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.

Anemia and Immunosuppressive Regimen in Renal Transplanted Patients: Single-Center Retrospective Study.

We compared retrospectively the level of hemoglobin and the percentage of patients with anemia among 59 kidney transplant recipients receiving everolimus, cyclosporine, and corticosteroids and 128 treated with cyclosporine, mycophenolic acid, and corticosteroids. We also compared age at the time of transplantation, sex and ferritine, serum creatinine, creatinine clearance, folic acid, cyanocobalamine levels, use od recombinant erythropoietin, mean corpuscolar volume at the last ambulatory control. Statistical analysis included Student t test, χ(2) test, and logistic regression. The analysis was performed using SPSS software. We observed no difference in terms of hemoglobin levels in patients treated with everolimus (12.9 ± 1.6 vs 12.7 ± 1.5 g/dL). Anemia (defined as hemoglobin <13 g/dL in men and <12 g/dL in women, or need to use erythropoietin) was found in 49% and 45% of patients in the 2 groups respectively (P = .6). The other parameters evaluated were similar except for the mean corpuscular volume, which was significantly lower in the everolimus group. In the multivariate analysis only serum creatinine and estimated glomerular filtration rate influenced the level of hemoglobin. We observed no differences in terms of development of anemia in renal transplanted patients treated with everolimus-based regimen.

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.

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.

Kidney graft survival rates do not improve by era: the impact of the age factor.

We performed this study to evaluate whether older ages of donors and recipients negatively affected long-term graft survival. We compared 5-year graft survival rates of 89 recipients transplanted between 1991 and 1995 (period A) versus 221 recipients transplanted between 1996 and 2000 (period B). Acute rejection rates and the number of donors and recipients >50 years of age were compared in the two periods. The 5-year graft survival rate in period B was 76.3% versus 82% in period A. In period B, the acute rejection incidence was 18% versus 40% in period A (P < .001). The overall 5-year graft survival was 86.2% for donors aged 21-50 years and 65.7% for donor's aged >50 years (P < .0001) in period A versus 84.1% and 68%, respectively, in period B (P = .0023). In period A, 23.6% of donors and 35.9% of recipients were >50 years old, versus 50.2% and 42.9%, respectively, in period B. The graft survival rate in period B was worse than in period A, although the acute rejection rate was lower. The older age of both donors and recipients in period B seemed to be an important cause of worse outcomes.

Preemptive therapy for the prevention of cytomegalovirus disease in renal transplant recipients: our preliminary experience.

BACKGROUND: Cytomegalovirus (CMV) disease represents an important cause of morbidity in renal transplant recipients. We report our preliminary evaluation of the efficacy and security of preemptive therapy to manage renal transplant recipients with evidence of active CMV replication. METHODS: Preemptive therapy with gancyclovir and/or valgancyclovir (VGCV) was recently substituted for CMV antiviral prophylaxis at our institution. Between May 2006 and December 2007, all patients undergoing renal transplantation were included in a CMV infection surveillance program. Blood samples to determine CMV viral load were obtained weekly during the first 4 months. Asymptomatic patients, with a viral load determined using polymerase chain reaction (PCR) with CMV DNA >100,000 copies/mL, were treated with VGCV for 3 months or until resolution of viral replication. Until April 2006, patients undergoing renal transplantation received CMV prophylaxis with oral acyclovir and pp65 antigenemia was the test for CMV infection surveillance. The group on preemptive therapy was compared with a historical group on prophylaxis therapy: 100 renal patients who underwent transplantation between April 2004 and 2006. RESULTS: Among 96 recipients, quantitative determination of viral DNA in blood was elevated in 14 asymptomatic patients, who were treated with oral VGCV for 3 months. The patients were followed up for a median time of 13.3 months. None of the 14 patients who received VGCV developed CMV disease. CONCLUSION: VGCV administered as preemptive therapy was safe and efficacious to prevent CMV disease.

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.

Excellent outcome of renal transplantation using single old kidneys in old recipients.

Aim of this monocentric study is to compare the outcome of 101 renal transplants performed in patients older than 55 years with single kidney retrieved from donors older than 50 years, with 263 transplants performed in patients younger than 55 years transplanted with young kidneys. Delayed graft function (DGF) had similar incidence (24 vs 23%). Acute rejections (AR) were fewer in younger recipients without statistical significance. A 6-month serum creatinine < 130 mmol/L was less frequent in older recipients (RR 1.20; p=0.004). 5-year patient survival rate was lower in older patients (80.6% vs 92.6%; p=0.009). Crude 5-year graft survival rate was lower in older recipients (68.5% vs 84.5%; p=0.004). Adjusting for death with functioning kidney 5-year graft survival was still, but not significantly, lower in older recipients (82.8% vs 90%; p=NS). This data outline that graft survival rate must be always adjusted for death with functioning grafts and that excellent outcomes with a 5-year graft survival, higher that 80% can be obtained in old patients using single cadaveric kidneys.

Younger dialytic patients are really at risk to be not transplanted. The Tuscany experience.

The huge increase in organ donation (27.2 pmp in 2002), that characterized our regional transplant program was mainly due to the increase of marginal (older) donors. As allocating organs coupling donor and recipient age is mandatory, aim of this study was to verify the consequences of such retrieval policy over the renal transplant activity. According our longitudinal data younger uremic patients in Tuscany waiting list for transplantation, have the lowest chance to receive kidney transplantation, mainly with respect to older patients that are easily removed from the waiting list. This unfair condition need to be corrected either by promoting living donation, either increasing cadaveric donation from younger donors.

Hyperhomocysteinemia in renal transplant patients: an independent factor of cardiovascular disease.

Hyperhomocysteinemia (Hcy) is an independent factor of cardiovascular disease, which is the main cause of morbidity and mortality both in uremic and kidney transplant patients. The aim of the study was to determine Hcy, plasminogen activator inhibitor (PAI-1) and lipoprotein (a) (Lp(a)) serum levels in 70 patients with a well functioning renal transplant. We also verified whether these levels were modified by a multivitamin therapy. The genetic polymorphism of the methylenetetrahydrofolate reductase (MTHFR) enzyme which plays a main role in Hcy metabolism, was studied as well. We found Hcy, PAI-1 and Lp(a) levels significantly elevated with respect to healthy control subjects. The thermolabile form of the MTHFR enzyme was linked to higher Hcy levels. After a short time on therapy with B6, B12 and folic acid vitamins, Hcy and PAI-1 decreased to normal levels. The authors conclude that high Hcy levels could be a relevant covariate for cardiovascular disease in transplant patients and they suggest that vitamin supplementation be recommended as a part of therapy.

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

The aim of this study was to verify the safety and long-term efficacy of Palmaz stent insertion in the treatment of transplant renal artery stenosis (TRAS) in kidney transplantation. Nine of our transplanted patients were submitted to Palmaz stent insertion because of recurrence of renal artery stenosis after previous percutaneous transluminal angioplasty or because of severe ostial stenosis. The post-stenting results were excellent in all patients, with a follow-up period ranging from 1 to 3 years. The mean blood pressure (one-third systolic pressure plus two-thirds diastolic pressure) fell from 118.11 +/- 7.44 to 103.21 +/- 9.25 mmHg; P < 0.001. Renal artery peak blood flow velocity as determined by Doppler sonography fell from 352 +/- 73.24 cm/s to 169.8 +/- 23.35 cm/s; P < 0.001. The serum creatinine 1-year after stenting was 1.3 +/- 0.3 mg/dl with a slight reduction with respect to the pre-stenting values (1.5 +/- 0.3 mg/dl; NS). As no complication occurred, we conclude that insertion of the Palmaz stent is a safe and effective way to treat recurrence of artery stenosis or ostial stenosis in renal transplanted patients.

Fate of kidneys from the same donor grafted into different recipients: do they behave similarly and are they influenced by donor-related factors?

BACKGROUND: The fate of paired kidneys might be similar and could therefore reflect the influence of donor-related factors on graft outcome. PATIENTS AND METHODS: To verify whether two kidneys retrieved from a single donor and grafted into different recipients have similar short, and middle-term outcomes we investigated the clinical outcome of 103 pairs of cadaveric kidneys grafted into 206 recipients. We evaluated the influence of donor-related factors such as age, sex and cause of death, and of the storage solution and method of harvesting. The incidence of delayed graft function was considered as the short-term outcome and serum creatinine levels at two years as the middle-term outcome. We evaluated the difference from expected frequencies in the incidence of delayed graft function and the incidence of similar serum creatinine levels in each pair of recipients. Univariate analysis of possible risk factors was made by the t-test, chi2 test and Fisher test, as appropriate. Multivariate analysis was done by logistic regression analysis with a forward stepwise variable selection. RESULTS: Delayed graft function was seen in both recipients from the same donor 2.5 times more than the expected frequency (p<0.001). Serum creatinine levels were similar in both recipients with a higher frequency than expected (p<0.01). Multivariate analysis showed that donor-related factors on graft function were age, cause of death and storage solution. CONCLUSIONS: Paired kidneys have similar performances in both the short and the long term. Major donor-related factors in delayed graft function are age and the storage solution. Major donor-related factors in graft function are age and cause of death.

Mycophenolate mofetil (MMF) in the treatment of chronic renal rejection.

BACKGROUND: Experimental studies suggest the efficacy of MMF in the treatment of chronic renal rejection in rats. Studies on the efficacy of MMF in chronic renal rejection in man are scarce and controversial. AIM: The aim of this study was to verify in a prospective non-randomized study the efficacy of MMF given at the dose of 2 g/day in substitution of azathioprine (AZA) in the chronic rejection of cadaveric kidney transplantation. PATIENTS AND METHODS: Twelve patients with histologically proven chronic renal rejection were enrolled. The patients were 5 males and 7 females. Mean age 38.3 +/- 13.8 years, with a mean duration of transplant of 39 +/- 19 months. Mean serum creatinine values at -6, -3, 0, +3, +6, +12 months were respectively 1.72 +/- 0.33, 1.84 +/- 0.36, 2.15 +/- 0.50, 1.88 +/- 0.54, 1.81 +/- 0.71, 1.73 +/- 0.58 mg/dl. Mean creatinine clearance values were 58.85 +/- 10.06,48.8 +/- 13.3,45.8 +/- 10.2, 54.7 +/- 13.3, 51 +/- 12.7, 57.7 +/- 18.5 ml/min. Mean deltaGFR before MMF was -2.15 ml/month. RESULTS: After MMF introduction, the overall GFR decrease attenuated. In particular in seven patients after MMF administration, we obtained a significant reduction of mean serum creatinine value (1.84 +/- 0.55 vs. 1.38 +/- 0.41mg/dl; p = 0.004). In three patients, we obtained a stabilization in GFR. Two patients were slowly progressing even after MMF introduction. After a switch to MMF in almost all patients, we obtained an improvement of renal function. In three patients, we obtained a stabilization of renal function without regression. In particular, seven patients showed a remarkable improvement of renal function. CONCLUSIONS: In conclusion our data even if concerning a small number of patients, confirm the efficacy of MMF in the treatment of renal allograft chronic dysfunction.

Limits of clinical signs and non-invasive techniques in detecting severe acute rejection.

We describe a cadaveric renal transplant patient with an early post-transplant period characterized by normal urine output, normal clinical and biological signs, and a slow decrease of serum creatinine; repeated ultrasonography, color doppler ultrasonography and renal angioscintigraphy were normal or consistent with a clinical diagnosis of mild acute tubular necrosis. Nevertheless a core renal biopsy revealed severe steroid-resistant acute rejection with diffuse infiltrates of lymphocytes and initial transmural arteritis.