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Pathophysiology of acute kidney injury

Acute kidney injury (AKI) is defined as a sudden decline in kidney function within hours to weeks, leading to the retention of waste products. The RIFLE criteria categorizes severity into risk, injury, and failure based on serum creatinine levels and urine output. AKI has distinct etiologies and is associated with various classifications including prerenal, intrinsic, and postrenal causes, with complications affecting 5% of hospital admissions and 30% of intensive care units.

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PATHOPHYSIOLOGY OF ACUTE KIDNEY INJURY Chairperson: Prof N M Biswas Presenter: Dr Snehasis Ghosh
Definition • Acute kidney injury is characterised by sudden impairment (hours to weeks) in kidney function resulting in the retention of nitrogenous and other waste products normally cleared by the kidneys.
AKI vs ARF • The term ARF fails to describe the dynamic process. • ‘Kidney’ is more familiar.
• The loss of kidney function is most easily detected by measurement of the serum creatinine • Serum creatinine is used to estimate the glomerular filtration rate (GFR). • Serum creatinine does not accurately reflect the GFR • Recognizing the need for a uniform definition for ARF, the ADQI group proposed a consensus graded definition, called the RIFLE criteria
RIFLE Criteria • The RIFLE criteria consists of three graded levels of injury (Risk, Injury, and Failure) • Based upon either the magnitude of elevation in serum creatinine or urine output, • Two outcome measures (Loss of renal function and End- stage renal disease) • The RIFLE strata are as follows
RIFLE Strata The 2nd International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group
Epidemiology • AKI complicates approximately 5% of hospital admissions. • Up to 30% of admissions to intensive care units. • The epidemiology of AKI differs tremendously between developed and developing countries • many etiologies for AKI are region-specific.
Classification • Historically, patients with AKI have been classified as being nonoliguric (urine output >400 mL/day), oliguric (urinary out-put <400 mL/day), or anuric (urinary output <100 mL/day)
Etiologic Classification of AKI Acute kidney injury Pre-renal Intrinsic Post-renal Glomerular Interstitial VascularTubular
A. Prerenal AKI : • Pre renal AKI is the most common(55 %) form of AKI • Represents a physiologic response to mild to moderate renal hypo perfusion. • Prerenal AKI is rapidly reversible upon restoration of renal blood flow and glomerular ultrafiltration pressure.
• More severe hypoperfusion may lead to ischemic injury of renal parenchyma and intrinsic renal AKI. • Thus, prerenal AKI and intrinsic renal AKI due to ischemia are part of a spectrum of manifestations of renal hypoperfusion.
.CAUSES-PRERENAL ARF HYPOVOLEMIA >HEMORRHAGE >G-I LOSSES >DECREASED INTAKE >URINARY LOSSES >SKIN LOSSES >OTHERS:BURNS,PANCREATITIS,SEVERE HYPOALBUMINEMIA ALTERED RENAL HEMODYNAMICS LOW CARDIAC OUTPUT STATES >CHF , VALVULAR HEART DISEASE , PPV SYSTEMIC VASODILATION >SEPSIS , ANTIHYPERTENSIVES , VASODILATORS , ANAPHYLAXIS RENAL VASOCONSTRICTION >CATECHOLAMINES , HYPERCALCEMIA, DRUGS IMPAIREMENT OF RENAL AUTOREGULATION >NSAIDs , ACE-I , ARBs HEPATORENAL SYNDROME
Pathophysiology: • Hypovolemia leads to glomerular hypoperfusion, but filtration rate are preserved during mild hypoperfusion through several compensatory mechanisms. • During states of more severe hypoperfusion, these compensatory responses are overwhelmed and GFR falls, leading to prerenal AKI.
Compensatory mechanisms  EXTRINSIC: Neurohormonal mechanisms (INCREASE MAP, IMPROVE INTRAVASCULAR VOLUME)  INTRINSIC:  Tubuloglomerular feedback  Afferent arteolar dilatation  Preferential efferent arteolar constriction (IMPROVE RENAL PLASMA FLOW, GLOMERULAR PRESSURE AND GFR)
• These compensatory renal responses are overwhelmed in moderate to severe hypoperfusion. • Lesser degrees of hypotension may provoke prerenal AKI in elderly or already compromised kidneys.
NSAIDS- they reduce affarent renal vasodilation ACEIs and ARBs- limit renal efferent vasoconstriction
INTRINSIC AKI CAUSES RENOVASCULAR >ATHEROEMBOLISM >MALIGNANT HTN > >HUS > DIC >PREECLAMPSIA GLOMERULAR >AGN TUBULES-ATN ISCHEMIA >MAJOR CARDIOVASCULAR Sx >TRAUMA >HEMORRHAGE >HYPOVOLEMIA TOXINS Exogenous: Radiocontrast dye,Antibiotics-Aminoglycosides,Chemotherapeutic agents- Cisplatin, Amphotericin-B, Ethylene glycol Endogenous: myoglobin,hemoglobin,calcium,uric acid SEPSIS INTERSTITIUM Allergic: Antibiotics : b-lactam ,quinolone , rifampin NSAIDs , pyelonephritis INTRATUBULAR OBSTRUCTION acyclovir, methotrexate , indinavir , myeloma proteins
Macrovascular causes of AKI • Occlusion of large renal vessels are uncommon • Occlusion must be bilateral or unilateral on solitary kidney • Atheroemboli are most common cause • Lodge in medium and small renal arteries and incite inflammatory reaction • Thromboemboli may originate from heart in patients with atrial arrythmia. • Renal vein thrombosis is rare cause- complication of nephrotic syndrome or severe dehydration.
Microvascular causes • Inflammatory (glomerulonephritis,vasculitis),noninflamatory (malignant hypertention),thrombotic microangiopathies and hyperviscosity syndromes- All compromise blood flow – severe enough to trigger superimposed ischemic ATN.
Acute Tubular Necrosis • Ischaemic ATN • Toxic ATN
Epihtelial cell injury • The major and most commonly injured epithelial cell involved in AKI from ischemia, sepsis, or other nephrotoxins is the proximal tubular cell(S3 segment of PT in outer stripe of medulla) • The S1 and S2 segments are most commonly involved in toxic nephropathy because of their high rates of endocytosis, which leads to increased cellular uptake of the toxin.
Morphologic changes • The classical hallmark of ATN is the loss of the apical brush border of the proximal tubular cells. • Patchy detachment and subsequent loss of tubular cells exposing areas of denuded tubular basement and focal areas of proximal tubular dilatation along with the presence of distal tubular casts.
• The sloughed tubule cells, brush border vesicle remnants, and cellular debris in combination with Tamm-Horsfall glycoprotein form the classical muddy-brown granular casts.
Ultrastructural changes • Epithelial cell structure and function are mediated in part by the actin cytoskeleton. • In proximal tubule cells the actin cytoskeleton forms a terminal web layer just below the apical plasma membrane. • The core mechanism of disruption is the depolymerization mediated by the actin-binding protein known as actin depolymerizing factor (ADF) or cofilin. • Ischemic insult results in cellular ATP depletion, which in turn leads to a rapid disruption of the apical actin and disruption and redistribution of the cytoskeleton F- actin core, resulting in formation of membrane-bound extracellular vesicles or blebs.
• Another important consequence of disruption of the actin cytoskeleton is the loss of tight junctions and adherens junctions. • The actin present in the terminal web is linked to zonula occludens, and hence any disruption of the terminal web results in disruption of the tight junctions. • Early ischemic injury causes opening of these tight junctions, which leads to increased paracellular permeability producing further backleak of the glomerular filtrate into the interstitium
• Normally, Na+-K+-ATPase pumps reside in the basolateral membrane of the tubular epithelial cell, but under conditions of ischemia, they redistribute to the apical membrane. • This occurs due to the disruption of the pumps’ attachment to the membrane via the spectrin/ actin cytoskeleton • This redistribution of the Na+-K+-ATPase pump results in bidirectional transport of Na and water across the epithelial cell apical membrane as well as the basolateral membrane- mechanism of high FeNa.
Overview of injured tubular cells
Apoptosis and Necrosis • Cells undergoing sublethal or less severe injury have the capability of functional and structural recovery if the insult is interrupted. • Cells that experience a more severe or lethal injury undergo apoptosis or necrosis.
Parenchymal inflammation • Early inflammation is characterized by margination of leukocytes to the activated vascular endothelium-adhesion-transmigration. • Mediators-TNF-α, IL-6, IL-1β, MCP-1, IL-8, transforming growth factor-β, and RANTES. • Toll-like receptor 2 (TLR2) has been shown to be an important mediator of endothelial ischemic injury.
Role of ROS,Heme oxygenase,HSP • Hydroxyl radical (HO–), peroxynitrite (ONOO– ), and hyperchlorous acid (OCl–) are generated in epithelial cells during ischemic injury by catalytic conversion. • Peroxidation of lipids in plasma and intracellular membranes. • Also have vasoconstrictive effects due to their capacity to scavenge nitric oxide
• The complex heat shock protein (hsp) system is induced to exceptionally high levels during stress conditions. • Overexpression of hsp25 has been shown to be protective against actin-cytoskeleton disruption. • (Hemeoxygenase 1)HO-1 include antiinflammatory, vasodilatory, cytoprotective, antiapoptotic, and cellular proliferative effects in the setting of AKI.
Endothelial dysfunction • Endothelial cells control vascular tone, regulation of blood flow to local tissue beds, modulation of coagulation and inflammation, and permeability. • Both ischemia and sepsis have profound effects on the endothelium.
Key events in endothelial cell activation and injury
Overview of pathogenesis of Ischemic ATN
Sepsis associated AKI • Genralised arterial vasodilation mediated by cytokines and upregulated iNOS- hypotension- early afferent arteolar vasodilation- renal vasoconstriction ( sympathetic nervous system activation,RAAS,vasopressin,endothelin) • Endothelial damage- microvascular thrombosis, leukocyte adhesion and migration, ROS – tubular injury.
Nephrotoxins associated AKI • High blood perfusion, medullary concentrating property. • Risk factors- Older age, CKD, prerenal azotemia, hypoalbuminemia.
Contrast agents induced AKI • Negligible with normal renal function. • Thought to occur from combination of 1. Hypoxia in renal outer medulla 2. Cytotoxic damage to tubules directly or via ROS 3. Transient tubule obstruction with precipitated contrast material.
Antibiotics • Aminoglycosides- Tubular necrosis(nonoliguric AKI) • Amphotericin B- Renal vasoconstriction via increased tubuloglomerular feedback, also tubular injury ( induces pores ). • Acyclovir- gets precipitated in tubules (risk increases in hypovolemia, bolus doses) • Foscarnet,Pentamidine,Cidofovir-Tubular necrosis • Penicillins,Quinolones,Sulfonamides,Rifampin- Acute interstitial nephritis.
Cytotoxic drugs • Platins- accumulates in pct and cause necrosis and apoptosis • Ifosfamide- Tubular toxicity(Type II renal tubular acidosis) • Bevacizumab,Mitomycin C- Thrombotic microangiopathy. • Cyclosporine- Afferent and efferent arteriolar vasoconstriction, tubular cell membrane damage
Environmental toxins • Ethylene glycol- metabolites cause direct tubular injury • Diethylene glycol- metabolite 2HEAA • Melamine-nephrolithiasis and AKI by tubular obstruction
Endogenous toxins • Myoglobin- muscle injury, rhabdomyolysis • Hemoglobin- massive hemolysis Cause intrarenal vasoconstriction, direct proximal tubular toxicity, mechanical obstruction. • Uric acid- Tumor lysis syndrome (serumlevel> 15 mg/dl)- precipitated in tubules • Myeloma light chains- intratubular casts with THP, direct tubular injury • Hypercalcemia- renal vasoconstriction,
Postrenal AKI • The normally unidirectional flow of urine is acutely blocked either partially or totally, leading to increased retrograde hydrostatic pressure and interference with glomerular filtration. • For AKI to occur in healthy individuals, obstruction must affect both kidneys unless only one kidney is functional, • Unilateral obstruction may cause AKI in the setting of significant underlying CKD or from reflex vasospasm of the contralateral kidney.
• Hemodynamic alterations are triggered by an abrupt increase in intratubular pressure. • Initial period of hyperaemia from afferent arteriolar dilation- followed by intrarenal vasoconstriction from the generation of angiotensin II, thromboxane A2, and vasopressin, and a reduction in NO production- decreased GFR.
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