La Salete Martins

Analysis of preformed donor-specific anti-HLA antibodies characteristics for prediction of antibody-mediated rejection in kidney transplantation

BACKGROUND The relevance of preformed donor specific antibodies (DSA) detected by Luminex assays, with a negative complement-dependent cytotoxicity (CDC) crossmatch, remains unsettled in kidney transplantation (KT). We aimed to analyze the impact of preformed DSA characteristics on kidney graft outcomes. METHODS In 462 patients that received a kidney graft in our unit, between 2007 and 2012, pre-transplant sera were analyzed by Luminex screening assay to determine the presence of anti-human leukocyte antigen (HLA) antibodies and single-antigen bead assay [positive if mean fluorescence intensity (MFI) ≥ 1000] to assign anti-HLA specificities. RESULTS Anti-HLA antibodies were present in 95 patients (20.6%), but only 40 (8.7%) had DSA. Antibody-mediated rejection (AMR) at 1-year was higher in patients with DSA (35.0%) than in those without them (0.9%) (P < 0.001). Only DSA with a MFI of >3000 were significantly associated with AMR occurrence. Receiver operator curves revealed that a MFI of >4900 in the highest DSA bead had a high sensitivity (85.7%) and that the sum of all DSA beads MFI > 11,000 had a high specificity (92.3%) for AMR prediction. Anti-thymocyte globulin versus basiliximab induction was more frequent in DSA+ AMR- (65.4%) versus DSA+ AMR+ (34.6%) patients (P = 0.072). Five-year censored graft survival was lower in DSA+ than in DSA- patients (respectively, 84.8% versus 94.9%, P = 0.006), although survival was only reduced in DSA+ AMR+ (68.8%) versus DSA+ AMR- (96.0%) patients (P = 0.038). CONCLUSIONS Preformed DSA is associated with kidney graft loss, in relation with AMR occurrence. DSA strength may be used to improve immunological risk stratification of sensitized patients and their clinical management.

Pulmonary alveolar proteinosis: a rare pulmonary toxicity of sirolimus.

The aim of our paper is to describe an unusual pulmonary toxicity of sirolimus (SRL) in a kidney transplant recipient. We present a 34‐year‐old woman with a second renal transplantation, complicated with steroid‐resistant acute rejection and chronic allograft dysfunction. Two years after initiating SRL, she presented complaints of progressive dyspnoea, nonproductive cough, chest pain and low‐grade fever of 1 month duration. She had chronic allograft nephropathy and slight elevation of lactic dehydrogenase levels. After exclusion of common reasons of this condition, a computed tomography (CT) of the thorax and bronchoscopy was performed, revealing ground‐glass opacification with polygonal shapes on CT and an opaque appearance with numerous macrophages on bronchoalveolar lavage. The alveolar macrophages stained positive by Periodic acid‐Schiff. Diagnosis of pulmonary alveolar proteinosis (PAP) was made and drug‐induced toxicity was suspected. SRL was withdrawn with marked improvement in the patients’ clinical and radiological status. PAP resolved within 3 months without further therapy. PAP is a very rare complication of SRL therapy with only a few cases described. Withdrawal of SRL with conversion to another immunosuppressant seems to be an appropriate procedure in this condition.

Cost analysis of renal replacement therapy by transplant in a system of bundled payment of dialysis

Rocha MJ, Ferreira S, Martins LS, Almeida M, Dias L, Pedroso S, Henriques AC, Almeida R, Cabrita A. Cost analysis of renal replacement therapy by transplant in a system of bundled payment of dialysis.

Estimating glomerular filtration rate in kidney transplantation: Still searching for the best marker.

Kidney transplantation is the treatment of choice for end-stage renal disease. The evaluation of graft function is mandatory in the management of renal transplant recipients. Glomerular filtration rate (GFR), is generally considered the best index of graft function and also a predictor of graft and patient survival. However GFR measurement using inulin clearance, the gold standard for its measurement and exogenous markers such as radiolabeled isotopes ((51)Cr EDTA, (99m)Tc DTPA or (125)I Iothalamate) and non-radioactive contrast agents (Iothalamate or Iohexol), is laborious as well as expensive, being rarely used in clinical practice. Therefore, endogenous markers, such as serum creatinine or cystatin C, are used to estimate kidney function, and equations using these markers adjusted to other variables, mainly demographic, are an attempt to improve accuracy in estimation of GFR (eGFR). Nevertheless, there is some concern about the inability of the available eGFR equations to accurately identify changes in GFR, in kidney transplant recipients. This article will review and discuss the performance and limitations of these endogenous markers and their equations as estimators of GFR in the kidney transplant recipients, and their ability in predicting significant clinical outcomes.

Impact of Pediatric Kidney Transplantation on Long-Term Professional and Social Outcomes

BACKGROUND Kidney transplantation in childhood and adolescence implies a set of challenges to long-term social and professional integration. The aim of this study was to characterize the academic activity and the professional situation of pediatric patients undergoing kidney transplantation. METHODS Through a questionnaire, we obtained information from all patients aged <18 years who underwent kidney transplantation between 1984 and 2009. RESULTS During this period, 104 kidney transplantations were performed in 96 patients whose mean age was 13.9 ± 2.8 years. As of March 2010, their mean age was 26.3 ± 5.6 years and 57.1% were male subjects. Eighty-one patients (87.1%) had functioning grafts with 12 (12.9%) undergoing dialysis. The distribution of academic qualifications was not substantially different from the Portuguese average: 1.1% were at the lowest level (vs 4.6%); 17.6%, middle lower level (vs 25.7%), 34.1%, middle level (vs 36.2%); 28.6%, middle higher level (vs 22.8%), and 18.7% had obtained a university degree (vs 10.7%). At the end of follow-up, 13 patients (14.3%) were students, 52 (58.2%) had paid employment, and 14 (15.4%) received a pension. The unemployment rate was 17.5% (vs 9.3% of the general Portuguese population). The proportion of unemployed and retired subjects was higher among patients who had lost their kidney graft (26.1% vs 7.5% and 34.8 vs 9.0%, respectively; P = .001). Twenty-nine patients (32.2%) had independent lodging, 21 (23.1%) were married, and 12 (13.2%) had children. Higher academic qualifications were associated with independent lodging (P = .001). Forty-three percent of patients had a mean height below the 5th percentile (-2 standard deviation). However, mean height did not correlate with academic qualifications, independent lodging, marital life, or procreation. CONCLUSION This group of patients showed encouraging academic, professional and social results. Graft loss may influence employment status.

Determining donor‐specific antibody C1q‐binding ability improves the prediction of antibody‐mediated rejection in human leucocyte antigen‐incompatible kidney transplantation

Detrimental impact of preformed donor‐specific antibodies (DSAs) against human leucocyte antigens on outcomes after kidney transplantation are well documented, however, the value of their capacity to bind complement for predicting antibody‐mediated rejection (AMR) and graft survival still needs to be confirmed. We aimed to study DSA characteristics (strength and C1q binding) that might distinguish harmful DSA from clinically irrelevant ones. We retrospectively studied 60 kidney‐transplanted patients with preformed DSA detected by single antigen bead (SAB) assays (IgG and C1q kits), from a cohort of 517 kidney graft recipients (124 with detectable anti‐HLA antibodies). Patients were divided into DSA strength (MFI < vs. ≥ 15 000) and C1q‐binding ability. AMR frequency was high (30%) and it increased with DSA strength (P = 0.002) and C1q+ DSA (P < 0.001). The performance of DSA C1q‐binding ability as a predictor of AMR was better than DSA strength (diagnostic odds ratio 16.3 vs. 6.4, respectively). Furthermore, a multivariable logistic regression showed that C1q+ DSA was a risk factor for AMR (OR = 16.80, P = 0.001), while high MFI DSAs were not. Graft survival was lower in high MFI C1q+ DSA in comparison with patients with C1q− high or low MFI DSA (at 6 years, 38%, 83% and 80%, respectively; P = 0.001). Both DSA strength and C1q‐binding ability assessment seem valuable for improving pretransplant risk assessment. Since DSA C1q‐binding ability was a better predictor of AMR and correlated with graft survival, C1q‐SAB may be a particularly useful tool.

Over Ten-Year Kidney Graft Survival Determinants

Kidney graft survival has been mainly evaluated using an up to 10-year threshold. Instead, in this study our aim was to evaluate predictive variables that impact long-term kidney graft survival (≥10 years). We enrolled 892 patients in our analysis: 638 patients with functioning graft at 10 years PT and 254 patients with graft failure at 10 years PT (considering patient death with a functioning graft <10 years PT as graft failure). Between groups comparisons were done using Mann-Whitney and chi-square test. To determine independent predictive variables for long-term graft survival a multivariate-adjusted logistic regression was performed. Significant predictors of long term graft survival were lower 12-month PT creatinine (OR = 0.26, P < 0.001), lower donor age (OR = 0.98, P = 0.004), shorter time on dialysis (OR = 0.93, P = 0.044), recipient positive CMV IgG (OR = 1.59, P = 0.040), absence of AR episodes (OR = 1.57, P = 0.047), 0 to 1 (versus 2) HLA-B mismatch (OR = 1.80, P = 0.004), and recipients male gender (OR = 1.84, P = 0.005). Our results show that an early KT, younger donor age, and an optimal first year graft function are of paramount importance for long-term graft survival. Measures that address these issues (careful donor selection, preemptive KT, and effective immunosuppressive protocols) are still warranted.

Pancreas-Kidney Transplantation: Complications and Readmissions in 9-Years of Follow-up

Over 9 years, we have performed 93 simultaneous pancreas-kidney transplants (SPKT). The morbidity of this procedure is high compared with kidney transplantation alone; readmissions are frequent and costs are higher. Herein we have presented the complications during follow-up of these 93 patients. Their mean age was 34 +/- 6 years and prior dialysis time was 32 +/- 25 months. The median hospital stay on the first admission for the transplant procedure was 22 days, including 2 days in the intensive care unit. Bleeding, thrombosis, and infection were the most frequent reasons for prolonged hospitalization. Thirty patients underwent >or=1 surgical reinterventions. Incidence of acute rejection episodes was 11.8%. After discharge, 74.2% of the patients had 197 readmission episodes with infection being the main cause, urinary tract infections, the most frequent; however, systemic viral and fungal infections required the longest readmission periods. The need for surgical interventions, graft dysfunction, and vascular problems were the remaining causes of readmission. At the end of follow-up, 87 patients were alive, 86 with well-functioning kidneys and 74 with normal functioning pancreata. Global survival rates for patient, kidney, and pancreas were 96%, 95%, and 81% at 1-year; 93%, 90%, and 79% at 5-years; and 93%, 90% and 79% at 9-years. Although pancreas-kidney transplant patients are complex presenting many management difficulties, our overall results represent a positive stimulus for diabetic patients.

Pancreatic autoantibodies after pancreas–kidney transplantation – do they matter?

Type 1 diabetes recurrence has been documented in simultaneous pancreas–kidney transplants (SPKT), but this diagnosis may be underestimated. Antibody monitoring is the most simple, noninvasive, screening test for pancreas autoimmune activity. However, the impact of the positive autoimmune markers on pancreas graft function remains controversial. In our cohort of 105 SPKT, we studied the cases with positive pancreatic autoantibodies. They were immunosuppressed with antithymocyte globulin, tacrolimus, mycophenolate, and steroids. The persistence or reappearance of these autoantibodies after SPKT and factors associated with their evolution and with graft outcome were analyzed. Pancreatic autoantibodies were prospectively monitored. Serum samples were collected before transplantation and at least once per year thereafter. At the end of the follow‐up (maximum 138 months), 43.8% of patients were positive (from pre‐transplant or after recurrence) for at least one autoantibody – the positive group. Antiglutamic acid decarboxylase was the most prevalent (31.4%), followed by anti‐insulin (8.6%) and anti‐islet cell autoantibodies (3.8%). Bivariate analysis showed that the positive group had higher fasting glucose, higher glycated hemoglobin (HbA1c), lower C‐peptide levels, and a higher number of HLA‐matches. Analyzing the sample divided into four groups according to pre‐/post‐transplant autoantibodies profile, the negative/positive group tended to present the higher HbA1c values. Multivariate analysis confirmed the significant association between pancreas autoimmunity and HbA1c and C‐peptide levels. Positivity for these autoantibodies pre‐transplantation did not influence pancreas survival. The unfavorable glycemic profile observed in the autoantibody‐positive SPKT is a matter of concern, which deserves further attention.

Steroid Withdrawal in Simultaneous Pancreas-Kidney Transplantation: A 7-Year Report

Simultaneous pancreas-kidney transplantation (SPK) is the treatment of choice for selected diabetic patients with end-stage renal disease. Maintenance steroid therapy is associated with significant morbidity and mortality among SPK transplant recipients. Steroid withdrawal regimens are becoming more common, albeit with reservations regarding its safety and efficacy. We performed a retrospective review of 77 SPK transplant recipients from May 2000 to December 2007. The subjects received induction therapy with thymoglobulin followed by maintenance immunosuppression with tacrolimus and mycophenolate mofetil. A late steroid withdrawal protocol was adopted. The rates of acute rejection, graft and patient survival, and side effects were analyzed. One-year patient, kidney, and pancreas survivals were 93%, 91%, and 86%, respectively. Eleven patients experienced acute rejection. Mean follow-up time was 1155.5 +/- 776.1 days. Prednisolone withdrawal was carried out between 6 and 12 months posttransplantation in 42 patients (77.8%) with at least 1 year follow-up; no case of acute rejection occurred. At present, 72 patients have a functioning kidney graft, and 65 patients also have a functioning pancreas graft. The mean serum creatinine is 1.12 +/- 0.49 mg/dL and the mean HbA1c concentration is 4.5% +/- 0.4%. The patients have a low prevalence of hypertension, hyperlipidemia, and obesity. Steroid withdrawal was successful and safe in the majority of in-study patients and safe without an increase of immune events. Our patient and graft outcomes are within other international SPK transplant units standards.