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 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.

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.

Acute sensory neuropathy associated with rabbit antithymocyte globulin.

Rabbit antithymocyte globulin (RATG) is indicated for the treatment of acute renal transplant rejection and has also been shown to be effective as an induction immunosuppressive agent after renal transplantation. We report a patient that developed a painful sensory neuropathy within an hour of receiving RATG. The neuropathic symptoms resolved within a month, and a careful review of his medications, exposures and comorbid conditions revealed no other causes of neuropathy. Since the administration of RATG and onset of symptoms were so closely related temporally and the symptoms resolved after the cessation of RATG, we believe it is likely this medication led to the development of neuropathy.

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.

IgA nephropathy and Reiter's syndrome. Report of two cases and review of the literature.

Immunoglobulin A (IgA) nephropathy is the commonest type of primary glomerulonephritis worldwide. It has previously been reported in association with the seronegative spondyloarthropathies (ankylosing spondylitis, Behcet's syndrome, psoriatic arthritis, Reiter's syndrome and the postenteritic arthritides). Since this condition was first described in 1968, 5 previous case reports of biopsy-proven IgA nephropathy associated with Reiter's syndrome have been published in the English-language literature. Here we report 2 more such cases, along with a review of the literature describing the association of IgA nephropathy and a number of other immune-complex-mediated glomerulonephritides with the seronegative spondyloarthropathies.

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.

Biopsy-proven resolution of immune complex-mediated crescentic glomerulonephritis with mycophenolate mofetil therapy in an allograft.

We report biopsy-proven resolution of immune-complex-mediated crescentic glomerulonephritis (ICMCGn) using mycophenolate mofetil (MMF). Therapy with steroids and cyclophosphamide failed twice in a 39-year-old white man who developed ICMCGn in his native kidneys, and subsequently in a human lymphocyte antigen-identical renal allograft. When he developed ICMCGn in a second, now cadaver, allograft, he was treated with steroids and MMF instead. His serum creatinine (Cr) improved from 4.4 mg/dL to 2.1 mg/dL. A biopsy 21 months later showed him to be free of glomerular disease. MMF is known to be an effective immunosuppressant. In our patient, ICMCGn, a notoriously difficult entity to treat effectively, seemingly resolved with MMF therapy. We suggest that MMF may be effective in the treatment of immunologically mediated pre-end-stage renal disease (ESRD). It should be considered in any posttransplantation setting where the original cause of organ failure is known to be immunologically mediated and likely to recur.

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.

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.

Extra-adrenal myelolipoma: report of two cases.

Myelolipomas are benign tumors composed of an admixture of mature adipose tissue and normal hematopoietic cells. The vast majority occur within the adrenal glands, but several extra-adrenal myelolipomas (EAMLs) have been reported. The typical EAML is a solitary, well-defined mass within the abdomen, most commonly in the retroperitoneal presacral area. EAMLs may produce symptoms related to their mass effect, but they are occasionally incidental findings. Most commonly, the patient is older than 40 years and has no hematologic abnormalities. It is important to distinguish EAMLs from other soft tissue tumors, in particular liposarcomas, myxoid malignant fibrous histiocytomas, and extramedullary hematopoietic tumors. We discuss two cases of EAML. The first was in the retroperitoneum of a 76-year-old woman. It is the largest EAML ever reported, measuring 26 cm x 15 cm x 11 cm. The second, a presacral mass in a 68-year-old man, was diagnosed preoperatively by percutaneous computed tomography-guided fine needle aspiration biopsy. Preoperative diagnosis facilitated surgical management in this case. We discuss the clinical, radiologic, and pathologic characteristics and the differential diagnosis of this rare entity.

The link between hypertension and nephrosclerosis.

Nephrosclerosis is literally defined as hardening of the kidneys (Greek derivation: nephros, kidney; sklerosis, hardening). It is the result of scarring or replacement of the normal renal parenchyma by dense collagenous tissue. In practice, nephrosclerosis refers to diseases with predominant pathologic changes occurring in the preglomerular microvasculature and secondarily involving the glomeruli and interstitium. The relationship between mild to moderate hypertension and either nephrosclerosis or end-stage renal disease (ESRD) remains circumstantial, although these syndromes have long been associated in the medical literature. Nephrologists credit hypertension as the etiology of nephrosclerosis in 25% of patients initiating Medicare-supported renal replacement therapy, even though other processes may cause similar renal pathologic findings. Strikingly, serum creatinine values infrequently increase in patients with long-standing mild to moderate hypertension. Patients classified as having hypertensive ESRD typically present with advanced disease, making the processes that initiated the renal disease difficult to detect. Nephrologists are twice as likely to label an African-American patient as having hypertensive nephrosclerosis, compared with a white patient, when presented with identical clinical histories. This review proposes that many patients classified as having hypertensive nephrosclerosis actually have intrinsic renal parenchymal diseases, renal artery stenosis, unrecognized episodes of accelerated hypertension, or a primary renal microvascular disease. The familial clustering of ESRD attributed to hypertension in African-Americans and the identification of genes associated with renal injury in animals support the concept that inherited factors may predispose to renal failure. African-American families often have members with ESRD from disparate etiologies, including hypertensive ESRD. This suggests that common mechanisms, be they inherited or environmental, underlie the development of progressive renal failure in diverse forms of nephropathy. Identification of the mechanisms producing susceptibility to progressive renal disease would support the concept that mild to moderate elevations in blood pressure per se are uncommon causes of nephrosclerosis.

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.

Clinical and pathologic features of fibrillary glomerulonephritis.

A diagnosis of fibrillary glomerulonephritis was made in 31 renal biopsies from 28 patients on the basis of the electron microscopic identification of glomerular deposits of randomly arranged fibrils that resembled amyloidosis but were larger. This accounted for approximately 1% of all nontransplant renal biopsy diagnoses. Renal biopsy specimens with parallel arrays of 30 nm to 50 nm microtubules (that is, immunotactoid glomerulopathy) were not included in the study. The patients had a mean age of 49 years with a range of 21 to 75. The male to female ratio was 1:1.8 and the ratio of Whites to Blacks was 8.3:1, which differs from the 3:1 ratio in our overall biopsy population. All patients had proteinuria (mean 6.0 g/day), and most had hematuria and renal insufficiency. After a mean follow-up of 24 months, there was 48% renal survival. The light microscopic appearance of the fibrillary glomerulonephritis was quite varied. Capillary wall thickening and matrix expansion were the most frequent alterations. Nineteen percent of specimens had crescents. Morphometric ultrastructural analysis demonstrated a mean fibril diameter of 22.4 +/- 7.4 nm. Immunofluorescence microscopy revealed that IgG was the dominant and often the only immunoglobulin class in immune deposits, and subclass analysis revealed that IgG4 was the dominant or exclusive subclass in all specimens tested. We hypothesize that the relatively homogeneous nature of the immunoglobulin in the immune deposits is the basis for the fibril formation.