Rituximab has shown encouraging results for the treatment of kidney transplantation recipients with focal segmental glomerulosclerosis (FSGS) recurrence. However, the correct, opportune, and safe use ...of rituximab for this indication remains to be determined.
This multicenter retrospective study reports on 19 new cases aged 35 (15-66) years who developed FSGS recurrence at 12 (1.5-27) days posttransplantation. Initial treatment consisted of plasma exchanges (PE), high doses of calcineurin inhibitors, and steroids. Rituximab was introduced either immediately (N = 6) or after failure of the initial treatment (N = 10) or failed attempted weaning from PE (N = 3).
Overall, we observed 9 of 19 complete remissions and 3 of 19 partial remissions. Estimated glomerular filtration rates (Modification of Diet in Renal Disease 4) were significantly higher in the responding patients than in nonresponding patients at month (M)12, M36, and M60. Overall, kidney survival at 5 years was 77.4% (95% range, 41.9-92.7). The 5-year graft survival rates in the responding patients and the nonresponding patients were 100% and 36.5%, respectively (P = 0.01). A further course of rituximab was required for 4 patients as a result of FSGS relapse, with good results. During the first year after renal transplantation, 14 patients developed severe infections (16 bacterial, 4 viral, 1 parasitic).
In kidney transplantation recipients with recurrent FSGS, rituximab therapy may be a recommended treatment for cases that have failed either the initial treatment or weaning from PE.
Acute kidney injury (AKI) is a major complication in patients with liver disease. Although hepatorenal syndrome is frequently involved, bile cast nephropathy, characterized by tubular bile cast ...formation, has been scarcely described in the setting of severe liver failure. Few renal histology studies are available in these patients. We describe a case of bile cast nephropathy in a patient with obstructive cholestasis caused by stones in the common bile duct. The kidney biopsy confirmed this diagnosis, with several green casts in tubular lumens, tubular injury, and bilirubin composition of the tubular casts with Hall stain. The patient had no confounding cause of kidney failure, and complete kidney recovery followed removal of the bile duct obstruction. This case shows that severe cholestasis is sufficient to cause AKI, and that AKI can be reversible after treatment of the biliary obstruction.
Protein energy wasting (PEW) including muscle atrophy is a common complication in chronic hemodialysis patients. The ubiquitin proteasome system (UPS) is the main proteolytic system causing muscle ...atrophy in chronic kidney disease and proteasome 20S is the catalytic component of the UPS. Circulating proteasome 20S (c20S proteasome) is present in the blood and its level is related to disease severity and prognosis in several disorders. We hypothesized that c20S proteasome could be related with muscle mass, other PEW criteria and their evolution in hemodialysis patients. Stable hemodialysis patients treated at our center for more than 3 months were followed over 2 years. C20S proteasome assay was performed at baseline. Biological and clinical data were collected, muscle mass was assessed by multi-frequency bio-impedancemetry, and nutritional scores were calculated at baseline, 1 year and 2 years. Hospitalizations and mortality data were collected over the 2 years. Forty-nine patients were included. At baseline, the c20S proteasome level was 0.400.26-0.55 mug/ml. Low muscle mass as defined by a lean tissue index (LTI) 10th in accordance with the International Society of Renal Nutrition and Metabolism guidelines was observed in 36% and PEW in 62%. Increased c20S proteasome levels were related with LTI at baseline (R = 0.43, p = 0.004) and with its 2 year-variation (R = -0.56, p = 0.003). Two-year survival rate was not different between higher and lower c20S proteasome values (78.9 vs 78.4%, p = 0.98 log-rank test). C20S proteasome is not a good marker for assessing nutritional status in hemodialysis patients and predicting patient outcomes.
Background
Muscle wasting is observed in the course of many diseases and also during physiological conditions (disuse, ageing). Skeletal muscle mass is largely controlled by the ubiquitin‐proteasome ...system and thus by the ubiquitinating enzymes (E2s and E3s) that target substrates for subsequent degradation. MuRF1 is the only E3 ubiquitin ligase known to target contractile proteins (α‐actin, myosins) during catabolic situations. However, MuRF1 depends on E2 ubiquitin‐conjugating enzymes for ubiquitin chain formation on the substrates. MuRF1‐E2 couples are therefore putative targets for preventing muscle wasting.
Methods
We focused on 14 E2 enzymes that are either expressed in skeletal muscle or up‐regulated during atrophying conditions. In this work, we demonstrated that only highly sensitive and complementary interactomic approaches (surface plasmon resonance, yeast three‐hybrid, and split green fluorescent protein) allowed the identification of MuRF1 E2 partners.
Results
Five E2 enzymes physically interacted with MuRF1, namely, E2E1, E2G1, E2J1, E2J2, and E2L3. Moreover, we demonstrated that MuRF1‐E2E1 and MuRF1‐E2J1 interactions are facilitated by telethonin, a newly identified MuRF1 substrate. We next showed that the five identified E2s functionally interacted with MuRF1 since, in contrast to the non‐interacting E2D2, their co‐expression in HEK293T cells with MuRF1 led to increased telethonin degradation. Finally, we showed that telethonin governed the affinity between MuRF1 and E2E1 or E2J1.
Conclusions
We report here the first MuRF1‐E2s network, which may prove valuable for deciphering the precise mechanisms involved in the atrophying muscle programme and for proposing new therapeutical approaches.
Previous studies have linked obesity to poor outcomes in renal transplant recipients, prompting many transplant centers to encourage weight loss pretransplant in obese patients. Here, we performed a ...single-center retrospective study to assess the effects of weight loss on graft and patient outcomes.
Data from 893 renal transplant recipients at our center from 2007 to 2011 were analyzed. First, renal transplant recipients with a history of obesity before transplant (42%) were compared with nonobese patients. Second, in the obese group, renal transplant recipients with significant weight loss (> 10%) before transplant were compared with other obese renal transplant recipients without significant weight loss.
Renal transplant recipients were predominantly white, with 74% having undergone living-donor transplant. Obese patients were older (56.6 vs 46.7 y old) and had more comorbidities and more surgical complications, in particular wound complications and incisional hernias, posttransplant than nonobese patients (14.7 vs 5.5%, respectively). Patient and graft survival rates were similar to those in nonobese patients. In the obese group, patient characteristics and medical or surgical complications after transplant did not differ between those with or without significant weight loss. However, obese patient and graft survival rates were lower in patients with weight loss than in obese patients without weight loss.
In our study, weight loss before transplant surgery in obese patients had no influence on surgical outcomes but was associated with a higher mortality rate. A prospective assessment of the impact of weight loss before surgery is needed to establish its usefulness.
Acute Kidney Injury (AKI) is frequently encountered in hospitalized patients where it is associated with increased mortality and morbidity notably affecting muscle wasting. Increased protein ...degradation has been shown to be the main actor of AKI-induced muscle atrophy, but the proteolytic pathways involved are poorly known. The Ubiquitin Proteasome System (UPS) is almost systematically activated in various catabolic situations, and the E3 ligases MuRF1 and MAFbx are generally up regulated in atrophying muscles. We hypothesized that the UPS may be one of the main actors in catabolic skeletal muscles from AKI animals. We used gentamicin-induced acute kidney disease (G-AKI) in rats fed a high protein diet to promote acidosis. We first addressed the impact of G-AKI in the development of mild catabolic conditions. We found that both muscle atrophy and UPS activation were induced with the development of G-AKI. In addition, the phasic muscles were more sensitive to 7-days G-AKI (−11 to −17%, P<0.05) than the antigravity soleus muscle (−11%, NS), indicating a differential impact of AKI in the musculature. We observed an increased expression of the muscle-specific E3 ligases MuRF1 and MAFbx in phasic muscles that was highly correlated to the G-AKI severity (R2=0.64, P<0.01 and R2=0.71, P<0.005 respectively). Conversely, we observed no variation in the expression of three other E3 ligases (Nedd4, Trim32 and Fbxo30/MUSA1). Altogether, our data indicate that MuRF1 and MAFbx are sensitive markers and potential targets to prevent muscle atrophy during G-AKI.
Background
Loss of muscle mass worsens many diseases such as cancer and renal failure, contributes to the frailty syndrome, and is associated with an increased risk of death. Studies conducted on ...animal models have revealed the preponderant role of muscle proteolysis and in particular the activation of the ubiquitin proteasome system (UPS). Studies conducted in humans remain scarce, especially within renal deficiency. Whether a shared atrophying programme exists independently of the nature of the disease remains to be established. The aim of this work was to identify common modifications at the transcriptomic level or the proteomic level in atrophying skeletal muscles from cancer and renal failure patients.
Methods
Muscle biopsies were performed during scheduled interventions in early‐stage (no treatment and no detectable muscle loss) lung cancer (LC), chronic haemodialysis (HD), or healthy (CT) patients (n = 7 per group; 86% male; 69.6 ± 11.4, 67.9 ± 8.6, and 70.2 ± 7.9 years P > 0.9 for the CT, LC, and HD groups, respectively). Gene expression of members of the UPS, autophagy, and apoptotic systems was measured by quantitative real‐time PCR. A global analysis of the soluble muscle proteome was conducted by shotgun proteomics for investigating the processes altered.
Results
We found an increased expression of several UPS and autophagy‐related enzymes in both LC and HD patients. The E3 ligases MuRF1 (+56 to 78%, P < 0.01), MAFbx (+68 to 84%, P = 0.02), Hdm2 (+37 to 59%, P = 0.02), and MUSA1/Fbxo30 (+47 to 106%, P = 0.01) and the autophagy‐related genes CTPL (+33 to 47%, P = 0.03) and SQSTM1 (+47 to 137%, P < 0.01) were overexpressed. Mass spectrometry identified >1700 proteins, and principal component analysis revealed three differential proteomes that matched to the three groups of patients. Orthogonal partial least square discriminant analysis created a model, which distinguished the muscles of diseased patients (LC or HD) from those of CT subjects. Proteins that most contributed to the model were selected. Functional analysis revealed up to 238 proteins belonging to nine metabolic processes (inflammatory response, proteolysis, cytoskeleton organization, glucose metabolism, muscle contraction, oxidant detoxification, energy metabolism, fatty acid metabolism, and extracellular matrix) involved in and/or altered by the atrophying programme in both LC and HD patients. This was confirmed by a co‐expression network analysis.
Conclusions
We were able to identify highly similar modifications of several metabolic pathways in patients exhibiting diseases with different aetiologies (early‐stage LC vs. long‐term renal failure). This strongly suggests that a common atrophying programme exists independently of the disease in human.
Abstract The use of plasma exchanges (PLEX) in systemic necrotizing vasculitides (SNV) still need to be codified. To describe indications, efficacy and safety of PLEX for the treatment of SNV, we ...conducted a multicenter retrospective study on patients with ANCA-associated vasculitis (AAV) or non-viral polyarteritis nodosa (PAN) treated with PLEX. One hundred and fifty-two patients were included: GPA (n = 87), MPA (n = 56), EGPA (n = 4) and PAN (n = 5). PLEX were used for rapidly progressive glomerulonephritis (RPGN) in 126 cases (86%), alveolar hemorrhage in 64 cases (42%), and severe mononeuritis multiplex in 23 cases (15%). In patients with RPGN, there was a significant improvement in renal function compared to baseline value (P < 0.0001), the plateau being reached at month 3 after PLEX initiation, and estimated glomerular filtration rate improved especially as the number of PLEX increased. In patients with alveolar hemorrhage, mechanical ventilation was discontinued in all patients after a median time of 15 days. Patients treated for mononeuritis multiplex showed improvement of severe motor weakness. After a median follow of 22 months, 18 deaths (12%) were recorded, mainly in patients with RPGN and within the first 6 months. Incidence of end-stage renal disease and/or death was similar between groups of different baseline renal function, but was increased in MPO-ANCA compared to PR3-ANCA. Adverse events attributable to PLEX were recorded in 63%. No death occurred during PLEX. This large series describes indications, efficacy and safety of PLEX in daily practice. Randomized controlled studies are ongoing to define optimal indications, PLEX regimen and concomitant medications.
Skeletal muscle mass is reduced during many diseases or physiological situations (disuse, aging), which results in decreased strength and increased mortality. Muscle mass is mainly controlled by the ...ubiquitin-proteasome system (UPS), involving hundreds of ubiquitinating enzymes (E2s and E3s) that target their dedicated substrates for subsequent degradation. We recently demonstrated that MuRF1, an E3 ubiquitin ligase known to bind to sarcomeric proteins (telethonin, α-actin, myosins) during catabolic situations, interacts with 5 different E2 enzymes and that these E2-MuRF1 couples are able to target telethonin, a small sarcomeric protein, for degradation. Amongst the E2s interacting with MuRF1, E2E1 was peculiar as the presence of the substrate was necessary for optimal MuRF1-E2E1 interaction. In this work, we focused on the putative role of E2E1 during skeletal muscle atrophy. We found that E2E1 expression was restricted to type I and type IIA muscle fibers and was not detectable in type IIB fibers. This strongly suggests that E2E1 targets are fiber-specific and may be strongly linked to the contractile and metabolic properties of the skeletal muscle. However, E2E1 knockdown was not sufficient for preserving the protein content in C2C12 myotubes subjected to a catabolic state (dexamethasone treatment), suggesting that E2E1 is not involved in the development of muscle atrophy. By contrast, E2E1 knockdown aggravated the atrophying process in both catabolic C2C12 myotubes and the Tibialis anterior muscle of mice, suggesting that E2E1 has a protective effect on muscle mass.
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