Clinical trial NCT02986984: Transformative Research in Diabetic Nephropathy
Official title: Transformative Research In DiabEtic NephropaThy
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Diabetic Nephropathies
Diabetic Glomerulosclerosis
Keywords: Diabetes
Chronic kidney disease
Progression
Genomics
Transcriptomics
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: MOUNT SINAI HOSPITAL
name: University of North Carolina
name: Northwestern University
name: University of New Mexico
name: Stanford University
name: The University of Texas Health Science Center at San Antonio
name: Ohio State University
name: Yale University
name: Albert Einstein College of Medicine
name: Oregon Health and Science University
name: Lehigh Valley Health Network
name: University of Arkansas
name: University of Southern California
name: University of Virginia
name: Regeneron Pharmaceuticals
name: Boehringer Ingelheim
name: GlaxoSmithKline
name: Gilead Sciences
name: Juvenile Diabetes Research Foundation
name: Novo Nordisk A/S
First posted: 2016-12-08
Enrollment: 400
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

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?

Eligibility 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

Primary outcomes:
measure: Rapid progression of kidney function loss
timeFrame: up to three years
Secondary outcomes:
measure: Serious Adverse Events
timeFrame: up to three years
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Bronx
country: United States
facility: Albert Einstein College of Medicine
state: New York
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Allentown
country: United States
facility: Lehigh Valley Health Network
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
Study officials:
affiliation: University of Pennsylvania
name: Katalin Susztak, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.