short speech describing the major pathophysiological processes responsible for acute kidney injury understood.

1. PATHOPHYSIOLOGY OF ACUTE
KIDNEY INJURY
Chairperson: Prof N M Biswas
Presenter: Dr Snehasis Ghosh

2. 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.

3. AKI vs ARF
• The term ARF fails to describe the dynamic
process.
• ‘Kidney’ is more familiar.

4. • 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

5. 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

6. RIFLE Strata
The 2nd International Consensus Conference of the Acute
Dialysis Quality Initiative (ADQI) Group

7. 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.

8. 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)

9. Etiologic Classification of AKI
Acute kidney injury
Pre-renal Intrinsic Post-renal
Glomerular Interstitial VascularTubular

11. 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.

12. • 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.

13. .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

14. 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.

15. 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)

16. • 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.

17. NSAIDS- they reduce affarent renal
vasodilation
ACEIs and ARBs- limit renal efferent vasoconstriction

19. 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

21. 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.

22. Microvascular causes
• Inflammatory
(glomerulonephritis,vasculitis),noninflamatory
(malignant hypertention),thrombotic
microangiopathies and hyperviscosity
syndromes- All compromise blood flow –
severe enough to trigger superimposed
ischemic ATN.

23. Acute Tubular Necrosis
• Ischaemic ATN
• Toxic ATN

24. 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.

26. 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.

27. • The sloughed tubule cells, brush border
vesicle remnants, and cellular debris in
combination with Tamm-Horsfall glycoprotein
form the classical muddy-brown granular
casts.

28. 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.

29. • 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

30. • 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.

31. Overview of injured tubular cells

32. 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.

34. 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.

35. 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

36. • 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.

37. 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.

38. Key events in endothelial cell
activation and injury

39. Overview of pathogenesis of Ischemic
ATN

40. 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.

41. Nephrotoxins associated AKI
• High blood perfusion, medullary concentrating
property.
• Risk factors- Older age, CKD, prerenal
azotemia, hypoalbuminemia.

42. 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.

43. 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.

44. 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

45. Environmental toxins
• Ethylene glycol- metabolites cause direct
tubular injury
• Diethylene glycol- metabolite 2HEAA
• Melamine-nephrolithiasis and AKI by tubular
obstruction

46. 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,

47. 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.

49. • 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.

50. Thank You