Angiotensin II Antagonism of TGF-Beta 1: A Candesartan Dose - TGF-Beta 1 Response Relationship Study

Transforming growth factor-beta 1 (TGF-beta 1) is a potent inducer of extracellular matrix production and of fibrogenesis and has been associated with the occurrence of diabetic micro- and macrovascular complications. Several in vitro and in vivo studies have implicated TGF-beta 1 in the pathogenesis of diabetic kidney disease. Recent animal and in vitro experiments have demonstrated that ACE inhibitors and Angiotensin II (AT-II) receptor antagonists, including candesartan, decrease the synthesis and secretion of renal TGF-beta 1 and prevent the development of glomerulosclerosis, interstitial fibrosis, and progressive renal dysfunction. These protective effects appear to be unrelated to the antihypertensive effects of the agents.

Limited data in humans have supported these findings in patients with diabetic nephropathy. A recent human study with the AT-II receptor antagonist losartan demonstrated that the ability to correct microalbuminuria was independent of blood pressure control and correlated with normalization of circulating levels of TGF-beta 1. The results were further supported by the observation that markers of collagen type 1 metabolism were normalized in hypertensives in whom TGF-beta 1 was normalized with treatment but remained unaltered in the remaining hypertensives despite blood pressure control. Such findings are consistent with the recent observation that the AT-II receptor antagonist irbesartan is renoprotective independently of its blood pressure-lowering effect in patients with type 2 diabetes and microalbuminuria.

The use of ACE-inhibitors and AT-II receptor antagonists as a means to reduce progression of renal fibrosis is becoming increasingly widespread. Dosage recommendations to achieve this goal are unclear prompting some experts to ask whether TGF-beta 1 rather than blood pressure should be a therapeutic target. Although not verified under chronic conditions, previous short-term studies with the AT-II antagonist candesartan have demonstrated different dose-response relationships to exist for blood pressure, renal plasma flow, and plasma renin activity. It is likely that dose-response relationship differences also exist between the aforementioned parameters (particularly blood pressure) and TGF-beta 1. In type 1 diabetic patients treated with captopril a relationship was demonstrated between percent change in plasma TGF-beta 1 and percent decline in GFR. In another study of 21 patients with a baseline GFR of <75 ml/min there was a striking correlation between the captopril-induced reduction in serum TGF-beta 1 and 2-year change in GFR (r = -0.73, p =0.0001). This latter observation is particularly important in demonstrating that the relationship between TGF-beta 1 and rate of decline in kidney function can be modified through pharmacologic intervention.

The dosage range for candesartan according to the FDA approved package insert is 4 to 32 mg daily, adjusted based on blood pressure response. Whether the dose that effectively lowers blood pressure is sufficient to suppress urinary TGF-beta 1 concentrations is unknown. In the absence of data, many experts are already suggesting doses higher than needed to control hypertension. Including a maximum dose of candesartan 64 mg in a dose titration scheme will be important to help resolve this issue. Furthermore, it is unclear if the candesartan dose/concentration - effect relationship for TGF-beta 1 and blood pressure are dissimilar. Information regarding the relationship between candesartan dose and effect on urinary TGF-beta 1 concentrations in patients with diabetic nephropathy would be valuable in tailoring therapy and enhancing our understanding of the optimal use of agents that modulate the renin-angiotensin system.

Recent data in experimental models of diabetes indicate that the renin angiotensin system interacts with advanced glycation end products (AGEs) to produce kidney damage in diabetes. ACE inhibition in diabetic rats reduced circulating and renal accumulation of AGEs, possibly by increasing expression of the soluble receptor for AGEs. In a rat model of normoglycemia with AGE infusion, increased kidney expression of renin angiotensin system components along with structural changes similar to those in diabetic models was observed. Renin angiotensin system activation and kidney structural changes were reversed by valsartan. Therefore, modulation of AGEs may also be an important mechanism of kidney protection by renin angiotensin system inhibition in diabetes. This hypothesis is unexplored in humans. An exploratory sub-study will assess whether candesartan reduces urinary excretion of carboxymethyllysine, a prominent AGE, in patients with diabetic nephropathy.