Effect of Renin-angiotensin-system Blockade on Urinary Free Light Chains in Patients With Type 2 Diabetes Mellitus

Phase 4

Completed

• Conditions: Type 2 Diabetes; Hypertension
• Interventions: Drug: amlodipine, hydralazine, terazosin or hydrochlorothiazide

• Registration Number: NCT02046395
• Lead Sponsor: Tulane University School of Medicine

Brief Summary

The purpose of this study is to study the effect of blocking the renin angiotensin system on urinary free light chain excretion as compared to urine microalbumin creatinine ratio in subjects with type 2 diabetes. The long term goal is to assess urinary free-light chains as a biomarker of earlier detection of kidney function impairment in subjects with diabetes mellitus.

Detailed Description

Free light chains (FLCs) are low-molecular-mass molecules (kappa and lambda light chains), which are by-products of normal immunoglobulin synthesis and are normally excreted through the kidneys. Presence of light chains in the urine is a marker of tubular dysfunction. In patients with impaired kidney function, serum concentrations and urinary excretion of polyclonal FLCs have been noted to be increased. Increased excretion of FLCs and other low-molecular weight proteins \[cystatin C, NGAL\] in the urine may contribute to progression of chronic kidney disease. Higher Cystatin C has been demonstrated to be related to development of albuminuria. Neutrophil gelatinase-associated lipcalin (NGAL) excretion in the urine is a marker of tubular injury in the kidney and has been shown to be elevated in subjects with type 1 and 2 diabetes mellitus (DM). Angiotensin-converting enzyme inhibitors (Ace Inh) and angiotensin II receptor blockers (ARB) class of drugs are renoprotective in nature and are the first line therapy for treatment of diabetic nephropathy. There is no longitudinal data evaluating the effect of Ace Inh and ARB class of drugs on urinary FLCs (UFLCs).

Our hypothesis is that UFLCs are increased in patients with DM with and without kidney disease and that treatment with Ace Inh and/or ARB will decrease UFLCs in these patients. Additionally, we will explore the change in other low molecular weight proteins \[cystatin C, and NGAL\] in response to treatment with Ace Inh and ARB.

Study Timeline

• Study Start: 2012-01
• Study First Submitted: 2014-01-23
• Study First Submitted QC: 2014-01-23
• Study First Posted: 2014-01-27
• Primary Completion: 2019-12
• Study Completion: 2019-12
• Disposition First Submitted: 2021-03-01
• Disposition First Submitted QC: 2021-03-01
• Disposition First Posted: 2021-03-08
• Results First Submitted: 2022-03-31
• Status Verified: 2023-08
• Results First Submitted QC: 2023-08-17
• Last Update Submitted: 2023-08-17
• Results First Posted: 2023-08-21
• Last Update Posted: 2023-08-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 28

Inclusion Criteria

• Type 2 Diabetes
• Hypertension
• Estimated glomerular filtration rate (eGFR) > 30 ml/min
• Use of Ace Inh and ARB for control of blood pressure who are willing to be placed on alternate drug(s) in the washout period for blood pressure control

Exclusion Criteria

• Pregnancy
• Patients with chronic kidney disease stage with eGFR < 30 ml/min (CKD stage IV and V)
• Nephrotic range proteinuria (urinary protein > 3.5 gm/day)
• History or renal transplantation
• History of multiple myeloma
• Known history of hypersensitivity reaction or intolerability to Ace Inh or ARB.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Washout Period for 30 days	amlodipine, hydralazine, terazosin or hydrochlorothiazide	In the washout period, the Ace Inh or ARB classes of medicine(s) that are part of the patient's antihypertensive regimen will be discontinued. The patient will be started on alternative therapy with medications that are approved by the Food and Drug Administration for treatment of high blood pressure (such as amlodipine, hydralazine, terazosin or Hydrochlorothiazide) for control of their blood pressure. The goal for their blood pressure will be set at \< 140/90 mm/Hg. The washout period will last for four weeks at the end of which the patient will enter the test period.

Primary Outcome Measures

Name	Time	Method
Change in Urine Microalbumin Creatinine Ratio	Visit 1 (Baseline), Visit 3 (Day 60)	Kidney function will be assessed throughout the study to assess changes in function prior to the washout of ACE/ARB medication and reintroduction of the ACE/ARB medication.

Secondary Outcome Measures

Name	Time	Method
Change in the Level of Urinary Free Light Chains	Visit 1 (Baseline), Visit 3 (Day 60)	In relation to kidney function and washout/reintroduction of ACE/ARB medication the level of urinary free light chains will be assessed.

Trial Locations

Locations (1)

Tulane University Health Sciences Center; 🇺🇸 New Orleans, Louisiana, United States