Rationale and design of the Transformative Research in Diabetic Nephropathy (TRIDENT) Study

Townsend, Raymond R.; Guarnieri, Paolo; Argyropoulos, Christos; Blady, Shira J.; Boustany-Kari, Carine M.; Devalaraja-Narashimha, Kishor; Morton, Lori; Mottl, Amy K.; Patel, Uptal D.; Palmer, Matthew; Ross, Michael J.; Sarov‐Blat, Lea; Steinbugler, Kathryn; Suszták, Katalin; Luciano, Randy L.; Canetta, Pietro A.; Campbell, Krik; Hogan, Jonathan J.; Lenz, Oliver; Szerlip, Harold M.; Bansal, Shweta; Brosius, C. M.; Schelling, J. R.; Almaani, Salem; Kretzler, Matthias; Isakova, Tamara; Avasare, Rupali S.; Lafayette, Richard A.

doi:10.1016/j.kint.2019.09.020

Cited by 26 publications

(18 citation statements)

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“…Details of the study design have been previously published. 28 In brief, patients with a clinical diagnosis of type I or type II DM undergoing clinically indicated kidney biopsy were consented for the study. Only participants with central pathology reading consistent with RPS diagnostic criteria for diabetic glomerulosclerosis were followed longitudinally.…”

Section: Study Populationmentioning

confidence: 99%

“…TRIDENT is a multicenter observational cohort aimed to identify changes associated with kidney function decline in patients with DM in an unbiased manner via multi-omics characterization of kidney tissue specimens. 28 In the present study, we analyzed histopathologic features obtained from a comprehensive descriptor-based scoring system, including LM and EM, in a subset of TRIDENT patients to explore the relationship between histopathologic changes, clinical parameters, and outcomes.…”

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confidence: 99%

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The Role of Glomerular Epithelial Injury in Kidney Function Decline in Patients With Diabetic Kidney Disease in the TRIDENT Cohort

Palmer

Abedini

Jackson

et al. 2021

Kidney International Reports

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Introduction Although diabetic kidney disease (DKD) is responsible for more than half of all chronic and end-stage kidney disease (ESKD), the association of light (LM) and electron microscopic (EM) structural changes with clinical parameters and prognosis in DKD is incompletely understood. Methods This is an interim analysis of 62 patients diagnosed with biopsy-confirmed DKD from the multicenter TRIDENT (Transformative Research in Diabetic Nephropathy) study. Twelve LM and 8 EM descriptors, representing changes in glomeruli, tubulointerstitium, and vasculature were analyzed for their relationship with clinical measures of renal function. Patients were followed every 6 months. Results Multivariable linear regression analysis revealed that estimated glomerular filtration rate (eGFR) upon enrollment correlated the best with interstitial fibrosis. On the other hand, the rate of kidney function decline (eGFR slope) correlated the most with glomerular lesions including global glomerulosclerosis and mesangiolysis. Unbiased clustering analysis based on histopathologic data identified 3 subgroups. The first cluster, encompassing subjects with the mildest histologic lesions, had the most preserved kidney function. The second and third clusters had similar degrees of kidney dysfunction and structural damage, but differed in the degree of glomerular epithelial cell and podocyte injury (podocytopathy DKD subtype). Cox proportional hazard analysis showed that subjects in cluster 2 had the highest risk to reach ESKD (hazard ratio: 17.89; 95% confidence interval: 2.13–149.79). Glomerular epithelial hyperplasia and interstitial fibrosis were significant predictors of ESKD in the multivariate model. Conclusion The study highlights the association between fibrosis and kidney function and identifies the role of glomerular epithelial changes and kidney function decline.

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Section: Study Populationmentioning

confidence: 99%

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confidence: 99%

The Role of Glomerular Epithelial Injury in Kidney Function Decline in Patients With Diabetic Kidney Disease in the TRIDENT Cohort

Palmer

Abedini

Jackson

et al. 2021

Kidney International Reports

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“…Data are lacking regarding the feasibility and safety of obtaining research kidney biopsy cores. To address this issue, we present an interim analysis of the Transforming Research in Diabetic Nephropathy (TRIDENT) study (Clinicaltrials.gov identifier: NCT02986984), a multicenter, longitudinal, observational cohort study of adults with diabetes undergoing clinically indicated kidney biopsies and consenting to an additional research biopsy core (1).…”

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confidence: 99%

The Feasibility and Safety of Obtaining Research Kidney Biopsy Cores in Patients with Diabetes

Hogan

Owen

Blady

et al. 2020

CJASN

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“…While structural injury, proteinuria and GFR all correlate with one another, they are not inextricably linked and so likely reflect different pathological processes. The precise molecular pathways that account for these are only starting to be unraveled in detail with the use of next generation sequencing with whole tissue RNASeq, single cell RNASeq and spatial transcriptomics to interrogate human kidney biopsy tissue in large multicentre consortia such as TRIDENT 27 and NIDDK's Kidney Precision Medicine Project.…”

Section: Discussionmentioning

confidence: 99%

Late intervention in the remnant kidney model attenuates proteinuria but not glomerular filtration rate decline

et al. 2021

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Aim The use of animal models to predict the response to new therapies in humans is a vexing issue in nephrology. Unlike patients with chronic kidney disease (CKD), few rodent models develop a progressive decline in glomerular filtration rate (GFR) so that experimental studies frequently report a reduction in proteinuria as the primary efficacy outcome. Moreover, while humans present with established kidney disease that continues to progress, many experimental studies investigate therapies in the prevention rather than in a therapeutic setting. Methods We used the remnant kidney (subtotal nephrectomy [SNX]) rat model that develops a decline in GFR in conjunction with heavy proteinuria and hypertension along with the histological hallmarks of CKD in humans, glomerulosclerosis and tubulointerstitial fibrosis. Using agents that had been shown to improve GFR as well as proteinuria in the prevention setting, angiotensin‐converting enzyme (ACE) inhibition with enalapril and SIRT1 activation with SRT3025, treatment was initiated 6 weeks after SNX. Results While enalapril reduced blood pressure, proteinuria and histological injury, it did not improve GFR, as measured by inulin clearance. SRT3025 improved neither GFR nor structural damage despite a reduction in proteinuria. Conclusion These findings demonstrate that neither a reduction in proteinuria nor a reversal of structural damage in the kidney will necessarily translate to a restoration of kidney function.

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Rationale and design of the Transformative Research in Diabetic Nephropathy (TRIDENT) Study

Cited by 26 publications

References 8 publications

The Role of Glomerular Epithelial Injury in Kidney Function Decline in Patients With Diabetic Kidney Disease in the TRIDENT Cohort

The Role of Glomerular Epithelial Injury in Kidney Function Decline in Patients With Diabetic Kidney Disease in the TRIDENT Cohort

The Feasibility and Safety of Obtaining Research Kidney Biopsy Cores in Patients with Diabetes

Late intervention in the remnant kidney model attenuates proteinuria but not glomerular filtration rate decline

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