Biomedical subjects
Publications and source records attributed to T J Neale.
Living-related renal transplantation as treatment for end-stage renal failure has not been used widely in Australasia. The results of such treatment in 31 patients at Wellington Hospital are described. The five year graft survival of 80.2% encourages us to continue with an active policy of living related transplantation.
Overt glomerulonephritis, detected by abnormal proteinuria, occurred in 3.3% of young (2.5 kg) male New Zealand White (NZW) rabbits. Histologically, mild to moderate mixed membranous and proliferative glomerulonephritis was observed. Glomerular deposits of IgG and C3 and electron microscopic findings were not typical of circulating immune complex accumulation, nor did they suggest anti-glomerular basement membrane (GBM) antibody. Segmental and less intense glomerular deposits of IgG were found in up to 48% of nonproteinuric NZW rabbits of the same age; histologic changes were minimal. IgG antibodies in sera from proteinuric rabbits or eluted from their kidneys reacted by indirect immunofluorescence with antigens distributed (discontinuously) along the glomerular capillary walls, and in some cases within the walls of small arteries of normal rabbit kidney sections. By indirect immunoperoxidase electron microscopy, the reactive antigens were present at the surfaces of the epithelial cell foot processes where they abut the GBM. This spontaneous glomerulonephritis appears to involve fixation of antibodies to antigens distributed in a discontinuous pattern in the glomerular capillary wall. The mechanism would be much like that causing anti-GBM antibody glomerulonephritis, except that the glomerular antigen is different. Possibly some forms of glomerulonephritis develop in humans as a result of a similar process.
Three patients with skin or muscle biopsy evidence of small vessel vasculitis presented with neurological symptoms: (1) frequent transient ischaemic attacks, (2) myalgia with encephalopathy, and (3) myalgia with marked weakness. The diagnosis of small vessel vasculitis needs consideration especially if presentation with polyneuropathy or cutaneous involvement is associated with elevation of ESR or serum immunoglobulins. Neurological illness may be a more common presentation of small vessel vasculitis than previously recognised.
The current studies were designed to assess the ability of mononuclear inflammatory cells to mediate glomerulonephritis (GN) by studying the effects of replacement of mononuclear inflammatory cells in rabbits depleted of all circulating leukocytes and in which an antibody-initiated, macrophage-dependent model of glomerular injury was induced. GN was initiated by the injection of passive autologous rabbit antisheep gamma-globulin serum following the injection of sheep antirabbit glomerular basement membrane antibody. A proliferative endocapillary GN regularly occurred in which macrophages were the predominant infiltrating cell (mean 48.4 +/- 16.1 SD macrophages/glomerulus) and heavy proteinuria developed (590 +/- 152 mg/24 hours). This lesion was shown to be dependent on the presence of circulating leukocytes as prior treatment with nitrogen mustard producing panleukopenia completely prevented macrophage accumulation (0.4 +/- 0.1 macrophages/glomerulus), abnormal proteinuria (5.1 +/- 1.6 mg/24 hours), and histologic evidence of injury. When peritoneal mononuclear inflammatory cells were given intravenously (10(8] to nitrogen mustard-treated rabbits that were given the GN-inducing antibodies, a proliferative GN developed with significant macrophage accumulation (14.2 +/- 4.8 macrophages/glomerulus), and some rabbits became proteinuric (38.8 +/- 15.3 mg/24 hours). Electron microscopy indicated that glomerular endothelial cells underwent swelling and separation from the basement membrane in relation to macrophage accumulation. Control nitrogen mustard-treated animals given 10(8) mononuclear inflammatory cells without the injection of disease-initiating antibodies did not have glomerular macrophage accumulation (0.8 +/- 0.3 macrophages/glomerulus), abnormal proteinuria (6.1 +/- 2.1 mg/24 hours), or any histologic abnormality. Thus, macrophages can accumulate in glomeruli in direct response to the deposition of antibody and produce a proliferative GN by both their own accumulation and their effects on intrinsic glomerular endothelial cells.
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Continuous ambulatory peritoneal dialysis (CAPD) is being increasingly used to treat chronic renal failure in New Zealand. Peritonitis due in particular to gram positive organisms remains the major complication. Three of 92 CAPD patients trained in the Wellington Renal Unit had tuberculous peritonitis, a previously rarely reported complication. Gram positive or Gram negative bacterial infections preceded or followed isolation of Mycobacterium tuberculosis. Differential peritoneal fluid leucocyte counts were not predictive of tuberculous infection and total leucocyte counts remained elevated in tuberculous patients treated for other concurrent bacterial peritonitides. Systemic toxicity was not encountered in these patients, symptoms being confined almost entirely to the peritoneum. CAPD was continued during treatment with anti-tuberculous therapy, in all three patients. However, peritoneal pain on dialysis fluid in-flow necessitated temporary hemodialysis management in two. Anti-tuberculous chemoprophylaxis may be prudent in the at-risk Polynesian patient with chronic renal failure who is being considered for CAPD management.
Ideas on the immunopathogenesis of glomerulonephritis are evolving to embrace a concept of a dynamic and constantly fluctuating involvement of immune reactants in the production of glomerular inflammation. The glomerulus should be regarded as a template around which the antibody-induced inflammatory events that constitute glomerulonephritis are initiated. Such lesions may be produced by direct antibody attack on glomerular antigens of either intrinsic structural or "planted" type, as discussed in this review, or by the deposition of circulating soluble immune complexes containing extraglomerular antigens. These mechanisms are not mutually exclusive and both may play a role in some situations. Intrinsic glomerular antigens are being increasingly better defined as to site, structure, function, and experimental animal models of spontaneous and induced glomerular injury resulting from direct antibody binding to nonclassic GBM capillary wall antigens are available for study. Similar nonclassic GBM antigens are likely to be found of importance in man. Anti-GBM antibody-induced glomerulonephritis continues to be the best understood example of direct attack on the glomerulus by antibody, and its nephritogenic noncollagenous GBM antigenic constituents are being characterized. The incorporation of extraneous substances as "planted" antigens within glomerular structures is now recognized in experimental animal models, and there is suggestive evidence to support the concept in man. Emphasis needs to be placed on the continuing interplay of free antibody and antigen with deposited reactants which, together with complement components, modulate the quality and quantity of the glomerular immune deposits.
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Antiglomerular antibodies have recently been found in immunoglobulin eluted from kidneys of rats with Heymann's nephritis. To demonstrate a role for these antibodies in the pathogenesis of Heymann's nephritis, paired-label radioisotope studies were used in the current study to quantitate binding of the eluted antibody to glomeruli of isolated perfused rat kidneys. In this perfusion situation, which largely excludes the formation of circulating immune complexes, specific binding of 0.9 to 3.2 per cent of the total eluate protein infused was found with 9 to 33 per cent of the bound protein recovered in the glomerular fractions. Specific glomerular binding was also observed after administration of the paired-label mixture to intact rats. Glomerular immunoglobulin deposits and subepithelial electron-dense deposits similar to those found in rats with Heymann's nephritis were produced by intravenous administration of the eluted antibody. Direct bonding of antibody to glomerular capillary wall antigens, in the manner similar to that established for antiglomerular basement membrane antibody, must be considered in the immunopathogenesis of Heymann's nephritis and potentially in some forms of human glomerular injury as well.
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Macrophages were shown by the use of glomerular cell culture and morphologic techniques to be present in large numbers within the glomeruli of rabbits with acute serum sickness (AcSS) and in a passive model of the autologous phase of antiglomerular basement membrane (GBM) antibody-induced glomerulonephritis (PAGBMN). To determine the part played by these cells in the glomerular injury, animals were treated with a sheep anti-rabbit macrophage serum (AMS) or normal sheep serum (NSS). NSS administration had no effect on the development of either model of glomerulonephritis. The use of AMS reduced the number of circulating monocytes and prevented the accumulation of macrophages within glomeruli in both models (AcSS/NSS, mean 126/glomerulus, range 40-251; AcSS/AMS, mean 8, range 1-44; PAGBMN/NSS, mean 52, range 27-69; PAGBMN/AMS, mean 5, range 2-7). The AMS-treated rabbits had only minor histologic lesion and profound reduction in proteinuria (AcSS/NSS, mean 516 mg/24 h, range 200-991; AcSS/AMS, mean 41, range 3-161; PAGBMN/NSS, mean 335, range 55-975; PAGBMN/AMS, mean 10, range 2-24). Similar studies in the heterologous phase of glomerular injury induced by the same anti-GBM antibody revealed no effect of the AMS on this polymorphonuclear leukocyte-related phase of injury, demonstrating the selectivity of the antisera. Complement depletion, with cobra venom factor, did not affect the development of glomerulonephritis nor the accumulation of macrophages in either model. Inhibition of macrophage accumulation can largely prevent these forms of experimental glomerulonephritis, thereby implicating macrophages as mediators of glomerular injury and consequent proteinuria.
The circulating immune complex (IC) mechanism of renal and vascular injury is now well established based on observations in experimental serum sickness in animals and detection of circulating and localized IC of known antigen and antibody content in glomerulonephritis (GN) in man. Studies continue on the factors responsible for formation and vascular deposition of circulating IC. Utilization of assays to detect circulating IC has revealed that some patients with chronic presumed IC GN have no unusual amount of circulating IC. The possibility that nephritic individuals may handle relatively normal amounts of circulating IC in a nephritogenic fashion points out the need to study host and genetic factors in the development of IC GN. Observations in experimental animals have demonstrated the nephritogenic potential of the direct reaction of antibody with antigens, either structural in nature or "planted" within the glomerulus in a discontinuous pattern. This suggests that some GN previously thought to be from deposition of circulating IC IC by the pattern of irregular Ig accumulation on immunofluorescence study might be the product of a direct reaction of antibody with glomerular capillary wall antigens. Models of such reactions involving nonclassic glomerular basement membrane (GBM) glomerular capillary wall antigens are being identified in animals and sought in man. Finally, the reaction of antibodies with foreign materials that are first trapped or "planted" within the glomerulus can be nephritogenic in animal models and conceivably in man. The local nephritogenic immune reaction within the glomerulus should not distract from the circulating IC mechanism but rather expand our ideas of how the immune system can damage the kidney.
Anti-basement membrane antibodies are now being associated with an increasing spectrum of disease, including Goodpasture's syndrome, rapidly progressive and occasionally milder forms of glomerulonephritis (GN), tubulointerstitial nephritis, pulmonary damage, and potentially other forms of tissue injury. We have developed a radioimmunoassay to detect circulating antiglomerular basement membrane (GBM) antibodies. The antigens for this assay are derived from the noncollagenous portion of the GBM remaining after collagenase digestion. After immunoabsorptive purification, the major antigens precipitated by human anti-GBM antibodies can be characterized by polyacrylamide gel electrophoresis (PAGE) into an unresolved high molecular weight fraction and two antigenic peaks of 54,000 and 27,000 daltons. The noncollagenous nature of the antigenic material has been confirmed by amino acid analysis. The radiolabelled antigen has proven useful in detecting circulating anti-GBM antibodies in over 500 patients. The assay is of use in monitoring the activity of disease and judging the patient's response to therapy. It is also useful in determining the timing of renal transplantation, if required. Differences in antigenic content of glomerular and tubular basement membranes (TBM) have been noted between individuals. These antigenic differences, under certain circumstances, can lead to the induction of anti-basement membrane antibody responses after transplantation.
Two young men with anti-glomerular basement membrane (anti-GBM) antibody-induced Goodpasture's syndrome are described. Despite the characteristic renal morphological features and high titers of anti-GBM antibody, they had normal renal function. Both patients recovered spontaneously without treatment and remain well with normal renal function more than four years after presentation. The use of more sensitive diagnostic techniques has demonstrated that there is a broad spectrum of clinical severity in this disease and that mild cases can be expected to have a good outcome.
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Fifty-nine patients were seen with oliguria in 1975. Forty had acute renal failure (ARF) and 19 rapidly reversible oliguria (RR). The causes of the oliguria were medical (64%), surgical (27%) and obstetrical (9%). The following were valuable in the assessment of patients with oliguria: urine sodium concentration (UNa) and osmolality, coagulation studies and high dose intravenous urography. Patients presenting with a high UNa or a coagulation abnormality were more likely to have ARF. Central venous pressure monitoring was helpful in the initial management but the administration of diuretics was not. Twenty patients with ARF were treated conservatively and the remainder by dialysis. Infection was both the commonest complication of ARF and the most frequent cause of death. Seventy percent of those with ARF died. Death was more common in the elderly or patients with a medical aetiology. The mortality of ARF remains high in spite of advances in the management of its metabolic and infective complications because of the acceptance of more high risk patients. An improved awareness of the preventable causes of oliguria is apparent.
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