Vascular endothelial function in cyclosporine and tacrolimus treated renal transplant recipients.

BACKGROUND: Endothelial dysfunction is an early key event in the development of arteriosclerotic cardiovascular disease (ASCVD), thus an early marker of subclinical ASCVD. Endothelial function is impaired in renal transplant recipients (RTR) treated with cyclosporine (CyA). Tacrolimus is associated with less hyperlipidemia and hypertension than CyA, however, there are no data on endothelial function in tacrolimus-treated RTR. METHODS: High-resolution brachial ultrasonography was used to assess endothelium-dependent dilatation (EDD), and endothelium-independent dilatation (EID) in 20 stable RTR and a control group of 10 healthy subjects without clinical evidence of ASCVD. The RTR group included patients receiving CyA (n=10) and tacrolimus (n=10). EDD and EID were measured as percent increase in brachial artery diameter in response to reactive hyperemia and nitroglycerin, respectively. RESULTS AND CONCLUSIONS: EDD was significantly lower in RTR versus controls (1.7+/-0.7 vs. 7.3+/-0.7%, P<0.0001), whereas EID was similar in the two groups. No significant differences were found in EDD or in EID between CyA- and tacrolimus-treated RTR. Glomerular filtration rate, plasma homocysteine, blood pressure, and lipid profiles were similar in CyA- and tacrolimus-treated RTR.

Recent advances in the diagnosis and management of infection in the organ transplant recipient.

Infection remains a significant cause of morbidity and mortality in organ transplant patients, with significant infection being found in more than half of these individuals posttransplant. The most important principles of patient treatment are prevention, early diagnosis, and specific therapy. The nature of the antimicrobial therapy required both for infection prevention and treatment is closely linked to the immunosuppressive therapy being administered. A particular challenge in the transplant patient is that the antiinflammatory effects of antirejection therapy tend to obscure the manifestations of infection until relatively late in the disease process, thus putting particular emphasis on more aggressive diagnostic approaches-imaging procedures, biopsy, and new techniques for microbial detection (antigen and DNA detection). Antimicrobial therapy can be administered in three ways: therapeutically, prophylactically, and preemptively. Particularly given the propensity for adverse interactions between antimicrobial agents and cyclosporine and tacrolimus, there is a particular emphasis on prophylactic and preemptive use of antimicrobials.

Prevention of recurrent cytomegalovirus disease in renal and liver transplant recipients: effect of oral ganciclovir.

BACKGROUND: Although the primary treatment of symptomatic cytomegalovirus (CMV) disease in organ transplant recipients is successful in >90% of individuals, relapsing disease, particularly in those with primary infection, remains an important problem. Previously, we had observed that the rate of symptomatic recurrence was >60% in those with primary disease (seronegative for CMV prior to transplant), and approximately 20% in those who were seropositive prior to transplant. The present study was undertaken to determine whether a maintenance regimen of oral ganciclovir for 2-3 months added to the routine 14-21 days of intravenous ganciclovir would further prevent symptomatic CMV recurrence. METHODS: From May 1995 until June 1998, all kidney and liver transplant recipients with confirmed tissue-invasive CMV disease or CMV syndrome were treated with 14-21 days of intravenous ganciclovir (5 mg/kg b.i.d. with dose adjusted for renal dysfunction) followed by 2-3 months of oral ganciclovir (2 g daily). The incidence of recurrence of CMV disease and/or viremia during and after oral therapy was then determined over a mean follow-up of 530.6 days. RESULTS: Thirty-seven patients, 19 kidney and 18 liver transplant recipients, were studied; 5 had biopsy-proven tissue-invasive disease (13.5) and 32 suffered a CMV syndrome (86.5). Twenty-one of these patients (58.6) were seronegative for CMV prior to transplant and received an allograft from a seropositive donor (D+/R-). Overall, 10 patients (27.0) developed CMV recurrence. Eight of 21 patients who were D+/R- for CMV (38.1) developed recurrence as opposed to 2 of 16 patients with other serologic status (12.5) (P=0.14). Patients with recurrent CMV disease and/or viremia had a peak antigenemia assay titer during their initial CMV event of 319.2 positive cells/2 slides compared with 109.8 positive cells/2 slides for patients without recurrent CMV infection (P=0.14); the trend of having a higher peak antigenemia assay titer among patients who recurred occurred both in patients who were at risk of primary CMV infection (D+/R- for CMV) and in those who were not. Two patients developed recurrent infection with strains of CMV that were resistant to ganciclovir. CONCLUSIONS: This new therapeutic regimen of oral ganciclovir following intravenous ganciclovir slightly reduced the overall rate of recurrent CMV disease and/or viremia, but it still did not adequately prevent CMV recurrence in patients who are at risk of primary infection prior to transplant. Of particular concern, 2 patients with primary infection treated with this regimen developed ganciclovir-resistant recurrent disease.

Safety and efficacy of granulocyte colony-stimulating factor in kidney and liver transplant recipients.

BACKGROUND: Leukopenia is not infrequently encountered following solid organ transplantation, most often in the setting of cytomegalovirus (CMV) disease and/or its treatment with ganciclovir. The present study was undertaken to determine the safety and efficacy of granulocyte colony-stimulating factor (G-CSF) in renal and liver transplant recipients with leukopenia. METHODS: Between 1 June 1991 and 1 June 1998, patients received G-CSF for 2 indications: 1) white blood cell count (WBC) < 3000/mm3, with a decline from baseline; 2) to shorten the duration of leukopenia associated with chemotherapy. A retrospective review of the outcome of such therapy was undertaken. RESULTS: 50 patients were given 100 courses of treatment with G-CSF; 35 of 168 liver transplant recipients (20.8%), 14 of 391 kidney transplant recipients (3.6%), and 1 of 4 recipients of combined liver-kidney transplants (25.0%) received from 1 to 9 courses of G-CSF. Presumed causes of leukopenia were identified as ganciclovir in 28 cases (28.0%), CMV in 21 (21.0%), chemotherapy in 12 (12.0%), sepsis in 11 (11.0%), azathioprine in 5 (5.0%), interferon in 3 (3.0%) and other causes in 20 cases (20.0%). The median length of therapy was 10.0 days (range 1-154 days) and the average dose of daily G-CSF received was 3.9+/-1.5 microg/kg/day. The average WBC was (2.4+/-1.3 )x 10(3)/microl at the beginning of therapy, and (13.8+/-9.1) x 10(3)/microl at the end of therapy. In 7 of 100 treatments (7.0%) a WBC of 5.0 x 10(3)/microl was not reached during G-CSF therapy; in 6 of these 7 cases, G-CSF therapy lasted fewer than 4 days. The mean time needed to reach a WBC count of 5 x 10(3)/microl was 3.7+/-3.3 days among 71 patients who had daily WBC counts sent. Eight G-CSF treatments (8.0%) were followed by episodes of rejection appearing during or within 2 months of treatment; 5 of them were biopsy-documented. No relation was found between the highest WBC obtained during G-CSF therapy and the risk of rejection. Eight patients (16.0%) died while receiving G-CSF, all from infection. Six of these 8 patients were receiving G-CSF for leukopenia secondary to sepsis. Overall, 25 patients (50.0%) received 49 courses of G-CSF secondary to CMV and/or ganciclovir therapy. In 40 of 49 courses (81.6%), ganciclovir could be continued at recommended doses. Twenty-one of 22 patients (95.5%) with symptomatic CMV infection had a clinical response to ganciclovir. Sixteen of 18 patients (88.9%) treated for a CMV infection and followed with serial antigenemia assays attained microbiological cure; both patients who did not were infected with ganciclovir resistant CMV. CONCLUSION: G-CSF was well tolerated in solid organ transplant recipients. It was particularly useful in patients with CMV disease, allowing optimal ganciclovir therapy.

Effect of oral acyclovir or ganciclovir therapy after preemptive intravenous ganciclovir therapy to prevent cytomegalovirus disease in cytomegalovirus seropositive renal and liver transplant recipients receiving antilymphocyte antibody therapy.

BACKGROUND: Organ transplant recipients who are seropositive for cytomegalovirus (CMV) and who are treated with antilymphocyte antibody (ALA) therapy have a high rate of symptomatic CMV disease. The intravenous administration of ganciclovir therapy once daily during ALA therapy decreased the incidence from 24% to 10% in patients receiving ALA as an induction therapy and from 64% to 22% in those treated for rejection. The present study was undertaken to determine whether a more intensive and sustained antiviral regimen could be more effective. METHODS: From April 1995 to December 1997, all CMV seropositive renal and liver transplant recipients who received ALA therapy were treated with intravenously administered ganciclovir (5 mg/kg/day with dose adjusted for renal dysfunction) for the length of ALA therapy and then with orally administered acyclovir (400 mg three times/day) or ganciclovir (1 gm twice/day) for 3 to 4 months. The incidence of CMV viremia and of CMV disease was determined during the 6 months after completion of ALA therapy. RESULTS: Forty-one patients (35 renal and 6 liver transplant recipients) were studied. CMV disease occurred in 2 patients (4.9%), both of whom were treated for rejection; it occurred in 1 of 21 patients (4.8%) treated with orally administered acyclovir, and in 1 of 20 patients (5%) treated with orally administered ganciclovir. The only patient who developed CMV disease in the ganciclovir group had received only 26 days of oral antiviral therapy. No CMV disease was documented in the group of patients receiving ALA therapy as induction therapy. CMV viremia occurred in three patients in the acyclovir group (14.3%) and in one patient in the ganciclovir group (5%). Among renal transplant recipients only, 1 of 35 patients developed CMV disease (2.9%) and no case of CMV disease was documented in patients treated with orally administered ganciclovir. All six patients receiving two courses of ALA therapy each were free of CMV disease. Toxicity of the regimen was minimal, and antiviral resistance did not develop. CONCLUSIONS: Preemptive antiviral therapy with intravenously administered ganciclovir during ALA therapy and then orally administered ganciclovir for 3 to 4 months provides virtually complete protection against the excessive rate of CMV disease that occurs in CMV seropositive allograft recipients receiving ALA therapy.

Urinary tract infection in the immunocompromised host. Lessons from kidney transplantation and the AIDS epidemic.

The occurrence of urinary tract infection and its clinical impact is determined, as with any infectious disease, by the interaction between the virulence of the infecting organism and the host defense mechanisms that can be mobilized. In the case of urinary tract infections, an anatomically and functionally intact kidney and urinary tract are the primary host defenses, with phagocytic function and immune mechanisms coming into play to limit the consequences of those infections. Of all the categories of immunocompromised hosts, the renal transplant patient is the one most susceptible to the direct and indirect consequences of urinary tract infections. In the first 3 months post transplant, the incidence of urinary tract infection is greater than 30%, and there is a relatively high rate of bacteremia and overt pyelonephritis of the allograft. After this time period, unless anatomic or functional derangement of the urinary tract is present, the direct clinical manifestations are far more benign. In addition to the direct effects of urinary tract infection on these patients, indirect effects are also important. These include the activation of CMV by TNF released as a consequence of a urinary tract infection and the initiation of allograft injury. Fortunately, low-dose trimethoprim-sulfamethoxazole or fluoroquinolones are safe and effective prophylactic strategies for preventing the direct and indirect consequences of urinary tract infections. Although the pathogenetic mechanisms are incompletely understood, data are emerging that AIDS patients have both an increased incidence and severity of urinary tract infection. The risk for urinary tract infections seem to be correlated with the degree of immune compromise and, perhaps, the amount of malnutrition and wasting that are present. The best strategies for preventing urosepsis in AIDS patients remain to be defined.

An oral platelet-activating factor antagonist, Ro-24-4736, protects the rat kidney from ischemic injury.

The role of platelet-activating factor (PAF) in ischemic acute renal failure was evaluated by administering an oral PAF antagonist (Ro-24-4736) to rats prior to or after interruption of blood flow to both kidneys for 30 min. In animals treated with the PAF antagonist prior to ischemia, renal function was less impaired and histological abnormalities was less pronounced when compared with postischemic kidneys from vehicle-treated animals. Serum creatinine (mg/ dl) 24 h following renal ischemia was 1.58 +/- 0.17 in the PAF antagonist-treated rats compared with 2.19 +/- 0.15 in rats given placebo (P < 0.01). There was less necrosis in the outer medulla of kidneys of PAF antagonist-treated animals (P < 0.01). Tissue myeloperoxidase activity at 48 and 72 h postischemia was lower in kidneys of PAF antagonist-treated rats (P < 0.05). The PAF antagonist was also protective when administered 30 min but not 2 h following the ischemic insult. The coincident use of anti-intercellular adhesion molecule-1 monoclonal antibody did not confer additional protection over that observed with the oral PAF antagonist alone. These data suggest that PAF contributes to the pathophysiology of renal ischemic injury, perhaps by its effects on leukocyte-endothelial interactions. An orally active PAF antagonist can protect against the development of ischemic acute renal failure.

Psychiatric disease and cytomegalovirus viremia in renal transplant recipients.

Although cytomegalovirus (CMV) is rarely cultured from peripheral-blood leukocytes of immunocompetent patients, it may be cultured from up to 60% of renal transplant recipients, 1 to 4 months after transplantation. During this same period, renal transplant recipients are often referred for psychiatric evaluation. Since CMV may infect the central nervous system, the relationship between isolation of CMV from peripheral-blood leukocytes (viremia) and psychiatric evaluation was investigated in 80 renal allograft recipients at the Massachusetts General Hospital. Five of 16 (31%) patients with viremia and 7 of 64 (11%) patients without viremia required psychiatric consultation (P = 0.04, two-tailed Fisher exact test). CMV viremia may be an important but treatable contributor to psychiatric symptoms in the transplant recipient.

Preemptive ganciclovir therapy to prevent cytomegalovirus disease in cytomegalovirus antibody-positive renal transplant recipients. A randomized controlled trial.

OBJECTIVE: To determine whether preemptive ganciclovir therapy administered daily during antilymphocyte antibody therapy can prevent cytomegalovirus disease in renal transplant recipients who are positive for cytomegalovirus antibody. DESIGN: Randomized, controlled, multicenter trial. SETTING: 6 university-affiliated transplantation centers. PATIENTS: 113 renal transplant recipients who were positive for cytomegalovirus antibody. INTERVENTION: Patients were randomly assigned to receive either 1) ganciclovir, 2.5 mg/kg body weight administered intravenously on every day that antilymphocyte antibody therapy was administered or 2) no anticytomegalovirus therapy. MEASUREMENTS: Patients were observed for 6 months after completion of antilymphocyte antibody therapy for development of cytomegalovirus disease and cytomegalovirus viremia. RESULTS: Cytomegalovirus disease occurred in 14% of patients (9 of 64) who received preemptive ganciclovir therapy and in 33% of controls (16 of 49) (P = 0.018). Cytomegalovirus was isolated from buffy-coat specimens from 17% of patients (11 of 64) receiving preemptive ganciclovir and from 35% of controls (17 of 49) (P = 0.03). Controlling for the reason (induction or treatment of rejection) for using antilymphocyte antibodies in a Cox proportional hazards model, we found that preemptive ganciclovir still protected against cytomegalovirus disease (adjusted relative risk, 0.27; 95% CI, 0.12 to 0.64). No adverse events were attributed to preemptive ganciclovir therapy during or within 6 months of its administration. CONCLUSIONS: Preemptive ganciclovir therapy administered daily during courses of treatment with antilymphocyte antibodies reduced the excessive occurrence of cytomegalovirus disease in renal transplant recipients who were positive for cytomegalovirus antibody. This approach, which links the most potent immunosuppression to intensive antimicrobial therapy, allows preventive therapy to be given to those patients at greatest risk for developing infectious complications. These patients are likely to benefit most from the preventive strategy.

New strategies for the control of viral infection in organ transplantation.

Control of viral infection in organ transplant recipients requires attention to the following interventions: prevention, whenever possible of viral acquisition; the proper deployment of active and passive immunization, with hyperimmune globulin preparations directed against cytomegalovirus, hepatitis B, varicella, and, perhaps, respiratory syncytial virus, offering significant benefit when used appropriately; and the prescription of antiviral agents at critical points in the post-transplant course. Two important principles should be kept in mind when approaching this problem: prevention is the goal, as treatment of established infection is fraught with difficulty; and effective preventative strategies must be linked to the intensity of the immunosuppressive program being employed. To achieve these goals, the addition of pre-emptive therapy (therapy geared to a laboratory marker of impending disease or to escalation in the immunosuppressive program) to standard prophylactic regimens represents a significant advance.

The infectious disease problems of the diabetic renal transplant recipient.

Approximately 30% of patients with end stage renal disease who undergo transplantation develop renal failure as a result of their long-standing diabetes mellitus. Therefore, diabetics warrant special attention in considering the infectious disease problems associated with transplantation. The three categories that should be considered in infections affecting the diabetic renal transplant recipient are discussed in this article.

Antimicrobial strategies in the care of organ transplant recipients.

Since the early days of transplantation, infection has been a major consequence of antirejection immunosuppressive therapy. Increasingly effective prophylactic and preemptive strategies are being developed to prevent the infectious consequences of immunosuppressive therapy. Although the data base is incomplete and there remains a compelling need for well-designed, randomized, comparative trials, the potential for controlling life-threatening viral, bacterial, fungal, and protozoal infections exists. The cornerstone of this effort is the recognition that effective immunosuppressive strategies require an antimicrobial program to make them safe and that such an antimicrobial program needs to be individualized in order to be appropriately matched with the needs of the antirejection program. Thus, escalation and de-escalation of the antimicrobial program should be carried out to match the immunosuppressive program. Infection and rejection remain closely intertwined, linked by the immunosuppressive program that is prescribed.

Viral infection in the renal transplant recipient.

The viral infections with greatest impact on the renal transplant recipient are those due to cytomegalovirus, Epstein-Barr virus, and the two hepatitis viruses, hepatitis B and C. All of these are modulated by the administered immunosuppressive therapy, and all have both direct and indirect effects on the transplant patient. The direct effects are the infectious disease clinical syndromes that are produced (fever and malaise, pneumonia, hepatitis, and so forth). The indirect effects are several--all of these viruses contribute to the patient's net state of immunosuppression, predisposing him or her to the development of opportunistic superinfection with a variety of pathogens. In addition, both Epstein-Barr virus and hepatitis B virus have been clearly linked to the development of certain malignancies (lymphoproliferative disease and hepatocellular carcinoma, respectively). Finally, cytomegalovirus has been linked to allograft injury. Although antiviral strategies effective for cytomegalovirus and Epstein-Barr virus infection are being developed, similar programs are not yet available for the hepatitis viruses.

Trimethoprim-sulfamethoxazole compared with ciprofloxacin for the prevention of urinary tract infection in renal transplant recipients. A double-blind, randomized controlled trial.

BACKGROUND: Prophylaxis with low-dose trimethoprim-sulfamethoxazole has been shown to be cost-effective in the prevention of urinary tract infections, pyelonephritis, urosepsis, and pneumocystis pneumonia in renal transplant recipients. Ciprofloxacin, effective against almost all urinary tract pathogens in this patient population, represents a promising alternative prophylactic agent for patients unable to tolerate trimethoprim-sulfamethoxazole due to toxicity. METHODS: We conducted a randomized, double-blind trial to compare low-dose trimethoprim-sulfamethoxazole with ciprofloxacin for the prevention of urinary tract infections in renal transplant recipients. Patients received either ciprofloxacin (250 mg) or trimethoprim-sulfamethoxazole (80 mg trimethoprim, 400 mg sulfamethoxazole) daily for 6 months following transplantation. Treatment was considered successful if patients completed the 6-month course and 3-month follow-up period without evidence of urinary tract infection or drug-related toxicities. RESULTS: Of 103 eligible patients, 51 received ciprofloxacin and 52 received trimethoprim-sulfamethoxazole. At 6 months, treatment was successful in 75% (38 of 51) receiving ciprofloxacin and 71% (37 of 52) treated with trimethoprim-sulfamethoxazole (P = 0.87, relative risk 1.04, 95% confidence limits 0.83 to 1.33). Thirteen patients (25%) receiving trimethoprim-sulfamethoxazole withdrew from the study-4 for resistant urinary tract infection and 9 for drug-related toxicity, while 3 (6%) of the patients receiving ciprofloxacin withdrew because of drug-related toxicity (P = 0.016, relative risk of urinary tract infection or adverse event 0.24, 95% confidence limits 0.07 to 0.78). At 9 months, all 38 patients who completed the 6-month course of ciprofloxacin remained free of urinary tract infection, while an additional 4 patients who had received trimethoprim-sulfamethoxazole prophylaxis (total of 8 patients over the 9 months) developed urinary tract infections (P = 0.006, Fisher's exact test for urinary tract infection alone). Pneumocystis pneumonia occurred in a total of 7 (14%) patients who were randomized to ciprofloxacin, but 2 of the 7 had withdrawn from the study at least 2 weeks prior to the diagnosis of pneumocystis pneumonia. There were no cases of pneumocystis pneumonia in patients receiving trimethoprim-sulfamethoxazole (P = 0.006). Following completion of the study, monthly aerosolized pentamidine administered in conjunction with ciprofloxacin has provided complete protection against urinary tract infection and pneumocystis pneumonia in 30 transplant recipients unable to tolerate trimethoprim-sulfamethoxazole therapy. CONCLUSIONS: Ciprofloxacin is at least as effective as trimethoprim-sulfamethoxazole in the prevention of urinary tract infection in renal transplant recipients, and is better tolerated. Ciprofloxacin prophylaxis is associated with a higher incidence of pneumocystis pneumonia than is trimethoprim-sulfamethoxazole therapy. An uncontrolled follow-up study suggests that ciprofloxacin prophylaxis combined with monthly aerosolized pentamidine may be efficacious in preventing both urinary tract infection and pneumocystis pneumonia in renal transplant recipients.

Opportunistic fungal and bacterial infection in the renal transplant recipient.

The risk of opportunistic infection in the renal transplant recipient is determined by the interaction between two factors: the epidemiologic exposures the individual encounters within the community and the hospital and a complex function termed the net state of immunosuppression. There are two general categories of opportunistic fungal infection in this patient population: (1) disseminated primary or reactivation infection with one of the geographically restricted systemic mycoses (histoplasmosis, coccidioidomycosis, blastomycosis, and paracoccidioidomycosis) and (2) opportunistic infection with fungal species that rarely cause invasive infection in the normal host (Aspergillus species, Candida species, Cryptococcus neoformans, and the Mucoraceae), with these last usually being acquired within the hospital environment. Newly available azole compounds, fluconazole and itraconazole, are exciting new alternatives to amphotericin in the treatment of at least some of these infections. The three most important forms of opportunistic bacterial infections are those due to Listeria monocytogenes, Nocardia asteroides, and a variety of mycobacterial species. Clinical diseases with these first two are effectively prevented by low-dose trimethoprim-sulfamethoxazole prophylaxis. There are two cardinal therapeutic rules to be followed by clinicians in dealing with these infections: prevention is better than treatment; when treatment is required, however, the major determinant of the success of therapy is the rapidity with which the diagnosis is made and effective therapy is initiated.