management of stage 3 chronic kidney disease (ckd) in general practice dr. valli manickam renal...
TRANSCRIPT
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