1. How to improve outcomes in Chronic Kidney Disease
Paul Cockwell
Consultant Nephrologist
Queen Elizabeth Hospital Birmingham

2. CKD is usually present in association with other chronic conditions

3. Number of co-morbidities
Heart of Birmingham PCT – Relative risk of death based on known comorbidities
Hazard Ratio of Death 1 2 3 4 5 6
Number of co-morbidities

4. 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

5. 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

6. 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

7. 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: 459–466

8. The Health improvement Network (THIN): 6
The Health improvement Network (THIN): 6.7 million patients from 426 primary care centres in the UK. CKD 3-5 prevalence
Jain, Calvert, Cockwell, McManus – under review

9. For patients with an eGFR <60 ml/min delta eGFR is as important as the overall value

10. 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

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

12. The CKD classification system

13. The Health improvement Network (THIN): 6
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

14. The CKD classification system

15. eGFR threshold and risk of Death or ESKD
O’Hare et al, JASN 2007

17. Risk of ESKD in respect of eGFR and proteinuria
ACR 30+ mg/mmol
ACR 3-29 mg/mmol
ACR < 3mg/mmol
Adapted from Levey et al KI 2011

18. Primary Care CKD Risk stratification BP management
Primary and secondary prevention of CVD
Monitoring
Referral into and communication with secondary care

19. 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

20. Secondary Care non-nephrology
Management of comorbidity
Drug dosing and toxicity
Management of AKI
Sense check for primary care
Referral to secondary care nephrology

24. Overall supporting information for the management of CKD
Minimising the risk for people with CKD of progression of CKD and Cardiovascular disease (CVD)
The BP target for non-proteinuric CKD without diabetes is <140/85
The BP target for diabetes and CKD is <130/80
The BP target for proteinuric CKD (ACR>30) without diabetes is <130/80
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.
The dose of ACEi/ARB should be used at the maximum tolerated. ACEi and ARBs should not be used in combination.
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
Primary and secondary prevention of CVD should be optimised; statins, anti-platelet drugs, and warfarin are not contraindicated in CKD.
NSAIDs should not be used
Management of complications of CKD
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.
Please refer any uncertainties about bone chemistry through the advice and guidance portal

26. eService (request) From: Vanessa Miller
Sent: Monday, March 05, :13 PM
To: Paul Cockwell
Cc: Barbara Joyce
Subject: 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,

27. 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 wishes
Paul (Cockwell)
________________________________________

30. THIN and QOF CKD1 Jain, Calvert, Cockwell, McManus – under review
Confirmed CKD
108,911
Labelled CKD
139,176
Miscoded
60705
Uncoded
30,440
Appropriately coded
78471
Jain, Calvert, Cockwell, McManus – under review

31. 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

32. 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 (mL/min/year)
130/85
140/90
Untreated
HTN -2 -4 -6 -8
-10
-12
-14
Parving HH, et al. Br Med J Moschio G, et al. N Engl J Med
Viberti GC, et al. JAMA Bakris GL, et al. Kidney Int
Klahr S, et al. N Eng J. Med Bakris GL. Hypertension
Hebert L, et al. Kidney Int The GISEN Group. Lancet
Lebovitz H, et al. Kidney Int
Bakris GL, et al. Am J Kidney Dis. 2000;36(3): ,

33. Accurate measurement of BP is crucial
Validated BP – BPTru

34. Standard clinic BPs vs BPTru

35. BP management – NICE guidelines

36. 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

37. In high risk groups ACEi/ARBs provide a 20% risk reduction in ESKD
From Weir, NephSap; Vol 5 No 10, 2011

38. ACE inhibitors and glomerular function
Glomerular pressure
PGC
Efferent dilatation
Proteinuria

40. Interstitial capillary density and renal outcome

43. 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

44. SHARP: Major Atherosclerotic Events25
Risk ratio 0.83 (0.74 – 0.94)
Logrank 2P=0.0022 20
Placebo 15
Proportion suffering event (%)
Eze/simv 10 5 1 2 3 4 5
Years of follow-up

45. SHARP: Cause-specific mortality
Event
Eze/simv
Placebo
Risk ratio & 95% CI
(n=4650)
(n=4620)
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
Stroke 68
(1.5%) 78
(1.7%)
(p=0.38)
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
354
(7.6%)
311
(6.7%)
8.6% SE 5.8
Subtotal: Any non-vascular
668
(14.4%)
612
(13.2%)
increase
(p=0.14)
Unknown cause
113
(2.4%)
115
(2.5%)
1.9% SE 4.2
Total: Any death
1142
(24.6%)
1115
(24.1%)
increase
(p=0.65)
0.6
0.8
1.0
1.2
1.4
Eze/simv
better
Placebo
better

46. SHARP: Major Atherosclerotic Events by renal status at randomization
Eze/simv
Placebo
Risk ratio & 95% CI
(n=4650)
(n=4620)
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)
No significant heterogeneity between non-dialysis and dialysis patients (p=0.25)
0.6
0.8
1.0
1.2
1.4
Eze/simv better
Placebo better

47. 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

48. 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!!

49. 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

50. Impact of AKI on Hospital Mortality
Multivariate analysis
Rise in creatinine during hospital admission
Multivariable odds ratio
for 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

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

56. 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