Cytokine release syndrome-associated encephalopathy in patients with COVID-19.

BACKGROUND AND PURPOSE: Neurological manifestations in coronavirus disease (COVID)-2019 may adversely affect clinical outcomes. Severe COVID-19 and uremia are risk factors for neurological complications. However, the lack of insight into their pathogenesis, particularly with respect to the role of the cytokine release syndrome (CRS), is currently hampering effective therapeutic interventions. The aims of this study were to describe the neurological manifestations of patients with COVID-19 and to gain pathophysiological insights with respect to CRS. METHODS: In this longitudinal study, we performed extensive clinical, laboratory and imaging phenotyping in five patients admitted to our renal unit. RESULTS: Neurological presentation included confusion, tremor, cerebellar ataxia, behavioral alterations, aphasia, pyramidal syndrome, coma, cranial nerve palsy, dysautonomia, and central hypothyroidism. Notably, neurological disturbances were accompanied by laboratory evidence of CRS. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was undetectable in the cerebrospinal fluid (CSF). Hyperalbuminorrachia and increased levels of the astroglial protein S100B were suggestive of blood-brain barrier (BBB) dysfunction. Brain magnetic resonance imaging findings comprised evidence of acute leukoencephalitis (n = 3, one of whom had a hemorrhagic form), cytotoxic edema mimicking ischaemic stroke (n = 1), or normal results (n = 2). Treatment with corticosteroids and/or intravenous immunoglobulins was attempted, resulting in rapid recovery from neurological disturbances in two cases. SARS-CoV2 was undetectable in 88 of the 90 patients with COVID-19 who underwent Reverse Transcription-PCR testing of CSF. CONCLUSIONS: Patients with COVID-19 can develop neurological manifestations that share clinical, laboratory and imaging similarities with those of chimeric antigen receptor T-cell-related encephalopathy. The pathophysiological underpinnings appear to involve CRS, endothelial activation, BBB dysfunction, and immune-mediated mechanisms.

Type 1 primary hyperoxaluria: A case report and focus on bone impairment of systemic oxalosis.

Primary hyperoxaluria is a rare genetic disorder characterized by oxalate overproduction, leading to kidney failure due to nephrocalcinosis, and is eventually responsible for systemic oxalosis. Bone impairment, secondary to oxalate deposits, is one of the many complications that may occur. Skeletal involvement can be difficult to diagnose because of lack of clinical symptoms and therefore needs to be confirmed by invasive testing, such as transiliac bone biopsy. If confirmed, bone oxalosis is the proof of disease severity and that combined liver-kidney transplantation should be performed.

Effect of an Early Switch to Belatacept Among Calcineurin Inhibitor-Intolerant Graft Recipients of Kidneys From Extended-Criteria Donors.

Transplant recipients receiving a kidney from an extended-criteria donor (ECD) are exposed to calcineurin inhibitor (CNI) nephrotoxicity, as demonstrated by severe delayed graft function and/or a low GFR. Belatacept is a nonnephrotoxic drug that is indicated as an alternative to CNIs. We reported 25 cases of conversion from a CNI to belatacept due to CNI intolerance within the first 6 mo after transplantation. The mean age of the recipients was 59 years, and 24 of 25 patients received ECD kidneys. At the date of the medication switch, 12 of 25 patients displayed a calculated GFR (cGFR) <15 mL/min, six patients remained on dialysis, and the biopsies showed evidence of acute tubular damage associated with severe vascular or tubulointerstitial chronic lesions. Three patients did not recover renal function, and three patients died during the follow-up period. Among the remaining patients, renal function improved: The cGFR was 18.28 ± 12.3 mL/min before the medication switch compared with 34.9 ± 14.5 mL/min at 1 year after conversion to belatacept (p = 0.002). Tolerance of and compliance with belatacept were good, and only one patient experienced acute rejection. Belatacept is an effective therapy that preserves renal function in kidney transplant patients who are intolerant of CNIs.

Ruling out nosocomial transmission of Cryptosporidium in a renal transplantation unit: case report.

BACKGROUND: Cryptosporidium spp. is a ubiquitous parasite affecting humans as well as domestic and wild vertebrates, causing diarrhea in both immunocompetent and immunocompromised hosts worldwide. Its transmission occurs primarily by the fecal-oral route. In humans, C. parvum and C. hominis are the most prevalent species, whereas immunocompetent and immunocompromised individuals can also be infected by other zoonotic species. Renal transplant patients are prone to develop cryptosporidiosis, which can induce severe and life-threatening diarrhea. CASE PRESENTATION: We report here a series of nearly concomitant cases of acute symptomatic cryptosporidiosis in three renal transplant patients attending the Strasbourg University Hospital Nephrology Unit. The clinical presentation was persistent diarrhea and acute renal failure. The diagnosis was confirmed by microscopic stool examination using a modified Ziehl-Neelsen staining method and species identification by molecular tools. All patients were treated with nitazoxanide and recovered from diarrhea after 14 days of therapy. CONCLUSION: Genotypic species identification was not consistent with an epidemic context, thus underlining the need for genotyping to monitor at risk patients.

Persistent hyperparathyroidism is a major risk factor for fractures in the five years after kidney transplantation.

The risk of fractures after kidney transplantation is high. Hyperparathyroidism frequently persists after successful kidney transplantation and contributes to bone loss, but its impact on fracture has not been demonstrated. This longitudinal study was designed to evaluate hyperparathyroidism and its associations with mineral disorders and fractures in the 5 posttransplant years. We retrospectively analyzed 143 consecutive patients who underwent kidney transplantation between August 2004 and April 2006. The biochemical parameters were determined at transplantation and at 3, 12 and 60 months posttransplantation, and fractures were recorded. The median intact parathyroid hormone (PTH) level was 334 ng/L (interquartile 151-642) at the time of transplantation and 123 ng/L (interquartile 75-224) at 3 months. Thirty fractures occurred in 22 patients. The receiver operating characteristic (ROC) curve analysis for PTH at 3 months (area under the ROC curve = 0.711, p = 0.002) showed that a good threshold for predicting fractures was 130 ng/L (sensitivity = 81%, specificity = 57%). In a multivariable analysis, independent risk factors for fracture were PTH >130 ng/L at 3 months (adjusted hazard ratio [AHR] = 7.5, 95% CI 2.18-25.50), and pretransplant osteopenia (AHR = 2.7, 95% CI 1.07-7.26). In summary, this study demonstrates for the first time that persistent hyperparathyroidism is an independent risk factor for fractures after kidney transplantation.

Epidemiology of posttransplant lymphoproliferative disorders in adult kidney and kidney pancreas recipients: report of the French registry and analysis of subgroups of lymphomas.

A registry of posttransplant lymphoproliferative disorders (PTLD) was set up for the entire population of adult kidney transplant recipients in France. Cases of PTLD were prospectively enrolled between January 1, 1998, and December 31, 2007. Ten-year cumulative incidence was analyzed in patients transplanted after January 1, 1989. PTLD risk factors were analyzed in patients transplanted after January 1, 1998 by Cox analysis. Cumulative incidence was 1% after 5 years, 2.1% after 10 years. Multivariate analysis showed that PTLD was significantly associated with: older age of the recipient 47-60 years and >60 years (vs. 33-46 years, adjusted hazard ratio (AHR) = 1.87, CI = 1.22-2.86 and AHR = 2.80, CI = 1.73-4.55, respectively, p < 0.0001), simultaneous kidney-pancreas transplantation (AHR = 2.52, CI = 1.27-5.01 p = 0.008), year of transplant 1998-1999 and 2000-2001 (vs. 2006-2007, AHR = 3.36, CI = 1.64-6.87 and AHR = 3.08, CI = 1.55-6.15, respectively, p = 0.003), EBV mismatch (HR = 5.31, CI = 3.36-8.39, p < 0.001), 5 or 6 HLA mismatches (vs. 0-4, AHR = 1.54, CI = 1.12-2.12, p = 0.008), and induction therapy (AHR = 1.42, CI = 1-2.02, p = 0.05). Analyses of subgroups of PTLD provided new information about PTLD risk factors for early, late, EBV positive and negative, polymorphic, monomorphic, graft and cerebral lymphomas. This nationwide study highlights the increased risk of PTLD as long as 10 years after transplantation and the role of cofactors in modifying PTLD risk, particularly in specific PTLD subgroups.

Post-transplant lymphoproliferative disorders: determination of donor/recipient origin in a large cohort of kidney recipients.

Although in previous studies most post-transplant lymphoproliferative disorders (PTLD) were reported to derive from recipient cells, some cases derived from donor lymphocytes have been reported. To provide a better description of the features and outcome of PTLD according to the origin of the lymphoma, we performed histologic and molecular studies of PTLD in kidney recipients. Forty-three specimens were analyzed by histochemistry, fluorescent hybridization of the Y chromosome and analysis of multiple short tandem repeat microsatellite loci. Sixteen tumors were shown to be of donor origin and 27 of recipient origin. Time to PTLD was shorter in donor-derived PTLDs (20 ± 27 vs. 69 ± 67 months, p = 0.013). Ten-year patient survival was similar among patients with recipient- and donor-derived PTLD, but when PTLD-related mortality was analyzed, there was a trend to better survival in patients with donor lymphomas. Among the 21 PTLDs localized in the allograft, 14 lymphomas were of donor origin and seven of recipient origin. No difference was found between the two groups. Our analysis of the origin of PTLDs in the largest cohort studied to date with a description of the clinical and histological characteristics of donor and recipient PTLDs should lead to a better understanding of lymphomagenesis.

Gestational choriocarcinoma transmission following multiorgan donation.

An accidental transmission of placental choriocarcinoma (CC) from a multiorgan donor to four recipients is reported. The donor was a 26-year-old pregnant woman, died from a cerebral hemorrhage. Histological examination demonstrated the presence of a placental CC. Diagnosis of CC transmission was established on the basis of an increase of human chorionic gonadotrophin hormone (hCG) level. The recipient of combined pancreas-kidney is still in complete remission 2 years after the beginning of chemotherapy without removal of the grafted organs which show optimal function. The recipient of a single kidney was rapidly transplantectomized and treated with actinomycin. At 2 years, she remains in remission. Liver recipient showed intestinal metastasis and died from digestive hemorrhage after an initial response to chemotherapy. Heart recipient had an initial remission under EMA-CO, but at the last report, he showed diffuse metastasis. Published reports on CC transmission are rare. The long-lasting remission of our pancreas-kidney recipient and her good outcome after 2 years make our observation original. Moreover, the high rate of transmission demonstrates the high malignant potential of CC in immunosuppressed patients. Chemotherapy combined or not with transplantectomy in case of nonvital organ, should be discussed.

Torquetenovirus viremia for early prediction of graft rejection after kidney transplantation.

OBJECTIVES: New biomarkers reflecting the degree of immunosuppression in transplant recipients are needed to provide an optimal personalized balance between rejection and infection risks. METHODS: For this purpose, we investigated TTV viremia dynamics in 66 kidney transplant recipients followed up for two years after transplantation, in relation to BK virus infection and graft rejection. RESULTS: After transplantation, TTV viremia rose by ≥2 log10 copies/mL from baseline to month 3, then declined by ≥1 log10 copies/mL thereafter. Higher TTV viremia was associated with recipients of a deceased donor, a lower count of CD8+ T cells and a higher BKV viremia. Importantly, TTV loads were significantly lower in KTR who would later display graft rejection; indeed, patients with TTV viremia lower than 3.4 log10 copies/mL at transplantation or lower than 4.2 log10 copies/mL at month 1 had a higher risk of developing graft rejection in the two following years (hazard ratio (HR) at D0 = 7.30, p = 0.0007 and HR at M1 = 6.16, p = 0.001). CONCLUSIONS: TTV viremia measurement at early times post transplantation predicts graft rejection and would represent a useful tool to improve kidney transplant monitoring.

[Methods of assessment of the renal function in kidney transplant patients]. / Quelles méthodes choisir pour évaluer la fonction rénale chez le transplanté?

Glomerular filtration rate (GFR), which evaluates the evolution of the renal function, can be directly assessed by the measure of urinary or plasmatic clearance of a specific marker that ideally should be freely filtrated, without haemodynamic or toxic effects and easily dosed. Unfortunately, such a sensible marker of renal function variations does not yet exist. Particularly for GFRs in the range of 60ml/min estimation formulas generally over or under-estimate the true GFR, especially the Cockcroft formula that estimates creatinine clearance. Therefore, it is recommended to use validated markers for the measurement of the true GFR (inulin, iohexol, Cr EDTA...), in particular for the follow-up of cohorts and for studies using GFR as an outcome measure. For daily clinical practice, it is possible to use estimation formulas, preferably the 4-variables MDRD equation. However, to optimize the accuracy of GFR measures estimated from these formulas, it is first necessary to control the homogenous calibration of creatinine measurement devices.

[Transplantation of patients with cardiovascular risk]. / La transplantation des patients à risque cardio-vasculaire.

Transplantation of patients with cardiovascular risk is becoming more frequent because of the recent changes in the characteristics of hemodialysis patients. Improvement in patient survival after transplantation has been reported in the whole cohort and is probably applicable to cardiovascular risk patients. Nevertheless, cardiovascular mortality is the leading cause of death after transplantation. Systematic screening of patients before transplantation and adapted treatment after transplantation are needed. After transplantation, immunosuppressive treatment should be tailored to the patient's profile and cardiovascular risk factors should be managed cautiously.

Long-term results of monoclonal anti-Il2-receptor antibody versus polyclonal antilymphocyte antibodies as induction therapy in renal transplantation.

We compared the influence of induction therapy on 5-year patient and graft survival as well as on renal function in 100 kidney graft recipients at low immunological risk treated with antilymphocyte globulin (n = 50) versus anti-IL-2R monoclonal antibody (n = 50) in a prospective multicenter study. Long-term immunosuppressive treatment included cyclosporine, mycophenolate mofetil, and a short course of steroids in all patients. Five year graft (86% vs 86%) and patient (94% vs 94%) survivals were identical in both study arms. Moreover, neither serum creatinine or proteinuria were significantly different between the two groups. Our results showed that the choice of the induction therapy seemed to not have a major impact on long-term outcomes among renal recipients at low immunological risk.

Intraoperative Pleth Variability Index Is Linked to Delayed Graft Function After Kidney Transplantation.

BACKGROUND: Delayed graft function (DGF) is an early postoperative complication of kidney transplantation (KT) predisposing to acute rejection and lower graft survival. Intraoperative arterial hypotension and hypovolemia are associated with DGF. Central venous pressure (CVP) is used to estimate volemia but its reliability has been criticized. Pleth variability index (PVI) is a hemodynamic parameter predicting fluid responsiveness. The aim of this study was to examine the relationship between intraoperative PVI and CVP values and the occurrence of DGF. METHODS: This was a prospective, noninterventional, observational, single-center study. All consecutive patients with KT from deceased donors were included. Recipients received standard, CVP, and PVI monitoring. Intraoperative hemodynamic parameters were recorded from recipients at 5 time points during KT. RESULTS: Forty patients were enrolled. There was a poor correlation between PVI and CVP values (r2 = 0.003; P = .44). Immediate graft function and DGF patients had similar hemodynamic values during KT, with the exception of PVI values, which were significantly higher in the DGF group. In particular, a PVI >9% before unclamping of the renal artery was the only predictive parameter of DGF in our multivariate analysis (P = .02). CONCLUSIONS: This study suggests that PVI values >9% during KT are associated with the occurrence of DGF.

Is sirolimus responsible for proteinuria?

Sirolimus (SRL) is suspected to induce proteinuria. We retrospectively studied proteinuria in a population of liver (n = 29) and kidney transplant (n = 30) recipients switched to SRL with progressive diminution or withdrawal of calcineurin inhibitors (CNI). We also observed estimated glomerular filtration rate (GFR), modification of treatment with antiproteinuric drugs, and changes in concentration of SRL. Collection of data started 3 months before SRL introduction at a mean follow-up of 21 months. Following SRL introduction, proteinuria was not detected in the 28 liver transplant patients, and was stable in the two others. In the kidney transplant group, proteinuria did not occur in 12 patients, remained stable in three, and was slightly increased in 14 (0.57 +/- 0.93 g/d vs 1.83 +/- 1.26 g/d). For all patients, eGFR remained stable; there was no difference in management of antiproteinuric drugs. As suspected, cyclosporin (CsA) and tacrolimus (FK) serum concentrations were decreased. We observed a significant correlation between the variation of proteinuria and the variation of serum concentration of CsA or FK (respectively, P = .001 and P = .007). On the other hand, we did not find any correlation between variation in proteinuria and concentration of SRL. This retrospective study suggests that in our cohort of liver transplant patients without previous renal damage, SRL did not provoke proteinuria. On the other hand, the slight aggravation of proteinuria in a subgroup of kidney transplant patients seems to be linked to the hemodynamic renal effects due to CNI withdrawal.

Current preventive strategies and management of Epstein-Barr virus-related post-transplant lymphoproliferative disease in solid organ transplantation in Europe. Results of the ESGICH Questionnaire-based Cross-sectional Survey.

There is limited clinical evidence on the utility of the monitoring of Epstein-Barr virus (EBV) DNAemia in the pre-emptive management of post-transplant lymphoproliferative disease (PTLD) in solid organ transplant (SOT) recipients. We investigated current preventive measures against EBV-related PTLD through a web-based questionnaire sent to 669 SOT programmes in 35 European countries. This study was performed on behalf of the ESGICH study group from the European Society of Clinical Microbiology and Infectious Diseases. A total of 71 SOT programmes from 15 European countries participated in the study. EBV serostatus of the recipient is routinely obtained in 69/71 centres (97%) and 64 (90%) have access to EBV DNAemia assays. EBV monitoring is routinely used in 85.9% of the programmes and 77.4% reported performing pre-emptive treatment for patients with significant EBV DNAemia levels. Pre-emptive treatment for EBV DNAemia included reduction of immunosuppression in 50.9%, switch to mammalian target of rapamycin inhibitors in 30.9%, and use of rituximab in 14.5% of programmes. Imaging by whole-body 18-fluoro-deoxyglucose positron emission tomography (FDG-PET) is used in 60.9% of centres to rule out PTLD and complemented computer tomography is used in 50%. In 10.9% of centres, FDG-PET is included in the first-line diagnostic workup in patients with high-risk EBV DNAemia. Despite the lack of definitive evidence, EBV load measurements are frequently used in Europe to guide diagnostic workup and pre-emptive reduction of immunosuppression. We need prospective and controlled studies to define the impact of EBV monitoring in reducing the risk of PTLD in SOT recipients.

[Treatment of lupus glomerulonephritis with intravenous cyclophosphamide]. / Traitement des glomérulonéphrites lupiques par le cyclophosphamide en emboles intraveineux.

The treatment of severe lupus nephritis remains problematic. We have analysed retrospectively 17 patients with corticoresistant lupus nephritis treated with pulse cyclophosphamide. Single monthly doses (500 mg/m2) were given by intravenous infusion with a mean of 10.4 infusions per patient (3 to 18). A comparison of parameters at entry and at the end of the treatment revealed an improvement in proteinuria (4.8 vs 1.9 g/24 h; p < 0.013) whereas mean serum creatinine level and SLAM (Systemic Lupus Activity Measure) remained stable. The results were identical at follow up (mean: 14.5 months). Most of the therapeutic effect was achieved as soon as the 6th pulse. Further treatment was beneficial for four patients only. None of the studied parameters (serum creatinine level, renal biopsy, SLAM) was predictive of a response to an extended course of pulse cyclophosphamide. The infusions were definitively stopped in one patient and delayed in two others because of serious adverse effects. The data indicate that, in mean term, monthly intravenous cyclophosphamide was associated with a substantial amelioration of 24 hours urinary protein level. An amelioration of the renal function was however, uncommon.

[Kidney and statins]. / Rein et statines.

Patients with chronic renal diseases (CRD) have a high prevalence of lipid abnormalities. Elevated levels of total and low density lipoprotein cholesterol are associated with cardiovascular diseases in patients with CRD. The 3-hydroxy-methylglutaryl co-enzyme A reductase inhibitors appear to be the most effective agents to lower LDL cholesterol in this category of patients and are generally safe if used with caution. They should be drugs of first choice in CRD but dosage reduction and close monitoring may be required to avoid side effects in case of renal failure or in combination with calcineurin inhibitors. Moreover recent studies suggest that in addition to lowering plasma LDL cholesterol, theses compounds may modify several factors implicated in the development of atherosclerosis and the progression of chronic renal failure. Such newly defined effects may contribute to extend the use of statins in the management of renal patients.

Epstein-Barr virus-related post-transplant lymphoproliferative disorder in solid organ transplant recipients.

Epstein-Barr virus (EBV) contributes to the pathogenesis of post-transplant lymphoproliferative disease (PTLD) in more than 70% of cases. EBV DNAemia surveillance has been reported to assist in the prevention and treatment of PTLD in hematopoietic stem-cell transplantation (HSCT) recipients. Derived from experience in HSCT and taking into account that PCR-based EBV monitoring techniques are currently available in most solid organ transplant (SOT) centres, there is a great interest in EBV surveillance and prevention of PTLD in SOT recipients. In the present document we have tried to address from a practical perspective different important topics regarding the prevention and management of EBV-related PTLD in SOT. To this end, available information on SOT was analysed and combined with potentially useful data from HSCT and expert observations. The document is therefore structured according to different specific questions, each of them culminating in a consensus opinion of the panel of European experts, grading the answers according to internationally recognized levels of evidence. The addressed issues were grouped under the following topics. (i) Timing and epidemiological data of PTLD. Prophylaxis guided by clinical risk factors of early and late PTLD in SOT. (ii) Relationship of EBV DNAemia load monitoring and the development of PTLD in solid organ transplant recipients. (iii) Monitoring of EBV DNAemia after SOT. Which population should be monitored? What is the optimal timing of the monitoring? (iv) Management of SOT recipients with persistent and/or increasing EBV DNAemia.

The influence of cytomegalovirus infections on patient and renal graft outcome: a 3-year, multicenter, observational study (Post-ECTAZ Study).

Cytomegalovirus (CMV) infections posttransplant may increase the risk of acute rejection, graft failure, patient death, opportunistic infections, malignancy, diabetes, and cardiovascular complications. ECTAZ, a multicenter, randomized trial compared safety and efficacy at 12 months (M12) of two doses daclizumab (54 patients, group D) with thymoglobulin (55 patients, group T), plus cyclosporine (CsA), mycophenolate mofetil and steroids in first cadaveric kidney transplant patients. D+/R- patients received oral ganciclovir prophylaxis for 90 days. Post-ECTAZ is a 36-month, multicenter, observational study including recipients who participated in ECTAZ trial. We studied the indirect effects of CMV infections, whether recipients experienced (CMVi+) or not (CMVi-) a CMV infection/syndrome/disease. We compared 49 patients in the group CMVi+ with 54 patients in the group CMVi-. At month 36 (M36), patient survival, graft survival and renal function were comparable. The incidence of biopsy-proven acute rejection was 16.3% in the CMVi+ group versus 24.1% in the CMVi- group (not significant). The incidence of infections was increased in the CMVi+ group (P = .004), but not diabetes, malignancies, and cardiovascular complications. Our study shows at M36 that CMV infection/syndrome/disease episodes were associated with a higher incidence of infections but no difference for other long-term complications. Our data suggest that anti-CMV prophylaxis could decrease the risk for long-term related CMV complications.