THE KIDNEY IN HYPOTENSIVE STATES. Benita S. Padilla, M.D.

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1 THE KIDNEY IN HYPOTENSIVE STATES Benita S. Padilla, M.D.

2 Objectives To discuss what happens when the kidney encounters low perfusion To discuss new developments and clinical application points in two scenarios The kidney in sepsis The kidney in acute decompensated heart failure

3 Determinants of renal blood flow (RBF) Cardiac output Renal perfusion pressure Difference between renal arterial and venous pressures Since venous pressure is negligible in normal circumstances, proportional to MAP Renal vascular resistance Regulated by afferent and efferent arterial tone

4 What happens in hypotensive states? The kidney tries to maintain glomerular filtration by a two step hemodynamic adaptation Pre-glomerular (afferent) vasodilatation through a myogenic response to tubuloglomerular feedback

5 What happens in hypotensive states? When there is a further fall in perfusion, there is post-glomerular (efferent) vasoconstriction to ensure preservation of filtration pressure Mediated by angiotensin II

6 The kidney in sepsis Traditional view focus on hemodynamics Reduction in RBF Acute tubular necrosis Treatment has been focused on increasing RBF by enhancing CO and perfusion pressure

7 The kidney in sepsis New evidence Histopathology of tubules The renal circulation The inflammatory response

8 The kidney in sepsis: The tubules Is there really acute tubular necrosis?

9 The kidney in sepsis: The tubules Rapid postmortem cardiac and renal harvest in 44 septic patients Compared to control hearts from 12 transplant and 13 brain dead patients Control kidneys from 20 trauma patients and 8 patients with cancer Takasu, 2013

10 The kidney in sepsis: The tubules Cell death is rare in sepsis-induced cardiac dysfunction, but cardiomyocyte injury occurs Renal tubular injury is common in sepsis (78% vs 1% in controls) BUT presents focally; most renal tubular cells appear normal The degree of cell injury and death does not account for severity of sepsis-induced organ dysfunction Takasu, 2013

11 The kidney in sepsis: Apoptosis vs. Necrosis Kidney biopsies from 19 consecutive patients who died from septic shock were compared with postmortem biopsies from 8 trauma patients and 9 patients with non-septic AKI Apoptosis: 6% in septic group vs. 1% in nonseptic group Lerolle, 2010

12 The kidney in sepsis: Apoptosis vs. Necrosis Therapeutic implication: once a cell has been severely injured, necrosis is difficult to prevent while the apoptotic pathway can be modulated to maintain cell viability Theoretically, the components of the apoptotic pathway that could be amenable to therapeutic modulation are numerous Rana, 2001

13 The kidney in sepsis: Novel therapeutic targets Caspase inhibition

14 The kidney in sepsis: The renal circulation Does the renal circulation participate in the systemic vasodilatation seen in severe sepsis?

15 The kidney in sepsis: The renal circulation Pig model where sepsis was introduced either by peritonitis or continuous IV infusion of Pseudomonas aeruginosa In animals who developed AKI, there was reduced RBF despite maintained CO Benes, 2011

16 The kidney in sepsis: The renal circulation Renal circulatory response to sepsis could not reliably be predicted from changes in systemic hemodynamics Supports selective renal vasoconstriction Benes, 2011

17 The kidney in sepsis: The renal circulation Another animal model: sheep sepsis model induced by continuous E. coli infusion Septic AKI was uniformly associated with renal vasodilatation and increased RBF Langerberg, 2006 and 2007

18 The kidney in sepsis: The renal circulation Two different animal models yielded contrasting results Immune and renal hemodynamic responses model specific?

19 The kidney in sepsis: Novel therapeutic targets Caspase inhibition Arginine vasopressin In an animal model, caused less tubular apoptosis, systemic inflammation and kidney damage than noradrenaline

20 The kidney in sepsis: Inflammatory response Pig model of P. aeruginosa sepsis Despite comparable septic insult and systemic hemodynamic response, only those pigs who developed AKI had a very early increase in the plasma levels of IL- 6, TNF a and TBARS Benes, 2011

21 The kidney in sepsis: Inflammatory response Several large cohorts of critically ill patients have shown that IL-6 could be a robust predictor of AKI Benes, 2011

22 The kidney in sepsis: Novel therapeutic targets Caspase inhibition Arginine vasopressin Elimination of inflammatory mediators by ultrafiltration

23 The kidney in sepsis: Novel therapeutic targets Caspase inhibition Arginine vasopressin Elimination of inflammatory mediators by ultrafiltration Ghrelin Peptide that exerts renal protective effects by inhibiting pro-inflammatory cytokines, particularly TNF a

24 The kidney in sepsis Pathogenesis of sepsis-induced AKI is much more complex than isolated hypoperfusion due to decreased CO and hypotension Renal microvascular alterations and inflammation probably have a major role and modulating them as a therapeutic target is the way forward

25 The kidney in heart failure... It s complicated

26 The cardiorenal syndromes Type 1: acute cardio renal syndrome Type 2: chronic cardio renal syndrome Type 3: acute reno cardiac syndrome Type 4: chronic reno cardiac syndrome Type 5: secondary cardio renal syndrome Report from the consensus conference of the Acute Dialysis Quality Initiative, Ronco, 2010

27 The cardiorenal syndromes Type 1: acute cardio renal syndrome Type 2: chronic cardio renal syndrome Type 3: acute reno cardiac syndrome Type 4: chronic reno cardiac syndrome Type 5: secondary cardio renal syndrome

28 Type 1 : Acute cardio renal syndrome The term WRF (worsening renal function) has been used to describe acute and/or sub-acute changes in patients in ADHF or ACS Commonly defined as an increase in serum creatinine by 0.3 mg/dl from baseline Serum creatinine rises only when GFR >50% so better markers of renal function are needed Between 30 to 60% with ADHF develop WRF worse prognosis

29 The kidney in heart failure... It s complicated Altered hemodynamics Neurohormonal activation Interaction is complex and bidirectional

30 Type 1: Acute cardiorenal syndrome Ronco 2008

31 Type 1: Acute cardiorenal syndrome Ronco 2008

32 The kidney in acute heart failure Decreased cardiac output (CO) Studies have shown that serum creatinine and egfr did not correlate with CO It is suggested that low CO and altered hemodynamics are not the primary determinants of renal dysfunction in HF patients Sinkeler, 2011

33 Type 1: Acute cardiorenal syndrome Ronco 2008

34 The kidney in acute heart failure The congestive state Until recently, it was assumed that the congestive state as such did not impact on renal function Several studies, however, recently demonstrated an association between venous congestion and worse renal function Sinkeler, 2011

35 The kidney in acute heart failure The congestive state Increased CVP was the most powerful predictor of WRF Not only intravascular congestion but also increased abdominal pressure may increased central and renal VP Mullens, 2011

36 The kidney in acute heart failure The congestive state Elevated renal VP distends the venules surrounding the distal nephron Compression of the tubules, increased tubular fluid pressure, backleak of filtrate into the interstitium Increased interstitial pressure leads to interstitial hypoxia and inflammation Lazzarini 2012

37 The kidney in acute heart failure The congestive state Venous congestion and associated endothelial stretch Increases production of pro-inflammatory cytokines Activates RAAS and SNS Sinkeler, 2012

38 The kidney in acute heart failure Volume targeting in HF Recent data on intervention in volume status in HF are scarce DOSE-AHF (Diuretic Optimal Strategy Evaluation in Acute Heart Failure) trial Examined efficacy and safety of different dosing strategies of furosemide in 308 patients with acute HF Felker, 2011

39 The kidney in acute heart failure Volume targeting in HF 2 x 2 factorial design, randomized to Low dose vs high dose furosemide Bolus q 12 vs continuous infusion Felker, 2011

40 The kidney in acute heart failure Volume targeting in HF High dose group had greater relief of dyspnea, greater net fluid loss, slightly more likely to have transient WRF At 60 days, there was no evidence of worse clinical outcomes Felker, 2011

41 The kidney in acute heart failure Volume targeting in HF Higher doses of furosemide have previously been considered to increase risk of WRF Yes, but his is transient, and relief of venous congestion may benefit the kidney in the long run

42 The kidney in acute heart failure Intrarenal mechanisms Adenosine an important intrarenal mediator of WRF Treat with adenosine antagonists? PROTECT trial rolofylline No cardiac or renal benefit. Excess neuro complications (seizures) Cotter, 2008

43 The kidney in acute heart failure Intrarenal mechanisms Increased AVP release in ADHF Treat with vasopressin antagonists? EVEREST trial tolvaptan Greater reduction in body weight, improvement in dyspnea but no change in outcomes. Kidney function stable Konstam, 2007

44 The kidney in hypotensive states

45 The kidney in hypotensive states In real life, it s so much more than just hypotension It s volume, hormones, cytokines, oxidative stress, etc, etc, etc Thank you