Titrating for antiproteinuric effect: the clue to renoprotection?

Proteinuria may be involved in the final common pathway of progressive renal function loss. If so, intervention treatment that reduces proteinuria might prevent or retard long-term renal function loss. In renal patients and in experimental renal disease the severity of proteinuria is associated with the rate of long-term renal function loss. Several large trials on the prevention of long-term renal function loss by antihypertensive treatment with ACE inhibitors (ACEi), were recently completed in diabetic and in non-diabetic renal disease. In those studies long-term renal function loss could indeed be retarded by ACEi; these ACEi regimens were associated with a more effective reduction of proteinuria than control regimens. In studies with a single treatment regimen (drug treatment or a protein restricted diet) a more effective reduction of proteinuria is associated with a more favourable long-term course of renal function as well. As reduction of proteinuria is mostly associated with a lower blood pressure (BP) the respective contributions of the fall in BP and in proteinuria are hard to dissect. Remarkably, however, the efficacy of the reduction of proteinuria (but not of BP) at onset of antihypertensive treatment is predictive of long-term renal outcome. Albeit consistent with a causal role of proteinuria reduction in renoprotection these data cannot distinguish between proteinuria as a marker or a mediator of renal damage. In view of the consistent association of antiproteinuric efficacy with long-term renal outcome we suggest that it would be worthwhile to attempt to improve long-term renoprotection by a strategy aimed at enhancing antiproteinuric efficacy. This approach is feasible as antiproteinuric efficacy of ACEi can be enhanced in several ways, ie, by dietary sodium and protein restriction and by adding a diuretic or indomethacin. Such a strategy would require that titration for adequate BP control is followed by titration for a maximal antiproteinuric effect. If this treatment strategy would improve long-term renal outcome, it would not only be a step forward in the clinical treatment of chronic renal failure, but it would also provide compelling evidence for a causal role of proteinuria in the progression of renal disease.