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

Abnormal renal function

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)

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/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

2° Hyperparathyroidism

Renal Failure

Ca

PTH

Phosphate

Bone Reabsorption Phosphaturia

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

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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.

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:

– 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)