• Decreased GFR = decreased functionality →

Categorize your patient

• As the damage increases, the GFR decreases
Definition → Complications → Death
• Markers of damage NGAL, KIM-1, and IL-18
• Previously acute renal failure
• Abrupt (within hours) decrease in kidney
function, which encompasses both injury
(structural damage) and impairment (loss of
function)
• Rarely has a sole and distinct pathophysiology
• Many patients with AKI have a mixed etiology
• Sudden reduction of kidney function causing
disruptions in fluid, electrolyte, and acid-base
balances
• Risk factors
• Retention of nitrogenous waste products
o Age: Decreasing functionality as age
• Increased serum creatinine (SCr) level
increases
• Decreased glomerular filtration rate (GFR)
▪ LBW– more at risk because of lesser
• Decline in UO over a given time interval
number of nephrons
Criteria ▪ When you reach the 3rd decade of life,
GFR will decrease by approx. 1ml/min
per year
▪ At 70 y/o, normal GFR of a healthy
individual is 70
▪ Uncontrolled diabetics – 13ml/min per
year decrease in GFR
o Race or ethnic group
▪ African-American descents have more
predicament to develop CKD
Conceptual Model for AKI
o Genetic factors
▪ Polycystic kidney diseases,
nephrolithiasis, etc
o HPN, DM, Metabolic syndrome
• AKI and CKD can coexist
• Duration of AKI – the longer the more insult to
the nephrons, possibly not recover
• The higher protein in urine = higher/larger
damage of glomerulus
• Most common cause of death in CKD:
cardiovascular events (electrolytes
• Increased risk: hypertension, genetics, diabetes derangement → arrythmia)
o Can be reversed, prevented and go back
to normal
• Increased risk → Noncompliance → Damage
• GFR: most reliable tool to check for kidney
function + used for disease progression
Major Risk Factors for AKI

Types of AKI

o Normal GFR is maintained by relative

resistance of the afferent and efferent
arterioles
o Mild hypovolemia and reduction in CO →
compensatory renal physiologic changes

Prerenal Azotemia

• Most common form of AKI

• Develops due to diminished perfusion of the
o Mediators:
kidney
▪ Angiotensin II (AT II)
• Can be due to absolute or relative decrease in
▪ Norepinephrine (NE)
circulating volume or abnormalities or renal
▪ Vasopressin/ADH (AVP/ADH)
hemodynamics
o AT II mediated renal EFFERENT
o Fever, vomiting, diarrhea, burns,
vasoconstriction
hemorrhage, and overuse of diuretics
o Myogenic reflex with AFFERENT arterioles
o Large volume of fluid collects in
that vasodilate
extravascular spaces – edema (interstitial
o Vasodilatory prostaglandins, kallikrein and
space) or ascites (peritoneal space)
kinnins, and NO are also produced
• Associated with decreased CO
▪ Triggered by decrease in volume
• Medications that interfere with renal
autoregulatory response
o NSAIDs, Angiotensin II inhibitors (acts of
afferent and efferent arterioles,
respectively)
• Physiology:
o Bp fluctuates throughout the day
 o RBF decreases to a level resulting in severe
cellular ATP depletion → acute cell injury
and dysfunction
o Renal ischemia induces structural and
functional alterations in renal proximal
tubular epithelial cells
o Disruption of the ability of renal tubular
epithelial cells and renal vascular
endothelial to maintain normal renal
• Prerenal pathophysiology: function
• Extension Phase
o Ushered by two major events:
▪ Continued hypoxia following the initial
ischemic event
▪ An inflammatory response
o More pronounced in the corticomedullary
(CMJ) or outer medullary region
▪ Depend on diffusion
Clinical & Cellular Phases of AKI o Renal vascular endothelial cell damage
likely plays a key role in the continued
ischemia of the renal tubular epithelium
o Cells continue to undergo injury and death
in the outer medulla
o In contrast, the proximal tubule cells in the
outer cortex, where blood flow has
returned to near normal levels now
undergo cellular repair and improve
morphologically
o GFR continues to fall
o Continued production and release of
chemokines and cytokines
• Maintenance Phase
o Cells undergo repair, migration, apoptosis,
and proliferation in an attempt to re-
establish and maintain cellular and tubular
integrity
o The GFR is stable
o Slowly improving cellular function and sets
the stage for improvement in organ
function
o Blood flow returns toward normal and
epithelial cells establish intracellular and
Phases of AKI
intercellular homeostasis
• Initiation Phase • Recovery Phase
o Renal tubular epithelial cell injury is a key o Cellular differentiation continues, epithelial
feature polarity is re-established and normal
cellular and organ function returns
 ▪ Creatinine starts to go down and GFR endogenous compounds (hemoglobin in
increases hemolysis, myoglobin in rhabdomyolysis)
that are potentially toxic or toxic to the
Intrinsic AKI
kidney
• Most common causes o Historically, classic ATN goes through an
o Sepsis oliguric phase (</=400 mL/24 hrs.) phase
o Ischemia of 1-2 weeks followed by non-oliguric
o Nephrotoxins phase (urine output >400ml/day) phase of
▪ Endogenous 10-14 days with eventual recovery of renal
▪ Exogenous function
• May lead to ATN but biopsy is lacking in most • Glomerular damage – AKI from glomerular
cases damage occurs in severe cases of acute GN
• Process of inflammation, apoptosis, and altered o Acute GN can be due to a primary renal
regional perfusion disease such as an idiopathic rapidly
progressive GN or as part of a systemic
disease such as SLE, bacterial
endocarditis, or Wegener’s granulomatosis
• Interstitial damage – can result from acute
interstitial nephritis due to an allergic reaction
to variety of medications
o Antibiotics – penicillins, cephalosporins,
sulfonamides
o Infection – bacterial illnesses such as
leptospirosis, legionella, rarely
pyelonephritis, and viral illnesses such as
Hanta virus
• Vascular damage – occurs because injury to
intrarenal vessels decreases renal perfusion
and diminishes GFR
o Malignant hypertension, atheroembolic
disese, preeclampsia/eclampsia, and
hemolyticuremic syndrome (HUS),
thrombocytopenia purpura (TTP)
Ischemia-Associated AKI

• Acute Tubular Necrosis (ATN) is the term used

to designate AKI resulting from damage to the
tubules. The two major causes of ATN are:
o Ischemic – resulting from severe or
protracted decrease in renal perfusion
o Nephrotoxic – resulting from exogenous
compounds (aminoglycosides, amphotericin
B, cis-platinum, radiocontrast media) and
Nephrotoxic Agents leading to AKI
Sepsis-Associated AKI
• AKI complicates >50% of cases of severe
sepsis → increase risk of death
• Typically occur in setting of hemodynamic
collapse → vasopressor support requiring
• Pathogenesis:
o Tubular injury → (+) tubular debris and
cast in urine
o Other factors: inflammation, mitochondrial
dysfunction, interstitial edema
• Pathophysiology: generalized arterial
vasodilation mediated by cytokines that
upregulate the inducible NO synthase
Ischemia-Associated AKI
• Kidneys
o 20% of CO
o 10% of resting O2 consumption
o 0.5% body mass
o Site of one of the most hypoxic regions in
the body → renal medulla
• Ischemia alone in normal kidney is not sufficient
to cause severe AKI
• AKI develops in the context of
o Limited renal reserve (CKD, old age)
o Coexisting insults (sepsis, vasoactive or
nephrotoxic drugs, rhabdo, SIRS assoc)
• Postoperative AKI
o Operations involving significant blood loss
and intraoperative
o Most commonly associated procedures
▪ Cardiac surgery with cardiopulmonary
bypass
▪ Vascular procedures with aortic
clamping
▪ Intraperitoneal procedures
o Severe AKI requiring dialysis ~1% of
cardiac and vascular procedures
o Pathophysiology: multifactorial
• Burns and Pancreatitis
o Extensive losses into the extravascular
components
o AKI complicates of burns affecting 25%
with >/= 10% BSA involvement
o Lead to dysregulated inflammation,
increased risk of sepsis, acute lung injury
o May develop abdominal compartment
syndrome – elevated intraabdominal
pressures >/= 20 mmHg → renal vein
compression and reduced GFR
• Diseases of the Microvasculature leading to
Ischemia
o Thrombotic microangiopathies (APAS,
radiation nephritis, etc
o Large vessel
Nephrotoxin-Associated AKI
• Kidney has very high susceptibility to
nephrotoxicity
o Extremely high blood perfusion
o High concentration of circulating
substances
• All structures of the kidneys are vulnerable to
toxic injury
• Risk factors
 o Old age o PCN, Cephalosporins, FQ, Sulfonamides,
o CKD Rifampin
o Prerenal azotemia ▪ Acute interstitial nephritis
o Hypoalbuminemia o Chemotherapeutic Agents
• Contrast agents ▪ Cisplatin and carboplatin → PT cell
o Iodinated contrast agents used for CV and necrosis and apoptosis
CT imaging ▪ Ifosfamide → hemorrhagic cystitis,
o Leading cause of AKI tubular toxicity, type II RTA (Fanconi’s
o Risk is negligible with normal renal function syndrome)
o Risk increases markedly and even the need ▪ Bevacizumab → thrombotic
for dialysis among CKD microangiopathy
o Most common clinical course of contrast o Toxic ingestions
nephropathy: ▪ Melamine contamination →
▪ Rise in SCR beginning 24-48 hrs ff nephrolithiasis and AKI
exposure ▪ Aristolochic acid → Chinese herb
▪ Peak within 3-5 days and resolving nephropathy/Balkan nephropathy
within 1 week • Endogenous toxins
o Results in combination of factors: o Myoglobin and Hgb → pigment
▪ Hypoxia in the outer renal medulla nephropathy
▪ Cytotoxic damage to the tubules o Rhabdomyolysis → intrarenal
▪ Transient tubule obstruction vasoconstriction, direct PT toxicity, and
o Gadolinium in MRI mechanical obstruction of the distal
▪ Warning nephron lumen with Tamm-Horsfall protein
▪ Nephrogenic systemic fibrosis (Uromodulin, most common protein in
▪ Sodium phosphate solutions as bowel urine)
purgatives ▪ Triad: Myalgias, weakness, darkened
• Phosphate nephropathy urine
• Antibiotics o Tumor lysis syndrome → post-cytotoxic
o Aminoglycoside therapy when massive release of uric acid
▪ Tubular necrosis (serum levels >15mg/dL) leads to its
▪ Occurs even at therapeutic range precipitation in tubules
▪ Typically, manifest after 5-7 days of ▪ Multiple myeloma and solid tumors
therapy ▪ Clue: hyperkalemia,
▪ Clue: hypomagnesemia hyperphosphatemia
o Amphotericin B o Myeloma → Light chain deposition disease
▪ Causes vasoconstriction and direct (LCDD)
tubular toxicity ▪ LC bind to Tomm-Horsfall protein to
▪ Dose and duration dependent from obstructing intratubular cast
▪ Clue: polyuria, hypomagnesemia, ▪ Clue: Hypercalcemia
hypocalcemia, and NAGMA o Allergic acute tubulointerstitial disease
o Acyclovir ▪ Drugs that associated with allergic
▪ Precipitate in tubules and cause response characterized by
obstruction • Inflammatory infiltrate
o Foscarnet, pentamidine, tenofovir,
cidofovir
▪ AKI due to tubular toxicity
Postrenal AKI • Serial blood tests with continued rise of SCr
• Occurs when unidirectional urine flow is represents clear evidence of AKI
acutely blocked, partially or totally Diagnosis
• Leads to increased retrograde hydrostatic
• Careful history taking and PE
pressure and interference with GFR
o Symptomatology, family hx, risk factors
• Bladder neck obstruction – common cause due
▪ Prerenal
to prostate disease, neurogenic bladder or
▪ Intrinsic
anticholinergic drugs
▪ Postrenal
• Other lower tract causes: obstructed indwelling
o Careful review of all medications
FC blood clots, calculi, and urethral structure
• Urine findings
• Pathophysiology: hemodynamic alteration
o Urine volume
triggered by abrupt increase in intratubular
▪ Oliguria: <400ml/24 hours
pressures
▪ Anuria: <100ml/24 hours
▪ Polyuria: >3L/24 hours
• Postrenal diuresis
o Urinalysis and Urinoscopy
▪ Urine physical characteristics
▪ Urine sediments (cellular and non-
cellular)
▪ Proteinuria (Nephrotic range
>3.5g/day)
▪ Hematuria
• Blood workups
• Renal failure indices
• Radiologic evaluation
o Renal UTZ
▪ Cannot detect stones lower than the
urether
Diagnosis o CT scan (plain)
• First step in the evaluation of patient with ▪ Standard for stones (plain helical)
azotemia is to determine if the disease is acute o Antegrade or retrograde pyelography
or chronic o Vascular imaging
• Once a diagnosis of ARF has been established, o MRI
it is important to determine the etiology of ARF • Kidney biopsy
o If the cause of AKI is not apparent based
Differentiating AKI from CKD on the clinical context, PE, labs, and
• Clues suggestive of CKD radiologic evaluation
o Radiologic studies o Can provide definitive diagnostic and
▪ Small, shrunken kidneys (<10cm) with prognostic information
cortical thinning on renal UTZ (<1cm) o Associated with risk of bleeding
▪ Evidence of renal osteodystrophy • Novel biomarkers
o Normocytic anemia in the absence of o Kidney injury molecule 1 (KIM-1)
blood loss ▪ Type 1 transmembrane protein
o Secondary hyperparathyroidism with expressed in PT cells injured with
hyperphosphatemia and hypocalcemia ischemia or nephrotoxins (Cisplatin)
o Broad casts in the urine
 ▪ Not expressed in large quantity in the
absence of tubular injury
o Neutrophil gelatinase associated lipocalin
(NGAL)
▪ Protein in granules of neutrophils
▪ Bind to iron siderophore complexes and
have tissue-protective effects in PT
▪ Highly upregulated after inflammation
and kidney injury
▪ Detected in plasma and urine within 2
hours of cardiopulmonary bypass-
associated AKI
o IL8 – mediate in ischemic PT injury
o L-type fatty acid binding protein –
expressed in ischemic PT

Clinical and Laboratory Variables in the

Differential Diagnosis between Prerenal
and Renal AKI

Treatment

• Prerenal ARF
o Aggressive resuscitation to correct
hemodynamics
• Intrinsic renal ARF
o Generally supportive maneuvers and
watchful waiting
 o Disease specific therapies may be
indicated in certain conditions – steroids,
immunosuppression, plasmapheresis
• Postrenal ARF
o Urgent relief of obstruction in partnership
with urologists
• Dialysis may be indicated in
o A – intractable Acidosis
o E – intractable Electrolyte abnormality
o I – Intoxication
o O – intractable fluid Overload
o U – Uremia
▪ Asterixis
• Other dialysis options
o Peritoneal dialysis
o Hemodialysis
▪ Conventional HD
▪ Slow low-efficiency hemodialysis
(SLED)
▪ Continuous renal replacement therapy
(CRRT)
• Renal transplantation
Recovery from AKI
• Significantly increased risk of in-hospital and
long-term mortality, longer length of stay and
increased costs
• Prerenal azotemia and postrenal azotemia
carry a better prognosis than most cases of
intrinsic AKI
o EXCEPT cardiorenal and hepatorenal
syndromes
• Post-discharge care for aggressive secondary
prevention of the kidney is prudent
• AKI patients are more likely to die prematurely
after they leave the hospital even if their kidney
function has recovered
• Inflammation or fibrosis of the renal interstitium
and atrophy of the tubular compartment are
common consequences
Allergic Interstitial Nephritis
• Accounts for >15% cases of unexplained ARF
• Classic presentation: fever, rash, peripheral
eosinophilia, oliguric renal failure 7-10 days of
treatment, rising SCR
• Atypical reaction can occur most notably with
NSAID (fever, rash, and eosinophilia – rare)
• Diagnosis
o Unexplained azotemia without oliguria
o Exposure
o Peripheral eosinophilia
o Urinalysis with pyuria, WBC casts, and
hematuria
Indications for Corticosteroids and
Immunosuppressives in Interstitial
Nephritis
Sjogren’s Syndrome
• Primarily targets exocrine glands especially
lacrimal and salivary
• Dry eyes and mouth (Sicca syndrome)
• Tubulointerstitial nephritis with lymphocytic
predominant infiltrate – most common renal
manifestation
Crystal Deposition Disorders and
Obstructive Tubulopathies
• ARF may occur when crystals are deposited in
tubular cells and interstitium or when tubules
are obstructed
o Sulfadiazine – toxoplasmosis tx (sheaf of
wheat sulfonamide crystals)
o Indinavir and atazanavir – HIV tx (parallel
clusters of needle shaped crystals)
o IV acyclovir – severe herpes infection
(blue-green birefringent needle-shaped
crystals)
• Precipitated by hypovolemia and is reversible
by saline volume repletion and drug withdrawal
• Acute tubular obstruction may cause oliguric
RF in acute urate nephropathy
o Severe hyperuricemia from TLS in lympho-
or myeloproliferative d/o treated with
cytotoxic agents
o May cause partial or complete obstruction
o UA: (+) dense precipitate of birefringent
uric acid, hematuria (macro/micro)
o Prophylactic allopurinol reduces the risk
but no benefit once TLS occurred
o In oliguria, increase tubular flow, increase
solubility of uric acid with alkaline diuresis
o HD or rasburicase, recombinant urate
oxidase, may be required
Vesicoureteral Reflux and Reflux
Nephropathy
• Consequence of vesicoureteral reflux (VUR) or
other urologic abnormalities in early childhood
• Previously called chronic pyelonephritis
(recurrent UTI)
• Abnormal retrograde urine flow from the
bladder into one or both ureters and kidneys
• Results in patchy scarring and tubular atrophy
→ loss of nephrons → hypertrophy of remnant
glomeruli → secondary FSGS
• Affected adults are frequently asymptomatic
but with hx of prolonged bedwetting, recurrent
UTI during childhood, variable renal
insufficiency, hypertension, mild to mod
proteinuria, unremarkable urine sediment
• Renal UTZ: asymmetric small kidneys with
irregular outlines, thinned cortices and regions
of compensatory hypertrophy
• Tx: surgical reimplantation of ureters in young
children but not in adolescent and adult after
scarring has occurred, aggressive BP control
Major Causes of Papillary Necrosis
Analgesic Nephropathy
• Results from long-term use of compound
analgesic preparations (phenacetin, aspirin,
caffeine)
• Classic form:
o Renal insufficiency
o Papillary necrosis
o Radiographic constellation of small,
scarred kidneys with papillary calcification
(best seen in CT scan)
• May have polyuria (impaired concentrating antithrombin deficiency, factor V Leiden,
ability), NAGMA (tubular damage) disseminated malignancy, oral
• ESRD 2 with analgesic nephropathy are at contraceptives)
increased risk of urothelial malignancy • Screening
o Doppler UTZ more sensitive than UTZ alone
o CT angiography is nearly 100% sensitive
o MRA but expensive
Thrombotic Microangiopathy (TMA) • Treatment
o Anticoagulation
• Injured endothelial cells that are thickened, o Tx for underlying cause
swollen, or detached mainly from arteries and o Endovascular thrombolysis in severe cases
capillaries o Nephrectomy for life-threatening
• Platelet and hyaline thrombi causing partial or complications
complete obstruction are integral to the o Vena caval filters to prevent migration of
histopathology thrombi
• TMA is usually the result of microangiopathic
hemolytic anemia (MAHA) with typical features
of thrombocytopenia and schistocytes
• In the kidney, TMA is characterized by swollen
endocapillary cells (endotheliosis), fibrin
thrombi, platelet plugs, arterial intimal fibrosis,
and MPGN pattern
• Diseases associated with this lesion
o TTP
o HUS
o Malignant hypertension
o Scleroderma renal crisis
o APAS
o Preeclampsia/HELLP (hemolysis, elevated
liver enzymes, low platelet count)
o HIV infection
o Radiation nephropathy
Renal Vein Thrombosis

• Present with flank pain, tenderness, hematuria,

rapid decline in renal function, and proteinuria,
or can be silent
• Occasionally identified during a workup for
pulmonary embolism
o Or SLE
• Left renal vein is more commonly involved, 2/3
cases are bilateral
• Etiologies:
o Endothelial damage (homocystinuria,
endovascular intervention, surgery)
o Venous stasis (dehydration, compression)
o Hypercoagulability (APAS, nephrotic
syndrome, esp MN, protein C and S,