11

Diabetes and Diabetes and Renal DiseaseRenal Disease

Dr Anne KleinitzDr Anne Kleinitz

KRSS GPKRSS GP

12/11/200912/11/2009

22

Learning ObjectivesLearning Objectives

• Type 1 vs Type 2 DM• Diabetes Management• Diabetic Complications• Diabetic Nephropathy & ESKD

33

Type 1 Vs Type 2 DMType 1 Vs Type 2 DM

44

Type 1• Young• Thin• Insulin deficient

(pancr. islet cell loss)

• Acute presentation• Ketoacidosis• Insulin initially

Type 2• Older ****• Overweight• Insulin resistant

(excess fat cell mass)

• Delayed diagnosis• Diet & pills• Insulin later or never

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Type 1 Type 2

Onset Acute (symptomatic)

Slow or insidious

Clinical features Weight lossPolyuriaPolydipsia

Obese/over wtStrong FHx EthnicityPCOS

Ketosis Often present Usually absent

Insulin (endog) Low or absent Normal or

Antibodies + ve ve

Assoc. autoimmune disorders

Yes No

66

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Type 1Type 1

• Immune destruction of insulin producing cells in pancreasleading to insulin deficiency.

• Prevalence– General population 12 – 17% – Indigenous 1%

• Acute onset, usually early in life

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Type 2Type 2

• Tissue resistance to insulin + defects in insulin secretion

• Gradual onset. One end of spectrum:– Insulin resistance but normal glucose

toleranceImpaired fasting glucose (IFG)Impaired glucose tolerance “pre-diabetes”

(IGT)Type 2 DM

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Normal IFG IGT Diabetes

Fasting <5.5 5.5 – 6.9 and

< 7 and ≥ 7.0

2 hr post 75g glucose

<7.8 <7.8 7.8 – 11 ≥11.1

Random < 5.5 ≥ 11.1

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Q. More common in T2 than T1?Q. More common in T2 than T1?

• Age < 20 years• Overweight• High levels of blood insulin• Prone to ketoacidosis• Albuminuria at time of diagnosis

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Q. More common in T2 than T1?Q. More common in T2 than T1?

• Age < 20 years NO**• Overweight YES• High levels of blood insulin YES• Prone to ketoacidosis NO• Albuminuria at time of diagnosis YES

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• Prevalance (estimated)– Australia - 7.5% (but ½ unDx!)

• Indigenous– > 25 yrs 10 – 30%– 3 – 4 x higher than general population– Higher in remote communities – Hospital admission for DM more common

• 12 x higher rates eg. Gestational DM

– Contributes to CVD – 67% with DM died of CVD (1997-99)

– Renal failure is also a common cause of death

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Age-adjusted Percentage of U.S. Adults Who Were Obese or Who Had Diagnosed Diabetes

Obesity (BMI ≥30 kg/m2)

Diabetes

1994

1994

2000

2000

2007

2007

No Data <14.0% 14.0-17.9% 18.0-21.9% 22.0-25.9% >26.0%

No Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0%

CDC’s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics

1144

1994

1155

1995

1166

1996

1177

1997

1188

1998

1199

1999

2200

2000

2211

2001

2222

2002

2233

2003

2244

2004

2255

2005

2266

2006

2277

2007

2288

Childhood DiabetesChildhood Diabetes

• Rising T2DM, parallel with obesity• 10-14% of new paediatric DM• ~ 50% in rural and remote• Many likely undiagnosed• Indigenous children disproportionately

represented– > ½ of children with T2DM are indigenous

• Mx – Diet, exercise, Metformin and Insulin

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Gestational diabetesGestational diabetes

• Temporary• Occurs in pregnancy and usually

disappears after delivery• Mother has much greater risk of

developing diabetes later• Morbidity

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Metabolic SyndromeMetabolic Syndrome“Syndrome X”“Syndrome X”

• Associated with increased risk of CVD, CKD and death.

• DIAGNOSIS1. Insulin resistance

• FBG > 5.6 or T2DM

2. Central Obesity • WC > 94cm

3. Abnormal lipid profile: HDL • Male < 1.03, Female < 1.29

– Hypertension• Sys > 130, dias >85

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3322

3333

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Treatment OptionsTreatment Options

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Treatment OptionsTreatment Options

• ↓Glucose load: ↓ meal size & sugars

• ↑Insulin release (“secretogogues”) sulphonourea eg

Gliclazide Insulin, Pancreas Tx

• ↓Insulin resistance (“insulin sensitizers”) Exercise & weight loss

Metformin or glitazones

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Diabetes managementDiabetes management

• Life-style– physical activity– Weight ↓– Smoking cessation– Alcohol reduction– Low fat diet

• Oral Medications– Increase insulin production (sulphonoureas)– Increase insulin sensitivity (metformin)

• Insulin

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4:00 16:00 20:00 24:00 4:00

Breakfast Lunch Dinner

8:0012:008:00

Time

Glargine

Short acting

Pla

sma insu

linShort-acting & Long-acting InsulinShort-acting & Long-acting Insulin

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Aims in Mx Aims in Mx (KAMSC Chronic Disease Protocol)(KAMSC Chronic Disease Protocol)

• HbA1C < 7%• Total cholesterol < 4 mmol/L• HDL > 1mmol/L, TG < 2, LDL < 1.8• BP < 125/80• BMI 17-25• WC < 100 cm• NO smoking• Alcohol – max 2 std drinks/day• Exercise > 20 mins > 4 day/wk• ACR < 3.5 mg/mmol

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Multidisciplinary Team CareMultidisciplinary Team Care

• Diabetes:– Endocrinology/Dietetics

• Microvascular Disease:– Ophthalmology/Nephrology/Podiatry

• Macrovascular Disease:– Vascular Surgery/Cardiology

4400

Specialised TreatmentsSpecialised Treatments• Insulin Pump

– Tight BSL control for brittle diabetes– Awaiting autofeedback sensors

• Pancreas Transplantation– Insulin independence– Operative mortality

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Diabetic ComplicationsDiabetic Complications

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Diabetic ComplicationsDiabetic Complications

• Microvascular– Retinopathy– Nephropathy– Neuropathy

• peripheral & autonomic

• Macrovascular– Cerebrovascular– Cardiovascular– Peripheral vascular

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Natural History of Type INatural History of Type I

5 stages

1. Hyperfiltration at diagnosis (low s. creat)

2. Microalbuminuria > 5-10 years (urine ACR)

3. Overt proteinuria with ↑BP & retinopathy for 2-5 years, minimal haematuria (MSU)

4. CKD with normal-sized kidneys (renal U/S)

5. ESKD 18-24 months after CKD

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Stage Diabetes Duration

Manifestations

1 0 – 3-5 Renal hypertrophy GFR

2 3-5 + Basement M thickeningMesangial expansion

3 7-15 + MicroalbuminuriaHPT

4 15-20 + ProteinuriaHPT↓ GFR

5 15 – 25+ ESKD

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Natural History of Type IINatural History of Type II

• Far commoner than Type I• Long asymptomatic phase• HPT, nephropathy & retinopathy often

present at time of Dx• Degree of proteinuria correlates with

general vascular risk and 20x CKD risk

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Hyperfiltration PhaseHyperfiltration Phase

• Elevated GFR 2o ↑BSL/BP/protein/obesity

• ↑Intra-glomerular pressure

• “Too good to be true” serum creatinine

• Accelerated progression to CKD

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Albuminuria then ProteinuriaAlbuminuria then Proteinuria

• Microalbuminuria first (lower MW)– Raised by ↑GFR (i.e. ↑BSL, ↑protein diet,

fever, exercise)

• Spot urine ACR or PCR– more convenient than 24hr collection– more accurate than urinalysis– adjusts for fluid intake– underestimates the muscular patient

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Diabetic NephropathyDiabetic Nephropathy

• From haemodynamic & metabolic stresses

• Metabolic stress – deposition of advanced glycosylation end

products in connective tissue & sml vessels.

• May take 10-20 yrs but many T2DM asymptomatic for several yrs, hence nephropathy may already be present at Dx

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• 1st clinical sign is microalbuminuria (ACR)• Kidney not able to catabolise albumin• This can also occur transiently with

– Fever– Exercise– Short term hyperglycaemia– High protein meal

• Hence, repeat at a later date/rule out reversible• DM + HPT, x 20 risk of progressive nephropathy• DM + HPT + poor diabetic & lipid control, x 40 risk

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Nephropathy Risk FactorsNephropathy Risk Factors

• DM Type & Duration– 20% of Type I after 20 years– 40% of Type II any duration

• Poor diabetic control• Hypertension• Aboriginal > Indian > Caucasian• Smokers• Family history

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Nephropathy Risk FactorsNephropathy Risk Factors

• Modifiable– HbA1c, BP & total cholesterol (Odds Ratio 43)

– Obesity, smoking

• Non-modifiable– Age, ethnicity, male sex

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Delaying ComplicationsDelaying Complications

• Tight diabetic control– Prevention of microvascular Cmplx

• Risk of hypos

• Tight BP control– Prevention and management of micro &

macro Cmplx– Use ACEI, ARB’s or both combined

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ACE Inhibitors can prevent ACE Inhibitors can prevent progression of renal failureprogression of renal failure

120

160

200

240

280

320

350

400

800 1 2 3 4 5 6

Years

Ann Intern Med 118 577-581.1993

Placebo

Enalapril 85

90

95

100

105

110

800 1 2 3 4 5 6

Years

Placebo

Enalapril

Normotensive Type 2 Diabetics

Proteinuria

(mg/day)

% Initial GFR

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ACEI/ARB Proteinuria ACEI/ARB Proteinuria RemissionRemission

H

L

H

L

30

40

50

60

70

80

90

2000Jan 2000

2001 2002

Creatinine - Plasma

umol

/L

H 0

500

1000

2000Jan 2000

2001 2002

Protein/Creat Ratio - Urine

mg/

mm

ol

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Use of ACEi/ARBsUse of ACEi/ARBs

BUT:• ARF risk if underperfused

• Hyperkalaemia risk with many types of pills (spironolactone)

SO:• Check BP & electrolytes at 1/12 and 6/12• Check all new pills

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Q. Which features are typical of Q. Which features are typical of diabetic CKD at presentation ?diabetic CKD at presentation ?

• Haematuria• Small scarred kidneys• Progress to ESKD in <2yrs• Associated retinopathy• β-blockers better than ACE-I Rx

5588

Q. Which features are typical of Q. Which features are typical of diabetic CKD at presentation ?diabetic CKD at presentation ?

• Haematuria NO• Small scarred kidneys NO• Progress to ESKD in <2yrs NO• Associated retinopathy YES• β-blockers better than ACE-I Rx NO

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Diabetes and ESKDDiabetes and ESKD

• Reducing insulin requirements• Difficult vascular access• Accelerated macrovascular disease• Advanced microvascular disease• Frequent sepsis• Silent ischaemia• 2-3 x death rate vs non-DM patients

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How can DM effect Dialysis?How can DM effect Dialysis?

• Autonomic neuropathy – may suffer hypotension increased by large fluid shift in HD

• Uncontrolled BSLs – may absorb some glucose in PD fluid

• Severe PVD – difficult to get vascular access for HD• PVD may also affect peritoneum and reduce PD

success • Increased risk of infections – problem in both• Transplants – new kidneys develop nephropathy, hence

good glycaemic control important

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Strict BSL Control in early Type IStrict BSL Control in early Type I

• Target HbA1c < 7%• For every 1%↓ HbA1c:

– 10% ↓CVD – 40% ↓Microvascular Cmplx

BUT:• Doubles risk of hypoglycaemia• Loss of control with DM duration:

– 50% at 3yr– 30% at 6yr– 15-25% at 9yr (= % patients with HbA1c < 7% on Met or OHA

alone)

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Strict BSL Control in DM CKDStrict BSL Control in DM CKD

AND:• Minimal benefit if overt proteinuria• Diabetes “cured” by advancing CKD

– reduced appetite and CHO intake– prolonged insulin half-life

– false elevation of HbA1c by 0.5-1%

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Metformin in CKDMetformin in CKD

• No hypos or weight gain• Inexpensive

BUT:– Renally-excreted– Excess doses → anorexia, diarrhoea– Dose adjust to GFR: 2g to 250mg/day– Protocol says

• eGFR 30 – 59 max 1gm/day

• cease when eGFR <30 but…

– Risk of fatal lactic acidosis if unwell

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Glitazones in DMGlitazones in DM

• Av.1% fall in HbA1c as monoRx or add-on• Preserves beta-cell fn - use early • Durable effect >3yrs

BUT:– 1-2/12 delayed onset – Average 4kg SC fat gain, visceral fat loss

– Oedema (Na+/H20, ↑vasc. permeability)

– Expensive

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Strict BP Control at any stageStrict BP Control at any stage

• ½’s (or even stops) rate of fall in GFR• Greater benefit than tight BSL control • Falling BP Target = 120/70 currently• Preferential use of ACEi/ARBs • Complete regression of proteinuria

possible• Helps all micro- & macrovascular disease

(Parving, UKPDS, Captopril Trial, MicroHOPE, IRMA/IDNT, JNC VI)

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Use of ACEi/ARBs: actionsUse of ACEi/ARBs: actions

• Antihypertensive– ↓ by salt excess, ↑by thiazides– need mean of 3 agents in mild CKD

• Antiproteinuric– 30-50%↓ alone, 40-70%↓ together

• Renoprotective– corrects ↑GFR, expected 30% ↑creatinine

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Laverman Kidney Int 2002

Combination ACEI/ARBs ↓ proteinuria by 90%

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ACEI/ARB Proteinuria ACEI/ARB Proteinuria RemissionRemission

H

L

H

L

30

40

50

60

70

80

90

2000Jan 2000

2001 2002

Creatinine - Plasma

umol

/L

H 0

500

1000

2000Jan 2000

2001 2002

Protein/Creat Ratio - Urine

mg/

mm

ol

6699

Use of ACEi/ARBs: risksUse of ACEi/ARBs: risks

BUT:• ON-TARGET – CVD & death if no

proteinuria• Risk of ARF

– Esp. if dry, in CCF, bilateral RAS, on NSAIDs

• Risk of hyperkalaemia in diabetic CKD– Esp. if high fruit/nut/choc diet, acidotic – Esp. if other K+-sparing Rx (NSAIDs,

spironolactone, trimethoprim)

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Use of ACEi/ARBs: guidelinesUse of ACEi/ARBs: guidelines

SO:• Always check BP & electrolytes 1

month after starting or adding thiazide• Check after 1 week in high-risk patients• Stop temporarily if unwell

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Thank YouThank You

Questions ?Questions ?

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ReferencesReferences

• Mark Thomas. Nephrologist. Royal Perth Hospital.

• Kidney Diseases, 5th Edition. National Kidney Foundation. 2009

• Couzos and Murray. Aboriginal Primary Health Care, an evidence based approach. 3rd edition. 2008

• Murtagh. Murtagh’s General Practice. 4th edition. 2007