Pregnancy-associated changes in urinary uromodulin excretion in chronic hypertension

Abstract

Background: Pregnancy involves major adaptations in renal haemodynamics, tubular, and endocrine functions. Hypertensive disorders of pregnancy are a leading cause of maternal mortality and morbidity. Uromodulin is a nephron-derived protein that is associated with hypertension and kidney diseases. Here we study the role of urinary uromodulin excretion in hypertensive pregnancy.

Methods: Urinary uromodulin was measured by ELISA in 146 pregnant women with treated chronic hypertension (n = 118) and controls (n = 28). We studied non-pregnant and pregnant Wistar Kyoto and Stroke Prone Spontaneously Hypertensive rats (n = 8/strain), among which a group of pregnant Stroke-Prone Spontaneously Hypertensive rats was treated with either nifedipine (n = 7) or propranolol (n = 8).

Results: In pregnant women, diagnosis of chronic hypertension, increased maternal body mass index, Black maternal ethnicity and elevated systolic blood pressure at the first antenatal visit were significantly associated with a lower urinary uromodulin-to-creatinine ratio. In rodents, pre-pregnancy urinary uromodulin excretion was twofold lower in Stroke-Prone Spontaneously Hypertensive rats than in Wistar Kyoto rats. During pregnancy, the urinary uromodulin excretion rate gradually decreased in Wistar Kyoto rats (a twofold decrease), whereas a 1.5-fold increase was observed in Stroke-Prone Spontaneously Hypertensive rats compared to pre-pregnancy levels. Changes in uromodulin were attributed by kidney injury in pregnant rats. Neither antihypertensive changed urinary uromodulin excretion rate in pregnant Stroke-Prone Spontaneously Hypertensive rats.

Conclusions: In summary, we demonstrate pregnancy-associated differences in urinary uromodulin: creatinine ratio and uromodulin excretion rate between chronic hypertensive and normotensive pregnancies. Further research is needed to fully understand uromodulin physiology in human pregnancy and establish uromodulin's potential as a biomarker for renal adaptation and renal function in pregnancy.

Keywords: Blood pressure; Chronic hypertensive pregnancy; Kidney physiology; Uromodulin.

Fig. 1

a Spot urinary uromodulin:creatinine ratio (mg/g) by gestational age (weeks) at sampling in participants with chronic hypertension (CHT) and controls. Repeated sampling episodes in a single participant are joined by solid lines. Trend lines with 95% confidence intervals were fitted using the Locally Estimated Scatterplot Smoothing (LOESS) method. No clear trend between urinary uromodulin:creatinine ratio and gestational age is observed in either CHT or controls. b Plot of change in urinary uromodulin:creatinine ratio (mg/g) and change in systolic and diastolic BP between sampling episodes in participants with repeated samples across pregnancy

Fig. 2

Uromodulin excretion rate increased pregnant Stroke-Prone Spontaneously Hypertensive rats a Systolic blood pressure measured by tail-cuff in Wistar Kyoto rats (WKY) (n = 8) and Stroke-Prone Spontaneously Hypertensive rats (SHRSP) (n = 8) before and during pregnancy. Repeated measure ANOVA with multiple comparisons. * p < 0.05, ***p < 0.001, ****p < 0.0001 strain difference in pregnant WKY and SHRSP. GD gestational day, PP pre-pregnancy. b The urinary uromodulin excretion in pregnant SHRSP increased compared to pregnant WKY. Repeated measure ANOVA with multiple comparisons. *p < 0.05 and **p < 0.01 difference compared to pre-pregnancy within the strain, a p < 0.05 pre-pregnancy strain difference. GD gestational day, PP pre-pregnancy. c There was no change in uromodulin mRNA level in pregnant (at GD 18.5) and age-matched non-pregnant female rats in both the strains (n = 8 per condition per strain). d Pregnant SHRSP (at GD 18.5) showed increase in total kidney uromodulin level compared to non-pregnant SHRSP and pregnant WKY. **p < 0.01, ****p < 0.0001 (Student’s t test). NP non-pregnan, P pregnant. The mRNA expression of e neutrophil gelatinase-associated lipocalin (NGAL) and f kidney injury marker-1 (KIM-1) were assessed in pregnant (at GD18.5) and age-matched non-pregnant female rats in both the strains. Student’s t test. NP Non-pregnant, P pregnant

Fig. 3

Effect of nifedipine and propranolol treatment on blood pressure and uromodulin. a Nifedipine (PNif, n = 7) reduced systolic blood pressure in pregnant SHRSP compared to propranolol (PProp, n = 8) and placebo pregnant SHRSP (n = 8). Repeated measure ANOVA with multiple comparisons. *p < 0.05 and ***p < 0.001 difference with nifedipine treatment in pregnant SHRSP, aa p < 0.01 difference between nifedipine- and placebo- treated pregnant SHRSP. Anti-hypertensive treatments in pregnant SHRSP did not reduce the kidney injury markers NGAL (b) and KIM1 (c). Student’s T test. Antihypertensive treatment did not change uromodulin in pregnant SHRSP at d mRNA level, e kidney protein level and f urinary excretion rate. Repeated measure ANOVA with multiple comparisons or Students’ T test. SHRSP-P: placebo treated pregnant SHRSP (n = 8); SHRSP-PNif: nifedipine treated pregnant SHRSP (n = 7) and SHRSP-PProp: propranolol treated pregnant SHRSP (n = 8)