Microbiology and outcomes of polymicrobial peritonitis associated with peritoneal dialysis: a register-based cohort study from the French Language Peritoneal Dialysis Registry.

BACKGROUND: Previous studies have reported that polymicrobial peritonitis in peritoneal dialysis (PD) is associated with poor outcomes, but recent data from European cohorts are scarce. METHODS: We included from the French Language Peritoneal Dialysis Registry all patients ≥18 years of age who started PD between January 2014 and November 2020. We compared microbiology and patient characteristics associated with mono- and polymicrobial peritonitis. We assessed patient outcomes after a first polymicrobial peritonitis using survival analysis with competing events. We differentiated microorganisms isolated from dialysis effluent as enteric or non-enteric pathogens. RESULTS: A total of 8848 patients contributed 13 023 patient-years of follow-up and 3348 culture-positive peritonitis episodes, including 251 polymicrobial ones. This corresponded to rates of 0.32 and 0.02 episodes/patient-year, respectively. For most patients (72%) who experienced polymicrobial peritonitis, this was their first peritonitis episode. Enteric pathogens were more frequently isolated in polymicrobial than in monomicrobial peritonitis (57 versus 44%; P < .001). In both cases of peritonitis with and without enteric pathogens, the polymicrobial versus monomicrobial character of the peritonitis was not associated with mortality in patients who did not switch to haemodialysis {adjusted cause-specific hazard ratio [acsHR] 1.2 [95% confidence interval (CI) 0.3-5.0], P = .78 and 1.1 [95% CI 0.7-1.8], P = .73, respectively}. However, the risks of death and switch to haemodialysis were higher for monomicrobial peritonitis with enteric pathogens compared with those without [acsHR 1.3 (95% CI 1.1-1.7), P = .02 and 1.9 (95% CI 1.5-2.4), P < .0001, respectively]. CONCLUSION: Isolation of enteric pathogens, rather than the polymicrobial character of the peritonitis, is associated with poorer outcomes.

Management of severe renal disease in anti-neutrophil-cytoplasmic-antibody-associated vasculitis: the place of rituximab and plasma exchange?

OBJECTIVE: The optimal induction therapy for severe glomerulonephritis of ANCA-associated vasculitis (AAV) is debated. We compared the efficacy of glucocorticoid and rituximab (RTX) or CYC induction therapy for severe AAV-related glomerulonephritis and evaluated the potential benefit of plasma exchange (PE) as adjunct therapy to CYC. METHODS: This retrospective, multicentre study included AAV patients with severe renal active disease (serum creatinine level ≥350 µmol/l and/or estimated glomerular filtration ratio ≤15 ml/min/1.73 m2). Propensity-score analysis was used to adjust for potential confounders. RESULTS: Between 2005 and 2017, 153 patients with AAV-related glomerulonephritis were studied (96 [60%] men; mean [s.d.] age 63 [13.1] years): 19 (12%) were treated with RTX and 134 (88%) with CYC. Remission rates did not differ between RTX- and CYC-treated groups. Although more patients with RTX than CYC were dialysis-free at month (M) 12 (79% vs 68%), the difference was not significant after adjustment. Among 134 patients with CYC-treated glomerulonephritis, 76 (57%) also had PE. M3 and M6 remission rates were comparable for weighted CYC groups with or without PE. For weighted groups, the dialysis-free survival rate with CYC was higher with than without PE at M6 (72% vs 64%; odds ratio 2.58) and M12 (74% vs 60%; odds ratio 2.78) reaching statistical significance at M12. CONCLUSION: We could not find any difference between RTX and CYC as induction therapy for patients with severe AAV-related glomerulonephritis. In patients receiving CYC induction regimen, the addition of PE conferred short-term benefits with higher dialysis-free rate at M12.

Kidney Histopathology Can Predict Kidney Function in ANCA-Associated Vasculitides with Acute Kidney Injury Treated with Plasma Exchanges.

BACKGROUND: Data from the PEXIVAS trial challenged the role of plasma exchange (PLEX) in ANCA-associated vasculitides (AAV). We aimed to describe kidney biopsy from patients with AAV treated with PLEX, evaluate whether histopathologic findings could predict kidney function, and identify which patients would most benefit from PLEX. METHODS: We performed a multicenter, retrospective study on 188 patients with AAV and AKI treated with PLEX and 237 not treated with PLEX. The primary outcome was mortality or KRT at 12 months (M12). RESULTS: No significant benefit of PLEX for the primary outcome was found. To identify patients benefitting from PLEX, we developed a model predicting the average treatment effect of PLEX for an individual depending on covariables. Using the prediction model, 223 patients had a better predicted outcome with PLEX than without PLEX, and 177 of them had >5% increased predicted probability with PLEX compared with without PLEX of being alive and free from KRT at M12, which defined the PLEX-recommended group. Risk difference for death or KRT at M12 was significantly lower with PLEX in the PLEX-recommended group (-15.9%; 95% CI, -29.4 to -2.5) compared with the PLEX not recommended group (-4.8%; 95% CI, 14.9 to 5.3). Microscopic polyangiitis, MPO-ANCA, higher serum creatinine, crescentic and sclerotic classes, and higher Brix score were more frequent in the PLEX-recommended group. An easy to use score identified patients who would benefit from PLEX. The average treatment effect of PLEX for those with recommended treatment corresponded to an absolute risk reduction for death or KRT at M12 of 24.6%. CONCLUSIONS: PLEX was not associated with a better primary outcome in the whole study population, but we identified a subset of patients who could benefit from PLEX. However, these findings must be validated before utilized in clinical decision making.

Arteriovenous fistulas thrombosis in hemodialysis patients with COVID-19.

BACKGROUND: The current Coronavirus disease 2019 (COVID-19) outbreak is associated with significant mortality, especially in patients suffering from end stage renal disease (ESRD) and hemodialysis patients. Several previous studies reported an over-risk of arterial and venous thrombosis, in particular pulmonary embolism and venous thrombosis of catheter in COVID19 patients in intensive care unit. However, arteriovenous fistula (AVF) thrombosis has rarely been reported yet in these patients. AVF thrombosis is a serious complication that impacts significantly patients outcome. Here, we aim to describe characteristics and prognosis of a cohort of COVID-19 hemodialysis (HD) patients presenting with AVF thrombosis. METHODS: In the Ile de France region (Paris area) during the March 11th-April 30th 2020 period, fistula thrombosis cases were collected among COVID-19 hemodialysis patients in seven dialysis units and in interventional vascular departments. These patients' characteristics were analyzed through a review of the patient's medical records. RESULTS: Seventeen patients were included in our study (median age 69 years). Ten patients (59%) were men. Ten patients (59%) were diabetic and 88% had a high blood pressure. The mortality rate in these patients was 47%. All thrombosis treated with a declotting procedures (64%) were successfully cleared, but with early relapse in 36%. CONCLUSION: Our study highlights AVF thrombosis as a severe complication in COVID-19 hemodialysis patients that contributed to the severity and accelerated death.

Response to plasma exchange and graft survival in recurrent focal and segmental glomerulosclerosis after transplantation: does the time of recurrence matter? A retrospective study.

Recurrence of primary focal and segmental glomerulosclerosis following kidney transplantation (rFSGS) is a frequent and severe disease. We studied the time to recurrence of FSGS and its impact on the response to plasma exchange (PE) and graft survival. Between 1990 and 2013, 2730 kidney transplants were performed, including 52 patients with a primary diagnosis of FSGS. Of these patients with primary FSGS, 34 (67%) developed rFSGS. We retrospectively divided these patients into two groups depending on the time to recurrence: early (up to three months after transplantation, n = 26) or late (more than three months after transplantation, n = 8). Survival did not significantly differ between the two groups. In cases of late recurrence, PE was started later and was performed less frequently, and remission was achieved after more PE sessions and longer PE treatment than for the early group (P = 0.01). In early recurrence, resistance to PE at 40 days was associated with no long-term response to PE. PE should be performed as soon as possible after rFSGS. Patients with late rFSGS need to be offered the same treatment regime as those with early rFSGS.

COVID-19 in Patients on Maintenance Dialysis in the Paris Region.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) represents a serious threat to patients on maintenance dialysis. The clinical setting, mortality rate, and prognostic factors in these patients have not been well established. METHODS: We included all dialyzed patients with COVID-19 referred to our dialysis center between March 11 and April 11, 2020. Data were obtained through the review of the medical records and were censored at the time of data cutoff, on May 11, 2020. RESULTS: Forty-four patients on maintenance dialysis with COVID-19 were referred to our dialysis unit during the COVID-19 epidemic. Median age was 61 years (interquartile range [IQR]: 51.5-72.5); 65.9% were men. Comorbidities included hypertension (97.7%), diabetes mellitus (50%), and chronic cardiac (38.6%) and respiratory (27.3%) diseases. Initial symptoms were fever (79.5%), shortness of breath (29.5%), cough (43.2%), and diarrhea (13.6%). Three profiles of severity were distinguished based on the World Health Organization (WHO) progression scale. Forty-one (93.2%) were hospitalized and only 3 were maintained on outpatient hemodialysis. Thirty-three (75%) patients required oxygen therapy, including 15 (45.5%) who were referred to the intensive care unit. Overall, 27.3% of patients died, and 58.5% were discharged from hospital, including only 2 (13.3%) of those admitted to the intensive care unit. By multivariate analysis, cough, thrombopenia <120 g/l, lactate dehydrogenase (LDH) level greater than 2 times the upper limit of normal, and blood C-reactive protein (CRP) >175 mg/l were significantly associated with death. CONCLUSION: A major outbreak of COVID-19 occurred in the Paris region, and spread among dialyzed patients. Our study underscores the severity of COVID-19 in these patients and identified prognostic markers.

CASK, the Soluble Glomerular Permeability Factor, Is Secreted by Macrophages in Patients With Recurrent Focal and Segmental Glomerulo-Sclerosis.

Introduction: Focal and segmental glomerulosclerosis (FSGS) is a frequent form of glomerulonephritis that may be caused by a soluble permeability factor and regulated by the immune system. We previously described a soluble form of calcium/calmodulin-dependent serine/threonine kinase (CASK) acting as a permeability factor in patients with recurrent FSGS (rFSGS). Here, we aimed to identify the immune cells associated with CASK secretion in patients with rFSGS. Methods: FACS, western blotting and immunoprecipitation were performed to detect CASK in peripheral blood mononuclear cells, including CD3+, CD20+, and CD14+subsets, from patients with rFSGS, healthy donors, transplant patients and patients with nephrotic syndrome due to diabetes mellitus, and in KHM2 cells. Results: CASK was produced mostly by monocytes in patients with rFSGS but not by T or B lymphocytes. It was not detectein cells from control patients. CASK was also produced and secreted by M2 polarized macrophages and KMH2 cells, but not by M1 polarized macrophages. CASK secretion was not not inhibited by brefeldin A, suggesting an absence of classical secretion pathway involvement. Within cells, CASK was partly colocalized with ALIX, a molecule involved in exosome development, and these two molecules were coprecipitated from M2 macrophages. Moreover, exosomes derived from M2 macrophages induced podocyte cytoskeleton alterations and increased podocyte motility. Conclusion: These results suggest that the soluble permeability factor CASK is secreted by monocytes and M2 macrophages, via exosomes, to alter the glomerular filtration barrier in rFSGS.

Laparoscopic sleeve gastrectomy for morbid obesity in renal transplantation candidates: a matched case-control study.

Obesity has become an important issue in patients with end-stage renal disease (ESRD). Since it is considered a relative contraindication for renal transplantation, bariatric surgery has been advocated to treat morbid obesity in transplant candidates, and laparoscopic sleeve gastrectomy (LSG) is the most reported procedure. However, comparative data regarding outcomes of LSG in patients with or without ESRD are scarce. Consecutive patients with ESRD (n = 29) undergoing LSG were compared with matched patients with normal renal function undergoing LSG in a 1:3 ratio using propensity score adjustment. Data were collected from a prospective database. Eligibility for transplantation was also studied. A lower weight loss (20 kg (16-30)) was observed in patients with ESRD within the first year as compared to matched patients (28 kg (21-34)) (P < 0.05). After a median follow-up of 30 (19-50) months in the ESRD group, contraindication due to morbid obesity was lifted in 20 patients. Twelve patients underwent transplantation. In patients with ESRD potentially eligible for transplantation, LSG allows similar weight loss in comparison with matched patients with normal renal function, enabling lifting contraindication for transplantation due to morbid obesity in the majority of patients within the first postoperative year.

Circulating CASK is associated with recurrent focal segmental glomerulosclerosis after transplantation.

INTRODUCTION: Focal and Segmental GlomeruloSclerosis (FSGS) can cause nephrotic syndrome with a risk of progression to end-stage renal disease. The idiopathic form has a high rate of recurrence after transplantation, suggesting the presence of a systemic circulating factor that causes glomerular permeability and can be removed by plasmapheresis or protein-A immunoadsorption. RESULTS: To identify this circulating factor, the eluate proteins bound on therapeutic immunoadsorption with protein-A columns were analyzed by comparative electrophoresis and mass spectrometry. A soluble form of calcium/calmodulin-dependent serine protein kinase (CASK) was identified. CASK was immunoprecipitated only in the sera of patients with recurrent FSGS after transplantation and not in control patients. Recombinant-CASK (rCASK) induced the reorganization of the actin cytoskeleton in immortalized podocytes, a redistribution of synaptopodin, ZO-1,vinculin and ENA. rCASK also induced alterations in the permeability of a monolayer of podocytes and increased the motility of pdodocytes in vitro. The extracellular domain of CD98, a transmembrane receptor expressed on renal epithelial cells, has been found to co-immunoprecipitated with rCASK. The invalidation of CD98 with siRNA avoided the structural changes of rCask treated cells suggesting its involvement in physiopathology of the disease. In mice, recombinant CASK induced proteinuria and foot process effacement in podocytes. CONCLUSION: Our results suggest that CASK can induce the recurrence of FSGS after renal transplantation.

Efficacy and Safety of Intra-gastric Balloon Placement in Dialyzed Patients Awaiting Kidney Transplantation.

BACKGROUND: The number of obese patients who are candidates for renal transplantation has considerably increased, but obesity can be a barrier to kidney transplantation. Weight loss is often difficult through diet alone. We studied the efficacy and tolerance of the intra-gastric balloon (IGB) procedure in obese patients who were undergoing dialysis and were candidates for a renal transplantation. PATIENTS AND METHODS: Obese patients (BMI > 30 kg/m2) who were candidates for renal transplantation were prospectively included in the study between 2010 and 2012. The balloon was inserted and removed during a gastric endoscopy under general anesthesia. The treatment lasted 6 months. The end point was a decrease in BMI after 6 months. Body impedance spectrometry (BIS) and nutritional statute were evaluated initially and then after IGB removal. RESULTS: Seventeen patients (nine females and eight males) with a mean age of 53.4 years [19.4-69.4] were included. The decrease in body mass index (BMI) during the 6-month placement was 3 kg/m2 (from 37.7 to 34.4 kg/m2). The mean weight loss was 7 kg. The mean percentage of excess weight loss after 6 months was 20.2 (± 11.4). The tolerance was good without any complications. Eleven patients underwent kidney transplantation. CONCLUSION: IGB in obese dialyzed patients who are candidates for renal transplantation is safe and effective. However, the amount of weight loss can vary.

Impact of arteriovenous fistula cannulation on the quality of dialysis.

INTRODUCTION: Adequate hemodialysis directly improves health. Puncturing an arteriovenous fistula (AVF) and the amount of blood recirculation greatly affect the quality of dialysis. Few studies have assessed the method to cannulate a fistula and its influence on efficiency of hemodialysis. METHODS: This prospective pilot study included 14 patients with end-stage renal failure receiving regular intermittent hemodialysis. Patients received three consecutive treatments with both needles directed upstream then three consecutive treatments with the venous needle directed upstream and the arterial needle directed downstream. With both techniques, the distance between the needles was kept constant at 2.5 cm. Recirculation rate and Kt/V ratio were measured during each treatment using thermodilution and a diascan Fresenius generator. FINDINGS: The 14 patients received 84 hemodialysis sessions: i.e., 8 (57.1%) males and 6 (42.8%) females, mean age 62.3 ± 15.57 years. Results showed that mean recirculation rates and Kt/V did not significantly differ between the two techniques. DISCUSSION: Because no significant difference was found between the two techniques, the direction of insertion of needles should be decided upon on a case-by-case basis depending on the anatomy of the AVF and the feasibility of the puncture.

Optimal management of primary focal segmental glomerulosclerosis in adults.

Focal segmental glomerulosclerosis (FSGS) is a frequent glomerular kidney disease that is revealed by proteinuria or even nephrotic syndrome. A diagnosis can be established from a kidney biopsy that shows focal and segmental glomerulosclerosis. This histopathological lesion may be caused by a primary podocyte injury (idiopathic FSGS) but is also associated with other pathologies (secondary FSGS). The first-line treatment for idiopathic FSGS with nephrotic syndrome is a prolonged course of corticosteroids. However, steroid resistance or steroid dependence is frequent, and despite intensified immunosuppressive treatment, FSGS can lead to end-stage renal failure. In addition, in some cases, FSGS can recur on a graft after kidney transplantation: an unidentified circulating factor may be implicated. Understanding of its physiopathology is unclear, and it remains an important challenge for the scientific community to identify a specific diagnostic biomarker and to develop specific therapeutics. This study reviews the treatment of primary FSGS and the recurrence of FSGS after kidney transplantation in adults.

Comparison of the AN69ST Membrane versus Citrate-Enriched Dialysate on Clotting Events during Hemodialysis without Systemic Anticoagulation.

BACKGROUND: The optimal management of anticoagulation in hemodialyzed patients with a high risk of bleeding is controversial. METHODS: We compared premature termination of dialysis caused by clotting events between AN69ST membranes (G1) and 0.8 mmol/L citrate-enriched dialysate (G2). The number of sessions that had increased venous pressure (VP) and variations in urea-reduction ratio (URR) were analyzed. RESULTS: Six hundred and two sessions were analyzed in 259 patients: 22.4% had sessions that ended prematurely (25% in G1 and 19.1% in G2, p = ns, OR 0.60 [0.34-1.08], p = 0.08). The increase in VP was lower in G2 (23 vs. 70, p < 0.001). URR was higher in G2 (0.56 vs. 0.60, p < 0.001). CONCLUSION: Clotting events that led to the termination of dialysis were comparable in the 2 groups. However, UUR was better in G2, and the number of patients with increased VP in the sessions was lower in G2. SHORT SUMMARY: Our study compared the effects of the AN69ST membrane and citrate-enriched dialysate on clotting events during the dialysis of 259 patients with a high risk of bleeding. URR was significantly better and fewer cases of increased VP occurred in the citrate group compared to the AN69 ST group. No significant difference was observed regarding the need to prematurely terminate a dialysis session.

[Role of cannabinoid receptors in renal diseases]. / Rôle des récepteurs cannabinoïdes au cours des maladies rénales.

Chronic kidney disease remains a major challenge for public health systems and corresponds to the replacement of renal functional tissue by extracellular matrix proteins such as collagens and fibronectin. There is no efficient treatment to date for chronic kidney disease except nephroprotective strategies. The cannabinoid system and more specifically the cannabinoid receptors 1 (CB1) and 2 (CB2) may represent a new therapeutic target in chronic kidney disease. Experimental data obtained in models of diabetes and obesity suggested that CB1 blockade and CB2 stimulation may slow the development of diabetic nephropathy. In human kidneys, CB1 expression is increased in various chronic nephropathies and correlates with renal function. Moreover, endogenous CB1 and CB2 ligands are greatly increased during renal fibrogenesis. A microarray analysis performed in an experimental model of renal fibrosis found that the gene encoding for the CB1 receptor was among the most upregulated genes. We also demonstrated that renal fibrogenesis could be reduced by CB1 inhibition and CB2 stimulation in an experimental model through a direct mechanism involving CB1 on myofibroblasts, which are the major effector cells during renal fibrosis. Therefore, CB1 blockers may represent a novel therapeutic target in chronic kidney disease and diabetes.

B7-1 Blockade Does Not Improve Post-Transplant Nephrotic Syndrome Caused by Recurrent FSGS.

FSGS is a common glomerular disorder that has a high propensity for recurrence after kidney transplant. The pathophysiology of FSGS is unknown, but podocytes seem to be the target of one or several circulating factors that lead to cytoskeleton reorganization and proteinuria. Research on podocytes has identified B7-1 as an important factor in podocyte biology and a new therapeutic target in renal disease. Indeed, in four patients with recurrent FSGS after transplant, treatment with the B7-1 blocker abatacept was associated with proteinuria remission. Here, we prospectively treated nine patients with recurrent FSGS after transplant using either abatacept or belatacept, a B7-1 blocker with higher affinity, and did not induce proteinuria remission. Furthermore, we did not detect B7-1 expression by immunofluorescence in podocytes of biopsy specimens from these or other kidney grafts or podocytes of native kidney biopsy specimens. In conclusion, B7-1 blockade did not induce FSGS remission after transplant in our study.

Polyomavirus-Specific Cellular Immunity: From BK-Virus-Specific Cellular Immunity to BK-Virus-Associated Nephropathy?

In renal transplantation, BK-virus (BKV)-associated nephropathy has emerged as a major complication, with a prevalence of 1-10% and graft loss in >50% of cases. BKV is a member of the polyomavirus family and rarely induces apparent clinical disease in the general population. However, replication of polyomaviruses, associated with significant organ disease, is observed in patients with acquired immunosuppression. Monitoring of specific immunity combined with viral load could be used to individually assess the risk of viral reactivation and virus control. We review the current knowledge on BKV-specific cellular immunity and, more specifically, in immunocompromised patients. In the future, immune-based therapies could allow us to treat and prevent BKV-associated nephropathy.

Cannabinoid receptor 1 is a major mediator of renal fibrosis.

Chronic kidney disease, secondary to renal fibrogenesis, is a burden on public health. There is a need to explore new therapeutic pathways to reduce renal fibrogenesis. To study this, we used unilateral ureteral obstruction (UUO) in mice as an experimental model of renal fibrosis and microarray analysis to compare gene expression in fibrotic and normal kidneys. The cannabinoid receptor 1 (CB1) was among the most upregulated genes in mice, and the main endogenous CB1 ligand (2-arachidonoylglycerol) was significantly increased in the fibrotic kidney. Interestingly, CB1 expression was highly increased in kidney biopsies of patients with IgA nephropathy, diabetes, and acute interstitial nephritis. Both genetic and pharmacological knockout of CB1 induced a profound reduction in renal fibrosis during UUO. While CB2 is also involved in renal fibrogenesis, it did not potentiate the role of CB1. CB1 expression was significantly increased in myofibroblasts, the main effector cells in renal fibrogenesis, upon TGF-ß1 stimulation. The decrease in renal fibrosis during CB1 blockade could be explained by a direct action on myofibroblasts. CB1 blockade reduced collagen expression in vitro. Rimonabant, a selective CB1 endocannabinoid receptor antagonist, modulated the macrophage infiltrate responsible for renal fibrosis in UUO through a decrease in monocyte chemoattractant protein-1 synthesis. Thus, CB1 has a major role in the activation of myofibroblasts and may be a new target for treating chronic kidney disease.