DKK3 for Prognosis and Monitoring of GFR Decline in Heart Failure

Urinary Dickkopf-3 for Prognosis and Monitoring of Glomerular Filtration Rate Decline in Patients With Heart Failure

The individual course of chronic kidney disease (CKD) may vary, and improved methods for identifying which patients will experience estimated glomerular filtration rate (eGFR) decline are needed. Recently, urinary dickkopf-3 (DKK3) has been proposed to predict eGFR decline in patients with CKD, independent of presence of albuminuria. The investigators sought to examine the association between changes in DKK3 levels and eGFR decline in patients with heart failure (HF).

Study Overview

• Status: Active, not recruiting
• Conditions: Heart Failure; Chronic Kidney Diseases
• Intervention / Treatment: Diagnostic test: No intervention

Detailed Description

The individual course of chronic kidney disease (CKD) may vary, and improved methods for identifying which patients will experience estimated glomerular filtration rate (eGFR) decline are needed. Recently, urinary dickkopf-3 (DKK3) has been identified as an stress-induced, renal tubular epithelia-derived, secreted glycoprotein that induces tubulointerstitial fibrosis. Urinary DKK3 has been found to predict eGFR decline in patients with CKD, independent of presence of albuminuria, but its association with eGFR decline in patients with heart failure (HF) is unknown. The investigators sought to examine the association between changes in DKK3 and eGFR decline in patients with HF.

• Study Type: Observational
• Enrollment (Estimated): 300

Contacts and Locations

Study Locations

• Germany
  • Hessen
    • Giessen, Hessen, Germany, 35392
      • University Clinic Giessen and Marburg - Campus Giessen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Outpatients ≥18 years of age with diagnosed HF or diabetes or hypertension

Description

Inclusion Criteria:

• Outpatients ≥18 years of age with diagnosed HF or diabetes or hypertension

Exclusion Criteria:

• CKD with estimated GFR <30 ml/min/1.73 m2
• CKD with extracorporeal or peritoneal ultrafiltration due to diuretic-resistant fluid overload
• autosomal dominant polycystic kidney disease
• active tumor disease
• inflammatory or autoimmune disease requiring systemic immunosuppressive treatment
• clinically apparent infections
• recipients of solid-organ transplants
• patients who received non-steroidal anti-inflammatory drugs or intravenous contrast media within 72 hours prior to recruitment

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
HF; Diagnosed heart failure as described by recent guidelines. Inclusion criteria will be applied: i) minimum one symptom typical of HF: positive physical examination (e.g., bilateral oedema, increased jugular pressure) or positive clinical history (e.g., orthopnoea, history of coronary vascular disease, history of arterial hypertension, exposition to cardiotoxic drug/radiation, diuretic use); b-type natriuretic peptide (BNP) or N-terminal pro-BNP levels ≥35 or ≥125 pg/ml, respectively; and iii) classification as New York Heart Association (NYHA) functional class 2 or 3. There is no prespecified inclusion criterion with respect to left ventricular ejection fraction as congestive symptoms and prevalence of kidney dysfunction are comparable in patients with HF across the left ventricular ejection fraction spectrum.	Diagnostic test: No intervention; No intervention
Hypertension; Diagnosed hypertension, with/without treatment	Diagnostic test: No intervention; No intervention
Diabetes mellitus/hypertension; Diagnosed diabetes mellitus, with/without treatment	Diagnostic test: No intervention; No intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Association between DKK3 and eGFR decline	DKK3 and eGFR (CKD-Epidemiology Collaboration equation)	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Persistent or worsening of HF	Cardiovascular death, hospital admission for decompensated HF, or clinical HF decompensation without hospital admission (but requiring parenteral HF therapy or changes in oral HF medications including diuretics)	24 months
Need for renal replacement therapy	Requirement of incident renal replacement therapy	24 months
Association between proteinuria and DKK3	DKK3 and proteinuria, albuminuria, and alpha 1 microglobulin excretion	24 months
Association of venous congestion/volume overload with DKK3	B-type natriuretic peptide, clinical examination, bioimpedance analysis, echocardiography	24 months
Association of right and left ventricular function with DKK3	Echocardiography	24 months

Collaborators and Investigators

• Sponsor: University of Giessen
• Investigators: Study Chair: Werner Seeger, MD, University Hospital Gießen

Publications and helpful links

General Publications

• Zewinger S, Rauen T, Rudnicki M, Federico G, Wagner M, Triem S, Schunk SJ, Petrakis I, Schmit D, Wagenpfeil S, Heine GH, Mayer G, Floege J, Fliser D, Grone HJ, Speer T. Dickkopf-3 (DKK3) in Urine Identifies Patients with Short-Term Risk of eGFR Loss. J Am Soc Nephrol. 2018 Nov;29(11):2722-2733. doi: 10.1681/ASN.2018040405. Epub 2018 Oct 2.
• Federico G, Meister M, Mathow D, Heine GH, Moldenhauer G, Popovic ZV, Nordstrom V, Kopp-Schneider A, Hielscher T, Nelson PJ, Schaefer F, Porubsky S, Fliser D, Arnold B, Grone HJ. Tubular Dickkopf-3 promotes the development of renal atrophy and fibrosis. JCI Insight. 2016 Jan 21;1(1):e84916. doi: 10.1172/jci.insight.84916.

Study record dates

Study Major Dates

• Study Start (Actual): October 14, 2019
• Primary Completion (Actual): January 21, 2023
• Study Completion (Estimated): March 31, 2024

Study Registration Dates

• First Submitted: September 27, 2019
• First Submitted That Met QC Criteria: September 27, 2019
• First Posted (Actual): October 1, 2019

Study Record Updates

• Last Update Posted (Estimated): December 7, 2023
• Last Update Submitted That Met QC Criteria: November 30, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Urologic Diseases; Disease Attributes; Renal Insufficiency; Chronic Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Heart Failure; Kidney Diseases; Renal Insufficiency, Chronic
• Other Study ID Numbers: AZ 122/19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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