Transformative Research in Diabetic Nephropathy (TRIDENT)

• ClinicalTrials.gov Identifier: NCT02986984
• Recruitment Status: Recruiting
• First Posted: December 8, 2016
• Last Update Posted: January 9, 2024
• Sponsor: University of Pennsylvania
• Collaborators: MOUNT SINAI HOSPITAL; University of North Carolina; Northwestern University; University of New Mexico; Stanford University; The University of Texas Health Science Center at San Antonio; Ohio State University; Yale University; Albert Einstein College of Medicine; Oregon Health and Science University; Lehigh Valley Health Network; University of Arkansas; University of Southern California; University of Virginia; Regeneron Pharmaceuticals; Boehringer Ingelheim; GlaxoSmithKline; Gilead Sciences; Juvenile Diabetes Research Foundation; Novo Nordisk A/S
• Information provided by (Responsible Party): University of Pennsylvania

Study Description

Brief Summary:

This is a prospective, observational, cohort study of patients with a clinical diagnosis of diabetes who are undergoing clinically indicated kidney biopsy. The intent is to collect, process, and study kidney tissue and to harvest blood, urine and genetic materials to elucidate molecular pathways and link them to biomarkers that characterize those patients have a rapid decline in kidney function (> 5 mL/min/1.73m2/year) from those with lesser degrees of kidney function change over the period of observation. High through-put genomic analysis associated with genetic and biomarker testing will serve to identify key potential therapeutic targets for DKD by comparing patients with rapid and slow progression patterns. Each participating clinical site will search for, consent, harvest the biopsy sample, and enroll the participants as required for the TRIDENT protocol.

Condition or disease	Intervention/treatment
Diabetic Nephropathies; Diabetic Glomerulosclerosis	Other: There is no intervention

Detailed Description:

Progress in the area of diabetic kidney research leading to new therapeutics development has been very limited. Indeed, no new medicines indicated for the treatment of chronic kidney disease (CKD) have been approved since ARB's have become standard of care nearly 15 years ago. Several factors explain the limited progress including but not limited to; a) animal and cell culture models do not recapitulate human DKD b) human genetic studies so far have failed to identify reproducible genetic variants associated with DKD c) the clinical manifestation of DKD is heterogeneous and might have even changed since the original description d) DKD is a clinical diagnosis and it is not clear what percentage of patients have histological disease.

Laboratory mice have served as invaluable tools to understand human disease development. As mouse genetic tools became readily available, it enabled us to perform time and cell type specific gene manipulation in animals to generate disease models and to understand the contributions of specific pathways. Unfortunately, mouse models do not recapitulate human diabetic kidney disease as animals develop only early DKD lesions; mesangial expansion and mild albuminuria11. Most models do not develop arterial hyalinosis, tubulointerstitial fibrosis and declining glomerular filtration rate (GFR); hallmarks of progressive DKD. There are several fundamental differences in gene expression patterns and physiology of human and murine kidneys. Such differences may explain the lack of translatability between mice and humans of pharmacological approaches aimed at treating DKD. This seems to be a general trend in other disease areas as well (for example Alzheimer's disease), leading to a recent movement toward translational and clinical research with increasing reliance on human samples.

Human genetic studies made paradigm-shifting observations in relatively rare monogenic forms of kidney diseases (including polycystic kidney disease and focal segmental glomerulosclerosis). Diabetic CKD on the other hand follows a complex polygenic pattern. Currently, the most powerful method to define the genetics of complex diseases such as DKD is genome wide association (GWAS), where associations between polymorphisms and the disease state are tested. Prior studies indicate that for complex traits, such as DKD, genetic polymorphisms that are associated with disease state are localized to the non-coding region of the genome12,13. Moreover, the genetic architecture of diabetic kidney disease has not been characterized and several large collaborations are currently addressing this issue14. Thus, the next challenge is to define target genes, target cell types and the mode of dysregulation caused by non-coding snips (SNPs15). Such studies require large collection of human tissue samples from disease relevant organs.

Diabetic kidney disease (DKD) remains a clinical diagnosis. Subjects with CKD in the presence of diabetes and albuminuria are considered to have diabetic nephropathy. Such definition is used in clinical practice and in research studies including clinical trials. Studies performed in 1980 provide the basis for the practice16,17. Investigators stage DKD as a progressive disease, beginning with the loss of small amounts of albumin into the urine (30-300mg/day; known as the stage of microalbuminuria, high albuminuria, occult or incipient nephropathy), then larger amounts (>300mg/day; known as macroalbuminuria, very high albuminuria or overt nephropathy), followed by progressive decline in kidney function (eGFR), renal impairment and ultimately ESRD 17-19. This paradigm has proved useful in clinical studies, especially in type 1 diabetes, for identifying cohorts at increased risk of adverse health outcomes. However, boundaries between stages of DKD are artificial and the relationship between urinary albumin excretion and adverse health outcomes is log-linear in clinical practice. Indeed, the American Diabetes Association recently abandoned staging of albuminuria (ACR) for a more-straightforward [ACR >30 mg/g, (albuminuria present); ACR <30 mg/g (albuminuria absent)] criterion. Moreover, many patients, and especially those with type 2 diabetes, do not follow this classical course in modern clinical practice. For example, many subjects with DKD do not manifest excessive urinary albumin loss20. Indeed, of the 28% of the UKPDS cohort who developed moderate to severe renal impairment, half did not have preceding albuminuria. In the Diabetes Control and Complications Trial (DCCT), of the 11% patients with type 1 diabetes who developed an eGFR<60 ml/min/1.73m2, 40% never had experienced overt nephropathy21. In addition, most patients with microalbuminuria do not progressively exhibit an increase in urinary albumin excretion as in the classical paradigm with treatment-induced and spontaneous 'remission' of albuminuria widely observed22,23. Consequently, individuals with microalbuminuria may better be regarded as being at increased risk of developing progressive renal disease (as well as cardiovascular disease and other diabetic complications), rather than as actually having DKD per se. While over the last 40 years it became evident that the original description of DKD needs revision, no alternative criteria have emerged given the lack of solid data on the correlation between histopathological (gold standard) DKD diagnosis and clinical manifestations. It is also possible that, with the introduction of better glycemic control and anti-renin (RAAS) blockade, the disease has evolved necessitating new observational cohorts to understand the clinical disease course and manifestations.

Diabetic kidney disease presents with a variable rate of kidney function decline24. Data from large observational cohorts indicate that GFR decline frequently does not follow a linear course. Several groups are working on modeling GFR decline patterns in patients. Such studies contributed to emphasizing patients termed as "rapid progressors". There is no consensus definition for rapid progression. Many studies define rapid progressors as patients with greater than 3 cc/year GFR decrease but alternative cut points such as even 10 cc/year has also been used. Identification and clinical characterization of rapid progressors became the center of several large scale efforts as these are the patients who would likely need intensive clinical management25. Furthermore recent post-hoc analyses of the Diabetic Nephropathy (IDNT and RENAAL) studies indicate that clinical trial outcomes are mostly driven by a small number of subjects with unusually rapidly progressive GFR decline i.e. subjects that display characteristics of rapid progressors. While investigators are still awaiting accurate descriptions, biomarker and clinical descriptive studies have yielded several interesting observations. Albuminuria remains one of the strongest risk factor for "FDA-approved" (hard) renal outcomes; doubling of serum creatinine, dialysis or death. Indeed some of the latest studies indicate that using a 4 or a 6 variable model, that includes albuminuria, age, sex, serum phosphate, serum calcium and serum albumin has C-statistics score of 0.84-0.91 to predict ESRD 26,27. During the last years several new biomarkers have been identified that can potentially identify patients who are at increased risk for rapid loss of kidney function. For example blood and urinary levels of kidney injury molecule (KIM1) shows promise to identify patients who are at risk for kidney function decline. Recently, investigators showed that circulating levels of tumor necrosis factor receptor 1 and 2 levels can identify patients with rapidly declining renal function 28. While these markers are generating increased interest; the critical questions remains; why do some patients follow a rapid decline in kidney function?

Study Design

• Study Type: Observational
• Estimated Enrollment: 400 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Transformative Research In DiabEtic NephropaThy
• Actual Study Start Date: December 2016
• Estimated Primary Completion Date: December 2024
• Estimated Study Completion Date: June 2025

Groups and Cohorts

Group/Cohort	Intervention/treatment
Confirmed Diabetic Nephropathy; Patients undergoing a clinically indicated kidney biopsy with a history of diabetes who satisfy pre-specified criteria for diabetic nephropathy.	Other: There is no intervention; There are no interventions; Other Name: There are no interventions
Confirmed Non-diabetic Nephropathy; Patients undergoing a clinically indicated kidney biopsy with a history of diabetes who fail pre-specified criteria for diabetic nephropathy.	Other: There is no intervention; There are no interventions; Other Name: There are no interventions

Outcome Measures

Primary Outcome Measures :

1. Rapid progression of kidney function loss [ Time Frame: up to three years ]
   • Identification of epigenetic, genetic, renal, genomic, and biomarker profiles that differentiates patients with rapid GFR decline (>5cc/min) from those with slower (<5cc/min) rate of progression.

Secondary Outcome Measures :

1. Serious Adverse Events [ Time Frame: up to three years ]
   Prolonged hospitalization or need for intervention after kidney biopsy

Biospecimen Retention:   Samples With DNA

Buffy Coat (Germline DNA) Kidney Biopsy Cores Urine and blood aliquots for RNA

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 100 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Probability Sample

Study Population

Adults (18 years of age and older) with diabetes who are scheduled to have a clinically-indicated kidney biopsy.

Criteria

Inclusion Criteria:

• Type 1 and 2 Diabetes by American Diabetes Association (ADA) criteria
• Willingness to comply with study requirements, including intention to fully participate in protocol-specified follow-up at a clinical study site
• Able to provide informed consent
• Adult participants
• Planned medically indicated kidney biopsy, prescribed by a practicing nephrologist

Exclusion Criteria:

• End Stage Renal Disease (ESRD), defined as chronic dialysis or kidney transplant
• History of receiving dialysis for more than 30 days prior to biopsy
• Institutionalized
• Solid organ or bone marrow transplant recipient at time of first kidney biopsy
• Less than 3-year life expectancy
• History of active alcohol and/or substance abuse that in the investigator's assessment would impair the subject's ability to comply with the protocol
• Unable to provide informed consent
• Evidence of active cancer requiring treatment, other than non-melanoma skin cancer

Contacts and Locations

Contacts

Contact: Raymond R Townsend, MD; 267-738-3431; townsend@upenn.edu

Locations

United States, Arkansas

University of Arkansas for Medical Sciences; Recruiting

Little Rock, Arkansas, United States, 72205

Contact: Tawana Gibbs 501-686-5301 TGibbs2@uams.edu

Principal Investigator: Manisha Singh, MD

United States, California

University of Southern California; Active, not recruiting

Los Angeles, California, United States, 90033

Stanford University; Recruiting

Palo Alto, California, United States

Contact: Kshama Mehta, PhD 650-736-1822 krmehta@stanford.edu

Principal Investigator: Richard Lafayette, MD

United States, Connecticut

Yale University; Recruiting

New Haven, Connecticut, United States, 06510

Contact: Katrina Blount 203-737-1575 katrina.blount@yale.edu

Principal Investigator: Randy Luciano, MD, PhD

United States, Illinois

Northwestern University; Recruiting

Chicago, Illinois, United States, 60611

Contact: Carlos Martinez 312-503-1808 carlos.martinez@northwestern.edu

Principal Investigator: Tamara Isakova, MD, MMsc

United States, Michigan

University of Michigan; Active, not recruiting

Ann Arbor, Michigan, United States, 48109

United States, New Mexico

University of New Mexico; Recruiting

Albuquerque, New Mexico, United States, 87131

Contact: Hugo Vilchis 505-272-5503 HVilchis@salud.unm.edu

Principal Investigator: Christos Argyropoulos, MD, MSc, PhD

United States, New York

Albert Einstein College of Medicine; Active, not recruiting

Bronx, New York, United States, 10461

Mount Sinai Hospital; Recruiting

New York, New York, United States, 10029

Contact: Stephanie Pagan 212-241-0059 stephanie.pagan@mssm.edu

Principal Investigator: Kirk Campbell, MD

Columbia University; Active, not recruiting

New York, New York, United States, 10032

United States, North Carolina

University of North Carolina; Recruiting

Chapel Hill, North Carolina, United States, 27599

Contact: Sara Kelley 919-445-2658 Sara_kelley@med.unc.edu

Principal Investigator: Amy K Mottl, MD, MPH

United States, Ohio

Ohio State University; Recruiting

Columbus, Ohio, United States, 43210

Contact: Melissa Riley 614-293-9904 Melissa.Riley@osumc.edu

Principal Investigator: Salem Almaani, MD, MS

United States, Oregon

Oregon Health & Science University; Recruiting

Portland, Oregon, United States, 97239

Contact: Tatevik Mazmanyan 503-494-9548 mazmanya@ohsu.edu

Principal Investigator: Rupali Avasare, MD

United States, Pennsylvania

Lehigh Valley Health Network; Recruiting

Allentown, Pennsylvania, United States, 18103

Contact: Mary Sobotor 610-402-1592 Mary.Sobotor@lvhn.org

Principal Investigator: Nelson Kopyt, DO

University of Pennsylvania; Recruiting

Philadelphia, Pennsylvania, United States, 19104

Contact: Mustafa AL-Obaidi, MD 215-349-8035 mustafa.alobaidi@pennmedicine.upenn.edu

Principal Investigator: Gaia Coppock, MD

United States, Texas

University of Texas Health Science Center at San Antonio; Recruiting

San Antonio, Texas, United States, 78229

Contact: Chakradhar Velagapudi 210-617-5300 ext 15323 velagapudi@uthscsa.edu

Principal Investigator: Shweta Bansal, MD

United States, Virginia

University of Virginia; Recruiting

Charlottesville, Virginia, United States, 22908

Contact: Igor Shumilin 434-924-9691 IAS2N@hscmail.mcc.virginia.edu

Principal Investigator: Julia Scialla, MD

Sponsors and Collaborators

University of Pennsylvania

MOUNT SINAI HOSPITAL

University of North Carolina

Northwestern University

University of New Mexico

Stanford University

The University of Texas Health Science Center at San Antonio

Ohio State University

Yale University

Albert Einstein College of Medicine

Oregon Health and Science University

Lehigh Valley Health Network

University of Arkansas

University of Southern California

University of Virginia

Regeneron Pharmaceuticals

Boehringer Ingelheim

GlaxoSmithKline

Gilead Sciences

Juvenile Diabetes Research Foundation

Novo Nordisk A/S

Investigators

• Principal Investigator: Katalin Susztak, MD; University of Pennsylvania

More Information

Publications of Results:

Abedini A, Zhu YO, Chatterjee S, Halasz G, Devalaraja-Narashimha K, Shrestha R, S Balzer M, Park J, Zhou T, Ma Z, Sullivan KM, Hu H, Sheng X, Liu H, Wei Y, Boustany-Kari CM, Patel U, Almaani S, Palmer M, Townsend R, Blady S, Hogan J, Morton L, Susztak K; TRIDENT Study Investigators. Urinary Single-Cell Profiling Captures the Cellular Diversity of the Kidney. J Am Soc Nephrol. 2021 Mar;32(3):614-627. doi: 10.1681/ASN.2020050757. Epub 2021 Feb 2.

Palmer MB, Abedini A, Jackson C, Blady S, Chatterjee S, Sullivan KM, Townsend RR, Brodbeck J, Almaani S, Srivastava A, Avasare R, Ross MJ, Mottl AK, Argyropoulos C, Hogan J, Susztak K. The Role of Glomerular Epithelial Injury in Kidney Function Decline in Patients With Diabetic Kidney Disease in the TRIDENT Cohort. Kidney Int Rep. 2021 Feb 3;6(4):1066-1080. doi: 10.1016/j.ekir.2021.01.025. eCollection 2021 Apr.

Hogan JJ, Owen JG, Blady SJ, Almaani S, Avasare RS, Bansal S, Lenz O, Luciano RL, Parikh SV, Ross MJ, Sharma D, Szerlip H, Wadhwani S, Townsend RR, Palmer MB, Susztak K, Mottl AK; TRIDENT Study Investigators. The Feasibility and Safety of Obtaining Research Kidney Biopsy Cores in Patients with Diabetes: An Interim Analysis of the TRIDENT Study. Clin J Am Soc Nephrol. 2020 Jul 1;15(7):1024-1026. doi: 10.2215/CJN.13061019. Epub 2020 Apr 27. No abstract available.

Other Publications:

Townsend RR, Guarnieri P, Argyropoulos C, Blady S, Boustany-Kari CM, Devalaraja-Narashimha K, Morton L, Mottl AK, Patel U, Palmer M, Ross MJ, Sarov-Blat L, Steinbugler K, Susztak K; TRIDENT Study Investigators. Rationale and design of the Transformative Research in Diabetic Nephropathy (TRIDENT) Study. Kidney Int. 2020 Jan;97(1):10-13. doi: 10.1016/j.kint.2019.09.020. No abstract available. Erratum In: Kidney Int. 2020 Apr;97(4):809.

• Responsible Party: University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT02986984
• Other Study ID Numbers: 824503
• First Posted: December 8, 2016
• Last Update Posted: January 9, 2024
• Last Verified: January 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Pennsylvania:

Diabetes; Chronic kidney disease; Progression; Genomics; Transcriptomics

Additional relevant MeSH terms:

Kidney Diseases; Diabetic Nephropathies; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Diabetes Complications; Diabetes Mellitus; Endocrine System Diseases