How to improve outcomes in Chronic Kidney Disease

Paul CockwellConsultant Nephrologist

Queen Elizabeth Hospital Birmingham

CKD is usually present in association with other chronic conditions

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Number of co-morbidities0 1 2 43 65

Heart of Birmingham PCT – Relative risk of death based on known comorbidities

Aims of the lecture

• To discuss risk stratification in CKD

• Outline the current evidence base for the management of CKD

• Discuss the relevance of AKI to CKD

Estimated prevalence of CKD in the UK is 13.5% - based on single tests

– 6% with stage 3-5 CKD (eGFR <60 ml/min)

– 9% with albuminuria

eGFR – brief summary• aMDRD – current internationally accepted standard for reporting

kidney function when the eGFR is abnormal (<60 ml/min)– aMDRD factors 4 variables – age, sex, ethnicity and creatinine – to

provide an eGFR

• Cockroft Gault eGFR – often used for drug dose adjustment– CG and MDRD eGFR are not equivalent

• CKD EPI eGFR – a new generation eGFRs that may supersede MDRD

Beware of the (inaccuracy) of eGFR

eGFR is not accurate when ≥ 60 mL/min

Greatest accuracy at 30–59 mL/min; even then ‘90% of eGFRs within 30% of iGFR’!!

Poggio et al. J Am Soc Nephrol. 2005; 16: 459–4667

The Health improvement Network (THIN): 6.7 million patients from 426 primary care centres in the UK. CKD 3-5 prevalence 2005-2009.

Jain, Calvert, Cockwell, McManus – under review

For patients with an eGFR <60 ml/min delta eGFR is as important

as the overall value

Proteinuria

When the term proteinuria is used people are usually referring to albuminuria

Albuminuria in clinical practice is now measured by a urinary Albumin Creatinine Ratio

An ACR of 100 = an AER of 1g/d

The CKD classification system

The Health improvement Network (THIN): 6.7 million patients from 426 primary care centres in the UK. Age stratified prevalence of CKD 3-5 in 2009.

Jain, Calvert, Cockwell, McManus – manuscript under review

The CKD classification system

O’Hare et al, JASN 2007

eGFR threshold and risk of Death or ESKD

Risk of ESKD in respect of eGFR and proteinuria

ACR < 3mg/mmol

ACR 3-29 mg/mmol

ACR 30+ mg/mmol

Adapted from Levey et al KI 2011

Primary Care CKD

• Risk stratification

• BP management

• Primary and secondary prevention of CVD

• Monitoring

• Referral into and communication with secondary care

Secondary Care - Nephrology

• Manage the established renal failure pathway– Enhanced monitoring and counseling– Prepare for dialysis– Assess for kidney transplantation

• Manage secondary complications of kidney disease– Anemia of CKD (ESA, functional iron deficiency)– Secondary hyperparathyroidism

Secondary Care non-nephrology

• Management of comorbidity

• Drug dosing and toxicity

• Management of AKI

• Sense check for primary care

• Referral to secondary care nephrology

Issue date: September 2008

NICE clinical guideline 73 Developed by the National Collaborating Centre for Chronic Conditions

Chronic kidney disease Early identification and management of chronic kidney disease in adults in primary and secondary care

http://www.nice.org.uk/Guidance/CG73

Overall supporting information for the management of CKD

Minimising the risk for people with CKD of progression of CKD and Cardiovascular disease (CVD)

1. The BP target for non-proteinuric CKD without diabetes is <140/85

2. The BP target for diabetes and CKD is <130/80

3. The BP target for proteinuric CKD (ACR>30) without diabetes is <130/80

4. ACE inhibitors or ARBs should be used in all people with diabetes and with microalbuminuria (ACR>3.5 mg/mmol in men and 2.5 mg/mmol in women) and all people without diabetes with an ACR>30 even if BP<130/80.

5. The dose of ACEi/ARB should be used at the maximum tolerated. ACEi and ARBs should not be used in combination.

6. If there is an eGFR decline of >25% on introduction of an ACEi/ARB or dose increase of an ACEi/ARB then the drug should be stopped and advice should be obtained from secondary care nephrology

7. Primary and secondary prevention of CVD should be optimised; statins, anti-platelet drugs, and warfarin are not contraindicated in CKD.

8. NSAIDs should not be used

Management of complications of CKD

9. People with CKD and a Hb < 10g/dl, who have had other causes of anaemia excluded should be considered for treatment of anaemia associated with CKD. Advice should be obtained from secondary care nephrology.

10. Please refer any uncertainties about bone chemistry through the advice and guidance portal

From: Vanessa MillerSent: Monday, March 05, 2012 1:13 PMTo: Paul CockwellCc: Barbara JoyceSubject: A&G

Please see the attached advice and guidance request.

This young lad came to see me with testicular pain. As part of the assessment I dipsticked his urine which came up as showing marked proteinuria. Subsequent ACR came back as slightly elevated at 6.6. I saw him on a further two occasions and his urine remained positive on dipstick. His renal profile came back normal; creatinine 88, and urea 3.8. CRP was also normal at 10 and he is normotensive with blood pressure of 117/68. There is no family history of renal disease.

I would be grateful for your opinion as to whether this needs any further investigation.

Yours sincerely,

eService (request)

eService (reply)Dear

Thanks for the referral.

This is probably orthostatic (postural) proteinuria. I would diptest or ACR the urine on an early morning specimen (first urine pass of the day) - if -ve or trace +ve reassure him. Orthostatic proteinuria is common in male adolescents and usually goes by the age of 30. If positive let me know and we should probably review him to make sure that there is no glomerular lesion.

Best wishesPaul (Cockwell)________________________________________

THIN and QOF CKD1Confirmed CKD108,911

Labelled CKD139,176

Miscoded60705

Uncoded30,440

Appropriately coded78471

Jain, Calvert, Cockwell, McManus – under review

Is this important? – Probably

If you have CKD and are on the register vs not on the register

• You have better BP control

• If you have diabetes, you have a better HbA1c

Meta Analysis: Lower Mean BP Results in Slower Rates of Decline in GFR in Diabetics and Non-Diabetics

95 98 101 104 107 110 113 116 119

r = 0.69; P < 0.05

MAP (mmHg)

GFR

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130/85 140/90

UntreatedHTN

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-14Parving HH, et al. Br Med J. 1989. Moschio G, et al. N Engl J Med. 1996.Viberti GC, et al. JAMA. 1993. Bakris GL, et al. Kidney Int. 1996.Klahr S, et al. N Eng J. Med 1994. Bakris GL. Hypertension. 1997.Hebert L, et al. Kidney Int. 1994. The GISEN Group. Lancet. 1997.Lebovitz H, et al. Kidney Int. 1994.

Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661., www.hypertensiononline.org

Accurate measurement of BP is crucial

Validated BP – BPTru

Standard clinic BPs vs BPTru

BP management – NICE guidelines

ACEi or ARBs and the kidneys – the evidence base

• People with diabetes and and ACR> 2.5 (men) or 3.5 (women) irrespective of BP

• Non-diabetic people with CKD and hypertension and ACR >30

• Non-diabetic people with CKD and ACR > 70 mg/mmol irrespective of BP

• No evidence for dual blockade

In high risk groups ACEi/ARBs provide a 20% risk reduction in ESKD

From Weir, NephSap; Vol 5 No 10, 2011

ACE inhibitors and glomerular function

PGC

Efferent dilatation

Glomerular pressure

Proteinuria

Interstitial capillary density and renal outcome

Statins – the SHARP study

• History of chronic kidney disease– not on dialysis: elevated creatinine on 2 occasions

• Men: ≥1.7 mg/dL (150 µmol/L)• Women: ≥1.5 mg/dL (130 µmol/L)

– on dialysis: haemodialysis or peritoneal dialysis• Age ≥40 years• No history of myocardial infarction or coronary

revascularization• Uncertainty: LDL-lowering treatment not definitely

indicated or contraindicated

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Years of follow-up

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%) Risk ratio 0.83 (0.74 – 0.94)

Logrank 2P=0.0022 Placebo

Eze/simv

SHARP: Major Atherosclerotic Events

SHARP: Cause-specific mortality

Risk ratio & 95% CIEvent PlaceboEze/simv

Eze/simvbetter

Placebobetter

(n=4620)(n=4650)

Coronary 91 (2.0%) 90 (1.9%) Other cardiac 162 (3.5%) 182 (3.9%) Subtotal: Any cardiac 253 (5.4%) 272 (5.9%) 7.4% SE 8.4

reduction (p=0.38) Stroke 68 (1.5%) 78 (1.7%)

Other vascular 40 (0.9%) 38 (0.8%) Subtotal: Any vascular 361 (7.8%) 388 (8.4%) 7.3% SE 7.0

reduction (p=0.30)

Cancer 150 (3.2%) 128 (2.8%) Renal 164 (3.5%) 173 (3.7%)

Other non-vascular

Subtotal: Any non-vascular 668 (14.4%) 612 (13.2%) 8.6% SE 5.8 increase (p=0.14)

Unknown cause 113 (2.4%) 115 (2.5%)

Total: Any death 1142 (24.6%) 1115 (24.1%) 1.9% SE 4.2 increase (p=0.65)

0.6 0.8 1.0 1.2 1.4

354 (7.6%) 311 (6.7%)

Risk ratio & 95% CIPlaceboEze/simv

Eze/simv better

Placebo better

(n=4620)(n=4650)

Non-dialysis (n=6247) 296 (9.5%) 373 (11.9%) Dialysis (n=3023) 230 (15.0%) 246 (16.5%)

Major atherosclerotic event 526 (11.3%) 619 (13.4%) 16.5% SE 5.4 reduction (p=0.0022)

0.6 0.8 1.0 1.2 1.4

SHARP: Major Atherosclerotic Eventsby renal status at randomization

No significant heterogeneity between non-dialysis and dialysis patients (p=0.25)

Key points!!

Around 50% of the increased mortality risk associated with conventional risk factors

However patients with CKD are less likely to be optimally treated for risk factors than patients

without CKD

With advanced CKD there is an increasing association with non-traditional risk-factors

Non-traditional risk factors and an evidence base

• Spironolactone – RCTs in process

• Bicarbonate – RCT in process

• Phosphate – phosphate binder RCT being commissioned

• Allopurinol – strong supportive evidence – needs an RCT!!

A major risk factor for CKD is AKI

Only one criteria is required to qualify for stage

Stage Serum creatinine criteria Urine output criteria

Stage 1 Increase serum creatinine of ≥0.3 mg/dL (≥26.4 μmol/L) or ≥1.5-2 times from baseline

<0.5 ml/kg/ hour for >6 hours

Stage 2 Increase serum creatinine to ≥2-3 times from baseline

<0.5 ml/kg/ hour for >12 hours

Stage 3 Increase serum creatinine to >3 times from baseline

or ≥4.0 mg/dL (≥354 μmol/L) with an acute increase of at least 0.5mg/dL (44 μmol/L)

or renal replacement therapy

<0.3 ml/kg/ hour for 24 hours or anuria for 12 hours

Mehta et al, Crit Care, 2007

Rise in creatinine during hospital admission

Multivariable odds ratiofor hospital mortality

≥ 0.3 mg/dL (26 μmol/L) 4.1

≥ 0.5 mg/dL (45 μmol/L) 6.5

≥ 1.0 mg/dL (90 μmol/L) 9.7

≥ 2.0 mg/dL (180 μmol/L) 16.4

Acute kidney injury, mortality, length of stay and costs in hospitalized patients• 19,982 patients admitted to academic medical centre• 9,205 patients with >1 creatinine results

Chertow et al. J Am Soc Nephrol. 2005; 16: 3365–3370

Multivariate analysis

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Impact of AKI on Hospital Mortality

ESRD: end-stage renal disease Okusa MD et al. Clin J Am Soc Nephrol. 2009; 4: 520–522

Likelihood of ESRD after AKI

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Conclusion

• Use eGFR and ACR to risk stratify for CKD

• 50% of the risk of adverse outcomes accompanying CKD is associated with conventional risk factors – optimise their management

• Focus your inpatient service on accurate AKI management