Individualization Of Immunosuppressive Therapy Research Articles

Protocol liver biopsies in stable long-term pediatric liver transplant recipients: risk or benefit?

Follow-up after pediatric liver transplantation (LTX) is challenging and needs to be refined to extend graft survival as well as general functional health and patients´ quality of life. Strategies towards individual immunosuppressive therapy seem to play a key role. Our aim was to evaluate protocol liver biopsies (PLB) as a tool in personalized follow up after pediatric LTX. Our retrospective analysis evaluates 92 PLB in clinically asymptomatic pediatric patients after LTX between 2009 and 2019. Histological findings were characterized using the Desmet scoring system. In addition to PLB, other follow-up tools like laboratory parameters, ultrasound imaging and transient elastography were evaluated. Risk factors for development of fibrosis or inflammation were analyzed. PLB revealed a high prevalence of graft fibrosis (67.4%) and graft inflammation (47.8%). Graft inflammation was significantly (P = 0.0353*) more frequent within the first 5 years after transplantation compared to later time points. Besides conventional ultrasound, the measurement of liver stiffness using transient elastography correlate with stage of fibrosis (r = 0.567, P = <0.0001***). Presence of donor-specific anti-human leukocyte antigen antibodies in blood correlates with grade of inflammation in PLB (r = 0.6040, P = 0.0018 **). None of the patients who underwent PLB suffered from intervention-related complications. Histopathological results had an impact on clinical decision making in one-third of all patients after PLB. PLB are a safe and useful tool to detect silent immune-mediated allograft injuries in the context of normal liver parameters.

Individualizing immunosuppression in lung transplantation.

Immunosuppression management after lung transplantation continues to evolve, with an increasing number of agents available for use in various combinations allowing for more choice and individualization of immunosuppressive therapy. Therapeutic developments have led to improved outcomes including lower acute rejection rates and improved survival. However, a one size fits all approach for any immunosuppressive strategy may not be best suited to the individual patient and ultimately patient specific factors must be considered when designing the immunosuppressive regimen. Recipient factors including age, race, co-morbidities, immunologic risk, genetic polymorphisms, concomitant and previous pharmacotherapy, and overall immunosuppression burden should be considered. There are several significant drug-drug interactions with select immunosuppressive agents utilized in lung transplant pharmacotherapy that must be considered when choosing and devising a dosing strategy for an individual immunosuppressive agent. Herein, considerations for immunosuppression management in the individual patient will be reviewed.

Kidney Transplantation Program in Montenegro

Abstract Introduction. There was no transplantation program in Montenegro until 2012. On the other hand, there were 93 patients with transplanted kidney. These transplantations were performed abroad; 15% in areas of black organ markets (India, Pakistan, Russian Federation). Beside the ethical problems, these transplantations carried a high risk of complications. Methods. Our health system had to ensure solution for patients with terminal organ failure. Preparation of all neccessary conditions for the beginning of transplantation program in Montenegro started in 2006 with different activities including public, legal, medical, educational and international cooperation aspects. Results. The first kidney transplantation from living donor in Montenegro was preformed on September 25th, 2012. In the period from 2012 until now 23 kidney transplantations from living related donor were performed and one kidney transplantation from deceased donor in the Clinical Center of Montenegro. In the a two year-follow-up period, all patients to whom kidney transplantation was performed are in a good condition and without serious complications in posttransplant period. Conclusion. Development of the transplantation program allowed controlled transplantation and safety of patients. Our next steps are development of deceased organ donor transplantation and achievement of higher rate of deceased donor organ transplantation and individualization of immunosuppressive therapy.

69-P: IMMUNE FUNCTION ASSAY (IMMUKNOW) AS A PREDICTOR OF ALLOGRAFT REJECTION AND INFECTION IN KIDNEY TRANSPLANTATION

The Cylex Immuknow (IK) assay provides a rapid and quantitative assessment of T-cell-mediated immune function. Studies have shown correlations between Immuknow assay and adverse events, such as immunosuppression and low or high calcineurin inhibitor–trough levels. We investigated the correlation between IK changes and rejection or infection in kidney transplant patients, and studied the potential application of the IK assays in optimizing individual immunosuppressive therapy. Immuknow assay was used to determine dynamic intracellular ATP changes in CD4 cells in 193 samples from both 42 kidney transplant patients and 25 healthy subjects. Patients were categorized into rejection, infection, and event-free groups. The IK values were assayed and analyzed between kidney transplant patients and healthy controls. Most IK values fluctuated between 200 and 599 ng/mL from pre-transplantation to 30 months post-transplantation. The mean IK values continuously increased throughout 30 months. Incidental allograft rejection patients had significantly higher IK values, compared to the event-free patients and controls. However, infection patients had significantly lower IK values. Seven days after treatment, IK values in rejection/infection patients were different compared to the values in autograft patients, and there was a significant correlation between calcineurin-inhibitor (FK506) trough levels and IK values in rejection/infection patients. Serum creatinine levels in the rejection patients were significantly higher than those in the event-free patients and C-reactive protein levels were significantly higher in the infection patients compared to the event-free patients. The IK assay combined with other biomarkers can be used to identify kidney transplant patients at high risk of rejection and infection.

Immune function assay (ImmuKnow) as a predictor of allograft rejection and infection in kidney transplantation

The Cylex ImmuKnow (IK) assay provides a rapid and quantitative assessment of T-cell-mediated immune function. Studies have shown correlations between ImmuKnow assay and adverse events, such as immunosuppression and low or high calcineurin inhibitor trough levels. We investigated the correlation between IK changes and rejection or infection in kidney transplant patients and studied the potential application of the IK assays in optimizing individual immunosuppressive therapy. ImmuKnow assay was used to determine dynamic intracellular ATP changes in CD4 cells in 193 samples from 42 kidney transplant patients and 25 healthy subjects. Patients were categorized into rejection, infection, and event-free groups. The IK values were assayed and analyzed between kidney transplant patients and healthy controls. Most IK values fell between 200 and 599 ng/mL from pre-transplantation to 30 months post-transplantation. The mean IK values continuously increased throughout 30 months. Incidental allograft rejection patients had significantly higher IK values compared with the event-free patients and controls. However, infection patients had significantly lower IK values. Seven days after treatment, IK values in rejection/infection patients were different compared with the values in autograft patients, and there was a significant correlation between calcineurin inhibitor (FK506) trough levels and IK values in rejection/infection patients. Serum creatinine levels in the rejection patients were significantly higher than those in the event-free patients, and C-reactive protein levels were significantly higher in the infection patients compared with the event-free patients. The IK assay combined with other biomarkers can be used to identify kidney transplant patients at high risk of rejection and infection.

Intracellular ATP Production in CD4+ T Cells as a Predictor for Infection and Allograft Rejection in Trough-Level Guided Pediatric Liver Transplant Recipients Under Calcineurin-Inhibitor Therapy

The assessment of cell-mediated immune responses through the measurement of intracellular adenosine-tri-phosphate (iATP) production (Cylex ImmuKnow) as a pharmacodynamic biomarker of immune function represents a potential tool to optimize individual immunosuppressive therapy independent of drug dosage or trough levels. This study aims to investigate the correlations between iATP and adverse events, immunosuppression, calcineurin-inhibitor-trough levels, and age. In this prospective trial, 31 nontransplant pediatric subjects and 50 consecutive children were included after they underwent liver transplantation (LTX). During the study period, 4 allograft rejections and 3 acute infections occurred. The patients were treated with cyclosporine, tacrolimus, mycophenolate mofetil, and everolimus either as monotherapy or in combinations. The reactivity of the immune system was measured as iATP concentration in CD4+ T-cells after in vitro stimulation by phytohemagglutinin. The iATP concentrations in patients with intercurrent, clinically significant infections were in the low immune response range (median iATP 181 versus 251 ng/mL, P = 0.308), whereas the patients with incidental allograft rejection had significantly higher iATP concentrations as compared with the event-free group (median iATP 444 versus 251 ng/mL, P = 0.017). However, there was a wide range of iATP concentrations in both nontransplant and LTX patient groups, and no clear iATP cut-off values for an increased risk of infection or rejection could be defined. Post LTX, stable-phase patients showed a significantly lower iATP compared with respective controls (median iATP 297 versus 384 ng/mL, P = 0.013). No significant correlation between calcineurin-inhibitor-trough concentrations and iATP was found. iATP was not correlated with age, but was inversely correlated with time after transplantation. The observed correlation between clinical events and iATP concentrations is similar to the findings previously reported in adult patients who underwent transplantation. The lack of correlation of iATP with trough drug concentrations suggests that the ImmuKnow assay provides independent information that may be useful to guide immunosuppressive therapy in pediatric (liver) transplant patients. However, the wide range of iATP levels in event-free patients suggests that serial iATP measurements will be necessary to assess and guide the individual immunosuppressive therapy. Further investigations are needed to evaluate and extend these findings.

Risk factors for development of cadiovascular diseases in patients with transplanted kidney

Cardiovascular diseases represent a considerable cause of death among patients with transplanted kidney. The study was aimed at defining risk factors, pathogenic progression mechanisms for cardiovascular diseases and pointing at clinical importance for early detection and timely treatment of cardiovascular diseases in patients with transplanted kidney. Expert papers and clinical studies dealing with etiopathogenesis, diagnosis and treatment of cardiovascular diseases in patients with transplanted kidney were analyzed. Increased incidence of cardiovascular diseases in patients with transplanted kidney is the consequence of high prevalence of traditional risk factors (obesity, cigarette smoking, hypertension, hyperlipidemia, diabetes mellitus), risk factors due to status of transplantation and its treatment (immunosuppressive agents, graft rejection, viral infections (cytomegalovirus) and risk factors due to chronic reduction of allograft (anemia, volume strain stress, hyperhomocysteinemia, oxidative stress, secondary hyperparathyroidism, microinflammation). Left ventricular hypertrophy, ischemic heart disease and heart weakness bear the highest prevalence among cardiovascular diseases. Early detection of disease in patients with increased risk for progression of cardiovascular diseases enables optimization and individualization of immunosu-ppressive therapy, reaching aimed values for cardiovascular risk factors, all with the view to reduce cardiovascular morbidity and mortality, increase of allograft survival and better life quality of patients with transplanted kidney.

Genetic Variation in the Effector Pathways of Cytotoxic T Lymphocytes Influences Alloimmune Reactivities Following Allogeneic Hematopoietic Stem Cell Transplantation

Abstract 3054 Background:Disease relapse, major infection and graft-versus-host disease (GVHD) are the leading causes of death following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Donor T lymphocytes play a critical role in alloimmune recognition and their ability to detect non-self-antigens can lead to GVHD or contribute to prevention of relapse and infection. Three effector pathways have been described for T-cell cytotoxicity: granzyme B/perforin, Fas/Fas ligand (FasL) and secreted molecules such as tumor necrosis factor (TNF)-alpha. Granzyme B is a proapoptotic serine protease. Fas is widely expressed in immunocompetent cells and non-lymphoid tissues. FasL is mainly expressed on activated cytotoxic T lymphocytes (CTLs). When CTLs recognize target cells, they become activated and express FasL which induces apoptosis of target cells. The Fas gene has been found to be silenced in many tumor types. The importance of those effector pathways for the development of acute GVHD (aGVHD) has been well established. In our previous study, we have reported donor and/or recipient TNF-alpha gene polymorphism influenced on the risk of aGVHD. Recently several important polymorphisms have been identified in granzyme B, Fas, and FasL genes and reported to be relevant to allograft rejection in solid organ transplant patients. However, such information is less available in allo-HSCT. This present study was designed to investigate the influence of donor and recipient genetic variations of effector pathway molecules on the abilities of T-cell alloimmune responses including GVHD, cytomegalovirus (CMV) infection within 100 days and disease relapse following allo-HSCT. Methods: The entire study population consisted of 138 pairs of recipients and their unrelated donors, who underwent HSCT in our Center from January 2001 to March 2009. Genomic DNA was extracted from peripheral blood samples obtained from recipients and donors before transplantation. Five single nucleotide polymorphisms (SNPs) including granzyme B +55(A/G), -295(C/T), Fas -1377(G/A), -670(T/C) and FasL -844 (T/C) were analyzed. Results: (1) Patients receiving stem cells from a donor with granzyme B +55 AA genotype developed aGVHD more frequently than those with mutated allele (AG or GG), which has been reported to be associated with low-producing of granzyme B by CTLs and incapable of inducing apoptosis. Multivariate analysis confirmed that donor with the granzyme B +55 AA genotype was an independent risk factor for aGVHD (RR=1.545, 95%CI: 1.012–2.357, P=0.044). (2) Donor with FasL -844 TT genotype, a genotype reported to a reduction in the expression of FasL on T cells, conferred protection against the risk of aGVHD (RR=2.981, 95% CI: 1.320–6.736, P=0.009), however was an independent risk factor for early CMV infection (RR: 3.658, 95% CI: 1.534–8.722, P=0.003). Patients experiencing aGVHD have a higher risk of developing early CMV infection (RR=1.931, 95% CI: 1.242–3.003, P=0.003), early CMV infection also was a significant factor impacting aGVHD (RR=1.630, 95%CI: 1.294–2.053, P<0.001). (3) Recipient with Fas -670 C- allele positive, a mutated allele with higher Fas expression, was associated with a significantly lower risk of relapse (RR=3.453, 95% CI: 1.699–7.091, P=0.001) as well as superior overall survival (84.2% vs 21.2%, P<0.001) in patients with acute myeloid leukemia (AML), but not in patients with other myelogenous or lymphoid malignancies. The polymorphic sites granzyme B -295(C/T), Fas -1377(G/A), did not correlate with the T-cell alloimmune reactivities. Conclusions: Genetic variation, other than HLA polymorphism, regulating the immune response may influence outcomes of patients undergoing allo-HSCT. Transplant patients would thus benefit from accurate risk assessment and individualization of immunosuppressive therapy, taking into account donor and recipient genetic data, as well as other risk factors. This study is the first report of relationship between donor or recipient genetic variations of effector pathway molecules and the abilities of T-cell alloimmune responses. According to our results, special targeting granzyme B and Fas/FasL pathways may be a promising therapeutic strategy in patients with aGVHD, CMV infection and leukemia relapse after allo-HSCT at least in AML patients harboring Fas -670 wild-type genotype. Disclosures:No relevant conflicts of interest to declare.

Individually Tailored Immunosuppression: Is There a Role for Biomarkers?

Therapeutic drug monitoring (TDM)7 of immunosuppressive drugs has evolved over the last few decades. The use of liquid chromatography–tandem mass spectrometry, for example, now provides robust and highly specific quantification in the clinical laboratory. Nevertheless, the measurement of immunosuppressive drug concentrations, even if carried out accurately and precisely, does not sufficiently reflect the effects of the applied drugs on immune cells, because of the considerable interindividual variation in the sensitivity to suppression of immune function. Irreversible chronic allograft rejection and the long-term side effects of immunosuppressive therapy are still major limiting factors in transplantation medicine. In this context, pharmacodynamic (PD) biomarkers are a potential key for further optimization of immunosuppressive therapy. The PD effects of immunosuppressive drugs can be assessed with the aid of an increasing number of different biomarkers. For achieving an individually tailored immunosuppression, these biomarkers could be helpful for such aspects as the weaning or minimization of immunosuppressive therapy, the optimization of multidrug regimens that takes into account the synergistic and antagonistic effects of immunosuppressive drugs, or even the identification of operationally tolerant patients after solid-organ transplantation. In this Q&A, 4 leading experts in the field of PD monitoring of immunosuppressive drugs share their thoughts on the analytical and clinical requirements, as well as the usefulness, of individual biomarkers. From your perspective, what are the requirements for an ideal biomarker for individualization of immunosuppressive therapy, e.g., after solid-organ transplantation? Merce Brunet: In clinical practice, all biomarkers may have some limitations, and it would be difficult to achieve the status of ideal biomarker. In solid-organ transplantation, biomarkers should be useful tools for optimizing immunosuppressant therapy and identifying patients at risk of rejection. Biomarker monitoring combined with pharmacokinetics (PK) is a requirement to achieve personalized therapy. Some of these biomarkers could be strongly related to the mechanism of …

Pathogenesis, diagnosis, and treatment of recurrent spontaneous abortion with immune type

Recurrent spontaneous abortion (RSA), defined as three or more consecutive pregnancy losses before 20 weeks of gestation, is difficult to treat in the clinical setting. It affects 1%-5% of women of reproductive age. In the investigations of immunopathogenesis, diagnosis, and treatment of RSA since the late 1980s, it was found that RSA was associated with abnormal maternal local or systemic immune response. The pathogenesis of autoimmune RSA was mainly associated with antiphospholipid antibody (APA), while that of alloimmune RSA was due to the disturbance of maternofetal immunological tolerance. Systemic etiological screening process and diagnosis systems of RSA with immune type were developed, and anticardiolipin (ACL or ACA) + anti-β2-GP1 antibody combining multiple assays for effective diagnosis of RSA with autoimmune type was first established. According to the dynamic monitoring of clinical parameters before and during gestation, low-dose, short-course, and individual immunosuppressive therapy and lymphocyte immunotherapy for RSA with immune type were carried out. The outcomes of the offsprings of patients with RSA were followed up, and the safety and validity of the therapies were confirmed. The research achievement leads to great progress in the diagnosis and treatment of RSA in China.

Progress in Transplantation

Transplantation is an important and, in most cases, the only available therapeutic option for saving the lives of patients with end-stage organ failure. Furthermore, transplantation is recognized as one of the major medical achievements over the last half century. Despite outstanding short-term graft and patient survival rates, organ transplantation continues to face several major challenges. These include a severe shortage of donor grafts, poor long-term graft survival resulting from chronic vascular rejection, and major side effects from long-term immunosuppressive therapy required for prevention of rejection. Over the next several years, it will be imperative to develop novel solutions to these challenges in organ transplantation. Increasing the availability and quality of organs for transplantation will reduce patient death while on the waiting list and facilitate long-term graft survival after transplantation. Further understanding of the molecular mechanisms of cell activation has led to the discovery of additional new immunosuppressive agents that can now be used to allow individualization of immunosuppressive therapy. There is also a need to develop new strategies to monitor the use of immunosuppressive agents to reduce the incidence and severity of renal and cardiovascular toxicity and the increased incidence of cancer in transplant patients. Inducing a state of transplantation tolerance (graft acceptance without requirement for long-term immunosuppression) further offers the hope of improving the longevity of transplanted organs and the quality of life resulting from avoidance of significant side effects associated with immunosuppressive therapy.

Clinical Impact of Polymorphisms of Transport Proteins and Enzymes Involved in the Metabolism of Immunosuppressive Drugs

Individualization of immunosuppressive therapy after solid organ transplantation is a goal that has been pursued for a long time. Nevertheless, in clinical practice, we are still stratifying patients in subgroups in which risk is assessed using demographic information and population analysis. Then, a combination of immunosuppressive drugs is chosen and doses are individualized to compensate for intra- and interindividual variabilities in drug pharmacokinetics, to obtain similar plasma/blood concentrations that are believed to be therapeutic, again based on data derived from population analysis. One step further in this strategy is to recognize, before initiation of immunotherapy, those patients at higher risk to be either under- or overexposed to currently used immunosuppressive drugs. Several studies have been undertaken to correlate single nucleotide polymorphisms in genes encoding transport proteins and metabolizing enzymes involved in the disposition of immunosuppressive drugs. Overall, the results from these studies have been mixed. The causes of these sometimes conflicting results include methodologic, genetic, or nongenetic factors. The degree of linkage disequilibrium, the measure of nonrandom associations between polymorphisms at different loci, not necessarily on the same chromosome, is perhaps the main genetic factor. The influence of the environment, physiology (such as kidney and liver functions), disease state, use of multidrug regimens, and inherent drug-to-drug interactions are present nongenetic factors. Moreover, it is also important to increase our knowledge of the genetic factors involved in the variabilities observed in drug responses of pharmacodynamics. True individualized therapy, with the ability to improve health outcomes of each transplant recipient, will depend on our knowledge of the genetic factors involved in immunological response and drug pharmacokinetics and pharmacodynamics.

CYP3A polymorphisms and immunosuppressive drugs in solid-organ transplantation

Most immunosuppressive drugs have a narrow therapeutic index and large interpatient variabilities in their pharmacokinetic and pharmacodynamic profiles. Identification of functional single-nucleotide polymorphisms in genes encoding for drug metabolizing enzymes has great potential to improve the drug efficacy and safety profiles, since these genetic factors may be important biomarkers for individualization of immunosuppressive therapy. This article summarizes current knowledge regarding the impact of CYP3A polymorphisms on immunosuppressive drug pharmacokinetics. Many retrospective studies have shown a clear relationship between CYP3A5*1/*3 polymorphism and tacrolimus pharmacokinetics, while the influence of CYP3A5*1/*3 or CYP3A4*/*1B on ciclosporin and sirolimus exposure are still questionable. CYP3A polymorphisms may partially contribute to the clinical variability of the enzyme-mediated drug interactions. Drug–drug interactions may also influence the phenotypic consequence of CYP3A polymorphisms. Population pharmacodynamic/kinetic/genomic modeling was proposed as an emerging and promising approach to quantitatively explore the contribution of genetic polymorphisms to the large interpatient variability in the pharmacokinetic and pharmacodynamic profiles of immunosuppressive drugs. Prospective, randomized studies in large patient populations are needed to further clarify the genetic effects of CYP3A on immunosuppressive drug exposure and response.

In vitro assays of allosensitization.

Current approaches to the management of immunosuppression are largely empiric and reactive rather than proactive due to our inability to predict accurately how the recipient immune system will respond to a given organ allograft. The validation of simple, reliable, non-invasive assays exploring allogeneic anti donor responsiveness or donor specific non-responsiveness are of interest for several reasons: (i) it would allow for early and non-invasive detection of acute or chronic allograft rejection such that intervention could be initiated before effector mechanisms and organ destruction occur, (ii) it would allow for individual immunosuppressive drug therapy thereby avoiding the unwanted consequences of over immunosuppression, and (iii) the identification of the immunological phenotype related to operational tolerance could allow for the complete cessation of immunosuppressants. This review will summarize in vitro assays of T cell reactivity that reflect allo-antigen-specific responses.

A clinical report of 6 cases of liver retransplantation

Objective To explore the factors influencing the Results of liver retransplantation and key points for the operation. Methods The clinical data of 6 patients who received liver retrans-plantation during July 2000 to April 2006 in our hospital were retrospectively analyzed. The reasons for liver retransplantation, different Method of operation and the result of liver retransplantation were also analyzed. Results The contribution of 6 liver retransplantations were: 1 case of the recurrence of liver carcinoma, 1 of the recurrence hepatitis, 2 of chronic rejection, 1 of hepatic artery thrombosis and 1 of FK506 injury of liver. Mean time between first and second transplantation was about 12.9 months. The average blood loss was about 14 050 ml. There were 3 deaths occurred per-operation.Conclusion Liver retransplantation is at high risk for the patients whose condition maybe bad before operation. It is very important to select correct patients and time for retransplantation. The key points to get high survival include accurate procedure, minimal hemorrhage during operation and individual immunosuppressive therapy. Key words: Liver transplantation; Retransplantation; Hemorrhage during operation

ModerneTherapie bei systemischem Lupus erythematodes

Even though no new treatment for systemic lupus erythematosus (SLE) has been approved in over 40 years, the treatment possibilities have expanded decisively in this time. The available evidence for most forms of therapy is rather thin, yet there is a wide consensus on an individual immunosuppressive therapy that is adjusted to the illness activity and severity. Various new substances, e.g. other immunosuppressants and anti-cell therapies have been tested, mostly in open studies. Considering the experience in other indications, mycophenolate mofetil and rituximab have a very promising potential to be approved for therapy of SLE. Aside from these, "old medications" such as antimalarial drugs still possess a high value. Besides the effective suppression of the illness activity, this is especially decisive for the improvement of the long-term prognosis, the treatment of co-morbidities and secondary prevention and the avoidance of negative effects of the illness and therapy, such as infections, osteoporosis, and premature arteriosclerosis. As these "simple" measures often remain disregarded in modern therapy, they will be focused on in this overview on the current treatment concepts for SLE and these aspects will be discussed in greater depth. With regard to new future therapies, we refer the reader to other current publications.

Pharmacodynamic monitoring of the immunosuppressive therapy in patients after heart transplantation: Whole blood flow cytometric analysis of lymphocyte function

Despite therapeutic monitoring and daily measurements of blood concentrations (pharmacokinetics) of immunosuppressive medications, immunosuppressive therapy remains still a challenge after heart transplantation (HTx) due to drug interactions, toxicities and individual responses to drug effects. We established whole blood flow cytometric assays of lymphocyte function to assess the pharmacodynamics of immunosuppressive therapy and investigated both pharmacokinetic and pharmacodynamic approaches after HTx. Our results showed that pharmacodynamic measurements provide a more direct assessment of the functional activity of immunosuppressants on immune cells compared to drug level monitoring alone. The information from both pharmacokinetic and pharmacodynamic monitoring has the potential to increase the efficacy and safety of individual immunosuppressive therapy after HTx.

Individualization of Immunosuppressive Therapy. III. Sirolimus Associated With a Reduced Incidence of Malignancy

Objective We examined the occurrence of neoplasms among 1008 renal transplant recipients treated with a sirolimus-cyclosporine (CsA) ± prednisone (Pred) regimen. Methods A comprehensive database of demographic, laboratory, clinical, and histopathologic features of these patients all followed in our transplant center was analyzed using Student t test and Mann-Whitney U test for continuous and chi-square test for categorical variables. Comparisons were performed with information in the Israel Penn International Transplant Tumor Registry (IPITTR). Results During the mean patient follow-up of 62.3 ± 26.1 months (range 27.1 to 131), 36 tumors occurred in 35 patients (3.6%) at 32.5 ± 29.8 months. The most common neoplasms were skin tumors (2.4%), a value that was significantly lower than the 6% rate observed with CsA-azathioprine-Pred treatment. Also, the 0.4% incidence of posttransplant lymphoproliferative disorders and 0.2% incidence of renal cell carcinomas were less than half of those previously reported with a combination of tacrolimus and mycophenolate mofetil. The distribution of tumor types was similar to that reported to the IPITTR. The mean trough drug concentrations in affected recipients at the time of diagnosis were within the putative target ranges. Conclusion Renal transplant recipients treated with the sirolimus-CsA ± Pred combination showed a low incidence of tumors of similar types as those encountered with other regimens.

Individualization of Immunosuppressive Therapy. II. Sirolimus as a Less Nephrotoxic Alternative to Calcineurin Inhibitors

The nephrotoxic effects of chronic administration of calcineurin inhibitors have created a demand for a potent immunosuppressive drug free of this side effect. Sirolimus (SRL) clearly displays fewer and a lesser degree of adverse effects on renal function by itself. However, in combination with calcineurin antagonists, it tends to augment the nephrotoxicity due, at least in part, to a pharmacokinetic interaction. The use of SRL for de novo immunosuppression (even with adjunctive mycophenolate mofetil) is probably not sufficient to avert alloimmune reactions. A useful combination with SRL can be achieved by reducing calcineurin inhibitor exposure by 80% for immediately functioning kidneys or by delaying its inception until renal graft recovery. SRL proffers additional benefits as an inhibitor of endothelial and smooth muscle cell proliferation, serving as the foundation of chronic immunosuppressive therapy.

Individualization of Immunosuppressive therapy: I. Sirolimus Improves Outcomes in African-American Renal Transplant Recipients

Introduction African-American renal transplant recipients are prone to acute rejection episodes and graft loss owing to genetic, pharmacokinetic, cultural, and socioeconomic factors. While more intense exposures to antirejection agents can mitigate this propensity, heightened immunosuppressive regimens are accompanied by an array of toxicities. Our study sought to examine the impact of a combination of sirolimus (SRL) and cyclosporine (CsA) on the outcomes of African-Americans vs Caucasians. Materials and Methods The outcomes of African-Americans treated with either CsA-prednisone (Pred, n = 90) or SRL-CsA-Pred (n = 86) were compared with 148 SRL-CsA-Pred-treated Caucasians. Results The addition of SRL to a CsA-Pred regimen reduced the rate of acute rejection episodes within 2 years in African-Americans from 43.3% to 17% ( P = .004), a value similar to that observed in Caucasian patients (18%). At 2 years, the graft survival rate of 79% among African-American patients treated with SRL-CsA-Pred was similar to that in the Caucasian cohort (80%). The respective patient survival rates also were similar: 93% and 90%, respectively. Multivariate analysis of 5-year outcomes among patients treated with SRL-CsA-Pred revealed the hazard ratios of African-Americans vs Caucasians to actually be reduced for acute rejection (.22; P = .01) and for death (.15; P = .01), but similar for chronic rejection (.77; P = NS) and graft loss (1.03; P = NS). Conclusion The use of SRL-based regimens mitigated the otherwise enhanced risk for acute rejection episodes or graft loss otherwise experienced by CsA-treated African-American renal transplant recipients.