Azathioprine-induced pure red cell aplasia: case report and review

The major adverse effect of azathioprine is its myelotoxicity, with leukocytes being affected more commonly than the other bone marrow elements. Although megaloblastic change is frequent, reportedly seen in 16% to 82% of bone marrow aspirates, long-term use of azathioprine rarely causes severe anemia. We report a case of refractory pure red cell aplasia resulting from long-term use of azathioprine in a renal transplant recipient and examine the possible underlying mechanisms. There was no response to dose reduction or to erythropoietin administration. However, there was immediate recovery after complete drug withdrawal. A review of the literature revealed that only ten cases of azathioprine-induced red cell aplasia have so far been described, all in transplant recipients.     

Pure red cell aplasia caused by Parvovirus B19 infection in solid organ transplant recipients: a case report and review of literature

Human Parvovirus B19 (PV B19) is one of the several recently described 'emerging viruses' and has been identified as the etiological agent of 'fifth disease' in childhood. Human PV B19, which is the etiological agent of transient erythroblastopenia in hemolytic anemia, is also a recognized rare cause of red cell aplasia in immunocompromised patients, including transplant recipients. To date, 26 cases of PV B19-induced red cell aplasia have been reported in solid organ transplant recipients. Twelve patients had cyclosporine-based immunosuppression and 14 had tacrolimus-based immunosuppression. Sixteen of these patients required treatment with commercial intravenous immunoglobulin alone, 1 required treatment with intravenous immunoglobulin and plasmapheresis, 4 required intravenous immunoglobulin and erythropoietin, 1 required treatment with intravenous immunoglobulin and conversion of tacrolimus to cyclosporine, 1 had improvement in hematocrit with erythropoietin alone and in 3 patients the disease was self-limiting. Herein, we report a case of pure red cell aplasia caused by acute PV B19 infection in a renal transplant recipient in whom the immunosuppressive regimen included prednisone, mycophenolate mofetil and tacrolimus and the red cell aplasia resolved with discontinuation of mycophenolate mofetil.     

Anti-erythropoietin antibodies followed by endogenous erythropoietin production in a dialysis patient

We present a case of a young girl with end-stage renal disease secondary to anti-glomerular basement membrane disease who was receiving maintenance peritoneal dialysis and developed pure red cell aplasia secondary to anti-erythropoietin (EPO) antibodies. This occurred 13 months after the initiation of EPO alfa therapy for anemia. Initially, the patient required intermittent red blood cell transfusions. After immunosuppressive therapy had been initiated with corticosteroids and cyclosporine, the EPO antibody levels decreased precipitously, associated with an increased level of endogenous EPO production. For the following 6 months, the patient maintained adequate (>10 g/dL) hemoglobin levels and did not require red cell transfusions.     

Declining incidence of wound infection in cadaveric renal transplant recipient

Over a five-year period 100 cadaveric renal transplants were performed. In 91 of these recipients, a prophylactic parenteral antibiotic (cefoperazone) was administered and closed wound drainage was used. Of these 91 patients, 33 received azathioprine/prednisone immunosuppression, whereas cyclosporine/prednisone with or without azathioprine was used in the remaining 58. The incidence of wound infections was significantly reduced from 12 per cent (4/33) in the azathioprine group to 1.7 per cent (1/58) in the cyclosporine group (p less than 0.01). When conventional immunosuppression (azathioprine/prednisone) is employed in renal transplantation, triple antibiotic prophylaxis that includes an aminoglycoside is most effective in preventing wound infections. A single non-nephrotoxic antibiotic, cefoperazone, offers similar protection in the cyclosporine/prednisone-treated renal transplant recipient.     

Treatment of invasive thymoma with myasthenia gravis: a case report responsive to azathioprine and methylprednisolone

The treatment of invasive thymomas associated with autoimmune diseases, such as myasthenia gravis (MG) and pure red cell aplasia, has not been established. In this paper, we report a 37-year-old patient with post thymectomy myasthenia gravis, who underwent subtotal resection of invasive thymoma with residual lesions of intrathoracic implants. He was treated with azathioprine (AZP) and methylprednisolone (MP). During two months from the start of this therapy, the clinical symptom was improved apparently and the recurrent tumor was reduced. Lasting 18 months of the treatment, he had to stop it because of the renal failure, but now he has no sign of the recurrence. Further studies with this combined regiments are warranted in the treatment of the invasive thymomas associated with autoimmune disease.     

Pulmonary infections. The Minnesota randomized prospective trial of cyclosporine vs azathioprine-antilymphocyte globulin for immunosuppression in renal allograft recipients

Nineteen of 224 renal allograft recipients who were prospectively randomized to receive either cyclosporine (n = 117) or azathioprine sodium-antilymphocyte globulin (n = 107) for immunosuppression suffered from one period of pneumonia (14 azathioprine and five cyclosporine recipients); two recipients of azathioprine had two episodes. Four patients in the azathioprine group and one in the cyclosporine group died, for mortalities of 3.7% and 0.85%, respectively. The percentage of pneumonia-free patients at one year was 96.3% in the cyclosporine group while it was 90.8% in the azathioprine group. Nondiabetics, women, and recipients of grafts from living related donors were at a statistically lower risk of developing pneumonia when treated with cyclosporine. Viral (cytomegalovirus), fungal (Candida, Aspergillus), and multibacterial causes of pneumonia each occurred with a similar incidence.     

Response to Cyclosporine A in a Patient with Pure Red Cell Aplasia Due to Antierythropoietin-α Antibodies

Reported cases of pure red cell aplasia (PRCA) from the administration of erythropoietin (EPO)‐α molecule in the United States are rare, and the optimal treatment is still unknown. We present a patient with end‐stage renal disease (ESRD) who became hyporesponsive and later unresponsive to EPO‐α treatment a few months after initiation of hemodialysis. A comprehensive anemia examination was negative while the patient became transfusion dependent. The diagnosis of EPO‐α‐induced PRCA was confirmed by bone marrow biopsy, by undetectable serum EPO levels following the administration of a large dose of EPO‐α, and by documenting the presence of EPO‐neutralizing antibodies. Administration of cyclosporine A in addition to prednisone enabled the patient to become transfusion and EPO independent. This case further documents the possible occurrence of PRCA with EPO‐α administration in the United States and reaffirms the potential beneficial effect of cyclosporine A.     

A randomized controlled trial of cyclosporine withdrawal in renal-transplant recipients: 15-year results

BACKGROUND: In renal transplantation, the immunosuppressive efficacy of cyclosporine is counterbalanced by its nephrotoxicity. Although cyclosporine improves short-term graft survival, its long-term effects are unclear. METHODS: Recipients of first cadaver renal transplants were randomized into three groups between 1983 and 1986: azathioprine and prednisolone alone (AP, n = 158), long term cyclosporine alone (Cy, n = 166), and short-term cyclosporine followed by azathioprine and prednisolone (CyAP, n = 165). All groups received methylprednisolone induction. RESULTS: There were no significant differences in patient survival at 15 years (48 vs. 56 vs. 51%, P = 0.14), and 15-year graft survival (censored for death) in those patients in the CyAP group (47 vs. 44 vs. 59%, P = 0.06) was not significantly different statistically. When deaths or graft losses before 12 months were censored, the differences in 15-year graft survival between the groups were significant (58%, 51%, 70%, P = 0.01). The CyAP group also had lower mean serum creatinine at all time points beyond 3 months posttransplant out to 10 years (143 vs. 169 vs. 131 micromoles/L, P = 0.04). Per protocol analysis, after censoring patients at change in therapy, increased the observed differences in 15-year graft survival between the groups (54 vs. 38 vs. 65%, P = 0.01). CONCLUSION: Survival and function of first cadaveric kidney transplants is improved by use of short-term cyclosporine followed by azathioprine and prednisolone. Long-term cyclosporine use reduces long-term graft survival.     

Beneficial effects of cyclosporine compared with azathioprine in cadaveric renal transplantation

Recent reports have intimated that the use of antilymphocyte globulin in combination with azathioprine and steroids has ameliorated the beneficial affects of cyclosporine. We believe that even in the absence of significant statistical differences between patient survival rates and graft survival rates of cyclosporine-treated renal transplant patients compared with conventionally treated renal transplant patients, there are distinct advantages to cyclosporine use in renal transplantation. Twenty-three consecutive cadaveric renal transplant patients who received azathioprine, prednisone, and antilymphoblast globulin were compared with 23 cadaveric renal transplant patients who received cyclosporine and prednisone. Fewer statistically significant rejection episodes, multiple rejection episodes, and cytomegalovirus infections were demonstrated in those who received cyclosporine. Most notably, cyclosporine decreased the initial hospital stay, was associated with fewer readmissions, and therefore markedly reduced the initial cost of transplantation.     

Response to cyclosporine A in a patient with pure red cell aplasia due to antierythropoietin-alpha antibodies

Reported cases of pure red cell aplasia (PRCA) from the administration of erythropoietin (EPO)-alpha molecule in the United States are rare, and the optimal treatment is still unknown. We present a patient with end-stage renal disease (ESRD) who became hyporesponsive and later unresponsive to EPO-alpha treatment a few months after initiation of hemodialysis. A comprehensive anemia examination was negative while the patient became transfusion dependent. The diagnosis of EPO-alpha-induced PRCA was confirmed by bone marrow biopsy, by undetectable serum EPO levels following the administration of a large dose of EPO-alpha, and by documenting the presence of EPO-neutralizing antibodies. Administration of cyclosporine A in addition to prednisone enabled the patient to become transfusion and EPO independent. This case further documents the possible occurrence of PRCA with EPO-alpha administration in the United States and reaffirms the potential beneficial effect of cyclosporine A.     

The effect of cyclosporin on renal function following cardiac transplantation: should one lessen the toxicity?

Between 1983 and 1988, 50 patients underwent cardiac transplantation at the Institut de Cardiologie de Montréal. During this period, four immunosuppression protocols were used, each including cyclosporine. A combination of cyclosporine and prednisone was used in the first 24 patients (group 1). Triple combination immunosuppression (cyclosporine, prednisone and azathioprine) was given perioperatively in 13 patients (group 2). The prophylactic use of rabbit antithymocyte globulin and late administration (4 days postoperatively) of cyclosporine to prevent early renal failure associated with cyclosporine therapy was chosen in 13 other patients (group 3). Owing to serious deterioration of renal function in 15 of the 24 group 1 patients, the serum creatinine levels reaching 255 +/- 51 mmol/L and the creatinine clearance 34 +/- 2 ml/min between 6 months and 4 years after transplantation, immunosuppression was modified to triple-combination therapy by the addition of azathioprine and a reduction of the serum levels of cyclosporine (group 4). Twelve of the 15 patients showed a substantial improvement in renal function from 3 to 18 months after these changes were introduced. No patient in groups 2 and 3 had late renal insufficiency, and in all group 3 patients renal function remained normal as in the immediate postoperative period. In conclusion, important modifications in protocol permitted a reduction of early and late renal failure due to cyclosporine after cardiac transplantation.     

Conventional immunosuppression after deliberate third party transfusions versus cyclosporine in living related renal transplant recipients

A total of 93 recipients of either HLA-identical (34) or 1-haplotype matched (59) living related donor renal transplants was assigned prospectively into immunosuppressive treatment groups on the basis of transfusion histories obtained at the initial evaluation for transplantation. Patients who received 0 to 2 third party transfusions were given no further transfusion, and received cyclosporine and prednisone immunosuppression after transplantation (cyclosporine group). Patients who received 3 or 4 third party transfusions were given additional transfusions until 5 had been received, and were managed with azathioprine and prednisone after transplantation (azathioprine group). Patients who already received 5 or more third party transfusions had no additional transfusions and were assigned to the azathioprine group. No patient had a positive crossmatch to the potential donor after initial evaluation and confirmation of a negative crossmatch. The number of rejection episodes per patient after transplantation was significantly higher in the azathioprine group for HLA-identical (p equals 0.001) and 1-haplotype (p equals 0.003) recipients. One-year patient survival rats for the HLA-identical cyclosporine and azathioprine groups were 100 and 94 per cent, respectively, with respective 1-year allograft survivals of 100 and 89 per cent in the 2 groups. In the 1-haplotype group 1-year patient survival rates were 95 and 94 per cent for the cyclosporine and azathioprine groups, respectively; allograft survival was 81 per cent for the cyclosporine group and 91 per cent for the azathioprine group. None of the observed differences in graft or patient survival between the 2 groups was statistically significant. Deliberate third party transfusions with conventional immunosuppression and cyclosporine immunosuppression are effective methods to treat recipients of living related donor renal transplants.     

Hypertension after renal transplantation. A comparison of cyclosporine and conventional immunosuppression

Hypertension is a common complication after renal transplantation and is associated with increased mortality. Cyclosporine is known to be nephrotoxic and raises blood pressure in recipients of cardiac and bone marrow transplants, but there is conflicting data on the role of cyclosporine after renal transplantation. We have examined this question in patients entered into the second Oxford prospective randomized comparison of short-term cyclosporine treatment alone with conversion to azathioprine and prednisolone at 90 days (CsA group), and conventional therapy with azathioprine and prednisolone throughout (AP group). Blood pressure and antihypertensive medication were similar in the CsA and AP treatment groups during the first 90 days. Following conversion from cyclosporine, mean blood pressure fell from 155/94 to 142/81 within 7 days, and this fall correlated with the change in plasma creatinine over the same period (r = 0.44, P less than 0.05). Blood pressure was subsequently lower in the converted patients than in those treated with AP throughout. Six months after transplantation patients converted from cyclosporine not only had lower blood pressure but also required fewer antihypertensive drugs than AP patients. This study demonstrates that cyclosporine may elevate the blood pressure in recipients of renal transplants. This effect may either be direct or mediated through the effect of cyclosporine on renal function. Administration of corticosteroids during the first three months after transplantation is implicated as a possible cause of persisting high blood pressure.     

Conversion from cyclosporine to azathioprine at three months reduces the incidence of chronic allograft nephropathy

BACKGROUND: Conversion from cyclosporine to azathioprine after renal transplantation has been shown to be beneficial in terms of allograft function, cardiovascular risk factor profile, and the incidence of gout. A higher incidence of acute rejection, however, has also been reported and uncertainty still exists about the long-term outcome after conversion. We report on the extended follow-up of an open-label, randomized trial that examined conversion to azathioprine as early as three months after transplantation. METHODS: One hundred twenty-eight patients were enrolled in this single-center study. Three months after transplantation they were randomly assigned to continue cyclosporine treatment (N = 68), or they were converted to azathioprine (N = 60). The steroid dose was temporarily increased in the patients who were converted. RESULTS: Patient survival was not different in the two groups. Graft survival tended to be lower (64.7% vs. 76.5% at 15 years) in the cyclosporine continuation group (P = 0.14) when data were analyzed on an intention to treat basis. The graft survival of the patients that stayed on their assigned treatment was significantly higher in the azathioprine arm, starting at two years' post-transplantation. The glomerular filtration rate was significantly higher in the patients who were converted to azathioprine. More allograft biopsies were taken from patients remaining on cyclosporine for suspicion of cyclosporine-related nephrotoxicity and prompted a high rate of late conversions (19%). The relative risk of chronic allograft nephropathy was significantly higher in the group that continued cyclosporine [relative risk, 4.3 (95% CI, 1.4 to 12.9); P = 0.009]. Conversion to azathioprine reduced the need of blood pressure and lipid-lowering drugs. CONCLUSION: Conversion to a calcineurin inhibitor-free immunosuppressive regiment three months after renal transplantation improved allograft function, reduced the need of cardiovascular risk factor-controlling medication, and reduced the incidence of chronic allograft nephropathy.     

Differences in gastric motor activity in renal transplant recipients treated with FK-506 versus cyclosporine

BACKGROUND: Little is known concerning gastric motility after renal transplantation and on the impact of immunosuppressants on gastric emptying. METHODS: Gastric emptying was measured in renal transplant recipients, taking different immunosuppressive therapy (steroids and cyclosporine/azathioprine/FK-506), and compared with normal volunteers. RESULTS: After renal transplantation, gastric emptying of liquids was normal, irrespective of the type of immunosuppression. However, solid gastric emptying was significantly faster in FK-506-treated patients compared with patients taking cyclosporine for all measured emptying parameters. Compared with normal volunteers solid gastric emptying was slower in patients taking cyclosporine, comparable in azathioprine treated patients, and characterized by an unusual short lag phase in patients taking FK-506. CONCLUSIONS: In stable renal transplant recipients gastric emptying of solids was significantly faster in patients on FK-506 compared with patients taking cyclosporine. Therefore, FK-506 may be the immunosuppressant of choice after solid organ transplantation in patients with problems related to gastroparesis.     

Epoetin-induced pure red cell aplasia successfully treated with androgens

Pure red cell aplasia (PRCA) is a severe, non-regenerative form of anaemia, with selective erythroid aplasia of the bone marrow. It appears as a severe complication of treatment for anaemia of end-stage renal insufficiency with erythropoiesis-stimulating agents. There is no definite treatment. We described for the first time a patient with chronic renal failure and antibody-mediated PRCA successfully treated with androgens.     

Hyperuricemia after renal transplantation

Hyperuricemia is common in cyclosporine-treated renal allograft recipients. An increased incidence of gout in patients receiving both diuretics and cyclosporine has been reported, but the effect of hyperuricemia on renal allograft function has not been studied. In a prospective, randomized trial of cyclosporine and prednisone versus azathioprine, prednisone, and antilymphocyte globulin for immunosuppression in renal allograft recipients, 105 of 131 cyclosporine and prednisone-treated patients (80 percent) experienced hyperuricemia (serum uric acid level above 8 mg/dl) and 13 of 131 (10 percent) were severely hyperuricemic (serum uric acid level above 14 mg/dl). In contrast, hyperuricemia developed in 63 of 115 patients (55 percent) treated with azathioprine, prednisone, and antilymphocyte globulin (p less than 0.002). Despite the frequent occurrence of hyperuricemia, gout was rare. Clinical gout developed in six patients in the cyclosporine and prednisone group and in 0 patients in the azathioprine, prednisone, and antilymphocyte globulin group between 1 and 43 months (median 22.5 months) after transplantation. Neither severe hyperuricemia nor diuretic therapy were associated with a significantly increased incidence of gout. The mean serum creatinine concentration of severely hyperuricemic patients (all on cyclosporine and prednisone) was similar to that of normouricemic cyclosporine and prednisone patients (1.8 mg/dl versus 1.6 mg/dl, p greater than 0.2), and the severely hyperuricemic patients had a 4-year graft survival rate of 90 percent. Asymptomatic hyperuricemia after renal transplantation does not adversely affect allograft function, requires no specific therapy, and is not a contraindication to use of diuretics.     

A prospective randomized trial on azathioprine addition to cyclosporine versus cyclosporine monotherapy at steroid withdrawal, 6 months after renal transplantation

BACKGROUND: Many attempts have been made to withdraw steroid therapy in renal transplant patients in order to avoid its many side effects. Results have been, so far, controversial. In this randomized prospective study, we compare the efficacy of azathioprine adjuncts to cyclosporine at the time of steroid withdrawal, 6 months after transplantation, versus Cyclosporine monotherapy, in preventing acute rejection. METHODS: One hundred and sixteen kidney transplant patients with good and stable renal function (creatininemia <2 mg/dl) received, in the first 6 months, cyclosporine + steroid. They were then randomized into two groups (A and B), and steroid therapy was withdrawn over 2 months. Group A (58 patients) continued on cyclosporine monotherapy, whereas group B (58 patients) added azathioprine (1 mg/kg/day) at the beginning of randomization and continued on cyclosporine + azathioprine. In both groups, patients resumed steroid therapy at the first episode of acute rejection. Follow-up after randomization was 5.3+/-1.6 years. RESULTS: After 5 years, the incidence of steroid resumption was 57% in group A and 29% in group B (P<0.02); of those, 68% and 88% of them were within 6 months from randomization. Anti-rejection therapy was always successful. Five-year patient and graft survival rates were 90% and 88% in group A and 100% and 91% in group B. Creatininemia did not differ, at follow-up. Side effects differed only for mild and reversible leukopenia caused by azathioprine in group B. CONCLUSION: Cyclosporine plus azathioprine is more effective than cyclosporine monotherapy in reducing the incidence of acute rejection after steroid withdrawal. Graft loss as a result of chronic rejection, mild in both groups, did not differ. Steroid withdrawal is feasible and advantageous, and the addition of azathioprine allowed 71% of our selected patients to remain steroid-free.     

Pustular psoriasis after renal transplantation

Cutaneous manifestations in renal transplant recipients are frequently represented by infections and cancerous lesions. However, dermatologic lesions secondary to autoimmune diseases are rare. We report a case of pustular psoriasis occurring after renal transplantation in a 31-year-old woman with a history of vitiligo. The patient was on hemodialysis for 2 years for undetermined chronic nephropathy. She received an HLA identical live related transplant from her brother. She was maintained on an immunosuppressive regimen of corticosteroids, azathioprine, and cyclosporine, which was replaced with mycophenolate mofetil because of neurotoxicity and azathioprine was stopped. Thirty-one months after renal transplantation, she developed pustular psoriasis which was treated with retinoids; she experienced a relapse and resistance to treatment despite the reintroduction of cyclosporine.     

Effect of treatment with cyclosporine versus azathioprine on incidence and severity of cytomegalovirus infection posttransplantation

The incidence and severity of cytomegalovirus (CMV) infection were evaluated in 24 renal transplant patients treated with steroids and cyclosporine and compared with 40 patients treated with steroids and azathioprine: 58% of patients receiving azathioprine and 33% of patients receiving cyclosporine required additional therapy with antithymocyte globulin (ATG) to treat steroid-resistant rejections. CMV antibody titers and cultures of urine and saliva were determined monthly for 4-6 months following transplant in all patients. Both the frequency of CMV infection (occurring in 58% of patients on steroids and cyclosporine and in 48% of patients on steroids and azathioprine) and its severity (21% of cyclosporine-treated patients and 22% of azathioprine-treated patients with symptoms) were similar in both groups. Use of ATG was associated with an increased incidence of CMV disease, especially for patients in the azathioprine group. Both the incidence of CMV disease, and the number of patients with symptoms in the azathioprine group were significantly lower when patients who had received ATG were excluded from analysis. When results were analyzed in just the cadaveric recipients in each group, the incidence and severity of CMV infection tended to be higher in azathioprine-treated patients compared with those maintained on cyclosporine. This could have been explained by the more frequent use of ATG in 84% of azathioprine maintained patients compared with 35% of cyclosporine-treated patients (P less than 0.002) since other factors, such as risk for CMV infection and Solumedrol dose for rejection were similar in both groups. The data demonstrate that ATG has a deleterious influence on the incidence and severity of CMV infection in renal transplant patients, even when the dosage of other immunosuppressive drugs is decreased during ATG therapy. Since patients treated with steroids and azathioprine tend to require ATG to treat steroid-resistant rejection more frequently than do patients on cyclosporine, this effect of ATG must be taken into account when evaluating CMV infection in patients on these two drug regimens.