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Emerging therapies for chronic kidney disease: what is their role?

Abstract

The prevalence of chronic kidney disease (CKD) is increasing worldwide. The best therapies currently available focus on the control of blood pressure and optimization of renin–angiotensin–aldosterone system blockade. Currently available agents are only partially effective against hard end points such as the development of end-stage renal disease and are not discussed in this Review. Many other agents have been shown to reduce proteinuria and delay progression in animal models of CKD. Some of these agents, including tranilast, sulodexide, thiazolidinediones, pentoxifylline, and inhibitors of advanced glycation end-products and protein kinase C, have been tested to a limited extent in humans. A small number of randomized controlled human trials of these agents have used surrogate markers such as proteinuria as end points rather than hard end points such as end-stage renal disease or doubling of serum creatinine level. Emerging therapies that specifically target and reverse pathological hallmarks of CKD such as inflammation, fibrosis and atrophy are needed to reduce the burden of this chronic disease and its associated morbidity. This Review examines the evidence for emerging pharmacological strategies for slowing the progression of CKD.

Key Points

  • Agents that block the renin–angiotensin–aldosterone system are the best of the currently available evidence-based therapies for slowing progression of chronic kidney disease (CKD), but are only partially effective

  • Many emerging therapies have shown promise in animal models of CKD, but have been less effective in humans

  • Regression of CKD in humans is rare

  • In the future, endothelin-receptor antagonists, agents that inhibit advanced glycation end-products and agents that reduce inflammation (for example, vitamin D and statins) might be useful in the treatment of human CKD

  • Experimental agents such as transforming growth factor β inhibitors, other growth factor inhibitors, small molecule inhibitors and cytokine inhibitors might also be useful in CKD in the future

  • All new therapies in CKD should be tested in conjunction with blockade of the renin–angiotensin–aldosterone system

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Figure 1: Kaplan–Meier curve showing the percentage of patients in the Reduction of Endpoints in NIDDM with Angiotensin II Receptor Antagonist Losartan (RENAAL) study reaching the end point of ESRD.

References

  1. 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).

    CAS  Article  Google Scholar 

  2. 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).

    CAS  Article  Google Scholar 

  3. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Randomised placebo controlled trial of the effect of Ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 349, 1857–1863 (1997).

  4. Nakao, N. et al. Combination treatment of angiotensin-ll receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 361, 117–124 (2003).

    CAS  Article  Google Scholar 

  5. Catapano, F. et al. Anti-proteinuric response to dual blockade of renin-angiotensin system in primary glomerulonephritis: meta-analysis and metaregression. Am. J. Kidney Dis. 52, 475–485 (2008).

    Article  Google Scholar 

  6. Mann, J. F. E. et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET STUDY): a multicentre randomised controlled trial. Lancet 372, 547–553 (2008).

    CAS  Article  Google Scholar 

  7. Kelly, D. J., Zhang, Y., Gow, R. & Gilbert, R. E. Tranilast attenuates structural and functional aspects of renal injury in the remnant kidney model. J. Am. Soc. Nephrol. 15, 2619–2629 (2004).

    CAS  Article  Google Scholar 

  8. Soma, J., Sugawara, T., Huang, Y. D., Nakajima, J. & Kawamura, M. Tranilast slows the progression of advanced diabetic nephropathy. Nephron 92, 693–698 (2002).

    CAS  Article  Google Scholar 

  9. Soma, J., Sato, K., Saito, H. & Tsuchiya, Y. Effects of tranilast in early stage diabetic nephropathy. Nephrol. Dial. Transplant. 21, 2795–2799 (2006).

    CAS  Article  Google Scholar 

  10. Holmes, D. R. et al. Results of Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) trial. Circulation 106, 1243–1250 (2002).

    Article  Google Scholar 

  11. Tamsma, J. T. et al. Expression of glomerular extracellular matrix components in human diabetic nephropathy: decrease of heparan sulphate in glomerular basement membrane. Diabetologia 37, 313–320 (1994).

    CAS  Article  Google Scholar 

  12. Gambaro, G. et al. Treatment with a glycosaminoglycan formulation ameliorates experimental diabetic nephropathy. Kidney Int. 46, 797–806 (1994).

    CAS  Article  Google Scholar 

  13. Soloni, A., Vergnani, L., Ricci, F. & Crepaldi, G. Glycosaminoglycans delay the progression of nephropathy in NIDDM. Diabetes Care 20, 819–823 (1997).

    Article  Google Scholar 

  14. Dedov, I., Shestakova, M., Vorontzov, A. & Palazzini, E. A randomized, controlled study of sulodexide therapy for the treatment of diabetic nephropathy. Nephrol. Dial. Transplant. 12, 2295–2300 (1997).

    CAS  Article  Google Scholar 

  15. Gambaro, G. et al. Oral sulodexide reduces albuminuria in microalbuminuric and macroalbuminuric type 1 and type 2 diabetic patients: the Di.N. A.S. randomized trial. J. Am. Soc. Nephrol. 13, 1615–1625 (2002).

    CAS  Article  Google Scholar 

  16. Heerspink, H. L. et al. Effects of sulodexide in patients with type 2 diabetes and persistent albuminuria. Nephrol. Dial. Transplant. 23, 1946–1954 (2008).

    CAS  Article  Google Scholar 

  17. http://www.drugs.com/clinical_trials/keryx-biopharmaceuticals-announces -sun-micro-phase-3-clinical-trial-fails-meet-primary-efficiacy-3536.html (2008).

  18. http://www.drugs.com/clinical_trials/keryx-biopharmaceuticals-announces -termination-sun-macro-phase-4-trial-3677.html (2008).

  19. Forbes, J. M. et al. Role of advanced glycation end products in diabetic nephropathy. J. Am. Soc. Nephrol. 14, S254–S258 (2003).

    CAS  Article  Google Scholar 

  20. Thomas, M. C., Forbes, J. M. & Cooper, M. E. Advance glycation end products and diabetic nephropathy. Am. J. Ther. 12, 562–572 (2005).

    Article  Google Scholar 

  21. Bolton, W. K. et al. Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am. J. Nephrol. 24, 32–40 (2004).

    CAS  Article  Google Scholar 

  22. Freedman, B. I. et al. Design and baseline characteristics for aminoguanidine clinical trial in overt type 2 diabetic nephropathy (ACTION II). Control. Clin. Trials 20, 493–510 (1999).

    CAS  Article  Google Scholar 

  23. Forbes, J. M. et al. Renoprotective effects of a novel inhibitor of advanced glycation. Diabetologia 44, 108–114 (2001).

    CAS  Article  Google Scholar 

  24. Miyata, T. et al. Angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors lower in vitro formation of advanced glycation end products: biochemical mechanisms. J. Am. Soc. Nephrol. 13, 2478–2487 (2002).

    CAS  Article  Google Scholar 

  25. Forbes, J. M. et al. Reduction of the accumulation of advanced glycation end products by ACE inhibition in experimental diabetic nephropathy. Diabetes 51, 3274–3282 (2002).

    CAS  Article  Google Scholar 

  26. Williams, M. E. et al. Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy. Am. J. Nephrol. 27, 605–614 (2007).

    CAS  Article  Google Scholar 

  27. 6-Month safety and efficacy study of TTP488 in patients with type 2 diabetes and persistent albuminuria [online]

  28. Burns, W. C. et al. Connective tissue growth factor plays an important role in advanced glycation end product induced-tubular epithelial-to-mesenchymal transition: implications for diabetic renal disease. J. Am. Soc. Nephrol. 17, 2484–2494 (2006).

    CAS  Article  Google Scholar 

  29. Adler, S. G. et al. Dose-escalation phase 1 study of FG-3019, anti-CTGF monoclonal antibody, in subjects with type I/II diabetes mellitus and microalbuminuria. J. Am. Soc. Nephrol. 17, 157A (2006).

    Article  Google Scholar 

  30. Peppa, M. et al. Prevention and reversal of diabetic nephropathy in db/db mice treated with Alagebrium (ALT-711). Am. J. Nephrol. 26, 430–436 (2006).

    CAS  Article  Google Scholar 

  31. Coughlan, M. T. et al. Role of the AGE crosslink breaker, alagebrium, as a renoprotective agent in diabetes. Kidney Int. 72, S54–S60 (2007).

    Article  Google Scholar 

  32. Zieman, S. J. et al. Advanced glycation end product crosslink breaker (alagebrium) improves endothelial function in patients with isolated systolic hypertension. J. Hypertens. 25, 577–583 (2007).

    CAS  Article  Google Scholar 

  33. Swaminathan, S. & Shah, S. V. Novel approaches targeted toward oxidative stress for the treatment of chronic kidney disease. Curr. Opin. Nephrol. Hypertens. 17, 143–148 (2008).

    CAS  Article  Google Scholar 

  34. Tuttle, K. R. et al. The effect of ruboxistaurin on nephropathy in type 2 diabetes. Diabetes Care 28, 2686–2690 (2005).

    CAS  Article  Google Scholar 

  35. Tuttle, K. R. et al. Kidney outcomes in long-term studies of ruboxistaurin for diabetic eye disease. Clin. J. Am. Soc. Nephrol. 2, 631–636 (2007).

    CAS  Article  Google Scholar 

  36. Agarwal, R. et al. A pilot randomized controlled trial of renal protection with pioglitazone in diabetic nephropathy. Kidney Int. 68, 285–292 (2005).

    CAS  Article  Google Scholar 

  37. Bakris, G. L. et al. Rosiglitazone reduces microalbuminuria and blood pressure independently of glycemia in type 2 diabetes patients with microalbuminuria. J. Hypertens. 24, 2047–2055 (2006).

    CAS  Article  Google Scholar 

  38. Kincaid-Smith, P., Fairley, K. F., Farish, S., Best, J. D. & Proietto, J. Reduction of proteinuria by rosiglitazone in non-diabetic renal disease. Nephrology (Carlton) 13, 58–62 (2008).

    CAS  Article  Google Scholar 

  39. Pistrosch, F. et al. Rosiglitazone improves glomerular hyperfiltration, renal endothelial dysfunction and microalbuminuria of incipient diabetic nephropathy in patients. Diabetes 54, 2206–2211 (2005).

    CAS  Article  Google Scholar 

  40. Guo, B. et al. Peroxisome proliferator-activated receptor-γ ligands inhibit TGF-β1-induced fibronectin expression in glomerular mesangial cells. Diabetes 53, 200–208 (2004).

    CAS  Article  Google Scholar 

  41. Nissen, S. E. & Wolski, K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med. 356, 2457–2471 (2007).

    CAS  Article  Google Scholar 

  42. Home, P. et al. Rosiglitazone evaluated for cardiovascular outcomes—an interim analysis. N. Engl. J. Med. 357, 28–38 (2007).

    CAS  Article  Google Scholar 

  43. Chen, Y. M., Lin, S. L., Chiang, W. C., Wu, K. D. & Tsai, T. J. Pentoxifylline ameliorates proteinuria through suppression of renal monocyte chemoattractant protein-1 in patients with proteinuric primary glomerular diseases. Kidney Int. 69, 1410–1415 (2006).

    CAS  Article  Google Scholar 

  44. Navarro, J. F., Mora, C., Muros, M. & García, J. Additive anti-proteinuric effect of pentoxifylline in patients with type 2 diabetes under angiotensin-2 receptor blockade: a short-term, randomized, controlled trial. J. Am. Soc. Nephrol. 16, 2119–2126 (2005).

    CAS  Article  Google Scholar 

  45. Lin, S. L., Chen, Y. M., Chiang, W. C., Wu, K. D. & Tsai, T. J. Effect of pentoxifylline in addition to losartan on proteinuria and GFR in CKD: a 12 month randomized trial. Am. J. Kidney Dis. 52, 464–474 (2008).

    CAS  Article  Google Scholar 

  46. McCormick, B. B. et al. The effect of pentoxifylline on proteinuria in diabetic kidney disease: a meta-analysis. Am. J. Kidney Dis. 54, 454–463 (2008).

    Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  48. Morigi, M. et al. Shigatoxin-induced endothelin-1 expression in cultured podocytes autocrinally mediates actin remodeling. Am. J. Pathol. 169, 1965–1975 (2006).

    CAS  Article  Google Scholar 

  49. Morigi, M. et al. In response to protein load podocytes reorganize cytoskeleton and modulate endothelin-1 gene: implication of permselective dysfunction of chronic nephropathies. Am. J. Pathol. 166, 1309–1320 (2005).

    CAS  Article  Google Scholar 

  50. Opocensky, M. et al. Late onset endothelin-A receptor blockade reduces podocyte injury in homozygous Ren-2 rats despite severe hypertension. Hypertension 48, 965–971 (2006).

    CAS  Article  Google Scholar 

  51. Ortmann, J. et al. Role of podocytes for reversal of glomerulosclerosis and proteinuria in ageing the kidney after endothelin inhibition. Hypertension 44, 974–981 (2004).

    CAS  Article  Google Scholar 

  52. Honing, M. L. et al. Selective ETA receptor antagonism with ABT-627 attenuated all renal effects of endothelin in humans. J. Am. Soc. Nephrol. 11, 1498–1504 (2000).

    CAS  PubMed  Google Scholar 

  53. Wenzel, R. R. et al. Avosentan reduces albumin excretion in diabetics with microalbuminuria. J. Am. Soc. Nephrol. 20, 655–664 (2009).

    Article  Google Scholar 

  54. Viberti, G. SPP301 (avosentan) ASCEND clinical results [online] (2008).

  55. Black, H. R. et al. Efficacy and safety of darusentan in patients with resistant hypertension: results from a randomized, double-blind, placebo-controlled dose-ranging study. J. Clin. Hypertens. (Greenwich) 9, 760–769 (2007).

    CAS  Article  Google Scholar 

  56. Campese, V. M., Nadim, M. K. & Epstein, M. Are 3-hydroxy-3-methylglutaryl-coA reductase inhibitors renoprotective? J. Am. Soc. Nephrol. 16, S11–S17 (2005).

    CAS  Article  Google Scholar 

  57. Athyros, V. G. et al. The effects of statins versus untreated dyslipidemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study. J. Clin. Pathol. 57, 728–734 (2004).

    CAS  Article  Google Scholar 

  58. Sandhu, S., Wiebe, N., Fried, L. F. & Tonelli, M. Statins for improving renal outcomes: a meta-analysis. J. Am. Soc. Nephrol. 16, 2006–2016 (2006).

    Article  Google Scholar 

  59. Douglas, K., O'Malley, P. G. & Jackson, J. L. Meta-analysis: The effect of statins on albuminuria. Ann. Intern. Med. 145, 117–124 (2006).

    CAS  Article  Google Scholar 

  60. Strippoli, G. F. et al. Effects of statins in patients with chronic kidney disease: Meta-analysis and meta-regression of randomised controlled trials. BMJ 336, 645–651 (2008).

    CAS  Article  Google Scholar 

  61. Kuriyama, S. et al. Reversal of anemia by erythropoietin therapy retards progression of chronic kidney failure, especially in nondiabetic patients. Nephron 77, 176–185 (1997).

    CAS  Article  Google Scholar 

  62. Gouva, C., Nikolopoulos, P., Ioannidis, J. P. & Siamopoulos, K. C. Treating anemia early in renal failure patients slows the decline of renal function: a randomized controlled trial. Kidney Int. 66, 753–760 (2004).

    Article  Google Scholar 

  63. Drüeke, T. B. et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N. Engl. J. Med. 355, 2071–2084 (2006).

    Article  Google Scholar 

  64. Singh, A. K. et al. Correction of anemia with epoetin alpha in chronic kidney disease. N. Engl. J. Med. 355, 2085–2098 (2006).

    CAS  Article  Google Scholar 

  65. Carlini, R. G. et al. Effect of recombinant human erythropoietin on endothelial cell apoptosis. Kidney Int. 55, 546–553 (1999).

    CAS  Article  Google Scholar 

  66. Pfeffer, M. A. Critical missing data on erythropoiesis-stimulating agents in CKD: first beat placebo. Am. J. Kidney Dis. 51, 366–369 (2008).

    Article  Google Scholar 

  67. Szeto, C. C. et al. Oral calcitriol for the treatment of persistent proteinuria in IgA nephropathy: an uncontrolled trial. Am. J. Kidney Dis. 51, 724–731 (2008).

    CAS  Article  Google Scholar 

  68. Agarwal, R. et al. Antiproteinuric effect of oral paricalcitol in chronic kidney disease. Kidney Int. 68, 2823–2828 (2005).

    CAS  Article  Google Scholar 

  69. Alborzi, P. et al. Paricalcitol reduces albuminuria and inflammation in patients with chronic kidney disease: a randomized double-blind pilot trial. Hypertension 52, 249–255 (2008).

    CAS  Article  Google Scholar 

  70. Shoben, A. B. et al. Association of oral calcitriol with improved survival in nondialyzed CKD. J. Am. Soc. Nephrol. 19, 1613–1619 (2008).

    CAS  Article  Google Scholar 

  71. Shillingford, J. M. et al. The m-TOR pathway is regulated by polycystin-1 and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc. Natl Acad. Sci. USA 103, 5466–5471 (2006).

    CAS  Article  Google Scholar 

  72. Qian, Q. et al. Sirolimus reduces polycystic liver volume in ADPKD patients. J. Am. Soc. Nephrol. 19, 631–638 (2008).

    CAS  Article  Google Scholar 

  73. Tao, Y. et al. Pathways of caspase-mediated apoptosis in autosomal dominant polycystic kidney disease (ADPKD). Kidney Int. 67, 909–919 (2005).

    CAS  Article  Google Scholar 

  74. Edelstein, C. L. Mammalian target of rapamycin and caspase inhibitors in polycystic kidney disease. Clin. J. Am. Soc. Nephrol. 3, 1219–1226 (2008).

    CAS  Article  Google Scholar 

  75. Torres, V. E. Role of vasopressin antagonists. Clin. J. Am. Soc. Nephrol. 3, 1212–1218 (2008).

    CAS  Article  Google Scholar 

  76. Chapman, A. B. Autosomal dominant polycystic kidney disease: time for a change? J. Am. Soc. Nephrol. 18, 1399–1407 (2007).

    CAS  Article  Google Scholar 

  77. Gattone, V. H., Wang, X., Harris, P. C. & Torres, V. E. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat. Med. 9, 1323–1326 (2003).

    CAS  Article  Google Scholar 

  78. Torres, V. E. et al. Phase 2 open label study to determine long term safety, tolerability and efficacy of split-dose tolvaptan in ADPKD [abstract]. J. Am. Soc. Nephrol. 18, 361A–362A (2007).

    Google Scholar 

  79. Torres, V. E. et al. “TEMPO 3/4 Trial” tolvaptan efficacy and safety in the management of polycystic kidney disease and its outcomes (TEMPO3/4) [online] (2008).

  80. Ruggenenti, P. et al. Safety and efficacy of long-acting somatostatin treatment in autosomal dominant polycystic kidney disease. Kidney Int. 68, 206–216 (2005).

    CAS  Article  Google Scholar 

  81. Wang, S. et al. Renal bone morphogenic protein-7 protects against diabetic nephropathy. J. Am. Soc. Nephrol. 17, 2504–2512 (2006).

    CAS  Article  Google Scholar 

  82. Zeisberg, M. et al. Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models. Am. J. Physiol. Renal Physiol. 285, F1060–F1067 (2003).

    CAS  Article  Google Scholar 

  83. Jung, D. S. et al. FR167653 inhibits fibronectin expression and apoptosis in diabetic glomeruli and in high-glucose-stimulated mesangial cells. Am. J. Physiol. Renal Physiol. 295, F595–F604 (2008).

    CAS  Article  Google Scholar 

  84. Ninichuk, V. et al. Multipotent mesenchymal stem cells reduce interstitial fibrosis but do not delay progression of chronic kidney disease collagen 4A3-deficient mice. Kidney Int. 70, 121–129 (2006).

    CAS  Article  Google Scholar 

  85. Ohtake, T. et al. Pathological regression by angiotensin ll type 1 receptor blocker in patients with mesangial proliferative glomerulonephritis. Hypertens. Res. 31, 387–394 (2008).

    CAS  Article  Google Scholar 

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Vilayur, E., Harris, D. Emerging therapies for chronic kidney disease: what is their role?. Nat Rev Nephrol 5, 375–383 (2009). https://doi.org/10.1038/nrneph.2009.76

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