Characteristics of T- and NK-cell Lymphomas After Renal Transplantation: A French National Multicentric Cohort Study.

BACKGROUND: Posttransplant lymphoproliferative disorders (PTLDs) encompass a spectrum of heterogeneous entities. Because the vast majority of cases PTLD arise from B cells, available data on PTLD of T or NK phenotype (T/NK-cell PTLD) are scarce, which limits the quality of the management of these patients. METHODS: All adult cases of PTLD diagnosed in France were prospectively recorded in the national registry between 1998 and 2007. Crosschecking the registry data with 2 other independent national databases identified 58 cases of T/NK-cell PTLD. This cohort was then compared with (i) the 395 cases of B-cell PTLD from the registry, and of (ii) a cohort of 148 T/NK-cell lymphomas diagnosed in nontransplanted patients. RESULTS: T/NK-cell PTLD occurred significantly later after transplantation and had a worse overall survival than B-cell PTLD. Two subtypes of T/NK-cell PTLD were distinguished: (i) cutaneous (28%) and (ii) systemic (72%), the latter being associated with a worse prognosis. Compared with T/NK-cell lymphomas of nontransplanted patients, overall survival of systemic T/NK-cell PTLD was worse (hazard ratio: 2.64 [1.76-3.94]; P < 0.00001). CONCLUSIONS: This difference, which persisted after adjustment on tumoral mass, histological subtype, and extension of the disease at diagnosis could be explained by the fact that transplanted patients were less intensively treated and responded less to chemotherapy.

New clinical forms of hereditary apoA-I amyloidosis entail both glomerular and retinal amyloidosis.

Apolipoprotein A1 amyloidosis (ApoAI) results from specific mutations in the APOA1 gene causing abnormal accumulation of amyloid fibrils in diverse tissues. The kidney is a prominent target tissue in ApoAI amyloidosis with a remarkable selectivity for the renal medulla. Here, we investigated six French families with ApoAI Glu34Lys, p.His179Profs∗47, and a novel p.Thr185Alafs∗41 variant revealing unprecedented clinical association of a glomerular with a retinal disease. Comprehensive clinicopathological, molecular and proteomics studies of numerous affected tissues ensured the correlation between clinical manifestations, including novel unrecognized phenotypes, and apoA-I amyloid deposition. These ophthalmic manifestations stemmed from apoA-I amyloid deposition, highlighting that the retina is a previously unrecognized tissue affected by ApoAI amyloidosis. Our study provides the first molecular evidence that a significant fraction of ApoAI amyloidosis cases with no family history result from spontaneous neomutations rather than variable disease penetrance. Finally, successful hepatorenal transplantation resulted in a life- and vision-saving measure for a 32-year-old man with a hitherto unreported severe ApoAI amyloidosis caused by the very rare Glu34Lys variant. Our findings reveal new modes of occurrence and expand the clinical spectrum of ApoAI amyloidosis. The awareness of glomerular and ocular manifestations in ApoAI amyloidosis should enable earlier diagnosis and avoid misdiagnosis with other forms of renal amyloidosis. Thus, documented apoA-I amyloid deposition in the retina offers new biological information about this disease and may change organ transplantation practice to reduce retinal damage in patients with ApoAI amyloidosis.

Opportunistic infections after conversion to belatacept in kidney transplantation.

BACKGROUND: Belatacept (bela) rescue therapy seems to be a valuable option for calcineurin inhibitor chronic toxicity in kidney transplantation. Nevertheless, the risk of infection associated with bela is not well reported. METHODS: We report the rate of opportunistic infections (OPI) after a switch to bela in a multicentric cohort of 280 kidney transplant patients. RESULTS: Forty-two OPI occurred in 34 patients (12.1%), on average 10.8 ± 11.3 months after the switch. With a cumulative exposure of 5128 months of bela treatment, we found an incidence of 0.008 OPI/month of exposure, and 9.8 OPI/100 person-years. The most common OPI was cytomegalovirus (CMV) disease in 18/42 OPI (42.9%) and pneumocystis pneumonia in 12/42 OPI (28.6%). Two patients presented a progressive multifocal leucoencephalopathy and two patients developed a cerebral Epstein-Barr virus-induced post-transplant lymphoproliferative disease. OPI led to death in 9/34 patients (26.5%) and graft failure in 4/34 patients (11.8%). In multivariate analysis, estimated glomerular filtration rate <25/mL/min/1.73 m2 on the day of the switch and the use of immunosuppressive agents before transplantation were associated with the occurrence of OPI. We found a higher rate of infection-related hospitalization (24.1 versus 12.3/100 person-years, P = 0.0007) and also a higher rate of OPI (13.2 versus 6.7/100 person-years, P = 0.005) in the early conversion group (within 6 months). CONCLUSIONS: The risk of OPI is significant post-conversion to bela and may require additional monitoring and prophylactic therapy, particularly regarding pneumocystis pneumonia and CMV disease. These data need to be confirmed in a larger case-control study.

Kaposi Sarcoma in HIV-positive Solid-Organ Transplant Recipients: A French Multicentric National Study and Literature Review.

BACKGROUND: Kaposi sarcoma is a vascular tumor related to herpesvirus-8 and is promoted by immunosuppression. For the last 15 years, human immunodeficiency virus (HIV) patients have had access to organ transplantation. The dual immunosuppression of HIV and immunosuppressive treatments might increase the risk and severity of Kaposi sarcoma. METHODS: We conducted a multicentric retrospective study by collecting cases from French databases and society members of transplanted patients, among which 7 HIV-infected patients who subsequently developed Kaposi sarcoma were included. RESULTS: In the CRISTAL database (114 511 patients) and the DIVAT (Données Informatisées et VAlidées en Transplantation) database (19 077 patients), the prevalence of Kaposi sarcoma was 0.18% and 0.46%, respectively, in transplanted patients; these values compare with 0.66% and 0.50%, respectively, in transplanted patients with HIV. The median time from HIV infection to Kaposi sarcoma was 20 years. Kaposi sarcoma occurred during the first year after transplantation in most cases, whereas HIV viral load was undetectable. Only 2 patients had visceral involvement. Five patients were treated with conversion of calcineurin inhibitor to mammalian target of rapamycin inhibitor, and 5 patients were managed by decreasing immunosuppressive therapies. At 1 year, 4 patients had a complete response, and 3 had a partial response. CONCLUSIONS: In our study, Kaposi sarcoma in transplanted patients with HIV did not show any aggressive features and was treated with the usual posttransplant Kaposi sarcoma management protocol.

Minimization of maintenance immunosuppressive therapy after renal transplantation comparing cyclosporine A/azathioprine or cyclosporine A/mycophenolate mofetil bitherapy to cyclosporine A monotherapy: a 10-year postrandomization follow-up study.

Long-term outcomes in renal transplant recipients withdrawn from steroid and submitted to further minimization of immunosuppressive regimen after 1 year are lacking. In this multicenter study, 204 low immunological risk kidney transplant recipients were randomized 14.2 ± 3.7 months post-transplantation to receive either cyclosporine A (CsA) + azathioprine (AZA; n = 53), CsA + mycophenolate mofetil (MMF; n = 53), or CsA monotherapy (n = 98). At 3 years postrandomization, the occurrence of biopsy for graft dysfunction was similar in bitherapy and monotherapy groups (21/106 vs. 26/98; P = 0.25). At 10 years postrandomization, patients' survival was 100%, 94.2%, and 95.8% (P = 0.25), and death-censored graft survival was 94.9%, 94.7%, and 95.2% (P = 0.34) in AZA, MMF, and CsA groups, respectively. Mean estimated glomerular filtration rate was 70.4 ± 31.1, 60.1 ± 22.2, and 60.1 ± 19.0 ml/min/1.73 m(2), respectively (P = 0.16). The incidence of biopsy-proven acute rejection was 1.4%/year in the whole cohort. None of the patients developed polyomavirus-associated nephropathy. The main cause of graft loss (n = 12) was chronic antibody-mediated rejection (n = 6). De novo donor-specific antibodies were detected in 13% of AZA-, 21% of MMF-, and 14% of CsA-treated patients (P = 0.29). CsA monotherapy after 1 year is safe and associated with prolonged graft survival in well-selected renal transplant recipient (ClinicalTrials.gov number: 980654).

One-year Results of the Effects of Rituximab on Acute Antibody-Mediated Rejection in Renal Transplantation: RITUX ERAH, a Multicenter Double-blind Randomized Placebo-controlled Trial.

BACKGROUND: Treatment of acute antibody-mediated rejection (AMR) is based on a combination of plasma exchange (PE), IVIg, corticosteroids (CS), and rituximab, but the place of rituximab is not clearly specified in the absence of randomized trials. METHODS: In this phase III, multicenter, double-blind, placebo-controlled trial, we randomly assigned patients with biopsy-proven AMR to receive rituximab (375 mg/m) or placebo at day 5. All patients received PE, IVIg, and CS. The primary endpoint was a composite of graft loss or no improvement in renal function at day 12. RESULTS: Among the 38 patients included, at 1 year, no deaths occurred, but 1 graft loss occurred in each group. The primary endpoint frequency was 52.6% (10/19) and 57.9% (11/19) in the rituximab and placebo groups, respectively (P = 0.744). Renal function improved in both groups, as soon as day 12 with no difference in serum creatinine level and proteinuria at 1, 3, 6, and 12 months. Supplementary administration of rituximab and total number of IVIg and PE treatments did not differ between the 2 groups. Both groups showed improved histological features of AMR and Banff scores at 1 and 6 months, with no significant difference between groups but with a trend in favor of the rituximab group. Both groups showed decreased mean fluorescence intensity of donor-specific antibodies as soon as day 12, with no significant difference between them but with a trend in favor of the rituximab group at 12 months. CONCLUSIONS: After 1 year of follow-up, we observed no additional effect of rituximab in patients receiving PE, IVIg, and CS for AMR. Nevertheless, our study was underpowered and important differences between groups may have been missed. Complementary trials with long-term follow-up are needed.

Eight-year results of the Spiesser study, a randomized trial comparing de novo sirolimus and cyclosporine in renal transplantation.

We present the results at 8 years of the Spiesser study, a randomized trial comparing de novo sirolimus and cyclosporine in kidney transplant recipients at low immunologic risk. We assessed estimated glomerular filtration (eGFR), graft, patient, and death-censored graft survival (log-rank compared), de novo DSA appearance, risk of malignancy, post-transplant diabetes mellitus (PTDM), and anemia. Intent-to-treat and on-treatment analyses were performed. Graft survival was similar in both groups (sirolimus: 73.3%, cyclosporine: 77.7, P = 0.574). No difference was observed between treatment groups concerning patient survival (P = 0.508) and death-censored graft survival (P = 0.858). In conditional intent-to-treat analysis, mean eGFR was greater in sirolimus than in cyclosporine group (62.5 ± 27.3 ml/min vs. 47.8 ± 17.1 ml/min, P = 0.004), in particular because graft function was excellent in patients maintained under sirolimus (eGFR = 74.0 ml/min). Importantly, no detrimental impact was observed in patients in whom sirolimus has been withdrawn (eGFR = 49.5 ml/min). Overall, 17 patients showed de novo DSAs, with no difference between the two groups (P = 0.520). Malignancy did not differ by treatment. An initial maintenance regimen based on sirolimus provides a long-term improvement in renal function for kidney transplant patients, especially for those maintained on sirolimus.

Post-transplantation lymphoproliferative disorder after kidney transplantation: report of a nationwide French registry and the development of a new prognostic score.

PURPOSE: Post-transplantation lymphoproliferative disorder (PTLD) is associated with significant mortality in kidney transplant recipients. We conducted a prospective survey of the occurrence of PTLD in a French nationwide population of adult kidney recipients over 10 years. PATIENTS AND METHODS: A French registry was established to cover a nationwide population of transplant recipients and prospectively enroll all adult kidney recipients who developed PTLD between January 1, 1998, and December 31, 2007. Five hundred patient cases of PTLD were referred to the French registry. The prognostic factors for PTLD were investigated using Kaplan-Meier and Cox analyses. RESULTS: Patients with PTLD had a 5-year survival rate of 53% and 10-year survival rate of 45%. Multivariable analyses revealed that age > 55 years, serum creatinine level > 133 µmol/L, elevated lactate dehydrogenase levels, disseminated lymphoma, brain localization, invasion of serous membranes, monomorphic PTLD, and T-cell PTLD were independent prognostic indicators of poor survival. Considering five variables at diagnosis (age, serum creatinine, lactate dehydrogenase, PTLD localization, and histology), we constructed a prognostic score that classified patients with PTLD as being at low, moderate, high, or very high risk for death. The 10-year survival rate was 85% for low-, 80% for moderate-, 56% for high-, and 0% for very high-risk recipients. CONCLUSION: This nationwide study highlights the prognostic factors for PTLD and enables the development of a new prognostic score. After validation in an independent cohort, the use of this score should allow treatment strategies to be better tailored to individual patients in the future.

Conversion from everolimus with low-exposure cyclosporine to everolimus with mycophenolate sodium maintenance therapy in kidney transplant recipients: a randomized, open-label multicenter study.

BACKGROUND: Data in kidney transplant recipients regarding elimination of calcineurin inhibitor (CNI) therapy from a de novo regimen based on low CNI exposure and an mTOR inhibitor are sparse, and restricted to CNI elimination within the first six months post-transplant. MATERIAL/METHODS: In a 12-month, randomized, multicenter, open-label study, kidney transplant patients who had received everolimus, low-exposure cyclosporine and corticosteroids from transplantation to month 12 (with proteinuria <1 g/24 h at month 12) were randomized to convert from cyclosporine to mycophenolate sodium 720 mg/day with increased everolimus exposure (6-10 ng/mL [CNI-free group], n=15) or continue unchanged (everolimus 3-8 ng/mL [CNI group], n=15). RESULTS: Median (range) baseline mGFR was 54 (21-87) mL/min and 37 (range 18-69) mL/min (p=0.053) in the CNI-free and CNI groups, respectively, compared to 56 (18-126) mL/min and 32 (12-63) mL/min at month 12 (p=0.007). The between-group difference in change in mGFR from baseline to month 12 post-conversion (the primary endpoint) was -14.4 mL/min (95% CI -29.3 to 0.6 mL/min, p=0.059 [least squares mean]). Changes in serum creatinine and estimated GFR to month 12 were significantly in favor of CNI-free patients. One CNI patient experienced biopsy-proven acute rejection. Study drug was discontinued due to adverse events in one CNI-free patient (7%) and three CNI-treated patients (20.0%). CONCLUSIONS: Elimination of CNI from a de novo regimen of everolimus with low-exposure CNI at one year post-transplant maintained efficacy and led to a non-significant but clinically relevant improvement in renal function, although patients numbers were low (n=30). Findings from this small study require confirmation in a larger controlled trial.

Early steroid withdrawal and optimization of mycophenolic acid exposure in kidney transplant recipients receiving mycophenolate mofetil.

BACKGROUND: Early posttransplant steroid withdrawal may increase the risk of acute rejection and the occurrence of subclinical acute rejection (SCAR). We assessed the feasibility and safety of early steroid withdrawal in low-risk patients receiving cyclosporine A (CsA) and the impact of optimization of mycophenolic acid exposure on steroid withdrawal success. METHODS: De novo, low-immunological risk kidney recipients received an anti-interleukin-2-receptor-α antibody induction, a short course of 7 days of corticosteroids, and CsA with 2-hr postdose concentration monitoring. They were randomized to adjusted dose (AD) of mycophenolate mofetil (MMF) using therapeutic drug monitoring (TDM) or a fixed-dose (FD) regimen. MMF 3 g was initiated posttransplant and then adjusted starting at week 2 to a 0 to 12 hr area under the concentration time curve of 40 mg · h/L versus 2 g daily, respectively. The primary endpoint was a composite of the proportion of patients experiencing biopsy-proven acute rejection (BPAR) and those with SCAR identified on the 3-month protocol biopsy. RESULTS: Among 247 analyzed patients, only 22 in the AD group and 17 in the FD group experienced BPAR or SCAR (P=0.46). The rate of SCAR was low: 4% (AD) and 2.5% (FD). No between-group difference in the incidence of BPAR was observed. TDM yielded MMF doses ranging from 1 to 4 g/d and significantly reduced interpatient variability at weeks 26 and 52 in the AD group. CONCLUSIONS: In low-immunological risk kidney recipients, MMF combined with CsA allows early corticosteroid discontinuation with good tolerability. In this group of patients, TDM of MMF does not improve clinical outcome.

Drug-resistant cytomegalovirus in transplant recipients: a French cohort study.

OBJECTIVES: Cytomegalovirus (CMV) drug resistance is a therapeutic challenge in the transplant setting. No longitudinal cohort studies of CMV resistance in a real-life setting have been published in the valganciclovir era. We report findings for a French multicentre prospective cohort of 346 patients enrolled at initial diagnosis of CMV infection (clinical trial registered at clinicaltrials.gov: NCT01008540). PATIENTS AND METHODS: Patients were monitored for detection of CMV infection for ≥2 years. Real-time detection of resistance by UL97 and UL54 gene sequencing and antiviral phenotyping was performed if viral replication persisted for >21 days of appropriate antiviral treatment. Plasma ganciclovir assays were performed when resistance was suspected. RESULTS: Resistance was suspected in 37 (10.7%) patients; 18/37 (5.2% of the cohort) had virological resistance, associated with poorer outcome. Most cases involved single UL97 mutations, but four cases of multidrug resistance were due to UL54 mutations. In solid organ transplant recipients, resistance occurred mainly during primary CMV infection (odds ratio 8.78), but also in two CMV-seropositive kidney recipients. Neither CMV prophylaxis nor antilymphocyte antibody administration was associated with virological resistance. CONCLUSIONS: These data show the feasibility of surveying resistance. Virological resistance was frequent in patients failing antiviral therapy. More than 1/5 resistant isolates harboured UL54 mutations alone or combined with UL97 mutations, which conferred a high level of resistance and sometimes were responsible for cross-resistance, leading to therapeutic failure.

Efficacy and safety of de novo or early everolimus with low cyclosporine in deceased-donor kidney transplant recipients at specified risk of delayed graft function: 12-month results of a randomized, multicenter trial.

Immediate or early use of proliferation signal inhibitor (PSI)/mammalian target of rapamycin (mTOR) inhibitor therapy can avoid high exposure to calcineurin inhibitors but concerns exist relating to the risk of delayed graft function (DGF) and impaired wound healing with the mTOR sirolimus. CALLISTO was a 12-month, prospective, multicenter, open-label study. Deceased-donor kidney transplant patients at protocol-specified risk of DGF were randomized to start everolimus on day 1 (immediate everolimus, IE; n = 65) or week 5 (delayed everolimus, DE; n = 74). Incidence of the primary endpoint (biopsy-proven acute rejection, BPAR; graft loss, death, DGF, wound healing complications related to transplant surgery or loss to follow-up) was 64.6% and 66.2% in the IE and DE groups, respectively, at month 12 (P = 0.860). The overall incidence of BPAR was 20.1%. Median estimated glomerular filtration rate was 48 ml/min/1.73 m(2) and 49 ml/min/1.73 m(2) in the IE and DE groups, respectively, at month 12. DGF and wound healing complications were similar between groups. Adverse events led to study drug discontinuation in 17 IE patients (26.2%) and 28 DE patients (37.8%) (NS). In conclusion, introduction of everolimus immediately or early posttransplant in DGF-risk patients is associated with good efficacy, renal function and safety profile. There seems no benefit in delaying initiation of everolimus.

Severe sirolimus-induced acute hepatitis in a renal transplant recipient.

Sirolimus is currently used as an immunosuppressive agent in kidney transplantation due to its lack of nephrotoxicity and antiproliferative properties. However, a large number of side effects has been described with the use of m-Tor inhibitors. Most are reversible when treatment is withdrawn. Hepatotoxicity is one of these side effects, considered as a benign condition and resulting generally in a transitory and small increase in transaminase levels. We report here, to the best of our knowledge, the first case of severe sirolimus-induced acute hepatitis confirmed by liver biopsy, in a renal transplant recipient. This condition was completely cured in few weeks after sirolimus withdrawal.

Incidence of delayed graft function and wound healing complications after deceased-donor kidney transplantation is not affected by de novo everolimus.

BACKGROUND: Concerns about delayed graft function (DGF) and wound healing complications with sirolimus has led to suggestions that everolimus introduction could be delayed after transplantation. METHODS: In a prospective, multicenter, open-label study, deceased-donor kidney transplant recipients at protocol-specified risk of DGF (defined as > or =1 dialysis session during the first week posttransplant excluding day 1) were randomized to start everolimus therapy on day 1 posttransplant (immediate everolimus [IE]), or from week 5 (delayed everolimus [DE]) with mycophenolic acid until everolimus was initiated. All patients received anti-interleukin-2 receptor antibodies, cyclosporine A, and corticosteroids. A planned 3-month analysis from this 12-month study is presented here. RESULTS: One hundred and thirty-nine patients were randomized (IE 65, DE 74). The primary composite endpoint: biopsy-proven acute rejection, graft loss, death, DGF, wound healing events, or lost to follow-up at month 3, occurred in 36 IE patients (55.4%) and 47 DE patients (63.5%, P=0.387). The incidence of DGF was similar between groups (IE 24.6%, DE 24.3%; n.s.). Wound healing events of any type occurred in 40.0% and 41.9% of IE and DE patients (n.s.); events relating to initial transplant surgery occurred in 36.9% IE patients and 37.8% DE patients (n.s.), most of which were fluid collections. Study drug was discontinued due to adverse events or graft loss in 13 IE (20.0%) and 17 DE patients (23.0%). CONCLUSIONS: Findings from this randomized, multicenter trial indicate that kidney function recovery, wound healing, efficacy, and tolerance are similar at 3 months posttransplant with immediate or DE in patients at protocol-specified risk of DGF.

Intracranial granuloma and skull osteolysis: complication of a primary cutaneous cryptococcosis in a kidney transplant recipient.

Cryptococcosis is the third most common invasive fungal infection in organ transplant recipients after candidiasis and aspergillosis. It occurs almost exclusively in the late posttransplantation period (>6 months after the initiation of immunosuppression). Subclinical onset of meningitis is the usual clinical presentation. Despite initiation of therapy, the mortality rate associated with this infection in this patient population remains high. To the best of our knowledge, this report describes one of the first cases of a rare entity: a primary cutaneous cryptococcosis in a renal transplant recipient disclosed by skull osteomyelitis and pseudotumoral intracranial extension. Surgical debridement and azole antifungal therapy were performed. Ten months after the onset of treatment, the patient feels good, clinical examination findings are normal, and no sign of evolutive cryptococcosis is noted.

An unusual recurrence of crescentic nephritis after renal transplantation for IgA nephropathy.

The recurrence of immunoglobulin A nephropathy (IgAN) after renal transplantation has been described in 40% to 50% of cases. For a long time, this type of recurrence was considered as a benign condition. However, recent data have shown that recurrent IgAN has become a significant cause of long-term allograft loss. The authors present here the case of a 47-year-old man with IgAN, which led to end-stage renal failure in 1999. In November 2000, he received a cadaveric renal allograft. Ten months later, acute nephritic syndrome and rapidly progressive renal failure developed. Renal biopsy showed extracapillary glomerulonephritis with crescent formation in one third of the glomeruli associated with necrosis. Steroid treatment was unsuccessful, and renal function progressively deteriorated with a creatinine level at 3.7 mg/dL 6 months after diagnosis of recurrence. This patient's graft probably will be lost in a few months.