The Paradox of the Low-Renin State in Diabetic Nephropathy

Although diabetic nephropathy is often a low renin state, the renin system appears to be implicated in its pathogenesis. In this study, it was hypothesized that the low plasma renin activity (PRA) is misleading, masking and perhaps reflecting an activated intrarenal renin system. PRA and renal vascular responses (inulin and para-aminohippurate clearance) to graded doses of an angiotensin II (AngII) antagonist, irbesartan, were assessed in eight healthy volunteers and 12 patients with type 2 diabetes mellitus and nephropathy on a 10 mmol Na intake, to activate the renin system. Basal PRA was suppressed in type 2 diabetes mellitus compared with the healthy subjects (0.58 +/- 0.14 versus 1.58 +/- 0.28 ng/L per s, mean +/- SEM; P < 0.01). Despite the low PRA, renal perfusion rose more in response to irbesartan in type 2 diabetes mellitus (714 +/- 83 to 931 +/- 116 ml/min; P = 0.002) than normal (624 +/- 29 to 772 +/- 49 ml/min; P = 0.008). The youngest patients were hyperfiltrating and showed the largest rise in renal plasma flow in response to irbesartan, whereas renal plasma flow rose less and GFR fell in patients with low basal GFR. PRA rose in response to irbesartan more gradually in the patients with type 2 diabetes mellitus, but ultimately matched the normal response. To account for the apparent paradox of a heightened renal hemodynamic response to an AngII antagonist in the face of a low PRA in type 2 diabetes mellitus, and the rise in PRA following the AngII antagonist, it is proposed that there is increased intrarenal AngII production in type 2 diabetes mellitus. This increase could account for suppressed circulating renin, the exaggerated renal vasodilator response to irbesartan, and the therapeutic effectiveness of interrupting the renin system in diabetic nephropathy.