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
Diabetes
Educator
Registered
Dietitian
Social
Work
Pharmacist

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

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%

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.

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.

Risk for hypoglycemia in veterans classified by presence or absence of chronic kidney disease
(CKD) and diabetes.
9
8
7
6
5
4
3
2
1
0
7,21
8,43
4,09
3,56
3,28
1,58
1,66
1,53
+CKD, +Diabetes
-CKD, +Diabetes
+CKD, -Diabetes
1,62
1
1
-CKD, -Diabetes
1
Glucose < 2.8 mmol/L
Glucose < 3.3 and >2.8 mmol/L
Glucose < 3.9 and >3.3 mmol/L
All p-values <0.0001, (95% CI)
Moen M F et al. CJASN 2009;4:1121-1127

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 ?
•


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 repaglinide 2 mg 10
– 14 mmol
 starch, veg.

22:00: bed: 9 - 12

No food

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 Diabetes Drugs/PD Blood Glucoses
Overnight symptoms of lows
08:30: eggs Humalog 40 U 7 - 15
2 bread, tea 2 litres 2.5 %
13:00: Humalog 40 U 8.7 – 11.9
Sandwich 2 litres 2.5 %
Veg., fruit
18:00: soup Humalog 40 U 8.7 – 11.3
Protein,2 starch 2 litres 2.5 %
Veg.
22:00: Lantus 60 U 11 – 15 no food 2 litres extraneal


Schedule Drugs and Solution Blood Glucose



06:00: off cycler 1.5 L 7.5 % extraneal
12
– 15

08:30: 2 toast, egg, Lantus 10 U 7 – 10

Coffee Humalog 4 U

12:00: sandwich Humalog 4 U 6 – 8
 water
 18:00: protein, veg Lantus 15 U

1 cup starch, fruit Humalog 4 U

22:00: toast, milk

Start cycler

5 L 2.5 %
3 L 4.5 %
6 - 10

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!

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.

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 Hg
Fasting glucose Random glucose lab /meter
Iron studies
Triglycerides TSH
Vitamin D B 12
WBC 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

‘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 ?

• 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

Official indication
Slide
Metformin
Antihyperglycemic Agents and Renal Failur e
Not recommended Caution / Reduced dose Safe
Terminal
(<15)
Severe (15-
29)
30
Moderate (30-59)
60
Mild (60-89)
Glyburide 30 50
15 Gliclazide/Glimepiride
Repaglinide
TZD
Sitagliptin
Saxagliptin
Linagliptin
Liraglutide
Exenatide
Acarbose
Yale JF. December 2011
Insulin
0
15
25
25
30
30
30
50
50
50
50
50 75
Glomerular Filtration Rate (ml/min)
100

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 vs Intraperitoneal
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
• 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 S usceptibility
Dicarbonyl stress
AGE’s Genes
Mitochondrial Superoxides
Oxidative stress metals ( free radicals)
Polysorbitol pathway
Hexosamine pathway Protective
Protein Kinase C Genes
Nitric Oxide Synthase
Growth Factors- VEGF, IGF, TGF
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
Diabetes
Educator
Registered
Dietitian
Social
Work
Pharmacist

“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…………

REFERENCES AVAILABLE :
Contact pat.holmes@albertahealthservices.ca

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 % Renal
Clearance
• Growth hormone 21,500 70 %
• Insulin 6000 33 %
• Injected insulin 6000 50 %
• PTH 1-84 9500 31 %
• Glucagon 3500 30 %

• 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
Before breakfast
24
2 hours pc breakfast
17
2 hours pc lunch
2 hours pc dinner
2
7
Final diagnosis of SDM
2
Impaired blood glucose
Diabetes level blood glucose
1 0
4
10
7
10
4
13
10
13

Acknowledgements and Thank you’s

HEMOGLOBIN A1C
Review
• Target Associated with best outcomes in CKD predialysis patients not established.
• Likewise for dialysis patients
• Problems with the use of HgbA1c in advanced CKD
• Alternative measure?
Glycated Albumin