Urinary Uromodulin, Dietary Sodium Intake and Ambulatory Blood Pressure in Patients With Chronic Kidney Disease

NCT06363097 | Completed

• 1 other identifier: ΔΔ5032
• Study Type: observational
• Target: 130
• Locations: 1 country
• Sites: 1

Brief Summary

In chronic kidney disease (CKD), hypertension is characterized by the phenomenon of sodium-sensitivity, i.e., the disproportionate increase in blood pressure (BP) due to an increase in dietary sodium consumption to maintain homeostasis through urinary sodium excretion. Impaired renal circulation, blunt suppression of renin-angiotensin-aldosterone system, sympathetic nervous system overactivity, paradoxically reduced levels of atrial natriuretic peptide and hyperinsulinemia represent the main pathophysiologic mechanisms. Accumulated evidence has suggested that uromodulin plays a central role in the development of sodium-sensitive hypertension. Uromodulin is a kidney-specific glycoprotein which is exclusively produced by the epithelial cells lining the thick ascending limb and early distal convoluted tubule. It is currently recognized as a multifaceted player in kidney physiology and disease, with discrete roles for intracellular, urinary, interstitial and serum uromodulin. Among these, urinary uromodulin modulates renal sodium handling through regulating tubular transporters that reabsorb sodium and are targeted by diuretics, i.e., the loop diuretic-sensitive Na+-K+-2Cl- cotransporter type 2 (NKCC2) and the thiazide-sensitive Na+/Cl- cotransporter (NCC). Given these roles, the contribution of uromodulin to sodium-sensitive hypertension has been proposed. In preclinical models, uromodulin deficiency causes decreased BP that is resistant to dietary salt, while uromodulin overexpression causes hypertension due to increased tubular sodium reabsorption that is responsive to furosemide. Genetic human studies have identified robust associations of specific UMOD gene variants with sodium sensitivity and incident hypertension risk, while comprehensive Mendelian randomization studies have affirmed these associations by highlighting the causal relationship between UMOD variants, urinary uromodulin levels and hypertension. Furthermore, clinical studies in both healthy individuals and hypertensive patients have indicated a link between sodium sensitivity and uromodulin, directly affecting mean BP levels and BP response to salt intake. With regards to CKD population, solid data on the link of uromodulin with sodium sensitivity are currently missing from the literature. There is only a pediatric study in the setting of CKD (stages 2-3), which failed to show an association between urinary uromodulin levels indexed to urinary creatinine (UMOD/uCr) and either 24-hour or office BP; however, this study has several limitations, and its results should be interpreted with caution. To best of our knowledge, there is no study up to date investigating the effect of dietary sodium intake on 24-hour ambulatory blood pressure depending on urinary uromodulin levels in adult CKD patients.

Conditions

Hypertension; Chronic Kidney Disease

Keywords

CKD; Uromodulin; sodium intake

Outcome Measures

Primary Outcomes (2)

• Effect of urinary uromodulin levels on the relationship between 24-hour urinary sodium excretion and 24-hour ambulatory systolic blood pressure.

  In patients with high and low urinary uromodulin excretion, investigation of the relationship of 24-hour urinary sodium excretion with 24-hour ambulatory systolic blood pressure.

  Baseline

• Effect of urinary uromodulin levels on the relationship between 24-hour urinary sodium excretion and 24-hour ambulatory diastolic blood pressure.

  In patients with high and low urinary uromodulin excretion, investigation of the relationship of 24-hour urinary sodium excretion with 24-hour ambulatory diastolic blood pressure.

  Baseline

Secondary Outcomes (36)

• Effect of urinary uromodulin levels on the relationship between nighttime/daytime ratio of urinary sodium excretion and 24-hour ambulatory systolic blood pressure.

  Baseline

• Effect of urinary uromodulin levels on the relationship between nighttime/daytime ratio of urinary sodium excretion and 24-hour ambulatory diastolic blood pressure.

  Baseline

• Effect of urinary uromodulin levels on the relationship between urinary sodium-to-potassium (Na+/K+) ratio and 24-hour ambulatory systolic blood pressure.

  Baseline

• Effect of urinary uromodulin levels on the relationship between urinary sodium-to-potassium (Na+/K+) ratio and 24-hour ambulatory diastolic blood pressure.

  Baseline

• The difference in 24-hour ambulatory brachial SBP/DBP between patients with high and low urinary uromodulin excretion.

  Baseline

Study Arms (2)

Low uromodulin group

Patients with urinary uromodulin levels below median.

High uromodulin group

Patients with urinary uromodulin levels above median.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

This study includes patients with CKD across all consecutive pre-dialysis stages.

You may qualify if:

• Age ≥18 years
• CKD defined based on the KDIGO criteria
• Provision of informed written consent

You may not qualify if:

• Kidney transplantation or end-stage kidney disease (ESKD) under hemodialysis or peritoneal dialysis
• Chronic atrial fibrillation or other diagnosed arrhythmia intervening with a proper 24-hour ABPM recording
• Inability to reliably complete the study questionnaires
• Pregnancy

Sponsors & Collaborators

• Aristotle University Of Thessaloniki: lead

Study Sites (1)

1st Department of Nephrology

Thessaloniki, Central Macedonia, 54642, Greece

Location

Related Publications (9)

• Karagiannidis AG, Theodorakopoulou MP, Pella E, Sarafidis PA, Ortiz A. Uromodulin biology. Nephrol Dial Transplant. 2024 Jun 28;39(7):1073-1087. doi: 10.1093/ndt/gfae008.

  PMID: 38211973 BACKGROUND

• Padmanabhan S, Melander O, Johnson T, Di Blasio AM, Lee WK, Gentilini D, Hastie CE, Menni C, Monti MC, Delles C, Laing S, Corso B, Navis G, Kwakernaak AJ, van der Harst P, Bochud M, Maillard M, Burnier M, Hedner T, Kjeldsen S, Wahlstrand B, Sjogren M, Fava C, Montagnana M, Danese E, Torffvit O, Hedblad B, Snieder H, Connell JM, Brown M, Samani NJ, Farrall M, Cesana G, Mancia G, Signorini S, Grassi G, Eyheramendy S, Wichmann HE, Laan M, Strachan DP, Sever P, Shields DC, Stanton A, Vollenweider P, Teumer A, Volzke H, Rettig R, Newton-Cheh C, Arora P, Zhang F, Soranzo N, Spector TD, Lucas G, Kathiresan S, Siscovick DS, Luan J, Loos RJ, Wareham NJ, Penninx BW, Nolte IM, McBride M, Miller WH, Nicklin SA, Baker AH, Graham D, McDonald RA, Pell JP, Sattar N, Welsh P; Global BPgen Consortium; Munroe P, Caulfield MJ, Zanchetti A, Dominiczak AF. Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension. PLoS Genet. 2010 Oct 28;6(10):e1001177. doi: 10.1371/journal.pgen.1001177.

  PMID: 21082022 BACKGROUND

• Trudu M, Janas S, Lanzani C, Debaix H, Schaeffer C, Ikehata M, Citterio L, Demaretz S, Trevisani F, Ristagno G, Glaudemans B, Laghmani K, Dell'Antonio G; SKIPOGH team; Loffing J, Rastaldi MP, Manunta P, Devuyst O, Rampoldi L. Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression. Nat Med. 2013 Dec;19(12):1655-60. doi: 10.1038/nm.3384. Epub 2013 Nov 3.

  PMID: 24185693 BACKGROUND

• Ponte B, Sadler MC, Olinger E, Vollenweider P, Bochud M, Padmanabhan S, Hayward C, Kutalik Z, Devuyst O. Mendelian randomization to assess causality between uromodulin, blood pressure and chronic kidney disease. Kidney Int. 2021 Dec;100(6):1282-1291. doi: 10.1016/j.kint.2021.08.032. Epub 2021 Oct 9.

  PMID: 34634361 BACKGROUND

• Ponte B, Pruijm M, Ackermann D, Olinger E, Youhanna S, Vogt B, Burnier M, Pechere-Bertschi A, Bochud M, Devuyst O. Uromodulin, Salt, and 24-Hour Blood Pressure in the General Population. Clin J Am Soc Nephrol. 2021 May 8;16(5):787-789. doi: 10.2215/CJN.11230720. Epub 2021 Jan 21. No abstract available.

  PMID: 33478975 BACKGROUND

• Torffvit O, Melander O, Hulten UL. Urinary excretion rate of Tamm-Horsfall protein is related to salt intake in humans. Nephron Physiol. 2004;97(1):p31-6. doi: 10.1159/000077600.

  PMID: 15153749 BACKGROUND

• Bakhoum CY, Anderson CAM, Juraschek SP, Rebholz CM, Appel LJ, Miller ER, Parikh CR, Obeid W, Rifkin DE, Ix JH, Garimella PS. The Relationship Between Urine Uromodulin and Blood Pressure Changes: The DASH-Sodium Trial. Am J Hypertens. 2021 Mar 11;34(2):154-156. doi: 10.1093/ajh/hpaa140.

  PMID: 32856709 BACKGROUND

• Bakhoum CY, Matheson MB, Greenberg JH, Furth SL, Ix JH, Garimella PS. Urine Uromodulin Is Not Associated With Blood Pressure in the Chronic Kidney Disease in Children Cohort. Hypertension. 2022 Oct;79(10):2298-2304. doi: 10.1161/HYPERTENSIONAHA.122.19566. Epub 2022 Aug 3.

  PMID: 35920156 BACKGROUND

• McCallum L, Brooksbank K, McConnachie A, Aman A, Lip S, Dawson J, MacIntyre IM, MacDonald TM, Webb DJ, Padmanabhan S. Rationale and Design of the Genotype-Blinded Trial of Torasemide for the Treatment of Hypertension (BHF UMOD). Am J Hypertens. 2021 Feb 18;34(1):92-99. doi: 10.1093/ajh/hpaa166.

  PMID: 33084880 BACKGROUND

MeSH Terms

Conditions

Renal Insufficiency, Chronic; Hypertension

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Vascular Diseases; Cardiovascular Diseases

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 9, 2024
• First Posted: April 12, 2024
• Study Start: September 4, 2023
• Primary Completion: April 30, 2025
• Study Completion: August 30, 2025
• Last Updated: January 27, 2026

Record last verified: 2026-01

Locations

GR (1)