Acute Kidney Injury

Definition
Sudden impairment of kidney function resulting in retention of Nitrogenous & other waste
by the kidney i.e. increased BUN& serum Cr + often reduced urine output
Laboratory definition:
A rise in SCr of >= 0.3mg/dL or 50% higher than baseline, within a 24-48 hr period OR
A reduction in urine output to 0.5ml/kg/hr for > 6 hrs
This is important to differentiate AKI from CKI however, it is difficult when there is no
recent baseline SCr reading available.
If so radiological studies (small shrunken kidneys + cortical thinning on US, or renal
osteodystrophy) or lab tests (Normocytic anaemia, 2 Hyperparathyroidism with
hyperphosphatemia and hypocalcemia) can help identify CKD
No set of tests, however, can rule out AKI superimposed on CKD since AKI is a frequent
complication in patients with CKD, further complicating the distinction
Epidemiology
AKI complicates 30% admissions in the ICU & is associated with a markedly increased risk
of death in hospitalized individuals
It is a major medical complication in the developing world owing to specific etiologies such
as snakes, bees, malaria, leptospirosis, crush injuries from earthquakes (and resultant
rhabdomyolysis)
Etiology
Pre-renal Azotemia
Intrinsic Renal Parenchymal disease
Postrenal obstruction

Pre-renal Azotemia

Definition:
A rise in SCr or BUN (f) inadequate renal plasma flow & intraglomerular hydrostatic
pressure to support normal glomerular filtration.
It involves no parenchymal damage to the kidney + is rapidly reversible once
intraglomerular hemodynamics are restored.
Causes:
Hypovolemia
Decreased effective circulating volume
CCF
Liver failure i.e. Hepatorenal Syndrome in advnaced cirrhosis
There is prerenal azotemia despite total body volume overload
Arterial vasodilation in the splanchnic circulation activation of
vasoconstrictor responses seen in hypovolemia AKI
Type 1 Hepatorenal syndrome: AKI persists despite volume administration and
withholding of diuretics
Type 2 Hepatorenal syndrome: Less severe form characterized by refractory
ascites
Decreased CO
NSAIDs/ ACE Inhibitors/ Ang II inhibitors/ Cyclosporine Inhibit renal autoregulation
Physiology of normal renal GFR autoregulation:
Maintained by relative resistances of afferent & efferent renal arterioles determines
glomerular plasma flow and transcapillary hydraulic pressure gradient drives
glomerular ultrafiltration
Mild hypovolemia/CO reductions compensatory renal physiologic changes:
Renal efferent vasoconstriction
Ang II mediated, in response to reduced renal blood flow
Renal afferent vasodilation
Myogenic Reflex within afferent arteriole: Low perfusion pressure afferent
arteriole dilation
Increased intrarenal synthesis of vasodilator molecules in response to low
perfusion pressure e.g. PGs, Kallikrein, Kinins, NO
Tubuloglomerular feedback: Decreased solute delivery to macula densa
dilation of juxtaposed afferent arteriole mediated by NO
N.B: There is a limit to this autoregulation it fails once systolic BP falls below 80
mmHg
The robustness of the autoregulatory response can be reduced due to:
I) Hyalinosis and myointimal hyperplasia (leading to structural narrowing and impaired
capacity for afferent vasodilation) caused by:
Atherosclerosis
Long standing HTN
Old age
N.B: Diabetes can cause hyalinosis in both afferent and efferent vessels??
II) Drugs
NSAIDs inhibit renal PG production limits renal afferent vasodilation
ACEInh/ARBs limit renal efferent vasoconstriction
Combined use of NSAIDs and ACEInh/ARBs high risk for developing prerenal
azotemia

Intrinsic AKI

Most common causes:

Sepsis
Ischaemia
Nephrotoxins
Pre-renal azotemia advancing to tubular injury e.g. ATN

Sepsis-associated AKI
AKI complicates 50% of severe sepsis & markedly increases risk of death
Pathophysiology:
Inflammation and interstitial edema
Tubular injury tubular debris and casts in injury
GFR reduction arises from generalised arterial vasodilation (efferent > afferent)
Cytokines that upregulate iNOS
Ischaemia-associated AKI
Despite receiving 10% of resting O2 consumption (and 20% of CO), the kidneys are also the
site of one of the most hypoxic regions in the body i.e. the renal medulla (esp. outer
medulla).
AKI associated with ischaemia tends to occur not when ischemia occurs alone, but when
ischaemeia occurs in the context of:
Limited renal reserve e.g. CKD or Older age
Sepsis
Nephrotoxic drugs
Rhabdomyolysis
Systemic Inflammatory states e.g. burns/pancreatitis
Post-operative period esp. after major operations involving significant blood loss and
intraoperative hypotension
Examples of surgeries:
Cardiac surgery with cardiopulmonary bypass
Vascular procedures with aortic cross clamping
Intraperitoneal procedures
RFs:
CKD
Older age
DM
CCF
Emergency procedures
Mechanism:
Persistent preglomerular vasoconstriction (f):
Tubuloglomerular feedback activation (f) enhanced solute delivery to macula
densa after proximal tubule injury
Increased basal vascular tone
Decreased vasodilatory responsiveness
Backleak of filtrate across ischemic and denuded tubular epithelium
Mechanical obstruction of tubules from necrotic debris

Burns & Acute pancreatitis

Mechanisms:
Extensive fluid loss into extravascular body compartments severe hypovolemia and
decreased CO increased neurohormonal activation
Dysregulated inflammation
Increased risk of sepsis and ALI
Abdominal compartment syndrome massive fluid resuscitation can lead to elevated
intraabdominal pressures renal vein compression and reduced GFR
Microvascular AKI ischaemia
Causes:
Thrombotic microangiopathies
APLS
Radiation nephritis
Malignant nephrosclerosis
TTP/HUS
Scleroderma
Atheroembolic disease
Large vessel disease causing AKI
Renal artery dissection
Renal artery thrombosis
Renal vein compression/thrombosis

Nephrotoxic-associated AKI
The kidney has high susceptibility to nephrotoxicity (f):
Extremely high BP & concentration of circulating substances along the nephron where
water is reabsorbed & medullary interstitium high-concentration exposure of toxins
to tubules, interstitium and EC
RFs:
CKD
Pre-renal azotemia
Old age
Hypoalbuminemia

Contrast Agents
Iodinated contrast agents (e.g. used for CT imaging) are the LEADING cause of AKI
The risk increases markedly in:
CKD
Diabetic nephropathy
Multiple myeloma
Clinical course:
Rise in SCr begins 24-48 hrs after exposure
SCr peaks 3-5 days
Resolves wtihin 1 week

Mechanisms:

Antibiotics
Aminoglycosides
Tubular necrosis
Can result in Non-oliguric AKI (10-30% of times)
Typically manifests after 5-7d of therapy & can present after drug is discontinued
Hypomagnesemia is a common finding
Amphotericin B
Causes renal vasoconstriction from an increase in tubuloglomerular feedback
Tubular necrosis mediated by ROS + binds to tubular membrane cholesterol and
introduces pores
Leads to: Polyuria, hypomagnesemia, hypocalcemia, metabolic acidosis (non anion
gap)
Vancomycin
Causes AKI when trough levels are high
Acyclovir
Causes AKI by tubular obstruction
Foscarnet
Pentamidine
Cidofovir
Secondary to acute interstitial nephritis (f) ABs such as penicillins, cephalosporins,
quinolones, sulfonamides, rifampin
Chemotherapeutic agents
Cisplatin
Carboplatin
Ifosfamide
Bevacizumab
Toxic ingestions
Ethylene gylcol
Present in car antifreeze
Metabolites can cause direct tubular injury
Diethylene glycol
Industrial agent
Melamine
May contaminate foodstuffs
Can cause nephrolithiasis and AKI
Balkan nephropahty
Endogenous toxins
Myoglobin
Can be released by injured muscle cells e.g. Rhabdomyolysis
Causes of Rhabdomyolysis include:
Traumatic crush injuries
Muscle ischemia during vascular/orthopedic surgery
Compression during coma/immobilisation
Prolonged seizure activity
Excessive exercise
Heat stroke/Malignant hyperthermia

Infections
Metabolic disorders e.g. hypophosphatemia, severe hypothyroidism
Myopathies e.g. durg-induced, metabolic, inflammatory
Mechanisms:
Intrarenal vasoconstriction
Direct proximal tubular toxicity
Mechanical obstruction of distal nephron when myoglobin/hemoglobin
precipitates with Tamm-Horsfall protein (favoured by acidic urine)
Hemoglobin
Uric acid
Tumour lysis syndrome after initiation of cytotoxic therapy in patients with highgrade lymphomas and ALL massive release of uric acid precipitation of uric
acid in renal tubules AKI
TLS also causes hyperkalemia and hyperphosphatemia
Myeloma light chains
Mechanisms:
Direct tubular toxicity
Binds to Tamm-Horsfall protien obstructing intratubular casts
Hypercalcemia intense vasoconstriction and volume depletion
Tumour lysis syndrome following initiation of treatment
Allergic acute tubulointerstitial disease
Allergic response to drugs characterised by an inflammatory infiltrate + peripheral &
urinary eosinophilia

Post-renal AKI

Unidirectional flow of urine is acutely blocked partially or totally retrograde hydrostatic

pressure reduced GFR
N.B: Normal urinary flow rates DO NOT rule out presence of partial obstruction as GFR is
normally 2X magnitude higher than the urinary flow rate
In healthy individuals, obstruction must affect both kidneys to cause AKI
In those with significant underlying CKD, unilateral obstruction can result in AKI
Causes:
Bladder neck obstruction e.g. BPH, Prostate Ca
Neurogenic bladder
Anticholinergic drugs
Obstructed Foley catheters
Calculi
Urethral strictures
Blood clots
Neoplasia
External compression e.g. retroperitoneal fibrosis, neoplasia, abscess, inadvertent
surgical damage
Pathophysiology:
Abrupt increase in intratubular pressures hyperemia from afferent arteriolar dilation
intrarenal vasoconstriction (f) Ang II, TXA2, Vasopressin, Reduction in NO
Reduced GFR (f) underperfusion of glomeruli

Complications of AKI
1. Uremia
Elevated BUN is a hallmark of AKI
Only when levels > 100 mg/dL does it cause problems such as mental status changes and
bleeding complications = Uremia????
The correlation of BUN and SCr concentrations with uremic symptoms is extremely
variable, due in part to differences in urea and creatinine generation rates across
individuals.
2. Hypervolemia and Hypovolemia
Oliguric/anuric AKI ECF volume expansion (Hypervolemia) weight gain,
dependent edema, raised JVP, Pulm edema, Acute lung injury characterised by increased
vascular permabiity and inflammatory cell infiltration (rare)
AKI recovery involves polyuria (due to osmotic diuresis from retained urea + delayed
recovery of tubular reabsorptive functions) hypovolemia
3. Hyponatremia
Following administration of excessive hypotonic crystalloids or isotonic dextrose
solutions
4. Hyperkalemia
The most concerning complication of AKI
Especially marked if underlying etiology is:
Rhabdomyolysis
Hemolysis
Tumour lysis syndrome
Can lead to: Muscle weakness, arrhythmias (can be fatal)
5. Acidosis
Raised anion gap metabolic acidosis
6. Hyperphosphatemia & Hypocalcemia
Hyperphosphatemia is more likely to occur in AKI arising due to:
Rhabdomyolysis
Hemolysis
Tumour lysis syndrome
Hypocalcemia can occur due to:
Hyperphosphatemia metastatic deposition of Calcium phosphate
Deranged Vit D-parathyroid axis
Hypocalcemia is often asymptomatic if mild; but if excessive can lead to:
Peri-oral parasthesias
Muscle cramps
Seizures
Carpopedal spasms
Prolonged QT interval
7. Hematological complicaitons
Anaemia (f) decreased erythropoieisis
Bleeding (f) platelet dysfunction
8. Infections
Infections are a common precipitant of AKI and also a dreaded complication of AKI.

 There is impaired host immunity in end-stage renal disease

9. Cardiac complciations e.g. arrhythmias, pericarditis, pericardial efflusion
10. Malnutrition due to the severely hypercatabolic state of AKI