Hypomagnesemia and renal magnesium wasting in renal transplant recipients receiving cyclosporine

Following the adoption and use of cyclosporine as the drug of choice in the management of renal allograft recipients, several cases of symptomatic hypomagnesemia were noted. These observations prompted the current prospective study of serum concentration and urinary excretion of magnesium in 27 renal transplant recipients treated with cyclosporine and prednisone. Relevant laboratory measurements were obtained shortly before and regularly after transplantation. The results were compared with those obtained in a group of 17 allograft recipients treated with azathioprine and prednisone. The cyclosporine-treated patients showed a significant reduction in the serum magnesium concentration and an inappropriately increased urinary excretion and fractional excretion of magnesium, suggesting renal magnesium wasting. The observed hypomagnesemia required magnesium supplementation in nearly all cyclosporine-treated patients. In contrast, azathioprine-treated patients showed normal serum magnesium concentrations and required no magnesium supplementation. In conclusion, administration of cyclosporine in renal allograft recipients appears to be commonly associated with renal magnesium wasting and hypomagnesemia. Therefore, it is recommended that serum levels of magnesium be monitored regularly in renal allograft recipients receiving cyclosporine and that magnesium supplementation be employed as needed to avoid magnesium depletion.     

Rejection theraples

One hundred thirty-eight primary liver allograft recipients received cyclosporine and prednisolone immunosuppression with azathioprine added during the induction phase. All rejections were biopsy-confirmed clinical rejections. Acute rejection was seen in 58.7% of the patients. The treatment of acute rejection was successful in 88.9% of treated patients. Rejection-related death was seen in 4.3%, and retransplantation was performed for acute or chronic rejection in 2.2% of the patients. The risk for dying increased with the number of rejection treatments.     

心脏移植围术期处理经验

目的:总结8例心脏移植围术期处理的临床经验.方法:8例晚期心肌病患者接受同种异体原位心脏移植术,围术期免疫抑制剂采用两剂赛尼哌加环磷酰胺诱导方案,维持治疗为环孢素A 霉酚酸酯(或硫唑嘌呤) 泼尼松三联方案,术后72 h内保持低水平的中心静脉压.结果:8例受者均存活,围术期及随访期间受者均无急性排斥反应、移植物功能不全、肝肾功能不全、严重机会性感染等并发症.结论:围术期适当强度的免疫抑制治疗,合理应用强心利尿和抗生素预防治疗是防治心脏移植术后并发症的有效方法.     

Efficacy of ketoconazole v nystatin in prevention of fungal infections in neutropenic patients

A prospective randomized study was undertaken in neutropenic patients to evaluate the efficacy of prophylactic ketoconazole v nystatin in reducing yeast infections. Eighteen patients received 500,000 units of nystatin suspension four times daily, and 18 patients received 200 mg of ketoconazole daily. The nystatin group experienced nine local yeast infections (four thrush, three esophagitis, and two vaginitis); three patients receiving ketoconazole had thrush. No cases of disseminated candidiasis occurred in either group. Ketoconazole was better tolerated than nystatin and neither drug caused toxic effects. In addition to being nontoxic and better tolerated, ketoconazole appeared to be slightly more effective than nystatin in reducing locally severe yeast infections.     

Comparative trial of ketoconazole and nystatin for prevention of fungal infection in neutropenic patients treated in a protective environment

In a randomized trial we compared ketoconazole (400 mg once daily, 27 patients) and nystatin (3 X 10(6) units four times daily, 29 patients) for prevention of fungal infection in neutropenic patients undergoing marrow transplantation in a protective environment. Fewer weekly surveillance cultures contained Candida species in ketoconazole recipients than in nystatin recipients (70 [26%] of 274 vs. 151 [47%] of 322; P less than .001). When all fungi were considered, the difference in colonization was less but was still significant (117 [43%] of 274 vs. 173 [54%] of 322; P = .01), primarily due to increased colonization of the rectum with Torulopsis glabrata among ketoconazole recipients (P less than .001). No difference in the incidence of local mucosal infection was seen. Two disseminated fungal infections occurred, both in nystatin recipients. Compliance with ketoconazole was significantly better than was compliance with nystatin (96% vs. 68%; P less than .001), but similar effects on colonization were found in an analysis adjusting for compliance. Ketoconazole was better tolerated and more effective than nystatin in reducing colonization due to Candida species but was also associated with significantly increased rates of colonization with T. glabrata.     

New strategies in GVHD prophylaxis

Despite immunosuppressive therapy using cyclosporine (CsA) and prednisolone and methotrexate (MTX), the incidence for aGVHD grade II to IV after transplantation from HLA matched unrelated donors (MUD) is 78%, the incidence for grade III and IV 36%. Since GVHD contributes to morbidity and mortality after MUD-BMT, a more effective prophylactic regimen is needed in order to prevent these transplant-associated complications. Recently, we described that mycophenolate mofetil (MMF, CellCept), an immunosuppressive agent successfully used for the prevention of acute rejection in renal allograft recipients, can safely and effectively be used for the treatment of aGVHD in hematopoietic stem cell transplantation. Information on the i.v. formulation of mycophenolic acid (MPA) is not yet available. Here we report on the i.v. formulation of MMF in hematopoietic stem cell recipients. MMF is effective in the prophylaxis of acute GVHD after stem cell transplantation; the optimal dosage needs further investigation. At the present time the relevance of measurement of plasma MPA concentrations on MMF dosage is not yet understood and further evaluation is required.     

Symposium on infectious complications of neoplastic disease (Part II). Chemoprophylaxis of fungal infections

As invasive fungal infection remains a common problem in the management of cancer patients, chemoprophylaxis of these opportunistic infections is desperately needed. The most frequently investigated antifungal agents have been nystatin, amphotericin B, and ketoconazole. In placebo-controlled studies, high doses of antifungal agents decreased the positive results from surveillance cultures, and there is some suggestion that such chemoprophylaxis may reduce the incidence of invasive candidiasis in neutropenic cancer patients. However, no oral chemoprophylaxis has effectively prevented aspergillosis or mucormycoses in these patients. There are still many areas of controversy, and the most adequate regimens, if any, remain to be defined.     

OKT3 prophylaxis in liver transplantation

In a randomized prospective study of liver transplant recipients, we compared prophylaxis with OKT3, steroids, and azathioprine to cyclosporine, steroids, and azathioprine. Seventy-two percent of patients receiving OKT3 prophylaxis were rejection free in the first 14 days compared to 41% in the cyclosporine group (P=0.02). However, after 14 days through a mean of 6.3 months, the overall incidence of rejection did not differ between the two groups (74% for the cyclosporine group and 48% for the OKT3 group). There was no increase in the rate of infectious complications noted in the OKT3-treated group. Thirty-nine percent of the OKT3-treated patients developed anti-OKT3 antibodies. Eight patients in the OKT3 group required reuse of OKT3 for rejection. Six of these continued to have greater than 10% CD3-positive cells with retreatment. Five were rescued successfully. With a mean survival of greater than 674±209 days in the OKT3-treated group and 626±242 days in the cyclosporine-treated group, no overall differences in graft and patient survival, liver function, renal function, late rejection incidence, or infectious complications were evident between the two groups. We conclude that OKT3 offers no long-term benefit compared to cyclosporine prophylaxis and should be reserved for treatment of rejection in patients in whom cyclosporine may be contraindicated.     

Rabbit antithymocyte globulin decreases acute rejection after lung transplantation: results of a randomized, prospective study.

STUDY OBJECTIVES: The efficacy of antithymocyte induction therapy in lung transplantation is controversial, and its use varies from center to center. We hypothesized that rabbit antithymocyte globulin (RATG) induction therapy would decrease acute rejection after lung transplantation, and we designed a single-center, randomized, prospective study to test this hypothesis. DESIGN: A total of 44 single or bilateral adult lung transplant recipients were randomly assigned to receive either RATG induction therapy (dosage, 1.5 mg/kg/d for 3 days) at the time of transplantation, along with conventional immunosuppression (cyclosporine, azathioprine, and prednisone), or conventional immunosuppression alone with no induction therapy. RESULTS: Although a similar number of biopsies were performed in each group, the number of patients experiencing biopsy-proven grade II or greater acute rejection was significantly reduced in the group receiving RATG induction therapy (23% incidence), as compared to the patients treated with conventional immunosuppression alone (55% incidence; p = 0.03). In addition, there was a nonsignificant reduction in the incidence of bronchiolitis obliterans syndrome at the conclusion of the study in patients who received RATG induction (20%), as compared to patients in the control group (38%). The incidence of posttransplant infections and malignancies were similar between the two groups. CONCLUSION: Induction therapy with RATG significantly reduces the incidence of acute allograft rejection after lung transplantation.     

Lack of effect of rapamycin in anti-CCP antibody production in a rheumatoid arthritis kidney allograft recipient

Autoimmune diseases may lead to end-stage renal disease and, as a consequence, kidney transplantation. Classical immunosuppressive drugs, such as cyclosporine or corticosteroids, are well-established therapies for both transplantation and autoimmune diseases. Rapamycin is a new immunosuppressant useful for allograft transplantation and with a promising future for autoimmune diseases, although it has not been extensively studied in humans. Here the case of a patient diagnosed with rheumatoid arthritis (RA) who received a renal allograft is reported. She was started on prednisolone, azathioprine and cyclosporine immunosuppression and changed to rapamycin instead of cyclosporine 4 years after transplantation, because of chronic allograft nephropathy. At present, the patient has a functioning graft. However, the arthritis symptoms reappeared after the change in immunosuppressant. Titers of RA-specific anti-cyclic citrullinated peptides antibodies increased whereas rheumatoid factor titers decreased. This case report suggests that rapamycin used for kidney transplantation might have a different influence on the spectrum of RA autoantibodies.     

Hypertension in cyclosporine-treated renal transplant recipients is sodium dependent

PURPOSE: Physicians increasingly prescribe cyclosporine as an immunosuppressive agent for both organ-transplant and non-organ-transplant recipients. Investigators have reported a high incidence of drug-induced hypertension even when clinical nephrotoxicity was not present. We wanted to determine the reason. PATIENTS AND METHODS: A comparison was made of hypertension in 15 cyclosporine-treated transplant recipients with that in a similar group of 15 azathioprine-treated transplant recipients. RESULTS: Hypertension in the cyclosporine group responded differently from that seen in the azathioprine group and from previously described forms of post-transplantation hypertension. Hypertensive cyclosporine-treated patients show a sodium acquisitive renal state that responds to sodium restriction. Unlike rat models, which suggest cyclosporine-induced stimulation of the renin-angiotensin system, or previous forms of post-transplant hypertension in humans, plasma renin levels were not elevated and blood pressure did not respond to a test dose of captopril. CONCLUSION: Hypertension in cyclosporine-treated patients is an iatrogenic form of hypertension that may be associated with an early, subtle, renal defect in sodium excretion, a genesis of hypertension that is consistent with Guyton's view of essential hypertension.     

Rejection in liver transplantation

One hundred four liver transplant recipients were retrospectively reviewed for the incidence of liver allograft rejection, the response to antirejection therapy and the impact of rejection on graft and patient survival. Liver biopsies were performed weekly during episodes of graft dysfunction and to follow response to treatment. Baseline immunosuppression consisted of cyclosporine and low-dose prednisolone. Rejection was treated with steroids and with OKT3 as rescue. Azathioprine was given to patients with preoperative or perioperative renal insufficiency and was added to patients' treatment after the first sign of rejection. Seven complications were observed in approximately 1,100 liver biopsies, only one necessitating surgery. We found that 39.4% of the patients never experienced acute rejection, and 60.6% had at least one episode of acute rejection. Overall, 42.3% of the patients had only one episode of acute rejection, 13.5% had two, 3.8% had three and 1% had five episodes of acute rejection. Sixty of 63 first acute rejection episodes occurred within 21 days of transplant. Primary disease, sex or patient age had no significant influence on the incidence of rejection. There was a lower incidence of rejection (p less than 0.005) in patients transplanted after October, 1986, despite lower mean cyclosporine levels. Mean cyclosporine level during the first postoperative month was 679 ng per ml vs. a mean level of 910 ng per ml prior to October, 1986, when the immunosuppressive protocol was altered. Antirejection therapy was very effective in that only two of the 63 patients had graft failure due to acute rejection. Both of these patients were subsequently retransplanted.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cyclosporine in heart transplant recipients: an exercise study of vasopressor effects.

The possible vasopressor effect of cyclosporine (CS) on both the systemic and pulmonary vascular beds has been investigated during bicycle exercise in 12 heart transplant recipients (mean age, 41 years) using pulmonary artery catheter measurements. Eight patients were taking cyclosporine and six azathioprine and prednisolone (AzS) as immunosuppressive therapy. With exercise, CS recipients show a significantly larger rise in systemic pressure than AzS recipients (P less than 0.001), with persistently higher pulmonary pressures (P less than 0.001). This suggests a generalized vasopressor effect of CS on the vasculature.     

Lymphoproliferative syndromes after cardiac transplantation and treatment with cyclosporine. Report of 4 cases]

Immunosuppressive therapies may induce neoplasia. The administration of cyclosporine is associated with an increased frequency of lymphoproliferative disorders when compared with conventional therapies. This risk is related to the type of organ transplanted and immunosuppression modalities (type and intensity). In heart transplantation, the incidence of non-Hodgkin's lymphoma varies between 11.9 and 1.5% with onset usually about 6 months after transplantation. Four case reports are presented; 3 lymphomas and 1 multiple myeloma that developed, in heart transplant recipients receiving triple-drug immunosuppression: azathioprine, cyclosporine and prednisolone. Clinical and immunohistological characteristics of posttransplant lymphomas are described and etiopathological mechanisms, especially the role of cyclosporine, in the development of these lymphoproliferative disorders, are discussed.     

Diagnosis and treatment of oropharyngeal candidiasis in patients infected with HIV: a critical reassessment.

Oropharyngeal candidiasis is the most common opportunistic infection seen in patients infected with the human immunodeficiency virus (HIV). As HIV disease progresses and immunosuppression worsens, the incidence and severity of oropharyngeal candidiasis increase. The predominant pathogen in initial and recurrent episodes is Candida albicans, which responds to a variety of topical (nystatin and clotrimazole) and systemic azole antifungal agents (ketoconazole, itraconazole, and fluconazole). Since the introduction of the oral azoles, increasing evidence indicates that C. albicans strains are developing resistance to azoles, particularly fluconazole, and other Candida strains are emerging that are intrinsically less susceptible to azole therapy. The advent of effective antiretroviral therapies for the treatment of HIV disease has led to a scenario in which antifungal strategies are likely to be highly effective. To minimize the risk of resistance, topical therapies should be considered first-line candidates for treatment of initial or recurrent cases of uncomplicated oropharyngeal candidiasis. Systemic azole therapy should be reserved for cases unresponsive to topical therapies or for more severe oropharyngeal candidiasis with esophageal involvement.     

Phase I-II trial of foscarnet for prevention of cytomegalovirus infection in autologous and allogeneic marrow transplant recipients.

The safety and efficacy of foscarnet for prevention of cytomegalovirus (CMV) infection was evaluated in 19 CMV-seropositive bone marrow transplant (BMT) recipients. All patients received intermittent intravenous (iv) foscarnet: 40 mg/kg every 8 h from 7 days before to day 30 after BMT, then 60 mg/kg once a day until day 75. The main toxicity was transient renal dysfunction, with a greater than 50 mumol/L increase in serum creatinine above baseline in 5 of the 7 autograft recipients and in 6 of the 12 allograft recipients. Only 4 allograft recipients developed CMV infection during foscarnet prophylaxis, and no patient showed evidence of CMV disease. Because 3 allograft recipients receiving concomitant iv amphotericin B showed rapid impairment of renal function, foscarnet prophylaxis should not be given to allograft recipients requiring amphotericin B; otherwise, foscarnet prophylaxis at this dose appears safe after BMT.     

Prevention of Symptomatic Recurrences of Esophageal Candidiasis in AIDS Patients after the First Episode: A Prospective Open Study

Objectives: To evaluate the efficacy and safety of lowdose antifungals as prophylaxis of recurrent esophageal candidiasis after the first episode in patients with AIDS. Methods: After the first episode of esophageal candidiasis, 122 consecutive AIDS patients were randomly assigned to two different regimens of continuous longterm antifungai prophylaxis (ketoconazole 200 mg or fluconazole 50 mg/day p.o.) or no antifungai therapy over a period of 2 yr. Patients were followed up by monthly clinical controls and upper GI endoscopy in the case of recurrence of esophageal symptoms. Results: One hundred and six patients were clinically evaluable over a mean observation time of 7.5 months. Prophylaxis with oral antifungals significantly reduced symptomatic relapses of esophageal candidiasis, the cumulative probability of relapse at 12 months being 38% in the prophylaxis group, compared with 84% in the untreated group. Both antifungals were sufficiently safe and well tolerated. The clinical response of a second episode of candidiasis to the reintroduction of standard oral antifungals was markedly worse in patients on prophylaxis (especially with ketoconazole) than in untreated patients, presumahly due to the development of resistance to the antifungal. Conclusions : Continuous prophylaxis with both fluconazole and ketoconazole is effective in preventing recurrences of Candida esophagitis in AIDS patients; however, the possihie emergence of strains resistant to these antifungals, as well as the high cost of the therapy, should raise doubts as to whether or not this type of prophylaxis should be extended to all AIDS patients with Candida esophagitis, rather than to limit its use to specific subgroups of patients, such as those with frequent symptomatic relapses.     

Ketoconazole-resistant Candida esophagitis in patients with acquired immunodeficiency syndrome

Although ketoconazole has been shown to be effective in treating esophageal candidiasis in other immunodeficiency states, similar studies have not been reported in patients with acquired immunodeficiency syndrome. Six patients with acquired immunodeficiency syndrome and oral and esophageal candidiasis who had been treated with ketoconazole for more than 2 mo were evaluated with barium esophagram and endoscopy with biopsy and brush cytology. All of the patients had persistent Candida esophagitis. In 2 patients, fungal cultures and sensitivity testing indicated Candida albicans resistant to ketoconazole in vitro. In patients with acquired immunodeficiency syndrome, esophageal candidiasis may not resolve with up to 6 mo of ketoconazole therapy and may require more vigorous antifungal therapy than in patients with other immunodeficiency states.     

Impaired liver function in stable renal allograft recipients

Hepatic failure as a cause of death is increased in stable renal allograft recipients when compared with patients on dialysis. In order to assess the magnitude and the natural history of the hepatic functional derangement, the kinetics of xenobiotics which are metabolized by cytosolic (galactose) or microsomal (prednisolone, cyclosporine A) enzymes were determined in 28 consecutive stable kidney transplant patients 1 month and 1 year after transplantation. Renal transplant patients had a decreased mean (+/- S.D.) galactose elimination capacity at 1 month (6.26 +/- 0.94 mg per min x kg) and at 1 year (5.93 +/- 0.96 mg per min x kg), when compared with a different group of 28 healthy control subjects (7.52 +/- 0.78 mg per min x kg, p less than 0.001) and a decreased total body clearance of prednisolone at 1 month (2.13 +/- 0.34 ml per min x kg vs. 2.71 +/- 0.43 ml per min x kg in controls, p less than 0.001), which further decreased over the following year to 1.76 +/- 0.32 ml per min x kg (p less than 0.001). The clearance of cyclosporine A declined significantly during the first year of successful transplantation (5.9 +/- 2.1 ml per min x kg vs. 4.9 +/- 1.2 ml per min x kg, p less than 0.05). In conclusion, a substantial proportion of stable renal transplant recipients have decreased cytosolic and microsomal liver functions despite the absence of clinical and laboratory evidence of significant liver disease.     

Phase III study comparing tacrolimus (FK506) with cyclosporine for graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation

We report the results of a phase III trial comparing tacrolimus (FK506) with cyclosporine for GVHD prophylaxis after allogeneic BMT. From February 1995 to July 1996, 136 patients were enrolled and followed up to September 1997. During the first 100 days post-transplant the incidence of grade II-IV acute GVHD (the primary end-point) was lower in the tacrolimus group (17.5%) compared with the cyclosporine group (48.0%, P < 0.0001). A significant difference was observed between the tacrolimus and cyclosporine groups when subset analyses were performed based on recipients from HLA-matched siblings (13.3% vs 41.3%, P = 0.015) or donors other than HLA-matched siblings (21.4% vs 53.8%, P= 0.0029). The incidence of chronic GVHD (47.3% and 47.8%) and Kaplan-Meier estimate of overall survival (62.9% and 65.2%) were similar between the tacrolimus and cyclosporine groups, respectively. The overall leukemia relapse rate was not significantly different between the tacrolimus and cyclosporine groups (19.6% and 11.4%, respectively). However, the relapse rate among recipients from HLA-matched siblings was significantly higher in the tacrolimus group (30.9%) compared with the cyclosporine group (3.6%, P = 0.013). These results suggest the merit of tacrolimus for the prophylaxis of acute GVHD, but a lack of merit for a graft-versus-leukemia effect among recipients from HLA-matched sibling donors.