Transcript Renal Protection From Bench to Bedside

Derby Nephrology Research
Management of Chronic Kidney
Disease in Primary Care
Maarten Taal
Consultant Renal Physician
Derby City General Hospital
Topics
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CKD Classification
Estimated GFR
Proteinuria
Slowing CKD progression
Cardiovascular Risk in CKD
Complications of CKD – anaemia and bone
disease
• Drugs in CKD
• CKD in Primary Care and when to Refer
• Renal Risk in Derby (R2ID) Study
Prevalence of CKD: NHANES
1999-2004
CKD 5
0.4%
CKD 4
CKD 3
5.4%
CKD 2
5.4%
CKD 1
5.7%
Total
16.8%
n=12,785
MMWR Morb Mortal Wkly Rep. 56:161; 2007
CKD Prevalence in the UK
• NEOERICA
• CKD stage 3-5 among 130,226
patients registered with GPs in Kent,
Manchester and Surrey
• Age-standardized prevalence:
males: 5.8% females: 10.6%
Stevens PE et al. KI 72:92; 2007
Measurement of renal function
Glomerular filtration rate
• The GFR (commonly expressed as mL/min)
is a measure of the blood volume filtered
by the kidney
• Accurate measurement is important for
assessment of the severity of renal
disease
Common clinical measures
• Serum creatinine
– Creatinine metabolite of creatine in
skeletal muscle
– Tubular excretion in proximal tubule (i.e.
not all is from passive filtration)
– Concentration dependant on renal
function, diet, muscle mass, age, gender,
ethnic background), affected by some
drugs
– NICE recommends 12h meat fast
Serum creatinine
• Advantages
– Simple to carry out
– Cheap
– Good serial measure
• Disadvantages
– Not accurate measure of GFR
– Non-linear relationship to GFR
Abnormal renal function
Creatinine clearance
• Combining urinary clearance and
serum creatinine
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GFR = U x V / P
U = urinary concentration
V = urinary volume
P = plasma concentration
Creatinine clearance
• Advantages
– More accurate than serum creatinine
– Combine with other tests (e.g protein)
• Disadvantages
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Costly
Inconvenient
Subject error
Secretion of creatinine is dependent on renal
function
– Not corrected for body surface area
Formulae to estimate GFR
• Cockcroft-Gault – not corrected for BSA
– (140-age) *LBW (kg) *1.22 / S Cr (umol/L)
(male)
– (140-age) *LBW (kg) *1.04 / S Cr (umol/L)
(female)
• Modified MDRD – corrected for BSA
– 2.59 x ((serum creatinine (umol/L)) exp[-1.154])
x (Age exp[-0.203]) x (0.742 if female) x (1.21
if African American)
Estimated GFR
MDRD formula:
2.59 x ((serum creatinine (umol/L)) exp[-1.154])
x (age exp[-0.203])
x (0.742 if female)
x (1.21 if African American)
Copyright ©2007 BMJ Publishing Group Ltd.
Giles, P. D et al. BMJ 334:1198-1200; 2007
MDRD formula: Limitations
• Underestimates GFR for values >60ml/min
• Variation in creatinine assays
• Not adequately validated in:
– Ethnic groups other than African American
– Elderly
– Extremes of body habitus
MDRD Formula: Solutions
• Standardise creatinine assays (National
External Quality Assurance Scheme)
• Modification of formula
• Do not report eGFR if >60ml/min
• Creatinine clearance or isotope GFR if
GFR>60
• Validation in different ethnic groups
• New formulae
• New markers – cystatin C
Proteinuria – detection and
monitoring
• Dipstick potentially misleading
• Albuminuria vs. Proteinuria
Albuminuria - Definitions
mg/day
mg/min
ACR
(mg/mmol)
<30
<20
Microalbuminuria
30-300
20-200
Overt
Albuminuria
>300
>200
<2.5 (m)
<3.5 (f)
>2.5 (m)
>3.5 (f)
>30
Normal
Proteinuria - Definitions
g/day
mg/mg
mg/mmol
Normal
<0.15
<0.2
<20
Mild
0.15-1.0
0.2-1.0
20-100
Moderate 1.0-3.5
1.0-3.5
100-350
Severe/
>3.5
Nephrotic
>3.5
>350
CKD Management Goals
• Slow progression of CKD
• Reduce Cardiovascular Risk
• Detect and treat complications of CKD
– Ca and phosphate
– Anaemia
• Avoid drug toxicity
• Appropriate referral
CKD Progression
0.008
0.007
FSGS
1/creatinine
0.006
0.005
0.004
0.003
0.002
Hypertension
Proteinuria
0.001
0
0
6
12
18
24
30
36
time (months)
42
48
54
60
CKD Progression - 2009
Systemic Hypertension
 Pgc
 SNGFR
1°Renal
Disease
Mechanical Stress
Nephron
Loss
Ang II
Proteinuria
Macrophages
Fibroblasts
2° FSGS
and TIF
TGF-
Cytokines
CAMs
Interventions for Slowing
CKD Progression
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Lower BP to <130/80mmHg
ACEI or ARB as first line
Minimise proteinuria (<1g/day)
Weight loss if obese
Smoking cessation
Interventions to Slow CKD Progression
Systemic Hypertension
 Pgc
 SNGFR
1°Renal
Disease
Treat
Hypertension
Weight loss
 Dietary Protein
Mechanical Stress
Nephron
Loss
Inhibit
RAS
Ang II
Proteinuria
Treat
Dyslipidaemia
Stop
Smoking
2° FSGS
and TIF
Macrophages
Fibroblasts
New
Anti-inflammatory
Anti-fibrotic
 Proteinuria
TGF-
Cytokines
CAMs
CV Risk in CKD
Age-Standardized Rates of Cardiovascular Events According to the Estimated GFR among
1,120,295 Ambulatory Adults
Go, A. S. et al.
NEJM 2004;351:1296-1305
Reducing CV Risk in CKD
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Control hypertension (<130/80mmHg)
ACEI or ARB as first choice
Treat dyslipidemia as for “high risk”
Smoking cessation
Aspirin for diabetics and ?others
Ca and phosphate control
Vitamin D Metabolism
UV light
7-dehydrocholesterol
Diet
Cholecalciferol
Liver
25OH-Cholecalciferol
Kidney
Prox Tubule Cells
Ca absorption in
Small intestine
1,25OH-Cholecalciferol
Calcium and Phosphate in CKD
• Failure of 1-hydroxylation of vitamin
D results in decreased intestinal Ca
absorption  hypocalcaemia
• Failure of renal phosphate excretion
 hyperphosphataemia
2° Hyperparathyroidism
 PTH
Bone
Reabsorption
 Phosphaturia
 Ca
 Phosphate
Renal
Failure
Consequences of Ca / P and
PTH Abnormalities
• Renal Osteodystrophy
– High turn-over: Osteitis fibrosa cystica
– Low turn-over: Adynamic bone disease
• Vascular calcification
• Increased mortality
• Other PTH effects
–  response to epoetins
–  immune response
Mean Coronary Calcium Score
Coronary Calcification
2500
No CAD
CAD
Dialysis
2000
1500
1000
500
0
28-39
40-49
50-59
60-69
Age (years)
Adapted from Braun J et al. Am J Kid Dis. 1996;27:394-401.
Ca x P and Survival on HD
1.2
1.0
.8
.6
Ca x P
> 5.50
.4
5.00-5.49
3.65-4.99
.2
-200
< 3.64
0
200
400
600
800
Survival (days)
1000
1200
1400
Taal et al.
Kidney Int
2003
Management of Ca /P Abn
• Phosphate control
– Dietary restriction
– Phosphate binders (CaCO3, Ca acetate, AlOH
sevelamer, lanthanum)
• 1- cholecalciferol replacement
– Increases intestinal Ca absorption
– Directly suppresses parathyroids
• Calcimimetics (cinacalcet)
– Modulate calcium sensing receptor
Erythropoietin
• EPO = main regulator of normal
erythropoiesis
• Primary source of EPO = kidney (90%)
• Primary site of EPO production =
renal peritubular capillary endothelial
cells ± interstitial fibroblasts
• Tissue hypoxia   EPO
Anaemia in CKD
• Is an important contributor to
symptoms of CRF:
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Tiredness and lethargy
Dyspnoea
Poor concentration /Memory
Anorexia
• Typically normochromic, normocytic
• Due primarily to deficient renal
production of erythropoietin
Anaemia management in CKD
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Correct iron deficiency (IV iron)
Treat inflammation
Treat hyperparathyroidism
Recombinant Epoetins – s.c. or i.v.
Target haemoglobin 10.5-12.5g/dl
Drug Toxicity in CKD
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NSAIDs
K-sparing diuretics
Trimethoprim
Metformin (avoid in GFR<40ml/min)
Gabapentin; Pregabalin
Opiates
ACEI or ARB in CKD - safety
Creatinine rise
• Predicts greater renoprotective efficacy
• Allow up to 30%  if not progressive
• Contraindicated in bilateral RAS
• Omit diuretics for 1-2 days
• Avoid NSAIDs
• Start low dose
• Check serum creatinine at 1 week
ACEI or ARB in CKD - safety
Hyperkalaemia
• Incidence of uncontrolled
hyperkalaemia 0-4% in 6 large studies
• Dietary advice
• Avoid K-sparing diuretics
High Potassium Foods
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Bananas, Oranges, Strawberries
Tomatoes, Sprouts
Jacket Potatoes, Chips, Crisps
Coffee, Chocolate, Nuts
Beer, Wine
“Lo-Salt”
Chronic diseases with
cardiovascular component
• Diabetes
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Lifestyle
Blood pressure
Cardiovascular risk
Glycaemic control
• CKD
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Lifestyle
Blood pressure
Cardiovascular risk
Specific measures
• IHD and
Cerebrovascular
– Lifestyle
– Blood pressure
– Cholesterol
Quality and Outcomes
Framework
• CKD 3-5 register
• CKD BP recorded
• CKD BP<140/85
• CKD+HT on ACEI/ARB
• DM BP recorded
• DM BP<145/85
• DM screen for albuminuria
• DM+albuminuria on ACEI/ARB
• DM eGFR/creatinine checked
Total
6
6
11
4
3
17
3
3
3
56 (1000)
When to refer
– stage
4 and 5 CKD (with or without diabetes)
– higher levels of proteinuria (ACR ≥ 70 mg/mmol, PCR ≥
100 mg/mmol, or urinary protein excretion ≥ 1 g/24 h)
unless known to be due to diabetes and already
appropriately treated
– proteinuria (ACR ≥ 30 mg/mmol, PCR ≥ 50 mg/mmol, or
urinary protein excretion ≥ 0.5 g/24 h) together with
haematuria
– rapidly declining eGFR (> 5 ml/min/1.73 m2 in 1 year,
or > 10 ml/min/1.73 m2 within 5 years)
– hypertension - poorly controlled despite the use of
at least four antihypertensive drugs at therapeutic doses
– people with, or suspected of having, rare or genetic
causes of CKD
– suspected renal artery stenosis
Who to Test for CKD
– diabetes
– hypertension
– cardiovascular disease (ischaemic heart
disease, chronic heart failure, peripheral vascular
disease and cerebral vascular disease)
– structural renal tract disease, renal calculi
or prostatic hypertrophy
– multisystem diseases with potential kidney
involvement – for example, systemic lupus
erythematosus
– family history of stage 5 CKD or hereditary
kidney disease
– opportunistic detection of haematuria or
proteinuria.
www.derby-cvsuccesszone.co.uk
Renal Risk in Derby (R2ID) Study
• Cohort study of patients with CKD 3
• Based in Primary Care
• Important unanswered questions:
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Characteristics of patients on CKD registers?
Risk of GFR decline in individual patients?
Cardiovascular risk in CKD?
Urine protein versus albumin to creatinine
Role of salt intake in CKD progression
R2ID Protocol
• 2300 patients with CKD stage 3
• Comprehensive clinical assessment
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Medical and Social History
Sodium intake questionnaire
Anthropomorphic measurements
Blood and urine biochemistry (urine ACR and PCR)
Skin AGE levels
Arterial pulsewave velocity
• Feedback letter to GP
2
R ID
Protocol
• Repeat clinical assessment at 1 year
• Collect data regarding outcomes at
year 2, 5 and 10:
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Change in GFR
ESRD
Cardiovascular events
Death (via Med Research Info Service)