Acute Kidney Injury - Pathogenesis

1. ACUTE KIDNEY INJURY

2. OUTLINE
• Epidemiology
• Definition - RIFLE , AKIN ,KDIGO
• Causes
• Pathology and Pathophysiology
• Nephrotoxins and AKI
• Approach to AKI
• Investigative modalities

3. EPIDEMIOLOGY
• A major public health problem globally associated with high
mortality,morbidity and long term risk of CKD
• CA-AKI/HA-AKI
• Relatively younger patients in India ( 40 to 50 years)
• 1 % at the time of admission to hospital
• 2 to 5 % indidence during hospitalization
• 1% in one month of post operative period for general surgery
cases.
• 50% to 65% in ICU patients

4. DEFINITION

5. RIFLE CRITERIA
• The acronym RIFLE denotes increasing severity classes Risk, Injury,
and Failure; and the two outcomes,Loss and End-stage renal
disease (ESRD).
• The three severity grades are defined on the basis of changes in
serum creatinine (SCr) or urine output where the worst of each
criterion is used, whereas the two outcome criteria, Loss and
ESRD, are defined by the duration of kidney failure.

7. AKIN CLASSIFICATION
Modification of RIFLE Criteria
1. Broadening of the ‘Risk’ category of RIFLE to include an increase in absolute SCr
concentration of at least 0.3 mg/dL (26.4 μmol/L) even if this does not reach the 50%
threshold as long as it is documented to occur within a 48-hour window .
2. Categorizing patients as ‘Failure’ if they are treated with renal replacement therapy
(RRT), regardless of what their SCr or urine output is at the point of initiation of RRT .
3. GFR was discarded as a criteria

8. KDIGO
• The KDIGO criteria only utilize changes in SCr and urine output, and
not changes in GFR for staging, with the exception of children under
the age of 18 years, for whom an acute decrease in estimated GFR
to < 35 mL/min per 1.73 m2 is included in the criteria for stage 3
AKI .

10. Caveats in using the serum creatinine
Reduction in creatinine production.
- Reduction in GFR canoccur in critically ill patients with unchanged
creatinine levels because of a reduction in creatinine generation
rate correlating with the degree of illness severity .
- Thus in sicker patients, increases in creatinine concentration could
be smaller and occur more slowly than in less sick patients with
the same AKI severity.

11. Risk factors for development of acute
kidney injury
AKI is most often a consequence of another severe disease. In
the large, international, multicentre BEST Kidney study in
Critically ill patients,
-Sepsis (47.5%)
-Major surgery (34.3%)
-Cardiogenic shock (26.9%)
-Hypovolaemia (25.6%)
-Drug-induced causes (19.0%)
- Hepatorenal syndrome (5.7%)
- Obstruction (2.6%)

12. Risk factors for development of acute
kidney injury
- Gene polymorphisms for a number of factors (ACE, cytokines,
hypoxia-inducible factor 1α and others)
- Older patients and men
- Multiple co-morbidities, including diabetes mellitus,
cardiovascular disease, chronic liver disease, malignancy.

13. CAUSES OF AKI

17. PATHOLOGY AND
PATHOPHYSIOLOGY OF AKI

18. Common morphologic findings
- Dilation of the tubules
- Flattening and desquamation of tubular epithelium
- Presence of granular and brownish-reddish casts
- Focal infiltration and oedema of the proximal tubular epithelium and the
interstitium.
- Mitotic figures in the proximal and distal epithelial cells; and occasional
tubular Necrosis
- Although glomerular abnormalities are rare, a common finding is that of
glomerular tubularization substitution of parietal epithelia of Bowman’s
capsule with proximal tubular epithelia

19. Renal blood flow and glomerular filtration rate
Proximal tubular pressure-
• Hydrostatic pressure more than doubles within the first 1–2 hours
post ischaemia, then slowly declines.
• Desquamation of tubular epithelium into the lumen
• Reason for lack of efficacy of treatments based solely on enhancing
RBF.
• Interstitial pressure – Tubulorrhexis leads to decline in proximal
tubular pressure and restoration of glomerular filtration, on the one
hand, and elevation of interstitial pressure (as discussed below), on
the other.

21. Epithelial and endothelial cell injury as a basis for
tubular and hemodynamic abnormalities
Epithelial cell injury
↓
Cell stress
↓
Elevation of cytosolic calcium concentration and activation of cysteine
proteases calpains.
↓
Calpastatin, which dissociates upon elevation of cytosolic calcium,
↓
Hydrolysis of plasma membrane and cytoskeletal proteins, especially
ankyrin and α-fodrin
↓
Activation of calpain results in proteolytic cleavage and disassembly of
focal adhesions, and collapse of the membrane-anchored cytoskeleton

22. Consequences of the hydrolysis of cytoskeletal
proteins
- Epithelial desquamation
- Desquamation from the basement membrane take place in
endothelial cells and result in the appearance of detached
cells in the circulation.
- Denuded patches of basement membrane become sites of
platelet aggregation, portals for leucocyte infiltration, and
foci of vasoconstriction

23. Endothelial cell injury
• Blood flow in glomerular and peritubular capillaries becomes
stagnant, retrograde, or oscillatory (alternating forward and
retrograde).
• The pro-inflammatory phenotype of endothelial cells is
activated when subjected to oscillatory shear stress .
1)Reduced bioavailable nitric oxide (NO) .
2)Downregulation of antioxidative peroxiredoxin and induction of
mitochondrial superoxide production and NADPH oxidase.
- Lead to endothelial cell activation and dysfunction.

24. Pathophysiologic consequences of
oscillating shear stress

25. Pathophysiologic consequences of
oscillating shear stress
- Laminar fluid shear stress is a physiological stimulus for
endothelial production of autocoids, nitric oxide synthase (NOS)
activation, and generation of NO .
- Stagnation of blood flow and oscillatory pattern ofblood flow, as
mentioned above, produce opposite effects, thus predisposing to
prevailing vasoconstriction.

26. R

27. Role of Endothelin
- Ischaemic, endotoxic,and nephrotoxic (ciclosporin, contrast media,
tumour necrosis factor(TNF), thrombin, epinephrine) insults
stimulate production and release of ET-1 from the activated
endothelial cells
- The coordination of this functional coupling between ET-1 and NO
systems is lost in AKI.
- eNOS - prevention of platelet aggregation and leucocyte–
endothelial cell adhesion and transmigration, the key anti-
inflammatory effects of NO.

28. Cellular actions of endotoxins:
Pathogenesis of sepsis induced AKI
• In endotoxic shock,renal ischaemia secondary to the fall of RBF
is no longer valid .
• Predominant vasodilatation of the efferent rather than afferent
arterioles imbalance in intraglomerular vasomotor control is
probably only one step in the development of the sepsis-
induced AKI.

29. Microcirculatory changes in Sepsis
• All septic patients demonstrated acute tubular lesions, intense glomerular
and interstitial infiltration by leucocytes, and presence of tubular cell
apoptosis (3% of tubular cells).
• LPS and TNF-ALFA induce apoptotic cell death.
• Upregulation of complement and coagulation cascade.
• Breach in the endothelial barrier.

30. Cellular actions of nephrotoxins
• The severity of critical illness requires the administration of
several therapeutics, increasing the risk of a drug-related
nephrotoxicity
• The role of drugs in the development of AKI is a major
contributing factor in 19–25% of AKI

31. • NSAIDS
• The NSAIDs block cyclooxygenase (COX), the enzyme that converts
arachidonicacid into the proinflammatory and afferent vasodilatory
prostaglandin.
• Calcineurin inhibitors-
- Acute (haemodynamically mediated) or chronic (interstitial damage) renal
side effects.
- Calcineurin inhibitors induce afferent arteriolar vasoconstriction due to an
increased endothelin and thromboxane A2 production and to reduction of
vasodilatory prostaglandins and nitric oxide production.
- This will provoke a reduction of RBF and GFR.

32. Aminoglycosides
• Proximal tubular damage-Rupture of lysosomes
• Production of ROS
• Stimulate production of ET-1 , PAF , TXA2
Cisplatin
• Cell cycle dysregulation,mitochondrial toxicity
• Acute phase-reversible renal vasoconstriction
• Chronic-Tubular atrophy,TI fibrosis
• Down regulation of TRPM6 and NCC in DCT-Loss of
Magnesium and sodium

33. Vancomycin –
• Proximal tubular cells
• Mitochondrial dysfunction,superoxide production,cell
apoptosis
Amphotericin B
• In upto 80% of patients
• Increased tubular permeability-Sodium,potassium and
Magnesium wasting
• Afferent arteriolar vasoconstriction

34. Radio contrast dyes (CM)
• Iodide ion-cytotoxic-Disrupts the cell membrane
• CM generates ROS/oxidative stress/vaso constriction
• Vasa recta in renal medulla is very sensitive to CM
Acute tubulointerstitial nephritis-
Hypersensivity reaction to drugs/infections/systemic disease

35. Osmotic Nephrosis –
• IVIg,Radiocontrast media,HES
• Renal failure appears 2-4 days after the drug
administration and is usually reversible

37. Post obstructive AKI –
• Intratubular precipitation of drugs and metabolites, or increased
resistance to urine flow in the lower urinary tract.
• The obstruction results in dilatation of the urinary tract above the site
of obstruction, increase of hydrostatic pressure, and a decrease of
GFR.
• Bilateral obstruction and hydronephrosis can lead to renal failure
• Intravenous high doses of aciclovir, methotrexate, sulfadiazine,
and foscarnet are some of the drugs leading to tubular precipitation
and potential obstructive nephropathy

38. • From injury to regeneration
• In clinical practice, a typical case of recovery from oliguric AKI is
seen as conversion to the diuretic phase accompanied by a
progressive increase in urine volume
• It is followed by recovery phase, characterized by a gradual
restoration of GFR, the process that may last 3–12 months and
rarely results in a complete functional Recovery
• The final result of AKI in a typical case is a variable combination of
tissue scarring and regeneration, shifted more towards scarring in
elderly individuals and towards regeneration in younger ones.

40. APPROACH TO PATIENT WITH AKI

41. Clinical evaluation of the patient with AKI
This evaluation should at least address six questions:
1. Is there immediate need for therapeutic intervention because of a life
threatening complication?
2. Is the renal dysfunction acute, acute-on-chronic, or chronic?
3. Is there evidence of true hypovolaemia or reduced effective arterial
blood volume, that is, is the AKI prerenal or renal and can renal
dysfunction be corrected by improving kidney perfusion?
4. Is there a major vascular occlusion?
5. Is there evidence of renal parenchymal disease other than ATN?
6. Is the cause of AKI urinary tract obstruction, that is, ‘post-obstructive’
AKI?

42. Differentiating acute from chronic
kidney disease
• Anaemia,hyperphosphataemia,hypocalcaemia,hyperparathyroidism,
neuropathy, band keratopathy, and imaging evidence of renal
osteodystrophy or of small scarred kidneys are useful pointers to a
chronic process.
• In CKD, the kidneys will usually be small (< 10 cm longitudinally in a
person of normal stature) and echogenic; however, normal-sized
kidneys on ultrasound do not absolutely exclude CKD.
• It should be remembered that anaemia, hyperphosphataemia, and
hypocalcaemia may also complicate prolonged AKI.

43. Urine volume in the diagnosis of AKI
• Urine volume in AKI can vary from oliguria (i.e. < 500 mL/24 hours
or < 20 mL/hour) and even anuria (i.e. < 100 mL/24 hours) to
polyuria.
• Achieve euvolemia
• Monitor hourly urine output to assess the initial response to fluid
resuscitation
• Incresed urine flow should not be regarded as primary treatment
goal.
• Oliguric vs Non oliguric AKI

44. • Anuria - RPGN,Acute cortical necrosis,Total arterial/venous
obstruction,complete urinary tract obstruction.
• Prerenal forms of AKI nearly always present with oliguria.

45. Physical examination in the differential
diagnosisof intrinsic AKI
• Blood pressure – Hypotension/Relative hypotension / Higher
than normal BP
• Skin examination-Vasculitis/Hypersensitivity/Athero emboli
• Neck - JVP
• CVS
• Pharyngeal examination
• Abdominal examination

46. Abdominal hypertension
• IAH- 12mmhg
• ACS- 20mmhg with new organ dysfunction / failure
• Primary vs Secondary ACS
• Assessment of the patient’s volume status/the effect
of a fluid challenge
• The general and renal response to a fluid challenge is often an
important diagnostic test in differentiating ‘transient’ AKI
from ‘established’ AKI, mostly ATN.

47. • When performing a fluid challenge, four items must be
defined in advance, which can be summarized by the
acronym, TROL:
1. Type of fluid (e.g. Ringer’s lactate or isotonic saline)
2. Rate of infusion (e.g. 500 mL in 30 min)
3. Objective (e.g. increase in arterial pressure to 75 mmHg or
urine output > 20 mL in 30 min)
4. Limits (e.g. a maximal increase in CVP of 3 mmHg from a
baseline of 12 mmHg).

49. EXCEPTIONS
• High FENa despite the presence of prerenal AKI occurs during
diuretic treatment, including mannitol,glycosuria,excretion of
alkaline urine.
• ATN in the setting of rhabdomyolysis and myoglobinuria,
haemolysis, cirrhosis, heart failure, sepsis , obstruction, acute
glomerulonephritis and radiocontrast nephropathy may be
associated with a low UNa (e.g. < 10 mmol/L) and FENa of
< 1 % .
• A urinary osmolality value > 500mOsm/kg indicates thus an
intact tubular function and is to be expected in prerenal AKI.

50. Urine dipstick
• The presence of > 1–2 g/day of urine protein suggests a glomerular
cause of AKI but in many cases of ATN significant proteinuria may
be present, due to disturbances of tubular albumin reabsorption.
The urine sediment
• Gross or microscopic haematuria, particularly with dysmorphic red
cells or red cell casts in the urinary sediment, suggests a glomerular
disease.
• Macroscopic Haematuria -vascular, interstitial, or other structural
renal cause of AKI (e.g. stone, tumour, infection, or trauma) and is
rarely seen with ATN.
• Eosinophiluria (> 1% of urine WBCs) - Allergic interstitial nephritis,
cholesterol embolism,or in some forms of glomerulonephritis.

51. The furosemide stress test
• 2-hour urine output after a standardized high-dose FST (1
mg/kg of furosemide in naïve patients or 1.5 mg/kg in those
with prior exposure to furosemide) in clinically euvolaemic
patients with early AKI has the predictive capacity to identify
those with severe and progressive AKI .
• The ideal cut-off for predicting progressive AKI during these first 2
hours was a urine volume of 200 mL (100 mL/hour) with a
sensitivity of 87.1% and a specificity of 84.1%.

52. IMAGING PROCEDURES

53. Renal ultrasonography
• Mandatory in patients with AKI if obstructive nephropathy is
suspected - Hydronephrosis
• Other sensitive ultrasonographic findings to rule out postrenal
AKI are a post–void residual bladder urine < 50 mL and
absence of pelvicalyceal dilatation.
• Increased cortical echogenicity can be seen in nephrotoxic
ATN where as enlarged hypoechoic cortex may be more
typical of ischemic ATN.

54. Renal Doppler Ultrasonography
• RRI-Renal resistivity index
• Differentiate transient AKI from established AKI
• RRI more than 0.74.
• The RRI predicted delayed AKI with high sensitivity and specificity
(0.85 and 0.94) respectively.

55. IVU AND CT SCAN
• Intravenous urography is nowadays largely abandoned in patients
with AKI given the need for potentially nephrotoxic contrast media.
• A plain radiograph of the abdomen is a mandatory investigation .
• CT is superior in the evaluation of ureteral obstruction, since it
can delineate the level of obstruction and define retroperitoneal
inflammatory tissue (in retroperitoneal fibrosis) or a retroperitoneal
malignant mass

56. MRI
• MR angiography can be useful for detecting abnormalities in the
renal artery and vein.
• The diagnosis of acute renal cortical necrosis in particular becomes
more reliable with gadolinium-enhanced MRI. The ‘rim sign’ is
characteristic for this infrequent cause of AKI.
• Increasingly reported incidence of the syndrome of nephrogenic
systemic fibrosis
• It is not recommended to use gadolinium-containing compounds
unless unavoidable, in patients with a GFR < 30–40 mL/min.

57. Renal angiography
- Blood clot - embolization, thrombosis
- Aneurysm
- Stenosis
- AVM
- Occlusion

58. Role of Renal Biopsy
• RPGN, vasculitis, and AIN.
• In patients diagnosed with AKI and normal-sized kidneys, who
do not recover kidney function after 3–4 weeks, a kidney biopsy
may be indicated to confirm the cause of AKI, to exclude other
treatable causes, and determine the prognosis.
• AKI after transplantation when it is often essential for
distinguishing between ischaemic AKI, acute rejection, and
calcineurin inhibitor toxicity.

59. SUMMARY-PATHOGENESIS
• The combination of haemodynamic and tubular dysfunction is
responsible for the pathogenesis of the syndrome of AKI.
• Haemodynamic compromise is in most cases a result of excessive
vasoconstriction and defective vasorelaxation, except for the
endotoxaemia-induced AKI.
• Tubulopathy, on the other hand, is manifested by the desquamation of
proximal tubular epithelia and obstruction of the distal nephron, leading
to the elevation of tubular hydrostatic pressure and equilibration of
glomerular filtration pressure, culminating in cessation of glomerular
filtration.
• Clinical AKI is a ‘tip of the iceberg’, whereas an asymptomatic, subclinical
response to various insults, including medications, represents an as yet
obscure and uninvestigated much larger proportion of cases.

60. SUMMARY-PATHOGENESIS
• AKI is an example example of localized and systemic inflammatory disease.
• The systemic inflammatory response, when sufficiently intense and/or
prolonged, may not only exacerbate the local disease, but can also involve
other organs (heart, lungs, liver, etc.) accounting for the increased
mortality even in cases of a mild AKI.
• This explains the old dictum that patients die not from AKI but with AKI.
• While therapies for ameliorating AKI per se are limited, an additional
potentially powerful strategy that could reap significant benefits in the
future is to tackle the intensity of the systemic inflammatory response.

61. THANK YOU