mTOR inhibition: the learning curve in kidney transplantation

All immunosuppressive medications require a learning curve that enables clinicians to improve the therapeutic index of agents. Mammalian target of rapamycin (mTOR) inhibitors are potentially a less nephrotoxic form of immunosuppression than calcineurin inhibitors (CNIs) that has been used in kidney transplant recipients for more than two decades. This drug class has a novel immunosuppressive action, probably mediated in part through inhibition of growth receptor signaling mechanisms. In addition, it has a unique drug toxicity, which is partially dose‐related. This medication class also possesses antiproliferative activity, which may be useful in‐post‐transplant patients with increased atherosclerotic and malignancy risks. mTOR inhibitors have been utilized for de novo immunosuppression with CNIs, corticosteroids, and antimetabolites. mTOR inhibitors also have been used as CNI‐sparing agents both early and late post‐transplant. Much debate remains over how to best utilize mTOR inhibition in kidney transplantation.     

Parvovirus 4 in French in-patients: a study of hemodialysis and lung transplant cohorts

The epidemiology and the clinical implication of human parvovirus 4 (PARV4) in human populations is still under evaluation. The distribution of PARV4 DNA was determined in cohorts of French hemodialysis and lung transplant patients. Plasma samples (n=289) were tested for PARV4 by real-time PCR assay (ORF2), and amplification products selected at random were sequenced. Analysis of available serological and biological markers was also undertaken. Fifty-seven samples out of 185 (30.8%) were positive for PARV4 DNA in the cohort of hemodialysis patients. A higher prevalence of the virus was identified in patients with markers of HBV infection. PARV4 was also identified in 14 out of 104 samples (13.5%) from lung transplant recipients, with no clear-cut association with available clinical markers. Point mutations located on the zone of real-time detection were identified for some amplification products. This study describes the detection of PARV4 in the blood of hemodialysis and lung transplanted patients with significant difference in prevalence in these two cohorts. Further studies will be needed in order to understand better both the potential implication in host health and the natural history of this virus.     

Stress, aggression, and puberty: neuroendocrine correlates of the development of agonistic behavior in golden hamsters

During puberty, agonistic behaviors undergo significant transitions. In golden hamsters, puberty is marked by a transition from play fighting to adult aggression. During early puberty, male golden hamsters perform play-fighting attacks. This response type is gradually replaced by adult attacks over the course of puberty. Interestingly, this behavioral transition does not appear to be controlled by changes in gonadal steroids. Instead, the shift from play fighting to adult aggression in male golden hamsters is driven by pubertal changes in glucocorticoid levels. Specifically, the transition from play fighting to adult aggression coincides with developmental increases in glucocorticoid levels, and external manipulations such as social stress or treatment with corticosteroid receptor agonists accelerate this behavioral shift. Moreover, the consequences of social stress differ greatly between juvenile and adult male golden hamsters. Although a single defeat during adulthood causes severe and long lasting behavioral and neuroendocrine consequences, socially subjugated juveniles show only transient behavioral effects. As such, it is likely that pubertal changes in the HPA axis are not only linked to the maturation of offensive responses but also determine the consequences of social stress. Combined, these studies in golden hamsters provide a novel mechanism for the development of agonistic behavior and suggest that age related differences in behavioral plasticity are mediated by the development of the HPA axis.     

Incidence and management of anemia in renal transplantation: an observational-French study

The management of anemia after kidney transplantation remains poorly explored. The Management of Anemia in French Kidney Transplant Patients (MATRIX) study is an observational study conducted in 10 academic hospitals among kidney-transplant patients designed to evaluate the prevalence, associated factors and management of post-transplant anemia. Over two consecutive weeks, 418 recipients (males: 248; age: 50.8+/-12.7 years) were included, all were transplanted for more than six months. Mean serum creatinine (Scr) was 152+/-67 micromol/l and mean hemoglobin (Hb) was 12.4+/-1.8 g/dl (males: 12.8+/-1.9 g/dl; females 11.9+/-1.6 g/dl). Irrespective of the delay following transplantation, 23% of patients (n=95) were severely anemic (Hb < or = 11 g/dl). Eighteen percent of the patients received an antianemic treatment (10% oral iron, 7% erythropoiesis stimulating agents (ESA), 4% folic acid) and only 35% of the severely anemic patients were actually treated (n=33). A significantly-negative correlation was observed between eGFR and Hb levels (R= -0.347, p<0.02). Ninety-six percent of the 193 patients transplanted for more than six months and a Scr greater than 150 micromol/l (n=185) suffered at least one comorbidity (89% hypertension, 32% hypercholesterolemia, 13% diabetes); this group represent the second cohort. Seventy-four percent of them were treated with mycophenolate mofetil, 16% with azathioprine, and 62% with an ACEI or angiotensin II receptor antagonists. Since the transplantation, 127 patients (66%) have been anemic (Hb < or = 11 g/dl) and 58% (n=112) were treated (iron and/or ESA, respectively 81 and 55%). Among the patients not treated for anemia, 74% had an Hb level below 12g/dl. ESA-treated patients received a mean dose of 8500 UI+/-2800 per week. Anemia is under-diagnosed and under-treated in renal-transplant recipients, despite its high prevalence. As expected, a correlation between renal function and Hb levels was observed, as in CKD patients. Prospective studies are underway to assess the consequences of postkidney transplant anemia on quality of life, cardiovascular morbidity and chronic allograft nephropathy and to define the benefit of the treatment.     

Micro-scale and meso-scale architectural cues cooperate and compete to direct aligned tissue formation

Tissue and biomaterial microenvironments provide architectural cues that direct important cell behaviors including cell shape, alignment, migration, and resulting tissue formation. These architectural features may be presented to cells across multiple length scales, from nanometers to millimeters in size. In this study, we examined how architectural cues at two distinctly different length scales, “micro-scale” cues on the order of ∼1–2 μm, and “meso-scale” cues several orders of magnitude larger (>100 μm), interact to direct aligned neo-tissue formation. Utilizing a micro-photopatterning (μPP) model system to precisely arrange cell-adhesive patterns, we examined the effects of substrate architecture at these length scales on human mesenchymal stem cell (hMSC) organization, gene expression, and fibrillar collagen deposition. Both micro- and meso-scale architectures directed cell alignment and resulting tissue organization, and when combined, meso cues could enhance or compete against micro-scale cues. As meso boundary aspect ratios were increased, meso-scale cues overrode micro-scale cues and controlled tissue alignment, with a characteristic critical width (∼500 μm) similar to boundary dimensions that exist in vivo in highly aligned tissues. Meso-scale cues acted via both lateral confinement (in a cell-density-dependent manner) and by permitting end-to-end cell arrangements that yielded greater fibrillar collagen deposition. Despite large differences in fibrillar collagen content and organization between μPP architectural conditions, these changes did not correspond with changes in gene expression of key matrix or tendon-related genes. These findings highlight the complex interplay between geometric cues at multiple length scales and may have implications for tissue engineering strategies, where scaffold designs that incorporate cues at multiple length scales could improve neo-tissue organization and resulting functional outcomes.     

Impaired expression of the peroxisome proliferator-activated receptor alpha during hepatitis C virus infection

BACKGROUND AND AIMS: Liver inflammation, fibrosis, and dyslipidemia are common features in patients with chronic hepatitis C virus (HCV) infection. Because peroxisome proliferator-activated receptor alpha (PPARalpha) is highly expressed in the liver and is involved in the regulation of lipid metabolism and inflammation, we sought to determine whether HCV infection may locally impair PPARalpha expression and activity. METHODS: PPARalpha expression was investigated in liver biopsy specimens of 86 untreated patients with HCV infection and controls, by using real-time polymerase chain reaction (PCR), Western blot analysis, and immunohistochemistry. PPARalpha activity was assessed by quantification of the key gene target carnitine palmitoyl acyl-CoA transferase 1 (CPT1A) messenger RNA (mRNA).The influence of HCV core protein on PPARalpha mRNA expression was analyzed in vitro by real-time PCR in HCV core-expressing HepG2 cells activated with the PPARalpha ligand fenofibric acid. RESULTS: Hepatic concentrations of PPARalpha and CPT1A expressed by hepatocytes were impaired profoundly in the livers of untreated patients with HCV infection compared with controls. A mean decrease of 85% in PPARalpha mRNA expression paralleled with a lack of CPT1A mRNA induction also were observed in HCV core-expressing HepG2 cells compared with controls. CONCLUSIONS: HCV infection is related to altered expression and function of the anti-inflammatory nuclear receptor PPARalpha. These results identify hepatic PPARalpha as one mechanism underlying the pathogenesis of HCV infection, and as a new therapeutic target in traditional treatment of HCV-induced liver injury.