Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy.

Antibodies to the phospholipase A2 receptor 1 (PLA2R1) have been reported in 70% of cases of idiopathic membranous nephropathy (IMN). The genetic susceptibility of IMN has been accounted for by HLA DQA1 and PLA2R1 genes. Here we retrospectively quantified PLA2R antibodies by ELISA, and genotyped DQ alleles and PLA2R1 single-nucleotide polymorphisms for association with clinical criteria for disease activity at the time of first sample and with outcome over a median total follow-up of 90 months. In 90 prevalent patients with biopsy-proven IMN, anti-PLA2R antibodies were present in 75% of patients with IMN with active disease and were significantly higher than in patients in partial or complete remission at the time of antibody measurement. There was a differential IgG subclass response (4>2>3>1) at an early stage, i.e., within 6 months of biopsy. Levels of PLA2R antibodies were significantly linked to DQA1*05:01 and DQB1*02:01. Survival analysis of patients with IMN showed that PLA2R antibodies are significantly linked with outcome. Thus, high levels of PLA2R antibodies are linked with active disease and a higher risk of declining renal function during follow-up. Future therapeutic trials in IMN should monitor anti-PLA2R, as patients with a high antibody burden may benefit from earlier therapeutic intervention.

Unilateral adrenal metastasis from non­small-cell lung cancer demonstrating very high FDG uptake with a standardized uptake value in excess of sixty.

We report the case of a 52-year-old man who presented with a 2-week history of dyspnea and wheeze. CT scan of the chest showed a large soft-tissue lesion in the right main bronchus extending into the trachea. Pathologic examination of endoscopic tracheal biopsies showed features consistent with a non­small-cell lung carcinoma. 18F-FDG PET/CT showed very high uptake of FDG in the bronchial tumor (high standardized uptake values: 25.1) and unexpected very intense uptake in the left adrenal gland (high standardized uptake values: 62.5). Laparoscopic adrenalectomy was performed, and subsequent histopathological examination confirmed metastatic non­small-cell carcinoma in the adrenal gland. Although adrenal malignancies are generally metabolically active, such high uptake of FDG within a metastatic lesion has not been reported previously.

Native nephrectomy for autosomal dominant polycystic kidney disease: before or after kidney transplantation?

UNLABELLED: Study Type - Therapy (case series). LEVEL OF EVIDENCE: 4. What's known on the subject? and What does the study add? The indications and timing of native nephrectomy in patients with autosomal dominant polycystic kidney disease (ADPKD) is controversial, especially for those undergoing renal transplantation. Post-transplant unilateral native nephrectomy appears to be the preferred intervention compared to pre-transplant native nephrectomy. There seems to be substantial additive risk to bilateral over unilateral nephrectomy, especially prior to transplantation. Pre-transplant native nephrectomy should only be carried out when there are clear indications such as massive size preventing allograft placement, severe pain, early satiety, recurrent bleeding and infections, or suspected malignancy. OBJECTIVE: To analyse indications, timing and outcomes of native nephrectomy in autosomal dominant polycystic kidney disease (ADPKD) patients listed for kidney transplantation. PATIENTS AND METHODS: A retrospective analysis of all ADPKD patients who had a native nephrectomy prior to or following transplantation between January 2003 and December 2009 at a single centre, including those undergoing the sandwich technique (removal of the most severely affected native kidney prior to transplantation, and the other afterwards), was undertaken. RESULTS: There were 35 individuals in our cohort (M : F = 16 : 19), with a median age of 51.5 years (range 43-65). Twenty patients were in the pre-transplant nephrectomy group, 12 in the post-transplant group, and three underwent the sandwich technique. Indications for nephrectomy varied but were most commonly pain/discomfort, space for transplantation, ongoing haematuria, recurrent infections, and gastrointestinal pressure symptoms (early satiety). Seven individuals in the pre-transplant group and three in the post-transplant group required critical care admission after nephrectomy. Transient renal graft dysfunction occurred in two post-transplant bilateral nephrectomy patients. Two patients in the bilateral nephrectomy pre-transplant group and one in the bilateral nephrectomy post-transplant group died in the immediate post-operative period. No complications were noted in the sandwich technique group. CONCLUSION: Native nephrectomy in ADPKD is a major undertaking associated with significant morbidity especially in the pre-transplant group. Post-transplant unilateral nephrectomy appears to be the safest approach with fewest complications.

Best practice: gross examination and sampling of surgical specimens from the urinary bladder.

This review examines aspects of handling biopsies and surgical specimens from the urinary bladder with the aim of providing guidance to ensure that the pathologist is fully able to inform clinicians of all relevant factors that might have bearing on management or prognosis. It also offers recommendations on good practice in reporting in the setting of the specialist multidisciplinary meeting and emphasises quality control of the process, referring to recently published guidelines and consensuses while admitting that many of the recommendations may not be supported by a strong evidence base. The role of urine cytology and the value of frozen sections in urological practice are discussed. Participation in regular clinical audit and the national urological pathology External Quality Assurance (EQA) are recommended.

Bayesian belief network for the Gleason patterns in prostatic adenocarcinoma: development of a diagnostic decision support system for educational purposes.

OBJECTIVE: To develop a Bayesian belief network (BBN) for Gleason grading of prostate adenocarcinoma. STUDY DESIGN: A shallow network was developed for Gleason grading with open-tree topology, with a root node containing 5 subjective diagnostic alternatives and 8 first-level descendant nodes for diagnostic features. Features or diagnostic clues of the descendant nodes were based on architecture of Gleason patterns. Data collected on 20 slides in the first and third slide circulations in the U.K.-based investigation of observer reproducibility of Gleason grading of prostatic biopsies were used. Circulations were called A and B. Level of agreement was studied using kappa statistics. RESULTS: Mean of percentage agreements between subjective Gleason major pattern attributed to slides by pathologists and subjective Gleason major pattern most frequently assigned to each slide was 85% in A and 88% in B. Mean of percentage agreements between BBN reading for slides read by pathologists and BBN reading most frequently seen in each slide was 77% in A and 70% in B. CONCLUSION: The BBN for Gleason grading is readily implemented, allowing use of linguistic variables and descriptive terms and accumulation of evidence presented by morphologic clues. This diagnostic decision support system has potential in pathology education.

Association between C4d staining in renal transplant biopsies, production of donor-specific HLA antibodies, and graft outcome.

BACKGROUND: We carried out a retrospective study of C4d staining in paraffin sections from renal transplant biopsies to determine the association between C4d staining, donor-specific antibodies (DSA), histological features, and graft outcome. METHODS: We studied 92 patients who had been biopsied for graft dysfunction. Biopsies were classified using Banff 97 criteria and features suggestive of antibody-mediated rejection were noted. Paraffin sections were stained with a polyclonal antibody using an immunoperoxidase technique. The presence of DSA in concurrent sera was determined by enzyme-linked immunosorbent assay and clinical data were reviewed. RESULTS: Of the 92 cases, 15% showed diffuse and 24% showed focal C4d positivity. The grafts failed in 36% of the diffuse (P<0.025), 23% of the focal, and 7% of the negative group at between one month and 15 years posttransplantation. Only patients in the group with diffuse C4d positivity had concurrent DSA (five cases, P<0.001). Of the five DSA-positive patients, three had type II acute rejection and two of these transplants subsequently failed. The remaining two had chronic allograft nephropathy with features of alloimmune injury. Only two of the nine DSA-negative/C4d-positive transplants had failed at the time of writing, in one case due to recurrent disease. CONCLUSION: We demonstrated a significant association between diffuse C4d staining, production of DSA, and graft failure. Although the concurrent detection of DSA and C4d positivity is uncommon in our patients, these results indicate that outcome in this group is poor and they may benefit from therapies directed at the humoral response.

The role of HLA-specific antibodies in kidney transplant rejection: published studies and local data.

The post-transplantation production of antibodies directed against donor HLA class I and class II mismatches has been shown to be associated with transplant rejection. Recipient sensitization against donor HLA plays a key role in transplant rejection; this risk is best minimized by efficient pre-transplant antibody detection and definition, effective pre-allocation cross-matching, and minimization of HLA mismatches between donor and recipient. The term "PRA" is of little value. Identification of the HLA specificity to which an antibody is directed is essential and now possible using contemporary methodology. It is now recognized that antibody-mediated rejection should be diagnosed on the basis of allograft dysfunction, characteristic features of histology, C4d immunohistology, and the presence of donor-specific antibodies. HLA-DP is becoming recognized as a "transplantation antigen." For the future, the repertoire of a histocompatibility laboratory must expand to include typing organ transplant recipients and donors for HLA-DP and also the definition of antibodies to DP. Antibodies to non-HLA targets should be an important consideration when assessing factors that influence transplant outcome.