Diabetes and Renal Disease

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Diabetes and Renal Disease

• Dr Anne Kleinitz
• KRSS GP
• 12/11/2009

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Learning Objectives

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

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Type 1 Vs Type 2 DM
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• 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

• Immune destruction of insulin producing cells in
  pancreas
• leading to insulin deficiency.
• Prevalence
• General population 12 17
• Indigenous 1
• Acute onset, usually early in life

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Type 2

• Tissue resistance to insulin defects in insulin
  secretion
• Gradual onset. One end of spectrum
• Insulin resistance but normal glucose tolerance
• Impaired fasting glucose (IFG)
• Impaired glucose tolerance pre-diabetes (IGT)
• Type 2 DM

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Q. More common in T2 than T1?

• Age lt 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?

• Age lt 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
• gt 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
CDCs Division of Diabetes Translation. National
Diabetes Surveillance System available at
http//www.cdc.gov/diabetes/statistics
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1994
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1995
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1996
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1997
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1998
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1999
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2000
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2001
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2002
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2003
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2004
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2005
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2006
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2007
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Childhood Diabetes

• Rising T2DM, parallel with ? obesity
• 10-14 of new paediatric DM
• 50 in rural and remote
• Many likely undiagnosed
• Indigenous children disproportionately
  represented
• gt ½ of children with T2DM are indigenous
• Mx Diet, exercise, Metformin and Insulin

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Gestational 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 SyndromeSyndrome X

• Associated with increased risk of CVD, CKD and
  death.
• DIAGNOSIS
• Insulin resistance
• FBG gt 5.6 or T2DM
• Central Obesity
• WC gt 94cm
• Abnormal lipid profile HDL
• Male lt 1.03, Female lt 1.29
• Hypertension
• Sys gt 130, dias gt85

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Treatment Options
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Treatment 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 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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Short-acting Long-acting Insulin
Breakfast
Lunch
Dinner
Short acting
Plasma insulin
Glargine
400
1600
2000
2400
400
800
1200
800
Time
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Aims in Mx (KAMSC Chronic Disease Protocol)

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

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Multidisciplinary Team Care

• Diabetes
• Endocrinology/Dietetics
• Microvascular Disease
• Ophthalmology/Nephrology/Podiatry
• Macrovascular Disease
• Vascular Surgery/Cardiology

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Specialised Treatments

• Insulin Pump
• Tight BSL control for brittle diabetes
• Awaiting autofeedback sensors
• Pancreas Transplantation
• Insulin independence
• Operative mortality

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Diabetic Complications
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Diabetic Complications

• Microvascular
• Retinopathy
• Nephropathy
• Neuropathy
• peripheral autonomic
• Macrovascular
• Cerebrovascular
• Cardiovascular
• Peripheral vascular

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Natural History of Type I

• 5 stages
• 1. Hyperfiltration at diagnosis (low s. creat)
• 2. Microalbuminuria gt 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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Natural 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 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 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 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 Factors

• DM Type Duration
• 20 of Type I after 20 years
• 40 of Type II any duration
• Poor diabetic control
• Hypertension
• Aboriginal gt Indian gt Caucasian
• Smokers
• Family history

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Nephropathy Risk Factors

• Modifiable
• HbA1c, BP total cholesterol (Odds Ratio 43)
• Obesity, smoking
• Non-modifiable
• Age, ethnicity, male sex

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Delaying Complications

• Tight diabetic control
• Prevention of microvascular Cmplx
• Risk of hypos
• Tight BP control
• Prevention and management of micro macro Cmplx
• Use ACEI, ARBs or both combined

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ACE Inhibitors can prevent progression of renal
failure
Normotensive Type 2 Diabetics
400
110
Proteinuria (mg/day)
Initial GFR
350
105
320
Placebo
100
280
Enalapril
240
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200
90
160
Placebo
Enalapril
85
120
80
80
0
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2
3
4
5
6
0
1
2
3
4
5
6
Years
Years
Ann Intern Med 118 577-581.1993
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ACEI/ARB Proteinuria Remission
Protein/Creat Ratio - Urine
1000
mg/mmol
500
H


0
2000
2001
2002
Jan 2000
Creatinine - Plasma
H


H


90
80
70
umol/L
60
50
L


L


40
30
2000
2001
2002
Jan 2000
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Use 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 diabetic CKD at
presentation ?

• Haematuria
• Small scarred kidneys
• Progress to ESKD in lt2yrs
• Associated retinopathy
• ß-blockers better than ACE-I Rx

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

• Haematuria NO
• Small scarred kidneys NO
• Progress to ESKD in lt2yrs NO
• Associated retinopathy YES
• ß-blockers better than ACE-I Rx NO

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Diabetes 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?

• 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 I

• Target HbA1c lt 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 lt 7 on
  Met or OHA alone)

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Strict 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 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 lt30 but
• Risk of fatal lactic acidosis if unwell

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Glitazones in DM

• Av.1 fall in HbA1c as monoRx or add-on
• Preserves beta-cell fn - use early
• Durable effect gt3yrs
• 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 stage

• ½s (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 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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Combination ACEI/ARBs ? proteinuria by 90
Laverman Kidney Int 2002
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ACEI/ARB Proteinuria Remission
Protein/Creat Ratio - Urine
1000
mg/mmol
500
H


0
2000
2001
2002
Jan 2000
Creatinine - Plasma
H


H


90
80
70
umol/L
60
50
L


L


40
30
2000
2001
2002
Jan 2000
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Use 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 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 You

• Questions ?

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References

• 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. Murtaghs General Practice. 4th edition.
  2007

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