Azathioprine hepatitis in kidney transplant recipients. A predisposing role of chronic viral hepatitis.

Influence of viral liver diseases on the occurrence of azathioprine hepatitis was evaluated in 21 kidney transplant recipients. Diagnosis of azathioprine hepatitis was always based on jaundice, which disappeared after azathioprine withdrawal in 18 patients and after azathioprine dose reduction in 3 patients. Histopathological diagnosis of azathioprine toxicity was ascertained in 14 patients. Rechallenge with azathioprine performed in 4 patients, within 2-4 months after the first jaundice episode, resulted in relapse of jaundice in all cases. Viral hepatitis B virus and hepatitis C markers were present in all 20 tested patients (serum hepatitis B surface antigen in 6 patients and anti-HCV antibodies in 17 patients). Biopsy-proven chronic hepatitis was observed in 18 patients, including 14 chronic active hepatitis, 3 chronic persistent hepatitis and cirrhosis in 1. In kidney transplant recipients, azathioprine hepatitis seems to be facilitated or induced by hepatitis B virus or hepatitis C virus chronic hepatitis. Azathioprine reduction or withdrawal should therefore be combined with the diagnostic evaluation and the treatment of viral liver diseases.

Acyclovir in preventing cytomegalovirus infection in kidney transplant recipients: a case-controlled study.

High dose oral acyclovir has been reported to be effective in preventing both cytomegalovirus (CMV) infection and disease in renal transplant recipients. We conducted a case-controlled study in which 42 cadaveric kidney transplant recipients were prophylactically treated with high dose oral acyclovir for 3 months and compared to historical controls matched for donor/recipient CMV serological status, age, sex, and immunosuppressive therapy. Before transplantation, study group patients received acyclovir intravenously (500 mg/m2 over 1 hour) which was subsequently given orally (basal dose--800 mg four times daily) from day 2 post-transplantation according to renal function. All patients received 14-day induction immunosuppressive therapy with either a polyclonal or a monoclonal antibody together with low dose steroids and azathioprine, cyclosporin being introduced at day 10 post-transplantation. Blood viral cultures as well as CMV antibody titers were performed in study group and control patients in the same laboratory, before transplantation, weekly until 3 months and then monthly until 6 months. CMV infection was defined as a positive blood or bronchoalveolar lavage viral culture or presence of CMV IgM or CMV IgG in a previously seronegative patient. Diagnosis of CMV disease also required the presence of at least one concomitant febrile illness, with or without other clinical symptoms, not attributable to another pathogen. All patients were followed for 3 months. Incidence of both CMV infection and disease was compared in the two groups using the log-rank test. With regard to CMV infection, we found significantly less CMV infection in CMV seropositive patients (regardless of donor CMV serological status) in the study group compared to historical controls (P = 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Granulocyte-associated immunoglobulins in renal transplant recipients with cytomegalovirus infection.

Cytomegalovirus (CMV) infections in renal transplant recipients must be diagnosed rapidly, since they can be life-threatening unless chemotherapy is started early. Detection of granulocyte-associated immunoglobulins was compared with conventional virological methods for diagnosis of CMV infection in 71 renal transplant recipients. The granulocyte-associated immunoglobulin test (GAIT) was positive in 31 of 34 patients with proven CMV infections on the day of admission. By conventional virological criteria the diagnosis of active CMV infection could be made only 3-24 days later. The GAIT remained negative in 14 healthy transplant recipients, but it was positive in 9 of 23 patients with non-CMV-related post-transplantation complications. The GAIT, which is not a virological method, could be useful for rapid diagnosis of CMV infection; its sensitivity was 0.91 and specificity 0.82 (for patients without detectable immunoglobulins on erythrocytes or platelets) and the processing time is only 3 h.

One-month prophylactic use of OKT3 in cadaver kidney transplant recipients.

Fifty-five recipients of first cadaveric renal allografts were randomly assigned to three treatment groups in order to compare the safety and efficacy of a mouse antihuman T cell monoclonal antibody (OKT3) given prophylactically for a one-month period. This long period of administration was made possible by concomitant administration of azathioprine. The immune response against the foreign immunoglobulin was thus delayed and decreased in both intensity and severity, and OKT3 treatment could be given during almost the entire month in the majority of patients. The 18 patients who were enrolled in this treatment group had significantly (P less than 0.01) fewer rejection episodes during the first month posttransplantation than the 19 patients allocated to the high-dose (HD) steroid control group or the 18 patients allocated to the low-dose (LD) control group. Actual 2-year as well as actuarial 4-year graft survival rates were 89% in the OKT3 group, whereas they were 70% and 67% respectively in the steroid control groups. Four-year serum creatinine levels were normal and doses of steroids and other immunosuppressive agents were lower in the OKT3 group as compared with the control groups. Tolerance to OKT3 was good, and while viral infections were more frequently observed in OKT3 treated patients, the total number and the severity of infectious episodes were similar in all groups. The combination of one-month OKT3 plus azathioprine prophylaxis followed by conventional azathioprine plus low-dose steroid maintenance produced very satisfactory long-term results comparable to the best results now being obtained with cyclosporine regimens.

Results of kidney transplantation at Necker Hospital.

From these data, it is possible to draw some partial conclusions: long-term therapy with ATG is only slightly better than a shorter course; OKT3 and ATG are both efficient in preventing rejection occurrences but OKT3 appears to be slightly better; given as prophylactic therapy, OKT3 induces better graft function; the combination of a 21-day course of OKT3 followed by CsA is probably detrimental to patients when compared to the combination of ATG + CsA.

[Preventive treatment of rejection by the prolonged administration of OKT3: decrease of the immune response of the host]. / Traitement prophylactique du rejet par l'administration prolongée d'OKT3: diminution de la réponse immune de l'hôte.

Clinical use of OKT3 for the treatment of ongoing rejection episodes has already been demonstrated as being highly effective. This work shows for the first time that combining azathioprine and OKT3 was able to delay as well as to decrease both the intensity and the quality of the anti-OKT3 immunization, allowing a 1-month prophylactic use of the MoAb. It also proves that OKT3 used prophylactically during one month can lead to 4-year first cadaver graft and patient survival rates better than those ever reported with any other immunosuppressive regimen. These results were obtained with lower doses of steroids and other immunosuppressive agents than in conventionally treated control patients. After the first two injections of OKT3, tolerance was perfect allowing out-hospital administration, and side effects consisted only in an increased number of viral infections instead of the bacterial infections observed in the conventional treatment groups. The prophylactic use of OKT3 should give even better results if it were possible to reach a 1-month administration schedule in all patients by modulating the dose of OKT3 according to the T3+ cell count and the monitoring of serum OKT3 levels.

Restriction of the human in vivo immune response against the mouse monoclonal antibody OKT3.

The murine monoclonal antibody OKT3 (IgG2a) was administered prophylactically to 17 renal allograft recipients (5 mg/day, i.v.), either alone or in association with corticosteroids (0.25 mg/kg/day) and azathioprine (3 mg/kg/day). In all patients the kinetics of the IgM and IgG anti-OKT3 response was monitored by means of immunofluorescence and ELISA. All patients treated with OKT3 alone showed a rapid and strong sensitization that completely neutralized the therapeutic effectiveness of the monoclonal antibody. The anti-OKT3 sensitization was manifested by accelerated OKT3 clearance and abrupt reappearance of circulating OKT3+ cells before the end of treatment. This immune response was significantly delayed and reduced in its incidence and intensity in patients receiving low dose corticosteroids and azathioprine in association to OKT3; mainly IgM anti-OKT3 antibodies that did not accelerate OKT3 clearance were then observed. The fine specificity of the antibodies produced was studied, using patients whole sera and various mouse IgG2a-affinity chromatography-purified serum fractions. The results obtained showed that the anti-OKT3 response was remarkably restricted to two main categories of antibodies: a) anti-idiotypic antibodies that inhibited OKT3 binding to T cells and abrogated its therapeutic activity and b) anti-mouse IgG2a (anti-isotypic) antibodies that did not neutralize OKT3 immunosuppressive activity. These results suggest that OKT3-immunized patients might still be sensitive to the immunosuppressive effect of other anti-T cell monoclonals that do not share the OKT3 idiotype and possibly isotype.

Prophylactic use of OKT3 monoclonal antibody in cadaver kidney recipients. Utilization of OKT3 as the sole immunosuppressive agent.

We describe the first clinical trial of OKT3, a monoclonal anti-T-cell antibody, for prevention of kidney transplant rejection. 13 patients receiving a first cadaveric kidney transplant were randomly assigned to conventional treatment with azathioprine and high-dose steroids (7 patients) or to treatment with daily injection of OKT3 alone (6 patients). The first OKT3 injection resulted in a dramatic decrease in T3+, T4+, and T8+ cells, while patients simultaneously experienced fever, chills, and diarrhea. These symptoms did not recur with subsequent injections. All six OKT3-treated patients had a rejection necessitating introduction of steroids 12.8 +/- 2.9 days after surgery. Rejection was related to appearance of anti-OKT3 antibodies leading to disappearance of detectable OKT3 in the serum. Modulating (T3-, T4+ or T3-, T8+) cells were observed in all patients but were functionally inactive. As no rejection was observed before day 9 posttransplant, despite the lack of additional immunosuppressive agents, we conclude that OKT3 is a powerful, well-tolerated immunosuppressive agent. However, it is highly immunogenic and anti-OKT3 antibodies lead to loss of clinical effectiveness in this protocol. The use of OKT3 alone for prevention of kidney graft rejection cannot be recommended until a method for reducing the effects of anti-OKT3 immunization is developed.

Nonsteroid antiinflammatory agents as a substitute treatment for steroids in ATGAM-treated cadaver kidney recipients.

A nonsteroid antiinflammatory agent (Ibuprofen) was used in a controlled randomized study to determine its ability to replace steroids in the prophylaxis of cadaveric kidney rejection. Thirty-three cadaver kidney recipients were randomly assigned either to a control group (16 patients) receiving azathioprine, high doses of prednisolone, and antithymocyte globulin (ATGAM) for three months, or to an experimental group (17 patients) receiving azathioprine and ATGAM according to the same protocol, ibuprofen instead of steroids. The frequency of rejection was higher in the experimental group (2.18 episodes per patient) than in the control group (1.44 episodes per patient). Nevertheless, in the experimental group 5 patients had no early rejection episode, 60% of early rejections were totally reversible without steroids, and 3 patients never received steroids at all during the first year and had normal renal function and biopsies. Steroids had to be introduced in the treatment of 14 patients, but after an average period of 32.5 days after surgery OKT3+ cell level was higher in the experimental group than in the control group, but similar to the OKT3+ cell level of patients receiving conventional therapy without ATGAM. Whatever the type of treatment, an increase in the OKT4+/OKT8+ ratio was associated in most cases with increased serum creatinine values. Conversely, a decreased OKT4+/OKT8+ ratio associated with renal failure was found in cases showing biological evidence of cytomegalovirus infection.

Interest in and limitations of monoclonal anti-T-cell antibodies for the follow-up of renal transplant patients.

The OKT series of anti-T-cell monoclonals has been used on 442 occasions in 41 renal allograft recipients in a 6-12 month follow-up study. Standard immunosuppressive therapy (including antithymocyte globulin in 26 patients) tended to decrease the helper-inducer/suppressor-cytotoxic cell ratio (OKT4/OKT8). Conversely, 71% of 35 renal failure episodes were associated with increased OKT4/OKT8 ratios. Twenty-three percent of renal failure episodes were associated with dramatically decreased OKT4/OKT8 ratios. At least half of these cases could be explained by a cytomegalovirus infection. In fact, similar infections were found in 6 out of 17 patients with low OKT4/OKT8 values in the absence of renal failure. These results prompt us to use anti-T cell monoclonals for the diagnosis of rejection because only nine episodes of transient increase in the OKT4/OKT8 ratio were observed in the absence of rejection. The interest of this new method for the immunological follow-up of transplanted patients is, however, limited by the difficulty in interpreting a significant percentage of tests because of (1) the presence of doubly labeled cells (OKT4+OKT8+) or the significant discrepancy between the number of OKT3+ cells and total cells labeled with OKT4 and/or OKT8 antibodies; (2) gross lymphocytopenia--most often observed in patients receiving antithymocyte globulins plus steroids; and (3) the clinically unexplained shifts in the T cell subset ratios mentioned above.

Disorders of calcium and phosphorus metabolism after successful kidney transplantation.

Systematic study undertaken of 44 transplant patients with plasma creatinine below 0.11 mmol/L indicated renal phosphorus leak in approximately two-thirds of them and increased plasma PTH in all but one. Plasma 1,25(OH)2D was elevated in half the patients in whom it was measured. The lack of correlation found between plasma 1,25(OH)2D and plasma PTH or phosphorus probably indicates tubular lesions resulting in decreased production of 1,25(OH)2D. A phosphorus restriction test in 12 hypophosphatemic patients demonstrated that the reduced renal phosphorus reabsorption probably was due to both persisting hyperparathyroidism and a PTH-independent phosphorus leak.

Plasma 1,25(OH)2D3 and iPTH in transplanted adults with persisting hypophosphataemia.

Hypophosphataemia is a common finding among kidney transplanted patients [1,2]. In a previous study in kidney transplanted children with plasma creatinine below 1.1mg/dl, we demonstrated [3] a negative correlation between plasma phosphorus and 1 alpha, 25-dihydroxyvitamin D3 (1,25(OH)2D3), the renal hormonal form of vitamin D. No such correlation was apparent in children with minimal increase in plasma creatinine. The aim of the present investigation carried out in hypophosphataemic transplanted adults was two-fold: 1) to determine whether hypophosphataemia results from persisting hyperparathyroidism or from a renal phosphorus leak, or both, and 2) to study the relation between plasma phosphorus, iPTH and 1,25(OH)2D3 in these patients.