Frontier Large Language Models for Comprehensive Medication Review in CKD Patients with Polypharmacy: A Trap-Embedded Synthetic Benchmark

Background

Patients with CKD and polypharmacy face high rates of drug-related problems, yet comprehensive medication review remains time-intensive and inconsistently performed. Large language models (LLMs) may augment this process, but existing benchmarks use multiple-choice formats that do not reflect open-ended, nephrology-specific review. We developed a trap-embedded synthetic CKD benchmark and evaluated five current-generation LLMs (GPT-5.4, Claude Sonnet 4.6, Gemini 3.1 Pro, Grok 4.1 Fast, DeepSeek R1; tested April–May 2026) for open-ended medication review.

Methods

Fifty synthetic CKD cases across three complexity groups (G3a–G3b [ n = 20], G4 [ n = 15], G5/G5D/transplant [ n = 15]) with 8–12 medications and ≥2 embedded clinical traps each were scored against nephrologist-adjudicated gold standards. Each model produced three independent responses per case (temperature 0; 750 total outputs). Primary endpoint was per-case macro F1; secondary endpoints were safety-critical omission rate, PI-adjudicated hallucination rate, and intra-model consistency. Blinded inter-rater reliability for gold-standard item detection was assessed on a 30% sample.

Results

Consensus-level macro F1 ranged from 0.41 (Claude Sonnet 4.6) to 0.49 (Grok 4.1 Fast) (Friedman P < 0.001). Phosphate binder timing (11%) and hyperkalemia combinations (33%) were poorly detected across all models. Safety-critical omission rate ranged from 22% to 48% ( P < 0.001); PI-adjudicated hallucination ranged from 0% (GPT-5.4) to 54% (DeepSeek R1), including fabricated dose caps and non-existent guideline citations. Blinded reliability for gold-standard item detection was high ( κ = 0.934, n = 92).

Conclusions

This nephrology-specific benchmark exposes clinically important LLM blind spots that generic multiple-choice evaluations would not detect. Heterogeneous hallucination and omission rates indicate that model selection and domain-specific guardrails should precede any clinical deployment of LLM-assisted CKD medication review. Prospective validation with real patient data and human comparators is required before deployment recommendations can be made.

Key Points

• All five LLMs poorly detected phosphate binder timing (11%) and hyperkalemia combinations (33%) in nephrology-specific medication review.

• Macro F1 ranged 0.41 to 0.49, safety-critical omissions 22–48%, and hallucination 0–54%, with qualitatively distinct error patterns.

• Open-ended scoring exposed LLM failures invisible to multiple-choice benchmarks, supporting specialty evaluation before deployment.