challenges of glucose control in ckd

Diabetes and KidneyDiabetes and Kidney

Dr.SampathkumarMD,DNB,DM,FRCP

MMHRC

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2 sides of the coin 2 sides of the coin

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ALL patients with Diabetes and ALL patients with Diabetes and Proteinuria/Renal failure have Proteinuria/Renal failure have

diabetic renal disease .diabetic renal disease .You may be wrong 50% of the

times !

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Common Pitfall

Indications for Renal Biopsy Indications for Renal Biopsy

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Diabetic N along with Infection Diabetic N along with Infection related GN related GN

Endocap. Prolif to 100% crescentsEndocap. Prolif to 100% crescents

Progressive grades of CKDProgressive grades of CKD

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Filtration Pressure +15 mm Hg Filtration Pressure +15 mm Hg

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Diabetic glomerular diseaseDiabetic glomerular diseaseFlitration Pressure +35Flitration Pressure +35

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80 mm

Renal and cv risk increases once Renal and cv risk increases once microalbuminuria crosses 6 mg/gmicroalbuminuria crosses 6 mg/g

Albuminuria Renal risk CV event

0-10 1 1

10-20 2.34 1.9

20-30 12.4 9.8

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New classification of albumin New classification of albumin excretionexcretion

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Traditional Vs Novel Traditional Vs Novel

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Non Proteinuric nephropathyNon Proteinuric nephropathy

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CKD

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This patient develops KWD within 5 years though his Hb A1 c was 6.5 %

Insulin dynamics in CKDInsulin dynamics in CKD

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Insulin half life in CKDInsulin half life in CKD

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Use of OHAs in CKDUse of OHAs in CKD

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Metformin Controversy Metformin Controversy in CKD….in CKD….

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Pharmacokinetics of MetforminPharmacokinetics of Metformin

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MALA- Metformin Associated MALA- Metformin Associated Lactic Acidosis Lactic Acidosis • Decreased Utilisation vs hepatic dysfn

ANAEROBIC GLYCOLYSIS

SHOCK STATES

LIVER DYSFNTYPE B

METFORMIN

•2-10 per 100,000 patients receiving metformin /year•MALA accounts for 0.1-1% total patients admitted to ICU•Mortality is high – 30-50%

Balance

2 sites where Metformin acts2 sites where Metformin acts

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Hypotension rather than Hypotension rather than metformin level which metformin level which determined Lactate accumulationdetermined Lactate accumulation

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Conclusion from this study

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SFU in CKDSFU in CKD

• Depends on Renal or Hepatic metabolism

• Depends also on whether metabolites have hypoglycemic effects

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Drug exposure(AUC) in renal impairment compared to patients Drug exposure(AUC) in renal impairment compared to patients with normal renal functionwith normal renal function

Drug Mild RI Moderate RI Severe RI Hemodialysis

Metformin NA NA NA NA

GlibenclamideM1+M2

NA NA -45% NA

GlimepirideM2

NA -55%+100%

-55%+400%

NA

Repaglinide NA +19% +32% +32%

Pioglitazone NA -17% to -43% 17% to -43% NA

Sitagliptin +61% +126% +277% +350%

Vildagliptin +40% +71% +100% NA

Saxagliptin(Active metabolite)

+16%+67%

+41%+192%

+108%+347%

NANA

Alogliptin +70% +110% +220% +280%

Linagliptin +29% +56% +41% +54%

Exenatide -19% -3% NA +227%

A.J Scheen. Expert Opinion on Drug Metabolism and Toxicology: 2013

Linagliptin in a recent study lowered albuminuria on top of Linagliptin in a recent study lowered albuminuria on top of standard ACEi/ARB therapy in patients with T2DMstandard ACEi/ARB therapy in patients with T2DM

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Linagliptin significantly lowers albuminuria on top of recommended standard treatment for diabetic nephropathy

1. Inclusion criteria: Stable ACE/ARB background; albuminuria 30−3000 mg/g creatinine; GFR > 30.*Albuminuria-lowering evidence for linagliptin will emerge from MARLINA 1218.89.

**ADA 2012, 953-P

Adjusted mean change in albuminuria(24 weeks)1

24 weeks’ treatmentEffect of linagliptin on albuminuria in humans*

n

95% CI

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-20%, +23%

168

-42%, -22%

Placebo Linagliptin

-4%

-33%

-29%p < 0.05

Albuminuria:

Early marker for renal damage

Marker for endothelial dysfunction

Cardiovascular risk factor

Lowering of albuminuria is associated with kidney & CV protection

Definitions

Microalbuminuria

UACR ≥ 30 mg/g creatinine < 300 mg/g creatinine

Macroalbuminuria

UACR ≥ 300 mg/g creatinine

-29% in albuminuria vs placeboafter 24 weeks’ treatment**

Proven renal safety with potential for additional kidney benefit– Mean GFR remains unchanged after treatment initiation with linagliptin up

to 24 weeks

-29% in albuminuria vs placeboafter 24 weeks’ treatment**

Albuminuria Lowering by Linagliptin is independent of the Improvement in Glucose

Linagliptin significantly lowers albuminuria on top of recommended standard treatment for diabetic nephropathy

1. Inclusion criteria: Stable ACE/ARB background; albuminuria 30−3000 mg/g creatinine; GFR > 30.*Albuminuria-lowering evidence for linagliptin will emerge from MARLINA 1218.89.

**ADA 2012, 953-P

Adjusted mean change in albuminuria(24 weeks)1

24 weeks’ treatmentEffect of linagliptin on albuminuria in humans*

n

95% CI

59

-20%, +23%

168

-42%, -22%

Placebo Linagliptin

-4%

-33%

-29%p < 0.05

Albuminuria:

Early marker for renal damage

Marker for endothelial dysfunction

Cardiovascular risk factor

Lowering of albuminuria is associated with kidney & CV protection

Definitions

Microalbuminuria

UACR ≥ 30 mg/g creatinine < 300 mg/g creatinine

Macroalbuminuria

UACR ≥ 300 mg/g creatinine

-29% in albuminuria vs placeboafter 24 weeks’ treatment**

Proven renal safety with potential for additional kidney benefit– Mean GFR remains unchanged after treatment initiation with linagliptin up

to 24 weeks

-29% in albuminuria vs placeboafter 24 weeks’ treatment**

Possible mechanism: The reno-

protective effect of linagliptin as

studies in preclinical modelInhibition of podocyte damage and

Inhibition of myofibroblast

transformation

Increased GLP-1 receptor

expression

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Extreme Hyperglycemia in CKDExtreme Hyperglycemia in CKD

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Case HistoryCase History

• 67 yrs old male in altered sensorium• Type 2 Diabetes, CAD • On OHA for the past 5 y• Fever,Dysuria – 7 d• Pain abdoment -1 d• Altered sensorium – 12 h• On Glimepride, Metformin ,Metoprolol,

Losartan, eplerenone,Asprin,atorvastatin

Phy ExaminationPhy Examination

• Significant volume depletion• FEBRILE -101,RR 19 /PM• BP -100/70• JVP-Collapsed• S1,S2 FAINT, Lung Bases - clear• Abdomen- Left Lumbar area tender • Catheter draining turbid urine• Drowsy, Neck supple,No FND,Plantar –

Flexor Bil

LabLab

• Urine – Pus cells +++, Bacteria ++• Hb – 9.8, TC – 18,300. P 84,L14,E2• B.Sugar- 604, B Urea – 87,S.Creat-2.3• Na -147,K – 6.2,Cl – 112, HCO3 – 18.PCO2- 35,pO2 -90• Ketone body – neg• ABG - P H – 7.32

Pyuria Hyperglycemia Azotemia HyperNa,HyperK,Met.Acidosis

3 major grades of insulin deficits 3 major grades of insulin deficits

WHY IS HE NOT WHY IS HE NOT KETONEMICKETONEMIC

Calculated osm

ECF hyperosmolality produces ICF ECF hyperosmolality produces ICF dehydrationdehydration

RF PREVENTS GLYCOSURIA

ICF ECF

Na , GK, P

Urea Water

Ethanol

Insulin lack and hyperosmolality drives K outside

60 kg / 10% Deficit/Na 147 60 kg / 10% Deficit/Na 147

6 / 3L

1 L/I hr

0.45%Sal.

H2O /po

Insulin therapy Insulin therapy

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Hemodialysis for severe Hemodialysis for severe hyperglycemia in CKDhyperglycemia in CKD

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Extreme hyperglycemia with ketoacidosis and hyperkalemia in a patient on chronic hemodialysis.Hemodial Int. 2008 Oct ;12 Suppl 2:S43-7.

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CAPD patientCAPD patient

• Dialysate contains • Glucose in high• Concentration

• Hyperglycemia severe and common

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Icodextrin use in diabetic patientIcodextrin use in diabetic patient• Icodextrin is

Polymer of Glucose• False high reading of

Blood Glucose if • GDH/PQQ strips

are used • Risk of iatrogenic

hypoglycemia due to misdiagnosis and over reaction

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Renal Transplantation.Renal Transplantation.

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Post transplant DiabetesPost transplant Diabetes

• Tacrolimus• Cyclosporine• Steroids• CMV• HCV • Metabolic syndrome

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45 yrs female , Renal TX in 45 yrs female , Renal TX in MMHRC at 1999.Presents with MMHRC at 1999.Presents with proteinuria , edemaproteinuria , edema

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Arteriolar hyalinosisArteriolar hyalinosis

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Hypoglycemia Vs Hyperglycemia in Hypoglycemia Vs Hyperglycemia in CKD- Tight rope walk!CKD- Tight rope walk!

If he falls your reputation also falls !!