Optimized fast non-singular integral terminal sliding mode control of immune response and HCMV infection of renal transplant recipient.

Kidneys are the most commonly transplanted organs, and renal transplant is the best treatment for patients with advanced stages of renal disease. Immunosuppressive drugs are used after renal transplant to prevent the body from rejecting the transplanted kidney and ensure its proper kidney functioning. However, suppression of the immune system increases the risk of viral infections and other complications. Therefore, careful monitoring and management of immunosuppressive and antiviral drugs are essential for the success of the transplants. This article presents a hybrid fast non-singular integral terminal sliding mode control technique to adjust the efficacies of these drugs in renal transplant recipients, ensuring successful transplants and preventing viral infections. The proposed strategy tracks system trajectories to reference values and adjusts the treatment plan accordingly. The Lyapunov stability theorem is used to prove the asymptotic stability of the closed-loop system. Several simulation studies are conducted in MATLAB/Simulink environment to evaluate the performance of the proposed control technique in maintaining a balance between over-suppression and under-suppression. Genetic Algorithm is used to optimize the gain values to further improve the performance of the proposed control technique. Its performance is compared with two other variants of terminal sliding mode controllers to demonstrate its effectiveness against them.

Effects of oral steroid sparing immunosuppressive drugs in long term maintenance treatment of chronic inflammatory demyelinating polyradiculoneuropathy.

Background and objectives: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired treatable autoimmune disorder. Due to limited availability and affordability of IV immunoglobulins and therapeutic plasma exchange in Pakistan, oral immunosuppressive drugs (ISDs) are used despite limited role in literature. The study aimed to determine the response to ISDs in CIDP patients by assessing the frequency of remission, reduction of disability using a neuropathy related disability score called Inflammatory Neuropathy Cause and Treatment score (or INCAT score), as well as reduction in steroid maintenance dose. Methods: The retrospective observational study of six months duration (May to October, 2020) was carried out in Aga Khan University Hospital, Karachi, Pakistan. Medical record of all the patients with idiopathic CIDP taking oral ISDs in last five years was selected which included bio-data, clinical signs and symptoms, medication details, and INCAT scores. Descriptive statistics were described i.e. frequency, percentages, mean/standard deviation using Microsoft Excel v.2021. Results: Out of thirteen patients, Azathioprine was used in nine, Mycophenolate mofetil in two and Cyclosporine in two, with remission (INCAT score improvement ≥ 1) achieved in eight, one and zero patients respectively. Duration of ISDs ranged from three to twenty-four months (average 15.8 months). Patients with monoclonal paraproteinemia and prior exposure to ISDs had a poor response to the introduction of subsequent ISDs. Conclusion: The study describes preliminary experience of the potential role of relatively cheaper and more convenient oral ISDs (especially Azathioprine) as an alternative or sparing agent to first line agents for CIDP and sets the stage for larger scale studies and randomized controlled trials.

A validated UPLC-MS/MS method for the quantification of immunosuppressive drugs in peripheral blood mononuclear cells using liquid-liquid extraction with low temperature purification without complex pretreatment steps.

Immunosuppressive drugs (ISDs) are given to avoid the allograft rejection after transplantation. The concentrations of ISDs should be closely monitored owing to their wide inter-individual variability in its pharmacokinetics and narrow therapeutic window. Currently, the whole blood concentration measurement is the major approach of therapeutic drug monitoring of clinical ISDs in organ transplantation. Its correlation with the efficacy of ISDs remains elusive. While the acute rejection after transplantation may occur even when whole-blood ISDs concentrations are within the target range. Since the site of action of ISDs are within the lymphocyte, direct measurement of drug exposure in target cells may more accurately reflect the clinical efficacy of ISDs. Although several methods have been developed for the peripheral blood mononuclear cells (PBMCs) extraction and drug concentration measurement, the complex pre-processing has limited the study of the relationship between intracellular ISDs concentrations and the occurrence of rejection. In this study, the extraction of ISDs in PBMCs was carried out by the liquid-liquid extraction with low temperature purification, without centrifugation. The lower limit of quantitation were 0.2 ng/mL for cyclosporine A, tacrolimus and sirolimus, 1.0 ng/mL for mycophenolic acid, and the within-run and between-run coefficient of variations were both less than 12.4 %. The calibration curves of mycophenolic acid had a linear range (ng/mL): 1.0-128.0 (r2 = 0.9992). The calibration curves of other three ISDs had a linear range (ng/mL): 0.2-20.48 (r2 > 0.9956). A total of 157 clinical samples were analyzed by the UPLC-MS/MS for ISDs concentration in blood or plasma ([ISD]blood or plasma) and the concentration within PBMCs ([ISD]PBMC). Although there was strong association between [ISD]PBMC and [ISD]blood or plasma, the large discrepancies between concentration within [ISD]blood or plasma and [ISD]PBMC were observed in a small proportion of clinical samples. The developed method with short analysis time and little amounts of blood sample can be successfully applied to therapeutic drug monitoring of ISDs in PBMCs for analysis of large numbers of clinical samples and is helpful to explore the clinical value of ISDs concentration in PBMCs.

Atypical posterior reversible encephalopathy syndrome: A lentiform fork sign following transplantation.

Key Clinical Message: Posterior Reversible Encephalopathy Syndrome, typically characterized by parieto-occipital vasogenic edema, can present atypically, as a bilateral symmetrical vasogenic edema in the basal ganglia, featuring the called "lentiform fork sign." Prompt recognition of such variations is crucial for accurate diagnosis and tailored management, highlighting the complexity of this syndrome's manifestations. Abstract: Posterior Reversible Encephalopathy Syndrome (PRES) manifests as transient neurological symptoms and cerebral edema, commonly associated with immunosuppressive drugs (ISDs) in transplant recipients. ISDs can lead to endothelial dysfunction and compromise the blood-brain barrier. Typically, PRES exhibits identifiable MRI patterns, often demonstrating vasogenic edema in the bilateral parieto-occipital white matter. Identifying unique presentations, such as the recently observed "lentiform fork sign," commonly seen in uremic encephalopathy, emphasizes this syndrome's broad spectrum manifestations. A 19-year-old male, who underwent bilateral lung and liver transplantation, experienced a bilateral tonic-clonic seizure of unknown onset 47 days post-surgery. MRI findings revealed an unconventional PRES pattern, featuring the "lentiform fork sign" as bilateral symmetrical vasogenic edema in the basal ganglia, surrounded by a hyperintense rim outlining the lentiform nucleus bilaterally. Subsequent management, including ISD modification and magnesium supplementation, resulted in clinical and neuroimaging resolution. An almost complete clinical and radiological resolution was achieved after 14 days. The occurrence of PRES in transplant recipients highlights the intricate interplay among ISDs, physiological factors, and cerebrovascular dynamics, potentially involving direct neurovascular endothelial toxicity and disruption of the blood-brain barrier. Neuroimaging plays a pivotal role in diagnosis. The distinctive "lentiform fork sign" was observed in this patient despite the absence of typical metabolic disturbances. Management strategies usually involve reducing hypertension, discontinuing ISDs, correcting electrolyte imbalances, and initiating antiseizure drugs if necessary. Identifying the presence of the "lentiform fork sign" alongside typical PRES edema in a patient lacking renal failure emphasizes that this manifestation is not solely indicative of uremic encephalopathy. Instead, it might represent the final common pathway resulting from alterations in the blood-brain barrier integrity within the deep white matter. Understanding such atypical imaging manifestations could significantly aid earlier and more precise diagnosis, influencing appropriate management decisions.

Role of T follicular helper cells in autoimmune rheumatic Diseases: A systematic review on immunopathogenesis and response to treatment.

BACKGROUND: T follicular helper (Tfh) cells are a subdivision of T helper cells involved in antigen-specific B cell immunity. Tfh cells play an essential role in the interaction of T cells/B cells in the germinal centers (GC), and dysregulation of Tfh actions can offer pathogenic autoantibody formation and lead to the development of autoimmune diseases. This study seeks to evaluate changes in Tfh frequency and its related cytokines in autoimmune disease, its association with disease phase, severity, prognosis, and the effect of immunosuppressive treatment on the Tfh population. METHOD: The study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Statement. Electronic databases, including PubMed, Scopus, Web of Science, and Embase, were systematically searched for potentially eligible studies up to January 1, 2024. RESULTS: We identified 4998 articles in the initial search, from which 1686 similar titles were removed. A total of 3312 articles were initially screened, and 3051 articles were excluded by title/abstract screening. A total of 261 studies were considered for full-text assessment, and 205 articles were excluded by reason. Finally, a total of 56 studies were included in our review. CONCLUSION: The population of Tfh cells is generally higher in autoimmune diseases versus Health control. Moreover, the number of Tfh cells is associated with the disease severity and can be considered for determining the prognosis of studies. Also, peripheral blood circulating Tfh (cTfh) cells are an available sample that can be used as an indicator for diagnosing diseases.

Evaluation of the Development of Post-Vaccination Immunity against Selected Bacterial Diseases in Children of Post-Solid-Organ-Transplant Mothers.

Pregnancy after organ transplantation is considered high-risk and requires supervision in specialized centers. The impact of immunosuppression on the developing fetus is still the subject of research. It has been shown that it affects lymphocyte populations in the first year of life. For this reason, researchers suggest postponing mandatory infant vaccinations. The aim of the study was to analyze the influence of intrauterine exposure of the fetus to immunosuppression on the immunogenicity of protective vaccinations against selected bacterial pathogens. The ELISA method was used to determine the concentration of post-vaccination IgG antibodies against diphtheria, tetanus, pertussis, tuberculosis, H. influenzae type B, and S. pneumoniae in 18 children of mothers who underwent organ transplantation. The results were compared with the control group (n = 21). A comparison of the incidence of adverse post-vaccination reactions between the analyzed groups was also performed. There were no statistically significant differences in the immunogenicity of the analyzed vaccines between children of mothers who underwent organ transplantation and the age-matched general pediatric population. There were no differences in the incidence of adverse post-vaccination reactions between the analyzed groups. The obtained results do not indicate the need to modify the current protective vaccination schemes against bacterial pathogens in children of mothers who underwent organ transplantation.

Available Therapeutic Options for Corneal Neovascularization: A Review.

Corneal neovascularization can impair vision and result in a poor quality of life. The pathogenesis involves a complex interplay of angiogenic factors, notably vascular endothelial growth factor (VEGF). This review provides a comprehensive overview of potential therapies for corneal neovascularization, covering tissue inhibitors of metalloproteinases (TIMPs), transforming growth factor beta (TGF-ß) inhibitors, interleukin-1L receptor antagonist (IL-1 Ra), nitric oxide synthase (NOS) isoforms, galectin-3 inhibitors, retinal pigment epithelium-derived factor (PEDF), platelet-derived growth factor (PDGF) receptor inhibitors, and surgical treatments. Conventional treatments include anti-VEGF therapy and laser interventions, while emerging therapies such as immunosuppressive drugs (cyclosporine and rapamycin) have been explored. Losartan and decorin are potential antifibrotic agents that mitigate TGF-ß-induced fibrosis. Ocular nanosystems are innovative drug-delivery platforms that facilitate the targeted release of therapeutic agents. Gene therapies, such as small interfering RNA and antisense oligonucleotides, are promising approaches for selectively inhibiting angiogenesis-related gene expression. Aganirsen is efficacious in reducing the corneal neovascularization area without significant adverse effects. These multifaceted approaches underscore the corneal neovascularization management complexity and highlight ideas for enhancing therapeutic outcomes. Furthermore, the importance of combination therapies and the need for further research to develop specific inhibitors while considering their therapeutic efficacy and potential adverse effects are discussed.

Antibody Response after 3-Dose Booster against SARS-CoV-2 mRNA Vaccine in Kidney Transplant Recipients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with a high rate of mortality in kidney transplant recipients (KTRs). Current vaccine strategies for KTRs seem to be unable to provide effective protection against coronavirus disease 2019 (COVID-19), and the occurrence of severe disease in some vaccinated KTRs suggested a lack of immunity. We initially analyzed the antibody response in a group of 32 kidney transplant recipients (KTRs) followed at the nephrology and dialysis unit of the Hospital Pio XI of Desio, ASST-Brianza, Italy. Thus, we studied the differences in antibody levels between subjects who contracted SARS-CoV-2 after the booster (8 individuals) and those who did not contract it (24 individuals). Furthermore, we verified if the antibody response was in any way associated with creatinine and eGFR levels. We observed a significant increase in the antibody response pre-booster compared to post-booster using both a Roche assay and DIAPRO assay. In the latter, through immunotyping, we highlight that the major contribution to this increase is specifically due to IgG S1 IgM S2. We observed a significant increase in IgA S1 and IgA NCP (p = 0.045, 0.02) in the subjects who contracted SARS-CoV-2. We did not find significant associations for the p-value corrected for false discovery rate (FDR) between the antibody response to all assays and creatinine levels. This observation allows us to confirm that patients require additional vaccine boosters due to their immunocompromised status and therapy in order to protect them from infections related to viral variants. This is in line with the data reported in the literature, and it could be worthwhile to deeply explore these phenomena to better understand the role of IgA S1 and IgA NCP antibodies in SARS-CoV-2 infection.

Solid organ transplantation and gut microbiota: a review of the potential immunomodulatory properties of short-chain fatty acids in graft maintenance.

Transplantation is the treatment of choice for several end-stage organ defects: it considerably improves patient survival and quality of life. However, post-transplant recipients may experience episodes of rejection that can favor or ultimately lead to graft loss. Graft maintenance requires a complex and life-long immunosuppressive treatment. Different immunosuppressive drugs (i.e., calcineurin inhibitors, glucocorticoids, biological immunosuppressive agents, mammalian target of rapamycin inhibitors, and antiproliferative or antimetabolic agents) are used in combination to mitigate the immune response against the allograft. Unfortunately, the use of these antirejection agents may lead to opportunistic infections, metabolic (e.g., post-transplant diabetes mellitus) or cardiovascular (e.g., arterial hypertension) disorders, cancer (e.g., non-Hodgkin lymphoma) and other adverse effects. Lately, immunosuppressive drugs have also been associated with gut microbiome alterations, known as dysbiosis, and were shown to affect gut microbiota-derived short-chain fatty acids (SCFA) production. SCFA play a key immunomodulatory role in physiological conditions, and their impairment in transplant patients could partly counterbalance the effect of immunosuppressive drugs leading to the activation of deleterious pathways and graft rejection. In this review, we will first present an overview of the mechanisms of graft rejection that are prevented by the immunosuppressive protocol. Next, we will explain the dynamic changes of the gut microbiota during transplantation, focusing on SCFA. Finally, we will describe the known functions of SCFA in regulating immune-inflammatory reactions and discuss the impact of SCFA impairment in immunosuppressive drug treated patients.

Data mining and safety analysis of traditional immunosuppressive drugs: a pharmacovigilance investigation based on the FAERS database.

OBJECTIVE: The purpose of this study aimed to explore the new and serious adverse events(AEs) of Tacrolimus(FK506), cyclosporine(CsA), azathioprine(AZA), mycophenolate mofetil(MMF), cyclophosphamide(CTX) and methotrexate(MTX), which have not been concerned. METHODS: The FAERS data from January 2016 and December 2022 were selected for disproportionality analysis to discover the potential risks of traditional immunosuppressive drugs. RESULTS: Compared with CsA, FK506 has more frequent transplant rejection, and is more related to renal impairment, COVID-19, cytomegalovirus infection and aspergillus infection. However, CsA has a high infection-related fatality rate. In addition, we also found some serious and rare AE in other drugs which were rarely reported in previous studies. For example, AZA is closely related to hepatosplenic T-cell lymphoma with high fatality rate and MTX is strongly related to hypofibrinogenemia. CONCLUSION: The AEs report on this study confirmed that the results were basically consistent with the previous studies, but there were also some important safety signals that were inconsistent with or not mentioned in previous published studies. EXPERT OPINION: The opinion section discusses some of the limitations and shortcomings, proposing the areas where more effort should be invested in order to improve the safety of immunosuppressive drugs.

Off-Label Immunosuppressant Drugs in Solid Organ Transplantation.

Once a solid organ transplantation (SOT) has been performed, it is necessary to prescribe immunosuppressant medication to prevent graft rejection. This task has the peculiarity that many of these drugs do not have specific indications for transplant use in the technical data sheets. We performed a review of different immunosuppressive drugs' information available at European and American regulatory agencies in order to analyze the approved indications by the type of SOT. In our work, besides showing these differences between different indication approvals in different SOT modalities, we also attempted to reflect other differences under the approved indications according to age group, formulation type, geographical area, etc. Although consensus documents on the subject have been published, the access to immunosuppressants depends on each country's regulation and healthcare system, and off-label prescription is a reality that healthcare professionals need to be familiar with.

Lymphoproliferative disorder progressing after partial remission following immunosuppressive drugs withdrawal in a patient with rheumatoid arthritis.

Lymphoproliferative disorders (LPDs) are serious complications that arise in patients with rheumatoid arthritis (RA) receiving immunosuppressive drugs (ISDs). Here, we reported a 73-year-old woman diagnosed with RA at 60 years of age and treated with methotrexate, bucillamine, prednisolone, and infliximab. She was referred to our hospital, Osaka Metropolitan University Hospital, with general malaise, pancytopenia, a right adrenal mass, and enlarged periaortic lymph nodes. Epstein-Barr virus was detected in serum. We suspected LPD development and performed a bone marrow biopsy, on which no malignant cells could be detected. Upon ISDs withdrawal, her symptoms and blood counts improved, and the right adrenal mass and enlarged lymph nodes regressed. The patient was followed up for clinical LPD. However, 7 months after the initial visit to our hospital, she developed fever and pancytopenia. A repeat bone marrow biopsy confirmed the diagnosis of Epstein-Barr virus-positive diffuse large B-cell lymphoma complicated by haemophagocytic syndrome. After pulse steroid therapy, the patient received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone therapy, which resulted in a complete response. In conclusion, when LPDs develop in patients with RA during ISD treatment, LPDs can progress and complicate haemophagocytic syndrome after partial remission following ISDs withdrawal. Therefore, we should carefully follow up RA patients with LPDs, and aim to achieve an early diagnosis of LPD and promptly initiate chemotherapy.

Single-centre experience with the treatment of high-prevalence metabolic syndrome in kidney transplant patients in Bosnia and Herzegovina.

Aim To analyse prevalence of metabolic syndrome (MS) in kidney transplant recipients at the University Clinical Centre Tuzla in Bosnia and Herzegovina (B&H), and determine effects of a modern drug therapy in achieving target metabolic control in kidney transplant patients. Methods A single-centre prospective study that included 142 kidney transplant patients over one year follow-up period was conducted. Patient data were collected during post-transplant periodical controls every 3 months including data from medical records, clinical examinations and laboratory analyses. Results Out of 142 kidney transplant patients, MS was verified in 85 (59.86%); after a pharmacologic treatment MS frequency was decreased to 75 (52.81%). After a one-year period during which patients were receiving therapy for MS, a decrease in the number of patients with hyperlipoproteinemia, decrease in average body mass index (BMI), glycemia and haemoglobin A1C (HbA1C) were observed. Hypertension did not improve during this period, which can be explained by transplant risk factors in the form of immunosuppressive drugs and chronic graft dysfunction. Conclusion A significant reduction in components of the metabolic syndrome after only one year of treatment was recorded, which should be the standard care of kidney transplant patients.

Evidence of the interactions between immunosuppressive drugs used in autoimmune rheumatic diseases and Chinese herbal medicine: A scoping review.

OBJECTIVES: Chinese herbal medicine (CHM) has been shown to be effective in autoimmune rheumatic diseases, but harmful herb-drug interactions might be inherent. We aim to review the evidence regarding herb-drug interactions between immunosuppressive drugs used in autoimmune rheumatic diseases and CHM. METHODS: We searched PubMed, EMBASE and CINAHL from inception till 30 April 2023 using keywords that encompassed 'herb-drug interactions', 'herbs' and 'immunosuppressants'. Articles were included if they contained reports about interactions between immunosuppressive drugs used in the treatment of rheumatic diseases with CHM. Level of evidence for each pair of interaction was graded using the algorithm developed by Colalto. RESULTS: A total of 65 articles and 44 unique pairs of interactions were identified. HDIs were reported for cyclophosphamide, cyclosporine, tacrolimus, methotrexate, mycophenolic acid, glucocorticoids, sulfasalazine, tofacitinib and biologic disease-modifying antirheumatic drugs. Among these, cyclosporine (n = 27, 41.5%) and tacrolimus (n = 19, 29.2%) had the highest number of documented interactions. Hypericum perforatum had the highest level of evidence of interaction with cyclosporine and tacrolimus. Consumption reduced the bioavailability and therapeutic effects of the drugs. Schisandra sphenanthera had the highest level of evidence of interaction with tacrolimus and increased the bioavailability of the drug. Majority of the articles were animal studies. CONCLUSION: Overall level of evidence for the included studies were low, though interactions between cyclosporine, tacrolimus, Hypericum perforatum and Schisandra sphenanthera were the most and well-documented. Healthcare professionals should actively enquire about the concurrent use of CHM in patients, especially when drugs with a narrow therapeutic index are consumed.

Clinical management strategies for recipients with renal graft loss / 器官移植

With the maturity of kidney transplantation, introduction of new immunosuppressive drugs and improvement of immunosuppressive regimen, the short-term survival rate of kidney transplant recipients has been significantly improved, whereas the long-term survival rate has not been significantly elevated. Kidney transplant recipients may have the risk of renal graft loss. Clinical management after renal graft loss is complicated, including the adjustment of immunosuppressive drugs, management of renal graft and selection of subsequent renal replacement therapy. These management procedures directly affect clinical prognosis of patients with renal graft loss. Nevertheless, relevant guidelines or consensuses are still lacking. Clinical management of patients after renal graft loss highly depend upon clinicians’ experience. In this article, the adjustment of immunosuppressive drugs, management of renal graft and selection of subsequent renal replacement therapy were reviewed, aiming to provide reference for prolonging the survival and improving the quality of life of these patients.

Development of a predictive nomogram for switching immunosuppressive drugs in pediatric liver transplant recipients.

Background: Tacrolimus (TAC) is the preferred calcineurin inhibitor (CNI) for pediatric liver transplant recipients. However, some recipients may not achieve the desired therapeutic window concentration of TAC, leading to poor prognosis. This study aimed to develop a clinical model that can predict the effectiveness of TAC in pediatric liver transplant recipients and help clinicians quickly identify cyclosporin as an alternative. Methods: We retrospectively analyzed data from 2,032 pediatric liver transplant recipients who underwent surgery at Renji Hospital, Shanghai Jiaotong University School of Medicine between 2006 and 2019. Demographic, comorbidity and pre-operative laboratory data were collected, and a nomogram was constructed using multivariate logistic regression analysis to estimate the risk of poor therapeutic outcomes for TAC-based immunosuppression. Results: The constructed nomogram included seven parameters, namely recipient CYP3A4 genotype, pre-transplant cholangitis, GRWR, spleen long diameter, serum albumin, graft volume reduction, and donor CYP genotype. The nomogram showed good discriminative ability with an area under the receiver operating characteristic curve (AUC) of 74.5% and good calibration. Decision curve analysis indicated a high potential clinical application of the model. Conclusion: This simple clinical model effectively predicts the risk of poor therapeutic outcomes in pediatric liver transplant recipients who receive TAC-based immunosuppression. Clinicians can use the model to identify cyclosporin as an alternative quickly, potentially improving patient prognosis.

Basic Understanding of Liver Transplant Immunology.

The liver is a specialized organ and plays an important role in our immune system. The liver constitutes parenchymal cells which are hepatocytes and cholangiocytes (60-80%) and non-parenchymal cells like liver sinusoidal endothelial cells (LSECs), hepatic satellite/Ito cells, Kupffer cells, neutrophils, mononuclear cells, T and B lymphocytes (conventional and non-conventional), natural killer cells, and natural killer T (NKT) cells. The liver mounts a rapid and strong immune response, under unfavorable conditions and acts as an immune tolerance to a variety of non-pathogenic antigens. This delicate and dynamic interaction between different kinds of immune cells in the liver maintains a balance between immune screening and immune tolerance. The liver allografts are privileged immunologically; however, allograft rejection is not uncommon and is classified as cell or antibody-mediated. Advancements in transplant immunology help in the prevention of allografts rejection by immune reactions of the host thus leading to better graft and host survival. Fewer patients may not require immunosuppression due to systemic donor-specific T-cell tolerance. The liver tolerance mechanism is poorly studied, and LSEC and unconventional lymphocytes play an important role that dampens T cell response either by inducing apoptosis of cells or inhibiting co-stimulatory pathways. Newer cell-based therapy based on Treg, dendritic cells, and mesenchymal stromal cells will probably change the future of immunosuppression. Various invasive and non-invasive biomarkers and artificial intelligence have also been investigated to predict graft survival, post-transplant complications, and immunotolerance in the future.

Should we abandon therapeutic drug monitoring of tacrolimus in whole blood and move to intracellular concentration measurements?

The measurement of whole blood (WB) concentrations has been the primary method for therapeutic drug monitoring of tacrolimus since its introduction in the field of organ transplantation. However, >99% of tacrolimus measured in WB is bound to erythrocytes and plasma proteins, which are the pharmacologically inactive fractions. The pharmacologically active fractions, the free (or unbound) tacrolimus in plasma and the intracellular tacrolimus, make up 1% or less of the WB concentration. The mechanism of action of tacrolimus is to inhibit the enzyme calcineurin within T lymphocytes and, therefore, measuring the intralymphocytic tacrolimus concentration may better reflect its pharmacodynamic effects and better correlate with clinical outcomes. However, studies on intracellular tacrolimus concentrations have shown conflicting results. In this review, we argue that we need to overcome the analytical limitations of current assays for the measurement of intracellular tacrolimus before moving this technique into the clinical setting. The validity and standardization of the cell isolation process before the measurement of the intracellular tacrolimus concentration is as important as the measurement itself but has received little attention in our view. Recent evidence suggests that the addition of an inhibitor of P-glycoprotein, an efflux transporter expressed on lymphocytes, prevents the expulsion of tacrolimus during the cell isolation process. Refining the technique for the intracellular tacrolimus concentration measurement should be the focus followed by clinical evaluation of its association with rejection risk.

Pregnancy after kidney transplantation: an observational study on maternal, graft and offspring outcomes in view of current literature.

Introduction: Pregnancy after kidney transplantation (KTx) is considered to have a high risk of non-negligible complications for the mother, the allograft, and the offspring. With an increased incidence of these pregnancies over the past decades, transplant nephrologists and specialized obstetricians face increasing challenges, with scarce literature regarding long-term outcomes. Methods: We retrospectively collected data from all women with at least one live birth pregnancy after KTx who were followed at our tertiary hospital between 2000 and 2021 to study maternal, graft and fetal outcomes. Results: Ten patients underwent 14 live birth pregnancies after KTx. Preponderant maternal complications were stage 1 acute kidney injury (43%), urinary tract infections (UTI, 43%), progression of proteinuria without diagnostic criteria for preeclampsia (29%), and preeclampsia (14%). Median baseline serum creatinine at conception was 126.5 µmol/L [median estimated glomerular filtration rate (eGFR) 49 mL/min/1.73m2], and eGFR tended to be lower than baseline at follow-ups. Overall, there was no increase in preexisting or occurrence of de novo donor-specific antibodies. No graft loss was documented within the 2-year follow-up. There were nine premature births (64%), with a median gestational age of 35.7 weeks. The median birth weight, height, and head circumference were 2,560 g, 45.5 cm, and 32.1 cm, respectively. These measurements tended to improve over time, reaching a higher percentile than at birth, especially in terms of height, but on average remained under the 50th percentile curve. Discussion: Overall, pregnancies after KTx came with a range of risks for the mother, with a high prevalence of cesarean sections, emergency deliveries, UTI, and preeclampsia, and for the child, with a high proportion of prematurity, lower measurements at birth, and a tendency to stay under the 50th percentile in growth charts. The short- and long-term impact on the allograft seemed reassuring; however, there was a trend toward lower eGFR after pregnancy. With these data, we emphasize the need for a careful examination of individual risks via specialized pre-conception consultations and regular monitoring by a transplant nephrologist and a specialist in maternal-fetal medicine during pregnancy. More data about the long-term development of children are required to fully apprehend the impact of KTx on offspring.