Phosphate may promote CKD progression and attenuate renoprotective effect of ACE inhibition

Abstract

Phosphate may promote the onset and progression of chronic nephropathies. Here we evaluated the relationships between baseline serum phosphate levels, disease progression, and response to ACE inhibition in 331 patients with proteinuric nephropathies in the prospective Ramipril Efficacy In Nephropathy (REIN) trial. Independent of treatment, patients with phosphate levels in the highest two quartiles progressed significantly faster either to ESRD or to a composite endpoint of doubling of serum creatinine or ESRD compared with patients with phosphate levels below the median (P < 0.001). Results were similar when we analyzed phosphate as a continuous variable (P ≤ 0.004). The renoprotective effect of ramipril decreased as serum phosphate increased (P ≤ 0.008 for interaction); this modification of the treatment effect by phosphate persisted despite adjusting for potential confounders such as GFR and urinary protein. In summary, these data suggest that phosphate is an independent risk factor for progression of renal disease among patients with proteinuric CKD, and high levels of phosphate may even attenuate the renoprotective effect of ACE inhibitors. Future trials should test whether reducing serum phosphate improves renal outcomes and optimizes the renoprotective effect of ACE inhibition.

Figure 1.

Distribution of baseline serum phosphate in the study population.

Figure 2.

Cumulative incidence of ESRD alone and in combination with doubling serum creatinine in patients stratified according to serum phosphate quartiles. I/II quartile: < 3.45 mg/dl. III quartile: 3.45 to 4.00 mg/dl. IV quartile: > 4.00 mg/dl.

Figure 3.

Effect modification of serum phosphate on the efficacy of ramipril for reducing the incidence rate of ESRD. Data are expressed as hazard ratio, 95% confidence interval, and P-value (see box). °Crude data. *Data adjusted for all variables listed in Table 4. **Shrinkage corrected.