Thyroid Hormones in ADPKD (REORIENTED)

Deciphering the Role of Thyroid Hormones in Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic, rare and life-threatening disease, characterized by the pathological formation of multiple fluid-filled cysts that arise from renal tubules and alter kidney architecture and function. In most patients, the progressive deterioration of renal function ultimately leads to end-stage kidney disease (ESKD) and the need for dialysis or kidney transplantation.

Save the conventional anti-hypertensive strategies, there are currently two disease-specific treatments for ADPKD (Tolvaptan and Octreotide-LAR). However, these drugs are only available to patients at high risk of progression to ESKD, while a remarkable number of ADPKD patients progress to ESKD despite the treatments.

Cyst formation in ADPKD is determined by mutations in two genes encoding two transmembrane proteins: polycystin1 and polycystin2. The pathogenesis of the disease involves a series of phenotypic alterations, including the de-differentiation of epithelial cells, uncontrolled proliferation and abnormal secretion of fluids in the cysts, metabolic remodeling, all phenomena that lead to the progressive loss of renal structure and function . Therefore, to try to investigate the mechanisms of the disease, the investigators should go in search of pleiotropic molecules capable of simultaneously modulating structure, function and metabolism.

Research done so far suggests that thyroid hormones (TH) may also act as pleiotropic modulators in the patho-biology of ADPKD. TH signals play a crucial role in the regulation of cell de-differentiation and cell cycle reactivation, as well as in the metabolism and evolution of cardiac and renal diseases. Interestingly, changes in TH levels have been detected in approximately 80% of patients with chronic renal failure (CKD), whereas patients with ADPKD show a higher incidence of clinical and subclinical hypothyroidism. Despite these evidences, the ability of TH to modulate anti-cystogenic and renoprotective processes in ADPKD has not yet been studied.

The objective of this study is to determine the levels of THs in the serum of ADPKD patients with normal renal function and mild, moderate or severe renal dysfunction, and to correlate them with renal functional parameters.

Study Overview

• Status: Completed
• Conditions: Autosomal Dominant Polycystic Kidney
• Intervention / Treatment: Other: Blood sampling

• Study Type: Interventional
• Enrollment (Actual): 91
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • BG
    • Ranica, BG, Italy, 24020
      • Centro di Ricerche Cliniche per le Malattie Rare "Aldo e Cele Daccò"

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Male and female ≥18 years old;
2. Diagnosis of ADPKD based on renal ultrasonography or genetic test;
3. Written informed consent

Exclusion Criteria:

1. Diagnosis of Hashimoto's disease, hyperthyroidism or pituitary disease or any other condition undergoing levothyroxine replacement
2. Patient with hypothyroidism treated with drug therapy
3. Active treatment with Tolvaptan and/or Octreotide-LAR;
4. Regular treatment with amiodarone, lithium, interferon or immunosuppressive drugs including steroids;
5. Active malignancy or acute or chronic inflammatory disease, HIV;
6. Dialysis or kidney transplantation;
7. Diabetes mellitus;
8. Hypocaloric diet or current dietary approaches to obtain weight loss.
9. Legal incapacity or any evidence that the patient will not be able to understand the study aims and procedures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: ADPKD patients; The study will include 90 patients with diagnosis of ADPKD based on renal ultrasonography findings or genetic test. Specifically, five groups of patients will be identified according to KDIGO classification: 18 subjects with normal or high renal function: eGFR ≥90 ml/min/1.73m2 - CKD G1 stage; 18 subjects with mildly decreased renal function: eGFR 89-60 ml/min/1.73m2 - CKD G2 stage; 18 subjects with mildly to moderately decreased renal function: eGFR 59 to 45 ml/min/1.73m2 - CKD G3a stage; 18 subjects with moderately to severely decreased renal function: eGFR 44 to 30 ml/min/1.73m2 - CKD G3b stage; 18 subjects with severely decreased renal function: eGFR 29 to 15 ml/min/1.73m2 - CKD G4 stage.

Other: Blood sampling; A blood sample of 15 ml will be collected for each patient.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Serum levels of total and free triiodothyronine (T3).	Once during the study.
Serum levels of total and free L-thyroxine (T4).	Once during the study.
Serum levels of total and free thyroid stimulating hormone (TSH).	Once during the study.
Serum levels of total and free reverse T3 (rT3).	Once during the study.

Collaborators and Investigators

• Sponsor: Mario Negri Institute for Pharmacological Research

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2023
• Primary Completion (Actual): February 16, 2024
• Study Completion (Actual): March 25, 2024

Study Registration Dates

• First Submitted: December 5, 2022
• First Submitted That Met QC Criteria: December 5, 2022
• First Posted (Actual): December 12, 2022

Study Record Updates

• Last Update Posted (Actual): March 28, 2024
• Last Update Submitted That Met QC Criteria: March 27, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Abnormalities, Multiple; Kidney Diseases, Cystic; Ciliopathies; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant
• Other Study ID Numbers: REORIENTED

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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