Marker Of Tubular 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.

Combined evaluation of liver and kidney function improves prediction of clinical outcome in patients with chronic heart failure and reduced ejection fraction

Abstract Background/Introduction The liver and the kidneys are important organs for body homeostasis and are both affected by heart failure (HF) either by systemic venous congestion or hypoperfusion. Purpose We aimed to verify whether the Model for End-stage Liver Disease eXcluding International normalized ratio (MELD-XI), as well as a combination of cholestatic liver and kidney function tests carry prognostic value in patients with chronic HF with reduced ejection fraction (HFrEF). The liver parameters included alkaline phosphatase (ALP), gamma glutamyl-transpeptidase (GGT), and total bilirubin, while kidney parameters consisted of eGFR and the tubular damage markers urinary N-acetyl-beta-D-glucosaminidase (NAG) and kidney injury molecule (KIM)-1. Methods We categorized 250 patients with HFrEF on the basis of baseline biomarker levels. We assumed elevated NT-proBNP indicates hemodynamic congestion necessary to induce congestive liver or kidney dysfunction. Thus, in every organ damage category, NT-proBNP level above median was incorporated, next to any 2 out of 3: ALP, GGT or total bilirubin above median for liver dysfunction; any 2 out of 3 NAG or KIM-1 above median or eGFR below median for kidney dysfunction; or coexistence of liver and kidney dysfunction as defined above. Additionally, a subgroup of patients with both NT-proBNP and MELD-XI above the median was analyzed. The primary endpoint was a composite of cardiovascular death, heart transplantation, LVAD implantation, and hospitalization for acute or worsened HF, whichever occurred first. Univariable and multivariable Cox proportional hazard regression models were used. Results Median (Q1-Q3) age of the study population was 68 (58-76) years; 184 (74%) were men, 62 (25%) in NYHA class III or IV, and mean left ventricular ejection fraction (LVEF) was 31±9%. During a median (Q1-Q3) follow-up of 2.2 (1.4-2.5) years, 66 (26%) patients reached the primary endpoint. We observed that liver dysfunction, kidney dysfunction or their coexistence was associated with significantly higher risk of reaching the primary endpoint (HR 3.54, 95% CI 1.75–7.16; HR 1.85, 95% CI 1.00–3.41; HR 2.52, 95% CI 1.03–6.11 respectively) in the clinically adjusted model (Table 1). Higher MELD-XI was associated with higher risk of reaching the primary endpoint in an unadjusted model but not in a clinically adjusted model. Figure 1 presents event-free survival probability of patients falling into organ dysfunction categories. Conclusions Our results show that markers of cholestatic liver function and kidney function predict unfavorable clinical outcome and provide better prognostic value in chronic HFrEF patients than the MELD-XI alone. Thus, screening for liver and kidney damage may help identify high-risk patients in whom more careful observation and individualized therapy is warranted.Fig 1.Event-free survival probability

Insights into the Novel Biomarkers Expressed in Diabetic Nephropathy: Potential Clinical Applications.

Diabetic nephropathy (DN) is increasing worldwide in parallel with type 2 diabetes mellitus. Identifying diagnostic biomarkers for DN at an early stage is crucial due to the considerable societal and economic burden associated with diabetes mellitus (DM) and its risk factors. In the past, early indicators of microvascular problems, such as microalbuminuria (MA), have been used to predict the possibility of developing advanced chronic kidney disease (CKD). However, because of the incapacity of MA to appropriately estimate DN, particularly, non-albuminuric DN, additional markers have been suggested for recognizing the early renal abnormalities and structural lesions, even before MA. This study aims to assess the existing and future biomarkers used to diagnose or predict early DN. This review provides comprehensive insight into diagnostic approaches for early detection of CKD, addressing the following areas: (i) markers of glomerular damage, (ii) markers of tubular damage, (iii) oxidative stress biomarkers, (iv) inflammatory biomarkers and (v) futuristic biomarkers such as micro-ribonucleic acids (miRNAs), proteomics, metabolomics and genomics and gut microbiota. Early detection of DN may lead to improvement in clinical management and quality of life, emphasizing the importance of identifying a specific and reliable predictive biomarker. Emerging serum and urinary biomarkers offer promise for early DN diagnosis, potentially reducing prevalence and preventing progression to end-stage renal disease (ESRD). Further advancements in miRNAs, proteomics, metabolomics genomics and gut microbiota offer prospects for even earlier and more precise DN diagnosis.

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.

Tubular biomarkers and histology in lupus nephritis.

The relevance of tubulo-interstitial involvement for kidney prognosis has recently been emphasized, but validated biomarkers for predicting histology are still lacking. The aim of our study was to evaluate different serum and urinary markers of tubular damage in patients with lupus nephritis (LN) and to correlate them with kidney histopathology. A single-center retrospective study was conducted from January 2016 to December 2021. Serum and urine samples were collected on the same day of kidney biopsy and correlated with histologic data from a cohort of 15 LN patients. We analyzed the following urinary markers, adjusted for urine creatinine: beta 2-microglobulin, alpha 1-microglobulin, NGAL, uKIM-1, MCP-1, uDKK-3, and uUMOD. The serum markers sKIM-1 and sUMOD were also analyzed. A positive and strong correlation was observed between the degree of interstitial fibrosis (rho = 0.785, p = .001) and tubular atrophy (rho = 0.781, p = .001) and the levels of uDKK3. uUMOD also showed an inverse and moderate correlation with interstitial fibrosis (rho = -0.562, p = .037) and tubular atrophy (rho = -0.694, p = .006). Patients with >10% cortical interstitial inflammation had higher levels of uKIM-1 [4.9 (3.9, 5.5) vs. 0.8 (0.6, 1.5) mcg/mg, p = .001], MCP-1 [3.8 (2. 3, 4.2) vs. 0.7 (0.3, 1.2) mcg/mg, p = .001], sKIM-1 [9.2 (5.9, 32.7) vs. 1.4 (0, 3.5) pg/mL, p = .001], and lower sUMOD [8.7 (0, 39.7) vs. 46.1 (35.7, 53) ng/mL, p = .028]. The use of specific urinary and serum biomarkers of tubular dysfunction or injury may help to predict certain histologic parameters in LN patients.

#211 Low albumin levels are associated with intrarenal complement C4d deposits in critically ill patients with ANCA-associated renal vasculitides

Abstract Background and Aims Despite serum albumin levels being predictive for clinical outcome in ANCA-associated renal vasculitis, implications providing a direct link between low serum albumin levels and intrarenal lesions remain elusive. Therefore, we here aimed to systematically assess the clinical relevance of low albumin levels and scrutinize clinicopathological correlations to expand our current knowledge. Method We here retrospectively enrolled biopsy-proven cases of ANCA-associated renal vasculitis between 2015 till 2020 in a single-center observational study. Survival-curve analyses on long-term renal survival and short-term clinical recovery were performed. Correlative analyses between serum albumin levels, laboratory parameters, proteinuria levels, and histopathological lesions including tubulointerstitial immune cell infiltrates, lesions analogous to the Banff score and intrarenal complement deposition of C3c and C4d were performed. Results We here show that hypoalbuminemia below the median of 2.4 g/dL impairs long-term renal survival especially in MPO-positive ANCA-associated renal vasculitis (p = 0.006, HR: 5.0, 95% CI: 1.2-21.5), while short-term clinical recovery particularly in critically ill patients is negatively affected by low serum albumin levels (p = 0.0082, HR: 3.6, 95% CI: 1.1-11.7). Low albumin levels are associated with the urinary marker of tubular damage in the total cohort (β = −0.5, p = 0.01), PR3-ANCA (β = −0.5, p = 0.04) and MPO-ANCA (p = 0.002, β = −0.8), but not in critically ill patients (β = −0.5, p = 0.07) implying hypoalbuminemia to occur by extrarenal causation in the state of critical illness. We identified plasmacytic infiltrates to correlate with low albumin levels in the total cohort (β = −0.6, p = 0.004) and in the subgroup of critically ill patients (β = −0.7, p = 0.005). Banff-scored interstitial inflammation (i) was further observed to inversely correlate with albumin levels (β = −0.7, p = 0.02). Intrarenal C4d deposition showed a significant correlation with low serum albumin levels in the glomerular tuft (β = −0.4, p = 0.04) and in interstitial arteries (β = −0.7, p = 0.01). Conclusion In conclusion, long-term renal outcome is significantly affected by low serum albumin levels especially in the setting of MPO-ANCA seropositivity. By contrast, short-term recovery was predicted by low albumin levels in critically ill patients with ANCA-associated renal vasculitis. We here provide evidence that low levels of serum albumin might directly affect tubulointerstitial inflammation as reflected by plasmacytic immune-cell infiltration, and intrarenal C4d complement deposition in ANCA-associated renal vasculitis.

#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.

Evaluation of Urinary L-FABP as a Tubular Damage Marker in Pediatric Neurogenic Bladder—A Pilot Study

Evaluation of Urinary L-FABP as a Tubular Damage Marker in Pediatric Neurogenic Bladder—A Pilot Study

Cardiovascular risk and renal injury profile in subjects with type 2 diabetes and non-albuminuric diabetic kidney disease

BackgroundIn the last years, the classical pattern of diabetic kidney disease (DKD) has been partially overcome, because of the uncovering of a new DKD phenotype with significant renal dysfunction without presence of albuminuria: the non-albuminuric DKD (NA-DKD). To date, the cardiovascular risk associated with this phenotype is still debated. We investigated the cardiovascular risk and renal injury profile of NA-DKD subjects in comparison with other DKD phenotypes.MethodsPulse wave velocity (PWV), intima-media thickness, presence of carotid atherosclerotic plaque, renal resistive index (RRI), and a panel of urinary biomarkers of kidney injury were evaluated in 160 subjects with type 2 diabetes, stratified according to estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR) into four groups: controls (UACR < 30 mg/g and eGFR ≥ 60 mL/min/1.73 m2), A-DKD (Albuminuric-DKD, UACR ≥ 30 mg/g and eGFR ≥ 60 mL/min/1.73 m2), NA-DKD (UACR < 30 mg/g and eGFR < 60 mL/min/1.73 m2), AL-DKD (Albuminuric and Low eGFR-DKD; UACR ≥ 30 mg/g and eGFR < 60 mL/min/1.73 m2).ResultsSubjects with NA-DKD showed a higher PWV (11.83 ± 3.74 m/s vs. 10.24 ± 2.67 m/s, P = 0.045), RRI (0.76 ± 0.11 vs. 0.71 ± 0.09, P = 0.04), and prevalence of carotid atherosclerotic plaque (59% vs. 31%, P = 0.009) compared with controls. These characteristics were similar to those of subjects with AL-DKD, whereas the profile of A-DKD subjects was closer to controls. After multiple regression analyses, we found that RRI, that is in turn influenced by eGFR (β = − 0.01, P = 0.01), was one of the major determinants of PWV (β = 9.4, P = 0.02). Urinary TreFoil Factor 3, a marker of tubular damage, was higher in NA-DKD subjects vs. controls (1533.14 ± 878.31 ng/mL vs. 1253.84 ± 682.17 ng/mL, P = 0.047). Furthermore, after multiple regression analyses, we found that urinary osteopontin was independently associated with PWV (β = 2.6, P = 0.049) and RRI (β = 0.09, P = 0.006).ConclusionsOur data showed a worse cardiovascular and renal injury profile in NA-DKD subjects. This finding emphasizes the central role of eGFR in the definition of cardiovascular risk profile of diabetic subjects together with albuminuria.

Validation of Townes As Mice As a Model of Chronic Kidney Disease and Venous Thrombosis Associated with Sickle Cell Trait

Individuals with sickle cell trait (SCT) are heterozygous carriers of the sickle beta-globin gene. Systematic analyses of large cohort studies over the past decade have established that SCT is a risk factor for a limited number of complications, most notably chronic kidney disease (CKD) and venous thrombosis (VT). SCT red blood cells (RBCs) can undergo sickling, although the degree and duration of hypoxia required to produce sickling are much greater than in sickle cell disease due to the lower intra-erythrocyte sickle hemoglobin beta (HbS) concentration of 25-45%. Hypoxia-mediated HbS polymerization can be enhanced by cellular dehydration, hyperosmolarity and/or acidosis that may be encountered in the renal inner medulla. Furthermore, prolonged exposure of SCT RBCs to profound hypoxia, such as in the nidus of a venous clot, will also result in sickling. The objective of this study was to determine if Townes AS mice manifest kidney dysfunction analogous to their SCT human counterparts. Furthermore, we evaluated whether VT was more pronounced in a well-described model of inferior vena cava (IVC) stasis. We used humanized male sickle cell trait (AS) and age-matched genetic control (AA) mice (n=7-16). Analysis of urinary renal biomarkers (albuminuria, proteinuria, kidney injury marker 1 (KIM-1), osmolality) and kidney function (transcutaneous measurement of glomerular filtration rate (GFR)) were conducted at 4-week intervals from 8 to 40 weeks of age. VT was induced by complete occlusion of the IVC in AA and AS mice. Sickling of RBCs was determined by histological and electron microscopy analysis of the IVC clot. Senicapoc, an oral Gardos channel inhibitor, was administered twice daily (20mg/kg, bid) for 2 weeks to prevent AS RBC dehydration and subsequent sickling. Human HbS accounts for 30.1% of total Hb expression in AS mice. Consistent with human SCT, peripheral blood counts did not differ from AA controls. Basal plasma thrombin-antithrombin complex levels were also not different between AA and AS mice. We performed a longitudinal study of renal structure and function in AA and AS mice over 40 weeks. At 8 weeks of age, AS mice exhibited no differences in any parameter compared to AA controls. However, AS mice subsequently developed albuminuria and a moderate but statistically significant increase in GFR (Figure 1). At 36 and 40 weeks of age, we observed progressive loss of kidney function demonstrated by statistically significant decreased GFR accompanied by a significant increase in albuminuria in AS mice (Figure 1). Over time, proteinuria gradually increased in AS mice, and had doubled by 40 weeks of age compared to AA controls (4.6 ±1.1 vs. 2.3 ±0.4 mg/24h, p&amp;lt;0.05). Increased levels of urinary KIM-1, a marker of tubular damage, were observed in AS mice throughout the duration of the study, with the highest levels at 16 weeks (228.3 ± 32.6 pg/24h vs. 53.8 ± 8.5 pg/24h, respectively, p˂0.05). Urine osmolality was not different at 8 weeks of age, but progressively declined in AS mice with statistically significant changes vs. controls starting at 24 weeks until the end of study (1946 ±63 vs. 2672 ±135 mOsm/kg at 40 weeks, p=0.002). Histologic analysis confirmed glomerular injury (congestion, glomerulosclerosis) and tubular injury (medullary congestion, interstitial fibrosis) in 40 week old AS mice. Following 24 hours of IVC stasis, thrombus weight was significantly increased (p&amp;lt;0.01) in AS mice (mean±SEM; 29.0 mg +/- 1.7; n=8) compared to AA controls (20.0 mg ± 1.7; n=7). Histologic and electron microscopic evaluation demonstrated that severe hypoxia (pO 2 ≈ 10 mm Hg) present in the nidus of venous thrombi was associated with extensive sickling of RBCs in AS mice. To determine if the enhancement of VT observed in AS mice was mediated by RBC sickling, mice were pretreated with Senicapoc or vehicle. Compared to vehicle-treated AS mice (27.3 mg ± 2.2 n=9) pre-treatment with Senicapoc significantly reduced (p&amp;lt;0.05) clot weight (18.1mg ± 1.1; n=7) to that observed in untreated AA controls. In aggregate, our data demonstrate that Townes AS murine nephropathy closely mimics the renal abnormalities (impaired urinary concentration and albuminuria with later onset loss of GFR) described in humans with SCT. Furthermore, we have established a mouse model of the venous thrombotic complications associated with SCT and have demonstrated that hypoxia-induced sickling of RBCs may contribute to enhanced VT observed in AS mice.

PREDICTIVE FACTORS AND CLINICAL AND PARACLINICAL FEATURES OF URINARY TRACT DYSFUNCTION IN PRETERM INFANTS

PREDICTIVE FACTORS AND CLINICAL AND PARACLINICAL FEATURES OF URINARY TRACT DYSFUNCTION IN PRETERM INFANTS

Tubular damage marker as a predictive factor for pathologically upstaged renal cell carcinoma.

To investigate if increased tubular damage biomarker can predict pathologically upstaged renal cell carcinoma (RCC), which may possess sub-radiologic invasive behavior, leading to surrounding tubular damage. We examined 1563 patients with surgically resected RCC between March 2016 and June 2021 from the prospective database SUPER-RCC-Nx. Exclusion criteria were cancer not originating from the kidneys, benign renal tumor, and end-stage renal disease. Of 1297 patients, 131 had a clinically high T stage (T3-4), whereas 1166 had a low one. Patients with a clinically low T stage were subgrouped into identical-stage (n = 1041) and upstaged (n = 125) groups, who were confirmed as a pathologically high T stage. The upstaged group had older age (p = 0.003), larger tumor size (5.72 ± 3.24 vs. 3.12 ± 2.08, p < 0.001), higher Fuhrman grade (grades 3-4) (57.3% vs. 47.1%, p = 0.032), and higher urine N-acetyl-beta-D-glucosaminidase/creatinine (NAG/Cr) (5.13 ± 4.78 vs. 4.05 ± 2.84, p = 0.026). Tumor size (> 4cm; odds ratio = 10.2, p < 0.001) and urine NAG/Cr (odds ratio = 1.16, p = 0.003) were independently associated with pathological upstaging in patients with normal renal function, while age and tumor size were significant risk factors in those with decreased renal function. The receiver operating characteristic curve analysis showed that the model using tumor size and urine NAG/Cr strongly predicted pathological upstaging (area under the curve, 0.84). Urine NAG/Cr may be a useful biomarker predicting pathologically upstaged RCC. Clinicians should be prudent in making management decisions when a large RCC is accompanied by an increased urine NAG/Cr.

Impact of multi-heavy metal exposure on renal damage indicators in Korea: An analysis using Bayesian Kernel Machine Regression.

Exposure to cadmium (Cd), arsenic (As), and mercury (Hg) is associated with renal tubular damage. People living near refineries are often exposed to multiple heavy metals at high concentrations. This cross-sectional study investigated the association between combined urinary Cd, As, and Hg levels and renal damage markers in 871 residents living near the Janghang refinery plant and in a control area. Urinary Cd, As, Hg, N-acetyl-β-D-glucosaminidase (NAG), and β2-microglobulin (β2-MG) levels were measured. The combined effects of Cd, As, and Hg on renal tubular damage markers were assessed using linear regression and a Bayesian Kernel Machine Regression (BKMR) model. The results of the BKMR model were compared using a stratified analysis of the exposure and control groups. While the linear regression showed that only Cd concentration was significantly associated with urinary NAG levels (β = 0.447, P value < .05), the BKMR model showed that Cd and Hg levels were also significantly associated with urinary NAG levels. The combined effect of the 3 heavy metals on urinary NAG levels was significant and stronger in the exposure group than in the control group. However, no relationship was observed between the exposure concentrations of the 3 heavy metals and urinary β2-MG levels. The results suggest that the BKMR model can be used to assess the health effects of heavy-metal exposure on vulnerable residents.

Free triiodothyronine predicts the risk of developing diabetic kidney disease

BackgroundLow levels of Free Triiodothyronine (FT3) are associated with poor survival in chronic kidney disease, and the aim of this study was to further assess the relationship between changes in FT3 levels and renal damage in patients with type 2 diabetes based on glomerular and tubular markers.MethodsWe retrospectively studied 452 type 2 diabetic patients, measured glomerular damage markers (UACR, eGFR) and tubular damage markers (NAG/Cr,β2-MG), analyzed the relationship between FT3 and renal damage by logistic regression models, and plotted restrictive cubic splines.Results41.6% of subjects had diabetic kidney disease (DKD), and the prevalence of DKD decreased progressively with increasing FT3 levels in the third quartile. Spearman correlation analysis showed that FT3 was negatively associated with UACR, NAG/Cr and β2-MG, while eGFR was positively associated with FT3. Multifactorial analysis, after adjusting for relevant confounders, revealed that compared with the lowest quartile of FT3, the highest quartile reduced the risk of developing urinary albumin (OR = 0.499,95% CI:0.289–0.856), moderate to severe impairment of glomerular filtration rate (OR = 0.106,95% CI:0.032–0.354), renal tubular marker β2 -MG positive (OR = 0.516,95% CI:0.299 to 0.883) and the risk of DKD occurrence (OR = 0.450,95% CI:0.260 to 0.774). In the sample model, FT3 levels below 4.39 pmol/L were associated with an increased risk of glomerular tubule injury and DKD occurrence.ConclusionsFT3 is closely associated with glomerular tubular injury and is a protective factor. As FT3 levels (< 4.39 pmol/L) decrease, the risk of developing DKD becomes higher, and FT3 can be used as an independent predictor of developing DKD.

Valproic acid treatment attenuates cisplatin-induced kidney injury by suppressing proximal tubular cell damage.

Cisplatin treatment is effective against several types of carcinomas. However, it frequently leads to kidney injury, which warrants effective prevention methods. Sodium valproic acid is a prophylactic drug candidate with a high potential for clinical application against cisplatin-induced kidney injury. Therefore, in this study, we aimed to elucidate the mechanism underlying the prophylactic effect of valproic acid on cisplatin-induced kidney injury in a mouse model and HK2 and PODO cells with cisplatin-induced toxicity. In the mouse model of cisplatin-induced kidney injury, various renal function parameters and tubular damage scores were worsened by cisplatin, but they were significantly improved upon combination with valproic acid. No difference was observed in cisplatin accumulation between the cisplatin-treated and valproic acid-treated groups in whole blood and the kidneys. The mRNA expression levels of proximal tubular damage markers, apoptosis markers, and inflammatory cytokines significantly increased in the cisplatin group 72 h after cisplatin administration but significantly decreased upon combination with valproic acid. In HK2 cells, a human proximal tubular cell line, the cisplatin-induced decrease in cell viability was significantly suppressed by co-treatment with valproic acid. Valproic acid may inhibit cisplatin-induced kidney injury by suppressing apoptosis, inflammatory responses, and glomerular damage throughout the kidneys by suppressing proximal tubular cell damage. However, prospective controlled trials need to evaluate these findings before their practical application.

Glomerulotubular function in transfusion-dependent thalassemia children: a prospective cohort study

Introduction: Thalassemia is the most common hemoglobinopathy in Indonesia. Chronic anemia, iron overload, and treatment with iron chelating agents are factors that contribute to kidney dysfunction in children with transfusion-dependent thalassemia (TDT). Urine neutrophil gelatinase-associated lipocalin (uNGAL) and urine albumin-creatinine ratio (uACR) are markers of glomerular and tubular damage. Objectives: To analyze the glomerulotubular function in TDT children. Patients and Methods: This prospective cohort study recruited 40 TDT children aged ≤18 years old from thalassemia transfusion outpatient clinic, Dr. Cipto Mangunkusumo general hospital, Jakarta, Indonesia between February and June 2021. Disease history, treatment, and anthropometry were obtained during enrollment (T0). Blood and urine samples were taken at enrollment (T0) and at 1 (T1), 2 (T2), and 3 (T3) month follow-up appointments. Data analyzed were iron chelating agent, ferritin, hemoglobin, estimated glomerular filtration rate (eGFR ), uNGAL, uACR levels. Results: We observed kidney hyperfiltration in more than 30% of the participants. Transfusion volume was the most dominant factor for eGFR (β=-0.974, P=0.022) and uNGAL (β=0.872, P=0.015). A low-proportion of albuminuria was found with duration of disease as the predominant factor (β=-0.946, P=0.000). Deferiprone (DFP) and deferasirox (DFX) showed comparable association with all kidney biomarkers. Conclusion: The findings of this study indicate glomerular hyperfiltration in TDT children as the main early sign of glomerulotubular function impairment. In addition, a small proportion of proteinuria was also found in our study. Thus, both biomarkers should be part of long term kidney follow up in TDT children.

Prognostic Value of Urinary N-Acetyl-β-d-Glucosaminidase as a Marker of Tubular Damage in Patients with Heart Failure and Mitral Regurgitation.

Mitral regurgitation (MR) has a high prevalence and aggravates hypoperfusion and hypoxia in heart failure (HF). Renal tubular epithelial cells are sensitive to hypoxia, and therefore tubulointerstitial damage is quite common in HF. However, the correlation between tubular dysfunction and MR has not been studied. The aim of this work was to evaluate the prognostic significance of urinary N-acetyl- -d-glucosaminidase (uNAG), a biomarker of renal tubular damage, in patients with HF and MR. This was a prospective cohort study of 390 patients (mean age 64 years; 65.6% male) with uNAG measurement on admission (expressed as urinary NAG/urinary creatinine) and at least 1 year of follow-up data. The pre-defined primary endpoint was the composite of all-cause mortality or rehospitalization for HF after discharge. Cox regression analysis, restricted cubic splines, and subgroup analysis were used to investigate the prognostic value of uNAG modeled as a categorical (quartiles) or continuous (per SD increase) variable. A total of 153 (39.23%) patients reached the composite endpoint over a median follow-up time of 1.2 years. The uNAG level correlated with the severity of HF and with the incidence of adverse events. In a multivariable Cox regression model, each SD (13.80 U/g Cr) of increased uNAG was associated with a 17% higher risk of death or HF rehospitalization (95% confidence interval, 2-33%, p = 0.022), and a 19% higher risk of HF rehospitalization (p = 0.027). Subgroup analysis revealed the associations between uNAG and poor prognosis were only significant in younger patients ( 65 years) and in patients without obvious cardiovascular comorbidities. uNAG levels at admission were associated with the risk of adverse outcomes in patients with HF and MR. Additional studies are needed to further investigate the heart-kidney interaction.

Nonalbuminuric diabetic kidney disease: what is known? Literature review

Urinal albumin excretion is widely used in clinical practice as an indicator of diabetic renal injury. In accordance with a classical conception of diabetic nephropathy clinical course, an albuminuria usually precedes a reduction of renal function.&#x0D; The review is devoted to discussion of an actual problem of contemporary nephrology, nonalbuminuric diabetic kidney disease (NADKD), its prevalence increasingly grows in population of patients with type 2 diabetes mellitus due to efficacy of glucose lowering, hypotensive, hypolipidemic therapy and smoking cessation. NADKD is more frequently revealed among females; it is associated with arterial hypertension and ischemic heart disease. Renal changes in patients with NADKD are heterogenous compared with albuminuric diabetic patients and interstitial changes as well as atherosclerosis can turn out to be the main morphological finding in the absence of glomerulopathy signs. Some modern pathophysiological mechanisms proposed today for understanding of NADKD such as vascular, inflammatory, acute renal injury and use of pharmacological agents with renoprotective properties are elucidated. Contemporary data about clinical characteristics of NADKD, as well as its prognostic value, diagnostics and monitoring and its association with cardiovascular risk are given. A prognostic significance of NADKD should be defined more precisely. NADKD is shown to increase a risk of myocardial infarction and stroke development as well as a death from cardiovascular causes in patients with diabetes mellitus. An importance of the search for alternative diagnostic markers for detecting renal injury in the absence of albuminuria is emphasized. The evaluations of the markers of tubular damage and interstitial fibrosis, as well as proteomic approaches, are considered today as perspective diagnostic and prognostic options in NADKD. The study of pathogenesis, pathomorphology, clinical course of NADKD, as well as the development of approaches for an early diagnostics and treatment of this complication of diabetes mellitus are determined as the tasks for future research.&#x0D;

#4479 KIM-1, IL-18 AND NGAL IN MACHINE LEARNING PREDICTION OF KIDNEY INJURY AMONG CHILDREN UNDERGOING HEMATOPOIETIC STEM CELL TRANSPLANTATION

Abstract Background and Aims Children undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT) are particularly vulnerable to acute kidney injury (AKI), especially in the early post-transplantation period. The major risk factors of AKI development are aggressive immunosuppression and infectious complications. In the meantime, malnutrition and hypermetabolic state of the patient, together with the routine intensive hydration during first 3 weeks after HSCT and subsequent forced diuresis, alter the serum creatinine concentration, modifying the estimated glomerular filtration rate (eGFR) value too. Therefore, the risk of underrating serum creatinine and overrating eGFR values is high, making the assessment of the degree of kidney damage during the first month after HSCT a challenge. Therefore, markers of tubular dysfunction and damage, like kidney injury molecule (KIM)-1, neutrophil gelatinase-associated lipocalin (NGAL) or interleukin (IL)-18, may be of added value while assessing renal function and analyzing the risk of AKI in this population. The aim of study was to assess the serum concentrations of damage biomarkers (KIM-1, NGAL, IL-18) in children undergoing alloHSCT, in relation to another surrogate marker of renal dysfunction, hyperfiltration. Another aim was to analyze the potential value of KIM-1, NGAL, and IL-18 as predictors of kidney damage in children after alloHSCT, with the use of artificial intelligence tools. Method The study group contained 22 children undergoing alloHSCT, followed up for 4 weeks after transplantation. Serum concentrations of KIM-1, NGAL, and IL-18 were assessed by ELISA in fixed time points (before HSCT, 1 day after HSCT, 1, 2 3, 4 weeks after transplantation). eGFR values (counted based on Schwartz formula) and the rate of hyperfiltration (eGFR &amp;gt; 140ml/min/1.73sq.m.) were evaluated at the beginning (before HSCT) and at the end (4 weeks after HSCT) of observation, when neither hydration nor diuretics were used. Statistical analysis was performed with the use of package Statistica, the comparisons between paired data were evaluated by using nonparametric tests (Friedman, Wilcoxon). Additionally, the patients within the database were randomly divided into two groups. The training group allowed to build a Random Forest Classifier (RFC) with the highest possible predictive power, while the testing group allowed to assess the effectiveness of prediction on new data and the clinical utility. Moreover, the contribution of individual variables was evaluated by GINI importance. Results KIM-1, NGAL, and IL-18 serum concentrations increased systematically until the 3rd week after HSCT, with statistically significant differences between subsequent observation points, then remained elevated until the 4th week after HSCT. Median eGFR values before transplantation and 4 weeks after HSCT were comparable, although the rate of patients with hyperfiltration increased. The RFC model built on the basis of 3 input variables, KIM-1, NGAL, and IL-18 concentrations in serum of children before HSCT, was able to effectively assess the rate of patients with hyperfiltration 4 weeks after the procedure. RF Classifier achieved AUROC of 0.8333, accuracy of 80.00%, positive predictive value of 0.8667, and sensitivity of 0.8000. The contribution of KIM-1, IL-18 and NGAL to the prediction in this model was comparable (33.73%, 32.77%, and 33.5%, respectively). Conclusion KIM-1, NGAL, and IL-18 are useful in assessing acute tubular damage in children after HSCT. Their values before HSCT may also serve as markers of incipient renal dysfunction 4 weeks after alloHSCT. The developed model seems a clinically useful tool to target patients who are at risk of kidney injury after HSCT. The Random Forest Classifier seems a promising tool for such analysis, that should be tested on a larger group of patients.

MWF RAT AS A NOVEL ANIMAL MODEL OF CARDIORENAL SYNDROME TYPE IV

Objective: Cardiorenal syndrome type 4 (CRS type 4) is characterized by primary chronic kidney disease (CKD) leading to cardiac dysfunction and an increase in cardiovascular events. There is an unmet need for suitable animal models of CRS to further define the pathogenesis and progression of CRS to test new therapeutic strategies. We aim to determine if CKD in aged Munich Wistar Frömter (MWF) rat may translate to cardiovascular alterations of CRS. Design and method: Profibrotic markers and angiotensin receptor (ATR) expression was measured by RT-q-PCR in kidney, aorta and heart from 22 and 45-week-old (aged) male MWF rats (n = 7-10/group). Results: Aged MWF showed higher renal expression of tubular damage markers (Kim-1 and Ngal) and profibrotic factors (Col1A1, Col3A1, TGF-beta) together with lower levels of AT2R. Thoracic aorta also exhibited increased expression of profibrotic CTGF-1 and Col1-A1, as well as a lower AT2R expression. Both age groups were hypertensive with similar systolic and diastolic blood pressure levels. However, aged MWF had an increased PWV and heart weight, together with increased intrinsic arterial stiffness and an outward hypertrophic remodeling in mesenteric arteries. In 45-week-old MWF, levels of cardiac CTGF-1, AT1R and AT2R were higher, whereas TGF-beta expression was lower. No differences were observed for Col1A1 or Col3A1. Conclusions: The presence of renal and vascular fibrosis, hypertension, arterial stiffness and cardiac hypertrophy, together with inflammation, vascular remodeling and early profibrotic cardiac environment, potentially counterregulated by AT2R make aged-MWF rat an useful model for CRS study.