Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies

Type of Study: A single-center, prospective, randomized, open-label, cross-over study comparing the effects of either Cibacen alone, valsartan (Val) alone or combination of Cibacen and Val treatment on proteinuria, renal hemodynamics, and glomerular permselectivity in patients with nondiabetic chronic nephropathies. Dosage Duration: Initially 10 mg once daily orally (8:00 a.m.) for Cibacen alone or 5 mg once daily orally for Cibacen and Val combination then increased to dose level 2 after 2 weeks, 20 mg once daily for Cibacen alone or 10 mg once daily for Cibacen and Val combination. Duration: 8 weeks. Comparative Drug: Initial valsartan alone dosage was 80 mg once daily orally (8:00 a.m.) or 40 mg once daily orally for valsartan and Cibacen combination then increased to dose level 2 after 2 weeks, 160 mg once daily orally for valsartan alone or 80 mg once daily orally for valsartan and Cibacen combination. Duration: 8 weeks. Authors Conclusions: In conclusion, we found that in chronic nondiabetic nephropathies the combination of low dose benazepril and valsartan was safe and well-tolerated. Combined therapy better reduced proteinuria than either agent alone. There was also a trend to greater proteinuria reduction with benazepril than with losartan alone, but the study was not powered to detect this difference. These findings call for randomized trials intended to assess whether the antiproteinuric and hemodynamic effects of combined ACEi [angiotensin-converting enzyme inhibitors] and ARA [angiotensin II receptor antagonists] may in the long-term confer more renoprotection than the two treatments alone, even at comparable blood pressure control. These trials should probably include patients with more severe, nephrotic, proteinuria who still have a poor prognosis on ACEi or ARA alone, but who also seem to benefit the most from the superior antiprotein-uric effect of combined therapy. Results: Despite comparable changes in systolic and diastolic arterial blood pressure and creatinine clearance, combined treatment with half doses of Cibacen and Val decreased 24-hour urinary protein excretion rate (-56% vs. baseline) more effectively than full doses of Cibacen (-45.9%, P = 0.02) or Val (-41.5%, P < 0.002) alone. Proteinuria reduction was numerically superior with Cibacen than with Val. In 13 patients, maximal proteinuria reduction was achieved with combined treatment, in 7 patients with Cibacen alone, while in 4 patients with Val alone. Patients with more proteinuria reduction with combined therapy had remarkably higher basal proteinuria. In these patients differences between the levels of proteinuria achieved with combined therapy (1.6 g/24 hours) and those achieved by the other 2 treatments (Cibacen, 2.4 g/24 hours; Val, 2.8 g/24 hours) averaged about 1 g/24 hours and were both highly significant. In the other 2 groups, differences between most effective treatment and the others ranged between 0.3 and 0.4 g/24 hours. Changes in urinary protein/urinary creatinine followed a similar trend with maximal and minimal reductions with combined and Val treatment, respectively, but without significant differences between Cibacen and Val. Serum albumin level increased with all treatments, the increase being more consistent with combined or Cibacen than with Val therapy. Total cholesterol and HDL-C decreased to a similar extent with all treatments. The GFR similarly and marginally increased during the 3 treatment periods. The ERPF increased during all treatment periods, but the increase during combined or Cibacen therapy numerically exceeded that observed during Val therapy. The changes in GFR and ERPF resulted in a greater reduction in FF during combined or Cibacen therapy as compared to Val therapy alone. RVR decreased during all treatment periods, but the decrease during combined and Cibacen was almost double compared to the decrease observed after Val therapy. As expected, changes in ERPF and RVR were significantly correlated in the study group as a whole and within each treatment group. The fractional clearances of neutral dextrans at baseline and at the end of the treatment periods with Val alone, Cibacen alone and Cibacen and Val combination were comparable. There was a borderline significant relationship between RVR and log-transformed 24-hour urinary protein excretion rate (P = 0.087). No relationship was found between GFR and 24-hour urinary protein excretion. However, when the analysis accounted for the borderline interaction between RVR and GFR (P = 0.089), GFR-adjusted RVR were significantly associated with 24-hour urinary proteins (P =.0.046). The study treatments were well-tolerated by all patients. No major change in serum creatinine and creatinine clearance occurred throughout the whole study period. Serum potassium similarly increased during each treatment period but the increase did not exceed 0.5 mEq/L versus baseline and no patient required reduction of drug dose or cessation of therapy because of hyperkalemia. Changes in hemoglobin were not associated with symptoms of anemia and did not require therapy. Adverse Effects: No patient had hyperkalemia. Free Text: Tests: diastolic and systolic arterial blood pressure, creatinine clearance, serum creatinine, potassium, albumin, total cholesterol, urinary excretion, high-density lipoprotein cholesterol (HDL-C), glomerular filtration rate (GFR), effective renal plasma flow (ERPF), filtration fraction (FF), and renal vascular resistances (RVR). Indications: 24 patients with chronic nephropathies (11 IgA nephritis, 4 chronic glomerulonephritis) Patients: 24 Caucasian outpatients, 23 males and 1 female (mean age 48.9 years). All patients received Cibacen alone, Val alone, and Cibacen and Val combination treatment in a crossover manner.