Recovery of kidney function after acute kidney disease-a multi-cohort analysis.

BACKGROUND: There are no consensus definitions for evaluating kidney function recovery after acute kidney injury (AKI) and acute kidney disease (AKD), nor is it clear how recovery varies across populations and clinical subsets. We present a federated analysis of four population-based cohorts from Canada, Denmark and Scotland, 2011-18. METHODS: We identified incident AKD defined by serum creatinine changes within 48 h, 7 days and 90 days based on KDIGO AKI and AKD criteria. Separately, we applied changes up to 365 days to address widely used e-alert implementations that extend beyond the KDIGO AKI and AKD timeframes. Kidney recovery was based on resolution of AKD and a subsequent creatinine measurement below 1.2× baseline. We evaluated transitions between non-recovery, recovery and death up to 1 year; within age, sex and comorbidity subgroups; between subset AKD definitions; and across cohorts. RESULTS: There were 464 868 incident cases, median age 67-75 years. At 1 year, results were consistent across cohorts, with pooled mortalities for creatinine changes within 48 h, 7 days, 90 days and 365 days (and 95% confidence interval) of 40% (34%-45%), 40% (34%-46%), 37% (31%-42%) and 22% (16%-29%) respectively, and non-recovery of kidney function of 19% (15%-23%), 30% (24%-35%), 25% (21%-29%) and 37% (30%-43%), respectively. Recovery by 14 and 90 days was frequently not sustained at 1 year. Older males and those with heart failure or cancer were more likely to die than to experience sustained non-recovery, whereas the converse was true for younger females and those with diabetes. CONCLUSION: Consistently across multiple cohorts, based on 1-year mortality and non-recovery, KDIGO AKD (up to 90 days) is at least prognostically similar to KDIGO AKI (7 days), and covers more people. Outcomes associated with AKD vary by age, sex and comorbidities such that older males are more likely to die, and younger females are less likely to recover.

Risk factor analysis for a rapid progression of chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is a growing global health concern. Identifying individuals in routine clinical care with new-onset CKD at high risk of rapid progression of the disease is imperative to guide allocation of prophylactic interventions, but community-based data are limited. We aimed to examine the risk of rapid progression, kidney failure, hospitalization and death among adults with incident CKD stage G3 and to clarify the association between predefined risk markers and rapid CKD progression. METHODS: Using plasma creatinine measurements for the entire Danish population from both hospitals and primary care, we conducted a nationwide, population-based cohort study, including adults in Denmark with incident CKD stage G3 in 2017-2020. We estimated 3-year risks of rapid progression (defined by a confirmed decline in estimated glomerular filtration rate of ≥5 mL/min/1.73 m2/year), kidney failure, all-cause hospitalization and death. To examine risk markers, we constructed a heat map showing the risk of rapid progression based on predefined markers: albuminuria, sex, diabetes and hypertension/cardiovascular disease. RESULTS: Among 133 443 individuals with incident CKD stage G3, the 3-year risk of rapid progression was 14.6% [95% confidence interval (CI) 14.4-14.8]. The 3-year risks of kidney failure, hospitalization and death were 0.3% (95% CI 0.3-0.4), 53.3% (95% CI 53.0-53.6) and 18.1% (95% CI 17.9-18.4), respectively. In the heat map, the 3-year risk of rapid progression ranged from 7% in females without albuminuria, hypertension/cardiovascular disease or diabetes, to 46%-47% in males and females with severe albuminuria, diabetes and hypertension/cardiovascular disease. CONCLUSION: This population-based study shows that CKD stage G3 is associated with considerable morbidity in a community-based setting and underscores the need for optimized prophylactic interventions among such patients. Moreover, our data highlight the potential of using easily accessible markers in routine clinical care to identify individuals who are at high risk of rapid progression.

Inflammatory cytokines break down intrinsic immunological tolerance of human primary keratinocytes to cytosolic DNA.

Keratinocytes are involved in protecting the body from infections and environmental challenges, but also in inflammatory conditions like psoriasis. DNA has emerged as a potent stimulator of innate immune responses, but there is largely no information of how keratinocytes respond to cytosolic DNA. In this study, we report that human keratinocytes are tolerant to cytoplasmic DNA. However, if treated with inflammatory cytokines, keratinocytes gained the capacity to respond to DNA through a mechanism antagonized by the antimicrobial peptide LL37, proposed to be involved in activation and regulation of skin inflammation. The DNA sensor IFN-inducible protein 16 (IFI16) colocalized with DNA and the signaling molecule stimulator of IFN genes (STING) in the cytoplasm only in cytokine-stimulated cells, correlating with recruitment of the essential kinase TANK-binding kinase 1. Moreover, IFI16 was essential for DNA-driven innate immune responses in keratinocytes. Finally, IFI16 was upregulated in psoriasis skin lesions and localized to the cytoplasm in a subpopulation of cells. Collectively, this work suggests that inflammatory environments in the skin can lead to breakdown of tolerance for DNA in keratinocytes, which could contribute to the development of inflammatory diseases.

Acute Kidney Injury Duration and 20-Year Risks of CKD and Cardiovascular Disease.

Introduction: Acute kidney injury (AKI) is associated with chronic kidney disease (CKD) and cardiovascular disease (CVD); however, it is unclear whether AKI duration affects the long-term risks of CKD and CVD. Therefore, we performed a population-based cohort study examining the associations between AKI duration and CKD and CVD. Methods: We identified patients with laboratory-recorded AKI in Denmark from 1990 through 2018. AKIs were categorized as rapid reversal AKI (≤48 hours), persistent AKI (2-7 days), and acute kidney disease (AKD) (>7 days). We estimated 20-year risks and adjusted hazard ratios (aHRs) of incident CKD and CVD. Results: The study comprised 169,582 patients with AKI, with 100,478 and 76,838 included in the analysis of CKD and CVD, respectively. The 20-year risks of CKD were 26.3%, 29.5%, and 28.7% for rapid reversal AKI, persistent AKI, and AKD, respectively. Compared with rapid reversal AKI, aHRs were 1.13 (95% confidence interval [CI], 1.08-1.19) for persistent AKI and 1.36 (95% CI, 1.30-1.41) for AKD. Risks and rates of overall CVD were similar for rapid reversal AKI, persistent AKI, and AKD. However, persistent AKI was associated with a slightly increased aHR of heart failure (1.09; 95% CI, 1.02-1.16), and aHRs of heart failure, ischemic heart disease, and peripheral artery disease were slightly increased for AKD (1.09 [95% CI, 1.03-1.15], 1.11 [95% CI, 1.03-1.19], and 1.10 [95% CI, 1.02-1.17], respectively). Conclusion: AKI duration was associated with development of CKD, but not overall CVD; however, rates of heart failure, ischemic heart disease, and peripheral artery disease increased slightly with AKI duration.

Defining Baseline Creatinine for Identification of AKI in Population-Based Laboratory Databases: A Danish Nationwide Cohort Study.

Background: The baseline creatinine level is central in the Kidney Disease Improving Global Outcomes (KDIGO) criteria of AKI, but baseline creatinine is often inconsistently defined or unavailable in AKI research. We examined the rate, characteristics, and 30-day mortality of AKI in five AKI cohorts created using different definitions of baseline creatinine. Methods: This nationwide cohort study included all individuals aged ≥18 years in Denmark with a creatinine measurement in 2017. Applying the KDIGO criteria, we created four AKI cohorts using four different baseline definitions (most recent, mean, or median value of outpatient creatinine 365-368 days before, or median value 90-98 days before, if available, otherwise median value 365-391 days before) and one AKI cohort not using a baseline value. AKI rate and the distribution of age, sex, baseline creatinine, and comorbidity were described for each AKI cohort, and the 30-day all-cause mortality was estimated using the Kaplan-Meier method. Results: The study included 2,095,850 adults with at least one creatinine measurement in 2017. The four different baseline definitions identified between 61,189 and 62,597 AKI episodes. The AKI rate in these four cohorts was 13-14 per 1000 person-years, and 30-day all-cause mortality was 17%-18%. The cohort created without using a baseline creatinine included 37,659 AKI episodes, corresponding to an AKI rate of 8.2 per 1000 person-years and a 30-day mortality of 23%. All five cohorts were similar regarding age, sex, and comorbidity. Conclusions: In a population-based setting with available outpatient baseline creatinine, different baseline creatinine definitions revealed comparable AKI cohorts, whereas the lack of a baseline creatinine when defining AKI led to a smaller AKI cohort with a higher mortality. These findings underscore the importance of availability and consistent use of an outpatient baseline creatinine, particulary in studies of community-acquired AKI.

Influenza A virus targets a cGAS-independent STING pathway that controls enveloped RNA viruses.

Stimulator of interferon genes (STING) is known be involved in control of DNA viruses but has an unexplored role in control of RNA viruses. During infection with DNA viruses STING is activated downstream of cGAMP synthase (cGAS) to induce type I interferon. Here we identify a STING-dependent, cGAS-independent pathway important for full interferon production and antiviral control of enveloped RNA viruses, including influenza A virus (IAV). Further, IAV interacts with STING through its conserved hemagglutinin fusion peptide (FP). Interestingly, FP antagonizes interferon production induced by membrane fusion or IAV but not by cGAMP or DNA. Similar to the enveloped RNA viruses, membrane fusion stimulates interferon production in a STING-dependent but cGAS-independent manner. Abolishment of this pathway led to reduced interferon production and impaired control of enveloped RNA viruses. Thus, enveloped RNA viruses stimulate a cGAS-independent STING pathway, which is targeted by IAV.

Interleukin-21 receptor signalling is important for innate immune protection against HSV-2 infections.

Interleukin (IL) -21 is produced by Natural Killer T (NKT) cells and CD4(+) T cells and is produced in response to virus infections, where IL-21 has been shown to be essential in adaptive immune responses. Cells from the innate immune system such as Natural Killer (NK) cells and macrophages are also important in immune protection against virus. These cells express the IL-21 receptor (IL-21R) and respond to IL-21 with increased cytotoxicity and cytokine production. Currently, however it is not known whether IL-21 plays a significant role in innate immune responses to virus infections. The purpose of this study was to investigate the role of IL-21 and IL-21R in the innate immune response to a virus infection. We used C57BL/6 wild type (WT) and IL-21R knock out (KO) mice in a murine vaginal Herpes Simplex Virus type 2 (HSV-2) infection model to show that IL-21 - IL-21R signalling is indeed important in innate immune responses against HSV-2. We found that the IL-21R was expressed in the vaginal epithelium in uninfected (u.i) WT mice, and expression increased early after HSV-2 infection. IL-21R KO mice exhibited increased vaginal viral titers on day 2 and 3 post infection (p.i.) and subsequently developed significantly higher disease scores and a lower survival rate compared to WT mice. In addition, WT mice infected with HSV-2 receiving intra-vaginal pre-treatment with murine recombinant IL-21 (mIL-21) had decreased vaginal viral titers on day 2 p.i., significantly lower disease scores, and a higher survival rate compared to infected untreated WT controls. Collectively our data demonstrate the novel finding that the IL-21R plays a critical role in regulating innate immune responses against HSV-2 infection.