The complement system's overactivation typically occurs during transplantation and in the post-transplant phase. Indeed, donor and recipient characteristics, various drugs (mTOR inhibitors, CNIs), viral infections and ischemia-reperfusion injury contribute to different levels of complement activation in this particular setting. Overactivation of the complement system can expose some patients to developed thrombotic microangiopathy (TMA), especially in the case of genetic background predisposition. The Post-transplant de novo TMA incidence ranges from 5% to 20%, representing an open challenge for clinicians. Our study aimed to determine whether patients who developed post-transplant TMA exhibit complement gene variants and whether these variants correlate with the phenotype and the graft outcome. We evaluated 7 patients who developed de novo post-transplant TMA between 2022 and 2023. Complement genes variations were screened by Next Generation Sequencing , and Multiplex Ligation Probe Amplification (MLPA). Clinical and biochemical data at the time of onset (T0) and during the follow-up (T1) (median time of 1 year) were collected from patients' records. Correlation between genetic variation and clinical presentation were evaluated. In the studied population, 71.4% were female and 28.6% were male, with an average age at transplantation of 49 years; 6/7 patients received transplants from deceased donors. Thrombotic microangiopathy (TMA) developed, on average, after a duration of 61.2 months post-transplant. All patients received the same immunosuppressive therapy (MMF + FK + steroids). Genetic analysis revealed that all patients who developed de novo TMA post-transplant exhibited a delCFHR3-1, with 6 of these being heterozygous and 1 homozygous. Additionally, patient 7 was found to carry a heterozygous deletion affecting SCR 14 of CFH (NM_000186.4; c.2422_2427del). None of the patients exhibited anti-CFH antibodies, which are associated with the presence of the deletion variant in the literature. Serological tests for CH50 and AP50 were within normal ranges, confirming their limited utility in the diagnostic phase, as TMA is a condition characterised by complement dysregulation at the endothelial level rather than in serum. Forty-two percent of patients experienced graft loss. Among these, only one patient had received anti-C5 therapy. The remaining four patients achieved complete resolution of TMA. Of these, one received a C5 inhibitor during the acute phase, while another was treated with plasma therapy. Additionally, one patient in this group exhibited a form of thrombotic microangiopathy (TMA) that appeared to be triggered by treatment with fluoroquinolones. In this last case the complete resolution of the haematological condition and organ damage was observed upon discontinuation of the offending agent. The delCFHR3-1 is associated with post-transplant TMA in our study cohort. Although the deletion is regarded as a polymorphic variant, our research suggests the utility of further exploring the role of this variant in complex scenarios such as transplantation, where complement activation is elevated. Further studies are warranted to elucidate the underlying mechanisms and therapeutic implications.

Abstract Peripheral blood mononuclear leukocytes (PBL) of uremic patients (u-PBL) prematurely die by apoptosis, thus sustaining leukopenia and immune dysfunction. Uremic retention solutes have been alleged to playing a causal role in this immune cell defect. However, both the molecular identity and pro-apoptotic mechanism of these solutes remain poorly characterized. In this study, we prepared a fraction of the uremic plasma (u-Pl) rich in these solutes (proteinaceous material with molecular weight > 50 kDa, namely the uremic-high MW fraction or u-HMW) that was used to demonstrate their pro-apoptotic activity in u-PBL. Such a detrimental activity was also confirmed in THP-1 and K562 mononuclear cells in association with increased cellular generation and secretion of H2O2, and JNK/cJun-dependent apoptotic signaling downstream of the endoplasmic reticulum stress response protein IRE1-α. The u-HMW also induced autophagy in THP-1 mononuclear leukocytes. These alterations of u-PBL proteostasis were associated with the presence in the proteome of these cells, but not of control PBL, of the main proteins and protein decoration targets (assessed by 2,4-diphenylhydrazine derivatization) of u-Pl and thus of u-HMW, namely albumin, transferrin and fibrinogen. These findings demonstrate that large solutes induce apoptosis in u-PBL leading to abnormal plasma protein endocytosis and terminal alteration of cellular proteostasis mechanisms. We define this response of PBL to large uremic solutes as the “immuno-proteostasis response” (IPR) of uremia.

INTRODUCTION:Uremic retention solutes have been alleged to induce the apoptotic program of different cell types, including peripheral blood mononuclear leukocytes (PBL), which may contribute to uremic leukopenia and immune dysfunction.METHODS:The molecular effects of these solutes were investigated in uremic PBL (u-PBL) and mononuclear cell lines (THP-1 and K562) exposed to the high molecular weight fraction of uremic plasma (u-HMW) prepared by in vitro ultrafiltration with 50 kDa cut-off microconcentrators.RESULTS:u-PBL show reduced cell viability and increased apoptotic death compared to healthy control PBL (c-PBL). u-HMW induce apoptosis both in u-PBL and c-PBL, as well as in mononuclear cell lines, also stimulating cellular H2O2 formation and secretion, IRE1-α-mediated endoplasmic reticulum stress signaling, and JNK/cJun pathway activation. Also, u-HMW induce autophagy in THP-1 monocytes. u-PBL were characterized by the presence in their cellular proteome of the main proteins and carbonylation targets of u-HMW, namely albumin, transferrin, and fibrinogen, and by the increased expression of receptor for advanced glycation end-products, a scavenger receptor with promiscuous ligand binding properties involved in leukocyte activation and endocytosis.CONCLUSIONS:Large uremic solutes induce abnormal endocytosis and terminal alteration of cellular proteostasis mechanisms in PBL, including UPR/ER stress response and autophagy, ultimately activating the JNK-mediated apoptotic signaling of these cells. These findings describe the suicidal role of immune cells in facing systemic proteostasis alterations of kidney disease patients, a process that we define as the immuno-proteostasis response of uremia.

Patients with severe COVID-19 both seroconvert earlier and develop higher concentrations of SARS- CoV-2-specific IgG than patients with mild symptoms. In this retrospective study we considered different categories of patients defined as "vulnerable" because affected by other pathologies, such as patients with genetic and cardiovascular diseases; patients with autoimmune dermatological dis- ease; kidney and lung transplant patients, and pregnant women because the prevalence of Covid-19 infection during pregnancy is not known. This study was performed at IRCCS San Matteo Hospital in Pavia, North Italy, a zone considered at high risk during the COVID-19 pandemic from June to December 2020. None of the positive screened patients had symptoms of COVID-19 infection at the time of inclusion in this study.

We propose a new organ-conditioning strategy based on mesenchymal stromal cell (MSCs)/extracellular vesicle (EVs) delivery during hypothermic perfusion. MSCs/EVs marker CD73 is present on renal proximal tubular cells, and it protects against renal ischemia-reperfusion injury by converting adenosine monophosphate into adenosine (ADO). In this study, after checking if CD73-silenced EVs (EVsi) would impact in vitro tubular-cell proliferation, we perfused kidneys of a rat model of donation after circulatory death, with Belzer solution (BS) alone, BS supplemented with MSCs, EVs, or EVsi. The ADO and ATP levels were measured in the effluents and tissues. Global renal ischemic damage score (GRS), and tubular cell proliferation index (IPT) were evaluated in the tissue. EVsi did not induce cell proliferation in vitro. Ex vivo kidneys perfused with BS or BS + EVsi showed the worst GRS and higher effluent ADO levels than the MSC- and EV-perfused kidneys. In the EV-perfused kidneys, the tissue and effluent ATP levels and IPT were the highest, but not if CD73 was silenced. Tissue ATP content was positively correlated with tissue ADO content and negatively correlated with effluent ADO level in all groups. In conclusion, kidney conditioning with EVs protects against ischemic damage by activating the CD73/ADO system.

Donation after circulatory death (DCD) allows expansion of the donor pool. We report on 11 years of Italian experience by comparing the outcome of grafts from DCD and extracorporeal membrane oxygenation (ECMO) prior to death donation (EPD), a new donor category. We studied 58 kidney recipients from DCD or EPD and collected donor/recipient clinical characteristics. Primary non function (PNF) and delayed graft function (DGF) rates, dialysis need, hospitalization duration, and patient and graft survival rates were compared. The estimated glomerular filtration rate (eGFR) was measured throughout the follow-up. Better clinical outcomes were achieved with EPD than with DCD despite similar graft and patient survival rates The total warm ischemia time (WIT) was longer in the DCD group than in the EPD group. Pure WIT was the highest in the class II group. The DGF rate was higher in the DCD group than in the EPD group. PNF rate was similar in the groups. Dialysis need was the greatest and hospitalization the longest in the class II DCD group. eGFR was lower in the class II DCD group than in the EPD group. Our results indicate good clinical outcomes of kidney transplants from DCD despite the long "no-touch period" and show that ECMO in the procurement phase improves graft outcome, suggesting EPD as a source for pool expansion.

The poor availability of kidney for transplantation has led to a search for new strategies to increase the donor pool. The main option is the use of organs from extended criteria donors. We evaluated the effects of hypothermic oxygenated perfusion (HOPE) with and without extracellular vesicles (EV) derived from mesenchymal stromal cells on ischemic/reperfusion injury of marginal kidneys unsuitable for transplantation. For normothermic reperfusion (NR), we used artificial blood as a substitute for red blood cells. We evaluated the global renal ischemic dam-age score (GRS), analyzed the renal ultrastructure (RU), cytochrome c oxidase (COX) IV-1 (a mitochondrial distress marker), and caspase-3 renal expression, the tubular cell proliferation index, hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) tissue levels, and effluent lactate and glucose levels. HOPE+EV kidneys had lower GRS and better RU, higher COX IV-1 expression and HGF and VEGF levels and lower caspase-3 expression than HOPE kidneys. During NR, HOPE+EV renal effluent had lower lactate release and higher glucose levels than HOPE renal effluent, suggesting that the gluconeogenesis system in HOPE+EV group was pre-served. In conclusion, EV delivery during HOPE can be considered a new organ preservation strategy for increasing the donor pool and improving transplant outcome.

Introduction: Acute kidney injury (AKI) is a common complication among hospitalized patients, potentially affecting short- and long-term clinical outcomes. In this retrospective study, we evaluated renal outcomes in noncritically ill patients who required acute hemodialysis (HD) because of an AKI episode occurring during hospitalization. Methods: Sixty-three hemodynamically stable patients with AKI undergoing acute intermittent HD were included. Kidney function was evaluated at baseline control (pre-AKI), at AKI diagnosis and during the follow-up. According to serum creatinine and the estimated glomerular filtration rate (eGFR), we defined three clinical conditions: renal recovery, different stages of acute kidney disease (AKD), and chronic kidney disease (CKD). Results: Among the 63 patients evaluated, 34 patients (54%) had a history of CKD. Six patients (10%) presented early full renal recovery. HD treatment was stopped in 38 patients (60%), while 25 patients (40%) required maintenance HD. Dialysis-independent patients presented lower comorbidity and higher baseline eGFR and delta creatinine, compared to dialysis-dependent patients. Baseline CKD, previous AKI episodes, and parenchymal causes of AKI were associated with a significant risk of dialysis dependence. At 1-month control, 15 patients (39%) presented AKD stage 0, 6 patients (16%) AKD stage 1, and 17 patients (44%) AKD stage 2-3. At 3-month control, 29 out of 38 patients recovering from AKI (76%) presented CKD. AKD stage was significantly correlated with the risk of CKD development, which, resulted higher in patients with lower baseline eGFR. Conclusions: AKI might represent a risk factor for the development of chronic kidney damage, even in noncritically ill patients.

Background Hyponatremia is the most common electrolyte disorder and it has been associated with increased mortality. Aims This study evaluated hyponatremia as a prognostic factor for severity and mortality. Methods We compared the prevalence of hyponatremia among patients who died during the year 2017 (from 1 January 2017 to 31 December 2017) with the prevalence of hyponatremia among subgroups of patients, i.e. outpatients, patients hospitalized for more than 2 days and patients admitted in the intensive care unit (ICU). We also described the mortality rate and the prevalence of comorbidities among hyponatremic patients, according to hyponatremia degree (slight, moderate, severe), basal characteristics, comorbidities and their outcome (discharged, hospitalized or died). Results In our population of a public hospital setting, hyponatremia was present at admission in 17% of deaths, and the comparison between hyponatremic and normonatremic patients in terms of mortality confirms the hypothesis that this disorder is in anyway strictly associated with vulnerability and with a poor prognosis. Conclusions We conclude that hyponatremia is a predictive marker for a bad clinical course, therefore patients with this electrolyte disorder should be carefully monitored.

Post-transplant neutropenia (PTN) is frequently reported in the first-year after transplantation. Although prevalence and clinical consequences are widely described, there are no guidelines to manage diagnosis and treatment. We report here a case of persistent PTN occurred in a patient undergoing a kidney transplant from an AB0-incompatible living donor. The desensitization protocol consisted of Rituximab administration and immunoadsorption while the pre-transplant protocol, which was initiated 14 days before the transplant, included Tacrolimus, Mofetil Mycophenolate (MMF), antimicrobial and antiviral prophylaxis. Induction therapy consisted of anti-thymocyte globulins and steroids, while maintenance after transplantation consisted of steroid, tacrolimus and MMF. When the first occurrence of leukopenia was observed six weeks after the transplant, firstly antimicrobial/antiviral prophylaxis was stopped and later also MMF treatment was interrupted but severe neutropenia relapsed after MMF resuming treatment. Immunological and virological causes were excluded. The patient was treated with Filgrastim. Bone marrow biopsy, which was performed to exclude a hematological cause of severe persistent neutropenia, revealed a bone marrow hypoplasia with neutrophils maturation interrupted at the early stages. This case highlights the need to establish diagnostic and therapeutic guidelines for PTN which take in consideration all the therapeutic steps including the pre-transplant phase in particular in the context of AB0i where immunosuppression is more consistent.

Few papers focused on association between hepatolithiasis (HL) and cholangiocarcinoma (CCC) in Western countries. The aims of this paper are to describe the clinical presentation, treatment, and postoperative outcomes of CCC with HL in a cohort of Western patients and to compare the surgical outcomes of these patients with patients with CCC without HL.Among 161 patients with HL from five Italian tertiary hepato-biliary centers, 23 (14.3%) patients with concomitant CCC were analyzed. The results of surgery in these patients were compared with patients with CCC without HL.The 60.9% of patients with HL received the diagnosis of CCC intra- or postoperatively, with a resectability rate of 91.3%. The postoperative morbidity was 61.6%. The 1- and 3-year survival rates were 78.6% and 21.0%, respectively. The recurrence rate was 44.4% and the 3-year disease-free survival rates were 18.8%. The comparison with patients with CCC without HL showed a higher resectability rate (p = 0.02) and a higher frequency of earlier stage (p = 0.04) in CCC with HL. Biliary leakage was more frequent in CCC with HL group (p = 0.01) compared to CCC without HL group. We found no differences in overall and disease-free survival between the two groups.Patients with HL and CCC showed a high resectability rate but a higher morbidity. Nevertheless, overall and disease-free survival of patients with CCC and HL showed no differences compared to those of patients with CCC without HL. Also in Western countries, HL needs a careful management for the possible presence of CCC.

Objective: Chronic renal antibody-mediated rejection (ABMR) is a common cause of allograft failure, but an effective therapy is not available. Extracorporeal photopheresis (ECP) has been proven successful in chronic lung and heart rejection, and graft versus host disease. The aim of this study was to evaluate the effectiveness of ECP in chronic ABMR patients. Patients and Methods: We investigated ECP treatment in 14 patients with biopsy-proven chronic ABMR and stage 2–3 chronic renal failure. The primary aim was to e valuate the eGFR lowering after 1 year of ECP therapy. The ECP responders (R) showed eGFR reduction greater than 20% vs the basal levels. We also evaluated the effectiveness of ECP on proteinuria, anti-HLA antibodies (HLAab), interleukin 6 (IL-6) serum levels, and CD3, CD4, CD8, CD19, NK, Treg and T helper 17 (Th17) circulating cells. Results: Three patients dropped out of the study. The R patients were eight (72.7%) out of the 11 remaining patients. Because ECP was not associated with any adverse reaction, the R patients continued such treatment for up to 3 years, showing a persisting eGFR stabilization. Twenty four hour proteinuria did not increase in the R patients over the follow-up when compared to the non-responder patients (NR). In the R patients, the HLAab levels were reduced and completely cleared in six out of eight patients when compared with the NR patients. The NR HLAab levels also increased after the discontinuation of the ECP. The ECP in the R patients showed a decrease in CD3, CD4, CD8, CD19, and NK circulating cells. The ECP treatment in the R patients also induced Tregs and Th17 cell increases, and a decrease of the IL-6 serum levels. Conclusions: ECP abates the HLAab titer and renal failure progression in patients with chronic renal ABMR, modulating the immune cellular and humoral responses.

Coronavirus is a high-risk pathogen for kidney transplant recipients receiving immunosuppressive therapy; Coronavirus disease 2019 (COVID-19) is an infection causing severe acute respiratory syndrome (SARS-CoV2), and progressive withdrawal of immunosuppressive drugs has been suggested in transplanted patients. At IRCCS San Matteo Hospital in Pavia, Northern Italy, during the pandemic we performed a screening and all transplanted patients were evaluated for IgG anti SARS-CoV-2; 12 of 201 kidney transplant recipients (6%) screened for IgG anti SARS-CoV-2 (s) developed kidney transplant rejection; 10 (83%) were negative and 2 (17%) resulted positive for SARS-CoV-2 IgG, while among 189 patients without rejection, 162 (86%) resulted negative and 27 (14%) positive (P=0.69). COVID 19 course may be more severe in kidney transplant recipients but it does not significantly increase risk of kidney rejection.

Elderly individuals with chronic disorders tend to develop inflammaging, a condition associated with elevated levels of blood inflammatory markers, and increased susceptibility to chronic disease progression. Native and adaptive immunity are both involved in immune system senescence, kidney fibrosis and aging. The innate immune system is characterized by a limited number of receptors, constantly challenged by self and non-self stimuli. Circulating and kidney resident myeloid and lymphoid cells are all equipped with pattern recognition receptors (PRRs). Recent reports on PRRs show kidney overexpression of toll-like receptors (TLRs) in inflammaging autoimmune renal diseases, vasculitis, acute kidney injury and kidney transplant rejection. TLR upregulation leads to proinflammatory cytokine induction, fibrosis, and chronic kidney disease progression. TLR2 blockade in a murine model of renal ischemia reperfusion injury prevented the escape of natural killer cells and neutrophils by inflammaging kidney injury. Tumor necrosis factor-α blockade in endothelial cells with senescence-associated secretory phenotype significantly reduced interleukin-6 release. These findings should encourage experimental and translational clinical trials aimed at modulating renal inflammaging by native immunity blockade.

Adenosine (Ado), the main substrate of ATP, is a potent endogenous anti-inflammatory nucleoside. Hypoxia induces ATP depletion, AMP extracellular increase that is phosphohydrolyzed to ADO by the enzyme ecto-5′-nucleotidase (CD73). Constitutive CD73 expression is higher in deep cortex outer medulla that is the most vulnerable region to ischemic injury. Notably CD73 is also expressed on Mesenchymal Stromal Cell (MSC) and is essential phenotypic marker. Previously in a rat model of Donation after Circulatory Death (DCD), we demonstrated that the perfusion of ischemic kidney with MSC or MSC derived Extracellular Vesicles (EV) protects tissue up regulating mitochondrial energetic metabolism genes. The aim of this study was to investigate the role of CD73/Ado system in MSC/EV protection from ischemia. Fisher rats were used as kidney donors and Lewis rats as MSC donors. MSC missing CD73 were produced by electroporation in the presence of specific siRNA to block CD73 expression (siMSC). EV were isolated from supernatants of MSC and siMSC (siEV) medium through differential ultracentrifugations. Size distribution and enumeration analysis were performed using NanoSight NS300. EV phenotypic characterization was performed in flow cytometer using CD45, CD49e, CD63, CD9, CD81 and CD73 monoclonal antibodies. DCD model was obtained by renal artery clamping for 20 minutes. This warm ischemia time represents the “no touch period” imposed by the Italian law to death declaration. After nephrectomy, kidneys were perfused in hypothermia (4°C) with Belzer Solution (BS), or BS supplemented with 3x106 MSC (MSC) or BS supplemented with 28,5x109 EV/siEV (EV/siEV). The effluent fluid (EF) was collected at the beginning (T0), every hours (T1, T2, T3) and at the end of the perfusion (T4). Ado and ATP determinations in EF and tissues were performed by HPLC and ELISA, respectively. EF Ado was significantly higher in MSC vs BS from T1 and in EV vs BS from T0 to T4 (p<0,05). Only in EV, EF Ado concentration increased over time from T2 to T4 ( p<0,05), while in BS, MSC and siEV there was a steady trend over time. There was a negative correlation between EF and tissue levels of Ado (r=0,67 p=0,01). Tissue ATP was higher in EV and significantly in MSC vs BS (p<0,01). There was a negative correlation between tissue ATP and EF ADO levels (r= 0,79 p< 0,0001). Tissue ATP/Ado ratio was significantly higher in EV vs BS (p<0,01). There was a negative correlation between tissue ATP/Ado ratio and EF Ado (r= 0,84 p < 0.0001). siEV cancelled EV effects on ATP and Ado levels in EF and renal tissue. CD73 expressed on MSC /EV impacts on cell energy metabolism pathway and ATP generation. This is the first evidence that MSC/EV act through CD73/Ado system to prevent ischaemic damage.

We report a preliminary experience of adjuvant therapy with Hemoperfusion (HP) in patients with Severe Acute Respiratory Syndrome-CoronaVirus 2 (SARS-CoV2) pneumonia. Currently, there are no approved treatments for CoronaVirus Disease 19 (COVID-19); however, therapeutic strategies based on the preclinical evidence include supportive measures, such as oxygen supplementation, antiviral, and anticoagulant agents. Despite these treatments, 10% of patients worsen and develop severe acute respiratory distress syndrome (ARDS). Since the pathogenic mechanism of ARDS is an uncontrolled inflammatory state, we speculate that removing inflammation effectors from blood may contrast tissue injury and improve clinical outcome. In a scenario of dramatic medical emergency, we conducted an observational study on 9 consecutive patients hospitalized in COVID Intensive Care Unit, where 5 of 9 consecutive patients were treated with HP, due to the emergency overload made it impossible to deliver blood purification in the other 4 patients. COVID-19 was diagnosed through the identification of virus sequences by reverse transcription-PCR on respiratory specimens. All patients had severe pneumonia requiring continuous positive airway pressure. HP was started in all patients 6–7 days after hospital admission. The treated patients (T) received 2 consecutive sessions of HP using CytoSorb cartridge. Our results show a better clinical course of T compared to control patients (C), in fact all T except 1 survived, and only 2 of them were intubated, while all C required intubation and died. Lymphocytopenia worsened in C but not in T. C-reactive protein decreased in both patients, but to a greater extent in T. IL-6, IL-8, and TNF-α decreased after HP, IL-10 did not change. Respiratory function remained stable and did not worsen in T compared to C. The limited sample size and observational study design preclude a sound statement about the potential effectiveness of HP in COVID-19 patients, but our experience suggests a potential therapeutic role of adjuvant CytoSorb HP in the early course of CO­VID-19 pneumonia. A randomized clinical trial is ongoing.

Stéphane Gaudry and colleagues1Gaudry S Hajage D Benichou N et al.Delayed versus early initiation of renal replacement therapy for severe acute kidney injury: a systematic review and individual patient data meta-analysis of randomised clinical trials.Lancet. 2020; 395: 1506-1515Summary Full Text Full Text PDF PubMed Scopus (97) Google Scholar found that early renal replacement therapy (RRT) in critically ill patients with acute kidney injury does not affect survival compared with a delayed RRT strategy. A major limitation of their meta-analysis is the clinical discretion on RRT timing and prescription. Furthermore, admission to intensive care units in the included studies allowed most patients with acute kidney injury to access treatment facilities, such as mechanical ventilation, which are not usually available in standard internal medicine or renal units. The Article1Gaudry S Hajage D Benichou N et al.Delayed versus early initiation of renal replacement therapy for severe acute kidney injury: a systematic review and individual patient data meta-analysis of randomised clinical trials.Lancet. 2020; 395: 1506-1515Summary Full Text Full Text PDF PubMed Scopus (97) Google Scholar shows no difference in 28-day mortality between groups receiving delayed and early RRT. However, only two of the eight included studies were carried out in renal units. These studies do not report the number of patients with chronic kidney disease and Kidney Disease: Improving Global Outcomes (KDIGO) category ,2KDIGOChapter 1: definition and classification of CKD.Kidney Int Suppl (2011). 2013; 3: 19-62Summary Full Text Full Text PDF PubMed Google Scholar or acute kidney injury stage, and data are missing on residual diuresis. Additionally, details on drug treatment in the Article,1Gaudry S Hajage D Benichou N et al.Delayed versus early initiation of renal replacement therapy for severe acute kidney injury: a systematic review and individual patient data meta-analysis of randomised clinical trials.Lancet. 2020; 395: 1506-1515Summary Full Text Full Text PDF PubMed Scopus (97) Google Scholar such as the antibiotic therapy given to 525 of the 1205 patients with sepsis, have not been reported. Such clinical aspects have also not been reported in the included studies, adding relevant limitations to this meta-analysis. In our opinion, the message that RRT in patients with acute kidney injury "can be safely postponed"1Gaudry S Hajage D Benichou N et al.Delayed versus early initiation of renal replacement therapy for severe acute kidney injury: a systematic review and individual patient data meta-analysis of randomised clinical trials.Lancet. 2020; 395: 1506-1515Summary Full Text Full Text PDF PubMed Scopus (97) Google Scholar should be taken cautiously. Even more caution should be taken for patients with acute kidney injury admitted to standard medical units rather than to intensive care units. We declare no competing interests. Delayed versus early initiation of renal replacement therapy for severe acute kidney injury: a systematic review and individual patient data meta-analysis of randomised clinical trialsThe timing of RRT initiation does not affect survival in critically ill patients with severe acute kidney injury in the absence of urgent indications for RRT. Delaying RRT initiation, with close patient monitoring, might lead to a reduced use of RRT, thereby saving health resources. Full-Text PDF Renal replacement therapy in acute kidney injuryStéphane Gaudry and colleagues1 compared delayed versus early initiation of renal replacement therapy (RRT) in patients with severe acute kidney injury. One strength of this meta-analysis was the use of the Grading of Recommendations, Assessment, Development, and Evaluation to assess the certainty of evidence.2,3 Gaudry and colleagues1 rated 28-day mortality, 60-day mortality, and hospital mortality as patient outcomes with high certainty of evidence, and they concluded that mortality does not differ significantly according to whether RRT is initiated early or is delayed in patients with acute kidney injury. Full-Text PDF Renal replacement therapy in acute kidney injury – Authors' replyWe disagree with Vincenzo Sepe and colleagues' comment about the timing and prescription of renal replacement therapy (RRT). In the randomised controlled trials included in our systematic review and individual patient data meta-analysis,1 the protocol was precise; it mandated starting RRT as soon as Kidney Disease: Improving Global Outcomes acute kidney injury stage 2 or 3 was present in the early strategy, and it had stringent criteria for initiating RRT in the delayed strategy, such as severe hyperkalaemia or acidosis, among others. Full-Text PDF

Abstract Background and Aims Chronic antibody-mediated rejection (cABMR) is the main cause of kidney allograft failure. Currently there is no effective treatment. Extracorporeal photopheresis (ECP) is an immunomodulating therapy that acts increasing regulatory T cells and reducing effector T cells. ECP has been used with success to treat heart and lung rejection, acute and chronic Graft versus Host Disease and few cases of acute antibody mediated kidney rejection. The aim of this study was to describe the preliminary experience of ECP use to treat kidney cABMR. Method This is an ongoing prospective observational study approved by the ethical committee of our institution. The study started in 2017 on kidney transplant recipients (KTR) with cABMR diagnosis bioptically proved. All patients received ECP in addition to the standard treatment. ECP schedule is reported in Figure 1. Serum and urine samples were collected at the beginning of the study and every 6 months during the follow up period. Analyzed variables were: glomerular filtration rate (GFR), urine albumin-creatinine ratio (UACR), Donor Specific Antibodies (DSA) measeured as Mean Intensity Fluorescence (MIF) by Luminex. Collected clinical data included: death, hospital admission number, cancer diagnosis, infections. Quality of life (QoL) scale was also recorded. Results We enrolled 6 KTR equally distributed in gender (3 M, 3 F) and aged 49.16 ± 7.15 years (mean±ds) . Median follow up time was 12 months (min 12 – max 36). All KTR had both class I and class II DSA with MFI > 5000 (min 5000 – max 36780). In all patients no GFR deterioration was observed during follow up. UACR improved in 3 KTR while remained stable in the other 3 patients. No deaths or infections or cancer diagnosis or hospital admissions occurred. QoL ameliorated in all KTR. DSA MIF decreased in all KTR and in 3 of them became even negative after 12 months of treatment. Conclusion ECP is a safe and effective treatment to slow down the deterioration of kidney function in cABMR patients. Further studies are necessary to identify the responder patients and to better tailor the treatment schedule.