Troy J. Plumb

Effector mechanisms in transplant rejection

Summary:  Antigens, provided by the allograft, trigger the activation and proliferation of allospecific T cells. As a consequence of this response, effector elements are generated that mediate graft injury and are responsible for the clinical manifestations of allograft rejection. Donor‐specific CD8+ cytotoxic T lymphocytes play a major role in this process. Likewise, CD4+ T cells mediate delayed‐type hypersensitivity responses via the production of soluble mediators that function to further activate and guide immune cells to the site of injury. In addition, these mediators may directly alter graft function by modulating vascular tone and permeability or by promoting platelet aggregation. Allospecific CD4+ T cells also promote B‐cell maturation and differentiation into antibody‐secreting plasma cells via CD40–CD40 ligand interactions. Alloantibodies that are produced by these B cells exert most of their detrimental effects on the graft by activating the complement cascade. Alternatively, antibodies can bind Fc receptors on natural killer cells or macrophages and cause target cell lysis via antibody‐dependent cell‐mediated cytotoxicity. In this review, we discuss these major effector pathways, focusing on their role in the pathogenesis of allograft rejection.

Requirements for T Lymphocyte Migration in Explanted Lymph Nodes

Although the requirements for T lymphocyte homing to lymph nodes (LNs) are well studied, much less is known about the requirements for T lymphocyte locomotion within LNs. Imaging of murine T lymphocyte migration in explanted LNs using two-photon laser-scanning fluorescence microscopy provides an opportunity to systematically study these requirements. We have developed a closed system for imaging an intact LN with controlled temperature, oxygenation, and perfusion rate. Naive T lymphocyte locomotion in the deep paracortex of the LN required a perfusion rate of >13 μm/s and a partial pressure of O2 (pO2) of >7.4%. Naive T lymphocyte locomotion in the subcapsular region was 38% slower and had higher turning angles and arrest coefficients than naive T lymphocytes in the deep paracortex. T lymphocyte activation decreased the requirement for pO2, but also decreased the speed of locomotion in the deep paracortex. Although CCR7−/− naive T cells displayed a small reduction in locomotion, systemic treatment with pertussis toxin reduced naive T lymphocyte speed by 59%, indicating a contribution of Gαi-mediated signaling, but involvement of other G protein-coupled receptors besides CCR7. Receptor knockouts or pharmacological inhibition in the adenosine, PG/lipoxygenase, lysophosphatidylcholine, and sphingosine-1-phosphate pathways did not individually alter naive T cell migration. These data implicate pO2, tissue architecture, and G-protein coupled receptor signaling in regulation of naive T lymphocyte migration in explanted LNs.

Antibiotic dosing during sustained low-efficiency dialysis: special considerations in adult critically ill patients.

Objective:To address issues of antibiotic dosing during sustained low-efficiency dialysis by using available pharmacokinetic data, intermittent and continuous renal replacement therapy dialysis guidelines, and our experience with sustained low-efficiency dialysis. Data Resources:Published clinical trials, case reports, and reviews of antibiotic dosing in humans during sustained low-efficiency dialysis. Data Extraction:A search of electronic databases (MEDLINE, PubMed, and Ovid) was conducted by using key words of extended daily dialysis, sustained low-efficiency dialysis, antibiotics, antimicrobial agents, and pharmacokinetics. MEDLINE identified 32 sustained low-efficiency dialysis articles, and PubMed identified 33 articles. All papers describing antibiotic clearance prospectively in patients were considered for this article. Data Synthesis:We identified nine original research articles and case reports that determined the impact of sustained low-efficiency dialysis on antibiotic clearance in patients. The blood and dialysate flow rates, duration of dialysis, type of filter, and the pharmacokinetic parameters were extracted from each article. If multiple articles on the same drug were published, they were compared for consistency with the aforementioned dialysis parameters and then compared with forms of continuous renal replacement therapy. Antibiotic clearance by sustained low-efficiency dialysis was determined to be similar or higher than continuous renal replacement therapy therapies. The estimated creatinine clearance during sustained low-efficiency dialysis was approximately 60 mL/min to 100 mL/min depending on the blood and dialysate flow rates and the type of filter used. Conclusions:The potential for significant drug removal during an 8-hr-or-longer sustained low-efficiency dialysis session is evident by the limited number of studies available. Because significant amounts of drug may be removed by sustained low-efficiency dialysis combined with altered pharmacokinetic variables in critically ill patients, the risk for suboptimal drug concentrations and pharmacodynamics must be considered. Appropriate dose and calculation of dosing intervals is essential to provide adequate antibiotic therapy in these patients. It is recommended that institutions who utilize sustained low-efficiency dialysis establish dosing guidelines for all pharmacists and physicians to follow to provide consistent delivery of antibiotics at adequate concentrations.

Risk factors for BK polyomavirus nephritis in renal allograft recipients.

Abstract:  Recurrent episodes of acute rejection (AR) and/or the intense immunosuppression used for their treatment have been proposed as risk factors for BK nephritis (BKN; BK refers to the initials of the first patient from whom this polyomavirus was isolated). To further examine the relationship between AR and BKN, we analyzed all kidney transplants performed at our center between January 1999 and August 2001 (n = 286). After a mean follow‐up of 737 ± 22 d, we identified nine cases of BKN (3.1%). The mean time to diagnosis of BKN was 326 ± 56 d. No patient with BKN had a prior history of AR. During the same period, 62 patients were diagnosed with AR (22%). The mean time to diagnosis of AR was 197 ± 40 d (p = 0.01 vs. time to diagnosis of BKN). Despite aggressive therapy with methylprednisolone and, in some cases, anti‐lymphocyte antibody, none of these patients with AR developed BKN. We compared the baseline characteristics of patients in both groups and found that BKN patients were more likely to be white people (78 vs. 44%, p = 0.05) and male (89 vs. 53%, p = 0.04). Moreover, the mean tacrolimus (TAC) levels before diagnosis were higher in BKN than in AR patients (11.7 ± 0.5 vs. 6.5 ± 0.6 ng/mL, p < 0.001). In summary, our study shows that BKN often occurs in the absence of prior episodes of AR. In addition, our findings suggest that white males exposed to higher TAC levels are at greater risk of developing BKN.

Eicosanoids: lipid mediators of inflammation in transplantation

Abstract.Eicosanoids are a family of lipid mediators derived from the metabolism of arachidonic acid. Eicosanoids, such as prostanoids and leukotrienes, have a wide range of biological actions including potent effects on inflammation and immunity. It has been almost 20 years since the first reports emerged suggesting a role for eicosanoids in transplantation. Since then, a number of functions have been ascribed to these mediators, ranging from immunomodulation to regulation of allograft hemodynamics. In this review, we will highlight the effects of eicosanoids in transplantation, focusing particularly on evidence provided by gene targeting studies. In the future, pharmacological manipulation of eicosanoids and their receptors may provide a novel approach for controlling inflammation and promoting allograft acceptance.

Development, Implementation, and Results of the ASN In-Training Examination for Fellows

The American Society of Nephrology and the fellowship training program directors in conjunction with the National Board of Medical Examiners developed a comprehensive assessment of medical knowledge for nephrology fellows in-training. This in-training examination (ITE) consisted of 150 multiple-choice items covering 11 broad content areas in a blueprint similar to the American Board of Internal Medicine certifying examination for nephrology. Questions consisted of case vignettes to simulate real-life clinical experience. The first examination was given in April 2009 to 682 fellows and six training program directors. Examinees felt that the examination was well structured and relevant to their training experience Longitudinal performance on the examination will be helpful in allowing training programs to utilize results from content areas in identifying deficits in medical knowledge as well as assessing the results of any curriculum changes.

Cetuximab in hemodialysis: A case report

Concurrent chemoradiotherapy with cisplatin is the standard therapy for patients with unresectable locally advanced head and neck squamous cell carcinoma. However, cisplatin administration in patients on hemodialysis is complicated by the need to perform hemodialysis immediately after the infusion. Concurrent chemoradiation with cetuximab has been approved in definitive treatment of locally advanced head and neck cancer. Although cetuximab is not excreted via the kidneys, its use in patients on hemodialysis has not been reported.

Endovascular treatment of arteriovenous graft pseudoaneurysms, indications, complications, and outcomes: A systematic review

There are limited data regarding endovascular treatment of arteriovenous graft (AVG) pseudoaneurysms using stent grafts. We performed a comprehensive literature review on the use of stent grafts in the treatment of AVG pseudoaneurysms. We included 10 studies (121 patients). The mean AVG age was 3.1 years (95% confidence interval [CI]: 2.2–4) and pseudoaneurysm mean diameter was 34 mm (95% CI: 23–46). The majority (71%) of the pseudoaneurysms were located on the arterial limb of the AVG and 77% presented with venous anastomosis stenosis requiring angioplasty. The mean number of stents used to treat one lesion was 1.4 (95% CI: 1.3–1.5). The technical success rate of pseudoaneurysm isolation was 100% in all studies and 100% of patients received hemodialysis using the AVG after pseudoaneurysm treatment without the need for catheter placement. The primary patency rates for 1, 3, and 6 months were 81%, 73%, and 24%. Secondary patency was 80%, 77%, and 74% at 1, 3, and 6 months. Arteriovenous graft thrombosis occurred in 12% of patients. Arteriovenous graft infection developed in 35% of cases. Arteriovenous graft pseudoaneurysm treatment using stent grafts is effective in managing even large pseudoaneurysms and has acceptable primary and secondary patency rates. Graft infection was a relatively frequent complication.

Type B Lactic Acidosis Associated With Multiple Myeloma

We present a 58-year-old man with recurrent multiple myeloma treated with 2 autologous stem cell transplantations. He was admitted for dyspnea and found to have severe type B lactic acidosis with serum lactate level of 193.6 mg/dL. This case reviews malignancy-associated type B lactic acidosis and discusses its etiology, pathogenesis, and management.

Role of thromboxane A2 in the induction of apoptosis of immature thymocytes by lipopolysaccharide.

ABSTRACT Lipopolysaccharide (LPS) causes apoptotic deletion of CD4+ CD8+ thymocytes, a phenomenon that has been linked to immune dysfunction and poor survival during sepsis. Given the abundance of thromboxane-prostanoid (TP) receptors in CD4+ CD8+ thymocytes and in vitro evidence that thromboxane A2 (TXA2) causes apoptosis of these cells, we tested whether enhanced generation of TXA2 plays a role in LPS-induced thymocyte apoptosis. Mice injected with 50 μg of LPS intraperitoneally displayed a marked increase in generation of TXA2 and prostaglandin E2 in the thymus as well as apoptotic deletion of CD4+ CD8+ thymocytes. Administration of indomethacin or rofecoxib inhibited prostanoid synthesis but did not affect thymocyte death. In contrast, thymocyte apoptosis in response to LPS was significantly attenuated in TP-deficient mice. These studies indicate that TXA2 mediates a portion of apoptotic thymocyte death caused by LPS. The absence of an effect of global inhibition of prostanoid synthesis suggests a complex role for prostanoids in this model.