Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors for people with chronic kidney disease and diabetes.

BACKGROUND: Diabetes is associated with high risks of premature chronic kidney disease (CKD), cardiovascular diseases, cardiovascular death and impaired quality of life. People with diabetes are more likely to develop kidney impairment, and approximately one in three adults with diabetes have CKD. People with CKD and diabetes experience a substantially higher risk of cardiovascular outcomes. Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors have shown potential effects in preventing kidney and cardiovascular outcomes in people with CKD and diabetes. However, new trials are emerging rapidly, and evidence synthesis is essential to summarising cumulative evidence. OBJECTIVES: This review aimed to assess the benefits and harms of SGLT2 inhibitors for people with CKD and diabetes. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 17 November 2023 using a search strategy designed by an Information Specialist. Studies in the Register are continually identified through regular searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled studies were eligible if they evaluated SGLT2 inhibitors versus placebo, standard care or other glucose-lowering agents in people with CKD and diabetes. CKD includes all stages (from 1 to 5), including dialysis patients. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed the study risk of bias. Treatment estimates were summarised using random effects meta-analysis and expressed as a risk ratio (RR) or mean difference (MD), with a corresponding 95% confidence interval (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The primary review outcomes were all-cause death, 3-point and 4-point major adverse cardiovascular events (MACE), fatal or nonfatal myocardial infarction (MI), fatal or nonfatal stroke, and kidney failure. MAIN RESULTS: Fifty-three studies randomising 65,241 people with CKD and diabetes were included. SGLT2 inhibitors with or without other background treatments were compared to placebo, standard care, sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitors, or insulin. In the majority of domains, the risks of bias in the included studies were low or unclear. No studies evaluated the treatment in children or in people treated with dialysis. No studies compared SGLT2 inhibitors with glucagon-like peptide-1 receptor agonists or tirzepatide. Compared to placebo, SGLT2 inhibitors decreased the risk of all-cause death (20 studies, 44,397 participants: RR 0.85, 95% CI 0.78 to 0.94; I2 = 0%; high certainty) and cardiovascular death (16 studies, 43,792 participants: RR 0.83, 95% CI 0.74 to 0.93; I2 = 29%; high certainty). Compared to placebo, SGLT2 inhibitors probably make little or no difference to the risk of fatal or nonfatal MI (2 studies, 13,726 participants: RR 0.95, 95% CI 0.80 to 1.14; I2 = 24%; moderate certainty), and fatal or nonfatal stroke (2 studies, 13,726 participants: RR 1.07, 95% CI 0.88 to 1.30; I2 = 0%; moderate certainty). Compared to placebo, SGLT2 inhibitors probably decrease 3-point MACE (7 studies, 38,320 participants: RR 0.89, 95% CI 0.81 to 0.98; I2 = 46%; moderate certainty), and 4-point MACE (4 studies, 23,539 participants: RR 0.82, 95% CI 0.70 to 0.96; I2 = 77%; moderate certainty), and decrease hospital admission due to heart failure (6 studies, 28,339 participants: RR 0.70, 95% CI 0.62 to 0.79; I2 = 17%; high certainty). Compared to placebo, SGLT2 inhibitors may decrease creatinine clearance (1 study, 132 participants: MD -2.63 mL/min, 95% CI -5.19 to -0.07; low certainty) and probably decrease the doubling of serum creatinine (2 studies, 12,647 participants: RR 0.70, 95% CI 0.56 to 0.89; I2 = 53%; moderate certainty). SGLT2 inhibitors decrease the risk of kidney failure (6 studies, 11,232 participants: RR 0.70, 95% CI 0.62 to 0.79; I2 = 0%; high certainty), and kidney composite outcomes (generally reported as kidney failure, kidney death with or without ≥ 40% decrease in estimated glomerular filtration rate (eGFR)) (7 studies, 36,380 participants: RR 0.68, 95% CI 0.59 to 0.78; I2 = 25%; high certainty) compared to placebo. Compared to placebo, SGLT2 inhibitors incur less hypoglycaemia (16 studies, 28,322 participants: RR 0.93, 95% CI 0.89 to 0.98; I2 = 0%; high certainty), and hypoglycaemia requiring third-party assistance (14 studies, 26,478 participants: RR 0.75, 95% CI 0.65 to 0.88; I2 = 0%; high certainty), and probably decrease the withdrawal from treatment due to adverse events (15 studies, 16,622 participants: RR 0.94, 95% CI 0.82 to 1.08; I2 = 16%; moderate certainty). The effects of SGLT2 inhibitors on eGFR, amputation and fracture were uncertain. No studies evaluated the effects of treatment on fatigue, life participation, or lactic acidosis. The effects of SGLT2 inhibitors compared to standard care alone, sulfonylurea, DPP-4 inhibitors, or insulin were uncertain. AUTHORS' CONCLUSIONS: SGLT2 inhibitors alone or added to standard care decrease all-cause death, cardiovascular death, and kidney failure and probably decrease major cardiovascular events while incurring less hypoglycaemia compared to placebo in people with CKD and diabetes.

The Impact of the COVID-19 Pandemic on Patients With CKD: Systematic Review of Qualitative Studies.

RATIONALE & OBJECTIVE: COVID-19 disproportionately affects people with comorbidities, including chronic kidney disease (CKD). We describe the impact of COVID-19 on people with CKD and their caregivers. STUDY DESIGN: A systematic review of qualitative studies. SETTING & STUDY POPULATIONS: Primary studies that reported the experiences and perspectives of adults with CKD and/or caregivers were eligible. SEARCH STRATEGY & SOURCES: MEDLINE, Embase, PsycINFO, CINAHL searched from database inception to October 2022. DATA EXTRACTION: Two authors independently screened the search results. Full texts of potentially relevant studies were assessed for eligibility. Any discrepancies were resolved by discussion with another author. ANALYTICAL APPROACH: A thematic synthesis was used to analyze the data. RESULTS: Thirty-four studies involving 1,962 participants were included. Four themes were identified: exacerbating vulnerability and distress (looming threat of COVID-19 infection, intensifying isolation, aggravating pressure on families); uncertainty in accessing health care (overwhelmed by disruption of care, confused by lack of reliable information, challenged by adapting to telehealth, skeptical about vaccine efficacy and safety); coping with self-management (waning fitness due to decreasing physical activity, diminishing ability to manage diet, difficulty managing fluid restrictions, minimized burden with telehealth, motivating confidence and autonomy); and strengthening sense of safety and support (protection from lockdown restrictions, increasing trust in care, strengthened family connection). LIMITATIONS: Non-English studies were excluded, and inability to delineate themes based on stage of kidney and treatment modality. CONCLUSIONS: Uncertainty in accessing health care during the COVID-19 pandemic exacerbated vulnerability, emotional distress, and burden, and led to reduced capacity to self-manage among patients with CKD and their caregivers. Optimizing telehealth and access to educational and psychosocial support may improve self-management and the quality and effectiveness of care during a pandemic, mitigating potentially catastrophic consequences for people with CKD. PLAIN-LANGUAGE SUMMARY: During the COVID-19 pandemic, patients with chronic kidney disease (CKD) faced barriers and challenges to accessing care and were at an increased risk of worsened health outcomes. To understand the perspectives about the impact of COVID-19 among patients with CKD and their caregivers, we conducted a systematic review of 34 studies involving 1,962 participants. Our findings demonstrated that uncertainty in accessing care during the COVID-19 pandemic exacerbated the vulnerability, distress, and burden of patients and impaired their abilities for self-management. Optimizing the use of telehealth and providing education and psychosocial services may mitigate the potential consequences for people with CKD during a pandemic.

Eradication of HCV by direct antiviral agents restores mitochondrial function and energy homeostasis in peripheral blood mononuclear cells.

Hepatitis C virus (HCV) adopts several immune evasion mechanisms such as interfering with innate immunity or promoting T-cell exhaustion. However, the recent direct-antiviral agents (DAAs) rapidly eliminate the virus, and the repercussions in terms of immune system balance are unknown. Here we compared the PBMCs transcriptomic profile of patients with HCV chronic infection at baseline (T0) and 12 weeks after the end of the therapy (SVR12) with DAAs. 3862 genes were differently modulated, identifying oxidative phosphorylation as the top canonical pathway differentially activated. Therefore, we dissected PBMCs bioenergetic profile by analyzing mitochondrial respiration and glycolysis at 4 timepoints: T0, 4 weeks of therapy, end of therapy (EoT), and SVR12. Maximal and reserve respiratory capacity considerably increased at EoT, persisting until SVR12. Notably, over time a significant increase was observed in respiratory chain (RC) complexes protein levels and the enzymatic activity of complexes I, II, and IV. Mitochondrial-DNA integrity improved over time, and the expression of mitochondrial biogenesis key regulators such as TFAM, Nrf-1, and PPARGC1A significantly increased at SVR12; hence, RC complexes synthesis and mitochondrial respiration were supported after treatment. HCV clearance with DAAS profoundly changed PBMCs bioenergetic profile, suggesting the immunometabolism study as a new approach to the understanding of viral immune evasion mechanisms and host adaptations during infections and therapies.

Risk of end-stage kidney disease in kidney transplant recipients versus patients with native chronic kidney disease: multicentre unmatched and propensity-score matched analyses.

BACKGROUND: In kidney transplant recipients (KTR), the end-stage kidney disease (ESKD) risk dependent on the risk factors acting in native chronic kidney disease (CKD) remains undefined. METHODS: We compared risk and determinants of ESKD between 757 adult KTR and 1940 patients with native CKD before and after propensity-score (PS) analysis matched for unmodifiable risk factors [(age, sex, diabetes, cardiovascular disease and estimated glomerular filtration rate (eGFR)]. RESULTS: In unmatched cohorts, eGFR was lower in CKD versus KTR (45.9 ± 11.3 versus 59.2 ± 13.4 mL/min/1.73 m2, P < 0.001). During a median follow-up of 5.4 years, the unadjusted cumulative incidence of ESKD was consistently lower in unmatched KTR versus CKD. Conversely, in PS-matched analysis, the risk of ESKD in KTR was 78% lower versus CKD at 1 year of follow-up while progressively increased over time resulting similar to that of native CKD patients after 5 years and 2.3-fold higher than that observed in CKD at 10 years. R2 analysis in unmatched patients showed that the proportion of the outcome variance explained by traditional ESKD determinants was smaller in KTR versus native CKD (31% versus 70%). After PS matching, the risk of ESKD [hazard ratio (HR), 95% confidence interval (95% CI)] was significantly associated with systolic blood pressure (1.02, 1.01-1.02), phosphorus (1.31, 1.05-1.64), 24-h proteinuria (1.11, 1.05-1.17) and haemoglobin (0.85, 0.78-0.93) irrespective of KTR status. Similar data were obtained after matching also for modifiable risk factors. CONCLUSIONS: In KTR, when compared with matched native CKD patients, the risk of ESKD is lower in the first 5 years and higher later on. Traditional determinants of ESKD account for one-third of the variability of time-to-graft failure.

Interventions for fatigue in people with kidney failure requiring dialysis.

BACKGROUND: Fatigue is a common and debilitating symptom in people receiving dialysis that is associated with an increased risk of death, cardiovascular disease and depression. Fatigue can also impair quality of life (QoL) and the ability to participate in daily activities. Fatigue has been established by patients, caregivers and health professionals as a core outcome for haemodialysis (HD). OBJECTIVES: We aimed to evaluate the effects of pharmacological and non-pharmacological interventions on fatigue in people with kidney failure receiving dialysis, including HD and peritoneal dialysis (PD), including any setting and frequency of the dialysis treatment. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 18 October 2022 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Studies evaluating pharmacological and non-pharmacological interventions affecting levels of fatigue or fatigue-related outcomes in people receiving dialysis were included. Studies were eligible if fatigue or fatigue-related outcomes were reported as a primary or secondary outcome. Any mode, frequency, prescription, and duration of therapy were considered. DATA COLLECTION AND ANALYSIS: Three authors independently extracted data and assessed the risk of bias. Treatment estimates were summarised using random effects meta-analysis and expressed as a risk ratio (RR) or mean difference (MD), with a corresponding 95% confidence interval (CI) or standardised MD (SMD) if different scales were used. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Ninety-four studies involving 8191 randomised participants were eligible. Pharmacological and non-pharmacological interventions were compared either to placebo or control, or to another pharmacological or non-pharmacological intervention. In the majority of domains, risks of bias in the included studies were unclear or high. In low certainty evidence, when compared to control, exercise may improve fatigue (4 studies, 217 participants (Iowa Fatigue Scale, Modified Fatigue Impact Scale, Piper Fatigue Scale (PFS), or Haemodialysis-Related Fatigue scale score): SMD -1.18, 95% CI -2.04 to -0.31; I2 = 87%) in HD. In low certainty evidence, when compared to placebo or standard care, aromatherapy may improve fatigue (7 studies, 542 participants (Fatigue Severity Scale (FSS), Rhoten Fatigue Scale (RFS), PFS or Brief Fatigue Inventory score): SMD -1.23, 95% CI -1.96 to -0.50; I2 = 93%) in HD. In low certainty evidence, when compared to no intervention, massage may improve fatigue (7 studies, 657 participants (FSS, RFS, PFS or Visual Analogue Scale (VAS) score): SMD -1.06, 95% CI -1.47, -0.65; I2 = 81%) and increase energy (2 studies, 152 participants (VAS score): MD 4.87, 95% CI 1.69 to 8.06, I2 = 59%) in HD. In low certainty evidence, when compared to placebo or control, acupressure may reduce fatigue (6 studies, 459 participants (PFS score, revised PFS, or Fatigue Index): SMD -0.64, 95% CI -1.03 to -0.25; I2 = 75%) in HD. A wide range of heterogenous interventions and fatigue-related outcomes were reported for exercise, aromatherapy, massage and acupressure, preventing our capability to pool and analyse the data. Due to the paucity of studies, the effects of pharmacological and other non-pharmacological interventions on fatigue or fatigue-related outcomes, including non-physiological neutral amino acid, relaxation with or without music therapy, meditation, exercise with nandrolone, nutritional supplementation, cognitive-behavioural therapy, ESAs, frequent HD sections, home blood pressure monitoring, blood flow rate reduction, serotonin reuptake inhibitor, beta-blockers, anabolic steroids, glucose-enriched dialysate, or light therapy, were very uncertain. The effects of pharmacological and non-pharmacological treatments on death, cardiovascular diseases, vascular access, QoL, depression, anxiety, hypertension or diabetes were sparse. No studies assessed tiredness, exhaustion or asthenia. Adverse events were rarely and inconsistently reported. AUTHORS' CONCLUSIONS: Exercise, aromatherapy, massage and acupressure may improve fatigue compared to placebo, standard care or no intervention. Pharmacological and other non-pharmacological interventions had uncertain effects on fatigue or fatigue-related outcomes in people receiving dialysis. Future adequately powered, high-quality studies are likely to change the estimated effects of interventions for fatigue and fatigue-related outcomes in people receiving dialysis.

New Frontiers in Sepsis-Induced Acute Kidney Injury and Blood Purification Therapies: The Role of Polymethylmethacrylate Membrane Hemofilter.

Acute kidney injury (AKI) is a common consequence of sepsis with a mortality rate of up to 40%. The pathogenesis of septic AKI is complex and involves several mechanisms leading to exacerbated inflammatory response associated with renal injury. A large body of evidence suggests that inflammation is tightly linked to AKI through bidirectional interaction between renal and immune cells. Preclinical data from our and other laboratories have identified in complement system activation a crucial mediator of AKI. Partial recovery following AKI could lead to long-term consequences that predispose to chronic dysfunction and may also accelerate the progression of preexisting chronic kidney disease. Recent findings have revealed striking morphological and functional changes in renal parenchymal cells induced by mitochondrial dysfunction, cell cycle arrest via the activation of signaling pathways involved in aging process, microvascular rarefaction, and early fibrosis. Although major advances have been made in our understanding of the pathophysiology of AKI, there are no available preventive and therapeutic strategies in this field. The identification of ideal clinical biomarkers for AKI enables prompt and effective therapeutic strategy that could prevent the progression of renal injury and promote repair process. Therefore, the use of novel biomarkers associated with clinical and functional criteria could provide early interventions and better outcome. Several new drugs for AKI are currently being investigated; however, the complexity of this disease might explain the failure of pharmacological intervention targeting just one of the many systems involved. The hypothesis that blood purification could improve the outcome of septic AKI has attracted much attention. New relevant findings on the role of polymethylmethacrylate-based continuous veno-venous hemofiltration in septic AKI have been reported. Herein, we provide a comprehensive literature review on advances in the pathophysiology of septic AKI and potential therapeutic approaches in this field.

Enhancing Immune Protection in Hemodialysis Patients: Role of the Polymethyl Methacrylate Membrane.

End-stage renal disease (ESRD) is characterized by deep disorders in both innate and adaptive immune systems that imply unbalance deactivation and immunosuppression. The central, widely recognized factors responsible for this immune dysregulation are uremia, uremic toxin retention, hemodialysis membrane biocompatibility, and related cardiovascular complications. Recently, several studies strengthened the concept that dialysis membranes are not considered as a simple diffusive/adsorptive device but as a platform to personalize a dialysis approach to improve the quality of life of ESRD patients. Therefore, understanding of the molecules associated with altered immune response is crucial and could lead to therapeutically intervention or adaptation of the dialysis procedure itself for the management of immunological dysfunction of ESRD patients. The polymethyl methacrylate (PMMA)-based membrane is characterized by a symmetrical structure with large-sized pores, providing a better hydrophobic and cationic adsorption capacity compared to the other synthetic membranes. Together with hydrophobic interactions, the high adsorption rate of cytokines (i.e., IL-6) can also be enhanced by the size of nano-pores placed on the membrane surface. PMMA membranes exhibit adsorptive properties for a large amount of uremic toxins including p-cresol and indoxyl sulfate, as well as ß2-microglobulin characterized by higher molecular weight, maintaining the diffusive clearance of small molecules like urea with a great biocompatibility. Besides exerting a strong anti-inflammatory effects in line with the improvement of immune responses in patients undergoing dialysis, PMMA also plays a role in modulating adaptive immune response, i.e., can clear blood from soluble CD40, a natural antagonist of the CD40/CD40L signaling that acts inhibiting immunoglobulin production by B cells. This review provides an overview of the main concepts and current understanding of immune dysfunction in hemodialysis and summarizes the recent findings regarding PMMA-based dialysis as potential strategy to restore immune balance in ESRD patients.

Extracellular vesicles derived from patients with antibody-mediated rejection induce tubular senescence and endothelial to mesenchymal transition in renal cells.

Extracellular vesicles (EV) are emerging mediators in several diseases. However, their role in the pathophysiology of antibody-mediated allograft rejection (AMR) has been poorly investigated. Here, we investigated the role of EV isolated from AMR patients in inducing tubular senescence and endothelial to mesenchymal transition (EndMT) and analyzed their miRNA expression profile. By multiplex bead flow cytometry, we characterized the immunophenotype of plasma AMR-derived EV and found a prevalent platelet and endothelial cell origin. In vitro, AMR-derived EV induced tubular senescence by upregulating SA-ß Gal and CDKN1A mRNA. Furthermore, AMR-derived EV induced EndMT. The occurrence of tubular senescence and EndMT was confirmed by analysis of renal biopsies from the same AMR patients. Moreover, AMR-derived EV induced C3 gene upregulation and CFH downregulation in tubular epithelial cells, with C4d deposition on endothelial cells. Interestingly, RNase-mediated digestion of EV cargo completely abrogated tubular senescence and EndMT. By microarray analysis, miR-604, miR-515-3p, miR-let-7d-5p, and miR-590-3p were significantly upregulated in EV from AMR group compared with transplant controls, whereas miR-24-3p and miR-29a-3p were downregulated. Therefore, EV-associated miRNA could act as active player in AMR pathogenesis, unraveling potential mechanisms of accelerated graft senescence, complement activation and early fibrosis that might lead to new therapeutic intervention.

mTOR inhibitors improve both humoral and cellular response to SARS-CoV-2 messenger RNA BNT16b2 vaccine in kidney transplant recipients.

Kidney transplant recipients (KTRs) have been considered as patients at higher risk of SARS-CoV-2-related disease severity, thus COVID-19 vaccination was highly recommended. However, possible interferences of different immunosuppression with development of both humoral and T cell-mediated immune response to COVID-19 vaccination have not been determined. Here we evaluated the association between mTOR-inhibitors (mTOR-I) and immune response to mRNA BNT162b2 (Pfizer-BioNTech) vaccine in KTR. To this aim 132 consecutive KTR vaccinated against COVID-19 in the early 2021 were enrolled, and humoral and T cell-mediated immune response were assessed after 4-5 weeks. Patients treated with mTOR-I showed significantly higher anti-SARS-CoV-2 IgG titer (p = .003) and higher percentages of anti-SARS-CoV-2 S1/RBD Ig (p = .024), than those without. Moreover, SARS-CoV-2-specific T cell-derived IFNγ release was significantly increased in patients treated with mTOR-I (p < .001), than in those without. Multivariate analysis confirmed that therapy with mTOR-I gained better humoral (p = .005) and T cell-mediated immune response (p = .005) in KTR. The presence of mTOR-I is associated with a better immune response to COVID-19 vaccine in KTR compared to therapy without mTOR-I, not only by increasing vaccine-induced antibodies but also by stimulating anti-SARS-CoV-2 T cell response. These finding are consistent with a potential beneficial role of mTOR-I as modulators of immune response to COVID-19 vaccine in KTR.

Rapamycin promotes autophagy cell death of Kaposi's sarcoma cells through P75NTR activation.

The mammalian target of rapamycin inhibitor (mTOR-I) Rapamycin, a drug widely used in kidney transplantation, exerts important anti-cancer effects, particularly in Kaposi's Sarcoma (KS), through several biological interactions. In this in vivo and in vitro study, we explored whether the activation of the autophagic pathway through the low-affinity receptor for nerve growth factor, p75NTR , may have a pivotal role in the anti-cancer effect exerted by Rapamycin in S. Our Kimmunohistochemistry results revealed a significant hyper-activation of the autophagic pathway in KS lesions. In vitro experiments on KS cell lines showed that Rapamycin exposure reduced cell viability by increasing the autophagic process, in the absence of apoptosis, through the transcriptional activation of p75NTR via EGR1. Interestingly, p75NTR gene silencing prevented the increase of the autophagic process and the reduction of cell viability. Moreover, p75NTR activation promoted the upregulation of phosphatase and tensin homolog (PTEN), a tumour suppressor that modulates the PI3K/Akt/mTOR pathway. In conclusion, our in vitro data demonstrated, for the first time, that in Kaposi's sarcoma, autophagy triggered by Rapamycin through p75NTR represented a major mechanism by which mTOR inhibitors may induce tumour regression. Additionally, it suggested that p75NTR protein analysis could be proposed as a new potential biomarker to predict response to Rapamycin in kidney transplant recipients affected by Kaposi's sarcoma.

Proteomics Insights into Medullary Sponge Kidney Disease: Review of the Recent Results of an Italian Research Collaborative Network.

BACKGROUND: Medullary sponge kidney (MSK) disease is a rare and neglected congenital condition typically associated with nephrocalcinosis/nephrolithiasis, urinary concentration defects, and cystic anomalies in the precalyceal ducts that, although sporadic in the general population, is relatively frequent in renal stone formers. The physiopathologic mechanism associated with this disease is not fully understood, and omics technologies may help address this gap. SUMMARY: The aim of this review was to provide an overview of the current state of the application of proteomics in the study of this rare disease. In particular, we focused on the results of our recent Italian collaborative studies that, analyzing the MSK whole and extracellular vesicle urinary content by mass spectrometry, have displayed the existence of a large and multifactorial MSK-associated biological machinery and identified some main regulatory biological elements able to discriminate patients affected by this rare disorder from those with idiopathic calcium nephrolithiasis and autosomal dominant polycystic kidney disease (including laminin subunit alpha 2, ficolin 1, mannan-binding lectin serine protease 2, complement component 4-binding protein ß, sphingomyelin, ephrins). KEY MESSAGES: The application of omics technologies has provided new insights into the comprehension of the physiopathology of the MSK disease and identified novel potential diagnostic biomarkers that may replace in future expensive and invasive radiological tests (including CT) and select novel therapeutic targets potentially employable, whether validated in a large cohort of patients, in the daily clinical practice.

Unraveling the Link between Interferon-α and Systemic Lupus Erythematosus: From the Molecular Mechanisms to Target Therapies.

Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease with a wide range of clinical expressions. The kidney is often affected, usually within 5 years of the onset of SLE, and lupus nephropathy (LN) carries a high risk for increased morbidity. The clinical heterogeneity of the disease is accompanied by complex disturbances affecting the immune system with inflammation and tissue damage due to loss of tolerance to nuclear antigens and the deposition of immune complexes in tissues. Several studies have reported that in human SLE, there is an important role of the Type-I-interferons (INF) system suggested by the upregulation of INF-inducible genes observed in serial gene expression microarray studies. This review aims to describe the transduction pathways of Type-I-interferons, in particular INFα, and its immune-regulatory function in the pathogenesis of SLE and, in particular, in LN. In addition, recent novelties concerning biologic therapy in LN will be discussed.

Pathological diagnosis of Coronavirus-related nephropathy: insight from postmortem studies.

A novel coronavirus pneumonia first occurred in Wuhan, China in early December 2019; the causative agent was identified and named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the World Health Organization (WHO), and the resulting disease termed coronavirus disease 2019 (COVID-19), according to the WHO coronavirus disease situation reports. This condition has spread rapidly all over the world and caused more than 125 million cases globally, with more than 2 million related deaths. Two previous outbreaks due to zoonotic coronaviruses have occurred in the last 20 years, namely the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), causing high morbidity and mortality in human populations upon crossing the species barriers. SARS-CoV-2, SARS-CoV, and MERS-CoV show several similarities in pathogenicity and clinical presentations, the latter ranging from asymptomatic infection to severe acute respiratory distress syndrome (ARDS) and multiorgan impairment. Acute kidney injury (AKI) has been commonly reported in patients with CoV infections; therefore, pathological analysis of renal parenchyma in these patients has been carried out in order to improve knowledge about underlying mechanisms. Viral infection has been demonstrated in the renal tubular epithelial cells by electron microscopy (EM), immunohistochemistry (IHC), and in situ hybridization (ISH), although with conflicting results. Light microscopy (LM) changes have been described in the renal parenchyma primarily in the form of acute renal tubular damage, possibly due to direct viral cytopathic effect and immune-mediated mechanisms such as cytokine storm syndrome. In this review, we describe and discuss the spectrum of histological, ultrastructural, and molecular findings in SARS-CoV, MERS-CoV, and SARS-CoV-2-related renal pathology obtained from postmortem studies, as well as intrinsic limitations and pitfalls of current diagnostic techniques.

DelCFHR3-1 influences graft survival in transplant patients with IgA nephropathy via complement-mediated cellular senescence.

IgA nephropathy (IgAN) is a frequent cause of chronic kidney disease (CKD) and progressive renal impairment. A native renal biopsy diagnosis of IgAN is a predictor of graft loss, with a relative risk of 47% but it is difficult to predict graft survival and progressive allograft dysfunction in these patients. Deletion of complement factor H-related genes 1 and 3 (delCFHR3-1) has been associated with a decreased risk of developing IgAN on native kidneys, but the impact on the graft in IgAN-transplanted patients is unknown. We hypothesized that delCFHR3-1 is also associated with the processes that influence graft survival in transplant recipients with IgAN and tested whether cellular senescence is involved in mediating graft damage. We found that patients carrying two copies of CFHR1-3 had a worse outcome (P = .000321) and presented increased FHR1 deposits at glomerular and tubulointerstitial level associated with higher expression of the senescence marker p16INK4a (P = .001) and tubulointerstitial fibrosis (P = .005). Interestingly, FHR1 deposits were associated with increased complement activation as demonstrated by C5b-9 deposits. These data support both the role of FHR1 in mediating complement activation and tubular senescence, and suggest the possibility of genotyping delCFHR3-1 to predict graft survival in IgAN-transplanted patients.

Iliac Pseudoaneurysm, Only a Manifestation With More Causes: A Case Report.

Pseudoaneurysm is due to a disruption in arterial wall continuity. It forms a sac that communicates with the vessel lumen and is surrounded by the compressed, surrounding tissues and not by the wall of the artery from which the lesion arises. Many causes can predispose to the formation of a pseudoaneurysm such as trauma, surgical procedures, anticoagulation. In our patient another important risk factor for the formation of a pseudoaneurysm is ADPKD (autosomal dominant polycystic kidney disease) that can cause vascular complication. The mechanisms leading to the genesis of the pseudoaneurysms in our patient are unknown, but the clinicians should bear in mind when evaluating this type of patients that ADPKD may have a various range of systemic cardiovascular manifestation.

Rapamycin Inhibitors for Eye Squamous Cell Carcinoma after Renal Transplantation: A Case Report.

INTRODUCTION: The immunosuppressive efficiency obtained in the last decades in kidney transplantation significantly improved graft survival. However, there is still a high risk and incidence of cancer in transplant patients strongly and directly related to the type of immunosuppression. An increasing body of evidence suggests that the PI3K/Akt/mTOR pathway may play a pivotal role in the development and progression of several neoplastic diseases. CASE PRESENTATION: We describe a 47-year-old male patient who received a cadaveric primary renal transplant in November 2008 developing a poorly differentiated infiltrating and ulcerated squamous cell carcinoma (SCC) at the eye level. In this patient, the modification of an immunosuppressive regimen with introduction of rapamycin (mTOR) inhibitors and withdrawal of calcineurin inhibitors (CNIs) led to the resolution of this severe condition. CONCLUSION: The introduction of mTOR inhibitors and withdrawal of CNIs in kidney-transplanted patients with de novo eye SCC should be considered in this clinical setting.

CD40 Cross-Linking Induces Migration of Renal Tumor Cell through Nuclear Factor of Activated T Cells (NFAT) Activation.

CD40 crosslinking plays an important role in regulating cell migration, adhesion and proliferation in renal cell carcinoma (RCC). CD40/CD40L interaction on RCC cells activates different intracellular pathways but the molecular mechanisms leading to cell scattering are not yet clearly defined. Aim of our study was to investigate the main intracellular pathways activated by CD40 ligation and their specific involvement in RCC cell migration. CD40 ligation increased the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun NH (2)-terminal kinase (JNK) and p38 MAPK. Furthermore, CD40 crosslinking activated different transcriptional factors on RCC cell lines: AP-1, NFkB and some members of the Nuclear Factor of Activated T cells (NFAT) family. Interestingly, the specific inhibition of NFAT factors by cyclosporine A, completely blocked RCC cell motility induced by CD40 ligation. In tumor tissue, we observed a higher expression of NFAT factors and in particular an increased activation and nuclear migration of NFATc4 on RCC tumor tissues belonging to patients that developed metastases when compared to those who did not. Moreover, CD40-CD40L interaction induced a cytoskeleton reorganization and increased the expression of integrin ß1 on RCC cell lines, and this effect was reversed by cyclosporine A and NFAT inhibition. These data suggest that CD40 ligation induces the activation of different intracellular signaling pathways, in particular the NFATs factors, that could represent a potential therapeutic target in the setting of patients with metastatic RCC.

Inhibition of Lysine 63 Ubiquitination Prevents the Progression of Renal Fibrosis in Diabetic DBA/2J Mice.

Diabetic nephropathy (DN) is the most frequent cause of end-stage renal disease. Tubulointerstitial accumulation of lysine 63 (K63)-ubiquitinated (Ub) proteins is involved in the progression of DN fibrosis and correlates with urinary miR-27b-3p downregulation. We explored the renoprotective effect of an inhibitor of K63-Ub (NSC697923), alone or in combination with the ACE-inhibitor ramipril, in vitro and in vivo. Proximal tubular epithelial cells and diabetic DBA/2J mice were treated with NSC697923 and/or ramipril. K63-Ub protein accumulation along with α-SMA, collagen I and III, FSP-1, vimentin, p16INK4A expression, SA-α Gal staining, Sirius Red, and PAS staining were measured. Finally, we measured the urinary albumin to creatinine ratio (uACR), and urinary miR-27b-3p expression in mice. NSC697923, both alone and in association with ramipril, in vitro and in vivo inhibited hyperglycemia-induced epithelial to mesenchymal transition by significantly reducing K63-Ub proteins, α-SMA, collagen I, vimentin, FSP-1 expression, and collagen III along with tubulointerstitial and glomerular fibrosis. Treated mice also showed recovery of urinary miR-27b-3p and restored expression of p16INK4A. Moreover, NSC697923 in combination with ramipril demonstrated a trend in the reduction of uACR. In conclusion, we suggest that selective inhibition of K63-Ub, when combined with the conventional treatment with ACE inhibitors, might represent a novel treatment strategy to prevent the progression of fibrosis and proteinuria in diabetic nephropathy and we propose miR-27b-3p as a biomarker of treatment efficacy.

Molecular Mechanisms of Premature Aging in Hemodialysis: The Complex Interplay Between Innate and Adaptive Immune Dysfunction.

Hemodialysis (HD) patient are known to be susceptible to a wide range of early and long-term complication such as chronic inflammation, infections, malnutrition, and cardiovascular disease that significantly affect the incidence of mortality. A large gap between the number of people with end-stage kidney disease (ESKD) and patients who received kidney transplantation has been identified. Therefore, there is a huge need to explore the underlying pathophysiology of HD complications in order to provide treatment guidelines. The immunological dysregulation, involving both the innate and adaptive response, plays a crucial role during the HD sessions and in chronic, maintenance treatments. Innate immune system mediators include the dysfunction of neutrophils, monocytes, and natural killer (NK) cells with signaling mediated by NOD-like receptor P3 (NLRP3) and Toll-like receptor 4 (TLR4); in addition, there is a significant activation of the complement system that is mediated by dialysis membrane-surfaces. These effectors induce a persistent, systemic, pro-inflammatory, and pro-coagulant milieu that has been described as inflammaging. The adaptive response, the imbalance in the CD4+/CD8+ T cell ratio, and the reduction of Th2 and regulatory T cells, together with an altered interaction with B lymphocyte by CD40/CD40L, have been mainly implicated in immune system dysfunction. Altogether, these observations suggest that intervention targeting the immune system in HD patients could improve morbidity and mortality. The purpose of this review is to expand our understanding on the role of immune dysfunction in both innate and adaptive response in patients undergoing hemodialysis treatment.

Recurrent Glomerulonephritis after Renal Transplantation: The Clinical Problem.

Glomerulonephritis (GN) continues to be one of the main causes of end-stage kidney disease (ESKD) with an incidence rating from 10.5% to 38.2%. Therefore, recurrent GN, previously considered to be a minor contributor to graft loss, is the third most common cause of graft failure 10 years after renal transplantation. However, the incidence, pathogenesis, and natural course of recurrences are still not completely understood. This review focuses on the most frequent diseases that recur after renal transplantation, analyzing rate of recurrence, epidemiology and risk factors, pathogenesis and bimolecular mechanisms, clinical presentation, diagnosis, and therapy, taking into consideration the limited data available in the literature. First of all, the risk for recurrence depends on the type of glomerulonephritis. For example, recipient patients with anti-glomerular basement membrane (GBM) disease present recurrence rarely, but often exhibit rapid graft loss. On the other hand, recipient patients with C3 glomerulonephritis present recurrence in more than 50% of cases, although the disease is generally slowly progressive. It should not be forgotten that every condition that can lead to chronic graft dysfunction should be considered in the differential diagnosis of recurrence. Therefore, a complete workup of renal biopsy, including light, immunofluorescence and electron microscopy study, is essential to provide the diagnosis, excluding alternative diagnosis that may require different treatment. We will examine in detail the biomolecular mechanisms of both native and transplanted kidney diseases, monitoring the risk of recurrence and optimizing the available treatment options.