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Background: Acromegaly is a rare disorder caused by excessive growth hormone (GH) secreted from a pituitary tumor. High levels of GH and insulin growth factor-1 can lead to renal hypertrophy, as well as to diabetes mellitus and hypertension, which negatively impact kidney function. It is believed that high GH may also be involved in the onset of diabetic nephropathy, the main cause of end-stage kidney disease in developed countries. Material and methods: This case–control study was conducted on 23 acromegalic patients and on a control group represented by 21 healthy subjects. The following parameters were determined for all the subjects: serum creatinine, serum urea, estimated glomerular filtration rate (eGFR), urinary albumin/creatinine ratio (UACR), nephrin and kidney injury molecule 1 (KIM-1). Results: Patients with acromegaly showed higher levels of UACR and lower levels of eGFR as compared to healthy subjects. No significant correlations were found between clinical or biochemical parameters associated with acromegaly and nephrin or KIM-1. Conclusions: There was no glomerular or proximal tubular damage at the time of the study, as proven by the normal levels of the biomarkers nephrin and KIM-1. Studies including more patients with uncontrolled disease are needed to clarify the utility of nephrin and KIM-1 for the detection of early kidney involvement in acromegalic patients.

Comorbidities associated with obesity, including diabetes and kidney diseases, greatly increase mortality rates and healthcare costs in obese patients. Studies in animal models and clinical trials have demonstrated that L-serine supplementation is a safe and effective therapeutic approach that ameliorates the consequences of obesity. However, little is known about the effects of L-Serine supplementation following high-fat diet (HFD) consumption and its role in the mRNA expression of markers of kidney injury. We provide a descriptive action by which L-serine administration ameliorated the consequences of HFD consumption in relation to weight loss, glucose homeostasis as well as renal mRNA expression of markers of kidney injury. Our results indicated that L-Serine supplementation in drinking water (1%, ad libitum for 12 weeks) in male C57BL/6J mice promoted a significant reduction in body weight, visceral adipose mass (epididymal and retroperitoneal fat pads) as well as blood glucose levels in mice consuming a HFD. In addition, the amino acid significantly reduced the mRNA expression of the Kidney Injury Marker 1 (KIM-1), P2Y purinoceptor 1 (P2RY1), as well as pro-inflammatory cytokines (IL-6 and TNFα). L-serine administration had no effect on mice consuming a standard chow diet. Collectively, our findings suggest that L-serine is an effective compound for long-term use in animal models and that it ameliorates the metabolic consequences of HFD consumption and reduces the elevated levels of renal pro-inflammatory cytokines occurring in obesity.

In this study, we assessed the impact of commercially available polymyxin B against VRP-034 (novel formulation of polymyxin B) using a validated in vitro human renal model, aProximateTM. Freshly isolated primary proximal tubule cells (PTCs) were cultured in Transwell plates and treated with various concentrations of the formulations for up to 48 h. The functional expression of megalin–cubilin receptors in PTC monolayers was validated using FITC-conjugated albumin uptake assays. Polymyxin B and VRP-034 were evaluated at six concentrations (0.3, 1, 3, 10, 30, and 60 µM), and nephrotoxicity was assessed through measurements of transepithelial electrical resistance (TEER), intracellular adenosine triphosphate (ATP) levels, lactate dehydrogenase (LDH) release, and novel injury biomarkers [kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and clusterin]. Additionally, histological analysis using annexin V apoptosis staining was performed. Our results indicated a significant decrease in TEER with polymyxin B at concentrations ≥10 μM compared to VRP-034. Toxic effects were observed from ATP and LDH release only at concentrations ≥30 μM for both formulations. Furthermore, injury biomarker release was higher with polymyxin B compared to VRP-034, particularly at concentrations ≥10 µM. Histologically, polymyxin B-treated PTCs showed increased apoptosis compared to VRP-034-treated cells. Overall, VRP-034 demonstrated improved tolerance in the aProximateTM model compared to polymyxin B, suggesting its potential as a safer alternative for renal protection.

With an increasing number of marginal donors, additional methods for the evaluation of cadaveric kidney quality are required. This study aimed to evaluate pretransplant deceased donor serum (s) and urine (u) biomarkers, including neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), interleukin-18, and C-X-C motif chemokine 10 (CXCL10) for predicting early and late graft function. In total, 43 deceased kidney donors and 76 corresponding recipients were enrolled. Delayed graft function (DGF) occurred in 27.6% of cases. sIL-18, sKIM-1, uNGAL, and uKIM-1 were predictors of DGF. A model incorporating sIL-18, uKIM-1, and clinical factors was developed to predict DGF (AUROC 0.863). Univariate analysis showed a negative association between uKIM and graft eGFR at 6, 12, 24, and 36 months, but this was not confirmed in the multivariate analysis. In conclusion, we report a superior performance of donor biomarkers for predicting DGF and later graft function over serum creatinine. Higher levels of donor sIL-18 and uKIM in conjunction with expanded-criteria donors and longer cold ischemia times predicted DGF. With no renal tubular damage in zero-time donor biopsies, higher pretransplant urine and serum NGAL levels were associated with better allograft function one year after transplantation, and sNGAL with graft function three years after transplantation.

Normalization of urinary biomarkers of kidney injury is a common practice in clinical and research settings to account for variations in urine concentration, and urinary creatinine is often used as a reference. However, to date, there is no consensus on the adjustment of urinary biomarkers with creatinine, and both absolute and creatinine-adjusted biomarker levels are adopted for making interpretations of kidney health. Hence, the present study aimed to investigate the associations of urinary creatinine with three widely used kidney injury biomarkers, KIM-1, NGAL, and cystatin C, to validate the applicability of urinary creatinine as a reference for normalization. A cross-sectional study was performed with 2100 students, 10–18 years of age in the Children’s Kidney Environmental Exposure Study (C-KidnEES) cohort established in Sri Lanka. As identified in linear regression analyses, normalization of urinary KIM-1, NGAL, and Cys-C to urinary creatinine did not result in significant under-adjustment or over-adjustment to the absolute urinary concentrations, giving no specific rationale for creatinine adjustment. Hence, absolute urinary concentrations of the above biomarkers can be adopted for the characterization of subclinical kidney injury in adolescents in community studies where early morning urine sampling is practiced. However, for spot urine samples, consideration of both absolute and creatinine-adjusted biomarker levels would be a better approach.

Vancomycin is a commonly used antibiotic in hospital settings, especially against Methicillin-resistant staphylococcus aureus (MRSA). One of the major adverse events of vancomycin use in adults is kidney injury. The drug concentration, specifically the area under the concentration curve, predicts kidney injury in adults receiving vancomycin. To attempt to reduce vancomycin-induced nephrotoxicity, we have successfully encapsulated vancomycin in polyethylene glycol-coated liposomes (PEG-VANCO-lipo). We have previously carried out in vitro cytotoxicity studies on kidney cells using PEG-VANCO-lipo and found it to be minimally toxic compared to the standard vancomycin. In this study, we have dosed male adult rats with PEG-VANCO-lipo or vancomycin HCl and compared plasma vancomycin concentrations and KIM-1 as an injury biomarker in rat urine. Male Sprague Dawley rats (350 ± 10 g) were administered vancomycin (n = 6) or PEG-VANCO-lipo (n = 6) 150 mg/kg/day for three days using an IV infusion in the left jugular vein catheter. Blood was collected for plasma at 15, 30, 60, 120, 240, and 1440 min after the first and the last IV dose. Urine was collected 0–2, 2–4, 4–8, and 8–24 h after the first and the last IV infusions using metabolic cages. The animals were observed for three days after the last compound administration. Vancomycin was quantified in plasma by LC-MS/MS. Urinary KIM-1 analysis was done by using an ELISA kit. Three days after the last dose, under terminal anesthesia with IP ketamine (65–100 mg/kg) and xylazine (7–10 mg/kg), rats were euthanized. Vancomycin urine and kidney concentrations and KIM-1 were lower on day three in the PEG-Vanco-lipo group compared to the vancomycin group (p < 0.05, ANOVA and/or t-test). There was a significant reduction in plasma vancomycin concentration on day one and day three (p < 0.05, t-test) in the vancomycin group compared to the PEG-VANCO-lipo group. Vancomycin-loaded PEGylated liposomes resulted in lower levels of kidney injury, as noted by a decrease in KIM-1 values. Moreover, longer circulation in plasma with increased concentration in plasma as opposed to the kidney was observed with the PEG-VANCO-lipo group. The results indicate the high potential of PEG-VANCO-lipo in decreasing the nephrotoxicity of vancomycin clinically.

Kidney transplantation is the best option for end-stage chronic kidney disease. Transplant viability is conditioned by drugs’ nephrotoxicity, ischemia–reperfusion damage, or acute rejection. An approach to improve graft survival is the identification of post-transplant renal function prognostic biomarkers. Our objective was to study three early kidney damage biomarkers (N-acetyl-d-glucosaminidase, NAG; neutrophil gelatinase-associated lipocalin, NGAL; and kidney injury molecule-1, KIM-1) in the initial period after transplantation and to identify possible correlations with main complications. We analysed those biomarkers in urine samples from 70 kidney transplant patients. Samples were taken on days 1, 3, 5, and 7 after intervention, as well as on the day that renal function stabilised (based on serum creatinine). During the first week after transplant, renal function improved based on serum creatinine evolution. However, increasing levels of biomarkers at different times during that first week could indicate tubular damage or other renal pathology. A relationship was found between NGAL values in the first week after transplantation and delayed graft function. In addition, higher NAG and NGAL, and lower KIM-1 values predicted a longer renal function stabilisation time. Therefore, urinary NAG, NGAL, and KIM-1 could constitute a predictive tool for kidney transplant complications, contributing to improve graft survival rates.

Nephrotoxicity is a serious complication that limits the clinical use of gentamicin (GEN). Parthenolide (PTL) is a sesquiterpene lactone derived from feverfew with various therapeutic benefits. However, PTL possesses low oral bioavailability. This study aimed to evaluate the therapeutic protective effects of PTL-phytosomes against GEN-induced nephrotoxicity in rats. The PTL was prepared as phytosomes to improve the pharmacological properties with a particle size of 407.4 nm, and surface morphology showed oval particles with multiple edges. Rats were divided into six groups: control, nano-formulation plain vehicle, PTL-phytosomes (10 mg/kg), GEN (100 mg/kg), GEN + PTL-phytosomes (5 mg/kg), and GEN + PTL-phytosomes (10 mg/kg). The administration of PTL-phytosomes alleviated GEN-induced impairment in kidney functions and histopathological damage, and decreased kidney injury molecule-1 (KIM-1). The anti-oxidative effect of PTL-phytosomes was demonstrated by the reduced malondialdehyde (MDA) concentration and increased superoxide dismutase (SOD) and catalase (CAT) activities. Furthermore, PTL-phytosomes treatment significantly enhanced sirtuin 1 (Sirt-1), nuclear factor erythroid-2-related factor-2 (Nrf2), NAD(P)H quinone dehydrogenase 1 (NQO1), and heme oxygenase-1 (HO-1). Additionally, PTL-phytosomes treatment exhibited anti-inflammatory and anti-apoptotic properties in the kidney tissue. These findings suggest that PTL-phytosomes attenuate renal dysfunction and structural damage by reducing oxidative stress, inflammation, and apoptosis in the kidney.

Background: Acromegaly is a rare disorder caused by excessive growth hormone (GH) secreted from a pituitary tumor. High levels of GH and insulin growth factor-1 can lead to renal hypertrophy, as well as to diabetes mellitus and hypertension, which negatively impact kidney function. It is believed that high GH may also be involved in the onset of diabetic nephropathy, the main cause of end-stage kidney disease in developed countries., Material and Methods: This case-control study was conducted on 23 acromegalic patients and on a control group represented by 21 healthy subjects. The following parameters were determined for all the subjects: serum creatinine, serum urea, estimated glomerular filtration rate (eGFR), urinary albumin/creatinine ratio (UACR), nephrin and kidney injury molecule 1 (KIM-1)., Results: Patients with acromegaly showed higher levels of UACR and lower levels of eGFR as compared to healthy subjects. No significant correlations were found between clinical or biochemical parameters associated with acromegaly and nephrin or KIM-1., Conclusions: There was no glomerular or proximal tubular damage at the time of the study, as proven by the normal levels of the biomarkers nephrin and KIM-1. Studies including more patients with uncontrolled disease are needed to clarify the utility of nephrin and KIM-1 for the detection of early kidney involvement in acromegalic patients.

Metabolic effects of physical activity may be reno-protective in the context of hypertension, although exercise stresses kidneys. Aldosterone participates in renal disease in hypertension, but exercise affects the plasma concentration of aldosterone. This study was designed to evaluate whether physical activity and pharmacological treatment by aldosterone have additive effects on renal protection in hypertensive rats. Female spontaneously hypertensive rats (SHR) or normotensive Wistar rats performed voluntary running wheel activity alone or in combination with aldosterone blockade (spironolactone). The following groups were studied: young and pre-hypertensive SHR (n = 5 sedentary; n = 10 running wheels, mean body weight 129 g), 10-month-old Wistar rats (n = 6 sedentary; n = 6 running wheels, mean body weight 263 g), 10-month-old SHRs (n = 18 sedentary, mean body weight 224 g; n = 6 running wheels, mean body weight 272 g; n = 6 aldosterone, mean body weight 219 g; n = 6 aldosterone and running wheels, mean body weight 265 g). Another group of SHRs had free access to running wheels for 6 months and kept sedentary for the last 3 months (n = 6, mean body weight 240 g). Aldosterone was given for the last 4 months. SHRs from the running groups had free access to running wheels beginning at the age of 6 weeks. Renal function was analyzed by microalbuminuria (Alb/Cre), urinary secretion of kidney injury molecule-1 (uKim-1), and plasma blood urea nitrogen (BUN) concentration. Molecular adaptation of the kidney to hypertension and its modification by spironolactone and/or exercise were analyzed by real-time PCR, immunoblots, and histology. After six months of hypertension, rats had increased Alb/Cre and BUN but normal uKim-1. Voluntary free running activity normalized BUN but not Alb/Cre, whereas spironolactone reduced Alb/Cre but not BUN. Exercise constitutively increased renal expression of proprotein convertase subtilisin/kexin type 9 (PCSK9; mRNA and protein) and arginase-2 (mRNA). Spironolactone reduced these effects. uKim-1 increased in rats performing voluntary running wheel activity exercise irrespectively of blood pressure and aldosterone blockade. We observed independent but no additive effects of aldosterone blockade and physical activity on renal function and on molecules potentially affecting renal lipid metabolism.

Diabetic nephropathy (DN) has become a leading cause of end-stage renal failure worldwide. The goal of the current study was to examine the protective effects of chitosan-loaded p-Coumaric acid nanoparticles (PCNPs) in nephrotoxicity induced by streptozotocin (STZ). Because of the antidiabetic, anti-inflammatory, and antioxidant properties of PCNPs, the development of DN may be considerably decreased. In this study, the rats received a single intraperitoneal injection (i.p.) of STZ (45 mg/kg) to induce DN. PCNPs were given orally 80 mg/kg b.w to the rats for a duration of four weeks. Body weight, kidney weight, blood glucose, and insulin levels were measured at the end of the experiment. Serum and urine parameters were also examined, along with the histological, immunobiological, and tumor necrosis factor (TNF) and interleukin-6 (IL-6) expression of the nephrotic rats. To comprehend the impact of PCNPs, the expression patterns of the kidney injury molecule (KIM-1) and glucose transporter-2 (GLUT-2) were evaluated. Administration of PCNPs significantly increased body weight, decreased kidney weight and also ameliorated blood glucose levels in the nephropathic rats. The administration of PCNPs also reverted the levels of urea, serum creatinine, urinary NAG, β-glucuronidase and albumin to near-normal levels. The administration of PCNPs also caused the levels of serum and urine parameters to return to near-normal levels. Additionally, the PCNP-treated rats had markedly reduced TNF-α, IL-6, and KIM-1 expressions as well as enhanced GLUT-2 mRNA expression. Our findings clearly showed that PCNP administration prevents the onset of DN in rats by lowering hyperglycemia, decreasing inflammation, and improving the expression of GLUT-2 mRNA in nephropathic rats.

Acute kidney injury (AKI) poses an increased risk factor for new AKI episodes, progression to chronic kidney disease, and death. A worsened evolution has been linked to an incomplete renal repair beyond the apparent functional recovery based on plasma creatinine (pCr) normalization. However, structural sequelae pass largely unnoticed due to the absence of specific diagnostic tools. The urinary kidney injury molecule 1 (KIM-1) participates in renal tissue damage and repair and is proposed as a biomarker of early and subclinical AKI. Thus, we study in this paper the evolution of KIM-1 urinary excretion alongside renal tissue sequelae after an intrinsic AKI episode induced by cisplatin in Wistar rats. Creatinine clearance, pCr, proteinuria and the fractional excretion of Na+ and glucose were used to monitor renal function. Renal tissue damage was blindly scored in kidney specimens stained with hematoxylin–eosin and periodic acid–Schiff. KIM-1 urinary excretion and renal mRNA expression were also assessed. Finally, we analyzed urinary KIM-1 in patients apparently recovered from AKI. Our results show that, after the normalization of the standard markers of glomerular filtration and tubular function, the extent of persistent histological findings of tissue repair correlates with the renal expression and urinary level of KIM-1 in rats. In addition, KIM-1 is also elevated in the urine of a significant fraction of patients apparently recovered from an AKI. Besides its potential utility in the early and subclinical diagnosis of renal damage, this study suggests a new application of urinary KIM-1 in the non-invasive follow-up of renal repair after AKI.

In this study, we assessed the impact of commercially available polymyxin B against VRP-034 (novel formulation of polymyxin B) using a validated in vitro human renal model, aProximate TM . Freshly isolated primary proximal tubule cells (PTCs) were cultured in Transwell plates and treated with various concentrations of the formulations for up to 48 h. The functional expression of megalin-cubilin receptors in PTC monolayers was validated using FITC-conjugated albumin uptake assays. Polymyxin B and VRP-034 were evaluated at six concentrations (0.3, 1, 3, 10, 30, and 60 µM), and nephrotoxicity was assessed through measurements of transepithelial electrical resistance (TEER), intracellular adenosine triphosphate (ATP) levels, lactate dehydrogenase (LDH) release, and novel injury biomarkers [kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and clusterin]. Additionally, histological analysis using annexin V apoptosis staining was performed. Our results indicated a significant decrease in TEER with polymyxin B at concentrations ≥10 μM compared to VRP-034. Toxic effects were observed from ATP and LDH release only at concentrations ≥30 μM for both formulations. Furthermore, injury biomarker release was higher with polymyxin B compared to VRP-034, particularly at concentrations ≥10 µM. Histologically, polymyxin B-treated PTCs showed increased apoptosis compared to VRP-034-treated cells. Overall, VRP-034 demonstrated improved tolerance in the aProximate TM model compared to polymyxin B, suggesting its potential as a safer alternative for renal protection.

Background: The human phospholipase B-II precursor (HPLBII-P) was originally purified from white blood cells but is also found in other cellular structures, such as kidney glomeruli and tubuli. The objective of this report was to investigate the relationship of HPLBII-P in urine to acute kidney injury in patients with COVID-19. Methods: Urine was collected at admission from 132 patients with COVID-19 admitted to the intensive care units (ICUs) because of respiratory failure. HPLBII-P was measured using a sensitive ELISA. For comparison, human neutrophil lipocalin (HNL) was measured in urine, using the ELISA configured with the monoclonal antibody 763/8F, as a sign of tubular affection in addition to routine biomarkers of kidney disease. Results: Overall, the concentrations of urinary HPLBII-P were almost 3-fold higher in patients with COVID-19 compared to healthy controls ( p < 0.0001) and with significantly higher concentrations even in patients with COVID-19 without signs of acute kidney injury (AKI) ( p < 0.001). HPLBII-P was further increased in patients with AKI ( p < 0.02). HPLBII-P was significantly increased in patients with diabetes mellitus ( p = 0.0008) and correlated to plasma glucose (r = 0.29, p = 0.001) and urine albumin concentrations (r = 0.55, p < 0.001). Conclusions: Urine concentrations of HPLBII-P are highly raised in the urine of patients with COVID-19 and relate to AKI and diabetes mellitus. HPLBII-P may reflect glomerular injury and/or increased glomerular cell activity in SARS-CoV-2 infections.

The intensifying world-wide spread of mycotoxigenic fungal species has increased the possibility of mycotoxin contamination in animal feed and the human food chain. Growing evidence shows the deleterious toxicological effects of mycotoxins from infants to adults, while large population-based screening programs are often missing to identify affected individuals. The kidney functions as the major excretory system, which makes it particularly vulnerable to nephrotoxic injury. However, few studies have attempted to screen for kidney injury biomarkers in large, mycotoxin-exposed populations. As a result, there is an urgent need to screen them with sensitive biomarkers for potential nephrotoxicity. Although a plethora of biomarkers have been tested to estimate the harmful effects of a wide spectrum of toxicants, β2-microglobulin (β2-MG) and N-acetyl-β-D-glucosaminidase (NAG) are currently the dominant biomarkers employed routinely in environmental toxicology research. Nevertheless, kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) are also emerging as useful and informative markers to reveal mycotoxin induced nephrotoxicity. In this opinion article we consider the nephrotoxic effects of mycotoxins, the biomarkers available to detect and quantify the kidney injuries caused by them, and to recommend biomarkers to screen mycotoxin-exposed populations for renal damage.

Emerging renal biomarkers (e.g., kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL)) are thought to be highly sensitive in diagnosing renal injury. However, global data on reference intervals for emerging biomarkers in younger populations are lacking. Here, we aimed to determine reference intervals for KIM-1 and NGAL across a pediatric population in Sri Lanka; a country significantly impacted by the emergence of chronic kidney disease of unexplained etiology (CKDu). Urine samples were collected from children (10–18 years) with no prior record of renal diseases from the dry climatic zone of Sri Lanka (N = 909). Urinary KIM-1 and NGAL concentrations were determined using the enzyme-linked immunosorbent assay (ELISA) and adjusted to urinary creatinine. Biomarker levels were stratified by age and gender, and reference intervals derived with quantile regression (2.5th, 50th, and 97.5th quantiles) were expressed at 95% CI. The range of median reference intervals for urinary KIM-1 and NGAL in children were 0.081–0.426 ng/mg Cr, 2.966–4.850 ng/mg Cr for males, and 0.0780–0.5076 ng/mg Cr, 2.0850–3.4960 ng/mg Cr for females, respectively. Renal biomarkers showed weak correlations with age, gender, ACR, and BMI. Our findings provide reference intervals to facilitate screening to detect early renal damage, especially in rural communities that are impacted by CKDu.

With an increasing number of marginal donors, additional methods for the evaluation of cadaveric kidney quality are required. This study aimed to evaluate pretransplant deceased donor serum (s) and urine (u) biomarkers, including neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), interleukin-18, and C-X-C motif chemokine 10 (CXCL10) for predicting early and late graft function. In total, 43 deceased kidney donors and 76 corresponding recipients were enrolled. Delayed graft function (DGF) occurred in 27.6% of cases. sIL-18, sKIM-1, uNGAL, and uKIM-1 were predictors of DGF. A model incorporating sIL-18, uKIM-1, and clinical factors was developed to predict DGF (AUROC 0.863). Univariate analysis showed a negative association between uKIM and graft eGFR at 6, 12, 24, and 36 months, but this was not confirmed in the multivariate analysis. In conclusion, we report a superior performance of donor biomarkers for predicting DGF and later graft function over serum creatinine. Higher levels of donor sIL-18 and uKIM in conjunction with expanded-criteria donors and longer cold ischemia times predicted DGF. With no renal tubular damage in zero-time donor biopsies, higher pretransplant urine and serum NGAL levels were associated with better allograft function one year after transplantation, and sNGAL with graft function three years after transplantation.

Acute Kidney Injury (AKI) affects up to 30% of the patients who undergo cardiac surgery (CVS) and is related to higher mortality. We aim to investigate molecular features associated with in-hospital AKI development and determine the predictive value of these features when analyzed preoperatively. This is a case-control study. From an initial cohort of 110 recruited subjects, a total of 60 patients undergoing cardiac surgery were included: 20 (33%) developed in-hospital AKI (CVS-AKI) and 40 did not (controls, CVS-C). Pre- and post-surgery samples were collected and a prospective study was carried out. A total of 312 serum samples and 258 urine samples were analyzed by nuclear magnetic resonance, mass spectrometry and ELISA. Six features predicted AKI development in pre-surgery samples: urinary kidney functional loss marker kidney injury molecule-1 (uKIM-1), 2-hydroxybutyric acid, 2-hydroxyphenylacetic acid, hippuric acid, phosphoethanolamine and spermidine. Two of them stood out as powerful predictors. Pre-surgery uKIM-1 levels were increased in CVS-AKI vs. CVS-C (AUC = 0.721, p-value = 0.0392) and associated strongly with the outcome (OR = 5.333, p-value = 0.0264). Spermidine showed higher concentration in CVS-AKI (p-value < 0.0001, AUC = 0.970) and had a strong association with the outcome (OR = 69.75, p-value < 0.0001). uKIM-1 and particularly spermidine predict in-hospital AKI associated with CVS in preoperative samples. These findings may aid in preventing postoperative AKI and improve prognosis of CVS.

Despite the crucial role of Polymyxin-B in treating life-threatening gram-negative infections, its clinical utility is limited due to the risk of acute kidney injury. In response, a novel formulation of polymyxin-B is being developed to mitigate drug-induced kidney injury. In this study, we have assessed the toxicity of four variants of that novel formulation (VRP034_F21-F24) in comparison with standard polymyxin-B using kidney injury biomarkers in rats. Sprague-Dawley rats were subcutaneously administered either polymyxin-B (control) or one of the four polymyxin-B formulations at a dose of 25 mg/kg/day (HED: 4 mg/kg/day) in four divided doses for two days. Serum samples were collected at baseline and at the end of day 2 for the determination of serum biomarkers. Necropsy was done on day 2 and kidney was collected for histopathological evaluation. In the control group, statistically significant increase (p < 0.0001) in all biomarkers was observed on day 2 as compared to baseline values [urea: 311%; creatinine: 700%; KIM-1: 180%; cystatin-C: 66%] and 50% of the animals died (one after the 7th dose and two after the 8th dose) before scheduled necropsy. In contrast, animals treated with novel formulations did not show a significant increase across any of the biomarkers and no mortality was observed. Histopathology of the control group kidney confirmed necrotic changes in tissues with congestion and vacuolization, whereas only minor tubular damage was noted in two formulation groups (VRP034_F21, F24) and no appreciable damage was detected in the other two groups (VRP034_F22-23). The novel formulation of polymyxin-B tested in this study significantly reduced the risk of polymyxin-induced kidney injury in rats.

Normalization of urinary biomarkers of kidney injury is a common practice in clinical and research settings to account for variations in urine concentration, and urinary creatinine is often used as a reference. However, to date, there is no consensus on the adjustment of urinary biomarkers with creatinine, and both absolute and creatinine-adjusted biomarker levels are adopted for making interpretations of kidney health. Hence, the present study aimed to investigate the associations of urinary creatinine with three widely used kidney injury biomarkers, KIM-1, NGAL, and cystatin C, to validate the applicability of urinary creatinine as a reference for normalization. A cross-sectional study was performed with 2100 students, 10-18 years of age in the Children's Kidney Environmental Exposure Study (C-KidnEES) cohort established in Sri Lanka. As identified in linear regression analyses, normalization of urinary KIM-1, NGAL, and Cys-C to urinary creatinine did not result in significant under-adjustment or over-adjustment to the absolute urinary concentrations, giving no specific rationale for creatinine adjustment. Hence, absolute urinary concentrations of the above biomarkers can be adopted for the characterization of subclinical kidney injury in adolescents in community studies where early morning urine sampling is practiced. However, for spot urine samples, consideration of both absolute and creatinine-adjusted biomarker levels would be a better approach.

Kidney transplantation is the best option for end-stage chronic kidney disease. Transplant viability is conditioned by drugs' nephrotoxicity, ischemia-reperfusion damage, or acute rejection. An approach to improve graft survival is the identification of post-transplant renal function prognostic biomarkers. Our objective was to study three early kidney damage biomarkers (N-acetyl-d-glucosaminidase, NAG; neutrophil gelatinase-associated lipocalin, NGAL; and kidney injury molecule-1, KIM-1) in the initial period after transplantation and to identify possible correlations with main complications. We analysed those biomarkers in urine samples from 70 kidney transplant patients. Samples were taken on days 1, 3, 5, and 7 after intervention, as well as on the day that renal function stabilised (based on serum creatinine). During the first week after transplant, renal function improved based on serum creatinine evolution. However, increasing levels of biomarkers at different times during that first week could indicate tubular damage or other renal pathology. A relationship was found between NGAL values in the first week after transplantation and delayed graft function. In addition, higher NAG and NGAL, and lower KIM-1 values predicted a longer renal function stabilisation time. Therefore, urinary NAG, NGAL, and KIM-1 could constitute a predictive tool for kidney transplant complications, contributing to improve graft survival rates.

Acute kidney injury (AKI) poses an increased risk factor for new AKI episodes, progression to chronic kidney disease, and death. A worsened evolution has been linked to an incomplete renal repair beyond the apparent functional recovery based on plasma creatinine (pCr) normalization. However, structural sequelae pass largely unnoticed due to the absence of specific diagnostic tools. The urinary kidney injury molecule 1 (KIM-1) participates in renal tissue damage and repair and is proposed as a biomarker of early and subclinical AKI. Thus, we study in this paper the evolution of KIM-1 urinary excretion alongside renal tissue sequelae after an intrinsic AKI episode induced by cisplatin in Wistar rats. Creatinine clearance, pCr, proteinuria and the fractional excretion of Na + and glucose were used to monitor renal function. Renal tissue damage was blindly scored in kidney specimens stained with hematoxylin-eosin and periodic acid-Schiff. KIM-1 urinary excretion and renal mRNA expression were also assessed. Finally, we analyzed urinary KIM-1 in patients apparently recovered from AKI. Our results show that, after the normalization of the standard markers of glomerular filtration and tubular function, the extent of persistent histological findings of tissue repair correlates with the renal expression and urinary level of KIM-1 in rats. In addition, KIM-1 is also elevated in the urine of a significant fraction of patients apparently recovered from an AKI. Besides its potential utility in the early and subclinical diagnosis of renal damage, this study suggests a new application of urinary KIM-1 in the non-invasive follow-up of renal repair after AKI.

Emerging renal biomarkers (e.g., kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL)) are thought to be highly sensitive in diagnosing renal injury. However, global data on reference intervals for emerging biomarkers in younger populations are lacking. Here, we aimed to determine reference intervals for KIM-1 and NGAL across a pediatric population in Sri Lanka; a country significantly impacted by the emergence of chronic kidney disease of unexplained etiology (CKDu). Urine samples were collected from children (10-18 years) with no prior record of renal diseases from the dry climatic zone of Sri Lanka (N = 909). Urinary KIM-1 and NGAL concentrations were determined using the enzyme-linked immunosorbent assay (ELISA) and adjusted to urinary creatinine. Biomarker levels were stratified by age and gender, and reference intervals derived with quantile regression (2.5th, 50th, and 97.5th quantiles) were expressed at 95% CI. The range of median reference intervals for urinary KIM-1 and NGAL in children were 0.081-0.426 ng/mg Cr, 2.966-4.850 ng/mg Cr for males, and 0.0780-0.5076 ng/mg Cr, 2.0850-3.4960 ng/mg Cr for females, respectively. Renal biomarkers showed weak correlations with age, gender, ACR, and BMI. Our findings provide reference intervals to facilitate screening to detect early renal damage, especially in rural communities that are impacted by CKDu.

Acute Kidney Injury (AKI) affects up to 30% of the patients who undergo cardiac surgery (CVS) and is related to higher mortality. We aim to investigate molecular features associated with in-hospital AKI development and determine the predictive value of these features when analyzed preoperatively. This is a case-control study. From an initial cohort of 110 recruited subjects, a total of 60 patients undergoing cardiac surgery were included: 20 (33%) developed in-hospital AKI (CVS-AKI) and 40 did not (controls, CVS-C). Pre- and post-surgery samples were collected and a prospective study was carried out. A total of 312 serum samples and 258 urine samples were analyzed by nuclear magnetic resonance, mass spectrometry and ELISA. Six features predicted AKI development in pre-surgery samples: urinary kidney functional loss marker kidney injury molecule-1 (uKIM-1), 2-hydroxybutyric acid, 2-hydroxyphenylacetic acid, hippuric acid, phosphoethanolamine and spermidine. Two of them stood out as powerful predictors. Pre-surgery uKIM-1 levels were increased in CVS-AKI vs. CVS-C (AUC = 0.721, p -value = 0.0392) and associated strongly with the outcome (OR = 5.333, p -value = 0.0264). Spermidine showed higher concentration in CVS-AKI ( p -value < 0.0001, AUC = 0.970) and had a strong association with the outcome (OR = 69.75, p -value < 0.0001). uKIM-1 and particularly spermidine predict in-hospital AKI associated with CVS in preoperative samples. These findings may aid in preventing postoperative AKI and improve prognosis of CVS.

Despite the crucial role of Polymyxin-B in treating life-threatening gram-negative infections, its clinical utility is limited due to the risk of acute kidney injury. In response, a novel formulation of polymyxin-B is being developed to mitigate drug-induced kidney injury. In this study, we have assessed the toxicity of four variants of that novel formulation (VRP034&#95;F21-F24) in comparison with standard polymyxin-B using kidney injury biomarkers in rats. Sprague-Dawley rats were subcutaneously administered either polymyxin-B (control) or one of the four polymyxin-B formulations at a dose of 25 mg/kg/day (HED: 4 mg/kg/day) in four divided doses for two days. Serum samples were collected at baseline and at the end of day 2 for the determination of serum biomarkers. Necropsy was done on day 2 and kidney was collected for histopathological evaluation. In the control group, statistically significant increase ( p < 0.0001) in all biomarkers was observed on day 2 as compared to baseline values [urea: 311%; creatinine: 700%; KIM-1: 180%; cystatin-C: 66%] and 50% of the animals died (one after the 7th dose and two after the 8th dose) before scheduled necropsy. In contrast, animals treated with novel formulations did not show a significant increase across any of the biomarkers and no mortality was observed. Histopathology of the control group kidney confirmed necrotic changes in tissues with congestion and vacuolization, whereas only minor tubular damage was noted in two formulation groups (VRP034&#95;F21, F24) and no appreciable damage was detected in the other two groups (VRP034&#95;F22-23). The novel formulation of polymyxin-B tested in this study significantly reduced the risk of polymyxin-induced kidney injury in rats.

Vancomycin-associated acute kidney injury (AKI) is a popular topic in the medical literature with few clear answers. While many studies evaluate the risk of AKI associated with vancomycin, few data are high quality and/or long in duration of follow-up. This review takes the clinician through an approach to evaluate a patient for risk of AKI. This evaluation should include patient assessment, antibiotic prescription, duration, and monitoring. Patient assessment involves evaluating severity of illness, baseline renal function, hypotension/vasopressor use, and concomitant nephrotoxins. Evaluation of antibiotic prescription includes evaluating the need for methicillin-resistant Staphylococcus aureus (MRSA) coverage and/or vancomycin use. Duration of therapy has been shown to increase the risk of AKI. Efforts to de-escalate vancomycin from the antimicrobial regimen, including MRSA nasal swabs and rapid diagnostics, should be used to lessen the likelihood of AKI. Adequate monitoring includes therapeutic drug monitoring, ongoing fluid status evaluations, and a continual reassessment of AKI risk. The issues with serum creatinine make the timely evaluation of renal function and diagnosis of the cause of AKI problematic. Most notably, concomitant piperacillin-tazobactam can increase serum creatinine via tubular secretion, resulting in higher rates of AKI being reported. The few studies evaluating the long-term prognosis of AKI in patients receiving vancomycin have found that few patients require renal replacement therapy and that the long-term risk of death is unaffected for patients surviving after the initial 28-day period.