Chronic Kidney Disease and Diabetes

Dr Garth Hanson

Talk

• Pathology of Diabetes Mellitus (DM)• DM and Renal Disease• Treatment of Hyperglycemia in DM • DM Treatment CKD Stage III – IV, Stage V HD,

Stage V PD and Renal Transplant• Special Considerations

Pathology of Diabetes

Hyperglycemia

Pancreas

Hyperglycemia

Reduced insulin production

Pancreas

muscle

Hyperglycemia

Reduced insulin production

Reduced uptake glucose

Pancreas

muscle liver

Hyperglycemia

Reduced insulin production

Reduced glycogen production or increased gluconeogenasis

Reduced uptake glucose

Hyperglycemia

Hyperglycemia

Non enzymatic glycation of tissues (AGE products)

Hyperglycemia

Non enzymatic glycation of tissues (AGE products)

Cytokine production (VGEF, TGF-beta)

Hyperglycemia

Non enzymatic glycation of tissues (AGE products)

Cytokine production (VGEF, TGF-beta)

Tissue ischemia due to microvascular damage

Hyperglycemia

Non enzymatic glycation of tissues (AGE products)

Cytokine production (VGEF, TGF-beta)

Tissue ischemia due to microvascular damage

?

Basement membrane thickening

Glomerular sclerosis

Mesangial expansion

Arteriolar hyalineosis

DM Pathology

DM and Renal Outcomes

DM and Renal Disease

Treatment of Hyperglycemia in DM

Reduce Glucose

muscle

liver

pancrease

kidney

intestine

DPP4

GLP

Reduce Glucose

muscle

liver

pancrease

kidney

intestine

DPP4

GLP

insulin

Reduce Glucose

muscle

liver

pancrease

kidney

intestine

DPP4

GLP

Alpha glucosidase inhib

insulin

Reduce Glucose

muscle

liver

pancrease

kidney

intestine

DPP4

GLP

metformin

Alpha glucosidase inhib

insulin

Reduce Glucose

muscle

liver

pancrease

kidney

intestine

DPP4

GLP

metformin

Alpha glucosidase inhib

insulin

meglithinidessulfonylureas

Reduce Glucose

muscle

liver

pancrease

kidney

intestine

DPP4

GLP

metformin

thioazolinadimediones Alpha glucosidase inhib

insulin

meglithinidessulfonylureas

Reduce Glucose

muscle

liver

pancrease

kidney

intestine

DPP4

GLP

metformin

thioazolinadimediones Alpha glucosidase inhib

DPP4 inhib

GLP 1 agonists

insulin

meglithinidessulfonylureas

Reduce Glucose

muscle

liver

pancrease

kidney

intestine

DPP4

GLP

metformin

thioazolinadimediones Alpha glucosidase inhib

DPP4 inhib

GLP 1 agonists

insulin

meglithinidessulfonylureas

SGLT2

DM Treatment in CKD

CKD Stage III - IV

• RAS Blockage/HTN control

• Lipids • Antiplatelet

/Anticoagulation• Glucose Control

CKD Stage III - IV

• RAS Blockage/HTN control

• Each 10 mmHg of systolic BP 13% reduction in microvascular complications (UKPDS)

• After ACCORD, target 140 mmHg and above 120 mmHg.

CKD Stage III - IV

• RAS Blockage/HTN control

• ACE and ARB reduce progression by 16% to 30%.

• Dual RAS blockage not helpful (ONTARGET, NEHRON-D, ALTITUDE)

• African Americans may not benefit as much.

• Long acting agents usually chosen (Ramipril, Perindopril)

CKD Stage III - IV

• Lipids • Secondary prevention of

CVD events definitely beneficial (TNT trail) target to 1.8 LDL

• Primary prevention of CVD likely beneficial (CARDS, SHARP).

• Combination therapy not likely of benefit (ACCORD, ENHANCE).

CKD Stage III - IV

• Lipids • Statin therapy does not

appear to reduce progression to ESRD (SHARP, CARDS).

• Watch high dose rosuvastatin and simvastatin

• atorvastatin safe at all doses

CKD Stage III - IV

• Antiplatelet /Anticoagulation

• Secondary prevention beneficial

• Primary prevention in doubt except for highest risk.

• Newer agents have little data

CKD Stage III - IV

• Glucose Control• DM 1 - 8% HA1C vs 9%-10%

reduced progression of nephropathy by 50%.

• DM 2 – UKDPS 21% reduction in progression of nephropathy, ACCORD 32% reduction in nephropathy with lower HA1C (under 7%) BUT mortality unchanged or increased.

CKD Stage III - IV

• Glucose Control• metformin should be

stopped at GFR 30 ml/min• Insulin has prolonged

halflife• Thiazolindinediones may

cause volume and bone issues

• SGLT2 inhibitors less efficacious under GFR 45 ml/min

CKD V-Hemodialysis

• RAS Blockage/HTN control

• Lipids • Antiplatelets

/Anticoagulation• Glucose Control

High Quality Evidence in HD

DM and Hemodialysis• DM monitoring

– HA1C may be inaccurate due to RBC turnover, uremic toxins, acidosis

– Low sugars more common due to prolonged insulin lifespan

– Tolerate very high glucose levels due to no urine output

• DM control– Insulin safest but use reduced dose– Linagliptin (Trajenta) safe– Repeglinide (Gluconorm) safe

CKD V-Peritoneal Dialysis

• RAS Blockage/HTN control

• Lipids • Antiplatelets

/Anticoagulation• Glucose Control

High Quality Evidence in PD

DM and PD

• DM monitoring– HA1C inaccurate with high turnover of RBC with

epo agents– Icodextran converted to maltose messes up

meters

• DM Treatment– May need massive insulin doses with glucose load

in PD fluid

CKD V-Transplant

• RAS Blockage/HTN control

• Lipids • Antiplatelets

/Anticoagulation• Glucose Control

DM and Transplants

• Prednisone will increase glucose intolerance• Calcinurin inhibitors (tac > cyclo) cause DM

due to islet cell toxicity• No metformin• Repeglinide, trajenta, insulin ok

Special Considerations

• Hyperglycemia– Very high levels can be tolerated– High K due to osmotic shift– Low Na due to osmotic shift– Treat with insulin infusion not fluid load

• Hypoglycemia– Anorexia due to uremia. Watch for malignancy and

infection– Avoid long acting oral agents and long acting insulin

Special Considerations

• Hypo alternating with Hyper– Gastroporesis may alter glucose absorption,

gastric emptying study will diagnose. Treat with promotility agents.

– Watch for non compliance with PD as cause (lower sugar load).

QUESTIONS?