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14 pages, 1684 KiB

Open AccessArticle

A Combined Biomarker That Includes Plasma Fibroblast Growth Factor 23, Erythropoietin, and Klotho Predicts Short- and Long-Term Morbimortality and Development of Chronic Kidney Disease in Critical Care Patients with Sepsis: A Prospective Cohort

by Luis Toro, Verónica Rojas, Carolina Conejeros, Patricia Ayala, Alfredo Parra-Lucares, Francisca Ahumada, Paula Almeida, María Fernanda Silva, Karin Bravo, Catalina Pumarino, Ana María Tong, María Eugenia Pinto, Carlos Romero and Luis Michea

Biomolecules 2023, 13(10), 1481; https://doi.org/10.3390/biom13101481 - 03 Oct 2023

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Abstract

Acute Kidney Injury (AKI) is a frequent complication in intensive care unit (ICU) patients that increases mortality and chronic kidney disease (CKD) development. AKI is associated with elevated plasma fibroblast growth factor 23 (FGF23), which can be modulated by erythropoietin (EPO) and Klotho. [...] Read more.

Acute Kidney Injury (AKI) is a frequent complication in intensive care unit (ICU) patients that increases mortality and chronic kidney disease (CKD) development. AKI is associated with elevated plasma fibroblast growth factor 23 (FGF23), which can be modulated by erythropoietin (EPO) and Klotho. We aimed to evaluate whether a combined biomarker that includes these molecules predicted short-/long-term outcomes. We performed a prospective cohort of ICU patients with sepsis and previously normal renal function. They were followed during their inpatient stay and for one year after admission. We measured plasma FGF23, EPO, and Klotho levels at admission and calculated a combined biomarker (FEK). A total of 164 patients were recruited. Of these, 50 (30.5%) had AKI at admission, and 55 (33.5%) developed AKI within 48 h. Patients with AKI at admission and those who developed AKI within 48 h had 12- and 5-fold higher FEK values than non-AKI patients, respectively. Additionally, patients with higher FEK values had increased 1-year mortality (41.9% vs. 18.6%, p = 0.003) and CKD progression (26.2% vs. 8.3%, p = 0.023). Our data suggest that the FEK indicator predicts the risk of AKI, short-/long-term mortality, and CKD progression in ICU patients with sepsis. This new indicator can improve clinical outcome prediction and guide early therapeutic strategies. Full article

(This article belongs to the Special Issue Biomarkers in Renal Diseases)

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14 pages, 1312 KiB

Open AccessArticle

PKD1 Mutation Is a Biomarker for Autosomal Dominant Polycystic Kidney Disease

by Tomoki Kimura, Haruna Kawano, Satoru Muto, Nobuhito Muramoto, Toshiaki Takano, Yan Lu, Hidetaka Eguchi, Hiroo Wada, Yasushi Okazaki, Hisamitsu Ide and Shigeo Horie

Biomolecules 2023, 13(7), 1020; https://doi.org/10.3390/biom13071020 - 21 Jun 2023

Cited by 1 | Viewed by 1357

Abstract

Background: Autosomal dominant polycystic kidney disease (ADPKD) occurs in 1 in 500–4000 people worldwide. Genetic mutation is a biomarker for predicting renal dysfunction in patients with ADPKD. In this study, we performed a genetic analysis of Japanese patients with ADPKD to investigate the [...] Read more.

Background: Autosomal dominant polycystic kidney disease (ADPKD) occurs in 1 in 500–4000 people worldwide. Genetic mutation is a biomarker for predicting renal dysfunction in patients with ADPKD. In this study, we performed a genetic analysis of Japanese patients with ADPKD to investigate the prognostic utility of genetic mutations in predicting renal function outcomes. Methods: Patients clinically diagnosed with ADPKD underwent a panel genetic test for germline mutations in PKD1 and PKD2. This study was conducted with the approval of the Ethics Committee of Juntendo University (no. 2019107). Results: Of 436 patients, 366 (83.9%) had genetic mutations. Notably, patients with PKD1 mutation had a significantly decreased ΔeGFR/year compared to patients with PKD2 mutation, indicating a progression of renal dysfunction (−3.50 vs. −2.04 mL/min/1.73 m²/year, p = 0.066). Furthermore, PKD1 truncated mutations had a significantly decreased ΔeGFR/year compared to PKD1 non-truncated mutations in the population aged over 65 years (−6.56 vs. −2.16 mL/min/1.73 m²/year, p = 0.049). Multivariate analysis showed that PKD1 mutation was a more significant risk factor than PKD2 mutation (odds ratio, 1.81; 95% confidence interval, 1.11–3.16; p = 0.020). Conclusions: The analysis of germline mutations can predict renal prognosis in Japanese patients with ADPKD, and PKD1 mutation is a biomarker of ADPKD. Full article

(This article belongs to the Special Issue Biomarkers in Renal Diseases)

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15 pages, 1888 KiB

Open AccessEditor’s ChoiceArticle

Dynamics of Urinary Extracellular DNA in Urosepsis

by Michaela Mihaľová, Nadja Šupčíková, Alexandra Gaál Kovalčíková, Ján Breza, Jr., Ľubomíra Tóthová, Peter Celec and Ján Breza, Sr.

Biomolecules 2023, 13(6), 1008; https://doi.org/10.3390/biom13061008 - 17 Jun 2023

Viewed by 1489

Abstract

Extracellular DNA (ecDNA) is a promising candidate marker for the early diagnosis and monitoring of urinary tract infections (UTIs). The aim of our study is to describe the dynamics of ecDNA in the plasma and urine of patients with urosepsis as well as [...] Read more.

Extracellular DNA (ecDNA) is a promising candidate marker for the early diagnosis and monitoring of urinary tract infections (UTIs). The aim of our study is to describe the dynamics of ecDNA in the plasma and urine of patients with urosepsis as well as in a mouse model of UTI. Samples of blood and urine were collected from adult patients with UTIs and obstructive uropathy (n = 36) during the first 3 days at the hospital and during a follow-up. Bacterial burden and urinary ecDNA were evaluated in a mouse UTI model (n = 26) at baseline; 24, 48, and 72 h after UTI induction; and 7 days after UTI induction. The plasma ecDNA did not change during urosepsis, but the plasma DNase activity increased significantly at the follow-up. The urinary ecDNA decreased significantly during hospitalization and remained low until the follow-up (90% lower vs. admission). No change was seen in the urinary DNase activity. C-reactive protein (CRP) and procalcitonin are positively correlated with plasma and urinary ecDNA. A UTI caused sepsis in 23% of mice. The urinary ecDNA decreased by three-fold and remained low until day 7 post-infection. Urinary bacterial burden is correlated with urinary ecDNA. Urinary ecDNA is a potential non-invasive marker for monitoring the effects of treatment during urosepsis and is related to UTI progression in the experimental animal model. Full article

(This article belongs to the Special Issue Biomarkers in Renal Diseases)

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14 pages, 478 KiB

Open AccessArticle

Renal Dysfunction Phenotypes in Patients Undergoing Obesity Surgery

by Pedro R. Pereira, João Pereira, Patrícia C. Braga, Sofia S. Pereira, Mário Nora, Marta Guimarães, Mariana P. Monteiro and Anabela Rodrigues

Biomolecules 2023, 13(5), 790; https://doi.org/10.3390/biom13050790 - 03 May 2023

Cited by 1 | Viewed by 1364

Abstract

Obesity surgery candidates are at an increased risk of kidney injury, but pre-operative evaluation usually neglects kidney function assessment. This study aimed to identify renal dysfunction in candidates for bariatric surgery. To reduce the sources of bias, subjects with diabetes, prediabetes under metformin [...] Read more.

Obesity surgery candidates are at an increased risk of kidney injury, but pre-operative evaluation usually neglects kidney function assessment. This study aimed to identify renal dysfunction in candidates for bariatric surgery. To reduce the sources of bias, subjects with diabetes, prediabetes under metformin treatment, neoplastic or inflammatory diseases were excluded. Patients’ (n = 192) average body mass index was 41.7 ± 5.4 kg/m². Among these, 51% (n = 94) had creatinine clearance over 140 mL/min, 22.4% (n = 43) had proteinuria over 150 mg/day and 14.6% (n = 28) albuminuria over 30 mg/day. A creatinine clearance higher than 140 mL/min was associated with higher levels of proteinuria and albuminuria. Univariate analysis identified sex, glycated hemoglobin, uric acid, HDL and VLDL cholesterol as being associated with albuminuria, but not with proteinuria. On multivariate analysis, glycated hemoglobin and creatinine clearance as continuous variables were significantly associated with albuminuria. In summary, in our patient population prediabetes, lipid abnormalities and hyperuricemia were associated with albuminuria, but not with proteinuria, suggesting different disease mechanisms might be implicated. Data suggest that in obesity-associated kidney disease, tubulointerstitial injury precedes glomerulopathy. A significant proportion of obesity surgery candidates present clinically relevant albuminuria and proteinuria along with renal hyperfiltration, suggesting that routine pre-operative assessment of these parameters should be considered. Full article

(This article belongs to the Special Issue Biomarkers in Renal Diseases)

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14 pages, 2434 KiB

Open AccessArticle

TNFR2 as a Potential Biomarker for Early Detection and Progression of CKD

by Irina Lousa, Flávio Reis, Sofia Viana, Pedro Vieira, Helena Vala, Luís Belo and Alice Santos-Silva

Biomolecules 2023, 13(3), 534; https://doi.org/10.3390/biom13030534 - 15 Mar 2023

Cited by 1 | Viewed by 1580

Abstract

The inflammatory pathway driven by TNF-α, through its receptors TNFR1 and TNFR2, is a common feature in the pathogenesis of chronic kidney disease (CKD), regardless of the initial disease cause. Evidence correlates the chronic inflammatory status with decreased renal function. Our aim was [...] Read more.

The inflammatory pathway driven by TNF-α, through its receptors TNFR1 and TNFR2, is a common feature in the pathogenesis of chronic kidney disease (CKD), regardless of the initial disease cause. Evidence correlates the chronic inflammatory status with decreased renal function. Our aim was to evaluate the potential of TNF receptors as biomarkers for CKD diagnosis and staging, as well as their association with the progression of renal lesions, in rat models of early and moderate CKD. We analyzed the circulating levels of inflammatory molecules—tumor necrosis factor-alpha (TNF-α), tumor necrosis factor receptor 1 (TNFR1) and 2 (TNFR2) and tissue inhibitor of metalloproteinase-1 (TIMP-1)—and studied their associations with TNFR1 and TNFR2 renal expression, glomerular and tubulointerstitial lesions, and with biomarkers of renal (dys)function. An increase in all inflammatory markers was observed in moderate CKD, as compared to controls, but only circulating levels of both TNFR1 and TNFR2 were significantly increased in the early disease; TNFR2 serum levels were negatively correlated with eGFR. However, only TNFR2 renal expression increased with CKD severity and showed correlations with the score of mild and advanced tubular lesions. Our findings suggest that renal TNFR2 plays a role in CKD development, and has potential to be used as a biomarker for the early detection and progression of the disease. Still, the potential value of this biomarker in disease progression warrants further investigation. Full article

(This article belongs to the Special Issue Biomarkers in Renal Diseases)

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17 pages, 8373 KiB

Open AccessArticle

Identification of the Subtypes of Renal Ischemia-Reperfusion Injury Based on Pyroptosis-Related Genes

by Xinhao Niu, Yin Celeste Cheuk, Xiao Li, Ruiming Rong, Xiaoqing Xu, Cuidi Xu, Yongsheng Luo, Pingbao Zhang and Jingjing Guo

Biomolecules 2023, 13(2), 275; https://doi.org/10.3390/biom13020275 - 01 Feb 2023

Cited by 2 | Viewed by 1290

Abstract

Ischemia-reperfusion injury (IRI) often occurs in the process of kidney transplantation, which significantly impacts the subsequent treatment and prognosis of patients. The prognosis of patients with different subtypes of IRI is quite different. Therefore, in this paper, the gene expression data of multiple [...] Read more.

Ischemia-reperfusion injury (IRI) often occurs in the process of kidney transplantation, which significantly impacts the subsequent treatment and prognosis of patients. The prognosis of patients with different subtypes of IRI is quite different. Therefore, in this paper, the gene expression data of multiple IRI samples were downloaded from the GEO database, and a double Laplacian orthogonal non-negative matrix factorization (DL-ONMF) algorithm was proposed to classify them. In this algorithm, various regularization constraints are added based on the non-negative matrix factorization algorithm, and the prior information is fused into the algorithm from different perspectives. The connectivity information between different samples and features is added to the algorithm by Laplacian regularization constraints on samples and features. In addition, orthogonality constraints on the basis matrix and coefficient matrix obtained by the algorithm decomposition are added to reduce the influence of redundant samples and redundant features on the results. Based on the DL-ONMF algorithm for clustering, two PRGs-related IRI isoforms were obtained in this paper. The results of immunoassays showed that the immune microenvironment was different among PRGS-related IRI types. Based on the differentially expressed PRGs between subtypes, we used LASSO and SVM-RFE algorithms to construct a diagnostic model related to renal transplantation. ROC analysis showed that the diagnostic model could predict the outcome of renal transplant patients with high accuracy. In conclusion, this paper presents an algorithm, DL-ONMF, which can identify subtypes with different disease characteristics. Comprehensive bioinformatic analysis showed that pyroptosis might affect the outcome of kidney transplantation by participating in the immune response of IRI. Full article

(This article belongs to the Special Issue Biomarkers in Renal Diseases)

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13 pages, 891 KiB

Open AccessFeature PaperArticle

Urinary Angiotensinogen and Progression of Chronic Kidney Disease: Results from KNOW-CKD Study

by Sang Heon Suh, Tae Ryom Oh, Hong Sang Choi, Eun Mi Yang, Chang Seong Kim, Eun Hui Bae, Seong Kwon Ma, Kook-Hwan Oh, Ji Yong Jung, Young Youl Hyun and Soo Wan Kim

Biomolecules 2022, 12(9), 1280; https://doi.org/10.3390/biom12091280 - 10 Sep 2022

Cited by 4 | Viewed by 1448

Abstract

The prognostic value of urinary angiotensinogen (UAGT) in patients with chronic kidney disease (CKD) has not been completely evaluated, although the association of UAGT with renal outcomes has been suggested in specific subsets of CKD. In the present study, to investigate the association [...] Read more.

The prognostic value of urinary angiotensinogen (UAGT) in patients with chronic kidney disease (CKD) has not been completely evaluated, although the association of UAGT with renal outcomes has been suggested in specific subsets of CKD. In the present study, to investigate the association of UAGT with renal outcomes in patients with non-dialysis CKD irrespective of the primary cause, a total of 1688 subjects from the Korean Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD) were prospectively analyzed. The subjects were divided into the quintile by UAGT to urine creatinine ratio (UAGT/Cr) level. The primary outcomes of interest were composite renal event, which included decline in kidney function and onset of end-stage renal disease during follow-up periods. The median follow-up duration was 6.257 years. Cox regression model analysis unveiled that the risk of composite renal event was significantly higher in the fifth quintile (adjusted hazard ratio 1.528, 95% confidence interval 1.156 to 2.021) compared to that of the first quartile. The association between high UAGT/Cr level and adverse renal outcome remained consistent in sensitivity analyses, including the analysis of the cause-specific hazard model. Subgroup analyses revealed that the association of UAGT level with renal outcomes is modified by certain clinical contexts, such as BMI and albuminuria. In conclusion, high UAGT level is associated with adverse renal outcomes in patients with non-dialysis CKD. Further studies are warranted to elaborate and expand the predictive role of UAGT as a biomarker for renal outcomes in CKD. Full article

(This article belongs to the Special Issue Biomarkers in Renal Diseases)

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15 pages, 5028 KiB

Open AccessArticle

Identification of Unique Genetic Biomarkers of Various Subtypes of Glomerulonephritis Using Machine Learning and Deep Learning

by Jianbo Qing, Fang Zheng, Huiwen Zhi, Hasnaa Yaigoub, Hasna Tirichen, Yaheng Li, Juanjuan Zhao, Yan Qiang and Yafeng Li

Biomolecules 2022, 12(9), 1276; https://doi.org/10.3390/biom12091276 - 10 Sep 2022

Cited by 1 | Viewed by 1561

Abstract

(1) Objective: Identification of potential genetic biomarkers for various glomerulonephritis (GN) subtypes and discovering the molecular mechanisms of GN. (2) Methods: four microarray datasets of GN were downloaded from Gene Expression Omnibus (GEO) database and merged to obtain the gene expression profiles of [...] Read more.

(1) Objective: Identification of potential genetic biomarkers for various glomerulonephritis (GN) subtypes and discovering the molecular mechanisms of GN. (2) Methods: four microarray datasets of GN were downloaded from Gene Expression Omnibus (GEO) database and merged to obtain the gene expression profiles of eight GN subtypes. Then, differentially expressed immune-related genes (DIRGs) were identified to explore the molecular mechanisms of GN, and single-sample gene set enrichment analysis (ssGSEA) was performed to discover the abnormal inflammation in GN. In addition, a nomogram model was generated using the R package “glmnet”, and the calibration curve was plotted to evaluate the predictive power of the nomogram model. Finally, deep learning (DL) based on a multilayer perceptron (MLP) network was performed to explore the characteristic genes for GN. (3) Results: we screened out 274 common up-regulated or down-regulated DIRGs in the glomeruli and tubulointerstitium. These DIRGs are mainly involved in T-cell differentiation, the RAS signaling pathway, and the MAPK signaling pathway. ssGSEA indicates that there is a significant increase in DC (dendritic cells) and macrophages, and a significant decrease in neutrophils and NKT cells in glomeruli, while monocytes and NK cells are increased in tubulointerstitium. A nomogram model was constructed to predict GN based on 7 DIRGs, and 20 DIRGs of each subtype of GN in glomeruli and tubulointerstitium were selected as characteristic genes. (4) Conclusions: this study reveals that the DIRGs are closely related to the pathogenesis of GN and could serve as genetic biomarkers in GN. DL further identified the characteristic genes that are essential to define the pathogenesis of GN and develop targeted therapies for eight GN subtypes. Full article

(This article belongs to the Special Issue Biomarkers in Renal Diseases)

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Review

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18 pages, 1065 KiB

Open AccessEditor’s ChoiceReview

Update on Diabetic Kidney Disease (DKD): Focus on Non-Albuminuric DKD and Cardiovascular Risk

by Sabrina Scilletta, Maurizio Di Marco, Nicoletta Miano, Agnese Filippello, Stefania Di Mauro, Alessandra Scamporrino, Marco Musmeci, Giuseppe Coppolino, Francesco Di Giacomo Barbagallo, Giosiana Bosco, Roberto Scicali, Salvatore Piro, Francesco Purrello and Antonino Di Pino

Biomolecules 2023, 13(5), 752; https://doi.org/10.3390/biom13050752 - 26 Apr 2023

Cited by 7 | Viewed by 5198

Abstract

The classic description of diabetic kidney disease (DKD) involves progressive stages of glomerular hyperfiltration, microalbuminuria, proteinuria, and a decline in the estimated glomerular filtration rate (eGFR), leading to dialysis. In recent years, this concept has been increasingly challenged as evidence suggests that DKD [...] Read more.

The classic description of diabetic kidney disease (DKD) involves progressive stages of glomerular hyperfiltration, microalbuminuria, proteinuria, and a decline in the estimated glomerular filtration rate (eGFR), leading to dialysis. In recent years, this concept has been increasingly challenged as evidence suggests that DKD presents more heterogeneously. Large studies have revealed that eGFR decline may also occur independently from the development of albuminuria. This concept led to the identification of a new DKD phenotype: non-albuminuric DKD (eGFR < 60 mL/min/1.73 m², absence of albuminuria), whose pathogenesis is still unknown. However, various hypotheses have been formulated, the most likely of which is the acute kidney injury-to-chronic kidney disease (CKD) transition, with prevalent tubular, rather than glomerular, damage (typically described in albuminuric DKD). Moreover, it is still debated which phenotype is associated with a higher cardiovascular risk, due to contrasting results available in the literature. Finally, much evidence has accumulated on the various classes of drugs with beneficial effects on DKD; however, there is a lack of studies analyzing the different effects of drugs on the various phenotypes of DKD. For this reason, there are still no specific guidelines for therapy in one phenotype rather than the other, generically referring to diabetic patients with CKD. Full article

(This article belongs to the Special Issue Biomarkers in Renal Diseases)

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15 pages, 2471 KiB

Open AccessReview

by John K. Maesaka, Louis J. Imbriano, Candace Grant and Nobuyuki Miyawaki

Biomolecules 2023, 13(4), 638; https://doi.org/10.3390/biom13040638 - 01 Apr 2023

Viewed by 1388

Abstract

The application of pathophysiologic tenets has created significant changes in our approach to hyponatremia and hyponatremia-related conditions. This new approach incorporated the determination of fractional excretion (FE) of urate before and after the correction of hyponatremia and the response to isotonic saline infusion [...] Read more.

The application of pathophysiologic tenets has created significant changes in our approach to hyponatremia and hyponatremia-related conditions. This new approach incorporated the determination of fractional excretion (FE) of urate before and after the correction of hyponatremia and the response to isotonic saline infusion to differentiate the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) from renal salt wasting (RSW). FEurate simplified the identification of the different causes of hyponatremia, especially the diagnosis of a reset osmostat and Addison’s disease. Differentiating SIADH from RSW has been extremely difficult because both syndromes present with identical clinical parameters, which could be overcome by successfully carrying out the difficult protocol of this new approach. A study of 62 hyponatremic patients from the general medical wards of the hospital identified 17 (27%) to have SIADH, 19 (31%) with reset osmostat, and 24 (38%) with RSW with 21 of these RSW patients presenting without clinical evidence of cerebral disease to warrant changing the nomenclature from cerebral to renal salt wasting. The natriuretic activity found in the plasma of 21 and 18 patients with neurosurgical and Alzheimer’s disease, respectively, was later identified as haptoglobin-related protein without signal peptide (HPRWSP). The high prevalence of RSW creates a therapeutic dilemma of deciding whether to water-restrict water-logged patients with SIADH as compared to administering saline to volume-depleted patients with RSW. Future studies will hopefully achieve the following: 1. Abandon the ineffective volume approach; 2. Develop HPRWSP as a biomarker to identify hyponatremic and a projected large number of normonatremic patients at risk of developing RSW, including Alzheimer’s disease; 3. Facilitate differentiating SIADH from RSW on the first encounter and improve clinical outcomes. Full article

(This article belongs to the Special Issue Biomarkers in Renal Diseases)

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