The RAAS in the pathogenesis and treatment of diabetic nephropathy (original) (raw)

• Kaschina, E. & Unger, T. Angiotensin AT1/AT2 receptors: regulation, signalling and function. Blood Press. 12, 70–88 (2003).
  Article CAS PubMed Google Scholar
• Morgan, T. Renin, angiotensin, sodium and organ damage. Hypertens. Res. 26, 349–354 (2003).
  Article CAS PubMed Google Scholar
• Harris, R. C. & Martinez-Maldonado, M. Angiotensin II-mediated renal injury. Miner. Electrolyte Metab. 21, 328–335 (1995).
  CAS PubMed Google Scholar
• Ruggenenti, P. R. G. Introduction. Semin. Nephrol. 24, 91–92 (2004).
  Article Google Scholar
• Ferrario, C. M. Role of angiotensin II in cardiovascular disease therapeutic implications of more than a century of research. J. Renin Angiotensin Aldosterone Syst. 7, 3–14 (2006).
  Article CAS PubMed Google Scholar
• Brewster, U. C. & Perazella, M. A. The renin–angiotensin–aldosterone system and the kidney: effects on kidney disease. Am. J. Med. 116, 263–272 (2004).
  Article CAS PubMed Google Scholar
• Cooper, M. E. The role of the renin–angiotensin–aldosterone system in diabetes and its vascular complications. Am. J. Hypertens. 17, 16S–20S (2004).
  Article CAS PubMed Google Scholar
• Carey, R. M. & Siragy, H. M. Newly recognized components of the renin–angiotensin system: potential roles in cardiovascular and renal regulation. Endocr. Rev. 24, 261–271 (2003).
  Article CAS PubMed Google Scholar
• Hilgers, K. F. & Mann, J. F. ACE inhibitors versus AT(1) receptor antagonists in patients with chronic renal disease. J. Am. Soc. Nephrol. 13, 1100–1108 (2002).
  CAS PubMed Google Scholar
• Siragy, H. M. & Carey, R. M. Protective role of the angiotensin AT2 receptor in a renal wrap hypertension model. Hypertension 33, 1237–1242 (1999).
  Article CAS PubMed Google Scholar
• Reudelhuber, T. L. The continuing saga of the AT2 receptor: a case of the good, the bad, and the innocuous. Hypertension 46, 1261–1262 (2005).
  Article CAS PubMed Google Scholar
• Silvestre, J. S. et al. Antiangiogenic effect of angiotensin II type 2 receptor in ischemia-induced angiogenesis in mice hindlimb. Circ. Res. 90, 1072–1079 (2002).
  Article CAS PubMed Google Scholar
• Ondetti, M. A., Rubin, B. & Cushman, D. W. Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. Science 196, 441–444 (1977).
  Article CAS PubMed Google Scholar
• Zatz, R. et al. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J. Clin. Invest. 77, 1925–1930 (1986).
  Article CAS PubMed PubMed Central Google Scholar
• Perico, N., Benigni, A. & Remuzzi, G. Present and future drug treatments for chronic kidney diseases: evolving targets in renoprotection. Nat. Rev. Drug Discov. 7, 936–953 (2008).
  Article CAS PubMed Google Scholar
• [No authors listed] Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN group. Lancet 349, 1857–1863 (1997).
• Lewis, E. J., Hunsicker, L. G., Bain, R. P. & Rohde, R. D. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N. Engl. J. Med. 329, 1456–1462 (1993).
  Article CAS PubMed Google Scholar
• Taguma, Y. et al. Effect of captopril on heavy proteinuria in azotemic diabetics. N. Engl. J. Med. 313, 1617–1620 (1985).
  Article CAS PubMed Google Scholar
• Bjorck, S., Mulec, H., Johnsen, S. A., Nordén, G. & Aurell, M. Renal protective effect of enalapril in diabetic nephropathy. BMJ 304, 339–343 (1992).
  Article CAS PubMed PubMed Central Google Scholar
• Parving, H. H., Hommel, E. & Smidt, U. M. Protection of kidney function and decrease in albuminuria by captopril in insulin dependent diabetics with nephropathy. BMJ 297, 1086–1091 (1988).
  Article CAS PubMed PubMed Central Google Scholar
• Brenner, B. M. et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N. Engl. J. Med. 345, 861–869 (2001).
  Article CAS PubMed Google Scholar
• Lewis, E. J. et al. 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).
  Article CAS PubMed Google Scholar
• de Zeeuw, D. et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 110, 921–927 (2004).
  Article CAS PubMed Google Scholar
• Casas, J. P. et al. Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis. Lancet 366, 2026–2033 (2005).
  Article CAS PubMed Google Scholar
• Remuzzi, G. & Ruggenenti, P. Overview of randomised trials of ACE inhibitors. Lancet 368, 555–556 (2006).
  Article PubMed Google Scholar
• Zatz, R. et al. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J. Clin. Invest. 77, 1925 (1986).
  Article CAS PubMed PubMed Central Google Scholar
• Perico, N. et al. Evidence that an angiotensin-converting enzyme inhibitor has a different effect on glomerular injury according to the different phase of the disease at which the treatment is started. J. Am. Soc. Nephrol. 5, 1139–1146 (1994).
  CAS PubMed Google Scholar
• Viberti, G., Mogensen, C. E., Groop, L. C. & Pauls, J. F. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. European Microalbuminuria Captopril Study Group. JAMA 271, 275–279 (1994).
  Article CAS PubMed Google Scholar
• ACE Inhibitors in Diabetic Nephropathy Trialist Group. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data. Ann. Intern. Med. 134, 370–379 (2001).
• Parving, H. H. & Hovind, P. Microalbuminuria in type 1 and type 2 diabetes mellitus: evidence with angiotensin converting enzyme inhibitors and angiotensin II receptor blockers for treating early and preventing clinical nephropathy. Curr. Hypertens. Rep. 4, 387–393 (2002).
  Article PubMed Google Scholar
• Yusuf, S. et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N. Engl. J. Med. 342, 145–153 (2000).
  Article CAS PubMed Google Scholar
• [No authors listed] Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 355, 253–259 (2000).
• Parving, H. H. et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N. Engl. J. Med. 345, 870–878 (2001).
  Article CAS PubMed Google Scholar
• Gall, M.-A., Hougaard, P., Borch-Johnsen, K. & Parving, H.-H. Risk factors for development of incipient and overt diabetic nephropathy in patients with non-insulin dependent diabetes mellitus: prospective, observational study. BMJ 314, 783–788 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Brenner, B. M. (Ed.) Brenner & Rector's The Kidney (W. B. Saunders, Philadelphia, 2008).
  Google Scholar
• Eurich, D. T., Majumdar, S. R., Tsuyuki, R. T. & Johnson, J. A. Reduced mortality associated with the use of ACE inhibitors in patients with type 2 diabetes. Diabetes Care 27, 1330–1334 (2004).
  Article CAS PubMed Google Scholar
• Adler, A. I. et al. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int. 63, 225–232 (2003).
  Article PubMed Google Scholar
• [No authors listed] Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. The EUCLID Study Group. Lancet 349, 1787–1792 (1997).
• Chaturvedi, N. et al. Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials. Lancet 372, 1394–1402 (2008).
  Article CAS PubMed Google Scholar
• Mauer, M. et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N. Engl. J. Med. 361, 40–51 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Baba, S. Nifedipine and enalapril equally reduce the progression of nephropathy in hypertensive type 2 diabetics. Diabetes Res. Clin. Pract. 54, 191–201 (2001).
  Article CAS PubMed Google Scholar
• Ruggenenti, P. et al. Preventing microalbuminuria in type 2 diabetes. N. Engl. J. Med. 351, 1941–1951 (2004).
  Article CAS PubMed Google Scholar
• Ruggenenti, P., Perna, A., Ganeva, M., Ene-Iordache, B. & Remuzzi, G. Impact of blood pressure control and angiotensin-converting enzyme inhibitor therapy on new-onset microalbuminuria in type 2 diabetes: a post hoc analysis of the BENEDICT trial. J. Am. Soc. Nephrol. 17, 3472–3481 (2006).
  Article CAS PubMed Google Scholar
• Haller, H. et al. Preventing microalbuminuria in patients with diabetes: rationale and design of the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study. J. Hypertens. 24, 403–408 (2006).
  Article CAS PubMed Google Scholar
• Patel, A. et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 358, 2560–2572 (2008).
  Article CAS PubMed Google Scholar
• Estacio, R. O. et al. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N. Engl. J. Med. 338, 645–652 (1998).
  Article CAS PubMed Google Scholar
• Lindholm, L. H. et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 359, 1004–1010 (2002).
  Article CAS PubMed Google Scholar
• Bloom, J. M. Losartan for cardiovascular disease in patient's with and without diabetes in the LIFE study. Lancet 359, 2201 (2002).
  Article PubMed Google Scholar
• Williams, B. et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 113, 1213–1225 (2006).
  Article CAS PubMed Google Scholar
• Barnett, A. H. et al. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N. Engl. J. Med. 351, 1952–1961 (2004).
  Article CAS PubMed Google Scholar
• Abuissa, H., Jones, P. G., Marso, S. P. & O'Keefe, J. H. Jr. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes: a meta-analysis of randomized clinical trials. J. Am. Coll. Cardiol. 46, 821–826 (2005).
  Article CAS PubMed Google Scholar
• Investigators, T. D. T. Effect of ramipril on the incidence of diabetes. N. Engl. J. Med. 355, 1551–1562 (2006).
  Article Google Scholar
• Ruggenenti, P., Bettinaglio, P., Pinares, F. & Remuzzi, G. Angiotensin converting enzyme insertion/deletion polymorphism and renoprotection in diabetic and nondiabetic nephropathies. Clin. J. Am. Soc. Nephrol. 3, 1511–1525 (2008).
  Article PubMed PubMed Central Google Scholar
• Marre, M. Genetics and the prediction of complications in type 1 diabetes. Diabetes Care 22 (Suppl. 2), B53–B58 (1999).
  PubMed Google Scholar
• Allen, T. J., Waldron, M. J., Casley, D., Jerums, G. & Cooper, M. E. Salt restriction reduces hyperfiltration, renal enlargement, and albuminuria in experimental diabetes. Diabetes 46, 19–24 (1997).
  Article CAS PubMed Google Scholar
• Fabris, B., Jackson, B. & Johnston, C. I. Salt blocks the renal benefits of ramipril in diabetic hypertensive rats. Hypertension 17, 497–503 (1991).
  Article CAS PubMed Google Scholar
• Vogt, L., Waanders, F., Boomsma, F., de Zeeuw, D. & Navis, G. Effects of dietary sodium and hydrochlorothiazide on the antiproteinuric efficacy of losartan. J. Am. Soc. Nephrol. 19, 999–1007 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Ekinci, E. I. et al. Effects of salt supplementation on the albuminuric response to telmisartan with or without hydrochlorothiazide therapy in hypertensive patients with type 2 diabetes are modulated by habitual dietary salt intake. Diabetes Care 32, 1398–1403 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Cianciaruso, B. et al. Salt intake and renal outcome in patients with progressive renal disease. Miner. Electrolyte Metab. 24, 296–301 (1998).
  Article CAS PubMed Google Scholar
• O'Hare, J. A. et al. Blood pressure may be sodium-dependent in diabetic patients without overt nephropathy. Ir. J. Med. Sci. 154, 455–460 (1985).
  Article CAS PubMed Google Scholar
• Weir, M. R. Impact of salt intake on blood pressure and proteinuria in diabetes: importance of the renin-angiotensin system. Miner. Electrolyte Metab. 24, 438–445 (1998).
  Article CAS PubMed Google Scholar
• De'Oliveira, J. M. et al. Autonomy of the renin system in type II diabetes mellitus: dietary sodium and renal hemodynamic responses to ACE inhibition. Kidney Int. 52, 771–777 (1997).
  Article CAS PubMed Google Scholar
• Jerums, G., Allen, T. J., Tsalamandris, C. & Cooper, M. E. Angiotensin converting enzyme inhibition and calcium channel blockade in incipient diabetic nephropathy. The Melbourne Diabetic Nephropathy Study Group. Kidney Int. 41, 904–911 (1992).
  Article CAS PubMed Google Scholar
• Ritchie, S. A. & Connell, J. M. The link between abdominal obesity, metabolic syndrome and cardiovascular disease. Nutr. Metab. Cardiovasc. Dis. 17, 319–326 (2007).
  Article CAS PubMed Google Scholar
• Reisin, E. & Jack, A. V. Obesity and hypertension: mechanisms, cardio-renal consequences, and therapeutic approaches. Med. Clin. North Am. 93, 733–751 (2009).
  Article CAS PubMed Google Scholar
• Sharma, A. M. Is there a rationale for angiotensin blockade in the management of obesity hypertension? Hypertension 44, 12–19 (2004).
  Article CAS PubMed Google Scholar
• Burgess, E. et al. Supramaximal dose of candesartan in proteinuric renal disease. J. Am. Soc. Nephrol. 20, 893–900 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Hollenberg, N. K. et al. Albuminuria response to very high-dose valsartan in type 2 diabetes mellitus. J. Hypertens. 25, 1921–1926 (2007).
  Article CAS PubMed Google Scholar
• Weir, M. R. et al. Antihypertensive effects of double the maximum dose of valsartan in African-American patients with type 2 diabetes mellitus and albuminuria. J. Hypertens. 28, 186–193 (2010).
  Article CAS PubMed Google Scholar
• Hou, F. F. et al. Renoprotection of Optimal Antiproteinuric Doses (ROAD) Study: a randomized controlled study of benazepril and losartan in chronic renal insufficiency. J. Am. Soc. Nephrol. 18, 1889–1898 (2007).
  Article CAS PubMed Google Scholar
• Ruggenenti, P., Cravedi, P. & Remuzzi, G. Proteinuria: increased angiotensin-receptor blocking is not the first option. Nat. Rev. Nephrol. 5, 367–368 (2009).
  Article CAS PubMed Google Scholar
• 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. 63, 1874–1880 (2003).
  Article CAS PubMed Google Scholar
• Jacobsen, P., Andersen, S., Rossing, K., Hansen, B. V. & Parving, H. H. Dual blockade of the renin-angiotensin system in type 1 patients with diabetic nephropathy. Nephrol. Dial. Transplant. 17, 1019–1024 (2002).
  Article CAS PubMed Google Scholar
• 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. 14, 992–999 (2003).
  Article CAS PubMed Google Scholar
• Mogensen, C. E. et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ 321, 1440–1444 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Campbell, R. et al. Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies. Kidney Int. 63, 1094–1103 (2003).
  Article CAS PubMed Google Scholar
• Ruggenenti, P. & Remuzzi, G. Proteinuria: is the ONTARGET renal substudy actually off target? Nat. Rev. Nephrol. 5, 436–437 (2009).
  Article PubMed Google Scholar
• Maschio, G. et al. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N. Engl. J. Med. 334, 939–945 (1996).
  Article CAS PubMed Google Scholar
• Locatelli, F. et al. Long-term progression of chronic renal insufficiency in the AIPRI Extension Study. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. Kidney Int. Suppl. 63, S63–S66 (1997).
  CAS PubMed Google Scholar
• Takaichi, K., Takemoto, F., Ubara, Y. & Mori, Y. Analysis of factors causing hyperkalemia. Intern. Med. 46, 823–829 (2007).
  Article PubMed Google Scholar
• Mann, J. F. et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 372, 547–553 (2008).
  Article CAS PubMed Google Scholar
• Epstein, M. Re-examining RAS-blocking treatment regimens for abrogating progression of chronic kidney disease. Nat. Clin. Pract. Nephrol. 5, 12–13 (2009).
  Article PubMed Google Scholar
• Lindeman, R. D., Tobin, J. & Shock, N. W. Longitudinal studies on the rate of decline in renal function with age. J. Am. Geriatr. Soc. 33, 278–285 (1985).
  Article CAS PubMed Google Scholar
• Ruggenenti, P. et al. Role of remission clinics in the longitudinal treatment of CKD. J. Am. Soc. Nephrol. 19, 1213–1224 (2008).
  Article PubMed PubMed Central Google Scholar
• Os, I., Gudmundsdottir, H., Kjeldsen, S. E. & Oparil, S. Treatment of isolated systolic hypertension in diabetes mellitus type 2. Diabetes Obes. Metab. 8, 381–387 (2006).
  Article CAS PubMed Google Scholar
• Ruggenenti, P. et al. Glomerular size-selective dysfunction in NIDDM is not ameliorated by ACE inhibition or by calcium channel blockade. Kidney Int. 55, 984–994 (1999).
  Article CAS PubMed Google Scholar
• Remuzzi, G., Benigni, A. & Remuzzi, A. Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J. Clin. Invest. 116, 288–296 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, Z. et al. Importance of baseline distribution of proteinuria in renal outcomes trials: lessons from the reduction of endpoints in NIDDM with the angiotensin II antagonist losartan (RENAAL) study. J. Am. Soc. Nephrol. 16, 1775–1780 (2005).
  Article CAS PubMed Google Scholar
• Bomback, A. S. & Klemmer, P. J. The incidence and implications of aldosterone breakthrough. Nat. Clin. Pract. Nephrol. 3, 486–492 (2007).
  Article CAS PubMed Google Scholar
• Rossi, G. P. Aldosterone breakthrough during RAS blockade: a role for endothelins and their antagonists? Curr. Hypertens. Rep. 8, 262–268 (2006).
  Article CAS PubMed Google Scholar
• Becker, G. J., Hewitson, T. D. & Chrysostomou, A. Aldosterone in clinical nephrology—old hormone, new questions. Nephrol. Dial. Transplant. 24, 2316–2321 (2009).
  Article CAS PubMed Google Scholar
• Struthers, A., Krum, H. & Williams, G. H. A comparison of the aldosterone-blocking agents eplerenone and spironolactone. Clin. Cardiol. 31, 153–158 (2008).
  Article PubMed PubMed Central Google Scholar
• Du, J. et al. Mineralocorticoid receptor blockade and calcium channel blockade have different renoprotective effects on glomerular and interstitial injury in rats. Am. J. Physiol. Renal Physiol. 297, F802–F808 (2009).
  Article CAS PubMed Google Scholar
• Piecha, G. et al. Regression of glomerulosclerosis in subtotally nephrectomized rats: effects of monotherapy with losartan, spironolactone, and their combination. Am. J. Physiol. Renal Physiol. 295, F137–F144 (2008).
  Article CAS PubMed Google Scholar
• Chrysostomou, A. & Becker, G. Spironolactone in addition to ACE inhibition to reduce proteinuria in patients with chronic renal disease. N. Engl. J. Med. 345, 925–926 (2001).
  Article CAS PubMed Google Scholar
• Navaneethan, S. D., Nigwekar, S. U., Sehgal, A. R. & Strippoli, G. F. Aldosterone antagonists for preventing the progression of chronic kidney disease: a systematic review and meta-analysis. Clin. J. Am. Soc. Nephrol. 4, 542–551 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Mehdi, U. F., Adams-Huet, B., Raskin, P., Vega, G. L. & Toto, R. D. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J. Am. Soc. Nephrol. 20, 2641–2650 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Bianchi, S., Bigazzi, R. & Campese, V. M. Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease. Kidney Int. 70, 2116–2123 (2006).
  Article CAS PubMed Google Scholar
• van den Meiracker, A. H. et al. Spironolactone in type 2 diabetic nephropathy: effects on proteinuria, blood pressure and renal function. J. Hypertens. 24, 2285–2292 (2006).
  Article CAS PubMed Google Scholar
• Epstein, M. et al. Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin. J. Am. Soc. Nephrol. 1, 940–951 (2006).
  Article CAS PubMed Google Scholar
• Khosla, N., Kalaitzidis, R. & Bakris, G. L. Predictors of hyperkalemia risk following hypertension control with aldosterone blockade. Am. J. Nephrol. 30, 418–424 (2009).
  Article CAS PubMed Google Scholar
• Estacio, R. O. Renin–angiotensin–aldosterone system blockade in diabetes: role of direct renin inhibitors. Postgrad. Med. 121, 33–44 (2009).
  Article PubMed Google Scholar
• Nguyen, G. et al. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J. Clin. Invest. 109, 1417–1427 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Nguyen, G. & Danser, A. H. Prorenin and (pro)renin receptor: a review of available data from in vitro studies and experimental models in rodents. Exp. Physiol. 93, 557–563 (2008).
  Article CAS PubMed Google Scholar
• Ichihara, A. et al. Inhibition of diabetic nephropathy by a decoy peptide corresponding to the “handle” region for nonproteolytic activation of prorenin. J. Clin. Invest. 114, 1128–1135 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Eder, J., Hommel, U., Cumin, F., Martoglio, B. & Gerhartz, B. Aspartic proteases in drug discovery. Curr. Pharm. Des. 13, 271–285 (2007).
  Article CAS PubMed Google Scholar
• Persson, F. et al. Renal effects of aliskiren compared with and in combination with irbesartan in patients with type 2 diabetes, hypertension, and albuminuria. Diabetes Care 32, 1873–1879 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Parving, H. H., Persson, F., Lewis, J. B., Lewis, E. J. & Hollenberg, N. K. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N. Engl. J. Med. 358, 2433–2446 (2008).
  Article CAS PubMed Google Scholar
• Garattini, S. & Bertele, V. Risk:benefit assessment of old medicines. Br. J. Clin. Pharmacol. 58, 581–586 (2004).
  Article PubMed PubMed Central Google Scholar
• Bilous, R. et al. Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials. Ann. Intern. Med. 151, 11–20 (2009).
  Article PubMed Google Scholar
• Andersen, N. H. et al. Long-term dual blockade with candesartan and lisinopril in hypertensive patients with diabetes: the CALM II study. Diabetes Care 28, 273–277 (2005).
  Article CAS PubMed Google Scholar
• Rossing, K., Christensen, P. K., Jensen, B. R. & Parving, H. H. Dual blockade of the renin–angiotensin system in diabetic nephropathy: a randomized double-blind crossover study. Diabetes Care 25, 95–100 (2002).
  Article CAS PubMed Google Scholar
• 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 26, 2268–2274 (2003).
  Article CAS PubMed Google Scholar
• Tutuncu, N. B., Gurlek, A. & Gedik, O. Efficacy of ACE inhibitors and ATII receptor blockers in patients with microalbuminuria: a prospective study. Acta Diabetol. 38, 157–161 (2001).
  Article CAS PubMed Google Scholar