Immunosuppressive Medications Wiseman, Alexander C
Clinical journal of the American Society of Nephrology,
02/2016, Letnik:
11, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Immunosuppressive agents are commonly used in the nephrologist's practice in the treatment of autoimmune and immune-mediated diseases and transplantation, and they are investigational in the ...treatment of AKI and ESRD. Drug development has been rapid over the past decades as mechanisms of the immune response have been better defined both by serendipity (the discovery of agents with immunosuppressive activity that led to greater understanding of the immune response) and through mechanistic study (the study of immune deficiencies and autoimmune diseases and the critical pathways or mutations that contribute to disease). Toxicities of early immunosuppressive agents, such as corticosteroids, azathioprine, and cyclophosphamide, stimulated intense investigation for agents with more specificity and less harmful effects. Because the mechanisms of the immune response were better delineated over the past 30 years, this specialty is now bestowed with a multitude of therapeutic options that have reduced rejection rates and improved graft survival in kidney transplantation, provided alternatives to cytotoxic therapy in immune-mediated diseases, and opened new opportunities for intervention in diseases both common (AKI) and rare (atypical hemolytic syndrome). Rather than summarizing clinical indications and clinical trials for all currently available immunosuppressive medications, the purpose of this review is to place these agents into mechanistic context together with a brief discussion of unique features of development and use that are of interest to the nephrologist.
The management of a kidney transplant program has evolved significantly in the last decades to become a highly specialized, multidisciplinary standard of care for end‐stage kidney disease. Transplant ...center job descriptions have similarly morphed with increasing responsibilities to address a more complex patient mix, increasing medical and surgical therapeutic options, and increasing regulatory burden in the face of an ever‐increasing organ shortage. Within this evolution, the role of the Kidney Transplant Medical Director (KTMD) has expanded beyond the basic requirements described in the United Network for Organ Sharing bylaws. Without a clear job description, transplant nephrology trainees may be inadequately trained and practicing transplant nephrologists may face opaque expectations for the roles and responsibilities of Medical Director. To address this gap and clarify the key areas in which the KTMD interfaces with the kidney transplant program, American Society of Transplantation (AST) formed a Task Force of 14 AST KTMDs to review and define the role of the KTMD in key aspects of administrative, regulatory, budgetary, and educational oversight of a kidney transplant program.
This report from the American Society of Transplantation Task Force describes the multifaceted position of kidney transplant medical director, which has evolved over the past decades with an increasing mandate for subspecialization, more complex medical management, and recognition of financial value to transplant programs.
Given appropriate management, soils may serve as a sink for carbon, and thereby play a potentially important role in helping countries meet CO
2 emission reductions as agreed to under the Kyoto ...Protocol. To fully judge the capacity of soils to store carbon, however, gaps regarding the mechanisms of organic carbon (OC) stabilization need to be filled. A number of studies have demonstrated the significance of oxides in the preservation of soil OC. Although oxides are known to strongly bind with clay minerals, potential interactions between these minerals in OC preservation in soils are often overlooked. The goal of this study was to, thus, examine possible interactions between clay minerals and oxides in the storage of soil OC. For this, we analysed how the OC, clay content, clay mineralogy and dithionite-extractable Fe (Fed) and oxalate-extractable Fe (Feo) and Al (Alo) concentrations of several sampled soils are statistically related. Samples from two Umbrisols, a Stagnic Acrisol, an Anthrosol/Vertisol/Gleysol-Chernozem and a Gleysol (FAO terminology) from profiles located in Hesse, Germany were analysed. Clay content exhibited a strong significant relationship with the OC concentrations of only two soils. Feo and Alo were found to be strongly related to the OC concentrations of most profiles. Some clay minerals such as chlorite displayed very strong relationships with OC and Feo and Alo concentrations. The results suggest that oxides interact with clay minerals in at least two of the soils examined, forming complexes or aggregates which may play an important role in stabilizing organic material. Future studies should also consider potential mineral interactions in the sequestration of OC in soils.
Measurements of total blood Hg (tHg), often used as a proxy for methyl Hg (MeHg) concentrations, are most commonly the focus of population-based studies. Data on Hg species in biomarkers can allow ...for a more nuanced characterization of environmental exposure sources and risk but their availability is limited, especially for newcomer populations. The purpose of the Metals in Newcomer Women (MNW) study was to address existing data gaps on metal concentrations and exposure sources in newcomer women (19–45 years) and to examine tHg, MeHg and inorganic Hg (iHg) in the blood of East and South Asian women recently arrived to Toronto. Study participants were recruited in 2015 (n = 211). Total Hg concentrations were determined using both ICP-Q-MS and isotope dilution (ID)-SPME-GC-ICP-MS. A sample subset (n = 76) was chosen for the analysis of blood MeHg and iHg concentrations (also using ID-SPME-GC-ICP-MS). Hierarchical regression models were used to assess associations between blood tHg concentrations and environmental exposure factors for MNW participants. For the sample subset, a log-linear model was used to examine associations between blood iHg and MeHg concentrations and fish consumption patterns. The geometric mean (GM) blood tHg concentration was 1.05 µg/L (95% CI: 0.88–1.25), which was elevated compared to Canadian-born women (GM: 0.57 µg/L; 95% CI: 0.49–0.66), in a specialized data analysis of the Canadian Health Measures Survey (CHMS). GM concentrations for iHg and MeHg were 0.21 µg/L (95% CI: 0.16–0.28) and 2.66 µg/L (95% CI: 2.00–3.55), respectively. Significant distal determinants associated with blood tHg concentrations were: level of educational attainment, having lived in a coastal/fishing community prior to arrival, and global region of origin. Use of iron supplements and consumption of higher mercury fish species were also associated with tHg concentrations in the fully adjusted model. The study results demonstrate that blood Hg concentrations in newcomer women are slightly elevated, with some individuals in exceedance of recommended concentrations for women of reproductive age. The consumption of fish species low in Hg is recommended for newcomer women, especially those who consume fish frequently.
Display omitted
•Blood Hg species were measured in newcomer women to Toronto.•Total Hg concentrations were elevated in newcomers relative to native-born women.•Level of education and place of origin predictors of total Hg.•Iron supplement intake associated with lower total Hg concentrations.•Total Hg and MeHg concentrations associated with medium/high Hg fish consumption.
•New composite shear connectors are proposed for timber-concrete composite beams.•Structural behaviour of FRP bar/plate is compared with steel plate/screw system.•Composite behaviour in TCC beams is ...investigated using a DIC-based technique.•Steel plate and FRP bar illustrated highest bending stiffness and composite action.•CFRP rebar and steel screw TCC beams demonstrated highest ultimate load.
This research proposes new types of shear connectors made of carbon fibre reinforced polymer (CFRP) composites for effective stress transfer between the timber and concrete sections in cross laminated timber (CLT)-concrete composite beams. New shear connectors are designed and made of bidirectional carbon fibre reinforced polymer (CFRP) composite plates and crossed CFRP reinforcing bars. The mechanical performance, bending stiffness, ductility, and interfacial slippage and strain of timber-concrete composite (TCC) beams with CFRP connectors are compared with those with steel plate and screw systems through four-point flexure testing. Local slip, interfacial slip and strain behaviour are comparatively analysed for connections with equivalent axial stiffness using a Digital Image Correlation (DIC) based technique, so that relative composite behaviour could be determined. Furthermore, a cost evaluation is undertaken to compare the feasibility of proposed shear connectors for construction of TCC systems. Results from flexural tests demonstrate that CFRP rod specimens experience higher ultimate load and bending stiffness in elastic loading stage and ductility in failure while slippage at serviceability and ultimate load is minimal. These results demonstrate that CFRP reinforcing bars can be used as an alternative to existing steel plate/screw systems. Although CFRP plate connectors show lower ultimate strength, bending stiffness and ductility, the performance of the system can be further improved by using sufficient anchorage systems at the end of CFRP plate within the concrete.
U.S. allocation policies currently place less emphasis on human leukocyte antigen (HLA) matching in pediatric kidney transplant candidates to minimize dialysis time. The impact this may have on ...pediatric recipients after graft failure has not been extensively examined.
Using the Scientific Registry of Transplant Recipients database, we examined HLA sensitization after graft loss and regraft survival of all pediatric primary kidney transplant recipients younger than 18 years transplanted between 1990 and 2008, stratified by HLA-DR mismatch (MM) of first and second kidney transplant.
Of 11,916 pediatric primary kidney transplant recipients, 2704 were relisted after first graft failure. 1847 received a retransplants, and 857 remained on the waiting list. Mean % panel reactive antibody increased from 6% to 45% for retransplant and from 8% to 76% for those on the waiting list. The degree of sensitization and waiting time to retransplantation increased with DR MM at first kidney transplantation. Two DR MM statuses at first transplant were associated with a 20% reduction in the hazard of receiving a retransplant (hazard ratio, 0.80 for 2 vs. 0-1 DR MM; P<0.001). Five-year retransplant graft survival was associated with the number of HLA MM at first and second kidney transplant. Retransplant graft survival was similar in the circumstance of a 0-1 DR MM living donor following a deceased donor, and the converse.
In pediatric recipients, increasing number of initial HLA-DR MMs is associated with HLA sensitization, longer waiting time, decreased rate of retransplant, and decreased regraft survival. Consideration of DR matching at first transplant may mitigate these risks.
During the last decade, the human polyomaviruses (BK virus and, much less commonly, JC virus) have entered the realm of routine clinical decision making for providers caring for kidney transplant ...recipients. The emergence of polyomavirus-associated nephropathy (PVAN) as an important clinical entity coincided with the development and use of more potent immunosuppression agents, currently the only clear risk factor for reactivation of the virus. Ongoing efforts to define the pathogenesis, clinical presentation, and appropriate management of PVAN have led to a greater ability to prevent and control viral-induced interstitial nephritis despite continued deficiencies in our understanding of risk factors for disease and lack of published prospective polyomavirus-specific antiviral trials. The purpose of this review is to summarize advances made during the last decade and highlight emerging data that address common clinical considerations the clinician currently faces in the understanding and management of PVAN.
Chronic Kidney Disease and Coronary Artery Disease Sarnak, Mark J.; Amann, Kerstin; Bangalore, Sripal ...
Journal of the American College of Cardiology,
10/2019, Letnik:
74, Številka:
14
Journal Article
Recenzirano
Odprti dostop
Chronic kidney disease (CKD) is a major risk factor for coronary artery disease (CAD). As well as their high prevalence of traditional CAD risk factors, such as diabetes and hypertension, persons ...with CKD are also exposed to other nontraditional, uremia-related cardiovascular disease risk factors, including inflammation, oxidative stress, and abnormal calcium-phosphorus metabolism. CKD and end-stage kidney disease not only increase the risk of CAD, but they also modify its clinical presentation and cardinal symptoms. Management of CAD is complicated in CKD patients, due to their likelihood of comorbid conditions and potential for side effects during interventions. This summary of the Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference on CAD and CKD (including end-stage kidney disease and transplant recipients) seeks to improve understanding of the epidemiology, pathophysiology, diagnosis, and treatment of CAD in CKD and to identify knowledge gaps, areas of controversy, and priorities for research.
Display omitted
•CKD is associated with very high risk of CAD. CAD management is complicated in CKD patients, due to comorbid conditions and potential side effects during interventions.•There are few trials related to CAD with focus on CKD patients, particularly in those with advanced CKD.•Additional prospective studies focusing on diagnosis, prevention, and treatment of CAD are needed in CKD.
Current organ allocation policy prioritizes placement of kidneys (with pancreas) to patients listed for simultaneous pancreas-kidney transplantation (SPK). Patients with type 2 diabetes mellitus ...(T2DM) may undergo SPK, but it is unknown whether these patients enjoy a survival advantage with SPK versus deceased-donor kidney transplantation alone (DDKA) or living-donor kidney transplantation alone (LDKA).
Using the Scientific Registry of Transplant Recipients database, patients with T2DM, age 18-59 years, body mass index 18-30 kg/m(2), who underwent SPK, DDKA, or LDKA from 2000 through 2008 were identified. Five-year patient and kidney graft survival rates were compared, and multivariable analysis was performed to determine donor, recipient, and transplant factors influencing these outcomes.
Of 6416 patients identified, 4005, 1987, and 424 underwent DDKA, LDKA, and SPK, respectively. On unadjusted analysis, patient and kidney graft survival rates were superior for LDKA versus SPK, whereas patient but not graft survival was higher for SPK versus DDKA. On multivariable analysis, survival advantage for SPK versus DDKA was related not to pancreas transplantation but younger donor and recipient ages in the SPK cohort.
Good outcomes can occur with SPK in selected patients with T2DM, but no patient or graft survival advantage is provided by added pancreas transplantation compared with DDKA; outcomes were superior with LDKA. These results support cautious use of SPK in T2DM when LDKA is not an option, with close oversight of the effect of kidney (with pancreas) allocation priority over other transplant candidates.
Donor-specific antibodies (DSAs) after kidney transplantation have been associated with poor graft outcomes in multiple studies. However, these studies have generally used stored sera or a single ...cross sectional screening test to identify patients with DSA. We evaluated the effectiveness of a prospective DSA screening protocol in identifying kidney and kidney/pancreas recipients at risk for poor graft outcomes.
From September 2007 through September 2009, 244 consecutively transplanted kidney and kidney/pancreas recipients without pretransplant DSA were screened for de novo DSA at 1, 6, 12, and 24 months and when clinically indicated.
DSA was detected in 27% of all patients by protocol or indication screening. Patients with DSA (DSA+) were significantly more likely to have experienced acute rejection (AR) compared with no DSA (DSA-) (29% vs. 9.5%, P<0.001), and lower estimated 2-year graft survival (83% vs. 98%, P<0.001). Only 3 of 19 DSA (+) patients with AR had DSA detected before the AR episode. When excluding patients with AR, 2-year graft survival was similar between DSA (+) and DSA (-) patients (100% vs. 99%) as was estimated glomerular filtration rate. Patients with DSA detected by protocol screening had similar outcomes compared with DSA (-), whereas those with DSA detected by indication experienced significantly worse outcomes.
Patients with de novo DSA experience worse graft outcomes due to previous/concurrent episodes of AR. A prospective DSA screening protocol failed to identify patients at risk for AR or poor short-term graft outcomes.
PDF
