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Acute kidney injury (AKI) is a complex clinical syndrome characterized by a rapid decline in kidney function, often resulting in complex metabolic and hormonal derangements. A major concern in managing AKI patients is the development of protein energy wasting (PEW), a condition marked by loss of lean body mass and negative impact on overall health outcomes. Additionally, the need of Kidney Replacement Therapy (KRT) for the most severe forms of AKI may further increase the risk of PEW, with a substantial impact on fluid and metabolic balance. Adequate nutritional support is crucial in the management of AKI, as it plays a pivotal role in muscle mass preservation, morbidity reduction and recovery of renal function. This paper aims to evaluate the current evidence regarding nutritional strategies in AKI patients, focusing on energy and protein requirements, timing and route of nutritional intervention, and impact of individualized nutrition plans on PEW prevention and management., Competing Interests: Declaration of competing interest There are no conflicts of interest for this work for all authors., (Copyright © 2024 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: Sustained-Low Efficiency Dialysis (SLED) is an increasingly used Kidney Replacement Therapy (KRT) modality in critically ill patients. This study was aimed at evaluating the safety and efficacy of simplified Regional Citrate Anticoagulation (RCA) for SLED using new hemodialysis equipment., Methods: The 8-hour SLED sessions were performed with a Surdial X Nipro ® hemodialysis machine and a cellulose triacetate filter. A concentrated citrate solution (ACD-A) was infused in predilution with a target circuit citrate concentration of 2.5-3 mmol/L. Blood recalcification in the extracorporeal circuit mainly occurred through the backfiltration phenomenon by dialysis fluid (Ca 2+ 1.5 mmol/L). Serum citrate levels were directly measured during KRT by enzymatic methods and an extensive daily laboratory workup was performed. Changes in laboratory variables at the end of the SLED sessions were analyzed with mixed-effects linear models for repeated measures., Results: Eighty-one SLED treatments were performed in 27 patients (APACHE II score 21 ± 6). The prescribed duration was attained for the majority of the treatments (72/81, 88%). No major bleeding episodes or side effects of citrate accumulation occurred. While calcium infusion was needed in 19/81 SLED sessions (23%), phosphate and magnesium supplementation was necessary following about 25% of all SLED sessions., Conclusions: Our simplified regional citrate anticoagulation protocol for SLED with a new "conventional" dialysis machine resulted safe and effective, also for critically ill patients, ensuring a good match between the prescribed and delivered dialysis dose. Close electrolyte monitoring and early supplementation allowed to tailor the dialysis prescription to the patient's actual needs, while avoiding KRT-related complications., Competing Interests: Declarations. Conflict of interest: The authors have no competing interests to declare that are relevant to the content of this article. Ethical approval: All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the local Ethics Committee (AVEN n° 3655, January 22nd, 2019). Informed consent to participate: Written informed consent was obtained from all patients., (© 2025. The Author(s) under exclusive licence to Italian Society of Nephrology.)

The role of the complement system in antibody mediated rejection (AMR) emerged in the last decades, and the demonstration of the presence of complement fragments in renal allograft biopsies is a consolidated diagnostic sign of AMR. However, antibodies against donor antigens may lead to microvascular inflammation and endothelial injury even in the absence of complement activation, and growing evidence suggests that complement-independent mechanisms may be prominent in late (i.e., occurring >6 months after transplantation) vs early AMR. Different donor specific antibodies (DSA) with different biological features and complement activation ability may be involved in late or early AMR. Downregulation of tissue complement inhibitors may happen early after transplantation, partially due to ischemia reperfusion injury, and could facilitate complement activation in early vs late AMR. Clinical and histological features of late AMR and C4d negative AMR seem to converge, and this narrative review analyzes the evidence that supports lower complement activation in late vs early AMR, including differential C4d staining prevalence based on the time after transplantation, differential response to anti-complement therapy and other direct and indirect signs of the complement system activation. The therapeutic approach in early vs late AMR should take into account possible differences in the pathophysiological mechanisms of microvascular inflammation and endothelial injury in early vs late AMR., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Introduction: Mucosal inflammation is involved in the pathophysiology of immunoglobulin-A nephropathy (IgAN); however, peripheral immune phenotype analyses of patients with IgAN often do not include unconventional T cells, the major subset in mucosal immunity., Methods: We measured serum total IgA, galactose-deficient IgA1 (gd-IgA1), secretory IgA (SIgA), B cell-activating factor (BAFF), and A proliferation-inducing ligand (APRIL) in 66 patients with IgAN and 30 healthy controls (HCs). We also quantified the total IgA and gd-IgA1 in stool supernatant along with the same coated on bacteria. In 35 patients and 14 controls, we performed extensive phenotyping using cytometry by Time-of-Flight (CyTOF) of circulating immune cells, including unconventional T cells (mucosal associated invariant T [MAIT] cells, γδ T, and natural killer [NK] T cells). The results were validated using RNAseq data from a larger cohort of 179 patients with IgAN, 140 patients with minimal change disease, and 91 HCs., Results: Patients with IgAN had higher circulating levels of total IgA, gd-IgA1, and APRIL, and higher IgA and gd-IgA1-coated gut bacteria than controls, whereas serum levels of SIgA and BAFF did not differ between groups. Patients with IgAN showed more class-switched memory (CSM) and double negative (DN) B cells than controls. MAIT cells and γδ T cells were significantly lower, and CD4 - CD8 - NK T cells were significantly higher in patients with IgAN than in HCs. We validated the significant decrease in MAIT cells in an independent cohort of patients with IgAN., Conclusion: The data indicate that patients with IgAN have increased circulating CSM and DN B cells associated with abnormal T cell immunity, involving defects in unconventional T cell frequency. This may suggest putative alterations at mucosal sites because of cell migration leading to altered IgA production., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Cholesterol crystal embolism (CCE) is an underrecognized multisystemic disease caused by the displacement of cholesterol crystals from atheromatous aortic plaques to distal vascular beds, leading to ischemic injury of target organs, particularly the kidneys, i.e., atheroembolic renal disease (ARD). According to recent research, cellular necrosis, induced by crystal-induced cytotoxicity, enhances the autoinflammatory cascade of the NLPR3 inflammasome, leading in turn to the so-called "necroinflammation". The purported involvement of the latter in CCE offers a rationale for the therapeutic approach with anti-inflammatory drugs such as glucocorticoids, the use of which has long been a matter of debate in CCE. Diagnostic delay and no consistent evidence regarding efficacious treatment, leading to inconsistency in clinical practice, may worsen the already poor prognosis of ARD. The possible role of glucocorticoids in the treatment of ARD is thereby herein explored in a narrative fashion, analyzing the limited data from case reports and clinical trials.

Despite the advances in the immunosuppressive therapies and improvements in short term allograft survival, Antibody-mediated rejection (AMR) still represents the leading cause of late allograft failure in kidney transplant recipients. We present an insidious case of late active AMR that evolved into a severe chronic active antibody-mediated rejection, that we treated with a multidrug approach. Then, we review the current literature on the pathogenesis, diagnosis and treatment of AMR. Antibody-mediated rejection (AMR) typically occurs when anti-HLA donor-specific antibodies (DSA) bind to vascular endothelial cells of the kidney graft. DSAs may preexist to transplantation (preformed DSA) or develop after transplantation (de novo DSA). Pathogenetic mechanisms of AMR involve complement-dependent, and -independent inflammatory pathways that are variably activated depending on antigen and antibody characteristics, or on whether rejection develops early (0-6 months) or late (beyond 6 months) post-transplantation. The Banff classification system categorizes AMR rejection into active antibody-mediated rejection, chronic active antibody-mediated rejection, and chronic (inactive) antibody-mediated rejection. Currently, there are no approved therapies, treatment guidelines being based on low-quality evidence. Therefore, standard of care therapy is consensus-based. In early rejection, it is usually based on plasma exchange, intravenous immune globulin, anti-CD20 antibodies, while complement-inhibitor eculizumab is used in severe and/or refractory cases, treatments with. Recent evidence suggests that late AMR may be effectively treated with anti-CD38 therapy, which targets long lived plasma cells and NK cells., (Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.)

Background and Aims: Hospitalized patients often have acute kidney disease (AKD) or chronic kidney disease (CKD), with important metabolic and nutritional consequences. Moreover, in case kidney replacement therapy (KRT) is started, the possible impact on nutritional requirements cannot be neglected. On this regard, the present guideline aims to provide evidence-based recommendations for clinical nutrition in hospitalized patients with KD., Methods: The standard operating procedure for ESPEN guidelines was used. Clinical questions were defined in both the PICO format, and organized in subtopics when needed, and in non-PICO questions for the more general topics. The literature search was from January 1st, 1999 until January 1st, 2020. Each question led to one or more recommendation/statement and related commentaries. Existing evidence was graded, as well as recommendations and statements were developed and agreed upon in a multistage consensus process., Results: The present guideline provides 32 evidence-based recommendations and 8 statements, defining how to assess nutritional status, how to define patients at risk, how to choose the route of feeding, and how to integrate nutrition with KRT. In the final online voting, a strong consensus was reached in 84% at least of recommendations and 100% of statements., Conclusion: The presence of KD in hospitalized patients identifies a highly heterogeneous group of subjects with widely varying nutrient needs and intakes. Considering the high nutritional risk related with this clinical condition, an individualized approach consisting of nutritional status evaluation and monitoring, frequent evaluation of nutritional requirements, and careful integration with KRT should be planned to avoid both underfeeding and overfeeding. Practical recommendations and statements were developed, aiming at defining suggestions for everyday clinical practice in the individualization of nutritional support in this patient setting. Literature areas with scarce or without evidence were also identified, thus requiring further basic or clinical research., Competing Interests: Conflict of interest The expert members of the working group were accredited by the ESPEN Guidelines Group, the ESPEN Education and Clinical Practice Committee, and the ESPEN executive. All expert members have declared their individual conflicts of interest according to the rules of the International Committee of Medical Journal Editors (ICMJE). If potential conflicts were indicated, they were reviewed by the ESPEN guideline officers and, in cases of doubts, by the ESPEN executive. None of the expert panel had to be excluded from the working group or from co-authorship because of serious conflicts. The conflict of interest forms are stored at the ESPEN guideline office and can be reviewed with legitimate interest upon request to the ESPEN executive., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Gastrointestinal severe adverse events such as ulceration and perforation have been reported for sodium or calcium polystyrene sulfonate and sevelamer. Howewer, their role in the pathogenesis is unclear. Chronic kidney disease is a well known risk factor, while the role of hypertension and/or diabetes is uncertain., Methods: A meta-analysis of the published literature was conducted to review the clinical features, risk factors and histopathological findings of patients who experienced gastrointestinal adverse events after administration of polystyrene sulfonate or sevelamer., Results: The meta-analysis indicated that patients were more likely to show necrosis and/or perforation when the resin used was polystyrene sulfonate compared to sevelamer (p < 0.001). Death was more likely in patients taking polystyrene sulfonate compared to sevelamer (p < 0.001)., Discussion: The results show that sevelamer is more likely to lead to inflammation or ulceration in the gastrointestinal tract than polystyrene sulfonate, which is more likely to be associated with severe gastrointestinal adverse events such as necrosis and/or perforation. Polystyrene sulfonate is significantly associated with death compared to sevelamer., (Copyright © 2024 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Introduction: It is unclear whether kidney transplant recipients with a biopsy diagnosis as a "borderline" acute T-cell mediated rejection (TCMR) requires the treatment with intravenous (iv) steroids pulse plus/minus intensification of the maintenance therapy (TRT) in comparison with the simple clinical follow-up (F-UP)., Methods: We retrospectively followed a consecutive series of kidney transplant recipients diagnosed with a borderline acute TCMR at biopsy by surveillance or clinical indication for 12 months and compared TRT and F-UP groups. We evaluated trends in renal function by measuring estimated glomerular filtration rate (eGFR) using multiple regression models. Repeated eGFR measures (REML) were adjusted for potential confounding factors for 12 months. The difference in 12-month eGFR values were observed in the TRT vs F-UP groups, type of biopsy, as well as the surveillance vs. clinical outcomes., Results: Out of 59 included patients, 37% of them were in the TRT group and remaining 63% in the F-UP group. As expected, the TRT group had, at the time of biopsy, lower eGFR value of 39.0 ml/min/m2 [16.5] in comparison to 49.6 [19.6] ml/min/m 2 in the F-UP group (P = 0.043), Similarly, the TRT group required more frequent clinical biopsies vs. F-UP group (68% vs. 32%; P = 0.014). However, the TRT group recovered kidney function reaching the eGFR values of the F-UP group at 12 months; the increase being significant only in patients who received indication biopsies (P < 0.001). The estimated adjusted TRT effect on 12-month eGFR change after indication biopsy was improved by +15.8 ml/min/1.73m 2 (95%CI: +0.1 to +31.4 ml/min/1.73 m2; P = 0.048 by three-way interaction term) compared to the F-UP group., Conclusion: Our preliminary study supports the indication for the treatment of acute borderline TCMR only in cases with biopsies performed by clinical indication., Competing Interests: Declaration of competing interest All the authors declared no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Estimation of muscle mass is a pivotal component in the diagnosis of protein-energy wasting and sarcopenia. While bioimpedance spectroscopy is a widely  accepted technique for the assessment of lean tissue related to the diagnosis of sarcopenia, to date skeletal muscle ultrasound (US) has not gained full acceptance for this purpose. The aim of this study was to assess the predictive value for mortality of the indexed thickness of the quadriceps vastus intermedius, as measured by US, compared to lean tissue index as estimated by bioimpedance spectroscopy, both combined with handgrip strength in a group of patients with end-stage kidney disease (ESKD) on maintenance hemodialysis (HD)., Methods: The cut-off values for low handgrip strength were < 27 kg for males and < 16 kg for females. The cut-off value for low lean tissue index was obtained from an age-matched healthy control group, with low lean tissue index being defined as values below the 10th percentile of the distribution of healthy subjects. The cut-off values for low quadriceps vastus intermedius thickness index were < 3.44 mm/m 2 for males and < 3.52 mm/m 2 for females., Results: Ultrasound and bioimpedance spectroscopy were performed in 99 patients, and handgrip strength was assessed in 64 patients, all on maintenance HD. After a median follow-up of 28 months (interquartile range 19-41 months) 38 patients died. Lean tissue index was not associated with mortality, while low quadriceps vastus intermedius thickness index and low handgrip strength were associated with an increased hazard of death. In the fully adjusted model, only the combination of low handgrip strength and low quadriceps vastus intermedius thickness index was significantly associated with higher mortality., Conclusion: When combined with low handgrip strength, low quadriceps muscle US outperformed low lean tissue index as assessed by bioimpedance spectroscopy in predicting mortality in a cohort of patients on maintenance HD. Ultrasound may be a useful and convenient technique for the assessment of sarcopenia and protein-energy wasting in this patient population., (© 2024. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Background: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. IgAN causes end-stage kidney disease (ESKD) in 30-40% of all cases. The activation of the complement system by pathological circulating IgAs, which is often associated with low serum C3 levels (LowC3), seems to play a crucial role. Previous studies have shown an association between histological evidence of TMA, which is the result of alternative complement activation, and poor outcomes. However, it is not known to what extent the decrease in serum C3 levels reflects ongoing TMA injury. Our study aimed at assessing the association between LowC3 and ESKD and whether this association reflects ongoing TMA. Methods: We enrolled all patients with biopsy-proven IgAN and followed-up patients until their last visit, ESKD, or death. Results: Of the 56 patients included in the study, 12 (21%) presented low serum C3 (LowC3) at the time of renal biopsy. TMA was significantly more frequent in the LowC3 group [7/12 (58%) vs. 9/44 (20%), p = 0.02]. After adjusting for potential confounders, LowC3 was strongly associated with an increased hazard of ESKD (hazard ratio [HR]: 5.84 [95%CI: 1.69, 20.15; p = 0.005). The association was not affected by adjusting for TMA. The estimated overall proportion of the relation between C3 and ESKD mediated by TMA was low and not statistically significant. Conclusions: Our study provides evidence that C3 hypocomplementemia is associated with an increased risk of ESKD through mechanisms that are largely independent from TMA.

Background: Since primary membranous nephropathy is a heterogeneous disease with variable outcomes and multiple possible therapeutic approaches, all 13 Nephrology Units of the Italian region Emilia Romagna decided to analyze their experience in the management of this challenging glomerular disease., Methods: We retrospectively studied 205 consecutive adult patients affected by biopsy-proven primary membranous nephropathy, recruited from January 2010 through December 2017. The primary outcome was patient and renal survival. The secondary outcome was the rate of complete remission and partial remission of proteinuria. Relapse incidence, treatment patterns and adverse events were also assessed., Results: Median (IQR) follow-up was 36 (24-60) months. Overall patient and renal survival were 87.4% after 5 years. At the end of follow-up, 83 patients (40%) had complete remission and 72 patients (35%) had partial remission. Among responders, less than a quarter (23%) relapsed. Most patients (83%) underwent immunosuppressive therapy within 6 months of biopsy. A cyclic regimen of corticosteroid and cytotoxic agents was the most commonly used treatment schedule (63%), followed by rituximab (28%). Multivariable analysis showed that the cyclic regimen significantly correlates with complete remission (odds ratio 0.26; 95% CI 0.08-0.79) when compared to rituximab (p < 0.05)., Conclusions: In our large study, both short- and long-term outcomes were positive and consistent with those published in the literature. Our data suggest that the use of immunosuppressive therapy within the first 6 months after biopsy appears to be a winning strategy, and that the cyclic regimen also warrants a prominent role in primary membranous nephropathy treatment, since definitive proof of rituximab superiority is lacking., (© 2023. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Background & Aims: Sars-Cov-2 pneumonia can lead to severe complications, requiring invasive mechanical ventilation and admission to the intensive care unit (ICU). Low muscle quantity and quality (the latter evaluated by the amount of ectopic fat infiltration in the muscle [myosteatosis]) at ICU admission are associated with worse outcomes in critically ill patients. The purpose of the present study is to assess muscle mass and myosteatosis of paravertebral skeletal muscle, in critically ill patients with Sars-Cov2 pneumonia and its association with mortality., Methods: We conducted a retrospective observational study in 110 critically ill patients with severe Sars-Cov-2 pneumonia that had a high - resolution chest Computerized Tomography (HR-CT) at ICU admission. We acquired CT images at the level of the thoracic 12 (T12) vertebral body and measured skeletal muscle area (SMA), intermuscular adipose tissue (IMAT), and low attenuation muscle area (LAMA). Patients were followed until ICU mortality or discharge., Results: Patients were 59.8 ± 8.1 years old, 77% were male. Seventy-nine percent of patients were considered at nutritional risk, and 22% were obese. Average Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 17 ± 5.4, and the overall ICU mortality was 48,2% (53/110). At ICU admission, both parameters of myosteatosis were associated with higher mortality (IMAT [per 10% increase] HR: 2.01 (95% Confidence Interval [CI] 1.27 to 3.17), P = 0.003; LAMA HR [per 10% increase]: 1.53 (95% CI 1.10 to 2.13), P = 0.012)., Conclusion: Myosteatosis as assessed by CT scans plays a relevant role as a prognostic marker in critically ill patients with Sars-Cov2 severe pneumonia., (Copyright © 2023 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1-associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele., (© 2023. The Author(s).)

The use of dabigatran in patients with non-valvular atrial fibrillation (AF) has widely increased in the last decades, due to its positive effects in terms of safety/efficacy. However, because of the risk of major bleeding, a great degree of attention has been suggested in elderly patients with multiple comorbidities. Notably, dabigatran mainly undergoes renal elimination and dose adjustment is recommended in patients with Chronic Kidney Disease (CKD). In this regard, the onset of an abrupt decrease of kidney function may further affect dabigatran pharmacokinetic profile, increasing the risk of acute intoxication. Idarucizumab is the approved antagonist in the case of dabigatran-associated major bleeding or concomitant need of urgent surgery, but its clinical use is limited by the lack of data in patients with Acute Kidney Injury (AKI). Thus, the early start of Extracorporeal Kidney Replacement Therapy (EKRT) could be indicated to remove the drug and to reverse the associated excess anticoagulation. Sustained Low-Efficiency Dialysis (SLED) could represent an effective therapeutic option to reduce the dabigatran plasma levels rapidly while avoiding post-treatment rebound. We present here a case series of three AKI patients with acute dabigatran intoxication, effectively and safely resolved with a single SLED session., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Hypophosphatemia is a common electrolyte disorder in critically ill patients undergoing prolonged kidney replacement therapy (KRT). We evaluated the efficacy and safety of a simplified regional citrate anticoagulation (RCA) protocol for continuous venovenous hemofiltration (CVVH), continuous venovenous hemodiafiltration (CVVHDF) and sustained low-efficiency dialysis filtration (SLED-f). We aimed at preventing KRT-related hypophosphatemia while optimizing acid-base equilibrium., Methods: KRT was performed by the Prismax system (Baxter) and polyacrylonitrile AN69 filters (ST 150, 1.5 m2, Baxter), combining a 18 mmol/L pre-dilution citrate solution (Regiocit 18/0, Baxter) with a phosphate-containing solution (HPO42- 1.0 mmol/L, HCO3- 22.0 mmol/L; Biphozyl, Baxter). When needed, phosphate loss was replaced with sodium glycerophosphate pentahydrate (Glycophos™ 20 mmol/20 mL, Fresenius Kabi Norge AS, Halden, Norway). Serum citrate measurements were scheduled during each treatment. We analyzed data from three consecutive daily 8-h SLED-f sessions, as well as single 72-h CVVH or 72-h CVVHDF sessions. We used analysis of variance (ANOVA) for repeated measures to evaluate differences in variables means (i.e. serum phosphate, citrate). Because some patients received phosphate supplementation, we performed analysis of covariance (ANCOVA) for repeated measures modelling phosphate supplementation as a covariate., Results: Forty-seven patients with acute kidney injury (AKI) or end stage kidney disease (ESKD) requiring KRT were included [11 CVVH, 11 CVVHDF and 25 SLED-f sessions; mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score 25 ± 7.0]. Interruptions for irreversible filter clotting were negligible. The overall incidence of hypophosphatemia (s-P levels <2.5 mg/dL) was 6.6%, and s-P levels were kept in the normality range irrespective of baseline values and the KRT modality. The acid-base balance was preserved, with no episode of citrate accumulation., Conclusions: Our data obtained with a new simplified RCA protocol suggest that it is effective and safe for CVVH, CVVHDF and SLED, allowing to prevent KRT-related hypophosphatemia and maintain the acid-base balance without citrate accumulation., Trial Registration: NCT03976440 (registered 6 June 2019)., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Sepsis-Associated Acute Kidney Injury is a life-threatening condition leading to high morbidity and mortality in critically ill patients admitted to the intensive care unit. Over the past decades, several extracorporeal blood purification therapies have been developed for both sepsis and sepsis-associated acute kidney injury management. Despite the widespread use of extracorporeal blood purification therapies in clinical practice, it is still unclear when to start this kind of treatment and how to define its efficacy. Indeed, several questions on sepsis-associated acute kidney injury and extracorporeal blood purification therapy still remain unresolved, including the indications and timing of renal replacement therapy in patients with septic vs. non-septic acute kidney injury, the optimal dialysis dose for renal replacement therapy modalities in sepsis-associated acute kidney injury patients, and the rationale for using extracorporeal blood purification therapies in septic patients without acute kidney injury. Moreover, the development of novel extracorporeal blood purification therapies, including those based on the use of adsorption devices, raised the attention of the scientific community both on the clearance of specific mediators released by microorganisms and by injured cells and potentially involved in the pathogenic mechanisms of organ dysfunction including sepsis-associated acute kidney injury, and on antibiotic removal. Based on these considerations, the joint commission of the Italian Society of Anesthesiology and Critical Care (SIAARTI) and the Italian Society of Nephrology (SIN) herein addressed some of these issues, proposed some recommendations for clinical practice and developed a common framework for future clinical research in this field., (© 2023. The Author(s).)

Black Americans have a significantly higher risk of developing chronic kidney disease (CKD), especially focal segmental glomerulosclerosis (FSGS), than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of Black Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1 -associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.

Background & Aims: Sarcopenia is prevalent in patients with end-stage kidney disease (ESKD) on hemodialysis (HD), and is associated with poor outcomes, while obesity may be protective. Sarcopenic obesity is associated with increased frailty, morbidity and mortality in the general population. Myosteatosis, i.e., muscle fat infiltration, has major effects on muscle strength and physical performance, but is poorly investigated in the nephrology setting. In the present study we aimed to assess the association between sarcopenic obesity, as diagnosed by abdominal CT, and mortality. Moreover, the relationship between myosteatosis, sarcopenic obesity and mortality was also investigated., Methods: This is a retrospective study in which ESKD patients on HD submitted to unenhanced abdominal CT for clinical reasons at least 6 months after dialysis initiation were evaluated for sarcopenic obesity and myosteatosis, defined as intermuscular fat area and low attenuation muscle area. Sarcopenic obesity was diagnosed in cases of low abdominal skeletal muscle area and high total fat area. Receiver-operating characteristics (ROC) analysis with Youden index was used to determine the cut-off for high total fat area. Intermuscular fat area and low attenuation muscle area were evaluated by applying the Hounsfield unit of interest (-190; -30, and -29; +29 respectively). Cox regression analysis was used to evaluate the association between predictors and mortality risk., Results: We enrolled 212 patients, aged 68.8 (±14.7) years, 65.5% (139/212) male. Median follow-up was 19.7 (interquartile range [IQR] 2.7-35) months. Sarcopenic obesity was diagnosed in 19.8% of patients and was associated with increased mortality (HR: 3.29 (1.72; 6.27), P < 0.001), and with the presence of myosteatosis. Both intermuscular fat area and low attenuation muscle area were associated with increased mortality in adjusted analyses., Conclusions: Patients with sarcopenic obesity have increased myosteatosis. Sarcopenic obesity and myosteatosis are associated with increased mortality in patients on HD., (Copyright © 2023 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Significance Statement: Congenital obstructive uropathy (COU) is a prevalent human developmental defect with highly heterogeneous clinical presentations and outcomes. Genetics may refine diagnosis, prognosis, and treatment, but the genomic architecture of COU is largely unknown. Comprehensive genomic screening study of 733 cases with three distinct COU subphenotypes revealed disease etiology in 10.0% of them. We detected no significant differences in the overall diagnostic yield among COU subphenotypes, with characteristic variable expressivity of several mutant genes. Our findings therefore may legitimize a genetic first diagnostic approach for COU, especially when burdening clinical and imaging characterization is not complete or available., Background: Congenital obstructive uropathy (COU) is a common cause of developmental defects of the urinary tract, with heterogeneous clinical presentation and outcome. Genetic analysis has the potential to elucidate the underlying diagnosis and help risk stratification., Methods: We performed a comprehensive genomic screen of 733 independent COU cases, which consisted of individuals with ureteropelvic junction obstruction ( n =321), ureterovesical junction obstruction/congenital megaureter ( n =178), and COU not otherwise specified (COU-NOS; n =234)., Results: We identified pathogenic single nucleotide variants (SNVs) in 53 (7.2%) cases and genomic disorders (GDs) in 23 (3.1%) cases. We detected no significant differences in the overall diagnostic yield between COU sub-phenotypes, and pathogenic SNVs in several genes were associated to any of the three categories. Hence, although COU may appear phenotypically heterogeneous, COU phenotypes are likely to share common molecular bases. On the other hand, mutations in TNXB were more often identified in COU-NOS cases, demonstrating the diagnostic challenge in discriminating COU from hydronephrosis secondary to vesicoureteral reflux, particularly when diagnostic imaging is incomplete. Pathogenic SNVs in only six genes were found in more than one individual, supporting high genetic heterogeneity. Finally, convergence between data on SNVs and GDs suggest MYH11 as a dosage-sensitive gene possibly correlating with severity of COU., Conclusions: We established a genomic diagnosis in 10.0% of COU individuals. The findings underscore the urgent need to identify novel genetic susceptibility factors to COU to better define the natural history of the remaining 90% of cases without a molecular diagnosis., (Copyright © 2023 by the American Society of Nephrology.)

Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations-eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations., (© 2023. The Author(s).)

Renal replacement therapies (RRT) are essential to support critically ill patients with severe acute kidney injury (AKI), providing control of solutes, fluid balance and acid-base status. To maintain the patency of the extracorporeal circuit, minimizing downtime periods and blood losses due to filter clotting, an effective anticoagulation strategy is required.Regional citrate anticoagulation (RCA) has been introduced in clinical practice for continuous RRT (CRRT) in the early 1990s and has had a progressively wider acceptance in parallel to the development of simplified systems and safe protocols. Main guidelines on AKI support the use of RCA as the first line anticoagulation strategy during CRRT in patients without contraindications to citrate and regardless of the patient's bleeding risk.Experts from the SIAARTI-SIN joint commission have prepared this position statement which discusses the use of RCA in different RRT modalities also in combination with other extracorporeal organ support systems. Furthermore, advise is provided on potential limitations to the use of RCA in high-risk patients with particular attention to the need for a rigorous monitoring in complex clinical settings. Finally, the main findings about the prospective of optimization of RRT solutions aimed at preventing electrolyte derangements during RCA are discussed in detail., (© 2023. The Author(s).)

Klebsiella pneumoniae is the most common Klebsiella species infecting animals and is one of the causing agents of mastitis in cows. The rise of antimicrobial resistance in K. pneumoniae, particularly in strains producing extended-spectrum β-lactamases (ESBLs) and/or carbapenemases, is of concern worldwide. Recently (Regulation UE No 2022/1255), carbapenems and cephalosporins in combination with β-lactamase inhibitors have been reserved only to human treatments in the European Union. The aim of this study was to investigate the role of cattle as carrier of human pathogenic carbapenem-resistant (CR) and ESBL-producing K. pneumoniae. On this purpose, a study involving 150 dairy farms in Parma province (Northern Italy) and 14 non replicate K. pneumoniae isolates from patients admitted at Parma University-Hospital was planned. Four multidrug resistant (MDR) K. pneumoniae strains were detected from 258 milk filters collected between 2019 and 2021. One carbapenemase KPC-3-positive K. pneumoniae ST307 (0.4 %; 95 % CI - 0.07 - 2.2) was detected in milk filters. The isolate also harboured OXA-9, CTX-M-15 and SHV-106 determinants, together with genes conferring resistance to aminoglycosides (aac(3')-IIa, aph (3″)-Ib, aph (6)-Id), fluoroquinolones (oqxA, oqxB, qnrB1), phosphonic acids (fosA6), sulphonamides (sul2), tetracyclines (tet(A)6) and trimethoprim (dfrA14). One KPC-3-producing K. pneumoniae ST307 was identified also among the human isolates, thus suggesting a possible circulation of pathogens out of the clinical settings. The remaining three bovine isolates were MDR ESBL-producing K. pneumoniae characterized by different genomic profiles: CTX-M-15, TEM-1B and SHV-187 genes (ST513); CTX-M-15 and SHV-145 (ST307); SHV-187 and DHA-1 (ST307). Occurrence of ESBL-producing K. pneumoniae in milk filters was 1.2 % (95 % CI 0.4-3.4). All the isolates showed resistance to aminoglycosides, 3rd-generation cephalosporins, and fluoroquinolones. Among the human isolates, two multidrug resistant ESBL-producing K. pneumoniae ST307 were found, thus confirming the circulation of this high-risk lineage between humans and cattle. Our findings suggest that food-producing animals can carry human pathogenic microorganisms harboring resistance genes against carbapenems and 3rd-generation cephalosporins, even if not treated with such antimicrobials. Moreover, on the MDR K. pneumoniae farms, the antimicrobial use was much higher than the Italian median value, thus highlighting the importance of a more prudent use of antibiotics in animal productions., Competing Interests: Declaration of competing interest On behalf of the authors of the manuscript entitled “Detection of carbapenemase- and ESBL-producing Klebsiella pneumoniae from bovine bulk milk and comparison with clinical human isolates in Italy” I do declare we have no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Immunoglobulin A (IgA) nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and it is characterized by mesangial IgA deposition. Asymptomatic hematuria with various degrees of proteinuria is the most common clinical presentation and up to 20%-40% of patients develop end-stage kidney disease within 20 years after disease onset. The pathogenesis of IgAN involves four sequential processes known as the "four-hit hypothesis" which starts with the production of a galactose-deficient IgA1 (gd-IgA1), followed by the formation of anti-gd-IgA1 IgG or IgA1 autoantibodies and immune complexes that ultimately deposit in the glomerular mesangium, leading to inflammation and injury. Although several key questions about the production of gd-IgA1 and the formation of anti-gd-IgA1 antibodies remain unanswered, a growing body of evidence is shedding light on the innate and adaptive immune mechanisms involved in this complex pathogenic process. Herein, we will focus on these mechanisms that, along with genetic and environmental factors, are thought to play a key role in disease pathogenesis., Competing Interests: Paolo Cravedi is an advisor for Chinook Therapeutics and Calliditas Therapeutics. The other authors have no conflict of interest to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background/objectives: Estimation of muscle mass is an integral part of nutritional assessment in End-Stage Kidney Disease (ESKD) patients on chronic hemodialysis (HD). In this respect, muscle ultrasound (US) is a valid and reliable tool but has not been previously related to outcomes in this population. Aims of this study were to assess the relationship between quadriceps muscle thickness as assessed by US and outcomes in ESKD patients on HD; we also compared US with anthropometry and malnutrition inflammation score (MIS)., Subjects/methods: In this prospective study, 181 prevalent patients on HD were included. Thickness of the quadriceps rectus femoris and vastus intermedius (VIT) were assessed separately using ultrasonography, and were indexed for height squared. Mid-arm muscle circumference (MAMC) and area (MAMA) were assessed by anthropometry. MIS was evaluated. In the absence of predetermined cut-offs, values below the median of the distribution of VIT index were considered low. Instead, cut-off for anthropometric values such as MAMC and MAMA were set at ≥90% of agreement with the 50th percentile of the sex- and age-specific normal distribution. Cox-regression analysis was used to assess the association of US, MIS, and anthropometric parameters with mortality., Results: Patients were followed for a median of 35 months. During this period 36% of patients died. Multivariable Cox-regression analysis (adjusted for demographic, biochemical and clinical variables), demonstrated that higher VIT distal index values were independently associated with lower mortality risk (HR: 0.76 (0.59-0.99); P = 0.040), whilst higher MIS values were independently associated with higher (HR 1.22 (1.10-1.35); P < 0.001) mortality risk. When assessing muscle parameters as categorical variables, both low VIT distal index (HR: 1.71 (1.01-2.89); 0.045) and MAMC (HR: 1.74 (1.02-2.96); 0.042) were independently associated with increased risk of death., Conclusion: Indexed distal VIT was independently associated with mortality both as continuous and as a categorical variable. Muscle US is a simple practical tool that adds prognostic information to the bedside nutritional assessment in ESKD patients on maintenance HD., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: In patients admitted to the Intensive Care Unit (ICU), Kidney Replacement Therapy (KRT) is an important risk factor for hypophosphataemia. However, studies addressing the development of hypophosphatemia during prolonged intermittent KRT modalities are lacking. Thus, we evaluated the incidence of hypophosphatemia during Sustained Low-Efficiency Dialysis (SLED) in ICU patients; we also examined the determinants of post-SLED serum phosphate level (s-P) and the relation between s-P and phosphate supplementation and ICU mortality., Methods: We conducted a retrospective analysis on a cohort of critically ill patients with severe renal failure and KRT need, who underwent at least three consecutive SLED sessions at 24-72 h time intervals with daily monitoring of s-P concentration. SLED with Regional Citrate Anticoagulation (RCA) was performed with either conventional dialysis machines or continuous-KRT monitors and standard dialysis solutions. When deemed necessary by the attending physician, intravenous phosphate supplementation was provided by sodium glycerophosphate pentahydrate. We used mixed-effect models to examine the determinants of s-P and Cox proportional hazards regression models with time-varying covariates to examine the adjusted relation between s-P, intravenous phosphate supplementation and ICU mortality., Results: We included 65 patients [mean age 68 years (SD 10.0); mean Acute Physiology and Chronic Health Evaluation II score 25 (range 9-40)] who underwent 195 SLED sessions. The mean s-P before the start of the first SLED session (baseline s-P) was 5.6 ± 2.1 mg/dL (range 1.5-12.3). Serum phosphate levels at the end of each SLED decreased with increasing age, SLED duration and number of SLED sessions (P < .05 for all). The frequency of hypophosphatemia increased after the first through the third SLED session (P = .012). Intravenous phosphate supplementation was scheduled after 12/45 (26.7%) SLED sessions complicated by hypophosphataemia. The overall ICU mortality was 23.1% (15/65). In Cox regression models, after adjusting for potential confounders and for current s-P, intravenous phosphate supplementation was associated with a decrease in ICU mortality [adjusted hazard ratio: 0.24 (95% confidence interval: 0.06 to 0.89; P = 0.033)]., Conclusions: Hypophosphatemia is a frequent complication in critically ill patients undergoing SLED with standard dialysis solutions, that worsens with increasing SLED treatment intensity. In patients undergoing daily SLED, phosphate supplementation is strongly associated with reduced ICU mortality., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

The capacity to deliver intradialytic parenteral nutrition (IDPN) for patients on hemodialysis (HD) diagnosed with protein energy wasting (PEW) in low resource settings is unknown. This study aimed to examine the extent of IDPN practice in HD units in Malaysia, and its implementation to treat PEW. We surveyed pharmacists (n = 56), who are central to parenteral nutrition delivery in Malaysia including IDPN. Seventeen healthcare stakeholders engaging with the Promoting Action on Research Implementation in Health Services (PARIHS) framework used the Likert scale to rate survey outcomes on IDPN implementation to treat PEW, according to the Evidence, Context, and Facilitation elements. IDPN for HD patients was available in 28 of 56 hospitals providing parenteral nutrition services, with only 13 hospitals (23.2%) providing IDPN to outpatients. Outpatient treatment was concentrated to urban locations (12/13) and significantly associated (p < 0.001) with resident nephrologists. The Evidence domain was rated poorly (2.18 ± 0.15) pertaining to IDPN indication when the oral spontaneous intake was ≤20 kcal/kg/day. The Context domain indicated good adherence to international best practice relating to IDPN administration (4.59 ± 0.15) and infusion time (4.59 ± 0.12). Poor adherence was observed in the Facilitation domain on ’Access to pharmacist and dietitian at HD units’ (2.65 ± 0.21) and ’Access to continuous medical education on managing PEW patients on HD’ (2.53 ± 0.15). The IDPN outpatient service was concentrated to urban hospitals with greater manpower resources. The PARIHS evaluation on IDPN implementation to treat PEW revealed facilitators in good practice adherence for prescribing and administration of IDPN but highlighted major barriers relating to IDPN indication and nutrient calculation.

Introduction: Proliferative lupus nephritis (LN) progresses to end-stage kidney disease (ESKD) in roughly 10% of the cases despite treatment. Other than achieving <0.8 g/24h proteinuria at 12 months after treatment, early biomarkers predicting ESKD or death are lacking. Recent studies encompassing not only LN have highlighted the central role of the alternative complement pathway (ACP), with or without histological evidence of thrombotic microangiopathy (TMA), as a key promotor of renal death., Methods: We assessed whether persistent isolated C3 hypocomplementemia (PI-LowC3), that is not accompanied by C4 hypocomplementemia, 6 months after kidney biopsy, is associated with an increased risk of death or ESKD in proliferative LN., Results: We retrospectively followed-up 197 patients with proliferative LN (51 with PI-LowC3) for a median of 4.5 years (interquartile-range: 1.9-9.0), 11 of whom died and 22 reached ESKD. After adjusting for age, gender, ethnicity, hypertension, mycophenolate, or cyclophosphamide use, PI-LowC3 was associated with a hazard ratio [HR] of the composite outcome ESKD or death of 2.46 (95% confidence interval [CI]: 1.22-4.99, P  = 0.012). These results were confirmed even after controlling for time-varying estimated glomerular filtration rate (eGFR) measurements in joint longitudinal-survival multiple regression models. After accounting for the competing risk of death, PI-LowC3 patients showed a strikingly increased risk of ESKD (adjusted HR 3.41, 95% CI: 1.31-8.88, P  = 0.012)., Conclusion: Our findings support the use of PI-LowC3 as a low-cost readily available biomarker, allowing clinicians to modify treatment strategies early in the course of disease and offering a rationale for complement blockade trials in this particularly at-risk subgroup of LN patients., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Hemodialysis is associated with high morbidity and mortality rates as well as low quality of life. Altered nutritional status and protein-energy wasting are important indicators of these risks. Maintaining optimal nutritional status in patients with hemodialysis is a critical but sometimes overlooked aspect of care. Nutritional support strategies usually begin with dietary counseling and oral nutritional supplements. Patients may not comply with this advice or oral nutritional supplements, however , or compliance may be affected by other complications of progressive chronic kidney disease. Intradialytic parenteral nutrition (IDPN) may be a possibility in these cases, but lack of knowledge on practical aspects of IDPN delivery are seldom discussed and may represent a barrier. In this review, we, as a consensus panel of clinicians experienced with IDPN, survey existing literature and summarize our views on when to use IDPN, which patients may be best suited for IDPN, and how to effectively deliver and monitor this strategy for nutritional support., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Objective: Malnutrition is a prevalent condition in maintenance hemodialysis (MHD) patients. This study aimed to evaluate the performance of the recently developed GLIM (Global Leadership Initiative on Malnutrition) in MHD by assessing the agreement, accuracy, sensitivity, specificity, and survival prediction of GLIM when compared to 7-point subjective global assessment (7p-SGA) and malnutrition inflammation score (MIS)., Design and Methods: We investigated 2 cohorts: MHD ltaly (121 adults from Italy; 67 ± 16 years, 65% men, body mass index 25 ± 5 kg/m 2 ) and MHD Brazil (169 elderly [age > 60 years] from Brazil; 71 ± 7 years, 66% men, body mass index 25 ± 4 kg/m 2 ), followed for all-cause mortality for median 40 and 17 months, respectively. We applied the 2-step approach from GLIM: (1) screening and (2) confirming malnutrition by phenotypic and etiologic criteria. For 7p-SGA and MIS, a score ≤5 and ≥8, respectively, defined malnutrition., Results: Malnutrition was present in 38.8% by GLIM, 25.6% by 7p-SGA, and 29.7% by MIS in the MHD Italy cohort, and in 47.9% by GLIM, 59.8% by 7p-SGA, and 49.7% by MIS in the MHD Brazil cohort. Cohen's kappa coefficient (κ) showed only "fair" agreement between GLIM and SGA (MHD Italy : κ = 0.26, P = .003; MHD Brazil : κ = 0.22, P = .003) and between GLIM and MIS (MHD Italy : κ = 0.33, P < .001; MHD Brazil : κ = 0.25, P = .001). Cox regression analysis showed that all 3 methods were able to predict mortality in crude analysis; however in the adjusted model, the association seemed more consistent and stronger in magnitude for 7p-SGA and MIS., Conclusion: In MHD patients, GLIM showed low agreement, sensitivity, and accuracy in identifying malnourished subjects by either 7p-SGA or MIS. Considering the specific wasting characteristics that predominate in MHD, the well-established 7p-SGA and MIS methods may be more useful in this clinical setting., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

This study is focused on resistance to carbapenems and third-generation cephalosporins in Gram-negative microorganisms isolated from swine, whose transmission to humans via pork consumption cannot be excluded. In addition, the common carriage of carbapenem-resistant (CR) bacteria between humans and pigs was evaluated. Sampling involved 300 faecal samples collected from slaughtered pigs and 300 urine samples collected from 187 hospitalised patients in Parma Province (Italy). In swine, MIC testing confirmed resistance to meropenem for isolates of Pseudomonas aeruginosa and Pseudomonas oryzihabitans and resistance to cefotaxime and ceftazidime for Escherichia coli , Ewingella americana , Enterobacter agglomerans , and Citrobacter freundii . For Acinetobacter lwoffii , Aeromonas hydrofila, Burkolderia cepacia , Corynebacterium indologenes , Flavobacterium odoratum , and Stenotrophomonas maltophilia , no EUCAST MIC breakpoints were available. However, ESBL genes ( bla CTXM-1 , bla CTX-M-2 , bla TEM-1 , and bla SHV ) and AmpC genes ( bla CIT , bla ACC , and bla EBC ) were found in 38 and 16 isolates, respectively. P. aeruginosa was the only CR species shared by pigs (4/300 pigs; 1.3%) and patients (2/187; 1.1%). P. aeruginosa ST938 carrying bla PAO and bla OXA396 was detected in one pig as well as an 83-year-old patient. Although no direct epidemiological link was demonstrable, SNP calling and cgMLST showed a genetic relationship of the isolates (86 SNPs and 661 allele difference), thus suggesting possible circulation of CR bacteria between swine and humans.

Introduction: Primary focal segmental glomerular sclerosis (FSGS) is a rare, likely immune-mediated disease. Rituximab (RTX) may play a role in management, although data in adults are scanty., Methods: We collected cases of RTX-treated primary FSGS within the Italian Society of Nephrology Immunopathology Working Group and explored response rate (24-hour proteinuria <3.5 g and <50% compared with baseline, stable estimated glomerular filtration rate)., Results: A total of 31 patients were followed for at least 12 months; further follow-up (median 17 months, interquartile range [IQR] 15-33.5) was available for 11. At first RTX administration, median creatinine and 24-hour proteinuria were 1.17 mg/dl (IQR 0.83-1.62) and 5.2 g (IQR 3.3-8.81), respectively. Response rate at 3, 6, and 12 months was 39%, 52%, and 42%, respectively. In the first 12 months, creatinine level remained stable whereas proteinuria and serum albumin level improved, with an increase in the proportion of patients tapering other immunosuppressants. There were 6 patients who were retreated with RTX within 12 months, either for proteinuria increase or refractory disease; only the 2 responders to the first RTX course experienced a further response. At univariate analysis, 6-month response was more frequent in steroid-dependent patients (odds ratio [OR] 7.7 [95% CI 1.16-52.17]) and those with proteinuria <5 g/24 h (OR 8.25 [1.45-46.86]). During long-term follow-up, 4 of 5 responders at 12 months maintained a sustained response, either without further immunosuppression (2 of 4) or with pre-emptive RTX (2 of 4); 1 relapsed and responded to RTX retreatment., Conclusion: RTX may be an option in primary FSGS, especially in steroid-dependent patients, with 24-hour proteinuria <5 g and previously responders to RTX. Optimal long-term management for responders is unclear, with some patients experiencing sustained remission and others requiring RTX retreatment, either preemptive or after rising proteinuria., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Background: IgA nephropathy (IgAN) has been anecdotally reported in association with atypical hemolytic uremic syndrome (aHUS). The association likely portends poor renal outcome, and the possible relationship with complement overactivation has yet to be elucidated. We evaluated a series of IgAN patients with aHUS and reviewed the available literature., Methods: Adult patients who received a diagnosis of IgAN and developed aHUS between January 2009 and December 2019 were included in this retrospective review., Results: We identified six IgAN-aHUS patients, all of whom developed end-stage kidney disease. At aHUS presentation all patients had decreased serum C3 levels. Predisposing pathogenetic variants and risk haplotypes for aHUS in CFH gene heterozygosity were documented in four out of six patients. Anti-CFH antibodies were found to be negative in the five tested patients. In the literature we identified 21 case reports involving aHUS-IgAN and six retrospective studies evaluating the presence of TMA at the time of renal biopsy. Hypertension, severe proteinuria, reduced sC3 and a worse renal prognosis were the common features of most cases., Conclusion: Our case series and literature review show that the onset of either aHUS or renal TMA in the course of IgAN are associated with very poor renal outcome. Activation of the alternative pathway revealed by consumption of serum C3 seems to play a major role. Our hypothesis is that the presence of a predisposing factor (e.g. dysregualtion of complement alternative pathway and/or other intrarenal precipitating factors) might be at the heart of aHUS-IgAN pathophysiology., (© 2021. Italian Society of Nephrology.)

Introduction: The Forkhead box protein P3 (FOXP3) is a transcription factor central to the function of regulatory T cells (Treg). Mutations in the FOXP3 gene lead to a systemic disease called immune dysregulation, polyendocrinopathy, and enteropathy, an X-linked syndrome (IPEX) characterized by the triad of early-onset intractable diarrhea, type 1 diabetes, and eczema. An atypical presentation of IPEX has been reported., Method: We report rare cases with equivocal clinical associations that included inflammatory, kidney, and hematologic involvements screened with massively parallel sequencing techniques., Results: Two patients with hemizygous mutations of FOXP3 [c.779T>A (p.L260Q)] and [c.1087A>G (p.I363V)] presented clinical manifestations not included in typical cases of IPEX: one was a 16-year-old male patient with an initial clinical diagnosis of autoimmune lymphoproliferative syndrome (ALPS) and who developed proteinuria and decreased kidney function due to membranous nephropathy, an autoimmune renal condition characterized by glomerular sub-epithelial antibodies. The second patient was a 2-year-old child with bone marrow failure who developed the same glomerular lesions of membranous nephropathy and received a bone marrow transplantation. High levels of IgG4 in serum, bone marrow, and kidney led to the definition of IgG4-related kidney disease (IgG4 RKD) in this young boy. The circulating Treg levels were normal in the former case and very low in the second., Conclusion: Two atypical associations of functional mutations of FOXP3 that include ALPS and IgG4 RKD are described. Membranous nephropathy leading to renal failure completed in both cases the clinical phenotypes that should be included in the clinical panorama of FOXP3  failure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gentile, Miano, Terranova, Giardino, Faraci, Pierri, Drago, Verzola, Ghiggeri, Verrina, Angeletti, Cafferata, Grossi, Ceccherini, Caridi, Lugani, Nescis, Fiaccadori, Lanino, Fenoglio and La Porta.)

Background and Aim: The novel coronavirus disease 2019 remains challenging. A large number of hospitalized patients are at a high risk of developing AKI. For this reason, we conducted a nationwide survey to assess the incidence and management of AKI in critically ill patients affected by the SARS-CoV-2 infection., Methods: This is a multicenter, observational, nationwide online survey, involving the Italian Society of Nephrology and the critical care units in Italy, developed in partnership between the scientific societies such as SIN and SIAARTI. Invitations to participate were distributed through emails and social networks. Data were collected for a period of 1 week during the COVID-19 pandemic., Results: A total of 141 responses were collected in the SIN-SIAARTI survey: 54.6% from intensivists and 44.6% from nephrologists. About 19,000 cases of COVID-19 infection have been recorded in hospitalized patients; among these cases, 7.3% had a confirmed acute kidney injury (AKI), of which 82.2% were managed in ICUs. Only 43% of clinicians routinely used the international KDIGO criteria. Renal replacement therapy (RRT) was performed in 628 patients with continuous techniques used most frequently, and oliguria was the most common indication (74.05%). Early initiation was preferred, and RRT was contraindicated in the case of therapeutic withdrawal or in the presence of severe comorbidities or hemodynamic instability. Regional anticoagulation with citrate was the most common choice. About 41.04% of the interviewed physicians never used extracorporeal blood purification therapies (EBPTs) for inflammatory cytokine or endotoxin removal. Moreover, 4.33% of interviewed clinicians used these techniques only in the presence of AKI, whereas 24.63% adopted them even in the absence of AKI. Nephrologists made more use of EBPT, especially in the presence of AKI. HVHF was never used in 58.54% of respondents, but HCO membranes and adsorbents were used in more than 50% of cases., Conclusion: This joint SIN-SIAARTI survey at the Italian Society of Nephrology and the critical care units in Italy showed that, during the COVID-19 pandemic, there was an underestimation of AKI based on the "non-use" of common diagnostic criteria, especially by intensivists. Similarly, the use of specific types of RRT and, in particular, blood purification therapies for immune modulation and organ support strongly differed between centers, suggesting the need for the development of standardized clinical guidelines., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 De Rosa, Marengo, Romagnoli, Fiorentino, Fanelli, Fiaccadori, Brienza, Morabito, Pota, Valente, Grasselli, Messa, Giarratano and Cantaluppi.)

Acute kidney injury (AKI), electrolyte, and acid-base disorders complicate the clinical course of critically ill patients with coronavirus-associated disease (COVID-19) and are associated with poor outcomes. It is not known whether the severity of clinical conditions at admission in the intensive care unit (ICU) changes the clinical significance of AKI and/or electrolyte or acid-base disorders developing during ICU stay. We conducted a retrospective study in critically ill patients with COVID-19 to evaluate whether the severity of clinical conditions at admission in the ICU affects the impact of AKI and of serum electrolytes or acid-base status on mortality. We carried out a 28-day retrospective follow-up study on 115 critically ill patients consecutively admitted to ICU for severe COVID-19 at a tertiary care university hospital and surviving longer than 24 h. We collected baseline demographic and clinical characteristics, and longitudinal data on kidney function, kidney replacement therapy, serum electrolytes, and acid-base status. We used Cox proportional hazards multiple regression models to test the interaction between the time-varying variates new-onset AKI or electrolyte or acid-base disorders and Sequential Organ Failure Assessment (SOFA) or Acute Physiology and Chronic Health Evaluation II (APACHE II) score at admission. After adjusting for age, sex, Charlson's comorbidity index, and AKI present at ICU admission, new-onset AKI was significantly associated with 28-day mortality only in the patients in the lowest and middle SOFA score tertiles [lowest SOFA tertile, hazard ratio (HR) 4.27 (95% CI: 1.27-14.44; P = 0.019), middle SOFA tertile, HR 3.17 (95% CI: 1.11-9.04, P = 0.031), highest SOFA tertile, HR 0.77 (95% CI: 0.24-2.50; P = 0.66); P = 0.026 for interaction with SOFA as a continuous variable]. After stratifying for APACHE II tertile, results were similar [adjusted HR (aHR) in the lowest tertile 6.24 (95% CI: 1.85-21.03, P = 0.003)]. SOFA or APACHE II at admission did not affect the relationship of serum electrolytes and acid-base status with mortality, except for new-onset acidosis which was associated with increased mortality, with the HR of death increasing with SOFA or APACHE II score ( P < 0.001 and P = 0.013, respectively). Thus, unlike in the most severe critically ill patients admitted to the ICU for COVID-19, in patients with the less severe conditions at admission the development of AKI during the stay is a strong indicator of increased hazard of death., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Regolisti, Maggiore, Di Mario, Gentile, Benigno, Gandolfini, Pistolesi, Morabito, Barbagallo, Picetti and Fiaccadori.)

Background and Aims: Skeletal muscle (SM) area, as measured by abdominal CT at the level of the third lumbar vertebra (L3), has been proposed as a proxy of whole body muscle mass. However, population-specific reference values are lacking. In the present study we aimed at: (1) detecting low SM area on abdominal CT images in patients on hemodialysis by applying cut-offs derived from a group of healthy subjects, and (2) estimating the independent risk of all-cause mortality associated with low SM area., Methods: We retrospectively enrolled 212 adult patients on hemodialysis, undergoing abdominal CT scan (study group), and 87 healthy kidney donors (reference group). We obtained the gender-specific 5th percentile values of the abdominal SM area distribution from both the whole control group and the subgroup of younger (29-60 years) subjects, which we used as reference cut-offs. Then we applied those cut-offs in the study group to identify patients with low SM area. We used survival and Cox regression analysis to evaluate the risk of all-cause mortality associated with low abdominal SM area., Results: In the fully adjusted Cox regression analysis, the patients with low abdominal SM area had a higher risk of death than the patients with values above the reference cut-off derived in the subgroup of younger controls (adjHR = 1.79 (1.21; 2.67), P = 0.004)., Conclusions: Abdominal CT imaging can be used to detect low abdominal SM area in patients on hemodialysis by applying cut-offs derived from healthy subjects sharing a similar ethnic background. Low SM area as assessed by CT is independently associated with all-cause mortality in ESKD patients on hemodialysis., (© 2021. Italian Society of Nephrology.)

Aim: Acute kidney injury (AKI) shows an increasing incidence, accounting for a remarkable proportion of nephrology team in-hospital activity. The aim was to describe main features and outcomes of AKI observed in patients admitted to a tertiary care hospital., Methods: We conducted a retrospective analysis in all consecutive AKI patients referred for nephrology consultation (November 2018-February 2020) focusing on the factors associated with in-hospital mortality within 90 days and kidney function recovery (KFR) upon discharge. Demographic, clinical and laboratory data, as well as main features of AKI episodes, were collected from medical records of the entire hospital stay. AKI was defined according to KDIGO Clinical Practice Guideline., Results: Among 1145 patients referred for nephrology consultation, 559 were evaluated for AKI (598 episodes). Pre-existing CKD was present in 54.7% of patients. In 69.2% of cases AKI was evaluated within 48 h from its onset. Most of the episodes (66.6%) were classified as KDIGO Stage 3. In-hospital mortality within 90 days since admission was 43.3%. Multivariate Cox regression analysis showed a higher mortality risk for advancing age (HR 1.02/unit, 95% CI 1.01-1.03) and oliguria (HR 1.91, 95% CI 1.45-2.52), while a higher eGFR (HR 0.72/unit, 95% CI 0.54-0.95) and KFR within 7 days (HR 0.62, 95% CI 0.41-0.94) were associated to a lower mortality. KFR was observed in 96.4% of survivors. In patients with partial KFR, the loss of eGFR was -29.2 ± 17.9 ml/min. KFR incidence rate was 6.79 per 100-person days (95% CI 6.72-6.87) in survivors and 2.30 (95% CI 2.25-2.35) in non-survivors., Conclusion: AKI-related nephrology activity accounts for most of the nephrologist workload as consultant. Referred AKI episodes are frequently severe and superimposed on CKD, carrying a relatively high mortality in a patient population developing AKI outside ICU. Early KFR appears strongly associated with a favourable impact upon in-hospital survival., (© 2021 Asian Pacific Society of Nephrology.)