Dual Blockade of the Renin-angiotensin-aldosterone System in Diabetic Nephropathy: The Role of Aldosterone

Abstract

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with both ACE inhibitors and angiotensin II receptor-blockers has been shown to reduce both albuminuria and blood pressure compared to either monotherapy. The mechanisms behind these beneficial effects are not known, and we hypothesized that the effect of dual RAAS blockade may be due to a more complete suppression of circulating aldosterone. We performed a combined analysis on three randomized, double-masked, cross-over trials where 51 type 1 diabetic patients suffering from diabetic nephropathy received 8 weeks of dual RAAS blockade using an angiotensin II receptor blocker in combination with an ACE inhibitor and 8 weeks of monotherapy with the same ACE inhibitor. Albuminuria, 24 h blood pressure, GFR, and plasma aldosterone were determined at the end of each treatment period. Compared to ACE inhibition alone, dual RAAS blockade lowered blood pressure by 7/5 mm Hg from 137/76 mm Hg, decreased albuminuria by 37 % from 558 mg/24 hour, and reduced plasma aldosterone by 28 % from 59 pg/ml and caused a reversible decline in GFR of 4 ml/min/1.73 m² (p ≤ 0.01 for all comparisons). There was and a significant correlation between changes in 24-hour diastolic blood pressure and changes in albuminuria. Furthermore, the antialbuminuric response to dual blockade was influenced by the ACE/ID polymorphism, that is, patients carrying the D-allele had a significantly lower reduction of 31 % compared to the 55 % in patients with the II genotype (p = 0.021). Multiple linear regression analysis revealed that ACE/ID genotypes and reduction in plasma aldosterone, diastolic blood pressure and GFR is associated with changes in albuminuria on dual blockade treatment (R² (adjusted) = 0.57, p < 0.001). Dual RAAS blockade is a new treatment concept that may offer additional cardiovascular and renal protection in type 1 diabetic patients with diabetic nephropathy. The beneficial response may be influenced by genetic factors and reductions in blood pressure and plasma aldosterone concentrations.

Albuminuria - Arterial blood pressure - ACE inhibitor - Angiotensin II receptor blocker - Aldosterone escape

References

• 1 The ACE Inhibitors in Diabetic Nephropathy Trialist  Group. Should all type 1 diabetic microalbuminuric patients receive ACE inhibitors? A meta-regression analysis.  Ann Intern Med. 2001;  134 370-379
• 2 Hommel E, Parving HH, Mathiesen E R, Edsberg B, Nielsen M D, Giese J. Effect of captopril on kidney function in insulin-dependent diabetic patients with nephropathy.  Br Med J. 1986;  293 466-470
• 3 Lewis E, Hunsicker L, Bain R, Rhode R. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy.  N Engl J Med. 1993;  329 1456-1462
• 4 Lewis E J, Hunsicker L G, Clarke W R, Berl T, Pohl M A, Lewis J B, Ritz E, Atkins R C, 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. 2001;  345 851-860
• 5 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. 2001;  345 870-878
• 6 Brenner B M, Cooper M E, de Zeeuw D, Keane W F, Mitch W E, Parving HH. Effects of Losartan on Renal and Cardiovascular outcomes in patients with type 2 diabetes and nephropathy.  N Engl J Med. 2001;  345 861-869
• 7 Epstein M. Aldosterone as a mediator of progressive renal dysfunction: evolving perspectives.  Intern Med. 2001;  40 573-583
• 8 Hostetter T H, Rosenberg M E, Ibrahim H N, Juknevicius I. Aldosterone in progressive renal disease.  Semin Nephrol. 2001;  21 573-579
• 9 Schjoedt K J, Andersen S, Rossing P, Tarnow L, Parving H H. Aldosterone escape during blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate.  Diabetologia. 2004;  47 1936-1939
• 10 Sato A, Hayashi K, Naruse M, Saruta T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy.  Hypertension. 2003;  41 64-68
• 11 Cicoira M, Zanolla L, Rossi A, Golia G, Franceschini L, Cabrini G, Bonizzato A, Graziani M, Anker S D, Coats A J, Zardini P. Failure of aldosterone suppression despite angiotensin-converting enzyme (ACE) inhibitor administration in chronic heart failure is associated with ACE DD genotype.  J Am Coll Cardiol. 2001;  37 1808-1812
• 12 Jacobsen P, Andersen S, Rossing K, Jensen B R, Parving H-H. Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy.  Kidney Int. 2003;  63 1874-1880
• 13 Rossing K, Jacobsen P, Pietraszek L, Parving H H. Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy: a randomized double-blind crossover trial.  Diabetes Care. 2003;  26 2268-2274
• 14 Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial.  Lancet. 2003;  361 117-124
• 15 Jacobsen P, Andersen S, Rossing K, Hansen B V, Parving HH. Dual blockade of the renin-angiotensin system in type 1 patients with diabetic nephropathy.  Nephrol Dial Transplant. 2002;  17 1019-1024
• 16 Jacobsen P, Andersen S, Jensen B R, Parving H H. Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy.  J Am Soc Nephrol. 2003;  14 992-999
• 17 Jacobsen P, Parving H H. Beneficial impact on cardiovascular risk factors by dual blockade of the renin-angiotensin system in diabetic nephropathy.  Kidney Int Suppl. 2004;  92 S108-S110
• 18 Parving HH, Jacobsen P, Tarnow L, Rossing P, Lecerf L, Poirier O, Cambien F. Effect of deletion polymorphism of angiotensin converting enzyme gene on progression of diabetic nephropathy during inhibition of angiotensin converting enzyme: observational follow up study.  Br Med J. 1996;  313 591-594
• 19 Jacobsen P, Rossing K, Rossing P, Tarnow L, Mallet C, Poirier O, Cambien F, Parving H-H. Angiotensin converting enzyme gene polymorphism and ACE inhibition in diabetic nephropathy.  Kidney Int. 1998;  53 1002-1006
• 20 Jacobsen P, Tarnow L, Carstensen B, Hovind P, Poirier O, Parving H H. Genetic variation in the Renin-Angiotensin system and progression of diabetic nephropathy.  J Am Soc Nephrol. 2003;  14 2843-2850
• 21 Andersen S, Tarnow L, Cambien F, Rossing P, Juhl T R, Deinum J, Parving HH. Renoprotective effects of losartan in diabetic nephropathy: Interaction with ACE insertion/deletion genotype?.  Kidney Int. 2002;  62 192-198
• 22 Andersen S, Tarnow L, Cambien F, Rossing P, Juhl T R, Deinum J, Parving HH. Long-Term Renoprotective Effects of Losartan in Diabetic Nephropathy: Interaction with ACE Insertion/Deletion genotype?.  Diabetes Care. 2002;  26 1501-1506
• 23 Epstein M, Buckalew V, Martinez F, Altamirano J, Roniker B, Kleiman J, Krause S. Antiproteinuric efficacy of eplerenone, enalapril, and eplerenone/enalapril combination therapy in diabetic hypertensives with microalbuminuria.  Am J Hypertens. 2002;  15 A24
• 24 Rachmani R, Slavachevsky I, Amit M, Levi Z, Kedar Y, Berla M, Ravid M. The effect of spironolactone, cilazapril and their combination on albuminuria in patients with hypertension and diabetic nephropathy is independent of blood pressure reduction: a randomized controlled study.  Diabet Med. 2004;  21 471-475
• 25 Huang X R, Chen W Y, Truong L D, Lan H Y. Chymase is upregulated in diabetic nephropathy: implications for an alternative pathway of angiotensin II-mediated diabetic renal and vascular disease.  J Am Soc Nephrol. 2003;  14 1738-1747
• 26 Hollenberg N K, Fisher N DL, Price D A. Pathways for angiotensin II generation in intact human tissue. Evidence from comparative pharmacological interruption of the renin system.  Hypertension. 1998;  32 387-392
• 27 Nussberger J, Brunner D B, Waeber B, Brunner H R. Plasma angiotensins under sustained converting enzyme inhibition with enalapril in normal humans.  J Hypertens Suppl. 1985;  3 Suppl 3 S269-S270
• 28 Cao Z, Bonnet F, Candido R, Nesteroff S P, Burns W C, Kawachi H, Shimizu F, Carey R M, De Gasparo M, Cooper M E. Angiotensin type 2 receptor antagonism confers renal protection in a rat model of progressive renal injury.  J Am Soc Nephrol. 2002;  13 1773-1787
• 29 Epstein M. Aldosterone as a mediator of progressive renal disease: pathogenetic and clinical implications.  Am J Kidney Dis. 2001;  37 677-688
• 30 Blasi E R, Rocha R, Rudolph A E, Blomme E A, Polly M L, McMahon E G. Aldosterone/salt induces renal inflammation and fibrosis in hypertensive rats.  Kidney Int. 2003;  63 1791-1800
• 31 Rocha R, Chander P N, Zuckerman A, Stier C T Jr. Role of mineralocorticoids in renal injury in stroke-prone hypertensive rats.  Hypertension. 1998;  32 598
• 32 Epstein M. Aldosterone as a determinant of cardiovascular and renal dysfunction.  J R Soc Med. 2001;  94 378-383