Marie-Noelle Peraldi

Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients.

Background. Sirolimus, a promising new immunosuppressive drug for organ transplantation, is currently associated with side effects, such as thrombocytopenia and hyperlipidemia. Methods. Eight renal transplant recipients, who developed unexplained interstitial pneumonitis during sirolimus therapy, were extensively re-screened for all causes of pneumonitis. Results. Interstitial pneumonitis was constantly characterized by bilateral interstitial infiltrates on chest x-rays and lung computed tomography scans, with marked general symptoms in all patients but one. Bronchoalveolar lavage (BAL) disclosed lymphocytic alveolitis (mainly of the CD4 type) in seven patients and alveolar hemorrhage in one. Transbronchial lung biopsies, performed in two patients, showed bronchiolitis obliterans with organizing pneumonia combined with lymphocytic interstitial pneumonitis. Pulmonary infections were ruled out by specific stainings and cultures of BAL, bronchial aspirates, and blood cultures. After the elimination of all possible causes, sirolimus-induced pneumonitis was considered probable. Discontinuation of sirolimus in seven cases and dose reduction in the remaining case dramatically improved clinical and radiological status within a few weeks and led to complete resolution within 3 months. Conclusions. Sirolimus is very probably responsible for interstitial pneumonitis on the following grounds: (a) occurrence of pneumonitis during sirolimus therapy; (b) absence of any other causes; and (c) resolution within 3 months of sirolimus discontinuation or dose reduction. Sirolimus should now be added to the list of possible causes of pulmonary complications after renal transplantation. Discontinuation or dose reduction of sirolimus led to complete and lasting resolution of symptoms.

Proteinuria following a switch from calcineurin inhibitors to sirolimus

Background. Sirolimus is an alternative option for kidney transplant patients treated with calcineurin inhibitors (CNI) when renal function is deteriorating. However, the incidence of proteinuria following a switch from CNI to sirolimus has caused concern, and was therefore investigated here. Methods. In a retrospective study, 68 renal transplant recipients were switched from CNI to sirolimus. Proteinuria was measured using 24-hour urine collection before the switch and collections 3, 6, 12, and 24 months thereafter. In addition, proteinuria was measured in patients who had to be switched back to CNI due to side effects. Survival analyses were performed. Results. Baseline proteinuria was 0.39±0.69 g/day in all 68 patients. It increased to a mean 1.44±1.90 g/day at 3 months (P<0.001) and remained elevated at 6, 12 and 24 months. When sirolimus was withdrawn after the CNI-sirolimus switch for 19 patients, proteinuria decreased from 1.95±2.06 g/day to 0.9±1.4 g/day (P<0.05). Proteinuria above 0.3 g/day before the CNI-sirolimus switch correlated significantly with the decrease of renal function thereafter. Conclusion. CNI-treated kidney transplant recipients may develop reversible proteinuria when switched to sirolimus.

High Sirolimus Levels May Induce Focal Segmental Glomerulosclerosis De Novo

Sirolimus has been associated with high-range proteinuria when used in replacement of calcineurin inhibitors in renal transplant recipients with chronic allograft nephropathy (CAN). Primary FSGS was demonstrated previously in some such patients, but the coexistence of CAN lesions made the interpretation uneasy. However, nephrotic syndrome and FSGS were observed recently in three patients who received sirolimus de novo, without medical history of primary FSGS or CAN. Markers of podocyte differentiation were studied in kidney biopsies of the three patients who received sirolimus de novo and of five patients who switched to sirolimus. All patients developed FSGS lesions of classic type (not otherwise specified), but only switched patients exhibited advanced sclerotic lesions. Immunohistochemistry showed that some podocytes in FSGS lesions had absent or diminished expression of the podocyte-specific epitopes synaptopodin and p57, reflecting dedifferentiation, and had acquired expression of cytokeratin and PAX2, reflecting a immature fetal phenotype. Such a pattern of epitope expression provides evidence for podocyte dysregulation. Moreover, a decrease in vascular endothelial growth factor expression was observed in some glomeruli. In conclusion, sirolimus induces FSGS that is responsible for proteinuria in some transplant patients.

Multivariate analysis of donor risk factors for graft survival in kidney transplantation.

Background. The results of the transplantation of marginal donor kidneys remain controversial. This study aimed to investigate the impact of donor risk factors as predictors of kidney-graft outcome. Methods. Allograft failure risk factors were studied in 7,209 cadaveric kidney-transplant recipients reporting to the Etablissement français des Greffes (EfG) from 1996 to 2000, of which 544 (7.6%) were from donors aged over 60. Both univariate and multivariate analysis were used to assess the effect of donor risk factors and were stratified according to recipient age. Results. Overall graft survival was 91.1% (95% confidence interval [CI] 90.5–91.8) at 1 year, 88.6% (95% CI 87.8–89.4) at 2 years, and 85.6% (95% CI 84.6–86.6) at 3 years posttransplant. Univariate analysis of risk factors showed a significant reduction of graft survival in recipients transplanted with kidneys coming from donors older than 60 years, donors with a history of hypertension, a cerebrovascular cause of death, and a preharvesting serum creatinine greater than 150 &mgr;mol/L. Multivariate analysis revealed significantly higher failure rate associated with cerebrovascular cause of death (RR=1.2, P =0.02), history of hypertension (RR=1.2, P =0.04), and elevated serum creatinine (RR=1.3, P =0.03), whereas donor age greater than 60 years was not found as an independent risk factor. Conclusions. Our results suggest that cerebrovascular cause of death, history of hypertension, and elevated creatinine are significant independent donor risk factors for graft survival, whereas donor age is a statistically significant, but dependent, risk factor. This result is important for the design of allocation and transplantation strategies for kidneys procured in elderly donors.

Human herpes virus-8 and other risk factors for Kaposi's sarcoma in kidney transplant recipients

Background. The exact reasons for the high incidence of Kaposis sarcoma (KS) after kidney transplantation are still unknown. Immunosuppression is classically considered as the main risk factor, but the relative risk contributed by the patients geographic origin and by human herpes virus (HHV)-8 infection still has to be determined. Methods. We carried out a retrospective and a prospective study among kidney transplant recipients (TP) to identify the risk factors for posttransplantation KS. Each of 30 KS patients was matched with two controls to investigate the association with geographic origin, immunosuppressive regimen, HHV-8 antibodies before and after transplantation, and other infections. Among TP with new onset of KS, we prospectively evaluated HHV-8 serology and viremia in response to decreased immunosuppression. Results. African and Middle East origins, past infection with hepatitis B, hemoglobin level <12 g/dl, lymphocyte count <750/mm 3 at the time of diagnosis and initial use of polyclonal antilymphocyte sera were risk factors for KS. After multivariate analysis, origin in Africa or Middle East and use of antilymphocyte sera for induction remained as independent risk factors. Sixty-eight percent (17/25) of TP with HHV-8 antibodies before or after transplantation developed KS compared with 3% (1/33) of seronegative TP (P<0.00001). HHV-8 DNA was detectable in seven of nine peripheral blood mononuclear cells (PBMC) and in six of six KS lesions at diagnosis; it became negative in PBMC in three of five patients in parallel with tumor regression. Conclusion. African and Middle East geographic origins, HHV-8 infection before and after kidney transplantation, and initial use of polyclonal antilymphocyte sera were independent risk factors for KS. The presence of HHV-8 antibodies before or after transplantation was highly predictive of the emergence of posttransplantation KS and conferred a 28-fold increased risk of KS (odds ratio=28.4; 95% confidence interval: 4.9-279). Detection of HHV-8 DNA within PBMC and KS lesions seems related to tumor burden and evolution.

Prognostic Value of Quantitative Kaposi Sarcoma–Associated Herpesvirus Load in Posttransplantation Kaposi Sarcoma

Organ transplant recipients have a higher risk of Kaposi sarcoma (KS). A quantitative real-time polymerase chain reaction assay was developed to evaluate KS-associated herpesvirus (KSHV) as a prognostic tool in transplant recipients with KS. Forty-three patients who developed KS after transplantation were included in a cross-sectional study to correlate virus load with transplantation or KS parameters. Seventeen patients (40%) had KSHV viremia (>100 copies/microg of DNA; median, 6067 copies/microg of DNA). Factors associated with these levels of viremia by univariate analysis were progression of KS (P=.00002), time from KS diagnosis (P=.0007), actual stage of KS (P=.006), initial stage of KS (P=.22), graft loss (P=.013), and time from transplantation (P=.0246). Disease progression remained associated with KSHV viremia in a multivariate analysis (P=.01). Thus, quantification of KSHV load in peripheral blood mononuclear cells could represent a useful tool for monitoring transplant recipients with KS.

Renal Transplantation in HIV‐Infected Patients: The Paris Experience

Kidney transplantation is now considered as a reasonable option for HIV‐infected patients with end‐stage renal disease. We describe here a retrospective study conducted in five transplantation centers in Paris. Twenty‐seven patients were included. Immunosuppressive protocol associated an induction therapy and a long‐term treatment combining mycophenolate mofetil, steroids and either tacrolimus or cyclosporine. All the patients had protocol biopsies at 3 months and 1 year. Patients survival was 100% at 1 year and 98% at 2 years. Graft survival at 1 and 2 years is 98% and 96% at 1 and 2 years, respectively. The mean glomerular filteration rate values at 12 and 24 months were 60.6 mL/min/1.73 m2 (range 23–98) and 65.4 mL/min/1.73m2 (range 24–110), respectively. Acute cellular rejection was diagnosed in four cases (15%). Because of high trough levels of calcineurin inhibitor, protease‐inhibitor therapies were withdrawn in 11 cases. HIV disease progression was not observed. One patient developed B‐cell lymphoma.

Candida albicans arteritis transmitted by conservative liquid after renal transplantation : A report of four cases and review of the literature

Background. Mycotic arteritis and/or aneurysms are infrequent complications of renal transplantation. They are mostly secondary to bacterial infection and rarely to Candida albicans. We report four cases of mycotic arteritis due to C. albicans after renal transplantation but which have been inoculated during organ harvesting or conservation. Methods. In all the four cases corresponding to two independent donors, C. albicans was isolated few days later in the systematic culture of the conservative liquid. We also review the clinical features and outcomes of 13 cases previously reported in the literature. Results. In two cases, the diagnosis of fungal arteritis was confirmed only during autopsy after the patient’s death due to massive bleeding. In the other two cases, the diagnosis was made on the arterial section of the anastomotic wall after detransplantation for massive bleeding for arterial leakage although an immediate antifungal treatment with fluconazole and caspofungin was given and was found to be inefficient. Conclusion. This is a serious complication of renal transplantation because it leads to graft loss in the majority of the cases and even to death in a few cases despite an efficient and rapid treatment. Routine fungal cultures of preservation media are important for early diagnosis and timely surgical interventions are life-saving.

Renal cell carcinoma of the grafted kidney: how to improve screening and graft tracking.

Renal cell carcinoma of transplanted kidneys is rare. We report three such cases among 1,250 kidney grafts that were performed or followed from 1968 to 2002. A strategy to diagnose these lesions is needed because of their rarity, late detection, and therapeutic repercussions. At the least, the strategy should include annual ultrasonography of the graft throughout its lifespan. Because the risk of tumor development in another organ from the same donor is not negligible, a national registry should be established to rapidly alert graft recipients with the same donor and other transplantation centers about the risk of graft tumors.

Oxidative Stress Mediates a Reduced Expression of the Activating Receptor NKG2D in NK Cells from End-Stage Renal Disease Patients

To characterize the immune defect of patients with end-stage renal disease (ESRD), we performed NK cell subset analysis in 66 patients with ESRD treated by hemodialysis (n = 59) or peritoneal dialysis (n = 7). Compared with healthy blood donors, patients undergoing chronic dialysis showed a profound decrease in NKG2D+ cells within both the CD8+ T cell (58% vs 67%, p = 0.03) and NK cell (39% vs 56%, p = 0.002) populations. CD56dim cells, which comprise the majority of NK cells in the periphery, were more affected in this regard than were CD56bright cells. Uremic serum could decrease NKG2D expression on NK cells from healthy donors. Among factors that could contribute to the decrease in NKG2D expression in ESRD patients, reactive oxygen species (ROS) play a major role. We found that catalase could reverse the effects of uremic serum on NKG2D expression (p < 0.001) and that ROS down-regulated NKG2D at the mRNA level and at the NK cell surface. Additionally, ESRD patients had both increased membrane-bound MHC class I-related chain A (MICA) on monocytes (p = 0.04) and increased soluble MICA (203 pg/ml vs 110 pg/ml; p < 0.001). Both ROS and uremic serum could significantly increase in vitro the expression of the NKG2D ligand MICA on the renal epithelial cell line HK-2. Taken together, these studies suggest for the first time that both low NKG2D expression and up-regulation of its ligand MICA are related to ROS production and may be involved in the immune deficiency of ESRD patients.