A 3 year old male with no significant past medical history presents to the emergency room with vomiting, diarrhea, and poor oral intake for the past 6 days. He had a fever (T 39) that started 6 days ago which lasted for 3 days. His mother noted a decrease in her son’s urinary output in the last 2 days, and noted that his urine is dark yellow. She denies any bloody stools, bloody urine, flank pain, trauma, recent skin or throat infections. He does not take any medications regularly, but he was given ibuprofen every 6 hours while he had a fever.

Exam: VS T 37.5, HR 140, RR 24, BP 82/44. Height 96 cm (50%ile) and weight 13.9 kg (41%ile). He appears lethargic. Pupils are equal and reactive, optic disc margins are sharp, sclera are white. Tympanic membranes appear normal. Oral mucosa appears sticky. He is tachycardic but has a regular rhythm, no murmur. Lung exam demonstrates good aeration, with no crackles or rhonchi. Abdomen is mildly distended, soft, non-tender, no masses or organomegaly. Normal male genitalia with no scrotal edema or inguinal hernias. No edema is noted in his legs, feet, or hands. No rashes are noted. His skin turgor is doughy and his capillary refill is prolonged at 3 to 4 seconds. He has normal tone with no obvious neurologic deficit.

A rapid IV fluid infusion with NS is initiated. His labs are significant for Na 132 mEq/L, CO2 11 mEq/L, BUN 32 mg/dL, Cr 1.0 mg/dL. He is subsequently admitted to the hospital for further work-up and management. Upon admission, additional urine labs are obtained: urine specific gravity is > 1.020, no hematuria or proteinuria present. Spot urine Na is < 10 mEq/L and urine creatinine is 80 mg/dL. The pediatric intern calculates the fractional excretion of sodium (FENa) and states that the calculation suggests the boy’s acute kidney injury is due to a prerenal cause.

Acute kidney injury (AKI) is an often under-recognized disorder in pediatric patients, affecting nearly one-third of all critically ill children (1,2,3). AKI, sometimes referred to as acute renal failure, is the sudden loss of renal function defined by a rapid decrease in glomerular filtration rate (GFR). This can clinically present as elevated serum creatinine (Cr), elevated blood urea nitrogen (BUN), electrolyte imbalances and/or decreased urinary output (2).

There are several causes of AKI which include infection, dehydration, nephrotoxic medications, glomerulonephritis, systemic diseases and even anatomic abnormalities. All causes of AKI can be sorted into one of three categories: prerenal AKI (caused by decreased renal perfusion), intrinsic AKI (caused by direct damage to the kidneys), and postrenal AKI (caused by obstruction of urinary flow) (2,4).

Prerenal AKI occurs as a result of decreased arterial blood flow to the kidneys, thus causing a decrease in renal perfusion and a diminished GFR (2). It is important to note that the cause of injury stems from an issue before the kidneys, hence the name prerenal AKI; common causes include dehydration, sepsis, hemorrhage, severe hypoalbuminemia, and cardiac failure (2,4). Regardless of the etiology, renal function may be preserved if the underlying cause is removed or reversed; however, if renal hypoperfusion is not corrected, ischemic acute tubular necrosis (intrinsic AKI) can occur (4).

Intrinsic AKI is characterized by direct damage to the kidneys, the most common being either hypoxic/ischemic injury or nephrotoxic injury (2). Both causes of injury can result in acute tubular necrosis, which is primarily seen in critically ill infants and children. Common nephrotoxic medications include aminoglycosides, intravascular contrast media, chemotherapeutic agents, and non-steroidal anti-inflammatory drugs (NSAIDs). Another common cause of intrinsic AKI in pediatric patients includes various forms of glomerulonephritis: post-infectious glomerulonephritis (most commonly post-streptococcal glomerulonephritis), lupus nephritis, Henoch-Schönlein purpura (HSP), membranoproliferative glomerulonephritis (MPGN), and anti-glomerular basement membrane (anti-GBM) nephritis (4). If severe, any of these forms of glomerulonephritis can lead to rapidly progressive glomerulonephritis, which is characterized histologically by crescent formation in the glomeruli (2). Vascular insults leading to intrinsic AKI include hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), and other forms of vasculitis. AKI caused by vascular insults causes injury to the intrarenal vessels, diminishing perfusion to the kidneys and therefore diminished GFR (2).

Lastly, postrenal AKI is characterized by obstruction in the urinary tract. The most common causes in infants and young children are due to congenital anomalies of the kidney and urinary tract (CAKUT). Examples of these include posterior urethral valves and bilateral ureteropelvic junction obstruction. In older children, common causes of postrenal AKI include nephrolithiasis, tumor, hemorrhagic cystitis, and neurogenic bladder (2,4).

A good history can help discern the exact cause of AKI. Questions regarding fluid intake, vomiting, and diarrhea can help determine if the child is suffering from dehydration. Bloody diarrhea that is now resolving is more suggestive of HUS. Asking about a recent history of pharyngitis or pyoderma can help determine if post-streptococcal glomerulonephritis is on the top of the differential diagnosis. Gross hematuria with or without flank pain can suggest nephrolithiasis. Also, asking about medication intake is important since some medications are nephrotoxic.

The diagnosis of AKI is clinical. As previously mentioned, a decrease in GFR, subsequent rise in BUN and creatinine and reduction in urine output are seen in AKI. In the pediatric setting, two classifications exist to define and stage AKI: the Pediatric Risk, Injury, Failure, Loss, End Stage Renal Disease (pRIFLE) classification and the Kidney Disease: Improving Global Outcomes (KDIGO). The pRIFLE system in Table 1 classifies AKI into three stages of severity (risk, injury, and failure) and two outcomes (loss and end-stage renal disease), whereas the KDIGO classification is defined by three stages of severity (1,3). Currently, the KDIGO classification is regarded as the more widely accepted definition and staging of AKI and is outlined in Table 2.

Table 1. pRIFLE Classification

Category	Estimated Creatinine Clearance	Urine Output
Risk (R)	Decrease by 25%	< 0.5 mL/kg/hr for 8 hrs
Injury (I)	Decrease by 50%	< 0.5 mL/kg/hr for 16 hrs
Failure (F)	Decrease by 75% or eGFR < 35 mL/min/1.73 m2	< 0.3 mL/kg/hr for 24 hrs or anuria for 12 hrs
Loss (L)	Loss of renal function > 4 weeks
End-Stage (E)	End Stage Renal Disease

Table 2. KDIGO Classification

Category	Serum Creatinine (SCr)	Urine Output
Stage 1	1.5 to 1.9 times baseline, or ≥ 0.3 mg/dL increase	< 0.5 mL/kg/hr for 6 to 12 hrs
Stage 2	2.0 to 2.9 times baseline	< 0.5 mL/kg/hr for ≥ 12 hrs
Stage 3	3.0 times baseline, or SCr ≥ 4.0 mg/dL, or Initiation of renal replacement therapy, or eGFR < 35 mL/min per 1.73 m2	< 0.3 mL/kg/hr for ≥ 24, or anuria for ≥ 12 hrs

While elevation in creatinine and/or reduction in urine output is enough to make the diagnosis of AKI, other studies can help determine the cause of AKI. A urinalysis can reveal many things; if hematuria, proteinuria, white blood cell casts, and/or red blood cell urinary casts are present, then glomerulonephritis is likely. White blood cells in urine are more suggestive of infection or possible glomerulonephritis. And eosinophils in urine suggest acute interstitial nephritis. Particularly useful for distinguishing between the three types of AKI is urine sodium and urine creatinine so that the provider can calculate the fractional excretion of sodium (FENa). A FENa < 1% suggests prerenal AKI, > 1% suggests intrinsic AKI, and > 4% suggests postrenal AKI; however this value varies in postrenal AKI and further studies should be done to confirm the cause of AKI (4). The FENa may be calculated as follows:

Imaging is not necessary to diagnose AKI but could be helpful in determining the cause of AKI. Ultrasound should be considered when the cause of renal dysfunction is unclear. An ultrasound can assess for anatomical abnormalities, nephrolithiasis, or hydronephrosis (which would suggest obstruction).

Management of AKI is primarily focused on treating or removing the underlying cause as well as supportive measures such as restoring fluid and electrolyte balance. Fluids, often intravenous fluids, are needed to improve the hydration status in children with prerenal AKI. In children with urinary obstruction, a urinary catheter may be placed to drain the urinary tract. In severe AKI with dramatically reduced urine output, patients can become fluid overloaded resulting in organ compromise (e.g., congestive heart failure). These patients may require diuretic therapy or even dialysis (3). The indications for acute dialysis not only include volume overload refractory to diuretics, but also hyperkalemia refractory to medical management, severe metabolic acidosis, and significant uremia (BUN approaching 100 mg/dL) (2,4).

The prognosis of AKI largely depends on the underlying etiology and the severity of AKI. Children with intrinsic AKI have a much lower mortality rate (less than 1%) than those in whom multiorgan failure is involved (2). Prompt recognition of AKI and the removal of the cause of AKI can improve the outcomes. Renal function may not recover completely from severe AKI caused by rapidly progressive glomerulonephritis, bilateral renal vein thrombosis, or bilateral cortical necrosis (4). Complications of AKI in pediatric patients include chronic renal insufficiency requiring dialysis, hypertension, renal tubular acidosis, and urinary concentrating defects, all of which may need to be managed long after recovery from AKI (2,3,4).

Questions
1. What are some common nephrotoxic medications in children?

2. What is the equation to calculate a patient’s fractional excretion of sodium (FENa)?

3. When would you calculate a patient’s FENa? And how can this help you clinically?

4. A 9-year-old boy is referred to the emergency department for evaluation after an urgent care clinic noted him to have an elevated creatinine of 1.2 mg/dL. You recognize that he has acute kidney injury so start asking more questions which reveals that he has had dark brown urine for the past three days and was treated with penicillin for strep throat two weeks ago. He otherwise has been drinking and eating well, not taking any other medications, no gross hematuria, no vomiting, no diarrhea, and no abdominal pain. What is the most likely cause of his acute kidney injury?
   a. Nephrotoxic medication
   b. Nephrolithiasis
   c. Post-streptococcal glomerulonephritis (PSGN)
   d. Hemolytic Uremic Syndrome (HUS)
   e. Prerenal cause

5. What are the indications for dialysis in children with acute kidney injury?

References
1. Andreoli SP. Acute kidney injury in children. Pediatr Nephrol. 2009;24(2):253-263. doi: 10.1007/s00467-008-1074-9.
2. Devarajan P. Chapter 550.1. Acute Kidney Injury. In: Kliegman RM, St. Geme JW, Blum NJ, et al (eds). Nelson Textbook of Pediatrics, 21st edition. 2020, Elsevier, Philadelphia, PA. pp. 2767-2774.
3. Sutherland SM, Byrnes JJ, Kothari M, Longhurst CA, Dutta S, Garcia P, Goldstein SL. AKI in hospitalized children: comparing the pRIFLE, AKIN, and KDIGO definitions. Clin J Am Soc Nephrol. 2015;10(4):554-561. doi: 10.2215/CJN.01900214.
4. Sethi SK, Bunchman T, Chakraborty R, Raina R. Pediatric acute kidney injury: new advances in the last decade. Kidney Res Clin Pract. 2021;40(1):40-51. doi: 10.23876/j.krcp.20.074.

Answers to questions
1. Aminoglycosides, intravascular contrast media, chemotherapeutic agents, and non-steroidal anti-inflammatory drugs (NSAIDs)
2. FENa = [ (urine sodium X serum creatinine) / (serum sodium X urine creatinine) ] X 100.
3. A provider would calculate a patient’s FENa when they recognize the patient has acute kidney injury and would like to know what is the type (or cause) of AKI. A FENa < 1% suggests prerenal AKI, > 1% suggests intrinsic AKI, and > 4% suggests postrenal AKI.
4. C. Post-streptococcal glomerulonephritis (PSGN)
5. Volume overload refractory to diuretics, hyperkalemia refractory to medical management, severe metabolic acidosis, and significant uremia (BUN greater than or approaching 100 mg/dL).