Prognostic and Diagnostic Values of Novel Serum and Urine Biomarkers in Lupus Nephritis: A Systematic Review.

INTRODUCTION: While renal biopsy remains the gold standard for diagnosing lupus nephritis (LN), the prognostic and diagnostic role of non-invasive biomarkers for LN is currently debated. METHODS: Available studies published in last 5 years (2015-2020) assessing the diagnostic and prognostic value of urinary and/or serological biomarkers in subjects with LN were analyzed in this systematic review. RESULTS: Eighty-five studies were included (comprehending 13,496 patients with systemic lupus erythematosus [SLE], 8,872 LN, 487 pediatric LN, 3,977 SLE but no LN, 160 pediatric SLE but no LN and 7,679 controls). Most of the studies were cross-sectional (62; 73%), while 14 (17%) were prospective. In sixty studies (71%), the diagnosis of LN was biopsy-confirmed. Forty-four out of 85 (52%) investigated only serological biomarkers, 29 studies (34%) tested their population only with urinary biomarkers, and 12 (14%) investigated the presence of both. Outcome measures to assess the clinical utility of the analyzed biomarkers were heterogeneous, including up to 21 different activity scores, with the SLEDAI (in 60%) being the most used. Despite some heterogeneity, promising results have been shown for biomarkers such as urinary monocyte chemoattractant protein, urinary adiponectin, and urinary vascular cell adhesion protein 1. DISCUSSION/CONCLUSION: While serum and urine biomarkers have the potential to improve diagnostic and prognostic pathways in patients with LN, the vast heterogeneity across studies severely limits their applicability in current clinical practice. With the kidney biopsy still representing the gold standard, future efforts should focus on harmonizing study inclusion criteria and outcomes, particularly in clinical trials, in order to improve comparability and facilitate the implementations of available biomarkers into the daily practice.

Increased urinary adiponectin level is associated with contrast-induced nephropathy in patients undergoing elective percutaneous coronary intervention.

BACKGROUND: Contrast-induced nephropathy (CIN) is one of major and serious complications in patients undergoing percutaneous coronary intervention (PCI). It is unknown whether increased urinary adiponectin (UAPN), a sensitive marker for early renal function impairment, is associated with an increased risk of CIN. Therefore, we prospectively investigate the association of UAPN with CIN. METHODS: We prospectively enrolled 208 patients who were undergoing elective PCI. The baseline UAPN was assessed prior to PCI. The ROC analysis was used to evaluate the predictive value of UAPN for CIN. Multivariate logistic regression analysis was performed to analyze the independent risk factors for CIN. RESULTS: Of 208 patients, CIN occurred in 19 patients (9.13%), and 6 of them (2.88%) required dialysis. Patients with CIN had a higher UAPN level than those without CIN (17.15 ± 12.36 vs. 10.29 ± 3.04 ng/ml, P < 0.01). ROC analysis showed that the optimal cutoff value of UAPN for predicting CIN was 12.24 ng/ml with 68.42% sensitivity and 76.72% specificity (AUC = 0.7204; 95% CI, 0.582-0.859; 푃< 0.01). Multivariate analysis demonstrated that UAPN (OR, 5.071; 95% CI,1.711-15.028; P < 0.01) and serum creatinine (Scr) > 124 µmol/L (OR, 4.210; 95% CI, 1.297-13.669; P < 0.01) were independently associated with CIN. CONCLUSIONS: Our present study showed that a higher baseline UAPN (≥12.24 ng/ml) level was significantly associated with an increased risk for developing CIN post PCI.

Urine biomarkers of chronic kidney damage and renal functional decline in childhood-onset systemic lupus erythematosus.

OBJECTIVES: To delineate urine biomarkers that reflect kidney structural damage and predict renal functional decline in pediatric lupus nephritis (LN). METHODS: In this prospective study, we evaluated kidney biopsies and urine samples of 89 patients with pediatric LN. Urinary levels of 10 biomarkers [adiponectin, ceruloplasmin, kidney injury molecule-1, monocyte chemotactic protein-1, neutrophil gelatinase-associated lipocalin, osteopontin, transforming growth factor-ß (TGFß), vitamin-D binding protein, liver fatty acid binding protein (LFABP), and transferrin] were measured. Regression analysis was used to identify individual and combinations of biomarkers that determine LN damage status [NIH-chronicity index (NIH-CI) score ≤ 1 vs. ≥ 2] both individually and in combination, and biomarker levels were compared for patients with vs. without renal functional decline, i.e., a 20% reduction of the glomerular filtration rate (GFR) within 12 months of a kidney biopsy. RESULTS: Adiponectin, LFABP, and osteopontin levels differed significantly with select histological damage features considered in the NIH-CI. The GFR was associated with NIH-CI scores [Pearson correlation coefficient (r) = - 0.49; p < 0.0001] but not proteinuria (r = 0.20; p > 0.05). Similar to the GFR [area under the ROC curve (AUC) = 0.72; p < 0.01], combinations of osteopontin and adiponectin levels showed moderate accuracy [AUC = 0.75; p = 0.003] in discriminating patients by LN damage status. Renal functional decline occurred more commonly with continuously higher levels of the biomarkers, especially of TGFß, transferrin, and LFABP. CONCLUSION: In combination, urinary levels of adiponectin and osteopontin predict chronic LN damage with similar accuracy as the GFR. Ongoing LN activity as reflected by high levels of LN activity biomarkers heralds renal functional decline. KEY MESSAGES: • Levels of osteopontin and adiponectin measured at the time of kidney biopsy are good predictors of histological damage with lupus nephritis. • Only about 20% of children with substantial kidney damage from lupus nephritis will have an abnormally low urine creatinine clearance. • Continuously high levels of biomarkers reflecting lupus nephritis activity are risk factors of declining renal function.

Analysis of the differential urinary protein profile in IgA nephropathy patients of Uygur ethnicity.

BACKGROUND: IgA nephropathy (IgAN) is one of the most common forms of idiopathic glomerular diseases and might lead to end-stage kidney disease. Accurate and non-invasive biomarkers for early diagnosis are required for early intervention and consequent therapy for IgAN patients. Because variance in the disease incidence and predisposing genes of IgAN has been detected among different ethnicities, the ethnicity factor should be considered in IgAN biomarker discovery. The differences in the protein profiles and pathological mechanisms of IgAN in patients of Uygur ethnicity need to be clearly illustrated. METHODS: In this study, we used urinary proteomics to discover candidate biomarkers of IgAN in patients of Uygur ethnicity. The urinary proteins from Uygur normal control and Uygur IgAN patients were extracted and analyzed using 2D-LC-MS/MS and isobaric tags for relative and absolute quantitation (iTRAQ) analysis. RESULTS: A total of 277 proteins were found to be differentially represented in Uygur IgAN compared with the respective normal controls. The bioinformatics analysis revealed that the immune response, cell survival, and complement system were activated in Uygur IgAN. Many differentially expressed proteins were found to be related to nephropathy and kidney injuries. Four candidate biomarkers were validated by Western blot, and these results were consistent with the iTRAQ results. ICAM1, TIMP1, SERPINC1 and ADIPOQ were upregulated in Uygur IgAN. Bioinformatic analysis revealed that the increase of ICAM1 and TIMP1 might be caused by IgAN, but the increase of SERPINC1 and ADIPOQ might be caused by proteinuria. SERPINC1 and ICAM1 were identified as the candidate biomarkers with excellent area-under-the-curve (AUC) values (0.84) for distinguishing Uygur IgAN from normal controls. CONCLUSIONS: Using urinary proteomic analysis, we identified several candidate biomarkers for IgAN in patients of Uygur ethnicity. These results will prove helpful for exploring the pathological mechanism of IgAN in patients of Uygur ethnicity and for developing better treatments for these patients.

Prospective validation of a novel renal activity index of lupus nephritis.

Objectives The renal activity index for lupus (RAIL) score was developed in children with lupus nephritis as a weighted sum of six urine biomarkers (UBMs) (neutrophil gelatinase-associated lipocalin, monocyte chemotactic protein 1, ceruloplasmin, adiponectin, hemopexin and kidney injury molecule 1) measured in a random urine sample. We aimed at prospectively validating the RAIL in adults with lupus nephritis. Methods Urine from 79 adults was collected at the time of kidney biopsy to assay the RAIL UBMs. Using receiver operating characteristic curve analysis, we evaluated the accuracy of the RAIL to discriminate high lupus nephritis activity status (National Institutes of Health activity index (NIH-AI) score >10), from low/moderate lupus nephritis activity status (NIH-AI score ≤10). Results In this mixed racial cohort, high lupus nephritis activity was present in 15 patients (19%), and 71% had proliferative lupus nephritis. Use of the identical RAIL algorithm developed in children resulted in only fair prediction of lupus nephritis activity status of adults (area under the receiver operating characteristic curve (AUC) 0.62). Alternative weightings of the six RAIL UBMs as suggested by logistic regression yielded excellent accuracy to predict lupus nephritis activity status (AUC 0.88). Accuracy of the model did not improve with adjustment of the UBMs for urine creatinine or albumin, and was little influenced by concurrent kidney damage. Conclusions The RAIL UBMs provide excellent prediction of lupus nephritis activity in adults. Age adaption of the RAIL is warranted to optimize its discriminative validity to predict high lupus nephritis activity status non-invasively.

The Association Between Adiponectin, Serum Uric Acid and Urinary Markers of Renal Damage in the General Population: Cross-Sectional Data from the Tromsø Study.

BACKGROUND/AIMS: Uric acid may cause renal damage, whereas adiponectin in some studies has been reported to have renoprotective properties. The renoprotective role of adiponectin under the influence of hyperuricemia has not been explored. We assessed the cross-sectional association between adiponectin, serum uric acid (SUA) and urinary biomarkers of glomerular and tubular damage (albumin-creatinine ratio [ACR] and N-acetyl-ß-D-glucosaminidase-creatinine ratio [NAG-CR]) in a large cohort from a general population. METHODS: Three urine specimens from 7062 persons, participating in the Tromsø Study, were collected. The adjusted associations between adiponectin and SUA as independent variables, and ACR ≥1.13 mg/mmol (albuminuria) and the upper gender specific 15 percentile of NAG-CR (high NAG-CR) as dependent variables, were assessed. RESULTS: Mean (standard deviation) age of the participants was 63.5 (9.2) years. Adiponectin was positively associated with albuminuria and high NAG-CR. SUA was associated with albuminuria (odds ratio [OR] 1.13; 95% Confidence Interval [CI] 1.05-1.21 per 59 µmol/L increase), but not with NAG-CR. There were no statistically significant interactions between SUA and adiponectin. CONCLUSIONS: Unexpectedly, adiponectin was positively associated with both urinary markers of renal damage. SUA was positively associated with albuminuria only. SUA and adiponectin added little beyond traditional cardiovascular risk factors to predict renal damage and did not interact in their associations with the urinary biomarkers. Longitudinal studies are needed before firm conclusions can be made.

Resistin as a potential marker of renal disease in lupus nephritis.

Systemic lupus erythematosus (SLE) and lupus nephritis (LN) have strong concomitance with cardiovascular disease that cannot be explained fully by typical risk factors. We examined the possibility that serum or urine expression of adipokines may act as biomarkers for LN, as these proteins have been associated previously with cardiovascular disease as well as SLE. Antibody arrays were performed on serum and urine from lupus patients and matched controls using a cross-sectional study design. From the initial array-based screening data of 15 adipokines, adiponectin, leptin and resistin were selected for validation by enzyme-linked immunosorbent assay (ELISA). Correlations were determined between adipokine expression levels and measures of disease activity or lupus nephritis. The expression of adiponectin and resistin was increased in both sera and urine from LN patients, while leptin was increased in LN patient sera, compared to matched controls. Serum resistin, but not urine resistin, was correlated with measures of renal dysfunction in LN. Serum resistin expression may be useful as a marker of renal dysfunction in patients with LN, although longitudinal studies are warranted. Further studies are necessary to determine if resistin has functional consequences in LN.

Urinary adiponectin and albuminuria in non-diabetic hypertensive patients: an analysis of the ESPECIAL trial.

BACKGROUND: Although adiponectin levels have been reported to be correlated with albuminuria, this issue remains unresolved in non-diabetic hypertensive subjects, particularly when urinary adiponectin is considered. METHODS: Urinary adiponectin levels were examined using an enzyme-linked immunosorbent assay in 229 participants. who used olmesartan as a hypertensive agent. Their albuminuria levels were measured for 16 weeks after randomization and initiation of conventional or intensive diet education. Linear or logistic regression models were applied, as appropriate, to explore the relationship with albuminuria itself or its response after the intervention. RESULTS: Urinary adiponectin levels were positively related to baseline albuminuria level (r = 0.529). After adjusting for several covariates, the adiponectin level was associated with the albuminuria level (ß = 0.446). Among the 159 subjects with baseline macroalbuminuria, the risk of consistent macroalbuminuria (> 300 mg/day) at 16 weeks was higher in the 3(rd) tertile of adiponectin than in the 1(st) tertile (odds ratio = 6.9), despite diet education. In contrast, among all subjects, the frequency of the normoalbuminuria achievement (< 30 mg/day) at 16 weeks was higher in the 1(st) tertile than in the 3(rd) tertile (odds ratio = 13.0). CONCLUSIONS: Urinary adiponectin may be a useful biomarker for albuminuria or its response after treatment in non-diabetic hypertensive patients.

Changes of adiponectin and its receptors in rats following chronic renal failure.

OBJECTIVE: To investigate changes of adiponectin and its receptors (Adipo R) in rats following chronic renal failure. METHODS: Male SD rats were randomly divided into two groups: control group and chronic renal failure (CRF) group. The CRF group were gavaged with adenine (300 mg/kg/d) for 4 weeks and the control group with drinking water. All rats were anesthetized at 2nd or 4th week and blood and urine samples were collected for detection of renal function, 24 h urine protein and adiponectin concentration. Renal tissues were also collected for HE staining, immunohistochemistry and RT-PCR screening. RESULTS: Compared with control group, the serum concentrations of urea and creatinine, 24 h urine protein excretion in the CRF group were significantly higher at 2nd week and further increased at 4th week (p < 0.05). The adiponectin levels in serum and urine in the CRF group were significantly higher than those of control group (p < 0.01). The renal expressions of Adipo R1 and Adipo R2 in CRF group were also significantly increased compared to control group (p < 0.01). The increased expressions of Adipo R1 and Adipo R2 were positively related to the adiponectin levels in serum, urine, and 24 h urine protein. CONCLUSION: The significant changes in expression of adiponectin and its receptors in rat CRF model could be an adaptive response that may provide the basis to understand pathological changes in chronic kidney disease.

Urinary adiponectin concentration is positively associated with micro- and macro-vascular complications.

BACKGROUND: A relationship between plasma adiponectin level and a number of metabolic conditions, including insulin resistance, obesity, and type 2 diabetes, has been reported. This study aimed to assess whether urinary adiponectin concentration is correlated with vascular complications. METHODS: The study comprised 708 subjects who enrolled in the Seoul Metro City Diabetes Prevention Program and were carefully monitored from September 2008 to December 2008. Levels of urinary adiponectin were measured using an enzyme linked immunosorbent assay (ELISA) kit (AdipoGen, Korea). Urinary albumin excretion was assessed by the ratio of urinary albumin to creatinine (A/C ratio). Participants were divided into three groups based on tertiles of urinary adiponectin concentration, and we investigated whether urinary adiponectin levels are associated with microalbuminuria and pulse wave velocity. RESULTS: Urinary adiponectin concentrations were significantly higher in subjects with microalbuminuria than subjects with normoalbuminuria (P < 0.001). Urinary adiponectin concentration was positively correlated with age, fasting plasma glucose level, HbA1C level, triglyceride level, HOMA-IR, systolic/diastolic blood pressure, and urinary A/C ratio (all P < 0.05). Subjects in the highest tertile of urinary adiponectin concentration had an increased likelihood of microalbuminuria than those in the lowest tertile (Odds ratio (OR), 6.437; 95% confidence interval (CI), 4.202 to 9.862; P < 0.001). After adjusting for age, sex, and estimated creatinine clearance rate (eCcr), the OR remained significant (OR, 5.607; 95% CI, 3.562 to 8.828; P < 0.001). Backward multiple linear regression analysis revealed urinary adiponectin concentration to be a significant determinant of mean brachial-ankle pulse wave velocity (baPWV). CONCLUSIONS: An increased urinary adiponectin concentration is significantly associated with microalbuminuria and increased mean baPWV. These results suggest that urinary adiponectin may play an important role as a biomarker for vascular dysfunction.

Molecular composition of adiponectin in urine is a useful biomarker for detecting early stage of diabetic kidney disease.

We previously developed two immune complex transfer enzyme immunoassays (ICT-EIA) to measure total adiponectin (T-AN) and high molecular weight adiponectin (H-AN) in urine and have verified their usefulness as biomarkers for diabetic kidney disease. In this study, we developed T-AN and H-AN assays using the sandwich EIA (Sand-EIA). The reactivities of Sand-EIAs were compared with ICT-EIAs by measuring size exclusion chromatography (SEC) fractions of urine and adiponectin standard. As a result, ICT-EIAs showed higher macromolecular specificity. We then analyzed the molecular profile of adiponectin in the urine of 5 patients with different eGFR stages by measuring SEC fractions of urine. The results showed that smaller adiponectin correlated relatively well with eGFR stage. Finally, because SEC is time-consuming, we investigated that the ratio of T-ANs by Sand-EIA and ICT-EIA could be a good indicator of the monomer adiponectin. The ratio was evaluated using 77 urine samples from patients with diabetes and showed a significant decrease at an earlier stage compared with other biomarkers. In conclusion, we demonstrated a new index to estimate monomer adiponectin in urine by using Sand-EIA and ICT-EIA, and urinary monomer adiponectin can be a good early indicator of deterioration of renal function in diabetic patients. J. Med. Invest. 70 : 464-470, August, 2023.

Development of fully automated and ultrasensitive assays for urinary adiponectin and their application as novel biomarkers for diabetic kidney disease.

Glomerular filtration rate (GFR) and urinary albumin excretion rate (UAER) are used to diagnose and classify the severity of chronic kidney disease. Total adiponectin (T-AN) and high molecular weight adiponectin (H-AN) assays were developed using the fully automated immunoassay system, HI-1000 and their significance over conventional biomarkers were investigated. The T-AN and H-AN assays had high reproducibility, good linearity, and sufficient sensitivity to detect trace amounts of adiponectin in the urine. Urine samples after gel filtration were analyzed for the presence of different molecular isoforms. Low molecular weight (LMW) forms and monomers were the major components (93%) of adiponectin in the urine from a diabetic patient with normoalbuminuria. Urine from a microalbuminuria patient contained both high molecular weight (HMW) (11%) and middle molecular weight (MMW) (28%) adiponectin, although the LMW level was still high (52%). The amount of HMW (32%) and MMW (42%) were more abundant than that of LMW (24%) in a diabetic patient with macroalbuminuria. T-AN (r = - 0.43) and H-AN (r = - 0.38) levels showed higher correlation with estimated GFR (eGFR) than UAER (r = - 0.23). Urinary levels of both T-AN and H-AN negatively correlated with renal function in diabetic patients and they may serve as new biomarkers for diabetic kidney disease.

Urinary adiponectin as a new diagnostic index for chronic kidney disease due to diabetic nephropathy.

Objective: The chronic kidney disease (CKD) is widely diagnosed on the basis of albuminuria and the glomerular filtration rate. A more precise diagnosis of CKD, however, requires the assessment of other factors. Urinary adiponectin recently attracted attention for CKD assessment, but evaluation is difficult due to the very low concentration of urinary adiponectin in normal subjects. Research design and methods: We developed an ultrasensitive ELISA coupled with thionicotinamide-adenine dinucleotide cycling to detect trace amounts of proteins, which allows us to measure urinary adiponectin at the subattomole level. We measured urinary adiponectin levels in 59 patients with diabetes mellitus (DM) and 24 subjects without DM (normal) to test our hypothesis that urinary adiponectin levels increase with progression of CKD due to DM. Results: The urinary adiponectin levels were 14.88±3.16 (ng/mg creatinine, mean±SEM) for patients with DM, and 3.06±0.33 (ng/mg creatinine) for normal subjects. The threshold between them was 4.0 ng/mg creatinine. The urinary adiponectin levels increased with an increase in the CKD risk. Furthermore, urinary adiponectin mainly formed a medium-molecular weight multimer (a hexamer) in patients with DM, whereas it formed only a low-molecular weight multimer (a trimer) in normal subjects. That is, the increase in urinary adiponectin in patients with DM led to the emergence of a medium-molecular weight form in urine. Conclusions: Our new assay showed that urinary adiponectin could be a new diagnostic index for CKD. This assay is a non-invasive test using only urine, thus reducing the patient burden.

Adiponectin is present in the urine in its native conformation, and specifically reduces the secretion of MCP-1 by proximal tubular cells.

AIM: To determine whether adiponectin detected in urine is present in its native form and if adiponectin receptors (AdipoR) present and functional in proximal tubular (HK-2) cells. BACKGROUND: Adiponectin is a protein with anti-inflammatory, anti-atherogenic and insulin-sensitizing properties. It has previously been detected antigenically in the urine in several forms of renal disease. METHODS: We compared the isoform distribution of urinary adiponectin in patients with proteinuric and non-proteinuric renal disease with that of matched controls using chromatography and enzyme-linked immunosorbent assay. We examined whether AdipoR were present in HK-2 cells by real-time reverse transcription polymerase chain reaction. Their functionality was investigated by determining the effect of recombinant adiponectin on adenosine monophosphate-activated protein kinase phosphorylation using western blotting, and on the secretion of monocyte chemotactic protein-1 and C3 using enzyme-linked immunosorbent assays. RESULTS: Adiponectin in the urine is physiologically intact and largely present as the low molecular weight isoform. Subjects with urinary protein >150 mg/L excreted significantly more adiponectin and its high and low molecular weight isoforms than those with <150 mg/L. mRNA for AdipoR were present in HK-2 cells, with levels of mRNA for AdipoR1 being 20 times greater than those for AdipoR2. Ligation of AdipoR on proximal tubular cells increased phosphorylation of adenosine monophosphate-activated protein kinase, and downregulated the secretion of the inflammatory cytokine monocyte chemotactic protein-1, but not of C3. CONCLUSION: Physiologically relevant isoforms of adiponectin are present in the urine of normal subjects and those with proteinuria. In addition, functional receptors for adiponectin are present in HK-2 cells. Abnormal levels of adiponectin in the urine may therefore activate these receptors, potentially resulting in anti-inflammatory activity.

A study of high-, middle- and low-molecular weight adiponectin in urine as a surrogate marker for early diabetic nephropathy using ultrasensitive immune complex transfer enzyme immunoassay.

Background For the early identification of patients at risk of developing diabetic nephropathy, we have developed an ultrasensitive immune complex transfer enzyme immunoassay to measure adiponectin in urine. Methods We developed immune complex transfer enzyme immunoassay for adiponectin and measured urinary adiponectin from 70 healthy subjects, 35 obese non-diabetic subjects and 20 patients with diabetes. Results The urinary adiponectin concentrations in patients with diabetes (3.3 ± 10.7 ng/mg creatinine) were significantly higher than those in obese subjects (0.54 ± 0.44; P < 0.01) and healthy subjects (0.46 ± 0.42; P < 0.001). The gel filtration elution profile of urine from healthy subjects showed traces of four immunoreactive peaks (high-, medium-, low-molecular weight and monomer molecules), despite the majority of blood adiponectin being high-molecular weight. However, urinary adiponectin molecules were more frequent in low-molecular weight as the estimate glomerular filtration rate decreased. Furthermore, as blood glucose concentrations rose, middle-molecular weight and high-molecular weight increased in urine. Further, urinary adiponectin concentrations correlated with estimate glomerular filtration rate ( r = -0.61, P < 0.001), but not urinary albumin. In addition, our analysis showed a significantly ( P < 0.001) higher value for urinary adiponectin in the G2 stage of chronic kidney disease classification where urinary albumin is not elevated. Conclusion Adiponectin increases in urine as renal function decreases, and urinary adiponectin may be useful as a surrogate marker for diabetic nephropathy risk.

Rapid detection of urinary soluble intercellular adhesion molecule-1 for determination of lupus nephritis activity.

The current methods of monitoring the activity of lupus nephritis (LN) may cause unnecessary hospital visits or delayed immunosuppressive therapy. We aimed to find a urinary biomarker that could be developed as a home-based test for monitoring the activity of LN.Urine samples were collected immediately before a renal biopsy from patients of suspected active LN, and also from patients with inactive LN, systemic lupus erythematous without LN or healthy controls. Biomarker search was conducted on a cytokine antibody array and confirmation was done by quantitative evaluation with enzyme-linked immunosorbent assay. The Mann-Whiney test or Student t test was used to compare the levels of 9 cytokines between different groups. The sensitivity and specificity of each cytokine for diagnosis of LN was evaluated by receiver operating characteristic curve. A rapid test based on colloidal gold immunochromatography was then developed for bedside or home use. Furthermore, an experimental e-healthcare system was constructed for recording and sharing the results of the rapid test a cloud-assisted internet of things (IoT) consisting of a sensing device, an IoT device and a cloud server.Adiponectin (Acrp30), soluble intercellular cell adhesion molecule-1 (sICAM-1), neural cell adhesion molecule 1 (NCAM-1), and CD26 were significantly higher in urine samples of active LN patients. sICAM-1 appeared more sensitive and specific among these candidates. When the cut-off value of sICAM-1 was set at 1.44 ng/mL, the sensitivity reached 98.33% with a specificity at 85.71%. The sICAM-1 strip test showed comparable sensitivity of 95% and a specificity of 83.3% for assessing the LN activity. Meanwhile, the e-healthcare system was able to conveniently digitize and share the sICAM-1 rapid test results.sICAM-1 appeared to be an excellent biomarker for monitoring LN activity. The e-healthcare system with cloud-assisted IoT could assist the digitalization and sharing of the bedside or home-based sICAM-1 test results.

Effects of age and gender on reference levels of biomarkers comprising the pediatric Renal Activity Index for Lupus Nephritis (p-RAIL).

BACKGROUND: Systemic Lupus Erythematosus (SLE) is a multisystem autoimmune disease that disproportionately effects women and children of minorities. Renal involvement (lupus nephritis, or LN) occurs in up to 80% of children with SLE and is a major determinant of poor prognosis. We have developed a non-invasive pediatric Renal Activity Index for Lupus (p-RAIL) that consists of laboratory measures that reflect histologic LN activity. These markers are neutrophil gelatinase associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), monocyte chemotactic protein (MCP-1), adiponectin (APN), ceruloplasmin (CP) and hemopexin (HPX). A major gap in the knowledge base and a barrier to clinical utility is how these markers behave in healthy children. We set out to establish a reference range for the p-RAIL markers in a population of healthy children, and to determine if levels of these markers fluctuate with age or gender. METHODS: Urine was collected from 368 healthy children presenting to Cincinnati Children's primary care clinic for well child visits and assayed for NGAL, KIM-1, MCP-1, APN, CP and HPX using commercially available kits or assay materials. RESULTS: Specimens were grouped by age (0-5 years (n = 94); 5-10 (n = 89); 10-15 (n = 93); 15-20 (n = 91)) and gender (M = 184, F = 184). For age and gender comparisons, values were log transformed prior to analysis. The medians (minimums, maximums) of each marker in the combined population were as follows: NGAL 6.65 (0.004, 391.52) ng/ml, KIM-1416.84 (6.22, 2512.43) pg/ml, MCP-1209.36 (9.49, 2237.06) pg/ml, APN 8.05 (0.07, 124.50) ng/ml, CP 465.15 (8.02, 7827.00) ng/ml, HPX 588.70 (6.85, 17,658.40)ng/ml. All p-RAIL biomarkers but adiponectin had weak but significant positive correlations with age, with NGAL being the strongest (r = 0.33, p < 0.001). For gender comparisons, NGAL, CP and HPX were elevated in females vs males (86%, p < 0.0001; 3%, p = 0.007, and 5%, p = 0.0005 elevation of the log transformed mean, respectively). CONCLUSIONS: We have established a reference range for the p-RAIL biomarkers and have highlighted age and gender differences. This information is essential for rational interpretation of studies and clinical trials utilizing the p-RAIL algorithm.

Exposure to phthalates in patients with diabetes and its association with oxidative stress, adiponectin, and inflammatory cytokines.

Epidemiologic studies have revealed higher concentrations of the metabolites of phthalic acid esters (mPAEs) in patients with type 2 diabetes. On the other hand, oxidative stress, adiponectin, and inflammatory cytokines play important roles in the pathogenesis of diabetes and its complications. However, little information is known about the association between exposure to PAEs and these physiological parameters. Hence, paired urine and blood samples were collected from a total of 329 volunteers, and 11 main mPAEs and malondialdehyde (MDA), as a biomarker of oxidative stress, were measured in the urine samples. Serum adiponectin and tumor necrosis factor-α (TNF-α), a biomarker of inflammation, were also measured. Multivariable linear regression was used to assess the association between urinary mPAEs and these physiological parameters in the total subjects and subjects stratified by age, sex, and body mass index (BMI) to elucidate their possible interactions. All 11 mPAEs were detected in the urine with detection rates of 42.9%-100% and geometric means of 0.30-54.52ng/mL (0.44-79.93µg/g creatinine). The mPAEs were all positively associated with MDA levels. There were significant positive associations between monomethyl phthalate (mMP) and TNF-α, and inverse associations between mMP and adiponectin levels. In the stratified analysis, there were age-, sex-, and BMI-specific differences for these associations. The positive associations between mPAEs and MDA were insignificant in some subgroups, especially in the larger age group. However, in the larger BMI group, summed metabolites of di-(2-ethylhexyl) phthalate (∑DEHP) and mono(2-ethylhexyl) phthalate were positively associated with TNF-α, and the concentrations of ∑DEHP were negatively associated with adiponectin. Our findings suggested that PAE exposure is associated with oxidative stress, adiponectin, and inflammatory cytokines in diabetic patients; further studies on toxicology and a comparison with general population are needed.

Urinary adiponectin and progression of diabetic nephropathy in type 1 diabetes.

The complex role of adiponectin in diabetic nephropathy.

Association between urinary adiponectin level and renal involvement in systemic lupus erythematous.

AIM: To assess association between urinary levels of adiponectin and severity of renal involvement in SLE patients. Also, this study aims to determine the value of urinary adiponectin levels to discriminate renal involvement in these patients. METHODS: In a multi-center cross-sectional survey, 50 consecutive patients diagnosed as having systemic lupus erythematosus (SLE) according to American College of Rheumatology criteria were classified into two groups with or without renal involvement (microscopic hematuria, reduced glomerular filtration rate < 25% of normal value, and proteinuria > 500 mg/24 h) which was confirmed by renal biopsy. Urinary adiponectin was measured by enzyme-linked immunosorbent assay. SLE disease activity levels were assessed by SLE Disease Activity Index (SLEDAI) score. RESULTS: Comparing urinary levels of adiponectin between the two groups indicated considerable discrepancy in this index between the groups with and without renal involvement (146.33 ± 258.83 ng/mL vs. 22.96 ± 44.33 ng/mL, P = 0.023). Also, urinary adiponectin/creatinine ratio was significantly higher in the former group (221.72 ± 414.58 vs. 19.99 ± 41.19, P = 0.019). Our study showed a higher mean SLEDAI score in those with renal involvement than others (23.60 ± 2.53 vs. 9.12 ± 3.03, P < 0.001). Multivariable linear regression analysis with the presence of potential confounders showed that the level of urinary adiponectin was significantly higher in those with renal involvement than other patients (ß = 0.470, P = 0.023). The optimal cut-off point for urinary adiponectin levels to discriminate renal involvement from normal renal state was 7.5 ng/mL, yielding a sensitivity of 80% and specificity of 52%. CONCLUSION: Urinary levels of adiponectin are significantly elevated in SLE patients with renal involvement. The measurement of this biomarker can be helpful to discriminate impaired from normal renal function in SLE patients.