Urinary cytomegalovirus excretion: The unresolved issues.

Cytomegalovirus (CMV) excretion in urine is frequently observed in clinical practice. However, the specific circumstances and pathophysiological mechanisms underlying this shedding remain largely unknown. Here, we address some of the key questions regarding urinary CMV excretion, focusing on new hypotheses raised by recent advances in the field. Cellular origins of CMV shedding, clinical contexts of occurrence, systemic spread of the virus versus compartmentalization in the urinary tract, and clinical impact are successively discussed.

Recognition of intraglomerular histological features with deep learning in protocol transplant biopsies and their association with kidney function and prognosis.

Background: The Banff Classification may not adequately address protocol transplant biopsies categorized as normal in patients experiencing unexplained graft function deterioration. This study seeks to employ convolutional neural networks to automate the segmentation of glomerular cells and capillaries and assess their correlation with transplant function. Methods: A total of 215 patients were categorized into three groups. In the Training cohort, glomerular cells and capillaries from 37 patients were manually annotated to train the networks. The Test cohort (24 patients) compared manual annotations vs automated predictions, while the Application cohort (154 protocol transplant biopsies) examined predicted factors in relation to kidney function and prognosis. Results: In the Test cohort, the networks recognized histological structures with Precision, Recall, F-score and Intersection Over Union exceeding 0.92, 0.85, 0.89 and 0.74, respectively. Univariate analysis revealed associations between the estimated glomerular filtration rate (eGFR) at biopsy and relative endothelial area (r = 0.19, P = .027), endothelial cell density (r = 0.20, P = .017), mean parietal epithelial cell area (r = -0.38, P < .001), parietal epithelial cell density (r = 0.29, P < .001) and mesangial cell density (r = 0.22, P = .010). Multivariate analysis retained only endothelial cell density as associated with eGFR (Beta = 0.13, P = .040). Endothelial cell density (r = -0.22, P = .010) and mean podocyte area (r = 0.21, P = .016) were linked to proteinuria at biopsy. Over 44 ± 29 months, 25 patients (16%) reached the primary composite endpoint (dialysis initiation, or 30% eGFR sustained decline), with relative endothelial area, mean endothelial cell area and parietal epithelial cell density below medians linked to this endpoint [hazard ratios, respectively, of 2.63 (P = .048), 2.60 (P = .039) and 3.23 (P = .019)]. Conclusion: This study automated the measurement of intraglomerular cells and capillaries. Our results suggest that the precise segmentation of endothelial and epithelial cells may serve as a potential future marker for the risk of graft loss.

Triglyceride-Glucose Index and Cardiovascular Events in Kidney Transplant Recipients.

Introduction: Kidney transplant recipients (KTRs) have an increased risk of cardiovascular (CV) events (CVEs) compared with the general population. The impact of insulin resistance on CV risk after transplantation is not well defined. Methods: We tested whether triglyceride-glucose (TyG) index, a surrogate marker of insulin resistance, may predict posttransplant CVEs in a cohort of 715 consecutive KTRs all included 1 year after transplant. Results: Follow-up was 9.1 ± 4.6 years. Mean TyG at inclusion was 4.75 ± 0.29 (median, 4.73 [4.14-5.84]). In multiple regression analysis, having a TyG above the median value was associated with higher body mass index (BMI), low high-density lipoprotein (HDL) cholesterol level, and greater urinary protein excretion. A total of 127 CVEs (17.7%) occurred during the study period. In univariate analysis, TyG was strongly associated with CVE occurrence (hazard ratio [HR] 2.06, 95% CI 1.42-3.50, for each increase of 0.1 in TyG, P < 0.001). The best predictive value was 4.87 (HR 6.32, 95% CI 3.30-12.11, P < 0.001). The risk of CVE gradually increased with higher TyG index (quartile 2, HR 1.71, 95% CI 0.84-5.20, P = 0.139; quartile 3, HR 3.12, 95% CI 1.61-6.02, P < 0.001; quartile 4, HR 7.46, 95% CI 4.03-13.80, P < 0.001, vs. quartile 1). TyG remained associated with CVE in multivariate analysis (HR 2.11, 95% CI 1.22-3.68, for each increase of 0.1 in TyG, P < 0.001). Conclusion: Insulin resistance, as measured by the TyG index is strongly associated with CVE in KTRs. Improving insulin sensitivity seems to be a major issue to prevent CV morbidity and mortality in this high-risk population.

Transfused Red Blood Cell Characteristics and Kidney Transplant Outcomes Among Patients Receiving Early Posttransplant Transfusion.

Importance: Red blood cell transfusion (RBCT) is frequently required in the early post-kidney transplant period, but long-term outcomes associated with RBCT is controversial. Therefore, it may be relevant to investigate the association between RBCT characteristics and transplant outcomes. Objective: To study the association between RBC storage duration and transplant outcomes. Design, Setting, and Participants: This was a nationwide retrospective cohort study based on data linking between 2 prospective French nationwide registries. Clinical transplant parameters, outcomes, and RBCT characteristics were extracted from the CRISTAL registry of the Agence de la Biomédecine and the national database of the Etablissement Français du Sang. All 12 559 patients having received a first kidney transplant in France between January 1, 2002, and December 31, 2008, were included. Patients were followed up from transplant to graft loss, death with a functional graft, or data retrieval in June 2016. Data were analyzed from April 2019 to June 2022. Exposures: Clinical outcomes of transplant recipients who underwent early RBCT were analyzed considering transfusion characteristics. Main Outcomes and Measures: Cox proportional hazards regression models were fitted to evaluate transplant failure defined as graft loss or death with a functional graft. Results: Among 12 559 patients who underwent kidney transplant, 3483 received an RBCT during the first 14 days posttransplant. The median (IQR) age of patients was 53.0 (41.5-61.2) years, and 1929 patients (55.4%) were male. Median (IQR) follow-up was 7.8 (7.6-8.0) years. In multivariable analysis, longer (vs shorter) storage duration of transfused RBC was associated with a decrease in risk of transplant failure (hazard ratio, 0.99; 95% CI, 0.98-1.00 for each additional storage day; P = .06). Patients transfused with at least 1 RBC unit stored for more than 20 days had a 5% absolute decrease in transplant failure at 3 years and 7% at 5 years compared with those who received RBC stored for less than 20 days. Conclusions and Relevance: In this study, longer RBC storage duration was associated with a decreased risk of transplant failure among patients who received kidney transplants and RBC transfusions. Preferential use of RBC with longer storage duration might improve kidney graft survival following transplant and transfusion.

Pre-transplant immune profile defined by principal component analysis predicts acute rejection after kidney transplantation.

Background: Acute rejection persists as a frequent complication after kidney transplantation. Defining an at-risk immune profile would allow better preventive approaches. Methods: We performed unsupervised hierarchical clustering analysis on pre-transplant immunological phenotype in 1113 renal transplant recipients from the ORLY-EST cohort. Results: We identified three immune profiles correlated with clinical phenotypes. A memory immune cluster was defined by memory CD4+T cell expansion and decreased naïve CD4+T cell. An activated immune cluster was characterized by an increase in CD8+T cells and a decreased CD4/CD8 ratio. A naïve immune cluster was mainly defined by increased naïve CD4+T cells. Patients from the memory immune profile tend to be older and to have diabetes whereas those from the activated immune profile were younger and more likely to have pre-transplant exposure to CMV. Patients from the activated immune profile were more prone to experience acute rejection than those from other clusters [(HR=1.69, 95%IC[1.05-2.70], p=0.030) and (HR=1.85; 95%IC[1.16-3.00], p=0.011). In the activated immune profile, those without previous exposure to CMV (24%) were at very high risk of acute rejection (27 vs 16%, HR=1.85; 95%IC[1.04-3.33], p=0.039). Conclusion: Immune profile determination based on principal component analysis defines clinically different sub-groups and discriminate a population at high-risk of acute rejection.

Automated evaluation with deep learning of total interstitial inflammation and peritubular capillaritis on kidney biopsies.

BACKGROUND: Interstitial inflammation and peritubular capillaritis are observed in many diseases on native and transplant kidney biopsies. A precise and automated evaluation of these histological criteria could help stratify patients' kidney prognoses and facilitate therapeutic management. METHODS: We used a convolutional neural network to evaluate those criteria on kidney biopsies. A total of 423 kidney samples from various diseases were included; 83 kidney samples were used for the neural network training, 106 for comparing manual annotations on limited areas to automated predictions, and 234 to compare automated and visual gradings. RESULTS: The precision, recall and F-score for leukocyte detection were, respectively, 81%, 71% and 76%. Regarding peritubular capillaries detection the precision, recall and F-score were, respectively, 82%, 83% and 82%. There was a strong correlation between the predicted and observed grading of total inflammation, as for the grading of capillaritis (r = 0.89 and r = 0.82, respectively, all P < .0001). The areas under the receiver operating characteristics curves for the prediction of pathologists' Banff total inflammation (ti) and peritubular capillaritis (ptc) scores were respectively all above 0.94 and 0.86. The kappa coefficients between the visual and the neural networks' scores were respectively 0.74, 0.78 and 0.68 for ti ≥1, ti ≥2 and ti ≥3, and 0.62, 0.64 and 0.79 for ptc ≥1, ptc ≥2 and ptc ≥3. In a subgroup of patients with immunoglobulin A nephropathy, the inflammation severity was highly correlated to kidney function at biopsy on univariate and multivariate analyses. CONCLUSION: We developed a tool using deep learning that scores the total inflammation and capillaritis, demonstrating the potential of artificial intelligence in kidney pathology.

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.

Early Post-Transplant Red Blood Cell Transfusion Is Associated With an Increased Risk of Transplant Failure: A Nationwide French Study.

Background: Red blood cell (RBC) transfusions are frequently required in the early period after kidney transplantation. However, the consequences of RBC transfusions on long-term outcomes are largely unrecognized. Methods: We conducted a nationwide French cohort study involving all 31 French kidney transplant centers. Patients having received a first kidney transplant between January 1, 2002 and December 31, 2008 were identified through the national registry of the French BioMedecine Agency (Agence de BioMédecine). Number and date of RBC transfusions were collected from the national database of the French transfusion public service. The primary endpoint was transplant failure defined as graft loss or death with a functional graft. Results: Among 12,559 patients included during the study period, 3,483 (28%) were transfused during the first 14 days post-transplant. Median follow-up was 7.6 (7.5-7.8) years. Multivariable analysis determined that post-transplant RBC transfusion was associated with an increased risk in transplant failure (HR 1.650, 95%CI [1.538;1.771] p<0.0001). Both sensitivity and propension score analyses confirmed the previous result. Conclusions: Early red blood cell transfusion after kidney transplantation is associated with increased transplant failure.

Bictegravir/emtricitabine/tenofovir alafenamide combination in the management of kidney transplant patients with HIV receiving immunosuppressants.

We report here a drug-drug interaction with tacrolimus in a HIV-positive patient with renal transplant, after switch from highly active antiretroviral therapy with boosted protease inhibitors to the combination bictegravir/emtricitabine/tenofovir alafenamide. Although the tacrolimus doses were adapted to take account of the pharmacokinetic interactions with protease inhibitors, a tacrolimus overdosage occurred in the patient nonetheless. Through this case report, we highlight the need to consider a sufficient timeframe of withdrawal of protease inhibitors, which induce a prolonged drug-drug interaction with tacrolimus. To conclude, we purport that the combination bictegravir/emtricitabine/tenofovir alafenamide could be an attractive alternative in the context of transplantation provided a discontinuation of boosted protease inhibitors for more than 48 hours before introducing tacrolimus.

End-Stage Renal Disease-Related Accelerated Immune Senescence: Is Rejuvenation of the Immune System a Therapeutic Goal?

End-stage renal disease (ESRD) patients exhibit clinical features of premature ageing, including frailty, cardiovascular disease, and muscle wasting. Accelerated ageing also concerns the immune system. Patients with ESRD have both immune senescence and chronic inflammation that are resumed in the so-called inflammaging syndrome. Immune senescence is particularly characterised by premature loss of thymic function that is associated with hyporesponsiveness to vaccines, susceptibility to infections, and death. ESRD-related chronic inflammation has multiple causes and participates to accelerated cardiovascular disease. Although, both characterisation of immune senescence and its consequences are relatively well-known, mechanisms are more uncertain. However, prevention of immune senescence/inflammation or/and rejuvenation of the immune system are major goal to ameliorate clinical outcomes of ESRD patients.

New Insights on End-Stage Renal Disease and Healthy Individual Gut Bacterial Translocation: Different Carbon Composition of Lipopolysaccharides and Different Impact on Monocyte Inflammatory Response.

Chronic kidney disease induces disruption of the intestinal epithelial barrier, leading to gut bacterial translocation. Here, we appreciated bacterial translocation by analyzing circulating lipopolysaccharides (LPS) using two methods, one measuring only active free LPS, and the other quantifying total LPS as well as LPS lipid A carbon chain length. This was done in end-stage renal disease (ESRD) patients and healthy volunteers (HV). We observed both higher LPS concentration in healthy volunteers and significant differences in composition of translocated LPS based on lipid A carbon chain length. Lower LPS activity to mass ratio and higher concentration of high-density lipoproteins were found in HV, suggesting a better plasma capacity to neutralize LPS activity. Higher serum concentrations of soluble CD14 and pro-inflammatory cytokines in ESRD patients confirmed this hypothesis. To further explore whether chronic inflammation in ESRD patients could be more related to LPS composition rather than its quantity, we tested the effect of HV and patient sera on cytokine secretion in monocyte cultures. Sera with predominance of 14-carbon chain lipid A-LPS induced higher secretion of pro-inflammatory cytokines than those with predominance of 18-carbon chain lipid A-LPS. TLR4 or LPS antagonists decreased LPS-induced cytokine production by monocytes, demonstrating an LPS-specific effect. Thereby, septic inflammation observed in ESRD patients may be not related to higher bacterial translocation, but to reduced LPS neutralization capacity and differences in translocated LPS subtypes.

Is COVID-19 infection more severe in kidney transplant recipients?

There are no studies which have compared the risk of severe COVID-19 and related mortality between transplant recipients and nontransplant patients. We enrolled two groups of patients hospitalized for COVID-19, that is, kidney transplant recipients (KTR) from the French Registry of Solid Organ Transplant (n = 306) and a single-center cohort of nontransplant patients (n = 795). An analysis was performed among subgroups matched for age and risk factors for severe COVID-19 or mortality. Severe COVID-19 was defined as admission (or transfer) to an intensive care unit, need for mechanical ventilation, or death. Transplant recipients were younger and had more comorbidities compared to nontransplant patients. They presented with higher creatinine levels and developed more episodes of acute kidney injury. After matching, the 30-day cumulative incidence of severe COVID-19 did not differ between KTR and nontransplant patients; however, 30-day COVID-19-related mortality was significantly higher in KTR (17.9% vs 11.4%, respectively, p = .038). Age >60 years, cardiovascular disease, dyspnea, fever, lymphopenia, and C-reactive protein (CRP) were associated with severe COVID-19 in univariate analysis, whereas transplant status and serum creatinine levels were not. Age >60 years, hypertension, cardiovascular disease, diabetes, CRP >60 mg/L, lymphopenia, kidney transplant status (HR = 1.55), and creatinine level >115 µmol/L (HR = 2.32) were associated with COVID-19-related mortality in univariate analysis. In multivariable analysis, cardiovascular disease, dyspnea, and fever were associated with severe disease, whereas age >60 years, cardiovascular disease, dyspnea, fever, and creatinine level>115 µmol/L retained their independent associations with mortality. KTR had a higher COVID-19-related mortality compared to nontransplant hospitalized patients.

Pre-transplant Thymic Function Predicts Is Associated With Patient Death After Kidney Transplantation.

Accelerated thymic involution is a main feature of end-stage renal disease (ESRD)-associated immune senescence. Recent evidences suggest that ESRD-associated immune senescence is associated with adverse outcomes in dialysis patients. However, no study focused on the association between pre-transplant thymic function and patient survival after transplantation. We conducted a prospective, multicenter study to assess whether pre-transplant thymic function measured by recent thymic emigrants (RTE) may predict death after first kidney transplantation. Results were tested in a validation cohort. Nine hundred and sixty-seven incident kidney transplant recipients were included in the prospective study. Mean follow up was 5.1 + 2.9 years. Eighty two patients (8.5%) died during follow up. Lower RTE levels were associated with a higher risk of death (2.53; 95%CI, 1.54-4.39 for each decrease of 1 log in RTE; p < 0.001). Cancer-related death was particularly increased in patients with low RTE levels (4.23; 95%CI, 1.43-12.13; p = 0.007). One hundred and thirty-six patients having received a first kidney transplantation were included in the validation cohort. Lower TREC levels were associated with higher risk of death (1.90; 95%CI, 1.11-3.51 for each decrease of 1 log in RTE; p = 0.025). RTE were not associated with death-censored graft loss. Pre-transplant thymic function is strongly associated with death after transplantation. Attempt to reverse ESRD-related thymic loss may prevent premature death.

An initial report from the French SOT COVID Registry suggests high mortality due to COVID-19 in recipients of kidney transplants.

Notwithstanding the ongoing coronavirus disease-2019 (Covid-19) pandemic, information on its clinical presentation and prognosis in recipients of a kidney transplant remain scanty. The aim of this registry-based observational study was to explore characteristics and clinical outcomes of recipients of kidney transplants included in the French nationwide Registry of Solid Organ Transplant Recipients with Covid-19. Covid-19 was diagnosed in symptomatic patients who had a positive PCR assay for SARS-CoV-2 or having typical lung lesions on imaging. Clinical and laboratory characteristics, management of immunosuppression, treatment for Covid-19, and clinical outcomes (hospitalization, admission to intensive care unit, mechanical ventilation, or death) were recorded. Risk factors for severe disease or death were determined. Of the 279 patients, 243 were admitted to hospital and 36 were managed at home. The median age of hospitalized patients was 61.6 years; most had comorbidities (hypertension, 90.1%; overweight, 63.8%; diabetes, 41.3%; cardiovascular disease, 36.2%). Fever, cough, dyspnea, and diarrhea were the most common symptoms on admission. Laboratory findings revealed mild inflammation frequently accompanied by lymphopenia. Immunosuppressive drugs were generally withdrawn (calcineurin inhibitors: 28.7%; antimetabolites: 70.8%). Treatment was mainly based on hydroxychloroquine (24.7%), antiviral drugs (7.8%), and tocilizumab (5.3%). Severe Covid-19 occurred in 106 patients (46%). Forty-three hospitalized patients died (30-day mortality 22.8%). Multivariable analysis identified overweight, fever, and dyspnea as independent risk factors for severe disease, whereas age over 60 years, cardiovascular disease, and dyspnea were independently associated with mortality. Thus, Covid-19 in recipients of kidney transplants portends a high mortality rate. Proper management of immunosuppression and tailored treatment of this population remain challenging.

A simple score to predict early death after kidney transplantation.

BACKGROUND: Few studies have focused on risk stratification for premature death after transplantation. However, stratification of individual risk is an essential step in personalized care. MATERIAL AND METHODS: We have developed a risk score of early post-transplant death (ORLY score) in a prospective multicentre cohort including 942 patients and validated our model in a retrospective independent replication cohort including 874 patients. RESULTS: 60 patients (6.4%) from the prospective cohort died during the first three-year post-transplant. Age, male gender, diabetes, dialysis duration and chronic respiratory failure were associated with early post-transplant death. The multivariable model exhibited good discrimination ability (C-index = 0.78, 95%CI [0.75-0.81]). ORLY score highly predicted early death after transplantation (1.34; 95%CI, 1.22 to 1.48 for each increase of 1 point in score; P < .001). The predictive value of the score in the validation cohort was close to that observed in the experimental cohort (1.41; 95%CI, 1.27 to 1.56 for each increase of 1 point in score; P < .001). Merging the two cohorts, four categories of risk could be individualized: low, 0-5 (n = 522, mean risk, 1%); intermediate, 6-7 (n = 739, mean risk 4.7%); moderate, 8-10 (n = 429, mean risk 10%); and high risk 11-15 (n = 132, mean risk 19%). CONCLUSIONS: The ORLY score discriminates patients with high risk of early death.