A simple and sensitive micro-haemagglutination inhibition assay for the semi-quantitation of the third component of complement.

C3-coated cells have been prepared by incubating sensitised erythrocytes with the appropriate dilutions of serum. Inhibition of agglutination of these cells by an anti-C3 serum provides a sensitive and specific assay for C3 detection and semi-quantitation.

Clinical and haemodynamic effects of minoxidil in refractory hypertension.

Thirteen patients whose hypertension had been resistant to conventional drug therapy, had minoxidil added to their regimen in doses from 5 to 60 mg/day. All responded with satisfactory reductions of blood pressure to mean values of 149/90mm Hg (supine) and 143/89mm Hg (standing). A significant portion of their previous antihypertensive therapy was either greatly decreased or withdrawn completely. Although fluid retention occurred in most patients as the dose of minoxidil was increased, this could be successfully checked by the use of diuretics. It was considered that in addition to beta-adrenoreceptor blocking drugs to control the reflexly induced cardiac stimulation, sufficiently aggressive diuretic therapy is mandatory to ensure the successful use of this drug. Haemodynamic evaluations in seven patients clearly showed that lowering of blood pressure was the result of decreases in peripheral vascular resistance as significant increases in the cardiac index occurred in all patients.

Identification of intrarenal fibrin deposition.

The site and extent of intrarenal fibrin deposition has been examined by routine histological staining, immunofluorescence, and electron microscopy in 109 patients with a wide variety of renal diseases. The findings have been correlated with the amount of urinary fibrin/fibrinogen degradation product (FDP) excretion as measured by the tanned red cell haemagglutination inhibition immunoassay. The results show that routine histological stains (Martius Scarlet Blue and Picro Mallory) are unreliable, particularly where there is mesangial accumulation of material or where the amount of fibrin deposited is small and confined to a subendothelial position. Similarly the electron microscope may overassess the degree of fibrin deposition, particularly if this is associated with the deposition of immunoglobulins and complement. There is a close relationship between the site and extent of fibrin, as detected by immunofluorescence, and the maximal urinary FDP excretion.

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.

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.

Quantitation of glomerular angiotensin II receptors in IgA nephropathy.

Mesangial cells have receptors for angiotensin II (AII) and contract in its presence. All is known also to increase the uptake of macromolecules by the mesangium. As a first step towards the investigation of a possible role for local disturbances of the renin-angiotensin system (RAS) in immune mediated mesangial proliferative glomerulonephritis, glomerular All receptors have been quantitated retrospectively in biopsy tissue from 20 patients with IgA nephropathy for comparison with 16 biopsies that showed only minor abnormalities by light microscopy and negative immunofluorescence. An autoradiographic technique using 125I labelled [Sar1, Ile8] All facilitated the quantitation of All receptors in frozen tissue sections. Following exposure to the treated sections, x-ray film was analyzed by computerized micro-densitometry. The data obtained were optical densities of areas corresponding to the presence of glomeruli verified by reference to adjacent sections stained with periodic acid-Schiff (PAS). There was no significant difference between patients 0.67 +/- 0.16 (mean +/- SD) and controls 0.61 +/- 0.15. Among patients there was no statistically significant correlation of glomerular All receptor density with either the degree of mesangial proliferation or the extent of hyperplasia of the juxtaglomerular apparatus (JGA). There was no apparent relationship with hypertension. The absence of an increase in glomerular All receptors despite proliferation of the glomerular mesangium may represent a local down regulation in patients with IgA nephropathy.

Glomerular IgG subclass distribution in human glomerulonephritis.

IgG subclass distribution was determined in glomerular immune deposits found in patients with membranous, mesangiocapillary, lupus and antiglomerular basement membrane antibody induced glomerulonephritis. In each disease category IgG3 was the predominant subclass found. In membranous, lupus and anti-glomerular basement membrane antibody induced nephritis the other subclasses were detected in significant but lesser amounts although in anti-glomerular basement membrane antibody induced nephritis IgG2 deposition was minimal. Particularly striking was the excess of IgG3 compared with other subclasses in mesangiocapillary glomerulonephritis and the greater amount of IgG4 in membranous glomeruli compared to the other disease categories. These findings indicate a difference between the distribution of IgG subclasses in normal plasma and glomerular immune deposits and may be of importance in the pathogenesis of the types of glomerulonephritis studied.

The syndrome of IgA nephropathy.

A review is presented of the current knowledge concerning the syndrome of IgA nephropathy. Primary and secondary forms can now be delineated and this division has improved understanding of immunopathogenetic mechanisms giving rise to glomerular mesangial IgA deposits. Attention is paid to disorders of antigen exclusion at mucosal surfaces, defective reticulo-endothelial sequestration, and altered immunoglobulin A production and regulation. Particular reference is made to these mechanisms with respect to primary IgA nephropathy, Henoch-Schoenlein purpura and mesangial IgA nephritis associated with alcoholic cirrhosis.

Thin membrane nephropathy: a clinico-pathological study.

Thin membrane nephropathy is common, representing approximately 11% of non-transplant renal biopsies. A family history of renal disease is present in at least 40% of patients. Electron microscopy is essential for its diagnosis. There are no immunofluorescence markers but light microscopic changes, usually mild, are invariably present and predict the ultrastructural findings although there is no correlation with their degree. The extent of the morphological changes bears no obvious relationship either to clinical or familial features. Immunogold studies indicate that there is reduction or loss of the subepithelial portion of the basement membrane, which apparently contains normal amounts of type IV collagen. Unnecessary urological investigations may be avoided by awareness of the condition and microscopic examination of urine for dysmorphic red blood cells. Prospective long-term studies are necessary to determine the nature and consequences of the condition.

The effect of treatment with prednisolone or cyclophosphamide-warfarin-dipyridamole combination on the outcome of patients with membranous nephropathy.

Between 1973 and 1986, 109 patients with membranous nephropathy have been evaluated with respect to clinical presentation, pathological features and factors determining prognosis. Secondary disease was present in 21, and a further 21 were lost or followed for less than 12 months. The remaining 67 with idiopathic membranous nephropathy were allotted to one of three groups. Group 0 (26 patients) received no active treatment, Group 1 (12 patients) a combination of cyclophosphamide, dipyridamole and warfarin, and Group 2 (21 patients) high dose alternate day prednisolone therapy. Eight patients received other treatment or presented with end stage renal disease. No significant difference in outcome could be detected between the groups. Remission rates were equivalent as were numbers of patients judged as having progressive disease. There was no statistical difference with respect to duration of nephrotic syndrome, plasma creatinine at the end of study and change in plasma creatinine. No demonstrable benefit was obtained in predicting the outcome of disease or response to treatment from conventional pathological grading of stages I to IV as approximately equal numbers of each stage fell into good and bad categories of outcome. Similarly unusual histological features such as mesangial proliferation and immunofluorescence for deposits other than IgG and C3 were not helpful. A different approach to treatment of idiopathic membranous nephropathy is strongly recommended.

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.

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.

Phenistix in screening.

Screening procedures have achieved notoriety in recent years because of their ability to detect diseases in their early phases and also because of their expense. This paper describes a little-known but simple urine screening test which, if used judiciously, may help with diagnosis and treatment, and yet remain relatively inexpensive.

Correlation of paramesangial deposits and glomerular sclerosis and/or hyalinosis in patients with IgA nephropathy.

Correlation of paramesangial deposits ("hemispherical body") and glomerular sclerosis and/or hyalinosis was examined by light microscopical analysis in 40 patients of IgA nephropathy. Correlation of paramesangial deposits and intensity of IgA or C3 deposition in glomeruli was also evaluated in these patients. The number of paramesangial deposits was markedly increased in patients with moderate and advanced stages of IgA nephropathy who showed marked glomerular sclerosis and/or hyalinosis. There was a significant correlation between the number of paramesangial deposits and the intensity of IgA deposits in glomeruli. It is suggested that the accumulation of paramesangial deposits might induce severe glomerular injuries such as glomerular sclerosis and/or hyalinosis.