The next generation of therapeutics for chronic kidney disease

Nature Reviews Drug Discovery

Volumn 15, Issue 8, 2016, Pages 568-588

  Breyer, Matthew D ^a   Susztak, Katalin ^b  

^a ELI LILLY AND COMPANY   (United States)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 (2 CHLOROPHENYL) 4 [3 (DIMETHYLAMINO)PHENYL] 5 METHYL 1H PYRAZOLO[4,3 C]PYRIDINE 3,6(2H,5H) DIONE; ABATACEPT; ANGIOTENSIN RECEPTOR ANTAGONIST; ATRASENTAN; AVOSENTAN; BARICITINIB; CANAGLIFLOZIN; CAPTOPRIL; CHEMOKINE RECEPTOR CCR2 ANTAGONIST; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; ECULIZUMAB; ENDOTHELIN RECEPTOR ANTAGONIST; FINERENONE; HEMOGLOBIN; LISINOPRIL; LOSARTAN; METELIMUMAB; MICRORNA 29; MINERALOCORTICOID ANTAGONIST; N BENZYL 2 CYANO 3 (3,4 DIHYDROXYPHENYL)ACRYLAMIDE; PIRFENIDONE; PLACEBO; RAMIPRIL; SELONSERTIB; SIMTUZUMAB; SPIRONOLACTONE; SULODEXIDE; TELMISARTAN; TRANILAST; UNINDEXED DRUG; URINARY TRACT AGENT;

ACUTE KIDNEY FAILURE; ALBUMINURIA; ALLERGIC DISEASE; AUTOINFLAMMATORY DISEASE; CHRONIC KIDNEY DISEASE; COMPLEMENT INHIBITION; DIABETES MELLITUS; DIABETIC NEPHROPATHY; DRUG DOSE INCREASE; DRUG DOSE TITRATION; DRUG WITHDRAWAL; END STAGE RENAL DISEASE; EPIGENETICS; EXPERIMENTAL KIDNEY DISEASE; FIBROSING ALVEOLITIS; FLUID RETENTION; FOCAL GLOMERULOSCLEROSIS; GLOMERULUS FILTRATION RATE; GLYCEMIC CONTROL; GLYCOCALYX; HEART FAILURE; HEMOLYTIC UREMIC SYNDROME; HUMAN; HYPERKALEMIA; HYPERTROPHIC SCAR; HYPOTENSION; INTERSTITIAL NEPHRITIS; KELOID; KIDNEY BLOOD FLOW; KIDNEY DISEASE; KIDNEY FIBROSIS; LIPID METABOLISM; LIVER FIBROSIS; LUNG FIBROSIS; MICROALBUMINURIA; MONOTHERAPY; NONHUMAN; PATIENT SELECTION; PERSONALIZED MEDICINE; PODOCYTE; PRIORITY JOURNAL; PROTEINURIA; RENAL PROTECTION; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; REVIEW; RHEUMATOID ARTHRITIS; SIDE EFFECT; SYSTEMIC SCLEROSIS; THROMBOTIC THROMBOCYTOPENIC PURPURA; ULCERATIVE COLITIS; ANIMAL; DRUG EFFECTS; FIBROSIS; KIDNEY CIRCULATION; MOUSE; PATHOPHYSIOLOGY; RENAL INSUFFICIENCY, CHRONIC;

ANIMALS; FIBROSIS; HUMANS; MICE; RENAL AGENTS; RENAL CIRCULATION; RENAL INSUFFICIENCY, CHRONIC;

EID: 84969972724     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd.2016.67     Document Type: Review

References (296)

1. Collins A. J, Foley R. N, Gilbertson D. T, & Chen S. C. United States Renal Data System public health surveillance of chronic kidney disease and end-stage renal disease. Kidney Int. Suppl. 5, 2-7 (2015).
2. Kovesdy C. P, et al. Outcomes associated with microalbuminuria: effect modification by chronic kidney disease. J. Am. College Cardiol. 61, 1626-1633 (2013).
3. Foley R. N, & Collins A. J. The USRDS: what you need to know about what it can and can't tell us about ESRD. Clin. J. Am. Soc. Nephrol. 8, 845-851 (2013).
4. Weiner D. E, et al. Kidney function and risk of cardiovascular disease and mortality in kidney transplant recipients: the FAVORIT trial. Am. J. Transplant. 12, 2437-2445 (2012).
5. Herzog C. A, et al. Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 80, 572-586 (2011).
6. Foley R. N, et al. Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999. J. Am. Soc. Nephrol. 16, 489-495 (2005).
7. Coresh J, et al. Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality. JAMA 311, 2518-2531 (2014).
8. Levey A. S, et al. Proteinuria as a surrogate outcome in CKD: report of a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am. J. Kidney Dis. 54, 205-226 (2009).
9. Inker L. A, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am. J. Kidney Dis. 63, 713-735 (2014).
10. Rahman M, et al. Association between chronic kidney disease progression and cardiovascular disease: results from the CRIC Study. Am. J. Nephrol. 40, 399-407 (2014).
11. Duffield J. S. Cellular and molecular mechanisms in kidney fibrosis. J. Clin. Invest. 124, 2299-2306 (2014).
12. Reidy K, Kang H. M, Hostetter T, & Susztak K. Molecular mechanisms of diabetic kidney disease. J. Clin. Invest. 124, 2333-2340 (2014).
13. Zhou D, & Liu Y. Renal fibrosis in 2015: understanding the mechanisms of kidney fibrosis. Nat. Rev. Neph. 12, 68-70 (2016).
14. Bielesz B, et al. Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans. J. Clin. Invest. 120, 4040-4054 (2010).
15. Higgins D. F, et al. Hypoxia promotes fibrogenesis in vivo via HIF 1 stimulation of epithelial-To mesenchymal transition. J. Clin. Invest. 117, 3810-3820 (2007).
16. Humphreys B. D, et al. Chronic epithelial kidney injury molecule 1 expression causes murine kidney fibrosis. J. Clin. Invest. 123, 4023-4035 (2013).
17. Woroniecka K. I, et al. Transcriptome analysis of human diabetic kidney disease. Diabetes 60, 2354-2369 (2011).
18. Zhou Y. H, et al. Steroids in the treatment of IgA nephropathy to the improvement of renal survival: a systematic review and meta-Analysis. PLoS ONE 6, e18788 (2011).
19. Perico N, Benigni A, & Remuzzi G. Present and future drug treatments for chronic kidney diseases: evolving targets in renoprotection. Nat. Rev. Drug Discov. 7, 936-953 (2008).
20. Denker M, et al. Chronic Renal Insufficiency Cohort Study (CRIC): overview and summary of selected findings. Clin. J. Am. Soc. Nephrol. 10, 2073-2083 (2015).
21. Simons J. L, et al. Modulation of glomerular hypertension defines susceptibility to progressive glomerular injury. Kidney Int. 46, 396-404 (1994).
22. Dunn B. R, et al. Prevention of glomerular capillary hypertension in experimental diabetes mellitus obviates functional and structural glomerular injury. J. Hypertens. 4 (Suppl.), S251-S254 (1986).
23. Hostetter T. H, Olson J. L, Rennke H. G, Venkatachalam M. A, & Brenner B. M. Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. J. Am. Soc. Nephrol. 12, 1315-1325 (2001).
24. MacKinnon M, et al. Combination therapy with an angiotensin receptor blocker and an ACE inhibitor in proteinuric renal disease: a systematic review of the efficacy and safety data. Am. J. Kidney Dis. 48, 8-20 (2006).
25. Hallan S, et al. Obesity, smoking, and physical inactivity as risk factors for CKD: are men more vulnerable?. Am. J. Kidney Dis. 47, 396-405 (2006).
26. Dobre M, Rahman M, & Hostetter T. H. Current status of bicarbonate in CKD. J. Am. Soc. Nephrol. 26, 515-523 (2015).
27. Zatz R, et al. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J. Clin. Invest. 77, 1925-1930 (1986).
28. 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. New Engl. J. Med. 329, 1456-1462 (1993).
29. Maschio G, et al. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. New Engl. J. Med. 334, 939-945 (1996).
30. Hou F. F, et al. Efficacy and safety of benazepril for advanced chronic renal insufficiency. New Engl. J. Med. 354, 131-140 (2006).
31. Lewis E. J, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. New Engl. J. Med. 345, 851-860 (2001).
32. Brenner B. M, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. New Engl. J. Med. 345, 861-869 (2001).
33. Parving H. H, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. New Engl. J. Med. 345, 870-878 (2001).
34. Schoolwerth A. C, et al. Renal considerations in angiotensin converting enzyme inhibitor therapy: a statement for healthcare professionals from the Council on the Kidney in Cardiovascular Disease and the Council for High Blood Pressure Research of the American Heart Association. Circulation 104, 1985-1991 (2001).
35. de Zeeuw D, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int. 65, 2309-2320 (2004).
36. Heerspink H. J. Therapeutic approaches in lowering albuminuria: travels along the renin-Angiotensin- Aldosterone-system pathway. Adv. Chron. Kidney Dis. 18, 290-299 (2011).
37. Fried L. F, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. New Engl. J. Med. 369, 1892-1903 (2013).
38. Marquez D. F, Ruiz-Hurtado G, Ruilope L. M, & Segura J. An update of the blockade of the renin angiotensin aldosterone system in clinical practice. Expert Opin. Pharmacother. 16, 2283-2292 (2015).
39. Gregg E. W, et al. Changes in diabetes-related complications in the United States, 1990-2010. New Engl. J. Med. 370, 1514-1523 (2014).
40. Xie X, et al. Renin-Angiotensin system inhibitors and kidney and cardiovascular outcomes in patients with CKD: a bayesian network meta-Analysis of randomized clinical trials. Am. J. Kidney Dis. 67, 728-741 (2015).
41. ONTARGET Investigators, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. New Engl. J. Med. 358, 1547-1559 (2008).
42. Parving H. H, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. New Engl. J. Med. 367, 2204-2213 (2012).
43. Pearce D, et al. Collecting duct principal cell transport processes and their regulation. Clin. J. Am. Soc. Nephrol. 10, 135-146 (2015).
44. Azibani F, Fazal L, Chatziantoniou C, Samuel J. L, & Delcayre C. Aldosterone mediates cardiac fibrosis in the setting of hypertension. Curr. Hypertension Rep. 15, 395-400 (2013).
45. Azibani F, et al. Aldosterone inhibits antifibrotic factors in mouse hypertensive heart. Hypertension 59, 1179-1187 (2012).
46. Ma J, et al. Plasminogen activator inhibitor 1 deficiency protects against aldosterone-induced glomerular injury. Kidney Int. 69, 1064-1072 (2006).
47. Juurlink D. N, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. New Engl. J. Med. 351, 543-551 (2004).
48. Saito M, Takada M, Hirooka K, Isobe F, & Yasumura Y. Serum concentration of potassium in chronic heart failure patients administered spironolactone plus furosemide and either enalapril maleate, losartan potassium or candesartan cilexetil. J. Clin. Pharm. Ther. 30, 603-610 (2005).
49. Esteghamati A, et al. Long-Term effects of addition of mineralocorticoid receptor antagonist to angiotensin II receptor blocker in patients with diabetic nephropathy: a randomized clinical trial. Nephrol. Dial. Transplant. 28, 2823-2833 (2013).
50. Bakris G. L, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. JAMA 314, 884-894 (2015).
51. US National Library of Medicine ClinicalTrials.gov [online], https: //clinicaltrials.gov/show/NCT02345057 (2015).
52. Dessapt-Baradez C, et al. Targeted glomerular angiopoietin 1 therapy for early diabetic kidney disease. J. Am. Soc. Nephrol. 25, 33-42 (2014).
53. Mogensen C. E. Progression of nephropathy in long-Term diabetics with proteinuria and effect of initial anti-hypertensive treatment. Scand. J. Clin. Lab Invest. 36, 383-388 (1976).
54. Mogensen C. E. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. New Engl. J. Med. 310, 356-360 (1984).
55. Osterby R. Renal pathology in diabetes mellitus. Curr. Opin. Nephrol. Hypertens. 2, 475-483 (1993).
56. Osterby R, et al. Neovascularization at the vascular pole region in diabetic glomerulopathy. Nephrol. Dial. Transplant. 14, 348-352 (1999).
57. Eremina V, et al. Glomerular-specific alterations of VEGF A expression lead to distinct congenital and acquired renal diseases. J. Clin. Invest. 111, 707-716 (2003).
58. Scott R. P, & Quaggin S. E. Review series: the cell biology of renal filtration. J. Cell Biol. 209, 199-210 (2015).
59. Dane M. J. C, et al. A microscopic view on the renal endothelial glycocalyx. Am. J. Physiol. Renal Physiol. 308, F956-F966 (2015).
60. Perrin R. M, Harper S. J, & Bates D. O. A role for the endothelial glycocalyx in regulating microvascular permeability in diabetes mellitus. Cell Biochem. Biophys. 49, 65-72 (2007).
61. Nieuwdorp M, et al. Endothelial glycocalyx damage coincides with microalbuminuria in type 1 diabetes. Diabetes 55, 1127-1132 (2006).
62. Nussbaum C, et al. Early microvascular changes with loss of the glycocalyx in children with type 1 diabetes. J. Pediatr. 164, 584-589.e1 (2014).
63. Heerspink H. L, et al. Effects of sulodexide in patients with type 2 diabetes and persistent albuminuria. Nephrol. Dial. Transplant. 23, 1946-1954 (2008).
64. Kristova V, Liskova S, Sotnikova R, Vojtko R, & Kurtansky A. Sulodexide improves endothelial dysfunction in streptozotocin-induced diabetes in rats. Physiol. Res. 57, 491-494 (2008).
65. Lewis E. J, et al. Sulodexide for kidney protection in type 2 diabetes patients with microalbuminuria: a randomized controlled trial. Am. J. Kidney Dis. 58, 729-736 (2011).
66. Basche M, et al. A Phase I biological and pharmacologic study of the heparanase inhibitor PI 88 in patients with advanced solid tumors. Clin. Cancer Res. 12, 5471-5480 (2006).
67. Barton M, Mullins J. J, Bailey M. A, & Kretzler M. Role of endothelin receptors for renal protection and survival in hypertension: waiting for clinical trials. Hypertension 48, 834-837 (2006).
68. Daehn I, et al. Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis. J. Clin. Invest. 124, 1608-1621 (2014).
69. de Zeeuw D, et al. The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy. J. Am. Soc. Nephrol. 25, 1083-1093 (2014).
70. Saleh M. A, Boesen E. I, Pollock J. S, Savin V. J, & Pollock D. M. Endothelin receptor A specific stimulation of glomerular inflammation and injury in a streptozotocin-induced rat model of diabetes. Diabetologia 54, 979-988 (2011).
71. Saleh M. A, Boesen E. I, Pollock J. S, Savin V. J, & Pollock D. M. Endothelin 1 increases glomerular permeability and inflammation independent of blood pressure in the rat. Hypertension 56, 942-949 (2010).
72. Kohan D. E, & Barton M. Endothelin and endothelin antagonists in chronic kidney disease. Kidney Int. 86, 896-904 (2014).
73. Boffa J. J, Tharaux P. L, Dussaule J. C, & Chatziantoniou C. Regression of renal vascular fibrosis by endothelin receptor antagonism. Hypertension 37, 490-496 (2001).
74. Hocher B, et al. Effects of endothelin receptor antagonists on the progression of diabetic nephropathy. Nephron 87, 161-169 (2001).
75. Mann J. F, et al. Avosentan for overt diabetic nephropathy. J. Am. Soc. Nephrol. 21, 527-535 (2010).
76. Ritz E, & Wenzel R. R. Endothelin antagonist as add on treatment for proteinuria in diabetic nephropathy: is there light at the end of the tunnel?. J. Am. Soc. Nephrol. 22, 593-595 (2011).
77. US National Library of Medicine ClinicalTrials.gov [online], https: //clinicaltrials.gov/show/NCT01858532 (2015).
78. Hodgin J. B, et al. Identification of cross-species shared transcriptional networks of diabetic nephropathy in human and mouse glomeruli. Diabetes 62, 299-308 (2013).
79. Bohle A, et al. The pathogenesis of chronic renal failure in diabetic nephropathy. Investigation of 488 cases of diabetic glomerulosclerosis. Pathol. Res. Pract. 187, 251-259 (1991).
80. Berthier C. C, et al. Enhanced expression of Janus kinase-signal transducer and activator of transcription pathway members in human diabetic nephropathy. Diabetes 58, 469-477 (2009).
81. Vlassara H, Brownlee M, Manogue K. R, Dinarello C. A, & Pasagian A. Cachectin/TNF and IL 1 induced by glucose-modified proteins: role in normal tissue remodeling. Science 240, 1546-1548 (1988).
82. Hasegawa G, et al. Possible role of tumor necrosis factor and interleukin 1 in the development of diabetic nephropathy. Kidney Int. 40, 1007-1012 (1991).
83. Niewczas M. A, et al. Serum concentrations of markers of TNFα and Fas-mediated pathways and renal function in nonproteinuric patients with type 1 diabetes. Clin. J. Am. Soc. Nephrol. 4, 62-70 (2009).
84. Niewczas M. A, et al. Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes. J. Am. Soc. Nephrol. 23, 507-515 (2012).
85. Hawari F. I, et al. Release of full-length 55 kDa TNF receptor 1 in exosome-like vesicles: a mechanism for generation of soluble cytokine receptors. Proc. Natl Acad. Sci. USA 101, 1297-1302 (2004).
86. Tartaglia L. A, Pennica D, & Goeddel D. V. Ligand passing: the 75 kDa tumor necrosis factor (TNF) receptor recruits TNF for signaling by the 55 kDa TNF receptor. J. Biol. Chem. 268, 18542-18548 (1993).
87. Pober J. S, Min W, & Bradley J. R. Mechanisms of endothelial dysfunction, injury, and death. Annu. Rev. Pathol. 4, 71-95 (2009).
88. Al Lamki R. S, et al. TNFR1-And TNFR2 mediated signaling pathways in human kidney are cell type-specific and differentially contribute to renal injury. FASEB J. 19, 1637-1645 (2005).
89. Tartaglia L. A, Rothe M, Hu Y. F, & Goeddel D. V. Tumor necrosis factor's cytotoxic activity is signaled by the p55 TNF receptor. Cell 73, 213-216 (1993).
90. Godwin P, et al. Targeting nuclear factor-kappa B to overcome resistance to chemotherapy. Frontiers Oncol. 3, 120 (2013).
91. Al Lamki R. S, & Mayadas T. N. TNF receptors: signaling pathways and contribution to renal dysfunction. Kidney Int. 87, 281-296 (2015).
92. Rastogi S, Rizwani W, Joshi B, Kunigal S, & Chellappan S. P. TNF-α response of vascular endothelial and vascular smooth muscle cells involve differential utilization of ASK1 kinase and p73. Cell Death Differ. 19, 274-283 (2012).
93. Tsai C. T, et al. TNF-α down-regulates sarcoplasmic reticulum Ca2+ ATPase expression and leads to left ventricular diastolic dysfunction through binding of NF 'B to promoter response element. Cardiovascular Res. 105, 318-329 (2015).
94. Moriwaki Y, et al. Effect of TNF-α inhibition on urinary albumin excretion in experimental diabetic rats. Acta Diabetol. 44, 215-218 (2007).
95. Matsushima K, Larsen C. G, DuBois G. C, & Oppenheim J. J. Purification and characterization of a novel monocyte chemotactic and activating factor produced by a human myelomonocytic cell line. J. Exp. Med. 169, 1485-1490 (1989).
96. Deshmane S. L, Kremlev S, Amini S, & Sawaya B. E. Monocyte chemoattractant protein 1 (MCP 1): an overview. J. Interferon Cytokine Res. 29, 313-326 (2009).
97. Marisa C, et al. MCP 1 and MIP 2 expression and production in BB diabetic rat: effect of chronic hypoxia. Mol. Cell. Biochem. 276, 105-111 (2005).
98. Mine S, et al. Increased expression levels of monocyte CCR2 and monocyte chemoattractant protein 1 in patients with diabetes mellitus. Biochem. Biophys. Res. Commun. 344, 780-785 (2006).
99. Wada T, et al. Up regulation of monocyte chemoattractant protein 1 in tubulointerstitial lesions of human diabetic nephropathy. Kidney Int. 58, 1492-1499 (2000).
100. Titan S. M, et al. Urinary MCP 1 and RBP: independent predictors of renal outcome in macroalbuminuric diabetic nephropathy. J. Diabetes Complications 26, 546-553 (2012).
101. Seok S. J, et al. Blockade of CCL2/CCR2 signalling ameliorates diabetic nephropathy in db/db mice. Nephrol. Dial. Transplant. 28, 1700-1710 (2013).
102. Awad A. S, et al. Monocyte/macrophage chemokine receptor CCR2 mediates diabetic renal injury. Am. J. Physiol. Renal Physiol. 301, F1358-F1366 (2011).
103. US National Library of Medicine ClinicalTrials.gov [online], https: //www.clinicaltrials.gov/ct2/show/.NCT01712061 (2014).
104. US National Library of Medicine. ClinicalTrials.gov [online], https: //clinicaltrials.gov/show/NCT01447147 (2014).
105. de Zeeuw D, 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. 3, 687-696 (2015).
106. Berger S, & Daha M. Complement in glomerular injury. Seminars Immunopathol. 29, 375-384 (2007).
107. Stark G. R, & Darnell J. E. Jr The JAK-STAT pathway at twenty. Immunity 36, 503-514, (2012).
108. Thacker S. G, et al. The detrimental effects of IFN-α on vasculogenesis in lupus are mediated by repression of IL 1 pathways: potential role in atherogenesis and renal vascular rarefaction. J. Immunol. 185, 4457-4469 (2010).
109. Alexander J. J, et al. Mouse podocyte complement factor H: the functional analog to human complement receptor 1. J. Am. Soc. Nephrol. 18, 1157-1166 (2007).
110. O'Shea, John J, & Plenge R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 36, 542-550 (2012).
111. Durant L, et al. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity 32, 605-615 (2010).
112. Sandborn W. J, et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. New Engl. J. Med. 367, 616-624 (2012).
113. Vyas D, O'Dell K. M, Bandy J. L, & Boyce E. G. Tofacitinib: the first Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis. Ann. Pharmacother. 47, 1524-1531 (2013).
114. Neusser M. A, et al. Human nephrosclerosis triggers a hypoxia-related glomerulopathy. Am. J. Pathol. 176, 594-607 (2010).
115. Banes A. K, et al. Angiotensin II blockade prevents hyperglycemia-induced activation of JAK and STAT proteins in diabetic rat kidney glomeruli. Am. J. Physiol. Renal Physiol. 286, F653-F659 (2004).
116. Marrero M. B, Banes-Berceli A. K, Stern D. M, & Eaton D. C. Role of the JAK/STAT signaling pathway in diabetic nephropathy. Am. J. Physiol. Renal Physiol. 290, F762-F768 (2006).
117. Fleischmann R, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. New Engl. J. Med. 367, 495-507 (2012).
118. Sawano A, et al. Flt 1, vascular endothelial growth factor receptor 1, is a novel cell surface marker for the lineage of monocyte-macrophages in humans. Blood 97, 785-791 (2001).
119. Santulli G. Angiopoietin-like proteins: a comprehensive look. Frontiers Endocrinol. 5, 4 (2014).
120. Tuttle K. R, et al. Baricitinib in diabetic kidney disease: results from a Phase 2, multicenter, randomized, double-blind, placebo-controlled study. 75th Annual Meeting of the American Diabetes Association [online], http: //app.core-Apps.com/tristar-ada15/abstract/.1678f29f2a56ce35baedcc25f3994ccb (2015).
121. Mathern D. R, & Heeger P. S. Molecules great and small: the complement system. Clin. J. Am. Soc. Nephrol. 10, 1636-1650 (2015).
122. Rother R. P, Rollins S. A, Mojcik C. F, Brodsky R. A, & Bell L. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat. Biotechnol. 25, 1256-1264 (2007).
123. Licht C, et al. Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2 year extensions of phase 2 studies. Kidney Int. 87, 1061-1073 (2015).
124. Flyvbjerg A. Diabetic angiopathy, the complement system and the tumor necrosis factor superfamily. Nat. Rev. Endocrinol. 6, 94-101 (2010).
125. Shao Z, & Schwarz H. CD137 ligand, a member of the tumor necrosis factor family, regulates immune responses via reverse signal transduction. J. Leukocyte Biol. 89, 21-29 (2011).
126. Hansen H. G, et al. Finding diabetic nephropathy biomarkers in the plasma peptidome by high-Throughput magnetic bead processing and MALDI-TOF MS analysis. Proteom. Clin. Appl. 4, 697-705 (2010).
127. Li L, et al. C3a receptor antagonist ameliorates inflammatory and fibrotic signals in type 2 diabetic nephropathy by suppressing the activation of TGF β/.smad3 and IKBα pathway. PLoS ONE 9 e113639 (2014).
128. Zhao Y, Conze D. B, Hanover J. A, & Ashwell J. D. Tumor necrosis factor receptor 2 signaling induces selective c-IAP1 dependent ASK1 ubiquitination and terminates mitogen-Activated protein kinase signaling. J. Biol. Chem. 282, 7777-7782 (2007).
129. Zhang C, et al. TNF-α suppresses prolyl 4 hydroxylase α1 expression via the ASK1-JNK-NonO pathway. Arterioscler. Thromb. Vascular Biol. 27, 1760-1767 (2007).
130. Yang M, et al. ASK1-JNK signaling cascade mediates Ad ST13 induced apoptosis in colorectal HCT116 cells. J. Cell. Biochem. 110, 581-588 (2010).
131. Nishitoh H, et al. ASK1 is essential for JNK/SAPK activation by TRAF2. Mol. Cell 2, 389-395 (1998).
132. Tesch G. H, et al. ASK1 inhibitor halts progression of diabetic nephropathy in Nos3 deficient mice. Diabetes 64, 3903-3913 (2015).
133. US National Library of Medicine ClinicalTrials.gov [online], https: //clinicaltrials.gov/ct2/show/.NCT02177786?term=GS-4997&rank=3 (2015).
134. Lin J. H, Zhang J. J, Lin S. L, & Chertow G. M. Design of a Phase 2 clinical trial of an ASK1 inhibitor, GS 4997, in patients with diabetic kidney disease. Nephron. Exp. Nephrol. 129, 29-33 (2015).
135. Ledo N, et al. Functional genomic annotation of genetic risk loci highlights inflammation and epithelial biology networks in CKD. J. Am. Soc. Nephrol. 26, 692-714 (2014).
136. Salmi M, Kalimo K, & Jalkanen S. Induction and function of vascular adhesion protein 1 at sites of inflammation. J. Exp. Med. 178, 2255-2260 (1993).
137. Smith D. J, et al. Cloning of vascular adhesion protein 1 reveals a novel multifunctional adhesion molecule. J. Exp. Med. 188, 17-27 (1998).
138. Koskinen K, et al. Granulocyte transmigration through the endothelium is regulated by the oxidase activity of vascular adhesion protein 1 (VAP 1). Blood 103, 3388-3395 (2004).
139. US National Library of Medicine ClinicalTrials.gov [online], https: //clinicaltrials.gov/ct2/show/.NCT02358096?term=NCT02358096&rank=1 (2015).
140. Friedman S. L, Sheppard D, Duffield J. S, & Violette S. Therapy for fibrotic diseases: nearing the starting line. Sci. Transl. Med. 5, 167sr161 (2013).
141. Huang S, & Susztak K. Epithelial plasticity versus EMT in kidney fibrosis. Trends Mol. Med. 22, 4-6 (2015).
142. Kopp J. B, et al. Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive renal disease. Lab. Invest. 74, 991-1003 (1996).
143. Voelker J. R, et al. Renal efficacy and safety of anti-TGF β1 therapy in patients with diabetic nephropathy. J. Am. Soc. Nephrol. 25 (Abstract edition), 1151 (2014).
144. Varga J, & Pasche B. Antitransforming growth factor-β therapy in fibrosis: recent progress and implications for systemic sclerosis. Curr. Opin. Rheumatol. 20, 720-728 (2008).
145. Porte J, & Jenkins G. Assessment of the effect of potential antifibrotic compounds on total and αVβ6 integrin-mediated TGF-β activation. Pharmacol. Res. Perspect. 2, e00030 (2014).
146. Eberlein C, et al. A human monoclonal antibody 264RAD targeting αVβ6 integrin reduces tumour growth and metastasis and modulates key biomarkers in vivo. Oncogene 32, 4406-4416 (2013).
147. Karimi-Shah B. A, & Chowdhury B. A. Forced vital capacity in idiopathic pulmonary fibrosis - FDA review of pirfenidone and nintedanib. New Engl. J. Med. 372, 1189-1191 (2015).
148. Xiang X. H, et al. Pirfenidone inhibits proliferation, arrests the cell cycle, and downregulates heat shock protein47 and collagen type I in rat hepatic stellate cells in vitro. Mol. Med. Rep. 12, 309-314 (2015).
149. RamachandraRao S. P, et al. Pirfenidone is renoprotective in diabetic kidney disease. J. Am. Soc. Nephrol. 20, 1765-1775 (2009).
150. Sharma K, et al. Pirfenidone for diabetic nephropathy. J. Am. Soc. Nephrol. 22, 1144-1151 (2011).
151. Pugliese G, Iacobini C, Blasetti Fantauzzi C, & Menini S. The dark and bright side of atherosclerotic calcification. Atherosclerosis 238, 220-230 (2015).
152. Drechsler C, et al. Galectin 3, renal function, and clinical outcomes: results from the LURIC and 4D studies. J. Am. Soc. Nephrol. 26, 2213-2221 (2015).
153. Matsumoto N, et al. A possible role of galectin 9 in the pulmonary fibrosis of patients with interstitial pneumonia. Lung 191 191-198 (2013).
154. Tager A. M, et al. The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat. Med. 14, 45-54 (2008).
155. Aikawa S, Hashimoto T, Kano K, & Aoki J. Lysophosphatidic acid as a lipid mediator with multiple biological actions. J. Biochem. 157, 81-89 (2015).
156. Castelino F. V, et al. Amelioration of dermal fibrosis by genetic deletion or pharmacologic antagonism of lysophosphatidic acid receptor 1 in a mouse model of scleroderma. Arthritis Rheumatism 63, 1405-1415 (2011).
157. Llona-Minguez S, Ghassemian A, & Helleday T. Lysophosphatidic acid receptor (LPAR) modulators: the current pharmacological toolbox. Progress Lipid Res. 58, 51-75 (2015).
158. Shigeki S, Murakami T, Yata N, & Ikuta Y. Treatment of keloid and hypertrophic scars by iontophoretic transdermal delivery of tranilast. Scand. J. Plast. Reconstr. Surg. Hand Surg. 31, 151-158 (1997).
159. Yamada H, Tajima S, & Nishikawa T. Tranilast inhibits collagen synthesis in normal, scleroderma and keloid fibroblasts at a late passage culture but not at an early passage culture. J. Dermatol. Sci. 9, 45-47 (1995).
160. Lau X, Zhang Y, Kelly D. J, & Stapleton D. I. Attenuation of Armanni-Ebstein lesions in a rat model of diabetes by a new anti-fibrotic, anti-inflammatory agent, FT011. Diabetologia 56, 675-679 (2013).
161. Gilbert R. E, et al. A purpose-synthesised anti-fibrotic agent attenuates experimental kidney diseases in the rat. PLoS ONE 7 e47160 (2012).
162. Decitre M, et al. Lysyl oxidase-like protein localizes to sites of de novo fibrinogenesis in fibrosis and in the early stromal reaction of ductal breast carcinomas. Lab. Invest. 78, 143-151 (1998).
163. Kim Y, Peyrol S, So C. K, Boyd C. D, & Csiszar K. Coexpression of the lysyl oxidase-like gene (LOXL) and the gene encoding type III procollagen in induced liver fibrosis. J. Cell. Biochem. 72, 181-188 (1999).
164. Van Bergen T, et al. The role of LOX and LOXL2 in scar formation after glaucoma surgery. Invest. Ophthalmol. Vis. Sci. 54, 5788-5796 (2013).
165. Yang T, et al. miR 29 mediates TGFβ1 induced extracellular matrix synthesis through activation of PI3K-AKT pathway in human lung fibroblasts. J. Cell. Biochem. 114, 1336-1342 (2013).
166. Qin W, et al. TGF-β/Smad3 signaling promotes renal fibrosis by inhibiting miR 29. J. Am. Soc. Nephrol. 22, 1462-1474 (2011).
167. Gomez I. G, et al. Anti-microRNA 21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways. J. Clin. Invest. 125, 141-156 (2015).
168. Niranjan T, et al. The Notch pathway in podocytes plays a role in the development of glomerular disease. Nat. Med. 14, 290-298 (2008).
169. Kramann R, et al. Pharmacological GLI2 inhibition prevents myofibroblast cell-cycle progression and reduces kidney fibrosis. J. Clin. Invest, http: //dx.doi. org/10.1172/JCI74929 (2015).
170. Sirin Y, & Susztak K. Notch in the kidney: development and disease. J. Pathol. 226, 394-403 (2012).
171. Kawakami T, Ren S, & Duffield J. S. Wnt signalling in kidney diseases: dual roles in renal injury and repair. J. Pathol. 229, 221-231 (2013).
172. Nathan D. M, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. New Engl. J. Med. 353, 2643-2653 (2005).
173. Adler A. I, et al. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int. 63, 225-232 (2003).
174. Susztak K, Raff A. C, Schiffer M, & Bottinger E. P. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes 55, 225-233 (2006).
175. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813-820 (2001).
176. Shurraw S, et al. Association between glycemic control and adverse outcomes in people with diabetes mellitus and chronic kidney disease: a population-based cohort study. Arch. Internal Med. 171, 1920-1927 (2011).
177. [No authors listed.] The effect of intensive treatment of diabetes on the development and progression of long-Term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. New Engl. J. Med. 329, 977-986 (1993).
178. Miao F, et al. Evaluating the role of epigenetic histone modifications in the metabolic memory of type 1 diabetes. Diabetes 63, 1748-1762 (2014).
179. Susztak K. Understanding the epigenetic syntax for the genetic alphabet in the kidney. J. Am. Soc. Nephrol. 25, 10-17 (2014).
180. El Osta A, et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J. Exp. Med. 205, 2409-2417 (2008).
181. Ko Y. A, et al. Cytosine methylation changes in enhancer regions of core pro-fibrotic genes characterize kidney fibrosis development. Genome Biol. 14, R108 (2013).
182. Kang H. M, et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat. Med. 21, 37-46 (2015).
183. Ly J. P, et al. The Sweet Pee model for Sglt2 mutation. J. Am. Soc. Nephrol. 22, 113-123 (2011).
184. Yale J. F, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetes Obes. Metab. 16, 1016-1027 (2014).
185. Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. New Engl. J. Med. 373, 2117-2128 (2015).
186. Vallon V, et al. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am. J. Physiol. Renal Physiol. 306, F194-F204 (2014).
187. Gembardt F, et al. The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension. Am. J. Physiol. Renal Physiol. 307, F317-F325 (2014).
188. Cherney D. Z, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 129, 587-597 (2014).
189. US National Library of Medicine ClinicalTrials.gov [online], https: //clinicaltrials.gov/ct2/show/.NCT02065791 (2015).
190. Hallman T. M, et al. The mitochondrial and kidney disease phenotypes of kd/kd mice under germfree conditions. J. Autoimmun. 26, 1-6 (2006).
191. Malaga-Dieguez L, & Susztak K. ADCK4 reenergizes nephrotic syndrome. J. Clin. Invest. 123, 4996-4999 (2013).
192. Wang Z, et al. Regulation of renal lipid metabolism, lipid accumulation, and glomerulosclerosis in FVBdb/db mice with type 2 diabetes. Diabetes 54, 2328-2335 (2005).
193. Li S, et al. Proximal tubule PPARα attenuates renal fibrosis and inflammation caused by unilateral ureteral obstruction. Am. J. Physiol. Renal Physiol. 305, F618-627 (2013).
194. Davis T. M, et al. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia 54, 280-290 (2011).
195. Ting R. D, et al. Benefits and safety of long-Term fenofibrate therapy in people with type 2 diabetes and renal impairment: the FIELD Study. Diabetes Care 35, 218-225 (2012).
196. Cefalu W. T, & Watson K. Intensive glycemic control and cardiovascular disease observations from the ACCORD study: now what can a clinician possibly think?. Diabetes 57, 1163-1165 (2008).
197. Noto D, Cefalu A. B, & Averna M. R. Beyond statins: new lipid lowering strategies to reduce cardiovascular risk. Curr. Atherosclerosis Rep. 16, 414 (2014).
198. Han S. H, et al. Deletion of Lkb1 in renal tubular epithelial cells leads to CKD by altering metabolism. J. Am. Soc. Nephrol. http: //dx.doi.org/10.1681/.ASN.2014121181 (2015).
199. Dugan L. L, et al. AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function. J. Clin. Invest. 123, 4888-4899 (2013).
200. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43-49 (2013).
201. Xu H. F, et al. MicroRNA21 regulation of the progression of viral myocarditis to dilated cardiomyopathy. Mol. Med. Rep. 10, 161-168 (2014).
202. Thum T, & Lorenzen J. M. Cardiac fibrosis revisited by microRNA therapeutics. Circulation 126, 800-802 (2012).
203. Chau B. N, et al. MicroRNA 21 promotes fibrosis of the kidney by silencing metabolic pathways. Sci Transl Med 4, 121ra118 (2012).
204. Lai J. Y, et al. MicroRNA 21 in glomerular injury. J. Am. Soc. Nephrol. 26, 805-816 (2015).
205. Nishikawa T, Edelstein D, & Brownlee M. The missing link: a single unifying mechanism for diabetic complications. Kidney Int. Suppl. 77, S26-S30 (2000).
206. Gorin Y, et al. Targeting NADPH oxidase with a novel dual Nox1/Nox4 inhibitor attenuates renal pathology in type 1 diabetes. Am. J. Physiol. Renal Physiol. 308, F1276-F1287 (2015).
207. Maalouf R. M, et al. Nox4 derived reactive oxygen species mediate cardiomyocyte injury in early type 1 diabetes. Am. J. Physiol. Cell Physiol. 302, C597-C604 (2012).
208. Aoyama T, et al. Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology 56, 2316-2327 (2012).
209. Hecker L, et al. Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci. Transl. Med. 6, 231ra247 (2014).
210. Lewis E. J, et al. Pyridorin in type 2 diabetic nephropathy. J. Am. Soc. Nephrol. 23, 131-136 (2012).
211. Dwyer J. P, et al. Pyridoxamine dihydrochloride in diabetic nephropathy (PIONEER-CSG 17): lessons learned from a pilot study. Nephron 129, 22-28 (2015).
212. Bechtel W, et al. Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat. Med. 16, 544-550 (2010).
213. Gilbert R. E, et al. Histone deacetylase inhibition attenuates diabetes-Associated kidney growth: potential role for epigenetic modification of the epidermal growth factor receptor. Kidney Int. 79, 1312-1321 (2011).
214. Van Beneden K, et al. Valproic acid attenuates proteinuria and kidney injury. J. Am. Soc. Nephrol. 22, 1863-1875 (2011).
215. Kos C. H, et al. Mice deficient in α-Actinin 4 have severe glomerular disease. J. Clin. Invest. 111, 1683-1690 (2003).
216. Pavenstädt H, Kriz W, & Kretzler M. Cell biology of the glomerular podocyte. Physiol. Rev. 83, 253-307 (2003).
217. Ly J, Alexander M, & Quaggin S. E. A podocentric view of nephrology. Curr. Opin. Nephrol. Hypertens. 13, 299-305 (2004).
218. George B, et al. Crk1/2 dependent signaling is necessary for podocyte foot process spreading in mouse models of glomerular disease. J. Clin. Invest. 122, 674-692 (2012).
219. Tian X, et al. Podocyte-Associated talin1 is critical for glomerular filtration barrier maintenance. J. Clin. Invest. 124, 1098-1113 (2014).
220. Soda K, et al. Role of dynamin, synaptojanin, and endophilin in podocyte foot processes. J. Clin. Invest. 122, 4401-4411 (2012).
221. Rutkowski J. M, et al. Adiponectin promotes functional recovery after podocyte ablation. J. Am. Soc. Nephrol. 24, 268-282 (2013).
222. Wharram B. L, et al. Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene. J. Am. Soc. Nephrol. 16, 2941-2952 (2005).
223. Greaves P, & Gribben J. G. The role of B7 family molecules in hematologic malignancy. Blood 121, 734-744 (2013).
224. Yu C. C, et al. Abatacept in B7 1 positive proteinuric kidney disease. New Engl. J. Med. 369, 2416-2423 (2013).
225. Korhonen R, & Moilanen E. Abatacept, a novel CD80/86 CD28 T cell co stimulation modulator, in the treatment of rheumatoid arthritis. Bas. Clin. Pharmacol. Toxicol. 104, 276-284 (2009).
226. Benigni A, Gagliardini E, & Remuzzi G. Abatacept in B7 1 positive proteinuric kidney disease. New Engl. J. Med. 370, 1261-1263 (2014).
227. Fiorina P, et al. Role of podocyte B7 1 in diabetic nephropathy. J. Am. Soc. Nephrol. 25, 1415-1429 (2014).
228. Schiffer M, et al. Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models. Nat. Med. 21, 601-608 (2015).
229. Maile L. A, et al. Insulin-like growth factor i signaling in smooth muscle cells is regulated by ligand binding to the 177CYDMKTTC184 sequence of the β3 subunit of αVβ3. Mol. Endocrinol. 20, 405-413 (2006).
230. Maile L. A, et al. A monoclonal antibody against αVβ3 integrin inhibits development of atherosclerotic lesions in diabetic pigs. Sci. Transl Med. 2, 18ra11 (2010).
231. Maile L. A, et al. Blocking αVβ3 integrin ligand occupancy inhibits the progression of albuminuria in diabetic rats. J. Diabetes Res. 2014, 10 (2014).
232. US National Library of Medicine ClinicalTrials.gov [online], https: //clinicaltrials.gov/ct2/show/.NCT02251067?term=NCT02251067&rank=1 (2015).
233. Afsar B, et al. Phosphodiesterase type 5 inhibitors and kidney disease. Int. Urol. Nephrol. 47, 1521-1528 (2015).
234. Crawford A, et al. Molecular and transcriptional basis of CD4+ T cell dysfunction during chronic infection. Immunity 40, 289-302 (2014).
235. Takata Y, et al. PPARd-mediated antiinflammatory mechanisms inhibit angiotensin II accelerated atherosclerosis. Proc. Natl Acad. Sci. USA 105, 4277-4282 (2008).
236. Ito H, et al. Hyperuricemia is independently associated with coronary heart disease and renal dysfunction in patients with type 2 diabetes mellitus. PLoS ONE 6, e27817 (2011).
237. Goicoechea M, et al. Allopurinol and progression of CKD and cardiovascular events: long-Term follow up of a randomized clinical trial. Am. J. Kidney Dis. 65, 543-549 (2015).
238. Goicoechea M, et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin. J. Am. Soc. Nephrol. 5, 1388-1393 (2010).
239. Siu Y. P, Leung K. T, Tong M. K, & Kwan T. H. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am. J. Kidney Dis. 47, 51-59 (2006).
240. Maahs D. M, et al. Uric acid lowering to prevent kidney function loss in diabetes: the preventing early renal function loss (PERL) allopurinol study. Curr. Diabetes Rep. 13, 550-559 (2013).
241. Nath K. A, Hostetter M. K, & Hostetter T. H. Pathophysiology of chronic tubulo-interstitial disease in rats. Interactions of dietary acid load, ammonia, and complement component C3. J. Clin. Invest. 76, 667-675 (1985).
242. Dobre M, et al. Persistent high serum bicarbonate and the risk of heart failure in patients with chronic kidney disease (CKD): a report from the Chronic Renal Insufficiency Cohort (CRIC) study. J. Am. Heart Associ. 4, e001599 (2015).
243. Strippoli G. F, Craig J. C, & Schena F. P. The number, quality, and coverage of randomized controlled trials in nephrology. J. Am. Soc. Nephrol. 15, 411-419 (2004).
244. Szczech L. A, et al. Primary care detection of chronic kidney disease in adults with type 2 diabetes: the ADD-CKD Study (awareness, detection and drug therapy in type 2 diabetes and chronic kidney disease). PLoS ONE 9, e110535 (2014).
245. Tuot D. S, et al. The Kidney Awareness Registry and Education (KARE) study: protocol of a randomized controlled trial to enhance provider and patient engagement with chronic kidney disease. BMC Nephrol. 16, 166 (2015).
246. Nitta K, Okada K, Yanai M, & Takahashi S. The Kidney Early Evaluation Program (KEEP) of Japan. Clin. Nephrol. 83, 52-55 (2015).
247. Narva A. S, Norton J. M, & Boulware L. E. Educating patients about CKD: the path to self-management and patient-centered care. Clin. J. Am. Soc. Nephrol. http: //dx.doi.org/10.2215/.CJN.07680715 (2015).
248. Sutton A. J, et al. Methods used in economic evaluations of chronic kidney disease testing - A systematic review. PLoS ONE 10, e0140063 (2015).
249. Fox C. H, et al. Improving evidence-based primary care for chronic kidney disease: study protocol for a cluster randomized control trial for translating evidence into practice (TRANSLATE CKD). Implement. Sci. 8, 88 (2013).
250. Levin A, Stevens P. E, Coresh J, & Levey A. Screening, monitoring, and treatment of stage 1 to 3 chronic kidney disease. Ann. Internal Med. 161, 81-82 (2014).
251. Hemmelgarn B. R, et al. Nephrology visits and health care resource use before and after reporting estimated glomerular filtration rate. JAMA 303, 1151-1158 (2010).
252. Hemmelgarn B. R, et al. Relation between kidney function, proteinuria, and adverse outcomes. JAMA 303, 423-429 (2010).
253. Zhang Z, et al. Importance of baseline distribution of proteinuria in renal outcomes trials: lessons from the reduction of endpoints in NIDDM with the angiotensin II antagonist losartan (RENAAL) study. J. Am. Soc. Nephrol. 16, 1775-1780 (2005).
254. Eijkelkamp W. B, 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. 18, 1540-1546 (2007).
255. Holtkamp F. A, et al. Albuminuria and blood pressure, independent targets for cardioprotective therapy in patients with diabetes and nephropathy: a post hoc analysis of the combined RENAAL and IDNT trials. Eur. Heart J. 32, 1493-1499 (2011).
256. Chou Y. H, et al. Clinical outcomes and predictors for ESRD and mortality in primary GN. Clin. J. Am. Soc. Nephrol. 7, 1401-1408 (2012).
257. Perkins B. A, et al. Regression of microalbuminuria in type 1 diabetes. New Engl. J. Med. 348, 2285-2293 (2003).
258. Levey A. S, et al. GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am. J. Kidney Dis. 64, 821-835 (2014).
259. Inker L. A, et al. GFR decline as an alternative end point to kidney failure in clinical trials: a meta-Analysis of treatment effects from 37 randomized trials. Am. J. Kidney Dis. 64, 848-859 (2014).
260. Lambers Heerspink H. J, et al. GFR decline and subsequent risk of established kidney outcomes: a meta-Analysis of 37 randomized controlled trials. Am. J. Kidney Dis. 64, 860-866 (2014).
261. Lambers Heerspink H. J, et al. Estimated GFR decline as a surrogate end point for kidney failure: a post hoc analysis from the Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan (RENAAL) study and Irbesartan Diabetic Nephropathy Trial (IDNT). Am. J. Kidney Dis. 63, 244-250 (2014).
262. Greene T, et al. Utility and validity of estimated GFR-based surrogate time to event end points in CKD: a simulation study. Am. J. Kidney Dis. 64, 867-879 (2014).
263. Schievink B, et al. Prediction of the effect of atrasentan on renal and heart failure outcomes based on short-Term changes in multiple risk markers. Eur. J. Prev. Cardiol. http: //dx.doi.org/.10.1177/2047487315598709 (2015).
264. Figarola J. L, Shanmugam N, Natarajan R, & Rahbar S. Anti-inflammatory effects of the advanced glycation end product inhibitor LR 90 in human monocytes. Diabetes 56, 647-655 (2007).
265. Parsa A, et al. APOL1 risk variants, race, and progression of chronic kidney disease. New Engl. J. Med. 369, 2183-2196 (2013).
266. [No authors listed.] Chapter 1: Definition and classification of CKD. Kidney Int. Suppl. 3, 19-62 (2013).
267. Tangri N, et al. A predictive model for progression of chronic kidney disease to kidney failure. JAMA 305, 1553-1559 (2011).
268. Landray M. J, et al. Prediction of ESRD and death among people with CKD: the Chronic Renal Impairment in Birmingham (CRIB) prospective cohort study. Am. J. Kidney Dis. 56, 1082-1094 (2010).
269. Gohda T, et al. Circulating TNF receptors 1 and 2 predict stage 3 CKD in type 1 diabetes. J. Am. Soc. Nephrol. 23, 516-524 (2012).
270. Sonoda Y, et al. Circulating TNF receptors 1 and 2 are associated with the severity of renal interstitial fibrosis in IgA nephropathy. PLoS ONE 10, e0122212 (2015).
271. Lee S. M, et al. Circulating TNF receptors are significant prognostic biomarkers for idiopathic membranous nephropathy. PLoS ONE 9, e104354 (2014).
272. Sabbisetti V. S, et al. Blood kidney injury molecule 1 is a biomarker of acute and chronic kidney injury and predicts progression to ESRD in type I diabetes. J. Am. Soc. Nephrol. 25, 2177-2186 (2014).
273. Fufaa G. D, et al. Association of urinary KIM 1, L FABP, NAG and NGAL with incident end-stage renal disease and mortality in American Indians with type 2 diabetes mellitus. Diabetologia 58, 188-198 (2015).
274. Kwon S. H, et al. KIM 1 expression predicts renal outcomes in IgA nephropathy. Clin. Exp. Nephrol. 17, 359-364 (2013).
275. Hosohata K, et al. Urinary Kim 1 is a sensitive biomarker for the early stage of diabetic nephropathy in Otsuka Long-Evans Tokushima Fatty rats. Diab. Vasc. Dis. Res. 11, 243-250 (2014).
276. Nielsen S. E, et al. The effect of RAAS blockade on markers of renal tubular damage in diabetic nephropathy: u NGAL, u-KIM1 and u LFABP. Scand. J. Clin. Lab. Invest. 72, 137-142 (2012).
277. Budoff M. J, et al. Relationship of estimated GFR and coronary artery calcification in the CRIC (Chronic Renal Insufficiency Cohort) Study. Am. J. Kidney Dis. 58, 519-526 (2011).
278. Hsu C. Y, & Bansal N. Measured GFR as gold standard - All that glitters is not gold?. Clin. J. Am. Soc. Nephrol. 6, 1813-1814 (2011).
279. Foster M. C, et al. Filtration markers as predictors of ESRD and mortality in Southwestern American Indians With type 2 diabetes. Am. J. Kidney Dis. 66, 75-83 (2015).
280. Lafayette R. A, & Lai G. Examining chronic kidney disease management in a single center. Clin. Nephrol. 62, 260-266 (2004).
281. Hsu C. Y, et al. Measured GFR does not outperform estimated GFR in predicting CKD-related complications. J. Am. Soc. Nephrol. 22, 1931-1937 (2011).
282. Ku E, et al. Change in measured GFR versus eGFR and CKD outcomes. J. Am. Soc. Nephrol. http: //dx.doi.org/10.1681/ASN.2015040341 (2015).
283. Davis C. F, et al. The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell 26, 319-330 (2014).
284. Antignac C, et al. The future of polycystic kidney disease research as seen by the 12 Kaplan Awardees. J. Am. Soc. Nephrol. 26, 2081-2095 (2015).
285. Hopp K, et al. Tolvaptan plus pasireotide shows enhanced efficacy in a PKD1 model. J. Am. Soc. Nephrol. 26, 39-47 (2015).
286. Patel V, Chowdhury R, & Igarashi P. Advances in the pathogenesis and treatment of polycystic kidney disease. Curr. Opin. Nephrol. Hypertens. 18, 99-106 (2009).
287. Genovese G, et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 329, 841-845 (2010).
288. Johnstone D. B, et al. APOL1 null alleles from a rural village in India do not correlate with glomerulosclerosis. PLoS ONE 7, e51546 (2012).
289. Nichols B, et al. Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1. Kidney Int. 87, 332-342 (2015).
290. US National Library of Medicine ClinicalTrials.gov [online], https: //clinicaltrials.gov/ct2/show/.NCT02156843?term=NCT02156843&rank=1 (2015).
291. US National Library of Medicine. ClinicalTrials.gov [online], https: //clinicaltrials.gov/show/NCT01683409 (2015).
292. de Zeeuw D, et al. CCR2 inhibitor CCX140 effective in phase 2 clinical trial in diabetic nephropathy. Nephrol. Dial. Transplant. 30 (Suppl. 3), iii531 (2015).
293. US National Library of Medicine ClinicalTrials.gov [online], https: //clinicaltrials.gov/ct2/show/.NCT01487109?term=NCT01487109&rank=1 (2015).
294. US National Library of Medicine. ClinicalTrials.gov [online], https: //clinicaltrials.gov/show/NCT01874431 (2014).
295. Ruilope L. M, et al. Rationale, design, and baseline characteristics of ARTS DN: a randomized study to assess the safety and efficacy of finerenone in patients with type 2 diabetes mellitus and a clinical diagnosis of diabetic nephropathy. Am. J. Nephrol. 40, 572-581 (2014).
296. US National Library of Medicine ClinicalTrials.gov [online], https: //clinicaltrials.gov/ct2/show/.NCT02010242?term=NCT02010242&rank=1 (2015).