Acute kidney injury during pregnancy leads to increased sFlt-1 and sEng and decreased renal T regulatory cells in pregnant rats with HELLP syndrome

Abstract

Background The incidence of acute kidney injury (AKI) during pregnancy precedes a high maternal mortality rate of 20–40%. AKI during pregnancy has multiple etiologies; however, the more common are maternal hypertensive disorders, which include preeclampsia and HELLP (hemolysis, elevated liver enzyme, low platelet) syndrome. Therefore, we sought to assess the impact of AKI on blood pressure, kidney injury, and anti-angiogenic factors during pregnancies with and without HELLP syndrome. Methods On gestational day (GD) 12, mini-osmotic pumps were inserted into a subset of normal pregnant (NP) rats infusing 4.7 μg/kg soluble fms-like tyrosine kinase-1 (sFlt-1) and 7 μg/kg soluble endoglin (sEng) to induce HELLP syndrome. On GD18, the renal pedicles were occluded for 45 min to induce AKI via bilateral ischemia reperfusion in a subset of NP (n = 18) or HELLP (n = 20) rats. Control NP (n = 20) and HELLP (n = 20) rats underwent a SHAM surgery on GD18. Plasma, urine, and maternal organs were saved for further analysis. Renal injury was assessed via renal histopathology, glomerular filtration rate (GFR), T cell infiltration, and assessment of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Data was measured via two-way analysis of variance with Tukey’s test for post hoc analysis. Results Blood pressures were increased in HELLP+AKI rats (p = 0.0001); both NP+AKI and HELLP+AKI rats had increased lactate dehydrogenase (p < 0.0001) and aspartate aminotransferase levels (p < 0.0001), and decreased platelet levels (p < 0.001) vs. NP rats. HELLP+AKI (p = 0.002) and HELLP rats (p = 0.0002) had evidence of renal fibrosis vs. NP rats. GFR was decreased in HELLP+AKI (p = 0.01) rats vs. NP rats. Urinary KIM-1 was increased in NP+AKI rats vs. NP (p = 0.003) and HELLP rats (p = 0.01). HELLP+AKI rats had increased urinary KIM-1 vs. NP (p = 0.0008) and HELLP rats (p = 0.004) and increased NGAL vs. HELLP rats (p = 0.002). HELLP+AKI rats had increased sFlt-1 (p = 0.009) vs. NP rats. NP+AKI (p = 0.02) and HELLP+AKI (p = 0.007) rats had increased sEng vs. NP rats. CD3+CD4+ T cells were significantly increased in HELLP+AKI rats vs. NP (p = 0.0002) and NP+AKI (p = 0.05) rats. T regulatory cells were significantly decreased in HELLP+AKI (p = 0.03) and NP+AKI (p = 0.02) rats vs. NP rats; there were no changes between groups in T helper 17 cells (p = 0.34). Conclusion The findings in this study suggest that AKI during pregnancy contributes to increased blood pressure and biochemical markers for HELLP syndrome, creates an anti-angiogenic imbalance, and exacerbates kidney injury as shown on histopathology, GFR, and kidney injury markers.

Indoxyl Sulfate Administration during Pregnancy Contributes to Renal Injury and Increased Blood–Brain Barrier Permeability

“…contribute to cardiovascular dysfunction and hypertension, there were no significant differences in blood pressure in the current study. We have previously published that experimental PR-AKI does not increase blood pressure when measured 24 h after injury, which is again confirmed with the current study [23]. Urine output was decreased in response to both PR-AKI and I.S.…”

“…On GD18, animals underwent a 45-min bilateral renal ischemia reperfusion surgery to induce AKI as described previously [23]. Following the induction of AKI, all rats, regardless of their grouping, were placed in metabolic cages overnight with water and standard rodent chow (0.4% sodium) to allow continuous urine collection.…”

“…Using a family-wise alpha level of 0.05, and assuming an effect size of Cohen's d = 2.44 (based on data from our original PR-AKI study [23]), our sample size provides over 85% power to compare each of the experimental groups with the NP control groups.…”

Urinary extracellular vesicles and micro-RNA as markers of acute kidney injury after cardiac surgery

“…Whether the observed rise in EV positive for β1-integrin correlates with inflammation levels needs further research. Levels of CD105 (endoglin) increase in response to AKI 21 or ischaemia/reperfusion 22 and can indicate endothelial activation.…”