Calcineurin inhibitors-related posterior reversible encephalopathy syndrome in liver transplant recipients: Three case reports and review of literature

BACKGROUND Posterior reversible encephalopathy syndrome(PRES),characterized by acute neurological deterioration and extensive white matter lesions on T2-fluid attenuated inversion recovery magnetic resonance imaging(MRI),is increasingly associated with calcineurin inhibitors(CNI)-related neurotoxicity.Prompt diagnosis is crucial,as early intervention,including the modification or discontinuation of CNI therapy,strict blood pressure management,corticosteroid treatment,and supportive care can significantly improve patient outcomes and prognosis.The growing clinical recognition of CNI-related PRES underscores the importance of identifying and managing this condition in patients presenting with acute neurological symptoms.CASE SUMMARY This report describes three cases of liver transplant recipients who developed PRES.The first case involves a 60-year-old woman who experienced seizures,aphasia,and hemiplegia on postoperative day(POD)9,with MRI revealing ischemic foci followed by extensive white matter lesions.After replacing tacrolimus,her symptoms improved,and no significant MRI abnormalities were observed after three years of follow-up.The second case concerns a 54-year-old woman with autoimmune hepatitis who developed headaches,seizures,and extensive white matter demyelination on MRI on POD24.Following the switch to rapamycin and the initiation of corticosteroids,her symptoms resolved,and she was discharged on POD95.The third case details a 60-year-old woman with hepatocellular carcinoma who developed PRES,evidenced by brain MRI abnormal-ities on POD11.Transitioning to rapamycin and corticosteroid therapy led to her full recovery,and she was discharged on POD22.These cases highlight the critical importance of early diagnosis,CNI modification,and stringent management in improving outcomes for liver transplant recipients with CNI related PRES.CONCLUSION Clinical manifestations,combined with characteristic MRI findings,are crucial in diagnosing PRES among organ transplant recipients.However,when standard treatments are ineffective or MRI results are atypical,alternative diagnoses should be taken into considered.

Treatment of young patients with lupus nephritis using calcineurin inhibitors

Recent advances in the management of lupus nephritis, together with earlier renal biopsy and selective use of aggressive immunosuppressive therapy, have contribut-ed to a favorable outcome in children and adolescents with systemic lupus erythematosus （SLE）. Neverthe-less, we believe that a more effective and less toxic treatment is needed to attain an optimal control of the activity of lupus nephritis. Recent published papers and our experiences regarding treatment of young patients with lupus nephritis using calcineurin inhibitors are re-viewed. Although it has been reported that intermittent monthly pulses of intravenous cyclophosphamide （IVCY） are effective for preserving renal function in adult pa-tients, CPA is a potent immunosuppressive agent thatinduces severe toxicity, including myelo- and gonadal toxicity, and increases the risk of secondary malig-nancy. Thus, treatment for controlling lupus nephritis activity, especially in children and adolescents, remains challenging. Cyclosporine A （CsA） and tacrolimus （Tac） are T-cell-specific calcineurin inhibitors that prevent the activation of helper T cells, thereby inhibiting thetranscription of the early activation genes of interleu-kin （IL）-2 and suppressing T cell-induced activation of tumor necrosis factor-α, IL-1β and IL-6. Therefore, both drugs, which we believe may be less cytotoxic, are attractive therapeutic options for young patients with lupus nephritis. Recently, a multidrug regimen of prednisolone （PDN）, Tac, and mycophenolate mofetile （MMF） has been found effective and relatively safe in adult lupus nephritis. Since the mechanisms of action of MMF and Tac are probably complementary, multidrug therapy for lupus nephritis may be useful. We propose as an alternative to IVCY, a multidrug therapy with mizoribine, which acts very similarly to MMF, and Tac, which has a different mode of action, combined with PDN for pediatric-onset lupus nephritis. We also believe that a multidrug therapy including CsA and Tac may bean attractive option for young patients with SLE and lupus nephritis

Calcineurin inhibitors and nephrotoxicity in children

Background Calcineurin inhibitors(CNIs)are commonly given to transplant recipients of kidneys and other solid organs and to patients with immune disorders,such as steroid-resistant nephrotic syndrome,steroid-dependent nephrotic syndrome,and frequent relapse nephrotic syndrome.Although CNIs remain the most effective available immunosuppressant agent,there is clinical concern regarding possible long-term nephrotoxicity.This concern is especially significant in children who have a longer life expectancy and greater growth rate.Data sources In this review,we analyzed the literatures to identify original articles that examined use of CNIs in children who received organ transplantation and nephropathy to assess the available evidence of their nephrotoxicity.PubMed,Elsevier,and Tompson ISI Web of Knowledge were searched for identifying relevant papers.Results Clinical research supports the presence of CNI-related nephrotoxicity.However,some researchers have questioned the prevalence and seriousness of chronic CNIs nephrotoxicity,especially because the pathological lesions typically associ-ated with long-term CNI use are nonspecific.Many researchers have focused on early markers of CNI nephrotoxicity,and the methods that may help prevent and manage nephrotoxicity.Conclusions Future research should focus on investigating early markers of CNI nephrotoxicity and strategies for improved immunosuppressant therapy,and developing alternative treatments.CNI-mediated nephrotoxicity should always be taken seriously in clinic.

Microproteinuria for detecting calcineurin inhibitor-related nephrotoxicity after liver transplantation

AIM： To investigate whether microproteinuria could be used as an early and sensitive indicator to detect calcineurin inhibitor （CNI）-related nephrotoxicity after liver transplantation.METHODS： All liver transplant recipients with normal serum creatinine （SCr） and detectable microproteinuria at baseline were included in this study. The renal function was monitored by the blood clearance of 99mTc-diethylenetriaminepentaacetic acid every 6 mo. Microproteinuria, SCr and blood urea nitrogen （BUN） were measured at entry and at subsequent follow-up visits. The patients were divided into different groups according to the mean values of glomerular filtration rate （GFR） at the follow-up time points： Group 1, GFR decreased from baseline by 0%-10%; Group 2, GFR decreased from baseline by 11%-20%; Group 3, GFR decreased from baseline by 21%-40%; Group 4, GFR decreased from baseline by 〉 40% and/or SCr was increasing.RESULTS： A total of 143 patients were enrolled into this study （23 females and 120 males）. The mean follow-up was 32 mo （range 16-36 mo）. Downward trends in renal function over time were observed in the study groups. SCr and BUN increased significantly only in Group 4 patients （P 〈 0.001）. β2-microglobulin （β2m） and al-microglobulin （αlm） significantly increased with the subtle change of renal function in recipients who were exposed to CNI-based immunosuppression regimens. The reductions in GFR were closely correlated with elevated cclm （P = -0.728, P 〈 0.001） and β2m （r2 = -0.787, P 〈 0.001）.CONCLUSION： β2m and α1m could be useful as early and sensitive indicators of CNI-induced nephrotoxicity.

Calcineurin Inhibitor Use and Myoclonus Association. Is There a Clinical Implication?

Background: Calcineurin Inhibitors (CNIs) play a pivotal role in anti rejection therapy for transplant patients. Neurotoxicity is a known side effect that usually manifests as encephalopathy but myoclonus has also been described. Perioperative myoclonus as a manifestation of neurotoxicity, has not been well studied. Methods: We retrospectively reviewed data from 842,762 patients from the Nationwide Inpatient Sample (NIS) database from January 2011 to December 2014. Of those records we compared 56,423 patients requiring CNIs and undergoing Heart Transplant (HT) with 786,339 patients undergoing Coronary Artery Bypass Graft (CABG) surgery as controls. The objective was to study the rates of myoclonus in patients undergoing cardiac surgery, especially those requiring CNIs, and study the outcome of those patients with myoclonus. The NIS database from January 2011 to December 2014 was the source for the analysis. Patients with underlying epilepsy or hypo-ischemic encephalopathy based on ICD-9-CM codes were excluded from the study. Results: A total of 147 patients (0.26%) were found to have myoclonus in the HT group versus 338 patients (0.04%) in the CABG group, p < 0.0001. No differences in the demographics were seen except for kidney disease which was higher in the HT group. The difference remained statistically significant after adjusting for confounders. Patients with myoclonus in both groups were more likely to have acute kidney injury and have a prolonged length of stay. Only patients with myoclonus in the CABG group had higher rates of discharge disposition to a nursing home and higher rates of in-Hospital mortality. A trend towards higher in-Hospital mortality was found in patients with myoclonus in the HT group. Conclusion: In this study we have compared the rate of myoclonus found in HT patients versus CABG patients. We have identified calcineurin inhibitors as potentially contributing to myoclonus due to its neurotoxic effects. The study also suggests that other disease processes like renal failure may also have an impact on the rate of myoclonus even in the absence of calcineurin inhibitors. Higher rates of myoclonus were seen in patients undergoing HT when compared to patients undergoing CABG, suggesting that CNIs may increase the risk for myoclonus. Myoclonus may be a clinical indicator of patient overall health including a more permeable blood brain barrier. In-Hospital mortality was higher in patients with myoclonus undergoing CABG and a trend towards significance in the HT group suggesting that it may be a marker of poor prognosis. More studies are needed to corroborate our findings.

Reversible Chronic Interstitial Nephritis Induced by Tacrolimus —Tacrolimus Chronic Interstitial Nephritis

Calcineurin inhibitors (CNI) are potent immunosuppressive agents in prophylaxis against graft rejection and autoimmune diseases including primary glomerulopathies. Previous research showed reversible;acute afferent arteriolar vasculopathy and irreversible chronic interstitial fibrosis associated with CNI nephrotoxicity. In this case report we describe a patient, with minimal change disease, that had developed chronic and progressive renal disease while receiving therapeutic dose of Tacrolimus. His serum creatinine had reached 537 umol/L and his nephrotic state worsened. Kidney biopsy showed chronic interstitial nephritis. Tacrolimus was discontinued and he was treated with 1 mg/kg prednisone in addition to Mycophenolate mofetil (MMF) 1 g twice daily. By the 2nd month;serum creatinine returned to normal and by the 3rd month serum albumin too. After 1 month of therapy;the dose of Prednisone was tapered down gradually till 5 mg daily by the end of 3rd month. Moreover, the dose of MMF was reduced to 500 mg X2 by the end of 3rd month. After 2 years of follow up;he remained stable and without relapse of NS or renal failure. In conclusion, reversible renal disease, due to chronic interstitial nephritis can be induced by CNI which is amenable to treatment with Prednisone and MMF.

Association between COVID-19 and chronic liver disease:Mechanism,diagnosis,damage,and treatment

As the outbreak evolves,our understanding of the consequences of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection and the resulting coronavirus disease 2019(COVID-19)on the liver has grown.In this review,we discussed the hepatotropic nature of SARS-CoV-2 and described the distribution of receptors for SARS-CoV-2(e.g.,angiotensin-converting enzyme 2)in the vascular endothelium and cholangiocytes of the liver.Also,we proposed mechanisms for possible viral entry that mediate liver injury,such as liver fibrosis.Due to SARS-CoV-2-induced liver damage,many COVID-19 patients develop liver dysfunction,mainly characterized by moderately elevated serum aminotransferase levels.Patients with chronic liver disease(CLD),such as cirrhosis,hepatocellular carcinoma,nonalcoholic fatty liver disease,and viral hepatitis,are also sensitive to SARS-CoV-2 infection.We discussed the longer disease duration and higher mortality following SARS-CoV-2 infection in CLD patients.Correspondingly,relevant risk factors and possible mechanisms were proposed,including cirrhosis-related immune dysfunction and liver decompensation.Finally,we discussed the potential hepatotoxicity of COVID-19-related vaccines and drugs,which influence the treatment of CLD patients with SARS-CoV-2 infection.In addition,we suggested that COVID-19 vaccines in terms of immunogenicity,duration of protection,and long-term safety for CLD patients need to be further researched.The diagnosis and treatment for liver injury caused by COVID-19 were also analyzed in this review.

Everolimus in de novo liver transplant recipients: a systematic review

BACKGROUND： Everolimus has no nephrotoxicity and is used to treat patients with post-liver transplant chronic renal insufficiency. The present systematic review was to evaluate the efficacy and safety of everolimus in de novo liver transplant patients.DATA SOURCES： Randomized controlled trials comparing everolimus for de novo liver transplant in Pub Med, the Cochrane Library, and Science Direct published up to March 31, 2014 were searched by two independent reviewers. Mean differences and 95% confidence interval（95% CI） for renal function, relative risk（RR） and 95% CI for treated biopsy-proven acute rejection（t BPAR）, graft loss, death, neoplasms/tumor recurrence, and adverse events were collected. Meta-analyses were performed with Rev Man version 5.10.RESULTS： A total of four randomized controlled trials covering 1119 cases were included. The meta-analyses revealed that compared with standard exposure of calcineurin inhibitors（CNIs）, everolimus combined with reduced CNIs improved creatinine clearance（calculated with the Cockcroft-Gault formula） by 5.13 m L/min at one year（95% CI： 0.42-9.84; P=0.03）, and decreased t BPAR（RR： 0.56; 95% CI： 0.35-0.90; P=0.02）. Everolimus initiation with CNIs elimination improved glomerular filtration rate（GFR, measured with the modification of diet in renal disease formula） of 10.42 m L/min/1.73 m2（95% CI： 3.44-17.41; P〈0.01） one year after treatment, but in-creased t BPAR（RR： 1.71; 95% CI： 1.15-2.53; P〈0.01）. Everolimus decreased the risk of neoplasms/tumor recurrence after liver transplant（RR： 0.60; 95% CI： 0.34-1.03; P=0.06）, but was associated with greater risk of adverse events which resulted in drug discontinuation（RR： 1.98; 95% CI： 1.49-2.64; P〈0.01）. CONCLUSIONS： Early introduction of everolimus combined with low-dose or no CNI in de novo liver transplant significantly improves renal function one year post treatment. Everolimus combined with low-dose CNI decreases the risk of t BPAR one year after liver transplant, but everolimus administered without CNIs increases t BPAR.

Liver transplantation during global COVID-19 pandemic

The coronavirus disease 2019(COVID-19)caused by severe acute respiratory disease respiratory syndrome coronavirus-2 has significantly impacted the health care systems globally.Liver transplantation(LT)has faced an unequivocal challenge during this unprecedented time.This targeted review aims to cover most of the clinical issues,challenges and concerns about LT during the COVID-19 pandemic and discuss the most updated literature on this rapidly emerging subject.

Epstein-Barr virus-associated monomorphic post-transplant lymphoproliferative disorder after pediatric kidney transplantation: A case report

BACKGROUND Post-transplant lymphoproliferative disease(PTLD)is the most common malignant tumor that occurs after kidney transplantation in children,and is associated with Epstein-Barr virus(EBV).CASE SUMMARY We report a case of PTLD that occurred in a 17-year-old female patient at 5 mo post-transplant.The first symptom was abdominal pain accompanied by fever,nausea,and vomiting.EBV-associated monomorphic PTLD with multiple abdominal nodules was diagnosed by pathology,clinical manifestations,imaging results,and the presence of EB-DNA.After successful treatment with rituximab,the abdominal nodules in the spleen and liver disappeared.CONCLUSION Early pathological biopsy to confirm the diagnosis is critical to treatment and prognosis.Reducing immunosuppression and rituximab therapy are effective methods for treating PTLD,but need to be initiated as early as possible.

Belatacept in renal transplantation in comparison to tacrolimus and molecular understanding of resistance pattern:Meta-analysis and systematic review

BACKGROUND The T-cell costimulation blocking agent belatacept has been identified as a possible substitute for calcineurin inhibitors,however,no consensus has been established against its use over the standard care agent Tacrolimus.AIM To evaluate the effectiveness of belatacept based maintenance immunosuppressive regimens in comparison to tacrolimus in renal transplantion.METHODS We did extensive search of all the available literature comparing the role of belatacept to tacrolimus in renal transplant recipients by searching the PubMed,Embase,Cochrane,Crossref,Scopus,clinical trials registry on October 5,2020.RESULTS The literature search identified four randomized controlled trials(n=173 participants)comparing belatacept with tacrolimus.There was no significant difference in estimated renal function at 12 mo[mean difference 4.12 mL/min/1.73 m^(2),confidence interval(CI):-2.18 to 10.42,P=0.20].Further,belatacept group was associated with significant increase in biopsy proven acute rejection[relative risk(RR)=3.27,CI:0.88 to 12.11,P=0.08]and worse 12 mo allograft survival(RR=4.51,CI:1.23 to 16.58,P=0.02).However,incidence of new onset diabetes mellitus was lower with belatacept at 12 mo(RR=0.26,CI:0.07 to 0.99,P=0.05).CONCLUSION The evidence reviewed in this meta-analysis suggested that belatacept-based maintenance immunosuppression regimens were associated with an increased risk allograft loss in renal transplant recipients with equivalent renal functioning against standard tacrolimus;however,observed significantly reduced new onset diabetes mellitus after transplantation incidence and lower serum low density lipid profile levels in belatacept group.In addition,the adaptation of belatacept in renal transplantation has been forestalled by increased rates of rejection and resistance owing to development of various effector memory T cells through,parallel differentiation and immunological plasticity.

Interactions between human microbiome,liver diseases,and immunosuppression after liver transplant

In liver transplant patients,solid tumors and post-transplant lymphoproliferative disorders have emerged as significant long-term mortality causes.In addition,it is assumed that de novo malignancy after liver transplantation(LT)is the secondleading cause of death after cardiovascular complications.Well-established risk factors for post-transplant lymphoproliferative disorders and solid tumors are calcineurin inhibitors,tacrolimus,and cyclosporine,the cornerstones of all immunosuppressive therapies used after LT.The loss of immunocompetence facilitated by the host immune system due to prolonged immunosuppressive therapy leads to cancer development,including LT patients.Furthermore,various mechanisms such as bacterial dysbiosis,activation through microbe-associated molecular patterns,leaky gut,and bacterial metabolites can drive cancerpromoting liver inflammation,fibrosis,and genotoxicity.Therefore,changes in human microbiota composition may contribute further to de novo carcinogenesis associated with the severe immunosuppression after LT.

Prophylaxis of chronic kidney disease after liver transplantation-experience from west China

AIM： TO evaluate the prophylaxis of chronic kidney dis- ease （CKD） after liver transplantation （LT） with low-dose calcineurin inhibitor （CNI） and mycophenolate mofetil （MMF）.

Effect of low-dose tacrolimus with mycophenolate mofetil on renal function following liver transplantation

AIM: To determine whether low-dose tacrolimus (TAC) combined with mycophenolate mofetil (MMF) is a safe approach to decrease the incidence of chronic kidney disease (CKD) in liver transplantation (LT) recipients. METHODS: We analyzed the medical records of 689 patients who underwent LT between March 1999 and December 2012 in a single Chinese center. Immunosuppression was initiated with a calcineurin inhibitor (TAC or CSA) and prednisone with or without MMF. CKD is defined by the glomerular filtration rate (GFR), estimated by an abbreviated Modification of Diet in Renal Disease formula, < 60 mL/min per 1.73 m(2) for at least 3 consecutive months after LT. Individuals with TAC trough concentrations <= 8 ng/mL at 3 mo after LT were defined as the low-dose group. The incidence of CKD within 5 years was compared between the TAC group and the CSA group, as well as between four subgroups (low-dose and high-dose TAC groups with or without MMF). RESULTS: No difference regarding the occurrence of pre-LT renal dysfunction or that of post-LT rejection was found between the TAC and CSA groups or between the four subgroups. With a definition of GFR < 60 mL/min per 1.73 m(2), the overall incidence of CKD was significantly higher in the CSA group than in the TAC group. The incidence of CKD in the low-dose TAC + MMF group (7.7%) was significantly lower than that observed in the low-dose TAC group (15.9%), high-dose TAC group (24.6%) and high-dose TAC + MMF group (18.5%). The cumulative 1-, 3- and 5-year incidence rates of CKD were 12.7%, 14.5% and 16.7%, respectively. The cumulative 5-year survival rates were 61.7% and 82.2% in patients with or without CKD, respectively. CONCLUSION: In LT patients, the choice of immunosuppressive therapy appears to affect renal function and patient survival. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

Current aspects of renal dysfunction after liver transplantation

The development of chronic kidney disease(CKD)after liver transplantation(LT)exerts a severe effect on the survival of patients.The widespread adoption of the model for end-stage liver disease score strongly impacted CKD incidence after the procedure,as several patients are transplanted with previously deteriorated renal function.Due to its multifactorial nature,encompassing pre-transplantation conditions,perioperative events,and nephrotoxic immunosuppressor therapies,the accurate identification of patients under risk of renal disease,and the implementation of preventive approaches,are extremely important.Methods for the evaluation of renal function in this setting range from formulas that estimate the glomerular filtration rate,to non-invasive markers,although no option has yet proved efficient in early detection of kidney injury.Considering the nephrotoxicity of calcineurin inhibitors(CNI)as a factor of utmost importance after LT,early nephroprotective strategies are highly recommended.They are based mainly on delaying the application of CNI during the immediate postoperativeperiod,reducing their dosage,and associating them with other less nephrotoxic drugs,such as mycophenolate mofetil and everolimus.This review provides a critical assessment of the causes of renal dysfunction after LT,the methods of its evaluation,and the interventions aimed at preserving renal function early and belatedly after LT.

The Beneficial Effect of Combination of Mycophenolate with Low-Dose Corticosteroids and Calcineurin-Inhibitor as Well as Angiotensin-Converting Enzyme Inhibitor or Angiotensin II Blocker in Induction and Maintenance of Remission in Corticosteroid- and Rituximab-Resistant Minimal Change Nephrotic Syndrome in Adults

Management of steroid-resistant minimal change disease remains elusive with international guidelines suggesting high-dose corticosteroids and/or Calcineurin inhibitors for months similar to those with refractory idiopathic FSGS. Unfortunately, with such approach, the overall remission rates were 47% - 66%. Moreover, complete remission rates were 32% - 47% and partial remission ones were 19% - 29%. Those limited options of treatment and their poor outcomes led us to conduct the present study to assess the efficacy and safety of a new combined drug-therapy at induction and subsequent maintenance of such disease. The regimen consisted of an initial induction phase of 3-month Prednisone, Calcineurin-inhibitor, Mycophenolate and ACEI/ARB. The latter was followed by a maintenance phase of minimal dose Prednisone and nearly 1/2 the induction dose of Calcineurin inhibitors to decrease their long-term side effects. The results were satisfactory with 14 of the 22 patients, had complete remission. Moreover, 5 patients manifested partial remission and only 3 did not respond. Creatinine clearance was maintained in patients with complete remission yet, was mildly reduced in the partial and non-responsive ones. The safety and efficacy of such new combined drug-therapy provide new tool and future prospective in management of such relentless disease.

Kidney disease in non-kidney solid organ transplantation

Kidney disease after non-kidney solid organ transplantation(NKSOT)is a common post-transplant complication associated with deleterious outcomes.Kidney disease,both acute kidney injury and chronic kidney disease(CKD)alike,emanates from multifactorial,summative pre-,peri-and post-transplant events.Several factors leading to kidney disease are shared amongst solid organ transplantation in addition to distinct mechanisms unique to individual transplant types.The aim of this review is to summarize the current literature describing kidney disease in NKSOT.We conducted a narrative review of pertinent studies on the subject,limiting our search to full text studies in the English language.Kidney disease after NKSOT is prevalent,particularly in intestinal and lung transplantation.Management strategies in the peri-operative and post-transplant periods including proteinuria management,calcineurin-inhibitor minimization/sparing approaches,and nephrology referral can counteract CKD progression and/or aid in subsequent kidney after solid organ transplantation.Kidney disease after NKSOT is an important consideration in organ allocation practices,ethics of transplantation.Kidney disease after SOT is an incipient condition demanding further inquiry.While some truths have been revealed about this chronic disease,as we have aimed to describe in this review,continued multidisciplinary efforts are needed more than ever to combat this threat to patient and allograft survival.

COVID-19 infection in a kidney transplant recipient—special emphasis on pharmacokinetic interactions:A case report

BACKGROUND Solid organ transplant recipients are considered to be at high-risk of developing coronavirus disease 2019(COVID-19)-related complications.The optimal treatment for this patient group is unknown.Consequently,the treatment of COVID-19 in kidney transplant recipients should be determined individually,considering patient age and comorbidities,as well as graft function,time of transplant,and immunosuppressive treatment.Immunosuppressive treatments may give rise to severe COVID-19.On the contrary,they may also lead to a milder and atypical presentation by diminishing the immune system overdrive.CASE SUMMARY A 50-year old female kidney transplant recipient presented to the transplant clinic with a progressive dry cough and fever that started three days ago.Although the COVID-19 test was found to be negative,chest computed tomography images showed consolidation typical of the disease;thus,following hospital admission,anti-bacterial and COVID-19 treatments were initiated.However,despite clinical improvement of the lung consolidation,her creatinine levels continued to increase.Ultrasound of the graft showed no pathology.The tacrolimus blood level was determined and the elevation in creatinine was found to be related to an interaction between tacrolimus and azithromycin.CONCLUSION During the COVID-19 pandemic,various single or combination drugs have been utilized to find an effective treatment regimen.This has increased the possibility of drug interactions.A limited number of studies published in the literature have highlighted some of these pharmacokinetic interactions.Treatments used for COVID-19 therapy;azithromycin,atazanavir,lopinavir/ritonavir,remdesivir,favipiravir,chloroquine,hydroxychloroquine,nitazoxanide,ribavirin,and tocilizumab,interact with immunosuppressive treatments,most importantly with calcineurin inhibitors.Thus,their levels should be frequently monitored to prevent toxicity.

Kidney transplantation after liver transplantation

Kidney transplantation after liver transplanta tion（KALT） offers longer survival and a better quality of life to liver transplantation recipients who develop chronic renal failure. This article aimed to discuss the efficacy and safety of KALT compared with other treatments. The medical records of 5 patients who had undergone KALT were retrospectively studied, together with a literature review of studies. Three of them developed chronic renal failure after liver transplanta tion because of calcineurin inhibitor（CNI）-induced neph rotoxicity, while the others had lupus nephritis or non-CNI drug-induced nephrotoxicity. No mortality was observed in the 5 patients. Three KALT cases showed good prognoses maintaining a normal serum creatinine level during entire follow-up period. Chronic rejection occurred in the other two patients, and a kidney graft was removed from one of them Our data suggested that KALT is a good alternative to dialysis for liver transplantation recipients. The cases also indicate that KALT can be performed with good long-term survival.

A randomized controlled trial to evaluate efficacy and safety of early conversion to a low-dose calcineurin inhibitor combined with sirolimus in renal transplant patients

Background:The calcineurin inhibitor(CNI)-based immune maintenance regimen that is commonly used after renal transplantation has greatly improved early graft survival after transplantation;however,the long-term prognosis of grafts has not been significantly improved.The nephrotoxicity of CNI drugs is one of the main risk factors for the poor long-term prognosis of grafts.Sirolimus(SRL)has been employed as an immunosuppressant in clinical practice for over 20 years and has been found to have no nephrotoxic effects on grafts.Presently,the regimen and timing of SRL application after renal transplantation vary,and clinical data are scarce.Multicenter prospective randomized controlled studies are particularly rare.This study aims to investigate the effects of early conversion to a low-dose CNI combined with SRL on the long-term prognosis of renal transplantation.Methods:Patients who receive four weeks of a standard regimen with CNI+mycophenolic acid(MPA)+glucocorticoid after renal transplantation in multiple transplant centers across China will be included in this study.At week 5,after the operation,patients in the experimental group will receive an additional administration of SRL,a reduction in the CNI drug doses,withdrawal of MPA medication,and maintenance of glucocorticoids.In addition,patients in the control group will receive the maintained standard of care.The patients’vital signs,routine blood tests,routine urine tests,blood biochemistry,serum creatinine,BK virus(BKV)/cytomegalovirus(CMV),and trough concentrations of CNI drugs and SRL at the baseline and weeks 12,24,36,48,72,and 104 after conversion will be recorded.Patient survival,graft survival,and estimated glomerular filtration rate will be calculated,and concomitant medications and adverse events will also be recorded.Conclusion:The study data will be utilized to evaluate the efficacy and safety of early conversion to low-dose CNIs combined with SRL in renal transplant patients.