tissue oxygenation in acute kidney injury...

Tissue oxygenation in acute kidney injury (AKI)

2019 Western Society of Pediatric Nephrology Conference Alexander Bullen, MD

January 26, 2019

Conflict of Interest Disclosure

• No conflicts of interest to disclose

Outline

• Renal Oxygenation and Hemodynamics

- Challenges of the kidney

- Role of renal blood flow (RBF)

• Alterations in renal oxygenation in AKI

- Background

- Sepsis-associated AKI

- Ischemia reperfusion AKI

Outline



- Role of renal blood flow


- Background



Challenges 1) There is regional heterogeneity in renal perfusion1,2

1Deng A et al. Am J. Physiol. Renal Physiol. 2010.

2Brezis et al. Am J. Physiol 1994.

Linear relationship of oxygen consumption to tubular Na reabsorption

• Majority of renal oxygen consumption is driven by Na reabsorption which is determined by GFR

• Tubular transport is among the principal determinants of intrarenal oxygenation.

Outline



- Role of the renal blood flow


- Background



Renal Blood Flow (RBF)

- Key determinant of oxygenation - Regional oxygen extraction remains stable over a wide range of RBF1

1Levy MN. Am J. Physiol, 1960.

Figure: Evans et al. Am J Physiol Renal Physiol, 2008.

Relationship between RBF and GFR

• RBF and GFR do not always change in parallel

- Vasoconstrictor and vasodilator factors1

- Efficiency among nephron segments2,3

1Navar et al. Physiol Rev, 1996

2Blantz et al. Curr Opin Nephrol Hypertens, 2004

3Gullans et al. Brenner and Rector’s The Kidney, 1996

Evans et al. Intrarenal oxygenation: unique challenges. Am J Physiol Renal Physiol 2008.

Outline


- Peculiarities of the kidney

- Role of RBF


- Background



Acute kidney injury (AKI)

• Common clinical entity (21.6% of hospitalized)1

• Associated with high mortality2,3 and development of CKD, even with apparent recovery4,5

1. Susantitaphong et al. CJASN, 2013

2. Duzova et al. Pediatr Nephrol, 2010

3. Fiser et al. Pediatr Crit Care Med, 2005

4. Jones et al. AJKD, 2012

5. Solhaug et al. Pediatr Nephrol , 1996

• Therapeutic challenge

- Complicated pathophysiology

- Multifactorial etiology

- Various preexisting comorbidities and predisposing conditions (models)

• Treatment mostly supportive

• Tissue hypoxia – Hallmark of pathogenesis of both acute1 and chronic renal disease2

1Bonventre et al. JASN 2003.

2Norman et al. Clin Exp Pharmacol Physiol. 2006

Outline



- Role of RBF


- Background



Sepsis-associated AKI (sAKI)

• Reduction in total RBF = etiology in sAKI 1

• Langenberg et al. found increased or unchanged RBF in 38% of animal studies of sepsis.2

1 Schrier et al. NEJM, 2004

2 Langenberg et al. Crit Care, 2005

Renal blood flow in septic AKI

1.Langenberg C et al. Critical Care, 2005.

62%

38%

RBF in experimental sepsis1

Decreased

Increased orunchanged

Clinical context

• AKI common in less severe sepsis

• AKI in more than 1/3 of pts with CAP despite only 16% admitted to ICU and <10% requiring vasopressors.1

1. Murugan R et al. Kidney Int. 2010;77:527-535.

Systemic Hemodynamic Parameters

Renal Parameters

Renal blood flow and oxygenation

Animal Data - sAKI

Author Experiment RBF

Langenberg et al. Intensive Care Med. 2007

sAKI - E. coli infusion in sheep

Increased

Benes et al. Crit Care. 2011

sAKI – Fecal peritonitis in sheep Decreased

Wang et al. Am J Pathol. 2012

sAKI – Mice early sepsis (4h) Decreased

Tran et al. J Clin Invest. 2011 sAKI – Mice persistent sepsis (18h) Decreased

Animal Data - sAKI

Authors Experiment Main Findings

Tran et al. J Clin Invest. 2011

Mice - LPS model at 18h using BOLD MRI No difference in tissue oxygenation

Wang et al. Am J Pathol. 2012

Mice – CLP at 18h Tissue hypoxia at 4 and 6h - pimonidazole

Clinical Data - sAKI

Authors Design Main Findings

Ricksten et al. Crit Care, 2018.

Prospective comparative. Renal blood flow: PAH Renal filtration fraction: Renal extraction of chromium-51 labeled EDTA. Renal oxygenation: estimated from renal oxygen extraction.

Lower renal oxygen delivery, impaired renal oxygenation, and tubular sodium reabsorption at a high oxygen cost compared with controls.

Prowle et al. Crit Care Med. 2012

Phase-contrast MRI in established sAKI

↓tissue oxygenation

• “The causative contribution of renal blood flow (RBF) to kidney dysfunction is particularly puzzling in sepsis, and there is widespread disagreement as to whether RBF is reduced, normal or even increased.”

Matejovic M, Ince C, Blantz R. Molitoris B, Rosner M, Okusa M, Kellum J, Ronco C, the ADQI XIII Work Group. Renal Hemodynamics in AKI: in Search of New Treatment Targets. J Am Soc Nephrol 27: 49-58, 2016.

Why the confusion?

0 2 4 6 8 10 12 14 16

Pig

Dog

Sheep

Rat

Mice

Rabbit

Species

Post EH et al. Renal perfusion in sepsis: from macro- to microcirculation. Kidney International (2017) 91, 45-60

Main point

• Significant variability in RBF in sAKI depending on the species and model of sepsis, especially on the early stages

Early changes in renal oxygen consumption

Authors Experiment Main Findings

Heemskerk et al. Nephrol Dial Transplant. 1997

Rats - E. Coli bacteremia or endotoxemia

-3h, ↓oxygen delivery ↑oxygen extraction. -↓Na transport in both. Renal oxygen consumption factored for Na reabsorption increased in both renal oxygen consumption

Porta et al. Crit Care. 2006 Pigs - Endotoxin infusion for 24h

↑Renal oxygen extraction at 12h and remained persistently elevated at 24h

Main Point

• Renal oxygen utilization increased despite a reduction in GFR and filtered tubular load

- Inefficiency in oxygen utilization for transport and/or

- Changes in basal metabolism of tubular cells

Hemodynamic changes in pediatric rat model

• CLP in rat pups 17-18 days old

• BP unchanged, but RBF decreased by 61%

Seely et al. Am J Physiol Renal Physiol, 2011.

Hemodynamic changes in pediatric rat model

• Renal microcirculatory analysis:

- ↓ number of continuously flowing cortical capillaries (69 48% by 6h) with a

- ↓ red blood cell velocity (66%)

- ↓ volumetric flow (57%)

Seely et al. Am J Physiol Renal Physiol, 2011.

The Microcirculation

• Alterations in sepsis in other organs – heart, gut, liver, brain1

• Increased proportion of capillary vessels revealing sluggish flows decrease in peritubular microvascular flow2

• Alterations in microcirculatory flow in renal cortex persisted despite improved systemic hemodynamics.3

1. De Backer D et al. Virulence. 2014;5:73-79.

2. Seely KA et al. Am J Physiol Ren Physiol. 2011;301:F209-F217.

3. Legrand M et al. Intensive Care Med. 2011;37:1534-1542.

Pathophysiology of sAKI

Ergin et al. Nephrology Dialysis Transplantation, 2014

Outline



- Role of RBF


- Background



Ischemia-reperfusion injury AKI (IR)

• Commonly seen:

- ICU patients

- Cardiac surgery with CPB1,2

1 Englberger et al. Crit Care, 2011

2 Lassnigg et al. JASN, 2004

RBF and oxygenation in animal models of IR Author Experiment Main Findings

Legrand et al. Am J. Physiol Renal Physiol, 2009.

Rats - 30 min of ischemia ↓RBF and cortical and medullary oxygenation at 3 h after reperfusion.

Siegemund et al. Anesth Analg, 2010.

Pigs - 45 min of ischemia ↓Reduced oxygenation and persistent hypoxia at 4 h of reperfusion

Pohlmann et al. PLos One, 2013.

Rats – 45 min of ischemia Cortical oxygenation at baseline after reperfusion, but outer medullary oxygenation remained persistently low

Abdelkader et al . Am J Physiol Renal Physiol, 2014

Rats – 60 min of ischemia/120 min reperfusion

No differences in cortical and inner medullary oxygenation from baseline during reperfusion

Clinical Data


Redfors et al. Crit Care Med, 2010. - Prospective, two-group comparative study. - RBF measured by: renal vein thermodilution technique and PAH,

↓GFR, RBF and Na resorption in AKI group, but renal oxygen extraction and oxygen consumption factored for Na reabsorption were nearly 2-fold higher.

Sward et al. Intensive Care Med, 2005.

Prospective two-agent interventional study RPF, GFR - infusion clearance technique for (51)Cr-labeled EDTA and paraaminohippurate

ANP: ↑ GFR, but no energy-conserving tubular effects. Furosemide: ↓ decreases tubular sodium reabsorption and renal oxygen consumption Conclusion: Furosemide has the potential to improve the oxygen supply/demand relationship in clinical ischemic acute renal failure.

Clinical Data


Lassnig et al. JASN, 2000. - 126 patients - Elective cardiac surgery - a) "renal-dose" dopamine (2

microg/kg per min) - b) furosemide (0.5 microg/kg per

min) - c) isotonic sodium chloride as

placebo

↓GFR by 12% with furosemide

Hypoxia inducible factor-1alpha (HIF-1 alpha)

• Master regulator of cellular hypoxia response

• HIF-1 target proteins functions

- vasomotor regulation

- angiogenic growth

- energy metabolism

- cell proliferation and survival1

1Gunaratnam et al. JASN 2009

• Mitochondrial metabolism

- Suppresses mitochondrial QO21

- Induces a subunit switch in complex IV of ETC to optimize its efficiency in hypoxia2

- Represses mitochondrial biogenesis and induces mitochondrial autophagy3

1 Semenza. Physiology. 2009 2 Wheaton et al. Am J. Physiol. Cell Physiol. 2010. 3 Zhang et al. J. Biol. Chem. 2008

• ….development of techniques that permit an integrative physiologic approach, including direct visualization of renal microvasculature and measurement of oxygen kinetics and mitochondrial function in intact tissue in all nephron segments, may provide new insights into how the kidney responds to various injurious stimuli and allow evaluation of new therapeutic strategies.”

Overall

• Renal hemodynamics and oxygenation have significant role in pathophysiology of AKI.

• Both preclinical and clinical studies indicate that despite reduced GFR and tubular reabsorptive load, oxygen extraction and consumption by the kidney is higher in AKI.

• Physiological biomarkers and techniques to study renal hemodynamics and tissue oxygenation and the development of novel therapeutic strategies to preserve their integrity in patients with AKI are essential

tissue oxygenation in acute kidney injury...

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