Pharmacokinetic Analysis of Mycophenolate Mofetil and Enteric-Coated Mycophenolate Sodium in Calcineurin Inhibitor-Free Renal Transplant Recipients.

BACKGROUND: Considerable interest exists in identifying calcineurin inhibitor (CNI)-free and thus, less-toxic immunosuppressive regimens, with mycophenolic acid (MPA)-based treatments being a suitable approach. Because pharmacokinetic analyses of MPA treatments in stable CNI-free renal transplant recipients are lacking, the authors aimed at comparing the steady-state pharmacokinetic characteristics of MPA in patients on stable treatment with mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS) plus prednisone (≤5 mg/d). METHODS: In the prospective, nonrandomized, open-label study, patients with stable transplant function since ≥6 months received their routine single dose of either MMF (n = 12) or EC-MPS (n = 11). The MPA plasma concentration was recorded over 12 hours. Parameters assessed were predose MPA concentration (C0), postdose minimum and maximum concentration (Cmin and Cmax), time to maximum concentration (Tmax), and area under the concentration-time curve (AUC) for the 12-hours of exposure (AUC0-12). RESULTS: Baseline characteristics were comparable between both the groups. Consistent with enteric coating, the mean Tmax was significantly longer after the intake of EC-MPS compared with MMF (2.2 versus 0.8 hours; P = 0.0002). The exposure measures Cmin, Cmax, and AUC0-12 were not significantly different despite the higher mean MPA equivalent dose in patients receiving MMF compared with those receiving EC-MPS (85% versus 64% of the recommended single dose, respectively). Exposures as reflected by the median AUC0-12 values were 50.7 and 58.7 mg·h·L with MMF and EC-MPS, respectively (P = 0.340). All patients achieved a target AUC of >30 mg·h·L, and 61% had an AUC of >50 mg·h·L. CONCLUSIONS: The study provides first results on the steady-state pharmacokinetics of the 2 MPA drugs in CNI-free immunosuppressant regimens. Pharmacokinetic parameters measured in this study under real-life conditions were comparable in patients receiving MMF or EC-MPS.

Platelet activation markers after conversion from azathioprine to sirolimus based immunosuppression in renal transplant recipients.

OBJECTIVE: Under immunosupression with sirolimus (rapamycin) procoagulant effects and platelet activation have been controversially discussed. METHODS: We evaluated patients of a prospectly designed substudy as part of a randomized trial investigating the effect of a switch from non-mTOR-based immunosuppression to sirolimus in renal transplant recipients. Our substudy consisted of 7 patients who switched therapy from azathioprine to sirolimus (conversion group) and 8 patients who remained on azathioprine (controls) before (V1) and after (V2) 3 months of treatment. In all patients we assessed flowcytometric markers of platelet activation (PAC-1), platelet degranulation (CD62P), formation of platelet leukocyte-aggregates (PLA), monocyte activation (CD11b), endogenous thrombin potential (ETP) and platelet aggregation. RESULTS: Both groups were similar in terms of baseline demographics and had stable transplant function for at least 6 months. CD62P increased significantly in the control group (p < 0.03). PLA were significantly reduced in the sirolimus conversion group at V2 (p < 0.02), whereas no effect was seen in the controls. Expression of PAC-1, CD11b, ETP-peak, ETP-time to peak, ETP-AUC and platelet aggregation showed no significant changes in both groups compared to V2. CONCLUSION: From clinical data, performing in depth platelet function testing, we found no evidence for increased platelet activation parameters in RTR who switched therapy from azathioprine to sirolimus.

De novo renal cell carcinoma of native and graft kidneys in renal transplant recipients.

OBJECTIVE: • To access the epidemiological, clinical and survival features of renal transplant patients with de novo renal cell carcinoma of native and graft kidneys. PATIENTS AND METHODS: • We performed a retrospective examination of the data of 2001 consecutive renal transplant recipients at our centre between November 1979 and January 2010. RESULTS: • In the patient cohort examined, 30 renal cell carcinomas were observed in 26 individuals (incidence 1.5%) with 25 tumours in the native and five in allograft kidneys. Mean tumour size in surgical specimens was 44 ± 36 mm. The rate of papillary cancer was 37.5%. • After a mean follow-up of 58.6 ± 62.3 months, 15.4% of the patients died from cancer and 57.7% were in complete remission. • Overall and tumour-specific survival rates at 1, 5 and 10 years were 86.1%, 75.1% and 43.8%, and 90.4%, 83.5% and 66.8%, respectively. CONCLUSIONS: • Due to increasingly improved survival after renal transplantation, de novo malignancies might soon become the main cause of intermediate- or long-term mortality. • Current data support an increased risk of renal cell carcinoma in renal transplant recipients in a particularly aggressive way, but low tendency for metachronous contralateral evolution. • With continuous radiological follow-ups, acceptable oncological outcome can be achieved. Graft tumours may have a favourable prognosis.

Development of urological cancers in renal transplant recipients: 30-year experience at the Frankfurt Transplant Center.

Fatal post-transplant malignancies with a high proportion of genitourinary neoplasms represent a serious long-term challenge. With continuous improvement of the allograft and patient survival, cancer development after renal transplantation may soon turn to the leading morbidity cause. In a retrospective single-center study of 1990 renal transplant recipients between November 1979 and November 2009, records of patients with urological neoplasms including epidemiological, clinical and survival parameters were accessed. Sixty-six de novo urological malignancies in 58 recipients were recorded in the study period, being most common after skin cancers (15.6% of enregistered tumors). From these, 29 were renal cell cancers, including five neoplasms of transplanted kidney, 24 transitional cell carcinomas, 11 prostate carcinomas, and two germ cell carcinomas with incidence rates of 1.5%, 1.2%, 0.9% and 0.2%, respectively. The patient follow up was virtually complete. Tumor-related death was found in 44% of cases. By multivariate analysis, no influence of either duration of dialysis, mode or duration of immunosuppression, gender or age at transplantation on overall patient survival could be demonstrated. This study, documenting a 30-year single center experience, emphasizes the increased risk for urological neoplasms occuring after renal transplantation. Screening strategies for urological cancers should be optimized.

Reactivation of hepatitis B two years after rituximab therapy in a renal transplant patient with recurrent focal segmental glomerulosclerosis: a note of caution.

We report on the reactivation of hepatitis B in a renal transplant patient who had been treated with rituximab for recurrent focal segmental glomerulosclerosis two and a half yr previously. He lost his anti-hepatitis B surface antigens and anti-hepatitis B core antigen antibodies and developed hepatitis B virus (HBV)-DNA positive hepatitis. Hepatitis C, which had been successfully treated by alpha interferon 10 yr before, remained quiescent. We suggest regular controls of HBV-DNA, anti-HBV antibodies and transaminases for prolonged periods in patients with status post-hepatitis B treated with rituximab. Prophylactic therapy with lamivudine and/or hepatitis B hyperimmune globulin may be considered in patients with a decrease in anti-HBV antibodies.

Anti-inflammatory effects of clopidogrel intake in renal transplant patients: effects on platelet-leukocyte interactions, platelet CD40 ligand expression, and proinflammatory biomarkers.

BACKGROUND: Increased platelet activation has been described during treatment with various immunosuppressive agents and may contribute to the high cardiovascular mortality rate in renal transplant patients. Platelets are thought to propagate the inflammatory process of atherosclerosis by interaction with leukocytes. METHODS: We tested an experimental therapy with clopidogrel in renal transplant patients treated with either tacrolimus (n = 20) or cyclosporine (INN, ciclosporin) (n = 19). All patients took low-dose steroids and had stable transplant function. Untreated healthy volunteers (n = 11) were included as the reference group. Degranulation (CD62P), glycoprotein IIb/IIIa receptor activation (PAC1), formation of platelet-leukocyte aggregates (monocyte-platelet-leukocyte aggregate, CD11b, mean fluorescence intensity), and platelet CD40 ligand (CD40L) expression (percent positive) were assessed by flow cytometry before therapy (visit 1) and after 4 weeks of clopidogrel (75 mg/d) intake (visit 2). To assess systemic anti-inflammatory effects, we measured levels of high-sensitivity C-reactive protein, soluble CD40L (sCD40L), monocyte chemoattractant protein 1, and matrix metalloproteinase 9 (MMP-9) by enzyme-linked immunosorbent assay. RESULTS: At visit 1, cyclosporine-treated patients had significantly enhanced CD62P and PAC1 expression and platelet-leukocyte aggregate formation, as well as elevated sCD40L concentrations, compared with tacrolimus-treated patients (all P < .03). Clopidogrel intake led to a significant decrease in platelet-leukocyte aggregate formation in tacrolimus-treated patients (median, 237 [interquartile range, 177-510] to 194 [interquartile range, 159-275] mean fluorescence intensity; P < .035) and cyclosporine-treated patients (median, 450 [interquartile range, 362-782] to 254 [interquartile range, 211-458] mean fluorescence intensity; P < .035). CD40L expression was reduced in tacrolimus-treated patients (median, 34 [interquartile range, 28-41] to 21 [interquartile range, 12-26] mean fluorescence intensity; P < .002) and cyclosporine-treated patients (median, 33 [interquartile range, 30-37] to 26 [interquartile range, 19-26] mean fluorescence intensity; P < .02). In addition, CD62P, PAC1, and CD11b were significantly reduced in both groups at visit 2 (P < .02). MMP-9 decreased from 88 ng/mL (range, 49-135 ng/mL) to 57 ng/mL (range, 38-73 ng/mL) (P < .05) in tacrolimus-treated patients and from 79 ng/mL (range, 54-148 ng/mL) to 66 ng/mL (range, 41-97 ng/mL) (P < .01) in cyclosporine-treated patients. The sCD40L concentration decreased significantly only in cyclosporine-treated patients (P < .004). In contrast, high-sensitivity C-reactive protein and monocyte chemoattractant protein 1 were not affected. CONCLUSION: The P2Y(12) receptor antagonist clopidogrel inhibits the expression of platelet activation markers and the interaction of platelets and leukocytes. Because the synthesis of vascular disease markers and inflammatory products such as sCD40L and MMP-9 has been inhibited, anti-inflammatory properties of clopidogrel are likely to be a result of decreasing platelet activation.

Immunosuppressive therapy regimen and platelet activation in renal transplant patients.

BACKGROUND: Increased platelet activation caused by an immunosuppressive therapy regimen may contribute to the high incidence of death from cardiovascular disease in renal transplant patients. Cyclosporine (INN, ciclosporin) and azathioprine are reported to activate platelets, but data are rare and controversial for tacrolimus and mycophenolate mofetil. METHODS: This cross-sectional study assessed markers of platelet degranulation (P-selectin; CD62), the activated glycoprotein IIb/IIIa receptor (PAC1, indicating the fibrinogen binding site), platelet aggregation, and secretion of platelet-derived growth factor (PDGF(AB)) in renal transplant patients treated with 4 different therapy regimens. Immunosuppression was based on low-dose steroids (5 mg/d prednisone) in combination with a single agent: (1) cyclosporine (n = 16), (2) azathioprine (n = 18), (3) tacrolimus (n = 17), or (4) mycophenolate mofetil (n = 13). Effects were compared with those in an age-matched control group of patients with hypertension (n = 11). RESULTS: In all renal transplant patient groups, unactivated platelets exhibited an increased expression of CD62. When stimulated with 2-micromol/L thrombin receptor-activating peptide, CD62 expression in platelets from patients treated with azathioprine (63% +/- 17%; P <.05), cyclosporine (51% +/- 23%; P <.05), and tacrolimus (50% +/- 22%; P <.05) was elevated compared with control subjects (33% +/- 19%). PAC1 expression was significantly increased in the patient groups that received azathioprine and cyclosporine. PDGF(AB) secretion was elevated in patients treated with azathioprine only (51 +/- 24 ng/10(9) platelets [versus 35 +/- 17 ng/10(9) platelets for control subjects]; P <.05). Platelet aggregation in response to collagen (0.5 microg/mL) was decreased in patients treated with tacrolimus (49% +/- 29%; P <.05) and mycophenolate mofetil (55% +/- 32%; P <.05) compared with control subjects (73% +/- 25%). CONCLUSION: This is the first study to compare the effects on platelet function of different immunosuppressive regimens that are based on monotherapy. All renal transplant patients showed preactivated platelets compared with those of patients with hypertension. However, the "newer" immunosuppressive agents tacrolimus and mycophenolate mofetil seemed to have fewer unfavorable effects on platelet CD62 expression and PAC1 expression and aggregation. Whether this finding is accompanied by fewer cardiovascular events remains to be elucidated.

Anti-inflammatory drugs modulate C1q secretion in human peritoneal macrophages in vitro.

The complement system plays an important role in the humoral immune response. Activation of the classical complement pathway is mediated by its subcomponent, C1q, which is involved in the pathogenesis of several autoimmune disorders. Among the main C1q-synthesising tissues, macrophages have been attributed as the main source. We investigated the effects of anti-inflammatory drugs (methylprednisolone and acetylsalicylic acid (ASA)) on C1q secretion in human peritoneal macrophages in vitro. The macrophages were isolated from peritoneal lavage fluid of patients with end-stage renal disease undergoing continuous ambulatory peritoneal dialysis, and were maintained in culture for up to 6 days. ASA decreased while methylprednisolone increased C1q secretion from human peritoneal macrophages in vitro, which correlated well with the percentage of CD14 positive cells after treatment. We conclude that different response of the macrophages to treatment with methylprednisolone and ASA may point out to the importance of macrophage activation after treatment, as well as an increased abundance of membrane C1q accompanied by increased phagocytosis.

Transitional cell carcinoma of the native urinary tract after kidney transplantation: recommendations following a long-term retrospective analysis.

INTRODUCTION: The aim of the current study was to explore the clinico-oncological characteristics, and the therapeutic and survival parameters, of renal transplant recipients who developed de novo transitional cell carcinoma (TCC) over a 30-year period at the authors' center. METHODS: Retrospective analysis of records from all registered patients who underwent kidney transplantation at the center between November 1979 and January 2010 who developed de novo TCC of the urinary tract. RESULTS: From all 2001 patients analyzed during the study period, 21 recipients developed 19 TCCs of the bladder and 6 TCCs of the upper urinary tract. Among bladder TCCs, 13 (68.4%) cases were confined to mucosa (pTa or carcinoma in situ, n = 7) or submucosa (pT1, n = 6) and 6 others (31.6%) infiltrated the detrusor muscle (≥p T2); the grading distribution was 5 cases of G1, 6 of G2 and 8 of G3. All recurrent cases (n = 8) revealed local or systemic progression. The overall and tumor-specific patient survival rates were 80.2%, 54.0% and 30.0% and 84.9%, 67.4% and 58.9% for 1, 5 and 10 years, respectively. CONCLUSIONS: In the light of the observed increased aggressiveness of TCC in renal transplant recipients, more frequent examinations and possibly more invasive follow-up protocols should be considered for patients with 1 or more risk factors for development of TCC. Urine cytology (including ureteral wash cytology) may be used as a reliable diagnostic tool in these patients. Prophylactic contralateral nephroureterectomy might be an option in patients at high risk.

Abrogation of nephrotic proteinuria by rituximab treatment in a renal transplant patient with relapsed focal segmental glomerulosclerosis.

Relapse of focal segmental glomerulosclerosis (FSGS) after renal transplantation is 20-40%. Recurrence after a first relapse is 80%. The only current treatment is plasmapheresis and/or cyclophosphamide. We report successful treatment of a second relapse in a 48-year-old patient. At age 33, FSGS was diagnosed. The patient began hemodialysis 1 year later. In her first renal transplant, she developed recurrent FSGS and reached terminal transplant failure 3 years later. Eight years later, a second transplant was performed. Immunosuppressive regimen: steroids, mycophenolate mofetil (MMF), tacrolimus (TAC), and rabbit anti-thymocyte globulin. Proteinuria of 2-6 g/day was detected and a biopsy showed recurrent FSGS. Plasmapheresis was started without success. Another biopsy still showed FSGS. The patient received two doses of rituximab (375 mg/m2 each) i.v. Three weeks later, proteinuria was 350 mg/day (serum-creatinine 1.6 mg/dl). Twelve months later, proteinuria was at 90 mg/day. Rituximab might be an option for recurrent FSGS after renal transplantation.

Long-term consequences of live kidney donation follow-up in 93% of living kidney donors in a single transplant center.

Live kidney donation is increasing rapidly. Increases of blood pressure and proteinuria but no accelerated loss of renal function in kidney donors have been described. The credibility of this research is hampered by retrieval rates of only 50-70% of donors. We studied renal function, blood pressure, proteinuria, parathyroid hormone, 1,25(OH)2 cholecalciferol and calcium and phosphate excretion in a live kidney donor cohort with a 93% retrieval rate. A comprehensive physical and laboratory examination including 24-h urine collection was conducted. None of the 152 donors had renal failure. Mean time after uninephrectomy was 11 +/- 7 (range: 1-28) years. GFR had declined by 25%. Blood pressure had increased from 125 +/- 15/79 +/- 11 to 134 +/- 19/81 +/- 9 mmHg (p < 0.01) but remained significantly below normal. Fifty six percent of donors developed proteinuria (>150 mg/day), but only 10% had albuminuria. Nineteen percent had increased PTH, 30% had a decreased tubular reabsorption rate of phosphate. Regarding risk factors for a higher loss of GFR, greater increases in blood pressure or proteinuria no consistent picture emerged. Because of the high incidence of proteinuria and possible changes in bone metabolism inclusion of kidney donors in registries appears worthwhile.