Gabriel M. Danovitch

Randomized Trial Of Tacrolimus (prograf) In Combination With Azathioprine Or Mychophenolate Mofetil Versus Cyclosporine (neoral) With Mycophenolate Mofetil After Cadaveric Kidney Transplantation1, 2

BACKGROUND Our clinical trial was designed to investigate the optimal combination of immunosuppressants for renal transplantation. METHODS A randomized three-arm, parallel group, open label, prospective study was performed at 15 North American centers to compare three immunosuppressive regimens: tacrolimus + azathioprine (AZA) versus cyclosporine (Neoral) + mycophenolate mofetil (MMF) versus tacrolimus + MMF. All patients were first cadaveric kidney transplants receiving the same maintenance corticosteroid regimen. Only patients with delayed graft function (32%) received antilymphocyte induction. A total of 223 patients were randomized, transplanted, and followed for 1 year. RESULTS There were no significant differences in baseline demography between the three treatment groups. At 1 year the results are as follows: acute rejection 17% (95% confidence interval 9%, 26%) in tacrolimus + AZA; 20% (confidence interval 11%, 29%) in cyclosporine + MMF; and 15% (confidence interval 7%, 24%) in tacrolimus + MMF. The incidence of steroid resistant rejection requiring antilymphocyte therapy was 12% in the tacrolimus + AZA group, 11% in the cyclosporine + MMF group, and 4% in the tacrolimus + MMF group. There were no significant differences in overall patient or graft survival. Tacrolimus-treated patients had a lower incidence of hyperlipidemia through 6 months posttransplant. The incidence of posttransplant diabetes mellitus requiring insulin was 14% in the tacrolimus + AZA group, 7% in the cyclosporine + MMF and 7% in the tacrolimus + MMF groups. CONCLUSIONS All regimens yielded similar acute rejection rates and graft survival, but the tacrolimus + MMF regimen was associated with the lowest rate of steroid resistant rejection requiring antilymphocyte therapy.

Sirolimus-associated pulmonary toxicity

Background. Pulmonary toxicity has recently been recognized as a potentially serious complication associated with sirolimus therapy. We further detail this condition on the basis of our own cases and those reported in the literature. Methods. We report three cases of suspected sirolimus-induced pulmonary toxicity that occurred in three renal transplant recipients and searched PubMed for all previously reported cases. Results. Including our current cases, 43 patients with sirolimus-induced pulmonary toxicity have now been reported. Clinical data were incomplete in 28 cases. Analysis of available data for 15 patients revealed that the most commonly presenting symptoms were dyspnea on exertion and dry cough followed by fatigue and fever. Chest radiographs and high-resolution computed tomography scans commonly revealed bilateral patchy or diffuse alveolo-interstitial infiltrates. Bronchoalveolar fluid analysis and lung biopsy in selected case reports revealed several distinct histologic features, including lymphocytic alveolitis, lymphocytic interstitial pneumonitis, bronchoalveolar obliterans organizing pneumonia, focal fibrosis, pulmonary alveolar hemorrhage, or a combination thereof. The diagnosis of sirolimus-associated pulmonary toxicity was made after an exhaustive work-up to exclude infectious causes and other pulmonary disease. Sirolimus discontinuation or dose reduction resulted in clinical and radiologic improvement in all 15 patients within 3 weeks. Conclusion. The temporal relationship between sirolimus exposure and onset of pulmonary symptoms in the absence of infectious causes and other alternative pulmonary disease and the associated clinical and radiologic improvement after its cessation suggests a causal relationship. Because the use of sirolimus in organ transplantation has become more widespread, clinicians must remain vigilant to its potential pulmonary complication.

Obesity and outcome following renal transplantation

Single institution series have demonstrated that obese patients have higher rates of wound infection and delayed graft function (DGF), but similar rates of graft survival. We used UNOS data to determine whether obesity affects outcome following renal transplantation.

Evaluation of living renal donors: The current practice of US transplant centers

To examine practice patterns regarding how living donors are evaluated and selected in the U.S., a survey was sent to all 231 United Network of Organ Sharing (UNOS)-approved transplant centers. Respondents from 75% of centers completed the questionnaire, all of whom utilize living donors for renal transplantation. Although the use of living-unrelated donors is also widely accepted (in 92% of centers), only 31% of responding centers performed such transplants in 1992, indicating a discrepancy between acceptance and actual practice. Morbidity (0.23%) and mortality (0.03%) of kidney donation continue to be low. The long-term risk of renal insufficiency in kidney donors appears to be similar to, or lower than, that in the general population. There is substantial variability in how potential donors are evaluated and what they are told regarding the risk involved in renal donation. There is also variability in exclusion criteria such as the acceptance of older donors (>55 years old); those with borderline-to-mild hypertension, and those with borderline low glomerular filtration rate. Larger centers tended to be less rigid in their exclusion criteria compared with smaller centers. While our results indicate widespread acceptance and use of living donors, they also highlight the need for future studies to examine the efficacy of tests used in the evaluation process and to determine the long-term risks of renal donation.

The effect of pravastatin on acute rejection after kidney transplantation--a pilot study.

Hyperlipidemia is an important complication of kidney transplantation affecting up to 74% of recipients. HMG-CoA reductase inhibitors are reported to provide safe and effective treatment for this problem. A recent study suggests that pravastatin, an HMG-CoA reductase inhibitor, also decreases the incidence of both clinically severe acute rejection episodes and natural killer cell cytotoxicity after orthotopic heart transplantation. We have performed a prospective randomized pilot study of the effect of pravastatin on these same parameters after cadaveric kidney transplantation. Graft recipients were randomized to receive pravastatin after transplantation or no pravastatin (24 patients in each group) in addition to routine cyclosporine and prednisone immunosuppression. Lipid levels, acute rejection episodes and serial natural killer cell cytotoxicities were followed for 4 months after the transplant. At the end of the study period, pravastatin had successfully controlled mean total cholesterol levels (202.6 +/- 9.3 vs. 236.5 +/- 11.9 mg/dl, P < 0.02), LDL levels (107.9 +/- 6.6 vs.149.6 +/- 10.7 mg/dl, P < 0.002), and triglyceride levels (118.8 +/- 14.2 vs. 157.2 +/- 13.8 mg/dl, P < 0.05). In addition, the pravastatin-treated group experienced a reduction in the incidence of biopsy-proven acute rejection episodes (25% vs. 58%, P = 0.01), the incidence of multiple rejections episodes (P < 0.05), and the use of both pulse methylprednisolone (P = 0.01) and OKT3 (P = 0.02). Mean natural killer cell cytotoxicity was similarly reduced (11.3 +/- 1.6 vs. 20.0 +/- 2.0% lysis of K562 target cells, P < 0.002). These data suggest that pravastatin exerts an additional immunosuppressive effect in kidney transplant recipients treated with cyclosporine-based immunosuppression.

The Medical Evaluation of Living Kidney Donors: A Survey of US Transplant Centers

The use of living donors for kidney transplantation in the United States is common, and long‐term studies have demonstrated the safety of donation by young, healthy individuals. However, transplant programs have little data to guide them in deciding which donors are unacceptable, and which characteristics are associated with kidney disease or poor psychosocial outcomes after donation. To document current practices in evaluating potential donors, we surveyed all US kidney transplant programs. Compared to a survey 12 years ago, medical criteria for donation are more inclusive in several areas. All responding programs now accept living unrelated donors. Most programs no longer have an upper age limit to be eligible. Programs are now more likely to accept donors with treated hypertension, or a history of kidney stones, provided that certain additional criteria are met. In contrast, medical criteria for donation are more restrictive in other areas, such as younger donor age and low creatinine clearance. Overall, significant variability remains among transplant programs in the criteria used to evaluate donors. These findings highlight the need for more data on long‐term outcomes in various types of donors with potential morbidities related to donation.

Systemic Lupus Erythematosus in Pregnancy

A retrospective analysis of the course of systemic lupus erythematosus in pregnant patients hospitalized at UCLA during a 15-year period provided important prognostic information. Women with systemic lupus erythematosus became pregnant if renal function was reasonably well preserved. Pregnancy infrequently posed a serious threat to the mother; the frequency of nonrenal complications in patients with systemic lupus erythematosus was very low, and the frequency of permanent deterioration of renal function was less than 10%. In contrast, the fetus was at high risk and was adversely affected even if mild renal involvement was detected in the mother. The prevalence of neonatal complications did not increase in the newborn; however, growth retardation did occur in the immediate neonatal period. The pharmacologic management of systemic lupus erythematosus does not require any important modifications in pregnant patients. During labor and in the postpartum period, however, an increase in the dosage of glucocorticoids may reduce postpartum exacerbations.

The Report of a National Conference on the Wait List for Kidney Transplantation

In March, 2002, over 100 members of the transplant community assembled in Philadelphia for a meeting designed to address problems associated with the growing number of patients seeking kidney transplantation and added to the waiting list each year. The meeting included representatives of nine US organizations with interests in these issues. Participants divided into work groups addressing access to the waiting list, assigning priority on the list, list management, and identifying appropriate candidates for expanded criteria donor kidneys. Each work group outlined problems and potential remedies within each area. This report summarized the issues and recommendations regarding the waiting list for kidney transplantation addressed in the Philadelphia meeting.

Human Immunodeficiency Virus (HIV) Infection and the Kidney

Since the first report on the acquired immunodeficiency syndrome (AIDS) in 1981, organ involvement of AIDS has increased. We discuss the effect of human immunodeficiency virus (HIV) infection, the causative agent of AIDS, on the field of nephrology. Hyponatremia, the commonest fluid and electrolyte abnormality, is caused by various pathophysiologic mechanisms, including adrenal insufficiency. The renal parenchymal complications are diverse, but a new entity, HIV-associated nephropathy, is becoming recognized because of its characteristic clinical and pathologic features, including the fact that it causes irreversible renal failure. HIV infection in patients with end-stage renal failure, both before and after initiation of maintenance dialysis, is a significant problem. The present methods of preventing spread of virus in dialysis units seem successful. Few patients who are infected with HIV or who have AIDS have had renal transplantation, although unsuspected viral infection of cadaveric organs remains a concern.

Outcomes of Kidney Transplantation From Older Living Donors to Older Recipients

BACKGROUND More than half the newly wait-listed patients for kidney transplantation in 2005 were older than 50 years, and 13% were older than 65 years. As waiting times for a deceased donor kidney increase, these older candidates are disadvantaged by rapidly deteriorating health, often resulting in death or removal from the wait list before transplantation. STUDY DESIGN An observational cohort study was conducted using data from the Organ Procurement Transplant Network/United Network for Organ Sharing. SETTING & PARTICIPANTS All adult kidney-only transplantations performed in recipients 60 years and older from 1996 to 2005 were included. PREDICTOR The recipient cohort was stratified into 4 groups based on donor source: older living donor (OLD: living donor age > 55 years), younger living donor (YLD: living donor age </= 55 years), standard criteria deceased donor (SCD), and expanded criteria deceased donor (ECD). OUTCOMES & MEASUREMENTS Early posttransplantation outcomes, graft survival, patient survival, renal function 1 year posttransplantation, and relative risk of graft loss and patient death were compared. RESULTS Of 23,754 kidney transplantations performed in recipients 60 years and older, 7,006 were living donor transplantations (1,133 were > 55 years [OLD] and 5,873 were <or= 55 years [YLD]), 12,197 from SCDs, and 4,551 from ECDs. Early posttransplantation outcomes were best in YLD transplantations, followed by SCD and OLD transplantations. OLD transplantations were associated with inferior 3-year graft survival rates (85.7%), but similar 3-year patient survival rates (88.4%) compared with YLD (3-year graft survival, 83.4%; patient survival, 87.4%) and had superior graft survival compared with all deceased donor options. Compared with OLD transplantations, ECD transplantations were associated with a greater risk of graft loss (hazard ratio, 2.36; 95% confidence interval, 1.18 to 4.74). LIMITATIONS Observational retrospective studies using registry data are subject to inherent limitations, including the possibility of selection bias. CONCLUSIONS With superior graft and patient survival in recipients of transplants from OLDs compared with SCDs and ECDs, OLDs may be an important option for elderly transplantation candidates and should be considered for older patients with a willing and suitable older donor.