Prolonged-Release Once-Daily Formulation of Tacrolimus Versus Standard-of-Care Tacrolimus in de novo Kidney Transplant Patients Across Europe.

Background: Tacrolimus is the calcineurin inhibitor of choice for preventing acute rejection episodes in kidney transplant patients. However, tacrolimus has a narrow therapeutic range that requires regular monitoring of blood concentrations to minimize toxicity. A new once-daily tacrolimus formulation, LCP-tacrolimus (LCPT), has been developed, which uses MeltDose™ drug-delivery technology to control drug release and enhance overall bioavailability. Our study compared dosing of LCPT with current standard-of-care tacrolimus [immediate-release tacrolimus (IR-Tac) or prolonged-release tacrolimus (PR-Tac)] during the 6 months following de novo kidney transplantation. Comparisons of graft function, clinical outcomes, safety, and tolerability for LCPT versus IR-Tac/PR-Tac were also performed. Methods: Standard immunological risk patients with end-stage renal disease who had received a de novo kidney transplant were randomized (1:1) to LCPT (N = 200) or IR-Tac/PR-Tac (N = 201). Results: Least squares (LS) mean tacrolimus total daily dose from Week 3 to Month 6 was significantly lower for LCPT than for IR-Tac/PR-Tac. Although LS mean tacrolimus trough levels were significantly higher for LCPT than IR-Tac/PR-Tac, tacrolimus trough levels remained within the standard reference range for most patients. There were no differences between the groups in treatment failure measures or safety profile. Conclusion: LCPT can achieve similar clinical outcomes to other tacrolimus formulations, with a lower daily dose. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT02432833.

Therapeutic Drug Monitoring Strategies for Envarsus in De Novo Kidney Transplant Patients Using Population Modelling and Simulations.

INTRODUCTION: Tacrolimus, the cornerstone of transplantation immunosuppression, is a narrow therapeutic index drug with a low and highly variable bioavailability. Therapeutic drug monitoring based on trough level assessment is mandatory in order to target a personalised exposure and avoid both rejection and toxicity. Population pharmacokinetic (POPPK) models might be a useful tool for improving early attainment of target range by guiding initial doses until steady state is reached and trough levels can be reliably used as surrogate marker of exposure. Here we present the first POPPK for predicting the initial doses of the once-daily prolonged release tacrolimus Envarsus (LCPT) in adult kidney recipients. METHODS: The model was developed exploiting the data from a recent pharmacokinetic randomised clinical study, in which 69 de novo kidney recipients, 33 of whom treated with LCPT, underwent an intensive blood sampling strategy for tacrolimus including four complete pharmacokinetic profiles. RESULTS: The complex and prolonged absorption of LCPT is well described by the three-phase model that incorporates body weight and CYP3A5 genotype as significant covariates accounting for a great proportion of the inter-patient variability: in particular, CYP3A5*1/*3 expressors had a 66% higher LCPT clearance. We have then generated by simulation a personalised dosing strategy based on the model that could improve the early attainment of therapeutic trough levels by almost doubling the proportion of patients within target range (69.3% compared to 36.1% with the standard body weight-based approach) on post-transplantation day 4 and significantly reduce the proportion of overexposed patients at risk of toxicity. CONCLUSIONS: A POPPK model was successfully developed for LCPT in de novo kidney recipients. The model could guide a personalised dosing strategy early after transplantation. For the model to be translated into clinical practice, its beneficial impact of earlier attainment of therapeutic trough levels should be demonstrated on hard clinical outcomes in further studies.

Frailty and Sarcopenia in Older Patients Receiving Kidney Transplantation.

Kidney transplantation is the treatment of choice for most of the patients with end-stage renal disease (ESRD). It improves quality of life, life expectancy, and has a lower financial burden to the healthcare system in comparison to dialysis. Every year more and more older patients are included in the kidney transplant waitlist. Within this patient population, transplanted subjects have better survival and quality of life as compared to those on dialysis. It is therefore crucial to select older patients who may benefit from renal transplantation, as well as those particularly at risk for post-transplant complications. Sarcopenia and frailty are frequently neglected in the evaluation of kidney transplant candidates. Both conditions are interrelated complex geriatric syndromes that are linked to disability, aging, comorbidities, increased mortality, and graft failure post-transplantation. Chronic kidney disease (CKD) and more importantly ESRD are characterized by multiple metabolic complications that contribute for the development of sarcopenia and frailty. In particular, anorexia, metabolic acidosis and chronic low-grade inflammation are the main contributors to the development of sarcopenia, a key component in frail transplant candidates and recipients. Both frailty and sarcopenia are considered to be reversible. Frail patients respond well to multiprofessional interventions that focus on the patients' positive frailty criteria, while physical rehabilitation and oral supplementation may improve sarcopenia. Prospective studies are still needed to evaluate the utility of formally measuring frailty and sarcopenia in the older candidates to renal transplantation as part of the transplant evaluation process.

Metabolic risk profile in kidney transplant candidates and recipients.

Metabolic risk factors of cardiovascular disease such as abnormal glucose regulation, obesity and metabolic syndrome, dyslipidaemia, metabolic bone disease, hyperuricaemia and other less traditional abnormalities are common in both kidney transplant candidates and recipients. In kidney transplant candidates, the presence of these risk factors may impede patient access to transplantation by increasing the risk of developing comorbidities while on the waiting list, prolonging the time to wait-listing and, in some patients, eventually jeopardizing their suitability for kidney transplantation or increasing the risk of severe perioperative complications. In transplant recipients, metabolic risk factors may be associated with increased mortality with a functioning graft and with reduced long-term renal graft survival. Although most transplant recipients have no contraindication to the use of drugs that undergo renal excretion, they may be at risk of drug-to-drug pharmacokinetic interactions with anti-rejection medicines. In this review, we have highlighted the main objectives of evaluating the metabolic abnormalities in transplant candidates and recipients, how this evaluation should be carried out in practice and what currently the most valuable treatment strategies are for modifying the associated risks. We conclude that, for every potential transplant candidate, every effort should be made to control metabolic abnormalities causing arterial calcification, which may impede access to transplantation and impair transplant outcome. In transplant recipients, metabolic abnormalities that result from adverse effects of anti-rejection therapy may be effectively controlled by lifestyle changes and judicious use of drugs for the treatment of abnormal glucose metabolism and dyslipidaemia.

Pharmacokinetics of Prolonged-Release Once-Daily Formulations of Tacrolimus in De Novo Kidney Transplant Recipients: A Randomized, Parallel-Group, Open-Label, Multicenter Study.

INTRODUCTION: Different prolonged-release formulations of tacrolimus are available. To date, the pharmacokinetic (PK) profile of LCP-tacrolimus (LCPT; Envarsus®) has not been compared with PR-Tac (Advagraf®) in de novo kidney transplant recipients. These profiles will guide clinical recommendations for the initiation and dose titration strategies of once-daily tacrolimus formulations. METHODS: This randomized, parallel-group, open-label, multicenter PK study randomized 75 de novo, adult, white kidney transplant recipients to LCPT 0.17 mg/kg/day (n = 37) or PR-Tac 0.20 mg/kg/day (n = 38) for 4 weeks. Dose adjustments were permitted to target a pre-defined therapeutic range based on measured trough blood concentrations. RESULTS: PK analysis (days 1, 3, 7 and 14) included 68 patients (LCPT, n = 33; PR-Tac, n = 35). Similar proportions of patients were within the pre-defined therapeutic tacrolimus trough blood concentration range, with < 12% in each group having below-target trough levels over the study period. LCPT demonstrated ~ 30% greater relative bioavailability [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 1.32 (p = 0.007); day 7, 1.25 (p = 0.051); day 14, 1.43 (p = 0.002)] and ~ 30% lower peak-to-trough percentage fluctuation of blood concentration [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 0.70 (p < 0.001); day 7, 0.68 (p < 0.001); day 14, 0.73 (p = 0.004)] in addition to longer time to maximum blood concentration (tmax), lower maximum concentration (Cmax) and a consistently lower daily dose (~ 40% dose reduction with LCPT vs. PR-Tac by day 28). Safety profiles were similar. CONCLUSION: In de novo kidney transplant recipients, prolonged-release formulations of tacrolimus can reach therapeutic concentrations in the immediate post-transplant period. LCPT has greater relative bioavailability and lower peak-to-trough fluctuation compared with PR-Tac. TRIAL REGISTRATION: Registered at ClinicalTrials.gov; study number NCT02500212. FUNDING: Chiesi Farmaceutici S.p.A.

Dietary protein and nutritional supplements in conventional hemodialysis.

Protein energy wasting (PEW) is a condition commonly occurring among patients with ESRD on hemodialysis. PEW is characterized by depletion of protein and energy stores and is caused by multiple factors related to chronic kidney disease, acute and chronic comorbidities and by renal replacement therapy itself. Anorexia is central in the pathogenesis of PEW; it is frequently observed in these patients whose protein and energy intakes are typically lower than guidelines recommendations. If untreated, PEW invariably leads to major complications, and may activate a vicious circle with further worsening of nutritional status. Dietary counseling and nutritional status monitoring play a key role in the prevention and treatment of PEW, since they allow an early identification of high risk patients, as well as the assessment of the response to nutritional intervention. Different nutritional approaches can be implemented following thorough nutritional counseling. These are chosen on the basis of patients' spontaneous dietary intake, severity of PEW and acute comorbidities. Initially, regular encounters with the dietitian allow patients to clarify doubts and strengthen basic concepts on nutrition to improve dietary intake and prevent PEW. When PEW is present or the patient is at high risk, the clinician may opt for the administration of oral intradialytic or daily supplements, aiming at increasing energy and protein intake, while in selected cases intradialytic parenteral nutrition may be used. This review addresses the main issues of nutritional status in ESRD patients on hemodialysis-its evaluation and monitoring, as well as at describing the available nutritional interventions.

Contrast medium induced acute kidney injury: a narrative review.

BACKGROUND AND AIMS: Contrast-induced acute kidney injury (CI-AKI) is the third leading cause of hospital-acquired acute kidney injury. It is more commonly observed following intra-arterial administration of iodinated contrast media (CM) for cardiac procedures in patients with pre-existing chronic kidney disease (CKD), and is associated with increased short- and long-term morbidity and mortality. This review investigates the key current evidence on CI-AKI definition, epidemiology and pathogenesis, as a basis for recommending preventive measures that can be implemented in clinical practice. METHODS: An extensive literature search was performed to identify the relevant studies describing the epidemiology, pathogenesis, outcome and prevention of CI-AKI. RESULTS AND CONCLUSION: Pre-existing CKD, intra-arterial administration and CM volume are the most important risk factors for CI-AKI. Since risk factors for CI-AKI are well defined, and the timing of renal insult is known, patients should be carefully stratified before the administration of CM, in order to reduce the negative impact of modifiable risk factors on renal function. The intravenous administration of moderate amounts of isotonic saline solution or bicarbonate solution still represents the principal intervention with documented and acceptable effectiveness for CI-AKI prevention. More data are needed on aggressive volume expansion strategies along with diuretics, targeting forced diuresis with high urinary output. The role of antioxidant agents remains controversial, and only moderate evidence exists in favour of N-acetylcysteine. Statins could contribute to reducing the incidence of CI-AKI, although their mechanism of action is not fully ascertained. No robust data demonstrate a reduction of CI-AKI incidence by peri-procedural hemodialysis/hemofiltration; renal replacement therapies may carry instead unnecessary risks. Remote ischemic preconditioning might represent a simple, non-invasive and cost effective preventive measure for CI-AKI prevention, but few data are currently available about its clinical application in patients at high risk of CI-AKI.

Rapid Biolayer Interferometry Measurements of Urinary CXCL9 to Detect Cellular Infiltrates Noninvasively After Kidney Transplantation.

INTRODUCTION: Measuring the chemokine CXCL9 in urine by enzyme-linked immunosorbent assay (ELISA) can diagnose acute cellular rejection (ACR) noninvasively after kidney transplantation, but the required 12- to 24-hour turnaround time is not ideal for rapid, clinical decision-making. METHODS: We developed a biolayer interferometry (BLI)-based assay to rapidly measure urinary CXCL9 in <1 hour. We validated this new assay versus standard ELISA in 86 urine samples from kidney transplantation recipients with various diagnoses. We then used BLI to analyze samples from 56 kidney transplantation recipients, including 46 subjects who experienced an acute rise in serum creatinine associated with biopsy-proven ACR (n = 22), subclinical rejection (n = 15), or no infiltrates (n = 9), and 10 stable kidney transplantation recipients with surveillance biopsies. To assess its usefulness in detecting adequacy of therapy we serially measured serum creatinine and urinary CXCL9 in 6 subjects after treatment for ACR, and correlated the results with histological diagnoses on follow-up biopsies. RESULTS: BLI accurately and reproducibly detected urinary CXCL9 in <1 hour. BLI-based results showed that urinary CXCL9 was >200 pg/ml in subjects with ACR and ≤100 pg/ml in subjects with stable kidney function without cellular infiltrates. In samples obtained after treatment for ACR, BLI CXCL9 measurements detected biopsy-proven intragraft infiltrates despite treatment-induced reduction in serum creatinine. DISCUSSION: Together, our proof-of-principle results demonstrate that BLI-based urinary CXCL9 detection has potential as a point-of-care noninvasive biomarker to diagnose and guide therapy for ACR in kidney transplantation recipients.

Once-daily prolonged-release tacrolimus formulations for kidney transplantation: what the nephrologist needs to know.

Tacrolimus has long been the cornerstone of the immunosuppressive standard-of-care in kidney transplantation. Until recently, only an immediate-release formulation of tacrolimus was available in the clinic for twice-daily administration, a schedule that is known to hamper prescription adherence and contributes to the already significant tacrolimus interactions with other drugs and meals. In order to improve patient compliance, two once-daily prolonged-release formulations of tacrolimus have recently been developed and approved. Here we will analyze the main characteristics of these two prolonged-release formulations with the aim to provide practical clinical information for a fully aware drug prescription. Finally, the theoretical advantages of the prolonged-release formulations in terms of prescription adherence, blood level steadiness and drug efficacy and tolerability will be critically reviewed, in order to define the profile of renal recipients who may benefit most from the switch to once-daily tacrolimus.

[Protein-energy wasting and nutritional supplementation in chronic hemodialysis]. / Deplezione proteico-energetica e supplementazione nutrizionale nei pazienti in emodialisi cronica.

Protein Energy Wasting (PEW) is a pathological condition characterized by a progressive reduction of protein and energy stores. PEW has a high prevalence among patients with CKD/ESRD (Chronic Kidney Disease/End Stage Renal Disease) and is closely associated with adverse clinical outcomes and increased rate of hospitalization, complications and mortality. The multifactorial pathogenesis of PEW is complex. A key role is played both by the reduced intake of nutrients and the condition of hypercatabolism/reduced anabolism typical of renal patients. The approach to prevent or treat PEW has several milestones such as reduction of potential risk factors, improvement in lifestyle and correction of any factor related to dialysis. It also needs a periodic assessment of nutritional status by using biochemical markers, body and muscle mass variables, nutritional scores and instrumental methods, aiming for an early diagnosis. In case of reduced protein and energy intake, the administration of nutrients during dialysis, or the use of oral supplements specific for renal patients are the first nutritional interventions recommended. In fact, oral nutritional supplementation represents the most effective nutritional approach to PEW prevention and treatment. It is simple and safe and it has a positive impact on quality of life and survival of haemodialysis patients. In the case of failure of oral supplementation, nutritional support should be enhanced by using intradialytic parenteral nutrition (IDPN). If the patient has difficulty in swallowing or IDPN is insufficient, total enteral nutrition should be considered.

Vascular endothelium as a target of immune response in renal transplant rejection.

This review of clinical and experimental studies aims at analyzing the interplay between graft endothelium and host immune system in renal transplantation, and how it affects the survival of the graft. Graft endothelium is indeed the first barrier between self and non-self that is encountered by host lymphocytes upon reperfusion of vascularized solid transplants. Endothelial cells (EC) express all the major sets of antigens (Ag) that elicit host immune response, and therefore represent a preferential target in organ rejection. Some of the Ag expressed by EC are target of the antibody-mediated response, such as the AB0 blood group system, the human leukocyte antigens (HLA), and MHC class I related chain A antigens (MICA) systems, and the endothelial cell-restricted Ag; for each of these systems, the mechanisms of interaction and damage of both preformed and de novo donor-specific antibodies are reviewed along with their impact on renal graft survival. Moreover, the rejection process can force injured EC to expose cryptic self-Ag, toward which an autoimmune response mounts, overlapping to the allo-immune response in the damaging of the graft. Not only are EC a passive target of the host immune response but also an active player in lymphocyte activation; therefore, their interaction with allogenic T-cells is analyzed on the basis of experimental in vitro and in vivo studies, according to the patterns of expression of the HLA class I and II and the co-stimulatory molecules specific for cytotoxic and helper T-cells. Finally, as the response that follows transplantation has proven to be not necessarily destructive, the factors that foster graft endothelium functioning in spite of rejection, and how they could be therapeutically harnessed to promote long-term graft acceptance, are described: accommodation that is resistance of EC to donor-specific antibodies, and endothelial cell ability to induce Foxp3+ regulatory T-cells, that are crucial mediators of tolerance.

A retrospective analysis of dermatological lesions in kidney transplant patients.

BACKGROUND & OBJECTIVES: Kidney transplantation is the best option for patients with end-stage renal disease (ESRD) failure. Prolonged use of immunosuppressive drugs often causes opportunistic infections and malignancies of skin and mucosae, but due to lack of a careful dermatological screening in several transplantation centers the diagnosis and the treatment of dermatological lesions in kidney transplant patients are underestimated. In addition after the introduction of interleukin (IL)-2 -receptor antagonists (basiliximab/daclizumab), mTOR inhibitors and mycophenolate mofetil (MMF)/mycophenolic acid (MPA) in new immunosuppressive protocols only a few studies have analyzed the skin and mucosal lesions in kidney transplant patients. This study was undertaken to evaluate the cutaneous and mucosal diseases after kidney transplantation, and to investigate the association between these and different immunosuppressive protocols and/or demographic features. METHODS: A retrospective analysis was done using medical records of kidney transplantation between 2000 and 2009 at the Transplant Unit of Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. The study included 183 patients (M 57.3%, F 42.7%) aged 51.5 ± 11.8 yr) with transplant age 52.3 ± 34.9 months. Induction therapy was basiliximab and steroids based; maintenance therapy included combination-regimes from cyclosporine, tacrolimus, steroids, mycophenolate mofetil (MM), mycophenolic acid (MPA), rapamycin, everolimus. Anti-rejection therapy was steroid and/or thymoglobulines based. Diagnosis of cutaneous disease was made through examination of skin, mucous membranes, nails and hair evaluation. Skin biopsies, specific cultures and serological tests were done when required. RESULTS: Skin and mucosal diseases were reported in 173 (95.7%) of patients; 88 (50.81%) showed viral lesions; 92 (53.01%) immunosuppression-related lesions; 28 (16.39%) benign tumours; 26 (15.3%) precancers /neoplastic lesions; 24 (14.21%) mycosis; 16 (9.29%) cutaneous xerosis, 15 (8.74%) dermatitis, while absence of cutaneous disease was evident only in 8 (4.37%) cases. An association between drug side effects and anti-rejection treatment ( P ≤ 0.01) and/or calcineurin-inhibitors (CNI) exposure ( P ≤ 0.01) was found. Longer exposure to immunosuppressive drugs (>60 months) was associated with pre-malignancy and malignancy lesions. INTERPRETATION & CONCLUSIONS: Cutaneous diseases are frequent in kidney transplanted patients. Continuous skin monitoring is necessary to make an early diagnosis and to start appropriate treatment.

The syndrome of inappropriate antidiuresis: pathophysiology, clinical management and new therapeutic options.

Hyponatremia is a marker of different underlying diseases and it can be a cause of morbidity itself; this implies the importance of a correct approach to the problem. The syndrome of inappropriate antidiuresis (SIAD) is one of the most common causes of hyponatremia: it is a disorder of sodium and water balance characterized by urinary dilution impairment and hypotonic hyponatremia, in the absence of renal disease or any identifiable non-osmotic stimulus able to induce antidiuretic hormone (ADH) release; according to its definition, it is diagnosed through an exclusion algorithm. SIAD is usually observed in hospitalized patients and its prevalence may be as high as 35%. The understanding of the syndrome has notably evolved over the last years, as reflected by the significant change in the name, once the syndrome of inappropriate secretion of ADH (SIADH), today SIAD. This review is up to date and it analyses the newest notions about pathophysiological mechanisms, classification, management and therapy of SIAD, including vaptans.

Mesenchymal stromal cells improve renal injury in anti-Thy 1 nephritis by modulating inflammatory cytokines and scatter factors.

MSC (mesenchymal stromal cells) can differentiate into renal adult cells, and have anti-inflammatory and immune-modulating activity. In the present study, we investigated whether MSC have protective/reparative effects in anti-Thy1 disease, an Ab (antibody)-induced mesangiolysis resulting in mesangioproliferative nephritis. We studied five groups of rats: (i) rats injected with anti-Thy1.1 Ab on day 0 (group A); (ii) rats injected with anti-Thy1.1 Ab on day 0+MSC on day 3 (group B); (iii) rats injected with anti-Thy1.1 Ab on day 0+mesangial cells on day 3 (group C); (iv) rats injected with saline on day 0+MSC on day 3 (group D); and (v) rats injected with saline on day 0 (group E). Rats were killed on days 1, 3, 7 and 14. MSC prevented the increase in serum creatinine, proteinuria, glomerular monocyte influx and glomerular histopathological injury. Furthermore, MSC suppressed the release of IL-6 (interleukin-6) and TGF-ß (transforming growth factor-ß), modulated glomerular PDGF-ß (platelet-derived growth factor-ß), and reset the scatter factors and their receptors, potentiating HGF (hepatocyte growth factor)/Met and inactivating MSP (macrophage-stimulating protein)/Ron (receptor origin nantaise). Few MSC were found in the kidney. These results indicate that MSC improve anti-Thy 1 disease not by replacing injured cells, but by preventing cytokine-driven inflammation and modulating PDGF-ß and the scatter factors, i.e. systems that regulate movement and proliferation of monocytes and mesangial cells.

[Non-heart-beating-donor transplant: the first experience in Italy]. / Trapianto di rene da donatore a cuore non battente: la prima esperienza in Italia.

A promising way to increase the number of kidneys for transplantation is to expand the donor pool by including non-heart-beating donors (NHBDs). The centers involved in NHBD transplantation programs have reported a 16-40% increase in kidney transplants. A key issue with NHBD is the significantly higher rate of delayed graft function (DGF) and primary non-function (PNF) compared with that associated with heart-beating donor (HBD) transplants. However, although transplants from NHBD are associated with a greater incidence of early adverse events, long-term graft survival appears to be similar to that observed after transplants from HBDs. In addition, the use of extracorporeal membrane oxygenation and mechanical perfusion, the careful selection of recipients and donors, and an adequate therapeutic strategy may at least partially reduce the risk of PNF and DGF and improve transplant outcome.

Severe symptomatic hyponatremia during sibutramine therapy: a case report.

Sibutramine, a serotonin reuptake inhibitor, currently is used in treatment of obesity. The known side effects of sibutramine, ie, hypertension and tachycardia, depend on its adrenergic and serotoninergic effects. We describe a case of life-threatening hyponatremia associated with sibutramine use in an obese woman. We hypothesize that sibutramine, through its effect on neurotransmitters, may induce antidiuretic hormone secretion and lead to a syndrome of inappropriate antidiuretic hormone secretion. We advise careful monitoring of water-electrolytic balance during sibutramine therapy.