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Kidney Disease: From Pathophysiology to Novel Therapeutic Approaches 2.0

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular Genetics and Genetic Diseases".

Deadline for manuscript submissions: closed (30 June 2024) | Viewed by 25947

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Prof. Dr. Gener Ismail

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Guest Editor

“Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania; Fundeni Clinical Institute, Bucharest, Romania
Interests: glomerular disorders; rare genetic kidney disorders; immunology; systemic autoimmune disorders with renal involvement; biomarkers; diabetic kidney disease
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Special Issue Information

Dear Colleagues,

This Special Issue, titled “Kidney Disease: From Pathophysiology to Novel Therapeutic Approaches 2.0”, continues to invite contributions of both original articles and reviews dedicated to improving the knowledge on kidney disorders, focusing on topics such as pathophysiology, renal pathology, biomarkers of renal disorders and novel therapeutic approaches. Submission can include not only the full spectrum of glomerular disorders but also genetic disorders, tubulopathies, diabetic nephropathy and renal transplantation.

Renal disorders have an increasing contribution to the global health burden, while end-stage kidney disease is among the leading causes of death worldwide. Tremendous advances have been achieved in recent decades regarding the understanding of the pathophysiology of kidney disorders, having been translated into improved outcomes of patients with chronic kidney disease and the development of novel therapies. Nevertheless, there are still many areas of uncertainty in need of addressing, with this Special Issue’s objective being to approach several of these issues.

Prof. Dr. Gener Ismail
Guest Editor

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Keywords

glomerular disorders
renal pathology
biomarkers
renal transplantation
genetic disorders
novel therapies
immunosuppression
diabetic nephropathy
tubulopathies

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Published Papers (9 papers)

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Research

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14 pages, 831 KiB

Open AccessArticle

The Influence of Tacrolimus Exposure and Metabolism on the Outcomes of Kidney Transplants

by Rima Maslauskiene, Ruta Vaiciuniene, Aurelija Radzeviciene, Peteris Tretjakovs, Gita Gersone, Edgaras Stankevicius and Inga Arune Bumblyte

Biomedicines 2024, 12(5), 1125; https://doi.org/10.3390/biomedicines12051125 - 18 May 2024

Cited by 2 | Viewed by 1071

Abstract

Tacrolimus (TAC) has a narrow therapeutic window and patient-specific pharmacokinetic variability. In our study, we analyzed the association between TAC exposure, metabolism, and kidney graft outcomes (function, rejection, and histological lesions). TAC trough (C₀), coefficient of variation (TAC CV), concentration/dose ratio (C/D), and biomarkers related to kidney injury molecule-1 (KIM-1) and neutrophil gelatinase lipocalin (NGAL) were analyzed. We examined 174 patients who were subjected to a triple immunosuppressive regimen and underwent kidney transplantation between 2017 and 2022. Surveillance biopsies were performed at the time of kidney implantation and at three and twelve months after transplantation. We classified patients based on their Tac C/D ratios, classifying them as fast (C/D ratio < 1.05 ng/mL × 1/mg) or slow (C/D ratio ≥ 1.05 ng/mL × 1/mg) metabolizers. TAC exposure/metabolism did not significantly correlate with interstitial fibrosis/tubular atrophy (IF/TA) progression during the first year after kidney transplantation. TAC CV third tertile was associated with a higher chronicity score at one-year biopsy. TAC C/D ratio at three months and Tac C₀ at six months were associated with rejection during the first year after transplantation. A fast TAC metabolism at six months was associated with reduced kidney graft function one year (OR: 2.141, 95% CI: 1.044–4.389, p = 0.038) and two years after transplantation (OR: 4.654, 95% CI: 1.197–18.097, p = 0.026), and TAC CV was associated with reduced eGFR at three years. uNGAL correlated with IF/TA and chronicity scores at three months and negatively correlated with TAC C₀ and C/D at three months and one year. Conclusion: Calculating the C/D ratio at three and six months after transplantation may help to identify patients at risk of suffering acute rejection and deterioration of graft function. Full article

(This article belongs to the Special Issue Kidney Disease: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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19 pages, 5216 KiB

Open AccessArticle

Overexpression of SMYD3 Promotes Autosomal Dominant Polycystic Kidney Disease by Mediating Cell Proliferation and Genome Instability

by Ewud Agborbesong, Julie Xia Zhou, Hongbing Zhang, Linda Xiaoyan Li, Peter C. Harris, James P. Calvet and Xiaogang Li

Biomedicines 2024, 12(3), 603; https://doi.org/10.3390/biomedicines12030603 - 7 Mar 2024

Cited by 2 | Viewed by 1839

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder worldwide and progresses to end-stage renal disease (ESRD). However, its precise mechanism is not fully understood. In recent years, epigenetic reprogramming has drawn increasing attention regarding its effect on cyst growth. However, considering the complexity of epigenetic mechanisms and the broad range of alterations of epigenetic components in ADPKD, identifying more specific epigenetic factors and understanding how they are mechanistically linked to promote cyst growth is relevant for the development of treatment for ADPKD. Here, we find that the histone methyltransferase SMYD3, which activates gene transcription via histone H3 lysine 4 trimethylation (H3K4me3), is upregulated in PKD1 mutant mouse and human ADPKD kidneys. Genetic knockout of SMYD3 in a PKD1 knockout mouse model delayed cyst growth and improved kidney function compared with PKD1 single knockout mouse kidneys. Immunostaining and Western blot assays indicated that SMYD3 regulated PKD1-associated signaling pathways associated with proliferation, apoptosis, and cell cycle effectors in PKD1 mutant renal epithelial cells and tissues. In addition, we found that SMYD3 localized to the centrosome and regulated mitosis and cytokinesis via methylation of α-tubulin at lysine 40. In addition, SMYD3 regulated primary cilia assembly in PKD1 mutant mouse kidneys. In summary, our results demonstrate that overexpression of SMYD3 contributes to cyst progression and suggests targeting SMYD3 as a potential therapeutic strategy for ADPKD. Full article

(This article belongs to the Special Issue Kidney Disease: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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20 pages, 3167 KiB

Open AccessArticle

Preoperative Function Assessment of Ex Vivo Kidneys with Supervised Machine Learning Based on Blood and Urine Markers Measured during Normothermic Machine Perfusion

by Wenke Markgraf and Hagen Malberg

Biomedicines 2022, 10(12), 3055; https://doi.org/10.3390/biomedicines10123055 - 28 Nov 2022

Cited by 6 | Viewed by 1570

Abstract

Establishing an objective quality assessment of an organ prior to transplantation can help prevent unnecessary discard of the organ and reduce the probability of functional failure. In this regard, normothermic machine perfusion (NMP) offers new possibilities for organ evaluation. However, to date, few studies have addressed the identification of markers and analytical tools to determine graft quality. In this study, function and injury markers were measured in blood and urine during NMP of 26 porcine kidneys and correlated with ex vivo inulin clearance behavior. Significant differentiation of kidneys according to their function could be achieved by oxygen consumption, oxygen delivery, renal blood flow, arterial pressure, intrarenal resistance, kidney temperature, relative urea concentration, and urine production. In addition, classifications were accomplished with supervised learning methods and histological analysis to predict renal function ex vivo. Classificators (support vector machines, k-nearest-neighbor, logistic regression and naive bayes) based on relevant markers in urine and blood achieved 75% and 83% accuracy in the validation and test set, respectively. A correlation between histological damage and function could not be detected. The measurement of blood and urine markers provides information of preoperative renal quality, which can used in future to establish an objective quality assessment. Full article

(This article belongs to the Special Issue Kidney Disease: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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18 pages, 3608 KiB

Open AccessArticle

Effect of Renal Ischemia Reperfusion on Brain Neuroinflammation

by Bina Lee, Ingabire Ines, Jihyun Je, Eun Jung Park, Hyemin Seong, Min Gi Jo, Hwajin Kim, Seon-Hee Kim, Seong Jae Kim, Hye Jung Kim, Minkyeong Kim, Sang Won Park and Seung Pil Yun

Biomedicines 2022, 10(11), 2993; https://doi.org/10.3390/biomedicines10112993 - 21 Nov 2022

Cited by 3 | Viewed by 2243

Abstract

Acute kidney injury (AKI) is an inflammatory sequence. It can lead to distant organ injury, including damage to the central nervous system (CNS), mediated by increased circulating cytokines and other inflammatory mediators. It can also lead to increased blood–brain barrier (BBB) permeability. However, the effect of AKI on the inflammatory response of the brain has not yet been investigated. Therefore, we observed the effect of AKI on BBB permeability, microglia and astrocyte activation, and neuronal toxicity in the brain. The striatum and ventral midbrain, known to control overall movement, secrete the neurotransmitter dopamine. The activation of microglia and astrocytes present in this area causes neuro-degenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The activation of astrocytes and microglia in the hippocampus and cerebral cortex, which are responsible for important functions, including memory, learning, concentration, and language, can trigger nerve cell apoptosis. The activation of astrocytes and microglia at this site is also involved in the inflammatory response associated with the accumulation of beta-amyloid. In the situation of kidney ischemia reperfusion (IR)-induced AKI, activation of microglia and astrocytes were observed in the striatum, ventral midbrain, hippocampus, and cortex. However, neuronal cell death was not observed until 48 h. Full article

(This article belongs to the Special Issue Kidney Disease: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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11 pages, 1091 KiB

Open AccessArticle

Differential Bias for Creatinine- and Cystatin C- Derived Estimated Glomerular Filtration Rate in Critical COVID-19

by Anders O. Larsson, Michael Hultström, Robert Frithiof, Ulf Nyman, Miklos Lipcsey and Mats B. Eriksson

Biomedicines 2022, 10(11), 2708; https://doi.org/10.3390/biomedicines10112708 - 26 Oct 2022

Cited by 4 | Viewed by 2163

Abstract

COVID-19 is a systemic disease, frequently affecting kidney function. Dexamethasone is standard treatment in severe COVID-19 cases, and is considered to increase plasma levels of cystatin C. However, this has not been studied in COVID-19. Glomerular filtration rate (GFR) is a clinically important indicator of renal function, but often estimated using equations (eGFR) based on filtered metabolites. This study focuses on sources of bias for eGFRs (mL/min) using a creatinine-based equation (eGFR_LMR) and a cystatin C-based equation (eGFR_CAPA) in intensive-care-treated patients with COVID-19. This study was performed on 351 patients aged 18 years old or above with severe COVID-19 infections, admitted to the intensive care unit (ICU) in Uppsala University Hospital, a tertiary care hospital in Uppsala, Sweden, between 14 March 2020 and 10 March 2021. Dexamethasone treatment (6 mg for up to 10 days) was introduced 22 June 2020 (n = 232). Values are presented as medians (IQR). eGFR_CAPA in dexamethasone-treated patients was 69 (37), and 74 (46) in patients not given dexamethasone (p = 0.01). eGFR_LMR was not affected by dexamethasone. eGFR_LMR in females was 94 (20), and 75 (38) in males (p = 0.00001). Age and maximal CRP correlated negatively to eGFR_CAPA and eGFR_LMR, whereas both eGFR equations correlated positively to BMI. In ICU patients with COVID-19, dexamethasone treatment was associated with reduced eGFR_CAPA. This finding may be explained by corticosteroid-induced increases in plasma cystatin C. This observation is important from a clinical perspective since adequate interpretation of laboratory results is crucial. Full article

(This article belongs to the Special Issue Kidney Disease: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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Review

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18 pages, 667 KiB

Open AccessReview

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors as a New Treatment Option for Anemia in Chronic Kidney Disease

by Piotr Bartnicki

Biomedicines 2024, 12(8), 1884; https://doi.org/10.3390/biomedicines12081884 - 18 Aug 2024

Viewed by 1578

Abstract

Anemia plays an important role in chronic kidney disease (CKD) progression because it worsens the quality of life and increases the risk of cardiovascular complications in CKD patients. In such cases, anemia is mainly caused by endogenous erythropoietin (EPO) and iron deficiencies. Therefore, KDIGO and ERBP guidelines for anemia treatment in CKD patients focus on recombinant EPO and iron supplementation. A recent new treatment option for anemia in CKD patients involves blocking the hypoxia-inducible factor (HIF) system with prolyl hydroxylase inhibitors (PHIs), what causes increasing endogenous EPO production and optimizing the use of iron. Clinical studies have shown that the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) covered in this manuscript—roxadustat, vadadustat, daprodustat, and molidustat—effectively increase hemoglobin (Hb) levels in both non-dialyzed and dialyzed CKD patients. Moreover, these medicines reduce blood lipid levels and do not accelerate CKD progression. However, blockage of the HIF system by HIF-PHIs may be associated with adverse effects such as cardiovascular complications, tumorogenesis, hyperkalemia. and retinopathy. More extensive and long-term clinical trials of HIF-PHIs-based anemia treatment in CKD patients are needed, and their results will indicate whether HIF-PHIs represent an effective and safe alternative to EPO and iron supplementation for anemia treatment in CKD patients. Full article

(This article belongs to the Special Issue Kidney Disease: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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16 pages, 956 KiB

Open AccessReview

Lipid Toxicity in the Cardiovascular-Kidney-Metabolic Syndrome (CKMS)

by John A. D’Elia and Larry A. Weinrauch

Biomedicines 2024, 12(5), 978; https://doi.org/10.3390/biomedicines12050978 - 29 Apr 2024

Cited by 1 | Viewed by 2147

Abstract

Recent studies of Cardiovascular-Kidney-Metabolic Syndrome (CKMS) indicate that elevated concentrations of derivatives of phospholipids (ceramide, sphingosine), oxidized LDL, and lipoproteins (a, b) are toxic to kidney and heart function. Energy production for renal proximal tubule resorption of critical fuels and electrolytes is required for homeostasis. Cardiac energy for ventricular contraction/relaxation is preferentially supplied by long chain fatty acids. Metabolism of long chain fatty acids is accomplished within the cardiomyocyte cytoplasm and mitochondria by means of the glycolytic, tricarboxylic acid, and electron transport cycles. Toxic lipids and excessive lipid concentrations may inhibit cardiac function. Cardiac contraction requires calcium movement from the sarcoplasmic reticulum from a high to a low concentration at relatively low energy cost. Cardiac relaxation involves calcium return to the sarcoplasmic reticulum from a lower to a higher concentration and requires more energy consumption. Diastolic cardiac dysfunction occurs when cardiomyocyte energy conversion is inadequate. Diastolic dysfunction from diminished ATP availability occurs in the presence of inadequate blood pressure, glycemia, or lipid control and may lead to heart failure. Similar disruption of renal proximal tubular resorption of fuels/electrolytes has been found to be associated with phospholipid (sphingolipid) accumulation. Elevated concentrations of tissue oxidized low-density lipoprotein cholesterols are associated with loss of filtration efficiency at the level of the renal glomerular podocyte. Macroscopically excessive deposits of epicardial and intra-nephric adipose are associated with vascular pathology, fibrosis, and inhibition of essential functions in both heart and kidney. Chronic triglyceride accumulation is associated with fibrosis of the liver, cardiac and renal structures. Successful liver, kidney, or cardiac allograft of these vital organs does not eliminate the risk of lipid toxicity. Lipid lowering therapy may assist in protecting vital organ function before and after allograft transplantation. Full article

(This article belongs to the Special Issue Kidney Disease: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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23 pages, 12048 KiB

Open AccessReview

Renal Papillary Necrosis (RPN) in an African Population: Disease Patterns, Relevant Pathways, and Management

by Guy Roger Gaudji, Meshack Bida, Marius Conradie, Botle Precious Damane and Megan Jean Bester

Biomedicines 2023, 11(1), 93; https://doi.org/10.3390/biomedicines11010093 - 29 Dec 2022

Cited by 2 | Viewed by 7430

Abstract

Renal papillary necrosis (RPN) is characterized by coagulative necrosis of the renal medullary pyramids and papillae. Multiple conditions and toxins are associated with RPN. Several RPN risk factors, or POSTCARDS, have been identified, with most patients presenting with RPN having at least two contributing risk factors. Currently, there is no specific test to diagnose and confirm RPN; however, several imaging tools can be used to diagnose the condition. RPN is currently underdiagnosed in African populations, often with fatal outcomes. In African clinical settings, there is a lack of consensus on how to define and describe RPN in terms of kidney anatomy, pathology, endourology, epidemiology, the identification of African-specific risk factors, the contribution of oxidative stress, and lastly an algorithm for managing the condition. Several risk factors are unique to African populations including population-specific genetic factors, iatrogenic factors, viral infections, antimicrobial therapy, schistosomiasis, substance abuse, and hypertension (GIVASSH). Oxidative stress is central to both GIVASSH and POSTCARDS-associated risk factors. In this review, we present information specific to African populations that can be used to establish an updated consensual definition and practical grading system for radiologists, urologists, nephrologists, nuclear physicians, and pathologists in African clinical settings. Full article

(This article belongs to the Special Issue Kidney Disease: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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16 pages, 648 KiB

Open AccessReview

Distal Renal Tubular Acidosis in Patients with Autoimmune Diseases—An Update on Pathogenesis, Clinical Presentation and Therapeutic Strategies

by Oana Ungureanu and Gener Ismail

Biomedicines 2022, 10(9), 2131; https://doi.org/10.3390/biomedicines10092131 - 31 Aug 2022

Cited by 6 | Viewed by 4675

Abstract

Distal renal tubular acidosis (DRTA) has been reported in association with autoimmune diseases, such as Sjögren’s syndrome, systemic lupus erythematosus (SLE), autoimmune hepatitis, primary biliary cirrhosis, rheumatoid arthritis and autoimmune thyroiditis. Whether we talk about the complete or incomplete form of DRTA associated with autoimmune diseases, the real incidence is unknown because asymptomatic patients usually are not identified, and most of the reported cases are diagnosed due to severe symptoms secondary to hypokalemia, a frequent finding in these cases. The mechanisms involved in DRTA in patients with autoimmune diseases are far from being fully elucidated and most of the data has come from patients with Sjögren’s syndrome. This review will present different hypotheses raised to explain this association. Also, aiming for a better understanding of the association between autoimmune diseases and DRTA, our review summarizes data from 37 case reports published in the last five years. We will emphasize data regarding clinical presentation, biological alterations, treatment and outcome. A very important question is whether immunosuppressive therapy is helpful in DRTA associated with autoimmune diseases. Because the pathology is rather rare, treatment is not standardized, and reported results are often contradictory. Corticosteroids are frequently used, but multiple other immunosuppressive drugs have been proposed and will be approached in this review. Full article

(This article belongs to the Special Issue Kidney Disease: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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