Progressive renal impairment in chronic kidney diseases (CKD) may cause inability to excrete
phosphate load, thus leading to the typical abnormalities of the mineral metabolism, such as
increased phosphate and reduced calcium levels, 1,25- dihydroxyvitamin D deficiency and
secondary hyperparathyroidism (HPT). Treatment with vitamin D analogues and/or phosphate
binders ameliorates these abnormalities that are also associated with accelerated renal
disease progression and increased cardiovascular risk. However in a post-hoc analysis of 331
patients with proteinuric chronic nephropathies included in the Ramipril Efficacy In
Nephropathy (REIN) trial, increasing serum phosphate levels at inclusion, even within the
normal reference range, were associated with an incremental risk of progression to End Stage
Renal Disease (ESRD). Moreover, increasing levels of serum phosphate were associated with a
progressively decreasing protective effect of ramipril therapy against progression to ESRD,
to the point that the benefit of Angiotensin-Converting-Enzyme (ACE) inhibition was almost
fully lost among patients with serum phosphate levels exceeding 4.5 mg/dL. This finding
provided convincing evidence that phosphate plays a direct pathogenic role in patients with
progressive nephropathies and that excess phosphate exposure may limit or even blunt the
renoprotective effect of ACE inhibitor therapy in this population.
Sevelamer carbonate is a newly approved phosphate binder for chronic kidney disease (CKD)
patients not yet on maintenance dialysis. Treatment with Sevelamer, in addition to correct
hyperphosphatemia, was also found to ameliorate abnormalities of the mineral metabolism
associated with accelerated renal disease progression and increased cardiovascular risk.
Moreover, Sevelamer therapy reduces proteinuria in an animal model of uremia, an effect that
in the long term might translate into significant renoprotection. These findings suggest that
serum phosphate might be a specific target for renoprotective therapy in CKD patients and
provide the background for randomized clinical trials to formally test whether reducing
phosphate exposure by phosphate binding agents may serve to optimize the renoprotective
effect of RAS inhibition in this population. Thus, whether phosphate reduction by Sevelamer
carbonate therapy may have a specific antiproteinuric effect in humans with chronic
nephropathies and residual proteinuria despite optimized RAS inhibitor therapy is worth
investigating.
Phase:
Phase 2
Details
Lead Sponsor:
Mario Negri Institute for Pharmacological Research