Marker Of Tubular Dysfunction Research Articles

Iron Deficiency and Renal Phosphate Handling: The Role of Maximal Tubular Reabsorption of Phosphate Normalized to Glomerular Filtration Rate (TmP/GFR) in Proximal Tubular Dysfunction.

Phosphate dysregulation is often associated with chronic kidney disease (CKD), and recent studies suggest that it may also be present in non-CKD patients with systemic conditions including iron deficiency anemia. This study aimed to evaluate the relationship between irondeficiency parameters (total iron-binding capacity {TIBC}, hemoglobin, and serum ferritin) and markers of proximal tubular dysfunction (the maximal tubular reabsorption of phosphate normalized to glomerular filtration rate {TmP/GFR} and tubular reabsorption of phosphate {TRP}) in non-CKD patients with iron deficiency anemia. This was a hospital-based analytical cross-sectional study conducted in the outpatient department and/or inpatient wards of the Department of Internal Medicine, Swaroop Rani Nehru (SRN) Hospital associated with Moti Lal Nehru (MLN) Medical College, Prayagraj, Uttar Pradesh, India, between July 2023 and August 2024. This study analyzed 40 anemic patients without CKD, with a mean age of 33.9 years. Most participants (n=24, 60%) were aged 18-35 years, and the majority (n=27, 67.5%) were female. Peripheral smear analysis revealed that 72.5% (n=29) had microcytic hypochromic anemia. Hemoglobin levels averaged 7.7 g/dL, serum iron was 91.0 µg/dL, total iron-binding capacity (TIBC) was 316.3 µg/dL, and serum ferritin was 199.7 ng/mL. Phosphate handling was assessed with TmP/GFR and tubular reabsorption of phosphate (TRP)showing mean values of 4.1 mg/dL and 99.2%, respectively. This study found that TmP/GFR had a significant positive correlation with TIBC (r=0.402, p=0.010), but non-significant negative correlations with hemoglobin and serum iron. TRP was negatively correlated with hemoglobin and serum ferritin, but not significantly. Among patients with microcytic hypochromic anemia, 55.2% (n=16) had increased TmP/GFR, and 61.1% (n=20) of patients with iron deficiency anemia exhibited increased TmP/GFR. Regression analysis revealed that TIBC significantly predicted TmP/GFR (p=0.022), indicating that higher TIBC values are associated with increased TmP/GFR, suggesting a potential link between iron metabolism and renal phosphate handling. Higher TIBC levels were associated with increased TmP/GFR, suggesting that iron deficiency anemia may influence proximal tubular function. The findings emphasize the importance of considering renal phosphate handling in patients with iron deficiency anemia.

Cardiorenal continuum: clinical and pathogenetic relationships between heart failure with preserved ejection fraction and renal tubular dysfunction

The article presents data on the high relevance of studying a renal tubular injury in heart failure with preserved ejection fraction (HFpEF). The available research data and prerequisites for HFpEF development and renal tubular injury in detail. Markers of tubulopathy are presented. The main paradigm of cardiorenal syndrome in HFpEF with renal tubular injury is discussed — the unity of risk factors and pathogenetic mechanisms (low-intensity chronic inflammation, endothelial dysfunction, profibrotic hyperactivity). The need to identify markers of tubular dysfunction is due to expanding preventive capabilities to slow down the cardiorenal continuum stages — a decrease in filtration function and further remodeling of the myocardium and vascular bed. The review presents the analysis of available Russian and foreign data and analytical portals.

#205 Features of chronic kidney disease in patients with obesity and arterial hypertension

Abstract Background and Aims to assess the indicators of composite body composition in patients with obesity and chronic kidney disease with arterial hypertension. Method 59 patients with obesity and arterial hypertension were examined. When selecting patients, inclusion criteria were taken into account: men and women aged 25 to 55 years, obesity (BMI more than 30 kg/m²; waist circumference (WC) more than 80 cm in women and more than 94 cm in men), presence of hypertension I– Stage II, grade 1–2, absence of renal pathology (history of kidney disease, structural changes in the parenchyma and vessels of the kidneys during ultrasound examination, changes in urinary sediment and urine density, proteinuria, decreased GFR less than 60 ml/min/1.73 m² ), signed informed consent. Metabolically complicated obesity was defined as the presence of abdominal obesity, a BMI of more than 30 kg/m2 in combination with hypertension and ≥ 2 cardiometabolic abnormalities. A metabolically healthy obesity phenotype was considered to be the presence of obesity without hypertension, dyslipidemia, or hyperglycemia. The results obtained during the study were compared with the indicators of a control group formed from 30 practically healthy individuals aged 25–55 years without obesity or overweight. Differences in age, gender, duration of hypertension and obesity were not established. Metabolic activity of adipose tissue was assessed by the level of leptin, soluble leptin receptors (sLR), adiponectin, resistin, free leptin index (FLI), leptin/adiponectin index (L/A). Renal function: GFR (CKD EPI and Hoek), serum and urine cystatin C, albuminuria. The composite composition of the body was studied using bioimpedance analysis using an ABC-01 Medass analyzer of body composition and balance of water sectors of the body. Results In a comparative analysis of the parameters of the composite body composition in the obese groups, the highest values ​​of fat mass (42.8 ± 6.8 and 35 ± 4.2 kg) and total fluid (40.2 ± 5.0 and 36.0 ± 2.8 kg) with a reduced proportion of 17 active cell mass (ACM) (53.0 ± 3.2 and 56.1 ± 3.4%) were detected in patients with complicated obesity (p < 0.05). Regardless of the obesity phenotype, correlations were established: between the level of diastolic blood pressure (DBP) and the volume of total (r1 = 0.42; r2 = 0.52) and extracellular fluid (r1 = 0.50; r2 = 0.60); level of DBP and urinary excretion of cystatin C (r1 = 0.51; r2 = 0.61) (p < 0.01). A decrease in the proportion of ACM in obese groups was associated with an increase in resistin levels (r1 = −0.56; r2 = −0.31). In obese groups, regardless of phenotype, fat mass was associated with leptin levels (r1 = 0.52; r2 = 0.42) and free leptin index (FLI) (r1 = 0.75; r2 = 0.46 ) (p < 0.05). In group 1, a positive correlation was additionally established for the volume of fat mass with systolic blood pressure (SBP) (r1 = 0.70) and DBP (r1 = 0.65), with the level of uric acid (r1 = 0.57), cholesterol LDL (r1 = 0.52), cystatin C in urine (r1 = 0.75) and insulin resistance index (HOMA-IR) (r1 = 0.65) (p < 0.01). Conclusion Body mass index does not determine the obesity phenotype. In patients with complicated obesity, the proportion of fat mass is higher than in metabolically healthy obesity and is associated with increased levels of glucose and uric acid. All obese patients are characterized by an increase in the percentage of total and extracellular fluid, associated with the level of blood pressure and urinary excretion of markers of tubular dysfunction.

Urinary Vitamin D Binding Protein: A Marker of Kidney Tubular Dysfunction in Patients at Risk for Type 2 Diabetes.

Recent studies have reported elevated urinary vitamin D binding protein (uVDBP) concentrations in patients with diabetic kidney disease, although the utility of uVDBP to predict deterioration of kidney function over time has not been examined. Our objective was to assess the association of uVDBP with longitudinal changes in kidney function. Adults at-risk for type 2 diabetes from the Prospective Metabolism and Islet Cell Evaluation (PROMISE) study had 3 assessments over 6 years (n = 727). Urinary albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) were used as measures of kidney function. Measurements of uVDBP were performed with enzyme-linked immunosorbent assay and normalized to urine creatinine (uVDBP:cr). Generalized estimating equations (GEEs) evaluated longitudinal associations of uVDBP and uVDBP:cr with measures of kidney function, adjusting for covariates. Renal uVDBP loss increased with ACR severity at baseline. Individuals with normoalbuminuria, microalbuminuria, and macroalbuminuria had median log uVDBP:cr concentrations of 1.62 μg/mmol, 2.63 μg/mmol, and 2.48 μg/mmol, respectively, and ACR positively correlated with uVDBP concentrations (r = 0.37; P < .001). There was no significant association between uVDBP and eGFR at baseline. Adjusted longitudinal GEE models indicated that each SD increase both in baseline and longitudinal uVDBP:cr was significantly associated with higher ACR over 6 years (β = 30.67 and β = 32.91, respectively). Conversely, neither baseline nor longitudinal uVDBP:cr measures showed a significant association with changes in eGFR over time. These results suggest that loss of uVDBP:cr over time may be a useful marker for predicting renal tubular damage in individuals at risk for diabetes.

The pathogenesis of albuminuria in cadmium nephropathy

BackgroundUrinary cadmium excretion (ECd) rises with renal tissue content of the metal. Whereas glomerulopathies are sometimes associated with massive albuminuria, tubular accumulation of Cd typically causes modest albuminuria. Since β2-microglobulinuria (Eβ2M) is an established marker of proximal tubular dysfunction, we hypothesized that a comparison of albuminuria (Ealb) to Eβ2M in Cd-exposed subjects would provide evidence of similar mishandling of both proteins. MethodsTo depict excretion rates per functional nephron, ECd, Ealb, and Eβ2M were normalized to creatinine clearance (Ccr), a surrogate for the glomerular filtration rate (GFR). Estimation of GFR itself (eGFR) was accomplished with CKD-EPI formulas (2009). Linear and logistic regression analyses were performed to relate Ealb/Ccr, Eβ2M/Ccr, and eGFR to several independent variables. Simple linear regressions of eGFR, Ealb/Ccr, and Eβ2M/Ccr on ECd/Ccr were examined before and after adjustment of dependent variables for age. All regressions were performed after log-transformation of ratios and standardization of all variables. Increments in Ealb/Ccr and Eβ2M/Ccr and decrements in eGFR were quantified through four quartiles of ECd/Ccr. ResultsAs age or ECd/Ccr rose, Ealb/Ccr and Eβ2M/Ccr also rose, and eGFR fell. In linear regressions, slopes relating Ealb/Ccr and Eβ2M/Ccr to ECd/Ccr were similar. After adjustment of dependent variables for age, coefficients of determination (R2) for all regressions rose by a multiple, and slopes approached unity. Ealb/Ccr and Eβ2M/Ccr were similarly associated with each other. Mean Ealb/Ccr and Eβ2M/Ccr rose and mean eGFR fell in stepwise fashion through quartiles of ECd/Ccr. Whereas Eβ2M/Ccr did not vary with blood pressure, Ealb/Ccr rose in association with hypertension in two of the four quartiles. ConclusionsOur data indicate that Cd in renal tissue affected tubular reabsorption of albumin and β2M similarly in a large cohort of exposed subjects. The results suggest that Cd reduced receptor-mediated endocytosis and subsequent lysosomal degradation of each protein by a shared mechanism.

Predictive Capacity of Plasma and Urinary Biomarkers for Persistent Albuminuria in Patients with Sickle Cell Disease

Introduction: Chronic kidney disease (CKD) is common in sickle cell disease (SCD) and is associated with increased mortality and morbidity. As albuminuria and changes in estimated glomerular filtration rate (eGFR) occur well after substantial structural and functional tissue damage have occurred, novel biomarkers are needed to predict CKD prior to its development. In this multicenter study, we investigated the association of multiple plasma and urine biomarkers with persistent albuminuria (PA) and their potential in predicting PA in patients with SCD. Methods: Adult subjects with HbSS or HbSb 0 thalassemia were enrolled in a prospective, longitudinal cohort study of CKD in SCD. We excluded patients with diabetic nephropathy, cancer, connective tissue disease, other glomerular diseases, end-stage kidney disease on dialysis, known infection with hepatitis (B or C) or HIV, and who had undergone bone marrow transplantation and solid organ transplantation. Participants were enrolled during routine clinical visits in the non-crisis, “steady states.” PA was defined as at least 2 of 3 spot urine albumin-creatinine ratio (ACR) values ≥30 mg/g or a single value ≥100 mg/g. At baseline evaluation, plasma was analyzed for biomarkers of coagulation activation (D-dimer, thrombin antithrombin complex [TAT], ratio of cleaved high molecular weight kininogen-to-intact high molecular weight kininogen [cHK/iHK]), endothelial dysfunction (endothelin-1 [ET1], vascular endothelial growth factor [VEGF], vascular cell adhesion molecule-1 [VCAM-1]), and urine was analyzed for kidney injury molecule 1 (KIM-1), nephrin and angiotensinogen (AGT) using commercially available ELISA. All urinary biomarkers were normalized to urine creatinine. For baseline values, a standard t-test was performed for continuous variables and a chi-square test was performed for categorical variables. Logistic regression analysis was performed to assess univariate predictors of research biomarkers for PA. Results: Of 278 evaluated subjects, 104 (37.4 %) had PA with a median ACR of 194.5 mg/g [IQR: 102.4, 487.1], and 174 subjects (62.6 %) did not have PA (non-PA) with a median ACR of 13.0 mg/g [IQR: 7.4, 22.4]. Subjects with PA were older, had lower hemoglobin and fetal hemoglobin, but higher systolic and diastolic blood pressures than those without PA (Table 1). Plasma VCAM-1, urinary KIM-1, and urinary AGT were significantly associated with PA with odds ratios of 1.001 (AUC: 0.636; 95% CI: 1.00, 1.002), 1.737 (AUC: 0.661; 95% CI: 1.226, 2.575), and 1.053 (AUC: 0.71; 95% CI: 1.029, 1.084), respectively (Table 2). Surprisingly, ET1 and urinary nephrin-creatinine ratio were not significantly associated with PA in this cohort. Conclusion: Urinary AGT exhibited the highest sensitivity for PA, while urinary KIM-1 was the most specific. The relatively modest sensitivity of KIM-1, a marker of renal tubular dysfunction, is likely because albuminuria in SCD results from both glomerular and tubular dysfunction. These results highlight the potential importance of urinary AGT as a key biomarker in identifying individuals at risk for PA. Our ongoing studies will evaluate the predictive capacity of these biomarkers for development of PA in SCD.

Assessment of Circulating Retinol Binding Protein-4 Levels in Patients with Compound Heterozygosity for Hb S and β-Thalassemia

Background: Retinol Binding Protein-4 (RBP-4) is a member of the lipocalin family of proteins and the major transport protein of the hydrophobic molecule retinol, also known as vitamin A, in the circulation. Expression of RBP4 is highest in the liver, where most of the body's vitamin A reserves are stored as retinyl esters. For the mobilization of vitamin A from the liver, retinyl esters are hydrolyzed to retinol, which then binds to RBP-4 in the hepatocyte. After associating with transthyretin (TTR), the retinol/RBP-4/TTR complex is released into the bloodstream and delivers retinol to tissues via binding to specific membrane receptors. While, after its dissociation from TTR and retinol release, retinol-free apo-RBP4 in the circulation is filtrated by the kidney. More than 99% of that is reabsorbed by the proximal renal tubule, which renders urinary RBP-4 a highly sensitive marker for tubular dysfunction. We and other have shown previously that the patients with Sickle Cell Disease (SCD) have deficiencies or suboptimal levels of vitamin A, while recently (Br J Haematol. 2023;doi:10.1111/bjh.18862) higher urine RBP-4 in patients with SCD especially in those with persistent albuminuria but without an association of urine RBP-4 levels with estimated glomerular filtration rate (eGFR). In this context, we aimed to investigate the potential clinical significance of circulating plasma RBP-4 levels and its association with disease features in Caucasian patients with compound heterozygosity for HbS and β-thalassemia (HbS/β thal). Patients and Methods: Ninety Caucasian adult patients with HbS/β thal at steady phase were included in the study, while 22 apparently healthy individuals of similar age and gender served as controls. None of the patients was diabetic and has received any transfusions at least 6-monthes before enrollment in the study. RBP-4 concentration was measured with an immunoturbidimetric assay applied in an automated chemistry analyzer, along with hematologic, and series of blood chemistry parameters reflecting renal, cardiac and endothelial dysfunction. eGFR values were calculated using the CKD-EPI (Cystatin C and/or Creatinine equations). Results: We found that: a) Plasma RBP-4 levels were significantly lower in patients with HbS/β thal compared to controls, 30.5±2.7mg/L (Confidence Intervals (CI): 28.8;32.2mg/mL) vs 36.3±3.6mg/L (CI: 32.7;39.9mg/mL), p&amp;lt;0.003. The patients with β + genotypehave higher RBP-4 levels than those with β 0 genotype (p&amp;lt;0.05), whereas patients treated with hydroxycarbamide(50/90) are more likely to express higher RBP-4 levels, p-trend=0.06; b) RBP-4 levels in patients with HbS/β thal correlated positively with their age, body mass index (BMI) and Hb levels (r=0.264, p=0.012; r=0.334, p=0.001 and r=0.209, p&amp;lt;0.05, respectively; c) RBP-4 levels in patients with HbS/β thal correlated with total bilirubin, total cholesterol, triglycerides and uric acid (r=-0.452, p&amp;lt;0.001; r=0.395, p=0.004; r=0.292, p=0.015 and r=0.435, p&amp;lt;0.001, respectively); d) RBP-4 levels in patients with HbS/β thal correlated negatively with eGFR values rho=-0.360, p=0.003 and hs-CRP concentrations r=-0.309, p=0.004 and e) No correlations were found between RBP-4 levels with markers of cardiac and endothelial dysfunction such as High Sensitivity Troponin T, Growth Differentiation Factor-15, von Willebrand factor antigen, Α Disintegrin and Metalloproteinase with Thrombospondin Type 1 Motif 13 antigen and P-Selectin, as well as with number of vaso-occlusive crisis and mean pulmonary arterial pressure in the patients. Conclusions: These findings demonstrate a multifactorial role of RBP-4 in patients with HbS/β thal as the circulating levels of the protein correlate significantly with markers of erythropoiesis, inflammation and renal function. It is unclear of this study if RBP-4 has any specific functions in patients with HbS/β thal. However, RBP-4 should be more investigated in order to determine its clinical significance and in the case of sickle cell nephropathy both plasma and urine measurements should be considered.

Renal Involvement in Multisystem Inflammatory Syndrome in Children: Not Only Acute Kidney Injury.

Kidney involvement has been poorly investigated in SARS-CoV-2 Multisystem Inflammatory Syndrome in Children (MIS-C). To analyze the spectrum of renal involvement in MIS-C, we performed a single-center retrospective observational study including all MIS-C patients diagnosed at our Pediatric Department between April 2020 and May 2022. Demographic, clinical, pediatric intensive care unit (PICU) admission's need and laboratory data were collected at onset and after 6 months. Among 55 MIS-C patients enrolled in the study, kidney involvement was present in 20 (36.4%): 13 with acute kidney injury (AKI) and 7 with isolated tubular dysfunction (TD). In eight patients, concomitant AKI and TD was present (AKI-TD). AKI patients needed higher levels of intensive care (PICU: 61.5%, p < 0.001; inotropes: 46.2%, p = 0.002; second-line immuno-therapy: 53.8%, p < 0.001) and showed lower levels of HCO3- (p = 0.012), higher inflammatory markers [neutrophils (p = 0.092), PCT (p = 0.04), IL-6 (p = 0.007)] as compared to no-AKI. TD markers showed that isolated TD presented higher levels of HCO3- and lower inflammatory markers than AKI-TD. Our results indicate a combination of both pre-renal and inflammatory damage in the pathogenesis of kidney injury in MIS-C syndrome. We highlight, for the first time, the presence of tubular involvement in MIS-C, providing new insights in the evaluation of kidney involvement and its management in this condition.

#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.

Proteomic characterization of acute kidney injury in patients hospitalized with SARS-CoV2 infection

BackgroundAcute kidney injury (AKI) is a known complication of COVID-19 and is associated with an increased risk of in-hospital mortality. Unbiased proteomics using biological specimens can lead to improved risk stratification and discover pathophysiological mechanisms.MethodsUsing measurements of ~4000 plasma proteins in two cohorts of patients hospitalized with COVID-19, we discovered and validated markers of COVID-associated AKI (stage 2 or 3) and long-term kidney dysfunction. In the discovery cohort (N = 437), we identified 413 higher plasma abundances of protein targets and 30 lower plasma abundances of protein targets associated with COVID-AKI (adjusted p < 0.05). Of these, 62 proteins were validated in an external cohort (p < 0.05, N = 261).ResultsWe demonstrate that COVID-AKI is associated with increased markers of tubular injury (NGAL) and myocardial injury. Using estimated glomerular filtration (eGFR) measurements taken after discharge, we also find that 25 of the 62 AKI-associated proteins are significantly associated with decreased post-discharge eGFR (adjusted p < 0.05). Proteins most strongly associated with decreased post-discharge eGFR included desmocollin-2, trefoil factor 3, transmembrane emp24 domain-containing protein 10, and cystatin-C indicating tubular dysfunction and injury.ConclusionsUsing clinical and proteomic data, our results suggest that while both acute and long-term COVID-associated kidney dysfunction are associated with markers of tubular dysfunction, AKI is driven by a largely multifactorial process involving hemodynamic instability and myocardial damage.

Renal protein reabsorption impairment related to a myxosporean infection in the grass frog (Rana temporaria L.).

A morphophysiological study of tubular reabsorption and mechanisms of protein endocytosis in the kidney of frogs (Rana temporaria L.) during parasitic infection was carried out. Pseudoplasmodia and spores of myxosporidia, beforehand assigned to the genus Sphaerospora, were detected in Bowman's capsules and in the lumen of individual renal tubules by light and electron microscopy. Remarkable morphological alteration and any signs of pathology in kidney tissue related to this myxosporean infection have not been noted. At the same time, significant changes in protein reabsorption and distribution of molecular markers of endocytosis in the proximal tubule (PT) cells in infected animals were detected by immunofluorescence confocal microscopy. In lysozyme injection experiments, the endocytosed protein and megalin expression in the infected PTs were not revealed. Tubular expression of cubilin and clathrin decreased, but endosomal recycling marker Rab11 increased or remained unchanged. Thus, myxosporean infection resulted in the alterations in lysozyme uptake and expression of the main molecular determinants of endocytosis. The inhibition of receptor-mediated clathrin-dependent protein endocytosis in amphibian kidneys due to myxosporidiosis was shown for the first time. Established impairment of the endocytic process is a clear marker of tubular cell dysfunction that can be used to assess the functioning of amphibian kidneys during adaptation to adverse environmental factors.

A marker of tubular dysfunction is lipocalin associated with gelatinase of neutrophils

The article reviews studies devoted to the prognostic effectiveness of neutrophil gelatinase-associated lipocalin (NGAL). NGAL is a predictor of acute kidney injury. The content of NGAL in urine is a more effective indicator for the diagnosis of acute kidney injury, compared to NGAL in serum and blood plasma. The results of this review prove that the predictive performance is also influenced by age, gender (higher predictive value in women than men), urinary tract infection and renal dysfunction (higher predictive value in patients with chronic kidney disease), etc.

Kidney Tubules — Scientific and Applied Value

Currently, there is a high scientific interest in studying the features of the structure and functions of the tubules of the kidneys. The relevance of the topic is due to the potential possibility of identifying various markers of tubular dysfunction and using them for early diagnosis of not only tubulopathies, but also glomerular disorders. In clinical practice, markers of tubular dysfunction are used insufficiently. The article presents information about the anatomical and functional features of the proximal and distal parts of the tubular apparatus, outlines highly organized mechanisms of intermolecular interaction, presents the main biologically active substances, the change in the concentration of which is a consequence of damage to the tubules. The presented manuscript is the product of a deep analysis and systematization of the available data in Russian and foreign information and analytical portals.

Renal Dysfunction in Pediatric Patients in Iraq With β-Thalassemia Major and Intermedia.

BackgroundWith optimum transfusion and chelation therapy, the survival of β-thalassemia patients and the incidence of various complications, including renal complications, have improved.ObjectivesTo investigate renal involvement in β-thalassemia patients using serum and urinary biochemical markers of glomerular and tubular dysfunction.MethodsThis case-control study included 69 β-thalassemia major (β-TM) patients, 23 β-thalassemia intermedia (β-TI) patients, and 100 healthy controls, all ranging from 1 to 16 years in age. Blood urea nitrogen (BUN), serum ferritin, serum and urinary levels of creatinine (Cr), uric acid (UA), calcium (Ca), phosphorus (Ph), magnesium (Mg), sodium (Na), and potassium (K), and the urinary albumin/creatinine ratio were evaluated.ResultsThe BUN level and the urinary Na/Cr, K/Cr, Ca/Cr, Mg/Cr, Ph/Cr, albumin/Cr, and UA/Cr ratios were significantly higher in the β-thalassemia patients than in the controls. In contrast, the serum Na, K, Ca, and Mg levels were significantly lower in the patients (P<0.05). An elevated urinary UA/Cr ratio was found in 61.9% of β-thalassemia patients, and an elevated urinary Ca/Cr, and urinary albumin/Cr ratio was found in 53.2%. An elevated Na/Cr ratio was found in 41.3%. The serum and urinary renal markers showed no significant differences between patients with β-TM and β-TI, except for microscopic hematuria, which was significantly higher in β-TI patients (34.8%) than in β-TM patients (13%), P>0.02. At an older age, high serum ferritin levels and deferoxamine therapy were associated with significant tubular and glomerular dysfunction in β-thalassemia patients.ConclusionsPediatric patients with β-thalassemia have significantly abnormal tubular and glomerular functions, necessitating early detection and monitoring to prevent/reverse renal function deterioration.

Proximal tubular dysfunction in pregnant women receiving tenofovir disoproxil fumarate to prevent mother-to-child transmission of hepatitis B virus

Data evaluating the risk of proximal tubular dysfunction in women receiving tenofovir disoproxil fumarate for the prevention of mother-to-child transmission (PMTCT) of HBV are scarce. To assess the risk of proximal tubulopathy in pregnant women receiving tenofovir disoproxil fumarate for PMTCT of HBV. We used urine samples collected from HBV monoinfected pregnant women who participated in a Phase III, multicentre, randomized, double-blind, placebo-controlled clinical trial assessing a tenofovir disoproxil fumarate short course from 28 weeks gestational age (28-wk-GA) to 2 months post-partum (2-months-PP) for PMTCT of HBV in Thailand. Markers of tubular dysfunction, including retinol binding protein, kidney injury molecule-1, α1-microglobuin and β2-microglobulin, were assayed at 28- and 32-wk-GA and 2-months-PP visits. Proximal tubulopathy was defined as the presence of ≥2 of the following: tubular proteinuria, euglycaemic glycosuria and increased urinary phosphate. A total of 291 women participated in the study. No kidney-related adverse events were severe, and none led to tenofovir disoproxil fumarate discontinuation. At 2-months-PP, 3 of the 120 (3%) evaluated women in the tenofovir disoproxil fumarate group experienced proximal tubulopathy versus 3 of 125 (2%) in the placebo group (P = 1.00). None of the six women met the criteria for proximal tubulopathy at 12-months-PP but proteinuria persisted in three of them. No growth abnormalities were found at 1 year of age in infants born to mothers with proximal tubulopathy at 2-months-PP. In these HBV-infected pregnant and breastfeeding women, tenofovir disoproxil fumarate administered from 28-wk-GA to 2-months-PP was not associated with a higher risk of proximal tubulopathy.

Glycosuria in primary glomerulopathies: prevalence and prognostic significance.

Introduction:Tubular damage is common in glomerular diseases (GD). Glycosuria is a marker of tubular dysfunction and may be used to detect tubular lesion and CKD progression. The aim of this study was to evaluate the prevalence and prognostic value of glycosuria at the time of diagnosis in primary glomerulopathies (PG).Methods: We conducted a 24-month retrospective study in patients diagnosed with PG in our center between 2009 and 2020. We excluded diabetic patients, use of SGLT2 inhibitors, transplant patients, and secondary GD. Patients were divided in two groups according to their glycosuria status at diagnosis.Results:We studied 115 patients. Global prevalence of glycosuria was 10% (n=11) and membranous nephropathy (MN) had the highest prevalence (n=5, 17.9%). We found that patients with glycosuria had higher serum creatinine (2.4 vs. 1.2 mg/dL, p=0.030), higher albuminuria (4.8 vs. 1.9 g/g, p=0.004), and lower serum albumin (2.3 vs. 3.2 g/dL, p=0.021). We did not find association with histological prognostic factors. At the end of follow-up, patients with glycosuria had higher prevalence of the composite outcome of stage 5D CKD or 50% increase in basal SCr (45.5% vs. 17.3%, p=0.037). In patients with MN, results were similar but we were able to find an association of glycosuria with more severe interstitial fibrosis and tubular atrophy (25.0 vs. 0.0 %, p=0.032).Conclusion: Ten percent of our patients with PG have glycosuria. Glycosuria at the time of diagnosis was associated with more severe clinical presentation and worst renal outcome. The association with higher albuminuria suggests that tubular function has an impact on the severity and outcomes of PG.

Study of uric acid excretion in children with beta-thalassemia major attending Alexandria University Children’s Hospital

Background It is evident that high cell turnover rate is present in patients suffering from β-thalassemia. This is mainly the result of not only chronic hemolysis but also ineffective erythropoiesis. It is thus expected that hyperuricemia will occur. Aim Our study was conducted to study uric acid excretion in β-thalassemia major patients and to determine its relationship to tubular dysfunction in those patients. Patients and methods This case–control study was performed on 60 patients with β-thalassemia major and 15 children who were healthy and well, playing the role of the control group. Thorough history taking, review of medical records, and complete physical examination were done for all patients. Evaluation of uric acid excretion, glomerular and tubular renal functions were performed and compared between patients and the control group. Results Hyperuricemia was found in 48.8% of patients; however, none of the patients had evidence of gouty arthritis or nephrolithiasis. Serum uric acid (SUA) levels in patients who had positive correlation with serum creatinine, urine P/Cr ratio and urine uric acid/glomerular filtration rate (UUA/GFR), negative correlation with eGFR and no correlation with urine calcium/creatinine (UCa/UCr) ratio, blood urea nitrogen (BUN), urine β2 MG, and urinary uric acid/creatinine (UUa/UCr) ratio were assessed. The mean SUA level, BUN, serum creatinine, and levels of eGFR were significantly higher in β-thalassemia patients in comparison to the control group. Urinary P/Cr ratio, urine uric acid/ glomerular filtration rate (UUA/GFR) ratio, β-2 microglobulin levels, UCa/UCr, and UUa/UCr were also higher in β-thalassemia patients in comparison to the control group. The present study has a mean age of 8.62 years for the cases studied, and investigations in patients revealed the following results: mean SUA 5.17 mg/dl, mean BUN 16.58 mg/dl, mean serum creatinine 0.49 mg/dl, mean urine P/Cr ratio 1.40, mean eGFR 141.42 ml/min/1.73 m2, mean UUA/GFR 0.55, mean urine β2 MG 0.18 µg/ml, mean UCa/UCr 0.44, UUa/UCr 1.46, and these results were statistically significantly higher in patients compared with controls. Conclusion Renal dysfunction and hyperuricemia are prevalent among patients with β-thalassemia major, mostly related to hyperfiltration and tubular dysfunction. Early markers of tubular dysfunction (urine β2 MG, UCa/UCr, UUa/UCr) and glomerular dysfunction (urine P/Cr ratio and urinary uric acid/GFR ratio) should be followed up regularly in β-thalassemia major patients.

Clinical and prognostic values of urinary alpha1-microglobulin as a tubular marker in acute heart failure

BackgroundAlthough urinary alpha-1-microglobulin has been used as a marker of tubular dysfunction, its clinical and prognostic values in patients with acute heart failure have not been validated. MethodsWe analyzed 623 patients (74 ± 13 years old, 60.0% male) with acute heart failure in whom urinary alpha-1-microglobulin (A1MG) levels were measured as tubular markers at the time of admission. The primary endpoint was all-cause mortality. ResultsThe median levels of urinary alpha-1-microglobulin with and without correction for urinary creatinine concentration were 8.80 (interquartile range: 4.20–17.7) mg/dL and 12.9 (5.92–30.7) mg/gCr, respectively. Urinary A1MG levels were significantly correlated with all of beta-2-microglobulin (r = 0.77), N-acetyl-β-D-glucosaminidase (r = 0.51), and estimated glomerular filtration rate (r = −0.42); however, alpha-1-microglobulin was most often predicted using beta-2-microglobulin or N-acetyl-β-D-glucosaminidase. During the 488-day (interquartile range: 185–938 days) follow-up, 141 deaths occurred. Higher A1MG levels were associated with higher mortality even after adjustment for other covariates. Only A1MG, but not beta-2-microglobulin or N-acetyl-β-D-glucosaminidase, yielded incremental prognostic information in addition to the preexisting prognostic factors (net-reclassification improvement: 0.254, P = 0.023; integrated discrimination improvement: 0.015, P = 0.028). ConclusionsIn patients hospitalized due to acute heart failure, urinary alpha-1-microglobulin was a marker of tubular dysfunction. High alpha-1-microglobulin was associated with all-cause mortality independent of glomerular function and was a better predictor of mortality than urinary beta-2-microglobulin.

Markers of Kidney Injury, Inflammation, and Fibrosis Associated With Ertugliflozin in Patients With CKD and Diabetes

IntroductionSodium-glucose cotransporter-2 (SGLT2) inhibitors improve cardiovascular and kidney outcomes through mechanisms that are incompletely understood. In this exploratory post-hoc analysis of the VERTIS RENAL trial, we report the association between the SGLT2 inhibitor, ertugliflozin, and markers of kidney injury, inflammation, and fibrosis in participants with type 2 diabetes (T2D) and stage 3 chronic kidney disease (CKD).MethodsParticipants were randomized to ertugliflozin (5 or 15 mg/d) or placebo, and plasma samples for biomarker analysis were collected at baseline, 26 weeks, and 52 weeks.ResultsErtugliflozin-treated participants had lower plasma levels of kidney injury molecule-1 (KIM-1) at 26 weeks (P = 0.044) and 52 weeks (P = 0.007) and higher eotaxin-1 at 52 weeks (P = 0.007) postrandomization compared with placebo. The change in KIM-1 was not associated with the baseline urine albumin to creatinine ratio (UACR) or the estimated glomerular filtration rate (eGFR, P interaction > 0.05). Additionally, the change in KIM-1 was positively correlated with the change in UACR in participants treated with ertugliflozin (P = 0.0071). No other significant associations between ertugliflozin and changes in the markers of tubular injury, inflammation, fibrosis, oxidative stress, and endothelial dysfunction were observed.ConclusionIn conclusion, in participants with T2D and stage 3 CKD, ertugliflozin was associated with a sustained lowering of the tubular injury marker KIM-1 regardless of baseline kidney function.

Uric Acid Abnormalities and Its Correlation with Splenectomy in Adult Transfusion Dependent Thalassemia Subjects (TDT)

Background: In thalassemia patients erythrocyte turnover rate increases due to chronic hemolysis and ineffective erythropoiesis leading to increase in uric acid production. Hyperuricosuria is one of the marker of proximal tubular dysfunction. Splenectomy can increase the risk of hyperuricemia by increasing erythrocyte turnover rate in Transfusion Dependent Thalassemia (TDT). Deferasirox enhances uric acid excretion from renal tubules leading to low serum uric acid levels. Methods: An institution based cross-sectional study was conducted from November 2018-March 2020 which included 60 adult TDT patients (≥18 years) attending Adult Thalassemia Day Care Centre at tertiary care hospital. Serum uric acid (mg/dl), 24 hour urinary uric acid (mg/dl), serum ferritin (ng/ml) were done. Results: Hyperuricemia was present in 20%, hypouricemia in 3.33%. Hyperuricosuria was present in 80%. Mean SUA levels were higher in males than females which was statistically significant (5.77±1.66 vs 4.64±1.44, p=0.007). There was statistically significant positive correlation between serum uric acid and serum creatinine(p = 0.0036) and age (p=0.0129). Hyperuricemia was more in subjects with intact spleen but was not statistically significant(p=0.104). Hyperuricemia had negative association with deferasirox therapy [1 (3.03%) vs 11 (40.74%), p=0.0004] compared with normouricemia subjects. Conclusion: Uric acid abnormalities were seen in 23.3% of patients. Hyperuricemia was present in one fourth of the patients and significant risk factors were increasing age, male gender, rising serum creatinine. Deferasirox therapy was negatively associated with hyperuricemia. Tubular dysfunction is relatively common in TDT as more than three fourth patients had hyperuricosuria. Regular monitoring of serum uric acid and urinary uric acid is recommended.