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Losartan reduces ensuing chronic kidney disease and mortality after acute kidney injury.

ABSTRACT: Acute kidney injury (AKI) is an important risk factor for incident chronic kidney disease (CKD). Clinical studies disclose that ensuing CKD progresses after functional recovery from AKI, but the underlying mechanisms remain illusive. Using a murine model representing AKI-CKD continuum, we show angiotensin II type 1a (AT1a) receptor signaling as one of the underlying mechanisms. Male adult CD-1 mice presented severe AKI with 20% mortality within 2 weeks after right nephrectomy and left renal ischemia-reperfusion injury. Despite functional recovery, focal tubular atrophy, interstitial cell infiltration and fibrosis, upregulation of genes encoding angiotensinogen and AT1a receptor were shown in kidneys 4 weeks after AKI. Thereafter mice manifested increase of blood pressure, albuminuria and azotemia progressively. Drinking water with or without losartan or hydralazine was administered to mice from 4 weeks after AKI. Increase of mortality, blood pressure, albuminuria, azotemia and kidney fibrosis was noted in mice with vehicle administration during the 5-month experimental period. On the contrary, these parameters in mice with losartan administration were reduced to the levels shown in control group. Hydralazine did not provide similar beneficial effect though blood pressure was controlled. These findings demonstrate that losartan can reduce ensuing CKD and mortality after functional recovery from AKI.

SUBMITTER: Cheng SY

PROVIDER: S-EPMC5039710 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Losartan reduces ensuing chronic kidney disease and mortality after acute kidney injury.

Cheng Shun-Yang SY Chou Yu-Hsiang YH Liao Fang-Ling FL Lin Chi-Chun CC Chang Fan-Chi FC Liu Chia-Hao CH Huang Tao-Min TM Lai Chun-Fu CF Lin Yu-Feng YF Wu Vin-Cent VC Chu Tzong-Shinn TS Wu Ming-Shiou MS Lin Shuei-Liong SL

Scientific reports 20160928

Acute kidney injury (AKI) is an important risk factor for incident chronic kidney disease (CKD). Clinical studies disclose that ensuing CKD progresses after functional recovery from AKI, but the underlying mechanisms remain illusive. Using a murine model representing AKI-CKD continuum, we show angiotensin II type 1a (AT1a) receptor signaling as one of the underlying mechanisms. Male adult CD-1 mice presented severe AKI with 20% mortality within 2 weeks after right nephrectomy and left renal isch ...[more]

PMID: 27677327

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Project description:Incident acute kidney injury and prevalent chronic kidney disease are commonly encountered in septic patients. We examined the differential effect of acute kidney injury and chronic kidney disease on the association between cumulative fluid balance and hospital mortality in critically ill septic patients.Retrospective cohort study.Urban academic medical center ICU.ICU adult patients with severe sepsis or septic shock and serum creatinine measured within 3 months prior to and 72 hours of ICU admission. Patients with estimated glomerular filtration rate less than 15?mL/min/1.73 m or receiving chronic dialysis were excluded.None.A total of 2,632 patients, 1,211 with chronic kidney disease, were followed up until hospital death or discharge. Acute kidney injury occurred in 1,525 patients (57.9%), of whom 679 (44.5%) had chronic kidney disease. Hospital mortality occurred in 603 patients (22.9%). Every 1-L increase in cumulative fluid balance at 72 hours of ICU admission was independently associated with hospital mortality in all patients (adjusted odds ratio, 1.06 [95% CI] 1.04-1.08; p < 0.001), and in each acute kidney injury/chronic kidney disease subgroup (adjusted odds ratio, 1.06 [1.03-1.09] for acute kidney injury+/chronic kidney disease+; 1.09 [1.05-1.13] for acute kidney injury-/chronic kidney disease+; 1.05 [1.03-1.08] for acute kidney injury+/chronic kidney disease-; and 1.07 [1.02-1.11] for acute kidney injury-/chronic kidney disease-). There was a significant interaction between acute kidney injury and chronic kidney disease on cumulative fluid balance (p =0.005) such that different cumulative fluid balance cut-offs with the best prognostic accuracy for hospital mortality were identified: 5.9?L for acute kidney injury+/chronic kidney disease+; 3.8?L for acute kidney injury-/chronic kidney disease+; 4.3?L for acute kidney injury+/chronic kidney disease-; and 1.5?L for acute kidney injury-/chronic kidney disease-. The addition of cumulative fluid balance to the admission Sequential Organ Failure Assessment score had increased prognostic utility for hospital mortality when compared with Sequential Organ Failure Assessment alone, particularly in patients with acute kidney injury.Higher cumulative fluid balance at 72 hours of ICU admission was independently associated with hospital mortality regardless of acute kidney injury or chronic kidney disease presence. We characterized cumulative fluid balance cut-offs associated with hospital mortality based on acute kidney injury/chronic kidney disease status, underpinning the heterogeneity of fluid regulation in sepsis and kidney disease.

Project description:BackgroundThe kynurenine pathway (KP) is the major catabolic pathway for tryptophan degradation. The KP plays an important role as the sole de novo nicotinamide adenine dinucleotide (NAD+) biosynthetic pathway in normal human physiology and functions as a counter-regulatory mechanism to mitigate immune responses during inflammation. Although the KP has been implicated in a variety of disorders including Huntington's disease, seizures, cardiovascular disease, and osteoporosis, its role in renal diseases is seldom discussed.SummaryThis review summarizes the roles of the KP and its metabolites in acute kidney injury (AKI) and chronic kidney disease (CKD) based on current literature evidence. Metabolomics studies demonstrated that the KP metabolites were significantly altered in patients and animal models with AKI or CKD. The diagnostic and prognostic values of the KP metabolites in AKI and CKD were highlighted in cross-sectional and longitudinal human observational studies. The biological impact of the KP on the pathophysiology of AKI and CKD has been studied in experimental models of different etiologies. In particular, the activation of the KP was found to confer protection in animal models of glomerulonephritis, and its immunomodulatory mechanism may involve the regulation of T cell subsets such as Th17 and regulatory T cells. Manipulation of the KP to increase NAD+ production or diversion toward specific KP metabolites was also found to be beneficial in animal models of AKI. Key Messages: KP metabolites are reported to be dysregulated in human observational and animal experimental studies of AKI and CKD. In AKI, the magnitude and direction of changes in the KP depend on the etiology of the damage. In CKD, KP metabolites are altered with the onset and progression of CKD all the way to advanced stages of the disease, including uremia and its related vascular complications. The activation of the KP and diversion to specific sub-branches are currently being explored as therapeutic strategies in these diseases, especially with regards to the immunomodulatory effects of certain KP metabolites. Further elucidation of the KP may hold promise for the development of biomarkers and targeted therapies for these kidney diseases.

Project description:BackgroundThe progression from acute kidney injury (AKI) to chronic kidney disease (CKD) is not well understood in children.ObjectivesWe aimed to develop a pediatric CKD definition using administrative data and use it to evaluate the association between AKI in critically ill children and CKD 5 years after hospital discharge.DesignRetrospective cohort study using chart collection and administrative data.SettingTwo-center study in Montreal, Canada.PatientsChildren (?18 years old) admitted to two pediatric intensive care units (ICUs) between 2003 and 2005. We a priori excluded patients with end-stage renal disease or no health care number. Only the first admission during the study period was included. We excluded patients who could not be linked to administrative data, did not survive hospitalization, or had preexisting renal disease.MeasurementsAcute kidney injury was defined using Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Patients were defined as having CKD 5 years post-discharge if they had ?1 CKD diagnostic code or ?1 CKD-specific medication prescription.MethodsChart data used to define the exposure (AKI) were merged with provincial administrative data used to define the outcome (CKD). Cox regression was used to evaluate the AKI-CKD association.ResultsA total of 2235 (56% male) patients were included, and the median admission age was 3.7 years. A total of 464 (21%) patients developed AKI during pediatric ICU admission. At 5 years post-discharge, 43 (2%) patients had a CKD diagnosis. Patients with both stage 1 and stage 2-3 AKI had increased risk of a CKD diagnosis, with the adjusted hazard ratios (95% confidence intervals) of 2.2 (1.1-4.5) and 2.5 (1.1-5.7), respectively (P < .001).LimitationsResults may not be generalizable to non-ICU patients. We were not able to control for post-discharge variables; future research should try to explore these additional potential risk factors further.ConclusionsAcute kidney injury is associated with 5-year post-discharge CKD diagnosis defined by administrative health care data.

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Losartan reduces ensuing chronic kidney disease and mortality after acute kidney injury.

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Losartan reduces ensuing chronic kidney disease and mortality after acute kidney injury.

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