Anne Scemla

Urinary C-X-C Motif Chemokine 10 Independently Improves the Noninvasive Diagnosis of Antibody–Mediated Kidney Allograft Rejection

Urinary levels of C-X-C motif chemokine 9 (CXCL9) and CXCL10 can noninvasively diagnose T cell-mediated rejection (TCMR) of renal allografts. However, performance of these molecules as diagnostic/prognostic markers of antibody-mediated rejection (ABMR) is unknown. We investigated urinary CXCL9 and CXCL10 levels in a highly sensitized cohort of 244 renal allograft recipients (67 with preformed donor-specific antibodies [DSAs]) with 281 indication biopsy samples. We assessed the benefit of adding these biomarkers to conventional models for diagnosing/prognosing ABMR. Urinary CXCL9 and CXCL10 levels, normalized to urine creatinine (Cr) levels (CXCL9:Cr and CXCL10:Cr) or not, correlated with the extent of tubulointerstitial (i+t score; all P<0.001) and microvascular (g+ptc score; all P<0.001) inflammation. CXCL10:Cr diagnosed TCMR (area under the curve [AUC]=0.80; 95% confidence interval [95% CI], 0.68 to 0.92; P<0.001) and ABMR (AUC=0.76; 95% CI, 0.69 to 0.82; P<0.001) with high accuracy, even in the absence of tubulointerstitial inflammation (AUC=0.70; 95% CI, 0.61 to 0.79; P<0.001). Although mean fluorescence intensity of the immunodominant DSA diagnosed ABMR (AUC=0.75; 95% CI, 0.68 to 0.82; P<0.001), combining urinary CXCL10:Cr with immunodominant DSA levels improved the diagnosis of ABMR (AUC=0.83; 95% CI, 0.77 to 0.89; P<0.001). At the time of ABMR, urinary CXCL10:Cr ratio was independently associated with an increased risk of graft loss. In conclusion, urinary CXCL10:Cr ratio associates with tubulointerstitial and microvascular inflammation of the renal allograft. Combining the urinary CXCL10:Cr ratio with DSA monitoring significantly improves the noninvasive diagnosis of ABMR and the stratification of patients at high risk for graft loss.

Diarrhea after kidney transplantation: a new look at a frequent symptom.

Diarrhea is a frequent but overlooked complication of kidney transplantation. Diarrhea is repeatedly neglected, often considered by patients and clinicians an unavoidable side effect of immunosuppressive regimens. It is, however, associated with a significant impairment in life quality. Severe and chronic posttransplant diarrhea may lead to dehydration, malabsorption, rehospitalization, immunosuppression, noncompliance, and a greater risk of graft loss and death. There is thus a need to optimize and standardize the management of posttransplant diarrhea with consistent diagnostic and therapeutic strategies. A recent study has suggested that the increased sensitivity of molecular tools might help in early pathogen identification and guidance of antimicrobial treatment. Most bacterial and protozoan infections are readily curable with appropriate antimicrobial agents; cryptosporidiosis and C. difficile infections may however be complicated by relapsing courses. In addition, identification of enteric viral genomes in stool has further reduced posttransplant diarrhea of unknown origin. Chronic norovirus-related posttransplant diarrhea, arising from the interplay of the virus and immunosuppressive drugs, has emerged as a new challenge in the field. Prospective and controlled studies are necessary to evaluate the efficacy and safety of innovative anti-norovirus therapeutics, as well as optimal immunosuppressive regimens, to enable viral clearance while preventing rejection and donor-specific antibody formation. This review seeks to provide a basis for the design of future clinical prospective studies.

Incidence of Infectious Complications in Highly Sensitized Renal Transplant Recipients Treated by Rituximab: A Case-Controlled Study

Background. Use of rituximab for various indications in renal transplantation is increasing. However, tolerance and complications associated with rituximab therapy remain controversial. Methods. We retrospectively analyzed severe infectious episodes during 2005 to 2007 in 38 renal transplant recipients treated with rituximab as induction therapy or for antibody-mediated rejection and compared this population with 26 highly sensitized renal transplant recipients who received comparable treatment but without rituximab. Results. Mean posttransplant follow-up was 25.5±11.5 and 34.6±16.4 months in the rituximab and control groups, respectively (P=0.01). A total of 84 severe infectious episodes occurred in 39 patients (rituximab 55.3% vs. controls 69.2% [NS]). Most frequent were bacterial infections (47.4% vs. 57.7%), followed by viral and fungal infections (10.6% vs. 15.4% and 7.9% vs. 7.7%, respectively), with no statistical difference between groups. Two patients died in each group. Three of these four deaths were related to infectious complications. Biologic parameters were similar in both groups. Serum creatinine levels were higher at months 3 and 12 in patients with severe infections, but we found no other difference between patients with or without infections. Specifically, rituximab was not associated with an increased risk of infection. Conclusions. In highly sensitized patients, rituximab therapy is not associated with an increased risk of severe infection.

Cryptosporidium spp. Infection in Solid Organ Transplantation: The Nationwide "TRANSCRYPTO" Study.

Background Diarrhea is a frequent complication of solid organ transplantation. Cryptosporidiosis is classically reported in patients with acquired immunodeficiency syndrome and emerged as a cause of persistent diarrhea in solid organ transplant patients. Methods Through the ANOFEL Cryptosporidium National Network and the French Transplantation Society, we collected all cryptosporidiosis cases identified in solid organ transplanted patients between 2006 and 2010 in France. Results We reported 47 solid organ transplant recipients (41 kidneys) with cryptosporidiosis, mostly men (68%), with a median age of 52 (6-70) years old. Five patients had additional immunodepression favoring cryptosporidiosis (CD40 ligand deficiency [n = 1], human immunodeficiency virus infection [n = 4]). Cryptosporidiosis occurred at a median time of 3.4 (0-19.8) years posttransplant. Exposure to environmental risk factors was found before infection onset in 18 patients. Time between first symptoms and diagnosis was 10 (2-110) days. Four patients had associated extraintestinal location (biliary tract [n = 3] and lung [n = 1]). Thirty-five patients received specific therapy against cryptosporidiosis ie nitozoxanide, 25 in monotherapy, and 10 in association with azithromycin, 13 in association with immunosuppression (IS) reduction. Four patients were cured with IS treatment tapering only. The others patients had neither IS reduction nor specific therapy against cryptosporidiosis. Cryptosporidiosis was complicated by renal failure in 15 patients. Symptoms resolved after a median of 10 days of treatment. Six patients relapsed and 3 died, 1 with evolutive infection. Conclusions Cryptosporidiosis is a late posttransplant infection that disseminated to biliar duct or lung in 9% of patients. When limited to digestive tract, infection may resolve without IS reduction.

Midterm Outcomes of 12 Renal Transplant Recipients Treated With Eculizumab to Prevent Atypical Hemolytic Syndrome Recurrence

Background Atypical hemolytic uremic syndrome (aHUS) is an orphan disease with a high rate of recurrence after kidney transplantation. However, reports of successful prevention of posttransplant aHUS recurrence with eculizumab emerged a few years ago. To further delineate its optimal use, we describe the largest series of kidney transplant recipients treated with prophylactic eculizumab. Methods Twelve renal transplant recipients with aHUS-related end-stage renal disease received eculizumab: 10 from day 0 and 2 at the time of recurrence (days 6 and 25). Clinical and histological features, complement assessment, and free eculizumab measurements were analyzed. The median follow-up was 24.6 months. Results Five patients had failed at least 1 previous renal transplant from aHUS. A genetic mutation was identified in 9 patients, anti-H antibodies were found in 2. No patient demonstrated biological recurrence of thrombotic microangiopathy under treatment. Three antibody-mediated rejections (AMRs) occurred without detectable C5 residual activity. AMR was associated with subclinical thrombotic microangiopathy in 2 patients. One patient lost his graft after several complications, including AMR. One patient experienced posttransplant C3 glomerulonephritis. The last median serum creatinine was 128.2 ± 40.8 &mgr;mol/L. Conclusions These data confirm that eculizumab is highly effective in preventing posttransplantation aHUS recurrence, yet may not fully block AMR pathogenesis.

Prognosis of Invasive Aspergillosis in Kidney Transplant Recipients: A Case-Control Study.

Background Invasive aspergillosis (IA) is a major cause of invasive fungal infection in kidney transplant recipients (KTR), and it has a high mortality rate. However, its impact on patients and graft survival has not been well defined in the current era of voriconazole first-line therapy. Methods We retrospectively collected all cases of KTR-associated IA occurring at Necker Enfants Malades Hospital, Paris, from 2003 to 2013. These cases were compared with a group of controls (1:3) who were matched by age, year of kidney transplantation, and sex. The characteristics of IA were also studied. Results Sixteen patients developed IA after KTR. Most IA cases were limited to the lungs (81.3%), with mild respiratory symptoms in only 53% of the patients. The patients were administered voriconazole (n = 15, 94%) and/or posaconazole (n = 2, 13%). The 12-week and 1-year postinfection survival rates were 94% and 81%, respectively. Compared with the controls (n = 46), patients and death-censored graft survivals rates were significantly lower after IA (P = 0.017 and 0.001, respectively). In the patients with IA, the occurrences of cardiovascular diseases before transplantation (P < 0.0001), delayed graft function (P < 0.0001), and infectious complications (0.0018) were significantly more frequent. Conclusions Even with voriconazole therapy, the prognosis of patients with IA after kidney transplantation is still poor. When the patients survive to IA, they have a high risk of graft loss.

Long-term outcomes of kidney transplantation in patients with high levels of preformed DSA: the Necker high-risk transplant program.

Background There is an increasing number of anti-HLA sensitized and highly sensitized renal transplant candidates on waiting lists, and the presence of donor-specific alloantibodies (DSAs) at the time of transplantation leads to acute and chronic antibody-mediated rejection (AMR). Acceptable short-term outcomes have been described, notably because of desensitization protocols, but mid- and long-term data are still required. Methods Our high immunologic risk program included 95 patients with high peak or day 0 DSA levels (mean fluorescence intensity [MFI] > 3000) with a complement-dependent cytotoxicity-negative crossmatch, who received a posttransplant desensitization protocol starting at day 0 with high-dose intravenous immunoglobulin, plasma exchanges, and eventually rituximab. Their characteristics were compared with a control group including 39 patients with a lower immunologic risk (MFI between 500 and 3000 at day 0) who received the same posttransplant desensitization. Results The median MFI of the immunodominant class I or II DSA in the peak or day 0 serum was 9421 (interquartile range, 4959-12 610). An AMR occurred during the first posttransplant year in 31 patients (32.6%), and at one year, the rate of chronic AMR was 39.5%. The 1-, 3-, 5- and 7-year death-censored allograft survival rates were 98%, 91%, 86%, and 78%, respectively, with concomitant recipient survival rates of 97%, 93%, 85%, and 79%, respectively. Conclusions These results suggest that DSA-sensitized patients with high MFI levels can receive transplantation across the HLA-barrier, with the use of an intensified posttransplant immunosuppressive therapy starting at day 0 combined with close clinical, immunologic, and histologic monitoring.