COVID-19 early curative treatments in kidney transplant recipients: is it really reasonable at the Omicron era?

Objective: Data about efficacy and safety of the latest COVID-19 treatments as nirmatrelvir/ritonavir (n/r) or Sotrovimab is scarce in solid organ transplant recipients in the Omicron era. This study aims at describing the outcome of kidney transplant recipients (KTRs) presenting Omicron infection according to their management: n/r, sotrovimab or no specific treatment. Patients and methods: We conducted a monocentric, retrospective observational study, including KTRs diagnosed Omicron infection between January and May 1st 2022 and compared their outcome (primary outcome defined as hospital admission for COVID-19 within a month after symptoms onset) according to early COVID-19 management. Results: Forty-five patients were included: 22 treated (12 n/r, 10 sotrovimab) and 23 with no specific treatment. The groups were statistically comparable. Two patients were admitted for COVID-19: one in each group, resulting in a non-different probability of the primary outcome at on month (p=0.9). Three patients presented tacrolimus overdose including two with acute kidney injury. Conclusions: There was no difference in outcome according to early therapeutic management: n/r, sotrovimab or no specific treatment. Our study both underlines a decreased severity of Omicron COVID-19 in KTRs (probably related to vaccinal immunity and decreased virulence of Omicron) and a potential severe adverse effects with n/r.

Objectif: Les données sur l'efficacité et la sécurité des derniers traitements de la Covid-19 sont peu nombreuses à l'ère du variant Omicron. Cette étude avait pour objectif de décrire l'évolution des transplantés rénaux (TR) présentant une infection à Omicron selon le traitement précoce reçu : nirmatrelvir/ritonavir (n/r), sotrovimab, ou pas de traitement. Patients et méthodes: Il s'agissait d'une étude monocentrique rétrospective observationnelle incluant tous les TR présentant une infection confirmée à Omicron entre le 1er janvier 2022 et le 1er mai 2022 et comparant leur évolution (critère de jugement principal : admission hospitalière pour Covid-19 à un mois du début des symptômes) selon leur prise en charge. Résultats: Quarante-cinq patients ont été inclus : 22 traités (12 n/r et 10 sotrovimab) et 23 non traités. Les groupes étaient statistiquement comparables. Seulement deux patients ont présenté le critère de jugement principal : un n/r et un non traité, avec une probabilité à un mois non différente (p = 0,9). Trois patients sur 12 ont en revanche présenté des surdosages en tacrolimus dans le groupe n/r, dont deux avec une insuffisance rénale aiguë. Conclusions: Dans les limites d'un petit effectif, nous n'avons pas montré de bénéfice au traitement précoce par n/r ou sotrovimab. On peut évoquer un effet de l'immunité vaccinale et une baisse de virulence du SARS-CoV-2. En revanche, les effets secondaires du n/r ne sont pas anodins avec des surdosages sévères malgré des protocoles de service précis. La balance bénéfice-risque de ces traitements doit être rediscutée.

Absence of Mortality Differences Between the First and Second COVID-19 Waves in Kidney Transplant Recipients.

Introduction: SARS-CoV-2 pandemic evolved in 2 consecutive waves during 2020. Improvements in the management of COVID-19 led to a reduction in mortality rates among hospitalized patients during the second wave. Whether this progress benefited kidney transplant recipients (KTRs), a population particularly vulnerable to severe COVID-19, remained unclear. Methods: In France, 957 KTRs were hospitalized for COVID-19 in 2020 and their data were prospectively collected into the French Solid Organ Transplant (SOT) COVID registry. The presentation, management, and outcomes of the 359 KTRs diagnosed during the first wave were compared to those of the 598 of the second wave. Results: Baseline comorbidities were similar between KTRs of the 2 waves. Maintenance immunosuppression was reduced in most patients but withdrawal of antimetabolite (73.7% vs. 58.4%, P < 0.001) or calcineurin inhibitor (32.1% vs. 16.6%, P < 0.001) was less frequent during the second wave. Hydroxychloroquine and azithromycin that were commonly used during the first wave (21.7% and 30.9%, respectively) but were almost abandoned during the second wave. In contrast, the use of high dose corticosteroids doubled (19.5% vs. 41.6%, P < 0.001). Despite these changing trends in COVID-19 management, 60-day mortality was not statistically different between the 2 waves (25.3% vs. 23.9%; Log Rank, P = 0.48) and COVID-19 hospitalization period was not associated with death due to COVID-19 in multivariate analysis (Hazard ratio 0.89, 95% confidence interval 0.67-1.17, P = 0.4). Conclusion: We conclude that changing of therapeutic trends during 2020 did not reduce COVID-19 related mortality among KTRs. Our data indirectly support the importance of vaccination and neutralizing monoclonal anti-SARS-CoV-2 antibodies to protect KTRS from severe COVID-19.

Immunosuppressive therapy after solid organ transplantation and the gut microbiota: Bidirectional interactions with clinical consequences.

Our understanding of the involvement of the gut microbiota (GM) in human health has expanded exponentially over the last few decades, particularly in the fields of metabolism, inflammation, and immunology. Immunosuppressive treatment (IST) prescribed to solid organ transplant (SOT) recipients produces GM changes that affect these different processes. This review aims at describing the current knowledge of how IST changes the GM. Overall, SOT followed by IST results in persistent changes in the GM, with a consistent increase in proteobacteria including opportunistic pathobionts. In mice, Tacrolimus induces dysbiosis and metabolic disorders, and alters the intestinal barrier. The transfer of the GM from Tacrolimus-treated hosts confers immunosuppressive properties, suggesting a contributory role for the GM in this drug's efficacy. Steroids induce dysbiosis and intestinal barrier alterations, and also seem to depend partly on the GM for their immunosuppressive and metabolic effects. Mycophenolate Mofetil, frequently responsible for digestive side effects such as diarrhea and colitis, is associated with pro-inflammatory dysbiosis and increased endotoxemia. Alemtuzumab, m-TOR inhibitors, and belatacept have shown more marginal impact on the GM. Most of these observations are descriptive. Future studies should explore the underlying mechanism of IST-induced dysbiosis in order to better understand their efficacy and safety characteristics.

High Mortality and Graft Loss after Infective Endocarditis in Kidney Transplant Recipients: A Case-Controlled Study from Two Centers.

Kidney transplant recipients (KTRs) tend to develop infections with characteristic epidemiology, presentation, and outcome. While infective endocarditis (IE) is among such complications in KTRs, the literature is scarce. We describe the presentation, epidemiology, and factors associated with IE in KTRs. We performed a retrospective case/control study which included patients from two centers. First episodes of definite or possible IE (Duke criteria) in adult KTRs from January 2010 to December 2018 were included, as well as two controls per case, and followed until 31 December 2019. Clinical, biological, and microbiological data and the outcome were collected. Survival was studied using the Kaplan-Meier method. Finally, we searched for factors associated with the onset of IE in KTRs by the comparison of cases and controls. Seventeen cases and 34 controls were included. IE was diagnosed after a mean delay of 78 months after KT, mostly on native valves of the left heart only. Pathogens of digestive origin were most frequently involved (six Enterococcus spp, three Streptococcus gallolyticus, and one Escherichia coli), followed by Staphylococci (three cases of S. aureus and S. epidermidis each). Among the risk factors evaluated, age, vascular nephropathy, and elevated calcineurin inhibitor through levels were significantly associated with the occurrence of IE in our study. Patient and death-censored graft survival were greatly diminished five years after IE, compared to controls being 50.3% vs. 80.6% (p < 0.003) and 29.7% vs. 87.5% (p < 0.002), respectively. IE in KTRs is a disease that carries significant risks both for the survival of the patient and the transplant.

Impact of sarcopenia on clinical outcomes of patients undergoing simultaneous liver and kidney transplantation: a cohort study.

BACKGROUND: The impact of sarcopenia in patients undergoing simultaneous liver and kidney transplantation (SLKT) has not been fully delineated. The aim of this single-centre-cohort-study was to evaluate the impact of sarcopenia on the clinical outcomes. METHODS: Between 2003 and 2018, 79 patients underwent SLKT. Sarcopenia was assessed via the total psoas muscle area (TPA) at the level of the 3rd. lumbar vertebra. Sarcopenia threshold was TPA < 1460 mm2 (women) and <1560 mm2 (men). We identified post-operative biliary, vascular and digestive complications. Survival analysis was performed by the Kaplan Meier method (log-rank test). RESULTS: We included 43/79 SLKT recipients (56%male, median age of 58 [53-63] years). The prevalence of cirrhosis was 74% (n = 32) with median MELD-score of 21 (20-22) and that of polycystic-liver-disease was 26% (n = 11). End-stage-renal-disease of unknown origin was 36.2% (n = 12). Dialysis before transplantation was performed in 54,8% (n = 23) of patients. The median TPA was 1138 (926-1510) mm2, and sarcopenia was detected in 72% of patients (n = 31). No difference in patient or death-censored graft-survival between sarcopenic and non-sarcopenic groups at 1 year was reported. Also, no differences at 6-months' post-transplant-complication-free and infection-free-survival rates were found. CONCLUSION: In this cohort of patients, no differences were observed in patients, grafts, complications or infection-free survival between sarcopenic or no sarcopenic SLKT patients. Future multi-centre studies are needed to validate and extend the generalisability of these findings.

An extension of the RITUX-ERAH study, multicenter randomized clinical trial comparing rituximab to placebo in acute antibody-mediated rejection after renal transplantation.

The treatment of active antibody-mediated rejection (ABMR) is still a matter of debate, the place of rituximab remaining controversial. The French multicenter double-blind RITUX-ERAH study included 38 patients with ABMR in the first year of renal transplantation. All patients received plasma exchanges, intravenous immunoglobulins, and corticosteroids and were randomly assigned rituximab or placebo infusion at day 5. Additional rituximab infusions were allowed. In the intention-to-treat analysis, 12-month graft survival and renal function were not different between the rituximab and placebo groups. Long-term data are needed to conclude. Evaluation of the 7-year outcomes of the RITUX-ERAH study patients according to the rituximab or placebo treatment received. Eleven patients received placebo and 27 at least one infusion of rituximab. Seven years after ABMR, death-censored kidney allograft survival and renal function were not different between the groups. The evolution of anti-HLA sensitization was similar. There was no statistically significant difference in the incidence of infectious or neoplastic complications, but to be noted, seven cancers developed in six patients treated with rituximab (mean period of 44 months post-ABMR). In this cohort, there was no benefit 7 years after ABMR of rituximab in addition to plasma exchanges, intravenous immunoglobulins, and steroids.

Gut microbiota composition alterations are associated with the onset of diabetes in kidney transplant recipients.

METHODS: Patients transplanted at our institution provided fecal samples before, and 3-9 months after KT. Fecal bacterial DNA was extracted and 9 bacteria or bacterial groups were quantified by qPCR. RESULTS: 50 patients (19 controls without diabetes, 15 who developed New Onset Diabetes After Transplantation, NODAT, and 16 with type 2 diabetes before KT) were included. Before KT, Lactobacillus sp. tended to be less frequently detected in controls than in those who would become diabetic following KT (NODAT) and in initially diabetic patients (60%, 87.5%, and 100%, respectively, p = 0.08). The relative abundance of Faecalibacterium prausnitzii was 30 times lower in initially diabetic patients than in controls (p = 0.002). The relative abundance of F. prausnitzii of NODAT patients was statistically indistinguishable from controls and from diabetic patients. The relative abundance of Lactobacillus sp. increased following KT in NODAT and in initially diabetic patients (20-fold, p = 0.06, and 25-fold, p = 0.02, respectively). In contrast, the proportion of Akkermansia muciniphila decreased following KT in NODAT and in initially diabetic patients (2,500-fold, p = 0.04, and 50,000-fold, p<0.0001, respectively). The proportion of Lactobacillus and A. muciniphila did not change in controls between before and after the transplantation. Consequently, after KT the relative abundance of Lactobacillus sp. was 25 times higher (p = 0.07) and the relative abundance of A. muciniphila was 2,000 times lower (p = 0.002) in diabetics than in controls. CONCLUSION: An alteration of the gut microbiota composition involving Lactobacillus sp., A. muciniphila and F. prausnitzii is associated with the glycemic status in KT recipients, raising the question of their role in the genesis of NODAT.

Access to the waiting list and to kidney transplantation for people living with HIV: A national registry study.

We compared access to a kidney transplantation (KT) waiting list (WL) and to KT between people living with HIV (PLHIV) and HIV-uninfected controls. Using the REIN (the national Renal Epidemiology and Information Network registry), we included all PLHIV initiating dialysis in France throughout 2006-2010 and HIV-uninfected controls matched for age, sex, year of dialysis initiation, and the existence of a diabetic nephropathy. Patients were prospectively followed until December 2015. We used a competitive risk approach to assess the cumulative incidence of enrollment on WL and of KT, with death as a competing event (subdistribution hazard ratio adjusted on comorbidities, asdHR). There were 255 PLHIV in the REIN (median age 47 years) of whom 180 (71%) were also found in the French Hospital Database on HIV (FHDH-ANRS CO4) including 126 (70%) known to be on antiretroviral therapy with HIV viral suppression (VS). Five years after dialysis initiation, 65%, and 76%, of treated PLHIV with VS, and of HIV-uninfected controls were enrolled on a WL (asdHR 0.68; 95% CI 0.50-0.91). Access to KT was also less frequent and delayed for treated PLHIV with VS (asdHR 0.75, 95% CI, 0.52-1.10). PLHIV continue to face difficulties to access KT.

Why kidneys fail post-partum: a tubulocentric viewpoint.

Kidneys may fail post-partum in a number of circumstances due, for example, to post-partum haemorrhage, preeclampsia, amniotic fluid embolism or septic abortion. All these conditions in pregnancy and post partum represent a threat not only to the endothelium but also to the renal tubular epithelium, and as such may lead to rapid and also irreversible impairment of the renal function. This paper is a non-systematic review of the literature and of our experience, in which we discuss the main open issues on kidney disease in pregnancy and following delivery, in particular as regards tubular damage, with the aim to help reasoning on acute kidney injury (AKI) following delivery. The review will emphasize the often under-estimated importance of the tubular epithelium in the peri-partum period and will: (1) describe the main characteristics of the renal tissues around delivery; (2) define pregnancy-related AKI according to recent Kidney Disease/Improving Global Outcome (KDIGO) guidelines; (3) discuss the most common circumstances of post-partum AKI; and (4) describe the input expected from urinalysis, renal imaging and kidney biopsy.

[Nephrotoxicity of antiretrovirals other than tenofovir]. / Néphrotoxicité des antirétroviraux autres que le ténofovir.

The remarkable improvement of the outcome of HIV infection came with the price of substantial toxicity of some antiretrovirals. The first molecules used to treat HIV included an important nephrotoxicity. Zalcitabine, stavudine and didanosine can induce severe lactic acidosis. Lactate production is enhanced and the renal capacity to regulate pH is overwhelmed. However, this side effect is not due to a direct dysfunction of the kidneys. Zalcitabine was withdrawn from the market because of this risk. Indinavir, a protease inhibitor, is soluble only in very acidic solutions. Consequently, the small fraction that is excreted in the urine precipitates and can be responsible for uro-nephrolithiasis, leukocyturia, cristalluria, obstructive acute kidney failure, and acute or chronic interstitial nephritis. This is the reason why indinavir is almost not prescribed nowadays, even if it is still marketed. In addition to the direct nephrotoxicity of some antiretrovirals, anti-HIV treatment also includes a toxicity which pathophysiology is not completely elucidated. This nephrotoxicity is the consequence of organ accelerated ageing and of an increased vascular risk. Kidney vascularization (from renal arteries to capillaries) is essential to kidney function and all cardiovascular risks are also renal risks. It is now clearly established that combined antiretroviral treatment increases the vascular risk. A better comprehension of the links between HIV infection, its treatment and very long-term kidney risk is needed to improve the complex management of patients who have now cumulated several decades of HIV infection and treatment with various toxicities.

Severe Strongyloidiasis in Solid Organ Transplant Recipients: Should We Preventively Treat the Recipient, the Donor, or Both?

Strongyloidiasis is caused by a soil-transmitted helminth that is endemic in tropical and subtropical countries. The parasite can complete its life cycle without leaving the host, allowing autoinfection and persistence. The risk of infection in travelers is low, but the disease may become lethal following immunosuppression. In case of solid organ transplantation, the risk of donor transmission has been suspected for several years. However, the management of live donors in this context has only recently been considered, and no guidelines exist for the management of deceased donors. To highlight the complexity of diagnosing, treating, and preventing strongyloidiasis donor transmission, we describe a case of possible transmission of severe strongyloidiasis to a kidney transplant recipient with limited travel history. Taking into account the difficulty of diagnosing chronic strongyloidiasis infection and the increase in travel and immunosuppressive treatments, we recommend pragmatic management guidelines to limit the risks of infection.

Prognostic Value of the Persistence of C1q-Binding Anti-HLA Antibodies in Acute Antibody-Mediated Rejection in Kidney Transplantation.

BACKGROUND: The differential pathogenicity of anti-HLA donor-specific antibodies (DSAs) is not fully understood. The presence of complement-binding DSAs helps in better defining the prognosis of acute antibody-mediated rejection (ABMR). The evolution of these antibodies after the treatment of ABMR is unknown. METHODS: We included patients from the French multicenter RITUX ERAH study diagnosed with acute ABMR within the first year of renal transplantation, with circulating anti-HLA DSAs and treated randomly by rituximab or placebo (and intravenous immunoglobulins, plasma exchange). We centrally analyzed serum samples at the time of ABMR, 3 and 6 months after ABMR, with anti-HLA DSAs specificities and C1q-binding capacity assessment. RESULTS: Twenty-five patients were included: 68% had C1q-binding DSAs at the time of ABMR. The presence of C1q-binding DSAs was associated with a poorer evolution of chronic glomerulopathy at 6 months (P = 0.036). The persistence of C1q-binding DSAs at 3 and/or 6 months after ABMR was associated with more severe chronic glomerulopathy (P = 0.006), greater C4d score deposition score at 6 months after ABMR (P = 0.008), and graft loss 5 years after ABMR (P = 0.029). C1q-binding capacity was associated with the DSA MFI but 5 C1q-binding DSAs in 4 patients had low MFI values without a prozone effect. CONCLUSION: The presence and persistence of anti-HLA C1q-binding DSAs after ABMR is a detrimental marker, leading to transplant glomerulopathy and graft loss. Assessment of the complement-binding capacities of DSAs could help decide treatment intensification.

Impact of lean mass and bone density on glomerular filtration rate estimation in people living with HIV/AIDS.

CONTEXT: Chronic kidney disease is a frequent complication in persons living with HIV/AIDS. Although previous studies have suggested that the CKD-EPI formula is appropriate to estimate glomerular filtration rate (GFR) in HIV-positive adults with normal kidney function, the optimal way to estimate GFR in those with Stage 3 chronic kidney disease is not known. Moreover, the impact of muscle mass on creatinine level and GFR estimation is unknown. AIM AND METHODS: Our study aimed to evaluate the accuracy of different diagnostic tests available compared to the gold standard measurement of GFR. A group of 44 HIV-1 patients with an estimated GFR between 60 and 30 ml/min/1.73 m2 were included in a single-center cross-sectional study. Serum creatinine and cystatin C were measured. GFR was estimated using Cockcroft-Gault, MDRD, sMDRD, CKD-EPI, CKD-EPIcyst, and CKD-EPIcyst/creat formulae and was measured using isotopic Chrome51 EDTA clearance. Bone density and muscle mass were measured by DXA scan. RESULTS: Mean age was 62±10 years. Mean BMI was 23±4 kg/m2. Prevalence of diabetes was 30% and of hypertension was 47%. Viral load was <40 copies/ml for 90% of the patients, and mean CD4 count was 446±191 cells/mm3. Mean measured GFR was 63.4±16.5 ml/min/1.73 m2. All formulae under-estimated GFR. The best relative precision and accuracy were provided by the CKP-EPI formula. sMDRD, CKD-EPIcyst, and CKD-EPIcyst/creat performed worse than the CKD-EPI formula. Body composition did not significantly influence accuracy or precision of GFR estimation. CONCLUSION: In HIV-infected patients in stable immunovirologic conditions with CKD stage 3 and high prevalence of metabolic associated conditions, the CKD-EPI formula performed best, although all formulae under estimate GFR.

[Molecular epidemiology and kinetics of early Escherichia coli urinary tract infections in kidney transplant recipients]. / Épidémiologie moléculaire et cinétique des infections urinaires précoces à Escherichia coli chez les sujets transplantés d'un rein.

BACKGROUND: Escherichia coli strains causing Urinary Tract Infections (UTI) have a fecal origin. METHODS: A fecal sample was collected before Kidney Transplantation (KT) and concomitantly with urine at each of the 15 E. coli UTIs which occurred in 11 KT recipients. Unique E. coli strains were identified among 25 isolates per feces and 5 isolates per urinary sample by random amplification of polymorphic DNA. Phylogenetic group (which is correlated to virulence in the E. coli species) was determined for each E. coli strain by a PCR based method. RESULTS: Forty-three unique fecal strains and 14 unique urinary strains were identified among 650 fecal isolates and 75 urinary isolates. Urinary strains frequently (55% of the cases) belonged to a phylogroup usually not linked to virulence. They were detected in the feces collected concomitantly in 60% of the cases. Urinary strains belonging to a phylogroup usually linked to virulence were more frequently dominant in the feces (100%) than urinary strains belonging to a non-pathogenic phylogroup (42%; P<0.05). Vesical catheter was a facilitating factor only for urinary strains belonging to non-pathogenic phylogroups. Thirty-three percent of the fecal strains were persisting in two consecutive fecal samples and 62% were detected for the first time at the UTI. Numerous pathway lead to UTIs: from a unique, virulent and persisting strain to a non-virulent recently acquired strain facilitated by a vesical catheter. CONCLUSION: Our work shows the diversity of host-microbial interactions which precede extra-intestinal virulence.