The role of immunosuppression in malignancies among 351 pediatric renal transplant patients.

The incidence of de novo malignancies over a 38 year experience in 351 children ranging in age from 2 to 18 years was investigated among subjects prescribed various immunosuppressive protocols. There were 14 children (3.98%) who showed de novo malignancies, namely, 4.86 cancers for every 1000 graft-function years (GFYs). Among patients who had grafts functioning for >10 years, 7.4% suffered from cancer. Nine patients survive without a recurrence at a mean of 12.5 +/- 6.6 years including 6 with graft function. Among group I who were treated with pre-calcineurin inhibitor (CNI) therapy 3 (3.8%) children (1 male and 2 females) developed a malignancy at a mean of 15.2 +/- 11.9 years posttransplant (range, 7-35), for 4.65 cancers every 1000 GFYs. Two of them survive with functioning grafts. Among group II, who were treated by CNIs there were 273 children including 24 retransplants. Group II showed 11 malignancies (4.0%), for 5.04 malignancies for every 1000 GFYs. The incidence of cancer was similar in the 2 groups, undergoing different immunosuppressive regimens; however, the malignancies in the CNI- group were more precocious, compared with those of the conventionally-treated cohort.

Malignancies in 2,753 kidney recipients transplanted during a 39-year experience.

An increased development of malignancies has been related to modern potent antirejection drugs. The purpose of this retrospective study was to assess the incidence and risk factors for invasive malignancies among 2753 kidney recipients (KRs), who were transplanted in two periods within our 39-year experience; before (group I) versus after (group II) the introduction of calcineurin inhibitors (CNIs). In group I, formed by 703 KRs under conventional therapy, 45 (6.4%) patients developed a malignancy, while in group II, treated with CNIs, of over 2050 KRs, 182 (8.9%) developed a malignancy different from noninvasive skin cancer. The incidence of malignancies was higher in the group of patients treated with CNIs (8.9% vs 6.4%), despite the shorter follow-up period. Moreover, the malignancy was more precocious in the CNI group, namely a mean time of onset of 75 versus 154 months in the conventionally treated group. The older mean age of recipients in group II affected by malignancies (43.6 years vs 34.6 years of the group I) played a significant (P < .001) role when associated with the more powerful immunosuppressive effect of CNIs, while recipient gender, dialysis period, donor source, and retransplants seemed to have few effects on malignancy development. Recipients over 60 under CNIs showed a 21% incidence of malignancies.

The long-term prognosis of renal transplant in patients with systemic vasculitis.

Little information is available about the long-term outcome of renal transplantation in patients with systemic vasculitis (SV). We compared the outcomes of 19 renal transplant recipients with SV with those of 38 controls matched for time of transplantation, age, gender and source of donor. The mean post-transplant follow-up was 58 +/- 57 months for vasculitic patients and 61 +/- 49 months for controls. The actuarial 10-year patient survival was 87% in vasculitic patients and 90% in controls, death-censored graft survival were 84% and 100%, respectively. The risks of acute and chronic rejection, and arterial hypertension were not significantly different between the two groups. Infection was significantly more frequent in vasculitic patients (74% vs. 34%; p = 0.01). Seven patients (36.8%) had a recurrence of vasculitis in mean 45 months after renal transplant (0.076/patients/year). After recurrence, one patient had an irreversible humoral rejection, another died from hemophagocytosis and another restarted dialysis 1 year later. Long-term patient and renal allograft survival in vasculitic patients was good. Although graft function recovered in most relapsers after reinforcement of immunosuppression, one patient died and two lost graft function.

Hepatitis C virus infection and rituximab therapy after renal transplantation.

BACKGROUND: Rituximab, a chimeric monoclonal antibody, has been successfully given in various diseases including HCV-associated mixed cryoglobulinemia. However, only preliminary data exists on its efficacy and safety after renal transplantation. METHODS: We report on a renal transplant recipient with chronic hepatitis C who received rituximab therapy for gastric cancer. Four rituximab infusions of 375 mg/m(2) were given. RESULTS: Rituximab therapy was complicated by cholestatic hepatitis C with very high HCV RNA levels; liver insufficiency occurred. The patient developed bacterial pneumoniae and respiratory insufficiency was the cause of death. Although other mechanisms cannot be excluded, we found that rituximab therapy was implicated in the pathogenesis of cholestatic hepatitis C in our patient. CONCLUSIONS: We suggest that rituximab therapy may be associated with significant side effects. More experience has to be accumulated before any conclusions on efficacy and safety of rituximab therapy after RT can be drawn.

A randomized trial of steroid avoidance in renal transplant patients treated with everolimus and cyclosporine.

In this randomized trial renal transplant recipients were treated with basiliximab, everolimus 3 mg/day, low-dose CsA. At transplantation, patients were randomized to stop steroids at the seventh day (group A) or to continue oral steroids in low doses (group B). Of the 113 patients enrolled, 65 were randomized to group A and 68 to group B. All patients were followed for 2 years. During the study 28 (43%) group A patients required reintroduced corticosteroids. One patient died, in group B. The Graft survival rate was 97% in group A and 90% in group B. There were more biopsy-proven rejections in group A (32% vs 16%; P = .044). The mean creatinine clearance was 54 +/- 21 mL/min in group A vs 56 +/- 22 mL/min in group B. Mean levels of serum cholesterol tended to be lower in group A, but the difference was of borderline significance (191 +/- 91 vs 251 +/- 188 mg/dL; P = .07). Vascular thrombosis (0 vs 5) and pneumonia requiring hospitalization (2 vs 7) tended to be more frequent in group B. Only three cases of CMV infection (1 vs 2) occurred. An immunosuppressive therapy with everolimus and low-dose CsA allows one to obtain excellent renal graft survival and stable graft function at 2 years. Early interruption of steroids in patients treated with this regimen may increase the risk of acute rejection, but neither affects graft survival nor graft function, while possibly reducing the risk of hyperlipemia and vascular thrombosis. About 60% of patients given everolimus and low-dose CsA can definitively stop steroids after 1 week.

Natural history of hepatitis C virus infection in adult renal graft recipients.

AIM: To study the natural history of hepatitis C virus infection in renal transplantation, 464 HbsAg negative patients were prospectively studied from 1989. METHODS: AntiHCV was tested by ELISA II and HCVRNA by Amplicor HCV RNA tests. RESULTS: Two hundred nine patients were antiHCV positive (C+). HCVRNA was confirmed in 89% of C+ patients. Compared with the 255 anti-HCV negative (C-), C+ had undergone longer periods of dialysis (P = .0001), were more transfused (P = .01), and included more retransplants (P = .002). Immunosuppression was azathioprine (AZA) plus steroids in 133 and cyclosporine (CsA) in 331 patients. Liver biopsy showed chronic active hepatitis in 50, cirrhosis in 8, and fibrosing cholestatic hepatitis in 2 patients. Histologic progression of liver disease was confirmed in 18 of 26 patients. The causes of death in 84 patients (51 C+ vs 33 C-) were cardiovascular disease in 49%, sepsis in 13%, liver failure in 14%, neoplasia in 21%, and hepatocarcinoma in 2%. The 14-year patient survival was 75% in C+ and 86% in C- (P = .002). By multivariate analysis, age (>40) (P = .001) and C+ (P = .019) correlated with a worse patient survival. If patients were stratified according to age (<40 vs > or =40), younger C+ patients had a lower survival probability (P = .03). The 14-year graft survival was 44% in C+ vs 60% in C- patients (P = .001) but pure graft survival was similar (68% in C+ vs 72% in C-) (P = .13). CONCLUSION: The presence of C+ significantly reduced both patient and graft survival in the long-term with liver failure being the second most frequent cause of death.

From cyclosporine to the future.

Most of the experience acquired in our unit with cyclosporine (CsA) comes from randomized trials. A first trial demonstrated that CsA-treated patients had a better 10-year graft survival than azathioprine-treated patients. A second trial showed equivalence between double therapy with CsA plus steroids and triple therapy with CsA, steroids, and azatioprine. A third trial showed similar 2-year graft survival with CsA monotherapy and triple therapy. A larger multicenter study that compared three different CsA-based regimens showed similar long-term graft survival with monotherapy, double therapy, and triple therapy. However, patients given monotherapy had less frequent steroid-related side-effects. Finally a more recent multicenter international trial showed that the rate of acute rejection can be reduced without increasing side effects by adding the monoclonal antibody basiliximab to the triple therapy. By reviewing our cumulative experience with CsA we found a mean graft half-life of 18.7 years for cadaver renal transplant recipients and 31.9 for the living transplant recipients. No significant attrition of graft function was found for patients with grafts functioning at 15 years. Two important issues with the present immunosuppression concern the long-term nephrotoxicity of calcineurin inhibitors and the cardiovascular disease, which is at least in part related to the use of steroids. To face these problems, we are currently involved in two multicenter trials, one comparing sirolimus plus mycophenolate mofetil to sirolimus plus low-dose CsA, while the other trial compares certican plus CsA to certican plus CsA plus corticosteroids.

[Living-donor kidney transplantation in the cyclosporine era]. / Il trapianto di rene da donatore vivente nell'era della ciclosporina.

BACKGROUND: Renal transplantation is the best possibile form of treatment for chronic renal failure. It offers the patient a longer life expectancy when compared to dialysis. Aim of the study was to evaluate our results with live donor transplantation and the variables that influenced the long-term patient and graft survival. METHODS: 190 patients received a live donor kidney transplantation in our Hospital between 1984 and 2000. Thirty-eight of them received a graft from an HLA identical donor, 130 from an HLA haploidentical donor, 22 from a living unrelated donor (spouse). Fourteen patients underwent a pre-emptive transplantation. Aim of the study was to evaluate which variables could influence the long-term patient and graft survival. RESULTS: The median follow-up of recipients was 69.5 months. The 10-year patient and graft survival were 94.7% and 73.4% respectively. Graft half-life was 29.6 years. Six patients died. Twelve patients lost their graft because of vascular thrombosis and five patients because of rejection within the first six months. After the first year, 11 patients lost their graft because of chronic rejection and 4 after recurrence of the original disease. One hundred and forty-four patients are still under observation, and at the last examination their mean plasma creatinine was 2.0+/-1.1 mg/dl. At univariate statistical analysis the absence of locus DR incompatibility was associated with a trend toward a better long-term survival of both patient and graft (P=0.05), while less than one year of dialysis showed a significantly better survival rate (P < 0.01). CONCLUSIONS: Living-donor transplantation offers an excellent long-term patient and graft survival.

Effect of increased arterial resistance index on long-term outcome of well-functioning kidney grafts.

An abnormal vascular status is present in the transplanted kidney. To define whether vascular factors might influence kidney function of the graft, the renal volume, blood flow and vascular resistance of a group of healthy subjects were compared with those of a group of well functioning renal transplants by color Doppler ultrasonography. Sixty healthy subjects and 75 well functioning cadaver renal transplant recipients were compared by color Doppler ultrasonography. Subsequently, 15 couples of donors and recipients of a living related renal graft were compared to observe the differences between the two organs of the same subject in a different environment. The variables studied were: the diameters and the volume of the kidney, renal blood flow and renal resistance index (RI). The group of cadaver renal transplant patients showed higher mean blood pressure (P = 0.009), higher serum creatinine levels (P = 0.0001) and lower endogenous creatinine clearance (P < 0.0001) than healthy controls. The length (P < 0.00001) and volume (P < 0.001) of the kidneys of cadaver transplanted patients were significantly greater than those of healthy subjects, while the length and volume of the living donors kidneys were identical to those of the recipients. RI, measured on renal vessels, showed lower values in healthy subjects and in kidney donors than in transplanted patients (P < 0.00001). Well functioning transplanted kidneys showed increased renal arterial RI. This non-immunologic factor did not appear to be detrimental with renal function in time, at least until 50 months after successful grafting.

Double recurrence of FSGS after two renal transplants with complete regression after plasmapheresis and ACE inhibitors.

A patient who had undergone a first cadaveric donor kidney transplantation for idiopathic focal segmental glomerular sclerosis (FSGS), had an immediate recurrence of a biopsy-proven FSGS that eventually led to graft failure within 5 years from transplantation. The patient underwent a second cadaveric transplantation 10 months later. An immediate recurrence of a biopsy-proven FSGS occurred that was treated with two protracted cycles of plasmapheresis of seven months each, with the addition of an ACE inhibitor from the beginning. A complete and stable remission of FSGS was observed, which continues after more than 6 years from the end of plasmapheresis. The recurrence of FSGS after a second transplantation has a poor prognosis, but prolonged plasmapheresis treatment, by removing circulating factors altering glomerular permselectivity, and the addition of ACE inhibitors, through their potential interference with TGF-beta, might be synergistic in obtaining permanent remission.

Long-term results with cyclosporine monotherapy in renal transplant patients: a multivariate analysis of risk factors.

There is little information on the long-term outcome of patients initially assigned to cyclosporine (CsA) monotherapy and requiring the addition of steroid therapy during follow-up. The aim of this report is to describe our experience with 143 first renal transplant recipients (120 cadaver transplants, 23 living donor transplants) randomized to receive CsA monotherapy as a treatment arm of three consecutive controlled clinical trials. Median follow-up was 86 months. Thirty-four percent of the patients remained on the original CsA monotherapy, whereas the remaining 66% required the addition of steroid therapy. Cumulative patient and graft survivals at 11 years were 0.89 (95% confidence interval [CI], 0.83 to 0.95) and 0.62 (95% CI, 0.52 to 0.72), respectively. The 11-year graft survival for converted patients was 0.53 (95% CI, 0.39 to 0.67). Cumulative graft half-life was 19.9 +/- 3.47 (SE) years. According to the Cox model, variables at transplantation that correlated with a lower 11-year graft survival were yearly increases in age (relative risk [RR], 1. 04; P = 0.039), monthly increases in hemodialysis duration (RR, 1.01; P = 0.029), no blood transfusion before transplantation (RR, 1.99; P = 0.043), CsA administration in a double daily dose (RR, 2.35; P = 0.008), and a cadaver donor transplant (RR, 4.76; P = 0.039). Multivariate analysis of time-dependent variables showed that delayed graft function recovery (RR, 2.20; P = 0.019) and the need to add steroid and/or azathioprine therapy (RR, 5.28; P = 0.000) were also correlated with a lower graft survival. Patients who added steroid therapy developed infections (P < 0.001), cataracts (P < 0.001), cardiovascular complications (P = 0.004), and arterial hypertension (P = 0.024) more frequently than patients remaining on CsA monotherapy. Patients administered CsA in a single daily dose received significantly less CsA over the years (P = 0.0042) than patients administered CsA in two divided doses. They also showed a trend toward greater creatinine clearance levels, although not statistically significant. In conclusion, this analysis showed that in patients assigned to CsA therapy alone, good long-term patient and graft survival probabilities can be obtained. In approximately one third of the patients, the use of steroids could be avoided for up to 11 years, and these patients had a better long-term outcome than those who required the addition of steroid therapy. Finally, in patients administered CsA in a single daily dose, the possibility of reducing CsA dosage probably led to better intrarenal hemodynamics with improving creatinine clearances.

The clinical status of cadaveric renal transplant patients treated for 10 year with cyclosporine therapy.

In this paper we assessed the clinical status of 150 cadaveric renal transplant patients who received cyclosporine without interruption for 10 yr. The mean creatinine clearance was 59.2 +/- 15.71 at 1 yr and 55.6 +/- 24.91 mL/min at 10 yr (p = 0.039). Patients were subdivided into four quartiles according to the mean creatinine clearance at 1 yr. The 14 patients with the lowest quartile showed a significant decrease of creatinine clearance from the 1st to 10th year (from 31.5 +/- 5.83 to 24.8 +/- 14.00 mL/min; p = 0.038) while no difference between the mean creatinine clearance at 1 and at 10 yr was found in the other three quartiles. At 10 yr, 84.6% patients needed antihypertensive therapy, a rate similar to that seen at 1 yr (81.4%). The mean plasma cholesterol (253 +/- 57.8 mg/dL) and triglyceride (197 +/- 113.1 mg/dL) at 10 yr were similar to those found at +/- yr (243 +/- 48.2 and 201 +/- 143.0 mg/dL, respectively). Most patients have a high degree of rehabilitation 10 yr after uninterrupted cyclosporine therapy and all patients but 3 were able to work.

Dimensional and hemodynamic differences between native and transplanted kidneys, evaluated by color Doppler ultrasonography.

Aim of the study was to asses the differences in size and hemodynamics in the normal kidney and well-functioning renal graft by color Doppler ultrasonography (CDU). Sixty healthy subjects, 75 well-functioning cadaver renal transplant recipients, 15 couples of living donors and related graft recipients were compared by CDU. Renal diameters, volume, renal blood flow (RBF) and renal resistance index (RI) were the variables studied. Cadaveric transplants, living donors and related recipients had a longer kidney (p<0.00001) and greater volume (p<0.001) than normal native kidneys. This was not associated with any significant increase in RBF. RI was lower in healthy subjects and in kidney donors than in transplant recipients (p<0.00001). Transplanted kidneys had a higher arterial RI but apparently normal function.