Guidelines for the diagnosis of antibody-mediated rejection in pancreas allografts-updated Banff grading schema.

The first Banff proposal for the diagnosis of pancreas rejection (Am J Transplant 2008; 8: 237) dealt primarily with the diagnosis of acute T-cell-mediated rejection (ACMR), while only tentatively addressing issues pertaining to antibody-mediated rejection (AMR). This document presents comprehensive guidelines for the diagnosis of AMR, first proposed at the 10th Banff Conference on Allograft Pathology and refined by a broad-based multidisciplinary panel. Pancreatic AMR is best identified by a combination of serological and immunohistopathological findings consisting of (i) identification of circulating donor-specific antibodies, and histopathological data including (ii) morphological evidence of microvascular tissue injury and (iii) C4d staining in interacinar capillaries. Acute AMR is diagnosed conclusively if these three elements are present, whereas a diagnosis of suspicious for AMR is rendered if only two elements are identified. The identification of only one diagnostic element is not sufficient for the diagnosis of AMR but should prompt heightened clinical vigilance. AMR and ACMR may coexist, and should be recognized and graded independently. This proposal is based on our current knowledge of the pathogenesis of pancreas rejection and currently available tools for diagnosis. A systematized clinicopathological approach to AMR is essential for the development and assessment of much needed therapeutic interventions.

Potential donor-recipient MYH9 genotype interactions in posttransplant nephrotic syndrome after pediatric kidney transplantation.

Recurrence of focal segmental glomerulosclerosis (FSGS) with nephrotic syndrome is relatively common after kidney transplantation in young recipients whose predialysis course consists of heavy proteinuria, hypertension and subacute loss of kidney function. The gene(s) mediating this effect remain unknown. We report an unusual circumstance where kidneys recovered from a deceased African American male donor with MYH9-related occult FSGS (risk variants in seven of eight MYH9 E1 haplotype single nucleotide polymorphisms) were transplanted into an African American male child with risk variants in four MYH9 E1 risk variants and a European American female teenager with two MYH9 E1 risk variants. Fulminant nephrotic syndrome rapidly developed in the African American recipient, whereas the European American had an uneventful posttransplant course. The kidney donor lacked significant proteinuria at the time of organ procurement. This scenario suggests that donor-recipient interactions in MYH9, as well as other gene-gene and gene-environment interactions, may lead to recurrent nephrotic syndrome after renal transplantation. The impact of transplanting kidneys from donors with multiple MYH9 risk alleles into recipients with similar genetic background at high risk for recurrent kidney disease needs to be determined.

Banff 07 classification of renal allograft pathology: updates and future directions.

The 9th Banff Conference on Allograft Pathology was held in La Coruna, Spain on June 23-29, 2007. A total of 235 pathologists, clinicians and scientists met to address unsolved issues in transplantation and adapt the Banff schema for renal allograft rejection in response to emerging data and technologies. The outcome of the consensus discussions on renal pathology is provided in this article. Major updates from the 2007 Banff Conference were: inclusion of peritubular capillaritis grading, C4d scoring, interpretation of C4d deposition without morphological evidence of active rejection, application of the Banff criteria to zero-time and protocol biopsies and introduction of a new scoring for total interstitial inflammation (ti-score). In addition, emerging research data led to the establishment of collaborative working groups addressing issues like isolated 'v' lesion and incorporation of omics-technologies, paving the way for future combination of graft biopsy and molecular parameters within the Banff process.

Banff schema for grading pancreas allograft rejection: working proposal by a multi-disciplinary international consensus panel.

Accurate diagnosis and grading of rejection and other pathological processes are of paramount importance to guide therapeutic interventions in patients with pancreas allograft dysfunction. A multi-disciplinary panel of pathologists, surgeons and nephrologists was convened for the purpose of developing a consensus document delineating the histopathological features for diagnosis and grading of rejection in pancreas transplant biopsies. Based on the available published data and the collective experience, criteria for the diagnosis of acute cell-mediated allograft rejection (ACMR) were established. Three severity grades (I/mild, II/moderate and III/severe) were defined based on lesions known to be more or less responsive to treatment and associated with better- or worse-graft outcomes, respectively. The features of chronic rejection/graft sclerosis were reassessed, and three histological stages were established. Tentative criteria for the diagnosis of antibody-mediated rejection were also characterized, in anticipation of future studies that ought to provide more information on this process. Criteria for needle core biopsy adequacy and guidelines for pathology reporting were also defined. The availability of a simple, reproducible, clinically relevant and internationally accepted schema for grading rejection should improve the level of diagnostic accuracy and facilitate communication between all parties involved in the care of pancreas transplant recipients.

Targeted enzyme therapy of experimental glomerulonephritis in rats.

We sought to determine whether systemic administration of proteases ameliorates membranous nephritis induced in rats by immunization and challenge with cationic bovine gamma globulin, and whether targeting of protease to glomerular capillaries increases efficacy. Proteases substituted with biotin were targeted via the cationic protein avidin A, which by virtue of its charge has affinity for the glomerular basement membrane. Despite identical pretreatment proteinuria, rats given untargeted protease (biotin-conjugated without avidin, or unconjugated plus avidin) had significantly less proteinuria than saline-treated controls and nephrotic rats given avidin plus biotin-conjugated (targeted) protease had even less proteinuria and reduced glomerular rat IgG and C3. Among more severely nephrotic rats, targeted protease was again more effective than untargeted protease at reducing proteinuria, and also decreased the size of electron-dense glomerular deposits, hypercholesterolemia, and creatininemia. Inactivated targeted proteases had no effect on proteinuria, hypercholesterolemia, or azotemia. Finally, active targeted protease did not affect proteinuria in the nonimmune mediated nephrosis induced by puromycin aminonucleoside. We conclude that systemic protease can specifically diminish glomerular immune deposits, proteinuria, hyperlipidemia, and creatininemia associated with experimental immune complex glomerulonephritis but not toxic nephrosis, and that targeted protease is more effective than untargeted protease.

Cardiomyopathy associated with the acquired immune deficiency syndrome.

Three cases of congestive cardiomyopathy complicating the acquired immune deficiency syndrome (AIDS) are reported. In one case, acute cardiac decompensation resulted in prolonged but ultimately reversible cardiogenic shock. In the second case, clinical signs of cardiac disease were precipitated by acute renal failure and fluid overload. In the third, congestive heart failure developed spontaneously and responded promptly to administration of diuretics but the patient died suddenly, apparently due to an arrhythmia. The etiology of cardiomyopathy in AIDS is unclear and the manifestations of cardiomyopathy in this setting range from subclinical to life threatening.

Enzyme histochemistry of monocytes/macrophages: a study in a murine model of immune complex-mediated glomerulonephritis.

In a model of immune complex glomerulonephritis in BALB/c mice, cells of monocyte/macrophage lineage (M phi), identifiable by electron microscopy, infiltrate the glomerulus. In spite of this, no unequivocal nonspecific esterase activity can be demonstrated histochemically in the glomeruli. On the other hand, many mononuclear cells with strong acid phosphatase activity are consistently present. This observation is in line with other studies that have demonstrated the heterogeneity of enzyme profiles in different M phi populations. Despite the wide acceptance of nonspecific esterases as markers for M phi, the present study indicates that exclusive reliance on a single marker in investigating the participation of M phi in a pathological process can lead to erroneous conclusions. Use of multiple markers and preferably multiple investigative modalities is recommended.

Intravascular papillary endothelial hyperplasia in a thrombosed renal allograft vein.

Intravascular papillary endothelial hyperplasia (IPEH) is a benign endothelial proliferation of unclear pathogenesis, usually associated with thrombus as an unusual mode of organization and occasionally coexisting with vascular neoplasms. A 65-year-old white woman with chronic renal disease caused by focal segmental glomerulosclerosis experienced the failure of a cadaveric renal allograft 10 days after implantation. Pathological manifestations in the resected graft included total infarction and thrombi in both the renal artery and vein, the latter of which showed typical histopathologic features of IPEH. Papillary formations with fibrinous cores lined by bland endothelial cells surrounded fresh and organizing thrombus, and the proliferation had a highly cellular peripheral zone not readily recognizable as vascular. Immunohistochemical stains for factor VIII, CD34, and in particular CD31, however, confirmed the nature of both the papillary and solid areas of the proliferation as vascular endothelium. We present the first report of this lesion in an allograft vessel, and we find its rapid development, in association with a thrombus of clinically discernable age, to be strong evidence supporting the hypothesis that IPEH represents an uncommon morphology of organizing thrombus.

Mesangiolytic glomerulopathy in a bone marrow allograft recipient.

A boy with null-cell leukemia received a bone marrow allograft after preparation with chemotherapy and total body irradiation. Cyclosporine A was not administered following transplantation. Renal biopsy performed 6 months after transplantation because of unexplained deterioration of renal function revealed diffuse mesangiolysis and glomerular sclerosis. The significance of this finding is discussed with reference to similar, recently reported cases.

Non-diabetic nodular glomerulosclerosis associated with p-ANCA seropositivity: a case report and review of the literature.

A 73-year-old white man with slowly progressive chronic renal failure and nephrotic-range proteinuria was found to have antineutrophil cytoplasmic antibody in a perinuclear pattern (p-ANCA) at a titer of 1:800. Renal histologic findings revealed an advanced scarring glomerulopathy with diffuse and nodular mesangial sclerosis. Light, electron, and immunofluorescence microscopic findings were highly suggestive of diabetic glomerulosclerosis. Interestingly, this patient had no history of diabetes mellitus or diabetic retinopathy. The presence of p-ANCA positivity can be found in patients with a broad range of renal histologic findings, and does not necessarily imply the existence of pauci-immune necrotizing crescentic glomerulonephritis. For this reason, we urge caution in the empiric cytotoxic treatment of p-ANCA-associated renal disease in stable patients. When possible, a tissue diagnosis should be made.

Membranoproliferative glomerulonephritis associated with sickle cell disease in two siblings.

The cases of two brothers with sickle-cell anemia complicated by the nephrotic syndrome and membranoproliferative glomerulonephritis are presented. The literature related to this infrequent association is reviewed and possible explanations for the occurrence of the latter in two brothers are discussed.

Immunocytochemical localization of renin in the developing ovine fetus.

The ontogeny of renin distribution in the outer cortical segments was studied by immunocytochemistry in two groups of ovine fetal kidneys; one set of fetal kidneys was obtained at 104-106 days (0.73 gestation, n = 6), and the other at 138-140 days (0.96 gestation, n = 6). Similar studies were performed in kidneys obtained from a lamb (2 weeks old) and from non-pregnant adult sheep, n = 4. Using rabbit anti-mouse renin antiserum that was proven to cross react with sheep renin and 0.033% 3',3'-diamino benzidine tetrachloride as a chromogen, immunoreactivity was found to be localized in the classical juxtaglomerular apparatus and the afferent arteriole in the immature fetuses, newborn lamb and adult sheep. In the mature fetuses a more extensive distribution was noted. Immunoreactivity was found in the afferent arteriole and the juxtaglomerular apparatus as well as other segments of the arterial vascular tree. These findings suggest that renal renin distribution in the lamb fetus is developmentally regulated. The results also correlate well with reports about renal cortical renin content and plasma renin activity at the stages studied. These observations further support the hypothesis that increased renal renin expression occurs in the fetus just prior to birth.

Lipid-laden foamy macrophages in renal cell carcinoma. Potential frozen section diagnostic pitfall.

Lipid-laden foamy macrophages are characteristic of xanthogranulomatous pyelonephritis (XGP). We have encountered a case of renal cell carcinoma (RCC), with extensive necrosis, in which confluent sheets of foamy macrophages were a dominant feature. We describe the case and discuss the potential frozen section diagnostic problem in attempting to distinguish between confluent sheets of xanthoma cells a "reactive" change in RCC and xanthoma cells as a fundamental component of XGP. We propose that awareness of that problem should prompt the pathologist to request additional samples.

Lobular carcinoma of the breast metastatic to the oral cavity mimicking polymorphous low-grade adenocarcinoma of the minor salivary glands.

The oral cavity is a rare site of metastatic lesions; however, metastatic breast carcinoma must be included in the differential diagnosis of tumors of that site in women. We describe a 54-year-old woman who presented with a lesion of the floor of the mouth that histologically resembled polymorphous low-grade adenocarcinoma of the minor salivary glands, which was eventually established to represent metastatic lobular breast carcinoma. The final diagnosis was based on comparison with a primary tumor resected 13 years earlier and immunohistochemical reactivity with antibodies to steroid receptors. Relevant aspects of lobular breast carcinoma, polymorphous low-grade adenocarcinoma, and metastatic oral cavity lesions are discussed.

Primary cerebral lymphoma with glomerular renal involvement.

We report a case of primary cerebral lymphoma metastasizing to the kidney with exclusive involvement of the glomeruli. We discuss the possible explanations of this unusual phenomenon, and present some of the unusual clinical features of the case. Nephropathologists interpreting glomerular hypercellularity should always consider metastatic neoplasms as a possible, though rare, cause.