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SuPAR links a dysregulated immune response to tissue inflammation and sepsis-induced acute kidney injury.

ABSTRACT: Acute kidney injury (AKI) secondary to sepsis results in poor outcomes and conventional kidney function indicators lack diagnostic value. Soluble urokinase plasminogen activator receptor (suPAR) is an innate immune-derived molecule implicated in inflammatory organ damage. We characterized the diagnostic ability of longitudinal serum suPAR levels to discriminate severity and course of sepsis-induced AKI (SI-AKI) in 200 critically ill patients meeting Sepsis-3 criteria. The pathophysiologic relevance of varying suPAR levels in SI-AKI was explored in a polymicrobial sepsis model in WT, (s)uPAR-knockout, and transgenic suPAR-overexpressing mice. At all time points studied, suPAR provided a robust classification of SI-AKI disease severity, with improved prediction of renal replacement therapy (RRT) and mortality compared with established kidney biomarkers. Patients with suPAR levels of greater than 12.7 ng/mL were at highest risk for RRT or death, with an adjusted odds ratio of 7.48 (95% CI, 3.00-18.63). suPAR deficiency protected mice against SI-AKI. suPAR-overexpressing mice exhibited greater kidney damage and poorer survival through inflamed kidneys, accompanied by local upregulation of potent chemoattractants and pronounced kidney T cell infiltration. Hence, suPAR allows for an innate immune-derived and kidney function-independent staging of SI-AKI and offers improved longitudinal risk stratification. suPAR promotes T cell-based kidney inflammation, while suPAR deficiency improves SI-AKI.

SUBMITTER: Nusshag C

PROVIDER: S-EPMC10132159 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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suPAR links a dysregulated immune response to tissue inflammation and sepsis-induced acute kidney injury.

Nusshag Christian C Wei Changli C Hahm Eunsil E Hayek Salim S SS Li Jing J Samelko Beata B Rupp Christoph C Szudarek Roman R Speer Claudius C Kälble Florian F Schaier Matthias M Uhle Florian F Schmitt Felix Cf FC Fiedler Mascha O MO Krautkrämer Ellen E Cao Yanxia Y Rodriguez Ricardo R Merle Uta U Eugen-Olsen Jesper J Zeier Martin M Weigand Markus A MA Morath Christian C Brenner Thorsten T Reiser Jochen J

JCI insight 20230410 7

Acute kidney injury (AKI) secondary to sepsis results in poor outcomes and conventional kidney function indicators lack diagnostic value. Soluble urokinase plasminogen activator receptor (suPAR) is an innate immune-derived molecule implicated in inflammatory organ damage. We characterized the diagnostic ability of longitudinal serum suPAR levels to discriminate severity and course of sepsis-induced AKI (SI-AKI) in 200 critically ill patients meeting Sepsis-3 criteria. The pathophysiologic releva ...[more]

PMID: 37036003

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Project description:ImportanceThe prevalence of obesity is increasing in the intensive care unit (ICU). Although obesity is a known risk factor for chronic kidney disease, its association with early sepsis-associated acute kidney injury (SA-AKI) and their combined association with patient outcomes warrant further investigation.ObjectiveTo explore the association between obesity, early SA-AKI incidence, and clinical outcomes in patients with sepsis.Design, setting, and participantsThis nationwide, prospective cohort study analyzed patients aged 19 years or older who had sepsis and were admitted to 20 tertiary hospital ICUs in Korea between September 1, 2019, and December 31, 2021. Patients with preexisting stage 3A to 5 chronic kidney disease and those with missing body mass index (BMI) values were excluded.ExposuresSepsis and hospitalization in the ICU.Main outcomes and measuresThe primary outcome was SA-AKI incidence within 48 hours of ICU admission, and secondary outcomes were mortality and clinical recovery (survival to discharge within 30 days). Patients were categorized by BMI (calculated as weight in kilograms divided by height in meters squared), and data were analyzed by logistic regression adjusted for key characteristics and clinical factors. Multivariable fractional polynomial regression models and restricted cubic spline models were used to analyze the clinical outcomes with BMI as a continuous variable.ResultsOf the 4041 patients (median age, 73 years [IQR, 63-81 years]; 2349 [58.1%] male) included in the study, 1367 (33.8%) developed early SA-AKI. Obesity was associated with a higher incidence of SA-AKI compared with normal weight (adjusted odds ratio [AOR], 1.40; 95% CI, 1.15-1.70), as was every increase in BMI of 10 (OR, 1.75; 95% CI, 1.47-2.08). While obesity was associated with lower in-hospital mortality in patients without SA-AKI compared with their counterparts without obesity (ie, underweight, normal weight, overweight) (AOR, 0.72; 95% CI, 0.54-0.94), no difference in mortality was observed in those with SA-AKI (AOR, 0.85; 95% CI, 0.65-1.12). Although patients with obesity without SA-AKI had a greater likelihood of clinical recovery than their counterparts without obesity, clinical recovery was less likely among those with both obesity and SA-AKI.Conclusions and relevanceIn this cohort study of patients with sepsis, obesity was associated with a higher risk of early SA-AKI and the presence of SA-AKI modified the association of obesity with clinical outcomes.

Project description:BackgroundKidney dysfunction is a common complication in septic patients. Studies have identified numerous risk factors for sepsis-associated acute kidney injury (S-AKI), yet there is wide variability in the incidence even among patients with similar risk factors, suggesting the presence of additional uncharacterized risk factors, including genetic differences. The expansion of biobanks, advances in genotyping, and standardized diagnostic criteria have enabled large-scale, hypothesis-generating studies into the genetic mechanisms underlying S-AKI. We hypothesize that the genetic pathway behind S-AKI has overlapping mechanisms with key differences based upon the specific subtype of acute kidney injury (AKI).MethodsTo test this hypothesis, we performed a genome-wide association study (GWAS) of S-AKI in three logistic regression models. Model 1, controlled for 1) age, 2) sex, 3) genotyping chip, and 4) the first five principal components. In Model 2, pre-sepsis baseline serum creatinine was added to the variables in Model 1. Finally, in Model 3, we controlled for the full range of patient, clinical, and ICU-related risk factors. Each of the 3-models were repeated in a pre-specified sensitivity analysis of higher severity S-AKI, defined as KDIGO Stage 2 or 3. We then compare associated variants and genes from our GWAS with previously published AKI sub-types and model other factors associated with S-AKI in our dataset.Findings3,348 qualifying Sepsis-3 patients have been genotyped in our dataset. Of these patients, 383 (11.4%) developed Stage 1, 2, or 3 AKI (primary outcome) and 181 (5.4%) developed Stage 2 or 3 AKI (sensitivity analysis). The median age was 61 years (interquartile range (IQR): 51,69), 42% were female, and the increase in SOFA score (between 48-hours before to 24-hours after the onset of suspected infection) was 2 (2-3). No variants exceeded our threshold for genome-wide significance (P<5x10-8), however, a total of 13 variants exceeded the suggestive (P<1x10-6) threshold. Notably, rs184516290 (chr1:199814965:G:A), near the NR5A2 gene, chr1:199805801:T:TA, also near the NR5A2 gene, and rs117313146 (chr15:31999784:G:C), near the CHRNA7 gene, were associated with S-AKI at the suggestive level in all three models presented. Variants in the suppressor of fused homolog (SUFU) gene, previously shown to be correlated with renal function in bacteremic patients, consistently exceeded the P<0.05 threshold in our models.ConclusionsWhile failing to identify any novel association for S-AKI at the level of genome-wide significance, our study did suggest multiple variants in previously characterized pathways for S-AKI including CHRNA7, NR5A2, and SUFU. We failed to replicate associations from multiple prior studies which may result from differences in how the phenotype was defined or, alternatively, limited genetic contribution and low heritability.

Dataset Information

SuPAR links a dysregulated immune response to tissue inflammation and sepsis-induced acute kidney injury.

Publications

suPAR links a dysregulated immune response to tissue inflammation and sepsis-induced acute kidney injury.

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