Autoreactive T cells target peripheral nerves in Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is a rare heterogenous disorder of the peripheral nervous system, which is usually triggered by a preceding infection, and causes a potentially life-threatening progressive muscle weakness1. Although GBS is considered an autoimmune disease, the mechanisms that underlie its distinct clinical subtypes remain largely unknown. Here, by combining in vitro T cell screening, single-cell RNA sequencing and T cell receptor (TCR) sequencing, we identify autoreactive memory CD4+ cells, that show a cytotoxic T helper 1 (TH1)-like phenotype, and rare CD8+ T cells that target myelin antigens of the peripheral nerves in patients with the demyelinating disease variant. We characterized more than 1,000 autoreactive single T cell clones, which revealed a polyclonal TCR repertoire, short CDR3ß lengths, preferential HLA-DR restrictions and recognition of immunodominant epitopes. We found that autoreactive TCRß clonotypes were expanded in the blood of the same patient at distinct disease stages and, notably, that they were shared in the blood and the cerebrospinal fluid across different patients with GBS, but not in control individuals. Finally, we identified myelin-reactive T cells in the nerve biopsy from one patient, which indicates that these cells contribute directly to disease pathophysiology. Collectively, our data provide clear evidence of autoreactive T cell immunity in a subset of patients with GBS, and open new perspectives in the field of inflammatory peripheral neuropathies, with potential impact for biomedical applications.

[Living-donor robotic-assisted kidney transplantation: French academic center experience]. / Transplantation rénale robot-assistée avec donneur vivant : expérience d'un centre universitaire français.

INTRODUCTION: The main objective was to report the intra-, post-operative and functional outcomes of living-donor robotic-assisted kidney transplantation (RAKT), performed by a surgeon skilled in robotic surgery. The secondary objective was to compare the results of RAKT, based on the surgeon's experience. METHODS: For this retrospective cohort study, we analyzed data from consecutive patients who underwent living-donor RAKT from July 2015 to March 2020 and compared the results of RAKT according to the surgeon's experience (group 1: 1-14th RAKT versus group 2: 15-29th RAKT). RESULTS: Twenty-nine living-donor RAKT were performed. The median age and BMI of the recipients were: 57.0 (44.0-66.0) years and 32.7 (23.5-39.6)kg/m2. The median overall operative time and median console time were: 140.0 (122.5-165.0) and 120.0 (107.5-137.5) minutes. The median rewarming time, arterial, venous and urinary anastomoses durations were: 35.0 (27.5-45.0), 15.0 (11.0-20.0), 12.0 (10.0-16.0), 20.0 (16.0-23.0) minutes. Two (6.9%) minor and 5 (17.2%) major (Clavien-Dindo≥III) postoperative complications occurred. At 2 years of follow-up, patient and transplant survival was 100% (n=29) and 93.1% (n=27). After the 14th RAKT, the rewarming time (P=0.01) and venous anastomosis duration (P=0.004) were statistically shorter. CONCLUSION: Living-donor robotic-assisted kidney transplantation, performed by a surgeon skilled robotic surgery, ensures good functional results in the medium term. LEVEL OF EVIDENCE: 3.

[Renal cell carcinoma in candidates for renal transplantation and recipients of a kidney transplant: The French guidelines from CTAFU]. / Recommandations françaises du Comité de transplantation de l'association française d'urologie (CTAFU) : carcinome rénal sur reins natifs chez le patient transplanté rénal ou en attente de transplantation.

OBJECTIVE: To define guidelines for the management of renal cell carcinoma of the native kidney (NKRCC) in kidney transplant (KTx) recipients and renal cell carcinoma (RCC) in end-stage renal disease (ESRD) patients candidates for renal transplantation. METHOD: A review of the literature following a systematic approach (Medline) was conducted by the CTAFU to report renal cell carcinoma epidemiology, screening, diagnosis and management in KTx candidates and recipients. References were assessed according to a predefined process to propose recommendations with the corresponding levels of evidence. RESULTS: ESRD patients are at higher risk of RCC with a standardized incidence ratio of approximately 4,5 as compared with general population. NKRCC tumors occur in 1 to 3 % of KTx recipients with a 10 to 15-fold increased risk as compared with general population, especially in patients with acquired multicystic kidney disease. Most authors suggest yearly monitoring of the native kidneys using ultrasound imaging. Radical nephrectomy (either open or laparoscopic approach) is the preferred treatment of NKRCC in KTx recipients and RCC in ESRD. Surveillance in a valid option in small or cystic renal masses. In the localized setting, change in immunosuppressive therapy is not recommended besides perioperative avoidance of mTOR inhibitor to limit morbidity. CTAFU does not recommend a mandatory waiting time after nephrectomy for RCC in ESRD patients candidates for renal tranplantation when tumor stage

[Living donor nephrectomy: The French guidelines from CTAFU]. / Recommandations françaises du Comité de transplantation de l'Association française d'urologie (CTAFU) : néphrectomie pour don de rein.

OBJECTIVE: To propose surgical recommendations for living donor nephrectomy. METHOD: Following a systematic approach, a review of the literature (Medline) was conducted by the CTAFU regarding functional and anatomical assessment of kidney donors, including which side the kidney should be harvested from. Distinct surgical techniques and approaches were evaluated. References were considered with a predefined process to propose recommendations with the corresponding levels of evidence. RESULTS: The recommendations clarify the legal and regulatory framework for kidney donation in France. A rigorous assessment of the donor is one of the essential prerequisites for donor safety. The impact of nephrectomy on kidney function needs to be anticipated. In case of modal vascularization of both kidneys without a relative difference in function or urologic abnormality, removal of the left kidney is the preferred choice to favor a longer vein. Mini-invasive approaches for nephrectomy provide faster donor recovery, less donor pain and shorter hospital stay than open surgery. CONCLUSION: These French recommendations must contribute to improving surgical management of candidates for kidney donation.

[Urinary stones in renal transplant recipients and donors: The French guidelines from CTAFU]. / Recommandations françaises du Comité de transplantation de l'association française d'urologie (CTAFU) : lithiase urinaire chez le receveur ou le donneur en transplantation rénale.

OBJECTIVE: To define guidelines for the management of kidney stones in kidney transplant (KTx) donor or recipients. METHOD: Following a systematic approach, a review of the literature (Medline) was conducted by the CTAFU to report kidney stone epidemiology, diagnosis and management in KTx donors and recipients with the corresponding level of evidence. RESULTS: Prevalence of kidney stones in deceased donor is unknown but reaches 9.3% in living donors in industrialized countries. Except in Maastrich 2 donors, diagnosis is done on systematic pre-donation CT scan according to standard french procedure. No prospective study has compared therapeutic strategies available for the management of kidney stones in KTx donor: ureteroscopy or an extra corporeal lithotripsy in case of living donor prior to donation, ex vivo approach (pyelotomy or ureteroscopy), ureterocopy in the KTx recipient or surveillance. De novo kidney stones result from a lithogenesis process to be identified and treated in order to avoid recurrences. The context of solitary functional kidney renders the prevention of recurrence of great importance. Diagnosis is suspected when identification of a renal graft dysfunction, hematuria or urinary tract infection with renal pelvis dilatation. Stone size and location are determined by computed tomography. There are no prospective, controlled studies on kidney stone management in the KTx. The therapeutic strategies are similar to standard management in general population. CONCLUSION: These French recommendations should contribute to improve kidney stones management in KTx donor and recipients.

Management of renal transplant urolithiasis: a multicentre study by the French Urology Association Transplantation Committee.

PURPOSE: Urolithiasis is rare among renal transplant recipients and its management has not been clearly defined. METHODS: This multicentre retrospective study was organised by the Comité de Transplantation de l'Association Française d'Urologie (French Urology Association transplantation committee). Statistical analysis was performed with SPSS 19 software. RESULTS: Ninety-five patients were included in this study. Renal transplant urolithiasis was an incidental finding in 55% of cases, mostly on a routine follow-up ultrasound examination. One half of symptomatic stones were due to urinary tract infection and the other half were due to an episode of acute renal failure. The initial management following diagnosis of urolithiasis was double J stenting (27%), nephrostomy tube placement (21%), or watchful waiting (52%). Definitive management consisted of: watchful waiting (48%), extracorporeal lithotripsy (13%), rigid or flexible ureteroscopy (26%), percutaneous nephrolithotomy (11%) and surgical pyelotomy (2%). All transplants remained functional following treatment of the stone. The main limitation is the retrospective design. CONCLUSIONS: The incidence of lithiasis could be higher in kidney transplanted patients due to a possible anatomical or metabolical abnormalities. The therapeutic management of renal transplant urolithiasis appears to be comparable to that of native kidney urolithiasis.

Prostate cancer before renal transplantation: A multicentre study.

INTRODUCTION: The surgical issues of renal transplantation (RT) after localized prostate cancer (PC) treatment and oncological outcomes after transplantation in patients on the waiting list with a history of PC were unknown. We conducted a retrospective multicentre study including all patients with PC diagnosed before the kidney transplantation. METHODS: Fifty-two patients were included from December 1993 to December 2015. The median age at diagnosis of PC was 59.8years old. RESULTS: The median PSA rate at diagnosis was 7ng/mL. Twenty-seven, Twenty-four, and one PC were respectively low, intermediate and high risk according to d'Amico classification. Forty-three patients were treated by radical prostatectomy (RP): 28 retropubic, 15 laparoscopic and 3 by a perineal approach. Eighteen patients had a lymph node dissection. Four patients were treated with external radiotherapy and 2 by brachytherapy. Eight patients underwent radiotherapy after surgery. The median time between PC treatment and RT was 35.7 months. The median operating time for the renal transplantation was 180min (IQR 150-190; min 90-max 310) with a median intraoperative bleeding of 200mL (IQR 100-290; min 50-max 2000). A history of lymphadenectomy did not significantly lengthen operative time (P=0.34). No recurrence of PC was observed after a median follow of 36months. CONCLUSION: PC discovered before RT should be treated with RP to assess the risk of recurrence and decrease waiting for a RT. If the PC is at low risk of recurrence, it seems possible to shorten the waiting time before the RT after a multidisciplinary discussion meeting. LEVEL OF EVIDENCE: 4.

Allelic and Epitopic Characterization of Intra-Kidney Allograft Anti-HLA Antibodies at Allograft Nephrectomy.

The reasons for the increased incidence of de novo anti-human leukocyte antibody (HLA) donor-specific antibodies (DSAs) observed after kidney allograft nephrectomy are not fully understood. One advocated mechanism suggests that at graft loss, DSAs are not detected in the serum because they are fixed on the nonfunctional transplant; removal of the kidney allows DSAs to then appear in the blood circulation. The aim of our study was to compare anti-HLA antibodies present in the serum and in the graft at the time of an allograft nephrectomy. Using solid-phase assays, anti-HLA antibodies were searched for in the sera of 17 kidney transplant patients undergoing allograft nephrectomy. No anti-HLA antibodies were detected in the graft if they were not also detected in the serum. Eleven of the 12 patients who had DSAs detected in their sera also had DSAs detected in the grafts. Epitopic analysis revealed that most anti-HLA antibodies detected in removed grafts were directed against the donor. In summary, our data show that all anti-HLA antibodies that were detected in grafts were also detected in the sera. These intragraft anti-HLA antibodies are mostly directed against the donor at an epitopic level but not always at an antigenic level.

[Polycystic kidney disease and kidney transplantation]. / Prise en charge de la polykystose rénale autosomique dominante avant transplantation rénale.

OBJECTIVES: To perform a state of the art about autosomal dominant polykystic kidney disease (ADPKD), management of its urological complications and end stage renal disease treatment modalities. MATERIAL AND METHODS: An exhaustive systematic review of the scientific literature was performed in the Medline database (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) using different associations of the following keywords (MESH): "autosomal dominant polykystic kidney disease", "complications", "native nephrectomy", "kidney transplantation". Publications obtained were selected based on methodology, language, date of publication (last 10 years) and relevance. Prospective and retrospective studies, in English or French, review articles; meta-analysis and guidelines were selected and analyzed. This search found 3779 articles. After reading titles and abstracts, 52 were included in the text, based on their relevance. RESULTS: ADPKD is the most inherited renal disease, leading to end stage renal disease requiring dialysis or renal transplantation in about 50% of the patients. Many urological complications (gross hematuria, cysts infection, renal pain, lithiasis) of ADPKD required urological management. The pretransplant evaluation will ask the challenging question of native nephrectomy only in case of recurrent kidney complications or large kidney not allowing graft implantation. The optimum timing for native nephrectomy will depend on many factors (dialysis or preemptive transplantation, complication severity, anuria, easy access to transplantation, potential living donor). CONCLUSION: Pretransplant management of ADPKD is challenging. A conservative strategy should be promoted to avoid anuria (and its metabolic complications) and to preserve a functioning low urinary tract and quality of life. When native nephrectomy should be performed, surgery remains the gold standard but renal arterial embolization may be a safe option due to its low morbidity.

Role of Sphingosine-1-Phosphate in Transplant Vasculopathy Evoked by Anti-HLA Antibody.

Transplant vasculopathy (TV) represents the main cause of late graft failure and limits the long-term success of organ transplantation. Cellular and humoral immune responses contribute to the pathogenesis of the concentric and diffuse intimal hyperplasia of arteries of the grafted organ. We recently reported that the mitogenic signaling, evoked in human vascular smooth muscle cells (hmSMC) by the anti-HLA class I monoclonal antibody W6/32, implicates neutral sphingomyelinase-2, suggesting a role for sphingolipids in intimal hyperplasia of TV. Here, we investigated whether the mitogenic sphingolipid, sphingosine-1-phosphate (S1P), is involved in intimal hyperplasia elicited by W6/32. Studies were done on cultured hmSMC and on an in vivo model of TV, consisting of human mesenteric arteries grafted into SCID/beige mice, injected weekly with W6/32. hmSMC migration and DNA synthesis elicited by W6/32 were inhibited by the sphingosine kinase-1 (SK1) inhibitor dimethylsphingosine, the anti-S1P antibody Sphingomab and the S1PR1/R3 inhibitor VPC23019. W6/32 stimulated SK1 activity, while siRNA silencing SK1, S1PR1 and S1PR3 inhibited hmSMC migration. In vivo, Sphingomab significantly reduced the intimal thickening induced by W6/32. These data emphasize the role of S1P in intimal hyperplasia elicited by the humoral immune response, and open perspectives for preventing TV with S1P inhibitors.