title: Early change in proteinuria as a surrogate outcome in kidney disease progression: a systematic review of previous analyses and creation of a patient-level pooled dataset.
abstract: BACKGROUND
  Proteinuria is a candidate surrogate end point for randomized controlled trials (RCTs) in chronic kidney disease (CKD). There is a reasonably sound biological basis for this hypothesis, but only preliminary empirical evidence currently exists.
  
  
  METHODS
  A systematic review and creation of a patient-level dataset of randomized controlled trials (RCTs) in CKD that reported changes in proteinuria and assessed progression of kidney disease as defined by dialysis, transplantation, death, or changes in GFR or creatinine were performed.
  
  
  RESULTS
  Systematic review. Seventy RCTs met the eligibility criteria; 17 eligible RCTs contained analyses of proteinuria as a predictor of outcomes; 15 RCTs concluded that greater proteinuria was associated with adverse outcomes. A majority were studies of diabetic or hypertensive kidney disease and tested renin-angiotensin system blockade. Definitions of predictor and outcome variables were too variable to conduct a meta-analysis of group data. Database creation. Over 4 years was required to create the patient-level dataset. The final dataset included 34 studies and > 9000 patients with a variety of CKD types and interventions.
  
  
  CONCLUSIONS
  There are a relatively small number of RCTs designed to rigorously test therapies for kidney disease progression. Current analyses of change in proteinuria as a predictor of CKD progression are heterogeneous and incomplete, indicating further evaluation in a pooled individual patient-level database is necessary to advance knowledge in this field.
authors.affiliation: Tufts Medical Center, Boston, MA, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Stoycheff
authors.forename: Kruti
authors.initials: K
authors.lastname: Pandya
authors.forename: Aghogho
authors.initials: A
authors.lastname: Okparavero
authors.forename: Abigail
authors.initials: A
authors.lastname: Schiff
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Levey
authors.forename: Tom
authors.initials: T
authors.lastname: Greene
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Stevens
mesh_terms: D015415:Biomarkers; D018450:Disease Progression; D006801:Humans; D007674:Kidney Diseases / Q000150:complications*; D011507:Proteinuria / Q000175:diagnosis* / Q000209:etiology*; D016032:Randomized Controlled Trials as Topic
chemical_list: D015415:Biomarkers
references.citation: Am J Kidney Dis. 2004 Jan;43(1):10-8
references.pmid: 14712422
references.citation: Kidney Int Suppl. 2004 Nov;(92):S99-101
references.pmid: 15485429
references.citation: Am J Kidney Dis. 2009 Aug;54(2):205-26
references.pmid: 19577347
references.citation: N Engl J Med. 2001 Sep 20;345(12):851-60
references.pmid: 11565517
references.citation: J Am Soc Nephrol. 2003 Jun;14(6):1578-83
references.pmid: 12761258
references.citation: Kidney Int. 2004 May;65(5):1842-9
references.pmid: 15086925
references.citation: Kidney Int. 2004 Oct;66(4):1596-605
references.pmid: 15458456
references.citation: Kidney Int. 2007 May;71(9):924-30
references.pmid: 17377504
references.citation: Am J Nephrol. 2004 Jan-Feb;24(1):32-40
references.pmid: 14685005
references.citation: Transplantation. 2001 Apr 27;71(8):1091-7
references.pmid: 11374408
references.citation: Lancet. 1999 Jul 31;354(9176):359-64
references.pmid: 10437863
references.citation: Nephrol Dial Transplant. 1994;9(11):1590-4
references.pmid: 7870348
references.citation: Lancet. 1999 Mar 13;353(9156):883-7
references.pmid: 10093981
references.citation: Clin Transplant. 2006 Jan-Feb;20(1):10-8
references.pmid: 16556147
references.citation: Stat Med. 1989 Apr;8(4):431-40
references.pmid: 2727467
references.citation: Kidney Int. 1997 Jun;51(6):1908-19
references.pmid: 9186882
references.citation: Kidney Int. 1995 Apr;47(4):1130-5
references.pmid: 7783410
references.citation: Transplant Proc. 2002 Aug;34(5):1635-7
references.pmid: 12176515
references.citation: J Am Soc Nephrol. 2001 Apr;12(4):791-799
references.pmid: 11274240
references.citation: Lancet. 2005 Mar 12-18;365(9463):939-46
references.pmid: 15766995
references.citation: Am J Kidney Dis. 2003 May;41(5):972-83
references.pmid: 12722031
references.citation: Clin J Am Soc Nephrol. 2006 Sep;1(5):925-32
references.pmid: 17699309
references.citation: J Hypertens. 2001 Oct;19(10):1871-6
references.pmid: 11593109
references.citation: Nephrol Dial Transplant. 2001 May;16(5):961-6
references.pmid: 11328901
references.citation: Transplantation. 2005 Jan 27;79(2):205-12
references.pmid: 15665769
references.citation: J Am Soc Nephrol. 1999 Aug;10(8):1772-7
references.pmid: 10446945
references.citation: Kidney Int. 2003 Sep;64(3):1027-34
references.pmid: 12911553
references.citation: N Engl J Med. 2006 Jan 12;354(2):131-40
references.pmid: 16407508
references.citation: Diabetes Care. 2000 Apr;23 Suppl 2:B54-64
references.pmid: 10860192
references.citation: Kidney Int. 2006 Aug;70(4):732-42
references.pmid: 16820790
references.citation: Arthritis Rheum. 2002 Aug;46(8):2121-31
references.pmid: 12209517
references.citation: Lancet. 1997 Jun 28;349(9069):1857-63
references.pmid: 9217756
references.citation: Nephrol Dial Transplant. 2004 Apr;19(4):852-7
references.pmid: 15031340
references.citation: Am J Kidney Dis. 1996 Apr;27(4):489-95
references.pmid: 8678058
references.citation: Am J Hypertens. 1992 Jul;5(7):423-30
references.pmid: 1637513
references.citation: Nephrol Dial Transplant. 2005 Oct;20(10):2139-45
references.pmid: 16030050
references.citation: N Engl J Med. 1989 Jan 5;320(1):8-13
references.pmid: 2642605
references.citation: Kidney Int. 2004 Jun;65(6):2309-20
references.pmid: 15149345
references.citation: Ann Intern Med. 1995 Nov 15;123(10):754-62
references.pmid: 7574193
references.citation: Contrib Nephrol. 1995;111:184-92; discussion 192-3
references.pmid: 7758341
references.citation: N Engl J Med. 2001 Sep 20;345(12):861-9
references.pmid: 11565518
references.citation: Nephrol Dial Transplant. 2003 Nov;18(11):2314-20
references.pmid: 14551359
references.citation: N Engl J Med. 1992 May 21;326(21):1373-9
references.pmid: 1569973
references.citation: BMJ. 2004 Feb 28;328(7438):495
references.pmid: 14960504
references.citation: Am J Kidney Dis. 2003 Mar;41(3 Suppl 1):S26-30
references.pmid: 12612947
references.citation: Clin J Am Soc Nephrol. 2006 Jul;1(4):874-84
references.pmid: 17699300
references.citation: Am J Kidney Dis. 2006 Feb;47(2):233-40
references.pmid: 16431252
references.citation: J Am Soc Nephrol. 2002 Jan;13(1):142-148
references.pmid: 11752031
references.citation: Ren Fail. 2004 Jul;26(4):453-9
references.pmid: 15462115
references.citation: Kidney Int Suppl. 2004 Nov;(92):S90-6
references.pmid: 15485427
references.citation: Ann Intern Med. 1982 Jun;96(6 Pt 1):728-36
references.pmid: 7046543
references.citation: Clin J Am Soc Nephrol. 2006 May;1(3):467-74
references.pmid: 17699247
references.citation: N Engl J Med. 1993 Nov 11;329(20):1456-62
references.pmid: 8413456
references.citation: Kidney Int. 2001 Apr;59(4):1484-90
references.pmid: 11260412
references.citation: BMJ. 1994 Oct 1;309(6958):833-7
references.pmid: 7950612
references.citation: N Engl J Med. 1996 Apr 11;334(15):939-45
references.pmid: 8596594
references.citation: Kidney Int Suppl. 1997 Dec;63:S58-62
references.pmid: 9407423
references.citation: Kidney Int. 1999 Dec;56(6):2220-6
references.pmid: 10594798
references.citation: N Engl J Med. 2007 Jun 7;356(23):2349-60
references.pmid: 17554116
references.citation: Kidney Int. 1992 Aug;42(2):452-8
references.pmid: 1405330
references.citation: J Am Soc Nephrol. 1998 Mar;9(3):444-50
references.pmid: 9513907
references.citation: Lancet. 1984 Dec 8;2(8415):1291-6
references.pmid: 6150320
references.citation: Kidney Int. 2001 Sep;60(3):1131-40
references.pmid: 11532109
references.citation: N Engl J Med. 1992 Aug 27;327(9):599-603
references.pmid: 1640953
references.citation: N Engl J Med. 1994 Mar 31;330(13):877-84
references.pmid: 8114857
references.citation: Nephrol Dial Transplant. 2001 Nov;16(11):2158-65
references.pmid: 11682661
references.citation: JAMA. 2002 Nov 20;288(19):2421-31
references.pmid: 12435255
references.citation: Lancet. 2003 Jan 11;361(9352):117-24
references.pmid: 12531578
references.citation: Kidney Int. 2003 Jun;63(6):2254-61
references.pmid: 12753315
references.citation: Am J Kidney Dis. 1996 Jun;27(6):765-75
references.pmid: 8651239
references.citation: Diabetes Res Clin Pract. 2006 Feb;71(2):156-63
references.pmid: 16009446
references.citation: J Am Soc Nephrol. 2003 Mar;14(3):641-7
references.pmid: 12595499
references.citation: J Am Soc Nephrol. 2005 Apr;16(4):1076-84
references.pmid: 15728784
references.citation: Ann Transplant. 2001;6(1):47-53
references.pmid: 11803607
references.citation: Kidney Int. 1998 May;53(5):1209-16
references.pmid: 9573535
references.citation: Am J Nephrol. 1996;16(6):489-99
references.pmid: 8955760
references.citation: Ann Intern Med. 1975 Nov;83(5):606-15
references.pmid: 1106278
references.citation: Kidney Int Suppl. 2002 Dec;(82):S64-7
references.pmid: 12410858
references.citation: Am J Kidney Dis. 2006 May;47(5):751-60
references.pmid: 16632013
references.citation: Ann Intern Med. 2003 Aug 19;139(4):244-52
references.pmid: 12965979
references.citation: Am J Kidney Dis. 2005 Feb;45(2):281-7
references.pmid: 15685505
references.citation: Blood Press. 1995 Mar;4(2):85-90
references.pmid: 7599759
references.citation: Arch Intern Med. 2005 Apr 25;165(8):947-53
references.pmid: 15851648
references.citation: Kidney Int. 1996 Nov;50(5):1651-8
references.pmid: 8914032