Neoplasia in analgesic nephropathy. A urothelial field change.

The association between analgesic nephropathy and urothelial cancer, usually in the renal pelvis, is well established. We report two such patients in whom careful morphologic study of nephrectomy specimens demonstrated severe and extensive urothelial dysplasia, with focal carcinoma in situ and grossly invisible invasive tumors. In one of these patients, no gross lesion was apparent in the urothelium. These findings support the development of invasive carcinoma through a phase of carcinoma in situ caused by the action of carcinogenic analgesic metabolites in the urine. Further, they indicate the need for caution in the assessment of urinary cytologic atypia and for care in the examination of excised urothelium in those patients.

Glomerular size and glomerulosclerosis in Australian aborigines.

We have previously described the prevalence of glomerulomegaly in biopsy specimens from Australian Aborigines with renal disease, a phenomenon documented in a number of other indigenous populations. Many of the biopsy specimens showed variable degrees of focal and segmental glomerulosclerosis (FSGS). Correlations between glomerular size and FSGS have been described in various animal models, as well as studies of humans. The aim of this study is to determine whether a relation exists between glomerular volume and severity of FSGS in biopsy specimens from Australian Aboriginals in the Northern Territory and Aboriginal inhabitants of the Tiwi Islands (Bathurst Island and Melville Island, Northern Territory, Australia). Consecutive clinical biopsy specimens were obtained from 78 non-Tiwi and 72 Tiwi Aboriginals. Glomerular volume was estimated using the stereological method of Weibel and Gomez. FSGS was graded from 0 to 4; 0 indicates no sclerosis and 4 indicates severe sclerosis. A biphasic relationship between glomerular size and severity of FSGS was identified. As the severity of FSGS increased from grade 0 to grade 3, glomerular size also increased. For both populations studied, glomeruli scored as grades 1, 2, and 3 were approximately 50% (P< 0.001), 65% (P< 0.001), and 100% (P< 0.001) larger than normal glomeruli, respectively. However, in glomeruli with grade 4 FSGS, glomerular size decreased to the size of normal glomeruli. These results show a biphasic relationship between severity of FSGS and glomerular size in Australian Aborigines.

Ultrastructural appearance of renal and other basement membranes in the Bull terrier model of autosomal dominant hereditary nephritis.

Bull terrier hereditary nephritis may represent a model for autosomal dominant Alport's syndrome because affected dogs have the typically lamellated glomerular basement membrane (GBM) and father-to-son disease transmission occurs. This study examined the ultrastructural appearance of the renal and extrarenal basement membranes and their composition in affected Bull terriers. Affected stillborn animals and puppies had subepithelial frilling and vacuolation of the GBM. In adult dogs, lamellation was common, and subepithelial frilling and vacuolation were less prominent. Foot-process effacement and mesangial matrix expansion occurred frequently. Basement membranes in the glomeruli, tubules, and Bowman's capsule were significantly thickened and often mineralized. Immunohistochemical examination showed alpha 1(IV) and alpha 2(IV) collagen chains in all renal basement membranes; alpha 3(IV), alpha 4(IV), and alpha 5(IV) chains in the GBM, distal tubular basement membrane, and Bowman's capsule; and the alpha 6(IV) chain in Bowman's capsule. Conversely, the basement membranes from the affected Bull terrier cornea, lens capsule, retina, skin, lung, and muscle had a normal ultrastructural appearance and were not thickened compared with membranes in normal age-matched dogs. The distribution of basement membrane abnormalities in Bull terrier hereditary nephritis may occur because the defective protein is present exclusively or more abundantly in the kidney and is structurally more important in the kidney or because of local intrarenal stresses.

Glomerulonephritis: approaches to classification.

Glomerulonephritis has many mechanisms and may take a variety of patterns. Almost as many classifications of glomerulonephritis exist as there have been classifiers. None is perfect. Morphological classification of glomerulonephritis is inadequate alone but provides useful information about the pattern of response to the injurious mechanism and may allow accurate assessment of prognosis. In this paper some approaches to the classification of glomerulonephritis are discussed, the major categories are reviewed and a prognostic method of classification is proposed.

Mitomycin C associated hemolytic uremic syndrome.

Mitomycin C associated Hemolytic Uremic Syndrome (HUS) is a potentially fatal but uncommon condition that is not yet widely recognised. It consists of microangiopathic hemolytic anemia, thrombocytopenia and progressive renal failure associated with mitomycin C treatment and affects about 10% of patients treated with this agent. The renal failure usually develops about 8-10 mth after start of mitomycin C treatment and the mortality is approximately 60% from renal failure or pulmonary edema. Renal lesions are similar to those seen in idiopathic HUS and include arteriolar fibrin thrombi, expanded subendothelial zones in glomerular capillary walls, ischemic wrinkling of glomerular basement membranes and mesangiolysis. The mechanism of action is postulated as mitomycin C-induced endothelial cell damage. We describe the clinical course and pathological findings in a 65 yr-old man with gastric adenocarcinoma who developed renal failure and thrombocytopenia while on treatment with mitomycin C and died in pulmonary edema.

Parotid cysts. An analysis of 16 cases and suggested classification.

Cystic lesions, greater than 8 mm in diameter, were found in 16 of 183 surgically excised parotid glands over an 8 yr period. Of these 16 cysts, 9 had developed in parotid neoplasms, usually of Warthin type. The remaining 7 were not associated with neoplasms and 5 were unilocular. The epithelial lining of non-neoplastic cysts was squamous in all but one case, and there was lymphoid tissue in the walls of 3 cysts. On the basis of these findings and a review of the literature, a morphological classification of parotid cysts is proposed. To the surgical pathologist, the major problems in dealing with parotid cysts are the recognition of associated neoplasms and of those cysts likely to have accompanying congenital abnormalities.

Electron microscopy in surgical pathology: a selective review.

The high resolution provided by electron microscopy can contribute to histomorphological diagnosis by allowing the detection of structures which are invisible to the light microscope. These structures include characteristic nuclear or cytoplasmic contours, intercellular attachments and intracellular components. The recognition of such features may allow specific diagnosis in lesions which cannot be precisely categorized by light microscopy. Electron microscopy is particularly useful for the diagnosis of neoplasms. This review describes some of the characteristic morphological features which can be demonstrated in neoplastic cells by electron microscopy and briefly considers several areas where the technique is of special value. Electron microscopy is now an integral part of the diagnostic process in surgical pathology and can be regarded as a routine technique rather than a special procedure to be delegated to others.

IgA nephropathy--accumulated experience and current concepts.

Primary IgA nephropathy is the most common form of glomerulonephritis in Australia. The condition presents in a variety of ways, but commonly with synpharyngitic hematuria, most often in young men in the third and fourth decades. The course of the disease is indolent but there is progression to renal failure in up to one quarter of cases. Renal biopsy morphology is variable but the essential immunofluorescence finding is diffuse mesangial IgA staining of greater intensity but often in association with other immunoglobulins. C3 is usually also present. Mesangial cellularity is increased in some two-thirds of cases, one third being of a minor focal or variable extent and one-third diffuse. Focal segmental lesions, hyaline nodules and vascular changes are frequent. Crescents are also often present. The etiology of the disease is uncertain but has been linked with HLA antigens, elevated serum IgA levels, IgA polymers, immune complexes and impaired T cell function. Secondary forms of mesangial IgA deposition occur with mucosal defects, hyperglobulinemia or impaired hepatobiliary clearance, and these may offer some insight into the immunopathogenesis of the primary disease.

Vascular IgA deposits in clinically normal skin of patients with renal disease.

Direct immunofluorescent tests for IgA deposits were done on biopsies of normal appearing skin from 49 patients with proven renal disease and 7 healthy individuals, in order to evaluate the method in the diagnosis of IgA nephropathy. Many of the 28 patients with IgA nephropathy had high levels of IgA deposition, often accompanied by notable deposits of IgM, Clq and fibrin, and less frequently by C3 and IgG, in small vessels of the superficial dermis. However, some of the 21 patients with other renal diseases had heavy deposits of IgA, limiting the usefulness of the test as a diagnostic aid.

Typing of intraglomerular mononuclear cells associated with transplant glomerular rejection.

To investigate the pathogenesis of glomerular injury in renal allografts, we have analyzed intraglomerular mononuclear cells from 20 biopsies with typical features of transplant glomerular rejection (TGR) (segmental or global occlusion of capillaries by swollen cells). Ten biopsies showing cellular rejection but no glomerular pathology were selected as controls. Microwave fixation and an avidin-biotin immunoperoxidase technique were used with the following monoclonal antibodies; Leu1 and OKT3 (pan T cell), Leu 3 a + b and OKT4 (helper T cell), OKT8 (cytotoxic T cell), OKB7 (B cell), OKM1 (monocyte) and OKDR (DR positive cell). The results showed a significant increase of T cells, helper T cells, cytotoxic T cells and monocytes in the patients with TGR compared with the controls (all p less than 0.001, Mann-Whitney U test). Of the T cell subsets, cytotoxic T cells outnumbered helper T cells by a mean ratio of 3.2:1. In the interstitium, the distribution of mononuclear cells was not different between the two patient groups. In both, T cells and monocytes were predominant and few B cells were found. The percentage of cytotoxic T cells was similar to that of helper T cells. In this study, there were at least four TGR patients without cytomegalovirus (CMV) infection and the distribution of intraglomerular mononuclear cells in these patients was indistinguishable from that of other TGR patients. There was no significant association of the distribution of mononuclear cells with the severity of glomerular damage. These results suggest that T cells, predominantly of the cytotoxic subset and monocytes are involved in the mediation of TGR.(ABSTRACT TRUNCATED AT 250 WORDS)

Sneddon's syndrome, anti-cardiolipin antibody and glomerular thrombosis.

Sneddon's syndrome, cerebrovascular thrombosis and livedo reticularis, is often a variant of the "primary" anti-phospholipid syndrome (PAPS). We report a woman with PAPS, presenting as Sneddon's syndrome, with renal impairment and glomerular thrombosis on renal biopsy. An IgG anti-cardiolipin antibody (aCL) was identified. The aCL was purified by affinity chromatography, gel filtration chromatography and ion-exchange chromatography, assayed in a modified ELISA and found to be of the type that requires the plasma protein beta 2-GPI to bind aCL. As beta 2-GPI has anticoagulant properties it is postulated that its interaction with aCL has a pathogenic role in the thrombotic lesions associated with aCL.

Glomerular transplant rejection: a distinctive pattern of early graft damage.

Five hundred seventy-six consecutive biopsy or nephrectomy specimens obtained during the first 6 months of transplantation from 300 grafts in 431 recipients were examined by light microscopy for focal or diffuse endocapillary hypercellularity. Forty-seven (8.2%) of the 576 specimens obtained from 37 (12.3%) of the 300 grafts exhibited segmental or global occlusion of capillaries by swollen cells in 40-100% of glomeruli per biopsy. The lesions occurred at any time after transplantation, but 34 (72.3%) were present by day 60 and 7 (14.9%) before day 10. Immunofluorescence in 39 affected biopsies revealed focal or segmental glomerular staining in 18 (46.2%), among which IgM was found most frequently, and was considered to be non-specific. Electron micrographs of 17 biopsies from 14 grafts revealed that glomerular capillaries were narrowed or occluded by mononuclear cells of uncertain type, possibly monocytes, as well as lymphocytes and a few neutrophils. Complement-fixing antibody titers to cytomegalovirus rose at least fourfold in 10 (45.5%) of the 22 patients studied, but glomerular lesions were no more severe in the seroconverters than in the non-converters, and there was no consistent temporal relationship between the occurrence of glomerular changes and seroconversion. Cellular or vascular rejection was present in most biopsies. One year graft survival was 34% among 35 accessed grafts with glomerular lesions, compared to 55% among 243 biopsied grafts with no glomerular changes. We consider that these lesions do not have a consistent association with cytomegalovirus infection and that they represent a distinctive form of glomerular rejection. Whether they indicate a poor graft survival, as the present results suggest but do not prove, requires further studies of other series of cases.

Recurrent focal glomerulosclerosis in renal transplants.

Among 431 renal transplants in 380 patients, 4 patients were identified with focal glomerulosclerosis characterized by presentation with corticosteroid-resistant nephrotic syndrome, early development of histological lesions, mesangial proliferation and rapid progression into chronic renal failure. After transplantation, all patients had early proteinuria and the 4 grafts surviving beyond 3 months developed recurrent glomerular lesions with severe nephrotic syndrome and progression to graft failure. In one patient, recurrent disease developed in two successive grafts. Focal glomerulosclerosis is a nonspecific glomerular lesion, but identification of specific clinical and pathological features may provide guidelines that will predict the risk of its recurrence in transplanted kidneys.

Controlled trial of phenytoin therapy in IgA nephropathy.

IgA nephropathy, a condition thought to cause slowly progressive renal damage, is frequently associated with high serum IgA levels. As phenytoin sodium lowers serum IgA concentrations, a controlled trial of therapy with this drug was conducted over a two-year period in patients with IgA nephropathy. Despite significant depression of serum IgA concentrations in the treatment group, there was no significant change in any other clinical, biochemical or pathological parameter, in either control or treatment groups. Indeed, there was evidence for a slow progression of renal damage in both groups. These observations suggest that the elevated serum IgA concentrations in IgA nephropathy are not of primary pahtogenetic significance but are rather a consequence of a basic abnormality in antigen processing and IgA production.

IgA nephropathy: a syndrome of uniform morphology, diverse clinical features and uncertain prognosis.

Isolated glomerulonephritis with mesangial IgA deposits was the most common single finding encountered in a large biopsy series in an Australian community and was found in 50 patients, 18% of those presenting for the investigation of primary glomerular disease. A uniform histopathological picture of mesangial enlargement, with or without focal and segmental features was present. A tendency to progression was suggested by the frequent presence of glomerulosclerosis, interstitial scarring and vascular hyalinization. Because of the uniform histological immunofluorescence and ultrastructural appearances, the term IgA nephropathy has been used for this condition. The clinical picture, however, was heterogenous. Presenting symptoms included macroscopic hematuria (34%), proteinuria (32%) acute nephritis (10%), nephrotic syndrome (6%), malignant hypertension (8%), acute renal failure (6%) and chronic renal failure (4%). There was a striking correlation of increased blood pressure and decreased renal function with increasing age. While the period of follow-up was too short to assess individual patient data, a gradual and progressive decrease in renal function over several decades is suspected in patients with this condition.

Plasmapheresis in glomerulonephritis.

Plasmapheresis together with immunosuppressive drug therapy has been used in the treatment of 17 patients with glomerulonephritis [Goodpasture's syndrome (4), systemic lupus erythematosus (4), mesangiocapillary glomerulonephritis (2), glomerulonephritis associated with cirrhosis (2), nonspecific mesangial proliferative glomerulonephritis (3), Henoch-Schoenlein purpura glomerulonephritis (1) and glomerulonephritis associated with infective endocarditis (1)]. Use of the Haemonetics Model 30 blood cell separator, exchanging two liters of plasma with 5% albumin in Hartmann's solution has provided a safe, effective but relatively expensive procedure, capable of producing a marked reduction of fibrinogen, complement components, anti-glomerular basement membrane antibody and immune complex concentrations. Removal of one or more of these factors is felt to be at least partly responsible for the improvement in renal function and clinical well-being demonstrated in patients with Goodpasture's syndrome, systemic lupus erythematosus and other forms of glomerulonephritis associated with the presence of circulating immune complexes.

Primary amyloid tumor of the breast. Case report and literature review.

An example of localized amyloid deposition in the breast of an elderly woman is reported. Fine needle aspiration biopsy yielded clumps of amorphous material, which stained violet with the May-Grünwald-Giemsa technique. The amyloid appeared to be of the AA type on histochemical analysis. The lesion was clinically associated, probably coincidentally, with a stage II carcinoma of the cervix. The nature and classification of amyloid is briefly reviewed, and the role of fine needle aspiration cytology in its diagnosis is discussed.