The Pathophysiology of Sepsis-Associated AKI

Kuwabara, S.; Goggins, Eibhlin; Okusa, Mark D.

doi:10.2215/cjn.00850122

Cited by 76 publications

(49 citation statements)

References 193 publications

(285 reference statements)

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“…It is not surprising that several reports addressed the presence of heterogeneity in aetiology, disease trajectory, prognosis and outcomes among patients with SA-AKI [ 13 , 14 ]. Furthermore, diverse pathophysiological mechanisms of SA-AKI are not well-understood yet [ 15 , 16 ]. These features make clinical managements of SA-AKI not optimal or standardized [ 3 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Unsupervised clustering identifies sub-phenotypes and reveals novel outcome predictors in patients with dialysis-requiring sepsis-associated acute kidney injury

et al. 2023

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Introduction Heterogeneity exists in sepsis-associated acute kidney injury (SA-AKI). This study aimed to perform unsupervised consensus clustering in critically ill patients with dialysis-requiring SA-AKI. Patients and Methods This prospective observational cohort study included all septic patients, defined by the Sepsis-3 criteria, with dialysis-requiring SA-AKI in surgical intensive care units in Taiwan between 2009 and 2018. We employed unsupervised consensus clustering based on 23 clinical variables upon initializing renal replacement therapy. Multivariate-adjusted Cox regression models and Fine–Gray sub-distribution hazard models were built to test associations between cluster memberships with mortality and being free of dialysis at 90 days after hospital discharge, respectively. Results Consensus clustering among 999 enrolled patients identified three sub-phenotypes characterized with distinct clinical manifestations upon renal replacement therapy initiation ( n = 352, 396 and 251 in cluster 1, 2 and 3, respectively). They were followed for a median of 48 (interquartile range 9.5–128.5) days. Phenotypic cluster 1, featured by younger age, lower Charlson Comorbidity Index, higher baseline estimated glomerular filtration rate but with higher severity of acute illness was associated with an increased risk of death (adjusted hazard ratio of 3.05 [95% CI, 2.35–3.97]) and less probability to become free of dialysis (adjusted sub-distribution hazard ratio of 0.55 [95% CI, 0.38–0.8]) than cluster 3. By examining distinct features of the sub-phenotypes, we discovered that pre-dialysis hyperlactatemia ≥3.3 mmol/L was an independent outcome predictor. A clinical model developed to determine high-risk sub-phenotype 1 in this cohort (C-static 0.99) can identify a sub-phenotype with high in-hospital mortality risk (adjusted hazard ratio of 1.48 [95% CI, 1.25–1.74]) in another independent multi-centre SA-AKI cohort. Conclusions Our data-driven approach suggests sub-phenotypes with clinical relevance in dialysis-requiring SA-AKI and serves an outcome predictor. This strategy represents further development toward precision medicine in the definition of high-risk sub-phenotype in patients with SA-AKI. Key messages Unsupervised consensus clustering can identify sub-phenotypes of patients with SA-AKI and provide a risk prediction. Examining the features of patient heterogeneity contributes to the discovery of serum lactate levels ≥ 3.3 mmol/L upon initializing RRT as an independent outcome predictor. This data-driven approach can be useful for prognostication and lead to a better understanding of therapeutic strategies in heterogeneous clinical syndromes.

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Section: Introductionmentioning

confidence: 99%

Unsupervised clustering identifies sub-phenotypes and reveals novel outcome predictors in patients with dialysis-requiring sepsis-associated acute kidney injury

et al. 2023

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“…Nonetheless, NLR potentially implicates an immune-inflammatory response in various pathological conditions ( 26 ). AKI has a multifactorial pathophysiology, among which inflammation plays a pivotal role in the development of AKI ( 28 , 29 ). This suggests that the NLR can be used as a useful marker of AKI progression and mortality.…”

Section: Discussionmentioning

confidence: 99%

Dynamic nature and prognostic value of the neutrophil-to-lymphocyte ratio in critically ill patients with acute kidney injury on continuous renal replacement therapy: A multicenter cohort study

Jung

Lee

et al. 2023

Front. Med.

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IntroductionPatients with acute kidney injury (AKI) receiving renal replacement therapy constitute the subgroup of AKI with the highest risk of mortality. Despite recent promising findings on the neutrophil-to-lymphocyte ratio (NLR) in AKI, studies have not yet addressed the clinical implication of the NLR in this population. Therefore, we aimed to examine the prognostic value of NLR in critically ill patients requiring continuous renal replacement therapy (CRRT), especially focusing on temporal changes in NLR.MethodsWe enrolled 1,494 patients with AKI who received CRRT in five university hospitals in Korea between 2006 and 2021. NLR fold changes were calculated as the NLR on each day divided by the NLR value on the first day. We performed a multivariable Cox proportional hazard analysis to assess the association between the NLR fold change and 30-day mortality.ResultsThe NLR on day 1 did not differ between survivors and non-survivors; however, the NLR fold change on day 5 was significantly different. The highest quartile of NLR fold change during the first 5 days after CRRT initiation showed a significantly increased risk of death (hazard ratio [HR], 1.65; 95% confidence intervals (CI), 1.27–2.15) compared to the lowest quartile. NLR fold change as a continuous variable was an independent predictor of 30-day mortality (HR, 1.14; 95% CI, 1.05–1.23).ConclusionIn this study, we demonstrated an independent association between changes in NLR and mortality during the initial phase of CRRT in AKI patients receiving CRRT. Our findings provide evidence for the predictive role of changes in the NLR in this high-risk subgroup of AKI.

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“…The patterns of injury are impacted further by associated comorbidities and components of clinical management. Research in sepsis-associated AKI presents another apt example of the evolution in knowledge [6]. Once simplified into a bipartite model of 'ischemia to the glomerulus' and 'tubular necrosis' , it has expanded into a sepsis 'portfolio' of injury, inclusive of (but not limited to): (a) glomerular capillary vasomotor instability, (b) microcirculatory dysfunction, (c) mitochondrial dysregulation, (d) inflammasome perturbations from endocrine and paracrine cytokine mediators, (e) disruption in pathogen-associated molecular activity receptors, (f ) tubular injury; (g) interstitial inflammation; (h) aberrant autophagy and efferocytosis of important repair molecules, and (i) impact of associated comorbidities and clinical strategies used to mitigate the insult (i.e.…”

Section: Mechanisms Contributing To Akimentioning

confidence: 99%

Acute kidney injury

2023

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The understanding of acute kidney injury (AKI) has evolved from the perception of a single disease to a multi-factorial syndrome with a complex and varying pathophysiology and prognosis. Before 2004, more than 50 different definitions of AKI (or 'acute renal failure') were in use and the reported incidences, prevalences and outcomes were very variable. The publication of the 'Risk, Injury, Failure, Loss, and End-stage kidney disease' (RIFLE) criteria in 2004, followed by the AKI Network (AKIN) classification in 2007, and the current AKI Kidney Disease Improving Global Outcomes (KDIGO) consensus classification in 2012 [1] have facilitated epidemiological studies showing a high prevalence of AKI worldwide, a link between AKI severity and outcomes, a high risk of short-and long-term complications, including chronic kidney disease (CKD) and major economic consequences [2, 3] (Fig. 1).AKI diagnosis and staging currently rely on a rise in serum creatinine (SCr) and/or decrease in urine output without consideration of the various aetiologies, sites and severity of injury, timing and course of disease and the response to therapy [4]. To compensate for these limitations, descriptors are often added, for instance, 'subclinical AKI' (tubular injury without a SCr rise or with a SCr rise not meeting AKI criteria), 'transient, sustained or persistent AKI' (based on the duration of SCr elevation), 'community' or 'hospital acquired' AKI, and 'recovered AKI' (SCr decrease after peak). However, there are no agreed definitions for these terms [4].

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The Pathophysiology of Sepsis-Associated AKI

Cited by 76 publications

References 193 publications

Unsupervised clustering identifies sub-phenotypes and reveals novel outcome predictors in patients with dialysis-requiring sepsis-associated acute kidney injury

Unsupervised clustering identifies sub-phenotypes and reveals novel outcome predictors in patients with dialysis-requiring sepsis-associated acute kidney injury

Dynamic nature and prognostic value of the neutrophil-to-lymphocyte ratio in critically ill patients with acute kidney injury on continuous renal replacement therapy: A multicenter cohort study

Acute kidney injury

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