Acute Tubular Necrosis

 Acute Kidney Injury (AKI)

• An increase in serum creatinine by ≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours,
• An increase in serum creatinine to ≥1.5 times the baseline level occurring within the prior 7 days, or
• A urine output reduction to <0.5 mL/kg/hour for a duration of 6 hours or more.

Acute Tubular Necrosis (ATN)

Ischaemic ATN

Common causes include

• Hypovolaemic states:
  • Gastrointestinal or renal fluid loss (e.g., diarrhoea, vomiting, diuretics)
  • Haemorrhage
  • Burns
  • Third-space sequestration (e.g., pancreatitis, peritonitis)
• Low cardiac output states:
  • Congestive heart failure
  • Myocardial infarction
  • Valvular disease
  • Arrhythmias
  • Pericardial tamponade
• Systemic vasodilation:
  • Sepsis
  • Anaphylaxis
  • Cirrhosis (due to effective hypovolaemia)
• Coagulopathy:
  • Disseminated intravascular coagulation (DIC)
• Surgical causes:
  • Procedures involving aortic clamping or renal artery occlusion (e.g., coronary artery bypass grafting, nephrectomy)

Population-specific patterns

• In high-income settings, ischaemic ATN is commonly associated with comorbidities such as hypertension, diabetes, heart failure, malignancy, or critical illness.
• In low-resource settings, it is more often due to volume depletion, infection, and pregnancy-related complications.

Nephrotoxic ATN

Exogenous nephrotoxins

• Aminoglycosides
  • Occurs in up to 30% of patients, especially with prolonged use or high levels.
  • Risk increased by liver or kidney disease, concomitant nephrotoxic agents, shock, older age, and female sex.
• Amphotericin B
  • Risk increases with cumulative doses >3 g, prolonged therapy, and critical illness.
  • Synergistic toxicity may occur with cyclosporine.
• Radiocontrast agents
  • Especially in patients with CKD, diabetes, heart failure, volume depletion, or concomitant use of ACE inhibitors or ARBs.
  • Preventive strategies include isotonic saline hydration prior to contrast exposure.
• Other agents
  • Cisplatin, ifosfamide, foscarnet, pentamidine, sulfa drugs, acyclovir, indinavir, tenofovir
  • Calcineurin inhibitors (e.g., cyclosporine, tacrolimus)
  • mTOR inhibitors (e.g., everolimus, temsirolimus)
  • Intravenous immunoglobulin with sucrose carriers
  • Ethylene glycol (a toxic alcohol)

Endogenous nephrotoxins

• Myoglobin
  • Released during rhabdomyolysis (e.g., crush injury, seizures, drug-induced myopathy).
  • Causes direct tubular toxicity, vasoconstriction, and intratubular obstruction.
• Haemoglobin
  • Seen in massive intravascular haemolysis (e.g., transfusion reactions).
  • Less directly toxic than myoglobin, but can cause tubular damage through haemodynamic instability and cast formation.
• Uric acid and calcium phosphate
  • Associated with high tumour burden or tumour lysis syndrome.
  • Crystals precipitate in tubules, causing obstruction and inflammation.
• Light chains
  • Found in multiple myeloma; cause both direct tubular toxicity and intraluminal cast nephropathy.

Sepsis-Associated ATN

• Sepsis is a major cause of ATN, particularly in ICU settings. 
• Mechanisms are multifactorial
  • Systemic hypotension and hypoperfusion leading to ischaemic injury
  • Endotoxaemia and inflammatory cytokine release inducing renal vasoconstriction and microcirculatory dysfunction
  • Oxidative stress and immune-mediated endothelial damage
  • Histological changes may include endothelial swelling, capillary obstruction by red cells, and tubular epithelial necrosis

COVID-19-Related ATN

• ATN is the predominant form of AKI observed in patients hospitalised with severe COVID-19. 
• Contributing factors include:
  • Haemodynamic instability
  • Rhabdomyolysis
  • Sepsis and inflammatory injury
  • Nephrotoxic medications and contrast exposure
  • Histological findings: acute tubular injury, pigmented casts, endothelial swelling, and segmental fibrin thrombi from COVID-related coagulopathy
  • Proteinuria, haematuria, and leukocyturia are frequently observed
• Risk factors for AKI in COVID-19 mirror those in other populations: advanced age, diabetes, CKD, cardiovascular disease, male sex, and severe hypoxia.

 Renal Vulnerability and Structural Predisposition

• The kidneys receive 20–25% of the cardiac output, but perfusion is unevenly distributed.
• The outer cortex receives the bulk of blood flow, while the outer medulla (especially the corticomedullary junction) exists in a state of relative hypoxia.
• The S3 segment of the proximal tubule, located in the outer medulla, is particularly vulnerable to ischaemia due to:
  • High metabolic demand
  • Limited oxygen availability
  • Exposure to reabsorbed toxins

Phases of ATN Progression

Initiation Phase

• Triggered by hypoperfusion or nephrotoxicity, leading to ATP depletion.
• Cellular energy failure disrupts:
  • Membrane ion transport
  • Cell volume regulation
  • Cytoskeletal integrity
• Results in:
  • Loss of brush border and cell polarity
  • Apical blebbing and detachment from the basement membrane
  • Sloughing of epithelial cells and cast formation
• There is a sudden drop in glomerular filtration rate (GFR) with a rise in serum creatinine and urea levels.
• Inflammatory responses are activated through endothelial injury and cytokine release.

Extension Phase

• Characterised by continued hypoxia and sustained inflammation in the outer medulla.
• Tubular cell injury extends into the thick ascending limb and proximal straight tubule.
• Prolonged endothelial dysfunction reduces medullary blood flow and impairs autoregulation.
• Ongoing tubular injury is mediated by:
  • Apoptosis and necrosis
  • Cytokine amplification
  • Oxidative stress and free radical generation
• Structural consequences include tubular obstruction, filtrate back-leak, and further GFR decline.

Maintenance Phase

• GFR stabilises at a low level, lasting days to weeks.
• Tubular cells undergo:
  • Limited repair and dedifferentiation
  • Apoptosis and proliferation
  • Migration to re-epithelialise the damaged nephron
• Functional impairment continues due to:
  • Inflammatory milieu
  • Tubular cast obstruction
  • Altered tubuloglomerular feedback (macula densa-mediated afferent vasoconstriction)
• Clinical signs include oliguria, fluid overload, metabolic acidosis, and electrolyte imbalance.

Recovery Phase

• Marked by restoration of epithelial integrity and return of tubular function.
• Growth factors stimulate regeneration, restoring polarity and ion transport mechanisms.
• Diuresis may occur due to delayed tubular function recovery or diuretic use.
• Serum creatinine and BUN gradually return to baseline.
• Recovery may be complete or partial, depending on the severity and duration of injury.

Key Cellular and Molecular Events

• ATP Depletion: Impairs active transport, causes cell swelling, and disrupts cytoskeletal structures.
• Ion Dysregulation: Intracellular sodium and calcium accumulation leads to cell injury and death.
• Oxidative Stress: Reperfusion generates reactive oxygen species that exacerbate injury.
• Endothelial Dysfunction: Reduces nitric oxide and prostacyclin synthesis, increasing vasoconstriction.
• Pro-inflammatory Cascade: Activation of TNF-α, IL-1, and other cytokines promotes immune cell infiltration.
• Modes of Cell Death:
  • Apoptosis (programmed cell death)
  • Necrosis (uncontrolled cell lysis)
  • Ferroptosis, necroptosis, and MPT-RN (mitochondrial permeability transition–regulated necrosis) are implicated in severe or prolonged injury.

Subtypes of Pathophysiological Response

Normotensive Ischaemic ATN

• Occurs in the absence of overt hypotension.
• Seen in patients with impaired renal autoregulation, e.g.:
  • Elderly individuals
  • Those with atherosclerosis, CKD, or hypertensive nephrosclerosis
  • Patients on NSAIDs or ACE inhibitors/ARBs

Sepsis-Associated ATN

• Often results from multifactorial mechanisms including:
  • Intra-renal vasoconstriction and blood flow redistribution
  • Cytokine-driven inflammation and endothelial activation
  • Nitric oxide dysregulation
  • Increased vascular permeability and mitochondrial dysfunction
• Renal blood flow may paradoxically increase despite local ischaemia at the microcirculatory level.

Final Common Pathways in ATN

• Afferent arteriolar vasoconstriction: Mediated by tubuloglomerular feedback and macula densa sensing increased distal sodium.
• Back-leak of filtrate: Resulting from epithelial denudation and disrupted tight junctions.
• Tubular obstruction: Caused by casts and cellular debris, impairing flow and promoting further injury.

 Key Findings from Epidemiological Studies

• PICARD Study (USA)
   The Program to Improve Care in Acute Renal Disease (PICARD) study, involving 618 ICU patients across five academic medical centres in the United States, identified:
  • 50% of AKI cases due to ischaemic ATN
  • 25% due to nephrotoxic ATN
  • An additional ~12% due to unresolved prerenal causes
     These findings underscore the predominance of ATN among ICU-acquired AKI cases.
• Madrid Acute Renal Failure Study Group (Spain)
   In an assessment of 748 patients across 13 tertiary hospitals:
  • 45% of AKI cases were attributed to ATN
  • The estimated population incidence of ATN was 88 cases per million inhabitants

General Trends and Global Estimates

ATN in Critical Care Settings

• ATN accounts for up to 76% of AKI cases in intensive care units.
• The high prevalence is linked to the vulnerability of ICU patients to hypotension, sepsis, nephrotoxins, and surgical complications.

Challenges in Measuring Incidence

• Variability in AKI definitions over time has contributed to inconsistent reporting.
• Subclinical AKI and unrecognised chronic kidney disease (CKD) may lead to under- or overestimation.

Incidence in the United States

• General population: 2–3 per 1000 individuals annually
• Medicare population (2011 data):
  • Ages 66–69: 14.9 per 1000
  • Ages 70–74: 18.8 per 1000
  • Age ≥85: 35.9 per 1000

Incidence in the United Kingdom

• Reported at 15 per 1000 adults per year, reflecting both hospital- and community-acquired AKI.

 Timeline and Precipitating Events

• Careful exploration of recent clinical events is vital to determine the cause and onset of acute kidney injury (AKI).
• Common precipitating factors include:
  • Major surgery (especially cardiac or vascular procedures)
  • Hypotensive episodes (e.g., intraoperative, post-trauma)
  • Sepsis or systemic infections
  • Volume depletion from vomiting, diarrhoea, haemorrhage, or burns
  • Drug exposures (e.g., nephrotoxic antibiotics, contrast media)

 Drug and Toxin Exposure

• A comprehensive medication history should assess for recent or chronic use of:
  • Nephrotoxic agents: aminoglycosides, NSAIDs, amphotericin B, cisplatin, calcineurin inhibitors (cyclosporine, tacrolimus)
  • Radiocontrast agents: particularly in patients with CKD or diabetes, or those receiving high/repeated contrast doses
  • Endogenous toxins:
    • Myoglobin from rhabdomyolysis (trauma, seizures, drug toxicity)
    • Haemoglobin from haemolysis (e.g., transfusion reactions)
    • Light chains in multiple myeloma
    • Uric acid from tumour lysis syndrome

Systemic and Chronic Conditions

• Several underlying medical conditions increase susceptibility to ATN:
  • Chronic kidney disease (CKD): Lower baseline GFR increases AKI risk
  • Diabetes mellitus: An independent predictor of AKI in various clinical settings
  • Chronic hypertension: Impaired renal autoregulation predisposes to ischaemic injury
  • Advanced age: Associated with vascular changes and decreased physiological reserve

Situations Implying Low Renal Perfusion

• Patients may describe:
  • Poor oral intake, anorexia, malaise, or thirst (suggestive of dehydration)
  • Orthostatic symptoms or dizziness due to intravascular volume depletion
  • Breathlessness or oedema in the setting of heart failure or cirrhosis
• Cardiovascular or respiratory events such as cardiac arrest or mechanical ventilation can also lead to altered haemodynamics and renal hypoperfusion.

Sepsis and Inflammation

• Sepsis is the leading cause of AKI in intensive care units globally.
• Sepsis-related ATN stems from a complex interplay of:
  • Systemic vasodilation
  • Inflammatory cytokine release
  • Endothelial dysfunction and microvascular compromise
  • Direct tubular cytotoxicity

Surgical and Perioperative Risks

• Cardiac surgery and vascular operations carry heightened ATN risk due to:
  • Hypoperfusion and ischaemia-reperfusion injury
  • Cross-clamping of major vessels above renal arteries
  • Use of nephrotoxic drugs or contrast agents perioperatively
• Renal transplant or cold ischaemia during renal surgery are also relevant historical details

Risk Factor Clustering

• The likelihood of ATN increases with multiple concurrent risk factors.
• For instance, a diabetic patient undergoing contrast-enhanced imaging during sepsis may be especially vulnerable.
• Some individuals exhibit greater sensitivity to short periods of hypoperfusion due to pre-existing renal or vascular pathology.

 Volume Depletion and Hypoperfusion

Common Signs Suggestive of Hypovolaemia or Shock

• Hypotension: Often present in patients with ischaemic ATN due to fluid loss or distributive shock (e.g. sepsis).
• Tachycardia: A compensatory response to hypotension or volume depletion.
• Dry mucous membranes, reduced skin turgor, and cool extremities: Classical indicators of dehydration.
• Orthostatic hypotension: May be noted on postural blood pressure testing in patients with depleted intravascular volume.
• Low jugular venous pressure (JVP): Supports a low central venous pressure state.

Findings Suggestive of Systemic Illness

Indicators of Sepsis or Systemic Inflammatory Response

• Fever and hypotension: May indicate sepsis as a precipitant of ATN.
• Signs of infection (e.g. pneumonia, cellulitis, urinary tract infection) may help localise the source of sepsis.
• Anasarca (generalised oedema): May be seen in advanced heart failure or liver disease contributing to reduced effective circulating volume.

Abdominal and Musculoskeletal Examination

• Abdominal distension: Can suggest intra-abdominal hypertension or abdominal compartment syndrome, which may impede renal perfusion.
• Muscle tenderness: May suggest rhabdomyolysis, a known cause of pigment-induced ATN.
• Ascites or hepatomegaly: May indicate underlying cirrhosis or hepatic dysfunction contributing to hypoperfusion and secondary ATN.

Oliguria or Anuria (Bedside Observation)

• Oliguria (<400 mL/day) is commonly seen in the maintenance phase of ATN.
• Anuria is less common but may occur in severe ischaemic injury or complete tubular obstruction.
• Nephrotoxic ATN may be non-oliguric, especially in contrast-induced or drug-related cases.

Signs of Complications or Comorbid Conditions

• Pulmonary oedema or crackles: May occur with fluid overload in oliguric ATN.
• Pallor and signs of uraemia (e.g. pericardial rub, confusion, asterixis) may be observed in advanced or prolonged cases.
• Hypertension or bradycardia: May occur due to fluid retention or rising urea levels.

Interpretation of Physical Findings

• Differentiate prerenal states from established ATN.
• Identify ongoing nephrotoxic exposure or systemic inflammatory conditions.
• Assess the severity of illness and potential complications (e.g., fluid overload, rhabdomyolysis, compartment syndrome).
• Guide further testing (e.g., urinalysis, renal imaging, creatine kinase levels).

 Blood and Biochemical Investigations

Basic Metabolic Profile

• Elevated serum creatinine and urea: Hallmark of reduced glomerular filtration.
• Urea-to-creatinine ratio:
  • ATN: typically <10:1 due to impaired tubular reabsorption.
  • Prerenal azotaemia: often >20:1 due to increased urea reabsorption.

Serum Electrolytes

• Hyperkalaemia, hyperphosphataemia, hypermagnesaemia
• Hyponatraemia and hypocalcaemia
• Metabolic acidosis (reduced bicarbonate)

Full Blood Count (FBC)

• Anaemia may be seen in ATN secondary to CKD, myeloma, haemolysis, or bleeding.

Coagulation Profile

• Platelet dysfunction due to uraemia may cause prolonged PTT or bleeding tendency.

Arterial Blood Gases (ABG)

• Useful for evaluating acid-base disturbances, particularly in oliguric or severe AKI.

Urinalysis and Urinary Studies

Dipstick and Microscopy

• Muddy brown granular casts are highly suggestive of ATN.
• Haem-positive dipstick with no red cells: suggests pigment nephropathy (rhabdomyolysis or haemolysis).
• Tubular epithelial cells or casts also support ATN diagnosis.

Urine Electrolytes and Osmolality

Urine Osmolality

• Prerenal Azotaemia: typically >500 mOsm/kg
• ATN: typically <350 mOsm/kg

Urine Sodium Concentration

• Prerenal Azotaemia: usually <20 mmol/L
• ATN: usually >40 mmol/L

Fractional Excretion of Sodium (FENa)

• Prerenal Azotaemia: <1%
• ATN: >2%

Fractional Excretion of Urea (FEUrea) (useful in patients on diuretics)

• Prerenal Azotaemia: <35%
• ATN: >50%

Crystals in Urine

• Ethylene glycol toxicity: calcium oxalate crystals
• Acyclovir toxicity: birefringent needle-shaped crystals

Urinary Myoglobin

• Elevated in rhabdomyolysis-induced ATN.

Imaging Studies

Renal Ultrasonography (with Doppler)

• First-line imaging to exclude obstructive uropathy.
• Assesses kidney size, cortical thickness, and echogenicity.
• UK Renal Association recommends:
  • Renal ultrasound within 24 hours of AKI presentation (or within 6 hours if obstruction suspected).

Abdominal X-ray

• Limited utility; may identify radiopaque stones but misses 30% of calculi.

Non-contrast CT Scan

• Superior to X-ray for identifying ureteric obstruction.
• Avoid contrast in suspected AKI.

MRI with Gadolinium

• Reserved for indeterminate cases.
• Group II gadolinium agents are safer in patients with renal impairment.

Histological Evaluation

Renal Biopsy

• Rarely needed; reserved for:
  • Unexplained AKI where vasculitis or glomerulonephritis is suspected.
  • Renal transplant recipients with suspected rejection.
• Histology in ATN:
  • Denuded tubular epithelium, cell swelling, cast formation
  • Loss of brush border, interstitial oedema, and WBC infiltration

Histological Patterns Identified in Clinical ATN

• Tubular cell sloughing: ~39%
• Tubular epithelial flattening: ~38%
• Tubular dilatation: ~37%
• Tubular cell necrosis: ~32%

Novel Biomarkers

Validated Early Biomarkers

• Neutrophil gelatinase-associated lipocalin (NGAL)
• Kidney injury molecule-1 (KIM-1)
• Interleukin-18 (IL-18)
• Cystatin C
• Liver-type fatty acid binding protein (L-FABP)
• NHE3 (sodium-hydrogen exchanger)

Emerging Combinations

• TIMP-2 × IGFBP-7: FDA-approved point-of-care test for predicting AKI in critically ill surgical patients.
• Predictive value enhanced when combined with furosemide stress testing (see below).

Limitations

• Still largely confined to research settings
• Not yet incorporated into routine clinical guidelines

Functional Assessment: Furosemide Stress Test (FST)

Procedure

• Administer 1.0–1.5 mg/kg IV furosemide
• Measure urine output over the next 2 hours

Interpretation

• <200 mL suggests poor prognosis and high likelihood of progressing to stage 3 AKI
• May outperform biomarkers in predicting need for renal replacement therapy (RRT)

Staging Acute Kidney Injury (KDIGO Criteria)

Stage 1

• Serum Creatinine:
  • 1.5–1.9 times baseline OR
  • Increase of ≥0.3 mg/dL (≥26.5 µmol/L)
• Urine Output
  • <0.5 mL/kg/h for 6–12 hours

Stage 2

• Serum Creatinine:
  • 2.0–2.9 times baseline
• Urine Output:
  • <0.5 mL/kg/h for ≥12 hours

Stage 3

• Serum Creatinine:
  • 3.0 times baseline OR
  • Increase to ≥4.0 mg/dL (≥353.6 µmol/L) OR
  • Initiation of renal replacement therapy (RRT)
• Urine Output:
  • <0.3 mL/kg/h for ≥24 hours OR
  • Anuria for ≥12 hours

Subcategories

• Acute Kidney Disease (AKD): AKI persisting 7–90 days
• Subclinical AKI: Presence of biomarkers with no overt functional loss

Key Differentials to Consider

Prerenal Azotaemia

• Cause: Hypoperfusion without intrinsic renal damage (e.g. dehydration, haemorrhage, heart failure)
• Distinguishing Features:
  • Typically reversible with fluid resuscitation
  • Oliguria is common
• Investigations:
  • Urea-to-creatinine ratio: >20:1
  • Urine sodium: <20 mmol/L
  • Urine osmolality: >500 mOsm/kg
  • Fractional excretion of sodium (FENa): <1%
  • Fractional excretion of urea (FEUrea): <35%

Intrinsic Renal Azotaemia (Non-ATN Causes)

Acute Glomerulonephritis (AGN)

• Cause: Immune-mediated glomerular inflammation
• Clues from Presentation:
  • Haematuria (often microscopic and dysmorphic)
  • Proteinuria (can be nephritic or nephrotic range)
  • Hypertension, oedema, and sometimes systemic features
• Urinalysis:
  • Red blood cell casts
  • FENa: >2%
  • FEUrea: >35%

Tubulointerstitial Nephritis (TIN)

• Cause: Typically drug-induced or due to infections/autoimmune disease
• Features:
  • Low-grade fever, rash, eosinophilia
  • History of recent antibiotic or NSAID use
• Urinalysis:
  • Sterile pyuria
  • Eosinophiluria (if tested)
  • Mild proteinuria and haematuria may be present

Chronic Kidney Disease (CKD)

• Cause: Progressive and irreversible loss of renal function over months to years
• Clues:
  • History of longstanding hypertension, diabetes, or known kidney disease
  • Small, shrunken kidneys on ultrasound
  • Normochromic normocytic anaemia
• Distinction:
  • CKD may decompensate with an acute insult, leading to “acute-on-chronic” kidney injury
  • Baseline creatinine levels and evidence of chronicity help differentiate

Drug-Induced Nephrotoxicity (Non-ATN Forms)

• Mechanisms:
  • Hemodynamic alterations (e.g. NSAIDs, ACEi)
  • Immune-mediated interstitial nephritis (e.g. β-lactam antibiotics)
  • Direct tubular toxicity (e.g. cisplatin, aminoglycosides)
• Pattern:
  • May mimic ATN but often has distinguishing features such as timing relative to drug exposure, systemic allergic symptoms, and biopsy findings in uncertain cases

Summary of Diagnostic Features Differentiating ATN and Mimics

ATN

• Muddy brown granular casts
• FENa >2%, FEUrea >50%
• Urine sodium >40 mmol/L
• Unresponsive to fluid resuscitation
• May follow hypotension, sepsis, or nephrotoxic exposure

Pre-renal Azotaemia

• Concentrated urine, low FENa (<1%)
• Rapid improvement with fluid therapy
• Urea-to-creatinine ratio >20:1

Acute Glomerulonephritis

• Red cell casts, significant proteinuria
• Systemic features (e.g. rash, arthritis) may be present

Tubulointerstitial Nephritis

• Fever, rash, eosinophilia
• Sterile pyuria and possible WBC casts

 General Supportive Care

Early Specialist Involvement

• Involvement of nephrologists or intensivists is recommended for patients with moderate to severe AKI.

Haemodynamic Optimisation

• Ensure adequate perfusion pressure and intravascular volume.
• Use vasopressors in vasodilatory shock under expert guidance.

Avoidance of Nephrotoxins

• Discontinue or minimise nephrotoxic agents (e.g. NSAIDs, aminoglycosides, radiocontrast, amphotericin B, cisplatin).

Medication Dose Adjustment

• Renally clear medications must be reviewed and adjusted based on GFR.

Electrolyte and Acid–Base Correction

• Monitor and treat hyperkalaemia, acidosis, and phosphate/calcium disturbances.

Fluid Management

Volume Expansion

• Isotonic crystalloids (normal saline or lactated Ringer’s) are first-line for volume resuscitation.
• Balanced crystalloids have theoretical advantages, but evidence does not show consistent superiority over normal saline.
• Avoid colloids (e.g. starches, albumin) due to risk of worsening AKI.

Goal-Directed Therapy (GDT)

• In critically ill patients, use dynamic haemodynamic parameters to guide fluid therapy.

Avoiding Fluid Overload

• Excessive fluid accumulation worsens outcomes in AKI; use conservative strategies once perfusion is restored.

Diuretics

Indications

• Only for volume overload, not for prevention or treatment of ATN itself.

Agents

• Furosemide or bumetanide can aid in managing hyperkalaemia and fluid balance.

Limitations

• Does not shorten duration of AKI or reduce need for renal replacement therapy (RRT).
• Monitor for electrolyte losses and acid–base disturbances (e.g. hypokalaemia, metabolic alkalosis).

Mannitol

• May be useful in early rhabdomyolysis-induced ATN

Contrast-Induced Nephropathy (CIN)

Preventive Measures

• IV isotonic saline 1 mL/kg/h for 6–12 hours before and 4–12 hours after contrast.
• Use iso- or low-osmolar contrast agents.
• Avoid high-osmolar contrast media.
• Do not use N-acetylcysteine (NAC) or sodium bicarbonate prophylactically — evidence does not support benefit.
• Suspend nephrotoxic agents and metformin before contrast use.

Outpatient or Urgent Procedures

• Administer isotonic saline for at least 1–3 hours before and 6 hours after the scan.

Renal Replacement Therapy (RRT)

Indications

• Refractory volume overload
• Severe hyperkalaemia
• Uraemic complications (pericarditis, encephalopathy)
• Severe metabolic acidosis (pH < 7.1)

Timing

• No consistent survival benefit between early vs delayed initiation.
• Individualised based on clinical condition and trends.

Modalities

• Intermittent haemodialysis: used in haemodynamically stable patients.
• Continuous renal replacement therapy (CRRT): preferred in unstable patients (e.g. CVVH, CVVHD, CVVHDF).
• Prolonged Intermittent Renal Replacement Therapy (PIRRT): useful in unstable patients on low-dose vasopressors.

Monitoring and Follow-Up

Acute Phase

• Track fluid balance, daily creatinine, electrolytes, and urine output.

Post-Discharge

• 3-month follow-up recommended to assess for renal recovery or progression to CKD.
• Monitor high-risk patients more frequently (e.g. prior CKD, diabetes, or prolonged AKI).

Complications to Manage

Electrolyte and Acid–Base Imbalances

• Hyperkalaemia: treat urgently to prevent arrhythmias.
• Hyponatraemia: correct slowly to avoid osmotic demyelination.
• Hyperphosphataemia, hypocalcaemia, and metabolic acidosis are common.

Fluid Overload

• Can cause pulmonary oedema, hypertension, and heart failure.

Uraemia

• Leads to bleeding, encephalopathy, nausea, and pericarditis.

Infection

• Occurs in 30–70% of cases; vigilant monitoring and appropriate antimicrobial therapy are essential.

Anaemia

• Multifactorial, often worsened by haemodilution, reduced erythropoiesis, and blood loss.

Prevention Strategies

General Measures (KDIGO Guidelines)

• Optimise fluid status and perfusion pressure.
• Avoid nephrotoxins where possible.
• Close monitoring of high-risk patients.
• Avoid hyperglycaemia.
• Use functional haemodynamic monitoring.

Drug-Specific Prevention

• Aminoglycosides: Use once-daily dosing.
• Amphotericin B: Use lipid formulations and maintain hydration.
• Cisplatin: Hydration; consider amifostine or switch to carboplatin.
• Calcineurin inhibitors: Monitor drug levels closely.

Rhabdomyolysis

• Early aggressive saline infusion to maintain urine output >300 mL/hour.
• Urine alkalinisation no longer routinely recommended.

Nutrition

KDIGO Recommendations

• Energy intake: 20–30 kcal/kg/day
• Protein intake:
  • 0.8–1.0 g/kg/day (non-catabolic, non-dialysis patients)
  • 1.0–1.5 g/kg/day (on dialysis)
  • Up to 1.7 g/kg/day (CRRT or hypercatabolic states)
• Prefer enteral over parenteral feeding

Investigational Therapies

• Emerging experimental treatments based on molecular mechanisms of injury include:
  • TLR4 antagonists, AT2 receptor agonists, Drp1 inhibitors, and RIPK1 inhibitors have shown renal protective effects in animal models.
  • Further human trials are needed before clinical use.

Short-Term Outcome

In-Hospital Mortality

• Approximately 50% overall
• 30% one-year survival

Higher Mortality Rates

• Up to 79% in critically ill ICU patients
• 60–70% in post-operative or sepsis-related ATN
• Patients requiring mechanical ventilation or with multi-organ failure face mortality rates of 50–80%

Predictors of Poor Prognosis

Factors associated with increased mortality include

• Male sex
• Advanced age
• Oliguria (associated with more severe tubular injury)
• High initial creatinine levels (>3 mg/dL)
• Poor nutritional status
• Comorbidities:
  • Diabetes mellitus
  • Cardiovascular disease
  • Stroke
  • Malignancy

Critical illness features

• Need for vasopressors or mechanical ventilation
• Sepsis
• Acute myocardial infarction
• Seizures or encephalopathy

Long-Term Outcomes

Renal Recovery

• Approximately 50% of survivors retain some level of renal impairment
• About 5% of patients progress to permanent dialysis
• 5% experience ongoing decline in renal function

Progression to CKD or ESRD

• AKI episodes significantly increase long-term risk for:
  • CKD (HR ~8.8)
  • ESRD (HR ~3.1)
  • Mortality (HR ~2.0)

Cardiovascular Risk

• Increased incidence of heart failure, stroke, and vascular events
• Thought to be due to persistent endothelial dysfunction and inflammation (“uraemic memory”)

Recovery After Hospitalisation

Patients Requiring Dialysis During AKI

• At 3 months: ~29.7% recovered renal function
• ~35.7% progressed to ESRD
• ~15.8% died

Six-Month Outcomes

• ~32.2% recovered kidney function
• ~48.8% developed ESRD
• ~16.9% died
  
  

Prognostic Impact of AKI Severity

• Patients with oliguric ATN have:
  • Greater severity of tubular necrosis
  • Higher rates of fluid and electrolyte disturbances
  • Poorer outcomes than non-oliguric ATN
• A rapid rise in creatinine or persistent anuria are indicators of worse prognosis

Impact of Co-Morbidities

• Pre-existing CKD increases the risk of both requiring dialysis during AKI and progressing to ESRD post-discharge
• In the ASSESS-AKI and SALTO trials, higher urine albumin:creatinine ratios and persistent renal dysfunction were associated with progression and death
• Long-term risk of CKD and cardiovascular events remains elevated even if creatinine returns to baseline

Data Highlights from National Registries and Trials

• USRDS (2001–2010):
  • ATN patients had higher chances of recovery compared to non-ATN ESRD
  • 12-week renal recovery: 23% (ATN) vs 2% (non-ATN ESRD)
  • Mortality at 1 year: 38% (ATN) vs 27% (controls)
• RENAL trial: 90-day survival ~38%, with most deaths occurring in first 3 months
• ELAIN trial: Suggested survival benefit with early dialysis in certain populations, though findings are not universally confirmed

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