Skip to main content

Advertisement

Log in

Direct inhibition of plasmatic renin activity with aliskiren: a promising but under-investigated therapeutic option for non-diabetic glomerulonephritis

  • Nephrology - Review
  • Published:
International Urology and Nephrology Aims and scope Submit manuscript

Abstract

Non-diabetic glomerulonephritis is a frequent cause of end-stage renal disease. The use of renin–angiotensin–aldosterone system blockers is a fundamental therapeutic approach. However, converting enzyme inhibitors (ACE-is) and angiotensin receptor blockers do not always achieve the desired target of proteinuria. The induction of the prorenin and renin up-regulation is a possible explanation. Aliskiren is the first drug acting as direct inhibitor of plasmatic renin activity, also able to interfere with the prorenin and renin profibrotic escape. We aimed at reviewing the literature for the assessment of potential efficacy and safety of aliskiren in the treatment of non-diabetic glomerulonephritis. The data on this topic are limited; however, we concluded for a possible usefulness of aliskiren. The renal safety profile appears potentially acceptable in non-diabetic patients although extreme carefulness, particularly with respect to long-term renal and cardiovascular tolerability, is recommended.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Moranne O, Watier L, Rossert J, Stengel B (2008) Group GN-PS: primary glomerulonephritis: an update on renal survival and determinants of progression. QJM 101(3):215–224

    Article  PubMed  CAS  Google Scholar 

  2. Chiurchiu C, Remuzzi G, Ruggenenti P (2005) Angiotensin-converting enzyme inhibition and renal protection in nondiabetic patients: the data of the meta-analyses. J Am Soc Nephrol 16(Suppl 1):S58–S63

    Article  PubMed  CAS  Google Scholar 

  3. Frampton JE, Curran MP (2007) Aliskiren: a review of its use in the management of hypertension. Drugs 67(12):1767–1792

    Article  PubMed  CAS  Google Scholar 

  4. Krebs C, Hamming I, Sadaghiani S, Steinmetz OM, Meyer-Schwesinger C, Fehr S, Stahl RA, Garrelds IM, Danser AH, van Goor H et al (2007) Antihypertensive therapy upregulates renin and (pro)renin receptor in the clipped kidney of Goldblatt hypertensive rats. Kidney Int 72(6):725–730

    Article  PubMed  CAS  Google Scholar 

  5. Veniant M, Menard J, Bruneval P, Morley S, Gonzales MF, Mullins J (1996) Vascular damage without hypertension in transgenic rats expressing prorenin exclusively in the liver. J Clin Invest 98(9):1966–1970

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Nguyen G, Danser AH (2008) Prorenin and (pro)renin receptor: a review of available data from in vitro studies and experimental models in rodents. Exp Physiol 93(5):557–563

    Article  PubMed  CAS  Google Scholar 

  7. Paul M (2006) Poyan Mehr A, Kreutz R: physiology of local renin-angiotensin systems. Physiol Rev 86(3):747–803

    Article  PubMed  CAS  Google Scholar 

  8. Moon JY (2013) Recent update of renin-angiotensin-aldosterone system in the pathogenesis of hypertension. Electrolyte Blood Press 11(2):41–45

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Ichihara A, Hayashi M, Kaneshiro Y, Suzuki F, Nakagawa T, Tada Y, Koura Y, Nishiyama A, Okada H, Uddin MN et al (2004) Inhibition of diabetic nephropathy by a decoy peptide corresponding to the “handle” region for nonproteolytic activation of prorenin. J Clin Invest 114(8):1128–1135

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Simeoni M, Cianfrone P, Comi N, Gentile I, Fabiano FF, Piraina V, Talarico R, Lucisano G, Rivoli L, Andreucci M et al (2015) Is it feasible to improve the duration and the efficiency of Ramipril anti-proteinuric response? G Ital Nefrol 32(1)

  11. Tylicki L, Lizakowski S, Rutkowski B (2012) Renin-angiotensin-aldosterone system blockade for nephroprotection: current evidence and future directions. J Nephrol 25(6):900–910

    Article  PubMed  CAS  Google Scholar 

  12. Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T, Sraer JD (2002) Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 109(11):1417–1427

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Huang Y, Noble NA, Zhang J, Xu C, Border WA (2007) Renin-stimulated TGF-beta1 expression is regulated by a mitogen-activated protein kinase in mesangial cells. Kidney Int 72(1):45–52

    Article  PubMed  CAS  Google Scholar 

  14. Prieto-Carrasquero MC, Kobori H, Ozawa Y, Gutierrez A, Seth D, Navar LG (2005) AT1 receptor-mediated enhancement of collecting duct renin in angiotensin II-dependent hypertensive rats. Am J Physiol Renal Physiol 289(3):F632–F637

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Danser AH, Derkx FH, Schalekamp MA, Hense HW, Riegger GA, Schunkert H (1998) Determinants of interindividual variation of renin and prorenin concentrations: evidence for a sexual dimorphism of (pro)renin levels in humans. J Hypertens 16(6):853–862

    Article  PubMed  CAS  Google Scholar 

  16. Miyata K, Satou R, Inui D, Katsurada A, Seth D, Davis A, Urushihara M, Kobori H, Mitchell KD, Navar LG (2014) Renoprotective effects of direct renin inhibition in glomerulonephritis. Am J Med Sci 348(4):306–314

    Article  PubMed  PubMed Central  Google Scholar 

  17. Huang J, Siragy HM (2009) Glucose promotes the production of interleukin-1beta and cyclooxygenase-2 in mesangial cells via enhanced (Pro)renin receptor expression. Endocrinology 150(12):5557–5565

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Advani A, Kelly DJ, Cox AJ, White KE, Advani SL, Thai K, Connelly KA, Yuen D, Trogadis J, Herzenberg AM et al (2009) The (Pro)renin receptor: site-specific and functional linkage to the vacuolar H+-ATPase in the kidney. Hypertension 54(2):261–269

    Article  PubMed  CAS  Google Scholar 

  19. Nguyen G, Delarue F, Berrou J, Rondeau E, Sraer JD (1996) Specific receptor binding of renin on human mesangial cells in culture increases plasminogen activator inhibitor-1 antigen. Kidney Int 50(6):1897–1903

    Article  PubMed  CAS  Google Scholar 

  20. Huang Y, Border WA, Noble NA (2007) Functional renin receptors in renal mesangial cells. Curr Hypertens Rep 9(2):133–139

    Article  PubMed  CAS  Google Scholar 

  21. Huang Y, Wongamorntham S, Kasting J, McQuillan D, Owens RT, Yu L, Noble NA, Border W (2006) Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. Kidney Int 69(1):105–113

    Article  PubMed  CAS  Google Scholar 

  22. Kaneshiro Y, Ichihara A, Sakoda M, Takemitsu T, Nabi AH, Uddin MN, Nakagawa T, Nishiyama A, Suzuki F, Inagami T et al (2007) Slowly progressive, angiotensin II-independent glomerulosclerosis in human (pro)renin receptor-transgenic rats. J Am Soc Nephrol 18(6):1789–1795

    Article  PubMed  CAS  Google Scholar 

  23. Sanoski CA (2009) Aliskiren: an oral direct renin inhibitor for the treatment of hypertension. Pharmacotherapy 29(2):193–212

    Article  PubMed  CAS  Google Scholar 

  24. Riccioni G (2011) Aliskiren in the treatment of hypertension and organ damage. Cardiovasc Ther 29(1):77–87

    Article  PubMed  CAS  Google Scholar 

  25. Feldman DL, Jin L, Xuan H, Contrepas A, Zhou Y, Webb RL, Mueller DN, Feldt S, Cumin F, Maniara W et al (2008) Effects of aliskiren on blood pressure, albuminuria, and (pro)renin receptor expression in diabetic TG(mRen-2)27 rats. Hypertension 52(1):130–136

    Article  PubMed  CAS  Google Scholar 

  26. Ferri N, Greco CM, Maiocchi G, Corsini A (2011) Aliskiren reduces prorenin receptor expression and activity in cultured human aortic smooth muscle cells. JRAAS 12(4):469–474

    PubMed  CAS  Google Scholar 

  27. McMurray JJ, Abraham WT, Dickstein K, Kober L, Massie BM, Krum H (2012) Aliskiren, ALTITUDE, and the implications for atmosphere. Eur J Heart Fail 14(4):341–343

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kelly DJ, Zhang Y, Moe G, Naik G, Gilbert RE (2007) Aliskiren, a novel renin inhibitor, is renoprotective in a model of advanced diabetic nephropathy in rats. Diabetologia 50(11):2398–2404

    Article  PubMed  CAS  Google Scholar 

  29. Lizakowski S, Tylicki L, Rutkowski B (2013) Direct renin inhibition–a promising strategy for renal protection? Med Sci Monit 19:451–457

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Gross O, Girgert R, Rubel D, Temme J, Theissen S, Muller GA (2011) Renal protective effects of aliskiren beyond its antihypertensive property in a mouse model of progressive fibrosis. Am J Hypertens 24(3):355–361

    Article  PubMed  CAS  Google Scholar 

  31. Li SY, Chen YT, Yang WC, Tarng DC, Lin CC, Yang CY, Liu WS (2012) Effect of add-on direct renin inhibitor aliskiren in patients with non-diabetes related chronic kidney disease. BMC Nephrol 13:89

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Wu MT, Tung SC, Hsu KT, Lee CT (2014) Aliskiren add-on therapy effectively reduces proteinuria in chronic kidney disease: an open-label prospective trial. JRAAS 15(3):271–277

    PubMed  CAS  Google Scholar 

  33. Moriyama T, Tsuruta Y, Kojima C, Itabashi M, Sugiura H, Takei T, Ogawa T, Uchida K, Tsuchiya K, Nitta K (2012) Beneficial effect of aliskiren combined with olmesartan in reducing urinary protein excretion in patients with chronic kidney disease. Int Urol Nephrol 44(3):841–845

    Article  PubMed  CAS  Google Scholar 

  34. Lopez V, Martin M, Cobelo C, Aranda P, Cabello M, Sola E, Gutierrez C, Burgos D, Martinez D, Hernandez D (2010) Renin-angiotensin system dual blockade using angiotensin receptor plus aliskiren decreases severe proteinuria in kidney transplant recipients. Transpl Proc 42(8):2883–2885

    Article  CAS  Google Scholar 

  35. Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, Chaturvedi N, Persson F, Desai AS, Nicolaides M et al (2012) Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 367(23):2204–2213

    Article  PubMed  CAS  Google Scholar 

  36. Li PK, Leung CB, Chow KM, Cheng YL, Fung SK, Mak SK, Tang AW, Wong TY, Yung CY, Yung JC et al (2006) Hong Kong study using valsartan in IgA nephropathy (HKVIN): a double-blind, randomized, placebo-controlled study. Am J Kidney Dis 47(5):751–760

    Article  PubMed  CAS  Google Scholar 

  37. Cheng J, Zhang X, Zhang W, He Q, Tao X, Chen J (2009) Efficacy and safety of glucocorticoids therapy for IgA nephropathy: a meta-analysis of randomized controlled trials. Am J Nephrol 30(4):315–322

    Article  PubMed  CAS  Google Scholar 

  38. Ballardie FW, Roberts IS (2002) Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy. J Am Soc Nephrol 13(1):142–148

    PubMed  CAS  Google Scholar 

  39. Coppo R, Peruzzi L, Amore A, Piccoli A, Cochat P, Stone R, Kirschstein M, Linne T (2007) IgACE: a placebo-controlled, randomized trial of angiotensin-converting enzyme inhibitors in children and young people with IgA nephropathy and moderate proteinuria. JASN 18(6):1880–1888

    Article  PubMed  CAS  Google Scholar 

  40. Chan LY, Leung JC, Tang SC, Choy CB, Lai KN (2005) Tubular expression of angiotensin II receptors and their regulation in IgA nephropathy. J Am Soc Nephrol 16(8):2306–2317

    Article  PubMed  CAS  Google Scholar 

  41. Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, Wang X, Maggioni A, Budaj A, Chaithiraphan S et al (2008) 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(9638):547–553

    Article  PubMed  CAS  Google Scholar 

  42. Messerli FH (2009) The sudden demise of dual renin-angiotensin system blockade or the soft science of the surrogate end point. J Am Coll Cardiol 53(6):468–470

    Article  PubMed  CAS  Google Scholar 

  43. Tang SC, Lin M, Tam S, Au WS, Ma MK, Yap DY, Ho YW, Lai KN (2012) Aliskiren combined with losartan in immunoglobulin A nephropathy: an open-labeled pilot study. Nephrol Dial Transplant 27(2):613–618

    Article  PubMed  CAS  Google Scholar 

  44. Woo KT, Choong HL, Wong KS, Tan HK, Foo M, Fook-Chong S, Lee EJ, Anantharaman V, Lee GS, Chan CM (2014) Aliskiren and losartan trial in non-diabetic chronic kidney disease. JRAAS 15(4):515–522

    PubMed  CAS  Google Scholar 

  45. Szeto CC, Kwan BC, Chow KM, Leung CB, Li PK (2013) The safety and short-term efficacy of aliskiren in the treatment of immunoglobulin a nephropathy–a randomized cross-over study. PLoS ONE 8(5):e62736

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  46. Wasserstein AG (1997) Membranous glomerulonephritis. J Am Soc Nephrol 8(4):664–674

    PubMed  CAS  Google Scholar 

  47. Polanco N, Gutierrez E, Covarsi A, Ariza F, Carreno A, Vigil A, Baltar J, Fernandez-Fresnedo G, Martin C, Pons S et al (2010) Spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy. J Am Soc Nephrol 21(4):697–704

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  48. Gupta A, Khaira A, Singh B, Bhowmik DM, Tiwari SC (2009) Aliskiren as an antiproteinuric add-on therapy in primary membranous nephropathy. Clin Exp Nephrol 13(4):402–403

    Article  PubMed  CAS  Google Scholar 

  49. Salgado A, Herrera-Diaz C (2012) Lupus Nephritis: an Overview of Recent Findings. Autoimmune Dis 2012:1–21

    Article  Google Scholar 

  50. Beck L, Bomback AS, Choi MJ, Holzman LB, Langford C, Mariani LH, Somers MJ, Trachtman H, Waldman M (2013) KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis. Am J Kidney Dis 62(3):403–441

    Article  PubMed  Google Scholar 

  51. Cheigh JS, Kim H, Stenzel KH, Tapia L, Sullivan JF, Stubenbord W, Riggio RR, Rubin AL (1990) Systemic lupus erythematosus in patients with end-stage renal disease: long-term follow-up on the prognosis of patients and the evolution of lupus activity. Am J Kidney Dis 16(3):189–195

    Article  PubMed  CAS  Google Scholar 

  52. Presta P, Presta P, Fuiano G, Lombardi G, Simeoni M, Rivoli L, Lombardi L, Coppolino G (2015) Successful conception and pregnancy in p-ANCA-associated vasculitis in course of treatment with immunosuppressive drugs and renal replacement therapy. Int J Rheum Dis 18(4):470–472

    Article  PubMed  CAS  Google Scholar 

  53. Yen TH, Yang HY, Yeh YH, Chu PH, Wen CJ, Fu JF, Wang IK, Liang CC, Chang CT, Chen KH et al (2013) Aliskiren attenuates proteinuria in mice with lupus nephritis by a blood pressure-independent mechanism. Lupus 22(2):180–189

    Article  PubMed  Google Scholar 

  54. Kitiyakara C, Eggers P, Kopp JB (2004) Twenty-one-year trend in ESRD due to focal segmental glomerulosclerosis in the United States. Am J Kidney Dis 44(5):815–825

    Article  PubMed  Google Scholar 

  55. D’Agati V (1994) The many masks of focal segmental glomerulosclerosis. Kidney Int 46(4):1223–1241

    Article  PubMed  Google Scholar 

  56. Collins AJ, Kasiske B, Herzog C, Chavers B, Foley R, Gilbertson D, Grimm R, Liu J, Louis T, Manning W et al. (2005) Excerpts from the United States Renal Data System 2004 annual data report: atlas of end-stage renal disease in the United States. Am J Kidney Dis, 45(1 Suppl 1):A5-7, S1-280

  57. Korbet SM (2003) Angiotensin antagonists and steroids in the treatment of focal segmental glomerulosclerosis. Semin Nephrol 23(2):219–228

    Article  PubMed  CAS  Google Scholar 

  58. Freiberger V, Amann K, Heemann U, Frank H (2009) Effect of a triple blockade of the renin-angiotensin-system in recurrent focal segmental glomerulosclerosis after kidney transplantation. Transpl Int 22(11):1110–1113

    Article  PubMed  Google Scholar 

  59. Gardenswartz MH, Lerner CW, Seligson GR, Zabetakis PM, Rotterdam H, Tapper ML, Michelis MF, Bruno MS (1984) Renal disease in patients with AIDS: a clinicopathologic study. Clin Nephrol 21(4):197–204

    PubMed  CAS  Google Scholar 

  60. Winston JA, Bruggeman LA, Ross MD, Jacobson J, Ross L, D’Agati VD, Klotman PE, Klotman ME (2001) Nephropathy and establishment of a renal reservoir of HIV type 1 during primary infection. N Engl J Med 344(26):1979–1984

    Article  PubMed  CAS  Google Scholar 

  61. Levin ML, Palella F, Shah S, Lerma E, Butter J, Kanwar YS (2001) Hiv-associated nephropathy occurring before HIV antibody seroconversion. Am J Kidney Dis 37(5):E39

    Article  PubMed  CAS  Google Scholar 

  62. Kumar D, Plagov A, Yadav I, Torri DD, Sayeneni S, Sagar A, Rai P, Adabala M, Lederman R, Chandel N et al (2012) Inhibition of renin activity slows down the progression of HIV-associated nephropathy. Am J Physiol Renal Physiol 303(5):F711–F720

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  63. Plagov A, Lan X, Rai P, Kumar D, Lederman R, Rehman S, Malhotra A, Ding G, Chander PN, Singhal PC (2014) Modulation of renin angiotensin system predominantly alters sclerotic phenotype of glomeruli in HIVAN. Histol Histopathol 29(12):1575–1581

    PubMed  CAS  PubMed Central  Google Scholar 

  64. Laurinavicius A, Hurwitz S, Rennke HG (1999) Collapsing glomerulopathy in HIV and non-HIV patients: a clinicopathological and follow-up study. Kidney Int 56(6):2203–2213

    Article  PubMed  CAS  Google Scholar 

  65. Kirchner JT (2002) Resolution of renal failure after initiation of HAART: 3 cases and a discussion of the literature. AIDS Read 12(3):103–105, 110–102

  66. Burns GC, Paul SK, Toth IR, Sivak SL (1997) Effect of angiotensin-converting enzyme inhibition in HIV-associated nephropathy. JASN 8(7):1140–1146

    PubMed  CAS  Google Scholar 

  67. Bolignano D, Pisano A, Coppolino G (2015) The DARK SIDE OF BLOCKing RAS in diabetic patients with incipient or manifested nephropathy. Exp Clin Endocrinol Diabetes. [Epub ahead of print]

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mariadelina Simeoni.

Ethics declarations

Conflict of interest

All authors have not to declare any financial conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Simeoni, M., Nicotera, R., Colao, M. et al. Direct inhibition of plasmatic renin activity with aliskiren: a promising but under-investigated therapeutic option for non-diabetic glomerulonephritis. Int Urol Nephrol 48, 229–237 (2016). https://doi.org/10.1007/s11255-015-1128-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11255-015-1128-4

Keywords

Navigation