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Perioperative Acute Kidney Injury (AKI) - 30 Marks

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DEFINITION AND DIAGNOSTIC CRITERIA

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EPIDEMIOLOGY AND SIGNIFICANCE

• AKI occurs in 5-25% of all hospitalized patients depending on definition used
• About one-quarter of all hospital-acquired renal failure cases occur in the perioperative period
• Perioperative AKI is especially common after cardiac surgery (incidence up to 30%), major vascular surgery, and transplantation
• AKI requiring dialysis carries 50-80% mortality in ICU settings
• Even mild AKI (Stage 1) increases mortality by 10-35%
• Long-term consequences: progression to CKD, cardiovascular events, prolonged hospital stay

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CAUSES OF PERIOPERATIVE AKI

Prerenal

• Hypovolaemia (third-space losses, bleeding, inadequate replacement)
• Sepsis and distributive shock
• Cardiac failure / low cardiac output states
• Low cardiac output due to anaesthesia and cardiopulmonary bypass
• Increased intra-abdominal pressure (abdominal compartment syndrome)
• Cirrhosis and hepatorenal syndrome
• Aortic cross-clamping

Intrinsic Renal

• Ischaemia-reperfusion injury (most common mechanism)
• Inflammation and sepsis
• Pre-existing CKD, diabetes, obesity
• Endogenous nephrotoxins: myoglobin (rhabdomyolysis), haemoglobin (haemolysis)
• Exogenous nephrotoxins: radiocontrast agents, aminoglycosides, NSAIDs, vancomycin + piperacillin-tazobactam combination
• Chloride-rich crystalloids and hydroxyethyl starch
• Blood transfusions

Postrenal (Obstructive)

• Blocked/displaced urinary catheter
• Prostate hypertrophy / neurogenic bladder
• Tumour / pelvic surgery

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PATHOPHYSIOLOGY / MECHANISMS

1. Ischaemia-Reperfusion Injury

• Reduction in renal blood flow (RBF) leads to medullary ischaemia, as the renal medulla normally operates near its oxygen extraction limit
• The thick ascending limb of the loop of Henle is most vulnerable
• Reperfusion generates reactive oxygen species (ROS) causing further tubular injury
• Endothelial injury leads to neutrophil adhesion, microvascular obstruction ("no-reflow" phenomenon)

2. Inflammation

• Surgical trauma activates systemic inflammatory response (SIRS)
• Pro-inflammatory cytokines (IL-1, IL-6, TNF-alpha) cause renal microvascular dysfunction
• Toll-like receptor activation on tubular cells amplifies injury

3. Nephrotoxicity

• Direct tubular cell toxicity from drugs, pigments, or contrast agents
• Aminoglycosides accumulate in proximal tubular cells causing apoptosis
• Myoglobin and haemoglobin cause tubular obstruction and direct toxicity

Renal Autoregulation

• Under normal conditions, RBF is autoregulated between MAP 70-130 mmHg
• Anaesthesia, vasodilators, and hypovolaemia can impair autoregulation and expose the kidney to perfusion pressure-dependent injury

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RISK FACTORS

Patient-Related (Non-modifiable)

• Advancing age (>65 years)
• Pre-existing CKD (most important single risk factor)
• Diabetes mellitus
• Hypertension and cardiovascular disease
• Liver disease / cirrhosis
• Obesity
• Low baseline GFR

Surgical Risk Factors

• Cardiac surgery with cardiopulmonary bypass
• Major vascular surgery (especially aortic cross-clamping)
• Emergency surgery
• Liver transplantation
• Major intra-abdominal surgery
• Surgery duration >3 hours

Anaesthetic/Perioperative Factors

• Intraoperative hypotension (MAP <65 mmHg sustained for >10 minutes)
• Hypovolaemia
• Use of nephrotoxic agents intraoperatively
• Hyperchloraemia from 0.9% saline
• Intraoperative blood transfusion

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ASSESSMENT OF RENAL FUNCTION IN THE PERIOPERATIVE PERIOD

Preoperative Assessment

• Serum creatinine - Baseline measurement; note that sCr does not rise until >50% of GFR is lost
• eGFR (CKD-EPI formula) - More accurate than creatinine alone
• Urine albumin-to-creatinine ratio - Proteinuria is an independent risk predictor
• BUN/Creatinine ratio - Helps differentiate prerenal (>20:1) from intrinsic renal disease

Intraoperative Monitoring

• Urine output: Target ≥0.5 mL/kg/h intraoperatively; however, intraoperative oliguria does NOT reliably predict postoperative AKI - fluids should not be given excessively to treat oliguria alone
• Blood pressure: Avoid sustained MAP <65 mmHg
• Serum creatinine trends: Serial measurements postoperatively

Novel Biomarkers (Emerging)

• Cystatin C: Rises earlier than creatinine; not yet standard perioperative practice
• NGAL (Neutrophil Gelatinase-Associated Lipocalin): Rises 2-6 hours after tubular injury
• [IGFBP7 × TIMP-2]: Cell cycle arrest markers in urine - available as NephroCheck® test; best validated for early risk stratification after cardiac surgery
• KIM-1, L-FABP, IL-18: Research use; correlate with tubular injury

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ANAESTHETIC CONSIDERATIONS AND EFFECTS ON THE KIDNEY

Regional Anaesthesia

• Epidural and spinal anaesthesia reduce renal and systemic sympathetic tone
• Sympathetic block above T4 also reduces cardiac sympathetic drive
• If regional anaesthesia drops MAP/cardiac output significantly, RBF decreases
• Evidence from meta-analyses suggests thoracic epidural anaesthesia may reduce perioperative AKI, though confidence intervals are wide
• Postoperative epidural analgesia may provide renal protection via maintained haemodynamics and reduced stress response

Inhalational Agents

• Methoxyflurane and enflurane (historical): caused fluoride-induced polyuric nephropathy - no longer used
• Sevoflurane: Generates inorganic fluoride AND compound A (nephrotoxic in rats), but NO clinical evidence of AKI in humans; likely safe due to shorter duration of fluoride exposure and intrahepatic metabolism of sevoflurane (vs. intrarenal for methoxyflurane)
• Desflurane, isoflurane: No nephrotoxic concerns
• Minimal flow anaesthesia with sevoflurane: avoid <1 L/min fresh gas flow to limit compound A accumulation (manufacturer's recommendation, though clinical evidence is lacking)

Intravenous Agents

• Propofol, fentanyl, midazolam: no direct nephrotoxicity
• NSAIDs (ketorolac): inhibit prostaglandin-mediated afferent arteriolar dilation - avoid in hypovolaemic states or CKD
• ACE inhibitors/ARBs: may exacerbate perioperative AKI especially in volume-depleted states - consider withholding morning of surgery in high-risk patients

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INTRAOPERATIVE HAEMODYNAMIC MANAGEMENT

Blood Pressure Targets

• Maintain MAP ≥65 mmHg; for patients with pre-existing hypertension or CKD, individualize targets (MAP ≥70-80 mmHg)
• Intraoperative hypotension (MAP <65 mmHg for >10 min) is a significant independent risk factor for AKI
• Vasopressors (norepinephrine, vasopressin) may be necessary to maintain renal perfusion pressure in vasodilatory states

Fluid Management

• Use balanced crystalloid solutions (Lactated Ringer's, Plasma-Lyte) as first choice - avoids hyperchloraemic metabolic acidosis associated with 0.9% normal saline
• Balanced solutions are associated with modest reductions in AKI incidence vs. 0.9% saline
• Avoid hydroxyethyl starch (HES): Associated with increased AKI risk and need for RRT in critically ill patients
• Goal-directed fluid therapy (GDT): May reduce AKI in elective surgical patients; however, overly restrictive protocols have paradoxically increased AKI risk in some studies - avoid both hypovolaemia and hypervolaemia
• Volume overload is independently associated with adverse outcomes in AKI

Monitoring of Fluid Status

• Central venous pressure (CVP): limited accuracy for fluid responsiveness
• Dynamic indices: pulse pressure variation (PPV), stroke volume variation (SVV) in mechanically ventilated patients
• Trans-oesophageal echocardiography (TOE): Gold standard for intraoperative fluid assessment

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ABDOMINAL COMPARTMENT SYNDROME AND AKI

• Intra-abdominal pressure (IAP) >20 mmHg = abdominal compartment syndrome
• Elevated IAP compresses renal parenchyma, reduces renal venous outflow, and decreases GFR
• Measurement: Foley catheter technique - instil 25 mL saline, clamp distal to port, transduce at mid-axillary line at end-expiration
• Treatment: surgical decompression (laparostomy)
• Normal IAP in obese patients may be up to 12 mmHg without end-organ dysfunction

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SPECIFIC CLINICAL SCENARIOS

Cardiac Surgery AKI

• Incidence: 10-30%; requiring dialysis: 1-5%
• Mechanisms: non-pulsatile flow on bypass, haemodilution, haemolysis, microemboli, systemic inflammatory response, hypothermia
• Protective strategies: off-pump coronary artery bypass (OPCAB), pulsatile perfusion, avoiding hypotension, tight glucose control
• Remote ischaemic preconditioning (RIPC): concept of brief limb ischaemia to protect kidneys via humoral mediators - results are mixed in large RCTs

Contrast-Induced AKI

• Risk highest in CKD + diabetes + volume depletion
• Pathophysiology: renal vasoconstriction + direct tubular toxicity
• Prevention: adequate IV hydration with 0.9% saline or sodium bicarbonate, use of iso-osmolar contrast agents, minimise contrast volume
• N-acetylcysteine (NAC): previously standard; meta-analyses and the large PRESERVE trial show NO benefit - no longer recommended
• Fenoldopam: does NOT reduce contrast-induced AKI
• Withhold nephrotoxic drugs (NSAIDs, metformin) before contrast

Rhabdomyolysis-Associated AKI

• Causes: prolonged surgery (compression injury), malignant hyperthermia, succinylcholine (masseter spasm), vigorous exercise, sepsis
• Myoglobin is directly nephrotoxic - causes tubular obstruction, free radical generation, vasoconstriction
• Urine: tea-coloured (pigmenturia); dipstick positive for blood but no RBCs on microscopy
• CK >5000 U/L: high risk for AKI
• Treatment: aggressive IV hydration (target UO 200-300 mL/h), urinary alkalinisation (controversial), avoid mannitol (evidence lacking)

AKI in Major Vascular Surgery

• Aortic cross-clamping above renal arteries causes direct ischaemia
• Suprarenal clamp time should be minimised
• Cold renal perfusion may provide protection
• Preoperative renal artery stenosis (RAS) is an important risk factor

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PHARMACOLOGICAL RENAL PROTECTION: EVIDENCE

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MANAGEMENT OF ESTABLISHED PERIOPERATIVE AKI

Principles

1. Identify and treat the cause - especially reversible causes (hypovolaemia, obstruction, nephrotoxins)
2. Maintain haemodynamic stability - MAP ≥65 mmHg
3. Avoid further nephrotoxins
4. Nutritional support - adequate protein intake; avoid protein restriction
5. Tight glycaemic control (glucose 140-180 mg/dL) - hyperglycaemia independently worsens AKI
6. Monitor and treat complications: hyperkalemia, metabolic acidosis, fluid overload, uraemia

Conventional Indications for Renal Replacement Therapy (RRT)

• Refractory Acidosis (pH <7.15)
• Refractory Electrolyte abnormalities (hyperkalemia K+ >6.5 mEq/L)
• Ingestion/toxin removal
• Refractory Oliguria/fluid Overload
• Uraemia (uraemic encephalopathy, pericarditis)

Timing of RRT

• Traditionally initiated at Stage 3 AKI
• ELAIN trial (cardiac surgery): Early RRT (Stage 2) - lower mortality (39.3% vs 54.7%) and better renal recovery at 90 days
• AKIKI, IDEAL-ICU, STARRT-AKI trials (general ICU): Delayed RRT was not inferior to early initiation; significant proportion of delayed-arm patients recovered without needing dialysis
• Current consensus: Individualise RRT timing based on clinical trajectory; emergency indications mandate immediate RRT; otherwise, watchful waiting is acceptable

Modalities of RRT

• No evidence that one modality is superior for mortality
• CRRT may provide better haemodynamic tolerance and solute control in the unstable patient

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POSTOPERATIVE MONITORING AND RECOVERY

• Serial serum creatinine measurements for 48-72 hours post-op in high-risk patients
• Monitor urine output trends
• Early nephrology consultation for Stage 2-3 AKI
• Discontinue nephrotoxic drugs
• Adjust drug doses for reduced GFR (antibiotics, LMWH, opioids)
• Most perioperative AKI is reversible if the cause is treated promptly
• Persistent AKI beyond 7 days: investigate for chronic component; assess for intrinsic renal pathology (renal biopsy may be needed)

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PREVENTION STRATEGIES: A SUMMARY

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RECENT EVIDENCE AND UPDATES (2024-2026)

• The ADQI/POQI joint consensus (Nat Rev Nephrol, 2021) on postoperative AKI in non-cardiac surgery emphasised that even small creatinine rises (Stage 1) are clinically significant and require follow-up.
• Biomarkers such as IGFBP7 × TIMP-2 (NephroCheck) are the most promising early markers for identifying patients at risk before creatinine rises.
• Preoperative risk models for AKI after non-cardiac surgery have been validated - PMID 38527923 (Br J Anaesth, 2024) - multivariable models incorporating lab values and clinical features outperform simple clinical scoring.
• The vancomycin + piperacillin-tazobactam combination has emerged as a significant and underrecognised perioperative nephrotoxin; alternatives should be considered.

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EXAM SUMMARY: KEY TAKE-HOME POINTS

1. KDIGO staging (sCr and UO criteria) is the standard definition - know all 3 stages
2. Mechanism = ischaemia-reperfusion + inflammation + nephrotoxins
3. Intraoperative hypotension (MAP <65 mmHg) and hypovolaemia are the single most important modifiable risk factors
4. Sevoflurane is clinically safe despite theoretical concerns (compound A, fluoride)
5. No drug prevents AKI - prevention is haemodynamic and nephrotoxin avoidance
6. Balanced crystalloids (LR, Plasma-Lyte) preferred; avoid 0.9% saline in large volumes; avoid HES
7. Oliguria alone does NOT mandate fluid loading - assess context
8. RRT: individualise timing; CRRT preferred in haemodynamic instability; no proven modality superiority for mortality
9. Novel biomarkers (NGAL, IGFBP7×TIMP-2, cystatin C) are promising but not yet standard of care
10. Post-AKI follow-up is mandatory - 25-35% progress to CKD within 2 years

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• Miller's Anesthesia, 10th Edition - Chapter on Renal Physiology and Pathophysiology, pp. 5662-5705
• Bailey and Love's Short Practice of Surgery, 28th Edition - Chapter 24, pp. 342-343
• Brenner and Rector's The Kidney, 2-Volume Set - AKI chapters
• Zhuo XY et al. Preoperative risk prediction models for AKI after noncardiac surgery. Br J Anaesth. 2024 Sep. [PMID: 38527923]
• KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl. 2012