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

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.

This is a cross-sectional study performed in the 1st Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece. For the purposes of this study, adult (aged ≥18 years) CKD patients (defined based on the KDIGO criteria) fulfilling the inclusion and exclusion criteria were invited to participate. All included patients signed a written informed consent form prior to study enrollment. The study protocol was approved by the Ethics Committee of the School of Medicine, Aristotle University of Thessaloniki and the and the Institutional Review Board of Hippokration Hospital, Thessaloniki, Greece. All procedures and evaluations are performed according to the Declaration of Helsinki 2013 Amendment and directives of the General Data Protection Regulation (GDPR).

Baseline evaluation includes the recording of demographics, anthropometric characteristics, CKD cause, comorbidities, concomitant medications, as well as a detailed physical examination and venous blood sampling for routine laboratory tests. Study participants are advised to refrain from food, caffeine, alcohol, or tobacco for 12 h and receive any standard medication before their morning appointment in the research laboratory to perform the assessments described below. Office BP measurements are performed thrice after 5-10 min of rest, in the sitting position, at the level of the brachial artery, with a validated oscillometric device \[Omron M3 Intellisense (Omron Healthcare, Kyoto, Japan)\] using a cuff of appropriate size, according to current guidelines. Afterwards, evaluation of patient's hydration status will be performed with lung ultrasound \[GE VScan (GE Healthcare, Horten, Norway)\] through quantification of US-B lines. The Mini-Mental State Exam (MMSE) is used for the assessment of cognitive function; sleep quality is evaluated by the Pittsburg Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS), while the severity of nocturia is also recorded. Following that, patients will undergo a 24-hour ambulatory BP monitoring (ABPM) with ABPMpro (SOMNOmedics, Randersacker, Germany) with an appropriately sized cuff. The device will take measurements every 20 minutes between 07:00 and 23:00 (daytime period) and every 30 minutes between 23:00 and 07:00 (nighttime period). Simultaneously, patients will perform a 24-hour urine collection, divided in two distinct periods (daytime and nighttime) with the use of two different containers matching the corresponding ABPM periods.

Eligibility Criteria:
Inclusion Criteria:

1. Age ≥18 years
2. CKD defined based on the KDIGO criteria
3. Provision of informed written consent

Exclusion Criteria:

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