Robotic stereotactic ablative radiotherapy for renal cell carcinoma in patients with impaired renal function.

BACKGROUND: Robotic stereotactic ablative radiotherapy (SABR) is currently under investigation as a noninvasive treatment option for patients with renal cell carcinoma (RCC). For radiation therapy of RCC, tumor motion and the need for high ablative doses while preserving the remaining renal parenchyma is a challenge. We aimed to analyze the safety and efficacy of robotic radiosurgery in RCC in a specific difficult subgroup of patients with impaired renal function. METHODS: We retrospectively identified all patients with RCC, treated with robotic SABR and motion compensation in our institution between 2012 and 2017. Either single fraction SABR of 24 or 25 Gy or 3 fractions of 12 Gy prescribed to the 70% isodose line was applied. Local control, overall survival, radiation side effects were evaluated together with renal function and tumor motion. RESULTS: We analyzed data of 13 lesions treated in 10 patients with clear cell RCC and a mean age of 70.5 ± 13.6 years (range: 48-87). Prior to SABR, 8 patients underwent previous complete and/or partial nephrectomy, 7 patients presented with chronic kidney disease ≥ stage 3. The median of minimum, mean and maximum planning target volume doses were 23.2, 29.5 and 35.0 Gy for single fraction and 24.4, 42.5 and 51.4 Gy for the three fractions regime. Persistent local control by robotic SABR was achieved in 9 out of 10 patients (92.3% of all lesions) within a median follow-up period of 27 month (range: 15-54). One patient underwent nephrectomy due to progressive disease and sufficient renal function of the contralateral kidney. Renal function remained stable with a mean estimated glomerular filtration rate (eGFR) of 51.3 ± 19.7 ml/min at baseline and 51.6 ± 25.8 ml/min at follow-up. The largest respiratory-induced tumor motion was seen in superior-inferior direction, compensated by the CyberKnife with mean targeting errors of maximal 2.2 mm. CONCLUSIONS: Robotic SABR is technically feasible for the treatment of RCC in preexisting kidney disease with good local tumor control at about 2 years follow-up. Robotic SABR with motion tracking offers a valid treatment option for patients, who are at increased risk for progression to end-stage renal disease due to partial nephrectomy or ablative techniques.

Donor-specific HLA antibodies in a cohort comparing everolimus with cyclosporine after kidney transplantation.

Donor-specific HLA antibodies (DSA) have a negative impact on kidney graft survival. Therefore, we analyzed the occurrence of DSA and antibody-mediated rejection (AMR) in patients from two prospective randomized trials in our center. At 3-4.5 months posttransplant 127 patients were randomized to continue cyclosporine or converted to everolimus therapy. The presence of DSA was prospectively assessed using Luminex assays. AMR was defined according to the Banff 2009 classification. Antibody screening was available in 126 patients with a median follow-up of 1059 days. Seven out of 65 (10.8%) patients on cyclosporine developed DSA after a median of 991 days. In comparison, 14/61 patients (23.0%) randomized to everolimus developed DSA after 551 days (log-rank: p = 0.048). Eight patients on everolimus compared to two patients on cyclosporine developed AMR (log-rank: p = 0.036). Four of 10 patients with AMR-all in the everolimus group-lost their graft. A multivariate regression model revealed everolimus, >3 mismatches and living donor as significant risk factors for DSA. Acute rejection within the first year, >3 mismatches, everolimus and living donor were independent risk factors for AMR. This single center analysis demonstrates for the first time that everolimus-based immunosuppression is associated with an increased risk for the development of DSA and AMR.

Late Steroid Withdrawal Following AB0-Incompatible Renal Transplantation.

BACKGROUND: Current evidence on steroid withdrawal following AB0-incompatible (AB0i) renal transplantation is low. We compared clinical outcomes of patients who agreed to late steroid withdrawal and patients who remained on steroid treatment. METHODS: Steroid withdrawal was carried out in 11 patients at ≥12 months after transplantation (group W). For comparison, we analyzed 19 patients who remained on triple immunosuppression including steroids (group M). Minimum follow-up was 24 months following transplantation and 12 months after steroid withdrawal. RESULTS: Baseline characteristics, including observation times, were not different between groups W and M. Graft survival was 100% in group W compared with 84% (16/19) in group M (P = .15). In group M, 1 patient experienced graft failure because of suspected antibody-mediated rejection (ABMR) following temporary cessation of mycophenolate treatment after a diagnosis of cryptococcal pneumonia. Two patients died with functioning graft because of sepsis. In group W, we observed 1 episode of ABMR following steroid withdrawal. At the end of follow-up, estimated glomerular filtration rates (eGFR) were 54 (19-91) versus 60 (15-85) mL/min/1.73 m2 in group W versus M, respectively (P = .67). CONCLUSIONS: Late steroid withdrawal following AB0i transplantation is feasible at a moderate risk of rejection. We recommend close monitoring of renal function and HLA antibodies during and after steroid withdrawal. On the other hand, the occurrence of severe infections causing death and graft loss in patients on triple maintenance immunosuppression including steroids should remind us to consider the overall immunosuppressive burden.

Pharmacokinetics of the immunosuppressant everolimus in maintenance renal transplant patients.

The novel macrocyclic immunosuppressant everolimus has been approved for use in renal and heart transplantation. The objective of this randomized, double-blind, placebo-controlled, dose-escalating Phase 1 study was to evaluate the pharmacokinetic profile of different dosing regimens of everolimus. Fifty-four subjects were randomized for 4-weeks treatment with everolimus (n = 44) or placebo (n = 10). Steady state was reached by day 4 of multiple dosing with evidence for dose-proportionality over the dose range tested. Systemic accumulation was 1.6- to 2.2-fold with multiple dosing. Steady-state predose trough concentrations were well correlated with AUC (r = 0.87, p < 0.001). Within-subject coefficients of variation for the tablet formulation ranged from 10-19% and between-subject coefficients from 34-60% for Cmax and AUC. There was no effect of common demographic parameters (age, sex, weight) on variability in steady-state exposure. These results support the clinical use of everolimus in renal transplantation.

Problems of cyclosporine absorption profiling using C2-monitoring.

UNLABELLED: The present study sought to validate the concept of C2 monitoring in 41 de-novo transplant patients treated with microemulsion of cyclosporine, mycophenolatesodium, steroids and basiliximab. RESULTS: After 6 months patient and graft survival was 98%, rejection rate was 19%. In the first week only a few patients achieved the suggested C2 levels (19% > 1500, 50% > 1200 ng/ml) despite an increased cyclosporine (CsA) dose. After 14 days 63% of patients reached C2 > 1500 ng/ml (83% C2 > 1200) despite decreased CsA dose. 35% of patients had intermittent high C0 (> 300) and low C2 (< 800), suggesting poor and/or slow absorption. Most of them suffered from CsA toxicity. There was a significant (p < 0.05) change of absorption as measured by C2/C0 leading to an increase of C2/dose. CONCLUSIONS: C2 monitoring may be useful to better estimate the CsA exposure in individual patients; however our results indicate some limitations of the current concept of C2 monitoring. Despite increase of dosage many patients do not reach the proposed levels. A significant proportion of patients are poor and/or slow absorbers. CsA toxicity may not be detected by C2 monitoring alone. With the use of basiliximab and mycophenolatesodium lower target levels seem to be sufficient.

Reactivation of tuberculosis after conversion from azathioprine to mycophenolate mofetil 16 years after renal transplantation.

The incidence of tuberculosis among transplant recipients is greater than in the general population. Mycophenolate mofetil (MMF) is a potent immunosuppressive agent that has become part of most standard immunosuppressive protocols after renal transplantation. We have recently shown that conversion from azathioprine (AZA) to MMF in patients with chronic allograft dysfunction may be beneficial. Here, we report a patient with a history of pulmonary tuberculosis during his childhood. This patient was converted from AZA to MMF therapy 16 years after allogenic renal transplantation because of chronic allograft dysfunction. Two months later, he developed axillary lymph node tuberculosis caused by Mycobacterium tuberculosis. Because he denied contact with infectious persons, we diagnosed reactivation of old dormant tuberculosis. After surgical extirpation, quadruple antituberculous therapy was administered for 3 months (isoniazid, rifampicin, ethambutol, and pyrazinamide), followed by dual therapy for 3 months (isoniazid and rifampicin), and monotherapy for another 3 months (isoniazid). In the follow-up period, he remained asymptomatic with stable graft function. We conclude that MMF therapy in renal allograft recipients may cause reactivation of old dormant tuberculosis, even in the very late posttransplantation period. In these patients, close monitoring and isoniazid prophylaxis may be useful.

Treatment of acute c-ANCA-positive vasculitis with mycophenolate mofetil.

Acute cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA)-positive vasculitis is usually treated with cyclophosphamide and corticosteroids. The incidence of cyclophosphamide-induced lung injury, a potentially life-threatening event, is about 1%. We report on a patient with a history of cyclophosphamide-induced lung injury 2 months after initial treatment of systemic c-ANCA-positive vasculitis. Six months later, the patient presented with acute renal failure caused by an acute relapse of vasculitis. Mycophenolate mofetil (MMF) is a potent immunosuppressive drug that recently has been shown to be effective in the maintenance therapy of c-ANCA-positive systemic vasculitis. With the patient's informed consent, we started treatment with MMF in combination with corticosteroids. Subsequently, anti-proteinase-3-titer (anti-Pr3-titer) returned to normal and renal function improved. In conclusion, MMF in combination with corticosteroids may be useful in the treatment of acute c-ANCA-positive vasculitis.

De novo hemolytic uremic syndrome postrenal transplant after cytomegalovirus infection.

After renal transplantation, hemolytic uremic syndrome (HUS) may occur as recurrent disease or de novo. Here, we describe the de novo occurrence of HUS immediately after the onset of primary cytomegalovirus (CMV) disease in two renal allograft recipients. Patient no. 1 had primary CMV disease with biopsy-proven CMV esophagitis 2 months after transplantation. Patient no. 2 experienced primary CMV disease with fever and leukopenia 8 years after transplantation. Both patients were treated with intravenous ganciclovir. Both patients developed HUS with biopsy-proven thrombotic microangiopathy in the renal allograft only a few days (3 to 5 days) after the onset of CMV disease. The short interval between the onset of CMV disease and HUS, as well as the parallel course of CMV viremia and HUS in both patients, indicate there may be a pathophysiological link between both diseases. However, because antiviral therapy with ganciclovir was started before the onset of HUS in both patients, we cannot definitely rule out that HUS was triggered by ganciclovir.

Non-radioactive determination of inosine 5'-monophosphate dehydro-genase (IMPDH) in peripheral mononuclear cells.

BACKGROUND: The immunosuppressive activity of mycophenolate mofetil (MMF) is based on the reversible inhibition of inosine 5'-monophosphate dehydrogenase (IMPDH) by mycophenolic acid (MPA). It was the aim of this study to develop a nonradioactive method for specific measurement of IMPDH activity in isolated peripheral mononuclear cells (MNC). METHODS: The procedure is based on the incubation of lysed MNC with inosine 5'-monophosphate (IMP) followed by direct chromatographic determination of produced xanthosine 5'-monophosphate (XMP). IMPDH activity was measured in MNC of MMF-treated patients and nontreated volunteers. RESULTS: The within-run (n = 10) and between-run (n = 20) coefficients of variation (CV) for IMPDH activity were < 8% and < 10%, respectively. IMPDH activity in 60 healthy volunteers (19-63 yr) ranged from 4.72 to 32.92 nmol/h/mg protein (mean = 18.39 +/- 6.24). The IC(50) for in vitro inhibition of IMPDH activity was about 2 to 3 microg/L. Application of a single dose of 1 g MMF in dialysis patients resulted in a significant inhibition (by 47-95%; p < 0.05) of IMPDH activity in lysed MNC. CONCLUSIONS: The proposed assay specifically and reliably measures IMPDH activity in MNC. The procedure is applicable to evaluate pharmacodynamic activity in MMF-treated patients. The observed interindividual variability of IMPDH activity may reflect pharmacodynamic differences in MMF-treated patients.

Clinical experience transferring kidney transplant patients from Sandimmun to Sandimmun Neoral--results after 3 months.

The new galenic formulation of cyclosporine prepared as microemulsion (Sandimmun Neoral, SN) shows a significantly improved correlation between both trough level (Cmin) and dose. Moreover, since the bioavailability is increased by 20 to 30% on average, it may lead to a drug overexposure in so far malabsorbing patients. In order to assess safety and to establish an appropriate procedure to switch patients safely from conventional Sandimmun to SN, we initialized an open, stratified (transplant age) clinical trial enrolling 302 patients of our outpatient clinic. We used a simple 1:1 conversion of the patient's total daily dose. Trough drug levels, as well as serum creatinine, liver enzymes, uric acid, and blood pressure values were measured at baseline, at days 4, 8, 15, 29, and at month 3 after drug substitution. Within the three month observation period, the cyclosporine dose was reduced by 14.2% (204 +/- 60 mg/day baseline vs. 175 +/- 54 mg/day after conversion, p < 0.05). By day 8, the 1:1 dosage conversion resulted in a modest mean increase in drug trough levels (114 ng/ml baseline vs. 120 ng/ml, p < 0.05). This increase was accompanied by a slight increase in mean serum creatinine concentration, a decrease in calculated creatinine clearance, and an increase in mean uric acid values (p < 0.05). Liver enzymes remained unchanged while systolic and mean arterial blood pressure decreased (p < 0.05). Parallel to dosage reduction, drug trough levels had decreased after 1 month to baseline (112 ng/ml) and remained there for the remainder of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Conversion to microemulsion cyclosporine in stable renal transplant patients: results after one year.

We switched 302 renal transplant patients from the conventional to a new microemulsion formulation of cyclosporine, to study the latter's safety and efficacy. We used a simple 1:1 conversion of the patient's total daily dose. We measured trough drug levels as well as serum creatinine, liver enzymes, uric acid, and blood pressure values at baseline and at days 4, 8, 15, 29, and months 3, 6 and 12 after drug substitution. Dose adjustments directed at trough levels 80-120 ng/ml were performed, starting at day 8. Within the 12-month observation period, the cyclosporine dose was reduced by 14.7% (204 +/- 60 mg/day baseline vs 174 +/- 51 mg/day after conversion, p < or = 0.001). By day 8, the 1:1 dosage conversion resulted in a modest mean increase in drug trough levels (114 ng/ml baseline vs 120 ng/ml, p < or = 0.01). This increase was accompanied by an increase in serum creatinine concentration, a decrease in calculated creatinine clearance, and an increase in uric acid values (p < or = 0.05). Liver enzymes remained unchanged while systolic and mean arterial blood pressure decreased (p < or = 0.05). After one month, drug trough levels had decreased to baseline (112 ng/ml) and remained there until month 6. They were significantly lower after 12 months (102 +/- 33 ng/ml, p < or = 0.001). Plasma creatinine values decreased to below baseline by month 6 (p < or = 0.001) and month 12 (p < or = 0.001). Twenty-four (8%) biopsy proven rejection episodes and 7 cases of cyclosporine attributed nephrotoxicity occurred in these 302 patients within these 12 months. We conclude, that a 1:1 conversion from conventional to the microemulsion form of cyclosporine is efficacious and safe. However, we advise an initial 10% decrease in dose reduction in those patients whose trough levels are in the high-normal range.

Pharmacodynamics of FTY720, the first member of a new class of immune-modulating therapeutics in transplantation medicine.

FTY is a novel immunomodulator currently undergoing clinical investigation and has the potential of improving immunosuppressive therapy after organ transplantation. Previous experimental studies in animals have shown that FTY has a unique mechanism of action. We have studied the pharmacodynamic effects of FTY in stable renal allograft recipients taking part in a phase I clinical trial. As in various animal models including non-human primates, a single oral dose of FTY (0.25 - 3.5 mg) significantly reduced peripheral lymphocyte count by 30 - 70%. The peripheral lymphocyte count returned to baseline within 24 hours. Only in those patients treated with the highest dose of FTY (3.5 mg), did peripheral lymphopenia persist for more than 96 hours. FTY reduced all lymphocyte subsets, T cells more than B cells and CD4+ cells more than CD8+ cells. The reduction in CD3+CD62L+ cell counts was more pronounced, whereas CD3+CCR5+ cell counts were less affected in comparison to the total number of CD3+ lymphocytes. We found only slightly increased apoptosis rates (< 5%) in peripheral lymphocytes, and this change does not explain the marked reduction in lymphocyte count. In cultured human lymphocytes only suprapharmacological doses of 10 microM FTY induced apoptosis (20.6 +/- 2.8%) after a 4-h incubation. More important, clinically relevant doses of 0.1 microM FTY increased lymphocyte mobility 2-fold. No effect of FTY on anti-CD3mAb-stimulated lymphocyte proliferation was detected and there was no change in phagocytosis rates in whole-blood cultures incubated with FTY. Further studies are necessary to investigate the mechanism of action of FTY in detail.

Clinical pharmacokinetics of tacrolimus in rescue therapy after renal transplantation.

Tacrolimus, a potent new immunosuppressive drug, was introduced for rescue therapy in 25 renal transplant recipients with ongoing rejection (n = 24) or severe cyclosporine toxicity (n = 1). A highly significant (p < 0.001) rise in serum creatinine from 138 +/- 14 (3 months before conversion) to 295 +/- 26 mumol/l preceded conversion to tacrolimus. Tacrolimus rescue therapy started 73 +/- 9 months after transplantation, the follow-up was 8 +/- 1 months. Outcome, pharmacokinetics, and side-effects were analyzed. Patient survival was 100% on tacrolimus therapy. Graft survival was 88% after 3 months, and 70% after 8 months. Serum creatinine remained stable during the observation period (Crea after 8 months: 271 +/- 26 mumol/l). Starting with an initial dose of 9.6 +/- 0.3 mg/day (0.14 +/- 0.01 mg/kg/day) we could reduce tacrolimus dose to 6.0 +/- 0.9 mg/day (0.09 +/- 0.02 mg/kg/day; p < 0.001) after 1 month. Tacrolimus trough levels were adjusted to a therapeutic window of 5-8 ng/ml. We had to perform 3.4 +/- 0.5 dose adjustments per patient mainly within the first month after conversion (70%). A high variability in interindividual tacrolimus dose was noted. Last cyclosporine dose was a good predictor of required tacrolimus dose after 1 month (r = 0.88; p < 0.001). Overall, 82 adverse events were noted, of which 29 (35%) were associated with high trough levels (> 10 ng/ml). In contrast, 3 patients with trough levels < 4 ng/ml had ongoing rejection. Blood pressure and routine laboratory data remained unchanged. Steroid dose could be tapered from 12 +/- 2 to 5 +/- 0.3 mg/day (p < 0.02). Gingival hyperplasia and hirsutism improved after conversion. We conclude: Tacrolimus conversion for rescue therapy after renal transplantation is efficient and safe with target trough levels between 5 -8 ng/ml. Frequent drug monitoring is necessary, especially within the first month after conversion. Previous cyclosporine dose can be used as a guideline for starting dose.

Effect of mycophenolate mofetil on IMP dehydrogenase after the first dose and after long-term treatment in renal transplant recipients.

OBJECTIVE: Mycophenolate mofetil (MMF) is routinely used as an immunosuppressant in a fixed daily dose regimen although it shows marked fluctuations in pharmacokinetics, and despite the fact that in regard to the active metabolite, mycophenolic acid (MPA), there is a well-known association between the pharmacokinetic parameters and clinical outcome. METHOD: In order to determine the time course and the variability in cellular target of MPA after renal transplantation, we investigated the pharmacodynamic response in 8 patients receiving 1 g MMF for the first time prior to renal transplantation and in 8 stable renal transplant patients maintained on long-term MMF therapy (1 g b.i.d.) for more than 1 year. The pharmacodynamic response was measured using inosine 5'-monophosphate dehydrogenase (IMPDH) activity in peripheral mononuclear cells. MPA plasma concentrations were measured in parallel, IMPDH activity in 89 healthy blood donors was used as a control. RESULTS: We observed a high interindividual variability in IMPDH activity in the 89 untreated healthy volunteers (4.0 - 32.9 nmol/h/mg protein), in 8 patients on dialysis (5.3 - 18.9 nmol/h/mg protein) and in 8 renal transplant patients under long-term MMF treatment (2.3 - 14.4 nmol/h/mg protein). The mean AUC0-12h for mycophenolic acid was 2-fold higher in patients receiving long-term treatment with MMF (62.2 +/- 16.6 mg x h/ml) compared to dialysis patients receiving 1 g MMF for the first time (31.5 +/- 15.6 mg x h/ml). Despite this pharmacokinetic difference there were no statistically significant differences in the cellular pharmacodynamic response. Minimal IMPDH activity (1.62 +/- 1.23 vs. 1.77 +/- 1.49 nmol/h/mg protein) and maximal IMPDH inhibition (87.5 +/- 0.08 vs. 77.4 +/- 18.8%) during the dosing interval were similar. CONCLUSIONS: The considerable interindividual variability in the pharmacokinetics of MMF as well as in the drug target support the use of pharmacodynamic drug monitoring to optimize MMF dosing and to reduce the risk of graft rejection and side effects.

Cyclosporin C2hour monitoring after renal transplantation.

Therapeutic drug monitoring of cyclosporin A (CsA) is essential because of its variable pharmacokinetics in individual patients and its narrow therapeutic window. In the past, standard trough level (C0) monitoring has been used, and although this method is currently the routine strategy, it has been shown that a single blood concentration measurement 2 hours after CsA administration (C2hour) is a significantly more accurate predictor of drug exposure and clinical events than trough concentrations. The CsA absorption profiling, in particular the measurement of C2hour, is a much more sensitive approach to assessing the pharmacokinetics and predicting the clinical effect in the individual patient. However, there are limited prospective data available examining the risks and benefits of C2hour monitoring in renal transplant recipients. Most studies focus on the early post-transplant phase, but there is little experience with C2hour monitoring in maintenance patients. Our experience in 127 stable long-term renal allograft recipients suggests that the therapeutic window for C2hour levels in patients during maintenance is lower than previously anticipated. Repeat determinations of both C0 and C2hour levels in 46 patients to determine precision of C2hour monitoring showed a high intrapatient variability. We observed only a slightly better coefficient of variation for C2hour than for C0 in repeat determinations. This suggests that drug monitoring using C2hour levels in transplant patients may provide a more accurate and reliable measure of drug exposure in the individual patient. However, CsA absorption showed only a weak correlation with dose during repeated measurements, suggesting high variability in absorption in these stable patients. We conclude that an adequate C2hour level soon after transplantation is associated with a reduced risk of acute rejection in adult renal transplant recipients. It is important to identify slow and poor absorbers in the initial phase after transplantation in order to avoid inappropriate increases in CsA dose. In maintenance patients, C2hour values between 500 and 600 ng/ml are effective and safe for providing effective rejection prophylaxis. Although mean C2hour levels do not seem to identify patients at risk of rejection, they may help to identify excessive immunosuppression and to improve long-term survival by reducing CsA toxicity.

Enteric-coated mycophenolate sodium: safe conversion from mycophenolate mofetil in maintenance renal transplant recipients.

Mycophenolate mofetil (MMF), in combination with cyclosporine and corticosteroids, improves long-term graft function and survival in renal transplant recipients. However, optimal MMF therapy may be limited by gastrointestinal (GI) intolerance, which may result in the need for MMF dose reduction, interruption, or discontinuation, leading to increased risk of acute rejection. Enteric-coated mycophenolate sodium (EC-MPS) is an advanced formulation delivering mycophenolic acid (MPA), developed with the objective of improving MPA-related upper GI adverse events. A pivotal, 12-month, phase III, randomized, multicenter, double-blind, double-dummy, parallel group study investigated whether stable renal transplant patients can be converted from MMF to EC-MPS therapy without compromising tolerability or efficacy. Stable renal transplant recipients received either MMF, 1000 mg b.i.d. (n=159), or EC-MPS, 720 mg b.i.d. (n=163), for 12 months. The incidence of GI adverse events was comparable between both treatment groups at 3 and 6 months, but there was a trend toward reduced severity of GI side effects in the EC-MPS group. There were fewer serious adverse events with EC-MPS and significantly fewer serious infections (P<.05). This comparable safety profile for EC-MPS and MMF also extended to elderly patients and patients with diabetes at baseline. For the composite efficacy variable of biopsy-proven acute rejection, graft loss, death, or loss to follow-up, EC-MPS had a lower 12-month efficacy failure rate (EC-MPS: 7.5% vs MMF: 12.3%; P=ns). These data demonstrate that stable renal transplant recipients receiving MMF can be converted to EC-MPS with no efficacy or tolerability compromise.