The TSC-mTOR signaling pathway regulates the innate inflammatory response.

The innate inflammatory immune response must be tightly controlled to avoid damage to the host. Here, we showed that the tuberous sclerosis complex-mammalian target of rapamycin (TSC-mTOR) pathway regulated inflammatory responses after bacterial stimulation in monocytes, macrophages, and primary dendritic cells. Inhibition of mTOR by rapamycin promoted production of proinflammatory cytokines via the transcription factor NF-kappaB but blocked the release of interleukin-10 via the transcription factor STAT3. Conversely, deletion of TSC2, the key negative regulator of mTOR, diminished NF-kappaB but enhanced STAT3 activity and reversed this proinflammatory cytokine shift. Rapamycin-hyperactivated monocytes displayed a strong T helper 1 (Th1) cell- and Th17 cell-polarizing potency. Inhibition of mTOR in vivo regulated the inflammatory response and protected genetically susceptible mice against lethal Listeria monocytogenes infection. These data identify the TSC2-mTOR pathway as a key regulator of innate immune homeostasis with broad clinical implications for infectious and autoimmune diseases, vaccination, cancer, and transplantation.

p38α senses environmental stress to control innate immune responses via mechanistic target of rapamycin.

The MAPK p38α senses environmental stressors and orchestrates inflammatory and immunomodulatory reactions. However, the molecular mechanism how p38α controls immunomodulatory responses in myeloid cells remains elusive. We found that in monocytes and macrophages, p38α activated the mechanistic target of rapamycin (mTOR) pathway in vitro and in vivo. p38α signaling in myeloid immune cells promoted IL-10 but inhibited IL-12 expression via mTOR and blocked the differentiation of proinflammatory CD4(+) Th1 cells. Cellular stress induced p38α-mediated mTOR activation that was independent of PI3K but dependent on the MAPK-activated protein kinase 2 and on the inhibition of tuberous sclerosis 1 and 2, a negative regulatory complex of mTOR signaling. Remarkably, p38α and PI3K concurrently modulated mTOR to balance IL-12 and IL-10 expression. Our data link p38α to mTOR signaling in myeloid immune cells that is decisive for tuning the immune response in dependence on the environmental milieu.

Use of Calcium Channel Blockers is Associated with Mortality in Patients with Chronic Kidney Disease.

BACKGROUND/AIMS: The use of antihypertensive medicines has been shown to reduce proteinuria, morbidity, and mortality in patients with chronic kidney disease (CKD). A specific recommendation for a class of antihypertensive drugs is not available in this population, despite the pharmacodynamic differences. We have therefore analysed the association between antihypertensive medicines and survival of patients with chronic kidney disease. METHODS: Out of 2687 consecutive patients undergoing kidney biopsy a cohort of 606 subjects with retrievable medical therapy was included into the analysis. Kidney function was assessed by glomerular filtration rate (GFR) estimation at the time point of kidney biopsy. Main outcome variable was death. RESULTS: Overall 114 (18.7%) patients died. In univariate regression analysis the use of alpha-blockers and calcium channel antagonists, progression of disease, diabetes mellitus (DM) type 1 and 2, arterial hypertension, coronary heart disease, peripheral vascular disease, male sex and age were associated with mortality (all p<0.05). In a multivariate Cox regression model the use of calcium channel blockers (HR 1.89), age (HR 1.04), DM type 1 (HR 8.43) and DM type 2 (HR 2.17) and chronic obstructive pulmonary disease (HR 1.66) were associated with mortality (all p < 0.05). CONCLUSION: The use of calcium channel blockers but not of other antihypertensive medicines is associated with mortality in primarily GN patients with CKD.

Kidney biopsy results versus clinical parameters on mortality and ESRD progression in 2687 patients with glomerulonephritis.

BACKGROUND: Physicians refer proteinuric patients to kidney biopsy in order to clarify the issue of underlying renal disease. We compared kidney biopsy results with classical outcome parameters in a large cohort of patients with biopsy proven glomerulonephritis (GN). METHODS: In a retrospective analysis, 2687 patients with different forms of GN from 123 Austrian centres were investigated. Patient characteristics, the diagnosis of GN and its respective subtype and clinical symptoms such as arterial hypertension, haematuria, amount of proteinuria and estimated glomerular filtration rate (eGFR) were tested for their association with all-cause mortality and progression to end-stage renal disease (ESRD). RESULTS: During a median follow-up of 129·9 months (IQR 89·6; 177·7), 688 patients (25·6%) died and 718 patients required dialysis (29·4%). In multivariate Cox's regression analysis age (HR 1·06), female sex (HR 0·71), eGFR (HR 0·74), the diagnosis of GN and its subtypes predicted patient survival (all P < 0·01), whereas the amount of proteinuria was not associated with patient survival. The incidence of progression to ESRD was associated with female sex (HR 0·71), eGFR (HR 0·65), amount of proteinuria (HR 1·15) and the diagnosis of GN and its subtypes (all P < 0·01). Nephrotic or nephritic syndromes were not associated with patient survival or progression to ESRD and did not add further predictive value to outcome of GN. CONCLUSIONS: Our study demonstrates histological diagnosis of GN and its specific subtype predicts patient survival and dialysis incidence. Therefore, kidney biopsy should be an integral part of routine diagnostic assessment in patients with any forms of suspected GN.

Low hepcidin triggers hepatic iron accumulation in patients with hepatitis C.

Persistent hepatitis C virus (HCV) infection is a major cause of chronic liver disease including fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Chronic hepatitis C (CHC) is also a problem in patients with chronic kidney disease (CKD), particularly in those on haemodialysis. Excessive iron in the liver of CHC patients contributes to hepatic fibrosis, cirrhosis and finally HCC, while iron depletion is beneficial. In CHC patients without CKD, in HCV-infected experimental animals and in cell culture studies, serum hepcidin levels and/or cellular hepcidin expression are low and directly suppressed by HCV, radical oxygen species, growth factors and/or transcription factors. In contrast, antiviral therapy (e.g. with pegylated interferon-alpha combined with ribavirin) raises hepcidin levels and reduces iron overload in patients with CHC. Hepcidin directly inhibits HCV replication mediated by STAT3 activation. HCV circumvents hepatic innate antiviral defence by lowering hepcidin. If hepcidin is also low in CKD patients with CHC, iron supplementation should be avoided even in CKD patients with CHC treated with erythropoiesis-stimulating agents.

Everolimus in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a slowly progressive hereditary disorder that usually leads to end-stage renal disease. Although the underlying gene mutations were identified several years ago, efficacious therapy to curtail cyst growth and prevent renal failure is not available. Experimental and observational studies suggest that the mammalian target of rapamycin (mTOR) pathway plays a critical role in cyst growth. METHODS: In this 2-year, double-blind trial, we randomly assigned 433 patients with ADPKD to receive either placebo or the mTOR inhibitor everolimus. The primary outcome was the change in total kidney volume, as measured on magnetic resonance imaging, at 12 and 24 months. RESULTS: Total kidney volume increased between baseline and 1 year by 102 ml in the everolimus group, versus 157 ml in the placebo group (P=0.02) and between baseline and 2 years by 230 ml and 301 ml, respectively (P=0.06). Cyst volume increased by 76 ml in the everolimus group and 98 ml in the placebo group after 1 year (P=0.27) and by 181 ml and 215 ml, respectively, after 2 years (P=0.28). Parenchymal volume increased by 26 ml in the everolimus group and 62 ml in the placebo group after 1 year (P=0.003) and by 56 ml and 93 ml, respectively, after 2 years (P=0.11). The mean decrement in the estimated glomerular filtration rate after 24 months was 8.9 ml per minute per 1.73 m2 of body-surface area in the everolimus group versus 7.7 ml per minute in the placebo group (P=0.15). Drug-specific adverse events were more common in the everolimus group; the rate of infection was similar in the two groups. CONCLUSIONS: Within the 2-year study period,as compared with placebo, everolimus slowed the increase in total kidney volume of patients with ADPKD but did not slow the progression of renal impairment [corrected]. (Funded by Novartis; EudraCT number, 2006-001485-16; ClinicalTrials.gov number, NCT00414440.)

Inhibition of mTOR blocks the anti-inflammatory effects of glucocorticoids in myeloid immune cells.

A central role for the mammalian target of rapamycin (mTOR) in innate immunity has been recently defined by its ability to limit proinflammatory mediators. Although glucocorticoids (GCs) exert potent anti-inflammatory effects in innate immune cells, it is currently unknown whether the mTOR pathway interferes with GC signaling. Here we show that inhibition of mTOR with rapamycin or Torin1 prevented the anti-inflammatory potency of GC both in human monocytes and myeloid dendritic cells. GCs could not suppress nuclear factor-κB and JNK activation, the expression of proinflammatory cytokines, and the promotion of Th1 responses when mTOR was inhibited. Interestingly, long-term activation of monocytes with lipopolysaccharide enhanced the expression of TSC2, the principle negative regulator of mTOR, whereas dexamethasone blocked TSC2 expression and reestablished mTOR activation. Renal transplant patients receiving rapamycin but not those receiving calcineurin inhibitors displayed a state of innate immune cell hyper-responsiveness despite the concurrent use of GC. Finally, mTOR inhibition was able to override the healing phenotype of dexamethasone in a murine lipopolysaccharide shock model. Collectively, these data identify a novel link between the glucocorticoid receptor and mTOR in innate immune cells, which is of considerable clinical importance in a variety of disorders, including allogeneic transplantation, autoimmune diseases, and cancer.

Cinacalcet effect on polymorphonuclear leucocytes of kidney transplant patients.

BACKGROUND: Polymorphonuclear leucocytes (PMNLs) play a key role in the nonspecific immune defence. Cinacalcet reduces serum calcium levels in kidney transplant recipients with mineral bone disorder associated with chronic kidney disease. We investigated essential functions of PMNLs of kidney transplant recipients with and without hypercalcaemia and with and without cinacalcet therapy. SUBJECTS AND METHODS: Oxidative burst, phagocytosis, apoptosis and intracellular calcium concentrations of PMNLs from normocalcaemic kidney transplant patients without (KT-NC) or with cinacalcet intake (KT-NC/CI), hypercalcaemic kidney transplant patients (KT-HC) and healthy subjects (HS) were investigated. RESULTS: Stimulation of oxidative burst of PMNLs from KT-HC patients by phorbol-12-myristate-13-acetate or Escherichia coli was significantly attenuated compared with PMNLs from KT-NC, KT-NC/CI and HS. Apoptosis of PMNLs from KT-HC patients was significantly decreased compared with cells from KT-NC, KT-NC/CI and HS. Apoptosis correlated significantly with serum calcium concentrations. Intracellular calcium concentrations and phagocytosis of PMNLs did not differ between groups. CONCLUSIONS: Our data indicate that stimulation of PMNL oxidative burst and apoptosis is significantly diminished in kidney transplant patients with hypercalcaemia, while kidney transplant patients with serum calcium levels normalized by cinacalcet have normal PMNL functions despite immunosuppressive therapy.

Significance of interdialytic weight gain versus chronic volume overload: consensus opinion.

Predialysis volume overload is the sum of interdialytic weight gain (IDWG) and residual postdialysis volume overload. It results mostly from failure to achieve an adequate volume status at the end of the dialysis session. Recent developments in bioimpedance spectroscopy and possibly relative plasma volume monitoring permit noninvasive volume status assessment in hemodialysis patients. A large proportion of patients have previously been shown to be chronically volume overloaded predialysis (defined as >15% above 'normal' extracellular fluid volume, equivalent to >2.5 liters on average), and to exhibit a more than twofold increased mortality risk. By contrast, the magnitude of the mortality risk associated with IDWG is much smaller and only evident with very large weight gains. Here we review the available evidence on volume overload and IDWG, and question the use of IDWG as an indicator of 'nonadherence' by describing its association with postdialysis volume depletion. We also demonstrate the relationship between IDWG, volume overload and predialysis serum sodium concentration, and comment on salt intake. Discriminating between volume overload and IDWG will likely lead to a more appropriate management of fluid withdrawal during dialysis. Consensually, the present authors agree that this discrimination should be among the primary goals for dialysis caretakers today. In consequence, we recommend objective measures of volume status beyond mere evaluations of IDWG.

The uraemic toxin phenylacetic acid contributes to inflammation by priming polymorphonuclear leucocytes.

BACKGROUND: The activation of polymorphonuclear leucocytes (PMNLs) causes inflammation and as a result cardiovascular disease, which is a main risk factor for increased morbidity and mortality in patients with chronic kidney disease. Toxins accumulating in uraemic patients play a major role in modulating essential PMNL functions and apoptosis, the latter being crucial for a coordinated resolution of inflammation. One uraemic toxin is phenylacetic acid (PAA). We therefore investigated whether PAA contributes to the deranged immune response in uraemia by modulating PMNL activities. METHODS: PMNL oxidative burst, phagocytosis and surface expression of the activation markers CD11b and CD18 were measured by flow cytometry in whole blood from healthy subjects in the presence and absence of PAA. Spontaneous apoptosis of isolated PMNLs was assessed by evaluating morphological features under the fluorescence microscope and by measuring the DNA content by flow cytometry. PMNL chemotaxis was tested by the under-agarose method. RESULTS: PAA significantly enhanced the stimulation of PMNL oxidative burst by Escherichia coli, phagocytosis of E. coli by PMNLs and the expression of CD11b and CD18 at the PMNL surface. PAA significantly decreased PMNL apoptosis resulting in an increased percentage of viable cells. PAA affected neither the oxidative burst stimulated by phorbol-12-myristate-13-acetate nor PMNL chemotaxis. CONCLUSIONS: PAA increases the activation of various PMNL functions and the expression of surface activation markers, while it attenuates PMNL apoptotic cell death. Therefore, PAA may contribute to the inflammatory state and consequently to increased cardiovascular risk in uraemic patients.

Novel views on new-onset diabetes after transplantation: development, prevention and treatment.

New-onset diabetes after transplantation (NODAT) is associated with increased risk of allograft failure, cardiovascular disease and mortality, and therefore, jeopardizes the success of renal transplantation. Increased awareness of NODAT and the prediabetic states (impaired fasting glucose and impaired glucose tolerance, IGT) has fostered previous and present recommendations, based on the management of type 2 diabetes mellitus (T2DM). Unfortunately, the idea that NODAT merely resembles T2DM is potentially misleading, because the opportunity to initiate adequate anti-hyperglycaemic treatment early after transplantation might be given away for 'tailored' immunosuppression in patients who have developed NODAT or carry personal risk factors. Risk factor-independent mechanisms, however, seem to render postoperative hyperglycaemia with subsequent development of overt or 'full-blown' NODAT, the unavoidable consequence of the transplant and immunosuppressive process itself, at least in many cases. A proof of the concept that timely preventive intervention with exogenous insulin against post-transplant hyperglycaemia may decrease NODAT was recently provided by a small clinical trial, which is awaiting confirmation from a multicentre study. However, because early insulin therapy aimed at beta-cell protection seems to contrast the currently recommended, stepwise approach of 'watchful waiting' prior to pancreatic decompensation, we here aim at reviewing recent concepts regarding the development, prevention and treatment of NODAT, some of which seem to challenge the traditional view on T2DM and NODAT. In summary, we suggest a novel, risk factor-independent management approach to NODAT, which includes glycaemic monitoring and anti-hyperglycaemic treatment in virtually everybody after transplantation. This approach has widespread implications for future research and is intended to tackle NODAT and also ultimately cardiovascular disease.

Solid phase detection of C4d-fixing HLA antibodies to predict rejection in high immunological risk kidney transplant recipients.

Protocols for recipient desensitization may allow for successful kidney transplantation across major immunological barriers. Desensitized recipients, however, still face a considerable risk of antibody-mediated rejection (AMR), which underscores the need for risk stratification tools to individually tailor treatment. Here, we investigated whether solid phase detection of complement-fixing donor-specific antibodies (DSA) has the potential to improve AMR prediction in high-risk transplants. The study included 68 sensitized recipients of deceased donor kidney allografts who underwent peritransplant immunoadsorption for alloantibody depletion (median cytotoxic panel reactivity: 73%; crossmatch conversion: n = 21). Pre and post-transplant sera were subjected to detection of DSA-triggered C4d deposition ([C4d]DSA) applying single-antigen bead (SAB) technology. While standard crossmatch and [IgG]SAB testing failed to predict outcomes in our desensitized patients, detection of preformed [C4d]DSA (n = 44) was tightly associated with C4d-positive AMR [36% vs. 8%, P = 0.01; binary logistic regression: odds ratio: 10.1 (95% confidence interval: 1.6-64.2), P = 0.01]. Moreover, long-term death-censored graft survival tended to be worse among [C4d]DSA-positive recipients (P = 0.07). There were no associations with C4d-negative AMR or cellular rejection. [C4d]DSA detected 6 months post-transplantation were not related to clinical outcomes. Our data suggest that pretransplant SAB-based detection of complement-fixing DSA may be a valuable tool for risk stratification.

Fluid overload in hemodialysis patients: a cross-sectional study to determine its association with cardiac biomarkers and nutritional status.

BACKGROUND: Chronic fluid overload is associated with higher mortality in dialysis patients; however, the link with cardiovascular morbidity has not formally been established and may be influenced by subclinical inflammation. We hypothesized that a relationship exists between fluid overload and [i] cardiovascular laboratory parameter as well as between fluid overload and [ii] inflammatory laboratory parameters. In addition, we aimed to confirm whether volume status correlates with nutritional status. METHODS: We recorded baseline characteristics of 244 hemodialysis patients at three hemodialysis facilities in Vienna (Austria) and determined associations with volume measurements using the body composition monitor (Fresenius/Germany). In one facility comprising 126 patients, we further analyzed cardiovascular, inflammatory and nutritional parameters. RESULTS: We detected predialysis fluid overload (FO) in 39% of all patients (n = 95) with FO defined as ≥15% of extracellular water (ECW). In this subgroup, the absolute FO was 4.4 +/-1.5 L or 22.9 ± 4.8% of ECW. A sub-analysis of patients from one center showed that FO was negatively associated with body mass index (r = -0.371; p = <0.001), while serum albumin was significantly lower in fluid overloaded patients (p = 0.001). FO was positively associated with D-Dimer (r = 0.316; p = 0.001), troponin T (r = 0.325; p < 0.001), and N-terminal pro-B-type natriuretic peptide (r = 0.436; p < 0.001), but not with investigated inflammatory parameters. CONCLUSIONS: Fluid overload in HD patients was found to be lower in patients with high body mass index, indicating that dry weight was inadequately prescribed and/or difficult to achieve in overweight patients. The association with parameters of cardiovascular compromise and/or damage suggests that fluid overload is a biomarker for cardiovascular risk. Future studies should determine if this applies to patients prior to end-stage renal disease.

Serum amyloid A in uremic HDL promotes inflammation.

Uremia impairs the atheroprotective properties of HDL, but the mechanisms underlying why this occurs are unknown. Here, we observed that HDL isolated from healthy individuals inhibited the production of inflammatory cytokines by peripheral monocytes stimulated with a Toll-like receptor 2 agonist. In contrast, HDL isolated from the majority of patients with ESRD did not show this anti-inflammatory property; many HDL samples even promoted the production of inflammatory cytokines. To investigate this difference, we used shotgun proteomics to identify 49 HDL-associated proteins in a uremia-specific pattern. Proteins enriched in HDL from patients with ESRD (ESRD-HDL) included surfactant protein B (SP-B), apolipoprotein C-II, serum amyloid A (SAA), and α-1-microglobulin/bikunin precursor. In addition, we detected some ESRD-enriched proteins in earlier stages of CKD. We did not detect a difference in oxidation status between HDL isolated from uremic and healthy patients. Regarding function of these uremia-specific proteins, only SAA mimicked ESRD-HDL by promoting inflammatory cytokine production. Furthermore, SAA levels in ESRD-HDL inversely correlated with its anti-inflammatory potency. In conclusion, HDL has anti-inflammatory activities that are defective in uremic patients as a result of specific changes in its molecular composition. These data suggest a potential link between the high levels of inflammation and cardiovascular mortality in uremia.

Early basal insulin therapy decreases new-onset diabetes after renal transplantation.

No effective interventions to reduce risk for new-onset diabetes after transplantation (NODAT), a condition associated with postoperative hyperglycemia and reduced patient and graft survival, have been established. In this 1-year, proof-of-concept clinical trial, we randomly assigned 50 renal transplant recipients to immediate-postoperative isophane insulin for evening blood glucose ≥140 mg/dl (treatment group) or short-acting insulin and/or oral antidiabetic agents for blood glucose ≥180-250 mg/dl (standard-of-care control group). We included only patients without a history of diabetes who received tacrolimus. By the third postoperative evening, all patients in the treatment group had blood glucose ≥140 mg/dl and were subsequently treated with basal insulin; during the first 3 weeks after transplantation, the mean ± SD daily insulin dosage was 17±11 IU/d. Among controls, 23 (92%) of 25 had blood glucose ≥200 mg/dl and 18 (72%) of 25 received standard-of-care antihyperglycemic treatment. Asymptomatic hypoglycemia occurred five times in the treatment group and once in the control group. Throughout follow-up, the treatment group had 73% lower odds of NODAT (odds ratio, 0.27) than the control group, and hemoglobin A1c was on average 0.38% lower in the treatment group than the control group. Twelve months after transplantation, all patients in the treatment group were insulin-independent, whereas 7 (28%) of 25 controls required antidiabetic agents. The groups did not differ for insulin sensitivity, but the treatment group showed better ß-cell function throughout the 1-year follow-up. In conclusion, this study suggests regimens that include basal insulin significantly reduce the odds for NODAT after renal transplantation, presumably via insulin-mediated protection of ß cells.

Antibody-mediated pure red cell aplasia in chronic kidney disease patients receiving erythropoiesis-stimulating agents: new insights.

Antibody-mediated pure red cell aplasia is a very rare but devastating condition affecting patients receiving treatment with erythropoiesis-stimulating agents. New cases continue to emerge, generally in clusters, consistent with an 'environmental' trigger to its pathogenesis. Defining the causes of antibody-mediated pure red cell aplasia is clearly of importance for patients with chronic kidney disease, but any developments in this area may also have relevance to other disease areas as therapeutic delivery of endogenous proteins rapidly increases. This review focuses on the current knowledge regarding the etiology of antibody-mediated pure red cell aplasia and the current approach to therapy.

Predialysis serum sodium level, dialysate sodium, and mortality in maintenance hemodialysis patients: the Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: Predialysis serum sodium concentrations recently have been linked to patient characteristics and outcomes in hemodialysis patients and may have implications for the dialysate sodium prescription. STUDY DESIGN: Prospective cohort study. PARTICIPANTS: 11,555 patients from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS), phases I (1996-2001) and III (2005-2008). PREDICTORS: Demographics, comorbid conditions, laboratory measurements (model 1); mean serum sodium level, dialysate sodium concentration (model 2). OUTCOMES: Serum sodium level, using adjusted linear mixed models (model 1); all-cause mortality, using Cox proportional hazards models (model 2). RESULTS: Median follow-up was 12 months, with 1,727 deaths (15%) occurring during the study period (12,274 patient-years). Mean serum sodium level in the DOPPS countries was 138.5 ± 2.8 mEq/L. Japan had the highest (139.1 ± 2.6 mEq/L) and Australia/New Zealand had the lowest mean serum sodium level (137.4 ± 2.8 mEq/L). Serum sodium level was associated positively with male sex, black race, body mass index, serum albumin level, and creatinine level and negatively with neurologic and psychiatric disease, white blood cell count, and intradialytic weight loss (0.16 mEq/L lower per 1% loss). Higher serum sodium level was associated with lower adjusted all-cause mortality in a continuous model (HR, 0.95 per 1 mEq/L higher; 95% CI, 0.93-0.97). Dialysate sodium prescription was not associated with serum sodium level. Mortality analyses restricted to the serum sodium tertile with the highest mortality (serum sodium <137 mEq/L) showed lower mortality risk in patients with dialysate sodium prescriptions >140 mEq/L. LIMITATIONS: Causality cannot be established in this observational study, which does not consider potential effects of dialysate sodium level on postdialysis thirst, dietary salt and water intake, interdialytic weight gain, and cardiovascular stability. CONCLUSIONS: Lower serum sodium levels are associated with certain hemodialysis patient characteristics and higher adjusted risk of death. The lower mortality observed in our adjusted analyses in patients with serum sodium levels <137 mEq/L dialyzed against dialysate sodium prescriptions >140 mEq/L is intriguing, may be related to intradialytic cardiovascular stability, and deserves further study.

Lisinopril pharmacokinetics and erythropoietin requirement in haemodialysis patients.

BACKGROUND: There is ongoing controversy whether angiotensin-converting enzyme inhibitors (ACE-I) contribute to anaemia by causing hyporesponsiveness to erythropoiesis-stimulating agents (ESA). However, it is unknown whether or not plasma levels or area under the curve (AUC) of ACE-I are associated with responsiveness to ESA therapy. MATERIALS AND METHODS: We examined the association between lisinopril AUC, lisinopril plasma levels and ESA requirements that was assessed using an ESA index [(ESA IU/week/body weight kg)/(haemoglobin g/dL)]. After screening 184 haemodialysis patients, 14 fulfilled the inclusion criteria, mainly long-term use of oral lisinopril in the upper end of dosage range for this population with stable haemoglobin levels and intravenous ESA therapy. Lisinopril plasma levels were measured at eight different time points (predialysis, immediate post-dialysis and hourly for 6h thereafter; AUC1), and the seven post-dialysis lisinopril plasma levels were used for calculation of AUC2. RESULTS: The mean ESA index of all patients was 27·90±25·84 (IU/week/kg)/(g/dL). Average lisinopril AUC1 was 1212·48±1209·75 [mg*h/L], whereas AUC2 averaged 947·67±977·07 [mg*h/L]. Two patients (14%) had no detectable lisinopril plasma levels, indicating their noncompliance. There was no association between ESA index and AUC or plasma levels of lisinopril at any time point for all 14 or for the 12 compliant patients. CONCLUSIONS: Our study shows that long-term, high-dose lisinopril therapy has no effect on ESA responsiveness. Thus, avoidance or a dose reduction of ACE-I in dialysis patients will not necessarily lead to reduced ESA requirements and costs.

Inorganic phosphate and FGF-23 predict outcome in stable systolic heart failure.

BACKGROUND: Recent studies show associations between inorganic phosphate and risk of heart failure in the general population as well as between fibroblast growth factor 23 (FGF-23) and outcome in coronary heart disease. This study was carried out to assess whether circulating levels of inorganic phosphate and FGF-23, a new central hormone in mineral bone metabolism, predict outcome in systolic heart failure. MATERIALS AND METHODS: Ninety-nine consecutive outpatients with systolic heart failure were enrolled. Mean (SD) age was 61 years (11), mean left ventricular ejection fraction (LVEF) was 33% (10), 82 patients were men, median estimated creatinine clearance was 83 mL/min (Q(1) -Q(3) 58-106), median NTproBNP level was 803 pg/mL (Q(1) -Q(3) 404-2757), median inorganic phosphate was 1·12 mM (Q(1) -Q(3) 1·02-1·22), median FGF-23 was 39·02 pg/mL (Q(1) -Q(3) 32·45-55·86) and median follow-up was 35 months. Associations between inorganic phosphate, FGF-23 and endpoints were assessed using Cox regression analyses. RESULTS: Inorganic phosphate and FGF-23 levels were significantly higher (P < 0·001 and P = 0·009) in patients reaching the combined endpoint of cardiac hospitalization or death. FGF-23 (ln) predicted all-cause mortality (hazard ratio (HR) 5·042, P = 0·032) in a model adjusted for age, gender, estimated creatinine clearance, LVEF, New York Heart Association (NYHA) stage and NTproBNP level. Inorganic phosphate predicted heart failure hospitalization (HR 26·944, P = 0·021), cardiac hospitalization (HR 16·016, P = 0·017) and the combined endpoint (HR 13·294, P = 0·015) in models adjusted for the same co-variables. CONCLUSION: The results of this study demonstrate the independent prognostic value of inorganic phosphate and FGF-23 in heart failure even in the context of established risk markers.

A versatile role of mammalian target of rapamycin in human dendritic cell function and differentiation.

The mammalian target of rapamycin (mTOR) regulates cell growth and survival and exists as rapamycin-sensitive mTOR complex (mTORC) 1 and as rapamycin-insensitive mTORC2. Although mTOR is a well-known regulator of diverse immune cells, its detailed role in human dendritic cell (DC) function and differentiation is only incompletely understood. In this study, we demonstrate divergent roles of mTOR during activation and differentiation of myeloid DCs (mDCs) and monocyte-derived DCs (moDCs). Inhibition of mTORC1 in mDCs activated with TLR-dependent or -independent stimuli increased proinflammatory cytokines and NF-κB, whereas IL-10 and STAT3 were blocked. Rapamycin regulated the costimulatory/surface molecules CD86, programmed death ligand-1, and CD25 on mDCs and significantly increased the T cell allostimulatory potential of mDCs. In contrast, rapamycin suppressed immunostimulatory molecules and the allostimulatory potential of LPS-stimulated moDCs by an inability to augment NF-κB signaling. In differentiating moDCs, the PI3K/Akt-dependent mTOR pathway was constitutively activated by GM-CSF to induce DC differentiation in an mTORC1-dependent manner. Inhibition of mTORC1 or mTORC1/2 during moDC differentiation decreased moDC survival and markedly hampered its immunostimulatory phenotype. Analyzing the fate of DCs in vivo, we found that kidney transplant patients treated with rapamycin displayed an increased immunostimulatory potential of mDCs compared with patients treated with calcineurin inhibitors. Furthermore, rapamycin did not interfere with mDC differentiation in these patients. Collectively, mTOR exerts divergent immunoregulatory functions during DC activation and differentiation depending on the DC type that lead to opposing T cell responses, which might be of clinical importance in transplantation, cancer, and also for novel vaccination strategies.