Genetic Testing to Understand and Address Renal Disease Disparities Across the United States (GUARDD-US)

GUARDD-US is a prospective, multicenter, unblinded, two arm randomized pragmatic clinical trial. Participants will be randomized in a 1:1 ratio to immediate APOL1 gene testing and return of results (ROR) to participant and provider (Intervention arm) versus delayed APOL1 gene testing and ROR to participant and provider (Control arm). The main study will compare outcomes between APOL1 positive participants in the Intervention arm (i.e., early knowledge of APOL1 status) to APOL1 positive participants in the Control arm (i.e., delayed knowledge of APOL1 status). Participants that are APOL1 negative in the Intervention and Control groups will not be included in the main study analyses.

GUARDD-US also includes a substudy to determine the effect of knowledge of genetic test results that predict efficacy of various antihypertensive medications on change in SBP from baseline to 3 months in APOL1 negative individuals at participating sites.

This substudy is listed separately on clinicaltrials.gov as NCT06748040 and Unique Protocol ID - PRO00102997_A

Study Overview

• Status: Completed
• Conditions: Hypertension; Chronic Kidney Disease
• Intervention / Treatment: Other: Timing of return of results

Detailed Description

High-risk variants in the APOL1 gene explain approximately 70% of the excess prevalence of CKD in African Americans (AAs), conferring a 5 times higher risk for hypertensive CKD and a 10 times higher risk for ESRD. A pilot study (GUARDD), showed that returning APOL1 gene test results had a statistically significant improvement in SBP at 3 months when comparing APOL1 positives to APOL1 negatives who received their genetic testing results and when comparing APOL1 positives that received their results early to overall controls who did not receive their results until after the 3 month visit. GUARDD was not however powered to evaluate the effects of having and knowing a positive APOL1 status on outcomes for those with high risk of developing CKD (i.e., comparing outcomes for APOL1 positive patients who know their genetic risk to APOL1 positive patients who do not know their genetic risk). A broader trial is needed to better determine the importance of APOL1 gene testing for improving the testing, diagnosis, and treatment of individuals at risk of CKD.

The primary aim is to determine the effect of participant and provider knowledge of a positive APOL1 status and accompanying guideline based clinical decision support (CDS) on blood pressure management on change in systolic blood pressure (SBP) from baseline to 3 months after randomization among the APOL1 positive participants. Secondary aims are to:

1. Determine the effect of participant and provider knowledge of a positive APOL1 status on the probability of documented CKD diagnosis.
2. Determine the effect of participant and provider knowledge of a positive APOL1 status on the probability of receiving a urine microalbumin/creatinine testing and ACE-I/ARB prescription based on results of the urine microalbumin level.
3. Explore cost effectiveness, mediators, moderators, psychobehavioral impact of results disclosure on participants, and effects of participant and provider knowledge of APOL1 status on provider treatment recommendations.

Approximately 6,750 participants of African ancestry age 18-70 with hypertension that either: 1) do not have diabetes and do not have CKD, or 2) have CKD. Participants with diabetes may be included as long as they also have CKD.

Population for Main Study:

Participants from Randomized Population (above) who test positive for APOL1

Main Study Analyses:

• To determine the effect of participant and provider knowledge of a positive APOL1 status on SBP, we will compare the change in SBP from baseline to 3 months of the Intervention - APOL1 positive group to the change in SBP from baseline to 3 months of the Control - APOL1 positive group using a two sided t-test, as appropriate, with an overall two-sided type I error of 0.05.
• The effect of knowledge of a positive APOL1 status on all secondary endpoints will be compared between Intervention - APOL1 positives to Control - APOL1 positives with the proportion difference test.
• Additional analyses will include analysis of time trends in SBP, subset analyses, and exploratory analyses of cost effectiveness, mediators, moderators, psychobehavioral impact of results disclosure on participants, and effects of knowledge of APOL1 status on provider treatment recommendations.

• Study Type: Interventional
• Enrollment (Actual): 6789
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida - Gainesville
    • Jacksonville, Florida, United States, 32209
      • University of Florida - Jacksonville
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
    • Indianapolis, Indiana, United States, 46202
      • Eskenazi Health
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • University Medical Center New Orleans
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
    • New York, New York, United States, 10035
      • The Institute for Family Health
  • North Carolina
    • Lumberton, North Carolina, United States, 28358
      • Southeastern Healthcare
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15261
      • University of Pittsburgh
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
    • Nashville, Tennessee, United States, 37208
      • Meharry Medical College
    • Nashville, Tennessee, United States, 37208
      • Nashville General Hospital
  • Texas
    • Dallas, Texas, United States, 75210
      • Baylor Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Self reported African ancestry
• English Speaking
• Age 18-70 years

• Have diagnosis of hypertension: Diagnosis of hypertension is defined by either:

  • ICD10 diagnosis codes (i.e., I10; I11.x; I12.x; I13.x; I16.x) OR
  • On active antihypertensive therapy for indication of hypertension OR
  • Having systolic blood pressure of 140 mm Hg or greater in at least 2 of the last 3 consecutive recorded values in the EHR OR
  • Having hypertension in the patient's medical record problem list
• Have been seen at ≥1 time in past year at a participating primary care site
• Either: 1) do not have diabetes and do not have CKD, or 2) have CKD; Participants with diabetes may be included as long as they also have CKD.

CKD is defined by either: A) ICD10 codes (i.e., N18.x; E08.22; E09.22; E10.22; E11.22;E13.22 (exclude Z94.0; N18.6; Z99.2)) OR B) Microalbumin/proteinuria level >30 mg/g for 2 time periods ≥ 3 months. Values taken within 12 months of enrollment, unless 2 values are unavailable, then review within 24 months of enrollment. OR C) 15 ≤ eGFR ≤ 60 ml/min for 2 time periods ≥ 3 months. GFRs are taken within 12 months of enrollment, unless 2 values are unavailable, then review within 24 months.

Diabetes is defined by: HbA1c ≥ 6.5 at least one time in the last year OR ICD10 diagnosis codes OR Having diabetes in the patient's medical record problem list.

Exclusion Criteria:

• Have diabetes, but no CKD.
• Are currently on dialysis (ICD 10 codes N18.6, Z99.2 and Z94.0)
• Have ESRD (eGFR<15 ml/min)
• Have a left ventricular assist device (LVAD)
• Have a terminal illness
• Have patient-reported known pregnancy at time of enrollment
• Have had a liver, kidney, or allogeneic bone marrow transplant
• Too cognitively impaired to provide informed consent and/or complete the study protocol
• Institutionalized or too ill to participate (i.e. incarcerated, psychiatric or nursing home facility)
• Plan to move out of the area within 6 months of enrollment
• Not a current patient seeing a provider who cares for their hypertension (i.e., family medicine, internal medicine, nephrology, HIV provider, cardiology, hypertension specialists) at a participating site
• Previously participated in the GUARDD pilot study OR have previously undergone APOL1 testing

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Immediate Return of Results; Immediate return of results to inform participant of APOL1 status (either positive or negative).	Other: Timing of return of results; Participants will be randomized to immediate versus delayed APOL1 return of results
Active Comparator: Delayed Return of Results; Delayed return of results of APOL1 status (either positive or negative) after the completion of the 6 month final study visit.	Other: Timing of return of results; Participants will be randomized to immediate versus delayed APOL1 return of results

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in Systolic Blood Pressure From Baseline to 3 Months for APOL1 Positive Participants.	Baseline to 3 month study visit

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in Number of Participants With Urine Microalbuminuria/Proteinuria Orders	Baseline to 6 month study visit
Number of Participants With Documented Order of Microalbuminuria/Proteinuria Tests	From baseline to 6 month study visit
Number of Participants With a Change in Documented Diagnosis for Stage 3 CKD and Above	From baseline to 6 month study visit
Number of Participants With Documented Diagnosis of CKD Stage 3 and Above	From baseline to 6 month study visit
Number of Participants With a Change in Documented Diagnosis for Any Stage CKD	From baseline to 6 month study visit
Number of Participants With Documented Diagnosis of All Stages of CKD	From baseline to 6 month study visit

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: Icahn School of Medicine at Mount Sinai; University of Florida; Vanderbilt University Medical Center; National Human Genome Research Institute (NHGRI); Indiana University School of Medicine
• Investigators: Study Director: Hrishikesh Chakraborty, DrPH, Duke University; Principal Investigator: Carol Horowitz, MD, Icahn School of Medicine at Mount Sinai

Publications and helpful links

General Publications

• Eadon MT, Cavanaugh KL, Orlando LA, Christian D, Chakraborty H, Steen-Burrell KA, Merrill P, Seo J, Hauser D, Singh R, Beasley CM, Fuloria J, Kitzman H, Parker AS, Ramos M, Ong HH, Elwood EN, Lynch SE, Clermont S, Cicali EJ, Starostik P, Pratt VM, Nguyen KA, Rosenman MB, Calman NS, Robinson M, Nadkarni GN, Madden EB, Kucher N, Volpi S, Dexter PR, Skaar TC, Johnson JA, Cooper-DeHoff RM, Horowitz CR; GUARDD-US Investigators. Design and rationale of GUARDD-US: A pragmatic, randomized trial of genetic testing for APOL1 and pharmacogenomic predictors of antihypertensive efficacy in patients with hypertension. Contemp Clin Trials. 2022 Aug;119:106813. doi: 10.1016/j.cct.2022.106813. Epub 2022 Jun 1.
• Eadon MT, Cavanaugh KL, She L, Steen-Burrell KA, Mohottige D, Nadkarni GN, Kitzman H, Chakraborty H, Empey PE, Limdi NA, Singh R, Beasley CM, Parker AS, Cicali EJ, Ramos MA, Clermont S, Dodgen L, Elwood EN, Robinson M, Umeukeje EM, Garcia Ortega A, Shroff N, Rosenman MB, Nguyen KA, Volpi S, Rider R, Dexter PR, Skaar TC, Peterson JF, Cavallari LH, Johnson JA, Wyatt CM, Orlando LA, Cooper-DeHoff RM, Horowitz CR; Implementing Genomics in Practice (IGNITE) Pragmatic Trials Network. Genetic Testing for APOL1 in Adults With Hypertension: The GUARDD-US Randomized Clinical Trial. JAMA Netw Open. 2026 Mar 2;9(3):e260528. doi: 10.1001/jamanetworkopen.2026.0528.

Helpful Links

• Genetic Testing for APOL1 in Adults With Hypertension: The GUARDD-US Randomized Clinical Trial

Study record dates

Study Major Dates

• Study Start (Actual): July 10, 2020
• Primary Completion (Actual): April 9, 2024
• Study Completion (Actual): May 17, 2024

Study Registration Dates

• First Submitted: December 5, 2019
• First Submitted That Met QC Criteria: December 5, 2019
• First Posted (Actual): December 10, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2026
• Last Update Submitted That Met QC Criteria: March 9, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Genomics; Kidney Disease; Genetic testing; APOL1; Renal Disease
• Additional Relevant MeSH Terms: Urogenital Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Chronic Disease; Disease Attributes; Renal Insufficiency; Pathological Conditions, Signs and Symptoms; Hypertension; Kidney Diseases; Renal Insufficiency, Chronic
• Other Study ID Numbers: PRO00102997; U01HG007269 (U.S. NIH Grant/Contract); U01HG010225 (U.S. NIH Grant/Contract); U01HG010248 (U.S. NIH Grant/Contract); U01HG010245 (U.S. NIH Grant/Contract); U01HG010232 (U.S. NIH Grant/Contract); U01HG010231 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Data Coordinating Center (DCC) will submit de-identified participant level datasets and associated documentation to the NHGRI's data repository - Genomic Analysis, Visualization and Informatics Lab-space (AnVIL), for use by other investigators. The datasets and associated documentation will be available after publication of the primary results manuscript. Documentation will include annotated case report forms, list of derived variables along with descriptions, and a description of the data model and de-identification process.
• IPD Sharing Time Frame: 3 months after publication
• IPD Sharing Access Criteria: Datasets will be designated as controlled access and researchers will be able to apply to NIH data access committees (DACs) for use of these datasets.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No