Rituximab in relapsing and de novo MPO ANCA-associated vasculitis with severe renal involvement: a case series.

BACKGROUND: Antineutrophil cytoplasmic antibody associated vasculitis (AAV) is a group of diseases associated in most cases with the presence of anti-neutrophil cytoplasmic antibodies (ANCAs). Rituximab- based remission induction has been proven effective in ANCA associated vasculitis but scarce data exist in forms with severe renal involvement. In this case series, we report the outcomes in patients with de novo or recurrent MPO-AAV and severe renal involvement treated with rituximab without cyclophosphamide (CYC). METHODS: In this single centre retrospective study, we analysed patients with a clinical diagnosis of de novo or recurrent AAV who met the following criteria: detection of P-ANCA, creatinine clearance lower than 30 ml/min, induction of remission therapy with rituximab without concomitant CYC and a follow up period of at least 6 months. The primary outcomes were complete remission after induction therapy, renal function recovery and mortality after the induction treatment. RESULTS: Eight patients met the inclusion criteria. The M:F ratio was 1:7, the average age was 54 years old and the median follow up was 10 months (7-72); in 2 patients there was a MPA renal limited vasculitis. A renal biopsy was performed in 7 patients. The median BVAS score at rituximab induction was 14(range 6-21). Two patients required haemodialysis before the induction treatment. Four patients developed end stage renal disease (ESRD) that required haemodialysis. These data show a remission of the disease, associated with a stabilization of the kidney function in 50% of patients. In 3 patients who did not show a response, there was also no response to CYC. CONCLUSIONS: This study shows a partial efficacy of rituximab in renal function recovery and a low risk of infectious complications in patients with MPO vasculitis with severe renal involvement, in particular in the short term. The optimal treatment in this subgroup of patients still has to be established because data are lacking.

5 year comparison of very low-dose cyclosporine and high-dose everolimus vs standard cyclosporine and enteric-coated mycophenolate in renal transplantation patients.

In this retrospective study, we compared the outcome of renal transplanted patients who received everolimus (EVR) (C0: 8-12 ng/mL)+cyclosporine (CsA) (C2: 150-300 ng/mL)+steroids, vs those who received enteric-coated mycophenolate sodium (EC-MPS) (1,440 mg/d)+CsA (C2: 500-700 ng/mL)+steroids. Efficacy was evaluated at 5 years. We found a nonsignificant trend toward a better 5-year graft survival (81.2% vs 68.6%) and better graft function (estimated glomerular filtration rate 71.8±35.7 vs 60.0±26.2 mL/min, P=.114) in favor of the EVR group. In our experience, EVR with a very low dose of CsA was associated with a nonstatistical trend toward better renal function and graft survival compared to a standard regimen of CsA and EC-MPS.

Conversion from calcineurin inhibitors to everolimus with low-dose cyclosporine in renal transplant recipients with squamous cell carcinoma of the skin.

Squamous cell carcinoma of the skin (SCC) is the most frequent cancer in renal transplant recipients. Conversion to mammalian target of rapamycin inhibitors after diagnosis of SCC may reduce the incidence of recurrence of skin cancer. This retrospective study evaluated the outcome of renal transplant recipients followed by the Renal Unit with posttransplant diagnosis of SCC treated with conversion from calcineurin inhibitors (CNIs) to Everolimus (EVR) associated with low-dose cyclosporine. Eleven patients developed SCC at a median time from renal transplantation of 107 months (range 36-264). Five patients with creatinine clearance (CCl) below 40 mL/min before conversion developed end stage renal disease (two cases) or further deterioration of renal function (two cases); only one patient in this group maintained a stable renal function. The remaining six patients with a CC1 greater than 40 mL/min and proteinuria below 0.8 g/24 hours maintained a stable renal function after conversion to EVR at a median follow-up of 22 months (range 15-75). Conversion from CNIs to EVR has been proven safe, effective, and associated with low recurrence of SCC in patients with a CCl >40 mL/min. In the case of preexisting deterioration of renal function or significant proteinuria, conversion to EVR should be carefully evaluated.

Donors positive for hepatitis B core antibodies in nonliver transplantations.

We reviewed available, particularly epidemiological data regarding transplantation of organs from donors positive for hepatitis B core antibodies (HBcAb) to evaluate the possibility of transmitting the disease. For nonhepatic organs, the risk is low: higher for lung but lower for kidneys and heart, according to the quantity of lymphoid tissue. The use of such organs is increasing owing to the worldwide organ shortage. Unfortunately, even if the use of HBcAb-positive donors does not seem to affect patient or graft survival, the United Network for Organ Sharing and United States Renal Data System registries do not have data on hepatitis B incidence after transplantation. Cohort data suggest that the use of such donors is safe if one follows suggested guidelines. In particular, recipients with no evidence of HBsAb should receive prophylaxis with either lamivudine or HB immunoglobulin. Our data show a 15%-20% incidence of HBcAb-positive donors, as in other European countries. The 1-year graft outcomes are good, with a 3% seroconversion rate to HB surface antigen.

Lower homocysteine levels in renal transplant recipients treated with everolimus: a possible link with a decreased cardiovascular risk?

Cardiovascular disease (CVD) is the main cause of morbidity and mortality in renal transplant recipients. The incidence of CVD in this setting is approximately 5-fold greater than in age- and and gender-matched subjects. This excess cardiovascular risk is not completely explained by traditional cardiac risk factors. It has been well documented that these patients show greatly increased prevalence of both fasting and postmethionine-loading hyperhomocysteinemia (hHcy) compared with the general population. An immunosuppressive therapy based on everolimus has been demonstrated to reduce the incidence major adverse coronary events at 4 years compared with azathioprine among heart transplant recipients. In contrast, scarce data are available on the impact of everolimus on emerging risk factors, such as homocysteine (Hcy), in renal transplant recipients. The aim of this study was to evaluate the possible impact of everolimus compared with other immunosuppressive regimes among 132 stable recipients, including 91 men and 41 women who were at least 1 year after transplant with stable renal function and no clinical evidence of acute or chronic renal graft rejections. We compared 31 subjects on everolimus immunosuppressive therapy (group A) versus 101 on immunosuppressive therapy based on cyclosporine, steroids, and mycophenolate. The Hcy levels were significantly lower among group A patients compared with group B: 16.5 +/- 5 micromol/L vs 21.2 +/- 11 micromol/L; P < .005. Hyper-Hcy, defined as Hcy levels >15 micromol/L, was diagnosed in 18 out of 31 patients (51%) of group A and in 82 out of 101 patients (81%) of group B. This preliminary study demonstrates a favorable impact of everolimus on a marker of atherothrombosis which is associated with a worse vascular prognosis.

Preemptive cadaveric renal transplantation: fairness and utility in the case of high donation rate-pilot experience of Tuscany region.

Preemptive kidney transplantation is performed before the initiation of chronic dialysis. Preemptive transplantation is the best treatment modality for patients reaching end-stage renal disease. The Tuscany region has experienced, in the last years, a marked increase in donation rate. Starting from 2006, the first Italian cadaveric preemptive transplant program was activated. The aim of our study was to investigate the characteristics and preliminary results of this program. Among 163 patients entered on to the waiting list for renal transplantation from October 2006 to October 2008, 120 (73.6%) were on dialysis for 21.3 +/- 17.8 months, whereas 43 patients (26.4%) had not yet been on dialysis (preemptive). Eighty two patients (50.3%) resided in Tuscany and 81 (49.7) outside Tuscany; 36.6% of Tuscany patients and 16% of extraregional patients (P = .003) were listed as preemptive. Fifty-eight of 163 (35.6%) patients were transplanted during the period after a mean waiting time of 10.3 +/- 6.4 months. The estimated overall man waiting time was 17.5 months (confidence interval (CI) = 15.8-19.2). Upon Cox multivariate analysis, the probability of transplantation was similar for preemptive and dialysed patients (relative risk [RR] 1.02, P = NS). According to local allocation policy, only residents of Tuscany showed a significant advantage in both groups (RR = 0.43, CI = 0.24-0.75, P = .003). Two-year graft and patients survivals were similar, but delayed graft function was lower in the preemptive group (13% vs 42%, P = .007). The 1-year serum creatinine was 1.56 +/- 0.43 in the preemptive group and 1.68 +/- 0.92 in the dialysis group (P = NS). No differences were observed concerning rejection rate. The preemptive listing rate for cadaveric renal transplantation was more than 35% for Tuscany patients.

Posttransplant proteinuria associated with everolimus.

Anti-mTOR may induce proteinuria when utilized after renal transplantation. Little is known about the pathogenesis and composition of proteinuria. To clarify this unresolved aspect, we analyzed urinary protein composition utilizing an integrated proteomics approach, including quantitative assays, 2-dimensional electrophoresis, MALDI-TOF, and Western blots among 48 renal transplant recipients treated with everolimus (EVL; n = 31) or enteric-coated mycophenolic acid (EC-MPA; n = 17). High (>3 g/d) or intermediate levels of proteinuria (1-3 g) developed in 12 EVL patients (39%) compared with 4 subjects (23%) in the EC-MPA group. Proteinuria, which started during the first 2 days after EVL, tended to reduce during the follow-up. Quantitative proteomics showed an increase in low molecular proteins beta2 microglobulin (P < .001) and alpha1 microglobulin (P < .025). Qualitative proteomics showed a marked increase among all urinary components in EVL and EC-MPA patients. Major changes involved typical components of glomerular damage: albumin, Zn-alpha1 glycoprotein, alpha2HS glycoprotein, and leucine-rich alpha2 glycoprotein. In addition, we observed specific biomarkers for EVL: clusters of alpha1-antitrypsin fragments and monoclonal lambda chains. In conclusion, EVL induced proteinuria of a mixed glomerular and tubular origin that correlated with the start of treatment and reached nephrotic ranges in few cases. The specific urinary markers may reflect renal alterations related to the transplant or specific alterations associated with the drug.

Chronic kidney disease is still present after renal transplantation with excellent function.

According to a k/DOQI work group, chronic kidney disease (CKD) can be present also in subjects with glomerular filtration rate (GFR) >90 mL/min or a serum creatinine (sCr) below 1.3 mg/dL. The aim of this study was to document the prevalence of clinical or biologic abnormalities among 190 cadaveric renal transplant patients with excellent and stable renal function at 6 months after transplantation as well as 5 years later. The recipients were 82 women and 108 men of mean age at transplantation of 44.56 +/- 11.73 years. All patients were on Neoral-based immunosuppression with at least 5-year follow-up. Mean sCr was 1.18 +/- 0.2 mg/dL. Mean GFR was 78.57 +/- 27.06 mL/min. Systolic blood pressure was >130 mm Hg in 56.6%, although 78.3% of patients were on antihypertensive therapy; 34.3% were anemic; 75.4% had serum cholesterol >200 mg/dL; 62.2% had serum triglyceride levels >170 mg/dL. Serum intact parathyroid hormone >100 pg/mL was observed in 38% of patients and 43% were on vitamin D supplementation, and 11.4% had developed posttransplant diabetes mellitus. With respect to controls, von Willebrand factor was higher in 81.2% (P < .0001; RR = 11); serum homocysteine levels in 75% (P < 0.001; RR = 7.61); PAI-1 in 37.5% (P = .0009; RR = 4). At 5 years posttransplantation we observed an overall improvement in these abnormalities. The vast majority of renal transplant patients with excellent graft function belong to stage 1 of CKD being affected by hypertension, dyslipidemia, anemia, and residual hyperparathyroidism. Markers of endothelial dysfunction were largely abnormal, a condition that could predispose to cardiovascular events.

Donor characteristics can influence transplant activities and the access to transplant for some age groups.

In recent years Italy has experienced a remarkable increase in organ donation and transplant rates for kidney transplantation. The organ donation rate has placed Italy among the European leaders, but a careful comparative evaluation of Italian and international registries data demonstrates that renal transplantations have not shared the same significant growth. In a decisive way donor characteristics have influenced not only the number of renal transplantations, but also the access to transplant for some age groups. We investigated the probability of transplantation from different age groups using the Kaplan-Meier method and the log-rank test. The 7-year probability of transplant was 72% for the 15 to 45 age group, 85.7% for the 46 to 55 age group, and 88.5% for the over 55 years group (P = .0029). Ethical considerations suggest new approaches of innovative promotion of living donor transplants and a revision of organ allocation criteria.

Immunosuppression in renal transplantation: viral diseases and chronic allograft nephropathy.

Chronic allograft dysfunction after renal transplantation can be ascribed to different causes, among which are viral infections. The aim of this work was to show the various ways by which different kinds of viruses affect transplant structure and function. Polyoma virus is an example of viruses directly affecting the kidney because of a specific tropism to the uroepitelial cells. Cytomegalovirus (CMV) has been chosen both because of the frequency of this infection and because CMV (as other viruses) can produce transplant vascular sclerosis. Finally, we describe hepatitis C virus (HCV) because of its capacity to induce renal lesions independently from chronic allograft nephropathy. Indeed HCV is likely to determine immunologically mediated nephritis in the transplanted kidney as well in the native one.

Efficacy and safety of Palmaz stent implantation in the treatment of renal artery stenosis in renal transplantation.

To verify the long-term efficacy and safety of Palmaz stent implantation in the treatment of transplant renal artery stenosis (TRAS), we reviewed the charts of 26 patients affected by TRAS and treated by percutaneous transluminal angioplasty (PTA) followed by permanent insertion of a Palmaz stent. The mean follow-up period was 43.31 +/- 33.6 months. The mean blood pressure fell significantly at 1 month after stenting (118 +/- 8.1 vs 101 +/- 7.8 mmHg; P < .0001); then remained stable. Renal artery blood flow, as determined by Doppler ultrasonography, was reduced from 352.5 +/- 56.5 to 157.3 +/- 53.7 cm/sec at 1 month after stenting (P < .0001). Renal function improved after stenting (serum creatinine 2.2 +/- 1.4 mg/dL preinsertion versus 1.72 +/- 1.05 at 3 years). In conclusion, in cases of severe or recurrent TRAS, stenting of the renal artery has proved to be an effective therapeutic tool. This method, which has low procedure costs and an extremely low complication rate has proved to be safe and to offer the potential of preserving luminal patency, improving the long-term efficacy of percutaneous angioplasty.