PLA2R and membranous nephropathy: A 3 year prospective Australian study.

AIM: The phospholipase A2 receptor (PLA2R) is the major target antigen in idiopathic membranous nephropathy (iMN). The aim of this prospective study was to determine the prevalence of anti-PLA2R in iMN in an Australian cohort. METHODS: Serum anti-PLA2R was measured using two techniques, an enzyme-linked immunosorbent assay (ELISA) and a cell-based indirect immunofluorescence test. Kidney biopsies were also examined for the presence of PLA2R using a polyclonal antibody. A group of 21 patients with iMN were compared with a group of 19 patients with secondary MN and other glomerular diseases. RESULTS: Seventeen of 21 patients with iMN were positive for anti-PLA2R on both ELISA and indirect immunofluorescence test, and 14 of these patients also had positive staining for PLA2R in the biopsy (tissue was unavailable in two patients). Three patients with iMN had positive staining in the biopsy only, and one patient was negative in both the serum and the biopsy. None of the patients with secondary MN or other glomerular diseases had anti-PLA2R antibodies or PLA2R in the biopsy. There was wide inter-individual variation in titre on ELISA, but serial levels within an individual patient enabled monitoring of disease, and a fall in titre correlated with clinical remission. CONCLUSIONS: This is the first Australian series to examine the incidence of anti-PLA2R in iMN. It is also unique in examining sera by two separate techniques in conjunction with tissue localization of PLA2R. We have shown 100% specificity of both serum anti-PLA2R and glomerular PLA2R in iMN, with a sensitivity of 81.0%. When serum testing is combined with tissue localization of PLA2R, the sensitivity increases to 95.2%.

Case report of interstitial nephritis induced by bevacizumab therapy for glioblastoma multiforme.

Glioblastoma multiforme is an aggressive malignant brain tumor. The monoclonal antibody, bevacizumab, is active in recurrent disease via inhibition of angiogenesis. Proteinuria and renal thrombotic microangiopathy are known complications. We report a case of a patient developing acute renal failure with biopsy-proven interstitial nephritis while receiving bevacizumab for recurrent disease. The patient was otherwise well with a history of controlled hypertension. Renal function improved with discontinuation of bevacizumab and the administration of corticosteroid therapy.

A case of triple pathology: seronegative anti-glomerular basement membrane antibody-mediated glomerulonephritis and membranous nephropathy in a patient with underlying diabetic kidney disease.

In diabetic patients with acute kidney injury (AKI), kidney biopsy often reveals non-diabetic kidney pathology. This case describes a patient with known Type 1 diabetes who presented with AKI, nephrotic syndrome and haematuria. Combination pathology of seronegative anti-glomerular basement membrane antibody-mediated glomerulonephritis (anti-GBM GN), membranous nephropathy (MN) and diabetic nephropathy (DN) was demonstrated. Strong linear GBM IgG-staining on biopsy with crescentic GN and clinical AKI led to a diagnosis of anti-GBM GN, although serum antibodies were not detectable. Features of DN, Kimmelstiel-Wilson nodules and albumin staining were also present, along with features of MN, such as subepithelial deposits on electron microscopy. Despite treatment with immunosuppression and plasmapheresis, there was no recovery of kidney function. Coexisting anti-GBM GN and MN is well recognized, but the concurrent diagnosis with DN has not been described.

The Oxford IgA nephropathy clinicopathological classification is valid for children as well as adults.

To study the predictive value of biopsy lesions in IgA nephropathy in a range of patient ages we retrospectively analyzed the cohort that was used to derive a new classification system for IgA nephropathy. A total of 206 adults and 59 children with proteinuria over 0.5 g/24 h/1.73 m(2) and an eGFR of stage-3 or better were followed for a median of 69 months. At the time of biopsy, compared with adults children had a more frequent history of macroscopic hematuria, lower adjusted blood pressure, and higher eGFR but similar proteinuria. Although their outcome was similar to that of adults, children had received more immunosuppressants and achieved a lower follow-up proteinuria. Renal biopsies were scored for variables identified by an iterative process as reproducible and independent of other lesions. Compared with adults, children had significantly more mesangial and endocapillary hypercellularity, and less segmental glomerulosclerosis and tubulointerstitial damage, the four variables previously identified to predict outcome independent of clinical assessment. Despite these differences, our study found that the cross-sectional correlation between pathology and proteinuria was similar in adults and children. The predictive value of each specific lesion on the rate of decline of renal function or renal survival in IgA nephropathy was not different between children and adults.

The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility.

Pathological classifications in current use for the assessment of glomerular disease have been typically opinion-based and built on the expert assumptions of renal pathologists about lesions historically thought to be relevant to prognosis. Here we develop a unique approach for the pathological classification of a glomerular disease, IgA nephropathy, in which renal pathologists first undertook extensive iterative work to define pathologic variables with acceptable inter-observer reproducibility. Where groups of such features closely correlated, variables were further selected on the basis of least susceptibility to sampling error and ease of scoring in routine practice. This process identified six pathologic variables that could then be used to interrogate prognostic significance independent of the clinical data in IgA nephropathy (described in the accompanying article). These variables were (1) mesangial cellularity score; percentage of glomeruli showing (2) segmental sclerosis, (3) endocapillary hypercellularity, or (4) cellular/fibrocellular crescents; (5) percentage of interstitial fibrosis/tubular atrophy; and finally (6) arteriosclerosis score. Results for interobserver reproducibility of individual pathological features are likely applicable to other glomerulonephritides, but it is not known if the correlations between variables depend on the specific type of glomerular pathobiology. Variables identified in this study withstood rigorous pathology review and statistical testing and we recommend that they become a necessary part of pathology reports for IgA nephropathy. Our methodology, translating a strong evidence-based dataset into a working format, is a model for developing classifications of other types of renal disease.

The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification.

IgA nephropathy is the most common glomerular disease worldwide, yet there is no international consensus for its pathological or clinical classification. Here a new classification for IgA nephropathy is presented by an international consensus working group. The goal of this new system was to identify specific pathological features that more accurately predict risk of progression of renal disease in IgA nephropathy, thus enabling both clinicians and pathologists to improve individual patient prognostication. In a retrospective analysis, sequential clinical data were obtained on 265 adults and children with IgA nephropathy who were followed for a median of 5 years. Renal biopsies from all patients were scored by pathologists blinded to the clinical data for pathological variables identified as reproducible by an iterative process. Four of these variables: (1) the mesangial hypercellularity score, (2) segmental glomerulosclerosis, (3) endocapillary hypercellularity, and (4) tubular atrophy/interstitial fibrosis were subsequently shown to have independent value in predicting renal outcome. These specific pathological features withstood rigorous statistical analysis even after taking into account all clinical indicators available at the time of biopsy as well as during follow-up. The features have prognostic significance and we recommended they be taken into account for predicting outcome independent of the clinical features both at the time of presentation and during follow-up. The value of crescents was not addressed due to their low prevalence in the enrolled cohort.

Margins and outcome of screen-detected breast cancer with extensive in situ component.

BACKGROUND: In situ disease surrounding invasive tumours is an important consideration in the management of patients with early breast cancer. This study of screen-detected breast cancers assessed the influence of in situ disease including an extensive in situ component (defined as ductal carcinoma in situ involving more than 25% of the area within the invasive tumour) on surgical management, local recurrence and survival of a group of patients. METHODS: A total of 595 cases of invasive breast cancer detected at St Vincent's BreastScreen were retrospectively reviewed to determine presence and extent of in situ disease, the surgical procedure and adequacy of excision. Outcome was examined in a cohort of 126 cases. RESULTS: A total of 438 (74%) patients had in situ foci in or around the invasive tumour and 107 (18%) were defined as extensive in situ component (EIC)-positive. The initial procedure was mastectomy in 20% of the cases and breast-conserving surgery in 80% including 18% who underwent further surgery. Re-excision (P = 0.02) or mastectomy (P = 0.01) was more often required in patients with EIC. After definitive local excision, margins were close or involved with invasive disease in 3% but the patients with EIC were more likely to have margins close or involved with in situ disease (16 vs 2%; P = 0.001). There were seven deaths and one local invasive recurrence in the follow-up group and none of the deaths were in patients who were EIC-positive. CONCLUSIONS: EIC predicts for a higher rate of re-excision and/or mastectomy. For patients with EIC, there is an acceptably low risk of local recurrence if margins are clear.

Painful diabetic mastopathy as a reason for mastectomy.

A 34 year old woman with longstanding insulin-dependent diabetes mellitus experienced disabling bilateral breast pain and tenderness associated with the benign breast lesions of diabetic mastopathy. Diabetic mastopathy is typically associated with nontender lesions, however we present a case where disabling pain and tenderness lead to bilateral mastectomy, as requested by the patient. This relieved the patient of her symptoms.