1. CKD: Does it really matter? Richard Smith Consultant Nephrologist

2. KIDNEYS

3. Significant biochemical changes have no ‘immediate’ clinical correlate Therefore for CKD(3) and AKI clinical awareness is essential Recognise the patient at risk Recognise the risk associated with CKD(3): Confers significant cardiovascular risk and risk of AKI Progression to RRT is rare (1.3%) Progression to worse CKD (and therefore worse cardiovascular risk) is common The talk in one slide: Risk management

4. RRT 60 50 40 30 20 10 eGFR CKD3 CKD4 X CKD: Does it really matter?

5. RRT 60 50 40 30 20 10 eGFR CKD3 CKD4 X CKD3: Does it really matter?

6. RRT 60 50 40 30 20 10 eGFR CKD3 CKD4 X CKD3: Does it really matter?

7. RRT 60 50 40 30 20 10 eGFR CKD3 CKD4 X CKD3: Does it really matter?

8. Mrs MA 74 year old eGFR 46ml/min/1.73m 2 Dipstick of urine revealed + protein Serum electrophoresis revealed a paraprotein with urinary BJP

9. May be flag for significant underlying disease Haematuria and proteinuria are flags for further investigation Relevant at all ages

10. Risks associated with CKD Cardiovascular Risk

11. (N=1,120,295) 1.0 1.4 2.0 2.8 3.4 Hazard ratio for CV event 0 1 2 3 4 Reduced kidney function is associated with a higher risk of CV events ≥6045-5930-4415-29<15 eGFR (mL/min/1.73m 2 ) Go et al. N Engl J Med 2004 351: 1296–1305 Tonelli et al. J Am Soc Nephrol 2006 17: 2034–2047 Eeg-Olofsson et al. J Internal Medicine 2010 268: 471–482 Khaw Nature Reviews Endocrinology 2009 5: 130-131 8.0-8.9 9.0-9.9 CKD3

12. Age-related glomerulosclerosis is amplified by systemic atherosclerosis Kasiske BL. Kidney Int 1987; 31: 1153-1159

13. Risk factors for cardiovascular disease Risk factors for chronic kidney disease Hypertension Smoking Obesity Diabetes Dyslipidaemia Reduced GFR Proteinuria Hypertension Smoking Obesity Diabetes Dyslipidaemia Atherosclerosis Heart failure

14. Patients with CKD are more likely to die than require dialysis Kaiser Permanente, Oregon: 27,998 CKD patients followed for 5y StageGFRRRTDeath 260-891.1%19.5% 330-591.3%24.3% 415-2919.9%45.7% Keith DS. Arch Intern Med 2004; 164: 659-663

15. SHARP: Major Atherosclerotic Events 5-year benefit per 1000 patients http://www.ctsu.ox.ac.uk/~sharp/

16. Risks associated with CKD Acute Kidney Injury

17. Mr PS 80 year old ‘Stable’ IHD Not diabetic No ACEI Acutely SOB with possible rigor Few crackles L base Clarithromycin prescribed

18. 24 hours later confused and hypotensive Emergency admission Treated as CAP according to hospital protocol Rx Vancomycin 1g x 2 Gentamicin 160mg x 2

19. 48 hours later AKI diagnosed Baseline eGFR 42ml/min/1.73m 2 4 week hospital admission Probably avoidable with recognition that patient likely to have CKD and risk conferred by this CKD Admission eGFR 22ml/min/1.73m 2 ‘48h’ eGFR 12ml/min/1.73m 2

20. Mrs JD 80 year old T2DM and IHD Rx ACEI eGFR 35ml/min/1.73m 2 eGFR 16ml/min/1.73m 2 Pharmacist recommended ibuprofen for hip pain

21. Should not deprive patients with CKD of potential benefits of ACEI/ARB Combination of CKD3 and ACEI/ARB carries significant risk of AKI Sick day rules important for patient and doctor Equivalent to diabetes

22. Recognising the at risk patient: ACEI ACEI/ARB essential part of managing IHD and preventing progression of CKD ACEI/ARB, IHD and CKD are important risk factors for AKI

23. What to do: Medications Acutely unwell patient with proven or possible CKD ACEI/ARBStop Loop DiureticsStop MetforminStop SUsReview MetiglinidesNo change GliptinsNo change StatinsNo change AspirinNo change NSAIDsStop/Avoid TrimethoprimAvoid

24. Check GFR if D iabetes Hypertension Cardiovascular disease Structural renal tract disease Renal calculi Prostatic hypertrophy Multisystem diseases with potential kidney involvement Opportunistic detection of haematuria or proteinuria Family history of stage 5 CKD or hereditary kidney disease

25. Risks associated with CKD Risk of progression (including to renal replacement therapy)

26. CKD progression Steps to identify progressive CKD Obtain a minimum of three eGFR over not less than 90 days In new cases of reduced eGFR repeat within 2 weeks to exclude acute deterioration CKD progression is a decline in eGFR of: > 5 ml/min/1.73m 2 within 1 year > 10 ml/min/1.73m 2 within 5 years

27. Hemmelgarn BR. Kidney International 2006: 29: 2155 10,184 community-dwelling subjects aged 66 or over Decline in eGFR greatest in diabetics (2.1 and 2.7 ml/min/1.73m 2 /year in F and M respectively) Decline in eGFR in non-diabetics: 0.8 and 1.4 ml/min/1.73m 2 /year in F and M respectively Decline more likely if baseline eGFR <30 Risk of decline of GFR in elderly people

28. Patients with CKD are more likely to die than require dialysis Kaiser Permanente, Oregon: 27,998 CKD patients followed for 5y StageGFRRRTDeath 260-891.1%19.5% 330-591.3%24.3% 415-2919.9%45.7% Keith DS. Arch Intern Med 2004; 164: 659-663

29. (N=1,120,295) 1.0 1.4 2.0 2.8 3.4 Hazard ratio for CV event 0 1 2 3 4 Reduced kidney function is associated with a higher risk of CV events ≥6045-5930-4415-29<15 eGFR (mL/min/1.73 m 2 ) Go et al. N Engl J Med 2004 351: 1296–1305 Tonelli et al. J Am Soc Nephrol 2006 17: 2034–2047 Eeg-Olofsson et al. J Internal Medicine 2010 268: 471–482 Khaw Nature Reviews Endocrinology 2009 5: 130-131 8.0-8.9 9.0-9.9 CKD3

30. Ongoing management to slow progression important RRT 60 50 40 30 20 10 eGFR CKD3 CKD4 X CKD3: What is all the fuss about?

31. Blood pressure control In people with CKD aim for: Systolic blood pressure below 140 mmHg (target range 120–139 mmHg) Diastolic blood pressure below 90 mmHg In people with CKD and diabetes or when ACR  70mg/mmol aim for: Systolic blood pressure below 130 mmHg (target range 120–129 mmHg) Diastolic blood pressure below 80 mmHg

32. ACEI/ARB in CKD

33. Glomerulopathy/Hyperfiltration: Good Real world kidney disease: More complicated! Microvascular disease v macrovascular disease ACEI and ARB

35. Macrovascular disease affecting the kidneys

36. Angiotensin II Glomerular permeability Glomerular pressure Interstitial fibrosis Proteinuria Progressive Renal Failure Heads you win……. X

37. ……. Tails you lose If primary problem is macrovascular disease ACEI/ARB will precipitate progressive decline in GFR

38. Time GFR Slowly deteriorating CKD ACEI/ARB Acute reduction in glomerular perfusion pressure – expected and OK – up to 20% Long-term stabilisation in GFR – most likely in proteinuric patients, because proteinuria indicates glomerular hyperperfusion/overwork Progressive fall in GFR, caused by macrovascular renal disease or other cause of global reduction in renal perfusion

39. How does diabetes damage the kidneys? Microvascular disease Diabetic nephropathy: Damage to glomerulus AND haemodynamic changes Manifest by albuminuria Macrovascular disease Decreased perfusion pressure Does not cause albuminuria T1DM Micro > macro T2DM Macro > micro RAS blockade beneficial RAS blockade not beneficial

40. 250 1000 500 125 Creatinine µmol/l 0 6 12 18 24 30 36 Time (months) Diabetic Nephropathy Treatment

41. MABP 125 115 105 95 105 95 85 75 65 GFR 1250 750 250 Albuminuria -24 -18 -12 -6 0 6 12 18 24 30 All is not lost

42. CKD3 matters! Be brave with ACEI/ARB but frequent monitoring necessary Be aware of possibility for AKI eGFR below 30ml/min makes secondary hyperparathyroidism and anaemia possible eGFR below 20ml/min should prompt RRT discussions eGFR below 15ml/min may need dialysis

43. Number of patients with haemoglobin <110 g/l in diabetic vs non-diabetic patients at various CKD stages Patients with diabetic Patients with nephropathy, n (%) non-diabetic kidney disease, n (%) CKD 1 1 (8) 3 (2.3) CKD 2 1 (3.5)9 (2.6) CKD 3 11 (10.4) 21 (3.2) CKD 4 25 (21.3) 33 (7.1) CKD 5 34 (85) 37 (20.1)

44. How prevalent is anaemia of CKD? eGFR (ml/min/1.73m 2 Median Hb in men (g/dl) Median Hb in women (g/dl) Prevalence of anaemia 6014.913.51% 3013.812.29% 1512.010.333%