Heart and Vessels

, Volume 28, Issue 4, pp 442–452

Efficacy analysis of the renoprotective effects of aliskiren in hypertensive patients with chronic kidney disease

  • Masanori Abe
  • Hiroko Suzuki
  • Kazuyoshi Okada
  • Noriaki Maruyama
  • Atsushi Inoshita
  • Seishiro Baba
  • Hiroyuki Takashima
  • Masayoshi Soma
Original Article

Abstract

We aimed to assess the effect of aliskiren treatment on blood pressure, albuminuria, and kidney function in patients with chronic kidney disease (CKD). We conducted a prospective, open-label study of 67 patients with CKD who were already being treated with other antihypertensives. Inclusion criteria were blood pressure (BP) ≥130/80 mmHg, albuminuria ≥30 mg/g, and estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m2. Subjects were treated with 150 mg/day aliskiren, which was increased to 300 mg/day for the 24-week study period. Aliskiren effectively reduced both systolic and diastolic BP, plasma renin activity (PRA), serum aldosterone concentration, albuminuria, urinary N-acetyl-glucosaminidase, and urinary β2-microglobulin levels. Although eGFR was significantly decreased after 4 weeks of aliskiren treatment, it recovered to a pretreatment level within 12 weeks of treatment initiation. There were no significant differences in the percent reduction of albuminuria or changes of eGFR levels when the subjects were divided into three groups on the basis of baseline eGFR (stages 1/2, 3, and 4) and the presence or absence of diabetes mellitus (DM group and non-DM group). Furthermore, in patients not treated with renin-angiotensin-aldosterone-system (RAAS) inhibitors, including angiotensin receptor blockers or angiotensin-converting enzyme inhibitors at baseline, changes in eGFR were significantly increased compared with those already treated with RAAS inhibitors at baseline. Aliskiren administration reduced BP, PRA, serum aldosterone levels, and albuminuria, while maintaining eGFR, regardless of the presence or absence of DM or the degree of eGFR.

Keywords

Albuminuria Aldosterone Aliskiren Chronic kidney disease Hypertension Plasma renin activity 

References

  1. 1.
    Ferrario C (2006) Role of angiotensin II in cardiovascular disease—therapeutic implications of more than a century of research. J Renin Angiotensin Aldosterone Syst 7:3–14PubMedCrossRefGoogle Scholar
  2. 2.
    Chobanian A, Bakris G, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ, the National High Blood Pressure Education Program Coordinating Committee (2003) The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA 289:2560–2572PubMedCrossRefGoogle Scholar
  3. 3.
    Jensen C, Herold P, Brunner H (2008) Aliskiren: the first renin inhibitor for clinical treatment. Nat Rev Drug Discov 7:339–410CrossRefGoogle Scholar
  4. 4.
    Azizi M, Menard J (2004) Combined blockade of renin-angiotensin system with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. Circulation 109:2492–2499PubMedCrossRefGoogle Scholar
  5. 5.
    Omae K, Ogawa T, Nitta K (2010) Therapeutic advantage of angiotensin-converting enzyme inhibitors in patients with proteinuric chronic kidney disease. Heart Vessels 25:203–208PubMedCrossRefGoogle Scholar
  6. 6.
    de Zeeuw D, Remuzzi G, Parving HH, Keane WF, Zhang Z, Shahinfar S, Snapinn S, Cooper ME, Mitch WE, Brenner BM (2004) Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 110:921–927PubMedCrossRefGoogle Scholar
  7. 7.
    Rossing P, Hommel E, Smidt UM, Parving HH (1994) Reduction in albuminuria predicts a beneficial effect on diminishing the progression of human diabetic nephropathy during antihypertensive treatment. Diabetologia 37:511–516PubMedCrossRefGoogle Scholar
  8. 8.
    Gansevoort RT, Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, Goresh J, the Chronic Kidney Disease Prognosis Consortium (2011) Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts. Kidney Int 80:93–104PubMedCrossRefGoogle Scholar
  9. 9.
    Tonelli M, Muntner P, Lloyd A, Manns BJ, James MT, Klarenbach S, Quinn RR, Wiebe N, Hemmelgarn BR, the Alberta Kidney Disease Network (2011) Using proteinuria and estimated glomerular filtration rate to classify risk in patients with chronic kidney disease. Ann Intern Med 154:12–21PubMedCrossRefGoogle Scholar
  10. 10.
    Levey AS, de Jong PE, Coresh J, Nahas MEL, Astor BC, Matsushita K, Gansevoort RT, Kasiske B, Eckardt KU (2011) The definition, classification, and prognosis of chronic kidney disease: a KDIGO controversies conference report. Kidney Int 80:17–28PubMedCrossRefGoogle Scholar
  11. 11.
    Pool JL, Schmieder RE, Azizi M, Aldigier JC, Januszewicz A, Zidek W, Chiang Y, Satlin A (2007) Aliskiren, an orally effective renin inhibitor, provides antihypertensive efficacy alone and in combination of valsartan. Am J Hypertens 20:11–20PubMedCrossRefGoogle Scholar
  12. 12.
    Oparil S, Yarows SA, Patel S, Fang H, Zhang J, Satlin A (2007) Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomized, double-blind trial. Lancet 370:221–229PubMedCrossRefGoogle Scholar
  13. 13.
    Ishibashi K, Kurisu S, Kato Y, Mitsuba N, Dohi Y, Nishioka K, Kihara Y (2011) Effects of aliskiren on the fibrinolytic system in patients with coronary artery disease receiving angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor blocker. Heart Vessels. doi:10.1007/s00380-011-0204-7
  14. 14.
    Persson F, Lewis JB, Rossing P, Hollenberg NK, Parving HH (2011) Aliskiren in combination with losartan reduces albuminuria independent of baseline blood pressure in patients with type 2 diabetes and nephropathy. Clin J Am Soc Nephrol 6:1025–1031PubMedCrossRefGoogle Scholar
  15. 15.
    Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK, AVOID Study Investigators (2008) Aliskiren combined with losartan in type-2 diabetes and nephropathy. N Engl J Med 358:2433–2446PubMedCrossRefGoogle Scholar
  16. 16.
    Nakamura T, Sato E, Amaha M, Kawagoe Y, Maeda S, Yamagishi S (2012) Addition of aliskiren to olmesartan ameliorates tubular injury in chronic kidney disease patients partly by reducing proteinuria. J Renin Angiotensin Aldosterone Syst 13:122–127Google Scholar
  17. 17.
    Persson F, Rossing P, Schjoedt KJ, Juhl T, Tarnow L, Stehouwer CD, Schalkwijk C, Boomsma F, Frandsen E, Parving HH (2008) Time course of the antiproteinuric and antihypertensive effects of direct renin inhibition in type 2 diabetes. Kidney Int 73:1419–1425PubMedCrossRefGoogle Scholar
  18. 18.
    Ito S, Nakura N, Le Breton S, Keefe D (2010) Efficacy and safety of aliskiren in Japanese hypertensive patients with renal dysfunction. Hypertens Res 33:62–66PubMedCrossRefGoogle Scholar
  19. 19.
    Ogawa S, Nako K, Okamura M, Senda M, Mori T, Ito S (2011) Aliskiren reduces albuminuria and oxidative stress, and elevates glomerular filtration rates in Japanese patients with advanced diabetic nephropathy. Hypertens Res 34:400–401PubMedCrossRefGoogle Scholar
  20. 20.
    Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR (2003) Development and progression of nephropathy in type 2 diabetes: United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 63:225–232PubMedCrossRefGoogle Scholar
  21. 21.
    Ogihara T, Kikuchi K, Matsuoka H, Fujita T, Higaki J, Horiuchi M, Imai Y, Imaizumi T, Ito S, Iwao H, Kario K, Kawano Y, Kim-Mitsuyama S, Kimura G, Matsubara H, Matsuura H, Naruse M, Saito I, Shimada K, Shimamoto K, Suzuki H, Takishita S, Tanahashi N, Tsuchihashi T, Uchiyama M, Ueda S, Ueshima H, Umemura S, Ishimitsu T, Rakugi H, Japanese Society of Hypertension Committee (2009) The Japanese Society of Hypertension guidelines for the management of hypertension (JSH 2009). Hypertens Res 32:3–107PubMedGoogle Scholar
  22. 22.
    Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T (2005) Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care 28:164–176PubMedCrossRefGoogle Scholar
  23. 23.
    Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A (2009) Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 53:982–992PubMedCrossRefGoogle Scholar
  24. 24.
    Kean WF, Eknoyan G (1999) Proteinuria, albuminuria, risk, assessment, detection (PARADE): positional paper of the National Kidney Foundation. Am J Kidney Dis 33:1004–1010CrossRefGoogle Scholar
  25. 25.
    McMurray JV, Pitt B, Latini R, Maggioni AP, Solomon SD, Keefe DL, Ford J, Verma A, Lewsey J (2008) Effects of the oral direct renin inhibitor aliskiren in patients with symptomatic heart failure. Circ Heart Fail 1:17–24PubMedCrossRefGoogle Scholar
  26. 26.
    Feldman DL, Jin L, Xuan H, Contrepas A, Zhou Y, Webb RL, Mueller DM, Feldt S, Cumin F, Maniara W, Persohn E, Schuetz H, Jan Danser AH, Nguyen G (2008) Effects of aliskiren on blood pressure, albuminuria, and (pro)renin receptor expression in diabetic TG(mRen-2)27 rats. Hypertension 52:130–136PubMedCrossRefGoogle Scholar
  27. 27.
    Fisher NDL, Jan Danser AH, Nussberger J, Dole WP, Hollenberg NK (2008) Renal and hormonal responses to direct renin inhibition with aliskiren in healthy humans. Circulation 117:3199–3205PubMedCrossRefGoogle Scholar
  28. 28.
    Kushiro T, Itakura H, Abo Y, Gotou H, Terao S, Keefe DL (2006) Aliskiren, a novel oral renin inhibitor, provides dose-dependent efficacy and placebo-like tolerability in Japanese patients with hypertension. Hypertens Res 29:997–1005PubMedCrossRefGoogle Scholar
  29. 29.
    Andersen K, Weinberger MH, Egan B, Constance CM, Ali MA, Jin J, Keefe DL (2008) Comparative efficacy and safety of aliskiren, an oral direct renin inhibitor, and ramipril in hypertension: a 6-month, randomized, double-blind trial. J Hypertens 26:589–599PubMedCrossRefGoogle Scholar
  30. 30.
  31. 31.
    Parving HH, Brenner BM, McMurray JJV, de Zeeuw D, Haffner SM, Solomn SD, Chaturvedi N, Persson F, Nicolaides M, Richard A, Xiang Z, Armbrecht J, Pfeffer MA (2012) Baseline characteristics in the aliskiren trial in type 2 diabetes using cardiorenal endpoints (ALTITUDE). J Renin Angiotensin Aldosterone Syst (epub ahead of print)Google Scholar
  32. 32.
    Textor SC, Bravo EL, Fouad FM, Tarazi RC (1982) Hyperkalemia in azotemic patients during angiotensin converting enzyme inhibition and aldosterone reduction with captopril. Am J Med 73:719–725PubMedCrossRefGoogle Scholar
  33. 33.
    Kostis JB, Shelton B, Gosselin G, Goulet C, Hood Jr WB, Kohn RM, Kubo SH, Schron E, Weiss MB, Willis PW, Young JB, Probstfield J, SOLVD Investigators (1996) Adverse effects of enalapril in the studies of left ventricular dysfunction (SOLVD). Am Heart J 131:350–55Google Scholar
  34. 34.
    Persson F, Lewis JB, Lewis EJ, Rossing P, Hollenberg NK, Parving HH, AVOID Study Investigators (2010) Impact of baseline renal function on the efficacy and safety of aliskiren added to losartan in patients with type 2 diabetes and nephropathy. Diabetes Care 33:2304–2309PubMedCrossRefGoogle Scholar
  35. 35.
    Persson F, Rossing P, Reinhard H, Juhl T, Stehouwer CDA, Schalkwijk C, Danser AHJ, Boomsma F, Frandsen E, Parving HH (2009) Renal effects of aliskiren compared to and in combination with irbesartan in patients with type 2 diabetes, hypertension and albuminuria. Diabetes Care 32:1873–1879PubMedCrossRefGoogle Scholar
  36. 36.
    Thomas MC, Burns WC, Cooper ME (2005) Tubular changes in early diabetic nephropathy. Adv Chronic Kidney Dis 12:177–186PubMedCrossRefGoogle Scholar
  37. 37.
    Sun Y, Zhang J, Lu L, Chen SS, Quinn MT, Weber KT (2002) Aldosterone-induced inflammation in the rat heart: role of oxidative stress. Am J Pathol 161:1773–1781PubMedCrossRefGoogle Scholar
  38. 38.
    Struthers AD, MacDonald TM (2004) Review of aldosterone- and angiotensin II induced target organ damage and prevention. Cardiovasc Res 61:663–670PubMedCrossRefGoogle Scholar
  39. 39.
    Yoshida K, Kim-Mitsuyama S, Wake R, Izumi Y, Yukimura T, Ueda M, Yoshiyama M, Iwao H (2005) Excess aldosterone under normal salt diet induces cardiac hypertrophy and infiltration via oxidative stress. Hypertens Res 28:447–455PubMedCrossRefGoogle Scholar
  40. 40.
    Shiffrin EL (2006) Effects of aldosterone on the vasculature. Hypertension 47:312–318CrossRefGoogle Scholar
  41. 41.
    Miyata K, Rahman M, Shokoji T, Nagai Y, Zhang GX, Sun GP, Kimura S, Yukimura T, Kiyomoto H, Kohno M, Abe Y, Nishiyama A (2005) Aldosterone stimulates reactive oxygen species production through activation of NADPH oxidase in rat mesangial cells. J Am Soc Nephrol 16:2906–2912PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2012

Authors and Affiliations

  • Masanori Abe
    • 1
  • Hiroko Suzuki
    • 1
  • Kazuyoshi Okada
    • 1
  • Noriaki Maruyama
    • 1
  • Atsushi Inoshita
    • 1
  • Seishiro Baba
    • 1
  • Hiroyuki Takashima
    • 1
  • Masayoshi Soma
    • 1
    • 2
  1. 1.Division of Nephrology, Hypertension and Endocrinology, Department of Internal MedicineNihon University School of MedicineTokyoJapan
  2. 2.Division of General Medicine, Department of Internal MedicineNihon University School of MedicineTokyoJapan

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