International Journal of Molecular Sciences

Editorial

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Open AccessEditorial

Editorial for Special Issue—Biomarkers of Renal Disease

by Joaquín García-Estañ and Felix Vargas

Int. J. Mol. Sci. 2020, 21(21), 8077; https://doi.org/10.3390/ijms21218077 - 29 Oct 2020

Cited by 1 | Viewed by 1384

Abstract

The National Institutes of Health (NIH) Biomarkers Definitions Group has defined a biomarker as “A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention [...] Full article

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

Research

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14 pages, 4881 KiB

Open AccessArticle

Trichostatin A Alleviates Renal Interstitial Fibrosis Through Modulation of the M2 Macrophage Subpopulation

by Wei-Cheng Tseng, Ming-Tsun Tsai, Nien-Jung Chen and Der-Cherng Tarng

Int. J. Mol. Sci. 2020, 21(17), 5966; https://doi.org/10.3390/ijms21175966 - 19 Aug 2020

Cited by 21 | Viewed by 2983

Abstract

Mounting evidence indicates that an increase in histone deacetylation contributes to renal fibrosis. Although inhibition of histone deacetylase (HDAC) can reduce the extent of fibrosis, whether HDAC inhibitors exert the antifibrotic effect through modulating the phenotypes of macrophages, the key regulator of renal [...] Read more.

Mounting evidence indicates that an increase in histone deacetylation contributes to renal fibrosis. Although inhibition of histone deacetylase (HDAC) can reduce the extent of fibrosis, whether HDAC inhibitors exert the antifibrotic effect through modulating the phenotypes of macrophages, the key regulator of renal fibrosis, remains unknown. Moreover, the functional roles of the M2 macrophage subpopulation in fibrotic kidney diseases remain incompletely understood. Herein, we investigated the role of HDAC inhibitors on renal fibrogenesis and macrophage plasticity. We found that HDAC inhibition by trichostatin A (TSA) reduced the accumulation of interstitial macrophages, suppressed the activation of myofibroblasts and attenuated the extent of fibrosis in obstructive nephropathy. Moreover, TSA inhibited M1 macrophages and augmented M2 macrophage infiltration in fibrotic kidney tissue. Interestingly, TSA preferentially upregulated M2c macrophages and suppressed M2a macrophages in the obstructed kidneys, which was correlated with a reduction of interstitial fibrosis. TSA also repressed the expression of proinflammatory and profibrotic molecules in cultured M2a macrophages and inhibited the activation of renal myofibroblasts. In conclusion, our study was the first to show that HDAC inhibition by TSA alleviates renal fibrosis in obstructed kidneys through facilitating an M1 to M2c macrophage transition. Full article

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

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9 pages, 1547 KiB

Open AccessArticle

Circulating Long Noncoding RNA LNC-EPHA6 Associates with Acute Rejection after Kidney Transplantation

by Koen E. Groeneweg, Jacques M.G.J. Duijs, Barend W. Florijn, Cees van Kooten, Johan W. de Fijter, Anton Jan van Zonneveld, Marlies E.J. Reinders and Roel Bijkerk

Int. J. Mol. Sci. 2020, 21(16), 5616; https://doi.org/10.3390/ijms21165616 - 05 Aug 2020

Cited by 9 | Viewed by 2265

Abstract

Acute rejection (AR) of a kidney graft in renal transplant recipients is associated with microvascular injury in graft dysfunction and, ultimately, graft failure. Circulating long noncoding RNAs (lncRNAs) may be suitable markers for vascular injury in the context of AR. Here, we first [...] Read more.

Acute rejection (AR) of a kidney graft in renal transplant recipients is associated with microvascular injury in graft dysfunction and, ultimately, graft failure. Circulating long noncoding RNAs (lncRNAs) may be suitable markers for vascular injury in the context of AR. Here, we first investigated the effect of AR after kidney transplantation on local vascular integrity and demonstrated that the capillary density markedly decreased in AR kidney biopsies compared to pre-transplant biopsies. Subsequently, we assessed the circulating levels of four lncRNAs (LNC-RPS24, LNC-EPHA6, MALAT1, and LIPCAR), that were previously demonstrated to associate with vascular injury in a cohort of kidney recipients with a stable kidney transplant function (n = 32) and recipients with AR (n = 15). The latter were followed longitudinally six and 12 months after rejection. We found higher levels of circulating LNC-EPHA6 during rejection, compared with renal recipients with a stable kidney function (p = 0.017), that normalized one year after AR. In addition, LNC-RPS24, LNC-EPHA6, and LIPCAR levels correlated significantly with the vascular injury marker soluble thrombomodulin. We conclude that AR and microvascular injury are associated with higher levels of circulating LNC-EPHA6, which emphasizes the potential role of lncRNAs as biomarker in the context of AR. Full article

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

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11 pages, 1447 KiB

Open AccessArticle

Uromodulin and microRNAs in Kidney Transplantation—Association with Kidney Graft Function

by Špela Borštnar, Željka Večerić-Haler, Emanuela Boštjančič, Živa Pipan Tkalec, Damjan Kovač, Jelka Lindič and Nika Kojc

Int. J. Mol. Sci. 2020, 21(16), 5592; https://doi.org/10.3390/ijms21165592 - 05 Aug 2020

Cited by 9 | Viewed by 2072

Abstract

Uromodulin and microRNAs (miRNAs) have recently been investigated as potential biomarkers for kidney graft associated pathology and outcome, with a special focus on biomarkers indicating specific disease processes and kidney graft survival. The study’s aim was to determine whether expression of serum uromodulin [...] Read more.

Uromodulin and microRNAs (miRNAs) have recently been investigated as potential biomarkers for kidney graft associated pathology and outcome, with a special focus on biomarkers indicating specific disease processes and kidney graft survival. The study’s aim was to determine whether expression of serum uromodulin concentration and selected miRNAs might be related to renal function in kidney transplant recipients (KTRs). The uromodulin concentration and expression of six selected miRNAs (miR-29c, miR-126, miR-146a, miR-150, miR-155, and miR-223) were determined in the serum of 100 KTRs with stable graft function and chronic kidney disease of all five stages. Kidney graft function was estimated with routine parameters (creatinine, urea, cystatin C, and Chronic Kidney Disease Epidemiology Collaboration study equations) and precisely measured using chromium-51 labelled ethylenediaminetetraacetic-acid clearance. The selected miRNAs were shown to be independent of kidney graft function, indicating their potential as biomarkers of associated kidney graft disease processes. In contrast, the serum uromodulin level depended entirely on kidney graft function and thus reflected functioning tubules rather than any specific kidney graft injury. However, decreased concentrations of serum uromodulin can be observed in the early course of tubulointerstitial injury, thereby suggesting its useful role as an accurate, noninvasive biomarker of early (subclinical) kidney graft injury. Full article

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

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11 pages, 567 KiB

Open AccessArticle

Proteomics-Based Machine Learning Approach as an Alternative to Conventional Biomarkers for Differential Diagnosis of Chronic Kidney Diseases

by Yury E. Glazyrin, Dmitry V. Veprintsev, Irina A. Ler, Maria L. Rossovskaya, Svetlana A. Varygina, Sofia L. Glizer, Tatiana N. Zamay, Marina M. Petrova, Zoran Minic, Maxim V. Berezovski and Anna S. Kichkailo

Int. J. Mol. Sci. 2020, 21(13), 4802; https://doi.org/10.3390/ijms21134802 - 07 Jul 2020

Cited by 20 | Viewed by 3934

Abstract

Diabetic nephropathy, hypertension, and glomerulonephritis are the most common causes of chronic kidney diseases (CKD). Since CKD of various origins may not become apparent until kidney function is significantly impaired, a differential diagnosis and an appropriate treatment are needed at the very early [...] Read more.

Diabetic nephropathy, hypertension, and glomerulonephritis are the most common causes of chronic kidney diseases (CKD). Since CKD of various origins may not become apparent until kidney function is significantly impaired, a differential diagnosis and an appropriate treatment are needed at the very early stages. Conventional biomarkers may not have sufficient separation capabilities, while a full-proteomic approach may be used for these purposes. In the current study, several machine learning algorithms were examined for the differential diagnosis of CKD of three origins. The tested dataset was based on whole proteomic data obtained after the mass spectrometric analysis of plasma and urine samples of 34 CKD patients and the use of label-free quantification approach. The k-nearest-neighbors algorithm showed the possibility of separation of a healthy group from renal patients in general by proteomics data of plasma with high confidence (97.8%). This algorithm has also be proven to be the best of the three tested for distinguishing the groups of patients with diabetic nephropathy and glomerulonephritis according to proteomics data of plasma (96.3% of correct decisions). The group of hypertensive nephropathy could not be reliably separated according to plasma data, whereas analysis of entire proteomics data of urine did not allow differentiating the three diseases. Nevertheless, the group of hypertensive nephropathy was reliably separated from all other renal patients using the k-nearest-neighbors classifier “one against all” with 100% of accuracy by urine proteome data. The tested algorithms show good abilities to differentiate the various groups across proteomic data sets, which may help to avoid invasive intervention for the verification of the glomerulonephritis subtypes, as well as to differentiate hypertensive and diabetic nephropathy in the early stages based not on individual biomarkers, but on the whole proteomic composition of urine and blood. Full article

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

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19 pages, 4600 KiB

Open AccessArticle

Differential Urinary Proteome Analysis for Predicting Prognosis in Type 2 Diabetes Patients with and without Renal Dysfunction

by Hee-Sung Ahn, Jong Ho Kim, Hwangkyo Jeong, Jiyoung Yu, Jeonghun Yeom, Sang Heon Song, Sang Soo Kim, In Joo Kim and Kyunggon Kim

Int. J. Mol. Sci. 2020, 21(12), 4236; https://doi.org/10.3390/ijms21124236 - 14 Jun 2020

Cited by 30 | Viewed by 4237

Abstract

Renal dysfunction, a major complication of type 2 diabetes, can be predicted from estimated glomerular filtration rate (eGFR) and protein markers such as albumin concentration. Urinary protein biomarkers may be used to monitor or predict patient status. Urine samples were selected from patients [...] Read more.

Renal dysfunction, a major complication of type 2 diabetes, can be predicted from estimated glomerular filtration rate (eGFR) and protein markers such as albumin concentration. Urinary protein biomarkers may be used to monitor or predict patient status. Urine samples were selected from patients enrolled in the retrospective diabetic kidney disease (DKD) study, including 35 with good and 19 with poor prognosis. After removal of albumin and immunoglobulin, the remaining proteins were reduced, alkylated, digested, and analyzed qualitatively and quantitatively with a nano LC-MS platform. Each protein was identified, and its concentration normalized to that of creatinine. A prognostic model of DKD was formulated based on the adjusted quantities of each protein in the two groups. Of 1296 proteins identified in the 54 urine samples, 66 were differentially abundant in the two groups (area under the curve (AUC): p-value < 0.05), but none showed significantly better performance than albumin. To improve the predictive power by multivariate analysis, five proteins (ACP2, CTSA, GM2A, MUC1, and SPARCL1) were selected as significant by an AUC-based random forest method. The application of two classifiers—support vector machine and random forest—showed that the multivariate model performed better than univariate analysis of mucin-1 (AUC: 0.935 vs. 0.791) and albumin (AUC: 1.0 vs. 0.722). The urinary proteome can reflect kidney function directly and can predict the prognosis of patients with chronic kidney dysfunction. Classification based on five urinary proteins may better predict the prognosis of DKD patients than urinary albumin concentration or eGFR. Full article

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

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Review

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16 pages, 1037 KiB

Open AccessReview

Acute Kidney Injury in Septic Patients Treated by Selected Nephrotoxic Antibiotic Agents—Pathophysiology and Biomarkers—A Review

by Nadezda Petejova, Arnost Martinek, Josef Zadrazil, Marcela Kanova, Viktor Klementa, Radka Sigutova, Ivana Kacirova, Vladimir Hrabovsky, Zdenek Svagera and David Stejskal

Int. J. Mol. Sci. 2020, 21(19), 7115; https://doi.org/10.3390/ijms21197115 - 26 Sep 2020

Cited by 43 | Viewed by 8954

Abstract

Acute kidney injury is a common complication in critically ill patients with sepsis and/or septic shock. Further, some essential antimicrobial treatment drugs are themselves nephrotoxic. For this reason, timely diagnosis and adequate therapeutic management are paramount. Of potential acute kidney injury (AKI) biomarkers, [...] Read more.

Acute kidney injury is a common complication in critically ill patients with sepsis and/or septic shock. Further, some essential antimicrobial treatment drugs are themselves nephrotoxic. For this reason, timely diagnosis and adequate therapeutic management are paramount. Of potential acute kidney injury (AKI) biomarkers, non-protein-coding RNAs are a subject of ongoing research. This review covers the pathophysiology of vancomycin and gentamicin nephrotoxicity in particular, septic AKI and the microRNAs involved in the pathophysiology of both syndromes. PubMED, UptoDate, MEDLINE and Cochrane databases were searched, using the terms: biomarkers, acute kidney injury, antibiotic nephrotoxicity, sepsis, miRNA and nephrotoxicity. A comprehensive review describing pathophysiology and potential biomarkers of septic and toxic acute kidney injury in septic patients was conducted. In addition, five miRNAs: miR-15a-5p, miR-192-5p, miR-155-5p, miR-486-5p and miR-423-5p specific to septic and toxic acute kidney injury in septic patients, treated by nephrotoxic antibiotic agents (vancomycin and gentamicin) were identified. However, while these are at the stage of clinical testing, preclinical and clinical trials are needed before they can be considered useful biomarkers or therapeutic targets of AKI in the context of antibiotic nephrotoxicity or septic injury. Full article

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

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21 pages, 542 KiB

Open AccessReview

Urinary Biomarkers for Diagnosis and Prediction of Acute Kidney Allograft Rejection: A Systematic Review

by Francesco Guzzi, Luigi Cirillo, Elisa Buti, Francesca Becherucci, Carmela Errichiello, Rosa Maria Roperto, James P. Hunter and Paola Romagnani

Int. J. Mol. Sci. 2020, 21(18), 6889; https://doi.org/10.3390/ijms21186889 - 19 Sep 2020

Cited by 18 | Viewed by 3175

Abstract

Noninvasive tools for diagnosis or prediction of acute kidney allograft rejection have been extensively investigated in recent years. Biochemical and molecular analyses of blood and urine provide a liquid biopsy that could offer new possibilities for rejection prevention, monitoring, and therefore, treatment. Nevertheless, [...] Read more.

Noninvasive tools for diagnosis or prediction of acute kidney allograft rejection have been extensively investigated in recent years. Biochemical and molecular analyses of blood and urine provide a liquid biopsy that could offer new possibilities for rejection prevention, monitoring, and therefore, treatment. Nevertheless, these tools are not yet available for routine use in clinical practice. In this systematic review, MEDLINE was searched for articles assessing urinary biomarkers for diagnosis or prediction of kidney allograft acute rejection published in the last five years (from 1 January 2015 to 31 May 2020). This review follows the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Articles providing targeted or unbiased urine sample analysis for the diagnosis or prediction of both acute cellular and antibody-mediated kidney allograft rejection were included, analyzed, and graded for methodological quality with a particular focus on study design and diagnostic test accuracy measures. Urinary C-X-C motif chemokine ligands were the most promising and frequently studied biomarkers. The combination of precise diagnostic reference in training sets with accurate validation in real-life cohorts provided the most relevant results and exciting groundwork for future studies. Full article

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

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25 pages, 819 KiB

Open AccessReview

Contribution of Predictive and Prognostic Biomarkers to Clinical Research on Chronic Kidney Disease

by Michele Provenzano, Salvatore Rotundo, Paolo Chiodini, Ida Gagliardi, Ashour Michael, Elvira Angotti, Silvio Borrelli, Raffaele Serra, Daniela Foti, Giovambattista De Sarro and Michele Andreucci

Int. J. Mol. Sci. 2020, 21(16), 5846; https://doi.org/10.3390/ijms21165846 - 14 Aug 2020

Cited by 31 | Viewed by 3451

Abstract

Chronic kidney disease (CKD), defined as the presence of albuminuria and/or reduction in estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m², is considered a growing public health problem, with its prevalence and incidence having almost doubled in the past three [...] Read more.

Chronic kidney disease (CKD), defined as the presence of albuminuria and/or reduction in estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m², is considered a growing public health problem, with its prevalence and incidence having almost doubled in the past three decades. The implementation of novel biomarkers in clinical practice is crucial, since it could allow earlier diagnosis and lead to an improvement in CKD outcomes. Nevertheless, a clear guidance on how to develop biomarkers in the setting of CKD is not yet available. The aim of this review is to report the framework for implementing biomarkers in observational and intervention studies. Biomarkers are classified as either prognostic or predictive; the first type is used to identify the likelihood of a patient to develop an endpoint regardless of treatment, whereas the second type is used to determine whether the patient is likely to benefit from a specific treatment. Many single assays and complex biomarkers were shown to improve the prediction of cardiovascular and kidney outcomes in CKD patients on top of the traditional risk factors. Biomarkers were also shown to improve clinical trial designs. Understanding the correct ways to validate and implement novel biomarkers in CKD will help to mitigate the global burden of CKD and to improve the individual prognosis of these high-risk patients. Full article

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

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20 pages, 1236 KiB

Open AccessReview

Changes in Novel AKI Biomarkers after Exercise. A Systematic Review

by Wojciech Wołyniec, Wojciech Ratkowski, Joanna Renke and Marcin Renke

Int. J. Mol. Sci. 2020, 21(16), 5673; https://doi.org/10.3390/ijms21165673 - 07 Aug 2020

Cited by 26 | Viewed by 4126

Abstract

More than 100 substances have been identified as biomarkers of acute kidney injury. These markers can help to diagnose acute kidney injury (AKI) in its early phase, when the creatinine level is not increased. The two markers most frequently studied in plasma and [...] Read more.

More than 100 substances have been identified as biomarkers of acute kidney injury. These markers can help to diagnose acute kidney injury (AKI) in its early phase, when the creatinine level is not increased. The two markers most frequently studied in plasma and serum are cystatin C and neutrophil gelatinase-associated lipocalin (NGAL). The former is a marker of kidney function and the latter is a marker of kidney damage. Some other promising serum markers, such as osteopontin and netrin-1, have also been proposed and studied. The list of promising urinary markers is much longer and includes cystatin C, NGAL, kidney injury molecule-1 (KIM-1), liver-type fatty-acid-binding protein (L-FABP), interleukin 18, insulin-like growth factor binding protein 7 (IGFBP-7), tissue inhibitor of metalloproteinases-2 (TIMP-2) and many others. Although these markers are increased in urine for no longer than a few hours after nephrotoxic agent action, they are not widely used in clinical practice. Only combined IGFBP-7/TIMP-2 measurement was approved in some countries as a marker of AKI. Several studies have shown that the levels of urinary AKI biomarkers are increased after physical exercise. This systematic review focuses on studies concerning changes in new AKI biomarkers in healthy adults after single exercise. Twenty-seven papers were identified and analyzed in this review. The interpretation of results from different studies was difficult because of the variety of study groups, designs and methodology. The most convincing data concern cystatin C. There is evidence that cystatin C is a better indicator of glomerular filtration rate (GFR) in athletes after exercise than creatinine and also at rest in athletes with a lean mass lower or higher than average. Serum and plasma NGAL are increased after prolonged exercise, but the level also depends on inflammation and hypoxia; therefore, it seems that in physical exercise, it is too sensitive for AKI diagnosis. It may, however, help to diagnose subclinical kidney injury, e.g., in rhabdomyolysis. Urinary biomarkers are increased after many types of exercise. Increases in NGAL, KIM-1, cystatin-C, L-FABP and interleukin 18 are common, but the levels of most urinary AKI biomarkers decrease rapidly after exercise. The importance of this short-term increase in AKI biomarkers after exercise is doubtful. It is not clear if it is a sign of mild kidney injury or physiological metabolic adaptation to exercise. Full article

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

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20 pages, 1720 KiB

Open AccessReview

Aminopeptidases in Cardiovascular and Renal Function. Role as Predictive Renal Injury Biomarkers

by Félix Vargas, Rosemary Wangesteen, Isabel Rodríguez-Gómez and Joaquín García-Estañ

Int. J. Mol. Sci. 2020, 21(16), 5615; https://doi.org/10.3390/ijms21165615 - 05 Aug 2020

Cited by 10 | Viewed by 3988

Abstract

Aminopeptidases (APs) are metalloenzymes that hydrolyze peptides and polypeptides by scission of the N-terminus amino acid and that also participate in the intracellular final digestion of proteins. APs play an important role in protein maturation, signal transduction, and cell-cycle control, among other processes. [...] Read more.

Aminopeptidases (APs) are metalloenzymes that hydrolyze peptides and polypeptides by scission of the N-terminus amino acid and that also participate in the intracellular final digestion of proteins. APs play an important role in protein maturation, signal transduction, and cell-cycle control, among other processes. These enzymes are especially relevant in the control of cardiovascular and renal functions. APs participate in the regulation of the systemic and local renin–angiotensin system and also modulate the activity of neuropeptides, kinins, immunomodulatory peptides, and cytokines, even contributing to cholesterol uptake and angiogenesis. This review focuses on the role of four key APs, aspartyl-, alanyl-, glutamyl-, and leucyl-cystinyl-aminopeptidases, in the control of blood pressure (BP) and renal function and on their association with different cardiovascular and renal diseases. In this context, the effects of AP inhibitors are analyzed as therapeutic tools for BP control and renal diseases. Their role as urinary biomarkers of renal injury is also explored. The enzymatic activities of urinary APs, which act as hydrolyzing peptides on the luminal surface of the renal tubule, have emerged as early predictive renal injury biomarkers in both acute and chronic renal nephropathies, including those induced by nephrotoxic agents, obesity, hypertension, or diabetes. Hence, the analysis of urinary AP appears to be a promising diagnostic and prognostic approach to renal disease in both research and clinical settings. Full article

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

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18 pages, 870 KiB

Open AccessReview

Roles Played by Biomarkers of Kidney Injury in Patients with Upper Urinary Tract Obstruction

by Satoshi Washino, Keiko Hosohata and Tomoaki Miyagawa

Int. J. Mol. Sci. 2020, 21(15), 5490; https://doi.org/10.3390/ijms21155490 - 31 Jul 2020

Cited by 27 | Viewed by 6813

Abstract

Partial or complete obstruction of the urinary tract is a common and challenging urological condition caused by a variety of conditions, including ureteral calculi, ureteral pelvic junction obstruction, ureteral stricture, and malignant ureteral obstruction. The condition, which may develop in patients of any [...] Read more.

Partial or complete obstruction of the urinary tract is a common and challenging urological condition caused by a variety of conditions, including ureteral calculi, ureteral pelvic junction obstruction, ureteral stricture, and malignant ureteral obstruction. The condition, which may develop in patients of any age, induces tubular and interstitial injury followed by inflammatory cell infiltration and interstitial fibrosis, eventually impairing renal function. The serum creatinine level is commonly used to evaluate global renal function but is not sensitive to early changes in the glomerular filtration rate and unilateral renal damage. Biomarkers of acute kidney injury are useful for the early detection and monitoring of kidney injury induced by upper urinary tract obstruction. These markers include levels of neutrophil gelatinase-associated lipocalin (NGAL), monocyte chemotactic protein-1, kidney injury molecule 1, N-acetyl-b-D-glucosaminidase, and vanin-1 in the urine and serum NGAL and cystatin C concentrations. This review summarizes the pathophysiology of kidney injury caused by upper urinary tract obstruction, the roles played by emerging biomarkers of obstructive nephropathy, the mechanisms involved, and the clinical utility and limitations of the biomarkers. Full article

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

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34 pages, 888 KiB

Open AccessReview

Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction

by Marco Quaglia, Guido Merlotti, Gabriele Guglielmetti, Giuseppe Castellano and Vincenzo Cantaluppi

Int. J. Mol. Sci. 2020, 21(15), 5404; https://doi.org/10.3390/ijms21155404 - 29 Jul 2020

Cited by 34 | Viewed by 6031

Abstract

New biomarkers of early and late graft dysfunction are needed in renal transplant to improve management of complications and prolong graft survival. A wide range of potential diagnostic and prognostic biomarkers, measured in different biological fluids (serum, plasma, urine) and in renal tissues, [...] Read more.

New biomarkers of early and late graft dysfunction are needed in renal transplant to improve management of complications and prolong graft survival. A wide range of potential diagnostic and prognostic biomarkers, measured in different biological fluids (serum, plasma, urine) and in renal tissues, have been proposed for post-transplant delayed graft function (DGF), acute rejection (AR), and chronic allograft dysfunction (CAD). This review investigates old and new potential biomarkers for each of these clinical domains, seeking to underline their limits and strengths. OMICs technology has allowed identifying many candidate biomarkers, providing diagnostic and prognostic information at very early stages of pathological processes, such as AR. Donor-derived cell-free DNA (ddcfDNA) and extracellular vesicles (EVs) are further promising tools. Although most of these biomarkers still need to be validated in multiple independent cohorts and standardized, they are paving the way for substantial advances, such as the possibility of accurately predicting risk of DGF before graft is implanted, of making a “molecular” diagnosis of subclinical rejection even before histological lesions develop, or of dissecting etiology of CAD. Identification of “immunoquiescent” or even tolerant patients to guide minimization of immunosuppressive therapy is another area of active research. The parallel progress in imaging techniques, bioinformatics, and artificial intelligence (AI) is helping to fully exploit the wealth of information provided by biomarkers, leading to improved disease nosology of old entities such as transplant glomerulopathy. Prospective studies are needed to assess whether introduction of these new sets of biomarkers into clinical practice could actually reduce the need for renal biopsy, integrate traditional tools, and ultimately improve graft survival compared to current management. Full article

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

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10 pages, 420 KiB

Open AccessReview

New Biomarkers in Acute Tubulointerstitial Nephritis: A Novel Approach to a Classic Condition

by Laura Martinez Valenzuela, Juliana Draibe, Xavier Fulladosa and Juan Torras

Int. J. Mol. Sci. 2020, 21(13), 4690; https://doi.org/10.3390/ijms21134690 - 30 Jun 2020

Cited by 10 | Viewed by 5201

Abstract

Acute tubulointerstitial nephritis (ATIN) is an immunomediated cause of acute kidney injury. The prevalence of ATIN among the causes of acute kidney injury (AKI) is not negligible, especially those cases related to certain drugs. To date, there is a lack of reliable non-invasive [...] Read more.

Acute tubulointerstitial nephritis (ATIN) is an immunomediated cause of acute kidney injury. The prevalence of ATIN among the causes of acute kidney injury (AKI) is not negligible, especially those cases related to certain drugs. To date, there is a lack of reliable non-invasive diagnostic and follow-up markers. The gold standard for diagnosis is kidney biopsy, which shows a pattern of tubulointerstitial leukocyte infiltrate. The urinalysis findings can aid in the diagnosis but are no longer considered sensitive or specific. Atthe present time, there is a rising attentiveness tofinding trustworthy biomarkers of the disease, with special focus in urinary cytokines and chemokines that may reflect kidney local inflammation. Cell-based tests are of notable interest to identify the exact drug involved in hypersensitivity reactions to drugs, manifesting as ATIN. Certain single-nucleotide polymorphisms in HLA or cytokine genes may confer susceptibility to the disease according to pathophysiological basis. In this review, we aim to critically examine and summarize the available evidence on this topic. Full article

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

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12 pages, 578 KiB

Open AccessReview

Role of the Furosemide Stress Test in Renal Injury Prognosis

by Armando Coca, Carmen Aller, Jimmy Reinaldo Sánchez, Ana Lucía Valencia, Elena Bustamante-Munguira and Juan Bustamante-Munguira

Int. J. Mol. Sci. 2020, 21(9), 3086; https://doi.org/10.3390/ijms21093086 - 27 Apr 2020

Cited by 12 | Viewed by 4416

Abstract

Risk stratification and accurate patient prognosis are pending issues in the management of patients with kidney disease. The furosemide stress test (FST) has been proposed as a low-cost, fast, safe, and easy-to-perform test to assess tubular integrity, especially when compared to novel plasma [...] Read more.

Risk stratification and accurate patient prognosis are pending issues in the management of patients with kidney disease. The furosemide stress test (FST) has been proposed as a low-cost, fast, safe, and easy-to-perform test to assess tubular integrity, especially when compared to novel plasma and urinary biomarkers. However, the findings regarding its clinical use published so far provide insufficient evidence to recommend the generalized application of the test in daily clinical routine. Dosage, timing, and clinical outcomes of the FST proposed thus far have been significantly different, which further accentuates the need for standardization in the application of the test in order to facilitate the comparison of results between series. This review will summarize published research regarding the usefulness of the FST in different settings, providing the reader some insights about the possible implications of FST in clinical decision-making in patients with kidney disease and the challenges that research will have to address in the near future before widely applying the FST. Full article

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

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9 pages, 3234 KiB

Open AccessReview

Glomerular Deposition of Nephritis-Associated Plasmin Receptor (NAPlr) and Related Plasmin Activity: Key Diagnostic Biomarkers of Bacterial Infection-related Glomerulonephritis

by Takahiro Uchida and Takashi Oda

Int. J. Mol. Sci. 2020, 21(7), 2595; https://doi.org/10.3390/ijms21072595 - 08 Apr 2020

Cited by 22 | Viewed by 6232

Abstract

It is widely known that glomerulonephritis (GN) often develops after the curing of an infection, a typical example of which is GN in children following streptococcal infections (poststreptococcal acute glomerulonephritis; PSAGN). On the other hand, the term “infection-related glomerulonephritis (IRGN)” has recently been [...] Read more.

It is widely known that glomerulonephritis (GN) often develops after the curing of an infection, a typical example of which is GN in children following streptococcal infections (poststreptococcal acute glomerulonephritis; PSAGN). On the other hand, the term “infection-related glomerulonephritis (IRGN)” has recently been proposed, because infections are usually ongoing at the time of GN onset in adult patients, particularly in older patients with comorbidities. However, there has been no specific diagnostic biomarker for IRGN, and diagnosis is based on the collection of several clinical and pathological findings and the exclusion of differential diagnoses. Nephritis-associated plasmin receptor (NAPlr) was originally isolated from the cytoplasmic fraction of group A streptococcus as a candidate nephritogenic protein for PSAGN and was found to be the same molecule as streptococcal glyceraldehyde-3-phosphate dehydrogenase and plasmin receptor. NAPlr deposition and related plasmin activity were observed with a similar distribution pattern in the glomeruli of patients with PSAGN. However, glomerular NAPlr deposition and plasmin activity could be observed not only in patients with PSAGN but also in patients with other glomerular diseases, in whom a preceding streptococcal infection was suggested. Furthermore, such glomerular staining patterns have been demonstrated in patients with IRGN induced by bacteria other than streptococci. This review discusses the recent advances in our understanding of the pathogenesis of bacterial IRGN, which is characterized by NAPlr and plasmin as key biomarkers. Full article

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

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Biomarkers of Renal Diseases

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