What is the recommended management for uremic encephalopathy in an adult with end‑stage renal disease (eGFR < 15 mL/min/1.73 m²) or acute renal failure?

Management of Uremic Encephalopathy in End-Stage Renal Disease

Initiate urgent hemodialysis when uremic encephalopathy is diagnosed in a patient with eGFR < 15 mL/min/1.73 m², as dialysis is the definitive treatment that reverses the accumulation of neurotoxic uremic solutes responsible for the encephalopathy. 1, 2

Immediate Recognition and Diagnosis

Uremic encephalopathy presents as a progressive neuropsychiatric syndrome ranging from mild confusion and attention deficits to delirium, asterixis, multifocal myoclonus, seizures, and ultimately coma in untreated patients with advanced renal failure 3, 4. The diagnosis is clinical and should be suspected when:

• Mental status changes progress from subtle cognitive slowing to overt confusion in the setting of severe azotemia 3
• Movement disorders appear, including tremor, asterixis (flapping tremor), and multifocal myoclonus 3, 4
• Seizures develop, which represent a medical emergency requiring immediate dialysis 3
• Cognitive deficits affect attention, memory, learning, and spatial orientation even before overt encephalopathy becomes clinically apparent 5, 6

The pathophysiology involves accumulation of uremic toxins, oxidative stress, hormonal disturbances, and imbalance of excitatory and inhibitory neurotransmitters 7. Importantly, cognitive dysfunction and metabolic brain alterations occur in CKD stages 4-5 long before classic uremic encephalopathy manifests 5.

Definitive Treatment: Dialysis Initiation

Dialysis must be initiated emergently when uremic encephalopathy is present, regardless of the specific eGFR value, because this represents an absolute clinical indication that supersedes GFR-based thresholds 1, 8, 2. The clinical indications for urgent dialysis include:

• Uremic symptoms including altered mental status, nausea, vomiting, pruritus, pericarditis 1, 8
• Refractory volume overload despite maximal diuretic therapy 1, 8
• Uncontrolled hypertension despite multiple antihypertensive agents 1, 8
• Severe electrolyte abnormalities such as hyperkalemia > 6.0 mmol/L refractory to medical management 1
• Progressive malnutrition or protein-energy wasting 1, 2
• Uremic bleeding or coagulopathy 1

First Dialysis Session Protocol

Use a "low and slow" approach for the initial hemodialysis treatment to minimize dialysis disequilibrium syndrome 8:

• Session duration: 2–2.5 hours (shorter than standard) 8
• Blood flow rate: reduced compared to maintenance dialysis 8
• Ultrafiltration: minimal during the first session 8
• Target Kt/V: lower than maintenance targets initially 2

This cautious approach prevents dialysis disequilibrium syndrome, which manifests as headache, nausea, muscle cramps, obtundation, and seizures due to rapid osmotic shifts 3.

Maintenance Dialysis Adequacy

Once stabilized, transition to standard hemodialysis prescription 2:

• Frequency: three times per week 2
• Duration: 3–4 hours per session 2
• Adequacy targets: URR ≥ 65% or single-pool Kt/V ≥ 1.2 2

Higher dialysis doses beyond Kt/V > 1.2 do not confer additional mortality benefit 2.

Medical Management During Acute Phase

Blood Pressure Control

• Target BP: < 130/80 mmHg 1, 8
• First-line agents: ACE inhibitors or ARBs should be continued unless dialysis has been initiated or intolerable adverse effects occur 1
• Monitoring: Check serum creatinine and potassium within 5–7 days after any dose adjustment 1
• Discontinuation criteria: Stop or reduce dose only if creatinine rises > 30% from baseline or potassium exceeds 5.5 mmol/L 1

The 2024 KDIGO guideline represents a paradigm shift, recommending continuation of ACE inhibitors/ARBs in stage 5 CKD rather than routine discontinuation 1.

Medication Adjustments

Avoid or adjust the following medications in patients with eGFR < 15 mL/min/1.73 m² 9:

• NSAIDs: Avoid entirely—they worsen renal function and increase hyperkalemia risk 9, 1
• Opioids: Use with extreme caution; reduce doses significantly 9
• Penicillins: Risk of neurotoxicity with high-dose benzylpenicillin (maximum 6 g/day) 9
• Tetracyclines: Can exacerbate uremia; reduce dose when eGFR < 45 mL/min/1.73 m² 9
• Metformin: Contraindicated when eGFR < 30 mL/min/1.73 m² 9

Electrolyte and Metabolic Management

• Hyperkalemia: Dietary potassium restriction to 2–3 g/day, sodium polystyrene sulfonate, and adequate dialysis 1, 2
• Metabolic acidosis: Corrected by dialysis 2
• Mineral-bone disorder: Monitor calcium, phosphorus, and PTH every 3–6 months 1

Nutritional Support

Protein intake: 1.2 g/kg/day (≥ 50% high-biological-value protein) once on hemodialysis 2

Energy intake: 35 kcal/kg/day for patients < 60 years; 30–35 kcal/kg/day for patients ≥ 60 years 2

Sodium restriction: < 2 g/day (< 5 g sodium chloride) 1

Phosphorus restriction: 800–1,000 mg/day 1

Monitor serum albumin every 3 months, as low albumin at dialysis initiation independently predicts higher mortality 2.

Monitoring Schedule Post-Dialysis Initiation

• Serum creatinine and eGFR: every 3 months 1
• Serum potassium: every 3 months, more frequently if on ACE inhibitors/ARBs 1
• Hemoglobin: every 3 months to screen for CKD-related anemia 1
• Nutritional markers (albumin, pre-albumin): every 3 months 1, 2
• Mineral-bone markers (calcium, phosphorus, PTH): every 3–6 months 1

Critical Pitfalls to Avoid

Never delay dialysis when uremic encephalopathy is present—this is an absolute indication regardless of eGFR, and delaying treatment increases mortality 1, 2

Never use aggressive first dialysis sessions—rapid correction causes dialysis disequilibrium syndrome with worsening neurological symptoms 8, 3

Never discontinue ACE inhibitors/ARBs prematurely based solely on eGFR < 15 mL/min/1.73 m²—continue unless dialysis is initiated or specific adverse effects occur 1

Never rely on serum creatinine alone—always calculate eGFR using validated equations (CKD-EPI or MDRD) 1, 8

Never assume cognitive dysfunction will fully resolve with dialysis—studies show hemodialysis may be associated with more severe cognitive impairment than CKD alone, possibly due to intradialytic hypotension and loss of residual kidney function 5, 2

Prognosis and Long-Term Considerations

Uremic encephalopathy typically improves with adequate dialysis, but subtle cognitive deficits often persist 5, 4. Patients on maintenance hemodialysis continue to experience impaired mentation, generalized weakness, and peripheral neuropathy despite adequate dialysis 3. Antioxidant therapy may serve as adjuvant treatment for persistent neurological complications 7.

Kidney transplantation offers the best long-term neurological outcomes, and living-donor pre-emptive transplantation should be considered when eGFR falls below 20 mL/min/1.73 m² with evidence of progressive, irreversible CKD 1.