Diabetic nephropathy is the commonest cause of end-stage renal disease and affects between 30 and 45% of patients with diabetes mellitus. There is no cure for diabetic nephropathy and the current management of this condition includes glycaemic control, blockade of the renin-angiotensin aldosterone system and lifestyle changes. However, many patients eventually progress to end-stage renal disease. The exact pathogenesis of diabetic nephropathy is still being researched, and recent advances have led to the development of several novel potential therapeutic targets. There are a number of different experimental therapies that are currently being assessed. Generally, these can be separated into drugs targeting vasculature/haemodynamic effects, drugs targeting inflammation and drugs targeting oxidative stress. Drugs targeting the vasculature include Tie-2 activators, -sodium-glucose transport protein 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) agonists. Anti-inflammatory therapies include inflammatory cytokines inhibitors, pentoxifylline, as well as anti-transforming growth factor α/-epiregulin therapies. Finally, anti-oxidative stress therapies include nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors and allopurinol. Many new trials are providing promising results and it is likely that some of these therapies will be available for clinical use within the next decade. This article will seek to outline the main advancements in each of these experimental therapies for diabetic nephropathy. Results: Abnormal vascular remodelling, inflammation and oxidative stress seem to be the 3 main sources from which future new drugs for diabetic kidney disease will originate.

1.
Gnudi L, GentileG, Ruggenenti P: The Patient with Diabetes Mellitus; in Turner N, Lamiere N, Goldsmith DJ,Wineearls CG, Himmelfarb J, Remuzzi G (ed): Oxford Textbook of Clinical Nephrology. Oxford, UK, Oxford University Press, 2016, vol. 2, pp 1199–1247.
2.
Campochiaro PA, Khanani A, Singer M, Patel S, Boyer D, Dugel P, Kherani S, Withers B, Gambino L, Peters K, Brigell M; TIME-2 Study Group: Enhanced benefit in diabetic macular edema from AKB-9778 Tie2 Activation combined with vascular endothelial growth factor suppression. Ophthalmology 2016; 123: 1722–1730.
3.
Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB; LEADER Steering Committee; LEADER Trial Investigators: Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375: 311–322.
4.
Mann JFE, Orsted DD, Brown-Frandsen K, Marso SP, Poulter NR, Rasmussen S, Tornoe K, Zinman B, Buse JB, LEADER Steering Committee and Investigators: Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med 2017; 377: 839–848.
5.
DeFronzo RA, Norton L, Abdul-Ghani M: Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol 2017; 13: 11–26.
6.
Sullivan T, Miao Z, Dairaghi DJ, Krasinski A, Wang Y, Zhao BN, Baumgart T, Ertl LS, Pennell A, Seitz L, Powers J, Zhao R, Ungashe S, Wei Z, Boring L, Tsou CL, Charo I, Berahovich RD, Schall TJ, Jaen JC: CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice. Am J Physiol Renal Physiol 2013; 305:F1288–1297.
7.
de Zeeuw D, Bekker P, Henkel E, Hasslacher C, Gouni-Berthold I, Mehling H, Potarca A, Tesar V, Heerspink HJ, Schall TJ; CCX140-B Diabetic Nephropathy Study Group: 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: 687–696.
8.
Boels MGS, Koudijs A, Avramut MC, Sol W, Wang G, van Oeveren-Rietdijk AM, van Zonneveld AJ, de Boer HC, van der Vlag J, van Kooten C, Eulberg D, van den Berg BM, DHT IJ, Rabelink TJ: Systemic monocyte chemotactic protein-1 inhibition modifies renal macrophages and restores glomerular endothelial glycocalyx and barrier function in diabetic nephropathy. Am J Pathol 2017; 187: 2430–2440.
9.
Menne J, Eulberg D, Beyer D, Baumann M, Saudek F, Valkusz Z, Wiecek A, Haller H; Emapticap Study Group: C-C motif-ligand 2 inhibition with emapticap pegol (NOX-E36) in type 2 diabetic patients with albuminuria. Nephrol Dial Transplant 2017; 32: 307–315.
10.
Tuttle KR, Brosius FC 3rd, Adler SG, Kretzler M, Mehta RL, Tumlin JA, Tanaka Y, Haneda M, Liu J, Silk ME, Cardillo TE, Duffin KL, Haas JV, Macias WL, Nunes FP, Janes JM: JAK1/JAK2 inhibition by baricitinib in diabetic kidney disease: results from a Phase 2 randomized controlled clinical trial. Nephrol Dial Transplant 2018, Epub ahead of print.
11.
Navarro-Gonzalez JF, Mora-Fernandez C, Muros de Fuentes M, Chahin J, Mendez ML, Gallego E, Macia M, del Castillo N, Rivero A, Getino MA, Garcia P, Jarque A, Garcia J: Effect of pentoxifylline on renal function and urinary albumin excretion in patients with diabetic kidney disease: the PREDIAN trial. J Am Soc Nephrol 2015; 26: 220–229.
12.
Sloan-Lancaster J, Raddad E, Deeg MA, Eli M, Flynt A, Tumlin J: Evaluation of the safety, pharmacokinetics, pharmacodynamics, and efficacy after single and multiple dosings of LY3016859 in healthy subjects and patients with diabetic nephropathy. Clin Pharmacol Drug Dev 2018, Epub ahead of print.
13.
Gorin Y, Cavaglieri RC, Khazim K, Lee DY, Bruno F, Thakur S, Fanti P, Szyndralewiez C, Barnes JL, Block K, Abboud HE: Targeting NADPH oxidase with a novel dual Nox1/Nox4 inhibitor attenuates renal pathology in type 1 diabetes. Am J Physiol Renal Physiol 2015; 308:F1276–F1287.
14.
Cha JJ, Min HS, Kim KT, Kim JE, Ghee JY, Kim HW, Lee JE, Han JY, Lee G, Ha HJ, Bae YS, Lee SR, Moon SH, Lee SC, Kim G, Kang YS, Cha DR: APX-115, a first-in-class pan-NADPH oxidase (Nox) inhibitor, protects db/db mice from renal injury. Lab Invest 2017; 97: 419–431.
15.
Liu P, Chen Y, Wang B, Zhang F, Wang D, Wang Y: Allopurinol treatment improves renal function in patients with type 2 diabetes and asymptomatic hyperuricemia: 3-year randomized parallel-controlled study. Clin Endocrinol (Oxf) 2015; 83: 475–482.
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