What is the recommended management of uremic syndrome in an adult with end‑stage renal disease (CKD stage 5) or acute kidney injury not yet on renal replacement therapy?

Management of Uremic Syndrome in Adults with CKD Stage 5 or AKI Not Yet on Dialysis

Initiate renal replacement therapy emergently when life-threatening complications develop—specifically persistent hyperkalemia (>6.5 mmol/L), severe metabolic acidosis refractory to bicarbonate, diuretic-unresponsive volume overload with pulmonary edema, or overt uremic symptoms including pericarditis, encephalopathy, seizures, or coma—rather than relying on serum creatinine or eGFR thresholds alone. 1, 2

Absolute Indications for Emergent Dialysis

The decision to initiate renal replacement therapy must be driven by clinical manifestations and life-threatening metabolic derangements, not arbitrary laboratory cutoffs. 1, 2

Life-Threatening Metabolic Indications

• Persistent hyperkalemia >6.5 mmol/L that fails to respond to medical management (calcium gluconate, insulin with glucose, beta-agonists) requires immediate dialysis due to imminent risk of fatal cardiac arrhythmias. 2

• Severe metabolic acidosis refractory to bicarbonate therapy, particularly when pH remains critically low despite medical intervention, mandates dialysis initiation. 3, 2

• Volume overload with pulmonary edema unresponsive to diuretic therapy constitutes an emergent indication, especially when respiratory compromise develops. 3, 1, 2

Overt Uremic Symptoms (Absolute Indications)

• Uremic pericarditis is an absolute indication for emergent dialysis due to risk of cardiac tamponade. 3, 2

• Uremic encephalopathy with altered mental status, confusion, seizures, or coma requires immediate dialysis. 3, 2, 4

• Seizures or coma in the setting of uremia mandate dialysis initiation. 2

• Symptomatic uremia (regardless of GFR level) including severe nausea, anorexia, pruritus, protein-energy malnutrition despite optimized intake, or bleeding diathesis warrants RRT. 1, 4, 5

Why Serum Creatinine and eGFR Should NOT Guide Timing

A critical pitfall is initiating dialysis based solely on creatinine or eGFR values. The evidence strongly argues against this approach:

• Serum creatinine-based eGFR is substantially influenced by muscle mass in advanced CKD, making it both a marker of sarcopenia and kidney function—not a pure measure of renal clearance. 1

• The IDEAL randomized controlled trial (828 patients) compared early initiation (eGFR 10-14 mL/min/1.73 m²) with late initiation (eGFR 5-7 mL/min/1.73 m²) and found no significant differences in all-cause mortality, cardiovascular events, infectious events, or dialysis-related complications. 1

• In the IDEAL trial, 76% of participants assigned to "late-start" required earlier initiation due to emergent uremic symptoms, demonstrating that clinical symptoms—not eGFR thresholds—drive timing decisions. 1

• The KDOQI 2015 guidelines explicitly state that sufficient data exist to discourage reliance on a single eGFR value for dialysis initiation. 1

• In otherwise asymptomatic individuals, maintenance dialysis should not be started solely because of a serum creatinine or eGFR value. 1

Modality Selection Based on Clinical Context

Hemodynamically Unstable Patients

• Continuous renal replacement therapy (CRRT) is preferred for hemodynamically unstable patients with acute kidney injury, providing superior fluid balance control and hemodynamic stability compared to intermittent hemodialysis. 3, 1, 2

• Specific indications for CRRT include: hemodynamic instability with hypotension, acute respiratory distress syndrome requiring improved gas exchange, septic shock with need for inflammatory mediator removal, cerebral edema or risk thereof, continuous volume removal requirements, and pulmonary edema requiring careful fluid balance. 1

• CRRT can be more safely performed due to a diminished tendency to exacerbate hypotension compared to intermittent hemodialysis. 3

Hemodynamically Stable Patients

• Intermittent hemodialysis is preferred for hemodynamically stable patients and is the modality of choice for most emergent indications when hemodynamic stability permits. 1, 2

• In acute settings with continuous metabolite release (such as tumor lysis syndrome), frequent (daily) dialysis is recommended, with timing and dose linked to the generation rate of toxins. 3, 1, 2

When NOT to Use Peritoneal Dialysis

• Peritoneal dialysis should be reserved for situations where other therapy modalities are unavailable. 3, 1

• The major drawback to PD in acute uremic syndrome is the lower efficiency in removing solute and fluid as compared with intermittent hemodialysis and CRRT, limiting its usefulness in patients who require significant solute removal (urea, potassium, phosphate). 3

• Do not use peritoneal dialysis for emergent indications—it is too inefficient for managing acute life-threatening complications. 2

Pathophysiology of Uremic Syndrome

Understanding the mechanisms helps guide supportive management while preparing for or during dialysis:

• Uremic syndrome involves accumulation of multiple uraemic toxins (both identified and unidentified) of low and high molecular weight, many of which are inadequately cleared by dialysis due to high protein binding or large molecular size. 6, 7

• Nervous system complications occur in every patient with uremic syndrome and include cognitive deterioration, encephalopathy, seizures, asterixis, myoclonus, restless leg syndrome, stroke, neuropathies, and myopathy. 4

• Pathogenic mechanisms include: neurotoxicity from uremic toxins, blood-brain barrier injury, neuroinflammation, oxidative stress, brain neurotransmitter imbalance, metabolic derangements (acidosis, hypocalcemia, hyperphosphatemia, hypomagnesemia, hyperkalemia), secondary hyperparathyroidism, anemia, nutritional deficiencies, and hyperhomocysteinemia. 4

• The uraemic syndrome is associated with cardiovascular disease, metabolic bone disease, inflammation, protein energy wasting, intestinal dysbiosis, anaemia, and neurological and endocrine dysfunction. 8

Practical Clinical Algorithm

Step 1: Assess for Absolute Indications (Initiate RRT Immediately)

• Hyperkalemia >6.5 mmol/L unresponsive to medical therapy 2
• Severe metabolic acidosis refractory to bicarbonate 2
• Pulmonary edema/volume overload unresponsive to diuretics 1, 2
• Uremic pericarditis 2
• Uremic encephalopathy, seizures, or coma 2

Step 2: Assess for Symptomatic Uremia (Strong Indication for RRT)

• Severe nausea, vomiting, anorexia 1, 5
• Protein-energy malnutrition despite optimized intake 1
• Pruritus, altered mental status 1, 5
• Uremic bleeding 1

Step 3: Choose Modality

• If hemodynamically unstable: CRRT 1, 2
• If hemodynamically stable: Intermittent hemodialysis 1, 2
• If continuous metabolite release (e.g., tumor lysis): Daily dialysis 1, 2
• Avoid peritoneal dialysis in acute/emergent settings 2

Step 4: Do NOT Initiate Based on eGFR/Creatinine Alone

• In asymptomatic patients, even with eGFR <10 mL/min/1.73 m², careful monitoring allows safe delay of dialysis. 1
• Assess trends, not single values. 2

Critical Pitfalls to Avoid

• Do not delay RRT until severe complications develop in critically ill patients—earlier intervention when absolute indications appear is safer. 1

• Do not use serum creatinine alone to guide timing decisions; always calculate GFR and prioritize clinical symptoms. 1, 2

• Do not use peritoneal dialysis for acute situations requiring rapid solute/fluid removal. 2

• In hemodynamically unstable patients, do not use intermittent hemodialysis—CRRT is preferred to avoid exacerbating hypotension. 2

• CRRT requires proper anticoagulation and continuous monitoring, increasing complexity and bleeding risk compared to intermittent hemodialysis. 1

• If hyperkalemia persists despite CRRT, verify CRRT function—check blood flow, dialysate composition, and prescription adequacy. 1