Chronic Kidney Disease Paul Cockwell Queen Elizabeth Hospital Birmingham
Paradigms for chronic disease 1. Acute and chronic disease is closely linked 2. Stratify risk and tailor interventions around failure of optimal medical management? 3. Comorbidities may provide novel therapeutic targets
67 year old Caucasian man under review in CKD clinic
vascular bed inflammation normal evolving disease established disease Eardley et al; Kidney International 2005-7
1 million nephrons/kidney unique vasculature Oxygenation po 2 6.5 13.5 po 2 3 6 po 2 1.3 2.6
High intraglomerular pressure promotes proteinuria and accelerated renal injury Glomerular pressure P GC Proteinuria AT II Inflammation Fibrosis
Chronic Kidney Disease (CKD) staging GFR stage ml/min GFR term G1 90 normal or high G2 60 89 normal or mild G3a 45 59 mild to moderate G3b 30 44 moderate to severe G4 15 29 severe G5 <15 kidney failure Albuminuria UACR mg/mmol Albuminuria A1 <3 normal A2 3 30 high (micro) A3 >30 very high (macro)
An ACR of 100 mg/mmol = AER of 1g/d Normal High (micro) Very High (macro) ACR (mg/mmol) <3 3-30 >30 PCR (mg/mmol) <15 15-50 >50 AER (mg/day) <10 10-300 >300 PER (mg/day <50 50-500 >500 Urine diptest -ve to trace Trace to 1+ >1+
Risk of end-stage renal failure (ESRF) 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
70 year female; egfr 20 ml/min, ACR 0.5 mg/mmol Risk of end-stage renal failure at 2-years? 1. 1.7% 2. 7% 3. 17% 4. 37%
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40 year male; egfr 20 ml/min, ACR 100 mg/mmol Risk of end-stage renal failure at 2-years? 1. 1.7% 2. 7% 3. 17% 4. 37%
Relative risk of death by stage of CKD (female) 18 16 14 12 10 8 6 4 2 0 ACR <3 mg/mmol ACR >30 mg/mmol egfr 60-74 CKD 3a CKD 3b CKD 4 CKD 5 15 based on Nitsch BMJ 346 (2013): doi:10.1136/bmj.f324.
Change in LV mass (g) following nephrectomy humans 12 months after living kidney donation Moody et al: Hypertension. 2016;67:368-377.
Evidence base for CKD Therapy Patient group Comment ACEi/ARB Diabetes & ACR>3 Include normotensive ACEi/ARB ACR >30 (no diabetes) Target BP <130/80 Antihypertensive conventional CKD ACR<30 Target BP <140/90 Statin (for CVD primary prevention) CKD 3-5 Not dialysis Recent phase 3 studies in CKD Target Comment Combined RAAS blockade NCT00549757 RAAS Study terminated Bardoxolone NCT01351675 Fibrosis Study terminated Immunosuppression (IgA nephropathy) NCT00554502 Anaemia NCT00093015 Inflammation Cardiovascular disease -ve and possible harm Increased risk of stroke with target Hb >120 g/l
Three paradigms for chronic disease 1. Acute and chronic disease is closely linked
CKD - Slow Progressor 45 40 35 30 25 20 15 Jan-14 Jul-14 Jan-15 Jul-15 Jan-16
Proteinuric CKD (fast progressor) 45 40 35 30 25 20 15 Jan-14 Jul-14 Jan-15 Jul-15 Jan-16
Acute Kidney Injury on CKD 45 40 35 30 25 20 15 Jan-14 Jul-14 Jan-15 Jul-15 Jan-16
Kidney International 2012;Vol 2: 1 141. Acute Kidney Injury (AKI) Staging Stage Creatinine from baseline Urine output 1 26.4 μmol/l or 1.5 2x <0.5 ml/kg/h for 6h 2 2 2.9 times <0.5 ml/kg/h for 12h 3 3 times or 352 μmol/l or on dialysis <0.3 ml/kg/h for 24h or anuria for 12h Only one criterion is required
Prognosis of AKI 40 35 30 25 20 15 10 5 0 36.1% 33% 16.3% 3.2% No AKI AKI 1 AKI 2 AKI 3 Adapted from Selby NM. et al. Clin J Am Soc Nephrol. 2012;7:533 540.
AKI (STOP) the major risk factor is CKD Sepsis/Ischaemia 1. Prerenal Toxins ATN 3. Obstruction Parenchymal (RPGN; AIN) 2. Intrinsic
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Stop ACEi and ARBs in AKI; avoid NSAIDS P GC NSAIDS ACE/ATII inhibitors RAS Dehydration Sepsis Pump failure
Three paradigms for chronic disease 1. Acute and chronic disease are intimately linked 2. Stratify risk and tailor interventions around failure of optimal medical management
CKD and no ACEi benefit? 45 40 ACEi commenced 35 30 25 20 15 Jan-14 Jul-14 Jan-15 Jul-15 Jan-16
Elevated serum mast-cell tryptase concentration predicts progression to ESRF in patients receiving treatment with an ACEi/ARB. Jesky et al; EJCI 2016
Can we use biomarkers in chronic disease to: pathotype for and by treatment response?? identify new targets for intervention?? Jesky et al; EJCI 2016
CKD and no ACEi benefit? 45 40 35 30 25 20 15 Jan-14 Jul-14 Jan-15 Jul-15 Jan-16
Change in GFR after stopping ACEi Ahmed AK et al NDT 2009: 25; 3977
Angiotensin Converting Enzyme inhibitor (ACEi) / Angiotensin Receptor Blocker (ARB) To STOP OR Not in Advanced Renal Disease CI: Prof Sunil Bhandari Consultant Nephrologist Honorary Clinical Professor
3 years follow-up 2 years recruitment CKD patients stage 4-5 ACEi/ARB treatments Eligible for STOP-ACEi study? Yes No Excluded Not Meeting Criteria Declined Other Reason Randomise 1:1 ratio, N=410 Control Arm: Continue ACEi/ARB N=205 Experimental Arm: Discontinue ACEi/ARB N=205 3 Year Follow-Up 3-monthly visits - routine tests (egfr, FBC, BCP, urinary PCR), BP, documentation of ESA dose, adverse events, compliance and changes in medication Extra tests at annual visits - QOL questionnaire, weight and BMI, 6-minute walk test, ECG, and bloods for C-reactive protein, cystatin-c, NT-proBNP, ACE/renin levels and biomarkers TARGET BP <140/85
Three paradigms for chronic disease 1. Acute and chronic disease is closely linked 2. Stratify risk and tailor interventions around failure of optimal medical management 3. Comorbidities may provide novel therapeutic targets.
Risk of death based on comorbidities: 31,245 primary care based patients with kidney function testing and comorbidities assigned 30 25 20 15 10 5 0 0 1 2 3 4 5 6 Number of co-morbidities Jesky et al; BMJ Open 2013
What is the commonest chronic disease? 1. Periodontitis 2. Type 2 diabetes 3. Chronic kidney disease 4. Obesity 5. Coronary artery disease 6. Peripheral vascular disease
Periodontitis
Severe Periodontitis 11% of adults 39% of adults with high risk CKD Sharma et al J Clin Periodontol (2014) 41:7, 653-6
NHANES III (1988-1994) Diabetes, periodontal status and mortality in patients with CKD Mean follow-up time 8 years (1 month-18 years) Cox PH regression analysis
Patient Reported Outcomes (PROs)? A PRO is any report of the status of a patient s health condition that comes directly from the patient, without interpretation of the patient s response by a clinician or anyone else. FDA guidance: Guidance for Industry, Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. 2009
PROs in Routine Practice Smartphone Tablet PC Phone Voice-Recognition Scanned Paper-Copy KDQOL-36 General Health (SF-12) Quality of Life CKD Symptoms
eprom SYSTEM - University Hospital Birmingham Patient receives automated message of reassurance for scores within normal limits Alert Monitoring Example screenshot from Danish Ambuflex system Patient and renal team alerted to closely monitor worsening symptoms and to take action if concerned Member of renal team contacts patient to determine need to escalate care Longitudinal eprom Data in Clinic Facilitates patient-centred care and shared decision making
Summary 1. Acute and chronic disease is closely linked 2. Stratify risk and tailor interventions around failure of optimal medical management 3. Comorbidities may provide novel therapeutic targets