Secretory immune responses in human kidneys.

The secretory immune system has been well studied in the intestinal, bronchial, and biliary systems and breast. Tissue studies of secretory immunoglobulins in the kidney are scanty, mostly related to nephropathies with IgA. Renal tissues from 37 autopsies selected for any history of renal dysfunction were processed for immunohistologic studies on frozen sections with several antisera, including a purified rabbit anti-human secretory component (SC). By immunohistology, gel diffusion, and immunoblotting, the anti-SC antibody reacted appropriately with purified human SC, saliva, intestinal epithelium, and breast milk and did not cross-react with immunoglobulin heavy or light chains, lactoferrin, and other tissue proteins. IgA and SC were seen in tubular casts in 70% of patients, whereas less impressive staining with IgM, IgG, and albumin was seen, respectively, in 24%, 13%, and 22% of the patients. SC was present in the cytoplasm of distal tubule and Henle's loop cells in 78% of specimens. A control group of 10 healthy individuals who died suddenly showed minimal staining of casts and tubules in 2 specimens. Renal pathology in the group with IgA-SC+ casts included acute tubular necrosis (54%), severe chronic renal disease (61%), and mild chronic renal injury (38%). The group with negative IgA-SC casts included acute tubular necrosis (64%), infectious interstitial nephritis (36%), and negligible renal disease (36%). This study suggests that discrete distal segments of the nephron may have the capability of secreting SC, which is probably coupled with serum-derived IgA and incorporated into luminal tubular secretions. The low level of immunosecretions in kidneys which are normal or minimally damaged suggests that this system may need to be turned on by unknown, probably pathogenic stimulating factors.

IgA-associated glomerular deposits in liver disease.

IgA-associated immunopathologic renal injury has been reported in patients with cirrhosis. In an effort to elucidate the pathogenesis of this phenomenon, the livers and kidneys obtained at autopsy from a group of patients with cystic fibrosis were studied; these patients were selected because of their broad spectrum of liver abnormalities. On the basis of histologic examination of sections of liver, the patients were divided into two groups: Group I (20 patients) included patients with focal biliary cirrhosis and multilobular biliary cirrhosis; all had anatomic distortion of the biliary system, and many had cholestasis. Group II (28 patients) showed no bile duct anomalies. Immunofluorescence studies of the corresponding kidneys for immunoglobulin, complement, and free secretory component (FSC) revealed significantly more numerous IgA-containing glomerular deposits in group I (P less than 0.02). Although FSC was virtually absent in these deposits, significant in vitro binding of this protein revealed the polymeric nature of the glomerular IgA. This is consistent with previous observations of elevated serum levels of polymeric IgA, which forms the dominant component of glomerular deposits in cirrhotic patients. Since IgA glomerular deposition occurred in patients with focal biliary and no hepatocellular dysfunction, it seems that the source of this polymeric IgA is related to its impaired serum clearance by a distorted and stagnant bile duct system. However, the mechanism that leads to the deposition of this immunoglobulin in the glomeruli and other tissues remains conjectural.

Spontaneous nephrotic syndrome in a genetic rat model.

Advances in our understanding of the mechanisms of proteinuria in humans have depended on a variety of animal models. Most of these have been partially satisfactory because they require pretreatment of the animal with chemicals or toxins or they depend on an aging-related glomerular protein leakiness. The strain in this study was obtained by Koletsky after selective inbreeding of the offspring from a hypertensive Kyoto-Wistar and a normotensive Sprague-Dawley rat. The affected animals appear in 25% of the litters, indicating an autosomal recessive gene, and present with a spontaneous and progressive nephrotic syndrome detected as early as 3-5 weeks and associated with obesity, hypertension, hypoalbuminemia, hypercholesterolemia, and hyperlipidemia. Preliminary morphologic and immunofluorescence studies of their kidneys show progressive glomerular segmental sclerotic lesions and prominent mesangial deposition of IgM, a picture which resembles a steroid-resistant form of idiopathic nephrotic syndrome in humans, namely, focal glomerular sclerosis.

Nontuberculous mycobacterial infections: comparison of the fluorescent auramine-O and Ziehl-Neelsen techniques in tissue diagnosis.

Nontuberculous (i.e., atypical) mycobacterial infections are increasing among pediatric and immunosuppressed patients, who commonly present with subcutaneous inflammatory masses or adenitis, which is often surgically excised. Since the most frequently isolated species also grow slowly in culture, early diagnosis may depend on histologic detection of a mycobacterial organism in the biopsy specimen. However, the histologic methods used for this purpose are of uncertain value in the diagnosis of these infections. Biopsy specimens from 22 patients with clinical histories highly consistent with nontuberculous mycobacteriosis in which part of the tissue was cultured were selected for study. Coded tissue blocks and control specimens were stained by the Ziehl-Neelsen (ZN) or auramine-O (A0) fluorescent technique and examined blindly for the presence of characteristic organisms. Results of these studies were compared with the culture results, and predictive values were calculated. This experience showed that the AO technique is technically simpler, allowing faster screening at lower power and showing greater sensitivity and predictive value of a negative result although less specificity than the ZN technique. The lower specificity of AO may be factitious and due to the detection in the tissue of organisms that did not grow in culture. Previous observations that nontuberculous mycobacterial infections may elicit tissue reactions that simulate cat-scratch disease, sarcoidosis, and nonspecific chronic inflammation were also confirmed.

Circulating immune complexes and the nephropathy of cystic fibrosis.

To explore the putative nephropathic role of Pseudomonas-associated immune complexes, the authors measured the quantity of immune complexes in sera obtained, before death, from 20 patients with cystic fibrosis, and compared these findings with the histologic features of the lesions and with immunofluorescence patterns of kidney tissue obtained at autopsy. The immune complexes were measured by solid-phase C1q (C1q immune complex) and conglutinin to detect complexes containing IgM, IgA, and IgG. Elevated levels of C1q immune complex (13 patients) suggested the possibility of renal deposition of C3 (P less than 0.005) and IgM (P less than 0.05). The only three patients with IgA tissue deposits had elevated levels of C1q immune complex with normal IgA immune complexes. No other assay findings correlated with the immunofluorescence findings. Despite the prominent C3 in tissue deposits, the histologic features were not significantly associated with the results of the immune complex assays. This study indicates that complement-activating IgM-containing complexes can be deposited in renal tissues of patients with cystic fibrosis, but their nephropathogenicity is doubtful. These observations of kidney lesions, which diminish the injurious role of immune complexes in cystic fibrosis, may be relevant to an understanding of the pathogenesis of the lung lesions, which recent studies have linked to the presence of immune complexes.

The nephropathy of cystic fibrosis: a human model of chronic nephrotoxicity.

Patients with cystic fibrosis are chronically exposed to several potentially nephrotoxic factors. These include bacterial infections with their associated immune complexes and the antibiotics (aminoglycosides) used in their treatment. In addition, diabetes mellitus, liver disease, and cor pulmonale, commonly seen in these patients, may produce renal injury. To assess the extent of this injury, we performed morphologic and immunopathologic studies of the kidneys of 34 patients at autopsy. The group included 23 female and 11 male patients; their ages ranged from 4 months to 35 years and their disease was diagnosed one month to 22 years prior to death. The histological changes included glomerulomegaly, a mesangiopathic lesion, and tubulointerstitial disease frequently associated with acute and chronic tubular injury. The last was characterized by abundant tubular lysosomal proliferation and tubular atrophy suggestive of chronic amino-glycoside injury. Diagnostic diabetic lesions were not seen. Immunofluorescence studies predominantly revealed deposits of IgM or C3, or both, in glomeruli and arterioles in 18 patients. Although an anti-Pseudomonas antiserum did not show bacterial antigens in the tissues, elution studies in two specimens demonstrated antibacterial antibodies. These observations, coupled with the finding of ultrastructural glomerular deposits, suggest immune complex-mediated injury. No correlation was found between the severity or type of renal histologic lesion and patient age or duration of cystic fibrosis. Despite the occurrence of renal failure in six patients, renal involvement is currently of limited clinical concern in cystic fibrosis. Nevertheless, continued exposure to bacterial immune complexes and aminoglycosides, among other factors, can result in potentially serious renal disease.

Dirofilaria immitis. 5. Immunopathology of filarial nephropathy in dogs.

Fourteen beagles infected with larvae (microfilariae) of Dirofilaria immitis, were randomly selected from another study in which the toxic effects of subfilaricidal doses of diethylcarbamazine were being evaluated. This group of 14 dogs, together with 4 uninfected control animals, were variably sacrificed between 14 and 25 months after larval inoculations, and the ensuing renal lesions were studied by light and ultrastructural microscopy and by immunofluorescence and antibody elution techniques. On the basis of these studies, two groups of animals were distinguished. The first group was characterized by a striking pattern of linear fluorescence and fine ultrastructural dense deposits along the glomerular basement membrane, poor antibody response, and an inability to clear microfilariae from the tissues and circulation. The second group, with a nonlinear pattern of fluorescence, was characterized by a strong immune response, efficient elimination of microfilariae, and immunofluorescence and ultrastructural evidence of predominantly mesangiopathic immune complex renal disease. In both groups, elution studies demonstrated tissue deposits of antiworm antibodies, suggesting a filaria-antibody immune-complex nephropathy. No evidence was found for the presence of anti-basement-membrane antibodies. On the basis of a previous experimental model, it is postulated that in the first group of animals with linear fluorescence, the observed lesions may represent a natural form of an immunopathogenic mechanism of glomerular damage in which filarial antigen becomes uniformly localized in the glomerulus and elicits an autologous antibody response. The possible role of the drug diethylcarbamazine in inducing this mechanism of immune injury is discussed.