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      The influence of multiple episodes of acute kidney injury on survival and progression to end stage kidney disease in patients with chronic kidney disease

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          Abstract

          Background

          Acute kidney injury (AKI) and chronic kidney disease (CKD) are common syndromes associated with significant morbidity, mortality and cost. The extent to which repeated AKI episodes may cumulatively affect the rate of progression of all-cause CKD has not previously been investigated. In this study, we explored the hypothesis that repeated episodes of AKI increase the rate of renal functional deterioration loss in patients recruited to a large, all-cause CKD cohort.

          Methods

          Patients from the Salford Kidney Study (SKS) were considered. Application of KDIGO criteria to all available laboratory measurements of renal function identified episodes of AKI. A competing risks model was specified for four survival events: Stage 1 AKI; stage 2 or 3 AKI; dialysis initiation or transplant before AKI event; death before AKI event. The model was adjusted for patient age, gender, smoking status, alcohol intake, diabetic status, cardiovascular co-morbidities, and primary renal disease. Analyses were performed for patients’ first, second, and third or more AKI episodes.

          Results

          A total of 48,338 creatinine measurements were available for 2287 patients (median 13 measures per patient [IQR 6–26]). There was a median age of 66.8years, median eGFR of 28.4 and 31.6% had type 1 or 2 diabetes. Six hundred and forty three (28.1%) patients suffered one or more AKI events; 1000 AKI events (58% AKI 1) in total were observed over a median follow-up of 2.6 years [IQR 1.1–3.2]. In patients who suffered an AKI, a second AKI was more likely to be a stage 2 or 3 AKI than stage 1 [HR 2.04, p 0.01]. AKI events were associated with progression to RRT, with multiple episodes of AKI progressively increasing likelihood of progression to RRT [HR 14.4 after 1 episode of AKI, HR 28.4 after 2 episodes of AKI]. However, suffering one or more AKI events was not associated with an increased risk of mortality.

          Conclusions

          AKI events are associated with more rapid CKD deterioration as hypothesised, and also with a greater severity of subsequent AKI. However, our study did not find an association of AKI with increased mortality risk in this CKD cohort.

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          Most cited references20

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          Acute kidney injury and chronic kidney disease: an integrated clinical syndrome.

          The previous conventional wisdom that survivors of acute kidney injury (AKI) tend to do well and fully recover renal function appears to be flawed. AKI can cause end-stage renal disease (ESRD) directly, and increase the risk of developing incident chronic kidney disease (CKD) and worsening of underlying CKD. In addition, severity, duration, and frequency of AKI appear to be important predictors of poor patient outcomes. CKD is an important risk factor for the development and ascertainment of AKI. Experimental data support the clinical observations and the bidirectional nature of the relationships between AKI and CKD. Reductions in renal mass and nephron number, vascular insufficiency, cell cycle disruption, and maladaptive repair mechanisms appear to be important modulators of progression in patients with and without coexistent CKD. Distinction between AKI and CKD may be artificial. Consideration should be given to the integrated clinical syndrome of diminished GFR, with acute and chronic stages, where spectrum of disease state and outcome is determined by host factors, including the balance of adaptive and maladaptive repair mechanisms over time. Physicians must provide long-term follow-up to patients with first episodes of AKI, even if they presented with normal renal function.
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            Kidney disease: improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury.

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              Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus.

              Prior studies have examined long-term outcomes of a single acute kidney injury (AKI) event in hospitalized patients. We examined the effects of AKI episodes during multiple hospitalizations on the risk of chronic kidney disease (CKD) in a cohort with diabetes mellitus (DM). A total of 4082 diabetics were followed from January 1999 until December 2008. The primary outcome was reaching stage 4 CKD (GFR of 0.3 mg/dl or a 1.5-fold increase in creatinine relative to admission. Cox survival models examined the effect of first AKI episode and up to three episodes as time-dependent covariates, on the risk of stage 4 CKD. Covariates included demographic variables, baseline creatinine, and diagnoses of comorbidities including proteinuria. Of the 3679 patients who met eligibility criteria (mean age = 61.7 years [SD, 11.2]; mean baseline creatinine = 1.10 mg/dl [SD, 0.3]), 1822 required at least one hospitalization during the time under observation (mean = 61.2 months [SD, 25]). Five hundred thirty of 1822 patients experienced one AKI episode; 157 of 530 experienced ≥2 AKI episodes. In multivariable Cox proportional hazards models, any AKI versus no AKI was a risk factor for stage 4 CKD (hazard ratio [HR], 3.56; 95% confidence interval [CI], 2.76, 4.61); each AKI episode doubled that risk (HR, 2.02; 95% CI, 1.78, 2.30). AKI episodes are associated with a cumulative risk for developing advanced CKD in diabetes mellitus, independent of other major risk factors of progression.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: Project administrationRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Software
                Role: Data curationRole: InvestigationRole: MethodologyRole: SoftwareRole: ValidationRole: Writing – original draft
                Role: Data curationRole: Validation
                Role: Data curationRole: Formal analysisRole: Validation
                Role: Formal analysisRole: InvestigationRole: Validation
                Role: ConceptualizationRole: Data curationRole: ResourcesRole: Supervision
                Role: Formal analysisRole: MethodologyRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: Software
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                18 July 2019
                2019
                : 14
                : 7
                : e0219828
                Affiliations
                [1 ] Department of Renal Medicine, Salford Royal NHS Foundation Trust, Salford, United Kingdom
                [2 ] Department of Biostatistics and Medical Informatics, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
                [3 ] CHICAS Research Group, Lancaster Medical School, Lancaster University, Lancaster, United Kingdom
                Kaohsiung Medical University Hospital, TAIWAN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-5420-5421
                Article
                PONE-D-18-35255
                10.1371/journal.pone.0219828
                6638939
                31318937
                c32ee846-e6d0-4a33-9577-515dc2f5ed4b
                © 2019 Sykes et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 10 December 2018
                : 2 July 2019
                Page count
                Figures: 4, Tables: 4, Pages: 14
                Funding
                The authors received no specific funding for this work.
                Categories
                Research Article
                Medicine and Health Sciences
                Nephrology
                Chronic Kidney Disease
                Medicine and Health Sciences
                Nephrology
                Renal Diseases
                Medicine and Health Sciences
                Endocrinology
                Endocrine Disorders
                Diabetes Mellitus
                Medicine and Health Sciences
                Metabolic Disorders
                Diabetes Mellitus
                Biology and Life Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Anatomy
                Renal System
                Kidneys
                Biology and Life Sciences
                Anatomy
                Renal System
                Medicine and Health Sciences
                Anatomy
                Renal System
                Biology and Life Sciences
                Nutrition
                Diet
                Alcohol Consumption
                Medicine and Health Sciences
                Nutrition
                Diet
                Alcohol Consumption
                Biology and Life Sciences
                Biochemistry
                Biomarkers
                Creatinine
                Medicine and Health Sciences
                Nephrology
                Glomerulonephritis
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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                Uncategorized

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