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Future and Novel Compounds in the Treatment of Diabetic Nephropathy

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Diabetic Nephropathy

Abstract

Despite adequate lifestyle interventions, metabolic control, and the use of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II-receptor blockers (ARBs), the risk of progression to end-stage renal disease and development of cardiovascular (CV) events in patients with diabetic nephropathy (DN) remains very high. Various new drugs that may reduce renal and CV morbidity and mortality are currently in clinical development and are reviewed in this chapter. The failure of late-stage clinical trials in the past 15 years has, however, highlighted the need for adapted clinical trial designs that preselect patients based on their individual drug response, i.e., personalized medicine. The concept of personalized medicine is only in its infancy in DN clinical trials.

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References

  1. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861–9.

    Article  CAS  PubMed  Google Scholar 

  2. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851–60.

    Article  CAS  PubMed  Google Scholar 

  3. Viberti G, Mogensen CE, Groop LC, Pauls JF. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. European microalbuminuria captopril study group. JAMA. 1994;271(4):275–9.

    Article  CAS  PubMed  Google Scholar 

  4. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;1(3):1–150.

    Google Scholar 

  5. National Kidney Foundation. KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis. 2012;60:850–86.

    Article  Google Scholar 

  6. Heerspink HJ, de Zeeuw D. The kidney in type 2 diabetes therapy. Rev Diabet Stud. 2011;8(3):392–402.

    Article  PubMed  Google Scholar 

  7. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.

    Article  CAS  PubMed  Google Scholar 

  8. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644.

    Article  CAS  PubMed  Google Scholar 

  9. Eijkelkamp WB, Zhang Z, Remuzzi G, et al. Albuminuria is a target for renoprotective therapy independent from blood pressure in patients with type 2 diabetic nephropathy: post hoc analysis from the reduction of endpoints in NIDDM with the angiotensin II antagonist losartan (RENAAL) trial. J Am Soc Nephrol. 2007;18(5):1540–6.

    Article  CAS  PubMed  Google Scholar 

  10. Vallon V, Platt KA, Cunard R, et al. SGLT2 mediates glucose reabsorption in the early proximal tubule. J Am Soc Nephrol. 2011;22(1):104–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375(9733):2223–33.

    Article  CAS  PubMed  Google Scholar 

  12. Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91(2):733–94.

    Article  CAS  PubMed  Google Scholar 

  13. Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159(4):262–74.

    Article  PubMed  Google Scholar 

  14. Liakos A, Karagiannis T, Athanasiadou E, et al. Efficacy and safety of empagliflozin for type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2014;16(10):984–93.

    Article  CAS  PubMed  Google Scholar 

  15. Fujita Y, Inagaki N. Renal sodium glucose cotransporter 2 inhibitors as a novel therapeutic approach to treatment of type 2 diabetes: clinical data and mechanism of action. J Diabetes Investig. 2014;5(3):265–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cefalu WT, Leiter LA, Yoon KH, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet. 2013;382(9896):941–50.

    Article  CAS  PubMed  Google Scholar 

  17. Del Prato S, Nauck M, Duran-Garcia S, et al. Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add-on therapy to metformin in patients with type 2 diabetes: 4-year data. Diabetes Obes Metab. 2015;17(6):581–90.

    Article  PubMed  CAS  Google Scholar 

  18. Ridderstrale M, Andersen KR, Zeller C, et al. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol. 2014;2(9):691–700.

    Article  PubMed  CAS  Google Scholar 

  19. Wilding JP, Woo V, Soler NG, et al. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med. 2012;156(6):405–15.

    Article  PubMed  Google Scholar 

  20. Rosenstock J, Jelaska A, Frappin G, et al. Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes. Diabetes Care. 2014;37(7):1815–23.

    Article  CAS  PubMed  Google Scholar 

  21. Neal B, Perkovic V, de Zeeuw D, et al. Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes. Diabetes Care. 2015;38(3):403–11.

    Article  CAS  PubMed  Google Scholar 

  22. Vallon V, Muhlbauer B, Osswald H. Adenosine and kidney function. Physiol Rev. 2006;86(3):901–40.

    Article  CAS  PubMed  Google Scholar 

  23. Thomson SC, Rieg T, Miracle C, et al. Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat. Am J Physiol Regul Integr Comp Physiol. 2012;302(1):R75–83.

    Article  CAS  PubMed  Google Scholar 

  24. Lytvyn Y, Skrtic M, Yang GK, Yip PM, Perkins BA, Cherney DZ. Glycosuria-mediated urinary uric acid excretion in patients with uncomplicated type 1 diabetes mellitus. Am J Physiol Renal Physiol. 2015;308(2):F77–83.

    Article  CAS  PubMed  Google Scholar 

  25. Rajasekeran H, Lytvyn Y, Cherney DZ. Sodium-glucose cotransporter 2 inhibition and cardiovascular risk reduction in patients with type 2 diabetes: the emerging role of natriuresis. Kidney Int. 2016;89(3):524–6.

    Article  CAS  PubMed  Google Scholar 

  26. Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia. 2017;60(2):215–25.

    Article  CAS  PubMed  Google Scholar 

  27. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323–34.

    Article  CAS  PubMed  Google Scholar 

  28. Zanatta CM, Gerchman F, Burttet L, et al. Endothelin-1 levels and albuminuria in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract. 2008;80(2):299–304.

    Article  CAS  PubMed  Google Scholar 

  29. Mallamaci F, Parlongo S, Zoccali C. Influence of cardiovascular damage and residual renal function on plasma endothelin in chronic renal failure. Nephron. 1993;63(3):291–5.

    Article  CAS  PubMed  Google Scholar 

  30. Kohan DE, Rossi NF, Inscho EW, Pollock DM. Regulation of blood pressure and salt homeostasis by endothelin. Physiol Rev. 2011;91(1):1–77.

    Article  CAS  PubMed  Google Scholar 

  31. Kohan DE, Pollock DM. Endothelin antagonists for diabetic and non-diabetic chronic kidney disease. Br J Clin Pharmacol. 2013;76(4):573–9.

    CAS  PubMed  Google Scholar 

  32. Dhaun N, Goddard J, Webb DJ. The endothelin system and its antagonism in chronic kidney disease. J Am Soc Nephrol. 2006;17(4):943–55.

    Article  CAS  PubMed  Google Scholar 

  33. Barton M, d'Uscio LV, Shaw S, Meyer P, Moreau P, Luscher TF. ET(A) receptor blockade prevents increased tissue endothelin-1, vascular hypertrophy, and endothelial dysfunction in salt-sensitive hypertension. Hypertension. 1998;31(1 Pt 2):499–504.

    Article  CAS  PubMed  Google Scholar 

  34. Barton M. Reversal of proteinuric renal disease and the emerging role of endothelin. Nat Clin Pract Nephrol. 2008;4(9):490–501.

    Article  CAS  PubMed  Google Scholar 

  35. Mann JF, Green D, Jamerson K, et al. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol. 2010;21(3):527–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hoekman J, Lambers Heerspink HJ, Viberti G, Green D, Mann JF, de Zeeuw D. Predictors of congestive heart failure after treatment with an endothelin receptor antagonist. Clin J Am Soc Nephrol. 2014;9(3):490–8.

    Article  PubMed  PubMed Central  Google Scholar 

  37. de Zeeuw D, Coll B, Andress D, et al. The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy. J Am Soc Nephrol. 2014;25(5):1083–93.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Andress DL, Coll B, Pritchett Y, Brennan J, Molitch M, Kohan DE. Clinical efficacy of the selective endothelin A receptor antagonist, atrasentan, in patients with diabetes and chronic kidney disease (CKD). Life Sci. 2012;91(13–14):739–42.

    Article  CAS  PubMed  Google Scholar 

  39. Kohan DE, Pritchett Y, Molitch M, et al. Addition of atrasentan to renin-angiotensin system blockade reduces albuminuria in diabetic nephropathy. J Am Soc Nephrol. 2011;22(4):763–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gagliardini E, Corna D, Zoja C, et al. Unlike each drug alone, lisinopril if combined with avosentan promotes regression of renal lesions in experimental diabetes. Am J Physiol Renal Physiol. 2009;297(5):F1448–56.

    Article  CAS  PubMed  Google Scholar 

  41. Zoja C, Cattaneo S, Fiordaliso F, et al. Distinct cardiac and renal effects of ETA receptor antagonist and ACE inhibitor in experimental type 2 diabetes. Am J Physiol Renal Physiol. 2011;301(5):F1114–23.

    Article  CAS  PubMed  Google Scholar 

  42. Komers R, Gipson DS, Nelson P, et al. Efficacy and safety of sparsentan compared with irbesartan in patients with primary focal segmental glomerulosclerosis: Randomized, controlled trial design (DUET). Kidney Int Rep. 2017;2(4):654–64. https://doi.org/10.1016/j.ekir.2017.02.019.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Komers R, Shih A, Belder R. Antihypertensive effects of sparsentan, a dual angiotensin II and endothelin type A receptor antagonist. J Am Soc Nephrol. 2016;27:788A.

    Google Scholar 

  44. Sato A, Funder JW, Saruta T. Involvement of aldosterone in left ventricular hypertrophy of patients with end-stage renal failure treated with hemodialysis. Am J Hypertens. 1999;12(9 Pt 1):867–73.

    Article  CAS  PubMed  Google Scholar 

  45. Epstein M. Aldosterone as a mediator of progressive renal disease: Pathogenetic and clinical implications. Am J Kidney Dis. 2001;37(4):677–88.

    Article  CAS  PubMed  Google Scholar 

  46. Messaoudi S, Azibani F, Delcayre C, Jaisser F. Aldosterone, mineralocorticoid receptor, and heart failure. Mol Cell Endocrinol. 2012;350(2):266–72.

    Article  CAS  PubMed  Google Scholar 

  47. Staessen J, Lijnen P, Fagard R, Verschueren LJ, Amery A. Rise in plasma concentration of aldosterone during long-term angiotensin II suppression. J Endocrinol. 1981;91(3):457–65.

    Article  CAS  PubMed  Google Scholar 

  48. Schjoedt KJ, Andersen S, Rossing P, Tarnow L, Parving HH. 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(11):1936–9.

    Article  CAS  PubMed  Google Scholar 

  49. Sato A, Hayashi K, Naruse M, Saruta T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension. 2003;41(1):64–8.

    Article  CAS  PubMed  Google Scholar 

  50. Schjoedt KJ, Rossing K, Juhl TR, et al. Beneficial impact of spironolactone in diabetic nephropathy. Kidney Int. 2005;68(6):2829–36.

    Article  CAS  PubMed  Google Scholar 

  51. Bolignano D, Palmer SC, Navaneethan SD, Strippoli GF. Aldosterone antagonists for preventing the progression of chronic kidney disease. Cochrane Database Syst Rev. 2014;(4):CD007004. https://doi.org/10.1002/14651858.CD007004.pub3.

  52. Chrysostomou A, Becker G. Spironolactone in addition to ACE inhibition to reduce proteinuria in patients with chronic renal disease. N Engl J Med. 2001;345(12):925–6.

    Article  CAS  PubMed  Google Scholar 

  53. Epstein M, Williams GH, Weinberger M, et al. Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin J Am Soc Nephrol. 2006;1(5):940–51.

    Article  CAS  PubMed  Google Scholar 

  54. Rossing K, Schjoedt KJ, Smidt UM, Boomsma F, Parving HH. Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: a randomized, double-masked, cross-over study. Diabetes Care. 2005;28(9):2106–12.

    Article  CAS  PubMed  Google Scholar 

  55. Lazich I, Bakris GL. Prediction and management of hyperkalemia across the spectrum of chronic kidney disease. Semin Nephrol. 2014;34(3):333–9.

    Article  CAS  PubMed  Google Scholar 

  56. Miao Y, Dobre D, Heerspink HJ, et al. Increased serum potassium affects renal outcomes: a post hoc analysis of the reduction of endpoints in NIDDM with the angiotensin II antagonist losartan (RENAAL) trial. Diabetologia. 2011;54(1):44–50.

    Article  CAS  PubMed  Google Scholar 

  57. Bakris GL, Agarwal R, Chan JC, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. JAMA. 2015;314(9):884–94.

    Article  CAS  PubMed  Google Scholar 

  58. Andersen K, Hartman D, Peppard T, et al. The effects of aldosterone synthase inhibition on aldosterone and cortisol in patients with hypertension: a phase II, randomized, double-blind, placebo-controlled, multicenter study. J Clin Hypertens (Greenwich). 2012;14(9):580–7.

    Article  CAS  Google Scholar 

  59. Calhoun DA, White WB, Krum H, et al. Effects of a novel aldosterone synthase inhibitor for treatment of primary hypertension: results of a randomized, double-blind, placebo- and active-controlled phase 2 trial. Circulation. 2011;124(18):1945–55.

    Article  CAS  PubMed  Google Scholar 

  60. Karns AD, Bral JM, Hartman D, Peppard T, Schumacher C. Study of aldosterone synthase inhibition as an add-on therapy in resistant hypertension. J Clin Hypertens (Greenwich). 2013;15(3):186–92.

    Article  CAS  Google Scholar 

  61. Menne J, Eulberg D, Beyer D, et al. C-C motif-ligand 2 inhibition with emapticap pegol (NOX-E36) in type 2 diabetic patients with albuminuria. Nephrol Dial Transplant. 2017;32(2):307–15.

    PubMed  Google Scholar 

  62. de Zeeuw D, Bekker P, Henkel E, et al. The effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy: a randomised trial. Lancet Diabetes Endocrinol. 2015;3(9):687–96.

    Article  PubMed  CAS  Google Scholar 

  63. Voelker J, Berg PH, Sheetz M, et al. Anti-TGF-beta1 antibody therapy in patients with diabetic nephropathy. J Am Soc Nephrol. 2017;28(3):953–62.

    Article  PubMed  Google Scholar 

  64. Scheele W, Diamond S, Gale J, et al. Phosphodiesterase type 5 inhibition reduces albuminuria in subjects with overt diabetic nephropathy. J Am Soc Nephrol. 2016;27(11):3459–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Boustany-Kari CM, Harrison PC, Chen H, et al. A soluble guanylate cyclase activator inhibits the progression of diabetic nephropathy in the ZSF1 rat. J Pharmacol Exp Ther. 2016;356(3):712–9.

    Article  CAS  PubMed  Google Scholar 

  66. UK HARP-III Collaborative Group. Randomized multicentre pilot study of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease: United Kingdom heart and renal protection (HARP)- III-rationale, trial design and baseline data. Nephrol Dial Transplant. 2017;32(12):2043–51.

    Google Scholar 

  67. Chow F, Ozols E, Nikolic-Paterson DJ, Atkins RC, Tesch GH. Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury. Kidney Int. 2004;65(1):116–28.

    Article  CAS  PubMed  Google Scholar 

  68. Nguyen D, Ping F, Mu W, Hill P, Atkins RC, Chadban SJ. Macrophage accumulation in human progressive diabetic nephropathy. Nephrology (Carlton). 2006;11(3):226–31.

    Article  Google Scholar 

  69. Tziastoudi M, Stefanidis I, Hadjigeorgiou GM, Stravodimos K, Zintzaras E. A systematic review and meta-analysis of genetic association studies for the role of inflammation and the immune system in diabetic nephropathy. Clin Kidney J. 2017;10(3):293–300.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Abbate M, Zoja C, Remuzzi G. How does proteinuria cause progressive renal damage? J Am Soc Nephrol. 2006;17(11):2974–84.

    Article  CAS  PubMed  Google Scholar 

  71. Tesch GH. MCP-1/CCL2: a new diagnostic marker and therapeutic target for progressive renal injury in diabetic nephropathy. Am J Physiol Renal Physiol. 2008;294(4):F697–701.

    Article  CAS  PubMed  Google Scholar 

  72. Salmi M, Kalimo K, Jalkanen S. Induction and function of vascular adhesion protein-1 at sites of inflammation. J Exp Med. 1993;178(6):2255–60.

    Article  CAS  PubMed  Google Scholar 

  73. Berthier CC, Zhang H, Schin M, et al. Enhanced expression of janus kinase-signal transducer and activator of transcription pathway members in human diabetic nephropathy. Diabetes. 2009;58(2):469–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kuhrt D, Wojchowski DM. Emerging EPO and EPO receptor regulators and signal transducers. Blood. 2015;125(23):3536–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Fraser D, Brunskill N, Ito T, Phillips A. Long-term exposure of proximal tubular epithelial cells to glucose induces transforming growth factor-beta 1 synthesis via an autocrine PDGF loop. Am J Pathol. 2003;163(6):2565–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Garud MS, Kulkarni YA. Hyperglycemia to nephropathy via transforming growth factor beta. Curr Diabetes Rev. 2014;10(3):182–9.

    Article  CAS  PubMed  Google Scholar 

  77. Maile LA, Busby WH, Sitko K, et al. Insulin-like growth factor-I signaling in smooth muscle cells is regulated by ligand binding to the 177CYDMKTTC184 sequence of the beta3-subunit of alphaVbeta3. Mol Endocrinol. 2006;20(2):405–13.

    Article  CAS  PubMed  Google Scholar 

  78. Yoon S, Gingras D, Bendayan M. Alterations of vitronectin and its receptor alpha(v) integrin in the rat renal glomerular wall during diabetes. Am J Kidney Dis. 2001;38(6):1298–306.

    Article  CAS  PubMed  Google Scholar 

  79. Maile LA, Busby WH, Nichols TC, et al. A monoclonal antibody against alphaVbeta3 integrin inhibits development of atherosclerotic lesions in diabetic pigs. Sci Transl Med. 2010;2(18):18ra11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Maile LA, Gollahon K, Wai C, Dunbar P, Busby W, Clemmons D. Blocking alphaVbeta3 integrin ligand occupancy inhibits the progression of albuminuria in diabetic rats. J Diabetes Res. 2014;2014:421827.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Persson F, Rossing P, Hovind P, et al. Endothelial dysfunction and inflammation predict development of diabetic nephropathy in the irbesartan in patients with type 2 diabetes and microalbuminuria (IRMA 2) study. Scand J Clin Lab Invest. 2008;68(8):731–8.

    Article  CAS  PubMed  Google Scholar 

  82. Dellamea BS, Pinto LC, Leitao CB, Santos KG, Canani LH. Endothelial nitric oxide synthase gene polymorphisms and risk of diabetic nephropathy: a systematic review and meta-analysis. BMC Med Genet. 2014;15:9. https://doi.org/10.1186/1471-2350-15-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Hanai K, Babazono T, Nyumura I, et al. Asymmetric dimethylarginine is closely associated with the development and progression of nephropathy in patients with type 2 diabetes. Nephrol Dial Transplant. 2009;24(6):1884–8.

    Article  CAS  PubMed  Google Scholar 

  84. Lajer M, Tarnow L, Jorsal A, Teerlink T, Parving HH, Rossing P. Plasma concentration of asymmetric dimethylarginine (ADMA) predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy. Diabetes Care. 2008;31(4):747–52.

    Article  CAS  PubMed  Google Scholar 

  85. Shibata R, Ueda S, Yamagishi S, et al. Involvement of asymmetric dimethylarginine (ADMA) in tubulointerstitial ischaemia in the early phase of diabetic nephropathy. Nephrol Dial Transplant. 2009;24(4):1162–9.

    Article  CAS  PubMed  Google Scholar 

  86. Lewicki JA, Brandwein HJ, Mittal CK, Arnold WP, Murad F. Properties of purified soluble guanylate cyclase activated by nitric oxide and sodium nitroprusside. J Cyclic Nucleotide Res. 1982;8(1):17–25.

    CAS  PubMed  Google Scholar 

  87. Stasch JP, Schmidt PM, Nedvetsky PI, et al. Targeting the heme-oxidized nitric oxide receptor for selective vasodilatation of diseased blood vessels. J Clin Invest. 2006;116(9):2552–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Evgenov OV, Pacher P, Schmidt PM, Hasko G, Schmidt HH, Stasch JP. NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov. 2006;5(9):755–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation. 2011;123(20):2263–73.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Stasch JP, Dembowsky K, Perzborn E, Stahl E, Schramm M. Cardiovascular actions of a novel NO-independent guanylyl cyclase stimulator, BAY 41-8543: in vivo studies. Br J Pharmacol. 2002;135(2):344–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Dautzenberg M, Keilhoff G, Just A. Modulation of the myogenic response in renal blood flow autoregulation by NO depends on endothelial nitric oxide synthase (eNOS), but not neuronal or inducible NOS. J Physiol. 2011;589(Pt 19):4731–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Just A, Arendshorst WJ. Nitric oxide blunts myogenic autoregulation in rat renal but not skeletal muscle circulation via tubuloglomerular feedback. J Physiol. 2005;569(Pt 3):959–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Shi Y, Wang X, Chon KH, Cupples WA. Tubuloglomerular feedback-dependent modulation of renal myogenic autoregulation by nitric oxide. Am J Physiol Regul Integr Comp Physiol. 2006;290(4):R982–91.

    Article  CAS  PubMed  Google Scholar 

  94. Dautzenberg M, Kahnert A, Stasch JP, Just A. Role of soluble guanylate cyclase in renal hemodynamics and autoregulation in the rat. Am J Physiol Renal Physiol. 2014;307(9):F1003–12.

    Article  CAS  PubMed  Google Scholar 

  95. Erdmann E, Semigran MJ, Nieminen MS, et al. Cinaciguat, a soluble guanylate cyclase activator, unloads the heart but also causes hypotension in acute decompensated heart failure. Eur Heart J. 2013;34(1):57–67.

    Article  CAS  PubMed  Google Scholar 

  96. Gheorghiade M, Greene SJ, Filippatos G, et al. Cinaciguat, a soluble guanylate cyclase activator: results from the randomized, controlled, phase IIb COMPOSE programme in acute heart failure syndromes. Eur J Heart Fail. 2012;14(9):1056–66.

    Article  CAS  PubMed  Google Scholar 

  97. Lapp H, Mitrovic V, Franz N, et al. Cinaciguat (BAY 58-2667) improves cardiopulmonary hemodynamics in patients with acute decompensated heart failure. Circulation. 2009;119(21):2781–8.

    Article  CAS  PubMed  Google Scholar 

  98. Benz K, Orth SR, Simonaviciene A, et al. Blood pressure-independent effect of long-term treatment with the soluble heme-independent guanylyl cyclase activator HMR1766 on progression in a model of noninflammatory chronic renal damage. Kidney Blood Press Res. 2007;30(4):224–33.

    Article  CAS  PubMed  Google Scholar 

  99. Kalk P, Godes M, Relle K, et al. NO-independent activation of soluble guanylate cyclase prevents disease progression in rats with 5/6 nephrectomy. Br J Pharmacol. 2006;148(6):853–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Fang L, Radovits T, Szabo G, Mozes MM, Rosivall L, Kokeny G. Selective phosphodiesterase-5 (PDE-5) inhibitor vardenafil ameliorates renal damage in type 1 diabetic rats by restoring cyclic 3′,5′ guanosine monophosphate (cGMP) level in podocytes. Nephrol Dial Transplant. 2013;28(7):1751–61.

    Article  CAS  PubMed  Google Scholar 

  101. Kuno Y, Iyoda M, Shibata T, Hirai Y, Akizawa T. Sildenafil, a phosphodiesterase type 5 inhibitor, attenuates diabetic nephropathy in non-insulin-dependent otsuka long-Evans Tokushima fatty rats. Br J Pharmacol. 2011;162(6):1389–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Lau DH, Mikhailidis DP, Thompson CS. The effect of vardenafil (a PDE type 5 inhibitor) on renal function in the diabetic rabbit: a pilot study. In Vivo. 2007;21(5):851–4.

    CAS  PubMed  Google Scholar 

  103. Grover-Paez F, Villegas Rivera G, Guillen OR. Sildenafil citrate diminishes microalbuminuria and the percentage of A1c in male patients with type 2 diabetes. Diabetes Res Clin Pract. 2007;78(1):136–40.

    Article  CAS  PubMed  Google Scholar 

  104. Judge P, Haynes R, Landray MJ, Baigent C. Neprilysin inhibition in chronic kidney disease. Nephrol Dial Transplant. 2015;30(5):738–43.

    Article  CAS  PubMed  Google Scholar 

  105. Potter LR. Natriuretic peptide metabolism, clearance and degradation. FEBS J. 2011;278(11):1808–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kahn JC, Patey M, Dubois-Rande JL, et al. Effect of sinorphan on plasma atrial natriuretic factor in congestive heart failure. Lancet. 1990;335(8681):118–9.

    Article  CAS  PubMed  Google Scholar 

  107. Northridge DB, Jardine AG, Alabaster CT, et al. Effects of UK 69 578: a novel atriopeptidase inhibitor. Lancet. 1989;2(8663):591–3.

    Article  CAS  PubMed  Google Scholar 

  108. Dalzell JR, Seed A, Berry C, et al. Effects of neutral endopeptidase (neprilysin) inhibition on the response to other vasoactive peptides in small human resistance arteries: studies with thiorphan and omapatrilat. Cardiovasc Ther. 2014;32(1):13–8.

    Article  CAS  PubMed  Google Scholar 

  109. Ferro CJ, Spratt JC, Haynes WG, Webb DJ. Inhibition of neutral endopeptidase causes vasoconstriction of human resistance vessels in vivo. Circulation. 1998;97(23):2323–30.

    Article  CAS  PubMed  Google Scholar 

  110. Mitchell GF, Izzo JL Jr, Lacourciere Y, et al. Omapatrilat reduces pulse pressure and proximal aortic stiffness in patients with systolic hypertension: results of the conduit hemodynamics of omapatrilat international research study. Circulation. 2002;105(25):2955–61.

    Article  CAS  PubMed  Google Scholar 

  111. von Lueder TG, Atar D, Krum H. Current role of neprilysin inhibitors in hypertension and heart failure. Pharmacol Ther. 2014;144(1):41–9.

    Article  CAS  Google Scholar 

  112. Kostis JB, Packer M, Black HR, Schmieder R, Henry D, Levy E. Omapatrilat and enalapril in patients with hypertension: the omapatrilat cardiovascular treatment vs. enalapril (OCTAVE) trial. Am J Hypertens. 2004;17(2):103–11.

    Article  CAS  PubMed  Google Scholar 

  113. Pickering TG. Effects of stress and behavioral interventions in hypertension: the rise and fall of omapatrilat. J Clin Hypertens (Greenwich). 2002;4(5):371–3.

    Article  Google Scholar 

  114. Solomon SD, Skali H, Bourgoun M, et al. Effect of angiotensin-converting enzyme or vasopeptidase inhibition on ventricular size and function in patients with heart failure: the omapatrilat versus enalapril randomized trial of utility in reducing events (OVERTURE) echocardiographic study. Am Heart J. 2005;150(2):257–62.

    Article  CAS  PubMed  Google Scholar 

  115. Solomon SD, Claggett B, Desai AS, et al. Influence of ejection fraction on outcomes and efficacy of sacubitril/valsartan (LCZ696) in heart failure with reduced ejection fraction: the prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure (PARADIGM-HF) trial. Circ Heart Fail. 2016;9(3):e002744.

    Article  CAS  PubMed  Google Scholar 

  116. Benigni A, Zoja C, Zatelli C, et al. Vasopeptidase inhibitor restores the balance of vasoactive hormones in progressive nephropathy. Kidney Int. 2004;66(5):1959–65.

    Article  CAS  PubMed  Google Scholar 

  117. Cheng ZJ, Gronholm T, Louhelainen M, et al. Vascular and renal effects of vasopeptidase inhibition and angiotensin-converting enzyme blockade in spontaneously diabetic goto-kakizaki rats. J Hypertens. 2005;23(9):1757–70.

    Article  CAS  PubMed  Google Scholar 

  118. Roksnoer LC, van Veghel R, van Groningen MC, de Vries R, Garrelds IM, Bhaggoe UM. Blood pressure-independent renoprotection in diabetic rats treated with AT1 receptor-neprilysin inhibition compared with AT1 receptor blockade alone. Clin Sci (Lond). 2016;130(14):1209–20.

    Article  CAS  Google Scholar 

  119. Suematsu Y, Miura S, Goto M, et al. LCZ696, an angiotensin receptor-neprilysin inhibitor, improves cardiac function with the attenuation of fibrosis in heart failure with reduced ejection fraction in streptozotocin-induced diabetic mice. Eur J Heart Fail. 2016;18(4):386–93.

    Article  CAS  PubMed  Google Scholar 

  120. Taal MW, Nenov VD, Wong W, et al. Vasopeptidase inhibition affords greater renoprotection than angiotensin-converting enzyme inhibition alone. J Am Soc Nephrol. 2001;12(10):2051–9.

    CAS  PubMed  Google Scholar 

  121. Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367(23):2204–13.

    Article  CAS  PubMed  Google Scholar 

  122. de Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med. 2013;369(26):2492–503.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Miao Y, Ottenbros SA, Laverman GD, et al. Effect of a reduction in uric acid on renal outcomes during losartan treatment: a post hoc analysis of the reduction of endpoints in non-insulin-dependent diabetes mellitus with the angiotensin II antagonist losartan trial. Hypertension. 2011;58(1):2–7.

    Article  CAS  PubMed  Google Scholar 

  124. de Zeeuw D, Remuzzi G, Parving HH, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int. 2004;65(6):2309–20.

    Article  PubMed  Google Scholar 

  125. Smink PA, Miao Y, Eijkemans MJ, et al. The importance of short-term off-target effects in estimating the long-term renal and cardiovascular protection of angiotensin receptor blockers. Clin Pharmacol Ther. 2014;95(2):208–15.

    Article  CAS  PubMed  Google Scholar 

  126. Schievink B, Grobbee D, Michael Lincoff A. Heart failure induced by aleglitazar treatment can be predicted based on short-term response in multiple risk markers. Submitted for publication.

    Google Scholar 

  127. Smink PA, Hoekman J, Grobbee DE, et al. A prediction of the renal and cardiovascular efficacy of aliskiren in ALTITUDE using short-term changes in multiple risk markers. Eur J Prev Cardiol. 2014;21(4):434–41.

    Article  CAS  PubMed  Google Scholar 

  128. Schievink B, de Zeeuw D, Parving HH, Rossing P, Lambers Heerspink HJ. The renal protective effect of angiotensin receptor blockers depends on intra-individual response variation in multiple risk markers. Br J Clin Pharmacol. 2015;80(4):678–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. de Zeeuw D, Heerspink HJL, Jardine M. Perkovic, vol. V. Renal trials in diabetes need a platform: time for a global approach? Lancet Diabetes Endocrinol; 2017;6(5):356–8.

    Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Nienke M. A. Idzerda, Michelle J. Pena, Dick de Zeeuw & Hiddo J. L. Heerspink

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  1. Nienke M. A. Idzerda
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  2. Michelle J. Pena
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  3. Dick de Zeeuw
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  4. Hiddo J. L. Heerspink
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  1. Department of Pathology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands

    Joris J. Roelofs

  2. Department of Internal Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands

    Liffert Vogt

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Idzerda, N.M.A., Pena, M.J., de Zeeuw, D., Heerspink, H.J.L. (2019). Future and Novel Compounds in the Treatment of Diabetic Nephropathy. In: Roelofs, J., Vogt, L. (eds) Diabetic Nephropathy. Springer, Cham. https://doi.org/10.1007/978-3-319-93521-8_29

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