Manfred Hecking

The multifunctional role of mTOR in innate immunity: implications for transplant immunity.

The mammalian target of rapamycin (mTOR) is an evolutionary conserved serine–threonine kinase that senses various environmental stimuli in most cells primarily to control cell growth. Restriction of cellular proliferation by mTOR inhibition led to the use of mTOR inhibitors as immunosuppressants in allogeneic transplantation as well as novel anticancer agents. However, distinct inflammatory side effects such as fever, pneumonitis, glomerulonephritis or anemia of chronic disease have been observed under this treatment regime. Apart from the mere cell‐cycle regulatory effect of mTOR in dividing cells, recent data revealed a master regulatory role of mTOR in the innate immune system. Hence, inhibition of mTOR promotes proinflammatory cytokines such as IL‐12 and IL‐1β, inhibits the anti‐inflammatory cytokine IL‐10 and boosts MHC antigen presentation via autophagy in monocytes/macrophages and dendritic cells. Moreover, mTOR regulates type I interferon production and the expression of chemokine receptors and costimulatory molecules. These results place mTOR in a complex immunoregulatory context by controlling innate and adaptive immune responses. In this review, we discuss the clinical consequences of mTOR‐inhibitor therapy and aim to integrate this recent data into our current view of the molecular mechanisms of clinically employed mTOR inhibitors and discuss their relevance with special emphasis to transplantation.

Proceedings From an International Consensus Meeting on Posttransplantation Diabetes Mellitus: Recommendations and Future Directions

A consensus meeting was held in Vienna on September 8–9, 2013, to discuss diagnostic and therapeutic challenges surrounding development of diabetes mellitus after transplantation. The International Expert Panel comprised 24 transplant nephrologists, surgeons, diabetologists and clinical scientists, which met with the aim to review previous guidelines in light of emerging clinical data and research. Recommendations from the consensus discussions are provided in this article. Although the meeting was kidney‐centric, reflecting the expertise present, these recommendations are likely to be relevant to other solid organ transplant recipients. Our recommendations include: terminology revision from new‐onset diabetes after transplantation to posttransplantation diabetes mellitus (PTDM), exclusion of transient posttransplant hyperglycemia from PTDM diagnosis, expansion of screening strategies (incorporating postprandial glucose and HbA1c) and opinion‐based guidance regarding pharmacological therapy in light of recent clinical evidence. Future research in the field was discussed with the aim of establishing collaborative working groups to address unresolved questions. These recommendations are opinion‐based and intended to serve as a template for planned guidelines update, based on systematic and graded literature review, on the diagnosis and management of PTDM.

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 β-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 β cells.

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.

Dialysate Sodium Concentration and the Association with Interdialytic Weight Gain, Hospitalization, and Mortality

BACKGROUND AND OBJECTIVES Recommendations to decrease the dialysate sodium (DNa) prescription demand analyses of patient outcomes. We analyzed morbidity and mortality at various levels of DNa, simultaneously accounting for interdialytic weight gain (IDWG) and for the mortality risk associated with lower predialysis serum sodium (SNa) levels. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We used multiply-adjusted linear mixed models to evaluate the magnitude of IDWG and Cox proportional hazards models to assess hospitalizations and deaths in 29,593 patients from the Dialysis Outcomes and Practice Patterns Study with baseline DNa and SNa as predictors, categorized according to lowest to highest levels. RESULTS IDWG increased with higher DNa across all SNa categories, by 0.17% of body weight per 2 mEq/L higher DNa; however, higher DNa was not associated with higher mortality in a fully adjusted model (also adjusted for SNa; hazard ratio [HR]=0.98 per 2 mEq/L higher DNa, 95% confidence interval [CI] 0.95-1.02). Instead, higher DNa was associated with lower hospitalization risk (HR=0.97 per 2 mEq/L higher DNa, 95% CI 0.95-1.00, P=0.04). Additional adjustments for IDWG did not change these results. In sensitivity analyses restricted to study facilities, in which 90%-100% of patients have the same DNa (56%), the adjusted HR for mortality was 0.88 per 2 mEq/L higher DNa (95% CI 0.83-0.94). These analyses represented a pseudo-randomized experiment in which the association between DNa and mortality is unlikely to have been confounded by indication. CONCLUSIONS In the absence of randomized prospective studies, the benefit of reducing IDWG by decreasing DNa prescriptions should be carefully weighed against an increased risk for adverse outcomes.

CMV Late Phase‐Induced mTOR Activation Is Essential for Efficient Virus Replication in Polarized Human Macrophages

Human cytomegalovirus (CMV) remains one of the most important pathogens following solid‐organ transplantation. Mounting evidence indicates that mammalian target of rapamycin (mTOR) inhibitors may decrease the incidence of CMV infection in solid‐organ recipients. Here we aimed at elucidating the molecular mechanisms of this effect by employing a human CMV (HCMV) infection model in human macrophages, since myeloid cells are the principal in vivo targets of HCMV. We demonstrate a highly divergent host cell permissiveness for HCMV with optimal infection susceptibility in M2 but not M1 polarized macrophages. Employing an ultrahigh purified HCMV stock we observed rapamycin‐independent viral entry and induction of IFN‐β transcripts, but no proinflammatory cytokines or mitogen‐activated protein kinases and mTOR activation early after infection. However, in the late infection phase, sustained mTOR activation was observed in HCMV‐infected cells and was required for efficient viral protein synthesis including the viral late phase proteins pUL‐44 and pp65. Accordingly, rapamycin strongly suppressed CMV replication 3 and 5 days postinfection in macrophages. In conclusion, these data indicate that mTOR is essential for virus replication during late phases of the viral cycle in myeloid cells and might explain the potent anti‐CMV effects of mTOR inhibitors after organ transplantation.

Efficacy and safety of vildagliptin in new-onset diabetes after kidney transplantation--a randomized, double-blind, placebo-controlled trial.

New‐onset diabetes after transplantation (NODAT) is a serious complication after kidney transplantation, but therapeutic strategies remain underexplored. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors selectively foster insulin secretion without inducing hypoglycemia, which might be advantageous in kidney transplant recipients (KTRs) with NODAT. We conducted a randomized, double‐blind, placebo‐controlled, phase II trial to assess safety and efficacy of the DPP‐4 inhibitor vildagliptin. Intraindividual differences in oral glucose tolerance test (OGTT)‐derived 2‐h plasma glucose (2HPG) from baseline to 3 months after treatment served as primary endpoint. Among secondary outcomes, we evaluated HbA1c, metabolic and safety parameters, as well as OGTTs at 1 month after drug discontinuation. Of 509 stable KTRs who were screened in our outpatient clinic, 63 (12.4%) had 2HPG ≥200 mg/dL, 33 of them were randomized and 32 completed the study. In the vildagliptin group 2HPG and HbA1c were profoundly reduced in comparison to placebo (vildagliptin: 2HPG = 182.7 mg/dL, HbA1c = 6.1%; placebo: 2HPG = 231.2 mg/dL, HbA1c = 6.5%; both p ≤ 0.05), and statistical significance was achieved for the primary endpoint (vildagliptin: 2HPG‐difference −73.7 ± 51.3 mg/dL; placebo: −5.7 ± 41.4 mg/dL; p < 0.01). Adverse events were generally mild and occurred at similar rates in both groups. In conclusion, DPP‐4 inhibition in KTRs with overt NODAT was safe and efficient, providing a novel treatment alternative for this specific form of diabetes.

Glucose Metabolism After Renal Transplantation

OBJECTIVE We determined prevalence, risk factors, phenotype, and pathophysiological mechanism of new-onset diabetes after transplantation (NODAT) to generate strategies for optimal pharmacological management of hyperglycemia in NODAT patients. RESEARCH DESIGN AND METHODS Retrospective cohort study comparing demographics, laboratory data, and oral glucose tolerance test (OGTT)-derived metabolic parameters from kidney transplant recipients versus subjects not receiving transplants. RESULTS Among 1,064 stable kidney transplant recipients (≥6 months posttransplantation), 113 (11%) had a history of NODAT and 132 (12%) had pretransplant diabetes. In the remaining patients, randomly assigned OGTTs showed a high prevalence of abnormal glucose metabolism (11% diabetes; 32% impaired fasting glucose, impaired glucose tolerance, or both), predominantly in older patients who received tacrolimus as the primary immunosuppressant. Compared with 1,357 nontransplant subjects, stable kidney transplant recipients had lower basal glucose, higher glycated hemoglobin, lower insulin secretion, and greater insulin sensitivity in each of the three subgroups, defined by OGTT 2-h glucose (<140, 140–199, ≥200 mg/dL). These findings were reinforced in linear spline interpolation models of insulin secretion and sensitivity (all P < 0.001) and in another regression model in which the estimated oral glucose insulin sensitivity index was substantially higher (by 79–112 mL/min m2) for transplant versus nontransplant subjects despite adjustments for age, sex, and BMI (all P < 0.001). CONCLUSIONS Glucose metabolism differs substantially between kidney transplant recipients and nontransplant controls. Because impaired insulin secretion appears to be the predominant pathophysiological feature after renal transplantation, early therapeutic interventions that preserve, maintain, or improve β-cell function are potentially beneficial in this population.

Vildagliptin and pioglitazone in patients with impaired glucose tolerance after kidney transplantation: a randomized, placebo-controlled clinical trial.

Background New-onset diabetes after transplantation (NODAT) is a serious complication after kidney transplantation affecting graft and patient survival. Currently, no guidelines exist for the management of renal transplant patients with impaired glucose tolerance (IGT), a risk factor for the development of NODAT and an independent predictor of death. Methods In a population of 48 stable renal transplant recipients at least 6 months from time of transplantation with newly diagnosed IGT, we tested the dipeptidylpeptidase-4 inhibitor vildagliptin, the thiazolidinedione pioglitazone, or placebo for 3 months in addition to lifestyle counseling. Outcome measures were difference in change in oral glucose tolerance test between the groups and between baseline and end of study as well as change in HbA1c, serum lipids, and renal and hepatic function. Results In both treatment groups, 2-hr plasma glucose at 3 months was significantly reduced compared with baseline (vildagliptin: −20±24 mg/dL; P=0.002 and pioglitazone: −23±29 mg/dL; P=0.004), and pioglitazone also significantly improved fasting plasma glucose (−11±14 mg/dL; P=0.003), although the primary outcome (difference in change in 2-hr plasma glucose among the three groups) did not reach statistical significance. Furthermore, HbA1c was decreased in both treatment arms (vildagliptin: −0.1%±0.3%; P=0.046 and pioglitazone: −0.2%±0.3%; P=0.029). In the placebo group, no significant changes in these parameters were observed. Only mild adverse events occurred and at a similar rate in all three groups. Conclusions These data demonstrate that both vildagliptin and pioglitazone are of potential benefit in patients with IGT after renal transplantation in addition to lifestyle modification.

Sodium Setpoint and Sodium Gradient: Influence on Plasma Sodium Change and Weight Gain

Background/Aims: In hemodialysis and hemodiafiltration patients, the plasma sodium (PNa) measured before dialysis can be regarded as the sodium setpoint. By the end of dialysis, the PNa typically approximates the prescribed dialysate sodium (DNa), the difference between DNa and PNa being considered the sodium gradient. We determined the relationship between setpoint, gradient and pre- to postdialysis PNa change (delta PNa), and studied associations with dialysis-related variables. Methods: Cohort study. Measurements from 132 patients during 12 consecutive treatments included PNa and DNa concentrations, pre- to postdialysis body weight and predialysis systolic blood pressure. Results: Sodium setpoints were normally distributed (137.9 ± 2.4 mmol/l), DNa prescriptions were non-normally distributed (138.9 ± 1.8 mmol/l). The sodium gradient correlated strongly with delta PNa (r = 0.76, p < 0.001). Both sodium gradient and delta PNa correlated with relative interdialytic weight gain (IDWG; r = 0.25, p = 0.004, and r = 0.44, p < 0.001, respectively), but not with predialysis systolic blood pressure. These correlations were consistent after exclusion of patients with urine volume >500 ml/day and patients undergoing sodium profiling, and increased after exclusion of patients with hemodiafiltration protocols. Predictors for having higher relative IDWG (≧2.8%) were delta PNa concentrations ≧0 mmol/l and younger age. Predictors for having a delta PNa concentration ≧0 mmol/l were lower sodium setpoints, higher DNa prescriptions, use of Nikkiso machines, sodium profiling and younger age. Patients with positive delta PNa despite negative gradients were significantly younger, used more Nikkiso machines and presented with higher IDWG. Conclusion: IDWG correlated with the sodium gradient and more strongly with delta PNa, suggesting the need for studying other outcomes, such as morbidity and mortality.