Acute Tubular Injury (ATI)

Basics

Description

  • Acute tubular injury (ATI) is the new nomenclature, now commonly used in place of acute tubular necrosis to define a sudden reduction in renal functioning, resulting from a myriad of different insults to the renal tubular epithelial cells.
  • ATI is the most common cause of acute kidney injury (AKI) in hospitalized patients, responsible for 33–45% of AKI cases. Thus, it becomes vitally important for clinicians to be familiar with this entity.
  • ATI is a term embodying damage to the renal tubular mechanism, specifically the epithelial cells, from nephrotoxic or ischemic insults.
    • A multitude of different pathologies and mechanisms can result in ATI, ranging from volume depletion states leading to impaired renal perfusion to atherosclerotic or embolic phenomena injuring the renal tubules, to iatrogenic mediated damage secondary to vascular interventions.
    • Of note, damage to the renal parenchyma, vasculature, and glomeruli have also been documented in cases of ATI (1).

Epidemiology

Incidence
  • A prospective, multicenter, community-based study in Spain estimated the overall incidence of AKI to be 209 cases per million population (PMP), with ATI representing the most common cause at of AKI at 45% (1).
  • Three large multicenter administrative databases demonstrated that approximately 2% of hospitalized patients in the United States had a diagnosis of AKI.
  • Estimated incidence of AKI globally during hospitalization is 5–7% (2), with up to 40% of critical care patients developing AKI (3).
  • The population incidence of AKI rose from 610 PMP in 1988 to 2,888 PMP in 2002, representing an increase of 11% per year since 1988 according to a large multicenter study.
  • A recent study studying AKI in the United States showed that AKI has been growing at a rate of 14% per year since 2001, with AKI being present in >35% of all in-hospital death cases. This highlights the clinical and public health significance of AKI and the challenges ahead for managing this disease entity.
  • A 20-center prospective study found an incidence of 7.7% of AKI in the ICU setting, with the principle cause attributed to ATI.
  • The PICARD multicenter study in the United States showed a 50% rate of ATI as the etiology of AKI.
  • Mortality rates from ATI in hospitalized and ICU patients are estimated at 37.1% and 78.6%, respectively.

Etiology and Pathophysiology

  • Two primary etiologies of ATI are postischemic (“ischemic”) and nephrotoxic, but mixed picture is most common presentation (3).
  • Septic shock is leading cause of postischemic ATI (1).
  • Nephrotoxic agents can be endogenous (hemoglobin and myoglobin) or exogenous (aminoglycosides, radiocontrast media, nonsteroidal anti-inflammatory drugs [NSAIDs], amphotericin B, cisplatinum, etc.) (2).
  • Ischemic ATI:
    • The clinical manifestations of ischemic ATI lie on a continuum, which include both changes in glomerular filtration that are traditionally labeled prerenal and direct tubular epithelial cell injury that is traditionally labeled intrarenal.
    • Classically, 1- to 2-week oliguric phase (≤400 mL/24 hours) followed by nonoliguric phase (>400 mL/day) of 10 to 14 days (2)
  • Causes of ischemic ATI can be further classified as follows:
    • Decreased effective arterial perfusion, renal vasculature vaso-occlusive disease, and renal vasculature vasoconstriction states
  • Decreased effective arterial perfusion:
    • Shock: septic, cardiogenic, hypovolemic, distributive
    • Autonomic dysfunction
    • Low oncotic pressure states: cirrhosis, nephrotic syndrome, protein-losing nephropathies
    • Adrenal dysfunction
    • Iatrogenic: medication induced, perioperative
  • Renal vasculature vaso-occlusive disease:
    • Renal artery stenosis
    • Atheroembolic disease
    • Thromboembolic phenomena
  • Renal vasculature vasoconstriction states:
    • Medication-induced
    • Toxin-mediated
  • Renal tubular epithelial damage most commonly occurs at the proximal tubules, and damaged cells; undergo one of three pathways: repair, apoptosis, and necrosis
  • Four phases of ATI:
    • Initiation—renal blood flow decreases, resulting in decrease in cellular adenosine triphosphate (ATP) and renal tubular epithelial injury.
    • Extension—continued corticomedullary junction hypoxia and inflammatory response by tubular cells (TNF-α, IL-1, IL-6, IL-8, etc.) and leukocytes
    • Maintenance—cells undergo repair.
    • Recovery (2)
  • Biopsy shows detachment of renal tubular epithelial cells from basement membrane, sloughing of cells into tubular lumen, effacement, loss of brush border in proximal tubular segments, formation of tubular casts, and interstitial edema (2).

Risk Factors

  • Decreased renal perfusion due to medication effects: NSAIDs, angiotensin-converting enzyme (ACE) inhibitors, cyclosporine (4)
  • Cardiovascular surgery, especially with suprarenal aortic clamping (3)
  • Risk factors for prerenal disease: hypovolemia, hypotension, and third space sequestration (e.g., heart failure and cirrhosis)
  • Additional risk factors: male sex, elderly, those with comorbid conditions, mechanical ventilation, multiorgan dysfunction/failure, sepsis, and oliguria (1)

General Prevention

  • Preservation of renal blood flow
  • Limit effects of IV contrast media:
    • Avoid contrast studies if possible.
    • Use low-osmolar contrast media (LOCM) in preference to high-osmolar or even iso-osmolar (5)[A].
    • Consider giving a statin, N-acetylcysteine, and saline to patients with chronic kidney disease; the combination has best evidence to prevent nephropathy (5)[A].
  • Avoid nephrotoxic antibiotics when able, and renally dose based on current kidney function.
  • In rhabdomyolysis, use fluids and mannitol if necessary to maintain urine output (UO) >300 mL/hr until no myoglobin in urine (6)[A].
  • Hospital protocols for management of hemodynamic and oxygenation parameters in perioperative setting or in patients with septic shock (7)

Commonly Associated Conditions

  • Septic shock
  • Renal artery stenosis
  • Chronic kidney disease
  • Rhabdomyolysis

Diagnosis

History

  • High clinical suspicion is paramount for prompt diagnosis.
  • History of episode of relative hypoperfusion or IV contrast exposure
  • Review of current medications to evaluate for nephrotoxic agents and excessive dosing
  • Identify potential prerenal and postrenal causes of AKI.

Physical Exam

  • Hemodynamic evaluation with respect to vitals
  • Baseline weight with comparison to current weight
  • Focused physical exam to evaluate for reversible causes or alternative diagnoses
  • Overall assessment of volume status
  • Evaluation for other causes

Differential Diagnosis

  • Prerenal azotemia
  • Acute interstitial nephritis
  • Glomerulonephritis
  • Vasculitis
  • Urinary tract obstruction

Diagnostic Tests & Interpretation

  • Initial labs: basic metabolic panel, urinalysis, urine osmolarity, serum osmolarity, urine Cr, urine sodium, microscopic evaluation of urine sediment
    • Identification of AKI, defined as an increase in serum Cr by ≥0.3 mg/dL within 48 hours, increase of baseline Cr by ≥1.5 × baseline in the last 7 days, or urine volume ≥0.5 mL/kg/hr for 6 hours (7)
    • Prerenal source suggested if BUN/Cr ratio of >20:1
  • Fractional excretion of sodium (FENa) = (serum Cr × urine sodium) / (serum sodium × urine Cr)
    • Tubular dysfunction leads to increase in urinary sodium concentration.
    • <1% = prerenal causes of AKI
    • >2% = ATI
    • Does not allow for early detection of ATI—takes time for serum Cr to rise
    • Cannot utilize FENa if patient takes diuretics
    • ATI caused by rhabdomyolysis, hemolysis, sepsis, cirrhosis, heart failure, and contrast nephropathy can be associated with low urinary sodium excretion (1).
  • Urine microscopy with muddy brown granular casts, epithelial cell casts, and renal tubular epithelial cells (present in 80% of cases of oliguric ATI) (1,4)
  • Urine osmolality of <450 mOsm/kg due to inability to concentrate urine due to disrupted basement membrane
  • Investigational biomarkers (urinary and serum proteins such as NGAL, KIM-1, cystatin C, IL-18 and NAG) show promise for early detection of ATI but need further study of clinical validity (2).
  • No gold standard identified for diagnosis

Treatment

General Measures

  • Identify and treat underlying causes, with clinical diligence to avoid further kidney injury once identified (5).
  • Discontinue any nephrotoxic medications, correct hypovolemia, and correct acid–base disturbances.
  • Renal perfusion is proportional to mean arterial pressure (MAP): cornerstone of care is optimizing hemodynamics (MAP and cardiac output) to maintain renal perfusion (4)[A].

Medication

  • Medications are not first line for ATI.
  • Furosemide administered early on may convert patient from oliguric to a nonoliguric ATI but has not been shown to decrease the duration of AKI, need for dialysis, or survival (4)[B].
  • Mannitol shown to protect kidney in animal models against ischemic injury and during renal transplantation, but studies in humans have not shown effectiveness in treatment of AKI (4)[B]
  • More studies needed to look at dopamine, mannitol, atrial natriuretic peptide, growth factors, and pentoxifylline for treatment of ATI

Issues For Referral

  • Consult nephrology early, especially if consideration for renal replacement therapy (RRT).
    • Reasons for referral: hyperkalemia, volume overload, oliguria/anuria
    • Notify nephrologist when serum Cr is ≥2.0 mg/dL.
    • RRT is required in 85% of patients with oliguric AKI and in 30% with nonoliguric AKI (4).
    • Delay in nephrology consultation may contribute to adverse outcomes.
  • Surgical referral for dialysis access as indicated

Additional Therapies

  • RRT—indicated for volume overload, hyperkalemia, acidosis, removal of known toxins, and uremia
    • Early identification of patients needing RRT who are not critically ill yields the most benefit.
    • There is no clinical difference between continuous versus intermittent options for RRT with regard to mortality (4).
  • Nutritional therapy: unclear benefit during first 2 weeks of ATI, but in patients unable to eat for 2 weeks, it is likely beneficial

Complications

  • Volume overload (from decreased clearance or over-administration of fluids) may lead to congestive heart failure (CHF) and pulmonary edema.
  • Electrolyte disturbances (hyperkalemia and hyperphosphatemia)
  • Metabolic acidosis
  • Uremia
  • Complications associated with RRT (e.g., access infection, blood clots, disseminated intravascular coagulation [DIC], hypotension, hypothermia, bleeding from anticoagulation)

Ongoing Care

Follow-up Recommendations

Patient Monitoring
Follow BUN/Cr, monitor UO, and evaluate hemodynamics. Once AKI resolves, UO usually returns and BUN/Cr returns to baseline.

Prognosis

  • All-cause mortality during hospitalization in patients with ATI is 37.1% for hospitalized patients and 78.6% for critical care patients.
  • Roughly 60% of patients who survive ATI will have full renal recovery (4).
  • Increased mortality in patients with ATI associated with male sex, advanced age, comorbid illness, malignancy, oliguria, sepsis, mechanical ventilation, multiorgan failure (4)

Additional Reading

  • Gilbert SJ, Weiner DE, Bomback AS, et al. National Kidney Foundation’s primer on kidney diseases. 7th ed. Philadelphia, PA: Elsevier; 2017.
  • Rahman M, Shad F, Smith MC. Acute kidney injury: a guide to diagnosis and management. Am Fam Physician. 2012;86(7):631–639. [PMID:23062091]

See Also

Algorithm: Acute Kidney Injury (Acute Renal Failure)

Codes

ICD-10

  • N17.0 Acute kidney failure with tubular necrosis

ICD-9

  • 584.5 Acute kidney failure with lesion of tubular necrosis

SNOMED

  • 35455006 Acute tubular necrosis (disorder)

Clinical Pearls

  • ATI has high mortality—early recognition as well as prevention of ATI are critical to improve survival.
  • No gold standard for diagnosis; clinicians must use data from the patient’s history, physical, and labs (2).
  • Suspect in patients with AKI in the setting of postischemic causes or nephrotoxic substance exposures with FENa of >2% or muddy brown casts or renal tubular epithelial cells in microscopic evaluation of the urinary sediment.
  • Treat underlying disorder; avoid further nephrotoxic insults, optimize hemodynamics, and monitor renal function. Optimizing renal perfusion is cornerstone in treatment of ATI.
  • Consult nephrologist once serum Cr is ≥2 mg/dL to decrease mortality.

Authors


Muhammad Durrani, DO, MS
Samaresh Dasgupta, DO, MHA, FACEP

Bibliography

  1. Esson ML, Schrier RW. Diagnosis and treatment of acute tubular necrosis. Ann Intern Med. 2002;137(9):744–752. [PMID:12416948]
  2. Basile DP, Anderson MD, Sutton TA. Pathophysiology of acute kidney injury. Compr Physiol. 2012;2(2):1303–1353. [PMID:23798302]
  3. Schiffl H, Fischer R. Clinical cause of presumed acute tubular necrosis requiring renal replacement therapy and outcome of critically ill patients: post hoc analysis of a prospective 7-year cohort study. Int Urol Nephrol. 2012;44(6):1779–1789. [PMID:21626130]
  4. Gill N, Nally JV Jr, Fatica RA. Renal failure secondary to acute tubular necrosis: epidemiology, diagnosis, and management. Chest. 2005;128(4):2847–2863. [PMID:16236963]
  5. Subramaniam RM, Suarez-Cuervo C, Wilson RF, et al. Effectiveness of prevention strategies for contrast-induced nephropathy: a systematic review and meta-analysis. Ann Intern Med. 2016;164(6):406–416. [PMID:26830221]
  6. Scharman EJ, Troutman WG. Prevention of kidney injury following rhabdomyolysis: a systemic review. Ann Pharmacother. 2013;47(1):90–105. [PMID:23324509]
  7. Kidney Disease: Improving Global Outcomes Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl. 2012;2(1):1–138.


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