Age-modified risk factors for mortality of non-elderly adult kidney transplant recipients: a retrospective database analysis.

PURPOSE: We aimed to investigate the role of the recipient's age strata in modifying the associations between risk factors and mortality in non-elderly adult kidney transplant (KT) recipients (KTR). METHODS: We stratified 108,695 adult KTRs between 2000 and 2016 with conditional 1-year survival after KT into cohorts based on age at transplant: 18-49 years and 50-64 years. We excluded KTRs aged < 18 years or > / = 65 years. KTRs were observed for 5 years during the 2nd through 6th years post-KT for the outcome, all-cause mortality. RESULTS: Increasing recipient age strata (18-49-year-old and 50-64-year-old) correlated with decreasing 6-year post-KT survival rates conditional on 1-year survival (79% and 57%, respectively, p < 0.0001). Middle adult age stratum was associated with a higher risk of all-cause mortality than young adult age stratum in KTRs of Hispanic/Latino and other races [HR = 1.23, 95% CI = 1.04-1.45 and HR = 1.51, 95% CI = 1.16-1.97, respectively] and with a primary native renal diagnosis of hypertension or glomerulonephritis [HR = 1.32, 95% CI = 1.12-1.55 and HR = 1.29, 95% CI = 1.10-151, respectively]. When compared with the young adult age stratum, the middle adult age stratum had a mitigating effect on the higher risk of mortality associated with sirolimus-mycophenolate or sirolimus-tacrolimus than the standard calcineurin inhibitor-mycophenolate regimen [HR = 0.75, 95% CI = 0.57-0.99 and HR = 0.71, 95% CI = 0.57-0.89, respectively]. CONCLUSION: Among adult non-elderly KTRs, the age strata, 18-49 years, and 50-64 years, have varying modifying effects on the strength and direction of associations between some specific risk factors and all-cause mortality.

Molecular structure and selective theophylline complexation by conformational change of diethyl N,N'-(1,3-phenylene)dicarbamate.

The receptor ability of diethyl N,N'-(1,3-phenylene)dicarbamate (1) to form host-guest complexes with theophylline (TEO) and caffeine (CAF) by mechanochemistry was evaluated. The formation of the 1-TEO complex (C12H16N2O4·C7H8N4O2) was preferred and involves the conformational change of one of the ethyl carbamate groups of 1 from the endo conformation to the exo conformation to allow the formation of intermolecular interactions. The formation of an N-H...O=C hydrogen bond between 1 and TEO triggers the conformational change of 1. CAF molecules are unable to form an N-H...O=C hydrogen bond with 1, making the conformational change and, therefore, the formation of the complex impossible. Conformational change and selective binding were monitored by IR spectroscopy, solid-state 13C nuclear magnetic resonance and single-crystal X-ray diffraction. The 1-TEO complex was characterized by IR spectroscopy, solid-state 13C nuclear magnetic resonance, powder X-ray diffraction and single-crystal X-ray diffraction.

Role of standard HLA mismatch in modifying associations between non-pharmacologic risk factors and solid organ malignancy after kidney transplantation.

BACKGROUND: Human leukocyte antigen mismatch(es) (HLA-mm) between donors and recipients has not been extensively studied either as a risk factor for solid organ malignancy (SOM) or as a modifier of associations between nonpharmacologic risk factors and SOM in kidney transplant recipients (KTRs). METHODS: In a secondary analysis from a previous study, 166,256 adult KTRs in 2000-2018 who survived the first 12 months post-transplant free of graft loss or malignancy were classified into 0, 1-3, and 4-6 standard HLA-mm cohorts. Multivariable cause-specific Cox regressions analyzed the risks of SOM and all-cause mortality (ac-mortality) in 5 years following the first KT year. Comparisons of associations between SOM and risk factors in HLA mismatch cohorts were made by estimating the ratios of adjusted hazard ratios. RESULTS: Compared with 0 HLA-mm, 1-3 HLA-mm was not associated, and 4-6 HLA-mm was equivocally associated with increased risk of SOM [hazard ratio, (HR) = 1.05, 95%, confidence interval (CI) = 0.94-1.17 and HR = 1.11, 95% CI = 1.00-1.34, respectively]. Both 1-3 HLA-mm and 4-6 HLA-mm were associated with increased risk of ac-mortality compared with 0 HLA mm [hazard ratio (HR) = 1.12, 95%, Confidence Interval (CI) = 1.08-1.18) and (HR = 1.16, 95% CI = 1.09-1.22), respectively]. KTR's history of pre-transplant cancer, age 50-64, and >/=65 years were associated with increased risks of SOM and ac-mortality in all HLA mismatch cohorts. Pre-transplant dialysis >2 years, diabetes as the primary renal disease, and expanded or standard criteria deceased donor transplantation were risk factors for SOM in the 0 and 1-3 HLA-mm cohorts and of ac-mortality in all HLA-mm cohorts. KTRs male sex or history of previous kidney transplant was a risk factor for SOM in the 1-3 and 4-6 HLA-mm cohorts and of ac-mortality in all HLA-mm cohorts. CONCLUSION: Direct association between SOM and the degree of HLA mismatching is equivocal and limited to the 4-6 HLA-mm stratum; however, the degree of HLA mismatching has significant modifying effects on the associations between specific nonpharmacologic risk factors and SOM in KTRs.

Common predictors of adverse outcomes in adult deceased donor kidney transplant recipients with varying sensitization.

OBJECTIVE: Our objective was to identify consistent predictors of multiple adverse outcomes of adult deceased donor (DD) kidney transplant recipients (KTRs) of varying sensitization status. METHODS: We used the national transplant database in studying 62037 adult DD-KTRs between Dec. 2007 and Jun. 2015 stratified into sensitization cohorts based on calculated panel reactive antibody (CPRA) of <10%, 10%-79%, and ≥80%. We used multivariable logistic regressions for the analysis of risks for delayed graft function (DGF), and of acute rejection (AR) and hospitalization in the first year of transplant, and Cox hazard regression for 5-year overall graft loss (OAGL) and death. RESULTS: The kidney donor risk index (KDRI) highest two quartiles ≥1.45 and 1.15-1.44 were the most consistent predictors for 100% of adverse outcomes (OAGL, death, DGF, AR, and hospitalization) with high significance (P<0.0001) across all sensitization cohorts. The two risk factors that were consistently associated with 80% of adverse outcomes across sensitization cohorts were: (1) pre-transplant dialysis duration >2 years was significantly associated with increased risks of overall graft loss, death, DGF, and hospitalization; and (2) Black KTR race was significantly associated with increased risks of DGF, AR, and hospitalization, and decreased risk of death. Diabetes and KTR age >65 (years) were significant risk factors for overall loss and death across sensitization cohorts. CONCLUSIONS: The two highest KDRI quartiles, pre-transplant dialysis duration >2 years, and African American recipient race are consistent predictors of multiple adverse outcomes in adult DDKTRs across sensitization strata and should be among the factors considered in clinical decision-making and research models in kidney transplantation.

Phenomenology and Physiology of Tacrolimus Induced Tremor.

Background: Tacrolimus is a potent immunosuppressant drug commonly used after solid organ transplant surgery. The use of this drug is frequently associated with the emergence of tremors. There is little information on the clinical and physiological characteristics of tacrolimus-induced tremors. Characterizing these tremors is essential as they can promote the development of specific therapies. Methods: We describe four patients placed on tacrolimus immunosuppressant therapy following kidney transplant surgery and who developed tremors impacting their daily functional activities. We describe the clinical and physiological characteristics of the tremor and the response generated after a limb cooling test. Results: A postural and kinetic tremor mainly involving the distal hands was observed in our cohort. In the accelerometer-based assessment, the tremor amplitude was noted to be mild to moderate, and the frequency was 5-6 Hz. Cooling the forearm and the hand led to a temporary albeit significant reduction of tremor amplitude (p = 0.03). Limb cooling lowered the tremor frequency by 1 Hz in two patients with no change in the other two patients, and the statistical comparison was not significant (p > 0.05). Conclusions: Limb cooling may be pursued as a therapeutic option for addressing tacrolimus-induced tremor, as the patients in our cohort benefitted from temporary tremor suppression.

Impact of antibody induction on the outcomes of new onset diabetes after kidney transplantation: a registry analysis.

PURPOSE: We conducted this observational study to examine the impact of antibody inductions administered at kidney transplant (KT) on outcomes of 5 year exposure to post-transplant diabetes (PTDM) in adult deceased-donor kidney transplant recipients (DDKTRs). We also studied the risk of PTDM associated with antibody inductions. METHODS: Using 2000-2016 Organ Procurement Transplantation Network data, we employed multivariable Cox models to determine the adjusted hazard ratios (HR) of death, and overall and death-censored graft loss (OAGL, DCGL; respectively) at the 5 year landmark period in antibody induction cohorts with and without PTDM at the 1 year post-transplant index time point. We used multivariable logistic regression in determining the risk factors for PTDM. All multivariable analyses were adjusted for the potential confounding effects of maintenance immunosuppression, steroid regimens, and other relevant covariates. RESULTS: 48,031 adult DDKTRs were classified into cohorts based on antibody induction at transplant: (anti-thymocyte globulin) ATG (n = 26, 788); (alemtuzumab) ALM (n = 5916); and interleukin-2 receptor antagonist (IL-2RA) (n = 15,327). PTDM was a risk factor for 5 year OAGL and death, not DCGL [(HR = 1.25, CI = 1.16-1.36), (HR = 1.13, CI = 1.06-1.21), and (HR = 1.05, CI = 0.96-1.16); respectively]. Induction regimens were not risk factors for 5 year outcomes in DDKTRs with and without PTDM. Risk factors for PTDM included DDKTR obesity, age > / = 50 years, acute rejection, and ATG induction, among others. CONCLUSIONS: In adult DDKTRs, after controlling the confounding effects of clinically relevant variables including maintenance and steroid regimens, PTDM at 1 year post-transplant is associated with death and OAGL, not DCGL in the following 5 years: induction received at KT did not modify these associations.

Association of HLA mismatch and MTOR inhibitor regimens with malignancy and mortality after kidney transplantation.

Background The association of mammalian target of rapamycin inhibitors (MTORI) with malignancies and mortality in kidney transplant recipients (KTR) with different degrees of human leukocyte antigen mismatch (HLA-mm) at transplant has not been previously studied. Methods Our observational cohort study included 166, 256 adult KTRs in 2000-2018. Immunosuppression in the first post-transplant year were MTORIs in 13,056 (7.85%) and non-MTORIs in 153,200 (92.15%). We used Cox multivariable regression models to determine the cause-specific hazard ratio (HRcs) of non-melanoma skin cancer (NMSC),solid organ malignancies (SOM)] and all-cause death (deathac); and the HR of the composite outcomes of NMSC or deathac and SOM or deathac associated with MTORI versus non-MTORI regimens in the overall study sample and the 0, 1-3, and 4-6 HLA-A, B and DR mm subgroups. Results NMSC risk was lower with MTORI than non-MTORI in all HLA-mm subgroups [(0 mm, HRcs = 0.67; 95% CI = 0.46-0.97, 1-3 mm, HRcs = 0.73; 95% CI = 0.61-0.87, 4-6 mm, HRcs = 0.69; 95% CI = 0.62-0.76)]. SOM risks were similar between regimens in the 0 HLA mm subgroup (HRcs = 1.10 (95% CI = 0.78-1.57) and lower with MTORI than non-MTORI in the 1-3, and 4-6 HLA-mm subgroups, [(HR = 0.84; (95% CI = 0.71-0.99), and (HR = 0.86; 95% CI = 0.78-0.94); respectively]. Risks of deathac and composite outcomes (NMSC or deathac and SOM or deathac) were higher with MTORI than non-MTORI in almost all HLA-mm subgroups. Conclusion MTORIs are associated with protection from NMSC and SOM in almost all HLA-mm subgroups ca; however, their association with increased all-cause mortality in adult kidney transplant recipients needs further investigation.

Material Selection and Characterization for a Novel Frame-Integrated Curtain Wall.

Curtain walls are the façade of choice in high-rise buildings and an indispensable element of architecture for a contemporary city. In conventional curtain walls, the glass panels are simply supported by the metal framing which transfers any imposed load to the building structure. The absence of composite action between glass and metal results in deep frames, protruding to the inside, occupying valuable space and causing visual disruption. In response to the limited performance of conventional systems, an innovative frame-integrated unitized curtain wall is proposed to reduce structural depth to one fifth (80%) allowing an inside flush finish and gaining nettable space. The novel curtain wall is achieved by bonding a pultruded glass fiber reinforced polymer (GFRP) frame to the glass producing a composite insulated glass unit (IGU). This paper selects the candidate frame and adhesive materials performing mechanical tests on GFRP pultrusions to characterize strength and elasticity and on GFRP-glass connections to identify failure module and strength. The material test results are used in a computer-based numerical model of a GFRP-glass composite unitized panel to predict the structural performance when subjected to realistic wind loads. The results confirm the reduction to one fifth is possible since the allowable deflections are within limits. It also indicates that the GFRP areas adjacent to the support might require reinforcing to reduce shear stresses.

Effect of Paraffin and Silica Matrix Phase Change Materials on Properties of Portland Cement Mortars.

In the search for methods to incorporate Phase Change Materials (PCM) into Portland cement mortar mixtures, PCM based on paraffins adhered to a silica-based matrix appear as a suitable option. However, paraffin particles have been observed to escape from the silica matrix when water is added. There are only limited data on how the use of such PCM affects the behaviour of mortars. To evaluate the effect of this PCM addition, Portland mortar mixtures were elaborated with 5%, 10% and 15% of PCM content, and using CEM 42.5 I R and CEM I 52.5 R cement types. Physical properties such as density, open porosity, air content and water absorption were analysed for fresh and dry samples. The results obtained show that the PCM-added mixtures require greater water and cement amounts than the standard mortar mixtures to achieve similar compressive strengths. Compared to non-PCM mixtures the PCM-added mortars present a density lowering of 37% for fresh mixtures and near 45% for dry state forms. A maximum compressive strength of 15.9 MPa was reached for 15% PCM mixtures, while values beyond 40 MPa were achieved for 5% PCM mixtures. Thus, the proposed study contributes to broad the available knowledge of PCM cement mortar mixtures behaviour and their mix design.

A pilot study of immunosuppression resumption following BK viremia resolution.

BACKGROUND: Immunosuppression reduction for BK viremia is associated with de novo humoral responses, which are a risk factor for rejection and graft loss. In this pilot project, we tested a protocol of immunosuppression resumption to standard dose after viral clearance for optimal protection against humoral immunity in patients undergoing treatment for BK viremia. METHODS: Thirty-six consecutive kidney transplant recipients who developed BK viremia from 7/1/2014 to 11/18/2016 underwent immunosuppression reduction. After 4 weeks of absent viremia, mycophenolate mofetil (MMF) was increased by 500mg/day every 2 weeks up to standard dosage, followed by increase of tacrolimus trough levels to 5-7 ng/mL. If viremia recurred during the increase, immunosuppression was reduced in this same stepwise fashion, with stepwise increase again after 2 months of negative viremia. RESULTS: Mean tacrolimus trough level (ng/mL) was 8.3 ± 2.7 at viremia onset, 5.3 ± 3.6 at resolution, and 5.6 ± 2.0 at study end date. Mean daily dose (mg) of MMF was 1574 ± 355 at onset, 910 ± 230 at resolution, and 1377 ± 451 at study end date. Only one patient developed low level viremia recurrence (peak 2875 copies/mL) during the period of immunosuppression resumption that ultimately resolved. CONCLUSIONS: The results of our pilot project indicate that following BK viremia resolution, resumption of standard immunosuppression can be achieved safely without BK viremia recurrence. Larger trials with long-term follow up are required to determine whether such an approach improves long-term graft survival.

Outcomes of induction antibody therapies in the nonbroadly sensitized adult deceased donor kidney transplant recipients: a retrospective cohort registry analysis.

The outcomes of lymphocyte-depleting antibody induction therapy (LDAIT), [thymoglobulin (ATG) or alemtuzumab (ALM)] versus interleukin-2 receptor antagonist (IL-2RA) in the nonbroadly-sensitized [pretransplant calculated panel reactive antibody (cPRA), <80%] adult deceased donor kidney transplant recipients (adult-DDKTRs) are understudied. In this registry, study of 55 593 adult-DD-KTRs, outcomes of LDAIT [(ATG, N = 32 985) and (ALM, N = 9429)], and IL-2RA (N = 13 179) in <10% and 10-79% cPRA groups was analyzed. Adjusted odds ratio (aOR) of one-year biopsy-proven acute rejection (BPAR) was lower; while, aOR of 1-year composite of re-hospitalization, graft loss, or death was higher with LDAIT than IL2-RA in both cPRA groups. Adjusted odds ratio (aOR) of delayed graft function was higher with LDAIT than IL-2RA in the <10% cPRA group. Adjusted hazard ratio (aHR) of 5-year death-censored graft loss (DCGL) in both <80% cPRA groups seemed higher with ALM than other inductions [(<10% cPRA: ALM versus IL2RA, aHR = 1.11, 95% CI = 1.00-1.23 and ATG versus ALM: aHR = 0.84, 95% CI = 0.77-0.91; 10-79% cPRA: ALM versus IL2RA, aHR = 1.29, 95% CI = 1.02-1.64; and ATG versus ALM, aHR = 0.83, 95% CI = 0.70-0.98)]. Five-year aHR of death did not differ among induction therapies in both cPRA groups. In nonbroadly sensitized adult-DDKTRs, LDAIT is more protective against 1-year BPAR (not 5-year mortality) than IL-2RA; the trend of a higher 5-year DCGL risk with ALM than ATG or IL-2RA needs further investigation.

Outcomes of sirolimus regimens in 65-year-old and older kidney transplant recipients: a registry-based observational study.

PURPOSE: In large observational studies of adult kidney transplant recipients (KTRs) where older adults (65 years old and older) were not well represented, the mammalian target of rapamycin inhibitors (mTOR inhibitors) has poorer outcomes than the standard tacrolimus-mycophenolate-steroids (TAC-MPA-S) regimen. We conducted this study to compare the outcomes of regimens containing the common mTOR inhibitor, sirolimus (SRL) against TAC-MPA-S in older adult KTRs. METHODS: Using the 2000-2016 Scientific Registry of Transplant Recipients, Cox multivariable regression models were conducted to analyze the patient and graft outcomes associated with regimens containing SRL, steroids (S) and cyclosporine (CSA), tacrolimus (TAC), or mycophenolate (MPA) vs. the standard (TAC-MPA-S) regimen in older adult KTRs. RESULTS: Included in the analysis were 15,008 (95.19%) older adult KTRs on standard (TAC-MPA-S) regimen, 242 (1.53%) on SRL-MPA-S, 300 (1.90%) on SRL-TAC-S, and 217 (1.38%) on SRL-CSA-S. Compared with the standard regimen, the adjusted risks of all-cause death and overall graft loss over a maximum 5-year follow-up were highest with SRL-MPA-S, intermediate with SRL-TAC-S and not significantly different with SRL-CSA-S. The adjusted risks of all-cause death and overall graft loss were modified by a pre-transplant history of malignancy in older adult KTRs on SRL-TAC-S, not in those on SRL-MPA-S or SRL-CSA-S. CONCLUSIONS: In older adult kidney transplant recipients, SRL-TAC-S or SRL-MPA-S, but not SRL-CSA-S is associated with higher risks of death and allograft loss than standard TAC-MPA-S regimen and a pre-transplant malignancy history worsens these risks in patients on SRL-TAC-S. Confirmation of our findings by a prospective randomized trial is needed before translation into clinical practice can be recommended.

Postbiopsy arteriovenous fistula in renal allograft: An ultrasound case study.

Arteriovenous fistula is a well-known but rarely diagnosed complication of percutaneous renal biopsy. On Doppler sonography, these fistulae are characterized by a region of high velocity shifts and random color assignment due to vibrating interfaces in the perivascular tissue. Most of them resolve spontaneously, while larger symptomatic ones need intervention.

A User's Guide to Metaphors In Ecology and Evolution.

Biologists energetically debate terminology in ecology and evolution, but rarely discuss general strategies for resolving these debates. We suggest focusing on metaphors, arguing that, rather than looking down on metaphors, biologists should embrace these terms as the powerful tools they are. Like any powerful tool, metaphors need to be used mindful of their limitations. We give guidance for recognizing metaphors and summarize their major limitations, which are hiding of important biological detail, ongoing vagueness rather than increasing precision, and seeming real rather than figurative. By keeping these limitations in mind, metaphors like adaptive radiation, adaptive landscape, biological invasion, and the ecological niche can be used to their full potential, powering scientific insight without driving research off the rails.

Not all inflammation in a renal allograft is rejection.

High index of suspicion for adenovirus infection is required in renal graft dysfunction, especially in the setting of hematuria. Histology can mimic acute rejection, which creates a diagnostic dilemma. Tissue adenovirus immunostains, though usually reliable, may not be always positive like in our case.

Fever in a transplant recipient: think beyond infection.

Immune reconstitution inflammatory syndrome (IRIS) is an exaggerated inflammatory cascade initiated in response to immune recovery during the resolution of an infection. Reduction in calcineurin inhibitor levels in organ transplant recipients due to enhanced metabolism from interaction with rifampin can predispose these individuals to develop IRIS during the treatment of tuberculosis and mimic sepsis.

The skin-kidney connection: bullous pemphigoid associated with acute allograft rejection and membranous nephropathy.

Bullous pemphigoid has been linked to allograft rejection, as well as membranous nephropathy in renal transplant recipients. Although there is a possibility of multiple distinct autoimmune processes, immune stimulation induced by allograft rejection or antibasement zone antibody interactions are possible mechanisms for the simultaneous skin and renal involvement.