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.

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.

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.

The recurrence of focal segmental glomerulosclerosis in kidney transplant patients treated with cyclosporine.

To evaluate the rate of recurrence of focal segmental glomerulosclerosis (FSGS) in renal transplant patients treated with cyclosporine, we reviewed the outcome of 25 renal Tx performed in 24 patients who had FSGS as their original renal disease. After Tx, 6 patients were treated with steroids and azathioprine (follow-up: 42 +/- 34 months) and 19 with CsA (follow-up: 30 +/- 31 months). Two of 6 Aza treated patients (33%) developed recurrence of FSGS and nephrotic syndrome (NS). Both patients lost their graft because of FSGS 24 and 25 months after Tx. Ten of 19 patients (55%) given CsA showed recurrence of FSGS; one of them had had recurrence in the first graft treated with Aza. One patient lost his graft a few weeks after Tx because of acute rejection and 3 lost their graft because of FSGS 4-28 months after NS developed. One patient with NS died from pneumonia 14 months after Tx when his plasma creatinine was 2.7 mg/dl. Three other patients now have NS and plasma creatinine between 1.9 and 2.4 mg/dl 15-37 months after Tx. The last two patients have NS and normal renal function 10 and 31 months after Tx. In both groups, most patients developed NS within the first week after Tx. The patients with recurrence, given Aza or CsA, tended to be younger at the onset of the disease and to have a shorter duration of the disease, when compared with those without recurrence, but the differences were not statistically significant. In our experience neither CsA nor Aza showed any effect on the outcome of FSGS recurring in the graft.

A randomized trial comparing triple-drug and double-drug therapy in renal transplantation. Analysis at 7 years.

This is the 7-year update of a randomized trial comparing triple (TT) and double (DT) immunosuppressive therapy in renal transplantation. At 7 years, patient survival rate was 85% in DT vs. 87% in TT (P = NS); graft survival rate was 73% in DT and 68% in TT (P = NS); pure graft survival was 86% in DT vs. 77% in TT (P = 0.096). The 7-year graft survival rate was 67% for cadaver graft recipients vs. 92% for living-related graft recipients (P = 0.044). No difference in the slopes of plasma creatinine between the two groups was observed. Ten DT and 13 TT patients changed their original therapy: statistical analysis, however, was carried out according to intention to treat. Both CsA levels and doses were significantly higher in DT than in TT group (P < 0.001) at any time point up to the 7th year. At univariate analysis, a living-related donor kidney (P = 0.044) and immediate recovery of renal function (P < 0.001) were the only two parameters associated with graft survival at 7 years. At multivariate analysis, only early graft function recovery was correlated with late graft survival (RR = 10.480). Thus, even in the longterm, there is no difference between DT and TT, either in patient or in graft survival: at the doses we used, TT had a lower prevalence of late side effects than DT, however, long-term pure graft survival was better, although not significantly, in DT than in TT. The possibility of a safe shift from one regimen to the other one makes the two treatments complementary rather than alternatives.

A randomized prospective trial comparing cyclosporine monotherapy with triple-drug therapy in renal transplantation.

In a prospective trial 151 recipients of renal transplants were randomly assigned to treatment with CsA alone (74 patients) and to low dose of AZA, prednisolone, and CsA (77 patients). At two years, graft survival was 84% for the monotherapy and 90% for the triple therapy. This difference was not statistically significant. The number of rejection episodes was similar in the two groups, but the severity of rejection was significantly worse among the patients on monotherapy. More kidneys were lost because of rejection (6 versus 3), and a higher number of methylprednisolone pulses was used for treating rejection (5.2 +/- 2.3 versus 4.3 +/- 2.9; P = 0.0077). CsA nephrotoxicity episodes were more frequent among patients on monotherapy (23 versus 7; P less than 0.02). Infectious episodes were equally distributed between the two groups. Creatinine clearance was poorer in the monotherapy-treated patients at the third month (42 +/- 16 ml/min versus 48 +/- 15 ml/min; P = 0.02), but no differences were observed between the two groups since the sixth month after transplantation. Many patients on monotherapy required changes in maintenance therapy. In fact, one patient was switched to conventional immunosuppression because of Cremophor-induced anaphylaxis. Another patient who developed Kaposi's sarcoma 4 months after surgery was switched to steroids alone. Excluding 5 patients who lost their grafts a few days after transplantation, only 30 of 74 patients (40%) could be kept without steroids. We conclude that both the therapeutic protocols can give good results in renal allotransplantation; however, monotherapy could create some problems in keeping the balance between drug toxicity and significant immunosuppression. On the contrary, triple therapy is easier to handle, especially in the early posttransplant period when the differential diagnosis between acute rejection and CsA-related nephrotoxicity can be difficult even for a skilled clinician.

Effects of three immunosuppressive regimens on vertebral bone density in renal transplant recipients: a prospective study.

The influence of three different immunosuppressive regimens with cyclosporine (CsA) on the development of osteopenia in renal transplant patients was assessed. Fifty-three adults with first kidney transplants participated in a randomized trial to analyze the efficacy of three different immunosuppressive regimens: CsA alone (group 1), CsA plus steroids (group 2), and CsA plus steroids plus azathioprine (group 3). Lumbar spine bone mineral density was assessed by dual energy x-ray absorptiometry every 6 months for 18 months. The values for trabecular mass were expressed as bone mineral density and as a fraction of the standard deviation of the mean of the normal value for patient's sex and decade of age (Z-score). Statistical analysis was performed on Z-score and "Z-score change" (value after 6 months minus the basal value at transplantation). At the 18th month, the Z-score increased significantly in treatment group 1 without steroids (P=0.006) and decreased significantly in steroid-treated groups 2 (P<0.001) and 3 (P<0.001). Comparing the two genders, Z-score decreased less in premenopausal women than in men (P=0.018). "Z-score change" did not correlate with steroid dosage, was high in patients with high basal bone mineral density, and was directly associated with the duration of dialysis (P=0.008). In conclusion, premenopausal transplant recipients showed a lower decrease of lumbar bone mineral density than men. In transplant recipients given CsA with steroids, lumbar bone mineral density decreased significantly, while it increased significantly in patients given CsA alone.

The impact of azathioprine and cyclosporine on long-term function in kidney transplantation.

To assess the impact of cyclosporine on long-term kidney function in transplant patients, we retrospectively analyzed 273 patients on azathioprine and 308 on CsA with graft functioning at 1 year. To balance the length of follow-ups, the observation of patients was cut at 5 years. Actual graft survival rate at 5 years was similar in Aza and CsA (88% vs. 90%). Multivariate analysis in Aza pts showed that proteinuria (P = 0.006) and hypertension at 1 year (P = 0.002) increased the probability of irreversible graft failure by 2.47 and 2.85, respectively. In CsA patients, proteinuria (P = 0.007) and plasma creatinine higher than 2.5 mg/dl (P = 0.006) increased the probability of graft failure by 5.12 and 6.48, respectively. In both Aza and CsA patients with a follow-up of at least 5 years, plasma creatinine levels were significantly worse at 5 years vs. 1 year (P = 0.004). The slopes of plasma creatinine values plotted vs time were not different between the two groups. Chronic graft dysfunction (CGD) was defined as a stable increase of plasma creatinine of at least 50% above stable values at 1 year. The probability of remaining without CGD at 5 years was 75% for CsA and 80% for Aza patients (P = N.S.). Multivariate analysis of factors influencing the development of CGD showed that hypertension (P = 0.003) and proteinuria at 1 year (P = 0.081) increased the probability of developing CGD by 2.19 and 1.76, respectively, in Aza, while in CsA patients proteinuria only (P = 0.063) increased the probability of developing CGD by 2.29. Graft survival at 5 years after development of CGD was 34% in Aza and 53% in CsA-treated patients. These data confirm that in the long-term CsA does not cause a higher prevalence of CGD and show that, in the presence of CGD, CsA has a superior protective effect than Aza.

A randomized trial comparing triple-drug and double-drug therapy in renal transplantation.

A controlled trial was carried out in 86 cadaveric and 14 living haploidentical renal transplant recipients to compare the effects of low doses of cyclosporine (CsA), azathioprine (Aza) and steroids with those of higher doses of CsA plus steroids. Patients were followed for 12-26 months after transplantation. The actuarial 2-year patient and graft survival rate was 100% for living-donor transplants. In cadaver renal transplants the 2-year patient survival rate was 100% for patients assigned to the triple regimen and 93% for those allocated to the double regimen. The actuarial 2-year cadaver graft survival rates were 86% and 90.6%, respectively. There were significantly more patients who had severe infections (P less than 0.05), particularly interstitial pneumonia (P less than 0.005), in the double-therapy group. On the other hand, there were more patients who rejected and more patients with severe rejections; more pulses of steroids were also required for patients on the triple regimen, although these differences were not significant. The mean trough blood levels of cyclosporine at the various times were about half as high in patients on triple therapy. There were no differences between the two groups in creatinine clearance at any time. A control renal biopsy, taken from patients with stable renal function after 6-12 months, showed only mild abnormalities. The lesions were semiquantitatively assessed. There was a higher score for interstitial infiltrate in patients on triple therapy (P less than 0.05). On the other hand, the incidence and the mean score of interstitial fibrosis were greater in patients on double therapy, although these differences were not significant. Thus, although similar results were obtained with both regimens, at the doses we used double therapy seems to have more powerful immunosuppressive effects and may prevent rejection, either acute or chronic, better. However, it might expose the patient to a greater risk of infection and of cyclosporine-related nephrotoxicity than triple therapy.

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.

Corticosteroids in kidney transplant recipients. Safety issues and timing of discontinuation.

Corticosteroids have played a key role in the immunosuppression of organ transplantation. Unfortunately, the extensive use of these agents has resulted in disabling and life-threatening adverse effects in many patients. The advent of concomitant corticosteroid/cyclosporin regimens has allowed a reduction in the dosages of steroids administered, yet steroid-induced morbidity is still a major problem in many cyclosporin-treated renal transplant patients. After favourable initial experiences with cyclosporin monotherapy, several attempts at steroid-free immunosuppression in renal transplant patients have been undertaken, either by not starting steroids after transplantation or by stopping steroids in patients with stable graft function. Most controlled and uncontrolled trials showed that with either strategy short term graft survival was similar with or without steroids, but acute rejection was more frequent in patients not taking steroids. The percentage of patients who could be maintained steroid-free ranged from 28 to 94%, and was higher in patients who stopped steroids later than in those never receiving them. Little information is available about long term follow-up of these patients. Some studies reported late attrition of renal function in patients not taking steroids, while others reported a favourable outcome even in the long term. Steroid-free immunosuppression is feasible in renal transplant patients, but it requires careful monitoring of renal function and cyclosporin dosage. This strategy is particularly indicated in patients at high risk of cardiovascular disease or steroid-related complications, and in children. Nevertheless, several issues need to be better elucidated by further studies, namely the long term outcome of steroid-free immunosuppression, the advantages and disadvantages of steroid avoidance versus steroid withdrawal, and the criteria for selecting patients.

Comparison between immunofixation and crossed immunoelectrophoresis for the detection of C3 activation products.

C3 breakdown products were measured in 51 fresh and stored sera and/or EDTA plasma samples from 18 healthy subjects, 8 patients affected by essential mixed cryoglobulinaemia, and 15 patients with miscellaneous glomerulonephritis, by simultaneous crossed immunoelectrophoresis and immunofixation. C3 splitting products, as determined by both methods compared well, and showed a highly significant correlation. The advantages and reliability of these two methods are discussed. Immunofixation seems to be the most suitable for routine use in clinical practice, being less expensive and more rapid to perform.

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.

Intravenous methylprednisolone pulse therapy in essential mixed cryoglobulinemia nephropathy.

In 15 patients with essential mixed cryoglobulinemia, 24 exacerbations of renal disease, characterized by an increase in plasma creatinine (13 episodes) and/or proteinuria (18 episodes), were treated by 3 intravenous pulses of methylprednisolone (1 g each), followed by oral prednisone (0.5 mg/kg/day). Plasma creatinine levels fell within a week (P less than 0.025), while a significant decrease in urinary protein excretion was observed only after one month (P less than 0.05). After therapy, plasma creatinine levels remained stable in 8/10 patients for 3 to 60 months. These beneficial results suggest that MP pulses may be useful in the treatment of cryoglobulinemic nephropathy.

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.

[Results of renal transplantation from cadavers in 200 patients]. / Risultati del trapianto renale da cadavere in 200 pazienti.

We report our experience of 202 cadaveric renal transplant performed over a 9 year period. Actuarial patient survival rate was 87.5% at 1 year and 81% at 9 years; graft survival rate was 58.5% at 1 year and 43% at 9 years. In order to improve patient and graft survival, from September 1977 renal transplantation was performed only in patients with a previous careful clinical selection and who had received at least three blood transfusions. Out of 18 patient, actuarial patient and graft survival rate at 1 year were 100% and 76% respectively.

[Prognostic significance of anuric acute rejection]. / Significato prognostico del rigetto acuto anurico.

32 graft rejection episodes requiring dialysis within four days appeared in the first month after transplantation in 224 renal transplants. Our report shows that oliguric renal failure is not related to the severity of rejection but probably to the appearance of an acute tubular necrosis. Therefore graft renal failure requiring dialysis is not necessarily related to a bad prognosis.

[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.

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.