2024 HD Academy Pathophysiology of AKI PDF

NEPHROBERN Pathophysiology of Acute Kidney Injury (AKI) Thierry Francey Dr. med. vet., Dipl. ACVIM (SAIM), ECVIM-CA, Founder ACVNU Small Animal Internal Medicine / Nephrology...

NEPHROBERN Pathophysiology of Acute Kidney Injury (AKI) Thierry Francey Dr. med. vet., Dipl. ACVIM (SAIM), ECVIM-CA, Founder ACVNU Small Animal Internal Medicine / Nephrology Department of Clinical Veterinary Medicine Vetsuisse Faculty University of Bern (Switzerland) tf-2024 Outline: Pathophysiology of AKI Definition General pathophysiology of injury Renal repair Specific pathophysiology Ischemia – reperfusion Sepsis Toxic nephrosis Acute kidney injury (AKI) is increasingly recognized in small animal veterinary practice (). In recent years, there has been a focus on the identification of not only community- but also hospital- acquired AKI, with the latter recognized through increased awareness of risk factors that may drive development of AKI, enhanced ability to monitor and detect early change in kidney function, and the provision of advanced veterinary care for veterinary patients with AKI such as renal replacement therapies ().   Mortality rate: non-AKI 9% AKI 39%  Odds ratio for survival when AKI present (compared to no AKI): 0.2 77 dogs with abdominal surgery for septic peritonitis  Odds of survival to discharge decreased by 31 dogs (40%) with AKI 40% per 0.1 mg/dL increase in creatinine 18 @ presentation 13 post-op => what are the mechanisms of injury to the kidney ? Definition of AKI (hum) Acute kidney injury (AKI) is defined by a rapid increase in serum creatinine, decrease in urine output, or both. AKI is not a single disease but rather a loose collection of syndromes as diverse as sepsis, cardiorenal syndrome, and urinary tract obstruction.  Ischemia – reperfusion injury  Sepsis  Infection (leptospirosis, pyelonephritis)  Nephrotoxicity  Obstruction Ronco C, et al. Acute Kidney Injury. The Lancet (2019)  * "… a loose collection of syndromes" * * * * * * Ronco C, et al. Acute Kidney Injury. The Lancet (2019) Definition of AKI (vet) Acute kidney injury: spectrum of diseases associated with a sudden onset of renal parenchymal injury most typically characterized by generalized failure of the kidney to meet the excretory, metabolic, and endocrine demands of the body.  Rapid hemodynamic, filtration, tubulointerstitial, or outflow injury to the kidneys  Subsequent accumulation of metabolic toxins and dysregulation of fluid, electrolyte, and acid-base balance  AKI:  broad spectrum of acute diseases of the kidney  concept of a continuuum of functional and parenchymal damage Cowgill LD, Langston C. Acute Kidney Insufficiency. Nephrology and Urology of Small Animals (2011) Definition of AKI (vet) AKI can range from a mild renal insult to overt renal failure. The development of an AKI implies that there has been sudden renal injury, decline in renal function or both. AKI can be either community or hospital acquired: Community acquired AKI : the initial renal insult occurs whilst the patient is outside of the hospital setting. Delay of a few days between insult and presentation. Hospital acquired AKI: the initial insult occurs during the period of hospital treatment. Early detection is based on frequent monitoring of markers of renal function or injury and has important prognostic implication. IRIS AKI Consensus Group (2024) AKI: why a new name? Functional definition Lesional definition Acute renal failure Acute kidney injury Functional markers: GFR, surrogates of Injury markers: urine sediment, casts, GFR (creatinine, cystatin C, SDMA), USG renal glucosuria, uGGT, uNAG Long been the traditional definition due to Newer markers in development the lack of robust injury markers missing early phases can include early lesions (poor sensitivity, delayed increase) Pathophysiology - Historical Classification Pre-renal AKI Physiologic response to renal hypoperfusion without tubular injury. "Functional change in GFR". Integrity of the renal parenchyma not disrupted. Intrinsic renal AKI Parenchymal injury. Glomerular, tubular, vascular, interstitial. Post-renal AKI Impaired flow of urine (obstruction, rupture). General Pathophysiology – The Phases of AKI Renal lesion (kidney injury) I – Initiation II - Extension lethal lesion sublethal lesion III - Maintenance IV - Recovery Repair Scarring Uremic death Complete recovery Chronic kidney disease (= CKD IRIS 1) (chronic on acute) Mod. from Cowgill & Francey (2005) Basile DP, et al. Pathophysiology of Acute Kidney Injury. Compr Physiol (2012) Pathophysiology - Five Characteristics  Microvascular imbalance  Tubular dysfunction and intratubular obstruction  Cell death (apoptosis, necrosis)  Inflammation  Adaptive and maladaptive repair Zuk A, Bonventre JV. Acute kidney injury. Annu Rev Med (2016) Question The kidney receives 20% of the cardiac output, more than any other organ on a ml/g basis. Why then is it so sensitive to ischemic injury ? (Micro-)Vascular Imbalance in AKI  Imbalance vasodilatory – vasoconstrictive factors  Mismatch between O2 and nutrient delivery and energy demand  Often regional (and not generalized) in the kidney  Kidney not a priority organ  Complex relationship vascular - tubular compartments Waikar SS, et al. NKF Primer on Kidney Diseases (2014) Basile DP, et al. Pathophysiology of Acute Kidney Injury. Compr Physiol (2012) Endothelial Injury (Microvascular Events) Dysbalance between vasodilatory (PGE2, PGI2, NO) and vasoconstrictive (endothelin, prostanoids, ATII) mediators Energy deprivation of the endothelium → cell swelling, RBC sludging Increased permeability → edema Release of cytokines, chemokines, adhesion molecules → inflammation, edema, sludging  ↓ Parenchymal perfusion  ↓ O2 and nutrient transport  ↓ Tubular reabsroption function Peerapornratana S, et al. Acute Kidney Injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment. Kidney Int (2019) Peerapornratana S, et al. Acute Kidney Injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment. Kidney Int (2019) General Pathophysiology – At the Cellular Level…  Sublethal cell injury (loss of brush border and polarity, cellular detachment)  Apoptosis  Necrosis Molitoris & Finn. Acute Renal Failure (2001) General Pathophysiology – At the Cellular Level…  Cytoskeleton damage  Loss of polarity & loss of the brush border  Cell detachment (sloughing)  Necrosis or apoptosis  Backleak of filtrate  Migration, de-differentiation, proliferation of viable cells  Differentiation  Re-polarisation  Functional epithelial cell Waikar SS, et al. NKF Primer on Kidney Diseases (2014) Basile DP, et al. Pathophysiology of Acute Kidney Injury. Compr Physiol (2012) Epithelial Injury – Mechanisms of Cell Injury Ischemia → ATP depletion → loss of ionic gradients, perturbation of intercellular junctions, cell swelling, ↑ intracellular Ca, activation of intracellular lipases and proteases → mitochondrial dysfunction → activation of phospholipases → AA accumulation → production of eicosanoids (vasoactive, chemotactic) → functional and cytotoxic injury Reperfusion → reactive oxygen species (ROS) → lipid peroxidation, protein denaturation, DNA damage Epithelial Injury – Fate of Renal Tubular Cells Sublethal injury disruption of cytoskeletal network loss of polarization (Na-K-ATPase) loss of apical brush border loss of adhesion molecules (basolateral) cell detachment from the basement membrane Necrosis "chaotic" process with rupture of plasma cell membrane → release of proinflammatory cell content (DAMPs: IL33, F-actin, dsDNA, RNA…) Apoptosis highly regulated, programmed mechanism of cell death → not inflammatory Interstitial Events (Inflammation, Edema) Injury (Ischemia) → ATP depletion → HIF gene upregulation → Inflammation → ROS  Inflammation and recruitment of leukocytes as key mediators of all phases of AKI  Initially: activation of resident inflammatory cells Later: recruitment and invasion of WBC  All inflammatory cells involved (neutrophils, monocytes, dendritic cells, T cells)  M1 macrophages: inflammation in early phase M2 macrophages: anti-inflammatory post-ischemia; facilitate recovery  Systemic inflammation (IL6 in sepsis) can lead AKI Intrarenal inflammation induces inflammation in other organs (heart, lung, liver) Ostermann M, et al. Pathophysiology of AKI. Best Pract & Res Clin Anesth (2017) Ostermann M, et al. Pathophysiology of AKI. Best Pract & Res Clin Anesth (2017) Interstitial Events (Inflammation, Edema) DAMP: damage-associated molecular patterns released from injured tissues [histones, heat shock proteins, fragmented ECM…] PAMP: pathogen-associated molecular patterns released from pathogens  "Danger signals"  Both prime and signal to the immune system  Interaction with sensors of the innate immune system (pattern recognition receptors, PRR)  Glomerular filtration of DAMP/PAMP Tubular leakage → exposure of the renal parenchyma Peerapornratana S, et al. Acute Kidney Injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment. Kidney Int (2019) Inflammation - Central Role for Macrophages Biphasic phenotypes M1 pro-inflammatory (activated) o First 24-48h o M1-cytokines: IL-1, IL-6, IL-12, iNOS, TNF o Activated by binding of DAMPs / PAMPs to PRRs o → remove damaged and pathogenic particles M2 anti-inflammatory (reparative, pro-regenerative) o Secrete TGFβ, MMP o → suppress inflammatory response, contribute to tissue repair, vasculogenesis o M-CSF produced by PTC after injury Radi ZA. Immunopathogenesis of Acute Kidney Injury. Toxicol Pathol (2018) Huen SC, et al. Macrophages in Renal Injury and Repair. Annu Rev Phys (2017)  Tubular epithelium & tubular lumen Vascular endothelium AKI Interstitium Zuk A, Bonventre JV. Acute kidney injury. Annu Rev Med (2016)  Tubulo-Glomerular Feedback: function loss exacerbated Alicic RZ. Diabetic Kidney Disease. CJASN (2017) Tubulo-Glomerular Feedback: function loss exacerbated Proximal tubular injury & dysfunction  Increased solute delivery to the macula densa (Na, Cl) in the distal tubule  Afferent vasoconstriction  Decreased SN-GFR  Contribution to oliguria  Tubulo-Glomerular Feedback: function loss exacerbated Although controversial, evidence supports a role for chloride in the macula densa sensing mechanism, renin release, and regulation of GFR. TGF ultimately involves a complex interplay of additional factors, such as luminal osmolality, cell volume, cytosolic calcium, tubular flow, ATP, adenosine, nitric oxide, ANG II, atrial natriuretic peptide, dopamine, and other autocrine and paracrine factors. Rein JL et al. “I don’t get no respect”: the role of chloride in acute kidney injury. Am J Physiol Renal Physiol 316: F587–F605, 2019 Liu KD, et al. AKI!Now Initiative: Recommendations for awareness, recognition, and management of AKI. CJASN (2020)  After the Insult… Thadhani R, et al. Acute renal failure. NEJM (1996) Kidney Repair Adaptive repair → restore normal cell and tissue homeostasis → replacement of lost epithelial cells by proliferation Maladaptive repair When injury is severe or sustained Balance tips to maladaptive responses Macrophage infiltration correlates with scarring → cell and tissue malfunction → inflammation and fibrosis → progression to CKD Zuk A, Bonventre JV. Acute kidney injury. Annu Rev Med (2016)  Healthy Kidney Kidney Repair Activation of cellular stress response I N JURY Activation of cell death pathways Activation of the innate immune response AKI Adaptive response Maladaptive inflammatory pathways DAMPs : damage associated molecular patterns Recruitment of macrophages PRRs: pattern recognition receptors (M2, profibrotic, anti-inflammatory) - TLRs: Toll-like receptors Epithelial cells in G2/M arrest - NLRs: NOD-like receptors Cytokines & growth factors Pericytes dissociations from TGFβ endothelium → endothelial dysfunction, Clearance of cellular debris microvascular loss Tissue repair Maladaptive repair Fibrosis Myofibroblasts proliferation Pericytes proliferation Adaptive repair ECM deposition Normal cell & tissue homeostasis CKD Maladaptive Repair Role of macrophages Macrophage infiltration correlates with scarring and fibrosis (glom., interst., tubul., vasc.) Differential inflammatory signatures o Acute injury phase: pro-inflammatory signature M1 o Subacute, repair phase: wound healing signature M2 o Progression phase to CKD: pro-fibrotic signature M2 Role of tubular epithelial cells Expression of KIM-1 → secretion of MCP-1 → macrophage chemotaxis Cell-cycle perturbation (G2/M arrest mediated by cell-cycle regulatory protein p53) → pro-fibrotic cytokines (TGFβ, CTGF) → pro-inflammatory signalling factors → stress-induced senescence → maladaptive repair with inflammation and fibrogenesis Zuk A, Bonventre JV. Acute kidney injury. Annu Rev Med (2016) Maladaptive Response Zuk A, Bonventre JV. Acute kidney injury. Annu Rev Med (2016) Adaptive Response Basile DP, et al. Pathophysiology of Acute Kidney Injury. Compr Physiol (2012) Open question: Tubular repopulation from de- dedifferentiated surviving tubular cells or from tubular progenitor cells ? Most likely a combination of adaptive repair + regeneration of progenitor cells Angelotti ML, et al. Localization of injury and repair pathways. Critical Care Nephrology (2019) Epithelial-to-mesenchymal transition AKI "scar war" Ming-Chang H. Nature Rev Nephrol (2012)  Can we influence kidney repair? Lupus News Today (2015) Waikar SS, et al. NKF Primer on Kidney Diseases (2014) Antifibrotic strategies Tampe D, et al. Potential approaches to reverse or repair renal fibrosis. Nat Rev Nephrol (2016) AKD: acute kidney disease Ischemia Reperfusion Injury (IRI)  Proximal tubular cell @ cortico-medullary junction + outer medulla (high O2 consumption, marginal perfusion) IRI triggers an inflammatory cascade causing even more injury: Pro-inflammatory cytokines (IL6, TNF-α) Adhesion molecules expression (ICAM-1) Inflammatory leukotriene pathway (5-LO) Leukocyte infiltration and activation Generation of reactive oxygen species (ROS) at reperfusion phase initiates a cascade of deleterious cellular responses leading to inflammation, cell death, and acute kidney failure. Malek M, et al. Renal Ischemia / Reperfusion Injury; from Pathophysiology to Treatment. J Renal Inj Prev (2015) Immediately following ischemia Hours later ↓ Renal blood flow ∆ Regional repartition blood flow Basile DP, et al. Pathophysiology of Acute Kidney Injury. Compr Physiol (2012) Sepsis-induced AKI Combination of multiple mechanisms: Ischemia-reperfusion injury and microcirculatory dysfunction [endothelial injury, loss of glycocalyx] Inflammation [triggered by PAMP, DAMP and recognized by pattern recognition receptors] Metabolic reprogramming [cell survival prioritized at the expense of cell and organ function]  Histopathological findings not as severe as expected from the clinical picture  Heterogenous patchy tubular injury  Mininimal tubular epithelial cell death Peerapornratana S, et al. Acute Kidney Injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment. Kidney Int (2019) Nephrotoxic AKI Kidney predisposed to toxic injury: High blood supply (20% of cardiac output) Filtration and tubular concentration → exposure of the tubular epithelium Tubular reabsorption Multiple mechanisms Altered renal hemodynamics (NSAIDs, ACEi, ARB) Interstitial inflammation (acute eosinophilic interstitial nephritis) Direct tubular epithelial toxicity (ethylene glycol, aminoglycosides) Vascular injury (antineoplastics) Intratubular obstruction (sulfonamides, oxalate, melamine) Osmotic nephrosis (mannitol, HES)  Take home messages...  AKI often results from a complex interplay of multiple mechanisms that occur commonly in systemic diseases  Inflammation is a central event in AKI, even in non-infectious causes Tubular epithelium & tubular lumen Vascular endothelium AKI Interstitium