Urinary Retinol-binding Protein Research Articles

#1333 SGLT2 inhibitors as a treatment for Fanconi-Bickel syndrome: a case report

Abstract Background and Aims Fanconi-Bickel syndrome is an ultra-rare genetic disease characterized by SLC2A2 mutation encoding for the basolateral glucose transporter (GLUT2) in the proximal tubule of the nephron. This defective transport ultimately leads to accumulation of glycogen and dysfunction of proximal tubule cells. This manifests clinically as the renal Fanconi syndrome and eventually kidney failure. Systemic complications of proximal tubule injury include metabolic acidosis, bone demineralization and, for some not completely elucidated reasons, dysglycemia. Method We present the case of a 43-year-old man who was diagnosed with Fanconi-Bickel syndrome (homozygous splice site mutation in SLC2A2). He had a history of infantile-onset renal Fanconi syndrome, hypercalciuria and bilateral nephrolithiasis, osteoporosis, bilateral sensorineural deafness and non-insulin dependent type 2 diabetes. At referral the patient presented with CKD G2, non-anion gap metabolic acidosis, slightly elevated serum calcium, decreased serum phosphate, suppressed PTH and hypercalciuria (Table 1), despite oral supplementation of phosphate, bicarbonate and vitamin D. We hypothesized that SGLT2i in this patient may halt the progressive proximal tubule injury by preventive glucose uptake and help the management of diabetes. Results Fractional excretion of phosphate (FEPO4) and urinary retinol-binding protein (RBP)-creatinine ratio, two markers of proximal tubular injury, were stable after 2 months of SGLT2i therapy (Fig. 1). Conclusion To date, Fanconi-Bickel syndrome does not have a specific treatment. Standard of care includes supplements of fluids and electrolytes to counterbalance proximal tubular injury and management of complications such as diabetes. SGLT2i use has been described in a mouse model of another glycogen storage disease (GSD1b), whose underlying defect is different from that of Fanconi-Bickel but presents with a similar phenotype [2]. Data showed that gliflozins prevents glycogen accumulation and restores proximal tubule cells’ function. Using the same rationale, the administration of SGLT2i in adult patients with Fanconi-Bickel syndrome may prevent further proximal damage and slow the progression towards end-stage kidney disease. In conclusion, we hypothesize a potential benefit of SGLT2i in adult patients affected by Fanconi-Bickel syndrome.

Development of a time-resolved immunochromatographic test strip for rapid and quantitative determination of retinol-binding protein 4 in urine.

Urine retinol-binding protein 4 (RBP4) has recently been reported as a novel earlier biomarker of chronic kidney disease (CKD) which is a global public health problem with high morbidity and mortality. Accurate and rapid detection of urine RBP4 is essential for early monitor of impaired kidney function and prevention of CKD progression. In the present study, we developed a time-resolved fluorescence immunochromatographic test strip (TRFIS) for the quantitative and rapid detection of urine RBP4. This TRFIS possessed excellent linearity ranging from 0.024 to 12.50 ng/mL for the detection of urine RBP4, and displayed a good linearity (Y = 239,581 × X + 617,238, R2 = 0.9902), with the lowest visual detection limit of 0.049 ng/mL. This TRFIS allows for quantitative detection of urine RBP4 within 15min and shows high specificity. The intra-batch coefficient of variation (CV) and the inter-batch CV were both < 8%, respectively. Additionally, this TRFIS was applied to detect RBP4 in the urine samples from healthy donors and patients with CKD, and the results of TRFIS could efficiently discern the patients with CKD from the healthy donors. Thedeveloped TRFIS has the characteristics of high sensitivity, high accuracy, and a wide linear range, and is suitable for rapid and quantitative determination of urine RBP4.

Factors influencing the occurrence of hyperuricemia and poor cardiac and renal outcomes in chronic kidney disease.

The aim of our study was to analyze the factors influencing the occurrence of hyperuricemia and poor cardiac and renal outcomes in chronic kidney disease (CKD). One hundred and sixteen patients with CKD admitted to our hospital from January 2022 to September 2022 were picked as the subjects. Fasting venous blood of these subjects was collected to value the serum uric acid (SUA) levels on an automatic biochemical analyzer. Patients were then grouped as the CKD-only group (n=80) and hyperuricemia group (n=36), according to the SUA results, or the good prognosis group (n=88) and poor prognosis group (n=28), according to the presence of cardiovascular diseases. The changes in laboratory indexes and clinical data were analyzed and compared. Multivariate logistic regression analysis was used to analyze the risk factors for combined hyperuricemia and the risk factors for poor cardiac and renal outcomes in patients with CKD. The correlation between SUA level and cardiac and renal indexes was analyzed by Pearson analysis. Patients in the CKD hyperuricemia group had markedly higher content of systolic blood pressure (SBP), diastolic blood pressure (DBP), B-type natriuretic peptide (BNP), urinary retinol-binding protein (RBP), urinary N-acetyl-β-D glucosidase (NAG), much higher proportion of heart failure episodes history, and much lower content of total cholesterol (TC), albumin (Alb), hemoglobin (Hb), urinary α1-microglobulin (α1-MG), and glomerular filtration rate (eGFR) than the CKD-only group (p < 0.05). SUA, BNP, SBP, and history of heart failure episodes were independent risk factors for combined hyperuricemia in CKD patients (p < 0.05). Besides, eGFR, albumin, and hemoglobin were independent protective factors for combined hyperuricemia in CKD patients (p < 0.05). Compared with the good prognosis group, the content of BNP, SBP, DBP, urinary RBP, urinary NAG, and SUA was much higher, the proportion of heart failure episodes history was obviously higher, and the levels of Alb, Hb, TC, eGFR, and urinary α1-MG were sharply lower in the poor prognosis group (p < 0.05). SUA, BNP, SBP, and history of heart failure episodes were independent risk factors for poor cardiac and renal outcomes (p < 0.05), and eGFR was an independent protective factor for poor cardiac and renal outcomes in patients with CKD (p < 0.05). The SUA level in CKD patients was positively correlated with BNP and SBP (r=0.463, 0.215, p < 0.05), but negatively correlated with eGFR (r=0.463, 0.215, p < 0.05). The serum SUA level was elevated with the aggravation of the CKD stage. High serum SUA level is a risk factor for the development of hyperuricemia and poor cardio-renal outcomes in CKD patients, suggesting that early monitoring of changes in SUA levels may help assess the risk of cardio-renal outcomes in CKD patients.

Urinary orosomucoid and retinol binding protein levels as early diagnostic markers for diabetic kidney Disease

BackgroundDiabetic kidney disease (DKD) is the most common microvascular complication of diabetes, which has been a major cause of end-stage renal failure. Diagnosing diabetic kidney disease is important to prevent long-term kidney damage and determine the prognosis of patients with diabetes. In this study, we investigated the clinical significance of combined detection of urine orosomucoid and retinol-binding protein for early diagnosis of diabetic kidney disease.MethodsWe recruited 72 newly diagnosed patients with type 2 diabetes and 34 healthy persons from August 2016 to July 2018 at the First Affiliated Hospital of Henan Polytechnic University (Jiaozuo Second People’s Hospital). Using the Mogensen grading criteria, participants were classified as having diabetes or diabetic kidney disease, and healthy persons constituted the control group. Urine orosomucoid and retinol-binding protein levels were measured and correlated with other variables.ResultsWith the aggravation of renal damage, the level of urinary mucoid protein gradually increased. Urinary retinol-binding protein and microalbumin levels were significantly higher in the diabetes group than in control and nephropathy groups. Orosomucoid and retinol-binding protein might be independent risk factors for diabetes and diabetic kidney disease. Urinary orosomucoid significantly correlated with retinol-binding protein and microalbumin levels in the diabetic kidney disease group.ConclusionElevated urine orosomucoid and retinol-binding protein levels can be detected in the early stages of type 2 diabetic kidney disease. Both of these markers are important for diabetic kidney disease detection and early treatment.

Upregulation of the protein kinase Lyn is associated with renal injury in type 2 diabetes patients

Background The role of inflammation in the pathogenesis of type 2 diabetes mellitus (T2DM) is well established. Lyn, a member of the nonreceptor protein tyrosine kinase Src family, has been reported to modulate inflammatory signaling pathways. Methods Lyn expression was assessed in kidney biopsies of 11 patients with diabetic kidney disease (DKD) and in kidney tissues of streptozotocin (STZ)-induced DKD mice. 102 recruited T2DM patients were divided into three groups: normoalbuminuria, microalbuminuria and macroalbuminuria. Twenty-one healthy volunteers were recruited as a control group. Clinical data, blood and urine samples of all individuals were collected for analysis. Results Lyn expression was augmented in the kidneys of DKD patients and STZ-induced diabetic mice. Compared with control and normoalbuminuria groups, both mRNA and protein expression of Lyn in peripheral blood mononuclear cells (PBMCs) in the macroalbuminuria group were significantly increased (p < .05). Elevated Lyn levels were independently related to urine albumin/urine creatinine ratio and were positively associated with key inflammatory factors, namely interleukin-1β, monocyte chemoattractant protein-1, and tumor necrosis factor-α. Additionally, Lyn exhibited a noteworthy connection with renal tubular injury indicators, specifically urinary neutrophil gelatinase-associated lipocalin and urinary retinol binding protein. ROC curve analysis showed that Lyn could predict albuminuria in diabetic patients with an area under the curve of 0.844 (95% CI: 0.764–0.924). Conclusion Lyn levels in PBMCs exhibited a positive correlation with the severity of albuminuria, renal tubular damage, and inflammatory responses. Hence, Lyn may be a compelling candidate for predicting albuminuria levels in diabetes.

Diagnostic value of α1-MG and URBP in early diabetic renal impairment.

Aims/Introduction: Diabetic kidney disease (DKD) is defined as diabetes with impaired renal function, elevated urinary albumin excretion, or both. DKD is one of the most common microvascular complications of diabetes and plays an important role in the cause of end-stage renal disease (ESRD). About 5% of people with type 2 diabetes (T2DM) already have kidney damage at the time they are diagnosed, but other triggers of renal insufficiency, such as obesity, hyperlipidemia, glomerular atherosclerosis are often present, making it difficult to define "diabetic kidney disease" or "diabetic nephropathy" precisely in epidemiology or clinical practice. Therefore, the aim of this study is to identify diabetic patients with CKD at an early stage, and evaluate the value of tubular injury markers including α1-microglobulin (α1-MG), β2-microglobulin (β2-MG), N-acetyl-beta-D-glucosaminidase (NAG) and Urinary retinol binding protein (URBP) in the development of diabetes to DKD. Materials and methods: We recruited a total of 182 hospitalized patients with T2DM in the First Affiliated Hospital of Zhengzhou University from February 2018 to April 2023. We collected basic clinical characteristics and laboratory biochemical parameters of the patients. Based on their levels of urinary albumin creatinine ratio (UACR) and glomerular filtration rate (GFR), patients were divided into DM group (UACR≤30mg/g and eGFR≥90mL/min/1.73m2, n = 63) and DKD group (UACR>30mg/g or eGFR<90mL/min/1.73m2, n = 119) excluding other causes of chronic kidney disease. We further developed diagnostic models to improve the ability to predict the risk of developing DKD by screening potential risk factors using univariate and multivariate logistic regression analysis. Calibration plots and curve analysis were used to validate the model and clinical usefulness. Next, we screened patients with relatively normal estimated glomerular filtration rate (eGFR) (≥90mL/min/1.73m2) to investigate whether tubular injury markers could accurately predict the risk of DKD in patients with normal renal function. We defined the rate of GFR decline as a prognostic indicator of renal function in patients and collected the information of the re-hospitalized DKD patients to determine whether the relevant indicators had an impact on the renal prognosis. Results: The patients with DKD had higher levels of tubular injury markers than patients with DM. URBP, α1-MG, eGFR were statistically different in both univariate and multivariate logistic regression analyses and displayed great predictive power after modeling with an area under curve of 0.987. The calibration curve showed medium agreement. Decision curve showed it would add more net benefits for clinical decision. After adjusting eGFR and serum creatinine (Scr), URBP was demonstrated to be associated with early renal function impairment. Conclusion: Tubular injury markers play an important role in early diabetic renal function impairment.

Urinary matrix metalloproteinase-7 is a sensitive biomarker to evaluate renal tubular injury in patients with minimal change disease and focal segmental glomerulosclerosis.

To explore the advantages of urinary matrix metalloproteinase-7 (MMP-7) in evaluating renal tubular injury in minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) patients compared with urinary cystatin C (CysC) and retinol-binding protein (RBP). Serum and urine samples were collected from 20 healthy volunteers, and 40 MCD and 20 FSGS patients. Serum and urinary MMP-7 levels were measured by enzyme-linked immunosorbent assay. Urinary total protein, CysC and RBP levels were measured by automatic specific protein analyzer and compared with urinary creatinine level for calibration. The renal tissue serial sections were stained by MMP-7 immunohistochemistry and periodic acid-Schiff. Under light microscopy, MMP-7 granular weak positive expression was showed sporadically in the cytoplasm of a few renal tubular epithelial cells without obvious morphological changes in MCD patients, and MMP-7-positive expression was observed in the cytoplasm of some renal tubular epithelial cells in FSGS patients. There was no significant difference in serum MMP-7 level among the three groups. Compared with the control group, the urinary MMP-7 level in MCD patients was higher, but urinary CysC and RBP levels were not increased significantly. Compared with the control group and MCD patients, urinary MMP-7, CysC and RBP levels in FSGS patients were upregulated significantly. Urinary MMP-7 could not only evaluate the mild renal tubular epithelial cells injury in MCD patients with massive proteinuria, but also evaluate the continuous renal tubular epithelial cells injury in FSGS patients.

Correlation between urine vitamin D-binding protein and early-stage renal damage in Type 2 diabetes.

The excretion of urinary vitamin D-binding protein (uVDBP) is related to the occurrence and development of early-stage renal damage in patients with Type 2 diabetes (T2DM). This study aims to explore the significance of detecting uVDBP in T2DM patients and its relationship with renal tubules, and to provide a new direction for the early diagnosis of T2DM renal damage. A total of 105 patients with T2DM, who met the inclusion criteria, were included as a patient group, and recruited 30 individuals as a normal control group. The general information and blood and urine biochemical indicators of all subjects were collected; the levels of uVDBP, and a marker of tubular injury [urine kidney injury molecule 1 (uKIM-1), urine neutrophil gelatinase-associated lipocalin (uNGAL) and urine retinol-binding protein (uRBP)] were detected by enzyme-linked immunosorbent assay. The results were corrected by urinary creatinine (Cr) to uVDBP/Cr, uKIM-1/Cr, uNGAL/Cr and uRBP/Cr. The Pearson's and Spearman's correlation tests were used to analyze the correlation between uVDBP/Cr and urine albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR) and markers of tubular injury, and multivariate linear regression and receiver operating characteristic curve were used to analyze the correlation between uVDBP/Cr and UACR or eGFR. Compared with the normal control group, the uVDBP/Cr level in the patient group was increased (P<0.05), and which was positively correlated with UACR (r=0.774, P<0.01), and negatively correlated with eGFR (r=-0.397, P<0.01). There were differences in the levels of uKIM-1/Cr, uNGAL/Cr, and uRBP/Cr between the 2 groups (all P<0.01). The uVDBP/Cr was positively correlated with uKIM-1/Cr (r=0.752, P<0.01), uNGAL/Cr (r=0.644, P<0.01) and uRBP/Cr (r=0.812, P<0.01). The sensitivity was 90.0% and the specificity was 82.9% (UACR>30 mg/g) for evaluation of uVDBP/Cr on T2DM patients with early-stage renal damage, while the sensitivity was 75.0% and the specificity was 72.6% for evaluation of eGFR on T2DM patients with early-stage renal damage. The uVDBP/Cr can be used as a biomarker in early-stage renal damage in T2DM patients.

Urinary Markers of Tubular Injury and Renal Fibrosis in Patients with Type 2 Diabetes and Different Phenotypes of Chronic Kidney Disease

This study assessed the urinary excretion of markers and mediators of tubular injury and renal fibrosis in patients with type 2 diabetes (T2D) and non-albuminuric and albuminuric patterns of chronic kidney disease (CKD). One hundred and forty patients with long-term T2D and different patterns of CKD and twenty non-diabetic individuals were included. Urinary retinol-binding protein 4 (RBP-4), glutathione-S-transferase α1 and π (GST-α1 and GST-π), transforming growth factor β (TGF-β), type I and type IV collagen (Col1 and Col4), bone morphogenic protein 7 (BMP-7), and hepatocyte growth factor (HGF) were assessed by ELISA. Patients with T2D demonstrated increased urinary excretion of RBP-4, GST-π, Col4, BMP-7, and HGF (all p < 0.05 vs. control). The excretion of RBP-4, GST-π, Col1, and Col4 was increased in patients with elevated albumin-to-creatinine ratio (UACR; all p < 0.05 vs. control), while BMP-7 and HGF were increased innormoalbuminuric patients also (p < 0.05). Urinary RBP-4, GST-α1, Col1, Col4, and HGF correlated positively with UACR; meanwhile, no correlations with glomerular filtration rate were found. The results demonstrate that elevated urinary excretions of the markers of tubular injury (RBP-4, GST-π) and renal fibrosis (Col1, Col4), as well as HGF, an antifibrotic regulator, are associated with the albuminuric pattern of CKD in subjects with T2D.

Evaluation the effectiveness of the Jiangniaosuan formulation in the treatment of hyperuricemic nephropathy in patients with chronic kidney disease stages 3–4: Study protocol of a randomized controlled trial

BackgroundHyperuricemic nephropathy is a highly prevalent kidney disease induced by excessive accumulation and deposition of monosodium urate in kidney, which contributes to the loss of kidney function. The Jiangniaosuan formulation (JNSF) is a Chinese herbal medicine treatment. The aim of this study is to evaluate its efficacy and safety among patients with hyperuricemic nephropathy at chronic kidney disease (CKD) stages 3–4 and with obstruction of phlegm turbidity and blood stasis syndrome. MethodsOur research is designed as a single-centre, double-blinded, randomized, placebo-controlled trial for 118 patients diagnosed with hyperuricemic nephropathy at CKD stages 3–4 and with obstruction of phlegm turbidity and blood stasis syndrome in mainland China. Patients are to be randomized into two groups: either the intervention group which receives JNSF 20.4 g/day combined with febuxostat 20–40 mg/day, or the control group which receives JNSF placebo 20.4 g/day combined with febuxostat 20–40 mg/day. The intervention will be carried on for 24 weeks. The change in estimated glomerular filtration rate (eGFR) is set as the primary outcome. Secondary outcomes include changes in serum uric acid, serum nitric oxide, urinary albumin/creatinine ratio, urinary N-acetyl-β-D glucosaminidase, urinary β2 microglobulin, urinary retinol binding protein and TCM syndromes in 24 weeks. Statistical analysis will be formulated by SPSS 24.0. DiscussionThe trial will conduce to the comprehensive assessment in the efficacy and safety of JNSF among patients diagnosed with hyperuricemic nephropathy at CKD stages 3–4, and provide a clinical method available on systems of the combination of modern medicine and TCM.

Correlation of Renal Oxygenation with Renal Function in Chronic Kidney Disease: A Preliminary Prospective Study

Introduction: Chronic hypoxia is prevalent in chronic kidney disease (CKD), and blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) provides noninvasive evaluation of renal oxygenation. This study aimed to explore the correlation of renal oxygenation evaluated by BOLD-MRI with renal function. Methods: 97 non-dialysis patients with CKD stages 1–5 and healthy volunteers (HVs) were recruited in the study, all participants without diabetes. Based on their estimated glomerular filtration rate (eGFR), the patients were divided into two groups: CKD stages 1–3 (CKD 1–3) and CKD stages 4–5 (CKD 4–5). We measured cortical and medullary T2* (COT2* and MET2*) values in all participants by BOLD-MRI. Physiological indices were also recorded and compared among three groups. Correlation of T2* values with clinical characteristics was determined. Results: The COT2* values were significantly higher than MET2* values in all participants. The COT2* and MET2* values of three groups were ranked as HV > CKD 1–3> CKD 4–5 (p r > 0.4, p rs = −0.2301, p = 0.0265) and no correlation with the MET2* value (p > 0.05). Urinary microprotein, including urinary alpha1-microglobulin, urinary beta2-microglobulin (β2-MG), and urinary retinol-binding protein (RBP), showed strong correlation with COT2* and MET2* values. According to the analysis of receiver operating characteristic curve, the optimal cut-points between HV and CKD 1–3 were “Conclusion: The decline of renal oxygenation reflected on T2* values, especially in cortex, may be an effective diagnostic marker for early detection of CKD.

Insights into the health status of the general population living near an electroplating industry zone: metal elevations and renal impairment.

A cross-sectional study was conducted in 2016 in Zhejiang Province, China, to evaluate the body burdens of metals and metalloids associated with renal dysfunction in populations living near electroplating industries. We recruited 236 subjects and performed physical examinations, determined the blood and urinary levels of arsenic (As), cadmium (Cd), chromium (Cr), manganese (Mn), nickel (Ni), lead (Pb), antimony (Sb), and selenium (Se) by an inductively coupled plasma mass spectrometer (ICP-MS), and measured three renal impairment biomarkers, namely nacetyl-β-D-glucosaminidase (NAG), retinol-binding protein (RBP), and β2-microglobulin (BMG). The proportion of abnormal nasal symptoms in the exposure group (10.1%) was much higher than in the control group (0; p < 0.05). The blood and urinary levels of As, Cd, and Se in the exposure group were significantly higher than those in the control group (p < 0.05). The blood levels of Mn and Pb, as well as the urinary levels of Cr and Ni, were significantly higher in the exposure group than in the control group (p < 0.05). The exposure group demonstrated higher levels of NAG, RBP, and BMG than the control group (0.51 vs. 0.14mg/g creatinine, 12.79 vs. 9.26IU/g creatinine, and 1.39 vs. 0.78mg/g creatinine, respectively; p < 0.05). Urinary BMG was positively correlated with urinary Cd levels (r = 0.223, p < 0.05), while urinary RBP was correlated with blood Cd levels (r = 0.151, p < 0.05) and urinary Cd, Cr, Ni, and Se levels (r = 0.220, 0.303, 0.162, and 0.306, respectively; p < 0.05). In conclusion, our study indicated that a population living in the vicinity of electroplating industries had high body burdens of certain metals and metalloids associated with non-negligible renal dysfunction.

Acute kidney injury (AKI) post-mRNA SARS-CoV-2 vaccine in patients with cancer, treated with immune check point inhibitor (ICPi): An immune double whammy!

Background: Immune check point inhibitors (ICPi) have become the first line treatment for most of the cancers and have shown promising results. However, they can provoke reactions, the most feared being immune related adverse events (irAE). Case presentation: We present a series of three cases, of patients recieving ICPi. All three patients developed AKI after administration of SARS-CoV-2 mRNA vaccine. Two patients had kidney-biopsy-proven acute interstitial nephritis (AIN) which responded to ICPi discontinuation and treatment with steroids. One had presumed AIN based on the high levels of CRP and urine retinol binding protein to creatinine ratio and responded to cessation of ICPi alone. Conclusion: These three cases demonstrate that a strong immune response from the SARS-CoV-2 mRNA vaccine combined with an uninhibited immune system under influence of ICPi led to an amplification of autoimmunity leading to AKI presenting as AIN.

Serum and urinary carnosinase-1 correlate with kidney function and inflammation

The carnosinase dipeptidase 1 (CNDP1) gene has been reported as a susceptibility locus for the development of diabetic kidney disease (DKD). While the (CTG)5 allele affords protection in the Caucasian population, we have previously shown that this allele is less frequently present in the Chinese population and therefore a protective role for the (CTG)5 allele is difficult to demonstrate. In the present study, we sought to assess if carnosinase-1 (CN-1) concentrations in serum and/or urine are associated with progression of DKD and to what extent CN-1 influences diabetes-associated inflammation. From a total of 622 individuals that enrolled in our study, 247 patients had type 2 diabetes without DKD, 165 patients had DKD and 210 subjects served as healthy controls. Uni- and multivariate regression analyses were performed to identify potential factors predicting urinary albumin creatinine ratio (UACR), estimated glomerular filtration rate (eGFR) and CN-1 concentration in serum and urine. The results indicated that serum CN-1 indeed correlated with eGFR (p = 0.001). In addition, urinary CN-1 associated with eGFR and tubular injury indicator: urinary cystatin C (Cys-C) and urinary retinol-binding protein (RBP). Interestingly, serum CN-1 also positively correlated with inflammatory indicators: neutrophils and lymphocytes. With regard to this, a STZ injected C57BL/6 mice model with surgically made skin wound was established for the generation of skin inflammation. This animal model further proved that the expression of CN-1 in liver and kidney increased remarkably in diabetic mice with skin wound as compared to those without. In conclusion, serum and urinary CN-1 significantly related to the surrogates of impaired renal function in diabetic patients; besides, CN-1 expression might also be associated with the process of inflammation.

Urinary RBP as an Independent Predictor of Renal Outcome in Diabetic Nephropathy.

Background Renal tubular impairment is prevalent in diabetic nephropathy (DN) and the histological severity predicted renal outcome. Biomarkers of tubular injury also increased in the urine of DN patients. The retrospective study aimed to assess the prognostic value of clinically widely applied urinary tubular injury markers, retinol-binding protein (RBP), β2-microglobulin (β2-MG) and N-acetyl-β-D-glucosaminidase (NAG) in DN. Method A total of 305 patients with biopsy-proven DN were enrolled. The baseline urine total protein and components including albumin, IgG, RBP, β2-MG and NAG were retrieved from medical records. The primary outcome was end stage renal disease (ESRD). Cox proportional hazard analysis and restricted cubic splines were performed to evaluate the association of parameters with ESRD. Nomograms were constructed and concordance index (C-index) was used to measure the prediction ability. Result The levels of urinary RBP, β2-MG and NAG were positively correlated with the severity of interstitial fibrosis and tubular atrophy (IFTA). Positive correlations were also observed among β2-MG, NAG and mesangial expansion. Urinary RBP was not correlated with any glomerular lesions. Urinary RBP, β2-MG and NAG were risk factors for ESRD in hazard analysis with adjustment for age, gender and body mass index (BMI). The hazard ratios increased with the increment of baseline levels. In the multivariate Cox model including serum creatinine (SCr), total urinary protein, urinary albumin, urinary IgG and the tubular injury biomarkers, urinary RBP (with every g/mol.Cr increase: HR 1.06, 95% CI 1.03-1.10, p =0.001) remained as an independent risk factor for ESRD in DN patients. Patients were divided by the medium value of urinary RBP into the low RBP and high RBP groups. Survival analysis showed that significantly more patients in the high RBP progressed to ESRD compared to those in the low RBP group (p =0.02) when urinary total protein was less than 3.5 g/g. The C-index of the nomogram incorporating age, gender, BMI, SCr and total urine protein was 0.757. The value increased to 0.777 after adding urinary RBP to the model. Conclusions Urinary RBP excretion was only correlated with the severity of IFTA and independently predicted ESRD in DN patients.

Hyperinsulinemia impairs the metabolic switch to ketone body utilization in proximal renal tubular epithelial cells under energy crisis via the inhibition of the SIRT3/SMCT1 pathway.

ObjectiveTo investigate the effects and mechanism of hyperinsulinemia on the metabolic switch to β‐hydroxybutyrate (BHB) absorption and utilization under a starvation or hypoxic environment in proximal tubular epithelial cells.MethodsA high-fat diet-induced hyperinsulinemia model in ZDF rats was used to test the expression of key enzymes/proteins of ketone body metabolism in the kidney. Notably, 12-week-old renal tubule SMCT1 specific knockout mice (SMCT1 flox/floxCre+) and control mice (SMCT1 flox/floxCre-) were used to confirm the roles of SMCT1 in kidney protection under starvation. The changes of key enzymes/proteins of energy metabolism, mitochondrial function, and albumin endocytosis in HK2 cells under low glucose/hypoxic environments with or without 50 ng/mL insulin were studied. Silent information regulation 2 homolog 3 (SIRT3) was overexpressed to evaluate the effect of hyperinsulinemia on the metabolic switch to BHB absorption and utilization through the SIRT3/SMCT1 pathway in HK2 cells.ResultsIn ZDF rats, the expression of HMGCS2 increased, the SMCT1 expression decreased, while SCOT remained unchanged. In renal tubule SMCT1 gene-specific knockout mice, starvation for 48 h induced an increase in the levels of urine retinol-binding protein, N-acetyl-β-glucosaminidase, and transferrin, which reflected tubular damages. In HK2 cells under an environment of starvation and hypoxia, the levels of key enzymes related to fatty acid oxidation and ketone body metabolism were increased, whereas glucose glycolysis did not change. The addition of 2 mmol/l BHB improved ATP production, mitochondrial biosynthesis, and endocytic albumin function, while cell apoptosis was reduced in HK2 cells. The addition of 50 ng/ml insulin resulted in the decreased expression of SMCT1 along with an impaired mitochondrial function, decreased ATP production, and increased apoptosis. The overexpression of SIRT3 or SMCT1 reversed these alterations induced by a high level of insulin both in low-glucose and hypoxic environments.ConclusionsThe increased absorption and utilization of BHB is part of the metabolic flexibility of renal tubular epithelial cells under starvation and hypoxic environments, which exhibits a protective effect on renal tubular epithelial cells by improving the mitochondrial function and cell survival. Moreover, hyperinsulinemia inhibits the absorption of BHB through the inhibition of the SIRT3/SMCT1 pathway.

The Clinical Significance of Urinary Retinol-Binding Protein 4: A Review.

Effective biomarkers for early diagnosis, prognostication, and monitoring in renal diseases (in general) comprise an unmet need. Urinary retinol-binding protein 4, which is the most sensitive indicator of renal tubular damage, holds great promise as a universal biomarker for renal pathologies, in which tubular injury is the driving force. Here, we summarize the most important existing data on the associations between urinary retinol-binding protein 4 and renal diseases and highlight the untapped potential of retinol-binding protein 4 in clinical use.

Construction of Prediction Model of Renal Damage in Children with Henoch-Schönlein Purpura Based on Machine Learning.

Objective The children with Henoch-Schönlein purpura (HSP) may suffer from renal insufficiency, which seriously affects the life and health of the children. This study aims to construct a prediction model of Henoch-Schönlein purpura nephritis (HSPN). Methods A total of 240 children with HSP treated in dermatology and pediatrics in our hospital were selected. The general information, patients' clinical symptoms, and laboratory examination indicators were collected for feature selection, and the XGBoost algorithm prediction model was built. Results According to the input feature indexes, the top ten crucial feature indicators output by the XGBoost model were urine N-acetyl-β-D-aminoglucosidase, urinary retinol-binding protein, IgA, age, recurrence of purpura, purpura area, abdominal pain, 24-h urinary protein quantification, percentage of neutrophils, and serum albumin. The areas under the curves of the training set (0.895, 95% CI: 0.827-0.963) and test set (0.870, 95% CI: 0.799-0.941) models were similar. Conclusion The prediction model based on XGBoost is used to predict HSP renal damage based on clinical data of children, which can reduce the harm caused by invasive examination for patients.

The potential use of urinary transferrin, urinary adiponectin, urinary Retinol Binding Protein, and serum zinc alpha 2 glycoprotein levels as novel biomarkers for early diagnosis of diabetic nephropathy: A case-control study

Background and aimsThe level of albuminuria is used to evaluate diabetic nephropathy (DN). However, to detect or predict the early stages of DN, better biomarkers are needed. MethodsThis study is a case-control observational study. 80 Egyptians participated in the study: 60 patients with type 2 diabetes mellitus (T2DM) were divided into three groups (20 patients each), and 20 healthy subjects with matched age and gender were used as controls. Demographic and laboratory data were analyzed. An enzyme-linked immunosorbent assay was used to determine the levels of four biomarkers of DN; urinary adiponectin (ADP), urinary transferrin, serum Zinc Alpha 2 Glycoprotein (ZAG), and urinary Retinol Binding Protein (RBP). ResultsThe levels of DN biomarkers urinary ADP, transferrin, RBP, and serum, ZAG were significantly higher in patients with T2DM than in controls. The ROC curve of the validity of the simultaneous use of all four biomarkers in predicting albuminuria indicates a sensitivity of 90% and a specificity of 90%. The Area Under the Curve (AUC) was 0.948, the 95% confidence interval was 0.998–0.897, and the p-value was 0.001. ConclusionsIn patients with T2DM, urine adiponectin, transferrin, RBP, and serum ZAG concentration may be useful biomarkers in the early diagnosis of DN. A further longitudinal prospective study is required to explore the potential utility of these biomarkers.

Chronic lymphocytic leukemia and light chain proximal tubulopathy: A rare presentation of a common disease

Chronic lymphocytic leukemia (CLL) is the most common leukemia in developed countries. Kidney injuries related to CLL can occur via several mechanisms. Approximately 30%–40% of CLL patients with a kidney biopsy have monoclonal-protein related lesions. However, such lesions mostly involve glomeruli with only rare instances of tubule-interstitial disorders. There is only a single case report of a CLL patient who presented with crystalline light chain proximal tubulopathy (LCPT). Fanconi syndrome (FS) may provide clinical clues in these patients. We report a case of a CLL patient who presented with hypokalemia in the setting of advanced kidney failure in which serum monoclonal IgG kappa was detected. The patient demonstrated typical signs and symptoms of FS. The urinary retinol binding protein was also extremely elevated (638 times upper normal limit). A kidney biopsy revealed non-crystalline LCPT with CLL infiltration. FS in CLL is an extremely rare presentation, as only four cases had been previously reported. Of these, only a single case had crystalline LCPT. Our case is the first report of non-crystalline LCPT in a CLL patient. Obinutuzumab and Venetoclax were started to address the CLL, and an improvement in kidney function was noted thereafter.