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THE KIDNEY IN HYPOTENSIVE STATES
Benita S. Padilla, M.D.
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
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
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
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
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
The kidney in sepsis
New evidence
Histopathology of tubules
The renal circulation
The inflammatory response
The kidney in sepsis: The tubules
Is there really acute tubular necrosis?
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
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
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 non-septic group
Lerolle, 2010
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
The kidney in sepsis: Novel therapeutic targets
Caspase inhibition
The kidney in sepsis: The renal circulation
Does the renal circulation participate in the systemic vasodilatation seen in severe sepsis?
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
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
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
The kidney in sepsis: The renal circulation
Two different animal models yielded contrasting results
Immune and renal hemodynamic responses model specific?
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
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
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
The kidney in sepsis: Novel therapeutic targets
Caspase inhibition
Arginine vasopressin
Elimination of inflammatory mediators by ultrafiltration
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
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
The kidney in heart failure
. . . It’s complicated
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
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
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
The kidney in heart failure
. . . It’s complicated
Altered hemodynamics
Neurohormonal activation
Interaction is complex and bidirectional
Type 1: Acute cardiorenal syndrome
Ronco 2008
Type 1: Acute cardiorenal syndrome
Ronco 2008
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
Type 1: Acute cardiorenal syndrome
Ronco 2008
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
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
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
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
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
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
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
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
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
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
The kidney in hypotensive states
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
