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American Journal of Transplantation 05/2013; 13(5):1367-8. · 6.39 Impact Factor
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ABSTRACT: The specificity of chronic histological lesions induced by calcineurin inhibitors (CNI) is often questioned, but few studies have directly compared long-term lesions in renal-transplant patients who received this treatment and those who did not. We therefore conducted a retrospective study of 141 kidney-transplant recipients treated with (n = 48) or without (n = 93) cyclosporine (CsA) to compare the histological lesions observed at 3-month, 24-month and 10-year protocol biopsies. All of the chronic elementary lesions (glomerulosclerosis, interstitial fibrosis, tubular atrophy, arteriolar hyalinosis, fibrointimal thickening) progressed in frequency and severity in both groups, although significantly more in the CsA group. Ten-year biopsy results showed that 92% of patients in the CsA-treated group and 65% in the control group had arteriolar hyalinosis lesions. When we focused on muscular arteriolar hyaline deposits more specific to CsA arteriolopathy, we observed these lesions in 68% of CsA patients and 28% of patients who had never received CsA. CsA was not the sole factor involved in the development of arteriolar hyalinosis and was independently associated with an increased risk of graft loss. In summary, we observed that histological lesions commonly attributed to CsA nephrotoxicity were not sufficiently specific to definitively diagnose CNI nephrotoxicity.
American Journal of Transplantation 08/2011; 11(12):2635-46. · 6.39 Impact Factor
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A Servais,
V Meas-Yedid,
L H Noël,
F Martinez,
C Panterne, H Kreis,
J Zuber,
M O Timsit,
Ch Legendre,
J C Olivo-Marin,
E Thervet
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ABSTRACT: Screening renal biopsies (RB) may assess early changes of interstitial fibrosis (IF) after transplantation. The aim of this study was to quantify IF by automatic color image analysis on sequential RB. We analyzed RB performed at day (D) 0, month (M) 3 and M12 from 140 renal transplant recipients with a program of color segmentation imaging. The mean IF score was 19 ± 9% at D0, 27 ± 11% at M3 and 32 ± 11% at M12 with a 8% progression during the first 3 months and 5% between M3 and M12. IF at M3 was correlated with estimated glomerular rate (eGFR) at M3, 12 and 24 (p < 0.02) and IF at M12 with eGFR at M12 and 48 (p < 0.05). Furthermore, IF evolution between D0 and M3 (ΔIFM3-D0) was correlated with eGFR at M24, 36 and 48 (p < 0.03). IF at M12 was significantly associated with male donor gender and tacrolimus dose (p = 0.03). ΔIFM3-D0 was significantly associated with male donor gender, acute rejection episodes (p = 0.04) and diabetes mellitus (p = 0.02). Thus, significant IF is already present before transplantation. IF evolution is more important during the first 3 months and has some predictive ability for change in GFR. Intervention to decrease IF should be applied early, i.e. before 3 months, after transplantation.
American Journal of Transplantation 06/2011; 11(7):1456-63. · 6.39 Impact Factor
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ABSTRACT: Jean Hamburger, one of the pioneers of scientific medicine in the mid-20th century, who was involved in the inception of intensive care, nephrology, hemodialysis and scientific clinical research, has also been one of the very few fathers of human organ transplantation. He was involved in the primary French kidney transplantations in 1950, and in 1952, he realized the first allotransplantation in the world of a kidney removed from a voluntary living donor. At the same time, he was the first to describe the various clinical and pathological aspects of acute rejection. He suggested the use of cortisone for the treatment of rejection as early as 1950 and promoted nonlethal body irradiation, which was successfully used in 1959 both by John Merrill in Boston and by himself in Paris, to prevent allograft rejection. In October 1962, in collaboration with Maurice Goulon, he was the first to use a kidney removed from an individual in 'coma dépassé'. He and his group contributed to transplant immunosuppression, to transplant immunology, to organ preservation, to acute and chronic rejection pathology and so on. As early as 1956-1957, he understood the potential importance of Jean Dausset's discovery for transplantation.
American Journal of Transplantation 11/2010; 10(11):2392-5. · 6.39 Impact Factor
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G Canaud,
F Bienaimé,
L-H Noël,
V Royal,
M-A Alyanakian,
M-D Dautzenberg,
M Rabant,
J Posson,
E Thervet,
D Anglicheau, H Kreis,
F Martinez,
C Legendre,
J Zuber
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ABSTRACT: The impact of antiphospholipid antibodies (APA) on clinical outcome and graft histology following renal transplantation remains poorly known and controversial. We retrospectively explored the functional and histological significance of APA, primarily lupus anticoagulant (LA), in kidney transplant recipients using a systematic evaluation of 3- and 12-month posttransplant screening biopsies and glomerular filtration rate measurements (mGFR). During the study period, 37 patients had APA (2.7%), primarily LA, and 12 fulfilled antiphospholipid syndrome (APS) diagnostic criteria (0.8%) at the time of transplantation. Early after transplantation, 4 of the 12 APS patients died. Early thrombosis of graft vessels and deep venous thrombosis occurred more frequently in APA+ patients than in controls (27% vs. 7%, p < 0.05 and 35% vs. 14%, p < 0.05, respectively). The survival rate was significantly lower in patients with APS. Strikingly, the hallmark lesions of APS-associated nephropathy (APSN) were found in most of screening graft biopsies in APA+ patients but not in the controls. Accordingly, APA+ patients had a dramatic increase in chronic vascular scores and a faster decline in mGFR at 1 year. In conclusion, renal transplantation may be life-threatening in APS patients, and the presence of LA at the time of transplantation is associated with a high rate of allograft APSN and poor transplantation outcomes.
American Journal of Transplantation 09/2010; 10(9):2051-60. · 6.39 Impact Factor
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Ch Legendre, H Kreis,
F Martinez,
R Snanoudj,
M F Mamzer,
R Sberro,
L Bererhi,
D Anglicheau,
J Zuber,
A Loupy,
E Thervet,
N Pallet,
A Sartorius,
D Bertrand,
G Canaud,
L H Noël,
M Rabant,
M O Timsit,
A Méjean
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ABSTRACT: The results of our last 5 years activity in kidney transplantation clearly show that it is possible to perform high-risk transplantations with very acceptable results: ECD kidneys, dual transplantation, recipients with DSAs. In depth statistical analysis of these data should allow a clearer definition of the best strategies to use in these situations.
Clinical transplants 01/2010;
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R Snanoudj,
M Rabant,
M O Timsit,
A Karras,
E Savoye,
L Tricot,
A Loupy,
C Hiesse,
J Zuber, H Kreis,
F Martinez,
E Thervet,
A Méjean,
T Lebret,
C Legendre,
M Delahousse
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ABSTRACT: It has been suggested that dual kidney transplantation (DKT) improves outcomes for expanded criteria donor (ECD) kidneys. However, no criteria for allocation to single or dual transplantation have been assessed prospectively. The strategy of DKT remains underused and potentially eligible kidneys are frequently discarded. We prospectively compared 81 DKT and 70 single kidney transplant (SKT) receiving grafts from ECD donors aged >65 years, allocated according to donor estimated glomerular filtration rate (eGFR): DKT if eGFR between 30 and 60 mL/min, SKT if eGFR greater than 60 mL/min. Patient and graft survival were similar in the two groups. In the DKT group, 13/81 patients lost one of their two kidneys due to hemorrhage, arterial or venous thrombosis. Mean eGFR at month 12 was similar in the DKT and SKT groups (47.8 mL/min and 46.4 mL/min, respectively). Simulated allocation of kidneys according to criteria based on day 0 donor parameters such as those described by Remuzzi et al., Andres et al. and UNOS, did not indicate an improvement in 12-month eGFR compared to our allocation based on donor eGFR.
American Journal of Transplantation 11/2009; 9(11):2542-51. · 6.39 Impact Factor
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L Zafrani,
L Truffaut, H Kreis,
D Etienne,
C Rafat,
S Lechaton,
D Anglicheau,
J Zuber,
M Ciroldi,
E Thervet,
R Snanoudj,
M F Mamzer,
F Martinez,
M O Timsit,
L Bergougnoux,
C Legendre
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ABSTRACT: Neutropenic episodes in kidney transplant patients are poorly characterized. In this retrospective study, neutropenia was experienced by 112/395 patients (28%) during the first year posttransplant. The only factor found to be significantly associated with the occurrence of neutropenia was combined tacrolimus-mycophenolate therapy (p < 0.001). Neutropenic patients experienced more bacterial infections (43% vs. 32%, p = 0.04). Grade of neutropenia correlated with the global risk of infection. Discontinuation of mycophenolic acid (MPA) due to neutropenia was associated with an increased incidence of acute rejection (odds ratios per day 1.11, 95% confidence intervals 1.02-1.22) but not with reduced renal function at 1 year. The time from onset of neutropenia to MPA discontinuation correlated with the duration of neutropenia. Granulocyte colony-stimulating factor (G-CSF) administration was safe and effective in severely neutropenic kidney graft recipients, with absolute neutrophil count >1000/microL achieved in a mean of 1.5+/-0.5 days. Neutropenia is an important and frequent laboratory finding that may exert a significant influence on outcomes in kidney transplantation. As well as leading to an increased incidence of infection, it is associated with a higher rate of allograft rejection if MPA is discontinued for >6 days (p = 0.02). G-CSF accelerates recovery of neutropenia and may be a good therapeutic alternative for severely neutropenic patients.
American Journal of Transplantation 06/2009; 9(8):1816-25. · 6.39 Impact Factor
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J Zuber,
D Anglicheau,
C Elie,
L Bererhi,
M-O Timsit,
M-F Mamzer-Bruneel,
M Ciroldi,
F Martinez,
R Snanoudj,
C Hiesse, H Kreis,
F Eustache,
K Laborde,
E Thervet,
C Legendre
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ABSTRACT: Assessment of sex hormones in organ transplant recipients suggests that sirolimus may impair testicular function. The aim of this study was to evaluate the frequency and severity of sirolimus-associated alterations in sperm parameters and their impact on fathered pregnancy rate. An observational study was carried out in male patients aged 20-40 years who received a kidney transplant during 1995-2005. Patients were sent a questionnaire by post, and sperm analysis was proposed. The fathered pregnancy rates according to the immunosuppressive regimen were estimated and compared using the Poisson model. Complete information was obtained from 95 out of 116 recipients. Patients treated with sirolimus throughout the post-transplant period had a significantly reduced total sperm count compared to patients who did not receive sirolimus (28.6 +/- 31.2 x 10(6) and 292.2 +/- 271.2 x 10(6), respectively; p = 0.006), and a decreased proportion of motile spermatozoa (22.2 +/- 12.3% and 41.0 +/- 14.5%, p = 0.01). Moreover, the fathered pregnancy rate (pregnancies/1000 patient years) was 5.9 (95% CI, 0.8-42.1) and 92.9 (95% CI, 66.4-130.0) in patients receiving sirolimus-based and sirolimus-free regimens, respectively (p = 0.007). Of six patients in whom sirolimus treatment was interrupted, only three showed a significant improvement in sperm parameters. Sirolimus is associated with impaired spermatogenesis and, as a corollary, may reduce male fertility.
American Journal of Transplantation 06/2008; 8(7):1471-9. · 6.39 Impact Factor
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J M Morales,
J M Campistol, H Kreis,
G Mourad,
J Eris,
F P Schena,
J M Grinyo,
G Nanni,
A Andres,
N Castaing,
Y Brault,
J T Burke
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ABSTRACT: This open-label, phase 3b, extension trial in renal transplant recipients (Sirolimus Study 311) assessed the long-term safety of sirolimus (SRL) administered with cyclosporine (CsA) (SRL + CsA group, n = 98) or without CsA (SRL group, n = 69). Renal transplant recipients who had either completed one of seven previous SRL studies sponsored by Wyeth Research or had participated for > or =3 months and reached a protocol-designated endpoint were eligible for enrollment. Data were available for 167 patients, all of whom initially received steroids. Mean total SRL exposure was 1526 days, including previous study participation. After enrollment in the extension study, there were significantly more acute rejections in the SRL + CsA group (6.1% vs 0%, P < .05). Differences in rates of graft loss (3.1% vs 1.4%) and death (6.1% vs 1.4%) were not significantly different between SRL + CsA and SRL groups, respectively. At 48 months after transplantation, calculated GFR (53.4 vs 70.9 mL/min) and hemoglobin (124.9 vs 136.6 g/L) were significantly better in the SRL group. Lipid values were not significantly different between groups at 48 months. The incidence of treatment-emergent increased creatinine, anemia, hypertension, headache, epistaxis, abnormal kidney function, and upper respiratory infection were significantly higher in the SRL + CsA group, whereas no adverse events were significantly higher in the SRL group. Malignancies were reported more frequently (11.2% vs 0%) with SRL + CsA. Results from this extension study indicate that SRL-based therapy without CsA is a safe alternative to combination therapy with CsA, offering long-term improvement in renal function with no increased risk of late acute rejection.
Transplantation Proceedings 04/2005; 37(2):693-6. · 1.00 Impact Factor
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ABSTRACT: Postransplant lymphoproliferative disorders are well known complications of solid organ transplant, usually associated with Epstein-Barr virus (EBV).
A 25 year old renal transplant patient presented with two subcutaneous nodules on the lower limb that appeared 3 years after a second renal transplantation. Biopsy of one nodule showed an EBV associated plasmocytoma located in the subcutaneous tissue. A complete systemic evaluation showed no evidence of extracutaneous involvement. The patient was treated with anti CD20 therapy (rituximab), and complete remission was achieved.
Extranodular localisations of postransplant lymphoproliferative disorders are usually reported, but cutaneous localizations are rarely described. Histological presentation are various, but plasmocytoma-type is infrequent. Initial therapy of cutaneous EBV-associated postransplant lymphoproliferative disorders without extracutaneous involvement consists in reduction of the immunosuppression therapy and/or an antiviral treatment and prolonged surveillance. Treatment with monoclonal anti-CD20 antibodies (rituximab) is proposed.
Annales de Dermatologie et de Vénéréologie 01/2005; 131(12):1081-4. · 0.72 Impact Factor
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ABSTRACT: Opportunistic infection is a major threat to immunocompromised patients. However, infection due to Mycobacterium xenopi is rare in renal transplant recipients. We report two new cases of M. xenopi pulmonary infection (one case of interstitial pneumopathy and one of a pulmonary nodule) in renal transplant recipients, detected in the same center at an interval of a few months. Both patients were on an immunosuppressive regimen including a recent switch to sirolimus. Sirolimus is a new immunosuppressive drug already known to be responsible for interstitial pneumonitis. It also inhibits interleukin-12-induced proliferation of activated T lymphocytes, which is critical for the development of the cell-mediated immunity that protects against mycobacteria. These two case reports suggest that sirolimus therapy may lead to an impairment of the immune response against intracellular pathogens such as M. xenopi.
Transplant Infectious Disease 01/2005; 6(4):179-82. · 2.22 Impact Factor
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Transplantation Proceedings 06/2003; 35(3 Suppl):52S-57S. · 1.00 Impact Factor
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B Charpentier,
C G Groth,
L Bäckman,
J-M Morales,
R Calne, H Kreis,
P Lang,
J-L Touraine,
K Claesson,
J M Campistol,
D Durand,
L Wramner,
C Brattström
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ABSTRACT: In 11 European centers, first cadaveric renal allograft recipients were randomized to CsA (n = 42) or sirolimus (n = 41). Dosing of these agents was concentration-controlled and open-labeled. All patients received corticosteroids and azathioprine. At 12 months, graft survival (98% sirolimus vs 93% CsA), patient survival (100% vs 98%), and incidence of biopsy-confirmed acute rejection (41% vs 38%) were similar. Serum creatinine was lower with sirolimus, significantly (P </=.05) so at 3 and 4 months, and serum uric acid and magnesium were normal. Laboratory abnormalities were reported significantly more often with sirolimus, which included hypertriglyceridemia (51% vs 12%), hypercholesterolemia (44% vs 14%), thrombocytopenia (37% vs 0%), leukopenia (39% vs 14%), and, of lesser importance, increased liver enzymes and hypokalemia. These abnormalities improved 2 months after transplantation when the sirolimus target trough level was lowered from 30 to 15 ng/mL. Occurrence of cytomegalovirus was comparable (14% vs 12%), but incidence of herpes simplex (24% vs 10%, P =.08) and pneumonia (17% vs 2%, P =.03) were higher with sirolimus. No gingival hyperplasia was seen with sirolimus, tremor was rare, and hypertension was less frequent (17% vs 33%). Two malignancies were observed with CsA, none with sirolimus. Results at 12 months suggest that sirolimus can be used as base therapy in the prophylaxis of acute renal transplant rejection, and has a safety profile that differs from that of CsA.
Transplantation Proceedings 05/2003; 35(3 Suppl):58S-61S. · 1.00 Impact Factor
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ABSTRACT: To determine whether bolus doses of methylprednisolone affect the steady-state trough concentrations of sirolimus.
Fourteen renal transplant recipients received concentration-controlled sirolimus therapy in combination with azathioprine and steroids (n=8) or mycophenolate mofetil and steroids (n=6). Bolus doses of methylprednisolone (mean total dose over 1-5 days, 1694 mg; range, 500-3000 mg) were given for the treatment of acute rejection. For each patient, the sirolimus dose (mean, 24.1 mg; range, 3.3-52.5 mg) was the same before and during methylprednisolone therapy.
Mean sirolimus whole blood trough concentrations before and after treatment with methylprednisolone were 28.8 ng ml-1 (range, 13.9-45.3 ng ml-1), and 28.5 ng ml-1 (range, 13.0-47.9 ng ml-1), respectively (P=0.85; 95% confidence interval on the difference -3.3, 4.0 ng ml-1).
Bolus methylprednisolone treatment does not affect steady-state sirolimus trough concentrations.
British Journal of Clinical Pharmacology 08/2002; 54(1):65-8. · 2.96 Impact Factor
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ABSTRACT: Sirolimus, a promising new immunosuppressive drug for organ transplantation, is currently associated with side effects, such as thrombocytopenia and hyperlipidemia.
Eight renal transplant recipients, who developed unexplained interstitial pneumonitis during sirolimus therapy, were extensively re-screened for all causes of pneumonitis.
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.
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.
Transplantation 10/2001; 72(5):787-90. · 4.00 Impact Factor
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Transplantation 09/2001; 72(5):773-774. · 4.00 Impact Factor
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ABSTRACT: This study evaluated whether cyclosporine (CsA) could be eliminated from a sirolimus (Rapamune, rapamycin, SRL)-CsA-steroid (ST) regimen at 3 months.
This was an open-label study conducted in Europe, Australia, and Canada. Upon enrollment, 525 primary (90%) or secondary (10%) renal allograft recipients with cadaveric (89%) or living (11%) donors received 2 mg of sirolimus (troughs>5 ng/ml), CsA, and steroids. At 3 months+/-2 weeks, eligible patients were randomized (1:1) to remain on SRL-CsA-ST or to have CsA withdrawn and therapy continued with SRL (troughs 20-30 ng/ml)-ST.
At 12 months, overall graft and patient survival were 89.1% and 94.9%, respectively. In the 430 (82%) randomized patients, there was no difference in graft survival (95.8% vs. 97.2%, SRL-CsA-ST vs. SRL-ST) or patient survival (97.2% vs. 98.1%, respectively). The incidence of biopsy-confirmed primary acute rejection was 13.1% during the prerandomization period. After randomization, the acute rejection rates were 4.2% and 9.8% for SRL-CsA-ST and SRL-ST, respectively (P=0.035). Renal function (calculated glomerular filtration rate, 57 vs. 63 ml/min, P<0.001) and blood pressure significantly improved when CsA was withdrawn. Hypertension, CsA nephrotoxicity, hyperuricemia, and Herpes zoster occurred statistically more frequently in patients remaining on CsA, whereas thrombocytopenia, abnormal liver function tests, and hypokalemia were reported more often for SRL-ST therapy.
Sirolimus, CsA, and steroids for 3 months posttransplant, followed by elimination of CsA, is a safe and effective alternative to continuous therapy with sirolimus, CsA, and steroids that can result in better renal function and lower blood pressure.
Transplantation 09/2001; 72(5):777-86. · 4.00 Impact Factor
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ABSTRACT: Human apolipoprotein (apo) AIV might play a role in post-transplant reverse cholesterol transport, which appears to be comparable to that seen in healthy subjects. However, there may be subtle differences between healthy individuals and renal transplant recipients, given the other abnormalities of lipoprotein metabolism in the latter. Therefore, the aim of the present study was to investigate possible changes of serum apo AIV levels in renal transplant recipients, and to evaluate potential factors influencing these levels.
Total and free serum apo AIV was determined in 36 clinically stable renal transplant recipients and in 20 sex- and age-matched healthy control subjects.
Mean total serum apo IV concentrations (+/- SD) were significantly higher in renal transplant recipients than in control subjects (202 +/- 102 vs 79 +/- 45 mg/l, p < 0.01). The percentage of lipoprotein-free fractions of apo AIV was comparable in both groups. The elevated total serum concentrations of apo AIV were mainly related to creatinine clearance and partially to serum triglyceride levels in renal transplant recipients.
Our data suggest that the observed elevation of serum apo AIV concentrations in renal transplant recipients is essentially related to the presence of impaired renal function.
Clinical nephrology 03/2001; 55(2):156-8. · 1.17 Impact Factor
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Nephrology Dialysis Transplantation 02/2001; 16(1):18-20. · 3.40 Impact Factor
