Manifestation Of Chronic Kidney Disease Research Articles

Current Understanding of Cardiovascular Calcification in Patients with Chronic Kidney Disease.

The burden of chronic kidney disease (CKD) is increasing, posing a serious threat to human health. Cardiovascular calcification (CVC) is one of the most common manifestations of CKD, which significantly influences the morbidity and mortality of patients. The manifestation of CVC is an unusual accumulation of mineral substances containing calcium and phosphate. The main component is hydroxyapatite. Many cells are involved in this process, such as smooth muscle cells (SMCs) and endothelial cells. CVC is an osteogenic process initiated by complex mechanisms such as metabolic disorders of calcium and phosphorus minerals, inflammation, extracellular vesicles, autophagy, and micro-RNAs with a variety of signaling pathways like Notch, STAT, and JAK. Although drug therapy and dialysis technology continue to advance, the survival time and quality of life of CVC patients still face challenges. Therefore, early diagnosis and prevention of CKD-related CVC, reducing its mortality rate, and improving patients' quality of life have become urgent issues in the field of public health. In this review, we try to summarize the state-of-the-art understanding of the progression of CVC and hope that it will help in the prevention and treatment of CVC in CKD.

Glycolysis in Peritubular Endothelial Cells and Microvascular Rarefaction in CKD.

Peritubular endothelial cell dropout leading to microvascular rarefaction is a common manifestation of chronic kidney disease (CKD). The role of metabolism reprogramming in peritubular endothelial cell loss in CKD is undetermined. Single-cell sequencing and metabolic analysis were used to characterize metabolic profile of peritubular endothelial cells from CKD patients and from CKD mouse models. In vivo and in vitro models demonstrated metabolic reprogramming in peritubular endothelial cells in conditions of CKD and its contribution to microvascular rarefaction. Here, we identified glycolysis as a top dysregulated metabolic pathway in peritubular endothelial cells from CKD patients. Specifically, CKD peritubular endothelial cells were hypoglycolytic while displaying an anti-angiogenic response with decreased proliferation and increased apoptosis. The hypoglycolytic phenotype of peritubular endothelial cells was recapitulated in CKD mouse models and in peritubular endothelial cells stimulated by hydrogen peroxide (H2O2). Mechanically, oxidative stress, through activating a redox sensor kruppel-like transcription factor 9, downregulated the glycolytic activator 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (PFKFB3) expression, thereby reprogramming peritubular endothelial cells towards a hypoglycolytic phenotype. PFKFB3 overexpression in peritubular endothelial cells restored H2O2-induced reduction in glycolysis and cellular ATP levels, and enhanced the G1/S cell cycle transition, enabling peritubular endothelial cells to improve proliferation and reduce apoptosis. Consistently, restoration of peritubular endothelial cell glycolysis in CKD mice, via overexpressing endothelial Pfkfb3, reversed the anti-angiogenic response in peritubular endothelial cells and protected the kidney from microvascular rarefaction and fibrosis. In contrast, suppression of glycolysis by endothelial Pfkfb3 deletion exacerbated microvascular rarefaction and fibrosis in CKD mice. Our study revealed a disrupted regulation of glycolysis in peritubular endothelial cells as an initiator of microvascular rarefaction in CKD. Restoration of peritubular endothelial cell glycolysis in CKD kidney improved microvascular rarefaction and ameliorated fibrotic lesions.

Appropriateness of Ketoanalogues of Amino Acids, Calcium Citrate, and Inulin Supplementation for CKD Management: A RAND/UCLA Consensus.

Current treatment for chronic kidney disease (CKD) focuses on improving manifestations and delaying progression. Nutritional approaches play a crucial role in CKD management, and various supplements have become available. Ketoanalogues of amino acids (KAs), calcium citrate, and inulin have been proposed as suitable supplements, yet their widespread use has been limited due to insufficient evidence. This study aimed to generate general guidance statements on the appropriateness of these supplements through a RAND/UCLA consensus process. A RAND/UCLA consensus panel was convened to evaluate the appropriateness of these supplements in different clinical scenarios. In this study, we present a subgroup analysis focusing on a panel of eleven clinical nephrologists from among the experts. Supplementation of low-protein diets (LPDs) and very low-protein diets (VLPDs) with KA was considered appropriate to reduce manifestations and delay CKD outcomes, supplementation with calcium citrate is considered appropriate to reduce CKD manifestations, and supplementation with inulin is considered appropriate to delay CKD outcomes and manage comorbidities. Based on a combination of clinical experience and scientific evidence, the panel reached a consensus that KA supplementation of LPD and VLPD, calcium citrate, and inulin are appropriate in patients with CKD across various scenarios.

Reduction in Serum Concentrations of Uremic Toxins Driven by Bifidobacterium Longum Subsp. Longum BL21 is Associated with Gut Microbiota Changes in a Rat Model of Chronic Kidney Disease.

Gut microbiota dysbiosis and consequent impairment of gut barrier function, culminating in elevated levels of uremic toxins, are prevalent in chronic kidney disease (CKD) patients. These toxins, notably indoxyl sulphate (IS), indole-3-acetic acid (IAA), and trimethylamine oxide (TMAO), are implicated in a spectrum of CKD-related complications, including cardiovascular disease, bone and mineral disorders, and inflammation. The specific impacts of various probiotics on these CKD manifestations remain unexplored. This study delved into the potential of dietary probiotic interventions, particularly Bifidobacterium longum subsp. longum BL21, to modulate gut microbiota and mitigate metabolic disorders in a CKD rat model. Over a six-week period, we administered a dietary regimen of BL21 and conducted comprehensive analyses, including serum uremic toxin quantification and 16S rRNA gene sequencing, to systematically profile gut microbial alterations at the phylogenetic level. Our findings reveal that BL21 intervention significantly ameliorated CKD-induced disruptions in gut microbial populations, enhancing both microbial richness and the relative abundance of key taxa. Importantly, BL21 appeared to exert its beneficial effects by modulating the abundance of crucial species such as Barnesiella and Helicobacter. Functionally, the intervention markedly normalized serum levels of IS, IAA, and TMAO, while potentially attenuating p-cresol sulphate (PCS) and p-cresol glucuronide (PCG) concentrations. Consequently, BL21 demonstrated efficacy in regulating gut microbiota and curtailing the accumulation of uremic toxins. Our results advocate for the utilization of BL21 as a dietary intervention to diminish serum uremic toxins and re-establish gut microbiota equilibrium at the phylogenetic level, underscoring the promise of probiotic strategies in the management of CKD.

The role of aetiology in cardiac manifestations of chronic kidney disease: the CPH-CKD ECHO study

PurposeWe investigated the associations between cardiac parameters and aetiologies of CKD in an exploratory study.MethodsThe study population consisted of 883 participants, 174 controls and 709 patients with aetiologies of CKD including diabetic nephropathy/renovascular KD in diabetes mellitus, hypertensive/renovascular nephropathy, tubulointerstitial nephritis, glomerulonephritis/vasculitis, polycystic KD (PKD), and CKD of unknown origin. Echocardiographic measures included left ventricular (LV) ejection fraction, global longitudinal, area, and radial strain, E/e’ ratio, and LV mass index. These were compared between each aetiological group and controls in unadjusted and adjusted analysis.ResultsIn unadjusted analysis, patients with diabetic nephropathy/renovascular KD in diabetes mellitus, had impaired LV ejection fraction (Median [IQR]: 56% [49.9,60.69] vs. 60.8% [57.7,64.1]), global longitudinal (mean ± SD: 13.1 ± 3.5% vs. 15.5 ± 2.6%), area (24.1 ± 5.8% vs. 28.5 ± 4.2%), and radial strain (36.2 ± 11.2% vs. 44.1 ± 9.7%), and increased LV mass index (89.1 g/m2 [71.8,104.9] vs. 69,0 g/m2 [57.9,80.8]) and E/e’ ratio (10.6 [8.5,12.6] vs. 7 [5.8,8.3], p < 0.001 for all) compared with controls. Associations were similar for CKD of unknown origin. Patients with hypertensive/renovascular nephropathy had impaired global longitudinal and area strain, and higher E/e’ ratio. Patients with glomerulonephritis/vasculitis had higher LV mass index, while patients with PKD had better global longitudinal strain than controls. All findings remained significant in adjusted analysis, except for the impaired global longitudinal strain in hypertensive/renovascular nephropathy.ConclusionGlomerulonephritis/vasculitis, hypertensive/renovascular nephropathy, CKD of unknown origin, and diabetic nephropathy/renovascular KD in diabetes mellitus were increasingly associated with adverse cardiac findings, while PKD and tubulointerstitial nephritis were not. Aetiology might play a role regarding the cardiac manifestations of CKD.Graphical A graphical summary of the study population and main results. Abbreviations: DN = Diabetic nephropathy and renovascular kidney disease in diabetes mellitus, PKD = Polycystic kidney disease, CKDu = Chronic kidney disease of unknown origin, LVEF = Left ventricular ejection fraction, LVMi = Left ventricular mass index, E/e’ ratio = Early mitral inflow velocity to mitral annular early diastolic velocity ratio, GLS = Global longitudinal strain, GAS = Global area strain, GRS = Global radial strain.

The c-Abl-RACK1-FAK signaling axis promotes renal fibrosis in mice through regulating fibroblast-myofibroblast transition

BackgroundRenal fibrosis is a prevalent manifestation of chronic kidney disease (CKD), and effective treatments for this disease are currently lacking. Myofibroblasts, which originate from interstitial fibroblasts, aggregate in the renal interstitium, leading to significant accumulation of extracellular matrix and impairment of renal function. The nonreceptor tyrosine kinase c-Abl (encoded by the Abl1 gene) has been implicated in the development of renal fibrosis. However, the precise role of c-Abl in this process and its involvement in fibroblast-myofibroblast transition (FMT) remain poorly understood.MethodsTo investigate the effect of c-Abl in FMT during renal fibrosis, we investigated the expression of c-Abl in fibrotic renal tissues of patients with CKD and mouse models. We studied the phenotypic changes in fibroblast or myofibroblast-specific c-Abl conditional knockout mice. We explored the potential targets of c-Abl in NRK-49F fibroblasts.ResultsIn this study, fibrotic mouse and cell models demonstrated that c-Abl deficiency in fibroblasts mitigated fibrosis by suppressing fibroblast activation, fibroblast-myofibroblast transition, and extracellular matrix deposition. Mechanistically, c-Abl maintains the stability of the RACK1 protein, which serves as a scaffold for proteins such as c-Abl and focal adhesion kinase at focal adhesions, driving fibroblast activation and differentiation during renal fibrosis. Moreover, specifically targeting c-Abl deletion in renal myofibroblasts could prove beneficial in established kidney fibrosis by reducing RACK1 expression and diminishing the extent of fibrosis.ConclusionsOur findings suggest that c-Abl plays a pathogenic role in interstitial fibrosis through the regulation of RACK1 protein stabilization and myofibroblast differentiation, suggesting a promising strategy for the treatment of CKD.

Editor’s Pick: Correlation of Cutaneous Manifestations with the Severity of Disease in Patients with Chronic Kidney Disease and Effect of Hemodialysis: An Observational Study

Aim: Chronic kidney disease is a non-communicable disease, and is the sixth fastest growing contributor of morbidity and mortality. Hemodialysis is one of the important therapeutic modalities that can improve survival in these patients, and can increase their life expectancy, but the cutaneous disorder can precede or follow the initiation of hemodialysis. Methods: This is a retrospective, observational study with a sample size of 250 patients, with a glomerular filtration rate &lt;60 mL/min/1.73 m2 for a minimum duration of 3 months or more, undergoing hemodialysis. Patients post-renal transplant, HIV-positive cases, and pregnant patients were excluded from the study. Studied cases were recruited equally into two groups: the dialytic group (Group A) and non-dialytic group (Group B). Results: In the authors’ study, the prevalence of dermatological manifestations was 79% in the dialytic group and 75% in the non-dialytic group. The most common finding overall was xerosis (58%), which was more common in the dialytic (66%) group, both in number of patients and severity. The second most common finding was pallor (55%), which was seen more in the dialytic group (60%). Other major findings were pruritus (49%) and hyperpigmentation (37%). The intensity of pruritus was higher in non-dialytic patients. Specific cutaneous manifestations, such as Kyrle’s disease, were seen only in eight patients. Skin infections were seen in 17% of patients overall, and there was no major difference seen in both groups. The prevalence of nail findings, mucosal changes, and hair changes was also high in the dialytic group. Other specific cutaneous manifestations, like calciphylaxis, uremic frost, and nephrogenic fibrosing dermopathy, were not seen in the authors’ study. Hemodialysis has increased the life expectancy of patients with end-stage renal disease and has also brought about a rise in the number of manifestations, by giving time for these changes to occur. The severity of symptoms was also higher in patients on dialysis. This could be because of the higher mean duration of disease in the dialytic group compared to the non-dialytic group. Conclusion: Dermatological manifestations of chronic kidney disease were significantly associated with the mean duration of disease, which was higher in patients on dialysis. There was a higher prevalence of non-specific dermatological findings, such as xerosis, hyperpigmentation, nail findings, hair, and mucosal changes in the dialytic group, except pruritus. Any such cutaneous marker in the absence of a primary dermatological problem warrants a thorough search, including blood, urine, and radiological investigations, to rule out kidney disease.

CLINICAL DIAGNOSTIC ALGORITHMS OF ACTION IN THE PRACTICE OF A DOCTOR OF GENERAL PRACTICE – FAMILY MEDICINE DISEASES OF THE URINARY SYSTEM IN CHILDREN

Chronic kidney disease (CKD) is the presence of markers of pathological changes in the urinary system lasting more than 12 weeks, regardless of their cause. The number of cases in children with diseases of the urinary system has documented confi rmed chronic kidney disease according to the implemented regional registry of patients with CKD, but its signifi cant spread is observed. Early manifestations of CKD are often underestimated and not treated in time. CKD and chronic renal failure are not a narrowly defi ned nephrological problem. Nowadays, military aggression and the consequences of the 2019 coronavirus pandemic (COVID-19), which led to the destruction of standard ways (patient clinical routes) in the provision of medical care, the issue of providing medical care to children on the basis of evidence- based and personalized medicine is of particular relevance in Ukraine, which, according to the WHO strategy, should meet the needs and be safe,eff ective, timely and of appropriate quality. The introduction of innovations in pediatric practice in terms of standardization of medical care helps the physician to act eff ectively in specifi c clinical situations, avoiding ineff ective actions. Involvement of specialists of other specialties (general practitioners- family medicine, endocrinologists, urologists, cardiologists, pediatricians, ophthalmologists) in the management of CKD without coordination of cooperation to ensure the principle of continuity complicates the diagnostic and/or therapeutic support of the patient. Early diagnosis, proper management tactics of pediatric patients with diseases of the urinary system at the outpatient stage is an important component in the provision of integrated, patient- oriented medical care in the practice of a general practitioner- family medicine. The article highlights the clinical and diagnostic algorithms of action of a general practitioner- family medicine regarding the tactics ofmanagement of pediatric patients with the most common nephrological symptoms: leukocyturia (bacteriuria), proteinuria and erythrocyturia. The scientifi c research was carried out within the framework of the Department of Pediatrics, Neonatology and Perinatal Medicine of the Bukovinian State Medical University. The research topics included: Research project on «Chronobiological and adaptive aspects and features of autonomic regulation in pathological conditions in children of diff erent age groups» (State registration number: 0122U002245, duration: 01.01.2022-31.12.2026).

Interaction between anemia and hyperuricemia in the risk of all-cause mortality in patients with chronic kidney disease.

Both hyperuricemia and anemia are not only the manifestation of chronic kidney disease (CKD) but also related to its occurrence and development. A recent study has found that there was a synergetic effect between hyperuricemia and anemia on new-onset CKD. Herein we aimed to explore the roles of hyperuricemia and anemia in the all-cause mortality in patients with CKD. Data of adult patients with CKD were extracted from the National Health and Nutrition Examination Surveys (NHANES) database in 2009-2018 in this retrospective cohort study. Weighted univariate and multivariate COX regression analyses were used to investigate the associations of hyperuricemia and anemia with all-cause mortality, and the evaluation indexes were hazard ratios (HRs) and 95% confidence intervals (CIs). The interaction effect between hyperuricemia and anemia on the risk of all-cause mortality was assessed via relative excess risk due to interaction (RERI) and attributable proportion of interaction (AP). Subgroup analyses of age, gender, CVD, hypertension, DM, and cancer were also performed to assess this interaction effect. Among 3,678 eligible patients, 819 died from all causes. After adjusting for covariables, we found that CKD patients with anemia (HR = 1.72, 95%CI: 1.42-2.09) or hyperuricemia (HR = 1.21, 95%CI: 1.01-11.45) had a higher risk of all-cause mortality. There was a potential synergetic effect between anemia and hyperuricemia on all-cause mortality, with RERI of 0.630 and AP of 0.291. Moreover, this synergetic effect was also observed in ≥65 years old (AP = 0.330), male (AP = 0.355), hypertension (AP = 0.736), non-hypertension (AP = 0.281), DM (AP = 0.371), and cancer (AP = 0.391) subgroups. A potential synergetic effect between anemia and hyperuricemia on all-cause mortality was found in patients with CKD. However, further studies are needed to clarify the causal relationship between them.

Loss of MTX2 causes mitochondrial dysfunction, podocyte injury, nephrotic proteinuria and glomerulopathy in mice and patients.

Proteinuria is a common and important clinical manifestation of chronic kidney disease (CKD) and an independent risk factor for the progression of kidney disease. As a component of the glomerular filtration barrier (GFB), podocyte plays a key role in the pathogenesis of glomerular diseases and proteinuria. However, the pathophysiology of glomerular diseases associated with mitochondrial function is incompletely understood. Here, we identified three novel mutations in MTX2, encoding a membrane protein in mitochondria, associated with multisystem manifestations including nephrotic proteinuria and kidney injury in two Chinese patients. Conditional podocyte-specific Mtx2 knockout (Pod-Mtx2-KO) mice present a series of podocyte and glomerular abnormalities from 8 weeks to old age, including microalbuminuria, glomerular mesangial hyperplasia, fusion and effacement of foot process. MTX2 deficiency impaired podocyte functions in vitro, manifested by reductions of adhesion, migration and endocytosis, which were further restored by overexpression of MTX2. Moreover, MTX2 defects led to abnormal mitochondrial structure and dysfunction, evidenced with defects of complex I and III, increased production of reactive oxygen species (ROS), and decreased protein levels of Sam50-CHCHD3-Mitofilin axis in the mitochondrial intermembrane space bridging (MIB) complex which is responsible for maintaining mitochondrial cristae morphology. Collectively, these findings reveal that the normal expression of MTX2 in glomerulus plays an important role in the adhesion, migration, endocytosis, proliferation and other physiological functions of podocytes, which may be realized by maintaining the morphological structure and function of mitochondria. Abnormal expression of MTX2 can lead to mitochondrial dysfunction and structural abnormalities by Sam50-CHCHD3-Mitofilin axis in podocyte, which further induces podocyte injury, glomerular lesions and proteinuria.

Chronic kidney disease in patients with chronic heart failure infected with human immunodeficiency virus

Chronic kidney disease (CKD) is the most common manifestation of target organ damage in chronic heart failure (CHF). The aim of the study was to determine the risk factors associated with the course of CKD in patients with CHF infected with the human immunodeficiency virus (HIV). According to the results obtained, the prevalence of CKD among HIV-infected patients with CHF is 58.82%, which is 4 times more common than in patients with HIV infection without CHF. The dependence of glomerular filtration rate (GFR) on three main factors that reflect damage to the heart muscle – blood plasma NT-proBNP concentration, left ventricular ejection fraction (LVEF%) and left ventricular myocardial mass index (LVMI) was proved, which together, being included in the regression model, determine 42.2% of the variance of GFR values and are decisive in the development of CKD in patients with CHF on the background of HIV infection. The concentration of NT-proBNP in the blood plasma of patients with CHF equal to or greater than 683.65 pg/ml can be considered as a diagnostic criterion for the development of CKD in HIV-infected people with a sensitivity of the method of 75.0% and a specificity of 75.4%, respectively. In addition, risk factors for the development of CKD in patients with CHF and HIV infection are smoking, alcohol and drug use, a history of chronic and acute forms of coronary artery disease, atrial fibrillation, ventricular arrhythmias, diabetes mellitus, chronic viral hepatitis C, anemia and thrombocytopenia. Patients with CHF and CKD have a more rigid arterial wall – there is a significant excess of the stiffness indices of the aorta and peripheral arteries. Long-term use of antiplatelet agents, NRTIs, NNRTIs, and protease PIs may aggravate the course of CHF in HIV-infected people with CKD manifestations.

SETD2 deficiency promotes renal fibrosis through the TGF-β/Smad signalling pathway in the absence of VHL.

Renal fibrosis is the final development pathway and the most common pathological manifestation of chronic kidney disease. Epigenetic alteration is a significant intrinsic factor contributing to the development of renal fibrosis. SET domain-containing 2 (SETD2) is the sole histone H3K36 trimethyltransferase, catalysing H3K36 trimethylation. There is evidence that SETD2-mediated epigenetic alterations are implicated in many diseases. However, it is unclear what role SETD2 plays in the development of renal fibrosis. Kidney tissues from mice as well as HK2 cells were used as research subjects. Clinical databases of patients with renal fibrosis were analysed to investigate whether SETD2 expression is reduced in the occurrence of renal fibrosis. SETD2 and Von Hippel-Lindau (VHL) double-knockout mice were used to further investigate the role of SETD2 in renal fibrosis. Renal tubular epithelial cells isolated from mice were used for RNA sequencing and chromatin immunoprecipitation sequencing to search for molecular signalling pathways and key molecules leading to renal fibrosis in mice. Molecular and cell biology experiments were conducted to analyse and validate the role of SETD2 in the development of renal fibrosis. Finally, rescue experiments were performed to determine the molecular mechanism of SETD2 deficiency in the development of renal fibrosis. SETD2 deficiency leads to severe renal fibrosis in VHL-deficient mice. Mechanically, SETD2 maintains the transcriptional level of Smad7, a negative feedback factor of the transforming growth factor-β (TGF-β)/Smad signalling pathway, thereby preventing the activation of the TGF-β/Smad signalling pathway. Deletion of SETD2 leads to reduced Smad7 expression, which results in activation of the TGF-β/Smad signalling pathway and ultimately renal fibrosis in the absence of VHL. Our findings reveal the role of SETD2-mediated H3K36me3 of Smad7 in regulating the TGF-β/Smad signalling pathway in renal fibrogenesis and provide an innovative insight into SETD2 as a potential therapeutic target for the treatment of renal fibrosis.

Construction of predictive model of interstitial fibrosis and tubular atrophy after kidney transplantation with machine learning algorithms.

Background: Interstitial fibrosis and tubular atrophy (IFTA) are the histopathological manifestations of chronic kidney disease (CKD) and one of the causes of long-term renal loss in transplanted kidneys. Necroptosis as a type of programmed death plays an important role in the development of IFTA, and in the late functional decline and even loss of grafts. In this study, 13 machine learning algorithms were used to construct IFTA diagnostic models based on necroptosis-related genes. Methods: We screened all 162 "kidney transplant"-related cohorts in the GEO database and obtained five data sets (training sets: GSE98320 and GSE76882, validation sets: GSE22459 and GSE53605, and survival set: GSE21374). The training set was constructed after removing batch effects of GSE98320 and GSE76882 by using the SVA package. The differentially expressed gene (DEG) analysis was used to identify necroptosis-related DEGs. A total of 13 machine learning algorithms-LASSO, Ridge, Enet, Stepglm, SVM, glmboost, LDA, plsRglm, random forest, GBM, XGBoost, Naive Bayes, and ANNs-were used to construct 114 IFTA diagnostic models, and the optimal models were screened by the AUC values. Post-transplantation patients were then grouped using consensus clustering, and the different subgroups were further explored using PCA, Kaplan-Meier (KM) survival analysis, functional enrichment analysis, CIBERSOFT, and single-sample Gene Set Enrichment Analysis. Results: A total of 55 necroptosis-related DEGs were identified by taking the intersection of the DEGs and necroptosis-related gene sets. Stepglm[both]+RF is the optimal model with an average AUC of 0.822. A total of four molecular subgroups of renal transplantation patients were obtained by clustering, and significant upregulation of fibrosis-related pathways and upregulation of immune response-related pathways were found in the C4 group, which had poor prognosis. Conclusion: Based on the combination of the 13 machine learning algorithms, we developed 114 IFTA classification models. Furthermore, we tested the top model using two independent data sets from GEO.

Cardiac Stress in Chronic Kidney Disease: Unraveling the Myocardial Paradox

Chronic kidney disease (CKD) represents a complex and multifaceted clinical condition characterized by its intricate interaction with multiple organ systems. Among the systemic manifestations of CKD, the impact on the cardiovascular system is particularly profound. This article delves into the intricate relationship between CKD and cardiac strain, exploring the paradoxical nature of myocardial function in the context of renal dysfunction. We navigate the epidemiological landscape, describe pathophysiological mechanisms, investigate diagnostic modalities, and explore current and emerging therapeutic strategies aimed at controlling cardiac strain in CKD. This comprehensive analysis not only sheds light on the cardiac complexities within the CKD setting, but also underscores the need for a holistic approach to improve patient outcomes.

Imaging of Pulmonary Manifestations in Chronic Kidney Disease: A Review

AbstractLungs and kidneys share a symbiotic relationship in maintaining homeostasis of body. Hence, derangement of one system is bound to affect the functioning of the other. The thoracic manifestations of chronic renal failure present a wide spectrum ranging from problems related to fluid and salt balance, calcium–phosphate metabolism, compromised immunity, and additional issues related to different modes of dialysis. In most of the cases, chest radiograph coupled with ultrasound and computed tomography (CT) are sufficient to offer a definitive diagnosis. This review aims to summarize the imaging features of thoracic manifestations of chronic kidney disease (CKD) with emphasis on imaging-based discriminating features.

Role of beta 2 microglobulin in chronic kidney disease

The aim: to study the relationship of beta-2-microglobulin (beta-2 MG) with clinical and laboratory manifestations of chronic kidney disease (CKD).Patients and Methods. The results of a comprehensive examination of 284 people (118 males and 166 females) aged 18 to 86 years with various types of socially significant diseases were studied. All patients underwent thorough collection of clinical and anamnestic data, laboratory monitoring with the determination of the level of systolic and diastolic blood pressure (BP), body mass index, red blood, beta-2-microglobulin (B2M), lipid profile and proteinuria. Kidney function was assessed according to the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula using serum creatinine. The main group included 113 patients (55 men and 58 women, mean age 50.9±15.8 years), diagnosed with chronic kidney disease (CKD). The control group consisted of 171 people (63 men and 108 women) with various forms of socially significant diseases, but without signs of CKD. Statistical analysis was carried out using the programs Statistica 10.0 (StatSoft Inc., USA) and Microsoft Office Excel 2010 (Microsoft Corp., USA).Results. In the subgroup of patients with CKD, signs of renal failure were observed in 46 people in 40.7 % of cases. As CKD progressed, the signs of impaired metabolism of B2M were more severe: its serum level was 8.646 (7.892; 12.231) mg/l at C4 and 18.444 (11.225; 23.717) mg/l at C5 stages of CKD, and urinary excretion was 2.502 (0.305; 6.313) mg/l at C4 and 2.614 (1.535; 25.812) mg/l at C5 stages of CKD. Regardless of renal dysfunction, the median serum B2M level was clinically significantly higher in females (p&gt;0.05). Single-factor one-way correlation analysis showed statistically highly significant relationship was between serum B2M and creatinine levels both in the subgroup of patients with CKD (r = 0.905; p = 0.001) and in the total sample (r = 0.749; p = 0.001). There was a strong negative relationship between serum B2M levels and estimated glomerular filtration rate (GFR) (r = -0.717; p = 0.001). In individuals without CKD, an increase in serum creatinine was closely associated with an increase in urinary excretion of B2M (r=0.252; p=0.005). Simultaneously, in this category of patients, there was a close correlation between estimated GFR with serum B2M level (r= -0.433; p=0.002) and its urinary excretion (r= -0.247; p=0.005). A direct relationship between an increase in serum B2M and an increase in diastolic blood pressure (r=0.274; p=0.034) among CKD patients was established. In the total sample, a direct relationship between the value of systolic BP and serum B2M level (r= 0.223; p=0.01) was registered, as well as between diastolic BP (r= 0.268; p=0.01) and urinary excretion of B2M.Conclusion. As a result of the study, metabolism of B2M and its relationship with the clinical and laboratory manifestations of CKD were evaluated. The data obtained show high prognostic potential of changes in metabolism of B2M in the population of patients with various forms of socially significant diseases, as well as CKD, which allows to identify among them groups of patients with high and/or very high renal and cardiovascular risk, in order to take timely targeted therapy.

Suppression of Indoxyl Sulfate Accumulation Reduces Renal Fibrosis in Sulfotransferase 1a1-Deficient Mice.

Renal fibrosis is the final manifestation of chronic kidney disease (CKD); its prevention is vital for controlling CKD progression. Indoxyl sulfate (IS), a typical sulfate-conjugated uremic solute, is produced in the liver via the enzyme sulfotransferase (SULT) 1A1 and accumulates significantly during CKD. We investigated the toxicopathological role of IS in renal fibrosis using Sult1a1-KO mice and the underlying mechanisms. The unilateral ureteral obstruction (UUO) model was created; kidney IS concentrations, inflammation, and renal fibrosis were assessed on day 14. After UUO treatment, inflammation and renal fibrosis were exacerbated in WT mice, with an accumulation of IS in the kidney. However, they were significantly suppressed in Sult1a1-KO mice. CD206+ expression was upregulated, and β-catenin expression was downregulated in Sult1a1-KO mice. To confirm the impact of erythropoietin (EPO) on renal fibrosis, we evaluated the time-dependent expression of EPO. In Sult1a1-KO mice, EPO mRNA expression was improved considerably; UUO-induced renal fibrosis was further attenuated by recombinant human erythropoietin (rhEPO). Thus, UUO-induced renal fibrosis was alleviated in Sult1a1-KO mice with a decreased accumulation of IS. Our findings confirmed the pathological role of IS in renal fibrosis and identified SULT1A1 as a new therapeutic target enzyme for preventing and attenuating renal fibrosis.

#5741 POLYPLOID TUBULAR CELLS INITIATE A TGF-BETA CONTROLLED LOOP THAT SUSTAINS POLYPLOIDIZATION AND TUBULOINTERSTITIAL CROSSTALK DURING AKI-CKD TRANSITION

Abstract Background and Aims Acute Kidney Injury (AKI) is characterized by a sudden kidney failure accompanied by a transient decrease of kidney functionality. It is regarded as an important risk factor for chronic kidney disease (CKD) development, but the link is still elusive. Renal fibrosis, especially tubulointerstitial fibrosis, is the final manifestation of CKD and is characterized by an excessive synthesis and deposition of extracellular matrix associated with inflammatory infiltration, tubular epithelial (TC) cell damage and fibroblast activation. Although no targeted therapy yet exists to slow the progression of tubulointerstitial fibrosis, recent findings contributed to clarify the cellular and molecular mechanisms underlying its development and progression, posing TC at the center of this process. Accordingly, we have recently demonstrated that fibrosis and senescence are trade-offs of TC polyploidy occurring immediately after AKI to support fast kidney function recovery, but promoting consequent CKD. However, the mechanisms turning TC polyploidy to senescence and fibrosis still need to be elucidated. In this study, we propose that TC polyploidy is the primary driver of CKD progression after AKI. Methods Polyploid TC are characterized by an increased DNA content in the absence of cell division. To discriminate polyploid cells from actively proliferating cells, we employed a series of in vitro and in vivo transgenic models based on the Fluorescence Ubiquitin Cell Cycle Indicator (FUCCI) technology. AKI was triggered by unilateral ischemia reperfusion injury (IRI) or glycerol-induced rhabdomyolysis. This technology allows to follow the cell cycle phasing of living cells. Cell sorting and cytofluorimetric techniques were employed to isolate and characterize a subpopulation of polyploid TC that progressively accumulate DNA damage after AKI. These results were further corroborated by single cell RNA-sequencing (scRNA-seq) analyses in vitro and in vivo. Results In this study, we found that immediately after AKI, expression of cell cycle markers mostly identifies a population of DNA damaged polyploid TC. Employing transgenic mouse models and single cell RNA-sequencing we showed that after AKI, polyploid TC accumulate DNA damage and survive eventually resting in the G1 phase of cell cycle, while diploid cells do not survive DNA damage. This suggests that after AKI, polyploidization is a means to survive injury. Sorting of DNA-damaged polyploid TC showed that they express p21 and acquire a pro-fibrotic phenotype culminating in TGF-beta expression. in vitro analysis and single cell RNA-sequencing evidenced that TGF-beta directly promoted polyploidization, demonstrating that TC polyploidization is a self-sustained mechanism. Interactome analysis by single cell RNA-sequencing revealed that TGF-beta signaling fostered a reciprocal activation loop among polyploid TC, macrophages and fibroblasts to sustain kidney fibrosis and promote CKD progression. Conclusion Collectively, this study contributes to the ongoing revision of the paradigm of kidney tubule response to AKI supporting the existence of a tubulointerstitial crosstalk mediated by TGF-beta signaling produced by polyploid TC following DNA damage. Moreover, this study identifies polyploid TC as central actors during CKD progression with important implications for the development of novel targeted therapy to block CKD.

Hemoglobin Levels in Peruvian Patients with Chronic Kidney Disease at Different Altitudes.

Hurtado-Aréstegui, Abdías, Karina Rosales-Mendoza, Yanissa Venegas-Justiniano, José Gonzales-Polar, Rina Barreto-Jara, and Alaciel Melissa Palacios-Guillén. Hemoglobin levels in Peruvian patients with chronic kidney disease at different altitudes. High Alt Med Biol. 24:209-213, 2023. Background: Decreased hemoglobin is a manifestation of chronic kidney disease (CKD), and people who reside at high altitude adapt to hypoxia by increasing their hemoglobin. The study's objective was to determine the influence of altitude and the associated factors on the hemoglobin levels of patients with CKD who were not on dialysis (ND). Methods: This exploratory and cross-sectional study was carried out in three Peruvian cities, located at different altitudes: (1) "sea level" (161 m), (2) "moderate altitude" (2,335 m), and "high altitude" (3,399 m). The study included female and male individuals between 20 and 90 years old, with CKD stage 3a, through stage 5. Results: Of the 256 volunteers evaluated, 92 lived at sea level, 82 at moderate altitude, and 82 at high altitude. The three groups were similar in age, number of volunteers in each CKD stage, systolic blood pressure, and diastolic blood pressure. Hemoglobin levels were statistically different according to gender (p = 0.024), CKD stage, and altitude (p < 0.001). High-altitude dwellers had higher hemoglobin by 2.5 g/dl (95% confidence interval: 1.8-3.1, p < 0.001) than those living at lower altitudes (adjusted for gender, age, nutritional status, and smoking habit). For all CKD stages, the high-altitude population had higher hemoglobin levels than population at moderate altitude and at sea level. Conclusion: Subjects living at high altitude with CKD stages 3 to 5 who are yet ND have higher hemoglobin levels than those who live at moderate altitude and at sea level.

Soluble dipeptidyl peptidase-4 induces epithelial-mesenchymal transition through tumor growth factor-β receptor.

Kidney fibrosis is the final manifestation of chronic kidney disease, a condition mainly caused by diabetic nephropathy. Persistent tissue damage leads to chronic inflammation and excessive deposition of extracellular matrix (ECM) proteins. Epithelial-mesenchymal transition (EMT) is involved in a variety of tissue fibrosis and is a process during which epithelial cells transform into mesenchymal-like cells and lose their epithelial functionality and characteristics Dipeptidyl peptidase-4 (DPP4) is widely expressed in tissues, especially those of the kidney and small intestine. DPP4 exists in two forms: a plasma membrane-bound and a soluble form. Serum-soluble DPP4 (sDPP4) levels are altered in many pathophysiological conditions. Elevated circulating sDPP4 is correlated with metabolic syndrome. Because the role of sDPP4 in EMT remains unclear, we examined the effect of sDPP4 on renal epithelial cells. The influences of sDPP4 on renal epithelial cells were demonstrated by measuring the expression of EMT markers and ECM proteins. sDPP4 upregulated the EMT markers ACTA2 and COL1A1 and increased total collagen content. sDPP4 activated SMAD signaling in renal epithelial cells. Using genetic and pharmacological methods to target TGFBR, we observed that sDPP4 activated SMAD signaling through TGFBR in epithelial cells, whereas genetic ablation and treatment with TGFBR antagonist prevented SMAD signaling and EMT. Linagliptin, a clinically available DPP4 inhibitor, abrogated sDPP4-induced EMT. This study indicated that sDPP4/TGFBR/SMAD axis leads to EMT in renal epithelial cells. Elevated circulating sDPP4 levels may contribute to mediators that induce renal fibrosis.