Individual Recipients Research Articles

Single Kidney Transplantation from Young Pediatric Donors in the United States

To the Editor: We thank Tittelbach-Helmrich et al. for sharing their thoughts about our paper entitled ‘Single Kidney Transplantation from Young Pediatric Donors in the United States’ and appreciate the opportunity to respond. In short, our analysis found that single kidney transplant (KTX) graft survival from donors weighing >35 kg was similar to KTX with ideal standard criteria donors (SCDs); and, single grafts from donors 10–34 kg conferred graft loss risks similar to transplantation with nonideal SCDs. Tittelbach-Helmrich et al. object to the exclusion of the top and bottom weight percentiles in our analysis since these exclusions may skew the results. Importantly, we excluded cases from the top and bottom one percentile in order to avoid inclusion of pediatric donor weights that were considered unlikely or inaccurately coded rather than explicitly removing ‘rare cases’. Tittelbach-Helmrich et al. state ‘as shown by Kayler et al. early splitting in donors between 10 and 20 kg leads to results comparable with those from marginal adult donors. In contrast to Kaylers’ statement, we do not regard en bloc transplanted kidneys from young donors up to 20 kg as equal to organs from marginal donors…’. In response, we did not use the word ‘marginal’ anywhere in the manuscript. We did report that for single KTXs from 10 to 19 kg donors the adjusted hazard ratio was similar to the outcomes achieved with nonideal SCDs. This distinction is important, as nonideal SCDs are associated with significantly better survival than expanded criteria donors as described in the original methods. Another comment is that we failed to consider the importance of adequate recipient selection criteria. Our focus was to elucidate KTX outcomes from pediatric donors specifically by weight and number of kidneys transplanted. Therefore we adjusted for other potentially confounding variables relating to both the recipient and donor. We agree that questions remain about donor–recipient matching to achieve optimal outcomes. The results in our manuscript reflect outcomes based on current practice. Tittelbach-Helmrich et al. comment that dividing en-bloc kidneys does not always yield two transplantable organs due to an increased rate of discarded grafts. We found that among KTXs from donors 10–35 kg, both kidneys were transplanted in 86% of cases in which at least one was transplanted. Clearly, the second pediatric kidney is being transplanted a high proportion of the time. Finally, Tittelbach-Helmrich et al. advocate setting the cut-off for organ splitting at a donor weight of 20 kg (instead of the 10 kg concluded in our analysis). We found that whereas en bloc KTX from donors 10 to 35 kg do offer increased graft years, the protective benefit was substantially less than ‘half’ as compared to single kidneys in the same weight range. We therefore concluded that kidneys from pediatric donors 10–35 kg used as singles offer more cumulative graft years to the candidate population. Essentially, any increases in the cut-off for single kidney transplantation to a maximum of 35 kg would result in longer graft function for an individual recipient, but fewer cumulative graft years to candidates, as fewer transplants would be performed. The authors of this manuscript have no conflict(s) of interest as defined by the American Journal of Transplantation.

Evaluation of the CHOP cardiovascular score as a prognostic predictor of outcome in twin–twin transfusion syndrome after laser coagulation of placental vessels in a prospective cohort

To investigate the prognostic value of cardiac function assessment by the previously reported CHOP (Children's Hospital of Philadelphia) cardiovascular score in twin-twin transfusion syndrome (TTTS). All consecutive monochorionic pregnancies presenting with TTTS over a 24-month period were evaluated by preoperative echocardiography before percutaneous laser coagulation of chorionic vessels. Each of the 12 items of the CHOP score was evaluated prospectively and the cardiovascular score was categorized into stages using previously published cut-offs. The outcome considered for this study was neonatal survival of neither, one or both twins. In total, 215 pregnancies were enrolled. Due to technical issues, CHOP evaluation was incomplete in 16% of cases and follow-up was unavailable in 12%. Overall, there was a significant relationship between the CHOP score and the Quintero staging system, although this relationship was significantly reduced when parameters used in the Quintero system were removed from the CHOP score. Based upon neonatal survival, the CHOP score did not show any prognostic value regarding overall pregnancy outcome or individual recipient survival. Cardiac function assessment using the CHOP score is not of clinical use as a prognostic marker in TTTS. This suggests that cardiac function may not be of interest for preoperative staging when laser coagulation is the first-line treatment, other than to confirm the diagnosis of TTTS requiring surgery.

ChemInform Abstract: Pharmacology of Immunosuppressive Drugs

Immunosuppressive therapy of solid organ transplantation has become more potent, effective and selective since the results of earlier use of prednisone and azathioprine post renal transplantation. Calcineurin inhibitors and mycophenolate mofetil have been important additions to the effective antirejection armamentarium. Today, cyclosporin, tacrolimus, azathioprine, mycophenolate and prednisone are all effective immunosuppressive agents and are the cornerstone of immunosuppressive protocols used posttransplant. However, the use of these agents is hindered by a 20% rate of rejection, lack of selectivity and a high rate of major adverse drug reactions which ultimately lead to a decrease in patient and graft survival. A number of clinical trials are underway to compare efficacy, safety and tolerability of different combination protocols to improve patient and allograft survival and decrease adverse drug reactions. Clinical knowledge of the pharmacology, pharmacokinetics, pharmacodynamics, adverse drug reactions and therapeutic drug monitoring of antirejection agents is essential for designing an effective immunosuppressive protocol for individual solid organ transplant recipients. The clinical application of pharmacotherapeutic principles into the clinical practice will improve both long-term patient and allograft survival while minimizing systemic toxicity of immunosuppressive drugs.

Computer-control of surface science experiments with LabVIEW

LabVIEW TM 2009-based remote and process control program for an ultra-high vacuum system and a variety of surface science experiments is presented. The apparatus consists of five individual recipients for sample preparation, surface analysis, scanning tunneling microscopy and a central chamber connecting them by means of gate-valves. All processes like electron-beam heating, ion sputtering, gas exposure, thermal and electron-beam evaporation, analysis techniques, sample manipulation can run under full automatic control; transfers are supported. A variety of useful auxiliary functions are implemented to control bake-out processes, titanium sublimation pumps, pressure regulation of leak valves but also data acquiring, automatic reporting through ftp and emails, as well as external communication and control via a TCP/IP connection with a portable PC. Important features of the software include a time- control module to operate up to five channels (repetitive heating, sputtering, gas exposure, evaporation and manipulation to evaporation positions) as well as full process control. Such tools allows us to set up automatically processed experiments that include e.g. the preparation of single-crystal surfaces, their AES (Auger electron spectroscopy) and LEED (low energy electron diffraction) analysis as well as the evaporation and various treatments of thin films.

The Efficacy of Clinical Assessment in the Postoperative Monitoring of Free Flaps: A Review of 1140 Consecutive Cases

Effective postoperative monitoring of the vascular pedicle to a free flap can potentiate rapid return to the operating room in the setting of compromise, allowing for the potential to salvage the flap. The only ubiquitous method for postoperative monitoring of free flaps is clinical bedside monitoring, but although the use of clinical monitoring may be inferred in large reported series of free flaps, there has been little discussed in the literature of specific clinical outcome measures. The authors present their experience with 1140 consecutive cases of free tissue transfer and the use of clinical monitoring as a sole method of monitoring, and subgroup analysis of different recipient sites. There were 94 take-backs, four of which had no pedicle compromise (false-positives) and there were four false-negatives. The overall flap salvage rate was 62.8 percent and the false-positive rate was 0.4 percent. Subgroup analyses demonstrated statistically significant differences between recipient sites for the false-positive rates: fewer false-positives with breast reconstruction cases (p < 0.05) and significantly more false-positives in the extremity group (p < 0.05). There was an improved flap salvage rate in cases of venous compromise compared with arterial compromise (69 percent versus 51 percent, p = 0.015). This largest reported series to date provides an outcome-based analysis of postoperative monitoring for free flaps, providing a benchmark standard against which adjunctive monitoring techniques can be compared. Future studies need to be assessed in the context of individual recipient sites, with significant differences in monitoring outcomes between sites.

Lung transplantation using donors 55 years and older: is it safe or just a way out of organ shortage?☆

Lung organ scarcity has led to more generous acceptance of organs under the idea of extended-donor criteria. However, long-term effects have to be monitored to redefine present practice. In this study, we investigated the impact of donor age over 55 years in lung transplantation. In this retrospective study, 186 consecutive double-lung transplantation procedures from January 2000 to December 2008 were evaluated. A total of 19 recipients received lungs from donors aged 55 years or older (range 55-69 years) (group A) and 167 received lungs from younger donors (range 8-54) (group B). In-hospital mortality, intensive care unit (ICU) stay, rejection episodes, lung function and survival up to 5 years were evaluated. In-hospital mortality was similar in both groups (group A: 10.5%; group B: 13.7%). Postoperative ICU stay was 19+/-33 days versus 17+/-34 days (A vs B). Rejection episodes as well as postoperative lung function up to 5 years, and overall cumulative 5-year survival (group A: 52.4%; group B: 50.9%) did not reach statistical significance. However, a trend of increased bronchiolitis obliterans syndrome (BOS) prevalence and reduced lung function was noted. Cause of death showed no differences in both groups. Donor age > or =55 years does not compromise immediate and long-term results after lung transplantation, although long-term observation of patients receiving such an organ suggests earlier lung dysfunction. Due to the rising need of organs, lungs from donors aged 55 or older have to be considered for transplantation. However, the acceptance should be based on donor lung evaluation and individual recipient needs. Long-term outcomes over 5 years need to be further investigated.

Die Transplantation marginaler Lebern: Ein Ausweg aus dem Organmangeldilemma?

The transplantation of marginal organs or those meeting the so-called extended donor criteria (EDC) is today a significant option to alleviate the low availability or organs and to increase the number of transplantation which in turn is -accompanied by a lower mortality among wait-ing-list patients. However such an extension of the spender pool carries the risks of an increased incidence of organ dysfuntions and a higher recipient mortality. This situation presents an ethical problem when marginal organs are accepted for transplantation because the anticipated mortality for the individual recipient cannot be determined. The transplantation of marginal organs from -donors with a high MELD score seems to be linked to a higher mortality. In particular, the combina-tions of high donor age and long ischaemic time or advanced donor age and hepatitis C infection in the recipient are definitively associated with a significantly poorer organ survival rate. In view of the serious lack of organs, efforts should be made, for example, by shortening of the is-chae-mic time and the development of therapeutic strategies, to improve the function and increase the number of usable marginal organs and thus to increase pool of donor organs. The refusal of marginal organs on the basis of individual EDC without consideration of the status of recipient does not seem to be adequate.

Adult progenitor cell transplantation influences contractile performance and calcium handling of recipient cardiomyocytes

Adult progenitor cell transplantation has been proposed for the treatment of heart failure, but the mechanisms effecting functional improvements remain unknown. The aim of this study was to test the hypothesis that, in failing hearts treated with cell transplantation, the mechanical properties and excitation-contraction coupling of recipient cardiomyocytes are altered. Adult rats underwent coronary artery ligation, leading to myocardial infarction and chronic heart failure. After 3 wk, they received intramyocardial injections of either 10(7) green fluorescence protein (GFP)-positive bone marrow mononuclear cells or 5 x 10(6) GFP-positive skeletal myoblasts. Four weeks after injection, both cell types increased ejection fraction and reduced cardiomyocyte size. The contractility of isolated GFP-negative cardiomyocytes was monitored by sarcomere shortening assessment, Ca(2+) handling by indo-1 and fluo-4 fluorescence, and electrophysiology by patch-clamping techniques. Injection of either bone marrow cells or skeletal myoblasts normalized the impaired contractile performance and the prolonged time to peak of the Ca(2+) transient observed in failing cardiomyocytes. The smaller and slower L-type Ca(2+) current observed in heart failure normalized after skeletal myoblast, but not bone marrow cell, transplantation. Measurement of Ca(2+) sparks suggested a normalization of sarcoplasmic reticulum Ca(2+) leak after skeletal myoblast transplantation. The increased Ca(2+) wave frequency observed in failing myocytes was reduced by either bone marrow cells or skeletal myoblasts. In conclusion, the morphology, contractile performance, and excitation-contraction coupling of individual recipient cardiomyocytes are altered in failing hearts treated with adult progenitor cell transplantation.

What Price Accommodation? An Exploration of One Woman's Struggle to Sustain Privilege While Receiving an Old Age Pension

According to recent literature on privilege and oppression, system-wide structures of class, race, and gender inequality are sustained at both the macro- and microlevel of society simultaneously. As an analysis of the microlevel process of how privilege might be sustained, using one case study from archives of the Luella Hannan Memorial Foundation, this article documents how the process of receiving aid might seemingly take privilege away from older, formally privileged women, and how individual aid recipients might resist this lack of power or privilege. Overall, this case highlights the dynamic nature of an individual's privilege, the process by which privilege is pursued and sustained at the microlevel, and the different types of privilege (e.g., economic or social, institutionally sanctioned or personal, macro or micro) that an individual might pursue in varying circumstances.

Stratifying Risk and Targeting Immunosuppressive Strategies

Despite short-term improvements, long-term outcomes in renal transplantation have not improved. Late graft loss arises as a result of immunologic and nonimmunologic insults that lead to chronic allograft nephropathy. One of the major nonimmunologic factors is the toxicity associated with current immunosuppressive regimens. In addition to these key factors, the current rate of death in renal transplant recipients with a functioning graft arises as a result of both cardiovascular risk and malignancy, as well as the growing challenge from infections. Renal transplant recipients are not a homogenous population, and donor factors add a further variable. Each individual recipient–donor combination will have its own unique set of risks of both graft loss and patient death. The choice of immunosuppressive regimens for an individual recipient needs to consider his or her risk profile, for early rejection and for late cardiovascular disease and malignancy. This meeting has considered all of these factors, together with strategies to reduce risk and offer potential for improved long-term outcomes. This situation requires change in current practice and flexibility in our approach to the wide range of patients we manage on a daily basis.

International Financial Institutions and Post-communist Labour Reform: A Case of Utopian Liberalism?

Since 1999 the international financial institutions (IFI) such as the World Bank and IMF have reformed their approach to loan and grant conditionality. As part of the reforms recipient states are encouraged to consult widely with civil society organisations on the internal policy programmes promoted by the IFIs. Individual recipient countries are then assumed to take ownership of policy change without recourse to IFI sanctions. However, many of the policy changes encouraged by the IFIs remain locked in the neo-liberal prescriptive framework of labour market de-regulation, privatisation and public sector reform. As such the collective interests of labour remain threatened. The post Communist states of CEE and former Yugoslavia have been active in recent years in seeking funds from the IFIs. At the same time the legacy of strong labour codes is directly challenged by neo-liberal policy, thus creating a potential arena of contention. This paper examines the reality of the new IFI approach as it relates to la...

Aggressive Donor Care—To What End?

D rs DeBose and Salim provide a useful overview of some current accomplishments in organ procurement and offer an algorithm for treatment of hypotension and other clinical problems often encountered during donor care. Although it seems intuitive that proper critical care of the donor would yield the best possible organs for awaiting recipient(s), this part of the transplantation continuum has not received the scientific inquiry it deserves. There is very little evidence-based data to define ‘‘proper care’’ or to guide treatment to the desired goal of delivering optimal organs. Donor organs are often damaged during the evolution of brain death due to the catastrophic physiological mechanisms described in their article. Extensive experimental animal and human observational data confirm important changes in cardiovascular function, fluid and electrolyte balance, endocrine homeostasis, and proinflammatory mediator production, as they have referenced. The resultant organ dysfunction, although at times irreparable, can be reversed by skillful resuscitation, as demonstrated by a series of publications from Papworth Hospital in Cambridge during the 1990s. It is important, however, to consider not only the methods of intervention, as proposed in the protocol offered by DuBose and Salim, but also the treatment end points and the personnel to whom it is entrusted. Many authoritative groups have recommended guidelines for donor care that generally seek only to reestablish or maintain normal physiologic or laboratory values. The purpose of donor care, however, is to support whatever selection and allocation criteria will ultimately best serve the recipient. As such, organ acceptance and distribution are based upon a combination of donor and recipient characteristics. Some donor parameters are fixed, such as age, gender, medical/surgical/social history, cause of death, body size, and so on and cannot be altered during donor treatment. Others, however, such as cardiac contractility, vascular resistance, oxygenation, serum electrolyte concentrations, interstitial edema, and so on are amenable to therapy. Correcting the abnormalities is these latter criteria, as discussed by DeBose and Salim, may allow organs previously rejected to be transplanted and function normally. Criteria for organ acceptance, however, are often affected by the subjectivity of the transplant team and/or availability of donors at the time of a recipient’s urgent need. Acceptance criteria may then be ‘‘extended’’ so as to expand the general availability of organs or to rescue individual recipients. The extent to which individual criteria can be expanded while still yielding acceptable organs remains a major question in the procurement process. Similarly, how such ranges of physiological and fixed variables interrelate is unknown. For example, might a young male donor after trauma tolerate a lower mean arterial pressure, higher serum sodium, or greater anemia during donor care than an older woman who died because of an intracerebral hemorrhage, yet still yield organs of acceptable quality? An approach to such questions has been introduced by the Donor Risk Index which interrelates fixed variables, but how fixed variables relate to those that can be treated, how ‘‘treatable’’ variables interrelate and how donor and recipient variables can be matched remain unknown. Development of a risk-weighted assessment of individual and combined variables could be developed through a properly designed and powered research inquiry and remains an important challenge for the procurement community. From the Departments of Neurosurgery and Internal Medicine, The University of Texas Health Science Center at Houston Medical School, Houston, Texas.

Maintenance immunosuppressive therapy in adult renal transplantation: A single center analysis

In the present study we have analyzed the maintenance immunosuppression of renal transplant patients followed at the Medical University of Vienna. Since more than thousand renal transplant patients are registered and treated at this center, our data reveal the pattern as well as the current and past practices of the prescription of immunosuppressive drugs in a large outpatient setting. The majority of patients displayed a transplant vintage of more than 5 years and used calcineurin inhibitors (CNIs), and/or steroids and/or antimetabolites reflecting the general prescription profile of immunosuppressive drugs in renal transplant recipients. However, the selection of immunosuppressive combinations as well as the dynamics of the immunosuppressive regimen in the life of the stable allograft recipient – minimization, conversion and/or withdrawal of one or more of each of the drugs – are not founded on strong data derived from adequately powered clinical trials but rather follows a mixture of various smaller and medium-sized clinical studies and the individual center attitude based on mostly center-specific uncontrolled clinical observations. Hence, the maintenance immunosuppression of transplant patients is the result of a strong empirical attitude and only adequately powered prospective trials may inform us which immunosuppressive regimen and overall strategy will be ideal for the individual renal transplant recipient.

What Determines Bilateral Aid Allocations? Evidence From Time Series Data

AbstractThis paper models the allocation of bilateral foreign development aid to developing countries. A simple theoretical framework is developed, in which aid is treated as a private good of a donor country bureaucratic group responsible for bilateral aid allocation. This model is applied to time series data for ten principal recipients of bilateral official development assistance. Features of this application are that it caters for the joint determination of aid allocations and for donor allocation behavior to differ among individual recipient countries. Results indicate that both recipient need and donor interest variables determine the amount of foreign aid to developing countries, and that donor allocation behavior often differs markedly among recipients.

Outcomes of lung transplantation for cystic fibrosis in a large UK cohort

Background:Lung transplantation is an important option to treat patients with advanced cystic fibrosis (CF) lung disease. The outcomes of a large UK cohort of CF lung transplantation recipients is reported.Methods:Retrospective...

Management of cardiovascular disease in renal transplant recipients.

Cardiovascular disease is a major cause of graft loss and the leading cause of death in renal transplant recipients. Although there are robust data on the frequency of risk factors and their contributions to cardiovascular disease in this population, few trials have demonstrated the benefit of modifying these risk factors to reduce cardiovascular events. Nevertheless, it is widely accepted that the clinical acumen filtered through the best available studies in the general population be used to treat individual renal transplant recipients given their high cardiovascular mortality. Transplant task forces and the Kidney Disease Outcomes Quality Initiative have created guidelines for this purpose. This review examines the data available for prevention and treatment of major risk factors contributing to cardiovascular disease in renal transplant recipients. The contribution of immunosuppressive agents to each risk factor and the evidence to support lifestyle modification as well as drug therapy are examined. Reducing cardiovascular risk factors requires an integrative approach that is best accomplished by a team of health care professionals. It creates a significant challenge but one that must be met if allograft survival is to improve.

Quand faut-il inscrire un patient sur la liste d’attente de transplantation rénale ?

Practices for enrollment on kidney transplantation waiting lists are variable between geographical areas and centers. Early referral of patients with chronic renal failure (CRF) to a nephrologist, particularly one practicing in a transplantation center, is a prerequisite to early enrollment. Despite improved survival in elderly transplant recipients, being aged over 65 years is still a barrier against enrollment. Furthermore certain comorbid conditions such as diabetes mellitus are often wrongly considered as contraindications for transplantation. If nephrological management is initiated early, enrollment could (should?) be considered before the terminal phase of CRF, with the hope of preemptive transplantation with the known advantages not only for the individual recipient but also for the community in general. Glomerular filtration rate below 20 ml/minute could be a reasonable cutoff for enrollment. Patients referred late to a nephrologist will require dialysis. Dialysis center staff should be well trained in delivering appropriate information on kidney transplantation and initiating evaluation. A consultation with a transplantation specialist should be rapidly scheduled.

&lt;span xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:m="http://www.w3.org/1998/Math/MathML" style="font-style:italic;"&gt;Strange Harvest: Organ Transplants, Denatured Bodies, and the Transformed Self&lt;/span&gt; (review)

Reviewed by: Strange Harvest: Organ Transplants, Denatured Bodies, and the Transformed Self Edward R. Garrity Jr. By Lesley A. A. Sharp. Berkeley: Univ. of California Press, 2006. Pp. 322. $24.95 (paper). In Strange Harvest: Organ Transplants, Denatured Bodies, and the Transformed Self, Lesley Sharp engages her readers in an exploration of organ transplantation. Her leadership guides the reader on both a philosophical and a sociological journey into Organ Transfer, the term she prefers for her long-standing field studies. This is not light reading for the simple passage of time, but rather a challenging study of a field imbued with emotion, religion, spirituality, and personal acceptance of very difficult problems. How individuals deal with the issues addressed forms the structure of the discussion, from the vivid descriptions of the heartbreaking realization that a loved one has died, to the all-too-real problem that donor families may be directed how to grieve their losses and recipients celebrate their gains. Sharp deals with the topics in four chapters, with detail gathered from interviews with recipients, donor families and especially donor mothers, organ procurement organization representatives, and transplant professionals. Each chapter deals with a different issue and its subissues in a scholarly way. Sharp has produced a treatise that reflects unique insight into provocative areas, grounded in sound research. This is a timely and highly educational text suited for graduate and undergraduate students, as well as those involved in transplantation. It is thoroughly engaging and provides new views into some murky areas of transplantation. The first chapter,"We Are the Dead Men," deals with the never-ending controversy surrounding brain death. Among the questions addressed are the definition of brain death, the possibility of the twice or even thrice dead, and, if donors are dead, why anesthesia is a part of the donor operation. As a transplant physician, I find these topics engaging, challenging, highly stimulating, and sometimes bothersome, each begging for ongoing and thorough exploration of the unknown or unknowable. From the viewpoint of the non-medical public (especially donor kin), each issue accentuates the emotion of the donor situation and the fragile understanding we have about the process of death, and certainly its timing. Chapter 2,"Memory Work," details the feelings and communications of transplant recipients and donor relations, as well as perceptions from the outside world of the non-transplanted. Central to this chapter are the memories of the recipients of their prior lives and of their donors; of donor families for their loved ones; and of the uninitiated into the touchy struggles of transplant recipients. Rare is the individual recipient who suffers no buyer's remorse over the receipt of an organ and has no challenges in ongoing life. Rare is the donor family (especially mother) who feels that their loved one has received all the recognition deserved. And rarer still are the non-involved who can understand the trials of either the recipient or the donor family. Particularly difficult is the [End Page 302] perception of censoring felt by the donor family who wish to publicly memorialize the dead but are directed to stick with a scripted and palatable formula for public discussion. Sharp describes both the emotions felt in this circumstance and the hostility that may result, and how transplant public policy is evolving due to the efforts of those who see the control as unwarranted and overly sanitized. The result is that Sharp captures the sense of denial of grieving that many donor families feel and the complex sensations of the recipients, who are sometimes asked to suffer silently because they have been given a gift and are thus expected to just be grateful.This chapter provides a clear view into these several problems. Chapter 3, "Public Encounters as Subversive Acts," addresses the issues surrounding the discovery and identification of anonymous donors or recipients of their organs. It is only relatively recently that much attention has been paid to donors and their families by the transplant community or that various fetes have been held in honor of the recipients. Based on the old premise that organ donation ought to be anonymous, the hide-and-seek of a recipient's search for donor information was...

Pharmacodynamic Parameters of Immunosuppressive Drugs Are Not Correlated with Age, Duration of Dialysis, Percentage of Lymphocytes or Lymphocyte Stimulation Index in Renal Transplant Recipients

The lymphocyte immunosuppressant-sensitivity test (LIST) has been reported extensively as being able to estimate the pharmacological efficacy of immunosuppressive drugs in individual patients. This study measured the IC50 values for 6 drugs, cyclosporine, tacrolimus, methylprednisolone, 6-mercaptopurine, mycophenolic acid, and mizoribine, against mitogen-induced proliferation of peripheral-blood lymphocytes in 29 renal transplant recipients. We also examined relationship between the IC50 values and 4 factors; age, duration of dialysis, percentage of lymphocytes in total white blood cells, and blastogenesis stimulation index by mitogen. There were no significant correlations between the IC50 values and these factors, except that the tacrolimus IC50 value was correlated weakly with the stimulation index (p<0.05, r=-0.429). It was concluded that the pharmacological efficacy of immunosuppressive drugs cannot be inferred from the patient characteristics or their laboratory data. LIST is an effective method to elucidate the pharmacodynamic properties of immunosuppressive agents in individual renal transplant recipients without being influenced by the recipient clinical data.

Cell Therapy in a Mouse Model of Immune-Mediated Bone Marrow Failure.

Immune-mediated bone marrow (BM) failure has been modeled in the mouse by infusion of lymph node cells from allogeneic C57BL/6 (B6) donors into major or minor histocompatibility antigen-mismatched recipients (Chen et al., Blood 2004; Bloom et al., Exp Hematol 2004, Chen et al., J Immunol 2007). Co-infusion of limited numbers of CD4+CD25+ regulatory T lymphocytes (Tregs) can alleviate clinical manifestations by suppressing the expansion of pathogenic T cells (Chen et al., J Immunol 2007). In the current study, we investigated the effectiveness of Tregs and suppressor cells contained in BM stroma in this fatal disease. Infusion of fewer than 3 × 103 Tregs to each recipient mouse had only a minor effect in preserving BM cells and did not prevent pancytopenia. Fifteen-50 × 103 thymic Tregs was moderately protective: blood WBC, RBC, platelet and BM cell counts at three weeks after cell infusion were 197%, 116%, 155% and 158% of those of control animals that did not receive Treg infusion; 5–10 × 103 B6 splenic Tregs produced the largest effect as WBC, RBC, platelet and BM cell counts were 275%, 143%, 276%, and 198% of controls. Overall, Treg therapy was helpful but its effectiveness was limited and variable among individual recipients as no antigen-specific Tregs can be identified for the treatment of BM failure. Learned about the immunosuppressive effects of mesenchymal stem cells (MSCs), we went on to test the effectiveness of stromal cells as another therapeutic modality for BM failure, since stromal cells contain MSCs. These cells were derived from B6 BM by culture in α-modified Eagle medium at 33°C with 5% CO2 for two weeks. After separating the non-adherent cells, we detached the adherent stromal cells and infused them into TBI + B6 LN-infused C.B10 mice. Injection of 106 stromal cells at the time of LN cell infusion effectively preserved WBCs (3.09 ± 0.51 vs 0.61 ± 0.18), RBCs (8.72 ± 0.14 vs 3.52 ± 0.46), platelets (924 ± 93 vs 147 ± 25) and BM cells (186.6 ± 8.7 vs 52.7 ± 7.8) when compared to LN-cell-infused mice without stromal cell addition. Delayed stromal cell injection at day 9 after LN cell infusion had only a mild effect on the preservation of RBCs (147%), platelets (276%) and BM cells (223%) and no effect on WBCs (64%), and infusion of non-adherent cells from the same stromal cell culture had no therapeutic effect. Stromal cell-infused mice had higher proportion of FoxP3+CD4+ cells in the peripheral blood (59.7 ± 10.7% vs 29.8 ± 5.4%) and more Lin−CD117+CD34− hematopoietic stem and progenitor cells in the BM (591 ± 95 vs 60 ± 43, thousand) in comparison to LN cell infused mice without stromal cell treatment. Mitigation of pathogenic T cells, including both CD4 and CD8 T lymphocytes, is the potential mechanism for the effectiveness of Treg and stromal cell therapies that helped to protect hematopoietic stem and progenitor cells in the BM of affected animals. [Display omitted]