Urine Biomarkers of Kidney Tubule Health and Risk of Incident CKD in Persons Without Diabetes: The ARIC, MESA, and REGARDS Studies.

Rationale & Objective: Tubulointerstitial damage is a feature of early chronic kidney disease (CKD), but current clinical tests capture it poorly. Urine biomarkers of tubulointerstitial health may identify risk of CKD. Study Design: Prospective cohort (Atherosclerosis Risk in Communities [ARIC]) and case-cohort (Multi-Ethnic Study of Atherosclerosis [MESA] and Reasons for Geographic and Racial Differences in Stroke [REGARDS]). Setting & Participants: Adults with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and without diabetes in the ARIC, REGARDS, and MESA studies. Exposures: Baseline urine monocyte chemoattractant protein-1 (MCP-1), alpha-1-microglobulin (α1m), kidney injury molecule-1, epidermal growth factor, and chitinase-3-like protein 1. Outcome: Incident CKD or end-stage kidney disease. Analytical Approach: Multivariable Cox proportional hazards regression for each cohort; meta-analysis of results from all 3 cohorts. Results: 872 ARIC participants (444 cases of incident CKD), 636 MESA participants (158 cases), and 924 REGARDS participants (488 cases) were sampled. Across cohorts, mean age ranged from 60 ± 10 to 63 ± 8 years, and baseline eGFR ranged from 88 ± 13 to 91 ± 14 mL/min/1.73 m2. In ARIC, higher concentrations of urine MCP-1, α1m, and kidney injury molecule-1 were associated with incident CKD. In MESA, higher concentration of urine MCP-1 and lower concentration of epidermal growth factor were each associated with incident CKD. In REGARDS, none of the biomarkers were associated with incident CKD. In meta-analysis of all 3 cohorts, each 2-fold increase α1m concentration was associated with incident CKD (HR, 1.19; 95% CI, 1.08-1.31). Limitations: Observational design susceptible to confounding; competing risks during long follow-up period; meta-analysis limited to 3 cohorts. Conclusions: In 3 combined cohorts of adults without prevalent CKD or diabetes, higher urine α1m concentration was independently associated with incident CKD. 4 biomarkers were associated with incident CKD in at least 1 of the cohorts when analyzed individually. Kidney tubule health markers might inform CKD risk independent of eGFR and albuminuria.

This study analyzed 3 cohorts (ARIC, MESA, and REGARDS) of adults without diabetes or prevalent chronic kidney disease (CKD) to determine the associations of 5 urinary biomarkers of kidney tubulointerstitial health with incident CKD, independent of traditional measures of kidney health. Meta-analysis of results from all 3 cohorts suggested that higher baseline levels of urine alpha-1-microglobulin were associated with incident CKD at follow-up. Results from individual cohorts suggested that in addition to alpha-1-microglobulin, monocyte chemoattractant protein-1, kidney injury molecule-1, and epidermal growth factor may also be associated with the development of CKD. These findings underscore the importance of kidney tubule interstitial health in defining risk of CKD independent of creatinine and urine albumin.

Effect of access sheath diameter used in percutaneous nephrolithotomy on renal function: a prospective randomized study.

We aimed to determine the effect of the access sheath diameter used in percutaneous nephrolithotomy (PNL) on renal function. We also investigated the predictors of impaired renal function. Data were prospectively collected from patients who underwent PNL from December 2020 to December 2021. The patients were randomized into two groups according to access sheath diameter: Group 1 (22 Fr, n = 44) and Group 2 (28 Fr, n = 44). Relative renal function (RRF) was calculated by technetium-99 m dimercaptosuccinic acid scintigraphy, and glomerular filtration rate (GFR) was calculated by diethylenetriamine pentaacetic acid scintigraphy. A difference of 5% or more in RRF was considered a significant functional change. Preoperative and postoperative Kidney Injury Molecule-1 (KIM-1) levels were measured. Preoperative demographic data and stone characteristics were similar between the groups. There were also no statistically significant differences between the groups in terms of scar development, changes in RRF, GFR, or KIM-1/creatinine (Cr) (p > 0.05). Significant deterioration in RRF was detected in a total of six (6.8%) patients, three in each group. The factors predicting loss of function were analyzed by regrouping the patients without loss of function as Group A (n = 82) and those with loss as Group B (n = 6). Only stone volume was statistically significant in multivariate analysis (p = 0.002). Access sheath diameter had no significant effect on renal function after PNL. However, the stone volume was found to independently correlate to a loss of renal function after PNL.

Magnitude of Urine Albumin and KIM-1 Changes Can be Used to Differentiate Glomerular Injury From Tubular Injury in Rats.

Emerging urinary kidney safety biomarkers have been evaluated in recent years and have been shown to be superior to the serum parameters blood urea nitrogen (BUN) and creatinine (sCr) for monitoring kidney injury in the proximal tubule. However, their potential application in differentiating the location of the initial kidney injury (eg, glomerulus vs tubule) has not been fully explored. Here, we assessed the performance of two algorithms that were constructed using either an empirical or a mathematical model to predict the site of kidney injury using a data set consisting of 22 rat kidney toxicity studies with known urine biomarker and histopathologic outcomes. Two kidney safety biomarkers used in both models, kidney injury molecule 1 (KIM-1) and albumin (ALB), were the best performers to differentiate glomerular injury from tubular injury. The performance of algorithms using these two biomarkers against the gold standard of kidney histopathologic examination showed high sensitivity in differentiating the location of the kidney damage to either the glomerulus or the proximal tubules. These data support the exploration of such an approach for use in clinical settings, leveraging urinary biomarker data to aid in the diagnosis of either glomerular or tubular injury where histopathologic assessments are not conducted.

The Influence of Tacrolimus Exposure and Metabolism on the Outcomes of Kidney Transplants.

Tacrolimus (TAC) has a narrow therapeutic window and patient-specific pharmacokinetic variability. In our study, we analyzed the association between TAC exposure, metabolism, and kidney graft outcomes (function, rejection, and histological lesions). TAC trough (C0), coefficient of variation (TAC CV), concentration/dose ratio (C/D), and biomarkers related to kidney injury molecule-1 (KIM-1) and neutrophil gelatinase lipocalin (NGAL) were analyzed. We examined 174 patients who were subjected to a triple immunosuppressive regimen and underwent kidney transplantation between 2017 and 2022. Surveillance biopsies were performed at the time of kidney implantation and at three and twelve months after transplantation. We classified patients based on their Tac C/D ratios, classifying them as fast (C/D ratio < 1.05 ng/mL × 1/mg) or slow (C/D ratio ≥ 1.05 ng/mL × 1/mg) metabolizers. TAC exposure/metabolism did not significantly correlate with interstitial fibrosis/tubular atrophy (IF/TA) progression during the first year after kidney transplantation. TAC CV third tertile was associated with a higher chronicity score at one-year biopsy. TAC C/D ratio at three months and Tac C0 at six months were associated with rejection during the first year after transplantation. A fast TAC metabolism at six months was associated with reduced kidney graft function one year (OR: 2.141, 95% CI: 1.044-4.389, p = 0.038) and two years after transplantation (OR: 4.654, 95% CI: 1.197-18.097, p = 0.026), and TAC CV was associated with reduced eGFR at three years. uNGAL correlated with IF/TA and chronicity scores at three months and negatively correlated with TAC C0 and C/D at three months and one year. Conclusion: Calculating the C/D ratio at three and six months after transplantation may help to identify patients at risk of suffering acute rejection and deterioration of graft function.

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.

Comparison of Urinary Biomarkers in Diagnosis of Ureteropelvic Junction Obstruction and Differentiation from Nonobstructive Dilatation.

Background and Aims: Differentiation of nonobstructive dilatation (NOD) from ureteropelvic junction obstruction (UPJO) is a challenge in children with antenatally detected hydronephrosis. The aim of this study is to compare the utility of urinary biomarkers: carbohydrate antigen (CA 19-9), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule (KIM) in diagnosing UPJO. Methods: A prospective study was conducted after obtaining ethical clearance between 2021 and 2022. Group 1 - control group (n = 30): children with normal antenatal ultrasound with no urinary symptoms. Group 2 - study group (n = 48): children with unilateral hydronephrosis: Group 2a - NOD (n = 24): children stable on ultrasound and diuretic renogram and Group 2b - UPJO (n = 24): children who worsened to Grade 4 hydronephrosis on ultrasound/worsening of differential renal function (10% drop) on renogram who underwent pyeloplasty. Urinary biomarkers NGAL, KIM-1, and CA 19-9 were measured using the enzyme-linked immune absorbent assay method. Results: The urine CA 19-9 level was 128.05 ± 4.08 U/mL in the UPJO group, and this was significantly higher (P = 0.001) than NOD, 70.29 ± 4.41, and controls, 1.91 ± 1.57. The urine NGAL level was 21.41 ± 4.44 pg/mL in UPJO, and this was significantly higher than controls, 2.669 ± 0.513, but not NOD, 24.55 ± 2.67. The urine KIM level was 817 ± 15.84 pg/mL in the UPJO group, and this was significantly higher than controls, 285 ± 8.10, but not NOD, 768.23 ± 15.12. Receiver operating characteristic analysis of CA 19-9 revealed a urine biomarker cutoff of 95 U/mL for diagnosing UPJO (sensitivity 95%; specificity 96%; and area under the curve 0.99). Conclusions: CA 19-9 is a superior marker compared to NGAL and KIM in differentiating UPJO from NOD. Further studies with larger numbers are warranted.

Prognostic Biomarkers and AKI: Potential to Enhance the Identification of Post-Operative Patients at Risk of Loss of Renal Function.

Acute kidney injury (AKI) is a common complication after surgery and the more complex the surgery, the greater the risk. During surgery, patients are exposed to a combination of factors all of which are associated with the development of AKI. These include hypotension and hypovolaemia, sepsis, systemic inflammation, the use of nephrotoxic agents, tissue injury, the infusion of blood or blood products, ischaemia, oxidative stress and reperfusion injury. Given the risks of AKI, it would seem logical to conclude that early identification of patients at risk of AKI would translate into benefit. The conventional markers of AKI, namely serum creatinine and urine output are the mainstay of defining chronic kidney disease but are less suited to the acute phase. Such concerns are compounded in surgical patients given they often have significantly reduced mobility, suboptimal levels of nutrition and reduced muscle bulk. Many patients may also have misleadingly low serum creatinine and high urine output due to aggressive fluid resuscitation, particularly in intensive care units. Over the last two decades, considerable information has accrued with regard to the performance of what was termed "novel" biomarkers of AKI, and here, we discuss the most examined molecules and performance in surgical settings. We also discuss the application of biomarkers to guide patients' postoperative care.

Kidney damage is common after major surgery with a recent study showing almost 1 in 5 patients suffer kidney damage. The usual tests for measuring kidney function are excellent in the outpatient but not so good in acute scenario's. Therefore, there has been a lot of interest in new markers of kidney damage (so-called novel biomarkers) which perform well acutely and allow earlier detection of damage allowing treatment to be started earlier. This article summarises the currently available biomarkers for use post-operatively and points out the different information that can be achieved by using them routinely.

The Value of Urinary NGAL, KIM-1, and IL-18 Measurements in the Early Detection of Kidney Injury in Oncologic Patients Treated with Cisplatin-Based Chemotherapy.

Cisplatin is still a widely used anticancer drug characterized by significant nephrotoxicity. Acute kidney injury (AKI), diagnosed based on the Kidney Disease: Improving Global Outcomes (KDIGO) criteria, has limitations, including a delayed increase in creatinine. We determined the usefulness of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18) in diagnosing AKI according to the KDIGO criteria in patients treated with cisplatin. We recruited 21 subjects starting cisplatin-based chemotherapy (Cisplatin-based group) and 11 treated with carboplatin-based chemotherapy or 5-fluorouracil regimens (non-cisplatin-based group). Blood and urine samples were collected during four subsequent cycles of chemotherapy (68 and 38 cycles, respectively). AKI occurred in four patients in the cisplatin-based group (5.9% of 68 cisplatin-based chemotherapy cycles). Among them, three urinary markers were increased by over 100% in two cases, two in one case and one in another. A doubling of at least one investigated parameter was observed more frequently during cisplatin-based chemotherapy (80.3% vs. 52.8%; OR = 3.65, 95% CI: 1.49-8.90; p < 0.01). The doubling of at least one new urinary AKI marker was more common in patients receiving cisplatin and frequently was not associated with overt AKI. Thus, a subclinical kidney injury detected by these markers occurs more frequently than deterioration in kidney function stated with creatinine changes.

Biomarkers for Diabetic Nephropathy with a Focus on Kidney Injury Molecule-1 (KIM-1).

Diabetic Nephropathy (DN), with an increasing rate of mortality and morbidity, is considered the main cause of End-Stage Renal Disease (ESRD). A wide spectrum of biomarkers exist for early detection of DN, but they suffer from low specificity and sensitivity, indicating the urgent demand for finding more effective biomarkers. Also, the pathophysiology of tubular damage and its relation to DN are not yet completely understood. Kidney Injury Molecule-1 (KIM-1) is a protein that is expressed at substantially low contents in the kidney under physiological conditions. A number of reports have demonstrated the close relationship between urine and tissue KIM-1 levels and kidney disorders. KIM-1 is known as a biomarker for diabetic nephropathy and renal injury. In this study, we aim to review the potential clinical and pathological roles of KIM-1 in diabetic nephropathy.

Moringa oleifera leaves extract loaded gold nanoparticles offers a promising approach in protecting against experimental nephrotoxicity.

Cisplatin is one of the most important antitumor drugs, however; it has numerous adverse effects like nephrotoxicity which is considered one of cisplatin uses . The study was planned to evaluate the nephroprotective effect of M. oleifera leaves extract loaded gold nanoparticles (Au-NPs) against cisplatin-induced nephrotoxicity in rats. Initially, total phenolic contents (TPC) and the antioxidant activity of the M. oleifera leaves extract were evaluated and recorded 8.50 mg/g and 39.89 % respectively. After that, the dry leaves of M. oleifera were grinded into fine powder and extracted using water extraction system. Then, different volumes (0.5, 1 and 2 mL) of M. Oleifera were blended with constant volume of Au-NPs (1 mL). Both Au-NPs and M. oleifera extract loaded Au-NPs were investigated using transmission electron microscope (TEM) that illustrated the deposition of M. Oleifera onto Au-NPs. The experimental study was performed on seventy male albino rats alienated into seven groups. Group I healthy rats, group II injected with one dose of cisplatin (CisPt), groups from III to VII treated groups received CisPt then received M. Oleifera leaves extract alone and /or Au-NPs with different ratios and concentrations. After the experiment' time, serum urea and creatinine, kidney injury molecule-1 (KIM-1), advanced oxidation protein products (AOPP), monocyte chemoattractant protein-1 (MCP-1), tumor necrotic factor-α (TNF-α), and interleukin-6 (IL-6) were evaluated as markers of renal nephrotoxicity. The kidneys of rats were excised for malondialdehyde (MDA), nitric oxide (NO), and superoxide dismutase (SOD) assessments. Induction of CisPt showed a highly significant disturbance in oxidant/anti-oxidant balance and inducing inflammatory cascades supporting nephrotoxicity, while treatment with M. Oleifera leaves extract, Au-NPs, and the different concentrations of the extract loaded on Au-NPs had a crucial role in attenuating oxidative stress, enhancing antioxidant systems, and reducing inflammatory biomarkers, although the most significant results showed a powerful scavenging activity against nephrotoxicity induced by CisPt was obtained with M. Oleifera leaves extract loaded on Au-NPs with a concentration of 2:1 respectively.

No impact of a high-fat meal coupled with intermittent hypoxemia on acute kidney injury biomarkers in adults with and without obstructive sleep apnea.

Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxemia, which is associated with progressive loss of kidney function, where postprandial fluctuations in renal physiology may further compromise oxygen supply and kidney function. Therefore, we measured biomarkers of acute kidney injury (AKI) following a high-fat meal with and without intermittent hypoxemia. Eighteen healthy young men (mean age [SD]: 22.7 years [3.1]) and seven middle-aged to older individuals with OSA (54.4 years [6.4]) consumed a high-fat meal during normoxia or intermittent hypoxemia (~15 hypoxic cycles per hour, ~85% oxyhemoglobin saturation) for 6 h. We observed no changes in estimated glomerular filtration rate and plasma concentrations of creatinine, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) at any measured time points. In both groups, plasma concentrations of interleukin-18 (IL-18) increased after 6 h during normoxia only (p = 0.033, ηp 2 = 0.122), and plasma concentrations of liver-type fatty acid-binding protein (L-FABP) transiently decreased after 3 h in both conditions (p = 0.008, ηp 2 = 0.152). These findings indicate that AKI biomarkers are not acutely elevated during the postprandial state with or without intermittent hypoxemia, suggesting that other mechanisms may play more important roles in the progression of kidney disease in OSA.

Expression and Significance of KIM-1, NGAL, and HO-1 in Patients with Acute Kidney Injury After Cardiac Valve Replacement.

Objective: To investigate the changes and significance of perioperative expression levels of kidney injury molecule-1 (KIM-1), neutrophil gelatinase-related lipocalin (NGAL), and heme oxygenase-1 (HO-1) in patients with acute kidney injury (AKI) after cardiac valve replacement under cardiopulmonary bypass. Methods: A total of 80 patients were divided into the AKI group and non-AKI group based on the postoperative occurrence of AKI. The expression levels of urinary KIM-1, NGAL, serum creatinine, urea nitrogen, and HO-1 were compared between the two groups before surgery and at 12 h, 24 h, and 48 h after surgery. Results: There were 22 patients with postoperative AKI (AKI group), the incidence of postoperative AKI were 27.5%, and there were 58 patients without AKI (non-AKI group). There was no significant difference in general clinical data between the two groups (P > 0.05). Compared between AKI group and preoperative group, KIM-1, NGAL, HO-1, blood creatinine, and BUN levels were significantly increased, with significant differences (P < 0.05). Compared with non-AKI groups, KIM-1, NGAL, HO-1, blood creatinine, and blood urea nitrogen levels increased at all time points, but the difference was not significant (P > 0.05). Compared with AKI group and non-AKI group, KIM-1, NGAL, HO-1, blood creatinine, and BUN levels increased significantly, the differences were statistically significant (P < 0.05). Conclusion: AKI can easily occur after cardiac valve replacement and postoperative expression levels of KIM-1, NGAL, and HO-1 can be early warning indicators of postoperative AKI.

Acute kidney injury biomarkers and hydration assessments following prolonged mild hypohydration in healthy young adults.

The high prevalence of inadequate hydration (e.g., hypohydration and underhydration) is concerning given that extreme heat increases excess hospitalizations for fluid/electrolyte disorders and acute kidney injury (AKI). Inadequate hydration may also be related to renal and cardiometabolic disease development. This study tested the hypothesis that prolonged mild hypohydration increases the urinary AKI biomarker product of insulin-like growth factor-binding protein 7 and tissue inhibitor of metalloproteinase-2 ([IGFBP7·TIMP-2]) compared with euhydration. In addition, we determined the diagnostic accuracy and optimal cutoffs of hydration assessments for discriminating positive AKI risk ([IGFBP·TIMP-2] >0.3 (ng/mL)2/1,000). In a block-randomized crossover design, 22 healthy young adults (11 females and 11 males) completed 24 h of fluid deprivation (hypohydrated group) or 24 h of normal fluid consumption (euhydrated group) separated by ≥72 h. Urinary [IGFBP7·TIMP-2] and other AKI biomarkers were measured following the 24-h protocols. Diagnostic accuracy was assessed via receiver operating characteristic curve analysis. Urinary [IGFBP7·TIMP-2] [1.9 (95% confidence interval: 1.0-2.8) vs. 0.2 (95% confidence interval: 0.1-0.3) (ng/mL)2/1,000, P = 0.0011] was markedly increased in hypohydrated versus euhydrated groups. Urine osmolality (area under the curve: 0.91, P < 0.0001) and urine specific gravity (area under the curve: 0.89, P < 0.0001) had the highest overall performance for discriminating positive AKI risk. Optimal cutoffs with a positive likelihood ratio of 11.8 for both urine osmolality and specific gravity were 952 mosmol/kgH2O and 1.025 arbitrary units. In conclusion, prolonged mild hypohydration increased urinary [IGFBP7·TIMP-2] in males and females. Urinary [IGFBP7·TIMP-2] corrected to urine concentration was elevated in males only. Urine osmolality and urine specific gravity may have clinical utility for discriminating positive AKI risk following prolonged mild hypohydration.NEW & NOTEWORTHY This study found that prolonged mild hypohydration in healthy young adults increased the Food and Drug Administration approved acute kidney injury (AKI) biomarker urinary insulin-like growth factor-binding protein 7 and tissue inhibitor of metalloproteinase-2 [IGFBP7·TIMP-2]. Urine osmolality and specific gravity demonstrated an excellent ability to discriminate positive AKI risk. These findings emphasize the importance of hydration in protecting renal health and lend early support for hydration assessment as an accessible tool to assess AKI risk.

Acute Kidney Injury after Multiple Cycles of Cisplatin Chemotherapy: A Nomogram for Risk Assessment.

INTRODUCTION: Acute kidney injury (AKI) caused by cisplatin is common and has a higher incidence of multiple use, resulting in a poor short- and long-term prognosis for patients. There is currently no good premedication AKI risk assessment tool. The aim of this study was to establish an AKI risk assessment nomogram for patients with multiple cisplatin applications. METHODS: This study was a retrospective analysis of patients who were treated with non-first-time cisplatin chemotherapy regimen at Changzhou Second People's Hospital affiliated to Nanjing Medical University from January 2016 to January 2022. All data from the development group were used to screen the impact factors of AKI via univariate and multivariate analyses. A nomogram was developed based on these impact factors and verified with verification group. The area under the curve (AUC) of receiver operating characteristic (ROC) curve, calibration curves, and decision curve analyses (DCAs) were used to evaluate the nomogram. RESULTS: Among the 256 patients enrolled in 450 cycles of chemotherapy, 282 were in the development cohort (97 AKI), and 168 were in the validation cohort (61 AKI). Multivariate logistic regression revealed that age, hypertension, diabetes, serum cystatin C (sCysC), urinary kidney injury molecule-1 (uKim1), and a single dose of cisplatin were independently associated with AKI. The results showed that our model yielded satisfied diagnostic performance with an AUC value of 0.887 and 0.906 using the development group and on verification group. The calibration plots and DCA showed the superior clinical applicability of the nomogram. These results were verified in the validation cohort. CONCLUSION: A nomogram combining functional (sCysC) and tubular (uKim1) injury biomarkers with conventional clinical factors might assess the risk of AKI after multiple cycles of cisplatin chemotherapy.

Low level mancozeb exposure causes copper bioaccumulation in the renal cortex of rats leading to tubular injury.

Mancozeb is a widely-used, broad-spectrum contact dithiocarbamate fungicide. Dithiocarbamates are known to trans-chelate metals. This study was designed to evaluate the potential of Mancozeb to mobilize and bioaccumulate essential trace metals in various tissues. Long-Evans rats were orally gavaged with 0, 50, or 100 mg/kg/day of Mancozeb for 28 days. Mancozeb caused a significant increase in copper and manganese in the hippocampus and manganese in the liver. Exceedingly higher level of copper was detected in the renal cortex using ICP-OES in both dose groups. This was confirmed histologically in the tubular epithelial cells. In addition, copper-associated protein levels were also increased. Copper bioaccumulation in the renal cortex was accompanied by oxidative damage and tubular insult indicated by increased 4-HNE, KIM-1, and NGAL immunoreactivity. These findings demonstrate that low-dose Mancozeb exposure is a potential risk for kidney injury due to copper overload and warrants further in vivo and human population-based investigations.

Regulation of PKC/TLR-4/NF-kB signaling by sulbutiamine improves diabetic nephropathy in rats.

One of the serious complications of diabetes mellitus is diabetic nephropathy (DN) which may finally lead to renal failure. The current study aimed to explore the effect of sulbutiamine, a synthetic derivative of vitamin B1, in streptozotocin (STZ)-induced DN and related pathways. Experimental DN was successfully induced 8 weeks after a single low dose of STZ (45 mg/kg, I.P.). Four groups of rats were used in this study and divided randomly into: control group, diabetic group, sulbutiamine control (control + sulbutiamine) group, and sulbutiamine-treated (60 mg/kg) (diabetic + sulbutiamine) group. The fasting blood glucose level (BGL), the levels of kidney injury molecule-1 (Kim-1), urea and creatinine in serum, as well as the renal content of malondialdehyde (MDA), protein kinase C (PKC), toll-like receptor-4 (TLR-4) and nuclear factor kappa B (NF-κB) were determined. Additionally, tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and transforming growth factor-ß1 (TGF-ß1) contents were evaluated immunohistochemically. Sulbutiamine treatment decreased fasting BGL and improved the kidney function tests compared to diabetic rats. Moreover, TLR-4, NF-κB, MDA and PKC contents were substantially reduced following sulbutiamine treatment compared to the diabetic group. Sulbutiamine managed to obstruct the production of the pro-inflammatory TNF-α and IL-1ß and suppressed TGF-ß1 level, in addition to attenuating the histopathological changes associated with DN. This study revealed, for the first time, the ability of sulbutiamine to ameliorate STZ-induced diabetic nephropathy in rats. This nephroprotective outcome of sulbutiamine against DN may be attributed to glycemic control in addition to its anti-oxidative, anti-inflammatory and anti-fibrotic effects.

Urinary KIM-1 is not correlated with gestational age among 5-year-old children born prematurely.

Background: Preterm birth is associated with decreased nephron endowment. Currently, there is no reliable non-invasive biomarker to identify or monitor decreased nephron number in at-risk patients. Urinary Kidney Injury Molecule-1 (KIM-1) is a biomarker of acute and chronic renal injury. We measured urinary KIM-1 among a wide array of other potential biomarkers. Methods: We conducted an ambispective cohort study of 5-years-old children born prematurely and healthy controls identified from city schools. Detailed anthropometrics, renal ultrasound dimensions, and biochemical parameters were measured. Urinary KIM-1 was measured using Luminex® technology. Age independent z-scores were calculated and compared. Spearman correlations were used for estimating the association between measures and KIM-1. Results: We enrolled 129 children, 97 (75.2%) born pre-term and 32 (24.8%) healthy controls born at full-term. Pre-term patients had significantly lower weight and body surface area than controls. Pre-term patients and controls did not differ in current age, sex, race, height, blood pressure, urinary sodium, fractional sodium excretion, serum creatinine and estimated GFR. All spearman correlation between KIM-1 and gestational age, renal and serum measurements were weak without statistical significance. Conclusion: In 5-year-old children born prematurely, KIM-1 was not correlated with gestational age. Further prospective studies need to confirm this finding.

Early-Onset albuminuria and Associated Renal Pathology in Leucine-Rich Repeat Kinase 2 Knockout Rats.

Activating mutations of the leucine-rich repeat kinase 2 (LRRK2) gene are associated with Parkinson disease (PD), prompting development of LRRK2 inhibitors as potential treatment for PD. However, kidney safety concerns have surfaced from LRRK2 knockout (KO) mice and rats and from repeat-dose studies in rodents administered LRRK2 inhibitors. To support drug development of this therapeutic target, we conducted a study of 26 weeks' duration in 2-month-old wild-type and LRRK2 KO Long-Evans Hooded rats to systematically examine the performance of urinary safety biomarkers and to characterize the nature of the morphological changes in the kidneys by light microscopy and by ultrastructural evaluation. Our data reveal the time course of early-onset albuminuria at 3 and 4 months in LRRK2 KO female and male rats, respectively. The increases in urine albumin were not accompanied by concurrent increases in serum creatinine, blood urea nitrogen, or renal safety biomarkers such as kidney injury molecule 1 or clusterin, although morphological alterations in both glomerular and tubular structure were identified by light and transmission electron microscopy at 8 months of age. Diet optimization with controlled food intake attenuated the progression of albuminuria and associated renal changes.

Urinary levels of kidney injury molecule-1 (KIM-1) and interleukin-18 (IL-18) in children and adolescents with hyperuricemia.

PURPOSE: Hyperuricemia may lead to silent tissue damage and increase the risk of some diseases, including kidney diseases. Increased serum uric acid concentration induces inflammatory pathways and promotes kidney damage. This study aimed to determine whether hyperuricemia influences the levels of urinary kidney injury markers in children and adolescents with hyperuricemia, assessed by the urinary concentrations of interleukin-18, a biomarker of inflammation, and kidney injury molecule-1 (KIM-1), a biomarker of kidney injury. MATERIAL AND METHODS: The study included 73 children and adolescents (32 males and 41 females) aged 2-18 years. They were divided into two groups: hyperuricemia (HU) group (n â€‹= â€‹48) and normouricemia - reference group (R) (n â€‹= â€‹25). The concentrations of urinary interleukin-18 and KIM-1 were measured using an ELISA kit and were normalized for urinary creatinine (cr.) concentration. RESULTS: The median interleukin-18/cr. Levels in the HU group were significantly higher than in the R group (median, Q1-Q3) 21.83 (11.32-35.96) and 12.68 (7.11-24.04), respectively, (p â€‹< â€‹0.05). The KIM-1/cr. in the HU group and the R group were (median, Q1-Q3) 0.79 (0.45-1.03) and 0.81 (0.59-1.01), respectively, and the difference was not significant. KIM-1/cr. did not differ between the groups. Interleukin-18/cr. ratio correlated positively with serum uric acid concentration (r â€‹= â€‹0.24, p â€‹< â€‹0.05). CONCLUSIONS: Interleukin-18/cr., but not KIM-1/cr. was higher in children with hyperuricemia. Hyperuricemia results in increased IL-18 in urine, in absence of other markers of kidney injury, suggesting inflammation in the kidney. Additional studies on the adults should be done, to confirm this hypothesis.

Immunohistochemical Panels to Evaluate Important Immunophenotypes of Human Mesonephros.

Background. The immunophenotypes and potential excretory function of human mesonephros are not well studied. Methods. Five mesonephros specimens of human embryos from the 6th to 10th weeks of gestation were stained with immunohistochemical markers. Results. PAX8 was universally expressed in all renal tubules, while α-methyacyl-CoA racemase (AMACAR) was positive in proximal tubules and GATA3 was positive in distal tubular mesonephric structures. At the 8th weeks of gestation, the mesonephric glomeruli were characterized by opened glomerular capillary loops with Periodic Acid Schiff (PAS)-positive glomerular basement membranes and GATA3-positive mesangial-like cells. By the 8th week, proximal tubules showed PAS-positive brush borders, indicating reabsorption capacity, and the proximal tubules also demonstrated positivity with kidney injury molecule-1 (KIM-1), representing tubular response to injury. Conclusion. Our overall findings show detailed phenotypes of the glomerular and tubular structures of the mesonephros and indicate that at the 8th week of gestation, the mesonephros may carry out temporary excretory function before metanephros becomes fully functional.