In a 72‑year‑old man with acute‑on‑chronic renal failure (severe uremia, markedly reduced eGFR), rhabdomyolysis (elevated creatine kinase), normonatremia, normokalemia, and moderate‑to‑severe depression refusing dialysis, which physical investigations should be requested and serially monitored, what cardiac complications are anticipated, which factors guide choice of antidepressant, how does ageing modify pharmacodynamics in renal impairment, how should antidepressant therapy be initiated and what parameters should be followed, and what modifications are required if he subsequently receives haemodialysis?

Management of Severe Depression with Acute-on-Chronic Renal Failure and Rhabdomyolysis

Physical Investigations to Request and Monitor

Immediately obtain and serially monitor serum creatinine, eGFR (daily during acute phase), electrolytes (sodium, potassium daily to twice daily), creatine phosphokinase, calcium, phosphate, uric acid, complete blood count, and urinalysis with urine myoglobin. 1, 2

Initial Laboratory Assessment

• Serum creatinine and eGFR daily to track trajectory and guide management decisions, as elderly patients require close monitoring during the acute phase 1, 2
• Electrolytes (sodium and potassium) daily to twice daily, as elderly patients are at higher risk for life-threatening hyperkalemia and hyponatremia, particularly when starting antidepressants 1, 2, 3, 4
• Creatine phosphokinase (CPK) daily until declining and below 1000 U/L, as values >5000 U/L significantly increase acute kidney injury risk 5, 6
• Calcium and phosphate levels every 1-2 days, as hypocalcemia during the oliguric phase can transition to hypercalcemia during recovery 7
• Uric acid levels, as profound hyperuricemia (often >15 mg/dL) is characteristic of rhabdomyolysis-induced renal failure 7
• Urinalysis with urine myoglobin to confirm myoglobinuria and monitor clearance 5, 7

Ongoing Monitoring Parameters

• Daily weights at the same time after voiding to assess volume status and guide diuretic therapy 8
• Hourly urine output monitoring via bladder catheter given Stage 3 AKI (creatinine 475 μmol/L) 2
• Recheck fasting glucose and HbA1c within 4 weeks of starting antidepressant, then at 3 months, as SNRIs and SSRIs can worsen glycemic control 9, 4
• Liver function tests, lipids, and prolactin at baseline, then at 3 months and annually 9
• Electrocardiogram at baseline before starting antidepressant to assess for conduction abnormalities 9, 3

Cardiac Risks in This Patient

This patient faces substantial cardiac risk from severe electrolyte disturbances (particularly hyperkalemia and hypocalcemia), volume overload, uremic pericarditis, and potential QTc prolongation from both uremia and future antidepressant therapy. 9, 7

Immediate Cardiac Threats

• Hyperkalemia-induced arrhythmias, as potassium 4.8 mmol/L may rise rapidly with ongoing rhabdomyolysis and renal failure 9, 6
• Hypocalcemia during the oliguric phase can cause cardiac arrhythmias and neuromuscular irritability 7
• Volume overload and pulmonary edema from inability to excrete sodium and water, leading to acute decompensated heart failure 9
• Uremic pericarditis if dialysis is delayed, which can progress to cardiac tamponade 9

Antidepressant-Related Cardiac Considerations

• QTc prolongation risk is increased in renal failure due to electrolyte abnormalities and drug accumulation 9, 3
• Orthostatic hypotension from antidepressants combined with volume depletion or overload can precipitate falls and further injury 1, 3
• Bradycardia or tachycardia may occur, particularly if the patient has underlying coronary disease 9, 3

Factors Influencing Choice of Antidepressant

Prioritize antidepressants with minimal renal clearance, no active metabolites requiring renal excretion, low risk of hyponatremia, minimal drug-drug interactions, and favorable cardiovascular safety profiles in renal impairment. 3, 4, 10

Renal Clearance and Metabolism

• Avoid antidepressants requiring significant renal clearance or with renally-eliminated active metabolites, as duloxetine and sertraline have metabolites that accumulate in severe renal impairment 3, 4
• Sertraline pharmacokinetics and protein binding are unaffected by renal disease according to FDA labeling, making it a reasonable first-line choice 3
• Duloxetine should be avoided in severe renal impairment (GFR <30 mL/min), as plasma concentrations of metabolites increase substantially 4

Hyponatremia Risk

• All SSRIs and SNRIs carry significant hyponatremia risk via SIADH, with elderly patients and those on diuretics at highest risk 3, 4
• Cases with serum sodium <110 mmol/L have been reported with both sertraline and duloxetine, requiring discontinuation and medical intervention 3, 4
• Monitor sodium levels twice weekly for the first month after starting any SSRI or SNRI in this high-risk patient 3, 4

Cardiovascular Safety

• Sertraline is not associated with significant ECG abnormalities and has been studied in post-MI patients, though this patient's acute renal failure represents higher risk 3
• Avoid tricyclic antidepressants due to anticholinergic burden, cardiac conduction effects, and orthostatic hypotension risk in elderly patients with renal failure 9

Drug-Drug Interaction Considerations

• Avoid combining SSRIs with NSAIDs, as this combination more than doubles AKI progression risk and increases bleeding risk 1, 2
• Never combine macrolides with statins if the patient requires antibiotics, due to rhabdomyolysis risk from CYP3A4 inhibition 2
• Consider serotonin syndrome risk if the patient receives tramadol or other serotonergic agents for pain management 3

Rhabdomyolysis Considerations

• SSRIs, including escitalopram, have been associated with rhabdomyolysis, particularly when combined with alcohol or other risk factors 10
• Vigilant monitoring is required if reintroducing an SSRI after rhabdomyolysis resolution, as recurrence has been documented 10

How Ageing Alters Pharmacodynamics in Renal Impairment

Ageing combined with renal impairment creates a "double hit" through reduced hepatic metabolism, decreased renal clearance, altered volume of distribution, increased blood-brain barrier permeability, and enhanced sensitivity to adverse effects including orthostatic hypotension, hyponatremia, and cognitive impairment. 9, 1, 2

Pharmacokinetic Changes

• Reduced hepatic metabolism occurs with ageing, as hepatic blood flow decreases and cytochrome P450 activity declines, prolonging drug half-lives 9, 2
• Decreased renal clearance from both ageing (GFR declines ~1 mL/min/year after age 40) and acute kidney injury leads to accumulation of parent drugs and active metabolites 9, 2
• Altered volume of distribution due to increased body fat and decreased total body water in elderly patients affects lipophilic antidepressants 9
• Reduced protein binding from hypoalbuminemia in renal failure increases free drug concentrations and pharmacologic effects 9, 2

Pharmacodynamic Changes

• Enhanced blood-brain barrier permeability in elderly patients increases CNS drug effects and adverse reactions 9
• Increased sensitivity to anticholinergic effects including confusion, urinary retention, constipation, and falls 9
• Greater risk of orthostatic hypotension due to impaired baroreceptor sensitivity and reduced compensatory mechanisms 1, 3
• Heightened hyponatremia susceptibility from age-related changes in ADH regulation and renal concentrating ability 3, 4

Clinical Implications

• Creatinine-based eGFR estimates are less reliable in elderly patients due to decreased muscle mass, potentially overestimating renal function 1, 2
• "Start low, go slow" dosing is mandatory, but therapeutic doses must eventually be reached to treat depression effectively 9, 1
• Therapeutic drug monitoring should be considered for medications with narrow therapeutic windows 2

Antidepressant Treatment Approach and Monitoring Parameters

Initiate sertraline 25 mg daily (half the standard starting dose) after ensuring hemodynamic stability and electrolyte correction, with twice-weekly sodium monitoring for one month, weekly clinical assessment for orthostatic hypotension and falls, and dose titration every 2-3 weeks based on tolerability to a target of 50-100 mg daily. 1, 3

Pre-Treatment Requirements

• Optimize volume status and correct electrolyte abnormalities before starting antidepressant therapy, as hyponatremia and volume depletion increase SIADH risk 1, 2, 3
• Discontinue all nephrotoxic medications immediately, including NSAIDs, as they account for 20-25% of AKI cases and combining them with antidepressants increases bleeding risk 1, 2
• Obtain baseline ECG, electrolytes, renal function, and liver function tests before initiating therapy 9, 3

Initial Dosing Strategy

• Start sertraline at 25 mg daily (50% dose reduction from standard 50 mg starting dose) given severe renal impairment and elderly age 3
• Sertraline is preferred over duloxetine because sertraline pharmacokinetics are unaffected by renal disease, whereas duloxetine is contraindicated in severe renal impairment (GFR <30 mL/min) 3, 4
• Avoid mirtazapine initially despite its favorable renal profile, as sedation and weight gain may worsen mobility and complicate volume assessment 9

Dose Titration Protocol

• Increase sertraline by 25 mg every 2-3 weeks if tolerated, targeting 50-100 mg daily for therapeutic effect 3
• Maximum dose should not exceed 100 mg daily in severe renal impairment until renal function improves 3
• Reassess dose as renal function improves, as drug clearance will increase during recovery 2, 3

Monitoring Parameters During Treatment

• Sodium levels twice weekly for 4 weeks, then weekly for 2 months, as SIADH typically develops within the first 2-3 months of SSRI therapy 3, 4
• Orthostatic vital signs weekly (lying and standing blood pressure) to detect symptomatic hypotension and fall risk 1, 3
• Weekly assessment for signs of hyponatremia: headache, confusion, memory impairment, weakness, unsteadiness, which may lead to falls 3, 4
• Renal function (creatinine, eGFR) every 2-4 weeks after medication changes, then quarterly once stable 8, 2
• Suicidality assessment weekly for 4 weeks, then biweekly for 8 weeks, as elderly patients with medical illness have elevated suicide risk 3
• Therapeutic response assessment at 4-6 weeks using standardized depression scales, with full response expected by 8-12 weeks 3

Critical Safety Monitoring

• Immediately discontinue sertraline if symptomatic hyponatremia develops (sodium <125 mmol/L or any level with symptoms) and institute appropriate medical intervention 3, 4
• Hold sertraline if rhabdomyolysis recurs (CPK >1000 U/L with rising trend), as SSRIs have been implicated in rhabdomyolysis recurrence 10
• Monitor for serotonin syndrome if any serotonergic agents are added (tramadol, triptans, other antidepressants) 3
• Assess for urinary retention, particularly if anticholinergic medications are co-prescribed, as duloxetine specifically carries this risk 4

Management of Common Adverse Effects

• For asymptomatic mild hyponatremia (130-135 mmol/L): fluid restriction to 1000-1500 mL/day and close monitoring 9, 3
• For symptomatic hypotension without volume overload: reduce sertraline dose by 50% and reassess in one week 3
• For persistent nausea or diarrhea: take medication with food and consider temporary dose reduction 3

Treatment Modifications if Patient Receives Dialysis

If hemodialysis is initiated, continue sertraline at the same dose without supplementation post-dialysis, as sertraline is highly protein-bound (98%) and not significantly removed by dialysis; however, intensify sodium monitoring to three times weekly and reassess volume status before each dialysis session. 9, 3

Dialysis-Specific Pharmacokinetic Considerations

• Sertraline is not dialyzable due to high protein binding (98%) and large volume of distribution, so no dose adjustment or post-dialysis supplementation is required 3
• Duloxetine is also highly protein-bound and unlikely to be removed by hemodialysis, but remains contraindicated in severe renal impairment regardless of dialysis 4
• Continuous renal replacement therapy (CRRT) is preferred over intermittent hemodialysis in hemodynamically unstable elderly patients, as CRRT minimizes intravascular volume shifts and hypotensive episodes 9, 2

Enhanced Monitoring During Dialysis

• Check sodium levels three times weekly (pre-dialysis), as dialysate composition and ultrafiltration can rapidly alter sodium balance in patients on SSRIs 3, 4
• Assess orthostatic vital signs before and after each dialysis session, as volume removal increases orthostatic hypotension risk from antidepressants 1, 3
• Monitor for dialysis disequilibrium syndrome, which can mimic or exacerbate SSRI-induced hyponatremia symptoms (confusion, headache, seizures) 9

Volume Status Management

• Coordinate antidepressant dosing with dialysis schedule: administer sertraline after dialysis sessions to minimize nausea and ensure consistent absorption 3
• Adjust "dry weight" target carefully, as antidepressants may cause fluid retention via SIADH, requiring increased ultrafiltration 3, 4
• Avoid aggressive ultrafiltration if orthostatic hypotension develops, as this increases fall risk in elderly patients on antidepressants 1, 2

Electrolyte Management on Dialysis

• Use higher sodium dialysate (140-145 mEq/L) if SIADH develops, to prevent further hyponatremia 9, 3
• Monitor potassium closely, as correction of hyperkalemia through dialysis may unmask hypokalemia from poor oral intake in depressed patients 9
• Assess calcium and phosphate weekly, as correction during dialysis may affect mood and neuromuscular symptoms 9, 7

Psychiatric Considerations During Dialysis

• Depression often worsens after dialysis initiation due to lifestyle restrictions, dietary limitations, and loss of independence, requiring dose optimization rather than discontinuation 8
• Suicidality risk increases in dialysis patients, necessitating weekly assessment for the first month after dialysis initiation 8, 3
• Cognitive function may improve with dialysis, potentially allowing better assessment of true depression severity versus uremic encephalopathy 9

Long-Term Management

• Renal function will not recover if chronic dialysis continues, so maintain antidepressant dosing based on severe renal impairment guidelines indefinitely 9, 3
• If kidney transplantation occurs, reassess antidepressant dosing 2-4 weeks post-transplant as renal clearance improves, and monitor for drug interactions with immunosuppressants 2
• Quarterly monitoring of sodium, renal function, and therapeutic response is appropriate once stable on dialysis 8, 3