
Diabetes and CKD
Uremia alters the entire metabolism including that of
carbohydrates, proteins and fats. It also causes
electrolyte disturbances and upsets mineral and
hormonal homeostasis. Directly or indirectly, glucose
metabolism is disturbed by all these things’.
Kumar, K.V. S. et al: Glycemic Control in Patients of Chronic Kidney
Disease. \www.ijddc.com/article.asp?issn=0973-3939;year=2007;
volume27; issue=4
International Journal of Diabetes in Developing Countries.
DIABETES IN STAGES 4 / 5
Chronic Kidney Disease associated with :
INCREASED INSULIN RESISTANCE –
Factors include uremia, anemia, elevated
PTH, deficient Vit D, metabolic acidosis,
increased plasma FFA, atherogenic lipid
profiles, increased pro-inflammatory
cytokines
DECREASED INSULIN DEGRADATION –
PARTICULARLY AT GFR< 20%
Question?
Should we apply clinical practice
guidelines, based on studies on
people with adequate kidney
function, to Stage 5 CKD and
Peritoneal Dialysis?
What is missing?
We are missing:
The role of the kidney in glucose
metabolism:
A practical treatment model.
Target blood glucose ranges in PD.
Lab/meter comparisons
Research
CV risk in PD populations + Diabetes Why is glycemic control important?
•
•
•
•
Hypoglycemia
Hyperglycemia
Glucose variability
Inflammatory response to both hyperglycemia and
PD solutions.
Hypoglycemia : The
Treatment Limiting
Factor
Recovery from hypoglycemia is
impaired.
Key factors: renal atrophy, growth
hormone and IGF aberrations, blunted
glucagon and epinephrine response,
prolonged action of insulin
Severe hypoglycemia can lead to falls,
cardiac ischemia and arrhythmias,
seizures, brain damage.
Incident Rate Ratios
Risk for hypoglycemia in veterans classified by
presence or absence of chronic kidney disease
(CKD) and diabetes.
8.43
9
8
7
7.21
6
4.09
5
4
3.56
3
2
1.62
3.28
1
1.58
1
1.66
1
1.53
0
Glucose < 2.8 mmol/L
Glucose < 3.3 and >2.8 mmol/L
1
+CKD, +Diabetes
-CKD, +Diabetes
Glucose < 3.9 and >3.3 mmol/L
+CKD, -Diabetes
-CKD, -Diabetes
Moen M F et al. CJASN 2009;4:1121-1127
All p-values <0.0001, (95% CI)
Prolonged action of insulin is not the
only factor.
Without a model of renal glycemic
function, we are:
Looking for lows in all
the wrong places !
MOST OF OUR LIVES ARE SPENT IN THE
POSTPRANDIAL STATE
Postprandial state
Postabsorptive state
Fasting state
Breakfast
Lunch
Dinner
0.00 am
4.00 am
Monnier L. et al. European Journal of Clinical Investigation 2000; 30 Suppl 2:3–11.
The Kidneys:
Contribute to blood glucose 24/7 !
A safety catch to provide constant
glucose balancing.
Eliminate excess glucose
Gluconeogenesis: fasting, post
absorptive and post prandial
Recovery from hypoglycemia
The Diabetes Insulin Model:
No Kidney Disease
Based on excessive gluconeogenesis
The liver gets most of the credit for
hyperglycemia
Kidneys thought to contribute about 20 % of
glucose in fasting state.
Cano: Up to 54 % after hypoglycemia
Bedtime long acting insulin used to prevent
fasting hyperglycemia.
No consideration of renal disease.
When Do We Need Insulin ?
•
Lifestyle Assessment: Pre Care
 Schedule
Glucoses
 04:00: up to eat
 Cereal/ milk 4 X weekly
Diabetes Drugs
Blood
query low?
 08:00: 2 toast, tea
repaglinide 2 mg
3 - 12 mmol
 12:00: soup or sandwich
repaglinide 2 mg
8 – 10 mmol
 18:00: protein, 1/2 cup
 starch, veg.
repaglinide 2 mg
10 – 14 mmol
 22:00: bed:
 No food
9 - 12
From observation, people
have difficulty going without
carbohydrate
for more than 4 – 6 hours.
For both Pre Care and PD
clients:
Determine
when people are
fasting from
carbohydrates.
Glucose Patterns in Peritoneal
Dialysis:
Look for both hyperglycemia and hypoglycemia.
Unique use of diabetes drugs
Unique dietary strategies
Unique intake of carbohydrate from peritoneal
dialysis solutions.
CAPD
Schedule
Overnight
Diabetes Drugs/PD
Blood Glucoses
symptoms of lows
08:30: eggs
2 bread, tea
Humalog 40 U
2 litres 2.5 %
7 - 15
13:00:
Sandwich
Veg., fruit
Humalog 40 U
2 litres 2.5 %
8.7 – 11.9
18:00: soup
Protein,2 starch
Veg.
Humalog 40 U
2 litres 2.5 %
8.7 – 11.3
22:00:
no food
Lantus 60 U
2 litres extraneal
11 – 15
CCPD
 Schedule

 06:00: off cycler

Drugs and Solution
Blood Glucose
1.5 L 7.5 %
extraneal
12 – 15
 08:30: 2 toast, egg,
 Coffee
Lantus 10 U
Humalog 4 U
7 – 10
 12:00: sandwich
 water
Humalog 4 U
6–8
 18:00: protein, veg
 1 cup starch, fruit
Lantus 15 U
Humalog 4 U
 22:00: toast, milk
 Start cycler

6 - 10
5 L 2.5 %
3 L 4.5 %
Goals of Diabetes Care Specific to
Peritoneal Dialysis
Prevent hyper- and hypo - glycemia
Stabilize blood glucose patterns
Adapt to diet and gastro intestinal disorders
Adapt diabetes therapies to dialysis prescription
Promote ULTRAFILTRATION and volume control
Prevent infections
Prevent further complications of diabetes
ENHANCE PATIENT WELL-BEING
PD Solutions and Glycemic control
With the use of dextrose
solutions, high MW
glucose polymers such
as icodextrin and nonglucose based solutions
such as Nutraneal – the
CHALLENGE is to
control glycemia in an
environment of
intermittently high and
prolonged glucose
exposure.
1744- red wine
used as osmotic
agent in
peritoneal
lavage!
Post prandial period after
meals and with PD solutions:
How do we interpret
non fasting
blood glucoses ?
Canadian Clinical Practice Guidelines 2013
FPG or preprandial PG target of 4.0–7.0
mmol/L and a 2-hour pc target of 5.0–10.0
mmol/L
ADA: 4 .4 – 7.2
pc < 10 mmol
[Grade B, Level 2 (2) for type 1; Grade B,
Level 2 (1,11) for type 2 diabetes].
Canadian Clinical Practice Guidelines
2013
LACK of evidence-based research where
effect of postprandial glucose values on
outcome is the major objective of the study.
Most of the large outcome trials conducted
so far have been mostly based on
preprandial glucose and A1C targets.
? Contribution of Post prandial
hyperglycemia to complications as an
independent variable.
PD patients have:
2 hours immediate post prandial period
4 hours total post prandial.
Overlap with 16 hours daily of CAPD.
Add 8 hours for CCPD.
14 – 16 hour daily immediate post prandial post
prandial period.
16 – 20 hour total post prandial period.
May retain some glucose solutions after draining.
How do we determine target glucose
goals?
For safety, aim for higher than 4 – 7 mmol ac
meals and higher than 5 – 10 pc meals.
Eg: 6 – 9 ac meals and 7 – 12 pc meals?
Encourage research re: blood glucose patterns and
target goals in PD.
Encourage focused SMBG
How do we determine the accuracy of
home glucose testing?
Lab/Meter comparisons.
Companies recommend fasting
comparisons.
PD patients live in post prandial state.
Lab/Meter Comparisons
Fasting lab/meter comparisons:
Venous and capillary blood samples
carry about the same amount of
glucose at 4.5 or more hours after
eating.
Up to 15 % difference is acceptable.
Post prandial period:
A glucose meter may read up to
30 % higher than the lab in the
immediate post prandial period.
Cembrowski, George et al: Assessing the Accuracy of Your Blood
Glucose Meter. Lifescan, 2000.
How do we interpret glucose readings
in peritoneal dialysis?
Assume there is 15 – 20 % less
glucose in veins than in capillary
blood samples.
Base assumptions on frequent
lab/meter comparisons done in a non
fasting state.
How Do we interpret Hg A1C values?
Glycated hemoglobin (A1C) is an estimate of
mean glucose levels over the previous 3 to 4
months for most individuals.
Blood glucose (BG) in the previous 30 days
contributes 50% of the result.
The prior 90 to 120 days contributes 10% (2,3).
In renal disease, red blood cell physiology is an
strong contributor to the A1C value.
Assess Red Blood Cell Physiology and
Glycemia: Diabetes CPG 2013
•
•
•
•
•
•
•
•
•
•
Raise A1C
Hyperglycemia
Acidosis
Hypothyroidism
Iron deficiency anemia
B 12 deficiency
Splenectomy
Hemoglobinopathies
Hypoxia
Race other than
Caucasian (.3 - .5 %)
• Alcoholism
•
•
•
•
•
•
•
•
Lower A1C
Hypoglycemia
Increased RBC pH
Shortened lifespan of the
red blood cell
Erythropoeitin agents
Hemoglobinopathies
Blood loss with HD and
with frequent blood
sampling
Blood transfusions
TOOL: Hg A1C Profile
on Electronic Chart
Hg A1C
Fasting glucose
lab /meter
Iron studies
Triglycerides
Vitamin D
WBC
Hg
Random glucose
TSH
B 12
PTH
Glycated Albumin (fructosamine)
A measure of glycosolation of plasma
albumin.
Based on an expected 20 day half life of
albumin. Accurate in HD.
PD: loss of 5 – 15 gm protein daily via
dialysate, including albumin.
Add albumin losses via residual kidney
function.
Half life of albumin is variable and less than
20 days.
Optimization of Blood Glucose Values
Consider all factors affecting blood glucoses.
Blend SMBG tests, lab tests, diabetes drugs, PD
solutions, food, activity and PD changes.
* Consider abrupt onset of glucose diffusion at
start of PD and abrupt stop when PD glucose
solution is drained.
Teamwork: Client, family, nephrologist, dietitian,
renal nurses, endocrinologists, diabetes nurses,
social workers, pharmacists, family physician.
Peritoneal Membrane
Hypothesis: Chronic exposure to glucose
containing solutions promotes peritoneal
membrane damage over time (De Vriese).
“Glucose likely has a detrimental effect on the
peritoneal membrane both from systemic
hyperglycemia and from local effects of the
dialysate. [Chugh, et.al 2014]
Diabetes:
Uremic people with diabetes have a greater degree
of damage to the peritoneal membrane BEFORE
STARTING PD.
Can we minimize damage and prolong the PD
lifespan of the peritoneal membrane with
appropriate blood glucose control?
MEDIATORS OF ENDOTHELIAL
INFLAMMATION WITH
HYPERGLYCEMIA
MEDIATORS OF PERITONEAL
MEMBRANE INFLAMMATION
Ultrafiltration
‘Analysis of the data between small solute transport rate
and fluid transport parameters could contribute to an
understanding of why peritoneal ultrafiltration capacity is
often reduced in high transporters, as well as answer the
general question of whether fluid and solute pathways are
linked’.
Sobiecka, D. et al: Peritoneal Fluid Transport in CAPD
Patients with Different Transport Rates of Small Solutes.
Peritoneal Dialysis International; Vol 24, pp 240 – 251.
NEED FOR MORE RESEARCH INTO THE ROLE OF BETTER
GLYCEMIC CONTROL ON THE LONGEVITY OF THE
PERITONEAL MEMBRANE.
Glucose and Ultrafiltration- migration across
the peritoneal membrane
Canadian Clinical Practice Guidelines 2013
What we do not know???
Little evidence-based guidelines for
glycemic management in ESRD. In
Peritoneal dialysis lack of welldesigned, long-term outcome
studies on value of post-prandial
control .
Research Questions?
What blood glucose range is
associated with:
: safety
: optimal ultrafiltration?
: minimal use of hypertonic PD
solutions?
: minimized damage to the peritoneal
membrane ?
Proposed Method:
• Use Continuous Glucose Monitoring.
• Lab/meter/CGM/glucose meter
comparisons.
• Track use of various PD solutions
• Compare glycemic control and ultrafiltration.
• Over time, see if PD associated lifespan of
peritoneal membrane is extended in those
with (to be determined ) optimal blood
glucose control.
• Involve nephrology, PD nurses, diabetes
nurses, dietitians, pharmacists
Diabetes Drugs
Antihyperglycemic Agents and Renal Failure
Not recommended
Official
indication
Slide
Terminal
(<15)
Severe (1529)
Caution / Reduced dose
Mild (60-89)
Moderate (30-59)
Metformin
30
Glyburide
30
Safe
60
50
15
Gliclazide/Glimepiride
Repaglinide
30
TZD
Sitagliptin
Saxagliptin
50
50
15
30
Linagliptin
Liraglutide
50
Exenatide
30
Acarbose
50
25
Insulin
0
Yale JF. December 2011
25
50
75
Glomerular Filtration Rate (ml/min)
100
Drugs that are used
frequently are
Repaglinide (gluconorm)
and Insulins.
When do we need insulin with PD?
Need to consider :
Timing of diabetes drugs, start and finish
Abrupt start and stop to glucose diffusion.
Diabetes drugs working when diffusion
starts.
Prevent excessive ongoing action of
diabetes drugs after PD glucose diffusion
stops.
Consider impaired gluconeogenesis.
Hypoglycemia:
Adjust dose of diabetes drugs
that are working when
hypoglycemia occurs.
In PD, often we reduce the dose
of long acting insulin.
Add carbohydrates
Hyperglycemia:
Basal or long acting insulin dose titrated to
prevent hypoglycemia in periods of little
glucose intake.
Add adding short or rapid acting diabetes oral
drugs or insulins for hyperglycemic periods.
Minimize carbohydrate intake where possible.
Strategies:
Add bedtime carbohydrate/protein food.
Aim for blood glucoses of 10 – 12 at bedtime or;
Aim for blood glucose levels that lead to safe
morning blood glucoses.
Adjust diabetes drugs doses that are effective
when hypoglycemia and gluconeogenesis are
relevant factors.
Strategies Based on Lifestyle Analysis
and Safety
Move basal insulin to breakfast (CAPD)
Move basal insulin to supper (CCPD)
BID basal insulin ?
Add R “X” U at cycler start?
Add low dose H/NR for heater bag?
Leave candy/juice at bedside
(for sleeping in)
Rapid or short acting diabetes drugs with
meals or pc meals (GI concerns)
INSULIN THERAPY
Subcutaneous
Principles are the
same as for nondialysis patients.
Initial starting dose –
reduce by as much as
50%
Depends on uremia ,
nutritional status,
comorbidities
Titrate per SMBG
vs
Intraperitoneal
• requires much larger
doses
• Adjustments more
complex d/t
schedules, timing of
meals, etc.
• Risks - bacterial
contamination,
binding of insulin to
plastic tubing,
peritoneal fibroblast
proliferation, adverse
lipid profile
People with diabetes and kidney
disease already have increased
risks for microvascular and
cardiovascular disease.
Microvascular and cardiovascular
disease is complex.
Glycemia is a major factor.
Individuals can address glycemia.
There are other major factors.
PATHOGENESIS OF DIABETIC
COMPLICATIONS
Hyperglycemia
Glycation
Dicarbonyl stress
AGE’s
Mitochondrial Superoxides
Oxidative stress metals ( free radicals)
Polysorbitol pathway
Hexosamine pathway
Protein Kinase C
Nitric Oxide Synthase
Growth Factors- VEGF, IGF, TGF
Susceptibility
Genes
Protective
Genes
Retinopathy, Nephropathy, Neuropathy, CVD
Optimal management of vascular
disease and optimal glycemic control?
Need to consider:
1. Life support : dialysis
2. Prevention of acute diabetes problems: hypo and
hyper glycemia
3. Minimization of diabetes microvascular
complications
4. Preparation for transplant.
IMPENDIA AND EDEN combined trials
( Li, et. Al, JASN 2013)
Suggested that
glucose-sparing PD dialysis solutions
improve some metabolic parameters
of diabetes linked to CV disease.
But- may adversely affect volume control.
HUMAN BEHAVIOURAL
VARIABLES
PERHAPS MORE IMPORTANT THAN ANYTHING!!
CONSIDER:
What is person able / willing to do?
What are their own goals for therapy?
Effect on QOL
Cost
Capacity
Cultural beliefs
TEAMWORK- the power of a
multidisciplinary approach
Nephrologist
Nurse
Clinician
Patient and
family
Registered
Dietitian
Pharmacist
Diabetes
Educator
Social
Work
Canadian Clinical Practice
Guidelines 2013
Individualize !
“Many factors contribute to glycemic
control:
net effect is that insulin requirements are
not easily predicted and careful
individualized therapy is essential”
Berns, J et al: Management of Hyperglycemia with End
Stage Renal Disease. Up to date.
http//www.uptodate.com/home/store/do. Last updated
May 25, 2010.
THE FINAL WORD…………
Canadian Clinical Practice
Guidelines 2013
Individualize !
REFERENCES AVAILABLE :
Contact [email protected]
Appendix
Hormonal Recovery from Hypoglycemia
Long Duration of Type 1 and 2 DM :
• Loss of or impaired glucagon response in 1 -2 years
• Diminished epinephrine response in 10 years
• Require very low blood glucose to stimulate
epinephrine
• Diminished epinephrine response with age
and beta blockers
All individuals with Stage 4- 5 CKD:
• altered insulin and counter regulatory hormones.
FACTORS CONTRIBUTING TO
PERITONEAL TISSUE REMODELING IN
PERITONEAL DIALYSIS
Schilte, et al.,
2009
Contributing factors to Hypoglycemia:
Diabetes drugs
Exercise
Alcohol
Impaired digestion
Meal time carbohydrate intake
Impaired gluconeogenesis
Abrupt cessation of glucose intake via PD
Cycler malfunction
Counter regulatory changes
Renal Metabolism of Hormones
Mujais, S.K.: Nephrology, Dialysis , Transplantation
(2000), 15, (supp 1): 10 - 14
• Hormone
•
•
•
•
•
Molecular Mass/Daltons
Growth hormone
Insulin
Injected insulin
PTH 1-84
Glucagon
21,500
6000
6000
9500
3500
% Renal
Clearance
70 %
33 %
50 %
31 %
30 %
Prednisone
• Prednisone patterns are superimposed
on pre-existing glucose patterns.
• Two Phases:
• Period of hyperglycemia is dose
dependant.
• Lengthened with higher doses and
decreased with lower doses.
• Hypoglycemia most likely at 18 – 26
hours post administration.
Steroid Induced Diabetes
Iwamoto, T. et al: Steroid Induced Diabetes Mellitus and Related Risk Factors, 2004
Sampling Point Normal blood
glucose
Impaired blood Diabetes level
glucose
blood glucose
Before
breakfast
24
1
0
2 hours pc
breakfast
17
4
4
2 hours pc 2
lunch
2 hours pc
7
10
13
7
10
Final diagnosis
of SDM
10
13
dinner
2
Acknowledgements and Thank you’s
HEMOGLOBIN A1C
Review
• Target Associated with
best outcomes in CKD
predialysis patients not
established.
• Problems with the use
of HgbA1c in
advanced CKD
• Likewise for dialysis
patients
• Alternative measure?
Glycated Albumin