Complete Blockade of the Renin-Angiotensin System in Patients With Advanced Diabetic Nephropathy

We read with interest the article by Rossing et al. (1) in the January 2002 issue of Diabetes Care. We had previously assessed the effect of complete blockade of the renin-angiotensin system (RAS) in patients with advanced diabetic nephropathy (type 2 diabetes) and severe proteinuria (2). To do so, we studied 10 patients on prior treatment with ACE inhibitors at recommended doses, to which 50 mg/day of Losartan was added.

After 3 months of the combined therapy, urinary protein excretion decreased from a mean of 6.9 (95% CI 4.3–9.6) to 5.8 g/24 h (3–8.6) (P = 0.025) and, with the exception of two patients, was reduced in all cases. The proteinuria/urinary creatinine ratio also decreased from 7.6 (4.2–11.05) to 6.0 g/g (3.2–8.7) (P = 0.02). In one patient in which proteinuria did not vary, the proteinuria/creatinine ratio also decreased, reflecting a possible error in the quantification of the patient’s proteinuria instead of a lack of response to the treatment. The glomerular filtration rate (GFR), calculated using the mean of creatinine and urea clearance, a measurement that avoids the overestimation that creatinine clearance produces in the GFR (3), decreased slightly from 21.5 ± 8.5 to 19.9 ± 7.8 ml/min (P = 0.158). An interesting decrease in total cholesterol from 6.21 ± 1.03 to 5.33 ± 1.27 mmol/l (P = 0.036) was observed. Total proteins, serum albumin, protein intake, and mean arterial pressure (MAP) were not significantly modified. Only one patient had hyperkaliemia (from 5.1 to 7.2 mmol/l). No secondary effects were seen in the other patients. At 12 months of treatment, proteinuria decreased to 3.4 g/24 h and the proteinuria/urinary creatinine ratio to 3.6. GFR decreased by 0.83 ml · min⁻¹ · month⁻¹ in the first 6 months and only fell by 0.18 ml · min⁻¹ · month⁻¹ during the last 6 months. Two patients received the combined treatment for >42 months. During the first 18 months, proteinuria decreased by 74 and 67% in each case; GFR fell by 0.5 and 1 ml · min⁻¹ · month⁻¹, respectively; and MAP did not vary in the first case and decreased from 123 to 101 mmHg in the second. Over the following 24 months, proteinuria was <1 g/24 h in both cases and GFR increased in one patient by 2 ml/min and did not vary in the other patient. In this period, MAP and protein intake remained unvaried.

The data of Rossing et al. confirm that in the short term, complete blockade of the RAS system produces an antiproteinuric effect and affords a greater renoprotective effect since proteinuria is an important risk factor for kidney disease progression (4). Although our data can only be considered as observational findings, they do allow us to intuit that this renoprotective effect, due to the dual blockade of the RAS, will be increased when treatment is prolonged to medium or long term. Moreover, the observed decrease in total cholesterol levels would contribute to reducing both the progression of the nephropathy, since elevated serum cholesterol levels act as an independent promoter of progression in diabetic nephropathy (5), and the high cardiovascular risk seen in this type of patient.