Factors Associated With Genotypic Resistance and Outcome Among Solid Organ Transplant Recipients With Refractory Cytomegalovirus Infection.

Genotypically resistant cytomegalovirus (CMV) infection is associated with increased morbi-mortality. We herein aimed at understanding the factors that predict CMV genotypic resistance in refractory infections and disease in the SOTR (Solid Organ Transplant Recipients) population, and the factors associated with outcomes. We included all SOTRs who were tested for CMV genotypic resistance for CMV refractory infection/disease over ten years in two centers. Eighty-one refractory patients were included, 26 with genotypically resistant infections (32%). Twenty-four of these genotypic profiles conferred resistance to ganciclovir (GCV) and 2 to GCV and cidofovir. Twenty-three patients presented a high level of GCV resistance. We found no resistance mutation to letermovir. Age (OR = 0.94 per year, IC95 [0.089-0.99]), a history of valganciclovir (VGCV) underdosing or of low plasma concentration (OR= 5.6, IC95 [1.69-20.7]), being on VGCV at infection onset (OR = 3.11, IC95 [1.18-5.32]) and the recipients' CMV negative serostatus (OR = 3.40, IC95 [0.97-12.8]) were independently associated with CMV genotypic resistance. One year mortality was higher in the resistant CMV group (19.2 % versus 3.6 %, p = 0.02). Antiviral drugs severe adverse effects were also independently associated with CMV genotypic resistance. CMV genotypic resistance to antivirals was independently associated with a younger age, exposure to low levels of GCV, the recipients' negative serostatus, and presenting the infection on VGCV prophylaxis. This data is of importance, given that we also found a poorer outcome in the patients of the resistant group.

Specificities of Meningitis and Meningo-Encephalitis After Kidney Transplantation: A French Retrospective Cohort Study.

Kidney transplant recipients develop atypical infections in their epidemiology, presentation and outcome. Among these, meningitis and meningoencephalitis require urgent and adapted anti-infectious therapy, but published data is scarce in KTRs. The aim of this study was to describe their epidemiology, presentation and outcome, in order to improve their diagnostic and management. We performed a retrospective, multicentric cohort study in 15 French hospitals that included all 199 cases of M/ME in KTRs between 2007 and 2018 (0.9 case per 1,000 KTRs annually). Epidemiology was different from that in the general population: 20% were due to Cryptococcus neoformans, 13.5% to varicella-zoster virus, 5.5% to Mycobacterium tuberculosis, and 4.5% to Enterobacteria (half of which produced extended spectrum beta-lactamases), and 5% were Post Transplant Lymphoproliferative Disorders. Microorganisms causing M/ME in the general population were infrequent (2%, for Streptococcus pneumoniae) or absent (Neisseria meningitidis). M/ME caused by Enterobacteria, Staphylococci or filamentous fungi were associated with high and early mortality (50%-70% at 1 year). Graft survival was not associated with the etiology of M/ME, nor was impacted by immunosuppression reduction. Based on these results, we suggest international studies to adapt guidelines in order to improve the diagnosis and the probabilistic treatment of M/ME in SOTRs.

Anatomical variations of the renal artery based on the surgeon's direct observation: A French perspective.

INTRODUCTION: Renal arterial vasculature presents a great anatomical variation. A good knowledge of this anatomy is essential in the field of kidney transplantation. The aim of this study is to describe the anatomical variations of the renal arterial vasculature based on the retrieved but not transplanted kidneys (RNTK) and their contralateral grafted kidneys (CGK), which anatomy is described by surgeons themselves after aortic dissection during multi-organ procurement (MOP). MATERIAL AND METHODS: Using the "Crystal" database of the French "Agence de la biomédecine" (ABM), all RNTK were retrospectively selected over one year. Then, the arterial anatomy of each RNTK and their CGK was studied using the surgical and the histopathological reports. The surgical report was completed by the surgeon at the end of the MOP from deceased donors. The qualitative variables were expressed in numbers (percentage of the population) and were compared by a Chi2 test or an exact Fisher test depending on the sample size. A P-value of less than 0.05 was considered statistically significant. RESULTS: In total, 356 kidneys were studied (241 RNTK - 115 CGK), 69% had a single artery and 31% had multiple arteries (26% with two arteries and 5% with three or more). The incidence of multiple arteries was similar between the right and left kidneys (32% vs. 30% respectively). A modal arrangement with 1 artery on each side was present in 51% of cases. Thus, 1 in 2 donors had at least 2 arteries on one side. Multiple arteries were bilateral in 12% of cases. The RNTK group presented more kidneys with multiple arteries than the CGK group (35% vs. 22%). CONCLUSION: Our study shows a higher incidence of multiple renal arteries than the literature (31% vs. 25%). Thus, MOP can be considered as an accurate and reliable method of describing renal arterial anatomy, especially that some small arteries may be missed when using radiological or cadaveric dissection techniques.

[Impact of the COVID-19 pandemic on surgical activity within academic urological departments in Paris]. / Impact de la pandémie de COVID-19 sur l'activité chirurgicale au sein des services d'urologie de l'Assistance Publique ­ Hôpitaux de Paris.

INTRODUCTION: As a result of the COVID-19 pandemic in France, all non-emergency surgical activity has been cancelled since March 12, 2020. In order to anticipate the reinstatement of delayed interventions, surgical activity reduction analysis is essential. The objective of this study was to evaluate the reduction of urological surgery in adult during the COVID-19 pandemic compared to 2019. MATERIAL: The data regarding urological procedures realized in the 8 academic urological departments of Parisians centres (AP-HP) were compared over two similar periods (14-29 March 2019 and 12-27 March 2020) using the centralized surgical planning software shared by these centres. Procedure title, type of surgery and outpatient ratio were collected. The interventions were sorted into 16 major families of urological interventions. RESULTS: Overall, a 55% decrease was observed concerning urological procedures over the same period between 2019 and 2020 (995 and 444 procedures respectively). Oncology activity and emergencies decreased by 31% and 44%. The number of kidney transplantations decreased from 39 to 3 (-92%). Functional, andrological and genital surgical procedures were the most impacted among the non-oncological procedures (-85%, -81% and -71%, respectively). Approximatively, 1033 hours of surgery have been delayed during this 16-day period. CONCLUSION: Lockdown and postponement of non-urgent scheduled urological procedures decisions has led to a drastic decrease in surgical activity in AP-HP. Isolated kidney transplantation has been stopped (national statement). Urologists must anticipate for lockdown exit in order to catch-up delayed surgeries. LEVEL OF EVIDENCE: 3.

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.

Unique case report of a chromomycosis and Listeria in soft tissue and cerebellar abscesses after kidney transplantation.

BACKGROUND: Chromomycosis is a rare mycotic infection encountered in tropical and subtropical regions. The disease presents as a slowly-evolving nodule that can become infected with bacteria. Here, we describe a unique association of abscesses caused by a chromomycosis and Listeria monocytogenes in a kidney transplant recipient, and didactically expose how the appropriate diagnosis was reached. CASE PRESENTATION: A 49-year old male originating from the Caribbean presented a scalp lesion which was surgically removed in his hometown where it was misdiagnosed as a sporotrichosis on histology, 3 years after he received a kidney transplant. He received no additional treatment and the scalp lesion healed. One year later, an abscess of each thigh due to both F. pedrosoi and L. monocytogenes was diagnosed in our institution. A contemporary asymptomatic cerebellar abscess was also found by systematic MRI. An association of amoxicillin and posaconazole allowed a complete cure of the patient without recurring to surgery. Histological slides from the scalp lesion were re-examined in our institution and we retrospectively concluded to a first localisation of the chromomycosis. We discuss the possible pathophysiology of this very unusual association. CONCLUSION: In this case of disseminated listeriosis and chromomycosis, complete cure of the patients could be reached with oral anti-infectious treatment only.

[Ischemia-reperfusion. Preservation solution and hypothermic machine perfusion]. / Ischémie­reperfusion. Liquides de conservation et machines de perfusion en transplantation rénale.

AIMS: To describe ischemia-reperfusion mechanisms, the impact on kidney graft and strategies developed to minimize ischemia-reperfusion damages. 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: ischemia-reperfusion; organ preservation; hypothermic machine perfusion; renal transplantation. Publications obtained were selected based on methodology, language, date of publication and relevance. Prospective and retrospective studies, in English or French, review articles; meta-analysis and guidelines were selected and analyzed. This search found 1293 articles. After reading titles and abstracts, 88 were included in the text, based on their relevance. RESULTS: Ischemia-reperfusion injuries occur when blood supply of an organ is interrupted or drastically reduced. Ischemic damages started immediately after arterial clamping in donor, persist during cold ischemia time, and are increased after reperfusion because of increased oxygen levels, organ warming and recipient cell infiltration. Besides metabolic and biologic impact, IR induced dramatic immunologic impact through immunologic cells activation. CONCLUSIONS: Knowledge of IR mechanisms is crucial to improve organ storage strategies and to decreased impact of IR on long-term graft and patient survival. Hypothermic machine perfusion was associated with prolonged graft survival versus cold storage. Principles and results of hypothermic machine perfusion will be reported.

Pharmacological strategy designed to limit ischemia-reperfusion injury in brain dead donor kidneys.

Ischemia-reperfusion injury is a complex physiological process responsible for delayed renal function or primary graft non-function, explicitly when kidney allograft are issued from expanded criteria donor. The purpose of this review is to detail the detrimental phenomenons altering kidney allograft's integrity in brain dead donor, therefore suggesting pharmacological interventions aiming to reduce ischemia-reperfusion injuries and improving transplantation outcome. This ischemia-reperfusion phenomenon must therefore be anticipated through the whole procedure starting at the stage of conditioning of the potential donor. Hormonal and haemodynamic consequences of brain death modify perfusion and oxygenation conditions of the organs Thus, after describing the autonomic, metabolic, endocrine and chemokine storm occurring during brain death, the authors focus on strategies to prevent hemodynamic instability in the donor and to limit the consequences of hormonal and immunological changes on organs that will eventually be transplanted.

Ischemia-reperfusion: From cell biology to acute kidney injury.

Ischemia reperfusion injury occurs in the kidney when blood supply is interrupted in clinical settings such as kidney transplantation or nephron sparing surgery for renal tumors. These lesions lead to acute kidney injury (AKI) a detrimental situation associated with impaired short-term allograft function (delayed graft function or primary non function) but also long-term transplant survival through the onset of chronic allograft nephropathy. The present review details the cellular and molecular consequences of ischemia reperfusion in a native kidney as well as in a kidney graft after cold ischemia time, giving a comprehensive description of biological pathways involved during the phase of ischemia and during the reperfusion period where the rapid return to normoxia leads to a large burst of reactive oxygen species along with a dramatic reduction in antioxidant defenses. This work also focuses on the distinct susceptibilities of kidney cells to ischemia (endothelial vs epithelial) and the outcome of acute kidney injury.

Does machine perfusion decrease ischemia reperfusion injury?

In 1990's, use of machine perfusion for organ preservation has been abandoned because of improvement of preservation solutions, efficient without perfusion, easy to use and cheaper. Since the last 15 years, a renewed interest for machine perfusion emerged based on studies performed on preclinical model and seems to make consensus in case of expanded criteria donors or deceased after cardiac death donations. We present relevant studies highlighted the efficiency of preservation with hypothermic machine perfusion compared to static cold storage. Machines for organ preservation being in constant evolution, we also summarized recent developments included direct oxygenation of the perfusat. Machine perfusion technology also enables organ reconditioning during the last hours of preservation through a short period of perfusion on hypothermia, subnormothermia or normothermia. We present significant or low advantages for machine perfusion against ischemia reperfusion injuries regarding at least one primary parameter: risk of DFG, organ function or graft survival.

Ischemic pre- and post-conditioning: current clinical applications.

Ischemic conditioning is a phenomenon through which short sequences of ischemia-reperfusion applied to an organ confer some degree of protection towards future ischemic insults. This phenomenon was first observed in the mid-1980s in cardiac surgery, and has been since widely studied in different settings. Different sort of ischemic conditioning exist: local vs remote, direct or pharmacological, and with different timeframes of protection. Ischemic conditioning seems especially suited to applications in transplantation since schedules of both cold and warm ischemia, as well as reperfusion, are carefully and easily controlled, and the benefits of protecting fragile organs against ischemia-reperfusion injuries might help widen the pool of possible grafts and ensure better graft function and survival. The pathways through which ischemic conditioning work are many, offering both preservation of cell energy, protection against oxidative stress, better blood flow to organs and protection against apoptosis. In the field of pharmacological conditioning, which tries to mimic the protective effects of traditional ischemic conditioning without the potential side-effects associated with vessel clamping, many common-use drugs including anesthetics have been shown to be effective. Significant results have been obtained in small animal models, but while ischemic conditioning is successfully used in cardiac surgery, studies in large animal models and human applications in liver and kidney transplantation are still inconclusive.

De novo kidney graft tumors: results from a multicentric retrospective national study.

De novo tumors in renal allografts are rare and their prevalence is underestimated. We therefore analyzed renal cell carcinomas arising in renal allografts through a retrospective French renal transplant cohort. We performed a retrospective, multicentric survey by sending questionnaires to all French kidney transplantation centers. All graft tumors diagnosed after transplantation were considered as de novo tumors. Thirty-two centers participated in this study. Seventy-nine tumors were identified among 41 806 recipients (Incidence 0.19%). Patients were 54 men and 25 women with a mean age of 47 years old at the time of diagnosis. Mean tumor size was 27.8 mm. Seventy-four (93.6%), 53 (67%) and 44 tumors (55.6%) were organ confined (T1-2), low grade (G1-2) and papillary carcinomas, respectively. Four patients died of renal cell carcinomas (5%). The mean time lapse between transplantation and RCC diagnosis was 131.7 months. Thirty-five patients underwent conservative surgery by partial nephrectomy (n = 35, 44.3%) or radiofrequency (n = 5; 6.3%). The estimated 5 years cancer specific survival rate was 94%. Most of these tumors were small and incidental. Most tumors were papillary carcinoma, low stage and low grade carcinomas. Conservative treatment has been preferred each time it was feasible in order to avoid a return to dialysis.

History of first transplantations: Nothing is ever written. Part II.

The history of the first transplants is an ideal model for analyzing the different stages of disruptive innovation in surgery. Pioneers have often taken paths that were strewn with pitfalls, mistakes or failures. Sometimes victory, brilliant or more modest, lies at the end of this path. We propose to re-explore the extraordinary pathways that led to the first transplantations of the kidney, liver, lung and heart. That these first transplants should one day become possible required the concurrence of several factors: basic research, laboratory work to perfect the surgical techniques, a favorable legislative and societal context, and, above all, pioneering surgeons who would dare to apply their expertise to human subjects. Initial failures were not technical but immunological. Not everything would be perfect, especially ethical questions in some cases. Furthermore, initial results often humbled the greatest surgeons. Even though the historical and legislative contexts have evolved considerably as have science, society and the organization of the health system, this analysis of the past is rich in lessons for the modern surgeon who wishes to embark today along innovative pathways in the face of a still unresolved problem. Because nothing is ever carved in stone.

History of transplantation: Nothing is ever written. Part I.

The history of the first transplants is an ideal model for analyzing the different stages of disruptive innovation in surgery. Pioneers have often taken paths that were strewn with pitfalls, mistakes or failures. Sometimes victory, brilliant or more modest, lies at the end of this path. We propose to re-explore the extraordinary pathways that led to the first transplantations of the kidney, liver, lung and heart. That these first transplants should one day become possible required the concurrence of several factors: basic research, laboratory work to perfect the surgical techniques, a favorable legislative and societal context, and, above all, pioneering surgeons who would dare to apply their expertise to human subjects. Initial failures were not technical but immunological. Not everything would be perfect, especially ethical questions in some cases. Furthermore, initial results often humbled the greatest surgeons. Even though the historical and legislative contexts have evolved considerably as have science, society and the organization of the health system, this analysis of the past is rich in lessons for the modern surgeon who wishes to embark today along innovative pathways in the face of a still unresolved problem. Because nothing is ever carved in stone.

[Primary effusion lymphoma in two kidney transplant recipients]. / Lymphome des séreuses chez le transplanté rénal: deux cas.

BACKGROUND: Primary effusion lymphoma (PEL) is a highly malignant non-Hodgkin lymphoma associated with Kaposi's sarcoma-associated herpesvirus/human herpesvirus-8 infection (KSHV/HHV-8). It is chiefly seen in HIV patients and is rare in transplant recipients, possibly going unrecognized. OBSERVATION: We describe two male kidney transplant recipients, aged 47 and 51 years, followed for Kaposi's sarcoma in skin, lymph nodes, gastrointestinal (GI) tract and lung whose disease was poorly controlled by sirolimus and chemotherapy. Recurrent pleural effusion contrasted with reduction of cutaneous Kaposi lesions. KHSV viral loads were negative or very low in plasma, were negative or very low, whereas those in pleural effusion were high. Lymphoma cells were discovered only seven to nine months after the initial effusion despite repeated needle biopsies. In one patient, tumour cells were co-infected with Epstein-Barr virus. CONCLUSION: The contrast between a very low KHSV viral load in plasma and a very high viral load pleural effusion should alert physicians and prompt suspicion of PEL in Kaposi's sarcoma patients with recurrent serous effusion. The potential inhibitory role of sirolimus on PEL progression is discussed.

[Should temperature be monitorized during kidney allograft preservation?]. / Faut-il monitorer la température pendant la phase de préservation en transplantation rénale ?

GOAL: It is generally considered that kidney grafts should be preserved at 4 degrees C during cold storage. However, actual temperature conditions are not known. We decided to study the temperature levels during preservation with the Biotainer storage can and Vitalpack transport pack. MATERIAL: Temperature was monitored using the Thermobouton probe during preservation of pig kidneys, in the same conditions used with human grafts. The probe recorded the temperature level every 10 minutes during four days. We compared the results found with the new storage can with results obtained in the same conditions with the storage can formerly used by our team. We also studied the best position of the probe for temperature monitoring and the influence of the amount of ice within the transport pack on the temperature level. We then monitored the temperature during the conservation of actual human kidney grafts harvested at our institution from August 2007 to May 2008. RESULTS: The temperature levels were the same regardless of the position of the probe within the transport pack. The lowest temperature was maintained during 15 hours, and the temperature level stayed below 5 degrees C for 57 hours with the new storage can. The former storage can maintained the lowest temperature level for 80 minutes, and temperature reached 5 degrees C after 10 hours 40 minutes. Temperature levels were similar when 2 or 4 kg of crushed ice were used. We observed similar results when monitoring the conservation of human grafts. CONCLUSION: The new storage can affords more stable temperature levels when compared to the formerly used can. Since temperature is stable during conservation, continuous monitoring in everyday practice does not seem warranted.

Safety and efficacy of raltegravir in HIV-infected transplant patients cotreated with immunosuppressive drugs.

Solid organ transplantations (SOT) are performed successfully in selected HIV-infected patients. However, multiple and reciprocal drug-drug interactions are observed between antiretroviral (ARV) drugs and calcineurin inhibitors (CNIs) through CYP450 metabolization. Raltegravir (RAL), a novel HIV-1 integrase inhibitor, is not a substrate of CYP450 enzymes. We retrospectively reviewed the outcomes of 13 HIV-infected transplant patients treated by an RAL + two nucleosidic reverse transcriptase inhibitor (NRTI) regimen, in terms of tolerability, ARV efficacy (plasma viral load, CD4 cell count), drug interactions, RAL pharmacokinetics and transplant outcome. Thirteen patients with liver (n = 8) or kidney (n = 5) transplantation were included. RAL was initiated (400 mg BID) either at time of transplantation (n = 6), or after transplantation (n = 7). Median RAL trough concentration was 507 ng/mL (176-890), which is above the in vitro IC95 for wild type HIV-1 strains (15 ng/mL). Target trough levels of CNIs were promptly obtained with standard dosages of tacrolimus or cyclosporine. RAL tolerability was excellent. There was no episode of acute rejection. HIV infection remained controlled. After a median follow-up of 9 months (range: 6-14), all patients were alive with satisfactory graft function. The use of an RAL + two NRTI-based regimen is a good alternative in HIV-infected patients undergoing SOT.

Laparoscopic radical prostatectomy in kidney transplant patient: our first experience-a case report.

The association between prostate cancer and kidney transplantation has an unknown incidence despite an increased screening in that population. Radical prostatectomy remains the gold standard in treating localized tumors. Retropubic or perineal approaches are usually considered. The surgical aspects and successful outcome of laparoscopic radical prostatectomy in a kidney transplant recipient are reviewed.

Systematic microbiological tests in kidney transplantation and their value in predicting posttransplantation infection.

BACKGROUND: Immunosuppressive therapy has many side effects among which is an increased infectious risk for the recipient. Transmission of pathogens from the graft to the recipient has not been well evaluated; there are no guidelines regarding the need for microbiological tests on the graft prior to transplantation. We routinely performed such tests to evaluate the risk and determine whether a patient should receive preemptive antibiotic therapy after transplantation. We herein have reported our preliminary results. MATERIALS AND METHODS: We reviewed 150 consecutive renal transplantations from cadaveric heart-beating donors. Microbiological tests were systematically performed not only on the preservation solution, but also on graft artery, vein, ureter, and perirenal fat. We reviewed the recipient's medical history for clinically significant infectious episodes in the first month after transplantation. RESULTS: Thirty-one percent of all microbiological tests were positive with 23 patients showing multiple positive tests, 74% of which were concordant. We documented 3 cases of direct graft-to-recipient pathogen transmission, all of which presented with 3 positive concordant tests. Graft culture prior to transplantation is often positive, but in more than half of the cases positive tests are either isolated or discordant. We only treated patients with concordant test results; no adverse consequence was observed among the untreated patients. Transmission occurred only in patients with at least 3 concordant tests. CONCLUSIONS: Multiple microbiological tests on the graft prior to transplantation seemed useful to determine which patients would benefit from preemptive antibiotic therapy. Further studies may help to define which microbiological tests are the most important.