Neutrophil:lymphocyte ratio predicts short-term outcome of COVID-19 in haemodialysis patients.

BACKGROUND: Information regarding coronavirus disease 2019 (COVID-19) in haemodialysis (HD) patients is limited and early studies suggest a poor outcome. We aimed to identify clinical and biological markers associated with severe forms of COVID-19 in HD patients. METHODS: We conducted a prospective, observational and multicentric study. Sixty-two consecutive adult HD patients with confirmed COVID-19 from four dialysis facilities in Paris, France, from 19 March to 19 May 2020 were included.Blood tests were performed before diagnosis and at Days 7 and 14 after diagnosis. Severe forms of COVID-19 were defined as requiring oxygen therapy, admission in an intensive care unit or death. Cox regression models were used to compute adjusted hazard ratios (aHRs). Kaplan-Meier curves and log-rank tests were used for survival analysis. RESULTS: Twenty-eight patients (45%) displayed severe forms of COVID-19. Compared with non-severe forms, these patients had more fever (93% versus 56%, P < 0.01), cough (71% versus 38%, P = 0.02) and dyspnoea (43% versus 6%, P < 0.01) at diagnosis. At Day 7 post-diagnosis, neutrophil counts, neutrophil:lymphocyte (N:L) ratio, C-reactive protein, ferritin, fibrinogen and lactate dehydrogenase levels were significantly higher in severe COVID-19 patients. Multivariate analysis revealed an N:L ratio >3.7 was the major marker associated with severe forms, with an aHR of 4.28 (95% confidence interval 1.52-12.0; P = 0.006). After a median follow-up time of 48 days (range 27-61), six patients with severe forms died (10%). CONCLUSIONS: HD patients are at increased risk of severe forms of COVID-19. An elevated N:L ratio at Day 7 was highly associated with the severe forms. Assessing the N:L ratio could inform clinicians for early treatment decisions.

MMP9 and SCF protect from apoptosis in acute kidney injury.

Apoptosis of tubular epithelial cells is a hallmark of acute kidney injury (AKI), but the cellular events preceding apoptosis in this setting are incompletely understood. Because matrix metalloproteinase 9 (MMP9) degrades matrix components involved in cell survival, we studied the role of MMP9 in AKI. In the mouse model of folic acid-induced AKI, we observed a marked increase of MMP9 activity in the S3 segment of the proximal tubule (S3PT), correlating with the apoptotic phase. MMP9 deficiency increased apoptosis and the severity of renal lesions and substantially delayed recovery of renal function. MMP9-/- mice exhibited significant apoptosis in the S3PT and the intercalated cells of the collecting duct (I-CD), whereas wild-type mice exhibited none in these segments. Stem cell factor (SCF), an MMP9 substrate, was identified in the S3PT, and its receptor, c-Kit, was expressed in both the S3PT and I-CD. MMP9 released the soluble form of SCF (sSCF) from kidney cells in vivo and in vitro. In addition, SCF inhibited apoptosis of tubular cells in vitro, rescued MMP9-/- S3PT and I-CD from apoptosis in vivo, and improved renal function. An ischemia-reperfusion model of AKI produced similar results. In patients with AKI, urinary sSCF increased with acute tubular necrosis but not with prerenal azotemia. In conclusion, these data show that MMP9 protects the S3 segment of the proximal tubule and the I-CD from apoptosis in AKI, most likely by releasing sSCF.

Immunological strategies targeting B cells in organ grafting.

After delayed-type hypersensitivity and T cell cytotoxicity, the production of alloantibodies is the third effector mechanism contributing to graft injury. Histological characterization of antibody-mediated rejection and the detection of donor-reactive antibodies have highlighted the role of humoral immunity in acute and chronic rejection. A potential way of achieving central B cell tolerance is to induce complete chimerism with a myeloablative regimen and bone marrow transplant. However, nonmyeloablative regimens have been developed to create a state of "mixed chimerism" in patients without hematologic malignancies. Other strategies targeting B cells have been developed for the management of "high risk" clinical situations, including highly sensitized patients and transplantation with a positive crossmatch. These strategies have been extended to ABO incompatible transplantations and xenotransplantations. We will review therapeutic regimens that allow the removal or neutralization of pathogenic antibodies (immunoadsorption, plasmapheresis, intravenous globulins) and the blockade of memory B cell proliferation and differentiation into plasmocytes, including cyclophosphamide, the tacrolimus/mycophenolate mofetil combination, and anti-CD20 antibodies.

[Estimation of urea distribution volume in hemodialysis patients]. / Estimation du volume de distribution de l'urée chez le patient hémodialysé.

BACKGROUND: On-line urea clearance estimation, currently available on some dialysis monitors, makes it possible to calculate the dialysis dose Kt and thus allows to estimate Kt/V for each session, providing an estimation of urea distribution volume (V) at equilibrium assumed equal to total body water. METHODS: Three methods suitable for routinely estimating V, using the anthropometric Watson formula (V(Wat)), the body composition monitor (BCM) device (Fresenius Medical Care) based on bio-impedance analysis (V(imp)) and the indirect estimation (V(Daug)) obtained from measurement of Kt/(Kt/V)(sp) ratio respectively are compared during 25 dialysis sessions in 15 patients to a direct estimation (V(DDQ)) obtained by direct quantification of dialysis (DDQ) considered as the gold standard in hemodialysis patient.. RESULTS: V(Watson) overestimates V(DDQ) by about 20%. The values of V(imp) (29.1±5.6 L) and V(Daug) (29.5±4.6 L) are in agreement with V(DDQ) (29.9±5.2 L). Correlation coefficient with V(DDQ) is better for V(imp) (r=0.94) than for V(Daug) (r=0.85). CONCLUSION: Bio-impedancemetry using BCM and indirect method using the second generation Daugirdas equation are two methods of clinical interest for estimating V. Bio-impedancemetry does not require blood sample, but it needs to have a specific device at disposal.

Costimulation blockade and its possible future use in clinical transplantation.

The nonimmune effects of currently used immunosuppressive drugs result in a high incidence of late graft loss due to nephrotoxicity and death of patients. As an immune-specific alternative to conventional immunosuppressants, new biotechnology tools can be used to block the costimulation signals of T-cell activation. Many experimental studies--particularly preclinical studies in nonhuman primates--have focused on blocking the 'classical' B7/CD28 and CD40/CD40L pathways, which are critical in primary T-cell activation. Here, we review the limitations, the recent advances and the first large-scale clinical application of the CTLA4-Ig fusion protein to block the B7/CD28 costimulation pathway. We also focus on new B7/CD28 and tumor necrosis factor (TNF)/TNF-R family costimulatory molecules that can deliver positive or negative costimulation signals regulating the alloimmune response. Strategies that use single agents to block costimulation have often proved to be insufficient. Given the diversity of the different costimulation molecules, future strategies for human transplantation may involve the simultaneous blockade of several selected pathways or the simultaneous use of conventional immunosuppressants.