1. Diabetes and Renal Disease
Dr Anne Kleinitz
KRSS GP
12/11/2009 1

2. Learning Objectives Type 1 vs Type 2 DM Diabetes Management
Diabetic Complications
Diabetic Nephropathy & ESKD 2

3. Type 1 Vs Type 2 DM 3

4. Type 1 Type 2 Young Older **** Overweight Thin Insulin resistant
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 4

5. Type 1 Type 2 Onset Acute (symptomatic) Slow or insidious
Clinical features
Weight loss
Polyuria
Polydipsia
Obese/over wt
Strong FHx
Ethnicity
PCOS
Ketosis
Often present
Usually absent
Insulin (endog)
Low or absent
Normal or 
Antibodies
+ ve ve
Assoc. autoimmune disorders
Yes No 5

6. 6

7. 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 7

8. 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 8

9. 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 – 11
≥11.1
Random
< 5.5
≥ 11.1 9

10. Q. More common in T2 than T1? Age < 20 years Overweight
High levels of blood insulin
Prone to ketoacidosis
Albuminuria at time of diagnosis 10

11. 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 11

12. Prevalance (estimated) Indigenous
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 ( )
Renal failure is also a common cause of death 12

13. Age-adjusted Percentage of U. S
Age-adjusted Percentage of U.S. Adults Who Were Obese or Who Had Diagnosed Diabetes
Obesity (BMI ≥30 kg/m2)
1994
2000
2007
No Data <14.0% % % % >26.0%
Diabetes
1994
2000
2007
No Data <4.5% % % % >9.0%
CDC’s Division of Diabetes Translation. National Diabetes Surveillance System available at 13

14. 1994
Methodology
The percent of U.S. adults who are obese or who have diagnosed diabetes was determined by using data from the Behavioral Risk Factor Surveillance System (BRFSS, available at An ongoing, yearly, state-based telephone survey of the non-institutionalized adult population in each state, the BRFSS provides state-specific information on behavioral risk factors for disease and on preventive health practices. Respondents who reported that a physician told them they had diabetes (other than during pregnancy) were considered to have diagnosed diabetes. Self reported weight and height were used to calculate body mass index (BMI): weight in kilograms divided by the square of height in meters. A BMI greater than or equal to 30 was considered to be obese. Rates were age-adjusted using the 2000 U.S. Standard Population. 14

15. 1995 15

16. 1996 16

17. 1997 17

18. 1998 18

19. 1999 19

20. 2000 20

21. 2001 21

22. 2002 22

23. 2003 23

24. 2004 24

25. 2005 25

26. 2006 26

27. 2007 27

28. 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
> ½ of children with T2DM are indigenous
Mx – Diet, exercise, Metformin and Insulin 28

29. Gestational diabetes Temporary
Occurs in pregnancy and usually disappears after delivery
Mother has much greater risk of developing diabetes later
Morbidity
Gestational diabetes occurs during pregnancy in about 3–8% of females not previously diagnosed with diabetes. Screening tests for gestational diabetes are usually performed around the 24th–28th week of pregnancy. It is a temporary form of diabetes and usually disappears after the baby is born. However, it is a marker of much greater risk of developing Type 2 diabetes later in life. 29

30. Metabolic Syndrome “Syndrome X”
Associated with increased risk of CVD, CKD and death.
DIAGNOSIS
Insulin resistance
FBG > 5.6 or T2DM
Central Obesity
WC > 94cm
Abnormal lipid profile: HDL
Male < 1.03, Female < 1.29
Hypertension
Sys > 130, dias >85 30

31. Julia Marley’s study 31

32. 32

33. 33

34. Treatment Options 34

35. 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 35

36. Diabetes management Life-style Oral Medications Insulin
 physical activity
Weight ↓
Smoking cessation
Alcohol reduction
Low fat diet
Oral Medications
Increase insulin production (sulphonoureas)
Increase insulin sensitivity (metformin)
Insulin 36

37. Short-acting & Long-acting Insulin
Breakfast
Lunch
Dinner
Short acting
Plasma insulin
Glargine
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time 37

38. Aims in Mx (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 38

39. Multidisciplinary Team Care
Diabetes:
Endocrinology/Dietetics
Microvascular Disease:
Ophthalmology/Nephrology/Podiatry
Macrovascular Disease:
Vascular Surgery/Cardiology 39

40. Specialised Treatments
Insulin Pump
Tight BSL control for brittle diabetes
Awaiting autofeedback sensors
Pancreas Transplantation
Insulin independence
Operative mortality 40

41. Diabetic Complications41

42. Diabetic Complications
Microvascular
Retinopathy
Nephropathy
Neuropathy
peripheral & autonomic
Macrovascular
Cerebrovascular
Cardiovascular
Peripheral vascular 42

43. 43

44. Natural 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 months after CKD 44

45. Stage Diabetes Duration Manifestations 1 0 – 3-5 Renal hypertrophy
 GFR 2
3-5 +
Basement M thickening
Mesangial expansion 3
7-15 +
Microalbuminuria
HPT 4
Proteinuria
↓ GFR 5
15 – 25+
ESKD 45

46. 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 46

47. Hyperfiltration Phase
Elevated GFR 2o ↑BSL/BP/protein/obesity
↑Intra-glomerular pressure
“Too good to be true” serum creatinine
Accelerated progression to CKD 47

48. 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 48

49. Diabetic Nephropathy From haemodynamic & metabolic stresses
deposition of advanced glycosylation end products in connective tissue & sml vessels.
May take yrs but many T2DM asymptomatic for several yrs, hence nephropathy may already be present at Dx 49

50. 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 50

51. Nephropathy 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 51

52. Nephropathy Risk Factors
Modifiable
HbA1c, BP & total cholesterol (Odds Ratio 43)
Obesity, smoking
Non-modifiable
Age, ethnicity, male sex 52

53. Delaying 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 53

54. 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 95
200 90
160
Placebo
Enalapril 85
120 80 80 1 2 3 4 5 6 1 2 3 4 5 6
Years
Years
Ann Intern Med 54

55. ACEI/ARB Proteinuria Remission
Protein/Creat Ratio - Urine
1000
mg/mmol
500 H
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 55

56. 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 56

57. Q. Which features are typical of diabetic CKD at presentation ?
Haematuria
Small scarred kidneys
Progress to ESKD in <2yrs
Associated retinopathy
β-blockers better than ACE-I Rx 57

58. Q. Which features are typical of 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 58

59. 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 59

60. 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 60

61. Strict 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) 61

62. 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% 62

63. 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 <30 but…
Risk of fatal lactic acidosis if unwell 63

64. Glitazones 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 64

65. Strict 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) 65

66. 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 66

67. Combination ACEI/ARBs ↓ proteinuria by 90%
Laverman Kidney Int 2002 67

68. ACEI/ARB Proteinuria Remission
Protein/Creat Ratio - Urine
1000
mg/mmol
500 H
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 68

69. 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) 69

70. 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 70

71. Thank You
Questions ? 71

72. 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. Murtagh’s General Practice. 4th edition. 2007 72