Marker Of Renal Damage Research Articles

Renal tubular damage as an independent risk factor for all-cause and cardiovascular mortality in a community-based population: the Takahata study.

Renal tubular damage plays a crucial role in the development of end-stage kidney disease, a risk factor for cardiovascular events and mortality. However, the relationship between renal tubular damage and all-cause and cardiovascular mortality rates in the general population remains unclear. To address this gap, we conducted a cohort study in the general population using the urinary β2-microglobulin-creatinine ratio (UBCR) as a marker of renal tubular damage. This study included 3427 residents aged ≥ 40years in Takahata, Japan. We examined the association between the UBCR values in single-spot urine samples at enrollment and all-cause and cardiovascular mortality rates within a median follow-up of 9.2years. The participants were divided into two groups based on their UBCR levels (< 300μg/g and ≥ 300μg/g groups). Kaplan-Meier analysis showed a significantly higher incidence of all-cause and cardiovascular mortality rates in the high UBCR group (log-rank P < 0.01). Multivariable Cox proportional hazards model adjusted for age, sex, estimated glomerular filtration rate (eGFR), urine albumin level, smoking, and comorbidities showed a significantly higher hazard ratio of 1.49 (95% confidence interval (CI) 1.10-2.03, P = 0.01) for all-cause mortality and a hazard ratio of 1.73 (95% CI 1.00-2.98, P = 0.048) for cardiovascular mortality in the high-UBCR group. The net reclassification index was significantly improved by adding a high UBCR to the conventional risk factors. UBCR is an independent risk factor for all-cause and cardiovascular mortality in the general population, independent of eGFR and urinary albumin levels.

Lipid-core nanocapsules containing simvastatin do not affect the biochemical and hematological indicators of toxicity in rats.

Our research group previously studied the effectiveness of lipid-core nanocapsules (LNC) containing simvastatin (SV-LNC) in treating cognitive impairment in rats. While our results were promising, we needed to evaluate the potential toxicity of the nanoparticles themselves. This study aimed to compare the biochemical and hematological parameters of adult Wistar rats receiving LNC or SV-LNC to those receiving low doses of simvastatin crystals dispersed in a saline solution over 45days. We discovered that LNC and SV-LNC, which are both nanometers in size with low polydispersity index, negative zeta potential, and high SV encapsulation efficacy, were not more toxic than SV crystals based on various biochemical markers of hepatic, pancreatic, renal, mineral, bony, alkaline phosphatase, glucose, and uric acid damage. Furthermore, LNC exhibited no toxicity for hematological parameters, including red and white blood cell counts. Based on this animal model of toxicological study, our findings suggest that long-term administration of LNC is a safe and promising nanocarrier.

Persistent proteinuria is associated with the occurrence of cardiovascular disease: a nationwide population-based cohort study

Proteinuria is an important risk factor for cardiovascular disease (CVD) and acts as a surrogate marker of renal damage. This study aimed to determine the association between changes in proteinuria and the occurrence of CVD. In our study, 1,708,712 participants who consecutively underwent national health examinations from 2003−2004 (first period) to 2005−2006 (second period) were included. They were classified into four groups based on the presence of proteinuria at the two consecutive health examinations: (1) normal (0 → 0), (2) proteinuria-improved (participants who had improved proteinuria (+ 1 → 0, + 2 → ≤ +1 [0 or + 1], ≥ +3 → ≤ +2 [0, + 1 or + 2]), (3) proteinuria-progressed (0 → ≥ +1, + 1 → ≥ +2, + 2 → ≥ +3), and (4) proteinuria-persistent (+ 1 → +1, + 2 → +2, ≥ +3 → ≥ +3). We used a multivariate Cox proportional hazards model to assess the occurrence of CVD according to changes of presence and severity of proteinuria. During a median of 14.2 years of follow-up, 143,041 participants (event rate, 8.37%) with composite CVD were observed. Compared with the normal group, the risk of incident risk of CVD was increased according to the severity of proteinuria in each of the persistent, progressed, and improved groups (p for trend < 0.001). In a pairwise comparison, the risk of composite CVD in the improved (hazard ratio [HR]: 1.32, 95% confidence interval [CI]: 1.27–1.37), progressed (HR: 1.49, 95% CI: 1.44–1.54), and persistent groups (HR: 1.78, 95% CI: 1.64–1.94) were higher than that of the normal group. Furthermore, the improved group had a relatively lower risk of composite CVD compared to the persistent group (HR: 0.75, 95% CI: 0.69–0.83, p < 0.001). The incidence risk of composite CVD was associated with changes of presence and severity of proteinuria. Persistent proteinuria may be associated with increased risk of CVD, even compared with improved or progressed proteinuria status.

Serum and urinary monocyte chemoattractant protein-1 as markers of inflammation and renal damage in dogs with naturally occurring leishmaniosis

BackgroundRenal disease in canine leishmaniosis is of great importance owing to increased risk of mortality. In human visceral leishmaniosis, monocyte chemoattractant protein-1 (MCP-1) has been used as a marker of renal damage and inflammation. The purpose of this study was first to determine the serum MCP-1 and urinary MCP-1-to-creatinine ratio (uMCP-1/Cr) in healthy dogs and dogs with leishmaniosis at diagnosis, and second to determine whether these markers can differentiate disease severity at diagnosis.MethodsIn total, 19 healthy seronegative dogs and 38 dogs with leishmaniosis were included in the study. Dogs with leishmaniosis were classified as LeishVet clinical staging and as International Renal Interest Society (IRIS) staging. Serum and urinary MCP-1 concentrations were measured with an enzyme-linked immunosorbent assay. A receiver operating characteristic (ROC) curve determined disease severity at diagnosis between two LeishVet groups (Stage II versus stage III and IV).ResultsDogs in Leishvet stages IIb, III, and IV had a median serum MCP-1 and uMCP-1/Cr concentration higher than healthy dogs (P < 0.0001). No statistical differences were found in serum MCP-1 and uMCP-1/Cr between dogs in LeishVet stage IIa and healthy dogs. The dogs in LeishVet stage IV had significantly higher serum MCP-1 and uMCP-1/Cr compared with the dogs in LeishVet stage IIa (P < 0.0001). Serum MCP-1 and uMCP-1 were significantly higher in dogs in IRIS stage I and II + III + IV compared with healthy dogs. Dogs stage II + III + IV of IRIS had a significantly higher serum MCP-1 compared with dogs in IRIS stage I (P < 0.0001). The area under the ROC curve for serum MCP-1 was 0.78 [95% confidence interval (CI) 0.64–0.93] and for uMCP-1/Cr it was 0.86 (95% CI, 0.74–0.99). The optimal cutoff value for serum MCP-1 and uMCP-1/Cr was 336.85 pg/ml (sensitivity of 79% and specificity of 68%) and 6.89 × 10−7 (sensitivity of 84% and specificity of 79%), respectively.ConclusionsSerum MCP-1 and uMCP-1/Cr are increased in dogs with leishmaniosis compared with healthy dogs, suggesting the presence of inflammation and renal injury. Serum MCP-1 and uMCP-1/Cr were more elevated in the advanced stages of the disease compared with the moderate stages and, therefore, can be markers of the severity of the disease process.Graphical

In vivo assessment of the nephrotoxic effects of the synthetic cannabinoid AB-FUBINACA.

The widespread misuse of synthetic cannabinoids (SCs) has led to a notable increase in reported adverse effects, raising significant health concerns. SCs use has been particularly associated with acute kidney injury (AKI). However, the pathogenesis of SCs-induced AKI is not well-understood. We investigated the nephrotoxic effect of acute administration of N-[(1S)- 1-(aminocarbonyl)-2-methylpropyl]-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide (AB-FUBINKA) (3mg/kg for 5days) in mice. Various parameters of oxidative stress, inflammation, and apoptosis have been quantified. The expressions of mitochondrial complexes (I-V) in renal tissues were also assessed. Our findings showed that AB-FUBINACA induced substantial impairment in the renal function that is accompanied by elevated expression of renal tubular damage markers; KIM-1 and NGAL. Administration of AB-FUBINACA was found to be associated with a significant increase in the expression of oxidative stress markers (iNOS, NOX4, NOX2, NOS3) and the level of lipid peroxidation in the kidney. The expression of pro-inflammatory markers (IL-6, TNF-alpha, NF-kB) was also enhanced following exposure to AB-FUBINACA. These findings were also correlated with increased expression of major apoptosis regulatory markers (Bax, caspase-9, caspase-3) and reduced expression of mitochondrial complexes I, III, and IV. These results indicate that AB-FUBINACA can trigger oxidative stress and inflammation, and activate caspase-dependent apoptosis in the kidney, with these processes being possibly linked to disruption of mitochondrial complexes and could be an underlying mechanism of SCs-induced nephrotoxicity.

Increase in urine albumin-to-creatinine ratio as one of the earliest markers of renal damage in patients with hypertension and type 2 diabetes mellitus

Increase in urine albumin-to-creatinine ratio as one of the earliest markers of renal damage in patients with hypertension and type 2 diabetes mellitus

The Relationship between Serum Sodium Concentration and Albuminuria: A Retrospective Cohort Study.

Lowering dietary salt intake reduces albuminuria, an early marker of renal damage and a sensitive predictor of adverse cardiovascular outcomes. The mechanisms underlying this effect are uncertain but small changes in serum sodium concentration may be important: this retrospective cohort study investigated the hypothesis that higher serum sodium concentration is a risk factor for albuminuria (defined as a urine albumin:creatinine ratio [UACR], ≥3 mg/mmol). Primary care data from the Royal College of General Practitioners Research and Surveillance Centre were used to identify 47,294 individuals with a UACR result available between April 2010 and March 2015, and no known albuminuria prior to this. Exclusion criteria were missing or abnormal serum sodium concentration at baseline (&lt;135 or &gt;146 mmol/L); age &lt;18 years; diabetes mellitus; decompensated liver disease; heart failure; and stage 5 chronic kidney disease. After adjustment for known risk factors, there was a significant "U-shaped" relationship between serum sodium concentration and albuminuria. The lowest risk was associated with a serum sodium of 138-140 mmol/L. In comparison, the risk of albuminuria was 18% higher with a serum sodium of 135-137 mmol/L and 19% higher with a serum sodium of 144-146 mmol/L. There was no association between serum sodium concentration and blood pressure. The finding of a positive association between higher serum sodium concentration and albuminuria is in support of the hypothesis, but the inverse relationship between serum sodium concentration and albuminuria at lower concentrations warrants further explanation.

Liraglutide and resveratrol alleviated cyclosporin A induced nephrotoxicity in rats through improving antioxidant status, apoptosis and pro-inflammatory markers

The recent study delves into the role of both liraglutide and/or resveratrol on the nephropathic affection in rats treated with cyclosporine A (CsA). Rats were intoxicated with CsA (25 mg/kg) orally for 21 days and were supplemented with liraglutide (30 μg/kg) s/c daily and 20 mg/kg of resveratrol (20 mg/kg) orally. At the end of the experiment, serum samples and renal tissues were collected to determine renal damage markers, apoptotic markers, proinflammatory markers, and antioxidant status markers. Kidney function tests and antioxidant activity notably improved in the treated rats (CsA + Lir/CsA + Res/CsA + Lir + Res). Moreover, both Lir and/or Res enhanced Bcl-2 levels while down-regulating the Bax levels in rats treated with CsA. Interestingly, the immune-staining for tumor necrosis factor (TNF-α) was tested negative and mild positive in renal tissue of rats given Lir and/or Res while being treated with Cs A which indicated their anti-inflammatory effect that reduced the renal damage. The findings of this investigation revealed the ameliorative anti-inflammatory in addition to the antioxidant role of both liraglutide and resveratrol against the kidney damage caused due to CsA administration.

Role of NLRP3 inflammasome in cardiac damage in the setting of an acute cardiorenal syndrome

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): ISCIII, Ministerio de Universidades, Education and Research Council of Madrid, Biomedicine Network Comunidad de Madrid Background Acute kidney injury (AKI) is usually associated with an acute cardiac impairment known as cardiorenal syndrome type 3 (CRS3). AKI induces the activation of the immune system being the connection with the disturbance in remote organs as the heart. In response to tissue damage, different inflammatory pathways are activated. In this sense, activation of cardiac nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome has been studied in several cardiac pathologies. Nevertheless, the role of cardiac NLRP3 in ventricular cardiomyocytes as a consequence of renal damage is unknown. Purpose The overall aim of this study was to analyse the involvement of NLRP3 in AKI-induced cardiac damage in CRS3. Firstly, we evaluated the predictive value for mortality of the inflammatory component associated with the NLRP3 in a cohort of AKI patients. Then, we studied whether cardiac NLRP3 activation takes place after AKI induction and whether this may be associated with functional alterations in ventricular cardiomyocytes related to cardiac dysfunction and predisposition to ventricular arrhytmia. Methods We have studied cardiac alterations resulting from AKI induced by folic acid (FA, 250 mg/Kg) after 72 hours in wild-type (WT), Nlrp3-/- and WT AKI mice treated with the NLRP3 inhibitor MCC950 (10 mg/Kg). We examined plasma, renal and cardiac inflammatory components associated with NLRP3, as well as cardiomyocyte intracellular Ca2+ handling by confocal microscopy in all experimental groups. In AKI patients, we analysed systemic NLRP3-related cytokine levels and their possible relationship with markers of renal and cardiac damage and the prediction of mortality. Results FA-induced AKI caused a worsening of contractile function in WT cardiomyocytes due to decreased systolic Ca2+ release after 72 hours. It was accompanied by impaired Ca2+ reuptake via SERCA2a. Nevertheless, in both MCC950-treated and NLRP3-/- mice, these alterations were significantly prevented. During diastole, significant Ca2+ leakage from the sarcoplasmic reticulum was observed after 72 hours of AKI-induction, as well as increased pro-arrhythmogenic events. These alterations were prevented in both NLRP3-/- and MCC950-treated AKI mice. In AKI patients, we found that NLRP3-related cytokines increased from the time of admission to 72 hours, significantly associated with biomarkers of renal and cardiovascular damage, and exhibited a high potential to predict mortality. Conclusions AKI impairs the cytosolic Ca2+ handling in ventricular cardiomyocytes that are translated into contractile dysfunction and increased occurrence of pro-arrhythmogenic events. These cardiac alterations are strongly prevented under NLRP3 blockade, demonstrating the deleterious role of its cardiac activation in CRS3. In addition, results from AKI patients point to NLRP3 as relevant prognostic target in AKI patients at the time of admission to hospital.

#1554 The association between gut-derived metabolites and biomarkers of renal and cerebro-vascular damage in type 2 diabetes mellitus patients

Abstract Background and Aims Due to its numerous complications, type 2 diabetes mellitus (T2DM) has a major impact on the global economic burden and overall mortality. This condition modifies the metabolic microenvironment in targeted organs, such as the kidney and the brain, by its hyperglycemic nature. Gut microbiota seems to have significant interference with the renal-cerebral axis, especially in a dysbiosis state. The aim of the study was to quantify gut derived metabolites by metabolomic techniques and to evaluate their association with markers of endothelial, podocyte and proximal tubule damage and with cerebro-vascular hemodynamic indices. Method The metabolomic profiling was realized on serum and urine samples originated from 90 T2DM patients, divided into three subgroups, such as the following: 30 normal to mildly-, 30 moderately-, and 30 severely increased albuminuria, respectively, and 20 healthy subjects. The samples were examined by using untargeted and targeted ultra-high performance liquid chromatography coupled with electrospray-ionization quadroupole time-of-flight mass spectrometry (UHPLC-QTOF-ESI+-MS), in order to obtain the metabolic profile. The markers of renal damage such as synaptopodin (SP), podocalyxin (PD), N-acetyl-β-D-glucosaminidase (NAG), kidney injury molecule 1 (KIM-1), monocyte chemotactic protein 1 (MCP-1), and intercellular adhesion molecule 1 (ICAM-1) were assessed by ELISA technique. The hemodynamic cerebro-vascular indices were obtained by high resolution Doppler ultrasound of common carotid arteries (CCAs), internal carotid arteries (ICAs), and middle cerebral arteries (MCAs), bilaterally. The correlations between the metabolites, the markers of renal damage, and neurosonological indices were realized by univariable and multivariable linear regression analyses. Results UHPLC-QTOF-ESI+-MS targeted analysis and subsequent statistical assessments revealed a subset of metabolites with a specific pattern for the normal to mildly increased albuminuria subgroup. The metabolites identified as significant were, in serum: arginine (sArg), hippuric acid (sHA), indoxyl sulfate (sIS), butenoylcarnitine (sBCA), sorbitol (sSorb); and in urine, arginine (uArg), butenoylcarnitine (uBCA), indoxyl sulfate (uIS) and p-cresyl sulfate (uPCS). The univariable linear regression analysis revealed that sArg correlated positively with the breath-holding index (BHI) and negatively with intima media thickness (IMT) in ACI, MCP-1 and ICAM-1; sIS, sSorb, and sBCA correlated inversely with these parametes. The multivariable linear regression analysis displayed the specific correlations between metabolites, markers of endothelial dysfunction, and neurosonological indices, such as follows: sArg correlated with IMT and ICAM-1; sIS followed a predictive pattern along with resistance index (RI) in ACIs and ICAM-1; sBCA correlated with IMT and MCP-1 and sSorb correlated with ICAM-1 and BHI. The urine metabolites were correlated with markers of podocyte and proximal tubule dysfunction: uIS and uBCA were correlated with PD and urinary albumin to-creatinin ratio (uACR), and uPCR correlated with KIM-1 and uACR. Conclusion This study revealed a set of metabolites potentially derived from the intestinal microflora which may act as biomarkers for the early detection of both CMA and DKD in T2DM patients. SArg, sIS and, sBCA are indicators of renal endothelial dysfunction. Moreover, sArg and sIS reflect incipient common and internal carotid artery atherosclerosis, suggesting vascular remodeling at these levels. SSorb correlated with BHI, indicating blood-brain barrier dysfunction and CMA development. In urine, uBCA and uIS are indicators of podocytopathy, whereas uPCS is associated with proximal tubule damage in incipient DKD.

#2170 BET inhibitor nanotherapy reduces chronic kidney disease progression after ischemia-reperfusion injury

Abstract Background and Aims Targeting epigenetic mechanisms offer a potential breakthrough in addressing kidney diseases. Thus, inhibition of the bromodomain and extra-terminal (BET) domain proteins using the small molecule inhibitor JQ1, has shown promise in preclinical models of acute kidney injury (AKI) and chronic kidney disease (CKD). However, clinical translation faces hurdles like poor pharmacokinetics and side effects. To tackle this, we engineered liposomes loaded with JQ1 to enhance kidney drug delivery and minimize side effects. By optimizing the encapsulation of JQ1, our aim was to improve its efficacy compared to freely delivered JQ1 and reduce its cytotoxicity. Moreover, the therapeutic potential of this new nanoformulation to halt the acute renal ischemic injury and its transition to CKD will be explored. Method JQ1 was encapsulated in different types of lipid nanoparticles (NPs), and its effect was analyzed in vitro on the HK2 tubular epithelial line. Additionally, in vivo administration was carried out 1 hour after the induction of 45 minutes bilateral renal ischemia, and its effect was further analyzed at 24 h in the AKI setting or at 21 days for CKD. Non-encapsulated JQ1 was used as a control, and in vivo biodistribution studies were conducted using IVIS and fluorescent Cy5.5-labelled NPs. Damage markers, inflammatory burden and fibrosis development were analyzed through conventional techniques (Western blot, RT-PCR, IHC, flow cytometry), and functional parameters (BUN, Creatinine) were assessed through colorimetric assays. Results Three types of liposomal NPs were assayed to optimize JQ1 encapsulation, being the combined encapsulation of JQ1 in both the core and lipid layer the ones proving the best effectiveness. With an average hydrodynamic diameter of 78 nm, these NPs effectively reached the kidneys as assayed by in vivo biodistribution assays. In vitro assays performed on the HK2 cell line reveal their potential to inhibit TNF-α-induced inflammation. Importantly, in vivo dose-dependent studies determined that a 40 mg/kg dose was effective in post-ischemic acute kidney injury, showing a reduction in inflammatory (Il6, Csf2, Ccl2, Ccl5) and renal damage markers (Ngal), as well as reduced immune cell infiltration into the renal tissue of monocytes (CD45+CD11b+Ly6G−Ly6ChiF4/80low) and neutrophils (CD45+CD11b+Ly6GhiLy6Clow) quantified by flow cytometry. In accordance, decreased levels of serum BUN and Creatinine were detected in the group of mice treated with NPs-JQ1, indicating a better renal function. Of note, none of these effects were observed when the same dose of the unencapsulated inhibitor was used, demonstrating no effectiveness whatsoever. In the long term, by establishing an AKI to CKD transition model analysing fibrosis at 21 days post-ischemia induction, mice receiving a single dose of NPs-JQ1 early after damage displayed reduced fibrosis markers expression (α-SMA and Fibronectin), decreased collagen deposits quantified by Masson's Trichrome tissue staining and a partial recovery of the renal function. Conclusion The encapsulation of JQ1 in lipid nanoparticles is an effective strategy that allows for a decrease in the minimum effective dose of the drug. Due to its higher concentration and stability in the kidney, this therapy could be relevant in the treatment of renal pathologies and represents a significant step forward in the development of an innovative therapy for AKI-to-CKD transition. Our pioneering liposomal formulation not only expands the therapeutic potential of JQ1 but also addresses a significant barrier to its clinical translation in the nephrology field.

#553 Renal tubular damage is an independent risk factor for all-cause and cardiovascular mortality in a community-based population: the Takahata Study

Abstract Background and Aims Renal tubulointerstitial damage is a risk for renal failure. However, the association between renal tubulointerstitial damage and all-cause and cardiovascular mortality in the general population remains unclear. In this prospective cohort study, we examined this point using urinary β2-microglobulin/creatinine ratio (UBCR) as a marker of renal tubulointerstitial damage in the general Japanese population. Methods We examined the association between UBCR values at entry and all-cause and cardiovascular mortality during the follow-up period (median 9.2 years) in 3 427 residents (mean age 62.5 years, 45.1% male, mean eGFR 81.6 ml/min/1.73 m², ≥1+ protein 4.4%) of Takahata Town in Japan. Results Study participants were divided into two groups (low &amp;lt; 300 μg/gCre, high ≥300 μg/gCre) based on UBCR at entry. Kaplan-Meier analysis showed a significantly higher incidence of all-cause and cardiovascular mortality in the high UBCR group (Log-rank P &amp;lt; 0.01). A multivariate Cox proportional hazards analysis adjusted for age, sex, eGFR, urinary protein level, comorbidities, smoking status, and other background factors showed a hazard ratio of 1.47 (95% CI 1.09-2.00, P = 0.01) for all-cause mortality and a hazard ratio of 1.82 (95% CI 1.06-3.12, P = 0.03) for cardiovascular death in the high-UBCR group. The addition of high UBCR to conventional risk factors, including eGFR and urinary protein level, significantly improved the net reclassification improvement (NRI) for all-cause and cardiovascular mortality (P &amp;lt; 0.01). Conclusions UBCR, a marker of tubulointerstitial damage, was identified as a risk factor for all-cause and cardiovascular mortality in the general population independent of eGFR and urinary protein levels.

#648 Relationship between renal tubular damage, interstitial fibrosis and semaphorin class 3C

Abstract Background and Aims The detailed mechanism of interstitial fibrosis in CKD has not been clarified. In this study, we focused on semaphorin class 3C (SEMA3C), a secreted protein expressed in the renal tubules, that is involved in embryonic kidney development [1], and investigated the relationship between SEMA3C and renal tubular damage and interstitial fibrosis. Methods &amp;lt; Clinical research&amp;gt; We investigated the correlation between serum SEMA3C concentration and the renal tubular damage marker urinary β2 microglobulin (β2MG) concentration in the 191 patients who underwent kidney biopsy from 2017 to 2021 at Yamagata University. &amp;lt; In vivo study&amp;gt; We generated proximal tubule-specific SEMA3C knockout mice (PT-SEMA3C KO) from male mice (C57BL/6) using the Cre/loxP system. The PT-SEMA3C KO group and control group were fed a 0.2% adenine diet for 5 weeks to induce CKD. The area of interstitial fibrosis/tubular atrophy (IFTA) region was assessed by Masson-Trichrome staining. Results &amp;lt; Clinical research&amp;gt; The median age of the patients was 54 (IQR 38-68) years, 94 men and 97 women. Median serum SEMA3C concentration was 0.14 (IQR 0.07-0.35) ng/ml. Median urinary β2MG levels was 0.22 (IQR 0-1.79) mg/gCr. Spearman's correlation analysis showed a significant negative correlation between serum SEMA3C and urinary β2MG levels (r=-0.208, P=0.005), but no correlation between eGFR and Urinary protein/ creatinine. &amp;lt; In vivo study&amp;gt; IFTA region was 5.6% in the control group, compared to 11.2% in the PT-SEMA3C KO group (p=0.031). Interstitial fibrosis was significantly suppressed in the PT-SEMA3C KO mice (Fig. 1). Conclusion Our clinical and in vivo results indicate that serum SEMA3C is associated with renal tubular damage and interstitial fibrosis.

#2668 New treatments, new challenges: nephrotoxicity associated to naxitamab in patients with high-risk neuroblastoma

Abstract Background and Aims Neuroblastoma is the most common extracranial solid tumor in children, harboring a poor survival for those with high-risk (HR) tumors. Naxitamab (hu3F8) is a humanized monoclonal anti-disialoganglioside (GD2) antibody approved for the treatment of patients older than 1-year with refractory/relapsed HR-neuroblastoma limited to bone and/or bone marrow. First naxitamab (DanyelzaR) infusion was in 2017 in our institution and since then a large experience has been acquired with its use through several clinical trials as well as an expanded named patient access program. The objective is to describe the renal toxicity profile associated to naxitamab in patients with HR-neuroblastoma. Method Retrospective descriptive study including 244 patients treated with naxitamab (either on monotherapy or associated to chemotherapy) from June 2017 to December 2022 in whom renal involvement and/or hypertension (HT) was evaluated. Results Mean age of the cohort was 8 years (41% female -101- and 59% male -143-), presenting nephrotoxicity of some type up to 26.6% (n = 65): AHT (11.9%), acute renal damage (ARD 10.2%) and proteinuria (5.3%), developing all during the first 3 cycles. All of them were classified as mild adverse events (1-2) according to the Common Terminology Criteria for Adverse Events (CTCAE) scale, except for one patient with ARD grade 3 and two patients with HT grade 3. In the case of HT only in 6 patients an Ambulatory Blood Pressure Monitoring (ABPM) was performed, observing: 2 nocturnal-HT, 2 diurnal-HT without specific-pattern and 2 disautonomic-patterns. Among the ARD, all cases were tubular except for two patients who presented acute tubule-interstitial nephritis (AIN) (one with clinical-analytical pattern and another confirmed by biopsy). Eight of them (32%) had potential confounding factors (previous chemotherapy, ibuprofen or radiotherapy). Among patients with proteinuria (none in the nephrotic range): 38% tubular, 38% glomerular and 23% mixed. Two patients presented ARD + HT and 3 a combination of HT + ARD + proteinuria. All patients received prior chemotherapy and 2 developing chronic renal damage (CKD stage 2 and 3). Conclusion Short-and long-term follow-up, the systematic performance of ABPM, and the use of early markers of renal damage, could lead to a more efficient management of complications derived from this new treatment.

Amlodipine Protects against Methotrexate-Induced Acute Kidney Injury in Rats

Background Methotrexate (MTX) is a commonly used chemotherapy drug with known nephrotoxic effects, including the potential for acute kidney injury. However, the precise mechanism through which MTX induces nephrotoxicity remains unclear, though oxidative stress and direct toxic effects on renal tubules are believed to play key roles. Recent studies suggest that calcium channel blockers may offer promise in slowing down the progression of chronic kidney diseases. Objective The purpose of this study was to explore the potential of Amlodipine, a calcium channel blocker, to alleviate acute kidney injury caused by the administration of MTX in rats. Methods Three groups of twenty-four male Wistar rats were randomly assigned: Group 1—the control group was given normal saline orally. Group II, underwent five days of continuous administration of a single intraperitoneal (IP) dosage of 20 mg/kg MTX. The same dosage of MTX was given to Group III followed by an oral dose of Amlodipine at 5 mg/kg over the same period. Upon completion of the experiment, serum biochemical parameters, renal damage markers, oxidative stress, inflammatory markers, and kidney tissue histology were assessed. Results The results indicate that MTX administration significantly increased the levels of serum biochemical parameters, renal damage markers, inflammatory markers, oxidative stress markers, and induced alterations in kidney histology. However, the administration of Amlodipine following MTX treatment protected against these changes. Conclusion Amlodipine exhibits therapeutic potential in mitigating MTX-induced kidney injury in rats and its associated side effects.

Unraveling a Novel Mechanism of Altered Glomerular Hemodynamics in Pre-diabetic Obesity

Background: In pre-diabetic obesity, disrupted glomerular autoregulation leads to increased glomerular capillary pressure and renal blood flow, causing potential barotrauma-induced glomerular damage. A decrease in Afferent arteriole ( Af-Art) resistance causes higher glomerular capillary pressure but the underlying mechanism behind this, specifically in pre-diabetic obesity, remains unclear. Hyperinsulinemia is common in pre-diabetic obesity, but its role in reducing Af-Art resistance in the kidneys is unknown. Kidney blood flow is auto-regulated by vasoconstriction via tubuloglomerular feedback (TGF) and vasodilation through the Distal convoluted tubule-2/connecting tubule (DCT-2/CNT) mechanism. Our earlier studies indicate increased Af-Art dilation in pre-diabetic obese rats through the DCT-2/CNT mechanism without affecting TGF. This DCT-2/CNT induced Af-Art dilation requires initiation from epithelial sodium channels (ENaC) present at this tubular segment and interestingly insulin is a known ENaC activator. Hypothesis: We hypothesize that in the context of pre-diabetic obesity, hyperinsulinemia contributes to an increase in renal cortical blood flow (CBF) by increasing DCT-2/CNT-induced Af-Art dilation, subsequently leading to glomerular injury. Methods: We assessed the effects of insulin on Af-Art dilation by perfusing juxtaposed DCT-2/CNT segments with insulin in normal rabbits. Contribution of DCT-2/CNT induced Af-Art dilation was measured by co-administration of the ENaC blocker benzamil. To study hyperinsulinemia's role in an in-vivo setting without altering blood glucose levels, we used a hyperinsulinemic-euglycemic (HI-EUG) clamp in obese rats with intravenous (IV) glucose and insulin infusions. Renal CBF and blood pressure were monitored using a laser Doppler probe and femoral artery catheter, respectively, both with and without benzamil administration (400 μg/kg, IV). To evaluate insulin's potential role in causation of renal damage, we infused insulin directly into one kidney of lean rats for 6 weeks via a renal sub-capsular catheter, with the contralateral kidney serving as control. Glomerular basement membrane (GBM) thickness, a marker of renal damage, was measured via electron microscopy. Untargeted lipidomic analysis of the renal cortex was performed to identify potential renal damage pathways in insulin infused kidneys. Results: Insulin perfusion in rabbits' DCT-2/CNT potentiated the dilation of adherent Af-Art compared to control infusions with artificial tubular fluid. ENaC inhibition reversed the insulin-induced Af-Art dilation, confirming that insulin increases Af-Art dilation through the ENaC-initiated DCT-2/CNT mechanism. In obese rats, insulin delivery using a HI-EUG clamp resulted in a significant 20.8±4.9% increase in CBF, which was negated by the administration of the ENaC blocker benzamil, indicating the potential involvement of DCT-2/CNT-mediated vasodilation. Neither the HI-EUG clamp nor benzamil infusion affected blood pressure. Additionally, continuous direct insulin infusion into the kidneys of lean rats led to an increase in glomerular basement membrane (GBM) thickness and ceramide accumulation in the renal cortex, both indicative of renal damage. Conclusion: Our study demonstrates that insulin directly augments DCT-2/CNT-mediated Af-Art dilation and increases renal cortical blood flow in obese rats. Chronic renal insulin infusion led to structural changes and damage markers in the kidney, independent of blood glucose and blood pressure levels. Henry Ford Health System Internal Funding. Pilot and Feasibility grant from southeast center for integrated metabolomics. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Creatinine standardised Gamma glutamyl transferase can serve as an early diagnostic marker for renal damage in sickle cell nephropathy: A comparative study with moderately increased albuminuria

Creatinine standardised Gamma glutamyl transferase can serve as an early diagnostic marker for renal damage in sickle cell nephropathy: A comparative study with moderately increased albuminuria

Relationship between renal damage marker levels and the presence of bleeding in patients with atrial fibrillation and chronic kidney disease receiving rivaroxaban

Relationship between renal damage marker levels and the presence of bleeding in patients with atrial fibrillation and chronic kidney disease receiving rivaroxaban

Peripheral biomarkers as a predictor of poor prognosis in severe cases of COVID-19

We evaluated glycemia and triglyceride, hepatic, muscular, and renal damage markers, redox profile, and leptin and ghrelin hormone levels in COVID-19 patients. We also conducted statistical analysis to verify the potential of biomarkers to predict poor prognosis and the correlation between them in severe cases. We assessed glycemia and the levels of triglycerides, hepatic, muscular, and renal markers in automatized biochemical analyzer. The leptin and ghrelin hormones were assessed by the ELISA assay. Severe cases presented high glycemia and triglyceride levels. Hepatic, muscular, and renal biomarkers were altered in severe patients. Oxidative stress status was found in severe COVID-19 patients. Severe cases also had increased levels of leptin. The ROC curves indicated many biomarkers as poor prognosis predictors in severe cases. The Spearman analysis showed that biomarkers correlate between themselves. Patients with COVID-19 showed significant dysregulation in the levels of several peripheral biomarkers. We bring to light that a robust panel of peripheral biomarkers and hormones predict poor prognosis in severe cases of COVID-19 and biomarkers correlate with each other. Early monitoring of these biomarkers may lead to appropriate clinical interventions in patients infected by SARS-CoV2.

Nephroprotective Effect of Bergapten Against Cyclophosphamide-Mediated Renal Stress, Inflammation, and Fibrosis in Wistar Rats: Probable Role of NF-kB and TGF-β1 Signaling Molecules.

Cyclophosphamide (CPM) is a well-established antineoplastic drug with marked clinical outcomes in various types of cancers. Despite being a promising drug, its use is associated with significant renal toxicity and often limits its use, leading to compromised clinical outcomes. Therefore, this study explored the renal protective effect of bergapten (BGP), a natural bioactive compound that showed marked antioxidant, anti-inflammatory, anticancer, and neuroprotective effects. Till now, BGP has not been studied for its renal protective effect in an in vivo model. Animals were divided into control, toxic, BGP-3, BGP-10, and BGP Per se. The control group was treated with normal saline for 2 weeks. To the toxic group, CPM 200 mg/kg was given on day 7 as i.p. To BGP-3, 10, and Per se, BGP-3 and 10 mg/kg, ip was given 2 weeks with a single shot of CPM 200 day 7. To the Per se group, only BGP 10 mg/kg, ip was given from day 1 to day 14. After 14 days, animals were sacrificed, and kidneys were removed and studied for the markers of oxidative stress, inflammation, renal injury, renal fibrosis, and renal damage using biochemical, histopathological, and immunohistochemical studies. We found that BGP-10 effectively reversed the damage toward normal, whereas BGP-3 failed to exhibit a significant renal protective effect. We conclude that bergapten could be a potential renal protective drug, and hence, more detailed cellular molecular-based studies are needed to bring this drug from the bench to the bedside.