Sophie Caillard

Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation.

Efficacy and safety of mycophenolate mofetil (MMF) may be optimized with individualized doses based on therapeutic monitoring of its active metabolite, mycophenolic acid (MPA). In this 12‐month study, 137 renal allograft recipients from 11 French centers receiving basiliximab, cyclosporine A, MMF and corticosteroids were randomized to receive either concentration‐controlled doses or fixed‐dose MMF. A novel Bayesian estimator of MPA AUC based on three‐point sampling was used to individualize doses on posttransplant days 7 and 14 and months 1, 3 and 6. The primary endpoint was treatment failure (death, graft loss, acute rejection and MMF discontinuation). Data from 65 patients/group were analyzed. At month 12, the concentration‐controlled group had fewer treatment failures (p = 0.03) and acute rejection episodes (p = 0.01) with no differences in adverse event frequency. The MMF dose was higher in the concentration‐controlled group at day 14 (p < 0.0001), month 1 (p < 0.0001) and month 3 (p < 0.01), as were median AUCs on day 14 (33.7 vs. 27.1 mg•h/L; p = 0.0001) and at month 1 (45.0 vs. 30.9 mg•h/L; p < 0.0001). Therapeutic MPA monitoring using a limited sampling strategy can reduce the risk of treatment failure and acute rejection in renal allograft recipients 12 months posttransplant with no increase in adverse events.

Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression.

Background. Posttransplant lymphoproliferative disorders (PTLD) still represent a major preoccupation after renal transplantation, even in the most recent years. Methods. We analyzed the incidence, risk, and prognostic factors of PTLD in a cohort of kidney recipients using the United States Renal Data System. Results. Among 25,127 Medicare patients transplanted between 1996 and 2000, 344 developed a PTLD defined as a non-Hodgkin lymphoma (1.4%). History of pretransplant malignancy (adjusted hazard ratio [AHR]=3.54, CI 2.31–5.43), younger age (AHR=1.91, CI 1.18–3.1), fewer HLA matches (AHR=1.32, CI 1.1–1.59) and treatment by ATG (AHR=1.55, CI 1.2–1.99) and OKT3 (AHR=1.37, CI 1–1.76), especially if given for rejection therapy were associated with an increased risk of PTLD. Mycophenolate and azathioprine were associated with a lower risk of PTLD (AHR=0.6, CI 0.47–0.78 and AHR=0.66, CI 0.46–0.95, respectively). IL2-receptor inhibitors and sirolimus did not modify the risk of PTLD. Patients without induction therapy treated with tacrolimus were at greater risk of lymphoma than those treated with new formulations of cyclosporine and those treated with antimetabolites (mycophenolate and azathioprine) have a lower risk of PTLD than those without. Patients with PTLD had poor survival (64% vs. 80% at 5 years). Older age, pretransplant malignancy and OKT3 were risk factors for death whereas treatment with mycophenolate was associated with a better survival (AHR=0.49, CI=0.28–0.82). Conclusions. Our study highlights the contribution of patient history and immunosuppression in the risk of PTLD in the era of modern immunosuppression.

Pregnancy-Associated Hemolytic Uremic Syndrome Revisited in the Era of Complement Gene Mutations

In contrast to pregnancy-associated thrombotic thrombocytopenic purpura, the pathogenesis and presentation of pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS) remain ill-defined. We conducted a retrospective study to assess the presentation and outcomes of patients presenting with P-aHUS and the prevalence of alternative C3 convertase dysregulation. P-aHUS occurred in 21 of the 100 adult female patients with atypical HUS, with 79% presenting postpartum. We detected complement abnormalities in 18 of the 21 patients. The outcomes were poor: 62% reached ESRD by 1 month and 76% by last follow-up. The risk for P-aHUS was highest during a second pregnancy. Thirty-five women, 26 (74%) of whom had complement abnormalities, had at least one pregnancy before the onset of a non-pregnancy-related aHUS. Outcomes did not differ between patients with pregnancy-related and non-pregnancy-related aHUS. Mutations in the SCR19-20 domains of factor H were less frequent in P-aHUS patients compared with non-pregnancy-related aHUS. Pregnancies in female patients with complement abnormalities (n = 44) were complicated by fetal loss and preeclampsia in 4.8% and 7.7%, respectively. Better understanding of complement dysregulation in pregnancy complications is essential, especially to guide development of pharmacologic agents to modulate this system.

Sirolimus Versus Cyclosporine in Kidney Recipients Receiving Thymoglobulin®, Mycophenolate Mofetil and a 6-Month Course of Steroids

To evaluate the efficacy and tolerance of a calcineurin inhibitor (CNI)‐free regimen, 145 renal recipients were prospectively randomized to receive either sirolimus (n = 71) or cyclosporine (CsA; n = 74). All patients received polyclonal antilymphocyte antibodies, mycophenolate mofetil (MMF) and steroids (6 months). The primary endpoint, estimated glomerular filtration rate (eGFR) was not significantly different at 12 months comparing sirolimus‐ and CsA‐treated patients (60 ± 27 vs. 57 ± 21 mL/min). At 12 months, patient and graft survival, incidence of biopsy‐proven rejection and rates of steroid withdrawal were not statistically different (97% vs. 97%; 90% vs. 93%; 14.3% vs. 8.6% and 82.8% vs. 84.1%, respectively). Delayed and slow graft function (SGF) was not significantly different (18.6% vs. 12.3% and 11.4% vs. 13.7%, respectively). In patients who remained on treatment according to protocol at 12 months, eGFR was significantly higher with sirolimus (69 ± 19 vs. 60 ± 14 mL/min, p = 0.01). Overall study drug discontinuation rates were 28.2% with sirolimus and 14.9% with CsA. Adverse events (wound complications, mouth ulcers, diarrhea, hypokalemia, bronchopneumonia) and proteinuria >0.5 g/24h (38.8% vs. 5.6%, p < 0.001) were significantly more frequent in sirolimus‐treated patients. Cytomegalovirus (CMV) infections were significantly less frequent with sirolimus (6% vs. 23%, p < 0.01). A CNI‐free regimen using sirolimus‐MMF can achieve excellent renal function, but patients on sirolimus experienced a high rate of adverse events and study drug discontinuation.

Cardiovascular Mortality in Chronic Kidney Disease Patients Undergoing Percutaneous Coronary Intervention Is Mainly Related to Impaired P2Y12 Inhibition by Clopidogrel

OBJECTIVES We sought to determine whether low platelet response to the P2Y(12) receptor antagonist clopidogrel as assessed by vasodilator-stimulated phosphoprotein flow cytometry test (VASP-FCT) differentially affects outcomes in patients with or without chronic kidney disease (CKD) undergoing percutaneous coronary intervention (PCI). BACKGROUND Although both CKD and impaired platelet responsiveness to clopidogrel are strong predictors of unfavorable outcome after PCI, the impact of their association is unknown. The platelet VASP-FCT assay is specific for the P2Y(12) ADP receptor pathway. In this test, platelet activation is expressed as the platelet reactivity index (PRI). METHODS Four-hundred forty unselected patients (CKD: 126, estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m(2)), no-CKD: 314 eGFR >60 ml/min/1.73 m(2)) undergoing urgent (n = 336) or planned (n = 104) PCI were prospectively enrolled. In each subgroup, patients were classified as low-responders (LR: PRI ≥ 61%) or responders (R: PRI <61%) to clopidogrel. RESULTS At a mean follow-up of 9 ± 2 months, all-cause mortality, cardiac death, and possible stent thrombosis were higher in CKD than in no-CKD patients. Within the CKD group, the LR status was associated with higher rates of all-cause mortality (25.5% vs. 2.8%, p < 0.001), cardiac death (23.5% vs. 2.8%, p < 0.001), all stent thrombosis (19.6% vs. 2.7%, p = 0.003), and MACE (33.3% vs. 12.3%, p = 0.007). Conversely, in no-CKD patients, the LR status did not affect outcomes. Multivariate analysis identified Killip class ≥ 3, drug-eluting stent implantation, and the interaction between LR and CKD (hazard ratio: 11.96, 95% confidence interval: 1.22 to 116.82; p = 0.033) as independent predictors of cardiac death. CONCLUSIONS In CKD patients, the presence of low platelet response to clopidogrel is associated with worse outcomes after PCI.

Primary brain lymphomas after kidney transplantation: presentation and outcome.

Background. Non-Hodgkin’s lymphoma is the second most frequent neoplasia following solid-organ transplantation. The objective of this study is to describe the clinical, histologic, and radiologic features of primary posttransplantation brain lymphomas (PTBL) in addition to their outcome. Methods. Twenty-five kidney transplant patients with histologically proven PTBL from 11 French centers were retrospectively investigated. Results. Immunosuppressive regimen included induction with antithymocyte globulins (ATG) in 20 patients. Median overall delay between transplantation and lymphoma was 18 months (4–264). Six of 10 patients with late posttransplantation brain lymphomas (PTBL) occurrence (>3 years) had been recently switched from azathioprine to mycophenolate mofetil (median switch lymphoma delay 14 months). Cerebral computed tomography (CT) scans and magnetic resonance imaging (MRI) revealed multifocal lesions (n=18), with a ring contrast enhancement (n=20) similar to cerebral abscesses, as observed in HIV-related brain lymphomas. Histology showed large B-cell non-Hodgkin’s lymphoma in 87.5% of cases; Epstein-Barr virus (EBV) was detected in 95%. After lymphoma diagnosis, immunosuppressive treatment was reduced in all patients, and all but one received complementary treatment by surgery (n=2), anti-CD21 antibodies (n=2), chemotherapy including high-dose intravenous methotrexate (n=7), encephalic radiotherapy (n=5), or chemotherapy plus radiotherapy (n=8). Median overall survival was 26 months. Patients with a radiotherapy-based regimen seemed to have a longer survival (36 vs. 7 months, P <0.005). Conclusions. Our study showed that PTBL are EBV-induced large B-cell lymphomas, which mimic cerebral abscesses on imaging and whose occurrence may be influenced by immunosuppression modifications. Treatment by radiotherapy is associated with better survival.

Epidemiology of Posttransplant Lymphoproliferative Disorders in Adult Kidney and Kidney Pancreas Recipients: Report of the French Registry and Analysis of Subgroups of Lymphomas

A registry of posttransplant lymphoproliferative disorders (PTLD) was set up for the entire population of adult kidney transplant recipients in France. Cases of PTLD were prospectively enrolled between January 1, 1998, and December 31, 2007. Ten‐year cumulative incidence was analyzed in patients transplanted after January 1, 1989. PTLD risk factors were analyzed in patients transplanted after January 1, 1998 by Cox analysis. Cumulative incidence was 1% after 5 years, 2.1% after 10 years. Multivariate analysis showed that PTLD was significantly associated with: older age of the recipient 47–60 years and >60 years (vs. 33–46 years, adjusted hazard ratio (AHR) = 1.87, CI = 1.22–2.86 and AHR = 2.80, CI = 1.73–4.55, respectively, p < 0.0001), simultaneous kidney–pancreas transplantation (AHR = 2.52, CI = 1.27–5.01 p = 0.008), year of transplant 1998–1999 and 2000–2001 (vs. 2006–2007, AHR = 3.36, CI = 1.64–6.87 and AHR = 3.08, CI = 1.55–6.15, respectively, p = 0.003), EBV mismatch (HR = 5.31, CI = 3.36–8.39, p < 0.001), 5 or 6 HLA mismatches (vs. 0–4, AHR = 1.54, CI = 1.12–2.12, p = 0.008), and induction therapy (AHR = 1.42, CI = 1–2.02, p = 0.05). Analyses of subgroups of PTLD provided new information about PTLD risk factors for early, late, EBV positive and negative, polymorphic, monomorphic, graft and cerebral lymphomas. This nationwide study highlights the increased risk of PTLD as long as 10 years after transplantation and the role of cofactors in modifying PTLD risk, particularly in specific PTLD subgroups.

Dementia as a Predictor of Mortality in Dialysis Patients

The life expectancy of patients who have dementia and are initiated on dialysis in the United States has not been described in the medical literature. A retrospective cohort study was conducted of 272,024 Medicare/Medicaid primary patients in the US Renal Data System who were started on ESRD therapy between April 1, 1995, and December 31, 1999, and followed through December 31, 2001. Cox regression was used to calculate adjusted hazard ratios for risk for death after initiation of dialysis for patients whose dementia was diagnosed before the initiation of dialysis as shown by Medicare claims. The average time to death for patients with dementia was 1.09 versus 2.7 yr (P < 0.001) with an adjusted hazard ratio of 1.87 (95% confidence interval 1.77 to 1.98). The 2-yr survival for patients with dementia was 24 versus 66% for patients without dementia (P < 0.001 via log rank test). Dementia that is diagnosed before initiation on dialysis is an independent risk factor for subsequent death. Such patients should be considered for time-limited trials of dialysis and careful discussion in choosing whether to pursue initiation of dialysis or palliative care.

Myeloma, hodgkin disease, and lymphoid leukemia after renal transplantation : Characteristics, risk factors and prognosis

Background. Hodgkin disease and myeloma were recently included in the classification of posttransplant lymphoproliferative disorder (PTLD). However, because their incidence is low, not much is known about their particular features. Methods. The incidence, characteristics, risk, and prognostic factors of myeloma, Hodgkin disease, and lymphoid leukemia using the United States Renal Data System from 1991 to 2000 among 66,159 Medicare patients were analyzed. Results. In all, 1,169 recipients developed a lymphoid disease: 823 (1.2%) non-Hodgkins lymphomas (NHL), 160 (0.24%) myelomas, 60 (0.1%) Hodgkin lymphomas, and 126 (0.2%) lymphoid leukemias. Older age was associated with an increased risk of myeloma and leukemia. The incidence of hepatitis C virus infection was higher in recipients with myeloma (6.9 vs. 3.9%, P=0.05). Induction therapy was associated with a greater risk of myeloma and leukemia, but not Hodgkin disease. Azathioprine was associated with a lower risk of myeloma, and tacrolimus with a lower risk of Hodgkin disease. According to the type of malignancy, ten-year survival rates were significantly different: 42, 26, 55 and 39% respectively for NHL, myeloma, Hodgkin disease, and leukemia. Conclusion. These results support specific features and risk factors related to the occurrence of each type of lymphoid-proliferation and suggest for the first time a possible association between hepatitis C virus and myeloma in kidney transplant recipients.

Persistent Hyperparathyroidism Is a Major Risk Factor for Fractures in the Five Years After Kidney Transplantation

The risk of fractures after kidney transplantation is high. Hyperparathyroidism frequently persists after successful kidney transplantation and contributes to bone loss, but its impact on fracture has not been demonstrated. This longitudinal study was designed to evaluate hyperparathyroidism and its associations with mineral disorders and fractures in the 5 posttransplant years. We retrospectively analyzed 143 consecutive patients who underwent kidney transplantation between August 2004 and April 2006. The biochemical parameters were determined at transplantation and at 3, 12 and 60 months posttransplantation, and fractures were recorded. The median intact parathyroid hormone (PTH) level was 334 ng/L (interquartile 151–642) at the time of transplantation and 123 ng/L (interquartile 75–224) at 3 months. Thirty fractures occurred in 22 patients. The receiver operating characteristic (ROC) curve analysis for PTH at 3 months (area under the ROC curve = 0.711, p = 0.002) showed that a good threshold for predicting fractures was 130 ng/L (sensitivity = 81%, specificity = 57%). In a multivariable analysis, independent risk factors for fracture were PTH >130 ng/L at 3 months (adjusted hazard ratio [AHR] = 7.5, 95% CI 2.18–25.50), and pretransplant osteopenia (AHR = 2.7, 95% CI 1.07–7.26). In summary, this study demonstrates for the first time that persistent hyperparathyroidism is an independent risk factor for fractures after kidney transplantation.