Divergent effects of AKI to CKD models on inflammation and fibrosis

Abstract

Chronic kidney disease (CKD) is a condition with significant morbidity and mortality that affects 15% of adults in the United States. One cause of CKD is acute kidney injury (AKI), which commonly occurs secondary to sepsis, ischemic events, and drug-induced nephrotoxicity. Unilateral ischemia-reperfusion injury (UIRI) without contralateral nephrectomy (CLN) and repeated low-dose cisplatin (RLDC) models of AKI to CKD demonstrate responses characteristic of the transition; however, previous studies have not effectively compared the pathogenesis. We demonstrate both models instigate renal dysfunction, inflammatory cytokine responses, and fibrosis. However, the models exhibit differences in urinary excretory function, inflammatory cell infiltration, and degree of fibrotic response. UIRI without CLN demonstrated worsening perfusion and function, measured with Tc-mercaptoacetyltriglycine-3 imaging, and physiologic compensation in the contralateral kidney. Furthermore, UIRI without CLN elicited a robust inflammatory response that was characterized by a prolonged polymorphonuclear cell and natural killer cell infiltrate and an early expansion of kidney resident macrophages, followed by T-cell infiltration. Symmetrical diminished function occurred in RLDC kidneys and progressively worsened until day 17 of the study. Surprisingly, RLDC mice demonstrated a decrease in inflammatory cell numbers relative to controls. However, RLDC kidneys expressed increased levels of kidney injury molecule-1 (KIM-1), high mobility group box-1 ( HMGB1), and colony stimulating factor-1 ( CSF-1), which likely recruits inflammatory cells in response to injury. These data emphasize how the divergent etiologies of AKI to CKD models affect the kidney microenvironment and outcomes. This study provides support for subtyping AKI by etiology in human studies, aiding in the elucidation of injury-specific pathophysiologic mechanisms of the AKI to CKD transition.

Modeling acute kidney injury in kidney organoids with cisplatin

“…Such a scenario is more representative of chemotherapeutic low-dose cisplatin administered over an extended period of time, whereby sustained inflammation is a contributing factor to the transition from AKI to renal fibrosis and CKD (14). Our 4x 5 µM approach is also consistent with recent work in mice, where repeated low-dose cisplatin regimens were shown to induce inflammatory cytokines and fibrosis markers in contrast to the acute toxicity, high mortality and lack of fibrosis seen with a single high-dose treatment (1,3,15).…”

Dynamic signature of lymphangiogenesis during acute kidney injury and chronic kidney disease

“…Hence, we utilized another well-established model of kidney injury induced by the administration of cisplatin in the context of both AKI and CKD. To this end a single injection of 20 mg/kg of cisplatin was used to induce AKI (high dose, HD), while repeated dosing of 9 mg/kg of cisplatin was administered once a week for 4 weeks to induce CKD (repeated low dose, RLD) as previously reported [23, 24]. For the AKI studies, tissues were harvested at 72h post injury, while CKD studies were terminated at 28 days.…”

“…These animals were sacrificed 72 hours after injection. For the repeated low dose (RLD) model, age-matched C57BL/6 male mice (10–12 weeks of age) were briefly anesthetized with isoflurane, and 9 mg/kg body wt cisplatin (1.0 mg/ml solution in sterile 0.9% saline) were administered intraperitoneally once a week for 4 wk, adapted from Sharp et al and Black et al [23, 24].…”

The Predictive Value of Urinary Kidney Injury Molecular 1 for the Diagnosis of Contrast-Induced Acute Kidney Injury after Cardiac Catheterization: A Meta-Analysis

“…The pathophysiological changes of CKD, such as the activation of TGF- β , p53, and HIF pathways in kidney and CKD related chronic inflammation and vascular dysfunction, might contribute to the severe AKI progress [ 30 ]. On the contrary, some clinical studies found that KIM-1 did not provide robust prognostic information on the loss or renal function in CKD population [ 31 , 32 ]. Since the sample size was small in Wang et al [ 10 ] research, studies with a larger sample size are needed to clarify this problem.…”