Metabolomic and biochemical characterization of a new model of the transition of acute kidney injury to chronic kidney disease induced by folic acid

Abstract

Background Renal diseases represent a major public health problem. The demonstration that maladaptive repair of acute kidney injury (AKI) can lead to the development of chronic kidney disease (CKD) and end-stage renal disease has generated interest in studying the pathophysiological pathways involved. Animal models of AKI–CKD transition represent important tools to study this pathology. We hypothesized that the administration of multiple doses of folic acid (FA) would lead to a progressive loss of renal function that could be characterized through biochemical parameters, histological classification and nuclear magnetic resonance (NMR) profiling. Methods Wistar rats were divided into groups: the control group received a daily intraperitoneal (I.P.) injection of double-distilled water, the experimental group received a daily I.P. injection of FA (250 mg kg body weight−1). Disease was classified according to blood urea nitrogen level: mild (40–80 mg dL−1), moderate (100–200 mg dL−1) and severe (>200 mg dL−1). We analyzed through biochemical parameters, histological classification and NMR profiling. Results Biochemical markers, pro-inflammatory cytokines and kidney injury biomarkers differed significantly (P < 0.05) between control and experimental groups. Histology revealed that as damage progressed, the degree of tubular injury increased, and the inflammatory infiltrate was more evident. NMR metabolomics and chemometrics revealed differences in urinary metabolites associated with CKD progression. The main physiological pathways affected were those involved in energy production and amino-acid metabolism, together with organic osmolytes. These data suggest that multiple administrations of FA induce a reproducible model of the induction of CKD. This model could help to evaluate new strategies for nephroprotection that could be applied in the clinic.

Folic acid‐induced animal model of kidney disease

“…55 Therefore, FA-induced kidney disease can cover AKI, CKD, and the AKI-CKD transition. 54 Additionally, as FA is water-soluble and the injection is intraperitoneal, the procedure of kidney disease induction is simple and straightforward, without the need for surgery. Importantly, FA-induced kidney disease can recapitulate the clinical symptoms of human kidney disease and the model is highly reproducible.…”

“…Nonetheless, for a given age group of the same gender in a particular animal species, data may be comparable. For example, in the same lab setting, if every experimental condition is strictly followed, the severity of kidney disease induced by a single injection of FA may be classified based on BUN content as: mild, 40–80 mg/dl; moderate, 100–200 mg/dl; severe, greater than 200 mg/dl 54 . The values shown in the Table for blood BUN and creatinine as well as GFR, if any, are for reference only as these numbers may vary from investigator to investigator.…”

Data-dependent normalization strategies for untargeted metabolomics—a case study

“…It is an independent risk factor for cardiovascular disease and one of the causes of premature mortality. Moreover, the majority of the CKD cases is asymptomatic and not diagnosed until late stages, with limited therapeutic options available [1,2]. The state-of-the-art metabolomics technologies are considered as one of the most powerful analytical approaches with a big impact on the understanding of the molecular changes and pathogenesis of the disease.…”

Analysis of renal function in a Health Examination Population in Chengdu (2012-2018)

“…Since Cr concentration is susceptible to age, gender, race, and diet, which may lead to overestimated glomerular ltration rate (GFR), CysC contains potential advantages as an indicator of renal function as compared to Cr. Serum urea nitrogen (UN) is also of great signi cance in early diagnosis of kidney diseases [13,14]. In present study, we recruited 14,716 subjects from the Health Examination Center at West China Hospital, Sichuan University, and analyzed the annual renal function indicators from 2012 to 2018, including UA, CysC, Cr and UN, to reveal distribution characteristics of renal function level in the population.…”

“…Moreover, the cost of treatment for kidney diseases and related complications is a heavy nancial burden on health services around the world. Annual survey revealed that CKD cost about $35,000 to $100,000 per person per year [7,8]. In developing countries, due to infection, hazardous work and insu cient education, CKD poses a greater economic burden [6].…”