Urinary and plasma proteomics to discover biomarkers for diagnosing between diabetic nephropathy and minimal change nephrotic syndrome or membranous nephropathy.
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ABSTRACT:
SUBMITTER: Araumi A
PROVIDER: S-EPMC8379417 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Introduction: Minimal change disease (MCD) is a major cause of nephrotic syndrome. With a substantial number of patients requiring long-term immunosuppression leading to significant morbidity, the study aim was to determine MCD glomerular transcriptome to serve as a basis for biomarker discovery and novel drug target identification. Animal work showed podocyte injury induced by IL-7/IL-7R signaling (Zhai S, BBRC, 2018). Methods: Renal biopsies from adult patients representing the following groups were selected from the Norwegian Kidney Biopsy Registry: MCD (n=14), as well as normal tissue (n=8) and primary membranous nephropathy (MN; n=12) as the two reference groups. RNA for 75 base-pair paired-end RNASeq was obtained by dissecting glomeruli via laser capture microdissection (LCM) from FFPE cross-sections. Systematic delineation of condition-specific alteration in transcriptional landscapes was achieved by combining pathway-centered analyses with methodologies derived from network science and integrating multiple bioinformatics resources. Results: Compared to normal glomeruli, glomeuli from MCD displayed an inflammatory signature that appeared to be predominantly governed by the IL1 and IL7 systems. While enrichment of IL1 production and secretion was a shared feature of MCD and MN compared to normal tissue, responses involving IL7 pathway activation were unique to MCD. Indeed, IL7R expressed by glomeruli was the most up-regulated gene of to the interleukin-family in MCD vs normal controls. IL7 pathway activation was paralleled by significant enrichment in adaptive immune system processes and transcriptional regulation and depletion in pathways related to energy metabolism and transcription. Downregulation of these organ function-related themes again occurred predominately in MDC and were significantly less pronounced in MN. Conclusion: Our results demonstrate that archival FFPE-biopsies can be used to generate glomeruli-specific gene expression profiles suitable for systematic delineation of kidney-associated diseases. Here the latter provides a data-driven rationale to experimentally address these MCD-specific features as biomarkers and as novel drug targets. In this context inhibiting activation of the IL7 pathway may be particularly promising.
2023-01-25 | GSE216841 | GEO
Project description:IntroductionMinimal change disease (MCD) and membranous nephropathy (MN) are glomerular diseases (glomerulonephritis [GN]) that present with the nephrotic syndrome. Although circulating PLA2R antibodies have been validated as a biomarker for MN, the diagnosis of MCD and PLA2R-negative MN still relies on the results of kidney biopsy or empirical corticosteroids in children. We aimed to identify serum protein biomarker signatures associated with MCD and MN pathogenesis using aptamer-based proteomics.MethodsQuantitative SOMAscan proteomics was applied to the serum of adult patients with MCD (n = 15) and MN (n = 37) and healthy controls (n = 20). Associations between the 1305 proteins detected with SOMAscan were assessed using multiple statistical tests, expression pattern analysis, and systems biology analysis.ResultsA total of 208 and 244 proteins were identified that differentiated MCD and MN, respectively, with high statistical significance from the healthy controls (Benjamin-Hochberg [BH] P < 0.0001). There were 157 proteins that discriminated MN from MCD (BH P < 0.05). In MCD, 65 proteins were differentially expressed as compared with MN and healthy controls. When compared with MCD and healthy controls, 44 discriminatory proteins were specifically linked to MN. Systems biology analysis of these signatures identified cell death and inflammation as key pathways differentiating MN from MCD and healthy controls. Dysregulation of fatty acid metabolism pathways was confirmed in both MN and MCD as compared with the healthy subjects.ConclusionSOMAscan represents a promising proteomic platform for biomarker development in GN. Validation of a greater number of discovery biomarkers in larger patient cohorts is needed before these data can be translated for clinical care.
| S-EPMC9263421 | biostudies-literature
Project description:Background and objectivesThe impact of acute kidney injury (AKI) on the progression of renal function in idiopathic membranous nephropathy (iMN) with nephrotic syndrome (NS) patients have not yet been reported, we sought to investigate the incidence, clinical features and prognosis of AKI in iMN with NS patients and determine clinical predictors for progression from AKI to advanced chronic kidney disease (CKD) stage.MethodsWe analyzed clinical and pathological data of iMN with NS patients retrospectively collected from Jan 2012 to Dec 2018. The primary renal endpoint was defined as persistent eGFR <45ml/min per 1.73 m2 more than 3 months. Comparisons of survival without primary renal endpoint were performed by Kaplan-Meier curves and log-rank test. Univariate and multivariate Cox proportional hazard models were constructed to determine independent variables associated with primary renal endpoint .Results434 iMN with NS patients were enrolled. The incidence of AKI 1 stage, AKI 2 stage and AKI 3 stage was 23.1, 4.8 and 0.7% respectively. 66 (53.2%) patients with AKI had complete renal function recovery and 42 (33.9%) patients with AKI reached primary renal endpoint. Survival without primary renal endpoint was worse in AKI patients than No AKI patients (67.1 ± 5.3 and 43.7 ± 7.3% vs 99.5 ± 0.5 and 92.5 ± 4.2% at 2 and 4 years,p < 0.001). AKI was independently associated with primary renal endpoint, with an adjusted hazard ratio(HR) of 25.1 (95%CI 7.7-82.1, p < 0.001).ConclusionsAKI was usually mild and overlooked in iMN patients with NS, but it had a strong association with poor clinical outcomes and was an independent risk factor for CKD progression.
| S-EPMC8231360 | biostudies-literature
Project description:Diabetic nephropathy (DN) is a major complication in diabetic patients. Microalbuminuria testing is used to identify renal disease; however, its predictive value is questionable. We aimed to identify urinary biomarkers to early diagnosis nephropathy before identifiable alternations in kidney function or urine albumin excretion occurs. Proteomic approaches were used to identify potential urinary biomarkers and enzyme-linked immunosorbent assay was performed to verify the results. The data identified haptoglobin (HPT) and α-1-microglobulin/bikunin precursor (AMBP) as two biomarkers with the highest ability to distinguish between healthy individuals and patients with nephropathy, and between diabetic patients with and without DN. Further, the HPT-to-creatinine ratio (HCR) was evaluated as an independent predictor of early renal functional decline (ERFD) in a cohort with an average follow-up of 4.2 years. The area under the curve (AUC) value for ERFD prediction was significantly improved when the HCR biomarker was included in the model with albumin to creatinine ratio (ACR) and baseline characteristics (AUC values were 0.803 and 0.759 for HCR and ACR, respectively; p value was 0.0423 for difference between models). In conclusion, our results suggest that HCR represents an early indicator of nephropathy, and a marker related to ERFD among diabetic patients in Taiwan.
| S-EPMC6306863 | biostudies-literature
Project description:Background: Treatment for adult patients with refractory idiopathic membranous nephropathy (RIMN) by conventional immunosuppressive regimens is not satisfactory. This study aims to evaluate the effectiveness of Chinese herbal medicine, Shulifenxiao formula, as a promising regimen. Methods: A total of 31 RIMN patients resistant to corticosteroid or immunosuppressive agents were retrospectively analyzed. Shulifenxiao treatment lasted a minimum of 12°months in all patients and extended to 24°months in 11 patients. The primary outcomes [the complete remission (CR) and partial remission (PR)] and secondary outcomes (the serum creatinine and estimated glomerular filtration rate (eGFR) levels) were measured at 6, 12, 18, and 24°months. Results: The data provided an average follow-up of 21 ± 9.16°months from baseline. The remission was attained in 25/31 patients (80.7%: CR 29.0% and PR 51.6%) at 12°months and in 10/11 patients (90.9%: CR 54.6% and PR 36.4%) at 24°months, respectively. Proteinuria reduced from 6.02 g/d at baseline to 0.98 g/d at 12°months (p < 0.001) and to 0.27 g/d at 24°months (p = 0.003); serum albumin increased from 28 g/L to 37.2 g/L at 12°months (p < 0.001) and to 41.3 g/L at 24°months (p = 0.003); eGFR improved from 100.25 ml/min/1.73 m2 to 118.39 ml/min/1.73 m2 at 6°months (p < 0.001) and finally to 111.62 ml/min/1.73 m2at 24°months (p = 0.008). Only two patients developed subsequent relapse. Conclusion: Shulifenxiao formula as a clinical cocktail therapy serves as an alternative therapeutic option for steroid and immunosuppressant-resistant RIMN patients, with a favourable safety profile, though further studies are warranted. Clinical Trial registration: http://www.chictr.org.cn, Chinese Clinical Trials Registry [ChiCTR1800019351].
| S-EPMC8141813 | biostudies-literature
Project description:BackgroundA non-invasive diagnostic marker of membranous nephropathy (MN) is desirable. The urinary level of podocalyxin (PCX) is higher in various glomerular diseases, including MN. The aim of this study was to construct a diagnostic model of MN with the combination of urinary PCX and clinical parameters.MethodsWe performed this cross-sectional study to construct the diagnostic models for MN by using data and samples from the multicenter kidney biopsy registry of Nagoya University and its affiliated hospitals. Urinary (u-) PCX was measured by sandwich ELISA. We constructed 3 types of diagnostic models in 105 training samples: u-PCX univariate model, the combined model of clinical parameters other than u-PCX (clinical model), and the combined model of both u-PCX and clinical parameters (combined model). We assessed the clinical usefulness of the diagnostic models through the comparison of c-statistics and decision curve analysis (DCA) in 209 validation samples.ResultsThe clinical model consisted of age, glomerular filtration rate, and diabetes mellitus. In the training cohort, the c-statistics were 0.868 [95% CI, 0.799-0.937] in the combined model. In the validation cohort, sensitivity was 80.5% and specificity was 73.5% on the cut-off value. The net benefit of the combined model was better between threshold probabilities of 40-80% in DCA.ConclusionsIn this study, we demonstrated the utility of u-PCX as a diagnostic marker for MN and the clinical usefulness of the diagnostic models, through the combination of u-PCX and clinical parameters including age, glomerular filtration rate, and diabetes mellitus.
| S-EPMC5036798 | biostudies-literature
Project description:BackgroundIdiopathic membranous nephropathy (IMN) is a cause of nephrotic syndrome that is increasing in incidence but has unclear pathogenesis. Urinary peptidomics is a promising technology for elucidating molecular mechanisms underlying diseases. Dysregulation of the proteolytic system is implicated in various diseases. Here, we aimed to conduct urinary peptidomics to identify IMN-related proteases.ResultsPeptide fingerprints indicated differences in naturally produced urinary peptide components among 20 healthy individuals, 22 patients with IMN, and 15 patients with other kidney diseases. In total, 1,080 peptide-matched proteins were identified, 279 proteins differentially expressed in the urine of IMN patients were screened, and 32 proteases were predicted; 55 of the matched proteins were also differentially expressed in the kidney tissues of IMN patients, and these were mainly involved in the regulation of proteasome-, lysosome-, and actin cytoskeleton-related signaling pathways. The 32 predicted proteases showed abnormal expression in the glomeruli of IMN patients based on Gene Expression Omnibus databases. Western blot revealed abnormal expression of calpain, matrix metalloproteinase 14, and cathepsin S in kidney tissues of patients with IMN.ConclusionsThis work shown the calpain/matrix metalloproteinase/cathepsin axis might be dysregulated in IMN. Our study is the first to systematically explore the role of proteases in IMN by urinary peptidomics, which are expected to facilitate discovery of better biomarkers for IMN.
| S-EPMC8613922 | biostudies-literature
Project description:Semaphorin3A is a secreted protein known to be involved in organogenesis, immune responses and cancer. In the kidney, semaphorin3A is expressed in the glomerular podocytes, distal tubules and collecting tubules, and believed to play a role in the regulation of the kidney development and function. We examined the serum and urinary semaphorin3A levels in 72 patients with renal disease and 5 healthy volunteers. The patients had been diagnosed with thin basement membrane disease (n=4), minimal change nephrotic syndrome (MCNS; n=22), IgA nephritis (n=21), membranous nephropathy (n=16) and focal segmental glomerular sclerosis (n=9). The level of urinary semaphorin3A in MCNS patients tended to be relatively high among all disease groups. We also investigated the urinary semaphorin3A level in 7 patients with MCNS from disease onset to remission during the drug therapy. MCNS patients in pre-remission states had higher urinary semaphorin3A levels than those in post-remission states receiving immunosuppressive therapies. These results suggested that the urinary semaphorin3A level correlates with the MCNS activity. Semaphorin3A has the potential as a biomarker for MCNS to clarify the reactivity for therapy and may be useful in examining other glomerular diseases with proteinuria as well.
| S-EPMC5489052 | biostudies-literature
Project description:Urinary proteome was analyzed and quantified by Tandem Mass Tag (TMT) labeling followed by bioinformatics analysis to study DN pathophysiology and to identify biomarkers of clinical outcome. We included type 2 diabetic normotensive non-obese males with and without incipient DN (microalbuminuria). Sample collection included blood and urine at baseline (control and DN-basal) and, in DN patients, after 3 months of losartan treatment (DN-treated). Urinary proteome analysis identified 166 differentially abundant proteins between controls and DN patients, 27 comparing DN-treated and DN-basal patients, and 182 between DN-treated patients and controls. Mathematical modeling analysis identified 80 key proteins involved in DN pathophysiology, 15 in losartan effect and 7 of these 95 are essential in both processes. VCAM-1 and neprilysin are the only ones that are differentially expressed in the urinary proteome. We observed an increase of VCAM-1 urine levels in DN-basal patients compared to diabetic controls and an increase of urinary neprilysin in DN-treated patients with persistent albuminuria, the latter confirmed by ELISA . Our results point to neprilysin and VCAM-1 as potential candidates in DN pathology and treatment.
2018-05-22 | PXD009303 | Pride
Project description:BackgroundThe outcome of patients with primary membranous nephropathy (pMN) who present with nephrotic syndrome (NS) is variable and difficult to predict. The goal of this study was to develop a nomogram to predict the risk of progression for specific individuals.MethodsThis retrospective study involved biopsy-proven patients with pMN and NS treated between January 2012 and June 2018. The primary outcome of our investigation was progression, defined as a reduction of estimated glomerular filtration rate (eGFR) that was equal to or over 20% compared with baseline at the end of follow-up or the onset of end-stage renal disease (ESRD). We used backwards stepwise logistic regression analysis to create a nomogram to predict prognosis. The model was validated internally using bootstrap resampling.ResultsA total of 111 patients were enrolled. After a median follow-up of 40.0 months (range 12-92 months), 18.9% (21/111) patients showed progression. Backwards stepwise selection using the Akaike information criterion (AIC) identified the following four variables as independent risk factors for progression, which were all used in the nomogram: age ≥ 65 years [odds ratio (OR) 7.004; 95% confidence interval (CI) 1.783-27.505; p = 0.005], Ln (sPLA2R-Ab) (OR 2.150; 95% CI 1.293-3.577; p = 0.003), Ln (proteinuria) (OR 5.939; 95% CI 1.055-33.436; p = 0.043) and Ln (Uα1m/Cr) (OR 2.808; 95% CI 1.035-7.619; p = 0.043). The discriminative ability and calibration of the nomogram revealed good predictive ability, as indicated by a C-index of 0.888 (95% CI 0.814-0.940) and a bootstrap-corrected C-index of 0.869; calibration curves were also well fitted. A receiver operating characteristic (ROC) curve for the nomogram score revealed significantly better discrimination than each of the three risk factors alone, including Ln (sPLA2R-Ab) [area under the curve (AUC) 0.769], Ln (proteinuria) (AUC 0.653) and Ln (Uα1m) (AUC 0.781) in the prediction of progression (p < 0.05). The optimal cutoff value of the nomogram score was 117.8 with a positive predictive value of 44.4% and a negative predictive value of 98.5%.ConclusionThe nomogram successfully achieved good predictive ability of progression for patients with pMN who present with NS. It can therefore help clinicians to individualize treatment plans and improve the outcome of pMN.
| S-EPMC8782821 | biostudies-literature