Andrew Durward 2017 Orlando Cardio Renal Syndrome

In heart failure, worse renal function = worse outcome Renal function = mortality risk with heart failure Multiple processes Systemic haemodynamics (hypertension or hypotension) Neurohormonal activation (Renin angiotensin) Intrarenal microvascular Cellular dysregulation Oxidative stress Krumholtz Am J Cardiol. 2000;85:1110–1113.

AKI doesn’t mean ATN Pathogenesis Systemic effect Systemic effect with distal organ damage possible 12% PICU severe AKI 11% mortality AKI vs 2.5% without 23% shock NEJM 2017 Kaddourah troponin Humoral Inflammatory Epinephrine Angiotensin ADH Endothelin GENETIC RISK Local effect Altered sensitivity BNP NO Urodilatin Apoptosis Necrosis Hibernation

Diuresis resistance – kidneys don’t work ARF post liver transplant URODILATIN Local renal natriuretic peptide Infusion improves Urine output LOCAL EFFECT European Journal of Clinical Investigation (1994) 24, 632-639

Cardio-renal or Reno-cardiac Definition (which comes first?) Acute or chronic

Type 1) Acute cardio-renal (worsening cardiac function leads to AKI) Definition and classification (which comes first?) Type 1) Acute cardio-renal (worsening cardiac function leads to AKI) Type 2) Chronic cardio-renal Type 3) Acute reno-cardiac (fluid overload, arrhythmia K+, uremia) Type 4) Chronic reno-cardiac Type 5) Secondary systemic disease Sepsis, hepato – renal syndrome and immune mediated disease Acute hypertensive pulmonary oedema, cardiomyopathy Acute glomerular disease / nephritis Chronic glomerular disease Nephrol Dial Transplant (2010) 25: 1416–1420

Global versus regional haemodynamics 13% blood volume 13% Blood volume

SYSTEMIC VS REGIONAL PERFUSION GLOBAL Sys BP CVP Acid base Lactate Mix Venous NIRS Biomarkers REGIONAL Driving pressure = mean pressure - CVP J Clin Invest. 2011;121(11):4210-4221 Renal medulla ischaemia

Renal medullary ischaemia (Kidneys at limit of hypoxia) Renal ischaemic perfusion injury Oxidative stress and inflammation Molecular adaptive responses Haem Oxygenase ANP Angiopoetin REPERFUSION INJURY Regener Curr Opin Nephrol Hypertens. 2012 ; 21(1): 33–38

Polyuric oliguric polyuric 0 8 16 24 0 8 16 24 Expected post bypass response is avid water retention (ADH) Polyuria can be pathologic (loss of renal concentrating capacity)

Cardiac bypass and AKI

Type 1 Cardio-renal syndrome (heart drives renal injury) Worsening renal function with acute decompensated heart failure 25 to 33% with acute decompensated heart failure Associated with poor outcomes Timing and onset important (preventative strategies) 75% AKI in 1st 4 days PICU Basu NEJM 2017;376

Treatment- avoid hypotension (thresholds?) Inotropes may AKI 73 Poukkanen et al. Critical Care 2013, 17:R295

Role of high CVP in AKI 64% blood venous Mullens J Am Coll Cardiol. 2009

Optimise diuretics Fluid unloading Cytoprotection Vasodilators Vasodilation Fluid overload High CVP Diuresis Hypovolaemia Renal impairment

Optimise diuretics Fluid unloading Cytoprotection Vasodilators Higher vs lower Dose loop diuretics Loop diuretic infusions Combination therapy Adenosine blocker GTN (venodilator) Nitroprusside Nesiritide (BNP) Diuretics + CVVH Hypertonic saline Vasodilation Fluid overload High CVP Diuresis Hypovolaemia Renal impairment

Optimising diuretics : Adenosine blocker Plasma adenosine raised heart failure – local vasoconstrictor Locally produced in kidney (stress signal) Furosemide alone reduces GFR Gottlieb Circulation. 2002;105:1348-1353

Vasodilators and Nesiritide (recombinant BNP) Meta-analysis of Nesiritide = worsened cardiac failure (Sackner-Bernstein. Circulation 2005;111:1487-91) Low doses of nesiritide potentially renal protective Controversial N=7141 O’Connor N Engl J Med 2011;365:32-43

Fluid unloading : UNLOAD trial (adults) Ultrafiltration (500ml/hr) versus Intravenous (IV) Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure The ultrafiltration group = greater weight loss and volume removal at 48 h Dyspnoea score in both groups improved. Rehospitalisation and the total days of hospitalization were significantly lower in the ultrafiltration group at 3 months No change renal function long term

Fluid unloading : Ultrafiltration N=188 adult patients acute decompensated heart failure Change serum Cr and body weight at 96hrs Ultrafiltration group Higher adverse events 72% vs 57% at 60 days Bart N Engl J Med 2012; 367:2296-230

Vasodilator: Vasopressin blocker (adults) Selective V2 antagonists (tolvaptan) to mobilize aquaresis Efficacy of Vasopressin Antagonist in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial 4133 patients (359 centers in 20 countries) Produced weight loss (sodium increase) No long-term benefit vs placebo groups 1 year mortality 25.0% in the tolvaptan group and 26.0% in the placebo

Hypertonic saline: cardiac bypass (children) 7.2% Saline 6% HES vs 0.9% saline (4ml/kg) 52 children post cardiac bypass (VSD) Favourable haemodynamic effect Without added risk of tissue oedema

Paediatric ECMO and AKI N=154 children CVVH On ECMO (44%) 44% survived 26% Ongoing CCRT 96% recovered renal function at discharge N=43 children ECMO 32% needed dialysis for ARF (double creatinine) Survival only 19% vs 92% if no renal injury Weber Ann Thorac Surg. Nov; 1990 50(5):720–3 Padden Pediatr Crit Care Med. 2011; 12(2): 153–158

Outcome Cardiorenal Syndrome (Children) N=47 (Nigeria) 34% Mortality 20% Malaria Olowu, 2011, International Journal of Nephrology

Cell death rare in sepsis-induce cardiac dysfunction focal cardiac mitochondrial injury Renal tubular injury common but present focally; renal tubular regeneration can occur Organ injury is potentially reversible (hibernation) TUBULAR CELL ADAPTATION Am J Respir Crit Care Med Vol 187, Iss. 5, pp 509–517, 2013

Cardiorenal syndrome UNIFIED THEORY SYSTEMIC PROCESS Inflammation Hypertension/Hypotension Cardiac hormonal axis activated LOCAL PROCESS Microcirculatory dysfunction Bioenergetic failure TUBULAR CELL ADAPTATION 80% sepsis deaths unresolved infectious focus (autopsy) 50% undetected pneumonia Torgersen Anesth Analg 2009;108:1841–7

Conclusion – Cardio Renal syndrome Heart failure with worsening renal function  Varying chronicity and presentation Pathogenesis complex (haemodynamic and local renal factors) Poor outcome if untreated Therapeutic potential ( treat cause and supportive treatment)