Title

Role of Intratubular Pressure During the Ischemic Phase in Acute Kidney Injury

Document Type

Article

Publication Date

2017

Keywords

tubular pressure, acute kidney injury, micropuncture

Digital Object Identifier (DOI)

https://doi.org/10.1152/ajprenal.00527.2016

Abstract

Acute kidney injury (AKI) induced by clamping of renal vein or pedicle is more severe than clamping of artery, but the mechanism has not been clarified. In the present study, we tested our hypothesis that increased proximal tubular pressure (Pt) during the ischemic phase exacerbates kidney injury and promotes the development of AKI. We induced AKI by bilateral clamping of renal arteries, pedicles, or veins for 18 min at 37°C, respectively. Pt during the ischemic phase was measured with micropuncture. We found that higher Pt was associated with more severe AKI. To determine the role of Pt during the ischemic phase on the development of AKI, we adjusted the Pt by altering renal artery pressure. We induced AKI by bilateral clamping of renal veins, and the Pt was changed by adjusting the renal artery pressure during the ischemic phase by constriction of aorta and mesenteric artery. When we decreased renal artery pressure from 85 ± 5 to 65 ± 8 mmHg, Pt decreased from 53.3 ± 2.7 to 44.7 ± 2.0 mmHg. Plasma creatinine decreased from 2.48 ± 0.23 to 1.91 ± 0.21 mg/dl at 24 h after renal ischemia. When we raised renal artery pressure to 103 ± 7 mmHg, Pt increased to 67.2 ± 5.1 mmHg. Plasma creatinine elevated to 3.17 ± 0.14 mg·dl·24 h after renal ischemia. Changes in KIM-1, NGAL, and histology were in the similar pattern as plasma creatinine. In summary, we found that higher Pt during the ischemic phase promoted the development of AKI, while lower Pt protected from kidney injury. Pt may be a potential target for treatment of AKI.

acute kidney injury (AKI) is a syndrome characterized by an abrupt reduction in kidney function (1, 42), resulting in failure to maintain fluid, electrolyte and acid-base homeostasis, and retention of nitrogenous waste products (6, 30). AKI occurs in ~5% of all hospital admissions and is responsible for approximately two million deaths annually worldwide (33, 45, 46). AKI increases the risk of development of chronic kidney disease (CKD) (10, 11), exacerbates preexisting CKD, and can evolve into end-stage renal disease (ESRD) (19, 25, 48). Patients who survive an episode of AKI have poorer long-term outcomes with increased mortality and extensive morbidity (3, 23). Even though AKI is extensively studied, unfortunately, there is no approved therapy to prevent or treat AKI (20). Therefore, further understanding of the pathophysiological mechanism is crucial to develop therapeutic approaches for AKI.

Renal ischemia reperfusion is a common cause of AKI (7, 24, 31). After ischemia reperfusion, tubular epithelial cells undergo serious damage, such as apical brush-border disruption, swelling, detachment from the basement membrane, and even death with acute tubular necrosis, resulting in rapid loss of kidney function (7, 13, 31). Several factors, such as hypoxia-induced ATP depletion (4, 13, 21, 28), the imbalance between superoxide (29) and nitric oxide (9, 44, 49), and the inflammatory response have been demonstrated to play important roles in renal ischemia-reperfusion injury (36, 43, 44). However, the pathophysiological mechanisms of AKI are complicated and are not well elucidated. This is especially true regarding the role of hemodynamic alterations and changes in mechanical force in the development of AKI.

The commonly used AKI models induced by occlusions of renal blood flow are typically accomplished by clamping of the renal artery, pedicle (artery and vein), or vein. Previous studies have reported that renal vein or pedicle clamping produced more severe AKI than renal artery clamping alone, but the mechanism remains to be determined (22, 24, 35). In the present study, we tested our hypothesis that increased intratubular pressure of the proximal tubule (Pt) during the ischemic phase exacerbates kidney injury and promotes the development of AKI. We first measured Pt during the ischemic phase while clamping the arteries, pedicles, or veins, respectively, and found a positive correlation between the Pt and the severity of the AKI. To determine whether the Pt during the ischemic phase is a causal factor for the kidney injury, we adjusted the Pt by altering the renal artery pressure during clamping of the renal veins. We found that increasing the Pt during the ischemic phase worsens AKI while lowering the Pt protects renal function.

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Yes

Citation / Publisher Attribution

American Journal of Physiology-Renal Physiology, v. 312, issue 6, p. F1158-F1165

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