Protective Role of the Podocyte IL-15 / STAT5 Pathway in Focal Segmental Glomerulosclerosis.

Introduction: During glomerular diseases, podocyte-specific pathways can modulate the intensity of histological disease and prognosis. The therapeutic targeting of these pathways could thus improve the management and prognosis of kidney diseases. The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway, classically described in immune cells, has been recently described in detail in intrinsic kidney cells. Methods: We describe STAT5 expression in human kidney biopsies from patients with focal segmental glomerulosclerosis (FSGS) and studied mice with a podocyte-specific Stat5 deletion in experimental glomerular diseases. Results: Here, we show, for the first time, that STAT5 is activated in human podocytes in FSGS. In addition, podocyte-specific Stat5 inactivation aggravates the structural and functional alterations in a mouse model of FSGS. This could be due, at least in part, to an inhibition of autophagic flux. Finally, interleukin 15 (IL-15), a classical activator of STAT5 in immune cells, increases STAT5 phosphorylation in human podocytes, and its administration alleviates glomerular injury in vivo by maintaining autophagic flux in podocytes. Conclusion: Activating podocyte STAT5 with commercially available IL-15 represents a potential new therapeutic avenue for FSGS.

Microvasculature partial endothelial mesenchymal transition in early posttransplant biopsy with acute tubular necrosis identifies poor recovery renal allografts.

Acute tubular necrosis (ATN), a frequent histopathological feature in the early post-renal transplant biopsy, affects long-term graft function. Appropriate markers to identify patients at risk of no or incomplete recovery after delayed graft function are lacking. In this study, we first included 41 renal transplant patients whose biopsy for cause during the first month after transplantation showed ATN lesions. Using partial microvasculature endothelial (fascin, vimentin) and tubular epithelial (vimentin) to mesenchymal transition markers, detected by immunohistochemistry, we found a significant association between partial endothelial to mesenchymal transition and poor graft function recovery (Spearman's rho = -0.55, P = .0005). Transforming growth factor-ß1 was strongly expressed in these phenotypic changed endothelial cells. Extent of ATN was also correlated with short- and long-term graft dysfunction. However, the association of extensive ATN with long-term graft dysfunction (24 months posttransplant) was observed only in patients with partial endothelial to mesenchymal transition marker expression in their grafts (Spearman's rho = -0.64, P = .003), but not in those without. The association of partial endothelial to mesenchymal transition with worse renal graft outcome was confirmed on 34 other early biopsies with ATN from a second transplant center. Our results suggest that endothelial cell activation at the early phase of renal transplantation plays a detrimental role.

Metformin-related lactic acidosis with acute kidney injury: results of a French observational multicenter study.

Background: Metformin-associated lactic acidosis (MALA) and metformin-induced lactic acidosis (MILA) remain controversial entities. Metformin toxic effect depends on accumulation to lead to lactic acidosis (LA), particularly during an episode of acute kidney injury (AKI). In MILA, no other condition contributing to LA is found. The aims of this study were to describe the characteristics and prognosis of AKI associated with LA in metformin users and to clarify the role of this drug in the different types of LA.Methods: We performed a French multicenter retrospective study in diabetic patients treated by metformin presenting with LA in a context of AKI in 2015. 126 nephrology units (NU) and 23 intensive care units (ICU) were contacted. We individualized MILA and MALA patients in order to illustrate the role of metformin.Results: We included 173 patients (109 MILA, 64 MALA). 103 patients presented without hemodynamic instability (82 MILA and 21 MALA) whereas 70 patients were shocked including 27 MILA. The shock was associated with death with an odds ratio (OR) of 12.92 (p < .001). Digestive disorders (DD) were strongly associated with MILA (p = .0001). MALA was significantly associated with shock (p < .0001). The mortality rate was higher in MALA (26%) when compared with MILA (7%). Dialysis performed in 133 patients was significantly associated with shock, kalemia, lactate and serum creatinine levels. In multivariate analysis, metformin level was independently associated with pH or lactate level only in MILA patients.Conclusions: MILA is associated with DD and death is due to severe refractory acidosis leading to cardiovascular collapse attributed to metformin accumulation mainly via AKI. MALA patients are more frequently shocked and death is related to their underlying condition, metformin accumulation increasing LA.

LDL-apheresis to decrease sFlt-1 during early severe preeclampsia: Report of two cases from a discontinued phase II trial.

OBJECTIVE: Severe preeclampsia may require the delivery of the placenta to avoid life-threatening complications for the mother. Before 26 weeks of gestation, this often results in perinatal death. A decrease in soluble fms-like tyrosine kinase 1 (sFlt1), an anti-angiogenic factor central to the pathophysiology of the maternal syndrome, has been reported after LDL- apheresis. The present study tested whether LDL-apheresis could be used to allow women with early and severe preeclampsia to reach a gestational age where the baby had a viable chance of survival. STUDY DESIGN: A phase II prospective study. Adult women were included if they had very early (<26 weeks of gestation) preeclampsia without severe (<5th percentile) intra-uterine growth retardation. Treatment consisted of two weekly sessions (90 min each) of LDL-apheresis of whole blood. The primary endpoint was the status of the baby (dead or living) at 6 months post-delivery. Sample size and stopping rules were calculated assuming a desired success rate of at least 90%. RESULTS: The study was interrupted for safety reasons after the inclusion of two patients: both developed secondary uncontrolled hypertension and blurred vision during the first week of treatment. The first neonate, born at 25 + 3 weeks of gestation, died of sepsis at day 5; the second, born at 26 + 2 weeks of gestation, is still alive and well. In these two patients, the impact of apheresis sessions on sFlt1 concentrations was inconsistent. CONCLUSION: LDL-apheresis did not result in the prolongation of pregnancy in this phase II trial. Further studies will be needed to delineate the appropriate contours of this therapeutic strategy.

Portal hypertension with extensive fibrosis and plasma cell infiltration in multiple myeloma.

Plasma cell infiltration of the liver has been described in about 45% of patient with multiple myeloma in autopsy review; however, it is usually not associated with significant liver dysfunction. Indeed, only rare cases of massive plasma cell infiltration leading to non-obstructive cholestasis and hepatic failure have been described. Here, we report a case with a history of 8 years of MM with extensive liver fibrosis and portal hypertension with no other evidence aetiology unless massive plasma cell infiltration who presented a significant regression of both biological liver abnormalities and liver stiffness after ten months of chemotherapy concomitantly to a significant decrease of the IgG serum monoclonal band.

Rapidly evolving conjunctivitis due to Pasteurella multocida, occurring after direct inoculation with animal droplets in an immuno-compromised host.

BACKGROUND: The rare descriptions, in the literature, of ocular infections due to Pasteurella multocida include: endophtalmitis, keratitis and corneal ulcers, Parinaud's oculoglandular syndrome, and conjunctivitis. Here, we report a rare case of rapidly evolving conjunctivitis due to Pasteurella multocida, occurring after direct inoculation with animal droplets in an immuno-compromised host. CASE PRESENTATION: A 69-year-old, Caucasian male was referred to our department with purulent conjunctivitis, occurring five days after chemotherapy for an angioimmunoblastic-T-cell-lymphoma, and thirty-three hours after being struck in his right eye by his sneezing Dachshund dog. Physical examination revealed purulent conjunctivitis of the right eye associated with inflammatory edema of both lids. Direct bacteriological examination of conjunctival secretions showed gram-negative bacilli and regular, grey non-hemolytic colonies appearing the next day on blood agar. The oxidase test was positive for these colonies. An antibiotherapy associating intravenous amoxicillin and amoxicillin/clavulanate was administered. The outcome was favorable in the next three days allowing discharge of the patient with amoxicillin (2 g tid per os). CONCLUSION: This case report may be of interest for infectious diseases, ophthalmology or oncology specialists, especially nowadays with chemotherapy being administered in day care centres, where unusual home pathogens can be encountered in health related infections. In this case, previous animal contact and conjunctival samples showing Enterobacteriaceae like colonies with positive oxidase test were two important clues which could help clinicians to make the diagnosis of Pasteurella conjunctivitis in every day practice.