OVERVIEW: What every practitioner needs to know
Are you sure your patient has acute kidney injury? What are the typical findings for this disease?
Acute kidney injury (AKI) is becoming more prevalent in hospitalized children, and now more often results from another organ/system illness or its treatment. Advancements in acute dialysis technology and a recognition that even small reductions in kidney function may portend worse prognosis have led to more aggressive and earlier intervention in children with acute kidney injury. In addition, children who survive an AKI episode are likely at risk for the development of chronic kidney disease and injury.
The clinical features of AKI include the following:
Increased creatinine level
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Oliguria
Hyperkalemia
Acidosis
Volume overload
Hypertension
Hyperphosphatemia
Uremia
Hypocalcemia
Description of the problem: AKI in the child/newborn is defined as an abrupt cessation or diminution of kidney function. The time frame for pediatric AKI is now considered to be less than 48 hours. Multidimensional pediatric AKI definitions include the pediatric modified RIFLE criteria (pRIFLE = Risk, Injury, Failure, Loss, End-Stage kidney disease) and the Acute Kidney Injury Newtork (AKIN criteria).
What other disease/condition shares some of these symptoms?
Prerenal azotemia
What caused this disease to develop at this time?
The epidemiology of pediatric AKI has changed from the 1990s from primary kidney disease to another system illness or its treatment.
Exposure to nephrotoxic medications, including non-steroidal inflammatory medications, aminoglycosides, and iodonated contrast agents, is one of the most common causes of pediatric AKI and should be suspected in patients with nonoliguric AKI.
Only 7% of pediatric AKI results from a primary kidney disease in the tertiary hospital setting.
In the intensive care setting, multiorgan dysfunction syndrome, with primary cardiac, hepatic, hematologic, or pulmonary diagnoses are the most common.
Pediatric AKI occurs across the entire pediatric age spectrum from premature neonates to young adults.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
The following laboratory tests should be considered in a patient with suspected AKI:
Serum electrolytes, BUN, creatinine, calcium, phosphorus, magnesium, and uric acid levels.
Urinalysis with microscopy.
Urinary electrolyte (sodium, potassium, chloride), creatinine, and urea nitrogen (if patient is receiving a loop diuretic) determinations to calculate fractional excretion of sodium (FeNa) or fractional excretion of urea (FeUrea).
Urine culture (if patient has signs/symptoms of a urinary tract infection).
Urine examination for eosinophils (if patient is receiving a medication with potential to cause interstitial nephritis, most commonly beta-lactam antibiotics).
Creatine phosphokinase determination (if rhabdomyolysis is suspected based on clinical history of dehydration or muscle pain with appearance of apparent gross hematuria without red blood cells seen on microscopic examination).
Renal biopsy in cases of suspected rapidly progressive glomerulonephritis or if the cause of AKI is uncertain in setting or rapidly rising creatinine level.
Antinuclear antibody, anti-double stranded DNA, C3, C4, antinuclear cytoplasmic antibody, antiglomerular basement membrane antibody (if patient has history, signs and symptoms consistent with glomerulonephritis).
ADAMTS-13 activity/antibody (if thrombotic thrombocytopenic purpura [TTP] is suspected).
Stool for enteropathogenic
Escherichia coli(if hemolytic uremic syndrome [HUS] is suspected in children with bloody diarrhea).
24- hour urine examination for calcium, oxalate, citrate, cystine, uric acid (in patients with confirmed nephrolithiasis).
Normal laboratory values: The normal serum electrolyte and creatinine ranges vary by pediatric patient age as a result of nephron tubular maturation.
Table I lists the general ranges based on patient age. These should serve only as one piece of data to inform clinical decision making, as many electrolyte concentrations can be affected by dietary and other non-kidney function-related factors.
Table I.
| Infant | Child | Adolescent | |
|---|---|---|---|
| Sodium (meq/L) | 130-140 | 133-146 | 133-146 |
| Potassium (mEq/L) | 3.7-5.9 | 3.4-4.7 | 3.5-5.1 |
| Chloride (mEq/L) | 98-113 | 98-107 | 98-107 |
| Bicarbonate (mEq/L) | 16-24 | 22-26 | 22-26 |
| Blood urea nitrogen (mg/dL) | < 20 | < 20 | <20 |
| Creatinine (mg/dL) | 0.2-0.4 | 0.3-0.7 | 0.5-1.0 |
| Calcium (mg/dL) | 9.0-11.0 | 8.8-10.8 | 8.6-10.0 |
| Phosphorus (mg/dL) | 4.5-6.7 | 4.5-5.5 | 2.7-4.5 |
| Magnesium (mg/dL) | 1.3-2.0 | 1.3-2.0 | 1.3-2.0 |
| Uric Acid (mg/dL) | 2.4-6.4 | 2.4-5.9 | 2.4-7.2 |
Urine output
Typically, urine output is reported in terms of milliliters/kilogram of patient body weight/hour with a value of more than 1 ml/kg/h considered to be “normal.”
In AKI, the 1ml/kg/h threshold does not apply, as patients may have a “relative oliguria” if they have received large fluid volumes, which would require sufficiently greater urine volumes to maintain euvolemia. Thus, matching intake to output and assessing daily weight and edema status are crucial to determine if urine output is really “normal.”
Would imaging studies be helpful? If so, which ones?
The following imaging studies should be considered for children with AKI:
Renal ultrasonography to include the kidneys and bladder in almost all cases of AKI that is not reversed with fluid administration.
Abdominal computed tomography (CT) or ultrasonography (if trauma or abdominal mass is suspected).
Spiral CT (if nephrolithiasis is suspected).
Confirming the diagnosis
The diagnosis of AKI is based on increases in serum creatinine levels or decreases in urine output. Until recently, multiple diagnostic criteria were used that confounded analysis. Recent validation of the pRIFLE criteria has standardized the definition and diagnosis of AKI presence and severity.
pRIFLE creatinine based AKI criteria: Serum creatinine values are used to calculate an estimated creatinine clearance (eCCl) by the Schwartz formula:
eCCl (mL/min/1.73 m2) = k * patient height (cm)/serum creatinine (mg/dL), where k is a constant based on patient sex and age
-k values: low birthweight less than 1 year (0.33), full term less than 1 year (0.45), 2 to 12 years of age (0.55), 13 to 21-year-old female (0.55), 13 to 21-year-old male (0.70)
Use baseline and current serum creatinine values to calculate a change in eCCl
-if no baseline serum creatinine is available for 3 months before current value, assume eCCl = 120 mL/min/1.73 m2
pRIFLE AKI strata: eCCl change: less than 25% (no AKI), 25%-49% (pRIFLE-R), 50%-74% (pRIFLE-I), =75% or eCCl < 35 mL/min/1.73 m2 (pRIFLE-F)
pRIFLE urine output-based criteria: At least 8 hours of recorded urine output (UOP) is required to diagnose AKI with the pRIFLE UOP-based criteria
-pRIFLE AKI strata: less than 0.5 mL/kg/h for 8 hours (pRIFLE-R), less than 0.5 mL/kg/h for 16 hours (pRIFLE-I), less than 0.3 mL/kg/h for 24 hours or anuric for 12 hours (pRIFLE-F)
The differential diagnosis for pediatric AKI mainly focuses on the potential cause of AKI. These causes have classically been characterized as prerenal, intrinsic renal and postrenal.
Prerenal disease
Results from decreased renal blood flow leading to the kidney appropriately conserving volume. Prerenal azotemia has recently been retermed fluid-responsive AKI and is suggested by the following laboratory assessments:
BUN/Cr ratio greater than 20
[FeNa = (urine sodium/serum sodium)/(urine creatinine/serum creatinine) * 100%] <1%
This test is not valid in patients receiving loop diuretics, which lead to tubular sodium wasting.
[FeUrea = (urine urea nitrogen/blood urea nitrogen)/(urine creatinine/serum creatinine) * 100%] <35%
Causes:
Dehydration
Blood loss
Abdominal compartment syndrome
Intrinsic renal disease
Results from direct damage to the kidneys. Acute tubular necrosis (ATN)/ischemia-reperfusion injury has recently been termed fluid-nonresponsive and is suggested by the following laboratory assessment:
[FeNa = (urine sodium/serum sodium)/(urine creatinine/serum creatinine) * 100%] >3%
This test is not valid in patients receiving loop diuretics, which lead to tubular sodium wasting.
[FeUrea = (urine urea nitrogen/blood urea nitrogen)/(urine creatinine/serum creatinine) * 100%] <35%
Causes:
Glomerulonephritidies
HUS/TTP complex
Prolonged distributive shock
Cardiogenic shock
Nephrotoxic medications or other toxins
Urinary tract infection/pyelonephritis
HUS
Rhabdomyolysis
Tumor lysis syndrome
Interstitial nephritis
Renal arterial thrombosis (bilateral)
Renal vein thrombosis (bilateral)
Trauma
Postrenal disease
Results from obstruction to urinary flow from the level of the renal pelvis to the urethra. These entities can be congenital or acquired. The obstruction usually must be bilateral (above the level of the urethra) to cause kidney failure.
Causes:
Congenital:
Posterior urethral valves (males only)
Ureteral-vesical junction obstruction
Ureteral-pelvic junction obstruction
Severe vesicoureteral reflux
Eagle-Barrett (prune belly) syndrome
Acquired:
Trauma
Oncologic lesions (neuroblastoma, Wilm tumor most common)
Nephrolithiasis with obstructing stones
Ureteral/urethral/bladder clots
If you are able to confirm that the patient has acute kidney injury, what treatment should be initiated?
The therapy should be directed at the suspected underlying cause of AKI in the child. Currently, therapy is supportive for most causes of AKI.
Prerenal disease
Fluid Resuscitation
-Crystalloid (normal saline – 20 ml/kg time three doses then reassess)
Colloid (including blood or 5% albumin based on cause)
Paracentesis for abdominal compartment syndrome
Intrinsic renal disease
Acute tubular necrosis (ATN)
Supportive treatment:
Restore blood pressure with fluid resuscitation and vasoactive medications
Prevent severe fluid overload once blood pressure and end-organ perfusion is restored
Avoid unnecessary nephrotoxins
Initiate renal replacement therapy/extracorporeal membrane oxygenation if: ATN course is expected to be prolonged and administration of nutrition, blood products and medications would lead to worsening severe positive fluid accumulation
Glomerulonephritidies: Consider the following in cases of rapidly progressive (crescentic glomerulonephritis)
Corticsteroids
Cyclophosphamide
Plasma exchange
HUS/TTP complex:
HUS – Supportive care only (fluid, electrolyte restrictions, renal replacement therapy in severe cases)
TTP – Supportive care (fluid, electrolyte restrictions, renal replacement therapy in severe cases)
Plasma exchange (daily until platelet count > 150,000/mm3 for three consecutive days)
Shock:
Address underlying cause of shock
Fluid resuscitation
Vasoactive medications
Inotropes
Nephrotoxic medications and other toxins:
Discontinue the suspected nephrotoxic medication
Extracorporeal removal by renal replacement therapy or hemoperfusion if sustained elevated concentrations are life-threatening or could lead to permanent kidney damage
and compound is removable by extracorporeal therapies
Urinary tract infections/pyelonephritis:
Treat with appropriate antimicrobial agents
Rhabdomyolysis:
Hydrate with two to three times maintenance fluid (as long as patient is nonoliguric)
Alkalinize urine with sodium bicarbonate in maintenance fluid to achieve urine pH > 7
Tumor lysis syndrome:
Hydrate with two to three times maintenance fluid (as long as patient in nonoliguric)
Alkalinize urine with sodium bicarbonate in maintenance fluid to achieve urine pH greater than 7
Prescribe oral phosphorus binders
Prescribe urate oxidase
Renal replacement therapy for patients with hyperuricemia, hypocalcemia, and/or hyperphosphatemia refractory to medical management
Interstitial nephritis:
Corticosteroids
Renal artery thrombosis:
Systemic and/or direct anticoagulation
Vascular surgical thrombectomy
Renal vein thrombosis (bilateral):
Systemic anticoagulation
Trauma:
Surgical exploration as warranted
Postrenal disease
Congenital conditions
Posterior urethral valves:
Place indwelling urethral catheter
Consult pediatric urologist to fulgurate valves
Upper obstructive lesions
What are the possible outcomes of this disease?
The prognosis for pediatric acute kidney injury varies with patient age, severity of illness, and underlying diagnosis.
Two thirds of children who develop acute kidney injury and survive to hospital discharge will recover kidney function.
Children less than 1 year of age have worse survival prognosis.
Children admitted to an intensive care unit (ICU) have worse survival than those who are not.
Critically ill children receiving invasive mechanical intubation and vasoactive medication have an independent increased risk of mortality if they experience pRIFLE-I or pRIFLE-F AKI compared with no acute kidney injury or pRIFLE-R AKI.
Children with acute decompensated heart failure have an independent increased risk of death or requirement for a cardiac mechanical assist device if they experience a serum creatinine rise of greater than or equal to 0.3 mg/dL.
Thirty percent of children will be discharged with decreased kidney function.
Five percent of children will be discharged on dialysis.
Mortality for children increases with:
Increasing pRIFLE strata
Increasing severity of illness
Younger age (patients <1 year of age with higher mortality rates)
One third of patients who survive an AKI episode will have signs or symptoms of chronic kidney disease 3-5 years later.
Death or end-stage renal disease occurs in 12% of children with HUS.
Twenty-five percent of children who survive an HUS episode will have signs and symptoms of chronic kidney disease.
Children who survive an acute kidney injury episode should be followed periodically for:
Resolution of acute kidney injury
Development of signs and symptoms of chronic kidney disease, which include: proteinuria, decreased glomerular filtration rate, hypertension
The frequency of the follow up will depend on:
The severity of the acute kidney injury
The resolution of acute kidney injury
The presence of signs and symptoms of chronic kidney disease
What causes this disease and how frequent is it?
The pathophysiology of AKI is often multifactorial and is similar to that seen in adult patients. In general most pediatric AKI results from:
A hypoxic-ischemic-reperfusion injury caused by prolonged hypotension and decreased renal blood flow
Direct toxic effect to the proximal tubules by an exogenous or endogenous toxin
In either case, damage to the proximal tubule can lead to tubule cell sloughing into the proximal lumen, with obstruction to urinary flow and backleak though the tubules and into the glomerulus.
Once the injury has subsided, the proximal tubules must regenerate their integrity and polarity to resume normal function.
What is the evidence?
Akcan-Arikan, A, Zappitelli, M, Loftis, LL. “Modified RIFLE criteria in critically ill children with acute kidney injury”. Kidney Int. vol. 71. 2007. pp. 1028-3. (First publication to develop and validate the pediatric modified RIFLE criteria)
Plotz, FB, Bouma, AB, van Wijk, JA. “Pediatric acute kidney injury in the ICU: an independent evaluation of pRIFLE criteria”. Intensive Care Med. vol. 34. 2008. pp. 1713-7. (Second publication validating the pRIFLE criteria)
Zappitelli, M, Parikh, CR, Akcan-Arikan, A. “Ascertainment and epidemiology of acute kidney injury varies with definition interpretation”. Clin J Am Soc Nephrol. vol. 3. 2008. pp. 948-54. (Assessment of pRIFLE and AKIN AKI criteria, and assessment of the most optimal estimated baseline kidney function when a recent serum creatinine is not available)
Schneider, J, Khemani, R, Grushkin, C. “Serum creatinine as stratified in the RIFLE score for acute kidney injury is associated with mortality and length of stay for children in the pediatric intensive care unit”. Crit Care Med. vol. 38. 2010. pp. 933-9. (Large 3000-patient pediatric ICU study assessing associations between RIFLE and outcomes)
Askenazi, DJ, Feig, DI, Graham, NM. “3-5 year longitudinal follow-up of pediatric patients after acute renal failure”. Kidney Int. vol. 69. 2006. pp. 184-9. (Largest long-term follow-up of all-cause pediatric AKI)
Garg, AX, Suri, RS, Barrowman, N. “Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression”. JAMA. vol. 290. 2003. pp. 1360-70. (Large meta-analysis of HUS outcomes)
Hui-Stickle, S, Brewer, ED, Goldstein, SL. “Pediatric ARF epidemiology at a tertiary care center from 1999 to 2001”. Am J Kidney Dis. vol. 45. 2005. pp. 96-101. (Largest recent epidemiological study of AKI in the hospitalized pediatric population)
Vachvanichsanong, P, Dissaneewate, P, Lim, A, McNeil, E. “Childhood acute renal failure: 22-year experience in a university hospital in southern Thailand”. Pediatrics. vol. 118. 2006. pp. e786-91. (Demonstrates changing pediatric AKI epidemiology over 2 decades)
Bailey, D, Phan, V, Litalien, C. “Risk factors of acute renal failure in critically ill children: a prospective descriptive epidemiological study”. Pediatr Crit Care Med. vol. 8. 2007. pp. 29-35. (Assessment of AKI in a large ICU population)
Ongoing controversies regarding etiology, diagnosis, treatment
The most common clinical controversy occurs in timing of initiation of dialysis in critically ill children with AKI. It has become clear that waiting for standard indications for initiating chronic dialysis (severe acidosis, hypercalemia) is associated with worse outcomes in the acute setting. Currently, recommendations in the acute setting aim at starting dialysis earlier based on the following:
At a certain creatinine level
At a certain level of fluid overload
Novel urinary and serum biomarkers of AKI that detect AKI before a rise in serum creatinine have undergone signficant validation in the pediatric population. Current controversy exists on how to use these biomarkers (neutrophil gelatinase-associated lipocalin, interleukin-18, kidney injury molecule-1, liver type fatty acid binding protein) in clinical decision making.
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