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.

A cluster of haematuria cases in a pesticide-manufacturing plant.

In a pesticide manufacturing and formulating facility, 10 employees out of 48 were shown to have haematuria on dipstick testing. They included seven of the 27 production workers, all of whom had worked in both of two particular areas prior to the commencement of the routine urine testing. Five of the seven production workers with haematuria underwent further investigations, and in all five the haematuria was glomerular in origin. Two underwent renal biopsy, which showed irregular attenuation of the glomerular basement membrane (GBM) but no abnormality by light microscopy. Immunofluorescence studies were negative. This case series of glomerular haematuria is not readily explained by chance, false positive dipstick testing, or a recognizable non-occupational cause. Thin GBM disease, which is a benign condition, appears the likely explanation. Thin GBM disease is usually an autosomal dominant condition, but clustering of these genotypes in this small population is improbable.

Transient diabetes insipidus and acute fatty liver of pregnancy.

OBJECTIVE: To review the association of transient diabetes insipidus and acute fatty liver of pregnancy. DESIGN: A retrospective study. SETTING: Six women presenting with polyuria and polydipsia in the third trimester or in the immediate postpartum period, referred over a two and a half year period; five out of six were primigravida. All had raised liver transaminases and biopsy-proven acute fatty liver of pregnancy. Four out of six also had pre-eclampsia. SUBJECTS: Tertiary referral centre. MAIN OUTCOME MEASURES: There were no maternal deaths and only one fetal death. Desamino-cys-1-D-arg-8-vasopressin administration produced a reduction in urine output in all five women to whom it was administered. In all cases symptoms had resolved by the end of the fourth postpartum week. Three of the women have had subsequent pregnancies uncomplicated by either transient diabetes insipidus or acute fatty liver of pregnancy. CONCLUSIONS: The association of transient diabetes insipidus and acute fatty liver of pregnancy appears more common than previously recognised. Both may be part of the spectrum of pre-eclampsia.

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.

Recurrent mesangial IgA nephritis following renal transplantation.

Recurrence of mesangial IgA deposits in renal allografts of patients whose original disease was primary IgA nephropathy (IgAN) has been studied. Forty-six patients with primary IgAN received 51 renal allografts and have been followed for 3-183 months. A prospective study of 11 patients (11 biopsies) and a retrospective analysis of 17 patients (16 biopsies; 2 nephrectomy specimens) have been combined. Seventeen of the 29 allografts had recurrent mesangial IgA deposits and of these three patients have negative urinalysis, normal glomeruli by light microscopy, and stable renal function; six patients have microhaematuria, mesangial proliferative nephritis, but at present stable renal function; and five have mesangial proliferative glomerulonephritis with microhaematuria, heavy proteinuria, hypertension, and progressive allograft failure secondary to IgA disease alone, and one of these is now back on dialysis. Three other grafts with recurrent deposits are failing because of transplant glomerulopathy or rejection. The only predictor identified for recurrence of mesangial IgA deposits was length of time post-transplantation, with allograft tissue being studied at 45.9 +/- 10.0 versus 15.3 +/- 4.8 months (P = 0.008) post-transplantation in patients with and without recurrent deposits respectively. Cyclosporin A did not prevent recurrence. By virtue of a longer follow-up of patients post-transplantation than all other reported series, these results suggest that with increasing time post-transplantation recurrence of mesangial IgA disease will become increasingly important as a cause of progressive allograft dysfunction and failure unless effective treatment is found for the primary disease.

Immunohistochemical distribution and quantification of crystal matrix protein.

The aim of this study was to determine the immunohistochemical distribution and quantification of crystal matrix protein (CMP). CMP, a 31 kDa glycoprotein, is the principal macromolecule found in calcium oxalate crystals generated in human urine, and is a potent inhibitor of crystal aggregation. A polyclonal rabbit anti-human CMP antibody was used to examine renal tissue by immunohistochemical techniques and light microscopy (N = 45). Twenty-five other human organs were similarly assessed. Quantification was performed using a visual analogue scale. CMP was visible as cytoplasmic staining in the epithelial cells of the TALH and the distal convoluted tubule including the macula densa in a subgroup of nephrons. CMP was not identified elsewhere in the urinary tract or in the extrarenal organs examined. Despite a trend indicating that the kidneys of normal men had more CMP than those of normal women, the difference failed to reach significance (P = 0.11). There was, however, more CMP in the stone formers group compared with either normal men (P < 0.01) or normal women (P < 0.01). This protein may be an important determinant of calcium oxalate kidney stone disease.

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.

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)

Caecal adenocarcinoma metastatic to ovary inducing increased oestrogen production and postmenopausal bleeding.

This report describes a patient with a primary caecal adenocarcinoma metastatic to the right ovary, who presented with postmenopausal bleeding secondary to neoplastically induced excessive ovarian steroid production. Histopathological, electron microscopical, tumour tissue incubation and various endocrinological studies were performed to investigate the hormonal basis of this presentation. It is concluded that the elevated oestrogen levels responsible for the postmenopausal bleeding were not of direct ovarian origin, but were consequent upon nonovarian conversion of oestrogen precursors produced by tumour induced hyperplastic ovarian stromal tissue.

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.

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.

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.

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.

The immunochemical characterization of mesangial IgA deposits.

Mesangial deposits of IgA are found in IgA nephropathy, Schönlein-Henoch purpura (SHP) and in some patients with alcoholic cirrhosis and systemic lupus erythematosus (SLE). In this study the authors characterized the mesangial IgA deposits in patients with the above diseases using antiserums or monoclonal antibodies to A1, A2, J-chain and secretory component (SC), and examined SC binding in vitro. SC was not present, J-chain was ubiquitous, and A2 was found (with the use of monoclonal antibodies) rarely but with equal frequency in all groups. The SC binding capacity of the deposits differed between the groups and was found in 13 of 16 patients with alcoholic liver disease, 3 of 4 with SLE, 1 of 10 with primary IgA nephropathy, and none of 6 with SHP.