Symptômes psychotiques dans l’épisode maniaque. Un regard de psychiatre libéral

Private practice requires particular vigilance with regard to signs of mood instability in patients with bipolar disorders, in particular the manic aspect, because of the risk of disruption in care. Between the episodes, psychotic symptoms can be sequels or prodroms and, if so, often stereotyped from one episode to the next. During the manic episode, mood-congruent symptoms (grandiosity, possessing superpowers, having a special relationship with God or with celebrities) are most common, but mood-incongruent symptoms (delusions of persecution, auditory hallucinations, first-rank Schneiderian symptoms) are not uncommon. In the absence of delusions or hallucinations, the clinician must be alert to a decline in insight, or when the patient shows symptoms of formal thought disturbances. For certain classical authors, mania was, by itself, a psychotic experience. The relationship between the severity of mania and the existence of psychotic symptoms is strong, but not exclusive. Some patients that have not completely stopped their treatment can have moderate symptoms of mania, albeit with some psychotic symptoms. Congruent and non-congruent psychotic symptoms may persist beyond the manic episode, raising the question of schizoaffective (SA) disorder when elements of a diagnostic criteria for schizophrenia are met. SA is a disputed diagnostic category, whose stability over time is unsatisfactory. The management of psychotic symptoms with mania is difficult in private practice: a clinical case of a female bipolar patient with erotomania before and during manic episodes illustrates the difficulties of management when the patient's insight fluctuates. The side-effects of treatments, a hypomanic switch, induced by an antidepressant despite two mood stabilizers (lithium, valproate), followed by a period of mood instability and a lack of medical coordination had contributed to an interruption in care. Statistical multivariate analyses and the grouping of symptoms and patients together with factor and network analyses suggest a partial independence of psychotic symptoms from other manic symptoms and, in cluster analyses, the likelihood of a subgroup of manic patients with psychotic symptoms.     

Foot care knowledge,attitudes and practices among patients with diabetic foot and amputation in St. Kitts and Nevis

About one‐third of admissions to the surgical unit annually are diabetes foot infections in need of amputation In St. Kitts and Nevis. However, the risk factors related to diabetes foot and amputation remain unknown. This study investigated factors associated with diabetic foot and amputation (DFA). Retrospective case control study design, and purposive and quota sampling method was used to recruit the participants. Patients with and without DFA were interviewed at two main hospitals, several primary health centres, and a private doctor's office during July and August 2018. Self‐development questionnaires were applied to assess patients' demographic, physical and behaviour, foot care knowledge, attitudes, and practices related to DFA. Chi‐square, t‐test, and multiple logistic regressions were used to analyse the data. A total of 210 patients were evaluated, 89 had DFA, while 121 did not, with a mean age of 61.10 (SD = 11.85). Participants' responses indicated good knowledge, favourable attitudes, and adequate practices related to foot care. The two items of the questionnaire, ways to maintain blood flow in the lower extremities and wash their feet daily, had significant lower score in DFA group. In multiple logistic regression, knowledge, attitudes, and practices related to foot care were not a significant predictor of DFA. Being male was a predictor of DFA than female (OR = 3.53; 95% CI = 1.65‐7.57; P < .01). Participants who were currently unemployed were less likely to have DFA than those who were employed (OR = 0.38; 95% Cl = 0.17‐0.86; P < .05). Comparing patients with the longest experience of diabetes mellitus (31 years or more) with those who had diabetes for the shortest period of time (between 1 and 10 years) was less likely to have DFA (OR = 0.38; 95% CI = 0.15‐0.97; P = <.05). The combination of these independent variables could explain 29% of the variance in DFA. Based on these findings, strategies to prevent diabetic foot and amputation should focus on male and outdoor heavy worker, and longer duration of diabetes patients which are identified in this study.     

Tailored use of belatacept in adolescent kidney transplantation

Adolescent transplant recipients are at risk for nonadherence, development of de novo donor‐specific antibody (dnDSA), and allograft loss. Belatacept, a selective T cell costimulatory blocker, is associated with reduced dnDSA, improved renal function, and prolonged allograft survival when compared to calcineurin inhibitor‐based regimens in adults; however, its use in children is scant. Three adolescents were initiated on belatacept between August 2017 and September 2018 at the time of kidney transplantation. Selection criteria included age ≥ 14 and EBV IgG + serostatus. Intraoperative alemtuzumab and methylprednisolone were given as induction therapy. Tailored maintenance therapy included steroid‐free belatacept and sirolimus for two patients. One patient was initially maintained steroid‐free on belatacept and belimumab, an inhibitor of B cell activating factor to treat concurrent systemic lupus erythematous; steroids were added subsequently. Renal function, biopsy‐proven rejection, dnDSA, allograft survival, infection, nonadherence, and proteinuria were monitored. Renal function was 86, 73, 52 mL/min/1.73 m² at 20, 20, and 8 months, respectively. There was 100% adherence to therapy and no development of dnDSA. All patients had treatable infections. One developed steroid‐responsive acute cellular rejection. Belatacept‐based regimens can be tailored for adolescent recipients with good short‐term clinical outcomes.     

A prospective,iterative, adaptive trial of carfilzomib‐based desensitization

Proteasome inhibitor–based strategies hold promise in transplant but have yielded varying results. Carfilzomib, a second‐generation proteasome inhibitor, may possess advantages over bortezomib, the first‐generation proteasome inhibitors. The purpose of this study was to evaluate the safety, toxicity, and preliminary efficacy of carfilzomib in highly HLA‐sensitized kidney transplant candidates. Renal transplant candidates received escalating doses of carfilzomib followed by plasmapheresis (group A) or an identical regimen with additional plasmapheresis once weekly before carfilzomib dosing. Thirteen participants received carfilzomib, which was well tolerated with most adverse events classified as low grade. The safety profile was similar to bortezomib desensitization; however, neurotoxicity was not observed with carfilzomib. Toxicity resulted in permanent dose reduction in 1 participant but caused no withdrawals or deaths. HLA antibodies were substantially reduced with carfilzomib alone, and median maximal immunodominant antibody reduction was 72.8% (69.8% for group A, P = .031, 80.1% for group B, P = .938). After depletion, rebound occurred rapidly and antibody levels returned to baseline between days 81 and 141. Bone marrow studies revealed that approximately 69.2% of plasma cells were depleted after carfilzomib monotherapy. Carfilzomib monotherapy–based desensitization provides an acceptable safety and toxicity profile while leading to significant bone marrow plasma cell depletion and anti‐HLA antibody reduction.     

A randomized,phase 1b study of the pharmacokinetics,pharmacodynamics, safety,and tolerability of bleselumab,a fully human,anti‐CD40 monoclonal antibody,in kidney transplantation

This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of various doses of the anti‐CD40 monoclonal antibody bleselumab (ASKP1240) in de novo kidney transplant recipients receiving concomitant standard immunosuppression over 90 days posttransplant. Transplant recipients were randomized (1:1:1:1:1) to bleselumab 50 mg, 100 mg, 200 mg, or 500 mg, or placebo, in addition to standard maintenance immunosuppression. The primary pharmacokinetic endpoints were AUC_inf, C_max, and AUC_last. The primary pharmacodynamic endpoint was B cell CD40 receptor occupancy over time. Overall, 50 kidney transplant recipients were randomized; 45 received their randomized treatment (bleselumab [n = 37] or placebo [n = 8]). AUC_inf and AUC_last demonstrated a more than dose‐proportional increase in the range of 50‐500 mg, and C_max increased linearly with increasing dose. Maximal receptor occupancy for B cell CD40 was reached at all dose levels and was prolonged as dose increased. No kidney transplant recipients experienced cytokine release syndrome or a thromboembolic event. Treatment‐emergent anti‐bleselumab antibodies were found in one kidney transplant recipient in the bleselumab 50 mg group; these were detected only at Day 7. Overall, bleselumab demonstrated nonlinear pharmacokinetics and dose‐dependent prolonged B cell CD40 receptor occupancy and was well tolerated at all doses (ClinicalTrials.gov: NCT01279538).     

Intravenous immunoglobulin significantly reduces exposure of concomitantly administered anti‐C5 monoclonal antibody tesidolumab

Awareness of drug‐drug interactions is critical in organ transplant recipient management. However, biologic agents interfering with monoclonal antibodies is not widely considered. We report the effect of high‐dose intravenous immunoglobulin (IVIg) on safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of the human anti‐C5 monoclonal antibody tesidolumab (LFG316) in end‐stage renal disease patients awaiting kidney transplant. In this single‐center, phase 1, open‐label, parallel‐group study, 8 patients were assigned to receive either single‐dose tesidolumab + IVIg or tesidolumab alone, with 56‐day follow‐up. Within‐group PK parameters were consistent. Mean tesidolumab exposure decreased 34%, clearance increased 63%, and half‐life decreased 41% comparing tesidolumab + IVIg to tesidolumab alone. IVIg influence on tesidolumab elimination was most evident in the first 3 weeks. Complete suppression of both total and alternative complement activities was maintained for 4 weeks in the tesidolumab alone group and for 2 weeks in the tesidolumab + IVIg group. Tesidolumab was well tolerated. IVIg infused before tesidolumab affected tesidolumab PK and PD, resulting in a shortened period of full complement activity inhibition. These findings suggest a clinically relevant impact of IVIg on monoclonal antibody clearance and indirectly hint at an IVIg mechanism of action in treating autoimmune diseases and allosensitization by accelerating pathogenic IgG antibody degradation. Trial registration number: NCT02878616.     

Kidney retransplantation after anti–programmed cell death‐1 (PD‐1)–related allograft rejection

In this report, we describe the first kidney retransplantation performed after anti–programmed cell death‐1 (PD‐1)–related allograft rejection. In 2014, we administered pembrolizumab (anti–PD‐1) for ~9 months to a 57‐year‐old kidney transplant recipient with metastatic cutaneous squamous cell carcinoma (CSCC). The patient experienced both a complete antitumor response and T cell–mediated allograft rejection requiring reinitiation of hemodialysis. Four‐and‐a‐half years after initiating pembrolizumab, the patient remained without evidence of CSCC relapse and received a kidney transplant from a living‐unrelated donor. Ten‐and‐a‐half months after kidney retransplantation, the allograft is functioning well and the patient's CSCC remains in remission. This case illustrates the potential for PD‐1 blockade to bring about durable immune‐mediated tumor control in chronically immunosuppressed patients, and begins to address the feasibility of kidney retransplantation in patients who have previously received immune checkpoint inhibitor therapy for cancer. Results from this and future cases may help elucidate mechanisms of antitumor immunity and allograft tolerance, and inform updates to transplant decision models. Our report also underscores the need for clinical trials testing novel immunotherapy combinations in solid organ transplant recipients designed to uncouple antitumor and anti‐allograft immunity.     

Molecular diagnosis of kidney transplant failure based on urine

In light of the organ shortage, there is a great responsibility to assess postmortal organs for which procurement has been consented and to increase the life span of transplanted organs. The former responsibility has moved many centers to accept extended criteria organs. The latter responsibility requires an exact diagnosis and, if possible, omission of the harmful influence on the transplant. We report the course of a kidney transplant that showed a steady decline of function over a decade, displaying numerous cysts of different sizes. Clinical workup excluded the most frequent causes of chronic transplant failure. The filed allocation documents mentioned the donor’s disease of oral‐facial‐digital syndrome, a rare ciliopathy, which can also affect the kidney. Molecular diagnosis was performed by culturing donor tubular cells from the recipient´s urine more than 10 years after transplantation. Next‐generation panel sequencing with DNA from tubular urinary cells revealed a novel truncating mutation in OFD1, which sufficiently explains the features of the kidney transplants, also found in the second kidney allograft. Despite this severe donor disease, lifesaving transplantation with good long‐term outcome was enabled for 5 recipients.