Recurrent haematuria: role of renal biopsy and investigative morbidity.

The usefulness of renal biopsy in investigating unexplained haematuria was assessed by a study of 33 adults referred consecutively with this syndrome. Unequivocal abnormalities were seen on light microscopy or immunofluorescence in 31 of the 33 specimens of renal tissue examined. In 18 patients deposits of IgA were present in the mesangium. Loin pain occurred in only two of the 18 patients with mesangial IgA deposits, compared with 11 of the 15 patients without these deposits. Seven of the nine women in this series had had loin pain compared with only six of the 24 men. Thus a woman with loin pain and haematuria was not likely to have mesangial IgA nephropathy but this was found in 14 of the 18 men with unexplained painless haematuria. Failure to appreciate the role of renal biopsy in the investigation of unexplained haematuria may result in unnecessary radiology, considerable morbidity, and even in unjustified nephrectomy.     

Isolated glomerulonephritis with mesangial IgA deposits.

Mesangial deposits of IgA, occurring in the absence of systemic disease known to be associated with nephritis, were detected by immunofluorescence microscopy in renal biopsy specimens from 25 patients (4% of 630 specimens studied). Associated deposits of C3 were always present, usually with IgG, but IgM deposits were less common and C1q was never seen. On light microscopy most of the biopsy specimens showed mesangial of focal nuclear proliferation though some were normal. Fifteen of the 25 patients presented with macroscopic haematuria, which was usually recurrent and preceded by a sore throat, whereas the remaining, and usually older, patients presented with persistent proteinuria and were more likely to have impaired renal function. This incidence of "mesangial IgA disease" is less than that reported by French workers. There was a significantly high incidence of familial renal disease among these patients. No abnormalities of serum complement or IgA concentration were found.     

Glomerular Deposition of Properdin in Henoch-Sch?nlein Syndrome and Idiopathic Focal Nephritis

Biopsy of renal tissue from four patients with idiopathic focal nephritis and three patients with Henoch-Schönlein syndrome showed that C3 and properdin were deposited with IgA in the glomerular mesangium, C1q could not be detected. These observations suggest that glomerular injury in disorders characterized by mesangial deposits of IgA and C3 is mediated via the properdin system.     

Mesangioproliferative Glomerulonephritis in Mink with Encephalitozoonosis

Renal specimens from 6 mink with encephalitozoonosis were studied by light and electron microscopy and immunohistochemistry. The glomeruli of affected kidneys had a mesangioproliferative glomerulonephritis which was characterized by an increase in mesangial cells and matrix in most glomeruli. Some glomeruli were partially or completely sclerosed. There were protein or granular casts in the cortical and medullary tubules. Interstitial nephritis, vasculitis and tubular cysts were found. Electron microscopy demonstrated extensive matrix and increased cellularity in the mesangial areas. Glomeruli showed segmentally thickened or wrinkled capillary basement membranes. Electron dense deposits were found in the glomerular basement membranes and mesangium. Peroxidase-anti-peroxidase immunohistochemistry demonstrated that IgG and IgM positive material was present as granular deposits in the glomerular basement membrane and occasionally in the mesangium.     

Alcohol abuse-related mesangial glomerulonephritis: immunoelectron microscopy

Immunoelectron microscopy, using post-embedding immunohistochemistry with colloidal gold, was performed on renal samples from forensic autopsies. We confirmed that electron-dense deposits seen in alcohol abuse-related mesangial nephritis correspond to immunoglobulins, as has been shown previously by others in idiopathic cases. We investigated seven control samples and 13 specimens from individuals with evidence of alcohol abuse, six of whom had mesangial nephritis with IgA deposition. We found concentration of the gold particles over large electron-dense deposits in four of six cases of mesangial nephritis, confirming that they correspond to the IgA shown by immunofluorescence. Furthermore, a similar concentration of gold particles was not observed in control cases or in alcoholics without mesangial glomerulonephritis (4/6 vs 0/14; p = 0.005). IgM, seen as small aggregates, was confirmed in only two of six of the same cases. This is the first time that immunoelectron microscopy is performed on tissues obtained post mortem.     

Dermatitis herpetiformis: effect of gluten-free diet on skin IgA and jejunal structure and function.

To clarify the controversy about the effectiveness of a gluten-free diet in dermatitis herpetiformis, 10 highly motivated patients were investigated. The indices used to assess improvement included deposition of sub-epidermal IgA in unaffected skin, counts of intraepithelial lymphocytes, deposition of IgA in jejunal villi, and electrical tests of glucose absorption. In every patient subepidermal IgA concentrations fell after gluten withdrawal. In all but one patient the dose of dapsone necessary to control symptoms was reduced. Indeed, six patients stopped taking the drug completely within a year. In nine patients biopsy specimens were taken from the jejunum; seven showed abnormalities in jejunal morphology, eight had increased numbers of intraepithelial lymphocytes, and five had increased numbers of IgA-reactive cells in the lamina propria. Two of these three indices improved after gluten withdrawal, which confirmed that all nine patients were adhering to their diet. Routine screening for malabsorption proved to be unsatisfactory for showing the mild jejunal disease found in patients with dermatitis herpetiformis. The electrical test of glucose absorption showed subnormal results in all eight patients tested, however, and in six the results improved after gluten withdrawal.     

Immunoglobulin synthesis in the "resting" breast.

Nulliparous women have a greater risk of developing breast cancer than women who have borne children, but so far no functional differences in breast tissue have been reported between parous women and nulliparae. Macroscopically and histologically normal breast tissue was obtained from 74 women of reproductive age during biopsy of benign breast lesions and was examined for the presence of plasma cells by immunfluorescence. Immunoglobulin synthesis was detected by an in-vitro culture technique. Synthesis of IgA was detected in 81% of specimans of IgG in 45%, and of IgM in 3%. IgA synthesis much more intense than IgG or IgM synthesis. Plasma cells containing IgA were seen in 71% of the specimens examined, and 88% of specimens had deposits of IgA in the ductules. The findings were not significantly incluenced by the nature of the condition necessitating biopsy or by oral contraception. Nulliparous women showed no cyclical changes, but among parous women IgA synthesis was more intense during luteal phase of the menstrual cycle. This suggests that after the first pregnancy the breast is more sensitive to progesterone.     

Glomerulonephritis with mesangial deposits of IgA unassociated with systemic disease.

Typical features of IgA-associated nephritis were found in renal biopsies from 16 of 355 consecutive patients. Generalized segmental mesangial proliferation was noted in biopsies from most patients, and dense deposits were detected by electron microscopy in mesangial regions of approximately 50% of biopsies. Immunofluorescent studies showed IgA to be the predominant immunoglobulin in glomueruli; IgG was present in less than 50% of biopsies and IgM in only 12%. The serum IgA value was significantly increased (P les than 0.001) in 50% of patients and the mean IgA/IgG ratio was significantly increase (P less than 0.001) for the patient group as a whole, which suggests a selective increase in IgA. Mesangial deposits of C3 were present in 15 of 16 biopsies and properdin was noted in all biopsies tested; C4 was not demonstrated in any biopsy. This suggests activation of the alternative complement pathway. The results of this study support the concept that IgA-associated nephritis is a unique condition that in some patients gives rise to idiopathic recurrent hematuria. Although the prognosis is good in the majority of patients, the renal disease may progress.     

Experimental immune complex glomerulonephritis in the mouse with two types of immune complexes.

Immune complex glomerulonephritis was induced in three groups of mice by long-term immunization. Two antigens of similar molecular weight were used. The first group was immunized with ferritin (mol wt 480,000). In altered glomeruli deposits of immune complexes were seen in the subendothelial and subepithelial spaces of the glomerular basement membrane (GBM) and in the mesangium. The immune complex deposits were formed by amorphous matrix with marked dense molecules of ferritin. The second group was immunized with human fibrinogen (mol wt 450,000). The immune complex deposits were present in the intramembranous, subepithelial and subendothelial spaces of the GBM and in the mesangium. These deposits were relatively less electron-dense and had a fine granular structure. The third group of mice were immunized with both ferritin and fibrinogen simultaneously. Two types of deposits situated subendothelially in the GBM and in the mesangium were seen in one animal of this group. One type of deposit resembled structurally the ferritin-antiferritin complex deposits, the other resembled the fibrinogen-antifibrinogen complex deposits. The individual deposits in the GBM and in the mesangium formed discrete homogeneous masses. The two types of deposit were occassionally in direct contact with one another, but were more often completely separate and were never mixed. It can be assumed that in at least some phase of the experiment both types of complex were present in the circulating blood simultaneously. However, since none of the complexes deposited in the GBM or in the mesangium were mixed, it seems probable that each type of complex is deposited separately in the form of "clusters" composed of a single type of complex. The phagocytic activity of mesangial cells of animals with complex glomerulonephritis was not increased when compared with control animals.     

Spontaneous glomerular immunoglobulin deposition in young Sprague-Dawley rats

The frequency, age-onset and distribution of spontaneously deposited immunoglobulins (Igs) in glomeruli of Sprague-Dawley rats has been investigated. Groups of rats (n = 10) were examined at 4-7 day intervals from birth (presuckling) until 30 days of age. Findings were compared with circulating immunoglobulin concentrations in each age group. Immunoglobulins were undetectable in immature kidneys of newborn rats. However, as early as 5 days, scanty IgA and IgM deposits were observed predominantly in mesangial areas of mature glomeruli, corresponding to low circulating concentrations of these immunoglobulins. By contrast, glomerular IgG deposits were not observed until 21 days, despite relatively high concentrations of circulating maternal IgG from birth. Mesangial deposition of immunoglobulins increased with age. Absence of complement C3c or electron dense deposits associated with this mesangial localization suggests that immunoglobulins were not deposited as immune complexes. Accumulation of non-phlogogenic immunoglobulins in the mesangium of normal rats supports the concept that the mesangium is constantly perfused by circulating macromolecules and filtration residues. The results indicate problems of interpretation of the significance of endogenous immunoglobulin deposition in models of experimental glomerulonephritis, even in studies involving weanling rats.     

Canada's medical schools

A 20-year-old man with a 10-year history of glomerulonephritis presented with a purpuric rash on his legs. A renal biopsy specimen obtained when he was 11 years old had shown mesangial glomerulonephritis; staining 9 years later for IgA had negative results. A second renal biopsy, performed when the rash was present, revealed mesangial glomerulonephritis and mesangial deposits of IgA; biopsies of the involved skin showed leukocytoclastic vasculitis. In this case isolated glomerulonephritis appeared to change to a multisystem illness, with a different immunologic character, through one of several possible pathogenetic mechanisms.     

Characteristics of mutant mice (ICGN) with spontaneous renal lesions: a new model for human nephrotic syndrome

Spontaneous nephrotic mice (ICGN mice), a new mutant strain of mouse from outbred ICR, were clinically, macroscopically, histologically and immunohistochemically studied to establish their value as a model for human nephrotic syndrome. Most of the affected mice developed proteinuria, hypoproteinaemia and hypercholesterolaemia, and some of them developed systemic oedema. A high concentration of blood urea nitrogen (BUN) and a low haematocrit value were also observed. The kidneys of severe cases showed a decrease in size and had a yellowish granular surface. These findings indicated that the mice were terminally affected by chronic renal insufficiency. Histopathology demonstrated glomerular lesions consisting of thickened basement membranes of the capillary loops with irregular spike-like protrusions and enlargement of the mesangium unaccompanied by cellular proliferation. The immunofluorescence technique revealed positive granular staining for IgA, IgG and IgM and to a lesser extent for C3 along the capillary loops in affected mice. The similarity between this spontaneous disease and human nephrotic syndrome caused by idiopathic glomerular lesions is discussed. ICGN mice may be a useful animal model for this human disease.     

Dysgammaglobulinaemia in Tropical Sprue

Study of immunoglobulin levels in 16 Indian control subjects showed that, compared with a Danish control series, they had a significantly higher mean level of IgG, but not of IgA or IgM. By contrast, the IgG levels in eight patients with tropical sprue were decreased or low normal in six cases and raised in only one case. Two patients with tropical sprue had agamma-A-globulinaemia.Turnover studies with ¹²⁵I-labelled IgG showed a high rate of synthesis in three Indian controls and an appreciably reduced or low rate in seven of the eight cases of tropical sprue.     

Serology and tissue lesions in rabbits immunized with Streptococcus mutans

Rabbits were immunized i.v. or i.d. with sterile suspensions of disrupted Streptococcus mutans strain MT703 or K1R. Indirect immunofluorescence assays indicated that sera from four of 10 rabbits immunized i.d. contained antibodies reactive with monkey and human heart and kidney components; 19 of 24 rabbits immunized i.v. had antibodies reactive with these tissues. Heart-reactive antibodies were also detected by immunoelectrophoresis and indirect radioimmunoassay. These antibodies were absorbed well by cytoplasmic membranes, a whole cell extract, and an alkali extract of S. mutans but only weakly by intact bacteria. Between 6 and 8 weeks after the first i.v. administration of S. mutans vaccines, rabbits developed proteinuria and hematuria with subsequent weight loss and lethargy. Approximately 25% of the animals died from illness between the fifth and sixth month of immunization. In 13 of 15 rabbits, immune deposits of C3 and IgG, IgM, or IgA and fibrinogen were seen in kidneys within the glomeruli, basement membranes of the peritubular capillaries, and in the interstitium. In the heart, deposits were seen along the capillaries of the myocardium. In 8 of 14 rabbits, focal deposits of S. mutans antigen were detected in glomeruli and in the kidney interstitium. The kidneys showed gross pathologic and histopathologic changes. Most kidneys were pale and enlarged. Microscopic examination revealed hypercellularity of the glomeruli, presence of neutrophils, thickening of glomerular and tubular basement membranes, tubular atrophy, edema, and fibrosis of the interstitium. The kidney disease presented features of poststreptococcal glomerulonephritis. Microscopic examination of heart sections revealed mild perivascular infiltration by polymorphonuclear leukocytes and plasma cells in some of the rabbits.     

大鼠加速型抗肾小球基底膜（GBM）肾炎的研制

将正常兔ＩｇＧ与完全弗氏佐剂颈免疫大鼠,８天后注射亚致肾炎剂量的兔抗大鼠肾小球基底膜（ＧＢＭ）血清,结果大鼠尿蛋白量在注射该血清后第１天即明显升高,第３天达高峰;在第２１天时,血清肌酐显著升高。肾脏组织学检查：免疫荧光见第１天即有大鼠ＩｇＧ、Ｃ３和兔ＩｇＧ沿ＧＢＭ呈典型线状沉积;光镜见第１天肾小球内细胞数目明显增加,内皮细胞肿胀,肾小球内见中性粒细胞浸润,第７、１４．２１天时肾小球毛细血管丛系膜区增宽,系膜细胞增生,间质可见炎症细胞浸润,ＰＡＳＭ染色可见ＧＢＭ增厚,电镜见ＧＢＭ内有电子致密物线状沉积,上皮足突融合内皮窗孔消失,微血栓形成阻塞管腔,间质有细胞浸润和纤维化。     

Bound class M, A and G immunoglobulins in the thymus of myasthenia gravis patients]

Deposits of granular material containing IgM, IgA, and IgG were revealed in the thymus of patients with myasthenia by direct immunofluorescence. Treatment of the thymus sections by unlabeled preparations against individual classes of human immunoglobulins inhibited the reaction of the granular material with the homologous labeled preparations. Disappearance of fluorescence of these deposits was also seen in treatment of the sections with glycine-HCl-buffer, pH 2.8. These data permitted a suggestion that granular material represented immune complexes where IgM, IgA, and IgG served as antibody, and thymus tissue components--as an antigen. The presence of bound immunoglobulin in the thymus indicated that an autoimmune process directed against the tissues of this organ occurred in myasthenia.     

Immunopathological responses in women with chronic inflammatory diseases of the uterus and appendages and their therapeutic correction

A total of 145 women with chronic inflammatory diseases of uterus and appendages (IDUA) were examined. Bacterioscopy of smears and culture of vaginal, cervical canal and uterine cavity contents were performed in all patients. Direct immunofluorescence and PCR were used for detection of chlamydiae in scrapes and smears and in biopsy specimens taken from endometrium. The number of T lymphocytes and their subpopulations, B lymphocytes as well as the level of plasmatic cells synthesizing IgA, IgM and IgG and secretory IgA (sIgA), immune complexes and C3 component of the complement were determined in biopsy specimens of the endometrium. Pathomorphological examination revealed structural changes characteristic of the immunocomplex disease (secondary deficiency of sIgA, pronounced suppression of IgA production by plasmocytes along with an essential increase in the number of IgG synthesizing cells and immune complexes fixed to the venule endothelium) were detected. Lectin-histochemical study revealed considerable changes in secretory activity of endometrial epitheliocytes manifested by severe suppression of bactericidal activity of the uterine mucus. The detected disturbances of local protective reactions in the endometrium of women IDUA gave grounds for including immunomodulators into the traditional treatment scheme. The latter made it possible to increase essentially the therapeutic effect.     

Immunological studies in Bloom's syndrome. A follow-up report.

Longitudinal immunological studies were performed in five patients with Bloom's syndrome. Serum IgG concentration showed no age-related increase. IgA levels were below the 10th percentile in childhood, but rose to normal in all but one. IgM was decreased in four patients at diagnosis and remained so in three of them. Cellular immunity results were very variable, even within one patient. An immunologic attrition was not demonstrated.     

Pathogenic significance of IgA receptor interactions in IgA nephropathy

IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, frequently progresses to renal failure. The pathogenesis of this disease involves the deposition of undergalactosylated IgA1 complexes in the glomerular mesangium. How the IgA1 complexes are generated and why they are deposited in the mesangium remains unclear. We propose a model wherein two types of IgA receptors participate in sequential steps to promote the development of IgAN, with FcalphaRI (CD89) being initially involved in the formation of circulating IgA-containing complexes and, subsequently, transferrin receptor (CD71) in mediating mesangial deposition of IgA1 complexes.     

Cytologic findings in posttransplant lymphoproliferative disease

Transplant patients are at an increased risk of developing lymphoproliferative disorders (LPDs). To examine the role of cytology in diagnosing LPDs, the cytologic reports on all transplant patients seen at the University of Iowa from January 1983 to July 1988 were reviewed. Thirteen of 649 transplant patients developed LPD; 10 of those 13 patients had a total of 25 cytologic specimens obtained within two months of the diagnosis of LPD available for review. Ten specimens (four cerebrospinal fluids [CSFs], four effusions, one respiratory specimen and one liver aspirate) from six patients were positive for LPD. Immunophenotypic or immunogenotypic studies on cytologic specimens from four patients showed a clonal B-cell process. The cytologic features ranged from those of a plasmacytoid LPD to those of an immunoblastic or large-cell lymphoma. An additional seven specimens (five CSFs, one effusion and one liver aspirate) from four patients were suspicious for LPD, exhibiting rare atypical cells or cells with plasmacytoid features. Ten patients died with LPD within 12 months; three are alive. Cytologic specimens, especially body fluids, are frequently positive in LPD and may be useful diagnostically. Since the differential diagnosis includes reactive lymphocytosis, confirmatory immunophenotypic or immunogenotypic studies are recommended.