Sunscreen compound benzophenone-3 and its relationship with white blood cell counts.

BACKGROUND: Evidence from animal models suggests a role for the organic ultraviolet filter benzophenone-3's (BP-3) on white blood cells (WBCs). However, BP-3's effect on WBCs in humans is unknown. MATERIALS AND METHODS: We used National Health and Nutrition Examination Survey data from 2003 to 2016. We included participants >6 years with data on urinary BP-3, urinary creatinine, and WBC count. Quintiles of urinary creatinine-normalized BP-3 (CnBP-3) levels were used in linear regression models adjusting for age, gender, race, body mass index (BMI), smoking status, education level, family income to poverty threshold ratio, survey cycle, and season. RESULTS: Of the 16 959 participants, 8564 (50.5%) were females, 6602 (38.9%) were White, and 3870 (22.8%) were Black. The mean (standard deviation) age was 37.6 (22.7) years, BMI was 26.8 (7.40) kg/m2, WBC count was 7.22 (2.53) × 109/L, neutrophil count was 4.15 (1.86) × 109/L, and lymphocyte count was 2.25 (1.33) × 109/L and median (interquartile range) of CnBP-3 was 12.1 (44.9) µg/gm. The highest quintile of CnBP-3 was associated with significantly lower WBC and neutrophil counts compared to the lowest quintile of CnBP-3 (Δ quintiles = -137 × 106/L, 95% CI: -249 to -24, p = 0.02 and = -177 × 106/L, 95% CI: -323 to -30, p = 0.02, respectively). In contrast, we did not observe a difference in lymphocyte count between the lowest and highest quintiles of CnBP-3 in unadjusted or adjusted analyses. CONCLUSION: We found an inverse relationship between BP-3 levels and WBC and neutrophil counts, and not with lymphocyte count. Further research is needed to confirm our findings.

The use of urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin for diagnosis of hepato-renal syndrome in advanced cirrhotic patients.

BACKGROUND: Chronic liver disease is a common and important clinical problem.Hepatorenal syndrome (HRS) is a life threatening complication. Serum creatinine (Cr) remains the only conventional indicator of renal function. However, the interpretation of serum Cr level can be confounded by malnutrition and reduced muscle mass often observed in patients with severe liver disease. Here, we present a cross-sectional study to explore the sensitivity and specificity of other markers as urinary KIM-1 and NGAL for cases of HRS. METHODS: Cross-sectional study was conducted on 88 patients who were admitted to Alexandria main university hospital. Enrolled patients were divided in two groups; group 1: patients with advanced liver cirrhosis (child B and C) who have normal kidney functions while group 2: patients who developed HRS. Stata© version 14.2 software package was used for analysis. RESULTS: Group 1 included 18 males and 26 females compared to 25 males and 19 females in group 2 (p = 0.135). Only the urinary KIM-1 showed a statistically significant difference between both groups in the multivariate logistic regression analysis adjusted for gender, serum bilirubin, serum albumin, INR, serum K, AST and ALT levels. CONCLUSION: In conclusion, our study aligns with prior research, as seen in the consistent findings regarding Urinary NGAL elevation in cirrhotic patients with AKI. Urinary KIM-1, independent of Urinary NGAL, may have a role in precisely distinguishing between advanced liver cirrhosis and HRS and merits further exploration.

Reactive oxygen species impair Na+ transport and renal components of the renin-angiotensin-aldosterone system after paraquat poisoning.

Paraquat (1,1'-dimethyl-4,4'-bipyridyl dichloride) is an herbicide widely used worldwide and officially banned in Brazil in 2020. Kidney lesions frequently occur, leading to acute kidney injury (AKI) due to exacerbated reactive O2 species (ROS) production. However, the consequences of ROS exposure on ionic transport and the regulator local renin-angiotensin-aldosterone system (RAAS) still need to be elucidated at a molecular level. This study evaluated how ROS acutely influences Na+-transporting ATPases and the renal RAAS. Adult male Wistar rats received paraquat (20 mg/kg; ip). After 24 h, we observed body weight loss and elevation of urinary flow and serum creatinine. In the renal cortex, paraquat increased ROS levels, NADPH oxidase and (Na++K+)ATPase activities, angiotensin II-type 1 receptors, tumor necrosis factor-α (TNF-α), and interleukin-6. In the medulla, paraquat increased ROS levels and NADPH oxidase activity but inhibited (Na++K+)ATPase. Paraquat induced opposite effects on the ouabain-resistant Na+-ATPase in the cortex (decrease) and medulla (increase). These alterations, except for increased serum creatinine and renal levels of TNF-α and interleukin-6, were prevented by 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (tempol; 1 mmol/L in drinking water), a stable antioxidant. In summary, after paraquat poisoning, ROS production culminated with impaired medullary function, urinary fluid loss, and disruption of Na+-transporting ATPases and angiotensin II signaling.

Biomonitoring and health risk assessment of exposure to phthalate esters in waste management workers.

Humans are at risk of exposure to phthalates due to the widespread use of plasticized plastics, and one of the major concerns is occupational exposure. The present study investigated occupational exposure to phthalates at one of the greatest solid waste management sites in the second-largest country in the Middle East. Carcinogenic and non-carcinogenic health risks were assessed by human biomonitoring (HBM). The concentration of phthalate esters was determined using gas chromatography-mass spectrometry (GC-MS), and the daily intake (DI) of phthalate was calculated based on the adjusted urinary creatinine concentrations. Moreover, carcinogenic and non-carcinogenic risks were assessed. Monte Carlo simulations were performed for uncertainty and sensitivity analysis. The highest concentration recorded was 130.80 µg/g creatinine for mono-ethyl phthalate (MEP) among the composting group, while the lowest concentration was 0.49 µg/g creatinine for Monobenzyl phthalate (MBzP) among the office group. All estimates of daily intake were below the reference concentration, and differences between the DI at site sections were statistically significant (p < 0.05). The non-carcinogenic risk level was negligible. The excess lifetime cancer risk (ELCR) values corresponding to di-(2-ethylhexyl) phthalate (DEHP) exposure were 2.07E-04 among the composting group and 2.07E-04 among the processing group, posing a definite risk. The carcinogenic risk value among the office group was in a possible risk category with ELCR values of 9.75 E-05. The on-site workers of waste management sites can be highly exposed to phthalates, and their health risk is considerable. Appropriate measures and interventions should be considered to reduce occupational exposure to phthalates.

Soluble tumor necrosis factor receptor type 1 is an alternative marker of urinary albumin-creatinine ratio and estimated glomerular filtration rate for predicting the decline of renal function in subjects with type 2 diabetes mellitus.

BACKGROUND: Urinary albumin-creatinine ratio (UACR) and estimated glomerular filtration rates (eGFR) help predict worsening diabetic kidney disease (DKD) but have their limitations. Soluble tumor necrosis factor receptor type 1 (sTNFR1) is a biomarker of DKD. The predictive abilities of sTNFR1 and UACR plus eGFR have not been compared. METHODS: This prospective cohort study included patients with type 2 diabetes (T2D) to identify the risk factors of worsening DKD. Renal events were defined as > 30 % loss in eGFR based on consecutive tests after 6 months. The associations of sTNFR1, UACR, and eGFR levels and the risks of renal events were tested using a Cox regression model and the area under the curve (AUC) was compared between sTNFR1 levels and UACR plus eGFR using receiver-operating characteristic (ROC) analysis. The accuracy of stratification was evaluated using Kaplan-Meier analysis. RESULTS: Levels of sTNFR1 and UACR were associated with risks of > 30 % decline in eGFR after adjusting for relevant factors. The association between sTNFR1 levels and renal outcomes was independent of UACR and eGFR at baseline. The AUC of sTNFR1 level was comparable with that of combined UACR and eGFR (0.73 vs. 0.71, respectively, p = 0.72) and the results persisted for quartile groups of sTNFR1 and risk categories of Kidney Disease: Improving Global Outcomes (KDIGO) (0.70 vs. 0.71, respectively, p = 0.84). Both stratifications by sTNFR1 levels and KDIGO were accurate. CONCLUSION: sTNFR1 could be an alternative marker for identifying patients with diabetes at risk of declining renal function.

Optimizing the approach to monitoring allograft inflammation using serial urinary CXCL10/creatinine testing in pediatric kidney transplant recipients.

BACKGROUND: Urinary CXCL10/creatinine (uCXCL10/Cr) is proposed as an effective biomarker of subclinical rejection in pediatric kidney transplant recipients. This study objective was to model implementation in the clinical setting. METHODS: Banked urine samples at a single center were tested for uCXCL10/Cr to validate published thresholds for rejection diagnosis (>80% specificity). The positive predictive value (PPV) for rejection diagnosis for uCXCL10/Cr-indicated biopsy was modeled with first-positive versus two-test-positive approaches, with accounting for changes associated with urinary tract infection (UTI), BK and CMV viremia, and subsequent recovery. RESULTS: Seventy patients aged 10.5 ± 5.6 years at transplant (60% male) had n = 726 urine samples with n = 236 associated biopsies (no rejection = 167, borderline = 51, and Banff 1A = 18). A threshold of 12 ng/mmol was validated for Banff 1A versus no-rejection diagnosis (AUC = 0.74, 95% CI = 0.57-0.92). The first-positive test approach (n = 69) did not resolve a clinical diagnosis in 38 cases (55%), whereas the two-test approach resolved a clinical diagnosis in the majority as BK (n = 17/60, 28%), CMV (n = 4/60, 7%), UTI (n = 8/60, 13%), clinical rejection (n = 5/60, 8%), and transient elevation (n = 18, 30%). In those without a resolved clinical diagnosis, PPV from biopsy for subclinical rejection is 24% and 71% (p = .017), for first-test versus two-test models, respectively. After rejection treatment, uCXCL10/Cr level changes were all concordant with change in it-score. Sustained uCXCL10/Cr after CMV and BK viremia resolution was associated with later acute rejection. CONCLUSIONS: Urinary CXCL10/Cr reliably identifies kidney allograft inflammation. These data support a two-test approach to reliably exclude other clinically identifiable sources of inflammation, for kidney biopsy indication to rule out subclinical rejection.

Comparison of body iodine pool assessment methods before radioiodine therapy.

INTRODUCTION AND OBJECTIVES: Radioactive iodine therapy (RAIT) is recommended to reduce the risk of recurrence and metastasis in patients with intermediate-high risk differentiated thyroid cancer (DTC). In preparation for RAIT, stimulation of thyroid-stimulating hormone and reduction of body iodine pool are important for treatment success. For this purpose, patients are asked to reduce their iodine intake before RAIT, and the body iodine pool can be evaluated by measuring iodine excretion in urine before treatment. The aim of our study is to compare the methods used to measure the body iodine pool in the evaluation of the restricted iodine diet (RID) effectiveness applied in the RAIT preparation. PATIENTS AND METHODS: Eighty DTC patients discontinued levothyroxine three weeks before RAIT and followed up with a RID two weeks before treatment. After two weeks of RID, all patients collected their 24-h urine the day before the RAIT date. Patients completed 24-h urine samples on the morning of the RAIT date and also provided a spot urine sample. The estimated 24-h creatinine excretion of the patients was calculated. Estimated 24-h urinary iodine excretion (UIE) was calculated using the spot urine iodine/creatinine (I/C) ratio of the patients. 24-h UIE, iodine concentration in spot urine, I/C ratios in spot urine and estimated 24-h UIE of the patients were analyzed by comparing with each other. RESULTS: In 99% of the patients, RID efficiency was sufficient according to 24-h UIE before RAIT. The mean 24-h UIE was 48.81 micrograms/day (mcg/day) in 24-h urine samples taken from the patients to evaluate the body iodine pool. The patients' iodine concentrations in spot urine, I/C ratios in spot urine, and estimated 24-h UIE were all statistically significantly lower than actual 24-h UIE, which was the reference method (p: 0.026 vs <0.001 vs 0.041). Moderate positive correlation between 24-h UIE and iodine concentration in spot urine (r: 0.440), I/C ratio in spot urine (r: 0.493), and estimated 24-h UIE (r: 0.560) found. The strongest correlation was obtained with the estimated 24-h UIE. CONCLUSION: The estimated 24-h UIE obtained by using the I/C ratio in spot urine can be used practically and safely as an alternative to UIE in 24-h urine, which is the gold standard method for evaluating body iodine pool.

Urinary neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury molecule-1 (uKIM-1) as markers of active lupus nephritis.

BACKGROUND AND OBJECTIVES: Despite much research about lupus nephritis, none of the urinary biomarkers has been proven to be truly reflecting lupus nephritis activity, response to treatment, or prognosis. We aimed to study urinary biomarkers in lupus nephritis and test their relation to kidney damage. PATIENTS AND METHODS: Forty patients with systemic lupus erythematosus (SLE) were divided into two graoups: (1) lupus nephritis group with biopsy-proven proliferative lupus nephritis (classes III and IV) and who did not receive immunosuppressive drugs within the preceding 3 months except for glucocorticoids and (2) lupus non-nephritis group with SLE patients without any renal manifestation. We assessed disease activity by the SLE disease activity index. uNGAL, uKim-1, uNGAL to urinary creatinine excretion (mg/dl), and uKim-1 to urinary creatinine excretion were measured in random spot urine samples at the time of renal biopsy and 6 months after the induction therapy. RESULTS: The LN group before treatment showed higher levels of uNGAL and uKIM-1 (P-value < 0.001). ROC analysis showed that uNGAL at level of > 59 has a 95 % sensitivity, a 100 % specificity, and an AUC = 0.996 in the ability to diagnose LN. While the uKIM-1 ROC showed that at level of > 1.6, it has an 85 % sensitivity, an 80 % specificity, and an AUC = 0.919. uNGAL and uKIM levels were significantly lower after treatment (P-value < 0.001). No significant correlations were found between urinary markers before and after treatment with other clinical, inflammatory, and serological markers of lupus nephritis. CONCLUSION: uNGAL, uKIM, uNGAL/Creat ratio, and uKIM/Creat ratio can be used as a predictor and a marker of disease activity for lupus nephritis. Key Points • Renal biopsy is the current standard for diagnosis of lupus nephritis and none of the urinary biomarkers has been fully concluded to have a diagnostic power to reflect the activity or the response to treatment. • However, based on the finding of the current study, uNGAL, uKIM, uNGAL/Creat ratio, and uKIM/Creat ratio showed significant diagnostic performance and were powerful indices of renal involvement in systemic lupus patients and as markers of disease activity.

Immune urinary biomarkers predict infant cardiac surgery-associated acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) occurs frequently after infant cardiac surgery and is associated with poor outcomes, including mortality and prolonged length of stay. AKI mechanisms are poorly understood, limiting therapeutic targets. Emerging data implicates dysregulated immune activation in post-cardiac surgery AKI development. We sought to identify immune-mediated AKI biomarkers after infant cardiopulmonary bypass (CPB)-assisted cardiac surgery. METHODS: A single-center prospective study of 126 infants less than 1 year old undergoing CPB-assisted surgery enrolled between 10/2017 and 6/2019. Urine samples were collected before CPB and at 6, 24, 48, and 72 h after surgery. Immune-mediated biomarkers were measured using commercial ELISA and Luminex™ multiplex kits. Based on subject age, neonatal KDIGO (< 1 month) or KDIGO criteria defined AKI. The Kruskal-Wallis rank test determined the relationship between urinary biomarker measurements and AKI. RESULTS: A total of 35 infants (27%) developed AKI. AKI subjects were younger, underwent more complex surgery, and had longer CPB time. Subjects with AKI vs. those without AKI had higher median urinary chemokine 10 (C-X-C motif) ligand levels at 24, 48, and 72 h, respectively: 14.3 pg/ml vs. 5.3 pg/ml, 3.4 pg/ml vs. 0.8 pg/ml, and 1.15 pg/ml vs. 0.22 pg/ml (p < 0.05) post-CPB. At 6 h post-CPB, median vascular cell adhesion protein 1 (VCAM) levels (pg/mL) were higher among AKI subjects (491 pg/ml vs. 0 pg/ml, p = 0.04). CONCLUSIONS: Urinary CXCL10 and VCAM are promising pro-inflammatory biomarkers for early AKI detection and may indicate eventual AKI therapeutic targets. A higher resolution version of the Graphical abstract is available as Supplementary information.

A Phase 2 Trial of Sibeprenlimab in Patients with IgA Nephropathy.

BACKGROUND: A proliferation-inducing ligand (APRIL) is implicated in the pathogenesis of IgA nephropathy. Sibeprenlimab is a humanized IgG2 monoclonal antibody that binds to and neutralizes APRIL. METHODS: In this phase 2, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial, we randomly assigned adults with biopsy-confirmed IgA nephropathy who were at high risk for disease progression, despite having received standard-care treatment, in a 1:1:1:1 ratio to receive intravenous sibeprenlimab at a dose of 2, 4, or 8 mg per kilogram of body weight or placebo once monthly for 12 months. The primary end point was the change from baseline in the log-transformed 24-hour urinary protein-to-creatinine ratio at month 12. Secondary end points included the change from baseline in the estimated glomerular filtration rate (eGFR) at month 12. Safety was also assessed. RESULTS: Among 155 patients who underwent randomization, 38 received sibeprenlimab at a dose of 2 mg per kilogram, 41 received sibeprenlimab at a dose of 4 mg per kilogram, 38 received sibeprenlimab at a dose of 8 mg per kilogram, and 38 received placebo. At 12 months, the geometric mean ratio reduction (±SE) from baseline in the 24-hour urinary protein-to-creatinine ratio was 47.2±8.2%, 58.8±6.1%, 62.0±5.7%, and 20.0±12.6% in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. At 12 months, the least-squares mean (±SE) change from baseline in eGFR was -2.7±1.8, 0.2±1.7, -1.5±1.8, and -7.4±1.8 ml per minute per 1.73 m2 in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. The incidence of adverse events that occurred after the start of administration of sibeprenlimab or placebo was 78.6% in the pooled sibeprenlimab groups and 71.1% in the placebo group. CONCLUSIONS: In patients with IgA nephropathy, 12 months of treatment with sibeprenlimab resulted in a significantly greater decrease in proteinuria than placebo. (Funded by Visterra; ENVISION ClinicalTrials.gov number, NCT04287985; EudraCT number, 2019-002531-29.).

Effect of tirzepatide on albuminuria levels and renal function in patients with type 2 diabetes mellitus: A systematic review and multilevel meta-analysis.

AIM: The present systematic review aimed to summarize the available evidence from published randomized controlled trials (RCTs) regarding the effect of tirzepatide on albuminuria levels and renal function in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: Medline (via PubMed), Cochrane Library and Scopus were searched until 20 October 2023. Double-independent study selection, data extraction and quality assessment were performed. Evidence was pooled with a three-level mixed-effects meta-analysis. RESULTS: In total, 9533 participants from eight RCTs were analysed. All RCTs had a low risk of bias, according to the Cochrane Collaboration tool (RoB2). Tirzepatide was associated with a significantly greater reduction in urine albumin-to-creatinine ratio compared with controls [mean difference (MD) -26.9%; 95% confidence interval (CI) (-34.76, -19.04); p < .001; level of evidence (LoE) moderate]. This effect remained significant in participants with baseline urine albumin-to-creatinine ratio ≥30 mg/g [MD -41.42%; 95% CI (-54.38, -28.45); p < .001; LoE moderate]. Based on subgroup analysis, the comparative effect of tirzepatide was significant against placebo and the insulin regimen, whereas no difference was observed compared with semaglutide. The beneficial effect of tirzepatide on albuminuria levels remained significant across all investigated doses (5, 10 and 15 mg), showing a dose-response relationship. A neutral effect was observed on the estimated glomerular filtration rate [MD 0.39 ml/min/1.73m2 ; 95% CI (-0.64, 1.42); p = .46; LoE moderate]. CONCLUSION: Our findings suggest that tirzepatide probably leads to a significant reduction in albuminuria across all administered doses, while its use is associated with a neutral effect on creatinine clearance as a measure of renal function.

Urinary Apolipoprotein A1 and Neutrophil Gelatinase-associated Lipocalin in Children with Idiopathic Nephrotic Syndrome.

Urinary biomarkers are a promising diagnostic modality whose role was explored in nephrotic syndrome (NS). We estimated urinary apolipoprotein A1 (Apo A1) and neutrophil gelatinase-associated lipocalin (NGAL) in children with first-episode NS (FENS) and controls with a longitudinal follow-up to see the serial changes during remission. The study groups comprised 35 children with FENS and an equal number of age- and sex-matched controls. Patients were followed up at regular intervals, and 32 patients were classified as having steroid-sensitive NS (SSNS) and 3 as having steroid-resistant NS (SRNS). The mean follow-up period was 8.7 ± 4.2 months. Three patients in the SSNS group were labeled as having frequent relapses or steroid-dependent disease during follow-up. Of the three children with SRNS, two had minimal changes in the disease and one had idiopathic membranous nephropathy. The levels of Apo A1:creatinine, NGAL:creatinine, and spot urinary protein:urinary creatinine ratios were significantly higher in children with FENS compared with controls. The levels of the urine biomarkers decreased significantly at subsequent follow-up with remission. The Apo A1 and NGAL levels in SSNS patients were significantly high compared with both the controls and FENS patients. Urinary Apo A1 levels in SRNS patients were lower at initial presentation. This longitudinal study revealed changes in the urinary Apo A1 and NGAL in NS over the course of the disease.

Solvation Plays a Key Role in Antioxidant-Mediated Attenuation of Elevated Creatinine Level: An In Vitro Spectroscopic Investigation.

An elevated level of creatinine (CRN) is a mark of kidney ailment, and prolonged retention of such condition could lead to renal failure, associated with severe ischemia. Antioxidants are clinically known to excrete CRN from the body through urine, thereby reducing its level in blood. The molecular mechanism of such an exclusion process is still illusive. As the excretion channel is urine, solvation of the solute is expected to play a pivotal role. Here, we report a detailed time-domain and frequency-domain terahertz (THz) spectroscopic investigation to understand the solvation of CRN in the presence of two model antioxidants, mostly used to treat elevated CRN level: N-Acetyl-l-cysteine (NAC) and ascorbic acid (ASC). FTIR spectroscopy in the mid-infrared region and UV absorption spectroscopy measurements coupled with quantum chemical calculations [at the B3LYP/6-311G++(d,p) level] reveal that both NAC and ASC form HBonded complexes with CRN and rapidly undergo a barrier-less proton transfer process to form creatinium ions. THz measurements provide explicit evidence of the formation of highly solvated complexes compared with bare CRN, which eventually enables its excretion through urine. These observations could provide a foundation for designing more beneficial drugs to resolve kidney diseases..

The relationships between sediment findings and culture results and the presence of proteinuria in canine urine samples.

OBJECTIVES: To assess relationships between urine sediment and microbial culture findings and the presence of proteinuria in canine urine samples, and to assess the change in the percentage of proteinuric samples and urine protein-to-creatinine ratio when urine abnormalities resolve. MATERIALS AND METHODS: Canine urine samples collected via cystocentesis and submitted for culture and contemporaneous urinalysis (including urine protein-to-creatinine ratio) were retrospectively identified. Dogs receiving corticosteroids were excluded. Associations between haematuria (red blood cells>5/high-power field), pyuria (white blood cells>5/high-power field), presence of microorganisms on microscopy, active sediment, and positive culture and proteinuria (urine protein-to-creatinine ratio>0.5) were investigated. Patient characteristics were considered possible confounders. In dogs with repeat urinalysis, the associations between active sediment and positive culture resolution on proteinuria and urine protein-to-creatinine ratio were assessed. RESULTS: One hundred and ninety-two of 491 samples were proteinuric (39.1%). Age was positively associated with proteinuria. In the multivariable analysis corrected for age, active sediment was the only variable significantly associated with proteinuria (adjusted odds ratio: 2.12; 95% confidence interval: 1.44 to 3.11); however, only 49.8% of samples with active sediment were proteinuric. Neither resolution of active sediment nor positive culture were associated with reduced proportions of proteinuric samples (from 57.9% to 42.1% and from 40.0% to 25.0%, respectively) or significant reductions in urine protein-to-creatinine ratio (median change: -0.16 and -0.14, respectively). CLINICAL SIGNIFICANCE: Attributing proteinuria to urinalysis abnormalities or a positive urine culture in canine cystocentesis samples is not supported by our findings, and could result in alternative causes of proteinuria (e.g. renal proteinuria) being overlooked.

Association between 1-year changes in urinary albumin-to-creatinine ratio and kidney disease progression in Japanese individuals with diabetes: a historical cohort study.

BACKGROUND: The National Kidney Foundation recently proposed a ≥ 30% decrease in urinary albumin-to-creatinine ratio (UACR) over 0.5-2 years as a surrogate endpoint for chronic kidney disease (CKD) progression in individuals with baseline UACR > 30 mg/g. This historical cohort study aimed to determine the applicability of a decrease in UACR, within as little as 1 year, as a surrogate endpoint for Japanese individuals with type 2 diabetes mellitus (T2D). METHODS: A total of 5067 individuals with T2D were divided into three groups based on 1-year change in UACR: ≥ 30% decrease (UACR decreased group), < 30% decrease and < 30% increase (UACR unchanged group), or ≥ 30% increase (UACR increased group). The primary endpoint was a composite of a ≥ 30% decline in estimated glomerular filtration rate (eGFR) or the initiation of kidney replacement therapy, whichever occurred first. RESULTS: At baseline, the proportions of individuals with normoalbuminuria, microalbuminuria, and eGFR ≥ 60 mL/min/1.73 m2 were 68.1%, 22.1%, and 75.5%, respectively. During a median follow-up of 6.8 years, 926 individuals (18.3%) reached the composite endpoint. Adjusted hazard ratios (vs. the UACR unchanged group) for the UACR decreased and increased groups were 0.758 (95% confidence interval [CI], 0.636-0.905; P = 0.002) and 1.304 (95% CI, 1.108-1.536; P = 0.001), respectively. CONCLUSIONS: These findings support the use of 1-year changes in UACR as a surrogate endpoint for the progression of CKD and the implementation of a ≥ 30% decrease in UACR as a positive efficacy endpoint in Japanese individuals with T2D and early-stage kidney disease.

Endotoxic kidney injury in Beagle dogs assessed by serum creatinine and symmetric dimethylarginine, and urinary neutrophil gelatinase-associated lipocalin and clusterin.

Sepsis of Gram negative bacterial origin results in lipopolysaccharide-induced endotoxemia. This often leads to acute kidney injury (AKI) and its recognition remains a challenge and delays treatment. As renal damage occurs before a rise in serum creatinine is detected, new early biomarkers of kidney injury need to be explored. The aim of this study was to determine changes in serum parameters of renal function and urine biomarkers of renal injury. This was a descriptive study. Endotoxemia was induced intravenously in six anaesthetized Beagles (T1). To achieve normotension, dogs received fluids (T2), followed by a continuous infusion of noradrenaline and dexmedetomidine or 0.9% NaCl (T3). Ten minutes later, the dogs received fluids (T4) and noradrenaline and dexmedetomidine or 0.9% NaCl in a crossover manner (T5). At each timepoint, blood and urine were collected for serum creatinine, urea, symmetric dimethylarginine, urine protein/creatinine (UPC) ratio, urine neutrophil-gelatinase-associated lipocalin (U-NGAL), U-NGAL/creatinine ratio, urine clusterin (U-clusterin) and U-clusterin/creatinine ratio. Data were analyzed using a mixed-effect model taking into account time and stage of veterinary AKI (VAKI). Three of six dogs had a VAKI stage ≥1; one with anuria and elevated creatinine. Serum creatinine (P < 0.001), U-NGAL/creatinine ratio (P = 0.01) and U-clusterin/creatinine ratio increased over time (P < 0.01). The UPC ratio (mean (range) 0.68 (0.35-2.3) versus 0.39 (0.15-0.71) P < 0.01) and U-NGAL (3164 pg/mL (100-147,555) versus 100 (100-14,524), P = 0.01) were higher in VAKI stage ≥1 versus stage 0, respectively. Endotoxemia induced VAKI stage ≥1 in half of the dogs. Repeated measurement of selected parameters could detect AKI early.

A prediction model on incident chronic kidney disease among individuals with type 2 diabetes in the United States.

AIM: Early identification of incident chronic kidney disease (CKD) in individuals with diabetes may help improve patients' clinical outcomes. This study aimed to develop a prediction equation for incident CKD among people with type 2 diabetes (T2D). MATERIALS AND METHODS: A time-varying Cox model was applied to data from the ACCORD trial to predict the risk of incident CKD. A list of candidate variables was chosen based on literature reviews and experts' consultations, including demographic characteristics, vitals, laboratory results, medical history, drug use and health care utilization. Model performance was evaluated. Decomposition analysis was conducted, and external validation was performed. RESULTS: In total, 6006 patients with diabetes free of CKD were included, with a median follow-up of 3 years and 2257 events. The risk model included age at T2D diagnosed, smoking status, body mass index, high-density lipoprotein, very-low-density lipoprotein, alanine aminotransferase, estimated glomerular filtration rate, urine albumin-creatinine ratio, hypoglycaemia, retinopathy, congestive heart failure, coronary heart disease history, antihyperlipidaemic drug use, antihypertensive drug use and hospitalization. The urine albumin-creatinine ratio, estimated glomerular filtration rate and congestive heart failure were the top three factors that contributed most to the incident CKD prediction. The model showed acceptable discrimination [C-statistic: 0.772 (95% CI 0.767-0.805)] and calibration [Brier Score: 0.0504 (95% CI 0.0477-0.0531)] in the Harmony Outcomes Trial. CONCLUSION: Incident CKD prediction among individuals with T2D was developed and validated for use in decision support of CKD prevention.

Comparison of cystocentesis versus home sampling to determine urinary protein: Creatinine ratio and urine specific gravity in cats.

BACKGROUND: Urinalysis is necessary for the diagnostic evaluation of chronic kidney disease in cats. Performing cystocentesis is not always feasible, but data comparing urine obtained by cystocentesis in the clinic with voided samples collected at home are lacking in cats. OBJECTIVES: To compare urinary protein:creatinine ratio (UPC) and urine specific gravity (USG) and to detect clinically relevant changes in proteinuria substage or urine concentration between urine collected at home and in-clinic by cystocentesis in cats. ANIMALS: Ninety-two healthy and diseased client-owned cats. METHODS: Prospective study. Owners collected voided urine at home and within 1 to 15 hours, cystocentesis was performed in the clinic. RESULTS: In a subset of motivated owners, 55% succeeded in collecting urine at home. Overall, UPC was higher (mean ±SD difference = 0.09 ±0.22; P < .001) and USG was lower (mean ±SD difference = -0.006 ±0.009; P < .001) in cystocentesis samples than in voided urine. Substantial agreement existed between sampling methods for UPC (weighted к = 0.68) and USG (к = 0.64) categories. A different proteinuria substage (UPC < 0.2, 0.2-0.4, >0.4) was present in paired urine samples from 28% of cats. In 18% of cats, urine concentrating ability (USG < or ≥1.035) differed between both samples. CONCLUSIONS AND CLINICAL IMPORTANCE: Home sampling of urine is a valid alternative to cystocentesis in cats. However, because clinically relevant differences in UPC and USG were present in 28% and 18% of cats, respectively, by the same collection method for monitoring each cat is advised.

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial.

BACKGROUND: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. METHODS: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to <60 mL/min per 1·73 m2 and ≥60 mL/min per 1·73 m2) and urine protein excretion at screening (≤1·75 g/day and >1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. FINDINGS: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. INTERPRETATION: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. FUNDING: Travere Therapeutics.

Total urinary polyphenol excretion: a biomarker of an anti-inflammatory diet and metabolic syndrome status.

BACKGROUND: Chronic inflammation is associated with noncommunicable diseases, including obesity, metabolic syndrome (MetS), and CVDs. The Mediterranean diet has been shown to have strong anti-inflammatory effects, attributed in part to the polyphenol richness of many of its components. OBJECTIVES: This study aimed to assess the value of polyphenols as a urinary biomarker of an anti-inflammatory diet and their influence on MetS status. METHODS: A longitudinal analysis was performed in Spain considering 543 participants with high CVD risk in a PREDIMED study. Approximately 52% of the participants were women and 48% were men with a mean age of 67.5 (5.9) y. Total polyphenol excretion (TPE) in urine was determined at baseline and 5 y of intervention using a validated Folin-Ciocalteu spectrophotometric method, and the dietary inflammatory index (DII) was calculated from a validated 137-item food-frequency questionnaire. Three categories were built according to tertiles of change in the DII score. Multivariable linear regression analyses were performed to assess the association of changes in TPE with changes in the DII scores and with MetS status at 5 y. RESULTS: Tertiles 2 and 3 compared with tertile 1 presented a lower anti-inflammatory potential of the diet and were inversely associated with TPE in women [-0.30 mg gallic acid equivalent (GAE)/g creatinine; 95% CI: -0.46, -0.15; P value = 0.006 and -0.29 mg GAE/g creatinine; 95% CI: -0.43, -0.15; P value = 0.005], respectively. The mean changes in TPE were 7.9 (56.1) mg GAE/g creatinine in women and 7.7 (48.2) mg GAE/g creatinine in men. In addition, TPE was inversely associated with changes in MetS status [-0.06 (-0.09; -0.02), P value = 0.009] in both men and women. CONCLUSIONS: Urinary polyphenols may be a potential biomarker of anti-inflammatory diet consumption in women and are prospectively associated with improvement in MetS.