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The newly developed sodium‐glucose cotransporter 2 inhibitors (SGLT2is) effectively modulate glucose metabolism in diabetes. Although clinical data suggest that SGLT2is (empagliflozin, dapagliflozin, ertugliflozin, canagliflozin, ipragliflozin) are safe and protect against renal and cardiovascular events, very little attention has been dedicated to the effects of these compounds on different electrolytes. As with other antidiabetic compounds, some effects on water and electrolytes balance have been documented. Although the natriuretic effect and osmotic diuresis are expected with SGLT2is, these compounds may also modulate urinary potassium, magnesium, phosphate, and calcium excretion. Notably, they have had no effect on plasma sodium levels and promoted only small increases in serum potassium and magnesium concentrations in clinical trials. Moreover, SGLT2is may induce an increase in serum phosphate, FGF‐23, and PTH; reduce 1,25‐dihydroxyvitamin D; and generate normal serum calcium. Some published and preliminary reports, as well as unconfirmed reports have suggested an association with bone fractures. Some homeostasis perturbations are transient, whereas others may persist, suggesting that the administration of SGLT2is may affect electrolyte balances in exposed subjects. Although current evidence supports their safety, additional efforts are needed to elucidate the long‐term impact of these compounds on chronic kidney disease, mineral metabolism, and bone health. Indeed, the limited follow‐up studies and the heterogeneity of the case‐mix of different randomized controlled trials preclude a definitive answer on the impact of these compounds on long‐term outcomes such as the risk of bone fracture. Here we review the current understanding of the mechanisms involved in electrolyte handling and the available data on the clinical implications of electrolytes and mineral metabolism perturbations induced by SGLT2i administration. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m2 and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.

Background Here, we isolated, expanded and functionally characterized regulatory T cells (Tregs) from patients with end stage kidney and liver disease, waiting for kidney/liver transplantation (KT/LT), with the aim to establish a suitable method to obtain large numbers of immunomodulatory cells for adoptive immunotherapy post-transplantation. Methods We first established a preclinical protocol for expansion/isolation of Tregs from peripheral blood of LT/KT patients. We then scaled up and optimized such protocol according to good manufacturing practice (GMP) to obtain high numbers of purified Tregs which were phenotypically and functionally characterized in vitro and in vivo in a xenogeneic acute graft-versus-host disease (aGVHD) mouse model. Specifically, immunodepressed mice (NOD-SCID-gamma KO mice) received human effector T cells with or without GMP-produced Tregs to prevent the onset of xenogeneic GVHD. Results Our small scale Treg isolation/expansion protocol generated functional Tregs. Interestingly, cryopreservation/thawing did not impair phenotype/function and DNA methylation pattern of FOXP3 gene of the expanded Tregs. Fully functional Tregs were also isolated/expanded from KT and LT patients according to GMP. In the mouse model, GMP Tregs from LT or KT patient proved to be safe and show a trend toward reduced lethality of acute GVHD. Conclusions These data demonstrate that expanded/thawed GMP-Tregs from patients with end-stage organ disease are fully functional in vitro. Moreover, their infusion is safe and results in a trend toward reduced lethality of acute GVHD in vivo, further supporting Tregs-based adoptive immunotherapy in solid organ transplantation. Electronic supplementary material The online version of this article (10.1186/s12967-019-2004-2) contains supplementary material, which is available to authorized users.

Dialysis is often considered slow, repetitive, and with programmed intervals. Patients often perceive it as time taken from their lives with a sense of ineluctability and emptiness, engendering a negative emotional and cognitive perception of the world and one's place in it. Today, it is possible to improve the quality of life of patients during hemodialysis using virtual reality (VR). This creation of a true multisensory experience may absorb the patient's perceptions during hemodialysis, improving his/her quality of life. An Italian multicenter, longitudinal experimental study will be conducted with a randomized, pre-post test design, with balanced allocation 1:1, in parallel groups with a control group in the standard care of patients diagnosed with chronic renal failure who are, undergoing hemodialysis treatment. A sample of 186 patients calculated with sample size (power = 80%, β = 0.2, α = 0.05) will be randomized into an experimental group exposed to VR, and a control group in standard care. The 2 groups will be studied over a period of 1 month, with 12 applications of VR and with measurements of the following outcomes: anxiety, fatigue, pruritus, arterial pressure, heart rate, respiration rate, and duration of the session at each hemodialysis session. This is the first international experimental protocol that examines the application of VR in patients undergoing hemodialysis. If the results show statistically and clinically significant differences, the VR could be an additional holistic intervention, which is evidence based, linked to the humanization of chronic, repetitive interventions, complementary to and synergistic with standard of care.

IL-17–producing CD4(+) (Th17) cells are pathogenically linked to autoimmunity and, specifically, to autoimmune kidney disease. The newly recognized immunoregulatory functions of erythropoietin (EPO) and its predominant intrarenal source suggested that EPO physiologically regulates Th17 cell differentiation, thereby serving as a barrier to development of autoimmune kidney disease. Using in vitro studies of human and murine cells and in vivo models, we show that EPO ligation of its receptor (EPO-R) on CD4(+) T cells directly inhibits Th17 cell generation and promotes transdifferentiation of Th17 cells into IL-17(–)FOXP3(+)CD4(+) T cells. Mechanistically, EPO/EPO-R ligation abrogates upregulation of SGK1 gene expression and blocks p38 activity to prevent SGK1 phosphorylation, thereby inhibiting RORC-mediated transcription of IL17 and IL23 receptor genes. In a murine model of Th17 cell–dependent aristolochic acid–induced interstitial kidney disease associated with reduced renal EPO production, we demonstrate that transgenic EPO overexpression or recombinant EPO (rEPO) administration limits Th17 cell formation and clinical/histological disease expression. EPO/EPO-R ligations on CD4(+) T cells abrogate, while absence of T cell–expressed EPO-R augments, Th17 cell induction and clinical/histological expression of pristane-induced glomerulonephritis (associated with decreased intrarenal EPO). rEPO prevents spontaneous glomerulonephritis and Th17 cell generation in MRL-lpr mice. Together, our findings indicate that EPO physiologically and therapeutically modulates Th17 cells to limit expression of Th17 cell–associated autoimmune kidney disease.

Background Extended criteria donors (ECD) are widely utilized due to organ shortage, but they may increase the risk of graft dysfunction and poorer outcomes. Hypothermic oxygenated perfusion (HOPE) is a recent organ preservation strategy for marginal kidney and liver grafts, allowing a redirect from anaerobic metabolism to aerobic metabolism under hypothermic conditions and protecting grafts from oxidative species–related damage. These mechanisms may improve graft function and survival. Objective With this study, we will evaluate the benefit of end-ischemic HOPE on ECD grafts for livers and kidneys as compared to static cold storage (SCS). The aim of the study is to demonstrate the ability of HOPE to improve graft function and postoperative outcomes of ECD kidney and liver recipients. Methods This is an open-label, single-center randomized clinical trial with the aim of comparing HOPE with SCS in ECD kidney and liver transplantation. In the study protocol, which has been approved by the ethics committee, 220 patients (110 liver recipients and 110 kidney recipients) will be enrolled. Livers and kidneys assigned to the HOPE group undergo machine perfusion with cold Belzer solution (4-10°C) and continuous oxygenation (partial pressure of oxygen of 500-600 mm Hg). In the control group, livers and kidneys undergoing SCS are steeped in Celsior solution and stored on ice. Using the same perfusion machine for both liver and kidney grafts, organs are perfused from the start of the back-table procedure until implantation, without increasing the cold ischemia time. For each group, we will evaluate clinical outcomes, graft function tests, histologic findings, perfusate, and the number of allocated organs. Publication of the results is expected to begin in 2021. Results Dynamic preservation methods for organs from high-risk donors should improve graft dysfunction after transplantation. To date, we have recruited 108 participants. The study is ongoing, and recruitment of participants will continue until January 2020. Conclusions The proposed preservation method should improve ECD graft function and consequently the postoperative patient outcomes. Trial Registration ClinicalTrials.gov NCT03837197; https://clinicaltrials.gov/ct2/show/NCT03837197 ; Archived by WebCite® at http://www.webcitation.org/76fSutT3R International Registered Report Identifier (IRRID) DERR1-10.2196/13922

BACKGROUND Extended criteria donors (ECD) are widely utilized due to organ shortage, but they may increase the risk of graft dysfunction and poorer outcomes. Hypothermic oxygenated perfusion (HOPE) is a recent organ preservation strategy for marginal kidney and liver grafts, allowing a redirect from anaerobic metabolism to aerobic metabolism under hypothermic conditions and protecting grafts from oxidative species–related damage. These mechanisms may improve graft function and survival. OBJECTIVE With this study, we will evaluate the benefit of end-ischemic HOPE on ECD grafts for livers and kidneys as compared to static cold storage (SCS). The aim of the study is to demonstrate the ability of HOPE to improve graft function and postoperative outcomes of ECD kidney and liver recipients. METHODS This is an open-label, single-center randomized clinical trial with the aim of comparing HOPE with SCS in ECD kidney and liver transplantation. In the study protocol, which has been approved by the ethics committee, 220 patients (110 liver recipients and 110 kidney recipients) will be enrolled. Livers and kidneys assigned to the HOPE group undergo machine perfusion with cold Belzer solution (4-10°C) and continuous oxygenation (partial pressure of oxygen of 500-600 mm Hg). In the control group, livers and kidneys undergoing SCS are steeped in Celsior solution and stored on ice. Using the same perfusion machine for both liver and kidney grafts, organs are perfused from the start of the back-table procedure until implantation, without increasing the cold ischemia time. For each group, we will evaluate clinical outcomes, graft function tests, histologic findings, perfusate, and the number of allocated organs. Publication of the results is expected to begin in 2021. RESULTS Dynamic preservation methods for organs from high-risk donors should improve graft dysfunction after transplantation. To date, we have recruited 108 participants. The study is ongoing, and recruitment of participants will continue until January 2020. CONCLUSIONS The proposed preservation method should improve ECD graft function and consequently the postoperative patient outcomes. CLINICALTRIAL ClinicalTrials.gov NCT03837197; https://clinicaltrials.gov/ct2/show/NCT03837197 ; Archived by WebCite® at http://www.webcitation.org/76fSutT3R INTERNATIONAL REGISTERED REPORT DERR1-10.2196/13922

In comparison with the international scenario, in Italy the penetration of several important scientific and technological innovations in the field of cardiovascular intervention appears to be inadequate both in terms of number of patients treated with respect to the actual need, and inhomogeneity between the different geographical areas of the country. One of the main institutional objectives of the Italian Society of Interventional Cardiology (SICI-GISE) is to develop a roadmap to guarantee homogeneous access throughout the whole national territory to treatments that are recommended by the major international guidelines. The present document focuses on four main areas of cardiovascular intervention: (i) transcatheter treatment of aortic valve stenosis, (ii) percutaneous mitral valve repair, (iii) prevention of cardioembolic stroke through percutaneous left atrial appendage occlusion in patients with non-valvular atrial fibrillation, (iv) optimization of coronary revascularization with the aid of the functional study of coronary lesions. The purpose of this document is to describe the clinical profile and the economic impact of the aforementioned methods, the current clinical, organizational and management barriers to treatment access in the national territory and the possible solutions for overcoming the aforementioned barriers.

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Patients affected by chronic kidney disease (CKD) or end-stage renal disease (ESRD) experience a huge cardiovascular risk and cardiovascular events represent the leading causes of death. Since traditional risk factors cannot fully explain such increased cardiovascular risk, interest in non-traditional risk factors, such as hyperhomocysteinemia and folic acid and vitamin B12 metabolism impairment, is growing. Although elevated homocysteine blood levels are often seen in patients with CKD and ESRD, whether hyperhomocysteinemia represents a reliable cardiovascular and mortality risk marker or a therapeutic target in this population is still unclear. In addition, folic acid and vitamin B12 could not only be mere cofactors in the homocysteine metabolism; they may have a direct action in determining tissue damage and cardiovascular risk. The purpose of this review was to highlight homocysteine, folic acid and vitamin B12 metabolism impairment in CKD and ESRD and to summarize available evidences on hyperhomocysteinemia, folic acid and vitamin B12 as cardiovascular risk markers, therapeutic target and risk factors for CKD progression.

Current guidelines encourage administering pneumococcal vaccine Prevnar-13 to patients with lupus, but whether such vaccinations affect disease severity is unclear. To address this issue, we treated 3-month-old MRL-lpr mice, that spontaneously develop a lupus-like syndrome, with Prevnar-13 or vehicle control. After 3 months, we quantified circulating anti-Pneumococcal polysaccharide capsule (PPS) antibodies and signs of disease severity, including albuminuria, renal histology and skin severity score. We also compared immunophenotypes and function of T and B cells from treated and untreated animals. Prevnar-13 elicited the formation of anti-pneumococcal IgM and IgG. Prevnar-13 treated animals showed reduced albuminuria, renal histological lesions, and milder dermatitis compared to vehicle-treated controls. Mitigated disease severity was associated with reduced and increased T follicular helper cells (TFH) and T follicular regulatory cells (TFR), respectively, in Prevnar-treated animals. T cells from Prevnar-13 vaccinated mice showed differential cytokine production after aCD3/aCD28 stimulation, with significantly decreased IL-17 and IL-4, and increased IL-10 production compared to non-vaccinated mice. In conclusion, pneumococcal vaccination elicits anti-pneumococcal antibody response and ameliorates disease severity in MRL-lpr mice, which associates with fewer TFH and increased TFR. Together, the data support use of Prevnar vaccination in individuals with SLE.

BACKGROUND: Chronic kidney disease (CKD) has become one of the most frequent non-infectious comorbidities in the aging HIV-infected population on long-standing combination antiretroviral therapy (cART). METHODS: We conducted a retrospective, cross-sectional study including HIV-infected adult patients attending our HIV outpatient clinic during the years 2017 and 2018 to assess prevalence and associated risk factors of CKD. Estimated glomerular filtration rate (eGFR) was measured by Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. CKD was diagnosed and classified according to the National Kidney Foundation guidelines. Logistic regression was employed to identify factors associated with CKD. RESULTS: We enrolled 2339 HIV-infected patients (91% were Caucasian) with a mean age of 45.3 years and a mean current CD4 lymphocyte count of 531 cells/mm3. CKD was diagnosed in 311 subjects (13.3%). Overall, 294 (12.6%) patients had albuminuria, 108 (4.6%) had eGFR

Quetiapine overdose, although rare, is mainly linked with tachycardia, QTc-interval prolongation, somnolence, coma, hyperglycemia, and eventually hepatotoxicity and myocarditis. Extracorporeal techniques for quetiapine removal might be helpful, but only a few cases are reported in the literature. We here describe the case of a 27-year-old healthy woman, admitted to our Intensive Care Unit after voluntary quetiapine intake and successfully treated with CytoSorb hemoperfusion in combination with continuous renal replacement therapy (CRRT), in order to accelerate quetiapine elimination. This is the first published experience about the potential application of hemoadsorption therapies, as CytoSorb sorbent, in large overdoses of quetiapine and this approach might be feasible to rapidly remove the substance from blood, stabilizing the patient condition.

Anabolic Androgenic Steroids (AAS) is an hormone family whose use has considerably increased among body-builders during the last decades. The AAS abuse, especially associated with other drugs or nutritional supplements and protein loads, may cause a variety of pathologies to several organs with a mechanism related to dosage, timing and substance. The kidney is the main metabolizer of these drugs and it can be acutely or chronically damaged with ESKD. The literature reports some cases of Focal Segmental Glomerulosclerosis (FSGS) in body-builders who abused of AAS. However, the link is not well understood and limited to some case-studies. In this paper, we report the case of a young body-builder who developed a FSGS collapsing variant with ESKD after prolonged abuse of AAS and a strongly hyperproteic diet and other dietary supplements. The patient underwent a genetic test because of the rapid and irreversibile onset of ESKD. The test showed a gene mutation of ACTN4, predisposing and causal of some genetic forms of FSGS. It was a very complex case, caused by several factors. The mutant protein of ACTN4 gene makes most vulnerable the cytoskeleton of the podocytes to external disturbances. That would explain why in those patients where the mutation has occurred, only those patients subject to "unfavorable environmental conditions", like the abuse of AAS, can develop a disease.

In the absence of a histhological diagnosis, persistent albuminuria is globally accepted as the main diagnostic criteria for diabetic kidney disease. In the present retrospective study, we evaluated data from an Italian cohort of 42 diabetic deceased donors (mainly type 2 diabetes). Using kidney biopsies obtained at time of donation to evaluate single or double allocation based on Karpinski score, we determined the prevalence of histological lesions attributable to diabetes. All 42 donors presented with normoalbuminuria and an estimated Glomerular Filtration Rate (CKD-EPI) > 60 ml/min/1.73m2. Of the 36 patients with available kidney biopsy, one was non interpretable and 32 had histopathological lesions consistent with diabetic kidney disease and encompassing all histological classes. Thus, we found a relatively high proportion of histologically proven diabetic kidney disease that was clinically undiagnosed as none of the patient had significant albuminuria and eGFR

The authors regret that 2 investigators were not included in the 311 Study Group. Members of the 311 Study Group are listed in the Appendix. The authors would like to apologize for any inconvenience caused.

Poor vitamin D status is common in patients with impaired renal function and represents one main component of the complex scenario of chronic kidney disease–mineral and bone disorder (CKD–MBD). Therapeutic and dietary efforts to limit the consequences of uremia-associated vitamin D deficiency are a current hot topic for researchers and clinicians in the nephrology area. Evidence indicates that the low levels of vitamin D in patients with CKD stage above 4 (GFR < 15 mL/min) have a multifactorial origin, mainly related to uremic malnutrition, namely impaired gastrointestinal absorption, dietary restrictions (low-protein and low-phosphate diets), and proteinuria. This condition is further worsened by the compromised response of CKD patients to high-dose cholecalciferol supplementation due to the defective activation of renal hydroxylation of vitamin D. Currently, the literature lacks large and interventional studies on the so-called non-calcemic activities of vitamin D and, above all, the modulation of renal and cardiovascular functions and immune response. Here, we review the current state of the art of the benefits of supplementation with native vitamin D in various clinical settings of nephrological interest: CKD, dialysis, and renal transplant, with a special focus on the effects on bone homeostasis and cardiovascular outcomes.

An amendment to this paper has been published and can be accessed via the original article.

The publisher regrets that the members of the 311 Study Group were not included as collaborative authors. Members of the 311 Study Group are listed in the Appendix. The publisher would like to apologize for any inconvenience caused.

Introduction: Infections represent a major complication after renal transplant with an important impact on allograft survival and outcome. Polyomaviruses (PyVs), a group of small and circular dsDNA viruses, mediate a broad spectrum of diseases in immune-compromised patients. NF-jB (nuclear factor kappalight-chain-enhancer of activated B cells) is a key regulator of immune and inflammatory responses and the -94ins/delATTG (rs28362491) polymorphism in the gene promoter has been widely investigated for clinical associations. To date, rs28362491 has been shown to influence the susceptibility to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and recently renal transplant rejection. Materials and Methods: We developed a high throughput mass spectrometry (MS)-based method to detect rs28362491 and 18 Py vs. types. Primer pairs of MS assay were designed within the specific large T antigen genes. Viral and human DNAs were extracted from blood samples of 43 kidney transplant recipients, before and after transplantation. Results: We analysed the correlation among Py vs. infections, rs28362491 genotype and post-transplant follow up. Five out of the 18 viral types tested were found in the specimens analysed: BKV, JCV, Merkel cell PyV, Human PyV6 and SV12. In our cohort, 14 patients showed SV12 infection: 10 cases were -94ins/-94ins, 4 were -94ins/-94del. All the patients with the NF-kB-94del/- 94del genotype were characterized by the absence of SV12 strain. No correlation between genotype and viral infection was observed for the other viral types. Conclusions: Our MS assay improved the Py vs. typing and allowed to drive towards the identification of novel biomarkers for the infective management of transplanted patients. The genetic background might modulate the viral infection susceptibility in renal transplant recipients.

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Non applicabile

The “weekend (WE) effect” defines the association between WE hospital admissions and higher rate of mortality. The aim of this study was to evaluate the relationship between WE effect and renal transplant recipients (RTRs) using the database of the Emilia-Romagna region (ERR), Italy. We included ERR admissions of RTRs ( International Classification of Diseases, Ninth Revision, Clinical Modification [ ICD-9-CM] code V420) between 2000 and 2013. In-hospital mortality, admissions due to cardiovascular events (CVEs), and the Elixhauser score were evaluated on the basis of ICD-9-CM codification. Out of 9063 hospital admissions related to 3648 RTRs (mean age 53 ± 13 years, 62.9% male), 1491 (16.5%) were recorded during the WE. During the follow-up period, 1581 (17.4%) patients deceased and 366 (4%) had CVEs. Length of hospital stay (LOS) was 9.7 ± 12.1 days. Logistic regression analysis showed that only LOS was independently associated with WE admissions (odds ratio: 1594, confidence interval: 1.385-1.833; P < .001). Renal transplant recipients are not exposed to higher risk of adverse outcome during WE admissions. However, WE admissions were characterized by an increased duration of hospitalization.

Parathyroid hormone (PTH) determination is essential for the diagnosis of renal osteodystrophy, but differences between the laboratory assays can lead to different therapies. This study compared the new Tosoh ST AIA-Pack Intact PTH assay (Tosoh Bioscience, San Francisco, CA, USA) with the Elecsys Intact PTH Roche assay (Roche Diagnostics GmbH, Mannheim, Germany), currently considered the gold standard. Nineteen chronic stable hemodialysis patients were enrolled to check PTH levels with the two assays. Median age was 71 years (range 26-84), M/F = 10/9. Blood samples were taken before the start of the same midweek dialysis session. Two blood vacuettes were collected and immediately transported to the central laboratory. The median PTH value was 268 (range 35-901 pg/dL) with the AIA-Pack versus 184 (range 39-552 pg/dL) with Elecsys. The Wilcoxon test showed a significant difference between the two methods (P 300 pg/dL four patients were detected with AIA-Pack (21.0%) versus six patients with Elecsys (31.6%). The two assays showed no differences for each of the three PTH ranges considered. The two PTH assays tested are different and the attending physician should be aware of the differences when patients change their dialysis facility.

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The sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a relatively new class of antidiabetic drugs that, in addition to emerging as an effective hypoglycemic treatment, have been shown to improve, in several trials, both renal and cardiovascular outcomes. In consideration of the renal site of action and the associated osmotic diuresis, a negative sodium balance has been postulated during SGLT2i administration. Although it is presumable that sodium and water depletion may contribute to some positive actions of SGLT2i, evidence is far from being conclusive and the real physiologic effects of SGLT2i on sodium remain largely unknown. Indeed, no study has yet investigated how SGLT2i change sodium balance in the long term and especially the pathways through which the natriuretic effect is expressed. Furthermore, recently, several experimental studies have identified different pathways, not directly linked to tubular sodium handling, which could contribute to the renal and cardiovascular benefits associated with SGLT2i. These compounds may also modulate urinary chloride, potassium, magnesium, phosphate, and calcium excretion. Some changes in electrolyte homeostasis are transient, whereas others may persist, suggesting that the administration of SGLT2i may affect mineral and electrolyte balances in exposed subjects. This paper will review the evidence of SGLT2i action on sodium transporters, their off-target effects and their potential role on kidney protection as well as their influence on electrolytes and mineral homeostasis.

Ifosfamide (IFO) is a nitrogen mustard alkylating agent, commonly used in the treatment of pediatric solid tumors, including Ewing tumors, osteosarcoma, rhabdomyosarcoma, non-Hodgkin’s lymphoma, as well as acute lymphoblastic leukemia that can cause both acute and chronic kidney injury, with a wide spectrum of clinical manifestations up to end-stage renal disease requiring dialysis. We report two cases of young patients with diagnosis of Ewing’s sarcoma of the chest and ulnar osteosarcoma treated with polychemotherapy including IFO who developed kidney injury. Both patients had IFO-induced karyomegalic interstitial nephritis (KIN) with two different clinical presentations and histological pictures. One patient experienced acute kidney injury a few weeks following IFO chemotherapy, the other 6 months later. the histological examinations revealed interstitial nephritis and karyomegalic cells in both cases. One of them was treated with steroids until remission, the other one with stabilization of kidney function. IFO-induced KIN is a complication of IFO treatment that can be treated with steroids. In general, kidney damage is asymptomatic and renal biopsy is an essential tool in IFO-treated patients to achieve a correct diagnosis and avoid empirical attempts with inappropriate and potentially harmful drugs. IFO tubular toxicity is known but there are other factors, mainly genetic polymorphisms influencing drug metabolism that might increase the susceptibility to kidney damage. The two cases of IFO-induced KIN described here showed different presentations and outcomes.

Chemotherapy and extracorporeal treatment reduce serum free light chains (FLCs) allowing the recovery of acute kidney injury (AKI) caused by myeloma cast nephropathy (MCN). We report the first case of recovery from AKI in a patient with MCN who underwent the removal of FLCs using the PEPA filter, with an undisclosed cut-off, combined with chemotherapy for multiple myeloma (MM).

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor is the cornerstone of the pharmacologic management of patients with acute coronary syndrome (ACS) and/or receiving coronary stents. Long-term (1 year) DAPT may further reduce the risk of stent thrombosis after percutaneous coronary intervention (PCI) and may decrease the occurrence of non-stent-related ischemic events in patients with ACS. Nevertheless, compared with aspirin alone, extended use of aspirin plus a P2Y12 receptor inhibitor may increase the risk of bleeding events that have been strongly linked to adverse outcomes including recurrent ischemia, repeat hospitalization, and death. Over the last years, multiple randomized clinical trials have been published comparing duration of DAPT after PCI and in ACS patients investigating either a shorter or prolonged DAPT regimen.Although current European Society of Cardiology guidelines provide backup to individualize treatment, it seems difficult to identify the ideal patient profile who could safely reduce or prolong DAPT duration in daily clinical practice. The aim of this consensus document is to review the contemporary literature on optimal DAPT duration and to guide clinicians in tailoring antiplatelet strategies in patients undergoing PCI or presenting with ACS.

Bacterial meningitis and septicemia are invasive bacterial diseases, representing a significant cause of morbidity and mortality worldwide. Both conditions are characterized by an impressive inflammatory response, resulting rapidly in cerebral edema, infarction, hydrocephalus, and septic shock with multiple organ failure. Despite advances in critical care, outcome and prognosis remain critical. Available adjunctive treatments to control the inflammatory response have shown encouraging results in the evolution of patients with sepsis and systemic inflammation, but meningococcal or pneumococcal infection has not been investigated. We herein report five patients with similar critical pathological conditions, characterized by pneumococcal or meningococcal sepsis and treated with hemoadsorption for cytokine removal. All patients showed a progressive stabilization in hemodynamics along with a rapid and marked reduction of catecholamine dosages, a stabilization in metabolic disorders, and less-than-expected loss of extremities. Therapy proved to be safe and well tolerated. From this first experience, extracorporeal cytokine removal seems to be a valid and safe therapy in the management of meningococcal and pneumococcal diseases and may contribute to the patient stabilization and prevention of severe sequelae. Further studies are required to confirm efficacy in a larger context.

BACKGROUND: Both amylase and resistive index (RI) are routinely measured after kidney transplant and proposed as markers of delayed graft function (DGF). MATERIAL AND METHODS: This retrospective cross-sectional study analyzed amylase and RI in 269 renal transplant recipients before and after transplantation, and at discharge. An increase above 20% of total amylase with/without RI>0.7 were evaluated as prognostic markers of DGF, hospitalization length and risk of rejection. RESULTS: Serum amylase increase >20% was found in 103/269 (38.3%) patients who showed DGF (45.6% vs. 25.3%, p=0.001) and had lower estimated glomerular filtration rate compared to those with an amylase increase 20% and RI>0.7 was associated with higher DGF occurrence (65% vs. 24%, p20% and RI>0.7 might require closer monitoring to diagnose DGF early and modify the therapeutic approach accordingly.

Kidney transplant is known to be the first choice therapy for end-stage chronic kidney disease, also for its positive effects on kidney transplant recipients cardiovascular morbidity and mortality. Several evidences evaluated the morphological changes in the left ventricle before and after transplantation, demonstrating a positive effect of at least partial regression of left ventricular hypertrophy (LVH) in kidney transplant recipients. Atrial pathology is likewise important in determining kidney transplant recipients outcomes. In this issue, Regale et al. focused on atrial morphological changes after kidney transplant and found retrospectively that left atrium dilatation tends to progress over time, but the minority of patients that present a reduction after transplant in atrial diameter has a benefit in terms of mortality. These new acquisitions focus on atrial pathology that, probably also thanks to the contribution of circulating mediators such as natriuretic peptides, can significantly influence morbidity and mortality after transplant. The evaluation of the of natriuretic peptide changes before and after transplant and the use of new classes of drugs acting on the natriuretic peptides system are new interesting research areas.

AIM To evaluate the effect of a 12-mo supervised aerobic and resistance training, on renal function and exercise capacity compared to usual care recommendations. METHODS Ninety-nine kidney transplant recipients (KTRs) were assigned to interventional exercise (Group A; n = 52) and a usual care cohort (Group B; n = 47). Blood and urine chemistry, exercise capacity, muscular strength, anthropometric measures and health-related quality of life (HRQoL) were assessed at baseline, and after 6 and 12 mo. Group A underwent a supervised training three times per week for 12 mo. Group B received only general recommendations about home-based physical activities. RESULTS Eighty-five KTRs completed the study (Group A, n = 44; Group B, n = 41). After 12 mo, renal function remained stable in both groups. Group A significantly increased maximum workload (+13 W, P = 0.0003), V’O2 peak (+3.1 mL/kg per minute, P = 0.0099), muscular strength in plantar flexor (+12 kg, P = 0.0368), height in the countermovement jump (+1.9 cm, P = 0.0293) and decreased in Body Mass Index (-0.5 kg/m2, P = 0.0013). HRQoL significantly improved in physical function (P = 0.0019), physical-role limitations (P = 0.0321) and social functioning scales (P = 0.0346). No improvements were found in Group B. CONCLUSION Twelve-month of supervised aerobic and resistance training improves the physiological variables related to physical fitness and cardiovascular risks without consequences on renal function. Recommendations alone are not sufficient to induce changes in exercise capacity of KTRs. Our study is an example of collaborative working between transplant centres, sports medicine and exercise facilities.

The incidence of the multiple organ dysfunction syndrome (MODS) is rapidly increasing in intensive care units (ICU). It usually combines with sepsis and is the most frequent cause of death in the ICU patients. The nature of the ICU patients has changed in the last years. It includes a variety of patients with severe cases due to major surgical interventions, trauma, hemodynamic instability, sepsis, and so on but also older people than previous times. All these situations can easily lead to MODS. In the prior years, the only available and efficient therapy was renal replacement therapy (RRT) for treating acute renal failure, but the development of technology also gives us devices to support the other systems. The adequacy of any artificial organ support is evaluated by how closely it mimics the flexibility and efficacy of the organ systems it seeks to substitute or support. In a sequence of events, such as that created by sepsis and MODS, all these criteria should be applied at the same time but for different organs and different tasks. RRT and especially continuous renal replacement therapies (CRRT) allowed extracorporeal treatment in critically ill patients with hyper catabolism and fluid overload with excellent hemodynamic stability. New techniques in CRRT as high volume hemofiltration have been applied in septic patients with very promising results. In the light of these observations, a new thought arises: Can extracorporeal blood purification have a positive impact on different organ systems? A possible answer might come from the simple observation that all organs share one aspect in common: contact with blood. All extracorporeal therapies also have one aspect in common: treatment of blood. Based on these observations and knowledge of the molecular biology of sepsis, a "humoral" theory of MODS makes pathophysiological sense and its consequence triggers the need to consider extracorporeal therapies as multiple organ support therapies and not just as single organ support.

Tubulo-interstitial nephritis (TIN) in patients affected by inflammatory bowel disease, both ulcerative colitis and Crohn’s disease, is usually considered as drug-associated to aminosalicylate. We report a rare case of granulomatous active tubulo-interstitial nephritis in a young patient with a recent diagnosis of ulcerative colitis naïve to aminosalicylate treatment. The patient has been successfully treated with steroids administration. Our purpose is to sensitize that TIN should always to be considered in differential diagnosis an extra-intestinal manifestation of bowel disease.

The incidence of the multiple organ dysfunction syndrome (MODS) is rapidly increasing in intensive care units (ICU). It usually combines with sepsis and is the most frequent cause of death in the ICU patients. The nature of the ICU patients has changed in the last years. It includes a variety of patients with severe cases due to major surgical interventions, trauma, hemodynamic instability, sepsis, and so on but also older people than previous times. All these situations can easily lead to MODS. In the prior years, the only available and efficient therapy was renal replacement therapy (RRT) for treating acute renal failure, but the development of technology also gives us devices to support the other systems. The adequacy of any artificial organ support is evaluated by how closely it mimics the flexibility and efficacy of the organ systems it seeks to substitute or support. In a sequence of events, such as that created by sepsis and MODS, all these criteria should be applied at the same time but for different organs and different tasks. RRT and especially continuous renal replacement therapies (CRRT) allowed extracorporeal treatment in critically ill patients with hyper catabolism and fluid overload with excellent hemodynamic stability. New techniques in CRRT as high volume hemofiltration have been applied in septic patients with very promising results. In the light of these observations, a new thought arises: Can extracorporeal blood purification have a positive impact on different organ systems? A possible answer might come from the simple observation that all organs share one aspect in common: contact with blood. All extracorporeal therapies also have one aspect in common: treatment of blood. Based on these observations and knowledge of the molecular biology of sepsis, a "humoral" theory of MODS makes pathophysiological sense and its consequence triggers the need to consider extracorporeal therapies as multiple organ support therapies and not just as single organ support.

The aging kidney is more susceptible to injury. Thus, it is not surprising that acute kidney injury (AKI) is a disorder with a relative high incidence in the elderly population, especially those with critical illness. Given the comorbid conditions common in the geriatric population as well as the increase in exposure to various nephrotoxic insults, it is likely that the incidence of AKI will grow in the coming decades. Thus, it is critical to gain an understanding of the cellular and molecular pathways operative in increasing the susceptibility to AKI with an aim to design therapies that will mitigate the risk of AKI. In the meanwhile, meticulous attention to preventative strategic is critical. When AKI does occur and renal replacement therapy is needed, individual decision making is required and should not be based on age alone.

Coupled plasma filtration adsorption (CPFA) is a detoxification system that combines a plasma adsorption circuit with a continuous renal replacement therapy. The circuit consists of a plasma filter, a resin/adsorbent cartridge and a haemofilter. It differs from many other types of extracorporeal therapies in that the upper part of the circuit can be considered a “closed loop”. In this manner, the plasma separated by the plasma filter passes through an adsorbent cartridge containing a resin with high affinity to many cytokines, mediators and toxins/poisons. After passing through the cartridge, the purified plasma is returned to the patient. The second part of the circuit, the haemofilter, can then be used to remove small toxins that are not adsorbed by the resin or to modulate the patient hematic volume. Although more complex, the use of a plasma-separation step prior to the passage through the resin cartridge offers advantages over adsorption by haemoperfusion. The plasma passes through the resin cartridge with a lower velocity than the blood flow, and this allows better contact time for the toxins with the resin, and more thorough penetration into the resin pores. The adsorption of many toxins is highly dependent on a factor expressed as linear velocity. In addition, the plasma does not contain cells or a very limited number of platelets, allowing less potential activation upon contact with the resin. Although the technique was originally developed for the treatment of sepsis and septic shock, there are many additional applications where there can be an advantage of having access to larger molecular weight toxins (compared to haemofiltration) and avoiding the loss of important physiologic substances such as albumin. Some of these new applications, in patients with or without acute kidney injury, include liver failure, rhabdomyolysis, severe autoimmune exacerbations and poisonings. In this article, we discuss some of the basic principles involved in sorbent technology, and how these may contribute to treatment efficacy, review the actual experiences with CPFA and finally discuss the results of recent human studies and their implications. Video Journal Club “Cappuccino with Claudio Ronco” at http://www.karger.com/?doi=490234.

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Spontaneous urea dissociation in water solution is a prominent source of protein carbamylation in our body. Protein carbamylation is a well-known phenomenon since early seventies. Some years ago, much interest in the diagnostic power of carbamylated protein arouse. Recently the target of the researches focused on its potential cardiovascular pathogenicity. Some authors claimed that this could be a reason for higher cardiovascular mortality in uremic patients. Nutritional therapy, amino acids supplementation and intensive dialysis regimen are some of the therapeutic tools tested to lower the carbamylation burst in this population.

BACKGROUND: The objective of this study was to compare perioperative and early oncological outcomes of a matched cohort of patients who underwent retroperitoneal robot-assisted partial nephrectomy (RP-RAPN) and open partial nephrectomy (OPN) for clinically localized renal tumors. PATIENTS AND METHODS: We performed a retrospective analysis of patients who underwent RP-RAPN and OPN treated at 2 referral centers from January 2011 to December 2015. We focused on the following postoperative outcomes: warm ischemia time (WIT), operative time, blood loss, intra- and postoperative complications, estimated glomerular filtration rate (eGFR), hospital stay, and positive surgical margins. Because of inherent differences between patients in terms of baseline and disease characteristics, we relied on a propensity score-matched analysis to adjust for these differences. RESULTS: Globally, 104 patients were retrospectively evaluated and compared (52 matched individuals). RP-RAPN and OPN groups were comparable in terms of median age, body mass index, Charlson Comorbidity Index, clinical tumor size, preoperative aspects and dimensions used for anatomic classification and radius, exophyic/endophytic, nearness, anterior/posterior location score. Overall median operative time and WIT were significantly higher in the RP-RAPN group compared with the OPN group (P < .001). Intraoperative (3.8% vs. 0%) and postoperative (21.2% vs. 7.7%) complication rates were higher in the OPN group (P < .001). No statistically significant differences in postoperative eGFR were found. Median length of stay was significantly shorter in the RP-RAPN group (3 vs. 5 days; P < .001). The incidence of positive surgical margins was comparable (3.8%). Trifecta was reached in 82.6% after RP-RAPN and 71.1% after OPN (P = .002). CONCLUSION: Retroperitoneal robot-assisted partial nephrectomy offered promising perioperative, early oncological, and functional outcomes, reinforcing the role of robotics as an alternative to open approach for partial nephrectomy.

none 11 no Background: Sodium prescription in patients with intradialytic hypotension remains a challenge for the attending nephrologist, as it increases dialysate conductivity in hypotension-prone patients, thereby adding to dietary sodium levels. Methods: New sodium prescription strategies are now available, including the use of a mathematical model to compute the sodium mass to be removed during dialysis as a physiological controller. Results: This review describes the sodium load of patients with end-stage renal disease on chronic hemodialysis (HD) and discusses 2 strategies to remove excess sodium in patients prone to intradialytic hypotension, namely, Profiled HD and the hemodiafiltration Aequilibrium System. Conclusion: The Profiled HD and Aequilibrium System trial both proved effective in counteracting intradialytic hypotension. mixed Donati, Gabriele; Ursino, Mauro; Spazzoli, Alessandra; Natali, Nicolã²; Schillaci, Roberto; Conte, Diletta; Angeletti, Andrea; Croci Chiocchini, Anna Laura; Capelli, Irene; Baraldi, Olga; La Manna, Gaetano Donati, Gabriele; Ursino, Mauro; Spazzoli, Alessandra; Natali, Nicolã²; Schillaci, Roberto; Conte, Diletta; Angeletti, Andrea; Croci Chiocchini, Anna Laura; Capelli, Irene; Baraldi, Olga; La Manna, Gaetano

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