A randomized crossover trial of regional anticoagulation modalities for intermittent hemodialysis.

INTRODUCTION: The optimal regional anticoagulation (RA) of dialysis filters in patients at risk of bleeding remains elusive. Inducing hypocalcemia within the filter by using a calcium-free dialysate has emerged as an easy-to-use heparin-free RA, including in critically ill patients, but comparative studies are lacking. METHODS: We conducted a multicentre, randomized, crossover trial to compare the efficacy and tolerance of two RAs (heparin-coated membrane (HCM) or calcium free dialysate with calcium reinjection according to ionic dialysance (CFD)) in patients requiring hemodialysis and at risk of bleeding. During the study period, each patient received two dialysis sessions (one with each RA in a randomly assigned order). The primary endpoint was the proportion of dialysis sessions completed (≥ 240 min). RESULTS: 94 patients were included in the intention-to-treat analysis, including 16 critically ill patients (17.0%). Coagulation and inflammation parameters, as well as hemodynamic status at baseline, were balanced between groups. Premature coagulation of the filter occurred in 19 HCM (20.9%) compared to 3 (3.2%) CFD sessions. In half of the sessions with premature termination, coagulation occurred before 180 minutes. The proportion of patients who completed the CFD session while failing to complete the HCM session (n = 17) was significantly higher than the proportion of patients who completed the HCM session while failing to complete the CFD session (n = 1; p < 0.001). Hemodynamic and metabolic tolerance were not different between groups. CONCLUSIONS: In individuals at risk of bleeding, RA with calcium-free dialysate significantly reduces the incidence of premature dialysis termination compared to heparin-coated membrane without safety concerns. Trial registration and statistical analysis plan: ClinicalTrials.gov identifier: NCT03842657.

Corrigendum: Severe toxic rhabdomyolysis under combined palbociclib and simvastatin treatment: A case report.

[This corrects the article DOI: 10.3389/fonc.2022.1026434.].

Progression of histological lesions after ABO incompatible kidney transplantation.

Recent large meta-analyses suggested a poorer long-term patients' and grafts' outcomes after ABO incompatible (ABOi) living-donor kidney transplantation (LDKT) compared to ABO compatible LDKT. However, little is known about the long-term histological pattern after ABOi LDKT. We compared the histological features observed on protocol biopsies from 03/11 to 11/19 in 94 ABOi LDKT (including 14 with preformed Donor Specific Antibodies, pDSAs), 27 LDKT ABO compatible (ABOc) with pDSAs, and 21 ABOc without pDSAs) during the first five years post transplantation. During the first 5 years post-transplantation, a progression of chronic lesions (patients with a ci >0 raised from 11% to 65%, p<0.0001, patients with a ct >0 raised from 29% to 78%, p<0.0001) was observed in ABOi LDKT without pDSAs. Histological patterns of evolution were comparable to those observed in ABOc kidney transplant patients. Microvascular inflammation was lower in ABOi LDKT without pDSAs compared to those with pDSAs (ABOi or ABOc). At last follow-up, 28 months, IQR (15-48) post-transplantation, 29 patients (36%) had a severe graft dysfunction (defined by a CKD-epi eGFR < 30 mL/min/1.73m²). The donor age was a predictive factor for the development of severe kidney allograft dysfunction at last follow-up (HR= 1.05, 95% CI [1.05-1.10], p= 0.03). Hence, long-term histological analysis of ABOi LDKT shows only an increase of chronic interstitial and tubular atrophy changes, without active lesions. These data confirm that ABOi LDKT programs can be securely developed.

Anti-SARS-CoV-2 spike protein and neutralizing antibodies at 1 and 3 months after three doses of SARS-CoV-2 vaccine in a large cohort of solid organ transplant patients.

The immunogenicity of the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccine was improved by the administration of a third dose. The aim of our retrospective study was to assess the evolution of binding and neutralizing antibody concentration until 3 months after the third dose in a large cohort of solid organ transplant (SOT) patients (n = 872). At 1 month after the third dose, anti-SARS-CoV-2 antibodies were detected by means of enzyme-linked immunosorbent assay tests in 578 patients (66.3%). In a subgroup of patients, 70% (180 out of 257) had anti-SARS-CoV-2 antibody concentrations ranging from 1.2 to 18 411 binding antibody units (BAU)/ml and 48.5% (115 out of 239) had a neutralizing antibodies titer that can confer clinical protection against SARS-CoV-2. Three-hundred ninety-three patients out of the 416 (94.5%) who were seropositive at month 1 and were tested at 3 months after vaccination remained seropositive. Between months 1 and 3 after vaccination, binding and neutralizing antibodies concentrations decreased significantly. The proportion of protected patients against the SARS-CoV-2 also slightly decreased. In conclusion, this study shows that although two-third of SOT develop anti-SARS-CoV-2 antibodies after three doses, one-third of them remain weak or non-protected. It is important to measure anti-SARS-CoV-2 antibodies to define the strategy that can optimize SOT protection against SARS-CoV-2.

Heparin-free regional anticoagulation of haemodialysis filters with calcium-free dialysate: is citrate mandatory?

BACKGROUND: There is an unmet need to develop safe and successful heparin-free regional anticoagulation modalities in haemodialysed patients at risk of bleeding. Whether the addition of citrate as a prefilter injection or in the dialysate itself is required to reach anticoagulation objectives when calcium-free dialysate is used as regional anticoagulation remains unclear. METHODS: In this monocentric retrospective study, we report our experience of 908 dialysis sessions performed with a calcium-free citrate-containing dialysate and calcium reinjection according to the ionic dialysance, without additional heparin. RESULTS: Premature termination for filter clotting occurred in 20 sessions (2.2%) and duration of session was >4.5 h in 135 (15%; maximum duration 6 h). In addition, we could investigate the citrate, calcium and acid-basis status during haemodialysis sessions performed with (citrate group, n = 20 sessions) or without (citrate-free group, n = 19 sessions) citrate in the dialysate. In 20 sessions performed in patients with underlying liver disorders and using calcium-free citrate-containing dialysate, patients' ionized calcium (iCa) and serum citrate levels were stable and remained within the normal range, respectively. Post-filter iCa was below 0.4 mmol/L in 19/20 sessions and citrate was 0.304 mmol/L (range: 0.011; 0.548). In 19 sessions that used calcium and citrate-free dialysate, post-filter iCa was 0.41 mmol/L (0.34; 0.5) and all sessions extended to 4 h or beyond. CONCLUSIONS: Regional anticoagulation of haemodialysis with a calcium-free dialysate and calcium reinjection according to the ionic dialysance is safe. Adding citrate to the dialysate is not mandatory to prevent dialysis circuit clotting in most patients.

Hemodynamic and Metabolic Tolerance of Acetate-Free Biofiltration in Mechanically Ventilated Critically Ill Patients: A Real-Life Study.

Intradialytic hypotension can lead to superimposed organ hypoperfusion and ultimately worsens long-term kidney outcomes in critically ill patients requiring kidney replacement therapy. Acetate-free biofiltration (AFB), an alternative technique to bicarbonate-based hemodialysis (B-IHD) that does not require dialysate acidification, may improve hemodynamic and metabolic tolerance of dialysis. In this study, we included 49 mechanically ventilated patients requiring 4 h dialysis (AFB sessions n = 66; B-IHD sessions n = 62). Whereas more AFB sessions were performed in patients at risk of hemodynamic intolerance, episodes of intradialytic hypotension were significantly less frequent during AFB compared to B-IHD, whatever the classification used (decrease in mean blood pressure ≥ 10 mmHg; systolic blood pressure decrease >20 mmHg or absolute value below 95 mmHg) and after adjustment on the use of vasoactive agent. Diastolic blood pressure readily increased throughout the dialysis session. The use of a bicarbonate zero dialysate allowed the removal of 113 ± 25 mL/min of CO2 by the hemofilter. After bicarbonate reinjection, the global CO2 load induced by AFB was +25 ± 6 compared to +80 ± 12 mL/min with B-IHD (p = 0.0002). Thus, notwithstanding the non-controlled design of this study, hemodynamic tolerance of AFB appears superior to B-IHD in mechanically ventilated patients. Its use as a platform for CO2 removal also warrants further research.

Weekly high-dose liposomal amphotericin B prevents invasive aspergillosis after heart transplantation.

BACKGROUND: Preventive strategies for invasive aspergillosis (IA) have still not been determined in heart transplant recipients whereas IA leads to a high mortality rate at 12 months posttransplantation. The use of voriconazole or echinocandins was proposed but can favor emergence of Aspergillus or Candida sp. resistant strains or promote neurological and liver disorders in some patients. OBJECTIVES: To assess whether universal prophylaxis with weekly high-dose of liposomal amphotericin-B (L-AmB) can safely prevent IA in heart transplant recipients. PATIENTS/METHODS: Retrospective before/after study that included 142 patients who received heart transplantation between 2010 and 2019 at the University Hospital of Toulouse (France). Weekly high dose of L-AmB (7.5 mg/kg/week) was used as universal prophylaxis from 2016 because of high environmental exposure to Aspergillus sp. and high incidence of IA. RESULTS: Cumulative 1-year incidence of IA decreased from 23% to 5% after introduction of L-Amb prophylaxis. Multivariate analysis (Cox model) identified L-AmB prophylaxis as a protective factor against IA (hazard ratio [HR] 0.21 [95% confidence interval 0; 0.92], p = .04), whereas postoperative renal replacement therapy was associated with IA (HR 3.6 [95% confidence interval 1.38; 9.3], p = .001), after correction for confounding effects (induction regimen, methylprednisolone pulses and history of hematological malignancy). The incidence of acute kidney injury requiring renal replacement therapy was similar in the two groups, suggesting a low risk of kidney toxicity when L-AmB is used weekly. No patient developed severe kidney electrolyte loss nor L-AmB-related anaphylaxis. CONCLUSIONS: Once-weekly high-dose L-AmB is safe and may prevent the development of IA after heart transplantation.

Expression of Exhaustion Markers on CD8+ T-Cell Patterns Predict Outcomes in Septic Patients Admitted to the ICU.

RATIONALE: There is an unmet need to improve the description of the state of T-cell exhaustion in patients with sepsis, its reproducibility and correlation with the outcomes before including immunotherapy (like recombinant interleukin-7 or immune checkpoint inhibitors) in the therapeutic armamentarium against sepsis. DESIGN: Observational prospective study. SETTING: Two ICUs in a teaching hospital (France). PATIENTS: Eighty patients with sepsis admitted to the ICU. INTERVENTIONS: Quantification of CD4+ and CD8+ T-cell exhaustion at days 1 and 3. Quantification of the exhaustion markers (programmed death [PD]-1, 2B4, and cluster of differentiation [CD] 160) on T cells, the number of CD4+ regulatory T cells (CD3+ CD4+ CD25hi CD127Lo cells), and the phorbol myristate acetate/ionomycin/ionomycin-induced cytokines production (tumor necrosis factor-α, interleukin-2, and interferon-γ). MEASUREMENTS AND MAIN RESULTS: Using unsupervised clustering analysis, patients could be split in three clusters according to their dominant pattern expression of exhaustion markers on CD8+ T cells (i.e., 2B4lowPD-1lowCD160low, 2B4hiPD-1hiCD160low, and 2B4hiPD-1lowCD160hi) regardless of their underlying morbidities. Only 2B4hiPD-1hiCD160low CD8+ T cells had cytokine production defect, whereas 2B4hi PD-1lowCD160hi pattern correlated with cytokine overproduction. Patients with a predominant "highly activated" 2B4hiPD-1lowCD160hi pattern did not develop secondary bacterial infections. By multivariate analysis, Simplified Acute Physiology Score 2 gravity score at day 1 (p = 0.003) and patterns of exhaustion markers on CD8+ T cells (p = 0.03) were associated with the risk of death. Neither the level of CD4+ regulatory T cells nor the CD4+ exhaustion patterns were associated with the outcomes. CONCLUSIONS: Easy-to-use multicolor flow cytometry assessing 2B4, PD-1, and CD160 expression on CD8+ T cells at day 1 identifies septic patients with poor outcome and discriminates patient subsets in who immunomodulatory drugs should be tested.

Plasma exchange and thrombotic microangiopathies: From pathophysiology to clinical practice.

Thrombotic microangiopathy (TMA) brings together many diseases that have a commonality in the apparition of mechanical hemolysis with consuming thrombopenia. In all cases, these diseases can be life threatening, thereby justifying the implementation of treatment as an emergency. First-line treatment represents plasma exchange. This treatment has proven efficiency in improving the vital patient's and functional prognosis. However, the administration methods of plasma exchange can be redefined in light of the understanding of the pathophysiology of TMA. The aim of this review is to try to define, from pathophysiology, the place of plasma exchanges in the modern therapeutic arsenal of TMA.

Short- and long-term renal outcomes following severe rhabdomyolysis: a French multicenter retrospective study of 387 patients.

BACKGROUND: Rhabdomyolysis is a life-threatening disease that can lead to severe hyperkalemia, acute kidney injury (AKI) and hypovolemic shock. The predictive factors of AKI and acute to chronic kidney disease (CKD) transition remain poorly described. METHODS: This multicenter retrospective study enrolled 387 patients with severe rhabdomyolysis (CPK > 5000 U/L). Primary end-point was the development of severe AKI, defined as stage 2 or 3 of KDIGO classification. Secondary end-points included the incidence of AKI to CKD transition. RESULTS: Among the 387 patients, 315 (81.4%) developed AKI, including 171 (44.1%) with stage 3 AKI and 103 (26.6%) requiring RRT. Stage 2-3 AKI was strongly correlated with serum phosphate, potassium and bicarbonate at admission, as well as myoglobin over 8000 U/L and the need for mechanical ventilation. 42 patients (10.8%) died before day 28. In the 80 patients with available eGFR values both before and 3 months after the rhabdomyolysis, the decrease in eGFR (greater than 20 mL/min/1.73 m2 in 23 patients; 28.8%) was correlated to the severity of the AKI and serum myoglobin levels > 8000 U/L at admission. CONCLUSIONS: Severe rhabdomyolysis leads to AKI in most patients admitted to an ICU. Mechanical ventilation and severity of the rhabdomyolysis, including myoglobin level, are associated with the risk of stage 2-3 AKI. The long-term renal decline is correlated to serum myoglobin at admission.

Outcomes of solid organ transplant recipients with invasive aspergillosis and other mold infections.

OBJECTIVES: To characterize the clinical presentation and outcomes of invasive mold infections (IMI) in solid organ transplant (SOT) recipients. METHODS: Inclusion of all SOT recipients with IMI diagnosed between 2008 and 2016 at a referral center for SOT. Univariable analyses identified factors associated with death at one year, and logistic regression models retained independent predictors. RESULTS: Of the 1739 patients that received a SOT during this period, 68 developed IMI (invasive aspergillosis [IA] in 58). Cumulative incidence of IMI at 1 year ranged from 1.2% to 18.8% (kidney and heart transplantation, respectively). At baseline, compared with other IMI, the need for vasoactive drugs was more frequent in patients with IA. During follow-up, 35 patients (51%) were admitted to the ICU and required mechanical ventilation (n = 27), vasoactive drugs (n = 31), or renal replacement therapy (n = 31). The need for vasoactive drugs (OR 7.34; P = .003) and a positive direct examination (OR 10.1; P = .004) were independently associated with the risk of death at 1 year in patients with IA (n = 33; 57%) CONCLUSIONS: Characteristics of IMI at presentation varied according to the underlying transplanted organ and the mold species. Following IA, one-year mortality may be predicted by the need for hemodynamic support and initial fungal load.

Anti-IL-2R blockers comparing with polyclonal antibodies: Higher risk of rejection without negative mid-term outcomes after ABO-incompatible kidney transplantation.

There is no recommendation regarding the type of induction therapy to use in ABO-incompatible (ABOi) kidney transplantation. The aim of this retrospective study was to compare the outcome of ABOi living donor kidney transplant (LDKT) recipients who received either polyclonal antibodies or anti-interleukin-2 receptor (IL-2R) blockers as an induction agent. All ABOi HLA-compatible patients that received a LDKT between 03/11 and 03/18 in three French transplantation center (Paris Saint-Louis, Paris Necker, and Toulouse) were included in the study. Fifty-eight patients were given polyclonal antibodies and 39 patients received anti-IL-2R blockers. We identified by a Cox proportional hazard model the use of polyclonal antibodies as a protective factor against acute rejection (HR = 0.4, 95%CI [0-0.9], P < .05). However, pathological findings on protocol biopsies at 1 year were similar in both groups, as were patient and graft survivals, renal function, and complications. We conclude that the acute rejection rate was significantly higher in patients given anti-IL-2R blockers compared to polyclonal antibodies. However, in our series, there was no negative impact on mid-term outcome.

Outcomes of kidney transplant recipients admitted to the intensive care unit: a retrospective study of 200 patients.

BACKGROUND: Risk of over-immunosuppression or immunization may mitigate the overall and long-term renal outcomes of kidney transplant recipients (KTR) admitted to the ICU in the modern era but remain poorly described. Thus, there is an unmet need to better characterize the survival of KTR admitted to the ICU, but also the renal and immunological outcomes of survivors. METHODS: Retrospective observational study that included 200 KTR admitted between 2010 and 2016 to the ICU of a teaching hospital (median age 61 years [IQR 50.7-68]; time from transplantation 41 months [IQR 5-119]). Survival curves were compared using the Log-rank test. RESULTS: Mortality rates following admission to the ICU was low (26.5% at month-6), mainly related to early mortality (20% in-hospital), and predicted by the severity of the acute condition (SAPS2 score) but also by Epstein Barr Virus proliferation in the weeks preceding the admission to the ICU. Acute kidney injury (AKI) was highly prevalent (85.1%). Progression toward chronic kidney disease (CKD) was observed in 45.1% of survivors. 15.1% of survivors developed new anti-HLA antibodies (donor-specific antibodies 9.2% of cases) that may impact the long-term renal transplantation function. CONCLUSIONS: Notwithstanding the potential biases related to the retrospective and monocentric nature of this study, our findings obtained in a large cohort of KTR suggest that survival of KTR admitted in ICU is good but in-ICU management of these patients may alter both survival and AKI to CKD transition, as well as HLA immunization. Further interventional studies, including systematic characterization of the Epstein Barr virus proliferation at the admission (i.e., a potential surrogate marker of an underlying immune paralysis and frailty) will need to address the optimal management of immunosuppressive regimen in ICU to improve survival but also renal and immunological outcomes.

Incidence of Donor-Specific Anti-HLA Antibodies in Non-HLA-Sensitized Patients Given Tacrolimus Once or Twice Daily During the First 2 Years After Kidney Transplant.

OBJECTIVES: Antibody-mediated rejection is a main cause of long-term kidney allograft loss. Nonad-herence and tacrolimus intrapatient variability have been identified as risk factors for developing de novo donor-specific antibodies. Tacrolimus, given once daily, can improve adherence and reduce variabilities among patients. The aim of this retrospective observational study was to compare the incidences of donor-specific antibodies at 2 years posttransplant in de novo kidney transplant recipients given tacrolimus either once or twice daily. MATERIALS AND METHODS: Non-HLA sensitized de novo kidney-transplant recipients given tacrolimus either once daily (n = 82) or twice daily (n = 168), combined with mycophenolic acid with or without steroids, were included in the study. All patients were screened for anti-HLA antibodies before transplant, at 6, 12, and 24 months posttransplant, and each time the patient presented with impaired kidney function. RESULTS: The 2-year incidence of donor-specific antibodies was 2.8%. During the follow-up period, 6 patients (3.6%) receiving tacrolimus twice daily and one patient (1.2%) receiving tacrolimus once daily developed a donor-specific antibody (P = .43). The incidence of antibody-mediated rejection was 4.8% under tacrolimus once daily and 2.7% under tacrolimus twice daily (P = .5). Tacrolimus intrapatient variability was similar with both formulations and was not associated with development of donor-specific antibodies. CONCLUSIONS: The use of tacrolimus-based immunosup-pression associated with mycophenolic acid was associated with a low risk of de novo donor-specific antibodies. After 2 years, the incidence of de novo donor-specific antibodies did not differ significantly between patients treated with tacrolimus once daily versus those treated with the twice-daily formulation.

The Effectiveness of Topical Cerium Nitrate-Silver Sulfadiazine Application on Overall Outcome in Patients with Calciphylaxis.

BACKGROUND: Calciphylaxis (CPX) is a rare and life-threatening disease characterized by vascular calcification and development of painful and necrotizing skin lesions with a challenging management. Mechanisms of CPX are complex and include an imbalance between vascular calcification promoters and inhibitors, and frequently vitamin K deficiency. OBJECTIVES: To describe the various presentations and identify predictive factors of death in patients with CPX. METHODS: In this multicenter retrospective study, we included 71 CPX patients followed in South-West France (n = 26) and in French Polynesia (n = 45), and who all received sodium thiosulfate (25 g thrice weekly for a median of 61 days). RESULTS: Characteristics at presentation significantly differed between metropolitan and Polynesian French patients. Polynesians were less frequently on regular dialysis at the onset of CPX, had a higher incidence of diabetes mellitus and obesity, more disturbances of calcium-phosphorus metabolism, and received vitamin K antagonists less frequently than patients from South-West France. Despite intensive management, the 1-year mortality rate was 66% and median time to death was 200 days (IQR, 40; 514). The number of body areas involved (i.e., three: OR 2.70 [1.09; 6.65], p = 0.031; four: OR 8.79 [1.54; 50.29], p = 0.015) was the only predictive factor for death, whereas application of topical cerium nitrate-silver sulfadiazine was protective (OR 0.44 [0.20; 0.99], p = 0.046). Surgical debridement, hyperbaric oxygenation therapy, and geographical origin were not associated with overall outcomes. CONCLUSIONS: Cerium nitrate may lead to vascular decalcification and chelation of reactive oxygen species, and prevent infection. Cerium nitrate-silver sulfadiazine was associated with better outcomes and should be tested in a prospective comparative trial in CPX patients.