Variability in response to albuminuria-lowering drugs: true or random?

Albuminuria-lowering drugs have shown different effect size in different individuals. Since urine albumin levels are known to vary considerably from day-to-day, we questioned whether the between-individual variability in albuminuria response after therapy initiation reflects a random variability or a true response variation to treatment. In addition, we questioned whether the response variability is drug dependent.

To determine whether the response to treatment is random or a true drug response, we correlated in six clinical trials the change in albuminuria during placebo or active treatment (on-treatment) with the change in albuminuria during wash-out (off-treatment). If these responses correlate during active treatment, it suggests that at least part of the response variability can be attributed to drug response variability. We tested this for enalapril, losartan, aliskiren, atrasentan and paricalcitol.

No correlation between the on- and off-treatment albuminuria change was observed in the placebo arm of all clinical trials (R²  < 0.01). However, we observed significant associations between the on- and off-treatment response (R² 0.14 to 0.57; all P < 0.015) for different albuminuria lowering drugs. Additionally, the albuminuria responses strongly correlated when the same individual was re-exposed to the same drug at the same dose: lisinopril 10 mg day^-1 (R²  = 53%; P < 0.01), losartan 50 mg day^-1 (R²  = 63%; P < 0.01).

The degree of albuminuria lowering with antialbuminuric drugs varies between patients. This variability in response appears drug-class independent. Identifying which factors determine this initial short-term variation in drug response appears important since the degree of albuminuria lowering is related to subsequent long-term renoprotection.