Diagnosis: Pre-Renal Acute Kidney Injury (AKI) & Acute Tubular Necrosis (ATN)
Case Summary: In this case, we have a woman who presents with multifocal pneumonia, evidence of hypovolemia on physical exam, and hypotension. She has an elevation in her creatinine from baseline 0.8 mg/dL to 1.75 mg/dL and is oliguric – does she meet criteria for AKI?
Check out the KDIGO 2012 AKI guidelines for an in-depth look at defining, staging, and categorization of AKI. The basic approach to AKI requires an assessment to determine if the etiology is pre-renal, intrinsic renal, or post-renal. Here’s our Guide to AKI that summarizes this approach.
On initial evaluation, this patient has evidence of pre-renal AKI in the setting of volume depletion and hypotension, and also likely the added injury of sepsis (more on this to come!). Objective data include her low urine sodium (suggesting a sodium avid state) and blood urea nitrogen (BUN) to creatinine ratio > 20, though the reliability of this ratio is variable. It may be helpful to calculate the fractional excretion of sodium (FENa) (or the fractional excretion of urea (FEUrea) if the patient is on diuretics). A FENa < 1% and an FEUrea < 35% is suggestive of pre-renal AKI. Of note, the fractional excretion of sodium can also be low in cases of AKI other than those due to pre-renal injury (i.e early glomerulonephritis, contrast injury, and has also been low in cases of acute tubular necrosis, perhaps due to the function of preserved tubules.) Interpret the FENa with a grain of salt (pun intended!) – there are several limitation to its utility.
In this setting, response to intravascular volume resuscitation can be helpful in distinguishing between pre-renal AKI due to hypovolemia and acute tubular necrosis (ATN). If volume restoration improves urine output and kidney function, we would favor a diagnosis of hypovolemia. If a kidney biopsy were to be performed in pre-renal AKI (biopsies are not regularly performed in these cases), we would expect to see mostly normal-appearing glomeruli, tubules, and interstitium. Other potential etiologies of pre-renal AKI include hepatorenal syndrome, cardiorenal syndrome, and nephrotic syndrome.
Prolonged pre-renal AKI leading to ischemia may lead to acute tubular necrosis or ATN; causes of ATN include ischemia, sepsis, and nephrotoxins. Several nephrotoxins including antibiotics (aminoglycosides, vancomycin), various chemotherapy agents, contrast, certain anti-retrovirals, and hypertonic agents can also cause ATN.
ATN is the result of ischemia, inflammation, endothelial damage, oxidative stress, and perpetuation of damage via intra-tubular obstruction with sloughed tubular cells. Animal models have also demonstrated the significance of ischemia-reperfusion injury (IRI) in the pathophysiology of ATN.
ATN has 3 distinct phases:
See more on the work of neighboring cells in the recovery phase here.
Sepsis has proven to be a common cause of acute kidney failure and more specifically ATN – even without evidence of hypotension or hypoperfusion of the kidney! The changes in microvascular circulation in sepsis are complex and not fully understood. Endotoxins likely play a significant role in immune dysregulation and activation leading to kidney injury. Various animal and human models exploring endotoxemia have even opened the door to potential therapeutic options in vasodilatory shock, such as the investigation of angiotensin II in the ATHOS-3 trial.
Though biopsy was not indicated in this case, dilated tubules and loss of the proximal tubular brush border are classic histologic signs of ATN. Casts may be seen within the tubular lumen. Flattened epithelial cells and large nuclei with prominent nucleoli and mitotic activity are suggestive of later stages of ATN.
For now, treatment for acute tubular necrosis is supportive care. Some patients will require renal replacement therapy in the interim, and high risk patients may remain dialysis dependent. For some historical perspective, take a look at this oldie but goodie from NEJM 1986!