Effects of Prolonged Administration of Tenofovir Disoproxil Fumarate-Containing Antiviral Regimen on Renal Function in Low-Risk of Kidney Injury HIV Patients.

This study intended to investigate the impact of long-term tenofovir fumarate (TDF) antiviral regimen on renal function in human immunodeficiency virus (HIV)-infected patients with low-risk of kidney injury. The observational study involving 100 HIV-infected patients without underlying diseases who achieved virological suppression and immunological recovery after sustained antiviral regimen of TDF+ lamivudine+ efavirenz (TLE) for 3.19 years. Renal function, including estimated glomerular filtration rate (eGFR), blood and urine ß2 microglobulin, and other parameters, was assessed every 3 months over a period of 2.5 years. The eGFR showed a slight increasement from 116.0 at month 0 to 119.7 at month 30. Blood ß2 microglobulin increased from 2.02 mg/L at month 0 to 2.77 mg/L at month 30. Compared to month 0, the difference in blood ß2 microglobulin was statistically significant at month 6 and months 12-30 (P < .05). The incidence of proximal renal tubular dysfunction fluctuated from 2% at month 0 to 2.5% at month 30. The urine ß2 microglobulin fluctuated from 0.5 (0.3-1.1) to 0.8 (0.5-1.35) mg/L at months 18-30, which was higher than 0.41 (0.18-1.1) mg/L at month 0 (P < .05). The abnormal concentration proportion of urine ß2 microglobulin fluctuated from 72.7% to 81.3% at months 18-30, which was higher than the proportion of 57.0% at month 0. The abnormal proportion of blood ß2 microglobulin, urine ß2 microglobulin, and proximal renal tubular dysfunction were not correlated with eGFR (r1 = 0.119, r2 = -0.008, r3 = -0.165, P > .05). Long-term TDF antiviral regimen in low-risk of kidney injury HIV-infected patients may lead to damage in the proximal renal tubules and glomeruli. Blood and urine ß2 microglobulin levels may be helpful in screening for renal dysfunction.

Predictive Value of Serum NGAL and ß2 Microglobulin in Blood and Urine amongst Patients with Acute Pancreatitis and Acute Kidney Injury.

OBJECTIVE: This study aimed to explore the predictive value of neutrophil gelatinase-associated lipocalin (NGAL) and ß2 microglobulin (ß2-MG) in blood and urine amongst patients with acute pancreatitis (AP) and acute kidney injury (AKI). METHODS: The clinical data of 80 patients with AP, who were treated in the study hospital from November 2019, to November 2022, were selected for retrospective analysis. They were divided into AKI group (n = 25) and non-AKI group (n = 55) in accordance with the presence of AKI. The levels of serum NGAL and ß2-MG in blood and urine were compared in both groups. Logistic regression analysis was used to explore the influencing factors of AKI in patients with AP and the receiver operating characteristic (ROC) curve was used to evaluate the predictive efficacy of serum NGAL and ß2-MG in the blood and urine of patients with AKI and AP. RESULTS: The AKI group had higher serum NGAL and ß2-MG in blood and urine than the non-AKI group. Logistic regression analysis showed that the high levels of serum NGAL and ß2-MG in blood and urine were risk factors for AKI in patients with AP (p < 0.05). The areas under the curve (AUC), sensitivity and specificity of the combined prediction were 0.97, 84.00% and 98.20%, respectively, showing a good prediction efficiency. CONCLUSIONS: The increased levels of serum NGAL and ß2-MG in blood and urine have a warning significance for patients with AP and AKI and a certain predictive value. So, their combination detection provides a reliable reference for the identification of clinical AKI.

Effect of renal tubular damage on non-cancer mortality in the general Japanese population living in cadmium non-polluted areas.

This study aimed to clarify the cause-effect relationship between renal tubular damage and non-cancer mortality in the general Japanese population. We conducted a 19-year cohort study including 1110 men and 1,03 women who lived in three cadmium-non-polluted areas in 1993 or 1994. Mortality risk ratios based on urinary ß2-microglobulin (ß2MG) and N-acetyl-ß-glucosaminidase (NAG) concentrations were estimated for specific non-cancer diseases using the Fine and Gray competing risks regression model. In men, continuous urinary NAG (+1 µg/g cre) concentrations were significantly correlated with increased mortality caused by diseases of the respiratory system (hazard ratio (HR): 1.09, 95% confidence interval (CI): 1.03-1.15). Urinary ß2MG (+100 µg/g cre) concentrations were significantly correlated with increased mortalities caused by kidney and urinary tract diseases (HR: 1.01, 95% CI: 1.00-1.03), renal diseases (HR: 1.01, 95% CI: 1.00-1.03), renal failure (HR: 1.02, 95% CI: 1.00-1.03), and external causes of mortality (HR: 1.01, 95% CI: 1.00-1.02). In women, urinary NAG (+1 µg/g cre) concentrations were significantly associated with increased mortality caused by ischemic heart diseases (HR: 1.02, 95% CI: 1.00-1.04) and kidney and urinary tract diseases (HR: 1.01, 95% CI: 1.00-1.04). Urinary ß2MG (+100 µg/g cre) concentrations were significantly correlated with increased mortality caused by cardiovascular diseases (HR: 1.01, 95%CI: 1.00-1.02), ischemic heart diseases (HR: 1.01, 95%CI: 1.00-1.02), and kidney and urinary tract diseases (HR: 1.02, 95% CI: 1.01-1.03). The present study indicates that renal tubular damage was significantly related to several non-cancer disease causes of mortality in Japan's general population living in cadmium-non-polluted areas.

Predictive Value of Serum NGAL and B2 Microglobulin in Blood and Urine amongst Patients with Acute Pancreatitis and Acute Kidney Injury

Objective: This study aimed to explore the predictive value of neutrophil gelatinase-associated lipocalin (NGAL) and β2 microglobulin (β2-MG) in blood and urine amongst patients with acute pancreatitis (AP) and acute kidney injury (AKI). Methods: The clinical data of 80 patients with AP, who were treated in the study hospital from November 2019, to November 2022, were selected for retrospective analysis. They were divided into AKI group (n = 25) and non-AKI group (n = 55) in accordance with the presence of AKI. The levels of serum NGAL and β2-MG in blood and urine were compared in both groups. Logistic regression analysis was used to explore the influencing factors of AKI in patients with AP and the receiver operating characteristic (ROC) curve was used to evaluate the predictive efficacy of serum NGAL and β2-MG in the blood and urine of patients with AKI and AP. Results: The AKI group had higher serum NGAL and β2-MG in blood and urine than the non-AKI group. Logistic regression analysis showed that the high levels of serum NGAL and β2-MG in blood and urine were risk factors for AKI in patients with AP (p < 0.05). The areas under the curve (AUC), sensitivity and specificity of the combined prediction were 0.97, 84.00% and 98.20%, respectively, showing a good prediction efficiency. Conclusions: The increased levels of serum NGAL and β2-MG in blood and urine have a warning significance for patients with AP and AKI and a certain predictive value. So, their combination detection provides a reliable reference for the identification of clinical AKI (AU)

Analysis of the ratio of urinary beta-2-microglobulin to total protein concentration in children with isolated tubulointerstitial disease.

BACKGROUND: Proteinuria is broadly classified into glomerular and tubular proteinuria. Urinary beta-2-microglobulin (ß2-MG) is known as a marker for detecting tubulointerstitial diseases. However, tubulointerstitial damage can also lead to an increase in urinary ß2-MG level in some patients with glomerular diseases. This study aimed to determine the ratio of urinary ß2-MG to total protein (TP) concentration in patients with both isolated tubulointerstitial and glomerular disease. METHODS: This multicenter, retrospective study included children with Dent disease or lupus nephritis in five facilities. Their urinary ß2-MG levels were > 1000 µg/L. Urinary ß2-MG and TP concentrations were obtained, and the ratio of urinary ß2-MG to TP concentration (µg/mg) was calculated. The Mann-Whitney U test was performed to compare this ratio between these children. The optimal cutoff value of the ratio for considering the presence of glomerular disease was obtained from the receiver operating characteristic (ROC) curve. RESULTS: We obtained information on 23 children with Dent disease and 14 children with lupus nephritis. The median ratios of urinary ß2-MG to TP concentrations in children with Dent disease and lupus nephritis were 84.85 and 1.59, respectively. The ROC curve yielded the optimal cutoff value of this ratio for distinguishing between these diseases, and the cutoff value was found to be 22.3. CONCLUSION: In children with tubulointerstitial diseases, the urinary ß2-MG concentration may be approximately 8.5% of the TP concentration. The possibility of presenting with glomerular disease should be considered in patients with a ratio of urinary ß2-MG to TP concentration of < 22.3 (µg/mg).

A 30-year follow-up study in a former cadmium-polluted area of Japan: the relationship between cadmium exposure and ß2-microglobulin in the urine of Japanese people.

Cadmium (Cd) is an environmental pollutant. Long-term exposure to Cd may lead to adverse health effects in humans. Our epidemiological studies showed that urinary Cd (U-Cd) concentrations increased from 2008 through 2014, although they decreased from 1986 through 2008. The aim of this study was to elucidate the long-term effects of the changing trend of cadmium exposure levels (U-Cd) on residents' renal function within 30 years after Cd exposure ceased. In 2016, urine samples were collected from each subject by visiting 20 elderly Japanese people (9 females and 11 males) living in the Kakehashi River basin, a previously Cd-polluted area in Ishikawa, Japan. The geometric means of the ß2-microglobulin (ß2-MG) and urinary Cd (U-Cd) continued to increase from 2014 until 2016. Furthermore, Cd concentration and ß2-MG in urine were still higher than those in the non-polluted areas in Japan. Multivariate linear regression was performed to associate ß2-MG (dependent variable) and U-Cd with sex and age (independent variables). Significant correlations were found among age, U-Cd, and ß2-MG, and these were clearer in females than in males. In summary, we propose that three decades after Cd exposure ceased, age is associated with ß2-MG more strongly than Cd for bodily impact. Moreover, renal tubular dysfunction is irreversible and worsens after exposure to Cd, with females being more sensitive to exposure.

Sex-specific differences in early renal impairment associated with arsenic, lead, and cadmium exposure among young adults in Taiwan.

Exposure to a single metal has been reported to damage renal function in humans. However, information regarding the association between multiple-metal exposure and markers for early renal impairment in different sexes among the young adult Taiwanese population is scarce. We assessed the association between exposure to arsenic (As), cadmium (Cd), and lead (Pb), and early renal impairment markers using urinary microalbumin (MA), ß2-microglobulin (ß2MG), and N-acetyl-beta-D-glucosaminidase (NAG) by analyzing 157 young adults aged 20‒29 years, in Taiwan. Inductively coupled plasma mass spectrometry was used to determine urinary As, Cd, and Pb levels. Regression models were applied to different sex groups. The results showed that after adjusting for potential confounding factors and each metal, urinary Cd levels were significantly positively associated with urinary MA (ß = 0.523, 95% CI: 0.147-0.899) and ß2MG (ß = 1.502, 95% CI: 0.635-2.370) in males. However, the urinary Cd level was significantly positively associated with only urinary NAG (ß = 0.161, 95% CI: 0.027-0.296) in females. This study thus indicates that the effect of exposure to metals (especially Cd) on early renal impairment among young adults in Taiwan is sex-specific. Our study results could contribute toward developing early intervention programs for decreasing the incidence of renal dysfunction. Further studies are warranted to confirm our findings and clarify the potential mechanisms involved.

CUBN gene mutations may cause focal segmental glomerulosclerosis (FSGS) in children.

BACKGROUND: Imerslund-Gräsbeck Syndrome (IGS) is mainly caused by CUBN gene biallelic mutations. Proteinuria accompanies IGS specific symptoms in about half of the patients, isolated proteinuria is rarely reported. Here we present 3 patients with isolated proteinuria and focal segmental glomerulosclerosis (FSGS) caused by CUBN gene biallelic pathogenic variants. METHOD: Whole exome sequencing was performed on three children with isolated proteinuria. CUBN gene biallelic pathogenic variants were found and then verified by sanger sequencing. Their clinical, pathological and molecular genetic characteristics were analyzed and correlated accordingly. RESULTS: All three children presented with isolated proteinuria, no megaloblastic anemia. Their urine levels of ß2 microglobulin were normal or slightly higher. Renal biopsies showed focal segmental glomerulosclerosis with mild glomerular mesangial hypercellularity, partial effacement of foot processes and podocyte microvillation. Two of them were found to carry compound heterozygous mutations and one homozygous mutation of CUBN gene. Totally four CUBN gene biallelic pathogenic variants were identified, including c.9287 T > C (p.L3096P), c.122 + 1G > A, c.7906C > T (p.R2636*), c.10233G > A (p.W3411*). Except for intron splice-site mutation, all other variants are located in highly conserved sites of CUB domain for binding to albumin. CONCLUSION: The results demonstrate that CUBN gene mutations may cause isolated proteinuria pathologically presented as FSGS. Our cases extend the spectrum of renal manifestation and genotype of CUBN gene mutations.

ß2-microglobulin measurement with dried urine spots for congenital anomalies of the kidney and urinary tract screening in 3-year-old children.

BACKGROUND: Screening using dipstick urinalysis has long been performed in 3-year-old children; however, it is ineffective in detecting congenital anomalies of the kidney and urinary tract (CAKUT). Measurement of the urinary ß2-microglobulin (ß2MG)/creatinine (Cr) ratio may be more effective for this purpose. Analysis of dried urine spots (DUS) on filter paper is suitable for mass screening since operational costs are low and samples are easy to collect and transport. We examined the accuracy of measuring the urinary ß2MG/Cr ratio in DUS on filter paper. METHODS: We collected 2,623 urine samples from 3-year-old children. ß2MG and Cr levels were measured in DUS on filter paper. We examined the correlation between the ß2MG/Cr ratios measured in DUS and using the conventional method in 640 samples using the coefficient of determination test. Children with high ß2MG/Cr ratios (>0.6 µg/mg Cr) in DUS samples were further examined to establish a definitive diagnosis. RESULTS: There was strong correlation between the two methods for determination of ß2MG levels (r2 = 0.68; P < 0.001) and ß2MG/Cr ratios (r2 = 0.69; P < 0.001). Of the 2,623 children, 38 (1.45%) had ß2MG/Cr ratios >0.6. Thirty-five children were subsequently examined, resulting in findings of renal hypodysplasia (n = 2, 0.08%), horseshoe kidney (n = 1, 0.04%), renal tubular dysfunction with hepatoblastoma (n = 1, 0.04%), data abnormality (high urine ß2MG level, n = 6, 0.23%; high serum Cr level, n = 1, 0.04%), and normal values (n = 24, 0.91%). CONCLUSIONS: We evaluated a practical method for measuring ß2MG/Cr ratios in DUS as a screening method to detect CAKUT in 3-year-old children.

Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary Biomarkers.

Cancer therapies targeting the vascular endothelial growth factor (VEGF) signaling pathway can lead to renal damage by disrupting the glomerular ultrafiltration apparatus. The objective of the current study was to identify sensitive biomarkers for VEGF inhibition-induced glomerular changes in rats. Male Sprague-Dawley rats were administered an experimental VEGF receptor (VEGFR) inhibitor, ABT-123, for seven days to investigate the correlation of several biomarkers with microscopic and ultrastructural changes. Glomeruli obtained by laser capture microdissection were also subjected to gene expression analysis to investigate the underlying molecular events of VEGFR inhibition in glomerulus. ABT-123 induced characteristic glomerular ultrastructural changes in rats, including fusion of podocyte foot processes, the presence of subendothelial electron-dense deposits, and swelling and loss of fenestrations in glomerular endothelium. The subtle morphological changes cannot be detected with light microscopy or by changes in standard clinical chemistry and urinalysis. However, urinary albumin increased 44-fold as early as Day three. Urinary ß2-microglobulin levels were also increased. Other urinary biomarkers that are typically associated with tubular injury were not significantly impacted. Such patterns in urinary biomarkers can provide valuable diagnostic insight to VEGF inhibition therapy-induced glomeruli injuries.

Serum and urinary biomarkers for early detection of acute kidney injury following Hypnale spp. envenoming.

BACKGROUND: Hump-nosed pit viper (HNV; Hypnale spp.) bites account for most venomous snakebites in Sri Lanka. Acute kidney injury (AKI) is the most serious systemic manifestation (1-10%) following HNV envenoming. We aimed to identify the value of functional and injury biomarkers in predicting the development of AKI early following HNV bites. METHODS: We conducted a prospective cohort study of patients with confirmed HNV envenoming presenting to two large tertiary care hospitals in Sri Lanka. Demographics, bite details, clinical effects, complications and treatment data were collected prospectively. Blood and urine samples were collected from patients for coagulation and renal biomarker assays on admission, at 0-4h, 4-8h, 8-16h and 16-24h post-bite and daily until discharge. Follow-up samples were obtained 1 and 3 months post-discharge. Creatinine (sCr) and Cystatin C (sCysC) were measured in serum and kidney injury molecule-1 (uKIM-1), clusterin (uClu), albumin (uAlb), ß2-microglobulin (uß2M), cystatin C (uCysC), neutrophil gelatinase associated lipocalin (uNGAL), osteopontin (uOPN) and trefoil factor-3 (uTFF-3) were measured in urine. Definite HNV bites were based on serum venom specific enzyme immunoassay. Kidney Disease: Improving Global Outcomes (KDIGO) criteria were used to stage AKI. Two patients had chronic kidney disease at 3 month follow-up, both with pre-existing abnormal sCr, and one developed AKI following HNV envenoming. RESULTS: There were 52 patients with confirmed HNV envenoming; median age 48y (Interquartile range [IQR]:40-59y) and 29 (56%) were male. Median time to admission was 1.87h (IQR:1-2.75h). Twelve patients (23%) developed AKI (AKI stage 1 = 7, AKI stage 2 = 1, AKI stage 3 = 4). Levels of five novel biomarkers, the functional marker serum Cystatin C and the damage markers urinary NGAL, cystatin C, ß2-microglobulin and clusterin, were elevated in patients who developed moderate/severe acute kidney injury. sCysC performed the best at 0-4 h post-bite in predicting moderate to severe AKI (AUC-ROC 0.95;95%CI:0.85-1.0) and no biomarker performed better than sCr at later time points. CONCLUSIONS: sCysC appears to be a better marker than sCr for early prediction of moderate to severe AKI following HNV envenoming.

Genetic background determines renal response to chronic lithium treatment in female mice.

Chronic lithium treatment for bipolar disease causes mainly side effects in the kidney. A subset of lithium users develops nephrogenic diabetes insipidus (NDI), a urinary concentrating disorder, and chronic kidney disease (CKD). Age, lithium dose, and duration of treatment are important risk factors, whereas genetic background might also play an important role. To investigate the role of genetics, female mice of 29 different inbred strains were treated for 1 year with control or lithium chow and urine, blood, and kidneys were analyzed. Chronic lithium treatment increased urine production and/or reduced urine osmolality in 21 strains. Renal histology showed that lithium increased interstitial fibrosis and/or tubular atrophy in eight strains, whereas in none of the strains glomerular injury was induced. Interestingly, lithium did not elevate urinary albumin-creatinine ratio (ACR) in any strain, whereas eight strains even demonstrated a lowered ACR. The protective effect on ACR coincided with a similar decrease in urinary IgG levels, a marker of glomerular function, whereas the adverse effect of lithium on interstitial fibrosis/tubular atrophy coincided with a severe increase in urinary ß2-microglobulin (ß2M) levels, an indicator of proximal tubule damage. Genetic background plays an important role in the development of lithium-induced NDI and chronic renal pathology in female mice. The strong correlation of renal pathology with urinary ß2M levels indicates that ß2M is a promising biomarker for chronic renal damage induced by lithium.

COVID-19-induced acute renal tubular injury associated with elevation of serum inflammatory cytokine.

BACKGROUND: Severe acute respiratory syndrome Coronavirus 2 has rapidly spread worldwide, with acute kidney injury (AKI) as one of the manifestations with unknown causal mechanisms. We aimed to investigate tubular injury by assessing tubular markers and their association with the severity of Coronavirus disease 2019 (COVID-19). METHODS: We examined the associations between laboratory markers and urinary levels of N-acetyl-ß-D-glucosaminidase (uNAG), ß2-microglobulin (u ß2MG), α1-microglobulin (u α1MG), and liver-type fatty acid binding protein (L-FABP). We studied 18 COVID-19 patients without previous chronic kidney disease and analyzed the relationship between the urinary biomarkers and inflammatory markers in patients with severe (n = 7) or non-severe (n = 11) COVID-19, defined by requirements of supplemental oxygen. RESULTS: Fourteen patients (78%) showed abnormal urinalysis findings and two (11%) developed AKI. Patients with severe COVID-19 had significantly higher levels of proteinuria, uNAG, uß2MG, uα 1MG, and L-FABP than those with non-severe disease. Serum levels of interleukin-6 (IL-6) were significantly higher on admission in all severe COVID-19 cases and correlated with the levels of L-FABP, uß2MG, uα1MG, uNAG, and proteinuria. Moreover, the changes in serum IL-6 (ΔIL-6) levels from baseline to 7 days after admission significantly correlated with ΔL-FABP and Δuß2MG. CONCLUSIONS: Levels of tubular injury markers, especially L-FABP and uß2MG, were significantly associated with IL-6 levels even in patients with no evident AKI. This suggests that L-FABP and uß2MG could be useful as early detective biomarkers for COVID-19 associated renal injury.

Dose-response evaluation of urinary cadmium and kidney injury biomarkers in Chinese residents and dietary limit standards.

BACKGROUND: Cadmium (Cd) is a common heavy metal that mainly causes renal damage. There is a lack of research on the large-scale and systematic evaluation of the association between urinary Cd (U-Cd) and various effect biomarkers among Chinese residents. METHODS: Based on the establishment process of dietary Cd limit standards by European Food Safety Authority (EFSA), the dose-response relationships between U-Cd and four biomarkers, ß2-microglobulin (ß2-MG), N-acetyl-ß-glucosidase (NAG), microalbumin (mALB), and retinol binding Protein (RBP) were explored, respectively. Toxicokinetic model was used to derive the dietary Cd exposure limit for Chinese residents after critical U-Cd concentration was calculated. RESULTS: As the sensitive biomarkers of renal injury, ß2-MG and NAG were selected to estimate the 95% confidence interval lower limit of the U-Cd benchmark dose (BMDL5) to be 3.07 and 2.98 µg/g Cr, respectively. Dietary Cd exposure limit was calculated to be 0.28 µg/kg bw/day (16.8 µg/day, based on the body weight of 60 kg), which was lower than the average Chinese Cd exposure (30.6 µg/day) by the China National Nutrient and Health Survey. CONCLUSION: This study established an overall association between U-Cd and renal injury biomarkers, and explored the Chinese dietary Cd exposure limits, which helps improve Chinese Cd exposure risk assessment and provides a reference basis for formulating reasonable exposure standards.

Development of a multiplex mass spectrometry method for simultaneous quantification of urinary proteins related to respiratory health.

Respiratory health of children is a health priority. Club cell protein (CC16) is an interesting biomarker of lung diseases and adverse effects towards the airway epithelium integrity. Osteopontin (OPN) and nuclear factor-kappa B (NF-κB) also play a role in respiratory health. The use of urine as biomarker source is useful in studies involving children but necessitates proper adjustment for physiological confounders influencing the urinary excretion, potentially characterized with beta-2-microglobulin (ß2M), retinol binding protein 4 (RBP4) or myoglobin (MYO), as well as adjustment for possible renal dysfunction, characterized by human serum albumin (HSA). The simultaneous quantification of all these proteins in urine could facilitate children's health monitoring. A multiple reaction monitoring method (MRM) was developed and validated for the relative quantification of the seven mentioned urinary proteins. A total of nine proteotypic peptides were selected and used for the relative quantification of the seven proteins. The MRM method was completely validated for all proteins and partially for OPN. LOQ's ranged from 0.3 to 42.8 ng/ml, a good reproducibility and a good linearity were obtained across the analytical measurement range (r2 > 0.98). The method yielded varying correlations (r2 of 0.78, 0.71, 0.34 and 0.15 for CC16, ß2M, RBP4 and HSA respectively) with available immunoassay data. It also allowed the identification and successful quantification of ß2M and RBP4 as a protein candidate for adjustment of renal handling and dysfunction. All proteins were detected in the urine samples except for MYO and NF-κB. Our validated MRM-method is able to simultaneously quantify in urine biomarkers of airway epithelium integrity and biomarkers of variation in renal function and urinary dilution. This will allow to investigate further in future studies if urine can be used as a good surrogate source for biomarkers of airway epithelium integrity, and to understand the complex relationship between cause and effect in children's respiratory health monitoring.

Ginkgo Biloba Extract EGB761 Ameliorates the Extracellular Matrix Accumulation and Mesenchymal Transformation of Renal Tubules in Diabetic Kidney Disease by Inhibiting Endoplasmic Reticulum Stress.

The study is aimed at investigating the effects of Ginkgo biloba extract EGB761 on renal tubular damage and endoplasmic reticulum stress (ERS) in diabetic kidney disease (DKD). A total of 50 C57BL/6 N mice were randomly divided into the normal group, DKD group, DKD+EGB761 group (36 mg/kg), and DKD+4-phenylbutyrate (4-PBA) group (1 g/kg). The DKD model was replicated by high-fat diet combined with intraperitoneal injection of streptozotocin (STZ). Renal tubular epithelial cells (HK-2) were divided into the control group, high-glucose group (30 mmol/L), EGB761 group (40 mg/L, 20 mg/L, 10 mg/L), TM group, and TM+4-PBA group. After 8 weeks of administration, expressions of serum creatinine (Scr), blood urea nitrogen (BUN), 24 h urinary protein (24 h Pro), fasting blood glucose (FBG), ß 2-microglobulin (ß 2-MG), and retinol binding protein 4 (RBP4) of mice were tested. The pathological changes of renal tissue were observed. The expressions of extracellular matrix (ECM) accumulation and epithelial-mesenchymal transition (EMT) markers α-smooth muscle actin (α-SMA), E-cadherin, fibronectin, and collagen IV, as well as the ERS markers GRP78 and ATF6, were tested by Western blot, qPCR, immunohistochemistry, or immunofluorescence. EGB761 could decrease the Scr, BUN, 24 h Pro, and FBG levels in the DKD group, alleviate renal pathological injury, decrease urine ß 2-MG, RBP4 levels, and decrease the expression of α-SMA, collagen IV, fibronectin, and GRP78, as well as ATF6, while increase the expression of E-cadherin. These findings demonstrate that EGB761 can improve renal function, reduce tubular injury, and ameliorate ECM accumulation and EMT in DKD kidney tubules, and the mechanism may be related to the inhibition of ERS.

Influence of maternal use of tenofovir disoproxil fumarate or zidovudine in Vietnamese pregnant women with HIV on infant growth, renal function, and bone health.

Tenofovir disoproxil fumarate (TDF) is still widely prescribed for human immunodeficiency virus (HIV)-infected pregnant women, despite its renal and bone toxicity. Although TDF-exposed infants often show transient growth impairment, it is not clear whether maternal TDF causes infantile rickets via maternal/fetal renal dysfunction in Asian populations. This prospective observational study was conducted in Vietnam and involved pregnant HIV-infected women treated with TDF-based regimen (TDF group) or zidovudine-based regimen (AZT-group). At birth, 3, 12, and 18 months of age, and included body length, weight, head circumference, serum alkaline phosphatase (ALP), creatinine, calcium, phosphorus, urine-ß2-microglobulin (U-BMG), percentage of tubular reabsorption of phosphate (%TRP), and radiographic wrist score for rickets. Age-adjusted multivariate linear regression analysis evaluated the association of TDF/AZT use during pregnancy with fetal renal function and bone health. The study included 63 mother-infant pairs (TDF group = 53, AZT group = 10). In the mothers, detectable U-BMG (>252 µg/L) was observed more frequently in the TDF- than AZT group (89 vs 50%, p<0.001), but other renal/bone parameters were similar. In infants, maternal TDF use was not associated with growth impairment, renal dysfunction, or abnormal bone findings, but with a slightly higher ALP levels (p = 0.019). However, shorter length was associated with maternal AZT (p = 0.021), and worse radiographic scores were associated with LPV/r (p = 0.024). In Vietnamese population, TDF usage during pregnancy was not associated with infant transient rickets, growth impairment, or renal dysfunction, despite mild maternal tubular impairment. Maternal AZT and LPV/r influenced infant growth and bone health, though further studies are needed to confirm this finding.

Acute Kidney Injury and Renal Tubular Damage in Children With Type 1 Diabetes Mellitus Onset.

CONTEXT: Acute kidney injury (AKI) and renal tubular damage (RTD), especially if complicated by acute tubular necrosis (ATN), could increase the risk of later chronic kidney disease. No prospective studies on AKI and RTD in children with type1diabetes mellitus (T1DM) onset are available. OBJECTIVES: To evaluate the AKI and RTD prevalence and their rate and timing of recovery in children with T1DM onset. DESIGN: Prospective study. SETTINGS AND PATIENTS: 185 children were followed up after 14 days from T1DM onset. The patients who did not recover from AKI/RTD were followed-up 30 and 60 days later. MAIN OUTCOME MEASURES: AKI was defined according to the KDIGO criteria. RTD was defined by abnormal urinary beta-2-microglobulin and/or neutrophil gelatinase-associated lipocalin and/or tubular reabsorption of phosphate < 85% and/or fractional excretion of Na (FENa) > 2%. ATN was defined by RTD+AKI, prerenal (P)-AKI by AKI+FENa < 1%, and acute tubular damage (ATD) by RTD without AKI. RESULTS: Prevalence of diabetic ketoacidosis (DKA) and AKI were 51.4% and 43.8%, respectively. Prevalence of AKI in T1DM patients with and without DKA was 65.2% and 21.1%, respectively; 33.3% reached AKI stage 2, and 66.7% of patients reached AKI stage 1. RTD was evident in 136/185 (73.5%) patients (32.4% showed ATN; 11.4%, P-AKI; 29.7%, ATD). All patients with DKA or AKI presented with RTD. The physiological and biochemical parameters of AKI and RTD were normal again in all patients. The former within 14 days and the latter within 2months. CONCLUSIONS: Most patients with T1DM onset may develop AKI and/or RTD, especially if presenting with DKA. Over time the physiological and biochemical parameters of AKI/RTD normalize in all patients.

First-week urine beta-2 microglobulin levels in term healthy neonates.

BACKGROUND: Beta-2 microglobulin (ß2mG) is a low-molecular-weight protein that is almost exclusively eliminated through the kidneys. It is freely filtered in the glomeruli and almost completely reabsorbed and degraded in the proximal tubules. Normal urinary ß2mG levels are very low (between 0.04 and 0.22 mg/L). No reference values are known in infants and young children. METHODS: Urinary ß2mG levels were measured in 103 healthy term neonates during the first week of life by nephelometric technology. RESULTS: The average level of urinary ß2mG was 0.65 mg/L (95% confidence interval between 0 and 10.8 mg/L). There was a minor difference between male and female neonates but it did not reach statistical significance. There was no effect of the gestational week, birth weight, or weight loss in the first week of life, on urinary ß2mG levels. CONCLUSIONS: First-week urinary ß2mG levels in healthy term infants were higher than adult levels. Incomplete maturation of kidney tubules in neonates could be a possible explanation. These can now be used in clinical practice and further studies that assess the degree of proximal tubular function in health and disease. Graphical abstract.

Tubulointerstitial Nephritis and Uveitis Syndrome: Characterization of Clinical Features.

Purpose: To describe clinical manifestations of patients with tubulointerstitial nephritis and uveitis syndrome (TINU) with a focus on posterior segment findings.Methods: Retrospective chart review.Results: 17 patients were diagnosed with TINU. Ten (59%) were female. Average age at presentation was 19 years (range 7-49). Urine ß2-microglobulin was elevated in all tested patients. Six patients (35%) had isolated anterior uveitis. Eleven (65%) had posterior segment findings. Three (18%) had multifocal choroidal lesions, seven (41%) had disc edema, four (24%) had macular edema, three (18%) had choroidal neovascular membranes, two (12%) had retinal vasculitis, one (6%) had disc neovascularization and vitreous hemorrhage, one (6%) had bilateral posterior scleritis. Eleven (65%) required systemic steroid therapy, seven (41%) required immunomodulatory therapy.Conclusions: TINU occurs in all age groups. Posterior segment manifestations are common. Most patients required systemic steroid therapy, with a significant number requiring long-term systemic immunomodulation. Careful fundus examination is required on all patients with TINU.