Carfilzomib-associated thrombotic microangiopathy: clinical features and outcomes.

BACKGROUND AND HYPOTHESIS: Carfilzomib, a new proteasome inhibitor indicated for patients with relapsed/refractory myeloma, has been associated with cases of thrombotic microangiopathy (CFZ-TMA). The role of variants in the complement alternative pathway and therapeutic potential of complement blockade with eculizumab remain to be determined. METHODS: We report 37 cases of CFZ-TMA recorded in the French reference center for TMA with their clinical characteristics, genetic analysis and outcome according to treatments. RESULTS: A trigger was identified in more than half of cases, including 8 influenza and 5 SARS-CoV-2 cases. All patients presented with acute kidney injury (AKI) (KDIGO stage 3 in 31 (84%) patients) while neurological (n=13, 36%) and cardiac damage (n=7, 19%) were less frequent. ADAMTS13 and complement activity were normal (n= 28 and 18 patients tested) and no pathogenic variant in the alternative complement pathway was found in 7 patients tested.TMA resolved in most (n=34, 94%) patients but 12 (44%) still displayed stage 3 AKI at discharge. Nineteen (51%) patients were treated with therapeutic plasma exchange, 14 (38%) patients received corticosteroids and 18 (50%) were treated with eculizumab. However none of these treatments demonstrated a significant impact on outcomes. CONCLUSION: This study is the largest case series of CFZ-TMA since its approval in 2012. Patients present with severe AKI and experience frequent sequelae. Complement variants and blockade therapy do not seem to play a role in the pathophysiology and prognosis of the disease.

Recognition of intraglomerular histological features with deep learning in protocol transplant biopsies and their association with kidney function and prognosis.

Background: The Banff Classification may not adequately address protocol transplant biopsies categorized as normal in patients experiencing unexplained graft function deterioration. This study seeks to employ convolutional neural networks to automate the segmentation of glomerular cells and capillaries and assess their correlation with transplant function. Methods: A total of 215 patients were categorized into three groups. In the Training cohort, glomerular cells and capillaries from 37 patients were manually annotated to train the networks. The Test cohort (24 patients) compared manual annotations vs automated predictions, while the Application cohort (154 protocol transplant biopsies) examined predicted factors in relation to kidney function and prognosis. Results: In the Test cohort, the networks recognized histological structures with Precision, Recall, F-score and Intersection Over Union exceeding 0.92, 0.85, 0.89 and 0.74, respectively. Univariate analysis revealed associations between the estimated glomerular filtration rate (eGFR) at biopsy and relative endothelial area (r = 0.19, P = .027), endothelial cell density (r = 0.20, P = .017), mean parietal epithelial cell area (r = -0.38, P < .001), parietal epithelial cell density (r = 0.29, P < .001) and mesangial cell density (r = 0.22, P = .010). Multivariate analysis retained only endothelial cell density as associated with eGFR (Beta = 0.13, P = .040). Endothelial cell density (r = -0.22, P = .010) and mean podocyte area (r = 0.21, P = .016) were linked to proteinuria at biopsy. Over 44 ± 29 months, 25 patients (16%) reached the primary composite endpoint (dialysis initiation, or 30% eGFR sustained decline), with relative endothelial area, mean endothelial cell area and parietal epithelial cell density below medians linked to this endpoint [hazard ratios, respectively, of 2.63 (P = .048), 2.60 (P = .039) and 3.23 (P = .019)]. Conclusion: This study automated the measurement of intraglomerular cells and capillaries. Our results suggest that the precise segmentation of endothelial and epithelial cells may serve as a potential future marker for the risk of graft loss.

Automated evaluation with deep learning of total interstitial inflammation and peritubular capillaritis on kidney biopsies.

BACKGROUND: Interstitial inflammation and peritubular capillaritis are observed in many diseases on native and transplant kidney biopsies. A precise and automated evaluation of these histological criteria could help stratify patients' kidney prognoses and facilitate therapeutic management. METHODS: We used a convolutional neural network to evaluate those criteria on kidney biopsies. A total of 423 kidney samples from various diseases were included; 83 kidney samples were used for the neural network training, 106 for comparing manual annotations on limited areas to automated predictions, and 234 to compare automated and visual gradings. RESULTS: The precision, recall and F-score for leukocyte detection were, respectively, 81%, 71% and 76%. Regarding peritubular capillaries detection the precision, recall and F-score were, respectively, 82%, 83% and 82%. There was a strong correlation between the predicted and observed grading of total inflammation, as for the grading of capillaritis (r = 0.89 and r = 0.82, respectively, all P < .0001). The areas under the receiver operating characteristics curves for the prediction of pathologists' Banff total inflammation (ti) and peritubular capillaritis (ptc) scores were respectively all above 0.94 and 0.86. The kappa coefficients between the visual and the neural networks' scores were respectively 0.74, 0.78 and 0.68 for ti ≥1, ti ≥2 and ti ≥3, and 0.62, 0.64 and 0.79 for ptc ≥1, ptc ≥2 and ptc ≥3. In a subgroup of patients with immunoglobulin A nephropathy, the inflammation severity was highly correlated to kidney function at biopsy on univariate and multivariate analyses. CONCLUSION: We developed a tool using deep learning that scores the total inflammation and capillaritis, demonstrating the potential of artificial intelligence in kidney pathology.

Deep learning automation of MEST-C classification in IgA nephropathy.

BACKGROUND: Although the MEST-C classification is among the best prognostic tools in immunoglobulin A nephropathy (IgAN), it has a wide interobserver variability between specialized pathologists and others. Therefore we trained and evaluated a tool using a neural network to automate the MEST-C grading. METHODS: Biopsies of patients with IgAN were divided into three independent groups: the Training cohort (n = 42) to train the network, the Test cohort (n = 66) to compare its pixel segmentation to that made by pathologists and the Application cohort (n = 88) to compare the MEST-C scores computed by the network or by pathologists. RESULTS: In the Test cohort, >73% of pixels were correctly identified by the network as M, E, S or C. In the Application cohort, the neural network area under the receiver operating characteristics curves were 0.88, 0.91, 0.88, 0.94, 0.96, 0.96 and 0.92 to predict M1, E1, S1, T1, T2, C1 and C2, respectively. The kappa coefficients between pathologists and the network assessments were substantial for E, S, T and C scores (kappa scores of 0.68, 0.79, 0.73 and 0.70, respectively) and moderate for M score (kappa score of 0.52). Network S and T scores were associated with the occurrence of the composite survival endpoint (death, dialysis, transplantation or doubling of serum creatinine) [hazard ratios 9.67 (P = .006) and 7.67 (P < .001), respectively]. CONCLUSIONS: This work highlights the possibility of automated recognition and quantification of each element of the MEST-C classification using deep learning methods.

Retrospective study of 59 cases of cancer-associated thrombotic microangiopathy: presentation and treatment characteristics.

BACKGROUND: Cancer-associated thrombotic microangiopathy (TMA) is a rare disease, with a poor prognosis. The classical treatment is urgent chemotherapy. Few data are available on the efficacy of plasma exchange (PE) and eculizumab in these patients. METHODS: Cases of cancer-related TMA treated between January 2008 and December 2019 in 12 French treatment centres were retrospectively analysed, excluding cases associated with chemotherapy and stem cell transplantation. Patients were divided into four groups depending on the treatment received: none, PE therapy alone, chemotherapy, with or without PE therapy, or eculizumab, with or without chemotherapy and PE therapy. RESULTS: The data of 59 patients with cancer-associated TMA were analysed. Twenty of these cases were related to a cancer recurrence. The cancer was metastatic in 90% of cases (53/59). Bone marrow invasion was observed in 20/41 biopsies. Some laboratory results, including disseminated intravascular coagulation high ferritin and C-reactive protein, were suggestive of cancer. None of the 16 patients whose alternative complement pathway was assessed had abnormal levels of protein expression or activity. The median survival time was 27 days. Chemotherapy was significantly associated with improved survival, with a 30-day survival rate of 85% (17/20) among patients who received PE and chemotherapy, versus 20% (3/15) among patients who received PE alone. Patients treated with eculizumab in addition to chemotherapy and PE therapy did not have longer overall survival or higher haematological remission rates than those treated with chemotherapy and PE therapy alone. Renal remission rates were non-significantly higher, and times to remission non-significantly shorter, in the eculizumab group. CONCLUSIONS: Nephrologists and oncologists should make themselves aware of cancer diagnoses in patients with TMA and bone marrow biopsies should be performed systematically in these cases. All 59 patients had poor survival outcomes, but patients treated with urgent initiation of chemotherapy survived significantly longer than those who were not.

Pre-Operative Factors Associated with the Occurrence of Acute Kidney Injury in Patients Aged 65 Years and Over Undergoing Non-Ambulatory Non-Cardiac Surgery.

This study sought to identify risk factors for acute kidney injury (AKI) from pre-operative variables in a population of subjects aged over 65. Eligible patients were aged 65 years or over who underwent scheduled non-cardiac, non-ambulatory surgery. Patients with a diagnosis of AKI recorded in the hospital's databases were considered since cases, from which 300 patients with no diagnosis of AKI, were drawn at random as controls. In total, 81 cases of post-operative AKI and 239 controls were identified. The incidence of post-operative AKI was 2.87%. Pre-operative creatinine level (p = 0.0001), a history of respiratory insufficiency (p = 0.04), prior vascular surgery (p = 0.0001) and abdominal surgery (p = 0.03) were associated with an increased risk of AKI after surgery. These four variables calculated a score and developed a nomogram for predicting occurrence of post-operative AKI. A history of renal disease was associated with increased risk of post-operative AKI, predominantly in cases of vascular or abdominal surgery.

Automatic Evaluation of Histological Prognostic Factors Using Two Consecutive Convolutional Neural Networks on Kidney Samples.

BACKGROUND AND OBJECTIVES: The prognosis of patients undergoing kidney tumor resection or kidney donation is linked to many histologic criteria. These criteria notably include glomerular density, glomerular volume, vascular luminal stenosis, and severity of interstitial fibrosis/tubular atrophy. Automated measurements through a deep-learning approach could save time and provide more precise data. This work aimed to develop a free tool to automatically obtain kidney histologic prognostic features. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In total, 241 samples of healthy kidney tissue were split into three independent cohorts. The "Training" cohort (n=65) was used to train two convolutional neural networks: one to detect the cortex and a second to segment the kidney structures. The "Test" cohort (n=50) assessed their performance by comparing manually outlined regions of interest to predicted ones. The "Application" cohort (n=126) compared prognostic histologic data obtained manually or through the algorithm on the basis of the combination of the two convolutional neural networks. RESULTS: In the Test cohort, the networks isolated the cortex and segmented the elements of interest with good performances (>90% of the cortex, healthy tubules, glomeruli, and even globally sclerotic glomeruli were detected). In the Application cohort, the expected and predicted prognostic data were significantly correlated. The correlation coefficients r were 0.85 for glomerular volume, 0.51 for glomerular density, 0.75 for interstitial fibrosis, 0.71 for tubular atrophy, and 0.73 for vascular intimal thickness, respectively. The algorithm had a good ability to predict significant (>25%) tubular atrophy and interstitial fibrosis level (receiver operator characteristic curve with an area under the curve, 0.92 and 0.91, respectively) or a significant vascular luminal stenosis (>50%) (area under the curve, 0.85). CONCLUSION: This freely available tool enables the automated segmentation of kidney tissue to obtain prognostic histologic data in a fast, objective, reliable, and reproducible way.

Chronic kidney disease linked to SARS-CoV-2 infection: a case report.

BACKGROUND: The recent COVID-19 pandemic has raised concerns about patient diagnosis and follow-up of chronically ill patients. Patients suffering from chronic illnesses, concomitantly infected by SARS-CoV-2, globally tend to have a worse prognosis and poor outcomes. Renal tropism and acute kidney injury following SARS-CoV-2 infection has recently been described in the literature, with elevated mortality rates. Furthermore, patients with pre-existing chronic kidney disease, infected by SARS-CoV-2, should be monitored carefully. Here, we report the case of a 69-year-old patient with splenic marginal zone lymphoma, suffering from longstanding chronic kidney disease following SARS-CoV-2 infection. CASE PRESENTATION: A 69-year-old male patient previously diagnosed with pulmonary embolism and splenic marginal zone lymphoma (Splenomegaly, Matutes 2/5, CD5 negative and CD23 positive), was admitted to the hospital with shortness of breath, fever and asthenia. A nasopharyngeal swab test was performed in addition to a CT-scan, which confirmed SARS-CoV-2 infection. Blood creatinine increased following SARS-CoV-2 infection at 130 µmol/l, with usual values at 95 µmol/l. The patient was discharged at home with rest and symptomatic medical treatment (paracetamol and hydration), then readmitted to the hospital in August 2020. A kidney biopsy was therefore conducted as blood creatinine levels were abnormally elevated. Immunodetection performed in a renal biopsy specimen confirmed co-localization of SARS-CoV2 nucleocapsid and protease 3C proteins with ACE2, Lewis x and sialyl-Lewis x antigens in proximal convoluted tubules and podocytes. Co-localization of structural and non-structural viral proteins clearly demonstrated viral replication in proximal convoluted tubules in this chronically ill patient. Additionally, we observed the co-localization of sialyl-Lewis x and ACE2 receptors in the same proximal convoluted tubules. Reverse Transcriptase-Polymerase Chain Reaction test performed on the kidney biopsy was negative, with very low Ct levels (above 40). The patient was finally readmitted to the haematology department for initiation of chemotherapy, including CHOP protocol and Rituximab. CONCLUSIONS: Our case emphasizes on the importance of monitoring kidney function in immunosuppressed patients and patients suffering from cancer following SARS-CoV-2 infection, through histological screening. Further studies will be required to decipher the mechanisms underlying chronic kidney disease and the putative role of sialyl-Lewis x and HBGA during SARS-CoV-2 infection.

Short- and long-term renal outcomes following severe rhabdomyolysis: a French multicenter retrospective study of 387 patients.

BACKGROUND: Rhabdomyolysis is a life-threatening disease that can lead to severe hyperkalemia, acute kidney injury (AKI) and hypovolemic shock. The predictive factors of AKI and acute to chronic kidney disease (CKD) transition remain poorly described. METHODS: This multicenter retrospective study enrolled 387 patients with severe rhabdomyolysis (CPK > 5000 U/L). Primary end-point was the development of severe AKI, defined as stage 2 or 3 of KDIGO classification. Secondary end-points included the incidence of AKI to CKD transition. RESULTS: Among the 387 patients, 315 (81.4%) developed AKI, including 171 (44.1%) with stage 3 AKI and 103 (26.6%) requiring RRT. Stage 2-3 AKI was strongly correlated with serum phosphate, potassium and bicarbonate at admission, as well as myoglobin over 8000 U/L and the need for mechanical ventilation. 42 patients (10.8%) died before day 28. In the 80 patients with available eGFR values both before and 3 months after the rhabdomyolysis, the decrease in eGFR (greater than 20 mL/min/1.73 m2 in 23 patients; 28.8%) was correlated to the severity of the AKI and serum myoglobin levels > 8000 U/L at admission. CONCLUSIONS: Severe rhabdomyolysis leads to AKI in most patients admitted to an ICU. Mechanical ventilation and severity of the rhabdomyolysis, including myoglobin level, are associated with the risk of stage 2-3 AKI. The long-term renal decline is correlated to serum myoglobin at admission.

[Premature immune senescence and chronic kidney disease: Update and perspectives]. / Maladie rénale chronique et immunosénescence prématurée : données et perspectives.

Immune senescence is associated with age-related diseases (i.e. infectious disease, cardiovascular diseases and cancers). Chronic kidney disease patients die prematurely when compared with general population, because of a higher occurrence of infections, cardiovascular events and cancer. These diseases are commonly observed in the elderly population and frequently associated with immune senescence. Indeed, chronic kidney disease causes a premature aging of the T lymphocyte compartment, widely related to a decrease in thymic function, a phenomenon that plays a key role in the onset of age-related diseases in chronic kidney disease patients. The degree of immune senescence also influences patients' outcome after renal transplantation, particularly the risk of acute rejection and infections. Partial reversion of pre-transplant immune senescence is observed for some renal transplant patients. In conclusion, to reduce the increasing incidence of morbidity and mortality of chronic kidney disease patients, a better knowledge of uremia-induced immune senescence would help to pave the way to build clinical studies and promote innovative therapeutic approaches. We believe that therapeutic reversion and immune senescence prevention approaches will be part of the management of chronic kidney disease patients in the future.

Fusobacterium nucleatum bacteremia with pneumopathy in a patient receiving eculizumab: A case report.

Fusobacterium nucleatum is a common oral commensal bacterium capable of severe invasive infections. We report a case of a diffuse bilateral pneumopathy with F. nucleatum-positive blood culture successfully treated by common antibiotics in a patient receiving eculizumab for a drug-induced thrombotic microangiopathy (TMA). It is the first described case of a severe F. nucleatum-associated infection in a patient undergoing terminal complement inhibitor therapy. We suggest providing preventive dental care before eculizumab initiation.

ESRD-associated immune phenotype depends on dialysis modality and iron status: clinical implications.

BACKGROUND: End-stage renal disease (ESRD) causes premature ageing of the immune system. However, it is not known whether hemodialysis (HD) and peritoneal dialysis (PD) similarly affect the T cell system. METHODS: The aim of our study was to analyse whether dialysis modality may mitigate ESRD-induced immune senescence. We explored a large population of patients (675 ESRD patients) and both confirmed and refined the results in a second cohort (84 patients). RESULTS: HD patients exhibited higher inflammatory monocytes counts (44/mm3 (1-520) vs 36/mm3 (1-161); p = 0.005). Patients on HD also had higher frequency of CD8 T cells (24% (7-61) vs 22% (8-42); p = 0.003) and reduced CD4/CD8 ratio. Such results were confirmed in the second cohort. Moreover, both CD4 + CD57 + CD28- (3.25% (0-38.2) vs 1.05% (0-28.5); p = 0.068) and CD8 + CD57 + CD28- (38.5% (3.6-76.8) vs 26.1 (2.1-46.9); p = 0.039) T cells frequencies were increased in HD patients. Telomere length did not differ according to dialysis modality, but was inversely related to ferritin levels (r = - 0.33; p = 0.003). There was a trend towards higher telomerase activity in PD patients (11 ± 13 vs 6 ± 11; p = 0.053). Thymic function was not different in PD and HD patients. Patients on PD before transplantation had a higher risk of acute rejection after kidney transplantation (HR, 1.61; 95%CI, 1.02 to 2.56; p = 0.041). CONCLUSIONS: More pronounced inflammation with hemodialysis may induce premature aging of the immune system. This observation correlates with a lower risk of acute kidney rejection in patients previously on HD. Clinical consequences in patients maintained on dialysis should be determined. TRIAL REGISTRATION: Trial registration: NCT02843867, registered July 8, 2016.

Late Persistent Positive EBV Viral Load and Risk of Solid Cancer in Kidney Transplant Patients.

BACKGROUND: Recent studies reported that posttransplant Epstein-Barr virus (EBV) replication is frequent and indicates overimmunosuppression. We hypothesized that long-term EBV replication may identify overimmunosuppressed patients at higher risk of cancer. METHODS: We analyzed a prospective cohort of renal transplant recipients having routine EBV PCR surveillance. All cancers (except EBV-related neoplasia) were recorded. RESULTS: Mean follow up was 94 + 23 months. Samples (8412) were available in 669 patients. Three hundred eighty-eight of the 669 patients (58%) had at least 1 positive viremia during follow-up.Epstein-Barr virus D+/R- patients (P = 0.046) as well as those having received antithymocyte globulin (P < 0.001) were more likely to develop persistent EBV viremia. Eighty-six patients (12.9%) developed a cancer during follow-up. The cumulated incidence of cancer was higher in patients with persistent high EBV replication (22.4% vs 10.2%, P = 0.005). The effect of persistent EBV infection remained significant even after adjustment for all confounding factors (hazard ratio, 1.69; 95% confidence interval, 1.10-2.61; P = 0.018). Age, history of antithymocyte globulin use, smoking, and history of cancer were also associated with cancer occurrence. CONCLUSIONS: Persistent high EBV viral load is associated with the occurrence of solid cancer. In this setting, more intensive screening and/or minimization of immunosuppressive treatment are probably required.

Clinicopathologic characteristics, treatment, and outcomes of tubulointerstitial nephritis and uveitis syndrome in adults: A national retrospective strobe-compliant study.

Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare disease, defined by the association of idiopathic acute TINU. The aim of our work was to determine the characteristics of adult TINU syndrome in France, and to assess factors (including treatment) influencing medium-term prognosis.We conducted a nationwide study including 20 French hospitals. Clinical, laboratory, and renal histopathologic data of 41 biopsy-proven TINU syndromes were retrospectively collected. The patients were diagnosed between January 1, 1999 and December 1, 2015.Twenty-five females and 16 males were included (F/M ratio: 1.6:1). The median age at disease onset was 46.8 years (range 16.8-77.4) with a median serum creatinine level at 207 µmol/L (range 100-1687) and a median estimated glomerular filtration rate (eGFR) at 27 mL/min per 1.73 m (range 2-73). Twenty-nine patients (71%) had a bilateral anterior uveitis and 24 (59%) had deterioration in general health at presentation. Moderate proteinuria was found in 32 patients (78%) (median proteinuria 0.52 g/24 h; range 0.10-2.10), aseptic leukocyturia in 25/36 patients (70%). The evaluation of renal biopsies revealed 41 patients (100%) with an acute tubulointerstitial nephritis, 19/39 patients (49%) with light to moderate fibrosis and 5 patients (12%) with an acute tubular necrosis. Thirty-six patients (88%) were treated with oral corticosteroids. After 1 year of follow-up, the median eGFR was 76 mL/min per 1.73 m (range 17-119) and 32% of the patients suffered from moderate to severe chronic kidney disease. Serum creatinine (P < 0.001, r = -0.54), serum bicarbonate and phosphate levels (respectively, P = 0.01, r = 0.53; and P = 0.04, r = 0.46), and age (P = 0.03, r = -0.37) at the 1st symptoms were associated with eGFR after 1 year. During the 1st year 40% of patients had uveitis relapses. The use of oral corticosteroids was not associated with a better kidney function but was associated with fewer uveitis relapses (P = 0.44 and 0.02, respectively).In our study, 32% of patients were suffering from moderate to severe chronic kidney disease after 1 year of follow-up, and 40% had uveitis relapses during this follow-up. This work also suggests that oral corticosteroids are effective for the treatment of TINU syndrome's uveitis.

Incidence and risk factors of anti-HLA immunization after pregnancy.

Pregnancy is the only natural source of anti-HLA immunization. The exact frequency of this immunization remains undetermined as prior studies either used methods with a low sensitivity or were performed late after delivery. We present here the first study on women at delivery evaluating anti-HLA immunization by Luminex. We also attempted to isolate factors influencing immunization, such as soluble HLA-G (sHLA-G) levels and genetic polymorphisms. With Luminex, anti-HLA immunization was observed in 54.4% of the women. As expected, immunization frequency increased with the number of children, reaching 74% in women with >2 deliveries. Among immunized women, strong cytotoxic Ab (as detected by Complement Dependent Cytotoxicity) were associated with a lower level of sHLA-G. None of the studied polymorphisms influenced immunization rate in the whole cohort. Among 94 first pregnant women with no history of miscarriage, the -174 IL-6 gene promoter mutation (G/C) appeared more frequently in non immunized women (69% vs. 45% in immunized ones, p=0.02). Lastly, the occurrence of a miscarriage before the first live delivery significantly decreased immunization. These results may help to understand mechanisms of pregnancy induced immunization. They also have an impact in the management of previous pregnant women requiring organ or hematopoietic stem cell transplantation.

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.

Thymic function, anti-thymocytes globulins, and cancer after renal transplantation.

BACKGROUND: Prolonged CD4 T cell lymphopenia after polyclonal antithymocyte globulins (ATG) is associated with an increased rate of cancers. Here, we examined whether pre-transplant thymic function estimated by TREC levels is predictive of cancer occurrence following ATG treatment. PATIENTS AND METHODS: The impact of TREC on cancer occurrence was analyzed in 115 consecutive incident renal transplant recipients having received ATG. RESULTS: Mean follow-up was 7.5±2.6years. After ATG induction, patients with the lowest pre-transplant TREC values had lower post-transplant CD4(+) and CD4(+) CD45RA(+) CD45RO(-) T cell counts, and a higher frequency of T cells with a regulatory phenotype (CD127(+)CD4(+)CD25(+)Foxp3(+)). Log-transformed pre-transplant TREC values were significantly lower in patients who developed cancer after transplantation (p<0.0001). The cumulative incidence of cancer was higher in patients having the lowest pre-transplant TREC values (T1 [low]: 47.4%, T2 [medium]: 12.5%, and T3 [high]: 2.7%; p<0.0001). In multivariate analysis, pre-transplant TREC value was the only predictive factor of cancer (HR, 0.39; 95% CI, 0.16 to 0.97, for one log (TREC/10(6) PBMC); p=0.046). CONCLUSIONS: Pre-transplant thymic function is associated with an increased rate of post-transplant cancer in patients having received ATG. Omitting ATG in recipients with low pre-transplant TREC values should be considered.

Prolonged CD4 T cell lymphopenia increases morbidity and mortality after renal transplantation.

Prolonged CD4 T cell lymphopenia after administration of polyclonal anti-thymocyte globulins increases the rate of posttransplantation morbidity, but whether impaired immune reconstitution affects survival is unknown. We studied the effect of CD4 T cell lymphopenia on survival in 302 consecutive prevalent renal transplant recipients and the role of thymic function in CD4 T cell reconstitution and posttransplantation outcomes in 100 consecutive incident renal transplant recipients. We followed the prevalent cohort for a mean duration of 92 months. Of these 302 patients, 81 (27%) had persistent CD4 T cell counts <300/mm3 and 36 (12%) died during follow-up. We observed a higher death rate in patients with CD4 T cell lymphopenia persisting for >1 year (24.1 versus 7.6%; P < 0.001). Furthermore, in Cox regression analysis, CD4 T cell lymphopenia associated with a nearly five-fold risk for death (adjusted hazard ratio [HR] 4.63; 95% confidence interval [CI] 1.91 to 10.65; P = 0.001). In the incident cohort, we estimated thymic function by T cell receptor excision circles (TRECs) per 150,000 CD3+ cells, which predicted efficient CD4 T cell reconstitution. Higher pretransplantation TREC values associated with lower risks for cancer (adjusted HR 0.39; 95% CI 0.15 to 0.97; P = 0.046) and infection (HR 0.29; 95% CI 0.11 to 0.78; P = 0.013). In summary, prolonged polyclonal anti-thymocyte globulin-induced CD4 T cell lymphopenia is an independent risk factor for death. Determination of pretransplantation thymic function may identify patients at higher risk for CD4 T cell lymphopenia and posttransplantation morbidity, including cancer and infections.