Migrasomes and exosomes; different types of messaging vesicles in podocytes.

Podocytes, highly specified kidney epithelial cells, live under several pathological stimuli and stresses during which they adapt themselves to keep homeostasis. Nevertheless, under extreme stress, a complex scenario of podocyte damage and its consequences occur. Podocyte damage causes foot process effacement and their detachment from the glomerular basement membrane, leading to proteinuria. Podocyte-derived extracellular vesicles (pEVs), mainly microparticles and exosomes are considered as signaling mediators of intercellular communication. Recently, it has been shown that throughout the injury-related migration procedure, podocytes are capable of releasing the injury-related migrasomes. Evidence indicates that at the early stages of glomerular disorders, increased levels of pEVs are observed in urine. At the early stage of nephropathy, pEVs especially migrasomes seem to be more sensitive and reliable indicators of podocyte stress and/or damage than proteinuria. This review highlights the current knowledge of pEVs and their values for the diagnosis of different kidney diseases.

Covid-19 and kidney injury: Pathophysiology and molecular mechanisms.

The novel coronavirus (SARS-CoV-2) has turned into a life-threatening pandemic disease (Covid-19). About 5% of patients with Covid-19 have severe symptoms including septic shock, acute respiratory distress syndrome, and the failure of several organs, while most of them have mild symptoms. Frequently, the kidneys are involved through direct or indirect mechanisms. Kidney involvement mainly manifests itself as proteinuria and acute kidney injury (AKI). The SARS-CoV-2-induced kidney damage is expected to be multifactorial; directly it can infect the kidney podocytes and proximal tubular cells and based on an angiotensin-converting enzyme 2 (ACE2) pathway it can lead to acute tubular necrosis, protein leakage in Bowman's capsule, collapsing glomerulopathy and mitochondrial impairment. The SARS-CoV-2-driven dysregulation of the immune responses including cytokine storm, macrophage activation syndrome, and lymphopenia can be other causes of the AKI. Organ interactions, endothelial dysfunction, hypercoagulability, rhabdomyolysis, and sepsis are other potential mechanisms of AKI. Moreover, lower oxygen delivery to kidney may cause an ischaemic injury. Understanding the fundamental molecular pathways and pathophysiology of kidney injury and AKI in Covid-19 is necessary to develop management strategies and design effective therapies.

Altered Th17/Treg ratio as a possible mechanism in pathogenesis of idiopathic membranous nephropathy.

Idiopathic membranous nephropathy (IMN) as a single organ autoimmune disease is a main cause of nephrotic syndrome in adults which is determined through autoantibodies to podocytes proteins. Th17/regulatory T (Treg) balance has emerged as a prominent factor in the regulation of autoimmunity. In this study, we evaluated the balance of Th17 and Treg cells, expression level of related master transcription factors, cytokines and microRNAs in mononuclear cells of peripheral blood of 30 patients with IMN and 30 healthy individuals before treatment. No significant variation was observed in Th17 cell frequency, retinoic acid receptor-related orphan nuclear receptor γt (RORÉ£t), signal transducer and Activator of transcription 3(STAT3), IL-17, and IL-23, while IL-21, IL-4, and IL-10 had significant increase in mRNA expression and protein level of peripheral blood mononuclear cells in IMN cases. Reduction in the percentage of Treg cells was also accompanied with significantly decreased expression of Forkhead box P3(FOXP3) and Transforming growth factor beta(TGF-ß) in IMN patients compared to the control group. Our study revealed that Th17 cells themselves might not be engaged in the pathogenesis of newly diagnosed patients with IMN; however, decreased T reg cells and increased ratio of Th17/Treg lymphocytes might display a role in the pathogenesis of IMN before treatment.

Glucocorticoid Receptor Polymorphisms and Avascular Osteonecrosis After Kidney Transplantation.

INTRODUCTION: Glucocorticoids (GCs) are commonly prescribed as immunosuppressive agents after kidney transplantation and their most common non-traumatic adverse effect is Avascular Necrosis (AVN) of the femoral head. In this regard, this study aimed to evaluate the glucocorticoid receptor (GR) polymorphisms among kidney transplant recipients and their potential role as a risk factor for the incidence of AVN. METHODS: In this study, 99 renal transplant recipients were evaluated for the correlations of GR polymorphisms including N363S (rs6195), BclI (rs41423247), ER22/23EK (rs6189/rs6190), and A3669G (rs6198) with AVN after renal transplantation. RESULTS: Results showed that none of the renal-transplanted patients neither with GC hypersensitive polymorphisms (N363S and BclI) nor with GC-resistant polymorphisms (A3669G and ER22/23EK) developed AVN (P > .05). In addition, the medications of the renal recipients with AVN were significantly different from the nonAVN patients (P < .001). CONCLUSION: The study results indicate that the GR polymorphisms have no critical roles in the susceptibility to AVN after renal transplantation. However, further studies to confirm the results are recommended.  DOI: 10.52547/ijkd.7221.

Immunosuppressant Management in Renal Transplant Patients with COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic poses a special risk for both immunosuppressed patients, especially transplant recipients. Although the knowledge about this infection is growing, many uncertainties remain, particularly regarding the kidney. Kidney transplant recipients (KDRs) should be considered immunocompromised hosts since a potential risk for infection, comorbidity, and immunosuppression exposure exists. Additionally, the management of immunosuppressive agents in KDRs remains challenging. Potential drug interactions with immunosuppressive treatment escalated the risk of unwanted side effects. In this review, we aimed to attain an augmented awareness and improved management immunosuppressant for COVID-19 KDRs.

Comparison between C4d immunohistochemical staining and other clinical-histopathological findings in IgA nephropathy.

INTRODUCTION: IgAN occurs following abnormal IgA deposition in the glomerular mesangial regions. It is the most common primary glomerular disease and one of the causes of ESRD, so it is necessary to identify clinical and histopathological findings that predict progression to ESRD. In the physiopathology of this disease, C4d causes serious renal injuries and should be counted as a significant prognostic factor too. This study examined C4d biomarker and compare it with findings affecting prognosis, to determine the predictive value of C4d in progression to ESRD in IgAN. MATERIALS AND METHODS: In this study, all biopsy samples of IgAN patients who referred to Imam Reza Hospital in Tabriz were collected for four years. Their samples were evaluated C4d immunohistochemical staining and positive samples have compared with Clinical-histopathological findings affecting prognosis. RESULTS: In this study, C4d positivity showed a significant association with mesangial hypercellularity (p = 0.001), segmental glomerulosclerosis (p = 0.003), and endocapillary hypercellularity (p = 0.001); however, it did not show a significant relationship with tubular atrophy/interstitial fibrosis (p = 0.08). The study also found that C4d positivity was significantly (p < 0.05) correlated with hypertension, increased proteinuria, hematuria, high creatinine, and decreased mean eGFR. CONCLUSION: This study showed that immunohistochemical staining of C4d is a useful method for evaluating the prognosis of the severity of renal injuries in patients with IgAN and could be a valuable alternative for most Clinical-histopathological factors routinely used as predictive factors for its progression to ESRD, especially when the biopsy specimen size is small and insufficient for other studies.

The clinical significance of the glucocorticoid receptors: Genetics and epigenetics.

The impacts of glucocorticoids (GCs) are mainly mediated by a nuclear receptor (GR) existing in almost every tissue. The GR regulates a wide range of physiological functions, including inflammation, cell metabolism, and differentiation playing a major role in cellular responses to GCs and stress. Therefore, the dysregulation or disruption of GR can cause deficiencies in the adaptation to stress and the preservation of homeostasis. The number of GR polymorphisms associated with different diseases has been mounting per year. Tackling these clinical complications obliges a comprehensive understanding of the molecular network action of GCs at the level of the GR structure and its signaling pathways. Beyond genetic variation in the GR gene, epigenetic changes can enhance our understanding of causal factors involved in the development of diseases and identifying biomarkers. In this review, we highlight the relationships of GC receptor gene polymorphisms and epigenetics with different diseases.

The impact of steroids on the injured podocytes in nephrotic syndrome.

Nephrotic syndrome (NS), a common chronic kidney disease, embraces a variety of kidney disorders. Though Glucocorticoids (GCs) are generally used in the treatment of NS, their mechanism of action is poorly understood. A plethora of evidence indicates that podocytes are considered as the main target cells for the therapeutic strategies to prevent NS. GCs regulate the transactivation and transrepression of genes in podocytes that affect their morphological and cytoskeletal features, motility, apoptosis and survival rate. Moreover, they prevent protein leakage through the glomerular barrier membrane by affecting the synthesis, trafficking and posttranslational modifications of slit diaphragms components, podocytes' intercellular junctions. The response to the treatment is variable among different ethnics and populations and resistance to the steroids is detected in almost 50% of adult patients. Not only do pharmacokinetics and pharmacogenetics of steroids play a role in GC resistance but also the genetic variations in one or more podocyte related genes are connected with the steroid resistance in cases with NS. The focus of this review is to explain the underlying cellular and molecular mechanisms of GCs in podocytes. Understanding the mechanisms by which the GCs and GCs receptors in podocytes regulate the gene expression network and crosstalk with other molecular pathways would guarantee an optimum therapeutic benefit of steroid treatment.

Gut microbiota; an overlooked effect of phosphate binders.

Hyperphosphatemia is a mineral bone-disease that increases cardiovascular complications and all-cause mortality in chronic kidney disease (CKD) patients. Oral phosphate binders absorb the dietary phosphate to prevent its high plasma levels. Moreover, they can adsorb some uremic toxins and decrease inflammation. A few recent studies highlight an ignored effect of phosphate binders on gut microbiota. Phosphorous is a major nutrient for survival and reproduction of bacteria and its intestinal concentration may impact the activity and composition of the gut microbiota. CKD is a state of an altered gut microbiome and bacterial-derived uremic toxins stimulate cardiovascular disease and systemic inflammation. The identification of the impact of phosphate binders on gut opens a new era in nephrology and fill the existing gap in interpretation of beneficial effects of phosphate binders. This review aims to highlight the impact of oral phosphate binders on the gut microbiome in CKD.

Serum Levels of CXCL10 and Vitamin D in Patients with Lupus Nephritis.

INTRODUCTION: Kidney involvement is a hallmark of systemic lupus erythematosus (SLE) and evaluation of its inflammatory response is demanding. It was the aim of the present study to evaluate the levels of CXCL10 and vitamin D in serum samples of cases with active lupus nephritis (LN). METHODS: Fifty lupus patients were enrolled in our study, 25 patients had lupus nephritis and 25 patients were without evidence of LN. Thirty-nine healthy subjects were also participated as a control group. Complete biochemical and serological parameters were measured and their correlation with serum levels of vitamin D and CXCL10 were assessed in the studied groups. RESULTS: Serum levels of CXCL10 were significantly elevated (P≤ 0.020), while vitamin D were diminished in SLE group and active LN as compared with healthy controls and SLE patients without nephritis, respectively. CXCL10 correlated with SLE disease activity index (SLEDAI) and renal activity (P < .05), while vitamin D correlated with C3 and anti-dsDNA antibody (P < .05). Based on the receiver operator characteristic (ROC) curve analysis, CXCL10 and vitamin D levels were not better than conventional biomarkers for discriminating LN patients from non-nephritis SLE patients; however, they could differentiate most of SLE cases from healthy individuals with area under the curve (AUC) ≥ 0.703 (P < .05). CONCLUSION: Results indicated the importance of elevated levels of CXCL10 and deficiency of vitamin D on the pathogenesis of active LN disease.

Plasma levels of miR-21, miR-150, miR-423 in patients with lupus nephritis.

INTRODUCTION: MicroRNAs (miRNA) are involved in the pathogenesis of systemic lupus erythematosus (SLE), an autoimmune disease, and can be considered as diagnostic and prognostic biomarkers. Lupus nephritis (LN) remains a major challenge of SLE since it damages the kidneys in the course of the disease. METHODS: The aim of this study was to investigate the diagnostic values of circulating miR-21, miR-148a, miR-150, and miR-423 involved in autoimmunity and kidney fibrosis in plasma samples of LN cases (N = 26) and healthy controls (N = 26) using quantitative- PCR (qPCR). The possible associations between the microRNAs and clinical parameters and their diagnostic values were also calculated. RESULTS: The levels of circulating miR-21 (P < .001) and miR-423 (P < .05) significantly increased, while miR-150 decreased in LN (P > .05) patients as compared with healthy controls. Receiver operating characteristic (ROC) analysis indicated that miR-21 was superior in discriminating LN patients from controls with an Area Under Curve (AUC) of 0.912 [95% CI = 0.83 to 0.99, P < .001], whereas the multivariate ROC curve analysis revealed the high accuracy [AUC = 0.93, P < .001, 79% sensitivity and 83% specificity] of the miR-21, -150, and -423 to differentiate LN from controls. CONCLUSION: The involvement of the studied miRNAs in renal fibrosis and the obtained results make it rational to speculate that they may be used as potential biomarkers in LN.

Altered levels of immune-regulatory microRNAs in plasma samples of patients with lupus nephritis.

Introduction: Lupus nephritis (LN) is a major cause of mortality and morbidity in the patients with lupus, a chronic autoimmune disease. The role of genetic and epigenetic factors is emphasized in the pathogenesis of LN. The aim of the present study was to evaluate the levels of immune-regulatory microRNAs (e.g., miR-31, miR-125a, miR-142-3p, miR-146a, and miR-155) in plasma samples of patients with LN. Methods: In this study, 26 patients with LN and 26 healthy individuals were included. The plasma levels of the microRNAs were evaluated by a quantitative real-time PCR. Moreover, the correlation of circulating plasma microRNAs with disease activity and pathological findings along with their ability to distinguish patients with LN were assessed. Results: Plasma levels of miR-125a (P = 0.048), miR-146a (P = 0.005), and miR-155 (P< 0.001) were significantly higher in comparison between the cases and controls. The plasma level of miR-146a significantly correlated with the level of anti-double strand-DNA antibody and proteinuria. Moreover, there was a significant correlation between miR-142-3p levels and disease chronicity and activity index (P <0.05). The multivariate ROC curve analysis indicated the plasma circulating miR-125a, miR-142-3p, miR-146, and miR-155 together could discriminate most of the patients with LN from controls with area an under curve (AUC) of 0.89 [95% CI, 0.80-0.98, P<0.001], 88% sensitivity, and 78% specificity. Conclusion: Based on the findings of the present study, the studied microRNAs may be involved in the pathogenesis and development of LN and have the potential to be used as diagnostic and therapeutic markers in LN.

Serum Levels of Vaspin and Its Correlation with Nitric Oxide in Type 2 Diabetic Patients with Nephropathy.

BACKGROUND: Diabetic Nephropathy (DN), a serious and prevalent complication of diabetes, has been rapidly raising worldwide. Vaspin, as an adipokine with anti-diabetic effects, is predominantly released from visceral adipose tissue. Moreover, vaspin has the stimulatory effect on nitric oxide (NO) bioavailability through the activation of NO synthase. OBJECTIVE: The aim of the present study was to investigate the serum levels of vaspin and their correlation with NO metabolite in diabetic patients with normal renal function and renal insufficiency. METHODS: Volunteers patients with non-nephropathy Type 2 Diabetic Mellitus (T2DM) as control (n=40, age= 56.95±6.11 years) and patients with diabetic nephropathy (DN) (n=40, age=57.85±5.63 years) as case group were enrolled in this study, and serum samples were collected for the measurement of vaspin levels by ELISA technique. Also, serum levels of NO metabolites were calorimetrically assessed. RESULTS: We found that vaspin levels significantly decreased in diabetic patients with nephropathic condition as compared with diabetic patients with normal renal function (p <0.04). In addition, serum levels of NO metabolites were significantly higher in diabetic patients with nephropathy in comparison with non-nephropathic diabetics (p<0.001). When patients with DN were studied, vaspin levels positively correlated with NO metabolites and Homeostasis model assessment of insulin resistance (HOMA-IR) levels. CONCLUSION: This study showed that low serum vaspin levels may be a risk factor for nephropathy in type II diabetic patients and increased levels of NO may be a defensive mechanism in the DN.

Correlation Between Circulating Visfatin and Nitric Oxide Metabolites Levels in Patients With Diabetic Nephropathy.

INTRODUCTION: Diabetic nephropathy is one of the serious complications of diabetes mellitus. Visfatin is an intracellular enzyme with insulin-mimicking effects. It enhances the expression of endothelial nitric oxide (NO) synthase in renal cells. This study aimed to investigate serum levels of visfatin and NO metabolites in patients with diabetic nephropathy. MATERIALS AND METHODS: A total of 80 diabetic patients were enrolled and classified into nephropathic and non-nephropathic patients. Serum visfatin and insulin levels were estimated using an enzyme-linked immunosorbent assay, and NO metabolites were estimated using a colorimetric assay. RESULTS: Serum visfatin and NO metabolites levels were significantly elevated in the patients with diabetic nephropathy. Serum visfatin levels and NO metabolites were significantly higher in the nephropathic patients (P = .003; 95% confidence interval, 2.29 to 10.81; P < .001; 95% confidence interval, 3.14 to 9.46, respectively) as compared to the control group, whereas homeostatic model assessment-insulin resistance was significantly lower (P = .02; 95% confidence interval, -1.51 to -1.01).There was no correlation between body mass index, blood pressure, lipid profile, insulin, and glucose levels and serum visfatin and NO metabolites levels. CONCLUSIONS: The results of this study demonstrated that there were high levels of visfatin and NO metabolites in patients with diabetic nephropathy. In addition, there was a positive correlation between visfatin and NO metabolites levels in nephropathic and non-nephropathic diabetic patients.