Derby Nephrology Research

Management of Chronic Kidney Disease in Primary Care

Maarten Taal Consultant Renal Physician Derby City General Hospital

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 (R 2 ID) Study

Prevalence of CKD: NHANES 1999-2004 0.4% CKD 5 CKD 4 CKD 3 CKD 2 CKD 1 Total 5.4% 5.4% 5.7% 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 – 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 – (140-age) *LBW (kg) *1.22 / S Cr (umol/L) (male) – (140-age) *LBW (kg) *1.04 / S Cr (umol/L) (female) • Modified MDRD – not corrected for BSA – 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 x ( age exp[-0.203]) x (0.742 if female ) (umol/L)) exp[-1.154]) 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

Normal mg/day <30 Micro albuminuria Overt Albuminuria 30-300 >300 mg/min <20 20-200 >200 ACR (mg/mmol) <2.5 (m) <3.5 (f) >2.5 (m) >3.5 (f) >30

Proteinuria - Definitions

g/day mg/mg mg/mmol Normal Mild <0.15

0.15-1.0

Moderate 1.0-3.5

Severe/ Nephrotic >3.5

<0.2

0.2-1.0

1.0-3.5

>3.5

<20 20-100 100-350 >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

0.006

0.005

0.004

0.003

0.002

0.001

0 0 Hypertension Proteinuria 6 12 18 24 30

time (months)

36 FSGS 42 48 54 60

1 °Renal Disease CKD Progression - 2009

Systemic Hypertension

 Pgc  SNGFR Mechanical Stress Nephron Loss

Ang II

Proteinuria Macrophages Fibroblasts 2 ° FSGS and TIF TGF  Cytokines CAMs

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

Interventions to Slow CKD Progression

Systemic Hypertension

Treat Hypertension 1 °Renal Disease  Pgc  SNGFR  Weight loss Dietary Protein Mechanical Stress Nephron Loss Inhibit RAS

Ang II

Proteinuria Treat Dyslipidaemia Macrophages Fibroblasts  Proteinuria Stop Smoking 2 ° FSGS and TIF New Anti-inflammatory Anti-fibrotic 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

• 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 Ca absorption in Small intestine Cholecalciferol Liver Diet 25OH-Cholecalciferol Kidney Prox Tubule Cells 1,25OH-Cholecalciferol

Calcium and Phosphate in CKD

• Failure of 1 absorption   -hydroxylation of vitamin D results in decreased intestinal Ca 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

2500

Coronary Calcification

2000 No CAD CAD Dialysis 1500 1000 500 0 28-39 40-49 50-59

Age (years)

60-69 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

.4

.2

-200 0 200 400 600 800 Survival (days) 1000 1200 1400 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 (CaCO 3 , 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% • Avoid NSAIDs • Start low dose  if not progressive • Contraindicated in bilateral RAS • Omit diuretics for 1-2 days • 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 • 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 appropriately treated (ACR ≥ 70 mg/mmol, PCR ≥ 100 mg/mmol, or urinary protein excretion ≥ 1 g/24 h) proteinuria (ACR ≥ 30 mg/mmol, PCR ≥ 50 mg/mmol, or urinary protein excretion ≥ 0.5 g/24 h) haematuria rapidly declining eGFR or > 10 ml/min/1.73 m2 within 5 years) hypertension - poorly controlled – people with, or suspected of having, causes of CKD suspected renal artery stenosis together with (> 5 ml/min/1.73 m2 in 1 year, despite the use of at least four antihypertensive drugs at therapeutic doses rare or genetic

– – –

Who to Test for CKD

diabetes hypertension cardiovascular disease (ischaemic heart disease, chronic heart failure, peripheral vascular – – – – or prostatic hypertrophy multisystem diseases erythematosus with potential kidney family history kidney disease of stage 5 CKD or hereditary opportunistic detection proteinuria.

of haematuria or

www.derby-cvsuccesszone.co.uk

Renal Risk in Derby (R 2 ID) 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

R

2

ID 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

R

2

ID 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)