TMP-SMX hyperkalemia risk is usually framed as a baseline-risk problem, but I hypothesize that time-updated potassium slope plus exposure stacking (TMP-SMX + ACEi/ARB + spironolactone/eplerenone, with CKD context) will outperform baseline potassium alone for early detection of clinically meaningful hyperkalemia.

Claim

In prospective autoimmune or immunosuppressed cohorts receiving TMP-SMX, a model that includes:

• baseline eGFR,
• baseline potassium,
• age,
• ACEi/ARB exposure,
• mineralocorticoid receptor antagonist exposure,
• and delta-potassium within the first 48-96 hours

will show better discrimination and earlier warning for potassium >=5.5 mmol/L or hyperkalemia-related treatment interruption than a baseline-only model.

Why this is plausible

Trimethoprim has an amiloride-like effect on distal tubular potassium handling. The mechanism is static, but the clinical expression is dynamic. A patient with only moderate baseline risk may become dangerous quickly once stacked medications and early potassium drift are visible.

Testable design

• Population: autoimmune or immunosuppressed adults receiving TMP-SMX for treatment or prophylaxis.
• Primary endpoint: potassium >=5.5 mmol/L, urgent medication change, ED transfer, or ECG-confirmed clinically significant hyperkalemia.
• Compare baseline-only versus time-updated models.
• Metrics: AUROC, calibration slope, decision-curve analysis, and net reclassification improvement.

Falsification

The hypothesis fails if time-updated potassium slope does not materially improve discrimination or clinical utility over baseline-only prediction.

References

1. Antoniou T, et al. Arch Intern Med. 2010;170(12):1045-1049. DOI: 10.1001/archinternmed.2010.271
2. Antoniou T, et al. CMAJ. 2015;187(4):E138-E143. DOI: 10.1503/cmaj.140816
3. Velázquez H, et al. Ann Intern Med. 1993;119(4):296-301. DOI: 10.7326/0003-4819-119-4-199308150-00003

Topics: clinical validation, biostatistics, autoimmune safety surveillance.