Topical Prescription Management.

With recent advances in topical therapies for atopic dermatitis (AD), steroid-sparing options like calcineurin inhibitors, Janus kinase (JAK) inhibitors, and phosphodiesterase-4 (PDE-4) inhibitors are becoming mainstays in therapy, underscoring the importance of careful selection and usage of topical corticosteroids (TCSs) to minimize side effects. Alongside the necessity of emollient use, these steroid-sparing alternatives offer rapid itch relief and efficacy in improving disease severity. While TCSs still hold a prominent role in AD management, promising novel topical treatments like tapinarof and live biotherapeutics to modulate the skin microbiome are also discussed. Overall, the recent addition of novel topical therapies offers diverse options for AD management and underscores the importance of topical treatments in the management of AD.

Effects of Antithymocyte Globulin, Basiliximab, and Induction-Free Treatment in Living Donor Kidney Transplant Recipients on Tacrolimus-Based Immunosuppression.

OBJECTIVES: Induction treatment in renal transplant is associated with better graft survival. However, intensified immunosuppression is known to cause unwanted side effects such as infection and malignancy. Furthermore, the effects of the routine use of immunosuppressants in low-risk kidney transplant recipients are still not clear. In this study, we assessed the first-year safety and efficacy of induction treatment. MATERIALS AND METHODS: We examined first living donor kidney transplant patients who were on tacrolimus based immunosuppression therapy. We formed 3 groups according to the induction status: antithymocyte globulin induction, basiliximab induction, and no induction. We collected outcome data on delayed graft function, graft loss, creatinine levels, estimated glomerular filtration rates, acute rejection episodes, hospitalization episodes, and infection episodes, including cytomegalovirus infection and bacterial infections. RESULTS: We examined a total of 126 patients (age 35 ± 12 years; 65% male). Of them, 25 received antithymocyte globulin, 52 received basiliximab, and 49 did notreceive any induction treatment. We did not observe any statistically significant difference among the 3 groups in terms of acute rejection episodes, delayed graft function, and first-year graft loss. The estimated glomerular filtration rates were similar among the groups. Overall bacterial infectious complications and cytomegalovirus infection showed similar prevalence among all groups. Hospitalization was less common in the induction-free group. CONCLUSIONS: In low-risk patients, induction-free regimens could be associated with a better safety profile without compromising graft survival. Therefore, induction treatment may be disregarded in first living donor transplant patients who receive tacrolimusbased triple immunosuppression treatment.

Assessing effectiveness of adding niosomal atorvastatin 1% ointment to topical calcineurin inhibitor treatment in non-segmental vitiligo.

BACKGROUND: Treatment of vitiligo is still a big challenge for dermatologists. The efficacy of statins in the treatment of vitiligo is controversial. AIM AND OBJECTIVE: We studied possible therapeutic effect of topical 1% niosomal atorvastatin ointment combined with topical 0.1% tacrolimus in treatment of non-segmental vitiligo. METHODS: This is a triple blind, pilot, randomized placebo-controlled trial (RCT) that was performed in dermatology clinic. All the patients used topical 0.1% tacrolimus cream twice daily (BD). Moreover, the intervention group participants used topical 1% niosomal atorvastatin ointment, and control group participants were prescribed placebo ointment, BD. Patients were evaluated using vitiligo area surface index (VASI) score and patients' satisfaction at baseline and after 3 months treatment. RESULTS: The mean patient satisfaction in the intervention and control groups were 5 ± 1.4 and 3.5 ± 1.9; the difference between groups was not statistically significant (p = 0.9). We found statistically significant difference in VASI score before and after treatment in both intervention and control groups (p = 0.01 and p = 0.03, respectively). However, comparison of the VASI score between groups was not statistically significant (p = 0.62). We also found no significant correlation between VASI score and other variables. CONCLUSION: The result of this study indicates that adding of niosomal atorvastatin 1% ointment to topical calcineurin inhibitor has no additional effect on non-segmental type of vitiligo. Further large studies with different combinations are recommended before any conclusive result can be concluded on efficacy of statins in vitiligo.

A phase II study of post-transplant cyclophosphamide combined with tacrolimus for GVHD prophylaxis after HLA-matched related/unrelated allogeneic hematopoietic stem cell transplantation.

A combination of three post-transplant drugs, cyclophosphamide (PTCy), a calcineurin inhibitor, and mycophenolate mofetil, has long been used for prophylaxis of graft-versus-host-disease (GVHD) after HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT). Recently, this combination has been used following HLA-matched allo-HCT as well, but the optimal combination of drugs for GVHD prophylaxis in an HLA-matched setting remains unclear. This prospective phase II study evaluated the safety and efficacy of PTCy plus tacrolimus (TAC) for GVHD prophylaxis after allo-HCT from HLA-matched related donors (MRD) or HLA-matched unrelated donors (MUD). The cumulative incidences of grades II-IV and III-IV acute GVHD at 100 days post-transplantation were 18% and 5.9%, respectively, in the MRD group, and 18% and 9.1%, respectively, in the MUD group. The cumulative incidences of moderate to severe chronic GVHD at 1 year were 12% and 9.1% in the MRD and MUD groups, respectively. The 1-year overall survival rates in the MRD and MUD groups were 88% and 64%, respectively, and the 1-year GVHD-free, relapse free survival rates were 59% and 50%, respectively. These results suggest that GVHD prophylaxis with a less intensive double drug combination (PT/Cy and TAC) might be feasible after HLA-matched allo-HCT.Clinical Trial Notation This trial was a prospective single-center trial registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; identification number: UMIN000023890) and the Japan Registry of Clinical Trials (jRCTs051180143).

Novel Effects of Combination Therapy Through Inhibition of Caspase-1/Gasdermin D Induced-Pyroptosis in Lupus Nephritis.

Objectives: Combination therapy with mycophenolate mofetil, tacrolimus and steroids are effective in achieving complete remission in lupus nephritis (LN). Combination therapy uniquely downregulated caspase-1 compared with monotherapies, which can cleave gasdermin D (GSDMD) and was recently identified as the pyroptosis executioner. We therefore investigated whether combination therapy enabled the suppression of caspase-1/GSDMD-mediated pyroptosis in LN. Methods: Expression and activation of GSDMD were detected in kidney specimens of the human and mouse with LN using immunohistochemical staining and immunoblotting. Primary podocytes isolated from MRL/lpr mice were incubated with LPS+ATP, and pretreated with monotherapy or combination therapy. Inhibition of caspase-1/GSDMD-induced pyroptosis by combination therapy were assessed in MRL/lpr mice and human specimens. Pyroptosis was examined using a FAM caspase-1 kit and flow cytometry. The correlation between pyroptosis in peripheral blood and the systemic lupus erythematosus disease activity index (SLEDAI) was analyzed. Results: Kidney tissue specimens from LN patients and mice exhibited greatly increased expression levels and cleavage of GSDMD. In cultured podocytes, combination treatment significantly suppressed the activation of NLRP3 and caspase-1 and reduced GSDMD N-terminal levels. Combination therapy repressed disease progression through inhibition of caspase-1/GSDMD-mediated pyroptosis in both humans and MRL/lpr mice. Caspase-1/PI positive cell numbers in peripheral blood were positively correlated with SLE-DAI. LN patients with complete remission and partial remission had remarkably reduced caspase-1/PI positive cell numbers compared to baseline. Ac-FLTD-CMK, a GSDMD-derived inhibitor, prevented the development of LN. Conclusion: Combination therapy suppressed caspase-1/GSDMD-mediated pyroptosis in vitro and in vivo and reduced disease progression.

Stratification of atopic dermatitis patients by patterns of response to proactive therapy with topical tacrolimus: low serum IgE levels and inadequately controlled disease activity at the start of treatment predict its failure.

PURPOSE: Topical calcineurin inhibitors (TCIs) are an important anti-inflammatory drug for treating atopic dermatitis (AD). However, those treatment responses are variable. In this study, we stratified AD patients by patterns of response to remission maintenance therapy (proactive therapy) with topical tacrolimus, a typical TCI. Thereafter, we explored patient features that predict the success or failure of proactive therapy using TCI (TCI proactive therapy). METHODS: A single-arm open-label clinical study aimed to evaluate the efficacy of TCI proactive therapy was conducted in 31 patients with AD. Patients were treated with TCS to induce remission (remission-induction period) followed by daily TCI ointment (0.1% tacrolimus) application for 4 weeks (maintenance therapy period), and twice-weekly application for 12 weeks (proactive therapy period). Based on its results, treatment outcomes were correlated with the patients' clinical and laboratory findings. RESULTS: Of the 31 patients enrolled in the study, 21 successfully completed maintenance therapy (TCI responders). Among them, 13 completed (proactive-completed group) and 8 failed proactive therapy (proactive-dropout group). At the beginning of maintenance therapy, the serum IgE level was significantly higher in the TCI responders than in those who failed maintenance therapy (p = 0.049). At the beginning of proactive therapy, the mean-SCORing Atopic Dermatitis (SCORAD) score was significantly different between the proactive-completed (11.7 ± 4.6) and proactive-dropout (16.6 ± 4.2) groups (p = 0.025). In proactive-dropout group patients, worsened disease activity correlated well with the elevation of serum lactate dehydrogenase (LDH) and Thymus and activation-regulated chemokine (TARC) levels and peripheral eosinophil count. CONCLUSION: AD patients were stratified into three different response patterns to TCI proactive therapy. Patients with less involvement of IgE in the pathogenesis and inadequate remission induction by TCS may not be expected to respond well to TCI proactive therapy.Key messagesAD patients can be stratified into three types according to their pattern of responsiveness to TCI proactive therapy.The efficacy of TCI proactive therapy is lower in AD patients with lower serum IgE levels.TCI proactive therapy should be done after the achievement of adequate remission induction by TCS.

Factors Affecting Time-Varying Clearance of Cyclosporine in Adult Renal Transplant Recipients: A Population Pharmacokinetic Perspective.

AIM: The pharmacokinetic (PK) properties of cyclosporine (CsA) in renal transplant recipients are patient- and time-dependent. Knowledge of this time-related variability is necessary to maintain or achieve CsA target exposure. Here, we aimed to identify factors explaining variabilities in CsA PK properties and characterize time-varying clearance (CL/F) by performing a comprehensive analysis of CsA PK factors using population PK (popPK) modeling of long-term follow-up data from our institution. METHODS: In total, 3674 whole-blood CsA concentrations from 183 patients who underwent initial renal transplantation were analyzed using nonlinear mixed-effects modeling. The effects of potential covariates were selected according to a previous study and well-accepted theoretical mechanisms. Model-informed individualized therapeutic regimens were also evaluated. RESULTS: A two-compartment model adequately described the data and the estimated mean CsA CL/F was 32.6 L h-1 (relative standard error: 5%). Allometrically scaled body size, hematocrit (HCT) level, CGC haplotype carrier status, and postoperative time may contribute to CsA PK variability. The CsA bioavailability in patients receiving a prednisolone dose (PD) of 80 mg was 20.6% lower than that in patients receiving 20 mg. A significant decrease (52.6%) in CL/F was observed as the HCT increased from 10.5% to 60.5%. The CL/F of the non-CGC haplotype carrier was 14.4% lower than that of the CGC haplotype carrier at 3 months post operation. CONCLUSIONS: By monitoring body size, HCT, PD, and CGC haplotype, changes in CsA CL/F over time could be predicted. Such information could be used to optimize CsA therapy. CsA dose adjustments should be considered in different postoperative periods.

Chronic liver graft-versus-host disease in allogeneic hematopoietic stem cell transplantation recipients during tapering or after stopping calcineurin inhibitors.

Chronic graft-versus-host disease (cGVHD) of the liver is often observed in allogeneic hematopoietic stem cell transplantation (allo-HSCT) during tapering or after stopping calcineurin inhibitors (CI). We conducted a retrospective analysis of 242 allo-HSCT recipients whose CI dose was reduced to less than 40 mg of cyclosporin A or 0.4 mg of tacrolimus to clarify the clinical characteristics of liver GVHD in patients on low-dose CI. Sixty patients (25%) developed clinically suspected liver cGVHD while on low-dose CI. Multivariate analysis showed that donor age ≥ 40 years [hazard ratio (HR) 2.20], myeloablative conditioning (HR 2.19), female donor to male recipient (HR 2.53) and recipient seropositivity for herpes simplex virus (HR 2.52) were significant risk factors for liver cGVHD during low-dose CI period. Peak aspartate aminotransferase and alanine aminotransferase levels were higher in patients with liver GVHD during low-dose CI period than in other periods. Twenty-seven patients were initially treated with resumption of CI or a CI dose increase and 21 responded. Among the 18 patients treated with corticosteroids, total bilirubin was a risk factor for failure of corticosteroid therapy. The results of this study clarified the clinical characteristics of liver GVHD in patients on low-dose CIs.

Appraisal of Proactive Topical Therapy in Atopic Dermatitis: Pros and Cons.

Atopic dermatitis is a common inflammatory skin disease that can affect both children and adults. It is a chronic disease with recurrent, highly pruritic eczematous lesions. Topical treatment with anti-inflammatory agents is the mainstay of treatment for atopic dermatitis, either in a reactive or proactive approach according to severity of the disease and always in combination with daily application of an emollient cream. Several studies have shown that proactive therapy with either topical corticosteroids or topical calcineurin inhibitors is significantly superior at reducing the number of flares and increasing the interval between flares compared with reactive therapy in patients with moderate and severe disease. The risk of side effects is considered low, and there seem to be no extra economic costs related to this treatment approach. Proactive therapy is an advisable treatment option for patients with moderate and severe atopic dermatitis to gain prolonged disease control; however, long-term safety data and data on when to stop do not yet exist.

Rationale and design of the OPTIMIZE trial: OPen label multicenter randomized trial comparing standard IMmunosuppression with tacrolimus and mycophenolate mofetil with a low exposure tacrolimus regimen In combination with everolimus in de novo renal transplantation in Elderly patients.

BACKGROUND: In 2019, more than 30 % of all newly transplanted kidney transplant recipients in The Netherlands were above 65 years of age. Elderly patients are less prone to rejection, and death censored graft loss is less frequent compared to younger recipients. Elderly recipients do have increased rates of malignancy and infection-related mortality. Poor kidney transplant function in elderly recipients may be related to both pre-existing (i.e. donor-derived) kidney damage and increased susceptibility to nephrotoxicity of calcineurin inhibitors (CNIs) in kidneys from older donors. Hence, it is pivotal to shift the focus from prevention of rejection to preservation of graft function and prevention of over-immunosuppression in the elderly. The OPTIMIZE study will test the hypothesis that reduced CNI exposure in combination with everolimus will lead to better kidney transplant function, a reduced incidence of complications and improved health-related quality of life for kidney transplant recipients aged 65 years and older, compared to standard immunosuppression. METHODS: This open label, randomized, multicenter clinical trial will include 374 elderly kidney transplant recipients (≥ 65 years) and consists of two strata. Stratum A includes elderly recipients of a kidney from an elderly deceased donor and stratum B includes elderly recipients of a kidney from a living donor or from a deceased donor < 65 years. In each stratum, subjects will be randomized to a standard, tacrolimus-based immunosuppressive regimen with mycophenolate mofetil and glucocorticoids or an adapted immunosuppressive regimen with reduced CNI exposure in combination with everolimus and glucocorticoids. The primary endpoint is 'successful transplantation', defined as survival with a functioning graft and an eGFR ≥ 30 ml/min per 1.73 m2 in stratum A and ≥ 45 ml/min per 1.73 m2 in stratum B, after 2 years, respectively. CONCLUSIONS: The OPTIMIZE study will help to determine the optimal immunosuppressive regimen after kidney transplantation for elderly patients and the cost-effectiveness of this regimen. It will also provide deeper insight into immunosenescence and both subjective and objective outcomes after kidney transplantation in elderly recipients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03797196 , registered January 9th, 2019. EudraCT: 2018-003194-10, registered March 19th, 2019.

Disruption of Tfh:B Cell Interactions Prevents Antibody-Mediated Rejection in a Kidney Transplant Model in Rats: Impact of Calcineurin Inhibitor Dose.

We aimed to investigate the mechanisms of humoral immune activation in ABMR using a MHC-mismatched rat kidney transplant model. We applied low dose cyclosporine A (loCNI) to allow donor-specific antibody (DSA) formation and rejection and high dose cyclosporine A (hiCNI) for non-rejection. DSA and leukocyte subsets were measured by flow cytometry. Germinal centers (GC), T follicular helper cells (Tfh), plasma cells and interleukin-21 (IL-21) expression were analyzed by immunofluorescence microscopy. Expression of important costimulatory molecules and cytokines was measured by qRT-PCR. Allograft rejection was evaluated by a nephropathologist. We found that DSA formation correlated with GC frequency and expansion, and that GC size was linked to the number of activated Tfh. In hiCNI, GC and activated Tfh were virtually absent, resulting in fewer plasma cells and no DSA or ABMR. Expression of B cell activating T cell cytokine IL-21 was substantially inhibited in hiCNI, but not in loCNI. In addition, hiCNI showed lower expression of ICOS ligand and IL-6, which stimulate Tfh differentiation and maintenance. Overall, Tfh:B cell crosstalk was controlled only by hiCNI treatment, preventing the development of DSA and ABMR. Additional strategies targeting Tfh:B cell interactions are needed for preventing alloantibody formation and ABMR.

Calcineurin Inhibitor Toxicity in Solid Organ Transplantation.

Calcineurin inhibitors (CNIs) have a substantial role in maintaining immunosuppression after solid organ transplantation (SOT). These drugs have a narrow therapeutic window, and individual doses and drug treatment monitoring are necessary. Still, a substantial proportion of patients suffer from short- or long-term calcineurin inhibitor toxicity (CNT), including kidney function impairment, hypertension, neurotoxicity, and metabolic disturbances. The authors discuss pathophysiology, clinical presentation, and histological features of CNT, with focus on renal manifestations. Furthermore, we elucidate recent and ongoing attempts to reduce the burden of CNT in SOT including CNI-sparing and CNI-free regimens.

Diagnosis and Management of Dermatitis, Including Atopic, Contact, and Hand Eczemas.

This is a comprehensive and current guide for the diagnosis, differential diagnosis, treatment, and management of eczematous dermatitis, with a focus on atopic dermatitis, irritant and allergic contact dermatitis, hand dermatitis including recurrent vesicular and hyperkeratotic types, asteatotic dermatitis, and nummular or discoid dermatitis. Diagnostic options highlighted are clinical history, physical examination, and patch testing. Therapeutic options highlighted are moisturizers, topical corticosteroids, topical calcineurin inhibitors, crisaborole, phototherapy, and systemic medications including biologics.

Approach to the Patient with Chronic Pruritus.

Chronic pruritus (itch lasting ≥6 weeks) is a bothersome chief complaint that may present in a broad variety of diseases. Most itch-causing diagnoses fit into 1 of 5 categories (inflammatory, secondary to systemic disease, neuropathic, chronic pruritus of undetermined origin, and psychogenic itch) and this broad differential can be narrowed using key findings in the history and physical. In this article, we discuss which key findings are most pertinent for narrowing this differential and guiding further workup and treatment, as well as how to treat many itchy conditions.

Association of ABCC2 Haplotypes to Mycophenolic Acid Pharmacokinetics in Stable Kidney Transplant Recipients.

Mycophenolic acid exhibits significant interpatient pharmacokinetic variability attributed to factors including race, sex, concurrent medications, and enterohepatic circulation of the mycophenolic acid glucuronide metabolite to mycophenolic acid. This conversion by enterohepatic circulation is mediated by the multidrug resistance-associated protein 2, encoded by ABCC2. This study investigated ABCC2 haplotype associations with mycophenolic acid pharmacokinetics in 147 stable kidney transplant recipients receiving mycophenolic acid in combination with calcineurin inhibitors. The role of the ABCC2 genotypes -24C>T (rs717620), 1249C>T (rs2273697), and 3972C>T (rs3740066) were evaluated in prospective, cross-sectional pharmacokinetic studies of stable recipients receiving mycophenolic acid and either tacrolimus or cyclosporine. Haplotype phenotypic associations with mycophenolic acid pharmacokinetic parameters were computed using THESIAS (v. 3.1). Four ABCC2 haplotypes with estimated frequencies greater than 10% were identified (H1:CGC [wild type], H9:CGT, H2:CAC, H12:TGT). There were no differences in haplotype frequencies by either race or sex. There were significant associations of pharmacokinetic parameters with ABCC2 haplotypes for mycophenolic acid clearance (L/h), mycophenolic acid AUC0-12h (mg·h/L), and the ratio of mycophenolic acid glucuronide to mycophenolic acid AUC0-12h . The wild-type haplotype ABCC2 CGC had greater mycophenolic acid AUC0-12h (P = .017), slower clearance (P = .013), and lower mycophenolic acid glucuronide to mycophenolic acid AUC0-12h ratio (P = .047) compared with the reduced function ABCC2 haplotype CGT. These differences were most pronounced among patients receiving tacrolimus cotreatment. No phenotypic associations were found with the cyclosporine-mycophenolic acid regimen. Variation in ABCC2 haplotypes contributes to subtherapeutic mycophenolic acid exposure and influences interpatient variability in pharmacokinetic phenotypes based on concurrent calcineurin inhibitor treatment.

Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial.

BACKGROUND: Voclosporin, a novel calcineurin inhibitor approved for the treatment of adults with lupus nephritis, improved complete renal response rates in patients with lupus nephritis in a phase 2 trial. This study aimed to evaluate the efficacy and safety of voclosporin for the treatment of lupus nephritis. METHODS: This multicentre, double-blind, randomised phase 3 trial was done in 142 hospitals and clinics across 27 countries. Patients with a diagnosis of systemic lupus erythematosus with lupus nephritis according to the American College of Rheumatology criteria, and a kidney biopsy within 2 years that showed class III, IV, or V (alone or in combination with class III or IV) were eligible. Patients were randomly assigned (1:1) to oral voclosporin (23·7 mg twice daily) or placebo, on a background of mycophenolate mofetil (1 g twice daily) and rapidly tapered low-dose oral steroids, by use of an interactive web response system. The primary endpoint was complete renal response at 52 weeks defined as a composite of urine protein creatinine ratio of 0·5 mg/mg or less, stable renal function (defined as estimated glomerular filtration rate [eGFR] ≥60 mL/min/1·73 m2 or no confirmed decrease from baseline in eGFR of >20%), no administration of rescue medication, and no more than 10 mg prednisone equivalent per day for 3 or more consecutive days or for 7 or more days during weeks 44 through 52, just before the primary endpoint assessment. Safety was also assessed. Efficacy analysis was by intention-to-treat and safety analysis by randomised patients receiving at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03021499. FINDINGS: Between April 13, 2017, and Oct 10, 2019, 179 patients were assigned to the voclosporin group and 178 to the placebo group. The primary endpoint of complete renal response at week 52 was achieved in significantly more patients in the voclosporin group than in the placebo group (73 [41%] of 179 patients vs 40 [23%] of 178 patients; odds ratio 2·65; 95% CI 1·64-4·27; p<0·0001). The adverse event profile was balanced between the two groups; serious adverse events occurred in 37 (21%) of 178 in the voclosporin group and 38 (21%) of 178 patients in the placebo group. The most frequent serious adverse event involving infection was pneumonia, occurring in 7 (4%) patients in the voclosporin group and in 8 (4%) patients in the placebo group. A total of six patients died during the study or study follow-up period (one [<1%] patient in the voclosporin group and five [3%] patients in the placebo group). None of the events leading to death were considered by the investigators to be related to the study treatments. INTERPRETATION: Voclosporin in combination with MMF and low-dose steroids led to a clinically and statistically superior complete renal response rate versus MMF and low-dose steroids alone, with a comparable safety profile. This finding is an important advancement in the treatment of patients with active lupus nephritis. FUNDING: Aurinia Pharmaceuticals.

Treatment of Hypertension Because of Immunosuppressive Therapy After Solid Organ Transplantation-Pharmacological Approach.

ABSTRACT: Solid organs transplantation procedures have been performed for more than half a century. Growing knowledge of immune response and development of new immunosuppressive regimens guarantee more and more successful outcomes. However, many of the applied drugs lead to cardiovascular complications, the most frequent of which is hypertension. This article describes epidemiology, pathogenetic mechanisms, and treatment of hypertension induced by immunosuppressive medication. The main impact is focused on drugs belonging to the following groups: calcineurin inhibitors, the inhibitors of the mammalian target of rapamycin, and glucocorticosteroids. We analyze the mechanism of action of the main hypertensive drugs and their influence on the reversing hypertonic action of the immunosuppressive agents. In the absence of current guidelines addressing this problem, this article is an attempt to fill the gap, helping clinicians to choose proper medication.

Long-Term Immunosuppression Management: Opportunities and Uncertainties.

The long-term management of maintenance immunosuppression in kidney transplant recipients remains complex. The vast majority of patients are treated with the calcineurin inhibitor tacrolimus as the primary agent in combination with mycophenolate, with or without corticosteroids. A tacrolimus trough target 5-8 ng/ml seems to be optimal for rejection prophylaxis, but long-term tacrolimus-related side effects and nephrotoxicity support the ongoing evaluation of noncalcineurin inhibitor-based regimens. Current alternatives include belatacept or mammalian target of rapamycin inhibitors. For the former, superior kidney function at 7 years post-transplant compared with cyclosporin generated initial enthusiasm, but utilization has been hampered by high initial rejection rates. Mammalian target of rapamycin inhibitors have yielded mixed results as well, with improved kidney function tempered by higher risk of rejection, proteinuria, and adverse effects leading to higher discontinuation rates. Mammalian target of rapamycin inhibitors may play a role in the secondary prevention of squamous cell skin cancer as conversion from a calcineurin inhibitor to an mammalian target of rapamycin inhibitor resulted in a reduction of new lesion development. Early withdrawal of corticosteroids remains an attractive strategy but also is associated with a higher risk of rejection despite no difference in 5-year patient or graft survival. A major barrier to long-term graft survival is chronic alloimmunity, and regardless of agent used, managing the toxicities of immunosuppression against the risk of chronic antibody-mediated rejection remains a fragile balance.

Efficacy and Safety of Everolimus With Reduced Tacrolimus in Liver Transplant Recipients: 24-month Results From the Pooled Analysis of 2 Randomized Controlled Trials.

BACKGROUND AND METHODS: Data from 2 randomized liver transplant trials (N = 772; H2304 [deceased donor, n = 488], H2307 [living donor, n = 284]) were pooled to further evaluate the efficacy and safety of everolimus with reduced tacrolimus (EVR + rTAC) versus standard tacrolimus (sTAC) regimen at month 24. RESULTS: EVR + rTAC was comparable to sTAC for composite efficacy failure of treated biopsy-proven acute rejection, graft loss, or death (9.8% versus 10.8%; difference, -1.0%; 95% confidence interval, -5.4 to 3.4; P = 0.641) at month 24. EVR + rTAC was superior to sTAC for the mean change in estimated glomerular filtration rate (eGFR) from randomization to month 24 (-8.37 versus -13.40 mL/min/1.73 m2; P = 0.001). A subanalysis of renal function by chronic kidney disease (CKD) stage at randomization showed significantly lower decline in eGFR from randomization to month 24 for patients with CKD stage 1/2 (eGFR ≥ 60 mL/min/1.73 m2) in EVR + rTAC group versus sTAC (-12.82 versus -17.67 mL/min/1.73 m2, P = 0.009). In patients transplanted for hepatocellular carcinoma (HCC) beyond Milan criteria, HCC recurrence was numerically lower although not statistically significant with EVR + rTAC versus sTAC group (5.9% [1 of 17] versus 23.1% [6 of 26], P = 0.215), while comparable in patients within Milan criteria (2.9% [3 of 102] versus 2.1% [2 of 96], P = 1.000), irrespective of pretransplant alpha-fetoprotein levels. CONCLUSIONS: EVR + rTAC versus sTAC showed comparable efficacy and safety with significantly better renal function, particularly in patients with normal/mildly decreased renal function (CKD stage 1/2) at randomization and a trend toward lower HCC recurrence in patients transplanted with HCC beyond Milan at month 24. Further long-term data would be required to confirm these results.