Relative carcinogenicity of tacrolimus vs mycophenolate after solid organ transplantation and its implications for liver transplant care

BACKGROUND De novo malignancy is a leading cause of late morbidity and mortality in liver transplant recipients.Cumulative immunosuppression has been shown to contribute to post-transplant malignancy(PTM)risk.There is emerging evidence on the differential carcinogenic risk profile of individual immunosuppressive drugs,independent of the net effect of immunosuppression.Calcineurin inhibitors such as tacrolimus may promote tumourigenesis,whereas mycophenolic acid(MPA),the active metabolite of mycophenolate mofetil,may limit tumour progression.Liver transplantation(LT)is relatively unique among solid organ transplantation in that immunosuppression monotherapy with either tacrolimus or MPA is often achievable,which makes careful consideration of the risk-benefit profile of these immunosuppression agents particularly relevant for this cohort.However,there is limited clinical data on this subject in both LT and other solid organ transplant recipients.AIM To investigate the relative carcinogenicity of tacrolimus and MPA in solid organ transplantation.METHODS A literature search was conducted using MEDLINE and Embase databases using the key terms“solid organ transplantation”,“tacrolimus”,“mycophenolic acid”,and“carcinogenicity”,in order to identify relevant articles published in English between 1st January 2002 to 11th August 2022.Related terms,synonyms and explosion of MeSH terms,Boolean operators and truncations were also utilised in the search.Reference lists of retrieved articles were also reviewed to identify any additional articles.Excluding duplicates,abstracts from 1230 records were screened by a single reviewer,whereby 31 records were reviewed in detail.Full-text articles were assessed for eligibility based on pre-specified inclusion and exclusion criteria.RESULTS A total of 6 studies were included in this review.All studies were large population registries or cohort studies,which varied in transplant era,type of organ transplanted and immunosuppression protocol used.Overall,there was no clear difference demonstrated between tacrolimus and MPA in de novo PTM risk following solid organ transplantation.Furthermore,no study provided a direct comparison of carcinogenic risk between tacrolimus and MPA monotherapy in solid organ transplantation recipients.CONCLUSION The contrasting carcinogenic risk profiles of tacrolimus and MPA demonstrated in previous experimental studies,and its application in solid organ transplantation,is yet to be confirmed in clinical studies.Thus,the optimal choice of immunosuppression drug to use as maintenance monotherapy in LT recipients is not supported by a strong evidence base and remains unclear.

Efficacy of prednisone combined with mycophenolate mofetil for immunoglobulin A nephropathy with moderate-to-severe renal dysfunction

BACKGROUND Immunoglobulin A nephropathy(IgAN)is a common form of chronic glomer-ulonephritis.Currently,IgAN is one of the main causes of chronic renal failure in China;its prognosis varies greatly between patients,with renal function at the time of diagnosis and prognosis being strongly correlated.Mycophenolate mofetil(MMF)is a drug with a good immunomodulatory effect and is commonly used clinically.However,its effects in IgAN have not yet been clearly demonstrated.Therefore,herein,we retrospectively compared the effectiveness and safety of prednisone alone or combined with MMF for the treatment of primary IgAN with moderate-to-severe renal impairment.METHODS Between January 2011 and December 2020,200 patients with moderate-to-severe IgAN were included in this study,all of whom were admitted to Wuxi People's Hospital affiliated with Nanjing Medical University.All patients underwent a renal puncture biopsy,which revealed primary IgAN with a glomerular filtration rate(GFR)of 30–60 mL/min.The patients were divided into a glucocorticoid therapy group(GTG)and an immunosuppressive therapy group(ITG)according to the different treatment regimens,with 100 patients in each group.Based on general treatments,such as angiotensin-converting enzyme inhibitors/angiotensin receptor blockers,patients in the GTG were administered prednisone 0.5–0.8 mg/(kg·d^(-1))for 4–8 wk,which was reduced by 5 mg every two weeks until the maintenance(30 mg/d)dose was reached and maintained for 12 mo.In the ITG,MMF was administered at 1.0 g/d for 6–12 mo,followed by a maintenance dosage of 0.5 g/d for 12 mo.Age,sex,blood pressure,24-h urinary egg white measurement,serum creatinine(Scr),blood uric acid,blood albumin,blood potassium(K),hemoglobin,GFR,alanine aminotransferase,total cholesterol(T-CHO),fasting blood glucose,and body mass index were recorded.The 24-h urinary protein,Scr,and GFR levels were recorded 3,6,9,and 12 mo after treatment.Follow-up data were also collected.RESULTS No discernible differences existed between the two groups in terms of age,sex,blood pressure,creatinine,24-h urinary protein level,GFR,or other biochemical indicators at the time of enrollment.Both regimens significantly reduced the 24-h urinary protein quantitation and stabilized renal function.Nine months after treatment,the 24-h urinary protein and Scr of the ITG decreased more significantly than those of the GTG.By the 12th month of treatment,the 24-h urinary protein and Scr in both groups continued to decrease compared to those by the 9th month.In addition,the overall response rate in the ITG was significantly higher than that in the GTG.The occurrence of side effects did not vary significantly between the two regimens;however,endpoint events were significantly more common in the GTG than in the ITG.The follow-up time for the GTG was noticeably lower than that for the ITG.CONCLUSION Prednisone combined with MMF was effective for the treatment of IgAN with moderate-to-severe renal dysfunction.

The Beneficial Effect of 3-Month-Induction Therapy with Corticosteroids and Mycophenolate Mofetil Followed by Maintenance Therapy with Yearly Rituximab Infusions as Sole Maintenance Therapy in Cryptogenic Chronic Hypersensitivity Pneumonitis

Background: The available data on cryptogenic chronic hypersensitivity pneumonitis (ccHP) indicate an inherited predisposition to disease with triggering autoimmune phenomena. Hence, we evaluated prospectively the role of a new autoimmune regimen in treatment of its severe and progressive disease. Patients and Methods: A total of 9 patients were included in the study. They had criteria for ccHP viz. 1) clinical features of cryptogenic progressive restrictive lung disease, 2) high-resolution computed tomographic pulmonary abnormalities, and 3) bronchoalveolar lavage lymphocytosis (>30%). The regimen consisted of an initial induction phase of 3-month Solumedrol 1 g IV daily for 3 days followed by 1 month of Prednisone (P) 60 mg/day to tapered down to discontinuation by 3rd month. They also had received Mycophenolate mofetil (MMF) 1 g twice daily for 3 months. This stage was followed by a maintenance phase of yearly Rituximab infusions (1 g followed by 1 g 2 weeks later). Results: compared to their previous 6 months deterioration;all patients showed significant improvement in their forced vital volume, diffusion capacity for carbon monoxide, 6-minutes-walk after the induction phase (at 3 months) which improved further at 15 months with Rituximab therapy. Conclusion: After 3-month induction therapy with P and MMF;yearly R treatment is a safe, practical and effective long-term therapy for ccHP.

Effect of Rituximab Versus Mycophenolate Mofetil or Cyclophosphamide as Control in Lupus Nephritis:A Meta-Analysis

Objective:To evaluate the effects of rituximab versus mycophenolate mofetil or cyclophosphamide as control in lupus nephritis by meta-analysis.Methods:A systematic search was carried out up to January 2022,obtaining 7 studies involving 645 participants with lupus nephritis at the commencement of the investigation;198 of them were treated with rituximab,while 447 were treated with mycophenolate mofetil or cyclophosphamide.We determined the odds ratio(OR)and mean difference(MD)with 95%confidence index(CI)to compare rituximab’s efficacy to that of mycophenolate mofetil or cyclophosphamide as control in lupus nephritis using random-or fixed-effects model by dichotomous or continuous techniques.Results:The rituximab group showed significantly higher complete renal remission rate(OR=2.52;95%CI 1.30-4.91,P=0.006)and total renal remission rates(OR=2.22;95%CI 1.36-3.63,P=0.001)than the control group.However,there was no significant difference in terms of end Systemic Lupus Erythematosus Disease Activity Index(SLEDAI)score(MD-1.16;95%CI-2.88-0.57,P=0.19),proteinuria(MD-0.31;95%CI-0.70-0.09,P=0.013),and serum creatinine(MD 0.01;95%CI-0.04-0.07,P=0.64)between the rituximab group and the control.Conclusion:Rituximab exhibited significantly greater complete renal remission rate and total renal remission rates,with no significant difference in terms of shorter-end SLEDAI,proteinuria,and serum creatinine,compared with the control in individuals with lupus nephritis.

Effects of Mycophenolate Mofetil on Renal Interstitial Fibrosis after Unilateral Ureteral Obstruction in Rats

To investigate the effects of mycophenolate mofetil (MMF) on the process of renal interstitial fibrosis,unilateral ureteral obstruction (UUO) model was established in rats Twenty Sprague-Dawley rats underwent UUO and received vehicle ( n =10) or MMF (20 mg kg -1 d -1 , by daily gastric gavage, n= 10) during a period of 5 days following surgery, and the additional 10 rats were served as sham-operated group The rats were killed 5 days after surgery Immunohistochemistry was performed on renal tissue for proliferating cell nuclear antigen (PCNA), α-smooth muscle actin (α-SMA) and type Ⅰ and Ⅲ collagen (colⅠ, colⅢ) Histological studies were also done by MASSON staining Five days after surgery, proliferating cells in tubules, interstitium as well as interstitial myofibroblast (MyoF) infiltration and interstitial colⅠ, colⅢ deposition were all significantly reduced by MMF treatment MMF also alleviated the histological changes of UUO rats These results suggested that the reduction of interstitial MyoF infiltration may be an important event by which MMF prevents renal injury caused by UUO and MMF could be used to limit the progression of renal fibrosis

The role of mycophenolate in the treatment of antineutrophil cytoplasmic antibody-associated vasculitis

Mycophenolic acid, the active metabolite for mycophenolate mofetil and mycophenolic sodium, is a strong, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase, the key enzyme in de novo synthesis of guanosine nucleotides leading to selective inhibition of lymphocyte proliferation. Mycophenolic acid has been evaluated as induction and remission maintenance agent in the treatment of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Since the course of disease of AAV usually requires long term immunosuppression, mycophenolate has been explored as a less toxic agent compared to cyclophosphamide and azathioprine. Mycophenolate is a potent immunosuppressive agent in the therapy of AAV, non-inferior to other available drugs with comparable side effect profile. Therefore, it could be a valuable alternative in cases of toxicity with life threatening side effects or intolerance to cyclophosphamide or azathioprine, in cases with high cumulative dose of cyclophosphamide, but also in cases with insufficient response. Several studies have shown a higher relapse rate following discontinuation of mycophenolate or in mycophenolate treated subjects that raises concerns about its usefulness in the treatment of AAV. This review describes the efficacy of mycophenolate in AAV as remission induction agent, as remission maintenance agent, and as therapeutic option in relapsing AAV disease, the relapse rate following discontinuation of mycophenolate, and the adverse events related to mycophenolate treatment.

Effect of mycophenolate mofetil plus adriamycin on HepG-2 cells

AIM:To investigate the influence of mycophenolate mofetil(MMF)plus adriamycin(ADM)on hepatocellular carcinoma(HCC)cells. METHODS:HCC cells were treated with 100μg/ml of MMF alone(MMF group),1μg/mL of adriamycin(ADM group)alone,or a combination of the drugs(MMF+ ADM group).We performed an 3-[4,5-dimethylthiazol2-yl]-2,5-diphenyl tetrazolium bromide(MTT)assay to measure the growth inhibition rate of HCC cells.Flow cytometry was used to determine the percentage of cells in different phases of the cell cycle and the number of apoptotic cells.Hoechst 33258 staining revealed the morphological changes associated with apoptosis in HCC cells. RESULTS:The results of MTT assays revealed that monotherapy with ADM or MMF showed inhibition of cell growth,while MMF+ADM therapy afforded an inhibition rate of more than 90%with cell distribution in G1 and G2/M phase greater than that in S phase. MMF+ADM treatment also downregulated Bcl-2 expression markedly.The growth of HCC cells was markedly inhibited and apoptosis was enhanced in all the 3 groups.Compared with other 2 groups,the MMF +ADM group showed more obvious apoptosis of cells. CONCLUSION:The MMF plus ADM combination exerts remarkable inhibitory effects on the growth of HCC cells.

Eco-friendly reduced graphene oxide for the determination of mycophenolate mofetil in pharmaceutical formulations

Graphene oxide(GO) was synthesized and characterized by scanning electron microscopy(SEM), energy dispersive X-ray spectroscopy(EDX), atomic force microscopy(AFM), X-ray diffraction(XRD), Fourier transform-infrared spectroscopy(FT-IR) and thermogravimetric analysis(TGA). GO was then electrochemically reduced and used for electrochemical study of mycophenolate mofetil(MMF). The electrochemically reduced graphene oxide(ERGO) film on glassy carbon electrode(GCE) showed enhanced peak current for electrooxidation of MMF. MMF exhibited two irreversible oxidation peaks at 0.84 V(peak a_1)and 1.1 V(peak a_2). Effects of accumulation time, pH and scan rate were studied and various electrochemical parameters were calculated. A differential pulse voltammetric method was developed for the determination of MMF in bulk samples and pharmaceutical formulations. Linear relationship was observed between the peak current and concentration of MMF in the range of 40 nM–15 μM with a limit of detection of 11.3 nM. The proposed method is simple, sensitive and inexpensive and, hence, could be readily adopted in clinical and quality control laboratories.

The effect of mycophenolate acid on hepatitis B virus replication in vitro

OBJECTIVE: To use 2.2.15 cell line to determine the effects of mycophenolate acid (MPA) on hepatitisB virus (HBV) replication and viral protein synthesis in vitro.METHODS: The 2.2.15 cells were treated with different concentration of MPA (1-50 μg/ml) for 12days. HBsAg and HBeAg were detected in the supernatant fluid by ELISA and intracellular HBV DNAwas analyzed quantitatively by slot blot hybridization.RESULTS: MPA could suppress the expression of HBsAg and HBeAg, and the higher concentration ofMPA induced lower expression of HBsAg and HBeAg. The suppression rates of MPA for HBsAg andHBeAg at a concentration of 50 μg/ml were 34.2% and 24.1% respectively. The expression of HBVDNA was only 49% as compared with controls when treated with MPA at a concentration of 50 μg/ml.CONCLUSIONS: Mycophenolate acid can suppress the expression of HBsAg and HBeAg as well as thereplication of HBV DNA in the 2.2.15 cell. The suppressive degree is dose-dependent.

Correlation of abnormal histology with endoscopic findings among mycophenolate mofetil treated patients

AIM To describe all abnormal histological findings and their associated endoscopic presentation in patients using mycophenolate mofetil(MMF).METHODS A retrospective review of all individuals prescribed MMF within 6 mo of a colonoscopy or flexible sigmoidoscopy between 07/2009 and 09/2015 was performed within Northwell Health system.Records were analyzed for age,gender,procedure indication,MMF indication,and both gross and microscopic findings.Only reports with abnormal histology were included.RESULTS One hundred and eighty-four procedures from 170 patients were found,of which 39 met inclusion criteria.Fifty-one point three percent were female.MMF was used for solid organ transplant in 71.8%.Diarrhea was the indication for 71.8% of colonoscopies.Fiftynine percent of reports revealed gross and microscopic abnormalities while 41.0% had only microscopic findings.Only 11 patients' reports(28.2%) indicated a specific histopathology of MMF colitis.Among the entire group,only 23.1% of abnormal histology was isolated proximal to the splenic flexure.CONCLUSION Our results demonstrate a high rate of left sided disease and microscopic findings without gross mucosal abnormalities among patients using MMF.Also,a broader definition of MMF-colonopathy may be appropriate,with a majority of our abnormal histology falling outside of the more narrowly defined MMF-colitis category.Given the high frequency of isolated microscopic abnormalities and distal disease,sigmoidoscopy with random biopsies may be an appropriate,less invasive initial endoscopic examination in selected MMF patients.

Protective Effect of Mycophenolate Mofetil(MMF) Against Short-term Acute Rejection of Kidney Transplant

To observe the protective effect of MMF against short term(3 months) acute rejection of renal transplantion. 112 patients undergone renal transplantation were randomly divided into two groups: MMF group (2.0 g/d) and azathioprine group. Patients in both groups received cyclosporine A (CsA) and steroid hormone treatment in the same way. In three months time, 10/60 cases in the MMF treated group showed acute rejection with an acute rejection rate of 16.6%. 22/52 patients of the AZA group had acute rejection with a rejection rate of 41.5%. The difference between the two groups is significant (P<0 01). Side effects manifested in MMF group includereduction of blood white cell count and platelet count (5 cases) and diarrhea (3 cases). They resume recovery after reduction of the dosage of or stoppage of MMF. Both hepatic renal functions are not affected. In AZA group, liver function is damaged in 9 patients. MMF is effective in the prevention or reduction of short term acute rejection of transplants. Its side effects are mild and reversible.

Mycophenolate mofetil toxicity mimicking acute cellular rejection in a small intestinal transplant

Mycophenolate mofetil(MMF) is an important medication used for maintenance immunosuppression in solid organ transplants. A common gastrointestinal(GI) side effect of MMF is enterocolitis, which has been associated with multiple histological features. There is little data in the literature describing the histological effects of MMF in small intestinal transplant(SIT) recipients. We present a case of MMF toxicity in a SIT recipient, with histological changes in the donor ileum mimicking persistent acute cellular rejection(ACR). Concurrent biopsies of the patient's native colon showed similar changes to those from the donor small bowel, suggesting a non-graft specific process, raising suspicion for MMF toxicity. The MMF was discontinued and complete resolution of these changes occurred over three weeks. MMF toxicity should therefore be considered as a differential diagnosis for ACR and graftversus-host disease in SITs.

Safety and Efficacy of Once-Daily Administration of Mycophenolate Mofetil in Kidney Transplant Patients—A New Treatment Option for Non-Adherence

Non-adherence to immunosuppressive therapy is associated with reduced graft survival. Fifteen long-term follow up kidney transplant patients with stable post-transplant clinical courses were enrolled in the study. All patients were prescribed to tacrolimus prolonged release, mycophenolate mofetil (MMF) and corticosteroid at the time of enrolment. Twice-daily administration of MMF was then converted to a single daily dose. As a result, all immunosuppressive agents were administered simultaneously at one time in the morning. The daily total doses of the three immunosuppressants were identical during the study period. No acute rejection or adverse event was observed during the study period. Blood urea nitrogen and estimated glomerular filtration rate did not change significantly after conversion to once-daily administration. The blood tacrolimus trough level and the Mycophenolic acid (MPA) trough level also did not change significantly after conversion to once-daily administration. Interestingly, the meanmedian MPA trough level remained >3 μg/ml even after conversion to once-daily administration. A sufficient plasma MPA level was maintained after conversion to once-daily administration, and no acute rejection was observed during the study period. To our knowledge, this study is the first to report that the plasma MPA concentration can be maintained after once-daily administration of MMF in long-term kidney transplant patients. Once-daily administration of immunosuppressive agents may improve long-term graft survival because of better treatment adherence due to the reduced dosing frequency. The safety or efficacy of conversion to once-daily administration of MMF should be evaluated in a future randomized controlled large-scale clinical study.

Combination treatment with telitacicept,mycophenolate mofetil and glucocorticoids for immunoglobulin A nephropathy:A case report

BACKGROUND Telitacicept reduces B cell activation and abnormal immunoglobulin A(IgA)antibody production by inhibiting the activity of B lymphocyte stimulator(BLyS)and a proliferation-inducing ligand(APRIL),thereby decreasing IgA deposition in the glomeruli and local inflammatory response.This ultimately protects the kidneys from damage.This mechanism suggests that Telitacicept has potential efficacy in the treatment of IgA nephropathy.CASE SUMMARY We present the case of a 24-year-old female who was diagnosed with IgA nephropathy due to significant proteinuria and mild renal impairment.Pathologically,she exhibited focal proliferative glomerulonephritis.Treatment with angiotensin II receptor blocker,hormones,and mycophenolate mofetil did not lead to a significant improvement in her condition.However,upon the addition of telitacicept,the patient’s renal function recovered and her proteinuria rapidly reduced.Hormones were swiftly tapered and discontinued,with no occurrence of severe infections or related complications.CONCLUSION Telitacicept combined with hormones and mycophenolate mofetil may be a safe and effective induction therapy for IgA nephropathy.

Correlations between serum kidney injury molecule-1,cystatin C and immunosuppressants:A cross-sectional study of renal transplant patients in Bahrain

Renal transplant patients receive several immunosuppressive drug regimens that are potentially nephrotoxic for treatment.Serum creatinine is the standard for monitoring kidney function;however,cystatin C(Cys C)and kidney injury molecule-1(KIM-1)have been found to indicate kidney injury earlier than serum creatinine and provide a better reflection of kidney function.Here,we assessed Cys C and KIM-1 serum levels in renal transplant patients receiving mycophenolate mofetil,tacrolimus,sirolimus,everolimus,or cyclosporine to evaluate kidney function.We used both the Chronic Kidney Disease Epidemiology Collaboration(CKD-EPI)2021 equation,which is based on creatinine and combined creatinine with Cys C,and the CKD-EPI 2012 equation,which is based on Cys C alone,to estimate glomerular filtration rate(GFR).Then,we assessed the association between serum KIM-1 and GFR<90 mL per minute per 1.73 m2.We observed significantly higher serum Cys C levels in patients with the elevated serum creatinine,compared with those with normal serum creatinine.The estimated GFRs based on creatinine were significantly higher than those based on the other equations,while a significant positive correlation was observed among all equations.Serum KIM-1 levels were negatively correlated with the estimated GFRs by the CKD-EPI Cys C and the combined creatinine with Cys C equations.A serum KIM-1 level above 0.71 ng/mL is likely to indicate GFR<90 mL per minute per 1.73 m2.We observed a significant correlation between serum creatinine and Cys C in our renal transplant patients.Therefore,serum KIM-1 may be used to monitor renal function when using potentially nephrotoxic drugs in renal transplants.

Immunoglobulin A glomerulonephropathy:A review

In this editorial,we comment on the article by Meng et al published in the World Journal of Clinical Cases.We comprehensively review immunoglobulin A nephro-pathy(IgAN),including epidemiology,clinical presentation,diagnosis,and management.IgAN,also known as Berger's disease,is the most frequent type of primary glomerulonephritis(GN)globally.It is mostly found among the Asian population.The presentation can be variable,from microscopic hematuria to a rapidly progressive GN.Around 50%of patients present with single or recurring episodes of gross hematuria.An upper respiratory infection and tonsillitis often precede these episodes.Around 30%of patients present microscopic hematuria with or without proteinuria,usually detected on routine examination.The diagnosis relies on having a renal biopsy for pathology and immunofluorescence microscopy.We focus on risk stratification and management of IgAN.We provide a review of all the landmark studies to date.According to the 2021 KDIGO(kidney disease:Improving Global Outcomes)guidelines,patients with non-variant form IgAN are first treated conservatively for three to six months.This approach consists of adequate blood pressure control,reduction of proteinuria with renin-angiotensin system blockade,treatment of dyslipidemia,and lifestyle modifications(weight loss,exercise,smoking cessation,and dietary sodium restrictions).Following three to six months of conservative therapy,patients are further classified as high or low risk for disease progression.High-risk patients have proteinuria≥1 g/d or<1 g/d with significant microscopic hematuria and active inflammation on kidney biopsy.Some experts consider proteinuria≥2 g/d to be very high risk.Patients with high and very high-risk profiles are treated with immunosuppressive therapy.A proteinuria level of<1 g/d and stable/im-proved renal function indicates a good treatment response for patients on immu-nosuppressive therapy.

Effects of mycophenolate mofetil,valsartan and their combined therapy on preventing podocyte loss in early stage of diabetic nephropathy in rats

Background Podocyte has inflammatory role in the development of diabetic nephropathy （DN）. Mycophenolate mofetil （MMF）, an anti-inflammatory agent, can suppress macrophage infiltration and reduce renal injury in streptozotocin-induced diabetic rats. Angiotensin II receptor blocker （ARB）, another renal protecting agent, can decrease podocyte loss in DN. In this study, we detected the expression levels of monocyte chemoattractant protein-1 （MCP-1） and nephrin to evaluate podocyte＇s role in inflammatory reaction in DN, observe and compare the effect of MMF alone and in combination with valsartan, on preventing podocyte loss in streptozotocin （STZ） induced diabetic rats. Methods Diabetic model was constructed in uninephrectomized male Wistar rats by single peritoneal injection of STZ （65 mg/kg）. The successfully induced diabetic rats were randomly divided into four groups： diabetes without treatment group （DM）, valsartan treated group （DMV）, MMF treated group （DMM）, and combined therapy group （DMVM）. Normal rats of the same sibling were chosen as control （NC）. At the end of the 8th week, serum biochemistry, 24-hour urinary protein （LIP） and the ratio of kidney weight/body weight （RWK/B） were measured. The rats were sacrificed for the observation of renal histomorphology through light and electron microscope. Nephrin, desmin and MCP-1 levels were detected by semi-quantitative immunohistochemical assays. Real-time quantitative PCR was used to detect the mRNA levels of nephrin and MCP-1. Results Compared with group NC, serum glucose level, 24-hour LIP and RWK/B in group DM were significantly higher （P〈0.01）, and the nephrin mRNA level in DM group was significantly lower （P〈0.05）. The nephrin mRNA expression levels in group DMV, DMM and DMVM were all higher than that of DM group （P〈0.05） and no significant differences were found among the three treatment groups （P〉0.05）. Treatment with MMF, valsartan or their combination could significantly decrease the 24-hour LIP and RWK/B, and suppress glomerulosclerosis and interstitial fibrotic lesions in diabetic rats. In diabetic rats, the high expressions of desmin and MCP-1 in kidney were suppressed by valsartan, MMF or their combination. Conclusions Podocytes are involved in the inflammatory reaction of diabetic rats. MMF could suppress MCP-1 and desmin expression, enhance nephrin expression, and attenuate proteinuria in diabetic rats. The combined therapy of valsartan and MMF did not show any superiority over monotherapies on renal protection. MMF may have renoprotective effect in early stages of diabetic nephropathy through preventing podocytes loss and anti-inflammatory activity.

Retrospective study of mycophenolate mofetil treatment in IgA nephropathy with proliferative pathological phenotype

Background Mycophenolate mofetil （MMF） and cyclophosphamide （CTX） are widely used in treating various kidney diseases.However,whether they are effective and which one is better for treating IgA nephropathy patients with proliferative pathological phenotype in renal diseases,such as endocapillary proliferation,cellular crescents,and/or capillary loops fibrinoid necrosis is still unknown.We,therefore,initiated a study to compare the effects of MMF and CTX in treating IgA nephropathy with the above pathological lesions.Methods One hundred and nineteen patients with IgA nephropathy who had at least one of the three aforementioned lesions were enrolled.All patients were treated with prednisone; 48 patients received prednisone only （Pred group）,40 received MMF and prednisone （MMF ＋ Pred group）,and 31 were treated with CTX and prednisone （CTX ＋ Pred group）.The median time of follow-up was 30 months （maximum：96 months）.The primary endpoint was defined as renal survival.The incidence of remission of proteinuria was the secondary endpoint.Results Serum creatinine in all groups declined significantly at different follow-up times （P=0.002）,and the differences among the three groups were significant （P＜0.001）.At 24 months of follow-up,the decline rates were 12.35％,32.95％,and 24.14％ in the Pred,MMF ＋ Pred,and CTX ＋ Pred groups respectively.For urine protein excretion,the decline rates were 49.12％ （Pred）,73.67％ （MMF ＋ Pred）,and 63.53％ （CTX ＋ Pred） respectively at 24 months of follow-up.The differences among the three groups were not significant （P=0.714）.Renal survival （the primary endpoint） was significantly different （P=0.027）; however,the sencondary endpoint was similar for all the three groups （P=0.100）.Conclusions For IgA nephropathy patients with endocapillary proliferation,cellular crescents,and/or fibrinoid necrosis of capillary loops,prednisone combined with MMF was more effective in lowering the serum creatinine than with CTX.Combined MMF and orednisone treatment led to a better renal survival compared to that of prednisone with CTX.

Pharmacokinetics of enteric-coated mycophenolate sodium in Chinese renal transplantation recipients

Background Mycophenolic acid （MPA） as an anti-proliferative immune-suppressive agent is used in the majority of immunosuppressive regimens in solid organ transplantation. This study aimed to investigate the pharmacokinetic （PK） characteristics of enteric-coated mycophenolate sodium （EC-MPS） and area under the curve （AUC） from 0 to 12 hours with limited sampling strategies （LSSs） in Chinese renal transplant recipients. Methods This study was conducted in 10 Chinese renal transplant patients receiving living donor and treated with EC-MPS, cyclosporine, and corticosteroids. MPA concentrations were measured by enzyme multiplied immunoassay technique （EMIT）. Whole 12-hour PK profiles were obtained on Day 4 after operation. LSSs with jackknife technique, multiple stepwise regression analysis, and Bland-Altman analysis were developed to estimate MPAAUC. Results The mean maximum plasma concentration, the mean time for it to reach peak （Tmax）, and the mean MPA AUC were （11.38±2.49） mg/L, （4.85±3.32） hours, and （63.19±13.54） mg.h.L1, respectively. Among the 10 profiles, MPA AUC of four patients was significantly higher than that of the other six patients, and the corresponding Tmax was significantly longer than that of the other six patients. No patient exhibited a second peak caused by enterohepatic recirculation. The best models were as follows： 27.46＋0.94C3＋3.24C8＋2.81C10 （f2=0.972）, which was used to predict AUC of fast metabolizer with a mean prediction error （MPE） of -0.21% and a mean absolute prediction error （MAE） of 2.59%; 36.65＋3.08Ce＋5.30C10-4.04C12 （r2=0.992）, which was used to predict AUC of slow metabolizer with a MPE of 0.58% and a MAE of 1.95%. Conclusions The PKs of EC-MPS had a high variability among Chinese renal transplant recipients. The preliminary PK data indicated the existence of slow and fast metabolizer. These findings may be associated with the enterohepatic rec.irculation.

Mycophenolate mofetil affects monocyte Toll-like receptor 4 signaling during mouse renal ischemia/reperfusion injury

Background Mycophenolate mofetil （MMF） has been used to prevent transplant rejection for many years and has been shown to have protective effects against renal failure. The objective was to investigate the effect of MMF on monocyte Toll-like receptor 4 （TLR4） signaling in the early stages of renal ischemia/reperfusion injury （IRI） of mice. Methods Sixty BALB/C mice were randomly divided into two groups： an IRI group, in which renal IRI was induced by clamping the renal pedicles for 45 minutes, and an MMF group, in which MMF was given （40 mg.kg-l.d-1, intraperitoneally） from 2 days before renal IRI. The plasma creatinine level and renal tissue damage of each group mice were observed 6, 12, 24, and 48 hours after reperfusion. The concentration of plasma high-mobility group box 1 （HMGB-1） （TLR4 ligand）, interleukin 6 （IL-6）, monocyte chemoattractant protein-1 （MCP-1）, and tumor necrosis factor a （TNF-cc） and the expression of TLR-4 on monocytes were determined. Results The plasma creatinine concentration in the MMF group was lower compared to the IRI group （after reperfusion of 6, 12, 24, or 48 hours, P 〈0.05）. Pathological analysis showed that the renal damage was slighter, TLR-4 expression was reduced （after reperfusion of 6, 12, 24, or 48 hours, P 〈0.05）, and the concentration of cytokines in the plasma was lower （P 〈0.05） in the MMF group. No differences in the concentrations of HMGB-1 were observed （P 〉0.05）. Conclusion Monocyte TLR4 signaling is important in the early stage of kidney IRI, but MMF can inhibit it and improve renal function.