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

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.

[1]  G. Riccioni Aliskiren in the treatment of hypertension and organ damage. , 2011, Cardiovascular therapeutics.

[2]  I. Roberts,et al.  Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy. , 2002, Journal of the American Society of Nephrology : JASN.

[3]  M. F. Michelis,et al.  Renal disease in patients with AIDS: a clinicopathologic study. , 1984, Clinical nephrology.

[4]  L. Peruzzi,et al.  IgACE: a placebo-controlled, randomized trial of angiotensin-converting enzyme inhibitors in children and young people with IgA nephropathy and moderate proteinuria. , 2007, Journal of the American Society of Nephrology : JASN.

[5]  H. van Goor,et al.  Antihypertensive therapy upregulates renin and (pro)renin receptor in the clipped kidney of Goldblatt hypertensive rats. , 2007, Kidney international.

[6]  S. Korbet Angiotensin antagonists and steroids in the treatment of focal segmental glomerulosclerosis. , 2003, Seminars in nephrology.

[7]  D. Bolignano,et al.  The Dark Side of Blocking RAS in Diabetic Patients with Incipient or Manifested Nephropathy. , 2015, Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association.

[8]  W. Border,et al.  Renin-stimulated TGF-beta1 expression is regulated by a mitogen-activated protein kinase in mesangial cells. , 2007, Kidney international.

[9]  B. C. Kwan,et al.  The Safety and Short-Term Efficacy of Aliskiren in the Treatment of Immunoglobulin A Nephropathy – A Randomized Cross-Over Study , 2013, PloS one.

[10]  F. Messerli The sudden demise of dual renin-angiotensin system blockade or the soft science of the surrogate end point. , 2009, Journal of the American College of Cardiology.

[11]  P. Singhal,et al.  Inhibition of renin activity slows down the progression of HIV-associated nephropathy. , 2012, American journal of physiology. Renal physiology.

[12]  H. Trachtman,et al.  KDOQI US commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis. , 2013, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[13]  R. Girgert,et al.  Renal protective effects of aliskiren beyond its antihypertensive property in a mouse model of progressive fibrosis. , 2011, American journal of hypertension.

[14]  V. D’Agati,et al.  Nephropathy and establishment of a renal reservoir of HIV type 1 during primary infection. , 2001, The New England journal of medicine.

[15]  G. Remuzzi,et al.  Angiotensin-converting enzyme inhibition and renal protection in nondiabetic patients: the data of the meta-analyses. , 2005, Journal of the American Society of Nephrology : JASN.

[16]  H. Kobori,et al.  AT1 receptor-mediated enhancement of collecting duct renin in angiotensin II-dependent hypertensive rats. , 2005, American journal of physiology. Renal physiology.

[17]  V. D’Agati The many masks of focal segmental glomerulosclerosis. , 1994, Kidney international.

[18]  P. Eggers,et al.  Twenty-one-year trend in ESRD due to focal segmental glomerulosclerosis in the United States. , 2004, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[19]  J. Berrou,et al.  Specific receptor binding of renin on human mesangial cells in culture increases plasminogen activator inhibitor-1 antigen. , 1996, Kidney international.

[20]  B. Rutkowski,et al.  Renin-angiotensin-aldosterone system blockade for nephroprotection: current evidence and future directions. , 2012, Journal of nephrology.

[21]  Ling Yu,et al.  Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. , 2006, Kidney international.

[22]  H. Siragy,et al.  Glucose promotes the production of interleukine-1beta and cyclooxygenase-2 in mesangial cells via enhanced (Pro)renin receptor expression. , 2009, Endocrinology.

[23]  C. Hung,et al.  Aliskiren attenuates proteinuria in mice with lupus nephritis by a blood pressure-independent mechanism , 2013, Lupus.

[24]  A. G. Wasserstein Membranous glomerulonephritis. , 1997, Journal of the American Society of Nephrology : JASN.

[25]  J. Ménard,et al.  Vascular damage without hypertension in transgenic rats expressing prorenin exclusively in the liver. , 1996, The Journal of clinical investigation.

[26]  K. Dickstein,et al.  Aliskiren, ALTITUDE, and the implications for ATMOSPHERE , 2012, European journal of heart failure.

[27]  K. Connelly,et al.  The (Pro)Renin Receptor: Site-Specific and Functional Linkage to the Vacuolar H+-ATPase in the Kidney , 2009, Hypertension.

[28]  M. Curran,et al.  Aliskiren: a review of its use in the management of hypertension. , 2007, Drugs.

[29]  A. Nishiyama,et al.  Slowly progressive, angiotensin II-independent glomerulosclerosis in human (pro)renin receptor-transgenic rats. , 2007, Journal of the American Society of Nephrology : JASN.

[30]  G. Fernández-Juárez,et al.  Spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy. , 2010, Journal of the American Society of Nephrology : JASN.

[31]  C. Sanoski Aliskiren: An Oral Direct Renin Inhibitor for the Treatment of Hypertension , 2009, Pharmacotherapy.

[32]  A. Corsini,et al.  Aliskiren reduces prorenin receptor expression and activity in cultured human aortic smooth muscle cells , 2011, Journal of the renin-angiotensin-aldosterone system : JRAAS.

[33]  D. Bhowmik,et al.  Aliskiren as an antiproteinuric add-on therapy in primary membranous nephropathy , 2009, Clinical and Experimental Nephrology.

[34]  Sanjiv J. Shah,et al.  Hiv-associated nephropathy occurring before HIV antibody seroconversion. , 2001, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[35]  B. Rutkowski,et al.  Direct renin inhibition – a promising strategy for renal protection? , 2013, Medical science monitor : international medical journal of experimental and clinical research.

[36]  H. Kobori,et al.  Renoprotective Effects of Direct Renin Inhibition in Glomerulonephritis , 2014, The American journal of the medical sciences.

[37]  Chien-Te Lee,et al.  Aliskiren add-on therapy effectively reduces proteinuria in chronic kidney disease: An open-label prospective trial , 2014, Journal of the renin-angiotensin-aldosterone system : JRAAS.

[38]  A. Danser,et al.  Prorenin and (pro)renin receptor: a review of available data from in vitro studies and experimental models in rodents , 2008, Experimental physiology.

[39]  R. Riggio,et al.  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. , 1990, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[40]  V. López,et al.  Renin-angiotensin system dual blockade using angiotensin receptor plus aliskiren decreases severe proteinuria in kidney transplant recipients. , 2010, Transplantation proceedings.

[41]  Nish Chaturvedi,et al.  Cardiorenal end points in a trial of aliskiren for type 2 diabetes. , 2012, The New England journal of medicine.

[42]  E. Persohn,et al.  Effects of Aliskiren on Blood Pressure, Albuminuria, and (Pro)Renin Receptor Expression in Diabetic TG(mRen-2)27 Rats , 2008, Hypertension.

[43]  S. Yusuf,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 , 2008, The Lancet.

[44]  G. Nguyen,et al.  Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. , 2002, The Journal of clinical investigation.

[45]  H. Hense,et al.  Determinants of interindividual variation of renin and prorenin concentrations: evidence for a sexual dimorphism of (pro)renin levels in humans , 1998, Journal of hypertension.

[46]  S. Tang,et al.  Tubular expression of angiotensin II receptors and their regulation in IgA nephropathy. , 2005, Journal of the American Society of Nephrology : JASN.

[47]  G. Coppolino,et al.  Successful conception and pregnancy in p‐ANCA‐associated vasculitis in course of treatment with immunosuppressive drugs and renal replacement therapy , 2015, International journal of rheumatic diseases.

[48]  Yuan Zhang,et al.  Aliskiren, a novel renin inhibitor, is renoprotective in a model of advanced diabetic nephropathy in rats , 2007, Diabetologia.

[49]  D. Tarng,et al.  Effect of add-on direct renin inhibitor aliskiren in patients with non-diabetes related chronic kidney disease , 2012, BMC Nephrology.

[50]  Qiang He,et al.  Efficacy and Safety of Glucocorticoids Therapy for IgA Nephropathy: A Meta-Analysis of Randomized Controlled Trials , 2009, American Journal of Nephrology.

[51]  A. Nishiyama,et al.  Inhibition of diabetic nephropathy by a decoy peptide corresponding to the "handle" region for nonproteolytic activation of prorenin. , 2004, The Journal of clinical investigation.

[52]  B. Stengel,et al.  Primary glomerulonephritis: an update on renal survival and determinants of progression. , 2008, QJM : monthly journal of the Association of Physicians.

[53]  S. Tam,et al.  Aliskiren combined with losartan in immunoglobulin A nephropathy: an open-labeled pilot study. , 2012, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[54]  Catalina Herrera-Díaz,et al.  Lupus Nephritis: An Overview of Recent Findings , 2012, Autoimmune diseases.

[55]  Mariadelina Simeoni,et al.  [Is it feasible to improve the duration and the efficiency of Ramipril anti-proteinuric response?]. , 2015, Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia.

[56]  K. Tsuchiya,et al.  Beneficial effect of aliskiren combined with olmesartan in reducing urinary protein excretion in patients with chronic kidney disease , 2012, International Urology and Nephrology.

[57]  H. Rennke,et al.  Collapsing glomerulopathy in HIV and non-HIV patients: a clinicopathological and follow-up study. , 1999, Kidney international.

[58]  W. Border,et al.  Functional renin receptors in renal mesangial cells , 2007, Current hypertension reports.

[59]  C. Chan,et al.  Aliskiren and losartan trial in non-diabetic chronic kidney disease , 2014, Journal of the renin-angiotensin-aldosterone system : JRAAS.

[60]  S. Yeh,et al.  Ocular Manifestations of Systemic Lupus Erythematosus: A Review of the Literature , 2012, Autoimmune diseases.

[61]  S. Sivak,et al.  Effect of angiotensin-converting enzyme inhibition in HIV-associated nephropathy. , 1997, Journal of the American Society of Nephrology : JASN.

[62]  J. Moon Recent Update of Renin-angiotensin-aldosterone System in the Pathogenesis of Hypertension , 2013, Electrolyte & blood pressure : E & BP.

[63]  Martin Paul,et al.  Physiology of local renin-angiotensin systems. , 2006, Physiological reviews.

[64]  K. Amann,et al.  Effect of a triple blockade of the renin‐angiotensin‐system in recurrent focal segmental glomerulosclerosis after kidney transplantation , 2009, Transplant international : official journal of the European Society for Organ Transplantation.

[65]  P. Singhal,et al.  Modulation of renin angiotensin system predominantly alters sclerotic phenotype of glomeruli in HIVAN. , 2014, Histology and histopathology.

[66]  Haifeng Guo,et al.  Excerpts from the United States Renal Data System 2004 annual data report: atlas of end-stage renal disease in the United States. , 2003, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[67]  K. Chow,et al.  Hong Kong study using valsartan in IgA nephropathy (HKVIN): a double-blind, randomized, placebo-controlled study. , 2004, American journal of kidney diseases : the official journal of the National Kidney Foundation.