WHAT CAUSES ACUTE KIDNEY INJURY AND HOW TO SPOT IT

Acute Kidney Injury (AKI) represents a significant medical challenge, characterized by a sudden decline in kidney function. Understanding AKI is crucial for healthcare professionals to provide timely and effective care, potentially preventing chronic kidney disease or other severe complications.

Definition of Acute Kidney Injury (AKI)

Acute Kidney Injury (AKI) is defined as a rapid decrease in the kidneys’ ability to filter waste products and excess fluid from the blood. This happens over a period of hours to days. The primary consequences of this functional decline include:

• Accumulation of Nitrogenous Waste Products: Substances typically excreted by the kidneys, such as urea and creatinine, build up in the blood. This is measured through serum blood urea nitrogen (BUN) and serum creatinine levels. A key diagnostic marker for AKI is a rapid rise in serum creatinine or a significant decrease in urine output compared to the patient’s baseline.
• Electrolyte and Acid-Base Imbalances: Impaired kidney function disrupts the regulation of electrolytes (like potassium, sodium, calcium, and phosphate) and acid-base balance, leading to potentially life-threatening abnormalities.
• Fluid Imbalance: The kidneys’ inability to excrete excess fluid can result in fluid overload, leading to edema and potentially pulmonary congestion.

Various classification systems exist for grading the severity of AKI, such as the AKIN (Acute Kidney Injury Network) criteria or the current standard, KDIGO (Kidney Disease: Improving Global Outcomes) criteria. These systems typically rely on changes in serum creatinine and/or reductions in urine output over specified time frames (e.g., a rise in serum creatinine by ≥ 0.3 mg/dL within 48 hours, or a rise to ≥ 1.5 times baseline known or presumed to have occurred within the prior 7 days, or a decrease in urine output to < 0.5 mL/kg/h for 6-12 hours). Regardless of the specific criteria used, the core definition centers on a sudden functional impairment.

The Main Causes Leading to Acute Kidney Injury

Understanding the cause of AKI is fundamental to its management. Causes are broadly categorized based on where the initial insult occurs relative to the kidney:

• Prerenal AKI: This is the most common category, accounting for approximately 60-70% of community-acquired AKI cases. It occurs when there is inadequate blood flow (perfusion) to the kidneys. The kidney structure itself is initially intact, but lack of blood supply limits its ability to filter. Common causes include:
  • Volume Depletion: Hemorrhage, severe vomiting or diarrhea, excessive diuresis, burns, dehydration.
  • Decreased Effective Circulating Volume: Conditions where total body fluid is normal or even increased, but blood isn’t adequately reaching the kidneys. Examples include heart failure (poor pump function), liver cirrhosis (fluid sequestered in the abdomen – ascites), severe sepsis (vasodilation and capillary leak), nephrotic syndrome (protein loss leading to low blood volume).
  • Systemic Vasodilation: Sepsis, anaphylaxis, anesthesia.
  • Renal Vasoconstriction: Certain medications (NSAIDs, ACE inhibitors/ARBs in specific settings like renal artery stenosis), contrast media, hypercalcemia.
  • Renal Artery Obstruction: Bilateral renal artery stenosis or thrombosis (though less common causes of acute global AKI).
• Intrinsic AKI: This occurs when damage occurs directly within the kidney structure itself. This category is diverse and includes insults to the glomeruli, tubules, interstitium, or renal vasculature. Common causes include:
  • Acute Tubular Necrosis (ATN): The most frequent cause of intrinsic AKI (discussed in detail in Step 3).
  • Acute Interstitial Nephritis (AIN): Often caused by allergic reactions to drugs (antibiotics like penicillins/cephalosporins, NSAIDs, PPIs) or infections. Characterized by inflammation in the kidney’s interstitium.
  • Acute Glomerulonephritis: Inflammation of the glomeruli, often caused by autoimmune diseases (e.g., lupus), infections (e.g., post-streptococcal), or certain medications. Leads to protein and blood in the urine.
  • Acute Vascular Syndromes: Conditions affecting the kidney’s blood vessels within the kidney, such as vasculitis, thrombotic microangiopathies (e.g., HUS, TTP), or atheroembolic disease.
• Postrenal AKI: This occurs when there is an obstruction to the outflow of urine from the kidneys. This backpressure impairs kidney function. Obstruction must typically be bilateral (affecting both kidneys) or affect a single functioning kidney to cause a rise in serum creatinine. Common causes include:
  • Lower Urinary Tract Obstruction: Prostatic hypertrophy (BPH) or prostate cancer in men, cervical cancer in women, neurogenic bladder, urethral strictures, bladder stones or tumors.
  • Upper Urinary Tract Obstruction: Kidney stones (bilateral or in a solitary kidney), tumors compressing the ureters (e.g., colorectal, gynecological), retroperitoneal fibrosis.

Identifying the correct category (Prerenal, Intrinsic, Postrenal) is a critical first step in managing AKI, as the initial treatment strategy depends heavily on the underlying cause.

Pathophysiology of AKI, with focus on Acute Tubular Necrosis (ATN)

The pathophysiology of AKI varies depending on the cause, but understanding the cellular and physiological processes is key.

• Prerenal Pathophysiology: Reduced renal perfusion (blood flow) triggers compensatory mechanisms to maintain glomerular filtration rate (GFR), such as activation of the renin-angiotensin-aldosterone system and sympathetic nervous system, leading to efferent arteriolar vasoconstriction and increased sodium and water reabsorption. However, if adequate perfusion is not restored, sustained ischemia eventually leads to cellular injury and transitions to intrinsic renal damage, specifically ATN.
• Postrenal Pathophysiology: Obstruction of urine outflow leads to increased hydrostatic pressure in Bowman’s space and the renal tubules. This elevated pressure opposes the hydrostatic pressure in the glomerular capillaries, reducing the net filtration pressure and thus the GFR. Prolonged obstruction can also cause ischemic damage to tubular cells and interstitial inflammation, leading to intrinsic damage.
• Intrinsic Pathophysiology – Focus on Acute Tubular Necrosis (ATN): ATN is the most common cause of intrinsic AKI and results from direct damage to the renal tubular epithelial cells. It typically occurs via two main mechanisms:
  • Ischemic ATN: This is the endpoint of prolonged and severe prerenal hypoperfusion. When renal blood flow falls below a critical threshold, tubular cells, which are metabolically highly active and require significant oxygen, become ischemic. This leads to cellular dysfunction (failure of ion pumps) and ultimately cell death (necrosis or apoptosis). The damage is often patchy but predominantly affects the proximal tubules and the thick ascending limb of the Loop of Henle, which are particularly vulnerable to ischemia.
  • Nephrotoxic ATN: This occurs due to exposure to substances that are directly toxic to tubular cells. Common nephrotoxins include certain antibiotics (aminoglycosides), contrast media (contrast-induced nephropathy), chemotherapy agents (cisplatin), heavy metals, and certain endogenous toxins (e.g., myoglobin from rhabdomyolysis, hemoglobin from hemolysis, paraproteins in multiple myeloma). The damage mechanism varies depending on the toxin; some are directly poisonous, while others require intracellular metabolism to become toxic or interfere with cellular processes like mitochondrial function.

Regardless of the cause (ischemia or nephrotoxins), established ATN involves a characteristic sequence of events:

1. Initiation Phase: The period of initial injury (ischemia or toxin exposure). GFR begins to decline.
2. Maintenance Phase: Tubular cell injury is established. There is widespread necrosis and/or apoptosis of tubular cells. Damaged and detached cells slough off, forming cellular casts that obstruct the tubular lumen. This obstruction further reduces GFR. In addition, the damaged epithelium becomes leaky, allowing glomerular filtrate to “backleak” into the interstitium and peritubular capillaries, further reducing effective filtration. Inflammation is also present. During this phase, urine output is often low (oliguric or anuric), and serum creatinine/BUN rise significantly. Electrolyte and acid-base abnormalities become prominent.
3. Recovery Phase: If the underlying cause is removed or corrected, tubular epithelial cells, which have regenerative capacity, begin to proliferate and differentiate, repairing the damaged tubules and restoring function. Urine output may increase dramatically (diuretic phase) as tubular function recovers but the ability to concentrate or dilute urine is still impaired. Eventually, the structural integrity and functional capacity of the tubules are restored, and GFR returns towards baseline. Full recovery can take days to weeks, and sometimes months.

Understanding ATN’s pathophysiology highlights why timely intervention is crucial, especially during the initiation phase, to prevent progression to the maintenance phase and improve the chances of complete recovery.

Approaching a Patient Presenting with Acute Kidney Injury, and Understand the Main Diagnostic Tests to be Ordered

Approaching a patient with suspected AKI follows a systematic scheme:

1. Recognize AKI: Identify the presence of AKI based on clinical suspicion (decreased urine output, symptoms of uremia) and biochemical criteria (rise in serum creatinine from baseline).
2. Assess Severity and Complications: Determine the degree of kidney function impairment (e.g., using KDIGO staging) and identify any life-threatening complications (e.g., severe hyperkalemia, metabolic acidosis, fluid overload, uremic symptoms).
3. Identify the Cause (Prerenal, Intrinsic, Postrenal): This is the most critical step and requires a combination of clinical assessment and diagnostic tests.
   • History: Ask about potential causes: recent illness (vomiting, diarrhea), fluid intake, bleeding, new medications (NSAIDs, ACE inhibitors, ARBs, antibiotics, contrast media), exposure to toxins, symptoms of obstruction (difficulty urinating, pain), underlying conditions (heart failure, liver disease, diabetes, autoimmune diseases).
   • Physical Examination: Assess hydration status (skin turgor, mucous membranes, orthostatic changes), vital signs (signs of sepsis, heart failure), signs of fluid overload (edema, rales), abdominal/pelvic exam (distended bladder, masses), look for rashes or joint involvement (suggesting systemic disease).
   • Review Medications: Essential step to identify nephrotoxins or drugs affecting renal perfusion/structure.
4. Order Diagnostic Tests:
   • Serum Chemistry:
     • Serum Creatinine and BUN: To confirm AKI diagnosis, monitor severity, and assess response to treatment.
     • Electrolytes (Sodium, Potassium, Chloride, Bicarbonate): To identify and manage imbalances, particularly hyperkalemia and metabolic acidosis.
     • Serum Glucose: Check for diabetes as a contributing factor.
     • Calcium and Phosphate: Can be abnormal in AKI, especially severe or prolonged cases.
   • Complete Blood Count (CBC): May show anemia (especially in pre-existing CKD), thrombocytopenia or microangiopathic hemolysis (in HUS/TTP).
   • Urinalysis: A cornerstone test. Look for:
     • Specific Gravity or Osmolality: Low in ATN (cannot concentrate urine), high in prerenal (kidneys trying to conserve water).
     • Proteinuria/Hematuria: Suggests glomerular or interstitial disease.
     • Cellular Casts: Red cell casts (glomerulonephritis), white cell casts (AIN, pyelonephritis), muddy brown granular casts and epithelial cell casts (ATN).
   • Urine Biochemistry: Can help differentiate prerenal AKI from ATN.
     • Fractional Excretion of Sodium (FENa): The percentage of filtered sodium that is excreted in the urine. FENa < 1% typically suggests prerenal AKI (kidneys avidly conserving sodium). FENa > 2% typically suggests ATN (damaged tubules cannot reabsorb sodium effectively). Note: FENa can be misleading in patients on diuretics, CKD, or with contrast nephropathy.
     • Fractional Excretion of Urea (FEUrea): An alternative to FENa, less affected by diuretics. FEUrea < 35% suggests prerenal, > 50% suggests ATN.
   • Imaging:
     • Renal Ultrasound: Essential test. Assesses kidney size (normal or enlarged in AKI, small/scarred suggests chronic kidney disease potentially contributing), rules out hydronephrosis (dilatation of the renal pelvis and ureters, indicating postrenal obstruction).
     • Other imaging (CT, MRI, angiography) may be needed depending on suspected cause (e.g., renal artery stenosis, abdominal/pelvic mass).
   • Other Specific Tests: Based on differential diagnosis – serology for autoimmune diseases (ANA, ANCA, complement levels), infectious workup, serum/urine protein electrophoresis (for myeloma).
   • Kidney Biopsy: Reserved for cases where the cause of intrinsic AKI is unclear (e.g., suspected glomerulonephritis, AIN, vasculitis) and the results will impact specific immunosuppressive therapy.

Managing a Patient with Acute Kidney Injury

Management of AKI is primarily supportive and aimed at addressing the underlying cause while preventing or treating complications.

1. Identify and Treat the Underlying Cause:
   • Prerenal: Restore adequate circulating volume and renal perfusion. Administer intravenous fluids (crystalloids are typically first-line). Treat underlying conditions like heart failure, sepsis, or hemorrhage. Discontinue medications impairing renal perfusion (NSAIDs, ACE inhibitors/ARBs if clinically indicated – careful consideration needed especially if patient was stable on them; loop diuretics if volume depleted).
   • Intrinsic: Remove the offending agent in nephrotoxic ATN (e.g., discontinue aminoglycosides, avoid further contrast exposure). Treat specific intrinsic causes: immunosuppression for glomerulonephritis or AIN, plasmapheresis for certain vascular syndromes. Support kidney function while the tubules potentially recover.
   • Postrenal: Relieve the obstruction promptly. This may involve Foley catheter insertion (for bladder outlet obstruction), placement of ureteral stents or percutaneous nephrostomy tubes (for upper tract obstruction), or surgical intervention.
2. Supportive Care and Management of Complications:
   • Fluid Balance Management: Careful monitoring of intake and output, daily weights. Manage fluid overload with diuretics (if tubular function allows) or fluid restriction. Manage volume depletion with fluids (as per prerenal treatment).
   • Electrolyte Abnormalities:
     • Hyperkalemia: A potentially life-threatening complication. Treat urgently with measures to shift potassium into cells (insulin and glucose, salbutamol), stabilize the cardiac membrane (calcium gluconate/chloride), and remove potassium from the body (kayexalate/patiromer, loop diuretics, or dialysis).
     • Hyponatremia/Hypernatremia: Manage fluid balance appropriately.
     • Hyperphosphatemia/Hypocalcemia: Phosphate binders, calcium supplementation if symptomatic.
   • Acid-Base Balance: Metabolic acidosis is common due to impaired acid excretion. Treat severe acidosis (pH < 7.1 or 7.2, depending on clinical context) with sodium bicarbonate, cautiously, or via dialysis.
   • Nutritional Support: Ensure adequate caloric intake while minimizing protein breakdown. Restrict protein if severe uremia is present and dialysis is not imminent, but do not severely restrict protein long-term. Manage nausea/vomiting.
   • Medication Management: Crucial step. Review all medications and adjust doses or discontinue those eliminated by the kidneys (e.g., many antibiotics, digoxin, metformin) to prevent accumulation and toxicity. Avoid further nephrotoxic agents.
   • Prevention of Further Injury: Avoid contrast media, NSAIDs, or other potentially nephrotoxic drugs. Prophylaxis for contrast-induced AKI may be considered in high-risk patients.
   • Monitoring: Regular monitoring of vital signs, urine output, electrolytes, creatinine, BUN, and fluid status is essential to track the course of AKI and the response to treatment.

Main Indications for Dialysis in Acute Kidney Injury Patients

Renal Replacement Therapy (RRT), typically hemodialysis or peritoneal dialysis, is indicated in AKI when medical management fails to control life-threatening complications or when severe uremia develops. The common indications are often summarized by the mnemonic AEIOU:

• A – Acidosis: Severe metabolic acidosis (typically pH < 7.1-7.2) that is refractory to bicarbonate therapy.
• E – Electrolyte Abnormalities: Life-threatening electrolyte imbalances, most commonly severe hyperkalemia (typically K+ > 6.5 mEq/L or rapidly rising, or associated with ECG changes) refractory to medical management. Severe hyponatremia or hypernatremia that cannot be managed medically.
• I – Intoxications: Certain dialyzable toxins or drugs (e.g., lithium, high doses of aspirin, methanol, ethylene glycol, some drug overdoses). Mnemonic SLIME: Salicylates, Lithium, Isopropanol, Methanol, Ethylene glycol.
• O – Overload: Severe fluid overload causing pulmonary edema or respiratory failure that is refractory to diuretic therapy.
• U – Uremia: Severe uremic symptoms, indicating significant accumulation of nitrogenous waste products. Examples include uremic pericarditis or pleuritis, uremic encephalopathy (confusion, lethargy, seizures, coma), uremic coagulopathy (significant bleeding diathesis).

Dialysis serves as a bridge, performing the kidney’s functions while hoping for recovery of native kidney function. The decision to initiate RRT is based on the severity of these complications and the patient’s overall clinical status, not solely on creatinine levels.

Conclusion

Acute Kidney Injury is a common and serious condition requiring a systematic approach. Prompt recognition, identification of the underlying cause (Prerenal, Intrinsic, or Postrenal), understanding the pathophysiology (especially ATN), appropriate diagnostic testing, and timely, targeted management are crucial for improving patient outcomes. While supportive care is the mainstay, recognizing the indications for renal replacement therapy is essential for managing life-threatening complications. A multidisciplinary approach involving nephrologists, intensivists, and other specialists is often necessary to optimize care for patients with AKI.