Hypertension and Diabetic Nephropathy

Nearly 20 years ago, Dr. B. Brenner and colleagues from Boston revised Dr. N. Bricker's "surviving nephron" concept and formulated the "hyperfiltration hypothesis" to account for the progressive nature of proteinuric renal diseases including diabetic nephropathy [1]. This group demonstrated in a series of elegant basic studies that reductions in renal mass and/or diabetes was accompanied by increases in single nephron glomerular filtration rate (SNGFR) as well as increases in glomerular hydrostatic pressure (Pgc). Angiotensin II was implicated as a major factor in these increases in SNGFR and Pgc, and ACE inhibitors were found to be protective [2;3]. Since these seminal studies, a number of other "adverse" effects of angiotensin II have been catalogued which are too numerous to cite in this brief review. Suffice it to say that whether the mechanisms proposed by Brenner, et al are the "correct" ones, reductions in angiotensin II clearly ameliorate experimental renal failure.

This basic work was rapidly extended to the clinic. Dr. E. Lewis and colleagues performed an extremely strong clinical study demonstrating that in insulin dependent (type I) diabetic nephropathy, ACE inhibitors were protective. In this seminal work, the protection from the ACE inhibitors appeared to be beyond that associated with their anti-hypertensive effects as the control group's BP was controlled to a comparable degree [4]. Following this study, a number of studies were published demonstrating that ACE inhibitors attenuated proteinuria in a variety of renal diseases. However, until very recently, good outcome data was not available for the common condition of adult onset (type II) diabetes mellitus with nephropathy. In the Sept 20th, 2001 issue of the N.Engl.J.Med., three trials are reported which demonstrate that interruption of the rennin-angiotensin system with angiotensin receptor blockers (ARBs) protects against progression of chronic renal failure in type II diabetic nephropathy [5-7]. These studies represent the largest nephrology trials completed in the world, to date. In these three studies, more than 3500 patients were randomized. All three studies showed a substantial reduction in the rate of progression of diabetic nephropathy in those patients treated with ARBs despite comparable levels of blood pressure control. It is important to note that the use of ACE inhibitors was not allowed in any of the control (or treatment groups) in these three studies. While these studies unequivocally demonstrate the benefit of addressing the angiotensin system in diabetic patients with nephropathy, two important questions remain. First, the studies did not compare the utility of ACE inhibitors with ARBs nor did they address whether combination therapy might be beneficial. Clearly, studies that address these latter issues will require even greater numbers of patients for adequate power. More importantly, it is important to note that the rate of progression in the treated groups was still considerable (as it was in the ACE inhibitor trial in type I diabetic nephropathy). The treatment of diabetic nephropathy as reported in these three studies is still less than ideal. Some hope for the future may be derived from the relatively high blood pressures (approximately 140/80) seen in the treatment groups; perhaps lowering BP to levels recommended by JNC VI (see guidelines at this website) will result in better outcomes.

In summary, it appears very clear that interruption of the renin-angiotensin system is warranted in patients with diabetic nephropathy. In my opinion, the use of either ACE inhibitors or ARBs in either form of diabetic nephropathy is warranted.

References
  1. Hostetter TH, Rennke HG, Brenner BM: The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies. Am.J.Med. 72:375-380, 1982
  2. Hostetter TH, Troy JL, Brenner BM: Glomerular hemodynamics in experimental diabetes mellitus Kidney Int. 19:410-415, 1981
  3. Anderson S, Brenner BM: Therapeutic benefit of converting-enzyme inhibition in progressive renal disease Am.J.Hypertens. 1:380S-383S, 1988
  4. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N.Engl.J.Med. 329:1456-1462, 1993
  5. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N.Engl.J.Med. 345:851-860, 2001
  6. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy N.Engl.J.Med. 345:861-869, 2001
  7. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P: The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N.Engl.J.Med. 345:870-878, 2001
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