Clinical trial NCT03272854: TransplantLines Insulin Resistance and Inflammation Biobank and Cohort Study
Official title: TransplantLines Insulin Resistance and Inflammation Biobank and Cohort Study
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Death
Graft Failure
Death, Cardiac
Diabetes
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
First posted: 2017-09-06
Enrollment: 606
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Stable outpatient renal transplant recipients more than 1 year after transplantation,

Brief summary: Short-term (1-year) results of renal transplantation are now excellent (over 95%). Long-term (10-year and longer) results are, however, still disappointing. Where most research has focused on immunosuppression and infections, the investigators hypothesize that in renal transplant recipient, amongst others overweight, obesity, chronic use of immunosuppressive drugs and impaired renal function contribute to insulin resistance and chronic low-grade inflammation, which pose the renal transplant recipients at increased risk for cardiovascular disease, decline of function of the transplanted kidney and other complications, including post-transplant diabetes. This study is a biobank and cohort study which investigates this hypothesis.

Detailed description: Short-term (1-year) results of renal transplantation are now excellent (over 95%). Long-term (10-year and longer) results are, however, still disappointing. Where most research has focused on immunosuppression and infections, the investigators hypothesize that in renal transplant recipient, amongst others overweight, obesity, chronic use of immunosuppressive drugs and impaired renal function contribute to insulin resistance and chronic low-grade inflammation, which pose the renal transplant recipients at increased risk for cardiovascular disease, decline of function of the transplanted kidney and other complications, including post-transplant diabetes. To investigate this hypothesis we have detailedly phenotyped 606 renal transplant recipients who at the time of inclusion all were one year or more after transplantation, therewith providing a representation of stable outpatient renal trannsplant recipients late after renal transplantation. At the time of these baseline measurements, we also created a biobank with plasma, serum and aliquots of 24h urine collections. Beyond baseline, we have a regular update on adverse events, including all-cause mortality, cause-specific mortality, graft failure and development of new-onset diabetes after transplantation (NODAT).

Eligibility criteria: Inclusion Criteria:

* More than one year after renal transplantation
* History of renal transplantation

Exclusion Criteria:

* Signs of active infection
* Signs of active cardiac decompensation
* Active malignancy other than skin cancer
* Prognosis \< 1 year

Primary outcomes:
measure: All-Cause Mortality
timeFrame: 30 years
measure: Graft Failure
timeFrame: 30 years
Secondary outcomes:
measure: New Onset Diabetes After Transplantation
timeFrame: 30 years
measure: Cardiovascular Mortality
timeFrame: 30 years
measure: Non-Cardiovascular Mortality
timeFrame: 30 years
Other outcomes:
measure: Venous Thrombosis
timeFrame: 30 years
Locations:
Study officials:
affiliation: University Medical Center Groningen
name: Stephan JL Bakker, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: de Vries AP, Bakker SJ, van Son WJ, van der Heide JJ, Ploeg RJ, The HT, de Jong PE, Gans RO. Metabolic syndrome is associated with impaired long-term renal allograft function; not all component criteria contribute equally. Am J Transplant. 2004 Oct;4(10):1675-83. doi: 10.1111/j.1600-6143.2004.00558.x.
citation: van Ree RM, de Vries AP, Oterdoom LH, The TH, Gansevoort RT, Homan van der Heide JJ, van Son WJ, Ploeg RJ, de Jong PE, Gans RO, Bakker SJ. Abdominal obesity and smoking are important determinants of C-reactive protein in renal transplant recipients. Nephrol Dial Transplant. 2005 Nov;20(11):2524-31. doi: 10.1093/ndt/gfi052. Epub 2005 Aug 22.
citation: Oterdoom LH, de Vries AP, van Son WJ, van der Heide JJ, Ploeg RJ, Gansevoort RT, de Jong PE, Gans RO, Bakker SJ. Validation of insulin resistance indexes in a stable renal transplant population. Diabetes Care. 2005 Oct;28(10):2424-9. doi: 10.2337/diacare.28.10.2424.
citation: Hartog JW, de Vries AP, Bakker SJ, Graaff R, van Son WJ, van der Heide JJ, Gans RO, Wolffenbuttel BH, de Jong PE, Smit AJ. Risk factors for chronic transplant dysfunction and cardiovascular disease are related to accumulation of advanced glycation end-products in renal transplant recipients. Nephrol Dial Transplant. 2006 Aug;21(8):2263-9. doi: 10.1093/ndt/gfl132. Epub 2006 Apr 5.
citation: van Ree RM, Oterdoom LH, de Vries AP, Gansevoort RT, van der Heide JJ, van Son WJ, Ploeg RJ, de Jong PE, Gans RO, Bakker SJ. Elevated levels of C-reactive protein independently predict accelerated deterioration of graft function in renal transplant recipients. Nephrol Dial Transplant. 2007 Jan;22(1):246-53. doi: 10.1093/ndt/gfl511. Epub 2006 Sep 23.
citation: Oterdoom LH, de Vries AP, Gansevoort RT, van Son WJ, van der Heide JJ, Ploeg RJ, de Jong PE, Gans RO, Bakker SJ. Determinants of insulin resistance in renal transplant recipients. Transplantation. 2007 Jan 15;83(1):29-35. doi: 10.1097/01.tp.0000245844.27683.48.
citation: Oterdoom LH, de Vries AP, Gansevoort RT, de Jong PE, Gans RO, Bakker SJ. Fasting insulin modifies the relation between age and renal function. Nephrol Dial Transplant. 2007 Jun;22(6):1587-92. doi: 10.1093/ndt/gfm037. Epub 2007 Feb 21.
citation: Gross S, van Ree RM, Oterdoom LH, de Vries AP, van Son WJ, de Jong PE, Navis GJ, Zuurman MW, Bierhaus A, Gans RO, Bakker SJ. Low levels of sRAGE are associated with increased risk for mortality in renal transplant recipients. Transplantation. 2007 Sep 15;84(5):659-63. doi: 10.1097/01.tp.0000280556.16275.2a.
citation: van Timmeren MM, Vaidya VS, van Ree RM, Oterdoom LH, de Vries AP, Gans RO, van Goor H, Stegeman CA, Bonventre JV, Bakker SJ. High urinary excretion of kidney injury molecule-1 is an independent predictor of graft loss in renal transplant recipients. Transplantation. 2007 Dec 27;84(12):1625-30. doi: 10.1097/01.tp.0000295982.78039.ef.
citation: Lijfering WM, de Vries AP, Veeger NJ, van Son WJ, Bakker SJ, van der Meer J. Possible contribution of cytomegalovirus infection to the high risk of (recurrent) venous thrombosis after renal transplantation. Thromb Haemost. 2008 Jan;99(1):127-32. doi: 10.1160/TH07-05-0340.
citation: Oterdoom LH, van Ree RM, de Vries AP, Gansevoort RT, Schouten JP, van Son WJ, Homan van der Heide JJ, Navis G, de Jong PE, Gans RO, Bakker SJ. Urinary creatinine excretion reflecting muscle mass is a predictor of mortality and graft loss in renal transplant recipients. Transplantation. 2008 Aug 15;86(3):391-8. doi: 10.1097/TP.0b013e3181788aea.
citation: van Ree RM, Oterdoom LH, de Vries AP, Homan van der Heide JJ, van Son WJ, Navis G, Gans RO, Bakker SJ. Circulating markers of endothelial dysfunction interact with proteinuria in predicting mortality in renal transplant recipients. Transplantation. 2008 Dec 27;86(12):1713-9. doi: 10.1097/TP.0b013e3181903d25.
citation: Hartog JW, Gross S, Oterdoom LH, van Ree RM, de Vries AP, Smit AJ, Schouten JP, Nawroth PP, Gans RO, van Son WJ, Bierhaus A, Bakker SJ. Skin-autofluorescence is an independent predictor of graft loss in renal transplant recipients. Transplantation. 2009 Apr 15;87(7):1069-77. doi: 10.1097/TP.0b013e31819d3173.
citation: Oterdoom LH, de Vries AP, van Ree RM, Gansevoort RT, van Son WJ, van der Heide JJ, Navis G, de Jong PE, Gans RO, Bakker SJ. N-terminal pro-B-type natriuretic peptide and mortality in renal transplant recipients versus the general population. Transplantation. 2009 May 27;87(10):1562-70. doi: 10.1097/TP.0b013e3181a4bb80.
citation: van Ree RM, de Vries AP, Oterdoom LH, Seelen MA, Gansevoort RT, Schouten JP, Struck J, Navis G, Gans RO, van der Heide JJ, van Son WJ, Bakker SJ. Plasma procalcitonin is an independent predictor of graft failure late after renal transplantation. Transplantation. 2009 Jul 27;88(2):279-87. doi: 10.1097/TP.0b013e3181ac9ea0.
citation: van Ree RM, de Vries AP, Zelle DM, de Vries LV, Oterdoom LH, Gans RO, Schouten JP, Lems SP, van Son WJ, Bakker SJ. Latent cytomegalovirus infection is an independent risk factor for late graft failure in renal transplant recipients. Med Sci Monit. 2011 Nov;17(11):CR609-617. doi: 10.12659/msm.882045.
citation: Said MY, Deetman PE, de Vries AP, Zelle DM, Gans RO, Navis G, Joosten MM, Bakker SJ. Causal path analyses of the association of protein intake with risk of mortality and graft failure in renal transplant recipients. Clin Transplant. 2015 May;29(5):447-57. doi: 10.1111/ctr.12536. Epub 2015 Apr 23.
citation: Eisenga MF, Dullaart RP, Berger SP, Sloan JH, de Vries AP, Bakker SJ, Gaillard CA. Association of hepcidin-25 with survival after kidney transplantation. Eur J Clin Invest. 2016 Dec;46(12):994-1001. doi: 10.1111/eci.12682. Epub 2016 Oct 26.
citation: Adepu S, Katta K, Tietge UJ, Kwakernaak AJ, Dam W, van Goor H, Dullaart RP, Navis GJ, Bakker SJ, van den Born J. Hepatic syndecan-1 changes associate with dyslipidemia after renal transplantation. Am J Transplant. 2014 Oct;14(10):2328-38. doi: 10.1111/ajt.12842. Epub 2014 Aug 25.
citation: Annema W, Dikkers A, de Boer JF, Dullaart RP, Sanders JS, Bakker SJ, Tietge UJ. HDL Cholesterol Efflux Predicts Graft Failure in Renal Transplant Recipients. J Am Soc Nephrol. 2016 Feb;27(2):595-603. doi: 10.1681/ASN.2014090857. Epub 2015 Aug 28.
citation: Leberkuhne LJ, Ebtehaj S, Dimova LG, Dikkers A, Dullaart RP, Bakker SJ, Tietge UJ. The predictive value of the antioxidative function of HDL for cardiovascular disease and graft failure in renal transplant recipients. Atherosclerosis. 2016 Jun;249:181-5. doi: 10.1016/j.atherosclerosis.2016.04.008. Epub 2016 Apr 8.
citation: Eisenga MF, Zelle DM, Sloan JH, Gaillard CAJM, Bakker SJL, Dullaart RPF. High Serum PCSK9 Is Associated With Increased Risk of New-Onset Diabetes After Transplantation in Renal Transplant Recipients. Diabetes Care. 2017 Jul;40(7):894-901. doi: 10.2337/dc16-2258. Epub 2017 May 1.
citation: Eisenga MF, Dullaart RPF, Berger SP, Touw DJ, Bakker SJL, Gaillard CAJM. Urinary prednisolone excretion is a determinant of serum hepcidin levels in renal transplant recipients. Am J Hematol. 2017 Aug;92(8):E173-E175. doi: 10.1002/ajh.24785. Epub 2017 Jun 9. No abstract available.
citation: Sotomayor CG, Eisenga MF, Gomes Neto AW, Ozyilmaz A, Gans ROB, Jong WHA, Zelle DM, Berger SP, Gaillard CAJM, Navis GJ, Bakker SJ. Vitamin C Depletion and All-Cause Mortality in Renal Transplant Recipients. Nutrients. 2017 Jun 2;9(6):568. doi: 10.3390/nu9060568.
citation: van Timmeren MM, Lems SP, Hepkema BG, Bakker SJ. Anti-human leukocyte antigen antibodies and development of graft failure after renal transplantation. Transplantation. 2009 Dec 27;88(12):1399-400. doi: 10.1097/TP.0b013e3181bc3ef0. No abstract available.
citation: Zelle DM, Corpeleijn E, van Ree RM, Stolk RP, van der Veer E, Gans RO, Homan van der Heide JJ, Navis G, Bakker SJ. Markers of the hepatic component of the metabolic syndrome as predictors of mortality in renal transplant recipients. Am J Transplant. 2010 Jan;10(1):106-14. doi: 10.1111/j.1600-6143.2009.02876.x. Epub 2009 Nov 24.
citation: van Ree RM, Gross S, Zelle DM, van der Heide JJ, Schouten JP, van Son WJ, Gans RO, Bakker SJ. Influence of C-reactive protein and urinary protein excretion on prediction of graft failure and mortality by serum albumin in renal transplant recipients. Transplantation. 2010 May 27;89(10):1247-54. doi: 10.1097/TP.0b013e3181d720e3.
citation: Zelle DM, Corpeleijn E, Stolk RP, de Greef MH, Gans RO, van der Heide JJ, Navis G, Bakker SJ. Low physical activity and risk of cardiovascular and all-cause mortality in renal transplant recipients. Clin J Am Soc Nephrol. 2011 Apr;6(4):898-905. doi: 10.2215/CJN.03340410. Epub 2011 Mar 3.
citation: Agarwal PK, Hellemons ME, Zelle DM, van Ree RM, van den Born J, van der Heide JJ, Gans RO, van Son WJ, Navis G, Bakker SJ. Smoking is a risk factor for graft failure and mortality after renal transplantation. Am J Nephrol. 2011;34(1):26-31. doi: 10.1159/000328903. Epub 2011 Jun 9.
citation: Zelle DM, Agarwal PK, Ramirez JL, van der Heide JJ, Corpeleijn E, Gans RO, Navis G, Bakker SJ. Alcohol consumption, new onset of diabetes after transplantation, and all-cause mortality in renal transplant recipients. Transplantation. 2011 Jul 27;92(2):203-9. doi: 10.1097/TP.0b013e318222ca10.
citation: Sinkeler SJ, Zelle DM, Homan van der Heide JJ, Gans RO, Navis G, Bakker SJ. Endogenous plasma erythropoietin, cardiovascular mortality and all-cause mortality in renal transplant recipients. Am J Transplant. 2012 Feb;12(2):485-91. doi: 10.1111/j.1600-6143.2011.03825.x. Epub 2011 Nov 4.
citation: Deetman PE, Zelle DM, Homan van der Heide JJ, Navis GJ, Gans RO, Bakker SJ. Plasma bilirubin and late graft failure in renal transplant recipients. Transpl Int. 2012 Aug;25(8):876-81. doi: 10.1111/j.1432-2277.2012.01515.x. Epub 2012 Jun 21.
citation: Zelle DM, Dorland HF, Rosmalen JG, Corpeleijn E, Gans RO, Homan van der Heide JJ, van Son WJ, Navis G, Bakker SJ. Impact of depression on long-term outcome after renal transplantation: a prospective cohort study. Transplantation. 2012 Nov 27;94(10):1033-40. doi: 10.1097/TP.0b013e31826bc3c8.
citation: Zelle DM, Corpeleijn E, Deinum J, Stolk RP, Gans RO, Navis G, Bakker SJ. Pancreatic beta-cell dysfunction and risk of new-onset diabetes after kidney transplantation. Diabetes Care. 2013 Jul;36(7):1926-32. doi: 10.2337/dc12-1894. Epub 2013 Feb 1.
citation: Zelle DM, Corpeleijn E, Klaassen G, Schutte E, Navis G, Bakker SJ. Fear of Movement and Low Self-Efficacy Are Important Barriers in Physical Activity after Renal Transplantation. PLoS One. 2016 Feb 4;11(2):e0147609. doi: 10.1371/journal.pone.0147609. eCollection 2016.
citation: Hellemons ME, Sanders JS, Seelen MA, Gans RO, Muller Kobold AC, van Son WJ, Postmus D, Navis GJ, Bakker SJ. Assessment of Cotinine Reveals a Dose-Dependent Effect of Smoking Exposure on Long-term Outcomes After Renal Transplantation. Transplantation. 2015 Sep;99(9):1926-32. doi: 10.1097/TP.0000000000000636.
citation: Meijer E, Bakker SJ, de Jong PE, Homan van der Heide JJ, van Son WJ, Struck J, Lems SP, Gansevoort RT. Copeptin, a surrogate marker of vasopressin, is associated with accelerated renal function decline in renal transplant recipients. Transplantation. 2009 Aug 27;88(4):561-7. doi: 10.1097/TP.0b013e3181b11ae4.
citation: Nauta FL, Bakker SJ, van Oeveren W, Navis G, van der Heide JJ, van Goor H, de Jong PE, Gansevoort RT. Albuminuria, proteinuria, and novel urine biomarkers as predictors of long-term allograft outcomes in kidney transplant recipients. Am J Kidney Dis. 2011 May;57(5):733-43. doi: 10.1053/j.ajkd.2010.12.022. Epub 2011 Apr 1.
citation: de Vries LV, Minovic I, Franssen CFM, van Faassen M, Sanders JS, Berger SP, Navis G, Kema IP, Bakker SJL. The tryptophan/kynurenine pathway, systemic inflammation, and long-term outcome after kidney transplantation. Am J Physiol Renal Physiol. 2017 Aug 1;313(2):F475-F486. doi: 10.1152/ajprenal.00690.2016. Epub 2017 May 10.
citation: Keyzer CA, Riphagen IJ, Joosten MM, Navis G, Muller Kobold AC, Kema IP, Bakker SJ, de Borst MH; NIGRAM consortium. Associations of 25(OH) and 1,25(OH)2 vitamin D with long-term outcomes in stable renal transplant recipients. J Clin Endocrinol Metab. 2015 Jan;100(1):81-9. doi: 10.1210/jc.2014-3012.
citation: Keyzer CA, Vermeer C, Joosten MM, Knapen MH, Drummen NE, Navis G, Bakker SJ, de Borst MH. Vitamin K status and mortality after kidney transplantation: a cohort study. Am J Kidney Dis. 2015 Mar;65(3):474-83. doi: 10.1053/j.ajkd.2014.09.014. Epub 2014 Nov 12.
citation: Baia LC, Humalda JK, Vervloet MG, Navis G, Bakker SJ, de Borst MH; NIGRAM Consortium. Fibroblast growth factor 23 and cardiovascular mortality after kidney transplantation. Clin J Am Soc Nephrol. 2013 Nov;8(11):1968-78. doi: 10.2215/CJN.01880213. Epub 2013 Aug 8.
citation: Anderson JLC, Bakker SJL, Tietge UJF. The triglyceride to HDL-cholesterol ratio and chronic graft failure in renal transplantation. J Clin Lipidol. 2021 Mar-Apr;15(2):301-310. doi: 10.1016/j.jacl.2021.01.009. Epub 2021 Feb 2.
citation: Sotomayor CG, Te Velde-Keyzer CA, Diepstra A, van Londen M, Pol RA, Post A, Gans ROB, Nolte IM, Slart RHJA, de Borst MH, Berger SP, Rodrigo R, Navis GJ, de Boer RA, Bakker SJL. Galectin-3 and Risk of Late Graft Failure in Kidney Transplant Recipients: A 10-year Prospective Cohort Study. Transplantation. 2021 May 1;105(5):1106-1115. doi: 10.1097/TP.0000000000003359.
citation: Szili-Torok T, Bakker SJL, Tietge UJF. Statin Use Is Prospectively Associated With New-Onset Diabetes After Transplantation in Renal Transplant Recipients. Diabetes Care. 2020 Aug;43(8):1945-1947. doi: 10.2337/dc19-1212. Epub 2020 May 22.
citation: Sotomayor CG, Gomes-Neto AW, van Londen M, Gans ROB, Nolte IM, Berger SP, Navis GJ, Rodrigo R, Leuvenink HGD, Schalkwijk CG, Bakker SJL. Circulating Advanced Glycation Endproducts and Long-Term Risk of Cardiovascular Mortality in Kidney Transplant Recipients. Clin J Am Soc Nephrol. 2019 Oct 7;14(10):1512-1520. doi: 10.2215/CJN.00540119. Epub 2019 Sep 17.
citation: Szili-Torok T, Annema W, Anderson JLC, Bakker SJL, Tietge UJF. HDL Cholesterol Efflux Predicts Incident New-Onset Diabetes After Transplantation (NODAT) in Renal Transplant Recipients Independent of HDL Cholesterol Levels. Diabetes. 2019 Oct;68(10):1915-1923. doi: 10.2337/db18-1267. Epub 2019 Aug 2.
citation: Sotomayor CG, Gomes-Neto AW, Eisenga MF, Nolte IM, Anderson JLC, de Borst MH, Oste MCJ, Rodrigo R, Gans ROB, Berger SP, Navis GJ, Bakker SJL. Consumption of fruits and vegetables and cardiovascular mortality in renal transplant recipients: a prospective cohort study. Nephrol Dial Transplant. 2020 Feb 1;35(2):357-365. doi: 10.1093/ndt/gfy248.