Acute Kidney Injury

AKI refers to a sudden decline in kidney function that causes disturbances in fluid, electrolyte, and acid-base balances because of a loss in clearance of small solutes and a decreased glomerular filtration rate (GFR)

AKI: A Common, Serious Problem

AKI is a common problem, with serious shortterm and long-term consequences The diagnosis of AKI is frequently delayed AKI is present in 5% of all hospitalized patients, and up to 30% of patients in ICUs The incidence is increasing at an alarming rate Mortality rate >50% in dialyzed ICU patients 25% of ICU dialysis survivors progress to end stage renal disease within 3 years

Diagnosis of AKI is Often Delayed

Elevation in serum creatinine is the current gold standard, but this is problematic Normal serum creatinine varies widely with age, gender, diet, muscle mass, muscle metabolism, medications, and hydration status In AKI, serum creatinine can take several days to reach a new steady state Up to 50% of kidney function may be lost before serum creatinine even begins to rise

Cause for AKI

Renal Cause - Glomerular disease - Tubular disease Ischemic / Toxic / Combination - Interstitial disease - Vascular disease

Cause for AKI

Post renal Cause (obstructive uropathy) - Stone, Clot, Tumor, Fibrosis - Urethral Obstruction (eg Prostate Disease)

Morphology of AKI

Clinical continuum of AKI

Morphology & clinical continuum

 Ischemic ATN is often described as a continuum of prerenal azotemia. Response to fluid repletion can help distinguish between the two: return of renal function within 24-72 hours usually indicate prerenal disease. Initiation phase: Hypoperfusion initiates cell injury that often leads to cell death. It is most prominent in straight portion of the proximal tubules and thick ascending limb of loop of Henle. The reduction in the GFR occurs not only from reduced filtration due to hypoperfusion but also from casts and debris obstructing the lumen, causing back leak of filtrate through the damaged epithelium (ineffective filtration). In addition, ischemia leads to decreased production of vasodilators (i.e. nitric oxide, prostacyclin) by tubular epithelial cells, leading to further vasoconstriction and hypoperfusion.

 Maintenance phase is characterized by stabilization of GFR at a very low level, and it typically lasts 1-2 weeks. Uremic complications typically develop during this phase. In addition to the above mentioned mechanism of injury, tubulo-glomerular feedback also plays a role by causing constriction of afferent arterioles by the macula densa cells, which detect and increased salt load in the distal tubules. During Recovery phase, there is regeneration of tubular epithelial cells. An abnormal diuresis sometimes occurs, causing salt and water loss and volume depletion. The mechanism of the diuresis is not completely understood, but it may in part be due to delayed recovery of tubular cell function in the setting of increased glomerular filtration. In addition, continued use of diuretics (often administered during initiation and maintenance phases) may also add to the problem.

Biomarkers: AMI versus AKI

Period 1960s Acute Myocardial Infarction LDH Acute Kidney Injury

1970s
1980s 1990s 2000s

CPK, myoglobin
CK-MB Troponin T Troponin I Multiple Therapies 50% Mortality

Biomarkers: AMI versus AKI

Period 1960s Acute Myocardial Infarction LDH Acute Kidney Injury Serum creatinine

1970s
1980s 1990s 2000s

CPK, myoglobin
CK-MB Troponin T Troponin I Multiple Therapies 50% Mortality

Serum creatinine
Serum creatinine Serum creatinine Serum creatinine Supportive Care High Mortality

Need early biomarkers of AKI for improved understanding, early treatment and better outcomes

Role of Biomarkers in AKI

Early prediction and diagnosis of AKI (before increase in serum creatinine) Identify the primary location of injury (proximal tubule, distal tubule, interstitium, vasculature) Pinpoint the duration (Prerenal, AKI, CKD) and severity Identify the etiology of AKI (ischemic, septic, toxic, combination)

Devarajan, Semin Nephrol 27:637-651, 2007 Devarajan, Contrib Nephrol 160:1-16 , 2008

Promising AKI Biomarkers

The adaptive response of the stressed kidney itself is providing us with biomarkers that inform early diagnosis, and outcomes:
Neutrophil gelatinase-associated lipocalin (NGAL) Interleukin 18 (IL-18) Kidney injury molecule 1 (KIM-1)
Supavekin et al, Kidney Int 63:1714-24, 2003 (ischemia) Kieran et al, Kidney Int 64:480-492, 2003 (ischemia) Amin et al, Environ Health Perspect 112:465-479, 2004 (cisplatin) Yuen et al, Physiol Genomics 25:375-386, 2006 (ischemia & HgCl) Hung et al, Food Chem Toxicol 45:1123-1130, 2007 (cisplatin) Grigoryev et al, J Am Soc Nephrol Jan 30, 2008 (ischemia) Devarajan, NEJM 358;3:312, 2008

Approach

TUBULOPATHY

Glomeruli Normal Minimal / No Interstitial Inflammation

CELLS

TUBE

LUMEN

Cytoplasmic swelling and vacuolation loss of brush border (detectable on PAS), loss of basolateral infoldings, and blebbing of apical cytoplasm Intracellular inclusions Extensive tubular cell necrosis Loss of individual tubular cells, gaps along the tubular basement membrane Attenuated cells lining the tubule Intraluminal proteinaceous cellular debris and casts Tubular dilatation with flattening of tubular epithelium Tubular rupture with urinary extravasation Regenerative changes (flattening of epithelial cells, cytoplasmic basophilia, heterogeneity in cell size and shape, higher N:C ratio in individual cells, and cellular mitoses)

NON SPECIFIC

ACUTE TUBULAR NECROSIS

Prof Colvin: Concern on MISSING ATN

CELLS

CYTOMEGALY

Anti Viral Agents

Tenofovir Adefovir Cidofovir
Very limited case reports available Mitochondrial changes with loss of cristae

CELLS

CYTOPLASMIC CHANGES

VACOLIZATION
COARSE
Ischemia Ethylene glycol Hypokalemia

FINE
Osmotic Nephrosis CNI Toxicity

Prof Colvin: Concern on MISSING ATN Guntur, Vijayawada

Aurangabad,

CELLS

CYTOPLASMIC CHANGES

PIGMENTS
Hemosiderin Active Hemolysis Always suspect PNH

CELLS

CYTOPLASMIC CHANGES

CRYSTALS
Endogenous
Increased [Urate & Oxalate] Disordered [Urate, Light chain
Fanconi Syndrome]

Exogenous
Anesthetic Drugs
[Methoxyflurane & Halothane]

Radio-contrast Dyes
[Oxaliuric Crystals]

Anti Bacterial Drugs

[Sulfonamides, Aminoglycosides]

Anti retroviral Drugs

[ Acyclovir, Indinavir]

Anti Fungal
[Amphotericin]

CELLS

NUCLEAR CHANGES

INCLUSIONS
Heavy Metals
Lead Bismuth

Virus
Cytomegalo Virus Polyoma Virus Adeno Virus

CELLS

NUCLEAR CHANGES

ATYPIA
Cis Platinum Busulfan Karyomegalic IN

LUMEN

CASTS

PIGMENTS
Lipofuscin Ischemia / Toxin Hemoglobin - Hemolglobinuria Myoglobin Myoglobinuria Bile Hepatorenal syndrome

LUMEN

CASTS

CELLULAR
Desquamated Ischemia / Toxin RBC - Hematuria Neutrophils Infection

LUMEN

CASTS

FRACTURE CASTS
Light chain cast nephropathy
[ Fracture cast + Cellular reaction]

To conclude
Patients with oliguric ATN have a worse prognosis than patients with non oliguric ATN. This probably is related to more severe necrosis and more significant disturbances in electrolyte balance. Rapid increase in serum creatinine (i.e. >3 mg/dl) probably also indicates a poorer prognosis. Again, this probably reflects more serious underlying disease. Of the survivors of ATN, approximately 50% have residual subclinical impairment of renal function, about 5% continue to undergo a decline in renal function following an initial recovery phase and about 5% never recover kidney function and require dialysis.

Pathological diagnosis - make any difference in PROGNOSIS?