Persistent acute kidney injury biomarkers: A systematic review and meta-analysis.

BACKGROUND: Various biomarkers reportedly predict persistent acute kidney injury (AKI) despite their varying predictive performance across clinical trials. This study aims to compare the accuracy of various biomarkers in predicting persistent AKI in different populations and regions. METHODS: In this meta-analysis, we searched for urinary C-C motif chemokine ligand 14 (CCL14), Tissue inhibitor of metalloproteinase-2&insulin-like growth factor-binding protein-7 (TIMP-2&IGFBP7), Neutrophil Gelatinase-Associated Lipocalin (NGAL), plasma Cystatin C (pCysC), Soluble urokinase plasminogen activator receptor (suPAR), Proenkephalin (PenK) and urinary dickkopf-3:urinary creatinine (uDKK3:uCr) from various databases including Medline, PubMed, Embase, and Cochrane. This was geared towards predicting persistent AKI in adults (>18 years). Hierarchically summarized subject work characteristic curves (HSROC) and diagnostic odds ratio (DOR) values were used to summarize the diagnostic accuracy of the biomarkers. Further, meta-regression and subgroup analyses were carried out to identify sources of heterogeneity as well as evaluate the best predictive biomarkers in different populations and regions. RESULTS: We screened 31 studies from 2,356 studies and assessed the diagnostic value of 7 biomarkers for persistent AKI. Overall, CCL14 had the best diagnostic efficacy with an AUC of 0.79 (95 % CI 0.75-0.82), whereas TIMP-2 & IGFBP7, NGAL, and pCysC had diagnostic efficacy of 0.75 (95 % CI 0.71-0.79),0.71 (95 % CI 0.67-0.75), and 0.7007, respectively. Due to a limited number of studies, PenK, uDKK3:uCr, and suPAR were not subjected to meta-analysis; however, relevant literature reported diagnostic efficacy above 0.70. Subgroup analyses based on population, region, biomarker detection time, AKI onset time, and AKI duration revealed that in the intensive care unit (ICU) population, the AUC of CCL14 was 0.8070, the AUC of TIMP-2 & IGFBP7 was 0.726, the AUC of pCysC was 0.72, and the AUC of NGAL was 0.7344; in the sepsis population, the AUC of CCL14 was 0.85, the AUC of TIMP-2&IGFBP7 was 0.7438, and the AUC of NGAL was 0.544; in the post-operative population, the AUC of CCL14 was 0.83-0.93, the AUC of TIMP-2&IGFBP7 was 0.71, and the AUC of pCysC was 0.683. Regional differences were observed in biomarker prediction of persistent kidney injury, with AUCs of 0.8558 for CCL14, 0.7563 for TIMP-2 & IGFBP7, and 0.7116 for NGAL in the Eurasian American population. In the sub-African population, TIMP-2 & IGFBP7 had AUCs of 0.7945, 0.7418 for CCL14, 0.7097 for NGAL, and 0.7007 for pCysC. for TIMP-2 & IGFBP7 was 0.7945, AUC for CCL14 was 0.7418, AUC for NGAL was 0.7097, and AUC for pCysC was 0.7007 in the sub-African population. Duration of biomarker detection, AKI onset, and AKI did not influence the optimal predictive performance of CCL14. Subgroup analysis and meta-regression of CCL14-related studies revealed that CCL14 is the most appropriate biomarker for predicting persistent stage 2-3 AKI, with heterogeneity stemming from sample size and AKI staging. CONCLUSION: This meta-analysis discovered CCL14 as the best biomarker to predict persistent AKI, specifically persistent stage 2-3 AKI.

Reproductive and developmental safety evaluation of Thymelaea hirsuta (L.) leaves aqueous extract in Wistar albino rats.

ETHNOPHARMACOLOGICAL RELEVANCE: The popularity of herbal medicine is expanding globally due to the common belief that herbal products are natural and nontoxic. Thymelaea hirsuta leaves are traditionally used for the treatment of recurrent abortion in humans and animals. However, a lack of safety evaluation of the plant, particularly in pregnant women, raises serious concerns regarding its potential embryotoxic effects. AIM OF THE STUDY: Therefore, the present study investigated the safety of Thymelaea hirsuta leaves aqueous extract (THLE) during pregnancy and lactation following maternal rat treatment. MATERIALS AND METHODS: THLE phytochemical compounds were identified using high-performance liquid chromatography (HPLC). THLE was orally administered to pregnant rats and lactating dams at dosages of 0, 250, 500, and 1000 mg/kg/day. At the end of the study, dam s' and pups' body weights, serum biochemical and hematological indices, and histopathological changes were investigated. For the fetal observation and histopathological changes were also evaluated. RESULTS: Our findings revealed that THLE is rich in different phenolic and flavonoid compounds. However, biochemical and hormonal parameters such as ALT, AST, and prolactin were significantly increased in dams treated with a higher dosage of THLE when compared to the control dams (P ≤ 0.05). Additionally, external, visceral and skeletal examinations of fetuses revealed a marked increase of malformation rates in treated fetuses. CONCLUSIONS: The results revealed that higher oral dosing of THLE during pregnancy could affect embryonic development in rats, while lower doses are safe and can be used during pregnancy and lactation to attain its beneficial effects.

Label-free detection of kidney stones urine combined with SERS and multivariate statistical algorithm.

Kidney stones are a common urological disease with an increasing incidence worldwide. Traditional diagnostic methods for kidney stones are relatively complex and time-consuming, thus necessitating the development of a quicker and simpler diagnostic approach. This study investigates the clinical screening of kidney stones using Surface-Enhanced Raman Scattering (SERS) technology combined with multivariate statistical algorithms, comparing the classification performance of three algorithms (PCA-LDA, PCA-LR, PCA-SVM). Urine samples from 32 kidney stone patients, 30 patients with other urinary stones, and 36 healthy individuals were analyzed. SERS spectra data were collected in the range of 450-1800 cm-1 and analyzed. The results showed that the PCA-SVM algorithm had the highest classification accuracy, with 92.9 % for distinguishing kidney stone patients from healthy individuals and 92 % for distinguishing kidney stone patients from those with other urinary stones. In comparison, the classification accuracy of PCA-LR and PCA-LDA was slightly lower. The findings indicate that SERS combined with PCA-SVM demonstrates excellent performance in the clinical screening of kidney stones and has potential for practical clinical application. Future research can further optimize SERS technology and algorithms to enhance their stability and accuracy, and expand the sample size to verify their applicability across different populations. Overall, this study provides a new method for the rapid diagnosis of kidney stones, which is expected to play an important role in clinical diagnostics.

Associations Among Circle-Based Kidney Allocation, Center Waiting Time, and Likelihood of Deceased-Donor Kidney Transplantation.

RATIONALE & OBJECTIVE: The kidney allocation system (KAS250), using circle-based distribution, attempts to address geographic disparities through broader sharing of deceased-donor kidney allografts. This study sought to evaluate the association between KAS250 and likelihood of deceased-donor kidney transplantation (DDKT) among waitlisted candidates, and whether the policy has differentially affected centers with shorter vs. longer waiting time. STUDY DESIGN: Retrospective cohort study. SETTING: & Participants: 160,941 candidates waitlisted at 176 transplant centers between 3/2017-3/2024. EXPOSURE: KAS250 allocation policy. OUTCOME: Rate of DDKT. ANALYTICAL APPROACH: Multivariable Cox regression, modeling KAS250 as a time-dependent variable. RESULTS: KAS250 was not independently associated with likelihood of DDKT overall (HR=1.01 vs. pre-KAS250, 95% C.I. 0.97-1.04). KAS250's association with likelihood of DDKT varied across centers from HR=0.18 (DDKT less likely after KAS250) to HR=17.12 (DDKT more likely) and varied even among neighboring centers. KAS250 was associated with decreased DDKT at 25.6% and increased DDKT at 18.2% of centers. Centers with previously long median waiting times (57+ months) experienced increased likelihood of DDKT after KAS250 (HR=1.20, 95% C.I. 1.15-1.26), whereas centers with previously short median waiting times (6-24mo.; HR=0.88, 0.84-0.92) experienced decreased likelihood of DDKT. LIMITATIONS: Retrospective study of allocation policy changes, confounded by multiple changes over the study timeframe. CONCLUSION: Association between KAS250 and DDKT varied across centers. For one-in-four centers, DDKT was less likely after KAS250 relative to pre-KAS250 trends. Candidates at centers with previously long waiting times experienced increased likelihood of DDKT after KAS250. Thus, broader distribution of kidneys may be associated with improved equity in access to DDKT, but additional strategies may be needed to minimize disparities between centers.

Cardiac magnetic resonance assessment of cardiac function across chronic kidney disease stages.

BACKGROUND: Cardiovascular disease prevalence remains high among chronic kidney disease (CKD) patients. Mechanisms and treatments to improve prognosis remain of paramount important and imaging biomarkers of left ventricular myocardial structure and function have better defined the phenotype of renal cardiomyopathy. The left atrial function and right heart remain are less well reported in CKD. This study used cardiac MRI to assess the interplay of left atrial and right ventricular function. METHODS: In a cross-sectional study, we examined 58 CKD patients (Group I: stages 2-3, n = 25; Group II: stages 4-5, n = 33). Additionally, 26 age-matched healthy controls were included. Comprehensive CMR protocols (1.5T) were employed, encompassing cine imaging, native T1 and T2 mapping, and tissue tracking strain analysis. LV, RV, and LA structure, function, and strain parameters were assessed. RESULTS: Compared to healthy controls, both groups I and II exhibited impaired RV and LA function. RVEDVi and RVESVi showed significant increases in both groups I and II (p < 0.001). All LV, RV, and LA strain parameters were reduced in the patient groups (all p < 0.001). In the univariate binary logistic regression, several parameters, including age, blood pressure, RV volumes and LV/RV strain were found to have a statistically significant association with CKD. In a multivariable model adjusted for other confounders, RV GLS and left atrial strain remained as independent significant predictors. CONCLUSIONS: RV size, LA strain and volume assessed by CMR serve as markers of RV and LA cardiac dysfunction in CKD patients with preserved LVEF. Greater attention should be given to RV and LA dysfunction for early identification of cardiac dysfunction in CKD patients.

Tumor characteristics in immunosuppressed and renal dysfunction populations.

PURPOSE: Renal transplantation and end-stage renal disease are increasingly common. Renal dysfunction and immunosuppression are two risk factors in the development of renal cell carcinoma. Carcinomas in these patients are thought to be more indolent, however data are limited and mixed. Our objective was to describe the histology of resected tumors from the transplant and renal dysfunction population and compare them to a control population. MATERIALS AND METHODS: This was a single-center retrospective cohort study of all patients who had a nephrectomy for a renal mass from 2009 to 2019. All transplant status and end-stage renal disease diagnoses were identified by diagnostic or procedural coding and confirmed by chart review. Our primary endpoint was the pathology for each patient's tumor. Tumors were classified into aggressive or nonaggressive categories based on their histology and grade. RESULTS: We identified 1,150 radical and partial nephrectomies, of which 1,057 met inclusion criteria. Of these, 68 patients (6.4%) had renal dysfunction or a kidney transplant on immunosuppression at time of nephrectomy. After pathologic review, 270 (25%) tumors were classified as aggressive, and 673 (64%) tumors were pT1a or pT1b. On multivariable logistic regression controlling for age and gender, renal dysfunction was not associated with having an aggressive tumor (OR 1.24, 95%CI 0.72-2.15; P = 0.44). CONCLUSIONS: We did not observe a relationship between renal dysfunction status and aggressive pathology. These data suggest that renal dysfunction and transplant patients are at similar risk for aggressive pathology as the general population and should be managed according to the same clinical guidelines.

Chronic kidney disease associated with extremely premature birth and extremely low birth weight may progress through the burden of growth.

Chronic kidney disease associated with low birth weight and/or premature birth (L/P-CKD) in infants may result from a decreased number of nephrons at birth. These infants may develop acute kidney injury due to exposure to nephrotoxic substances or other events during nephrogenesis in early infancy. Nonetheless, L/P-CKD progression remains unclear. We present three cases of L/P-CKD diagnosed after neonatal intensive care unit (NICU) discharge. Three patients were born extremely prematurely (gestational age, 24-26 weeks) with extremely low birth weight (606-906 g). They were admitted to the NICU (117-311 days) anad received several nephrotoxic medications during the early postnatal period. They showed elevated serum creatinine levels at 4 weeks after birth, which decreased to normal levels at NICU discharge. Proteinuria was first detected during adolescence (10-15 years) on annual school urine screening, with a remarkable increase in their height (18 - 50.8 cm), without known episodes of urinary tract infection, dehydration, lifestyle-related issues, such as excessive salt/protein intake, and extreme lack of exercise that might have caused kidney damage. Their kidneys were smaller than normal on renal ultrasonography. Open renal biopsy findings indicated glomerulomegaly and perihilar glomerulosclerosis in two of the three patients, suggesting glomerular hypertension. The remarkable differences between the body height before CKD and the timing of diagnosis of CKD could contribute to the progress of CKD. Long-term follow-up of low birth weight and extremely premature infants, from NICU discharge until adulthood, should be established.

Targeting RAC1 might be a potential therapeutic strategy for diabetic kidney disease: a Mendelian randomization study.

PURPOSE: This study aimed to ascertain the causal association between Ras-related C3 botulinum toxin substrate 1 (RAC1) and the incidence and progression of diabetic kidney disease (DKD) through Mendelian randomization analysis. METHODS: RAC1 expression, evaluated using expression quantitative trait loci data from the eQTLGen Consortium, was served as the exposure variable. Outcomes encompassed the risk of DKD, end-stage renal disease (ESRD), albuminuria assessed by the urinary albumin-to-creatinine ratio (ACR), and estimated glomerular filtration rate (eGFR) among individuals with diabetes. Causal associations were computed using the inverse variance weighted (IVW), weighted median, and MR-PRESSO models. Additionally, we conducted analyses for heterogeneity, horizontal pleiotropy, and sensitivity. RESULTS: This study revealed a causal association between the genetic activation of RAC1 and an elevated risk of DKD among individuals with diabetes [IVW, odds ratio (OR) = 1.28, 95% confidence intervals (CI) 1.08-1.51, P = 0.004]. Furthermore, increased expression of RAC1 was linked to a higher risk of ESRD (IVW, OR = 1.20, 95% CI 1.02-1.43, P = 0.032). Excessive RAC1 expression was causally associated with elevated ACR (IVW, ß = 0.052, 95% CI 0.003-0.100, P = 0.036). However, the analysis regarding RAC1 and eGFR showed significant heterogeneity and pleiotropy, with no discernible causal relationship. CONCLUSIONS: These findings suggested a positive correlation between the genetic activation of RAC1 and the incidence of DKD, the risk of ESRD, and exacerbated albuminuria among individuals with diabetes. Targeting RAC1 might potentially serve as a therapeutic strategy for DKD.

Estimating the prevalence of chronic kidney disease in the older population using health screening data in Japan.

BACKGROUND: In aging societies, the prevalence of chronic kidney disease (CKD) is expected to increase but may be underestimated because many asymptomatic patients remain undiagnosed. This study aimed to estimate the CKD prevalence among the general older population in Japan. METHODS: This cross-sectional study used health screening data from the Japan Health Insurance Association collected between April 2014 and March 2023. Data from older people aged 65-90 years who underwent renal function screening for estimated glomerular filtration rate (eGFR) and urine protein tests were analyzed. CKD was defined as eGFR < 60 mL/min/1.73 m2 or proteinuria ≥ 1 + . Inverse probability weighting was used to account for the selection bias. The variables used for weighting were age, sex, insurance status, and the number of previous screenings. RESULTS: Among 2.98 million older individuals, 588,809 (19.7%) had undergone screening (median [IQR] age, 69.9 [67.9-76.2] years, 337,862 women [57.4%]). Regarding the weighted CKD prevalence, 25.3% of the individuals aged 65-90 years had CKD; 11.8% of those aged 65-75 years and 34.6% of those aged 75 years and over showed an increase in prevalence with age. Among the patients with CKD, over half exhibited mild renal dysfunction without proteinuria. Hypertension and diabetes were common comorbidities in older patients with CKD. CONCLUSIONS: This cross-sectional study revealed that the weighted prevalence of CKD in the older population aged 65-90 years was high (one in four individuals), indicating that it increases with age. Further studies are required to examine the clinical significance of these findings.

Elevated serum GDF15 level as an early indicator of proximal tubular cell injury in acute kidney injury.

Acute kidney injury (AKI) is a high-burden medical condition, and current diagnostic criteria can only assess AKI after full manifestation. Stress marker growth differentiation factor 15 (GDF15) was reported to have a role in kidney injury of critical patients. Herein, we evaluated dynamic changes in GDF15 across diverse AKI scenarios and explored the underlying mechanisms of its induction. Serum parameters and renal lesions were analyzed in mouse models of unilateral ischemia-reperfusion injury (uni-IRI) and unilateral ureteral obstruction (UUO). The human proximal tubular (HK-2) cell line was stimulated with various conditions, and induction of GDF15 expression was determined. Serum GDF15 levels were rapidly induced within hours after injury in both animal models and declined thereafter. Renal GDF15 expression exhibited a temporary and early increased induction and was mainly located in aquaporin 1-positive proximal tubules in both unilateral AKI model tissues. In cell experiments, rapid GDF15 production was highly induced by t-BHP and CoCl2. Treatment with either an antioxidant or mitogen-activated protein kinase inhibitors abolished t-BHP- and CoCl2-mediated GDF15 expression. In addition, silencing nuclear factor erythroid 2-related factor 2 expression also reduced the basal and t-BHP- or CoCl2-mediated GDF15 expression level in HK-2 cells. Our data showed that elevated serum GDF15 levels could be detected early in unilateral AKI models without notable alterations in kidney function parameters. GDF15 expression was associated with oxidative stress- and hypoxia-mediated proximal tubular cell injury. These data document that elevated serum GDF15 can possibly serve as an early biomarker for proximal tubular cell injury in AKI.

A validated LC-MS/MS method for the simultaneous quantification of iothalamate and hippuran in serum and urine for non-radioactive kidney function assessment.

A novel liquid chromatography-tandem mass spectrometry method is described for the quantitative determination of the kidney function markers iothalamate and hippuran in human serum and urine. It is based on protein precipitation with methanol followed by dilution of the supernatant for serum and simple dilution for urine. The polar analytes are chromatographically separated by a 6.5-min gradient on a low-ligand density reversed-phase column; detection is performed by electrospray ionization tandem mass spectrometry in the positive ion mode against stable-isotope labeled internal standards. The results of a thorough method validation show that iothalamate and hippuran can be simultaneously quantified in the concentration ranges 0.500-30.0 ng/mL and 10.0-5000 ng/mL for serum and urine, respectively, with values for CV and absolute bias not exceeding 10 %, and with sufficient stability in all relevant matrices and solvents. The method was successfully applied for the analysis of serum and urine samples of multiple individuals who received both iothalamate and hippuran.

Chronic alcohol consumption aggravates acute kidney injury through integrin ß1/JNK signaling.

Alcohol abuse is one of the major public health problems in the world and is associated with various health conditions. However, little is known about the effect of alcohol consumption on acute kidney injury (AKI). In this study, we demonstrate that chronic and binge alcohol feeding with a Lieber-DeCarli diet containing 5 % ethanol for 10 days, followed by a single dose of 31.5 % ethanol by gavage, aggravated AKI after ischemia-reperfusion injury (IRI) in female, but not in male, mice. Kidney dysfunction, histopathology and tubular cell apoptosis were more severe in EtOH-fed female mice after IRI, compared to pair-fed controls. RNA sequencing and experimental validation uncovered that activation of integrin ß1 and its downstream c-Jun NH2-terminal kinase (JNK) aggravated AKI in EtOH-fed mice. Knockdown of integrin ß1 inhibited JNK phosphorylation and alleviated AKI in EtOH-fed mice, whereas activation of integrin ß1 by agonist antibody increased JNK phosphorylation, worsened renal histological injury and tubular cell apoptosis, and aggravated kidney dysfunction. In vitro, activation of integrin ß1 increased JNK phosphorylation and induced tubular epithelial cell apoptosis. The detrimental effect of EtOH feeding was primarily mediated by acetaldehyde, as its levels were increased in the blood, liver and kidney of female mice fed with ethanol. Acetaldehyde per se activated integrin ß1/JNK signaling and induced tubular cell apoptosis in vitro. These findings suggest that alcohol consumption increases vulnerability to AKI in female mice, which is probably mediated by acetaldehyde/integrin ß1/JNK signaling cascade.

Lower extremity amputation rates in patients with chronic kidney disease: A database study comparing patients with and without diabetes mellitus.

Lower extremity amputation (LEA) is one of the most feared consequences of diabetes mellitus (DM). The purpose of this study was to evaluate the impact of DM on LEA rates in patients at various stages of chronic kidney disease (CKD). A commercially available de-identified database was searched for patients undergoing LEA and for CKD patients, from 2010 to 2023. Patients with DM and patients without DM who were followed for at least 5 years were included. LEA rates were then compared for patients at all 5 CKD stages in patients with and without diabetes. Rates of all LEA were found to be significantly higher at all CKD stages for patients with diabetes (overall, minor and major LEA). Compared to patients without DM who have CKD stage 5 (end stage renal disease), patients with DM and CKD stage 5 have a 30 fold increased likelihood of undergoing overall LEA [OR 30.2 (24.48-37.19), p < 0.001], 29 fold increased likelihood of undergoing minor LEA [28.9i (22.91-36.35), p < 0.001] and 40 times fold increased likelihood of undergoing major LEA [40.1 (26.59-60.42), p < 0.001]. For all stages of CKD, independent of diabetes status, minor LEA were performed with greater frequency than major LEA. In patients with DM, LEA rates significantly increased with CKD progression between stages 2-5 with a substantial jump between stages 4 and 5 [OR 2.6 (CI 2.49-2.74), p < 0.001]. However, CKD progression between stages 1 and 2 was not significantly associated with increased LEA rates (OR 1.1 (CI 0.92-1.21), p = 0.24) in patients with diabetes. Patients with comorbid diabetes have elevated risk for LEA at all stages of CKD compared to those without diabetes.

Novel mutation in XPNPEP3 in a patient with heart failure without nephronophthisis-like nephropathy (NPHPL1): case report and literature review.

BACKGROUND X-PROLYL AMINOPEPTIDASE 3: (XPNPEP3) mutations are known to cause nephronophthisis-like nephropathy-1 (NPHPL1), a rare autosomal-recessive kidney disease characterized by progressive kidney failure and cystic kidney disease in childhood. The full phenotypic spectrum associated with mutations in XPNPEP3 is not fully elucidated. CASE PRESENTATION: A 13-year-old Chinese female patient with intellectual disability presented with a 2-year history of convulsions and fatigue, with a recent episode of swelling, breathlessness, and nocturnal dyspnea lasting 10 days. The patient was diagnosed with heart failure and kidney failure. Whole exome sequencing revealed a homozygous c.970-2 A > G mutation in XPNPEP3 associated with severe cardiac dysfunction and neurological symptoms, including epilepsy and intellectual disability. Notably, kidney ultrasound did not reveal the typical changes of NPHPL1, and kidney failure was hypothesized to be secondary to cardiac dysfunction rather than primary kidney pathology. CONCLUSIONS: This case suggests the possible association of additional phenotypic features associated with XPNPEP3 mutations, emphasizing the need for further investigation into the heterogeneous clinical presentations associated with XPNPEP3 mutations. The findings highlight the importance of considering alternative phenotypes in patients with genetic mutations traditionally associated with specific diseases. Segregation and functional analyses are necessary to determine causality between the c.970-2 A > G XPNPEP3 mutation and disease.

Associations between multi-metal joint exposure and decreased estimated glomerular filtration rate (eGFR) in solar greenhouse workers: A study of a unique farmer group.

BACKGROUND: Solar greenhouse workers, a unique farmer group, have been reported to have a higher risk of chronic kidney disease (CKD) compared to the general population, possible due to exposure to multiple metals. OBJECTIVE: This study aimed to investigate the associations between exposure to multiple metals and the estimated glomerular filtration rate (eGFR). METHODS: A cross-sectional study was conducted in the Northwest China. Urine samples were tested for concentration of 14 metals, including chromium, manganese, iron et al. Blood creatinine was measured to calculate eGFR, which was to evaluate the kidney function. Linear model and the Bayesian Kernel Machine Regression (BKMR) models were used to evaluate the associations between metals exposure and eGFR. RESULT: The study included 281 solar greenhouse workers, with 128 (45.6%) males and 153 (54.4%) females. The highest median concentrations of metals were zinc (418.55 µg/L), strontium (368.77 µg/L), and iron (55.73 µg/L), respectively. The linear model analysis showed that urinary levels of copper and zinc were negatively associated with eGFR [ß = -0.021, 95% CI (-0.048, -0.007); ß = -0.018, 95% CI (-0.068, -0.005)] considering a false discovery rate. BKMR results indicated a significant overall negative effect of 14 metals exposure on the eGFR when all metal levels were above the 50th percentile compared to the median value. CONCLUSIONS: The decrease in eGFR among solar greenhouse workers was related to mixed metal exposure. Reducing exposure to the metals of copper, zinc, and lead could effectively protects kidney function. Further prospective studies are needed to resolve concerns about reverse causality.

A promising application of kidney-specific cell-free DNA methylation markers in real-time monitoring sepsis-induced acute kidney injury.

Sepsis-induced acute kidney injury (SI-AKI) is a common clinical syndrome that is associated with high mortality and morbidity. Effective timely detection may improve the outcome of SI-AKI. Kidney-derived cell-free DNA (cfDNA) may provide new insight into understanding and identifying SI-AKI. Plasma cfDNA from 82 healthy individuals, 7 patients with sepsis non-acute kidney injury (SN-AKI), and 9 patients with SI-AKI was subjected to genomic methylation sequencing. We deconstructed the relative contribution of cfDNA from different cell types based on cell-specific methylation markers and focused on exploring the association between kidney-derived cfDNA and SI-AKI.Based on the deconvolution of the cfDNA methylome: SI-AKI patients displayed the elevated cfDNA concentrations with an increased contribution of kidney epithelial cells (kidney-Ep) DNA; kidney-Ep derived cfDNA achieved high accuracy in distinguishing SI-AKI from SN-AKI (AUC = 0.92, 95% CI 0.7801-1); the higher kidney-ep cfDNA concentrations tended to correlate with more advanced stages of SI-AKI; strikingly, SN-AKI patients with potential kidney damage unmet by SI-AKI criteria showed higher levels of kidney-Ep derived cfDNA than healthy individuals. The autonomous screening of kidney-Ep (n = 24) and kidney endothelial (kidney-Endo, n = 12) specific methylation markers indicated the unique identity of kidney-Ep/kidney-Endo compared with other cell types, and its targeted assessment reproduced the main findings of the deconvolution of the cfDNA methylome. Our study first demonstrates that kidney-Ep- and kidney-Endo-specific methylation markers can serve as a novel marker for SI-AKI emergence, supporting further exploration of the utility of kidney-specific cfDNA methylation markers in the study of SI-AKI.

Short term sodium glucose transport protein 2 inhibitors are associated with post contrast acute kidney injury in patients with diabetes.

Although sodium-glucose transport protein-2 (SGLT2) inhibitors (SGLT2i) do not increase the risk of acute kidney injury (AKI) in general, they may pose a risk in patients undergoing angiography. This prospective cohort study aimed to evaluate the safety and efficacy of SGLT2i for post-contrast AKI (PC-AKI) in patients with type 2 diabetes mellitus (T2DM). Following screening, 306 patients with T2DM selected to undergo coronary arterial angiography with or without percutaneous intervention were enrolled. Patients were divided into the SGLT2i exposure and non-exposure groups. The primary outcome was PC-AKI, defined as an increase in serum creatinine levels > 0.5 mg/dL (44.2 µmol/L), or 25% above the baseline, within 48-72 h after exposure to contrast medium. The incidence of PC-AKI in the overall T2DM population was 5.2% (16/306). Following 1:1 propensity score matching, the incidence of PC-AKI was significantly higher in the SGLT2i group than in the non-SGLT2i group (10.7% vs. 2.9%; P = 0.027), with an odds ratio of 4.5 (95% confidence interval: 1.0-20.2; P = 0.047). Furthermore, PC-AKI occurred at a higher rate among short-term users of SGLT2i than long-term users (20.5% vs. 3.4%, P = 0.018). Thus, our findings suggest an increased risk of PC-AKI associated with short-term SGLT2i therapy in patients with T2DM.

C-176 inhibits macrophage polarization towards M1-subtype and ameliorates LPS induced acute kidney injury.

Sepsis-induced acute kidney injury (SI-AKI) has become a focal point in nephrology research field due to its high mortality and potential progression to chronic kidney disease (CKD). The increase of M1 macrophages within renal tissue and their associated inflammatory responses are key contributors to renal inflammation and subsequent damage. Additionally, the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway is abnormally activated during the onset of acute kidney injury (AKI). However, the relationship between the activation of this pathway and the increase in M1 macrophages has not been fully elucidated. This study investigated the protective effects and underlying mechanisms of the STING pathway-specific inhibitor C-176 on LPS-induced AKI, using an LPS and IFN-γ induced M1 macrophage model and an LPS-induced sepsis AKI mouse model. The in vivo results demonstrate that C-176 intervention can alleviate acute kidney injury and improve renal function by reducing macrophage infiltration in renal tissue, decreasing the proportion of M1 macrophages, and mitigating the inflammatory response. Additionally, in vitro results indicate that C-176 intervention inhibits the polarization of M0 macrophages to M1 macrophages, promotes their polarization to M2 macrophages, and reduces the amounts of pro-inflammatory cytokines such as IL-6 and TNF-α at both the protein and gene expression levels. The biological effects of C-176 are associated with the inhibition of STING-IRF3 signaling pathway activation. In summary, the findings of this study have certain scientific significance and application value for exploring the pathogenesis and treatment methods of SI-AKI.

Lack of Cannabinoid Type 2 Promoter Activity in Normal or Injured Kidneys Using a Cnr2-GFP Reporter Mouse.

Introduction: Although cannabinoid type 2 (CB2) receptor activity is known to promote diverse biological functions in the kidney, published data regarding CB2 receptor protein levels and cellular distribution within the kidney is inconsistent. The goal of the present study was to investigate the changes of CB2 in the kidney obtained from mice exposed to various forms of kidney injury using a genetic mouse model expressing green fluorescent protein (GFP) driven by the endogenous cannabinoid receptor 2 (Cnr2) promoter. Materials and Methods: Kidney injury was established in a genetic mouse model expressing green fluorescent protein (GFP) driven by the endogenous Cnr2 promoter. Kidney injury was initiated by either treatment with different chemicals [cisplatin or lipopolysaccharide (LPS)] or by unilateral ureteral obstruction (UUO). Changes in the detection of GFP were used as a proxy for CB2 levels and localization. Histological changes due to the injury stimuli were observed by time-related, morphological changes in kidney cytoarchitecture and blood parameters, such as serum creatinine levels. Cnr2 mRNA levels were detected by reverse transcription coupled to polymerase chain reaction (RT-PCR) while protein changes in the tissue lysates were measured by Western blot analysis. Cellular localization of GFP was detected by fluorescent microscopy. Results: Our data demonstrated that there was no band or a minimally detectable band for GFP using kidney lysates from vehicle- or cisplatin-treated mice. A similar lack of GFP was detected in the UUO kidney versus the contralateral control kidney. This is consistent with the low, albeit detectable levels of Cnr2 mRNA in the kidney samples from control or cisplatin treatment. In frozen kidney sections from vehicle and cisplatin-treated mice, GFP fluorescence was not detectable in tubular epithelia, glomeruli or blood vessels in the cortex. Instead, GFP was detected in rare cells within the interstitial space. A second chemical injury model using LPS found a similar lack of GFP protein levels and an absence of legitimate GFP fluorescence in the main cell types within the kidney. Conclusion: These findings suggest that Cnr2 promoter activity is minimally active in normal or injured kidneys, and that pharmacological manipulation of CB2 receptors may be associated with receptors being expressed in cells recruited to the kidney.

Features selection in a predictive model for cardiac surgery-associated acute kidney injury.

BACKGROUND: Cardiac surgery-associated acute kidney injury (CSA-AKI) is related to increased morbidity and mortality. However, limited studies have explored the influence of different feature selection (FS) methods on the predictive performance of CSA-AKI. Therefore, we aimed to compare the impact of different FS methods for CSA-AKI. METHODS: CSA-AKI is defined according to the kidney disease: Improving Global Outcomes (KDIGO) criteria. Both traditional logistic regression and machine learning methods were used to select the potential risk factors for CSA-AKI. The area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of the models. In addition, the importance matrix plot by random forest was used to rank the features' importance. RESULTS: A total of 1977 patients undergoing cardiac surgery at Fuwai hospital from December 2018 to April 2021 were enrolled. The incidence of CSA-AKI during the first postoperative week was 27.8%. We concluded that different enrolled numbers of features impact the final selected feature number. The more you input, the more likely its output with all FS methods. In terms of performance, all selected features by various FS methods demonstrated excellent AUCs. Meanwhile, the embedded method demonstrated the highest accuracy compared with the LR method, while the filter method showed the lowest accuracy. Furthermore, NT-proBNP was found to be strongly associated with AKI. Our results confirmed some features that previous studies have reported and found some novel clinical parameters. CONCLUSIONS: In our study, FS was as suitable as LR for predicting CSA-AKI. For FS, the embedded method demonstrated better efficacy than the other methods. Furthermore, NT-proBNP was confirmed to be strongly associated with AKI.