Management of Chronic Management of Chronic Kidney Disease in Primary Kidney Disease in Primary
Care Care
Maarten TaalMaarten Taal
Consultant Renal Physician Consultant Renal Physician
Derby City General HospitalDerby City General Hospital
Derby Nephrology Research
Topics• 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
CKD 5 0.4%
CKD 4
CKD 3 5.4%
CKD 2 5.4%
CKD 1 5.7%
Total 16.8%
Prevalence of CKD: NHANES 1999-2004
MMWR Morb Mortal Wkly Rep. 56:161; 2007n=12,785
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
Creatinine clearance
• Combining urinary clearance and serum creatinine– 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– 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)
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/mmo
l)
Normal <30 <20 <2.5 (m)<3.5 (f)
Micro-albuminuria
30-300 20-200 >2.5 (m)>3.5 (f)
Overt Albuminuria
>300 >200 >30
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/Nephrotic
>3.5 >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
0.001
0.002
0.003
0.004
0.005
0.006
0.007
0.008
0 6 12 18 24 30 36 42 48 54 60
time (months)
1/cr
eati
nin
e
FSGS
HypertensionProteinuria
CKD Progression - 2009CKD Progression - 2009
Pgc SNGFR
NephronLoss
TGF-Cytokines
CAMs
MacrophagesFibroblasts
2°2° FSGSand TIF
Ang IIMechanical Stress
1°Renal Disease
Proteinuria
Systemic HypertensionSystemic Hypertension
Interventions for Slowing CKD Progression
• Lower BP to <130/80mmHg• ACEI or ARB as first line• Minimise proteinuria (<1g/day)• Weight loss if obese• Smoking cessation
Pgc SNGFR
NephronLoss
TGF-Cytokines
CAMs
MacrophagesFibroblasts
2°2° FSGSand TIF
Ang II
Mechanical Stress
1°Renal Disease
Proteinuria
Systemic HypertensionSystemic HypertensionTreat
Hypertension
Inhibit RAS
Proteinuria
NewAnti-inflammatory
Anti-fibrotic
Weight loss Dietary Protein
Stop Smoking
TreatDyslipidaemia
Interventions to Slow CKD Progression
Go, A. S. et al. NEJM 2004;351:1296-1305
Age-Standardized Rates of Cardiovascular Events According to the Estimated GFR among 1,120,295 Ambulatory Adults
CV Risk in CKD
Reducing CV Risk in CKD
• 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
Cholecalciferol Diet7-dehydrocholesterol
UV light
25OH-Cholecalciferol
1,25OH-Cholecalciferol
Liver
KidneyProx Tubule Cells
Ca absorption in Small intestine
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
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
Adapted from Braun J et al. Am J Kid Dis. 1996;27:394-401.
0
500
1000
1500
2000
2500
28-39 40-49 50-59 60-69
Age (years)
Mea
n C
oro
nar
y C
alci
um
Sco
re
No CADCADDialysis
Coronary Calcification
Ca x P and Survival on HD
Survival (days)
1400120010008006004002000-200
Cu
mu
lativ
e S
urv
iva
l1.2
1.0
.8
.6
.4
.2
Ca x P
>5.50
5.00-5.49
3.65-4.99
<3.64
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:– Tiredness and lethargy– Dyspnoea– Poor concentration /Memory– Anorexia
• Typically normochromic, normocytic• Due primarily to deficient renal
production of erythropoietin
Anaemia management in CKD
• 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
• 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
• Bananas, Oranges, Strawberries• Tomatoes, Sprouts • Jacket Potatoes, Chips, Crisps• Coffee, Chocolate, Nuts• Beer, Wine• “Lo-Salt”
Chronic diseases with cardiovascular component• Diabetes
– Lifestyle– Blood pressure– Cardiovascular risk– Glycaemic control
• CKD– Lifestyle– Blood pressure– Cardiovascular risk– Specific measures
• IHD and Cerebrovascular– Lifestyle– Blood pressure– Cholesterol
Quality and Outcomes Framework
• CKD 3-5 register 6• CKD BP recorded 6• CKD BP<140/85 11• CKD+HT on ACEI/ARB 4• DM BP recorded 3• DM BP<145/85 17• DM screen for albuminuria 3• DM+albuminuria on ACEI/ARB 3• DM eGFR/creatinine checked 3 Total 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.
Renal Risk in Derby (R2ID) Study
• Cohort study of patients with CKD 3• Based in Primary Care• Important unanswered questions:
– 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
– 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
R2ID Protocol
• Repeat clinical assessment at 1 year
• Collect data regarding outcomes at year 2, 5 and 10:– Change in GFR– ESRD– Cardiovascular events– Death (via Med Research Info Service)