1. Management of Stage 3 Chronic Kidney Disease (CKD) in General Practice
Dr. Valli Manickam
Renal Physician

2. Objectives:
Statistical data about CKD
Target values in ESKD
When to Refer patients

3. Why worry about CKD & ESKD?
Projected annual ESKD costs
400
500
600
700
800
900
1000
ESKD services ($millions)
Steady state
Linear growth
559.9
640.1
688.0
724.5
754.5
782.3
811.3
652.5
712.9
763.8
808.6
852.5
899.1
2004 5 6 7 8 9
2010
Cass et al Kidney Health Australia Report 2006

4. ESKD has a life expectancy between that of Colon Cancer & Lung Cancer
USRDS 2001

5. ESKD and Cardiovascular Mortality
Foley et al AJKD 1996

6. Why be interested? – Slowing progression
Creatinine Clearance (ml/min)
Residual Renal Function
Timely Start ? 25 30 20 10 15 5
Late Referral
Early Referral

7. CKD Definitions 1 2 3 4 5 Stage Description GFR (ml/min/1.73 m2)
Kidney Damage with Normal or  GFR
>90 (with proteinuria) 2
Kidney Damage with
Mild  GFR
60-89 3
Moderate  GFR
30-59 4
Severe  GFR
15-29 5
Kidney Failure
<15 or
(or dialysis)
Adapted from Am J Kidney Dis 2002; 39 (2, Suppl. 1): S17-S31 and using AusDiab data

8. Kidney Disease in Australia
The titanic/iceberg model
Adults over 25 years of age
Stage 5 – kidney failure
Stage 1-3
Stage 4 – GFR <30
1.7 MILLION
30,000
4.5+ MILLION AT RISK
Hypertension
or diabetes
16,000
AusDiab data, 2005

9. CKD and the risk of death,CV events and hospitalisation
All cause mortality
Cardiovascular mortality
N = 1,120,295
Go et al N Engl J Med 2004; 351:
Kaiser Permanente Renal Registry

10. Outcomes in patients with CKD Kaiser Permanente Longitudinal Study
n = 27988, FU = 66 mo
Patients with CKD are 20 times more likely to die from cardiovascular events than survive to reach dialysis
Keith et al Arch Int Med 2004

11. Estimated GFR (MDRD) Median and interquartile range
GFR and Ageing
Estimated GFR (MDRD) Median and interquartile range
Prevalence of
eGFR < 60 ml/min in popn
GFR declines by 5-8mL/min/1.73m2 each decade
NHANES III

12. Bruce the Battler
With CKD 12

13. Bruce the Battler Oral hypoglycaemics
Mr Bruce Battams seen 02/08
74 yo, retired
Smoker – 20 / day, alcohol - 30 g/day
Hypertension – 20 years
DM2 – 5 years
Oral hypoglycaemics
Diverticular disease
Infra-renal AAA – 4 cm
Incidental finding on CT for abdo pain
Stress echo - no inducible ischaemia
Medications: amlodipine, pravastatin, gliclazide, aspirin (low-dose) 13

14. Bruce the Battler BP 190 / 84 mmHg Peripheral pulses present
Murmur Aortic Sclerosis
eGFR mL/min/1.73m2
Creatinine 160 umol/L 37 [on 02/08]
115 umol/L 57 [on 09/07]
Chol mmol/L: TG mmol/L
FBC normal
UA trace protein, no RBC, no WBC 14

15. Question 1: Answer True or False
The absence of significant proteinuria makes diabetic kidney disease extremely unlikely
Quantitation of proteinuria will give important prognostic information
He should not be started on an RAS inhibitor* to slow progression of kidney disease as he has worsening kidney function
His smoking will worsen his kidney function
Lipid lowering therapy has been proven to slow progression of kidney disease
*ACE/ARB 15

16. Question 1 Mechanism not well understood
The absence of significant proteinuria makes diabetic kidney disease extremely unlikely
FALSE
20-30% of diabetic patients may have chronic kidney disease without evidence of proteinuria
Mechanism not well understood
Likely to progress with time
Minerva Endocrinol Sep;30(3):161-77 16

17. Question 1
Quantitation of proteinuria will give important prognostic information
TRUE
Increasing degrees of proteinuria lead to increasing risk of ESKD
Proteinuria a stronger marker of risk of progression to ESRD than baseline GFR
But eGFR strong predictor of morbidity and mortality
Reduction of proteinuria in proteinuric disease predicts reduced mortality and reduced progression to ESKD 17

18. Risk of ESKD related to baseline proteinuria (dipstick) over 18 year period
Iseki et al, Kidney Int 2003;63: 18

19. Macroalbuminuria is a better marker than GFR in predicting loss of kidney function
N=8952 – F/U 4yrs
Reduced GFR –
mean 45 mL/min/1.73m2
General Population + RBC urine
Macroalbuminuria
PREVEND Study J Am Soc Nephrol 2006; 17:2582–2590. 19

20. Mechanism not well understood
Recommended Targets in CKD
Proteinuria and ESRD:
20-30% of diabetic patients may have chronic kidney disease without evidence of proteinuria
Mechanism not well understood
Likely to progress with time
Minerva Endocrinol Sep;30(3):161-77

21. But eGFR strong predictor of morbidity and mortality
Increasing degrees of proteinuria lead to increasing risk of ESKD
Proteinuria a stronger marker of risk of progression to ESRD than baseline GFR
But eGFR strong predictor of morbidity and mortality
Reduction of proteinuria predicts reduced mortality and reduced progression to ESKD

22. Albuminuria and  GFR predict mortality and morbidity (RR)
Normal
Macroalbuminuria
 GFR
Mortality (RR) CV
non CV 1
2.6
1.5
3.4
3.0
Morbidity (RR)
1.4
2.3
PREVEND Study J Am Soc Nephrol 2006;17: 2582–2590. 22

23. Question 1
He should not be started on an RAS inhibitor to slow progression of kidney disease as he has worsening kidney function
FALSE
RAS inhibitors beneficial in decreasing mortality in those with GFR < 60 mL/min
RAS preferred agent for BP control in CKD, particularly in those with significant proteinuria 23

24. Risk Stratification - BP
10 mmHg  SBP results in 10.9% increase in RR of ESRD (RENAAL STUDY)
SBP = PP < DBP in prediction of ESRD
PP > SBP > DBP in prediction of mortality
PP > 70 mmHg   risk mortality in SHEP, FHS 24

25. RAS inhibitors beneficial in decreasing mortality in those with GFR < 60 mL/min
RAS preferred agent for BP control in CKD, particularly in those with significant proteinuria

26. Treatment of BP in CKD - ? which agent
ACEi / ARB
independent effect over BP alone
Multiple trials DM
CTS – ACEi
RENAAL – ATII
IDNT – ATII
Non-DM
GISEN
REIN
Bakris Et al AJKD 2000;36:

27. Target blood pressure < 140/90 mmHg <130/80 mmHg
Adults  65 years
(unless there is diabetes and/or renal insufficiency
and/or proteinuria 25 g/day)
< 140/90 mmHg
Adults <65 years and/or
Adults with diabetes and/or
Adults with renal insufficiency and/or
Adults with proteinuria g/day
<130/80 mmHg
Adults with proteinuria >1 g/day
(in people with and without diabetes)
< 125/75 mmHg

28. Question 1 Smoking is associated with kidney damage in the population
AusDiab Study
Smoking increases proteinuria and accelerates loss of GFR
Am J Med Sci 2005;330:

29. Question 1
Lipid lowering therapy has been proven to slow progression of kidney function
FALSE 29

30. Does treating lipids affect CKD progression?
No specific randomised trials
Post hoc analysis of CVD trials
CARE Pravastatin vs placebo
Fall in GFR 0.6 mL/min/1.73m2/yr if GFR < 50 mL/min
2.7 mL/min/1.73m2/yr if GFR < 40 mL/min
greater effect with increasing proteinuria
HPS 40 mg simvastatin vs placebo
attenuation in rise of serum creatinine
GREACE atorvastatin vs placebo
Atorvastatin increased CrCl 12%
placebo decrease in CrCl 5 %
Summary slides of what is known about effect of lipid lowering on renal function in humans
all post hoc subgroup analysis of CVD trials
CARE Cholesterol And Recurrent Events
HPS Heart Protection Study
GREACE Greek Atorvastatin and Coronary heart disease Evaluation
No trials in GFR <40 mL/min/1.73m2 30

31. Pravastatin reduces Absolute RR for CV events in DM & CKD –
similar benefit seen in all-cause mortality
Median F/U 64m
Tonelli et al JASN 2005;16:3748 31

32. Bruce the Battler Commenced on perindopril/indapamide
Seen 2 weeks later and reassessed:
BP 150 / 76 mmHg
Creatinine 189 umol/L (eGFR : 30 mL/min/1.73m2) – Previously Creat 160 umol/L and GFR 37 mls/mt in Feb 2008.
K 5.8 mmo/L
Urine ACR 9 mg/mmol 32

33. Question 2 Cease the ACEi and commence another drug
Do you :
Cease the ACEi and commence another drug
Cease the ACEi and check for a renal artery stenosis
Continue the ACEi and check for a renal artery stenosis
Add another drug for better BP control 33

34. My answer: Add another drug for better blood pressure control
Rationale:
A rise in creatinine of <30% is not unexpected after BP lowering and is a result of decreased perfusion
Target BP in CKD is <130/80 mmHg
ACEi may have particular benefit for kidney disease
K+ needs watching but not a concern at this level (? Give low K+ diet) 34

35. Bruce the Battler Seen 1 month later BP 134 / 68 mmHg
Creatinine 245 umol/L eGFR 23 mL/min
Ca 2.05 mmol/L PO mmol/L
Hb 98 g/L normocytic/normochromic
Urine dipstick normal 35

36. Question 3 What would you do? Refer for erythropoietin treatment
Check iron studies
Check Vit B12 and folate levels
Check Vitamin D and PTH
All of the above 36

37. Bruce the Battler My Answer: e. All of the above Results:
Ferritin 996 Tsat 55%
B12 and folate Normal
TSH Normal
PTH 18 pmol/L (N <8 pmol/L)
Vit D 25 nmo/L (mod deficiency) 37

38. CKD progression - Anaemia
Anaemia due to CKD begins at GFR < 60 mL/min
common when GFR < 30 mL/min (30-40%)
CKD anaemia is a diagnosis of exclusion
Need to ensure not Fe deficient or B12/folate deficient, or hypothyroid
Different reference range for Fe stores if on Erythropoietin
Ferritin > 300 ng/ml Tsat >20%
May respond to iv iron if stores low without need for erythropoietin
I.v. iron gives quicker and higher response than oral (and is better tolerated)
Gouva et al, Kidney Int 2004;66:

39. Anaemia is associated with mortality in dialysis patients
Adjusted RR of death due to any cardiac cause, according to Hct.
n= 50,579
Multiple observational studies show lower Hb associated with
adverse outcome
Li & Collins, Kidney International 2004;65:626–633 39

40. The target Hb for anaemia in CKD
Optimal Hb level not known
Observational – 110 – 120 g/L
RCT – no benefit above 120 g/L

41. CKD & Anaemia Summary Common and important to correct
Can’t start EPO till Hb <100g/L (PBS)
Need to have nephrologist endorsement to start
Ensure not iron deficient
All respond – need to dose titrate
Most self administer SC each 2- 4wks
All will need extra iron (oral or i.v.) 41

42. Bruce the Battler Seen 1 month later BP 134 / 68 mmHg
Creatinine 245 umol/l eGFR 23 mL/min
Ca 2.05 mmol/L PO mmol/L
Hb 98 g/L normocytic/normochromic
Urine dipstick normal 42

43. Why worry about Ca & PO4 in CKD Stages 3-5?
All patients develop Ca/PO4 disturbance (by CKD Stage 5)
Onset of Ca changes is early in CKD
Ca/PO4 disturbance causes
Bone disease
Soft tissue calcification (coronaries & valves)
Pruritus
Proximal myopathy
Premature death

44. Increased PO4 is associated with increased mortality even in normal Kidney Function
Hazard
ratio
S. PO4 mg/dL
Tonelli et al, Circulation 2006

45. PO4 and mortality in Dialysis45

46. Mechanisms of Ca/PO4 disturbance
Phosphate retention with reduced GFR results in increased s PO4 and suppresses Vit D3 production
Reduced Vit D3 leads to reduced Ca absorption and this plus high s PO4 leads to low s Ca
Ca x PO4 increases favouring tissue deposition
PTH stimulated by low Ca, high PO4 & low Vit D3
Clinical effects:
Low s Ca
High s PO4
High s PTH
Low Vit D3 [1,25 (OH)2D3 = calcitriol] 46

47. Changes in serum levels
Changes Ca/PO4 parameters with reducing GFR
Changes in serum levels
CKD
Stage
GFR
(mL/min/1.73m2)
1,25D
Phosphate
Calcium
PTH
60-90 2   
 2-fold 3
30-59   
 2-fold
15-30 4
  
 4-fold
<15 5

 
 8-fold 47

48. Assessment of Ca/PO4 disturbance* (CKD Mineral and Bone disorder)
What to measure
Calcium (corrected for albumin)
Phosphate
Alkaline phosphatase
Bicarbonate
PTH
(Vitamin D3)
How often?
12 monthly in CKD Stage 3
3 monthly in CKD Stage 4
*KDIGO position statement. Kid Intern 2006;69:1945 48

49. Goals of therapy for Ca/PO4 disturbance
Control s PO4 to <1.65 mmol/L
Keep s Ca in normal range ( mmol/L)
Keeps Ca x PO4 <4mmol/L
Keep s PTH to ~2-3 times normal

50. Therapy for Ca/PO4 disturbance
Control s PO4
Dietary restriction
Phosphate binders (prevent uptake)
Control s Ca
Adequate calcium intake
Calcitriol (increases uptake)
Control s PTH
Calcitriol
Cinacalcet
Parathyroidectomy

51. Ca++ / PO42- / PTH / Vit D in CKD
Changes by Stage of CKD
Clinical effects 51

52. Mechanism for Vit D effect on CVS
Fig. 7. Various mechanisms for how vitamin D and its metabolites
25(OH)D and 1,25(OH)2D and active analogs may affect the
cardiovascular system. 52

53. Who may be considered for referral to a nephrologist?
Anyone with
eGFR <30mL/min/1.73m2
Unexplained decline in kidney function (>15% drop in GFR over 3 months)
Proteinuria >1g/24hrs (protein:creatinine ratio of 100 1g/24hrs)
Glomerular haematuria (particularly if proteinuria present)
CKD and hypertension that is hard to get to target
Diabetes with eGFR <60mL/min/1.73m2
Unexplained anaemia (<100g/L) with eGFR <60mL/min/1.73m2
Clinical tip
When referring to a nephrologist ensure patient has had a recent kidney ultrasound, current blood chemistry and quantification of proteinuria
Anyone with an acute presentation and signs of acute nephritis should be regarded as a medical emergency and referred without delay

54. Who does not usually need to be referred to a nephrologist?
Don’t refer CKD Stage 2-3 if:
Stable eGFR mL/min/1.73m2
Minor proteinuria (<0.5g/d with no haematuria)
Controlled blood pressure
In CKD Stages 2-3
Don’t refer to nephrologist if targets of therapy are achieved
Pay attention to CVD risk reduction
Use ACE/ARB
Monitor 3-6 monthly
The decision to refer or not must always be individualised. In younger patients the indications for referral may be less stringent e.g. minor proteinuria and in older patients they may be more selective.

55. Conclusion
Early CKD is so common that it must be mainly managed in general practice
Therapy overlaps significantly with best practice in CV risk reduction and diabetes care
Key CKD management tasks
Lifestyle – Healthy diet & exercise, no smoking, weight control
Reduce CV risk
BP at target with ACE/ARB
Reduce proteinuria with ACE/ARB
Optimise haemoglobin, Ca/P and glycemia

56. THANK YOU