Padova, Italy, and Los Angeles, California

Correspondence: Professor Antonio Piccoli, Departmento di Scienze Mediche e Chirurgiche, Policlinico IV piano, Via Giustiniani, 2, I-35128 Padova, Italy E-mail: apiccoli@unipd.it

To the Editor: The effect of maximum tolerated doses of ramipril on proteinuria has been recently evaluated in 19 adult patients with chronic non-diabetic glomerulonephrities, nephrotic proteinuria (5.5 g/day, range 3.5 to 18.4), or normal or impaired filtration (serum creatinine 1.55 mg/dL, range 0.6 to 3.65), and undergoing treatment with angiotensin-converting enzyme (ACE) inhibitors for at least 6 months¹ (Figure 1, point a). Patients entered a 2-month washout period from antihypertensive medications with the exception of diuretics and occasional administration of nifedipine (Figure 1, point b). In a 2-month up-titration period (ramipril 2.5 to 20 mg/day), the maximum tolerated dose was identified (Figure 1, point c), continued for 2 additional months (ramipril alone or with indomethacin, in crossover (Figure 1, points d and e, respectively), and then withdrawn in the recovery (Figure 1, point f).

Figure 1.

Mean values of proteinuria as a function of the joint distribution of blood pressure. Systolic (SBP) and diastolic (DBP) at the screening of patients receiving angiotensin-converting enzyme (ACE) inhibitors at conventional dose (point a, 5.5 g/day), after 2-month washout (point b, 5.6 g/day), after the up-titration period (point c, 4.0 g/day), after 2 months of maximum dose of ramipril alone (point d, 4.0 g/day), or with indomethacin (point e, 3.9 g/day), and after recovery withdrawn (point f, 5.1 g/day).

Full figure and legend (30K)

A significant reduction of both proteinuria (28%; from 5.6 to 4.0 g/day, remission rate not reported) and non-selective glomerular membrane shunt parameter (_o) (greater than 50%) was observed by the end of the up-titration period and during the crossover phase and was attributed to the treatment with high doses of ramipril¹. During the study, however, blood pressure changed accordingly with a notable apparent threshold value of 130/80 mm Hg Figure 1, below which there was a reduction in both proteinuria and _o. Of note, before the study (Figure 1, point a), patients were already on ACE inhibitors, and thereafter, a greater proteinuria reduction was observed in patients receiving ramipril plus loop diuretics versus thiazides, further indicating a blood pressure, not ACE inhibitor effect, causing proteinuria reduction. Furthermore, in patients with non–insulin-dependent diabetes mellitus, whose blood pressure was maintained at 148/88 mm Hg or 150/86 mm Hg with perindopril or nitrendipine, respectively, neither proteinuria nor membrane pore size distribution changed after 10 weeks². In addition, the validity of _o parameter is called into question, as the calculation was based on measured clearances of dextrans and on arbitrary assumptions on model parameters, like the glomerular transmembrane hydraulic pressure and the ultrafiltration coefficient, which led to a non-unique identifiable model³.

In conclusion, blood pressure could act as an intermediate factor in the antiproteinuric effect of maximum ACE inhibition.