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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.

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.

Pentraxin 3 (PTX3) is an essential component of the innate immune system and a recognized modulator of Complement cascade. The role of Complement system in the pathogenesis of prostate cancer has been largely underestimated. The aim of our study was to investigate the role of PTX3 as possible modulator of Complement activation in the development of this neoplasia. We performed a single center cohort study; from January 2017 through December 2018, serum and prostate tissue samples were obtained from 620 patients undergoing prostate biopsy. A group of patients with benign prostatic hyperplasia (BPH) underwent a second biopsy within 12–36 months demonstrating the presence of a prostate cancer (Group A, n = 40) or confirming the diagnosis of BPH (Group B, N = 40). We measured tissue PTX3 protein expression together with complement activation by confocal microscopy in the first and second biopsy in group A and B patients. We confirmed that that PTX3 tissue expression in the first biopsy was increased in group A compared to group B patients. C1q deposits were extensively present in group A patients co-localizing and significantly correlating with PTX3 deposits; on the contrary, C1q/PTX3 deposits were negative in group B. Moreover, we found a significantly increased expression of C3a and C5a receptors within resident cells in group A patient. Interestingly, C1q/PTX3 deposits were not associated with activation of the terminal Complement complex C5b-9; moreover, we found a significant increase of Complement inhibitor CD59 in cancer tissue. Our data indicate that PTX3 might play a significant pathogenic role in the development of this neoplasia through recruitment of the early components of Complement cascade with hampered activation of terminal Complement pathway associated with the upregulation of CD59. This alteration might lead to the PTX3-mediated promotion of cellular proliferation, angiogenesis and insensitivity to apoptosis possible leading to cancer cell i

Natural killer cells (NK) represent a population of lymphocytes involved in innate immune response. In addition to their role in anti-viral and anti-tumor defense, they also regulate several aspects of the allo-immune response in kidney transplant recipients. Growing evidence suggests a key role of NK cells in the pathogenesis of immune-mediated graft damage in kidney transplantation. Specific NK cell subsets are associated with operational tolerance in kidney transplant patients. On the other side, allo-reactive NK cells are associated with chronic antibody-mediated rejection and graft loss. Moreover, NK cells can prime the adaptive immune system and promote the migration of other immune cells, such as dendritic cells, into the graft leading to an increased allo-immune response and, eventually, to chronic graft rejection. Finally, activated NK cells can infiltrate the transplanted kidney and cause a direct graft damage. Interestingly, immunosuppression can influence NK cell numbers and function, thus causing an increased risk of post-transplant neoplasia or infection. In this review, we will describe how these cells can influence the innate and the adaptive immune response in kidney transplantation and how immunosuppression can modulate NK behavior.

Italy was the first Western country to face the COVID-19 pandemic. Here we report the results of a national survey on kidney transplantation activity in February and March 2020, and the results of a three-round Delphi consensus promoted by four scientific societies: the Italian Society of Organ Transplantation, the Italian Society of Nephrology, the Italian Society of Anesthesia and Intensive Care, and the Italian Group on Antimicrobial Stewardship. All 41 Italian transplant centers were invited to express their opinion in the Delphi rounds along with a group of seven experts. The survey revealed that, starting from March 2020, there was a decline in kidney transplantation activity in Italy, especially for living-related transplants. Overall, 60 recipients tested positive for SARS-CoV2 infection, 57 required hospitalization, 17 were admitted to the ICU, and 11 died. The online consensus had high response rates at each round (95.8%, 95.8%, and 89.5%, respectively). Eventually, 27 of 31 proposed statements were approved (87.1%), 12 at the first or second round (38.7%), and 3 at the third (9.7%). Based on the Italian experience, we discuss the reasons for the changes in kidney transplantation activity during the COVID-19 pandemic in Western countries. We also provide working recommendations for the organization and management of kidney transplantation under these conditions.

Chronic antibody-mediated rejection (CAMR) is the major cause of kidney transplant failure. The molecular mechanisms underlying this event are still poorly defined and this lack of knowledge deeply influences the potential therapeutic strategies. The aim of our study was to analyze the phosphoproteome of peripheral blood mononuclear cells (PBMCs), to identify cellular signaling networks differentially activated in CAMR. Phosphoproteins isolated from PBMCs of biopsy proven CAMR, kidney transplant recipients with normal graft function and histology and healthy immunocompetent individuals, have been investigated by proteomic analysis. Phosphoproteomic results were confirmed by Western blot and PBMCs’ confocal microscopy analyses. Overall, 38 PBMCs samples were analyzed. A differential analysis of PBMCs’ phosphoproteomes revealed an increase of lactotransferrin, actin-related protein 2 (ARPC2) and calgranulin-B in antibody-mediated rejection patients, compared to controls. Increased expression of phosphorylated ARPC2 and its correlation to F-actin filaments were confirmed in CAMR patients. Our results are the first evidence of altered cytoskeleton organization in circulating immune cells of CAMR patients. The increased expression of phosphorylated ARPC2 found in the PBMCs of our patients, and its association with derangement of F-actin filaments, might suggest that proteins regulating actin dynamics in immune cells could be involved in the mechanism of CAMR of kidney grafts.

Background End-stage renal disease (ESRD) is associated with a broad spectrum of morphological and functional thyroid disorders. Recent studies have shown that low free triiodothyronine (fT3) levels are related to inflammatory status and endothelial activation in ESRD patients on haemodialysis (HD). Limited data exist about a possible relationship between dialysis regimen, namely long nocturnal haemodialysis (LNHD), and thyroid function parameters. The aim of this study was to evaluate the relationship between dialysis regimen and thyroid function, and consequently with the main patient outcomes. Methods To this purpose, we performed a retrospective, single-centre cohort study including 220 incident chronic HD patients treated during an 8-year period (from January 2010 to December 2017). The main clinical and haematochemical parameters, including thyroid function, were evaluated and related to the main patient outcomes. Results Patients with low fT3 levels (<3.05 ng/mL) showed significantly lower survival rates than patients with normal fT3 levels (>3.05 ng/mL) (P < 0.001), although there were no substantial differences in the demographic and clinical characteristics between the two groups. After propensity score 1:3 matching of 25 patients treated with nocturnal HD to 75 patients treated with diurnal HD, LNHD patients showed significantly higher survival rates (88.0% versus 61.3%, P = 0.001) and lower incidence of cardiovascular events than patients on diurnal dialysis (8.0% versus 40.0%, P = 0.001). Moreover, an 8-year time-dependent analysis showed that at any time, except for baseline, the rate of patients with fT3 levels >3.05 ng/mL was significantly higher in LNHD patients than in patients treated with diurnal dialysis. Conclusions Our data suggest that the application of alternative dialysis regimens, also reducing the frequency of low T3, could ameliorate outcomes and therefore reduce the incidence of cardiovascular events in HD patients.

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.

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Background: Anemia is a common complication of chronic kidney disease (CKD), but its incidence in nephrology settings is poorly investigated. Similarly, the risks of adverse outcomes associated with new-onset anemia are not known. Methods: We performed a pooled analysis of three observational cohort studies including 1031 non-anemic CKD patients with eGFR <60 mL/min/1.73 m2 regularly followed in renal clinics. We estimated the incidence of mild anemia (hemoglobin 11-12 g/dL in women and 11-13 g/dL in men) and severe anemia (hemoglobin <11 g/dL or use of erythropoiesis-stimulating agents) during a 3-year follow-up period. Thereafter we estimated the risk of end-stage kidney disease (ESKD) and all-cause death associated with new-onset mild and severe anemia. Results: The mean age was 63 ± 14 years, 60% were men and 20% had diabetes. The mean estimated glomerular filtration rate (eGFR) was 37 ± 13 mL/min/1.73 m2 and the median proteinuria was 0.4 g/day [interquartile range (IQR) 0.1-1.1]. The incidence of mild and severe anemia was 13.7/100 patients-year and 6.2/100 patients-year, respectively. Basal predictors of either mild or severe anemia were diabetes, lower hemoglobin, higher serum phosphate, eGFR <30 mL/min/1.73 m2 and proteinuria >0.50 g/day. Male sex, moderate CKD (eGFR 30-44 mL/min/1.73 m2) and moderate proteinuria (0.15-0.50 g/day) predicted only mild anemia. The incidence of anemia increased progressively with CKD stages (from 8.77 to 76.59/100 patients-year) and the proteinuria category (from 13.99 to 25.02/100 patients-year). During a median follow-up of 3.1 years, 232 patients reached ESKD and 135 died. Compared with non-anemic patients, mild anemia was associated with a higher adjusted risk of ESKD {hazard ratio [HR] 1.42 [95% confidence interval (CI) 1.02-1.98]} and all-cause death [HR 1.55 (95% CI 1.04-2.32)]. Severe anemia was associated with an even higher risk of ESKD [HR 1.73 (95% CI 1.20-2.51)] and death [HR 1.83 (95% CI 1.05-3.19)].

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.

A 59-year-old man undergoing dialysis was admitted to our hospital with lower limb ischemia; he had a story of long-term use of phosphate and potassium chelator. Because of anemia and repeated episodes of bowel bleeding, he underwent colonoscopy with a biopsy of the ileocecal valve and ulcerative lesions of the proximal descending colon

LPS-induced sepsis is a leading cause of acute kidney injury (AKI) in critically ill patients. LPS may induce CD80 expression in podocytes with subsequent onset of proteinuria, a risk factor for progressive chronic kidney disease (CKD) frequently observed after AKI. This study aimed to investigate the therapeutic efficacy of LPS removal in decreasing albuminuria through the reduction of podocyte CD80 expression. Between January 2015 and December 2017, 70 consecutive patients with Gram-negative sepsis-induced AKI were randomized to either have coupled plasma filtration and adsorption (CPFA) added to the standard care (n = 35) or not (n = 35). To elucidate the possible relationship between LPS-induced renal damage, proteinuria, and CD80 expression in Gram sepsis, a swine model of LPS-induced AKI was set up. Three hours after LPS infusion, animals were treated or not with CPFA for 6 h. Treatment with CPFA significantly reduced serum cytokines, C-reactive protein, procalcitonin, and endotoxin levels in patients with Gram-negative sepsis-induced AKI. CPFA significantly lowered also proteinuria and CD80 urinary excretion. In the swine model of LPS-induced AKI, CD80 glomerular expression, which was undetectable in control pigs, was markedly increased at the podocyte level in LPS-exposed animals. CPFA significantly reduced LPS-induced proteinuria and podocyte CD80 expression in septic pigs. Our data indicate that LPS induces albuminuria via podocyte expression of CD80 and suggest a possible role of timely LPS removal in preventing the maladaptive repair of the podocytes and the consequent increased risk of CKD in sepsis-induced AKI.

Urinary tract infections (UTIs) after kidney transplantation are associated with significant morbidity. However, data on the impact of UTI on graft survival are controversial. We conducted a retrospective cohort study of 380 kidney transplant patients. Recipients with symptomatic UTIs during the first year after transplantation were categorized into three groups: early (< 3 episodes from months 1st to 6th), late (< 3 episodes during months 7th to 12th) and recurrent (≥ 3 episodes throughout the whole first year). Graft function at three years was considered the primary outcome. Symptomatic UTIs occurred in 184 (48.4%) kidney transplant recipients during the first year; 83 (21.8%) patients developed early UTIs, 50 (13.2%) late UTIs and 51 (13.4%) recurrent UTIs. We observed a significant improvement in graft function after three years in all patients (P < 0.001) except those who had recurrent UTIs. A Kaplan–Meier analysis showed that recipients with recurrent UTIs had worse graft outcome (eGFR value < 60 mL/min/1.73 m2) (P = 0.01). Recurrent UTIs was an independent predictor of graft function at three years in a model adjusted for DGF and episodes of acute rejection (Hazard Ratio, 2.2; 95% CI, 1.3 to 3.5; P = 0.001). Recurrent symptomatic UTIs during the first year after transplantation have negative impact on long-term graft function.

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.

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.

Background: Hemodialysis patients present a dramatic increase in cardiovascular morbidity/mortality. Circulating immune cells, activated by both uremic milieu and dialysis, play a key role in the pathogenesis of dialysis-related vascular disease. The aim of our study was to identify, through a high-throughput approach, differences in gene expression profiles in the peripheral blood mononuclear cells (PBMCs) of patients treated with on-line hemodiafiltration and bicarbonate hemodialysis. Methods: The transcriptomic profile was investigated in PBMCs isolated from eight patients on on-line hemodiafiltration and eight patients on bicarbonate hemodialysis by microarray analysis. The results were evaluated by statistical and functional pathway analysis and validated by real time PCR (qPCR) in an independent cohort of patients (on-line hemodiafiltration N = 20, bicarbonate hemodialysis n = 20). Results: Eight hundred and forty-seven genes were differentially expressed in patients treated with on-line hemodiafiltration and bicarbonate hemodialysis. Thirty-seven functional gene networks were identified and atherosclerosis signaling was the top canonical pathway regulated by on-line hemodiafiltration. Among the genes of this pathway, on-line hemodiafiltration was associated with a reduced expression of Platelet-derived growth factor A chain (PDGF A), Clusterin, Monoamine Oxidase A, Interleukin-6 (IL-6) and Vascular Endothelial GrowthFactor C (VEGF-)C and with an increase of Apolipoprotein E. qPCR confirmed the microarray results. Platelet derived growth factor AA (PDGF-AA), IL-6 and VEGF-C serum levels were significantly lower in the on-line hemodiafiltration group. Finally, 10 patients previously on bicarbonate hemodialysis were switched to on-line hemodiafiltration and PBMCs were harvested after 6 months. The qPCR results from this perspective group confirmed the modulation of atherosclerotic genes observed in

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Background and aim: Over 80% (365/454) of the nation’s centers participated in the Italian Society of Nephrology COVID-19 Survey. Out of 60,441 surveyed patients, 1368 were infected as of April 23rd, 2020. However, center-specific proportions showed substantial heterogeneity. We therefore undertook new analyses to identify explanatory factors, contextual effects, and decision rules for infection containment. Methods: We investigated fixed factors and contextual effects by multilevel modeling. Classification and Regression Tree (CART) analysis was used to develop decision rules. Results: Increased positivity among hemodialysis patients was predicted by center location [incidence rate ratio (IRR) 1.34, 95% confidence interval (CI) 1.20–1.51], positive healthcare workers (IRR 1.09, 95% CI 1.02–1.17), test-all policy (IRR 5.94, 95% CI 3.36–10.45), and infected proportion in the general population (IRR 1.002, 95% CI 1.001–1.003) (all p < 0.01). Conversely, lockdown duration exerted a protective effect (IRR 0.95, 95% CI 0.94–0.98) (p < 0.01). The province-contextual effects accounted for 10% of the total variability. Predictive factors for peritoneal dialysis and transplant cases were center location and infected proportion in the general population. Using recursive partitioning, we identified decision thresholds at general population incidence ≥ 229 per 100,000 and at ≥ 3 positive healthcare workers. Conclusions: Beyond fixed risk factors, shared with the general population, the increased and heterogeneous proportion of positive patients is related to the center’s testing policy, the number of positive patients and healthcare workers, and to contextual effects at the province level. Nephrology centers may adopt simple decision rules to strengthen containment measures timely.

Background: Acute kidney injury (AKI), even if followed by renal recovery, is a risk factor for the future development of chronic kidney disease (CKD) and end-stage renal disease (ESRD). In the previous years, novel insights in the pathophysiology of CKD progression suggested a causal link between AKI and CKD due to a maladaptive repair after severe and repeated injury. Summary: Several pathological mechanisms have been proposed to contribute to the progression of AKI and transition to CKD/ESRD including hypoxia and microvascular rarefaction, alterations of renal resident cell phenotypes and functions, cell cycle arrest in the G2/M phase, persistent chronic inflammation, and development of interstitial fibrosis, mitochondrial fragmentation, epigenetic changes, activation of renin-angiotensin system (RAS), cell and tissue senescence. Furthermore, several clinical factors have been identified such as severity of AKI, age, and comorbidities. The identification of AKI-to-CKD biomarkers could improve the early identification of AKI patients with higher risk for CKD progression. However, although our understanding in the pathophysiology of AKI-to-CKD transition is significantly improved, no novel intervention has been validated. Potential therapeutic approaches to treat AKI and block the transition to CKD/ESRD have been recently reported, but they need further validations. Key Messages: Maladaptive repair after AKI is strongly associated to the development of CKD and long-term consequences. The prompt identification of patients at higher risk for late CKD progression and the development of new therapeutic interventions remain critical research goals.

Coagulation system is currently considered an integrated part of innate immunity. Clotting activation in response to bacterial surface along with complement cascade priming represents the first line of defense against pathogens. In the last three decades, we learned that several coagulation factors, including factor II or thrombin and factor X, can interact with specific cell surface receptors activated by an unusual proteolytic mechanism and belonging to a novel class of G-protein-coupled receptors known as protease-activated receptors (PARs). PARs are expressed by a variety of cells, including monocytes, dendritic cells, and endothelial cells and may play a key role in the modulation of innate immunity and in the regulation of its interaction with the adaptive branch of the immune system. Also, the fibrinolytic system, in which activation is controlled by coagulation, can interact with innate immunity, and it is a key modulator of extracellular matrix deposition eventually leading to scarring and fibrosis. In the setting of kidney transplantation, coagulation and fibrinolytic systems have been shown to play key roles in the ischemia/reperfusion injury featuring delayed graft function and in the pathogenesis of tissue damage following acute and chronic rejection. In the present review, we aim to describe the mechanisms leading to coagulation and fibrinolysis activation in this setting and their interaction with the priming of the innate immune response and their role in kidney graft rejection.

Objective/Background. To describe an uncommon, life-threatening condition such as angiosarcoma of a fistula for hemodialysis occurring in a transplant recipient affected by Lowe's syndrome. Summary. We present the case of a 56-year-old male kidney transplant recipient affected by Lowe's syndrome, also known as oculocerebrorenal syndrome, a rare X-linked disorder characterized by congenital cataracts, hypotonia, intellectual disability, and Fanconi-like renal tubular dysfunction, who was diagnosed with angiosarcoma of a functioning arteriovenous fistula for hemodialysis. Conclusion. Angiosarcoma is a rare soft tissue tumor, and only 22 cases of angiosarcoma of arteriovenous fistulae were described so far; although a correlation between Lowe's syndrome and a higher risk of tumor compared to the general population has not been described so far, the mechanisms of disease causation could be an interesting starting point for future studies on a possible connection between the two events.

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Background and objectives Active antibody-mediated rejection is the main cause of kidney transplant loss, sharing with SLE the alloimmune response and the systemic activation of the IFN-a pathway. IgE-mediated immune response plays a key role in the development of SLE nephritis and is associated with IFN-a secretion. The aim of our study was to investigate IgE-mediated immune response in antibody-mediated rejection. Design, setting, participants, & measurements This was a cross-sectional study of 56 biopsy-proven antibodymediated rejection study participants, 80 recipients with normal graft function/histology (control), 16 study participants with interstitial fibrosis/tubular atrophy, and six participants with SLE. We evaluated graft IgE deposition, tryptase (a mast cell marker), and CD203 (a specific marker of activated basophils) by immunofluorescence/confocal microscopy. In addition, we measured serum concentration of human myxovirus resistance protein 1, an IFN-a–induced protein, and anti-HLA IgE. Results We observed a significantly higher IgE deposition in tubules and glomeruli in antibody-mediated rejection (1766679 pixels) and SLE (1495643 pixels) compared with interstitial fibrosis/tubular atrophy (5826122 pixels) and control (253650 pixels). Patients with antibody-mediated rejection, but not control patients and patients with interstitial fibrosis/tubular atrophy, presented circulating anti-HLA IgE antibodies, although with a low mean fluorescence intensity. In addition, immunofluorescence revealed the presence of both mast cells and activated basophils in antibody-mediated rejection but not in control and interstitial fibrosis/tubular atrophy. The concentration of circulating basophils was significantly higher in antibody-mediated rejection compared with control and interstitial fibrosis/tubular atrophy. MxA serum levels were significantly higher in antibodymediated rejection compared with control and correlated with the extent of IgE deposition. Concl

Aims: To evaluate erythropoietic response rates to oral iron over time in iron-deficient anemic patients with nondialysis- dependent chronic kidney disease (NDCKD). Materials and methods: FIND-CKD was a 1-year, randomized, multicenter trial of iron therapy in patients with ND-CKD, anemia, and iron deficiency, without erythropoiesis- stimulating agent (ESA) therapy. Patients with active infection or C-reactive protein > 20 mg/L were excluded. In this post-hoc analysis, response was defined as ≥ 1 g/dL increase in hemoglobin (Hb) from baseline, before initiation of alternative anemia therapy (i.e., ESA, transfusion, or intravenous iron). Results: 308 patients received oral iron (200 mg elemental iron/day). Mean (SD) Hb at baseline was 10.4 (0.7) g/dL. At week 4, Hb data were available from 292 patients without alternative anemia therapy: 63/292 (21.6%) showed a response. Among the 229 nonresponders at week 4, 48.8% showed a cumulative response on ≥1 occasion by week 52 (11.1%, 19.9%, 25.9%, and 28.7% had a response at weeks 8, 12, 24, and 52, respectively), and 27.9% had received alternative iron therapy by week 52. Baseline levels of Hb, ferritin, and transferrin saturation were lower in responders than in nonresponders. Neither concomitant medication nor adherence (as assessed by medication count) was substantially different between early responders and nonresponders. Conclusion: Four weeks after starting oral iron therapy, only 21.6% of anemic patients with ND-CKD and iron deficiency showed an Hb increase of at least 1 g/dL. Among early nonresponders, < 30% responded at any subsequent time point. Earlier consideration of alternative therapy could improve anemia management in this population.

During sepsis, the increased synthesis of circulating lipopolysaccharide (LPS)-binding protein (LBP) activates LPS/TLR4 signaling in renal resident cells, leading to acute kidney injury (AKI). Pericytes are the major source of myofibroblasts during chronic kidney disease (CKD), but their involvement in AKI is poorly understood. Here, we investigate the occurrence of pericyte-to-myofibroblast trans-differentiation (PMT) in sepsis-induced AKI. In a swine model of sepsis-induced AKI, PMT was detected within 9 h from LPS injection, as evaluated by the reduction of physiologic PDGFRβ expression and the dysfunctional α-SMA increase in peritubular pericytes. The therapeutic intervention by citrate-based coupled plasma filtration adsorption (CPFA) significantly reduced LBP, TGF-β, and endothelin-1 (ET-1) serum levels, and furthermore preserved PDGFRβ and decreased α-SMA expression in renal biopsies. In vitro, both LPS and septic sera led to PMT with a significant increase in Collagen I synthesis and α-SMA reorganization in contractile fibers by both SMAD2/3-dependent and-independent TGF-β signaling. Interestingly, the removal of LBP from septic plasma inhibited PMT. Finally, LPS-stimulated pericytes secreted LBP and TGF-β and underwent PMT also upon TGF-β receptor-blocking, indicating the crucial pro-fibrotic role of TLR4 signaling. Our data demonstrate that the selective removal of LBP may represent a therapeutic option to prevent PMT and the development of acute renal fibrosis in sepsis-induced AKI.

The outcome of acute kidney injury (AKI) may vary from complete resolution to an incomplete recovery of renal function leading to chronic kidney disease (CKD). An increasing body of evidence suggests a causal link between AKI and the consequent development of CKD. The outcome of AKI depends, at the tissue level, on the balance of adaptive and maladaptive repair. Maladaptive repair is characterized by the development of interstitial fibrosis, persistent expression of fibrogenic factors, and delayed resolution of inflammation.Tubular and endothelial cells are the main actors in the pathogenesis of AKI and in the events leading to its resolution. However, in the last two decades we recognized the key role of other resident cells, including pericytes, in maladaptive repair. On the other hand, the activation of the innate immune system always has been considered essential in the development of renal injury and in its repair, although evidence now supports a key role also for infiltrating B and T cells in this setting. All of these changes observed in the process leading from acute to chronic tissue injury clearly suggest the acceleration of a physiologic senescence process. Thus accelerated cell and tissue senescence as the main pathogenic mechanism of maladaptive repair may represent a unifying hypothesis.