Consensus commentary and position of the Italian Society of Nephrology on KDIGO controversies conference on novel anemia therapies in chronic kidney disease.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are new drugs developed for the treatment of anemia associated with chronic kidney disease (CKD). This class of drugs stimulates endogenous erythropoietin production and, at the same time, improves iron absorption and mobilization of iron stores (less evident with daprodustat, vadadustat and enarodustat). Several studies have been published in the last few years showing that these agents are not inferior to standard therapy in correcting anemia associated with CKD. The efficacy of HIF-PHIs is coupled with a safety profile comparable to that of standard erythropoiesis stimulating agent (ESA) treatment. However, studies with HIF-PHIs were not long enough to definitively exclude the impact of new drugs on adverse events, such as cancer, death and possibly cardiovascular events, that usually occur after a long follow-up period. Kidney Disease: Improving Global Outcomes (KDIGO) recently reported the conclusions of the Controversies Conference on HIF-PHIs held in 2021. The goal of the present position paper endorsed by the Italian Society of Nephrology is to better adapt the conclusions of the latest KDIGO Conference on HIF-PHIs to the Italian context by reviewing the efficacy and safety of HIF-PHIs as well as their use in subpopulations of interest as emerged from more recent publications not discussed during the KDIGO Conference.

Fragility Fractures in End-Stage Chronic Kidney Disease (CKD) Population: Patient-Related and CKD-Related Factor Analysis-A Single-Center Experience.

Background: Chronic kidney disease (CKD) stands as a prevalent global health concern, and mineral and bone disease are among the most impactful consequences. A severe complication arising from mineral and bone disease is the occurrence of fragility fractures, which disproportionately affect individuals with CKD compared to the general population. The prevalence of these fractures impacts both survival rates and quality of life. The aims of this study are analyzing and identifying (i) patient-related risk factors and (ii) CKD-related risk factors to contribute to the development of preventive measures for fragility fractures for this population. Methods: A retrospective, single-center observational study was conducted, encompassing patient data from the years 2021 to 2023. Registry data were recorded, including patient-related and CKD-related data. Patients were interviewed about traumatological history, and their answers were recorded. Logistic regression analysis was employed to investigate the association between independent variables and dependent variables. Results: Eighty-four patients, with a mean age of 64.3 ± 15.2 years and a male percentage of 58.3%, were included in this study. Among them, 19.5% exhibited smoking habits. The mean Charlson Comorbidity Index was 3.06 ± 1.21. All patients were diagnosed with end-stage chronic kidney disease, with mean durations of 208 months from the diagnosis and 84.5 months from the beginning of dialysis. The logistic regression analysis, adjusted for age, sex, and CCI, revealed that smoking habits play a significant role as a risk factor for fragility fractures in lower limbs (p: 0.011 *). The incidence of fragility fractures increases directly proportionally to the time since diagnosis (p-value: 0.021 *) and the beginning of dialysis treatment (p-value: 0.001 *). Conclusions: Among patient-related factors, smoking habits seem to significantly affect lower-limb fracture rates (p < 0.05), whereas among CKD-related factors, time since CKD diagnosis and time since the beginning of dialysis treatment are directly related to higher risks of fragility fractures. No relevant correlations emerged in the studied treatments, except for a reduction in proximal femur fracture occurrence when patients underwent a combined treatment of a calcimimetic and a vitamin D analog.

Effects of low-sodium bread on dietary compliance and fecal cultivable bacteria in a randomized controlled pilot trial in hypertensive subjects.

High salt intake and compliance to low-sodium (LS) diets are critical in hypertension. Salt reduction in processed foods can help to achieve the target sodium intake. To verify the hypothesis that an innovative LS formulation of a traditional bread could result in a reduction of sodium intake and blood pressure, we performed a 6-month randomized controlled pilot trial on hypertensive patients. We additionally explored the effects of sodium restriction on blood pressure and fecal cultivable bacteria.Fifty-seven patients were randomized in three groups. Group A (n = 19) followed a free diet using standard bread (750 mg Na/100 g), group B (n = 18) followed a LS diet (2300 mg Na/die) using standard bread, group C (n = 20) followed a LS diet (2300 mg Na/die) using LS bread (280 mg Na/100 g). We measured 24-h urinary sodium, blood pressure, routine parameters, fecal microbial counts (26 patients).After 6 months, as compared to group A, group C showed a reduction of 24-h urinary sodium excretion (-908 mg/24 h), diastolic pressure (-9 mmHg) and microbial counts of Bacteroides, Porphyromonas, Prevotella, Enterobacteriaceae, Staphylococcus, Micrococcus. These results suggest that LS bread could increase the adherence to a LS diet, reducing sodium excretion, diastolic pressure and abundance of some fecal cultivable bacteria.Trial registration Registration nr. NCT03127553, on 25/04/2017.

A novel scenario in the therapeutic management of anemia of chronic kidney disease: placement and use of roxadustat.

Anemia is a frequent and early chronic kidney disease (CKD) complication. Its management is currently based on oral or intravenous iron supplements, erythropoiesis-stimulating agents, and red blood cell transfusions, when the benefits of transfusion outweigh the risks. Anemia in CKD patients is underdiagnosed and undertreated. Current standard of care is associated with challenges and therefore new treatment approaches have been sought. Hypoxia-inducible factor-prolyl-hydroxylase enzyme inhibitors are a new class of orally administered drugs used to treat anemia associated with CKD. Small-molecule hypoxia-inducible factor-prolyl-hydroxylase inhibitors have a novel mechanism of action that activates the hypoxia-inducible factor (oxygen-sensing) pathway resulting in a coordinated erythropoietic response, leading to increased endogenous erythropoietin production, improved iron absorption and transport, and reduced hepcidin. Roxadustat is the first hypoxia-inducible factor-prolyl-hydroxylase inhibitor approved by the European Medicines Agency (EMA) and reimbursed in Italy by the Italian Medicines Agency (AIFA) for the treatment of adult patients with symptomatic CKD-related anemia. This authorization was based on the outcome of a globally-conducted phase 3 clinical trial program comprising eight pivotal multicenter randomized studies. In the absence of up-to-date guidelines, we performed a critical appraisal of the placement and use of roxadustat in this therapeutic context.

Assessment and management of heart failure in patients with chronic kidney disease.

Heart failure (HF) and chronic kidney disease (CKD) are two pathological conditions with a high prevalence in the general population. When they coexist in the same patient, a strict interplay between them is observed, such that patients affected require a clinical multidisciplinary and personalized management. The diagnosis of HF and CKD relies on signs and symptoms of the patient but several additional tools, such as blood-based biomarkers and imaging techniques, are needed to clarify and discriminate the main characteristics of these diseases. Improved survival due to new recommended drugs in HF has increasingly challenged physicians to manage patients with multiple diseases, especially in case of CKD. However, the safe administration of these drugs in patients with HF and CKD is often challenging. Knowing up to which values ​​of creatinine or renal clearance each drug can be administered is fundamental. With this review we sought to give an insight on this sizable and complex topic, in order to get clearer ideas and a more precise reference about the diagnostic assessment and therapeutic management of HF and CKD.

COVID-19: The Dysregulated Response to Infection - Why Consider Polymethylmethacrylate Membrane in Hemodialysis Patients?

Since SARS-CoV-2 spread through China at the end of 2019, COVID-19 has been probably the most difficult challenge in the last decades for healthcare systems all around the world, still representing a danger for fragile patients with different comorbidities. Chronic dialysis patients affected by COVID-19 experienced severe disease with a higher mortality rate compared to the general population. Morbidity and mortality of this severe acute respiratory syndrome depend on both acute respiratory failure and systemic immunological involvement with consequent inflammation-mediated injury. Indeed, the most important determining factor of COVID-19 severity is the strength of the so-called "cytokine storm" associated with SARS-CoV-2 infection. Therefore, this severe infection varies clinically from an asymptomatic condition to a generalized and violent inflammatory response and acute respiratory distress syndrome, with consequent pulmonary interstitial edema and a high risk of multi-organ failure. The use of extracorporeal therapies targeting cytokine clearance to improve patients' outcomes has been widely debated, especially in end-stage kidney disease's patients on maintenance dialysis or in individuals affected by acute kidney injury admitted to intensive care units. Different studies were conducted to demonstrate how specific dialyzers could decrease the COVID-19 inflammatory state. The aim of this narrative review was to summarize main studies about this topic, focusing primarily on the role of polymethylmethacrylate dialyzer and underlining pros and cons of this sorbent.

Underlying Genetics of aHUS: Which Connection with Outcome and Treatment Discontinuation?

Atypical hemolytic uremic syndrome (aHUS) is a rare disease caused by a genetic dysregulation of the alternative complement pathway, characterized by thrombocytopenia, hemolytic anemia, and acute kidney injury, and included in the group of thrombotic microangiopathies. With the introduction of humanized monoclonal antibodies that inhibit C5 activation, the natural history of aHUS completely changed, with a better prognosis, a quick recovery of renal function, and a significant reduction of end-stage renal disease incidence. Nowadays, there is an increasing interest in the molecular and genetic bases of this severe disease. The aim of this narrative review is to provide readers with a practical guide about different possible involved genes, elucidating the specific role of each transcribed protein in the pathogenesis of aHUS. Moreover, we analyzed the main current evidence about the relationship among genetic mutations, outcomes, and the risk of recurrence of this manifold disease.

Prevalence, incidence, and treatment of anaemia in patients with non-dialysis-dependent chronic kidney disease: findings from a retrospective real-world study in Italy.

BACKGROUND: Limited data are available on the epidemiology and clinical management of anaemia in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). METHODS: This retrospective observational study was based on records from databases of five Local Health Units across Italy. Adults with reported NDD-CKD stage 3a-5 between 1 January 2014 and 31 December 2016 were identified. Annual prevalence and incidence of anaemia (age- and sex-standardised) and clinical management (erythropoiesis-stimulating agents [ESAs], intravenous [IV] iron, and blood transfusions) were evaluated. Eligibility for ESAs was defined by ≥ 2 records of Hb < 10 g/dL, or < 11 g/dL over 6 months. RESULTS: Overall, 101,143 individuals with NDD-CKD (3a-5) recorded between 2014 and 2016 were identified, of whom 40,020 (39.6%) were anaemic. Prevalence of anaemia was 33.8% in 2016 and incidence of anaemia was stable (11.4-12.4%) from 2014 to 2016. Prevalence and incidence of anaemia increased with CKD stage. Among eligible patients, 12.8% with Hb < 11 g/dL and 15.5% with Hb < 10 g/dL received ESAs, and the proportion treated increased with CKD stage. Among ESA-treated patients with at least 2 years of follow up, 18.4% and 19.3% received IV iron in the Hb < 11 and < 10 g/dL groups, respectively, and 16.5% and 19.4% received blood transfusions. Corresponding proportions for the overall anaemic cohort were 9.0% and 11.3%, respectively. CONCLUSIONS: Anaemia is a significant issue in patients with NDD-CKD. Low rates of ESA treatment indicate a potential treatment gap and suggest that anaemia may not be adequately controlled in many patients.

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.

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.

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.

Can SGLT2 inhibitors answer unmet therapeutic needs in chronic kidney disease?

Chronic kidney disease (CKD) is a global health problem, affecting more than 850 million people worldwide. The number of patients receiving renal replacement therapy (dialysis or renal transplantation) has increased over the years, and it has been estimated that the number of people receiving renal replacement therapy will more than double from 2.618 million in 2010 to 5.439 million in 2030, with wide differences among countries. The main focus of CKD treatment has now become preserving renal function rather than replacing it. This is possible, at least to some extent, through the optimal use of multifactorial therapy aimed at preventing end-stage kidney disease and cardiovascular events. Sodium/glucose cotransporter 2 inhibitors (SGLT2i) reduce glomerular hypertension and albuminuria with beneficial effects on progression of renal damage in both diabetic and non-diabetic CKD. SGLT2 inhibitors also show great benefits in cardiovascular protection, irrespective of diabetes. Therefore, the use of these drugs will likely be extended to the whole CKD population as a new standard of care.

Pre-Transplant Expression of CCR-2 in Kidney Transplant Recipients Is Associated With the Development of Delayed Graft Function.

Background: Delayed graft function (DGF) leads to a reduced graft survival. Donors' features have been always considered as key pathogenic factors in this setting. The aim of our study was to evaluate the recipients' characteristics in the development of DGF. Methods: We enrolled 932 kidney graft recipients from 466 donors; 226 recipients experienced DGF. In 290 donors, both recipients presented with early graft function (EGF, group A), in 50 both recipients experienced DGF (group B), and in 126 one recipient presented with DGF and the other with EGF (group C). In group C, we selected 7 couples of DGF/EGF recipients and we evaluated the transcriptomic profile by microarray on circulating mononuclear cells harvested before transplantation. Results were validated by qPCR in an independent group of 25 EGF/DGF couples. Findings: In the whole study group, DGF was associated with clinical characteristics related to both donors and recipient. In group C, DGF was significantly associated with body mass index, hemodialysis, and number of mismatches. In the same group, we identified 411 genes differently expressed before transplantation between recipients discordant for the transplant outcome. Those genes were involved in immune dysfunction and inflammation. In particular, we observed a significant increase in DGF patients in the expression of C-C chemokine receptor type 2 (CCR2), the monocyte chemoattractant protein-1 (MCP-1) receptor. CCR-2 upregulation was confirmed in an independent cohort of patients. Conclusions: Our results suggest that recipients' clinical/immunological features, potentially modulated by dialysis, are associated with the development of DGF independently of donors' features.

Management of the kidney transplant patient with Cancer: Report from a Multidisciplinary Consensus Conference.

INTRODUCTION: Cancer is the second most common cause of mortality and morbidity in Kidney Transplant Recipients (KTRs). Immunosuppression can influence the efficacy of cancer treatment and modification of the immunosuppressive regimen may restore anti-neoplastic immune responses improving oncologic prognosis. However, patients and transplant physicians are usually reluctant to modify immunosuppression, fearing rejection and potential graft loss. Due to the lack of extensive and recognised data supporting how to manage the immunosuppressive therapy in KTRs, in the context of immunotherapy, chemotherapy, radiotherapy and loco-regional treatments, a Consensus Conference was organised under the auspices of the European Society of Organ Transplantation and the Italian Society of Organ Transplantation. The conference involved a multidisciplinary group of transplant experts in the field across Europe. METHODS: The overall process included a) the formulation of 12 specific questions based on the PICO methodology, b) systematic literature review and summary for experts for each question, c) a two-day conference celebration and the collection of experts' agreements. The conference was articulated in three sessions: "Immunosuppressive therapy and immunotherapy", "Systemic therapy", "Integrated Therapy", while the final experts' agreement was collected with a televoting procedure and defined according to the majority criterion. RESULTS: Twenty-six European experts attended the conference and expressed their vote. A total of 14 statements were finally elaborated and voted. Strong agreement was found for ten statements, moderate agreement for two, moderate disagreement for one and uncertainty for the last one. CONCLUSIONS: The consensus statements provide guidance to transplant physicians caring for kidney transplant recipients with cancer and indicate key aspects that need to be addressed by future clinical research.

Emerging biomarkers of delayed graft function in kidney transplantation.

Delayed Graft Function (DGF) is one of the most common early complications in kidney transplantation, associated with poor graft outcomes, prolonged post-operative hospitalization and higher rejection rates. Given the severe shortage of high-quality organs for transplantation, DGF incidence is expected to raise in the next years because of the use of nonstandard kidneys from Extended Criteria Donors (ECD) and from Donors after Circulatory Death (DCD). Alongside conventional methods for the evaluation of renal allograft [e.g. serum creatinine Glomerular Filtration Rate (GFR), needle biopsy], recent advancements in omics technologies, including proteomics, metabolomics and transcriptomics, may allow to discover novel biomarkers associated with DGF occurrence, in order to identify early preclinical signs of renal dysfunction and to improve the quality of graft management. Here, we gather contributions from basic scientists and clinical researchers to describe new omics studies in renal transplantation, reporting the emerging biomarkers of DGF that may implement and improve conventional approaches.

Cytotoxic T Lymphocytes (CTLs) and Kidney Transplantation: An Overview.

Involvement of T lymphocytes in kidney transplantation is a well-developed topic; however, most of the scientific interest focused on the different type of CD4+ lymphocyte subpopulations. Few authors, instead, investigated the role of CD8+ T cells in renal transplantation and how deleterious they can be to long-term allograft survival. Recently, there has been a renewed interest in the CD8+ T cells involvement in the transplantation field with the aim to investigate the immunological mechanisms underlying the infiltration of CD8+ T cells and their biological functions in human kidney allografts. The purpose of the present review is to highlight the role of allo-reactive cytotoxic T lymphocytes (CTLs) CD8+ subset in allograft kidney recipients and their related clinical complications.

Pentraxin-3-mediated complement activation in a swine model of renal ischemia/reperfusion injury.

Pentraxins are a family of evolutionarily conserved pattern recognition molecules with pivotal roles in innate immunity and inflammation, such as opsonization of pathogens during bacterial and viral infections. In particular, the long Pentraxin 3 (PTX3) has been shown to regulate several aspects of vascular and tissue inflammation during solid organ transplantation. Our study investigated the role of PTX3 as possible modulator of Complement activation in a swine model of renal ischemia/reperfusion (I/R) injury. We demonstrated that I/R injury induced early PTX3 deposits at peritubular and glomerular capillary levels. Confocal laser scanning microscopy revealed PTX3 deposits co-localizing with CD31+ endothelial cells. In addition, PTX3 was associated with infiltrating macrophages (CD163), dendritic cells (SWC3a) and myofibroblasts (FSP1). In particular, we demonstrated a significant PTX3-mediated activation of classical (C1q-mediated) and lectin (MBL-mediated) pathways of Complement. Interestingly, PTX3 deposits co-localized with activation of the terminal Complement complex (C5b-9) on endothelial cells, indicating that PTX3-mediated Complement activation occurred mainly at the renal vascular level. In conclusion, these data indicate that PTX3 might be a potential therapeutic target to prevent Complement-induced I/R injury.

mTOR inhibition improves mitochondria function/biogenesis and delays cardiovascular aging in kidney transplant recipients with chronic graft dysfunction.

CVD remains the major cause of mortality with graft functioning in Kidney transplant recipients (KTRs), with an estimated risk of CV events about 50-fold higher than in the general population. Many strategies have been considered to reduce the CV risk such as the use of mTOR inhibitors. We evaluate whether chronic mTOR inhibition might influence CV aging in KTRs studying the molecular mechanisms involved in this effect. We retrospectively analyzed 210 KTRs with stable graft function on therapy with CNI and mycophenolic acid (Group A, 105 pts.), or with CNI and mTORi (Everolimus, Group B, 105 pts.). The presence of mTOR inhibitor in immunosuppressive therapy was associated to increase serum levels of Klotho with concomitant reduction in FGF-23, with a significant decrease in left ventricular mass. In addition, KTRs with mTORi improved mitochondrial function/biogenesis in PBMC with more efficient oxidative phosphorylation, antioxidant capacity and glutathione peroxidase activity. Finally, group B KTRs presented reduced levels of inflammaging markers such as reduced serum pentraxin-3 and p21ink expression in PBMC. In conclusion, we demonstrated that mTOR inhibition in immunosuppressive protocols prevents the occurrence and signs of CV aging in KTRs.