Management of Stage 3 Chronic Kidney

Disease (CKD) in General Practice

Dr. Valli Manickam

Renal Physician

Objectives:

• Statistical data about CKD • Target values in ESKD• When to Refer patients

400

500

600

700

800

900

1000

ES

KD

ser

vice

s ($

mill

ions

)

Steady state Linear growth

Steady state 559.9 640.1 688.0 724.5 754.5 782.3 811.3

Linear growth 559.9 652.5 712.9 763.8 808.6 852.5 899.1

2004 5 6 7 8 9 2010

Cass et al Kidney Health Australia Report 2006

Projected annual ESKD costs

Why worry about CKD & ESKD?

ESKD has a life expectancy between that of Colon Cancer & Lung Cancer

29.9

21.6

9.6 9.86.9

5.32.7 2.6

0

5

10

15

20

25

30

35

45-54 55-64Age

Est

imate

d Y

ears

of

Lif

e R

emain

ing

US General

Colon cancer

ESKD

Lung cancer

USRDS 2001

ESKD and Cardiovascular Mortality

Foley et al AJKD 1996

Cre

ati

nin

e C

lear

anc

e (m

l/min

)

Residual Renal

Function

Timely Start ?

25

30

20

10

15

5

0

Late Referral

Early Referral

Why be interested? – Slowing progression

Stage DescriptionGFR

(ml/min/1.73 m2)

1 Kidney Damage with Normal or GFR

>90 (with proteinuria)

2 Kidney Damage withMild GFR 60-89

3 Moderate GFR 30-59

4 Severe GFR 15-29

5 Kidney Failure <15 or(or dialysis)

CKD Definitions

Adapted from Am J Kidney Dis 2002; 39 (2, Suppl. 1): S17-S31 and using AusDiab data

Stage 5 – kidney failure

Stage 1-3

Stage 4 – GFR <30

1.7 MILLION

30,000

4.5+ MILLION AT RISKHypertension or diabetes

16,000

Kidney Disease in AustraliaThe titanic/iceberg model 

AusDiab data, 2005

Adults over 25 years of age

CKD and the risk of death,CV events and hospitalisation

Go et al N Engl J Med 2004; 351:1296-1305

N = 1,120,295 Kaiser Permanente Renal Registry

All cause mortality Cardiovascular mortality

Outcomes in patients with CKDKaiser Permanente Longitudinal Study

0

10

20

30

40

50

89-60 89-60(prot) 30-69 29-15

GFR (ml/min)

Eve

nt

(%)

Death

Dialysis/Tx

Keith et al Arch Int Med 2004

n = 27988, FU = 66 mo

Patients with CKD are 20 times more likely to die from cardiovascular events than survive to reach dialysis

GFR and Ageing

6.3

28.5

65

87.2

0102030405060708090

100

20-39 40-59 60-79 >80

Age

Prevalence of eGFR < 60 ml/min in popn

NHANES III

0

10

20

30

40

50

60

70

80

90

100

25-34 35-44 45-54 55-64 65-74 74-85 >85

age groups

ml/

min

Estimated GFR (MDRD)Median and interquartile range

GFR declines by 5-8mL/min/1.73m2 each decade

With CKD

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)

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 - 6.7 mmol/L: TG - 4.05 mmol/L• FBC normal• UA trace protein, no RBC, no WBC

Bruce the Battler

a. The absence of significant proteinuria makes diabetic kidney disease extremely unlikely

b. Quantitation of proteinuria will give important prognostic information

c. He should not be started on an RAS inhibitor* to slow progression of kidney disease as he has worsening kidney function

d. His smoking will worsen his kidney function

e. Lipid lowering therapy has been proven to slow progression of kidney disease

*ACE/ARB

Question 1: Answer True or False

a. 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. 2005 Sep;30(3):161-77

Question 1

b. 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

Question 1

Risk of ESKD related to baseline proteinuria (dipstick) over 18 year period

Iseki et al, Kidney Int 2003;63:1468-1476

N= 106,000

Macroalbuminuria is a better marker than GFR in predicting loss of kidney function

PREVEND Study J Am Soc Nephrol 2006; 17:2582–2590.

Macroalbuminuria

N=8952 – F/U 4yrs

General Population + RBC urine

Reduced GFR – mean 45 mL/min/1.73m2

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. 2005 Sep;30(3):161-77

– 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

Albuminuria and GFR predict mortality and morbidity (RR)

Normal Macroalbuminuria GFR

Mortality (RR)CVnon CV

1

1

2.6

1.5

3.4

3.0

Morbidity (RR)CV 1 1.4 2.3

PREVEND Study J Am Soc Nephrol 2006;17: 2582–2590.

c. 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

Question 1

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

– 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

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

0.5

1.5

2.5

3.5

4.5

90-99 80-89 60-69 50-59 40-49

GFR (ml/min)

Numb

er of

BP M

eds

Bakris Et al AJKD 2000;36:646-661

Target blood pressure

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 0.25-1.0 g/day

<130/80 mmHg

Adults with proteinuria >1 g/day (in people with and without diabetes)

< 125/75 mmHg

d. Smoking is associated with kidney damage in the population AusDiab Study• Smoking increases proteinuria and accelerates loss of GFR

Am J Med Sci 2005;330:111-119

Question 1

e. Lipid lowering therapy has been proven to slow progression of kidney function

FALSE

Question 1

• 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 placeboattenuation in rise of serum

creatinine GREACE atorvastatin vs placebo

Atorvastatin increased CrCl 12% placebo decrease in CrCl 5 %

No trials in GFR <40 mL/min/1.73m2

Does treating lipids affect CKD progression?

13.5

16.519

23.9

17

21

24

30.3

0

5

10

15

20

25

30

35

DM- CKD- n=14193

DM- CKD+ n=4099

DM+ CKD- n=873

DM+ CKD+ n=571

Ab

s R

R a

s%

Prava

PBO

Tonelli et al JASN 2005;16:3748

Pravastatin reduces Absolute RR for CV events in DM & CKD – similar benefit seen in all-cause mortality

Median F/U 64m

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

Do you :

a. Cease the ACEi and commence another drug

b. Cease the ACEi and check for a renal artery stenosis

c. Continue the ACEi and check for a renal artery stenosis

d. Add another drug for better BP control

Question 2

My answer:

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)

d. Add another drug for better blood pressure control

Bruce the Battler

Seen 1 month later

– BP 134 / 68 mmHg

– Creatinine 245 umol/L eGFR 23 mL/min– Ca 2.05 mmol/L PO4

1.54 mmol/L– Hb 98 g/L normocytic/normochromic– Urine dipstick normal

What would you do?

a. Refer for erythropoietin treatment

b. Check iron studies

c. Check Vit B12 and folate levels

d. Check Vitamin D and PTH

e. All of the above

Question 3

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)

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;66:753-760

Anaemia is associated with mortality in dialysis patients

• Multiple observational studies show lower Hb associated with adverse outcome

Adjusted RR of death due to any cardiac cause, according to Hct.

Li & Collins, Kidney International 2004;65:626–633

n= 50,579

The target Hb for anaemia in CKD

• Optimal Hb level not known

• Observational – 110 – 120 g/L

• RCT – no benefit above 120 g/L

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.)

Bruce the Battler

Seen 1 month later

– BP 134 / 68 mmHg

– Creatinine 245 umol/l eGFR 23 mL/min– Ca 2.05 mmol/L PO4

1.54 mmol/L– Hb 98 g/L normocytic/normochromic– Urine dipstick normal

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

Increased PO4 is associated with increased mortality even in normal Kidney Function

Tonelli et al, Circulation 2006

S. PO4 mg/dL

Hazard ratio

PO4 and mortality in Dialysis

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]

Changes in serum levels

CKD Stage PTHCalciumPhosphate1,25DGFR

(mL/min/1.73m2)

60-90

30-59

15-30

<15

2

3

4

5

2-fold

2-fold

4-fold

8-fold

Changes Ca/PO4 parameters with reducing GFR

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

Goals of therapy for Ca/PO4 disturbance

• Control s PO4 to <1.65 mmol/L

• Keep s Ca in normal range (2.2-2.6 mmol/L)

• Keeps Ca x PO4 <4mmol/L

• Keep s PTH to ~2-3 times normal

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

Ca++ / PO42- / PTH / Vit D in CKD

Changes by Stage of CKD

Clinical effects

Mechanism for Vit D effect on CVS

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 mg/mmol @ 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

Anyone with an acute presentation and signs of acute nephritis should be regarded as a medical

emergency and referred without delay

Clinical tipWhen referring to a nephrologist ensure patient has had a recent kidney ultrasound, current blood chemistry and quantification of proteinuria

Who does not usually need to be referred to a nephrologist?

Don’t refer CKD Stage 2-3 if:– Stable eGFR 30-89 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.

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

THANK YOU