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CompletedNCT03317925RETASKUpdated Nov 8, 2017

Renal Transplant Injury and the Renin-Angiotensin System in Kids (RETASK)

An observational study in Renal Transplant, Renin-Angiotensin System and Rejection Acute Renal, sponsored by Wake Forest University Health Sciences. Completed at 1 site in United States. Open to participants aged 1 Year to 20 Years. Per ClinicalTrials.gov, last updated 2017-11-08.

Sponsored by Wake Forest University Health Sciences · Observational

Study type
Observational
Model
Cohort
Time perspective
Prospective
Enrollment
29
Ages
1 Year to 20 Years
Sex
All
01

Study summary

In pediatric kidney transplant patients, rejection, medication toxicity and ischemia cause early and chronic renal allograft injury, which reduces graft lifespan and patient survival. Early detection of injury would facilitate prevention and treatment. The gold standard surveillance biopsy has limitations including delayed discovery of injury. No noninvasive test identifies graft injury before it is clinically apparent. This project's goal is to develop a novel early marker of subclinical graft injury to facilitate prompt recognition and treatment.

Read the detailed description

Kidney damage activates the traditional renin-angiotensin (Ang) system (RAS), characterized by Ang-converting enzyme (ACE)/Ang II/Ang II type 1 receptor. The Ang-converting enzyme 2 (ACE2)/Ang-(1-7)/Mas pathway counteracts this damage. The balance, or ratio, between levels of the ACE/Ang II and ACE2/Ang-(1-7) pathways may be clinically important because Ang-(1-7) counteracts Ang II-mediated injury. An increase in ACE and Ang II expression and a decrease in ACE2 and Ang-(1-7) expression on tubular cells may promote renal injury. Tubular damage may increase urinary loss of protective ACE2 and Ang-(1-7), propagating renal damage by allowing ACE and Ang II to stimulate inflammation and fibrosis unopposed. The investigators hypothesis is that a shift in the urinary ACE-to-ACE2 and Ang II-to-Ang-(1-7) ratios towards ACE2 and Ang-(1-7) predicts acute graft injury diagnosed on renal biopsy and predicts chronic graft damage on renal biopsy.

02

Conditions studied

  • Renal Transplant
  • Renin-Angiotensin System
  • Rejection Acute Renal
  • Rejection Chronic Renal
  • Rejection of Renal Transplant

Keywords

  • Pediatric Renal Transplant
  • Renal Allograft
  • Angiotensin II
  • Angiotensin-(1-7)
  • ACE
  • ACE2
03

Who can participate

Ages eligible
1 Year to 20 Years
Sexes eligible
All
Accepts healthy volunteers
No
Sampling method
Non-probability sample

Study population

This is an observational study with a convenience sample of patients recruited from Lucile Packard Children's Hospital kidney transplant evaluation clinic.

Inclusion criteria

  • Ages 1 - 20 years
  • Actively listed on the transplant list at Lucile Packard Children's Hospital at Stanford and received a renal transplant during the study enrollment period

Exclusion criteria

Exclusion Criteria:

  • Transplanted at a center other than Lucile Packard Children's Hospital at Stanford
04

Study design

Observational model
Cohort
Time perspective
Prospective
Enrollment
29 participants (actual)
Patient registry
No
Biospecimen retention
Samples without dna

Interventions

  • ProcedureRenal Transplantation

    Kidney transplantation and biomarkers that can identify injury after transplant.

05

What researchers measure

Primary outcomes

  1. Acute graft injury

    Renal biopsy-confirmed acute renal allograft injury as determined by a pathologist (binary yes or no)

    Time frame: Within six months after kidney transplant

Secondary outcomes

  1. Chronic graft damage

    Renal biopsy-confirmed chronic renal allograft damage as determined by a quantitative fibrosis pathology stain (percent fibrosis from 0 to 100%)

    Time frame: Six months after kidney transplant

  2. Renal function

    Glomerular filtration rate by the Schwartz equation (mL/min/1.73 m\^2)

    Time frame: Within six months after kidney transplant

  3. Proteinuria

    Urine protein-to-creatinine ratio above 0.2 mg/mg creatinine

    Time frame: Within six months after kidney transplant

06

Study locations

1 site
  • Wake Forest University Baptist Medical Center
    Winston-Salem, North Carolina 27157, United States
07

References and documents

Publications

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  • Jurewicz M, McDermott DH, Sechler JM, Tinckam K, Takakura A, Carpenter CB, Milford E, Abdi R. Human T and natural killer cells possess a functional renin-angiotensin system: further mechanisms of angiotensin II-induced inflammation. J Am Soc Nephrol. 2007 Apr;18(4):1093-102. doi: 10.1681/ASN.2006070707. Epub 2007 Feb 28. PubMed 17329576 ↗
  • Su Z, Zimpelmann J, Burns KD. Angiotensin-(1-7) inhibits angiotensin II-stimulated phosphorylation of MAP kinases in proximal tubular cells. Kidney Int. 2006 Jun;69(12):2212-8. doi: 10.1038/sj.ki.5001509. Epub 2006 May 3. PubMed 16672906 ↗
  • Moon JY. ACE2 and Angiotensin-(1-7) in Hypertensive Renal Disease. Electrolyte Blood Press. 2011 Dec;9(2):41-4. doi: 10.5049/EBP.2011.9.2.41. Epub 2011 Dec 31. PubMed 22438854 ↗
  • Ahmed AK, El Nahas AM, Johnson TS. Changes in matrix metalloproteinases and their inhibitors in kidney transplant recipients. Exp Clin Transplant. 2012 Aug;10(4):332-43. doi: 10.6002/ect.2012.0013. PubMed 22845765 ↗
  • Castoldi G, di Gioia CR, Travaglini C, Busca G, Redaelli S, Bombardi C, Stella A. Angiotensin II increases tissue-specific inhibitor of metalloproteinase-2 expression in rat aortic smooth muscle cells in vivo: evidence of a pressure-independent effect. Clin Exp Pharmacol Physiol. 2007 Mar;34(3):205-9. doi: 10.1111/j.1440-1681.2007.04573.x. PubMed 17250640 ↗
  • Mazanowska O, Kaminska D, Krajewska M, Zabinska M, Kopec W, Boratynska M, Chudoba P, Patrzalek D, Klinger M. Imbalance of metallaproteinase/tissue inhibitors of metalloproteinase system in renal transplant recipients with chronic allograft injury. Transplant Proc. 2011 Oct;43(8):3000-3. doi: 10.1016/j.transproceed.2011.08.012. PubMed 21996210 ↗
  • Ling XB, Sigdel TK, Lau K, Ying L, Lau I, Schilling J, Sarwal MM. Integrative urinary peptidomics in renal transplantation identifies biomarkers for acute rejection. J Am Soc Nephrol. 2010 Apr;21(4):646-53. doi: 10.1681/ASN.2009080876. Epub 2010 Feb 11. PubMed 20150539 ↗
  • Lutz J, Yao Y, Song E, Antus B, Hamar P, Liu S, Heemann U. Inhibition of matrix metalloproteinases during chronic allograft nephropathy in rats. Transplantation. 2005 Mar 27;79(6):655-61. doi: 10.1097/01.tp.0000151644.85832.b5. PubMed 15785371 ↗
  • Pan CH, Wen CH, Lin CS. Interplay of angiotensin II and angiotensin(1-7) in the regulation of matrix metalloproteinases of human cardiocytes. Exp Physiol. 2008 May;93(5):599-612. doi: 10.1113/expphysiol.2007.041830. Epub 2008 Feb 22. PubMed 18296491 ↗
  • Clark MA, Tallant EA, Diz DI. Downregulation of the AT1A receptor by pharmacologic concentrations of Angiotensin-(1-7). J Cardiovasc Pharmacol. 2001 Apr;37(4):437-48. doi: 10.1097/00005344-200104000-00011. PubMed 11300657 ↗
  • Brosnihan KB, Neves LA, Joyner J, Averill DB, Chappell MC, Sarao R, Penninger J, Ferrario CM. Enhanced renal immunocytochemical expression of ANG-(1-7) and ACE2 during pregnancy. Hypertension. 2003 Oct;42(4):749-53. doi: 10.1161/01.HYP.0000085220.53285.11. Epub 2003 Jul 21. PubMed 12874086 ↗
  • Koka V, Huang XR, Chung AC, Wang W, Truong LD, Lan HY. Angiotensin II up-regulates angiotensin I-converting enzyme (ACE), but down-regulates ACE2 via the AT1-ERK/p38 MAP kinase pathway. Am J Pathol. 2008 May;172(5):1174-83. doi: 10.2353/ajpath.2008.070762. Epub 2008 Apr 10. PubMed 18403595 ↗
  • Dong J, Wong SL, Lau CW, Lee HK, Ng CF, Zhang L, Yao X, Chen ZY, Vanhoutte PM, Huang Y. Calcitriol protects renovascular function in hypertension by down-regulating angiotensin II type 1 receptors and reducing oxidative stress. Eur Heart J. 2012 Dec;33(23):2980-90. doi: 10.1093/eurheartj/ehr459. Epub 2012 Jan 19. PubMed 22267242 ↗
  • Dai B, David V, Martin A, Huang J, Li H, Jiao Y, Gu W, Quarles LD. A comparative transcriptome analysis identifying FGF23 regulated genes in the kidney of a mouse CKD model. PLoS One. 2012;7(9):e44161. doi: 10.1371/journal.pone.0044161. Epub 2012 Sep 6. PubMed 22970174 ↗
  • Ejaz AA, Kambhampati G, Ejaz NI, Dass B, Lapsia V, Arif AA, Asmar A, Shimada M, Alsabbagh MM, Aiyer R, Johnson RJ. Post-operative serum uric acid and acute kidney injury. J Nephrol. 2012 Jul-Aug;25(4):497-505. doi: 10.5301/jn.5000173. PubMed 22684655 ↗
  • el-Agroudy AE, Hassan NA, Foda MA, Ismail AM, el-Sawy EA, Mousa O, Ghoneim MA. Effect of angiotensin II receptor blocker on plasma levels of TGF-beta 1 and interstitial fibrosis in hypertensive kidney transplant patients. Am J Nephrol. 2003 Sep-Oct;23(5):300-6. doi: 10.1159/000072820. Epub 2003 Aug 6. PubMed 12904684 ↗
  • Haririan A, Metireddy M, Cangro C, Nogueira JM, Rasetto F, Cooper M, Klassen DK, Weir MR. Association of serum uric acid with graft survival after kidney transplantation: a time-varying analysis. Am J Transplant. 2011 Sep;11(9):1943-50. doi: 10.1111/j.1600-6143.2011.03613.x. Epub 2011 Aug 3. PubMed 21812917 ↗
  • Kanellis J, Watanabe S, Li JH, Kang DH, Li P, Nakagawa T, Wamsley A, Sheikh-Hamad D, Lan HY, Feng L, Johnson RJ. Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension. 2003 Jun;41(6):1287-93. doi: 10.1161/01.HYP.0000072820.07472.3B. Epub 2003 May 12. PubMed 12743010 ↗
  • Numakura K, Satoh S, Tsuchiya N, Saito M, Maita S, Obara T, Tsuruta H, Inoue T, Narita S, Horikawa Y, Kagaya H, Miura M, Habuchi T. Hyperuricemia at 1 year after renal transplantation, its prevalence, associated factors, and graft survival. Transplantation. 2012 Jul 27;94(2):145-51. doi: 10.1097/TP.0b013e318254391b. PubMed 22728291 ↗
  • Feig DI. Hyperuricemia and hypertension. Adv Chronic Kidney Dis. 2012 Nov;19(6):377-85. doi: 10.1053/j.ackd.2012.05.009. PubMed 23089272 ↗
  • Szabo A, Lutz J, Schleimer K, Antus B, Hamar P, Philipp T, Heemann U. Effect of angiotensin-converting enzyme inhibition on growth factor mRNA in chronic renal allograft rejection in the rat. Kidney Int. 2000 Mar;57(3):982-91. doi: 10.1046/j.1523-1755.2000.00926.x. PubMed 10720951 ↗
  • Tylicki L, Biedunkiewicz B, Chamienia A, Wojnarowski K, Zdrojewski Z, Aleksandrowicz E, Lysiak-Szydlowska W, Rutkowski B. Renal allograft protection with angiotensin II type 1 receptor antagonists. Am J Transplant. 2007 Jan;7(1):243-8. doi: 10.1111/j.1600-6143.2006.01588.x. PubMed 17227571 ↗
  • Luque M, Martin P, Martell N, Fernandez C, Brosnihan KB, Ferrario CM. Effects of captopril related to increased levels of prostacyclin and angiotensin-(1-7) in essential hypertension. J Hypertens. 1996 Jun;14(6):799-805. doi: 10.1097/00004872-199606000-00017. PubMed 8793704 ↗
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  • Arbeiter K, Pichler A, Stemberger R, Mueller T, Ruffingshofer D, Vargha R, Balzar E, Aufricht C. ACE inhibition in the treatment of children after renal transplantation. Pediatr Nephrol. 2004 Feb;19(2):222-6. doi: 10.1007/s00467-003-1317-8. Epub 2003 Dec 13. PubMed 14673630 ↗
  • Oudit GY, Herzenberg AM, Kassiri Z, Wong D, Reich H, Khokha R, Crackower MA, Backx PH, Penninger JM, Scholey JW. Loss of angiotensin-converting enzyme-2 leads to the late development of angiotensin II-dependent glomerulosclerosis. Am J Pathol. 2006 Jun;168(6):1808-20. doi: 10.2353/ajpath.2006.051091. PubMed 16723697 ↗
  • Mizuiri S, Hemmi H, Arita M, Ohashi Y, Tanaka Y, Miyagi M, Sakai K, Ishikawa Y, Shibuya K, Hase H, Aikawa A. Expression of ACE and ACE2 in individuals with diabetic kidney disease and healthy controls. Am J Kidney Dis. 2008 Apr;51(4):613-23. doi: 10.1053/j.ajkd.2007.11.022. Epub 2008 Mar 4. PubMed 18371537 ↗
  • Mizuiri S, Hemmi H, Arita M, Aoki T, Ohashi Y, Miyagi M, Sakai K, Shibuya K, Hase H, Aikawa A. Increased ACE and decreased ACE2 expression in kidneys from patients with IgA nephropathy. Nephron Clin Pract. 2011;117(1):c57-66. doi: 10.1159/000319648. Epub 2010 Aug 4. PubMed 20689326 ↗
  • Mizuiri S, Aoki T, Hemmi H, Arita M, Sakai K, Aikawa A. Urinary angiotensin-converting enzyme 2 in patients with CKD. Nephrology (Carlton). 2011 Aug;16(6):567-72. doi: 10.1111/j.1440-1797.2011.01467.x. PubMed 21457402 ↗
  • Xiao F, Hiremath S, Knoll G, Zimpelmann J, Srivaratharajah K, Jadhav D, Fergusson D, Kennedy CR, Burns KD. Increased urinary angiotensin-converting enzyme 2 in renal transplant patients with diabetes. PLoS One. 2012;7(5):e37649. doi: 10.1371/journal.pone.0037649. Epub 2012 May 22. PubMed 22629438 ↗
  • Grimm PC, Nickerson P, Gough J, McKenna R, Stern E, Jeffery J, Rush DN. Computerized image analysis of Sirius Red-stained renal allograft biopsies as a surrogate marker to predict long-term allograft function. J Am Soc Nephrol. 2003 Jun;14(6):1662-8. doi: 10.1097/01.asn.0000066143.02832.5e. PubMed 12761269 ↗

Study documents

  • Protocol and statistical analysis plan · Oct 1, 2017

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

08

Registry details

Key details

Study ID
NCT03317925
Lead sponsor
Wake Forest University Health Sciences
Collaborators
Stanford University
Responsible party
Sponsor
First posted
Oct 23, 2017
Start date
Jul 16, 2014
Primary completion
Jan 20, 2016
Completion
Apr 26, 2017
Last update
Nov 8, 2017

Study contacts

Andrew M South, MD MS
principal investigator · Wake Forest University Health Sciences

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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