Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Trials
Published in: Trials 1/2018

Open Access 01-12-2018 | Study protocol

Intervention using vitamin D for elevated urinary albumin in type 2 diabetes mellitus (IDEAL-2 Study): study protocol for a randomised controlled trial

Authors: Shahrad Taheri, Muhammad Asim, Hassan al Malki, Omar Fituri, Manikkam Suthanthiran, Phyllis August, IDEAL-2 Study Team

Published in: Trials | Issue 1/2018

Login to get access

Abstract

Background

The prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide. T2DM is associated with serious macro- and microvascular complications. In particular, diabetic kidney disease (DKD), which begins with excessive urinary albumin excretion, has a significant impact on affected individuals and is costly to healthcare services. Inhibition of the renin–angiotensin–aldosterone system (RAAS) with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) significantly reduces albuminuria in diabetes, but this effect is not observed in all those treated. Active vitamin D analogues have been observed to be reno-protective through inhibition of RAAS in animal and human studies. Therefore, it can be hypothesised that an active vitamin D analogue will have an additional benefit to ACEI/ARB treatment for albuminuria reduction in DKD.

Methods

The planned study is an ongoing non-blinded randomised controlled parallel-group trial examining the impact, in individuals with T2DM, of the addition of bioactive vitamin D (calcitriol) to RAAS inhibition treatment using ACI or ARB on urinary albumin excretion over a period of 26 weeks. The primary outcome measure is the urinary albumin creatinine ratio. It is planned for the study to recruit 320 participants. Other outcome measures of interest include 24-h urine albumin (24 h UA) excretion, estimated glomerular filtration rate (eGFR), blood pressure and quality of life. Safety will be assessed throughout.

Discussion

If the addition of calcitriol to RAAS inhibition with ACEI or ARB safely results in a significant reduction in albuminuria, the study adds to the body of evidence supporting a role for vitamin D in reno-protection, will inform clinical practice and could result in significant reduction of healthcare costs associated with DKD.

Trial registration

ISRCTN, ISRCTN86739609. Registered on 7 June 2017. ClinicalTrials.gov, NCT03216564. Registered on 13 July 2017.
Appendix
Available only for authorised users
Literature
1.
2.
Foley RN, Collins AJ. End-stage renal disease in the United States: an update from the United States Renal Data System. J Am Soc Nephrol. 2007;18(10):2644–8.CrossRefPubMed
3.
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329(20):1456–62.CrossRefPubMed
4.
Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, 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.CrossRefPubMed
5.
Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, 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):851–860.
6.
Ruggenenti P, Cravedi P, Remuzzi G. The RAAS in the pathogenesis and treatment of diabetic nephropathy. Nat Rev Nephrol. 2010;6(6):319–30.CrossRefPubMed
7.
Parving HH, de Zeeuw D, Cooper ME, Remuzzi G, Liu N, Lunceford J, et al. ACE gene polymorphism and losartan treatment in type 2 diabetic patients with nephropathy. J Am Soc Nephrol. 2008;19(4):771–9.CrossRefPubMedPubMedCentral
8.
Azizi M, Menard J, Bissery A, Guyenne TT, Bura-Riviere A, Vaidyanathan S, et al. Pharmacologic demonstration of the synergistic effects of a combination of the renin inhibitor aliskiren and the AT1 receptor antagonist valsartan on the angiotensin II-renin feedback interruption. J Am Soc Nephrol. 2004;15(12):3126–33.CrossRefPubMed
9.
Muller DN, Luft FC. Direct renin inhibition with aliskiren in hypertension and target organ damage. Clin J Am Soc Nephrol. 2006;1(2):221–8.CrossRefPubMed
10.
Deb DK, Sun T, Wong KE, Zhang Z, Ning G, Zhang Y, et al. Combined vitamin D analog and AT1 receptor antagonist synergistically block the development of kidney disease in a model of type 2 diabetes. Kidney Int 2010; 77(11):1000–1009.
11.
Doorenbos CR, van den Born J, Navis G, de Borst MH. Possible renoprotection by vitamin D in chronic renal disease: beyond mineral metabolism. Nat Rev Nephrol. 2009;5(12):691–700.CrossRefPubMed
12.
Tan X, He W, Liu Y. Combination therapy with paricalcitol and trandolapril reduces renal fibrosis in obstructive nephropathy. Kidney Int. 2009;76(12):1248–57.CrossRefPubMedPubMedCentral
13.
Agarwal R. Vitamin D, proteinuria, diabetic nephropathy, and progression of CKD. Clin J Am Soc Nephrol. 2009;4(9):1523–8.CrossRefPubMed
14.
Klaus G. Renoprotection with vitamin D: specific for diabetic nephropathy? Kidney Int. 2008;73(2):141–3.CrossRefPubMed
15.
Tian J, Liu Y, Williams LA, de Zeeuw D. Potential role of active vitamin D in retarding the progression of chronic kidney disease. Nephrol Dial Transplant. 2007;22(2):321–8.CrossRefPubMed
16.
Makibayashi K, Tatematsu M, Hirata M, Fukushima N, Kusano K, Ohashi S, et al. A vitamin D analog ameliorates glomerular injury on rat glomerulonephritis. Am J Pathol. 2001;158(5):1733–41.CrossRefPubMedPubMedCentral
17.
Abe H, Iehara N, Utsunomiya K, Kita T, Doi T. A vitamin D analog regulates mesangial cell smooth muscle phenotypes in a transforming growth factor-beta type II receptor-mediated manner. J Biol Chem. 1999;274(30):20874–8.CrossRefPubMed
18.
Kuhlmann A, Haas CS, Gross ML, Reulbach U, Holzinger M, Schwarz U, et al. 1,25-Dihydroxyvitamin D3 decreases podocyte loss and podocyte hypertrophy in the subtotally nephrectomized rat. Am J Physiol Renal Physiol 2004; 286(3):F526–F533.
19.
Freundlich M, Quiroz Y, Zhang Z, Zhang Y, Bravo Y, Weisinger JR, et al. Suppression of renin-angiotensin gene expression in the kidney by paricalcitol. Kidney Int 2008; 74(11):1394–1402.
20.
Zhang Z, Sun L, Wang Y, Ning G, Minto AW, Kong J, et al. Renoprotective role of the vitamin D receptor in diabetic nephropathy. Kidney Int 2008; 73(2):163–171.
21.
Zhang Y, Deb DK, Kong J, Ning G, Wang Y, Li G, Chen Y, et al. Long-term therapeutic effect of vitamin D analog doxercalciferol on diabetic nephropathy: strong synergism with AT1 receptor antagonist. Am J Physiol Renal Physiol. 2009;297(3):F791–801.CrossRefPubMedPubMedCentral
22.
de Boer IH, Ioannou GN, Kestenbaum B, Brunzell JD, Weiss NS. 25-Hydroxyvitamin D levels and albuminuria in the Third National Health and Nutrition Examination Survey (NHANES III). Am J Kidney Dis. 2007;50(1):69–77.CrossRefPubMed
23.
Ravani P, Malberti F, Tripepi G, Pecchini P, Cutrupi S, Pizzini P. Vitamin D levels and patient outcome in chronic kidney disease. Kidney Int. 2009;75(1):88–95.CrossRefPubMed
24.
Fishbane S, Chittineni H, Packman M, Dutka P, Ali N, Durie N. Oral paricalcitol in the treatment of patients with CKD and proteinuria: a randomized trial. Am J Kidney Dis. 2009;54(4):647–52.CrossRefPubMed
25.
Alborzi P, Patel NA, Peterson C, Bills JE, Bekele DM, Bunaye Z, et al. Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: a randomized double-blind pilot trial. Hypertension 2008; 52(2):249–255.
26.
Szeto CC, Chow KM, Kwan BC, Chung KY, Leung CB, Li PK. Oral calcitriol for the treatment of persistent proteinuria in immunoglobulin A nephropathy: an uncontrolled trial. Am J Kidney Dis. 2008;51(5):724–31.CrossRefPubMed
27.
Agarwal R, Acharya M, Tian J, Hippensteel RL, Melnick JZ, Qiu P, et al. Antiproteinuric effect of oral paricalcitol in chronic kidney disease. Kidney Int 2005; 68(6):2823–2828.
28.
de Zeeuw D, Agarwal R, Amdahl M, Audhya P, Coyne D, Garimella T, et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet. 2010;376(9752):1543–51.CrossRefPubMed
29.
Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Greene DA. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care. 1994;17(11):1281–9.CrossRefPubMed
30.
Feldman EL, Stevens MJ. Clinical testing in diabetic peripheral neuropathy. Can J Neurol Sci. 1994;21(4):S3–7.CrossRefPubMed
31.
Pucci G, Cheriyan J, Hubsch A, Hickson SS, Gajendragadkar PR, Watson T, et al. Evaluation of the Vicorder, a novel cuff-based device for the noninvasive estimation of central blood pressure. J Hypertens. 2013;31(1):77–85.CrossRefPubMed
32.
Chan RW, Lai FM, Li EK, Tam LS, Chow KM, Li PK, et al. Messenger RNA expression of RANTES in the urinary sediment of patients with lupus nephritis. Nephrology (Carlton). 2006;11(3):219–25.CrossRef
33.
Avihingsanon Y, Phumesin P, Benjachat T, Akkasilpa S, Kittikowit V, Praditpornsilpa K, et al. Measurement of urinary chemokine and growth factor messenger RNAs: a noninvasive monitoring in lupus nephritis. Kidney Int. 2006;69(4):747–53.CrossRefPubMed
34.
Anglicheau D, Suthanthiran M. Noninvasive prediction of organ graft rejection and outcome using gene expression patterns. Transplantation. 2008;86(2):192–9.CrossRefPubMedPubMedCentral
35.
Muthukumar T, Dadhania D, Ding R, Snopkowski C, Naqvi R, Lee JB, et al. Messenger RNA for FOXP3 in the urine of renal-allograft recipients. N Engl J Med. 2005;353(22):2342–51.CrossRefPubMed
36.
Tatapudi RR, Muthukumar T, Dadhania D, Ding R, Li B, Sharma VK, et al. Noninvasive detection of renal allograft inflammation by measurements of mRNA for IP-10 and CXCR3 in urine. Kidney Int. 2004;65(6):2390–7.CrossRefPubMed
37.
Muthukumar T, Ding R, Dadhania D, Medeiros M, Li B, Sharma VK, et al. Serine proteinase inhibitor-9, an endogenous blocker of granzyme B/perforin lytic pathway, is hyperexpressed during acute rejection of renal allografts. Transplantation. 2003;75(9):1565–70.CrossRefPubMed
38.
Dadhania D, Muthukumar T, Ding R, Li B, Hartono C, Serur D, et al. Molecular signatures of urinary cells distinguish acute rejection of renal allografts from urinary tract infection. Transplantation 2003; 75(10):1752–1754.
39.
Li B, Hartono C, Ding R, Sharma VK, Ramaswamy R, Qian B, et al. Noninvasive diagnosis of renal-allograft rejection by measurement of messenger RNA for perforin and granzyme B in urine. N Engl J Med 2001; 344(13):947–954.
40.
Harvey SJ, Jarad G, Cunningham J, Goldberg S, Schermer B, Harfe BD, et al. Podocyte-specific deletion of dicer alters cytoskeletal dynamics and causes glomerular disease. J Am Soc Nephrol 2008; 19(11):2150–2158.
41.
Wang Q, Wang Y, Minto AW, Wang J, Shi Q, Li X, et al. MicroRNA-377 is up-regulated and can lead to increased fibronectin production in diabetic nephropathy. FASEB J. 2008;22(12):4126–35.CrossRefPubMedPubMedCentral
42.
Kato M, Zhang J, Wang M, Lanting L, Yuan H, Rossi JJ, et al. MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors. Proc Natl Acad Sci U S A. 2007;104(9):3432–7.CrossRefPubMedPubMedCentral
43.
Wang B, Koh P, Winbanks C, Coughlan MT, McClelland A, Watson A, et al. miR-200a Prevents renal fibrogenesis through repression of TGF-beta2 expression. Diabetes. 2011;60(1):280–7.CrossRefPubMed
44.
Krupa A, Jenkins R, Luo DD, Lewis A, Phillips A, Fraser D. Loss of MicroRNA-192 promotes fibrogenesis in diabetic nephropathy. J Am Soc Nephrol. 2010;21(3):438–47.CrossRefPubMedPubMedCentral
45.
Wang G, Kwan BC, Lai FM, Chow KM, Kam-Tao Li P, Szeto CC. Expression of microRNAs in the urinary sediment of patients with IgA nephropathy. Dis Markers. 2010;28(2):79–86.CrossRefPubMedPubMedCentral
46.
Tohid H, Choudhury SM, Agouba S, Aden A, Ahmed LHM, Omar O, et al. Perceptions and attitudes to clinical research participation in Qatar. Contemp Clin Trials Commun 2017; 8(12):241–247.
47.
de Borst MH, Hajhosseiny R, Tamez H, Wenger J, Thadhani R, Goldsmith DJ. Active vitamin D treatment for reduction of residual proteinuria: a systematic review. J Am Soc Nephrol. 2013;24(11):1863–71.CrossRefPubMedPubMedCentral
48.
Parvanova A, Trillini M, Podesta MA, Iliev IP, Ruggiero B, Abbate M, et al. Moderate salt restriction with or without paricalcitol in type 2 diabetes and losartan-resistant macroalbuminuria (PROCEED): a randomised, double-blind, placebo-controlled, crossover trial. Lancet Diabetes Endocrinol. 2018;6(1):27–40.CrossRefPubMed
49.
Krairittichai U, Mahannopkul R, Bunnag S. An open label, randomized controlled study of oral calcitriol for the treatment of proteinuria in patients with diabetic kidney disease. J Med Assoc Thail. 2012;95(Suppl 3):S41–7.
50.
Metadata
Title
Intervention using vitamin D for elevated urinary albumin in type 2 diabetes mellitus (IDEAL-2 Study): study protocol for a randomised controlled trial
Authors
Shahrad Taheri
Muhammad Asim
Hassan al Malki
Omar Fituri
Manikkam Suthanthiran
Phyllis August
IDEAL-2 Study Team
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Trials / Issue 1/2018
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-018-2616-5

Other articles of this Issue 1/2018

Trials 1/2018 Go to the issue

Study protocol

Lumen-apposing metal stents (LAMS) versus plastic stents for EUS-guided drainage of walled-off necrosis (WON) (LVPWON): study protocol for a multicenter randomized controlled trial

Study protocol

Balancing ACT: evaluating the effectiveness of psychoeducation and Acceptance and Commitment Therapy (ACT) groups for people with bipolar disorder: study protocol for pilot randomised controlled trial

Research

Exploring and adjusting for potential learning effects in ROLARR: a randomised controlled trial comparing robotic-assisted vs. standard laparoscopic surgery for rectal cancer resection

Study protocol

Photodynamic therapy with Bixa orellana extract and LED for the reduction of halitosis: study protocol for a randomized, microbiological and clinical trial

Study protocol

The efficacy of the traditional Chinese medicine Juanbi pill combined with methotrexate in active rheumatoid arthritis: study protocol for a randomized controlled trial

Study protocol

Improving partnerships with family members of ICU patients: study protocol for a randomized controlled trial