Cell-mediated immune response in acute poststreptococcal glomerulonephritis.

To evaluate the role of cell-mediated immunity in acute poststreptococcal glomerulonephritis (APSGN), we identified the immune cell population infiltrating the glomeruli. Renal biopsies were obtained from 22 patients with APSGN, 16 with overt and 6 with asymptomatic disease, one to 30 days after onset. Samples of normal renal tissue were used as controls. Frozen sections were examined using monoclonal antibodies that recognize various leukocyte surface markers. Double staining for granulocytes and monocyte/macrophages (M phi) was performed using chloro-esterase staining and indirect immuno-alkaline-phosphatase staining with Leu M-5 sequentially. In overt APSGN, there was a substantial increase in the total number of granulocytes and M phi with a slight increase in T cells. Numbers correlated with time after onset, as more leukocytic infiltration was observed when the tissue was taken earlier. Furthermore, a significant positive linear correlation was seen between helper/inducer T cells and M phi (r = 0.86, p < 0.01). Helper T cells tended to be increased to a higher proportion during the early stage, while suppressor T cells remained constant throughout the course. Analysis with anti-proliferating cell nuclear antigen antibody revealed increased glomerular cell proliferation in the early phase of APSGN. In asymptomatic patients, the total number of leukocytes was less than in the overt patients, but the proportions of infiltrating cells were similar. These data suggest that M phi are important effector cells causing endothelial and mesangial cell proliferation in APSGN. M phi infiltration in the glomeruli appears to be mediated by complement-induced chemotaxis and probably be an antigen-specific event related to the delayed type hypersensitivity mediated by helper/inducer T cells.

Role of a streptococcal antigen in the pathogenesis of acute poststreptococcal glomerulonephritis. Characterization of the antigen and a proposed mechanism for the disease.

We studied the significance of a streptococcal protein (preabsorbing Ag) (PA-Ag) in the pathogenesis of acute poststreptococcal glomerulonephritis (APSGN). This protein was isolated from nephritogenic streptococci. Purification of PA-Ag was achieved by chromatography, followed by Sephadex IEF. A single protein band at pH 4.7 was identified as PA-Ag. The m.w. was 43,000. Rabbit antisera against PA-Ag and sera of patients with APSGN showed identical precipitation lines by immunodiffusion. Antibodies to PA-Ag were found to be present in 30 of 31 patients with APSGN, in 1 of 36 patients with uncomplicated group A streptococcal upper respiratory tract infections, and in 1 of 36 normal adults. By using immunoelectrophoresis, it was found that PA-Ag activates the alternate pathway of C. Other water-soluble streptococcal fractions, used as controls, did not activate the C system. The demonstration that PA-Ag is present in the glomeruli in the early phase of APSGN and its ability to activate C3 and factor B suggest that PA-Ag may be involved in the pathogenesis of APSGN, via in situ C activation.

Hyponatremia in patients with the acquired immunodeficiency syndrome.

Of 103 patients with the acquired immunodeficiency syndrome (AIDS) admitted for acute opportunistic infections, 36 had serum sodium less than or equal to 130 mEq/l (130 mmol/l). In 12 the hyponatremia was associated with volume depletion and corrected with saline replacement therapy. In 23 it was associated with the syndrome of inappropriate antidiuretic hormones secretion (SIADH). One patient had adrenal insufficiency and the serum sodium corrected after steroid replacement. We conclude that hyponatremia is a common electrolyte abnormality in AIDS patients suffering acutely from opportunistic infections and that SIADH and volume depletion are important contributing factors.

Evidence for an HIV-related nephropathy: a clinico-pathological study.

The existence of an HIV-related nephropathy as a distinct disease entity is controversial. We observed a high incidence of renal disease in our AIDS patients. Of 182 patients, 59 patients (32.4%) were found to have heavy proteinuria (greater than 2 g/24 h). Of these, 24 patients had slow progression of renal insufficiency and 2 patients had rapid deterioration to end stage renal disease. There was a notable absence of hypertension in these cases. The incidence of proteinuria was similar in blacks and hispanics; however 22.8% of blacks had renal insufficiency as compared to 6.9% of hispanics. There was no difference in the incidence of heavy proteinuria between intravenous drug abusers (32.3%) and nonabusers (33.3%). Renal morphology when examined showed characteristic changes, including cytomembranous structures and virus-like particles. These changes were similar in patients with heavy or light proteinuria, though they were less severe in the latter. We conclude that a HIV-related nephropathy exist and the presence of cytomembranous structures and virus-like particles in the renal tissue raises the possibility of a viral etiology for this disorder.

Renal cytomembranous inclusions in idiopathic renal disease as predictive markers for the acquired immunodeficiency syndrome.

Tubuloreticular inclusions (TRI) and cylindrical confronting cisternae (CCC) are present in cells of patients with the acquired immunodeficiency syndrome (AIDS) and have also been detected in the kidneys of individuals with AIDS and heavy proteinuria. We examined renal biopsy tissue from 13 patients with proteinuria and/or renal insufficiency. At the time of biopsy, two of the patients had AIDS (group A), four had AIDS-related complex (ARC) (group B), and seven presented without any clinical signs or symptoms characteristic of AIDS or ARC. These seven had risk factors for AIDS, and systemic lupus erythematosus (SLE) was excluded in all. Abundant TRI were present in the renal endothelial and fibroblastic interstitial cells in all patients from group A and B and in four patients who had no evidence for AIDS or ARC at the time of biopsy (group C). These individuals were followed, and all developed AIDS within a period of 3 to 14 months. CCC were detected in two of two patients in group A, one of four in group B, and one of four in group C. TRI and CCC were not present in the renal tissue of the remaining three patients; they did not develop ARC or AIDS over a prolonged observation period. Our findings suggest that TRI and TRF are ultrastructural markers for human immunodeficiency virus (HIV) associated nephropathy and can be seen before AIDS has manifested itself. These structures may be of predictive value for the future development of AIDS in patients presenting with apparent idiopathic renal disease.

Renal ultrastructural markers in AIDS-associated nephropathy.

Renal tissues from two groups of patients with acquired immune deficiency syndrome (AIDS) were examined: Group A had severe proteinuria and varying degrees of renal insufficiency, designated AIDS-associated nephropathy (AAN), and Group B had no renal involvement. Control Group C consisted of patients with heroin-associated nephropathy (HAN) with proteinuria comparable to patients in Group A but without AIDS or its related complex (ARC). The most frequent finding, common to both AAN and HAN, was focal glomerular sclerosis. In contrast to HAN, AAN tissue showed mesangial hypocellularity, sparse interstitial infiltrates, severe tubular degenerative changes, tubular microcystic ectasia, Bowman's space dilatation, and presence of multiple complex inclusions both in the nuclei and cytoplasm in a variety of cells. Abundant tubuloreticular inclusions were found in the endothelial and occasionally in the interstitial cell cytoplasm. Nuclear bodies (NBs) were seen in greater frequency, complexity, size, and heterogeneity, and of budding configuration in Group A as compared with Groups B and C; NBs in Group C were mostly of simple types (I and II). In addition, a peculiar granulofibrillary transformation in many tubular and interstitial cell nuclei was observed in Group A. This transformation was rarely present in Group B and was never seen in Group C. Because complex NBs (Types III to V) and various intracytoplasmic and intranuclear inclusions present in Group A are often associated with viral invasion, their presence in kidneys of AIDS patients with proteinuria suggests a viral etiology for AAN.

IgA nephropathy occurring in the context of previous acute glomerulonephritis.

A 37-year-old female presented with acute onset of glomerulonephritis 10 days following an upper respiratory infection. Serum complement components were depressed and proteinuria exceeded 3.0 g daily. Renal biopsy revealed granular staining of IgG and C3 along the basement membrane as well as small amounts of IgA in a linear pattern. Gradual resolution of symptoms was followed by recrudescent proteinuria 2 years later. Renal biopsy at this time revealed large deposits of IgA in a mesangial staining pattern consistent with a diagnosis of IgA nephropathy. Possible mechanisms for this unusual morphologic transformation include enhanced mesangial permeability as well as mesangial sequestration of an exogenous antigen.

Pasteurella multocida septicemia and peritonitis in a patient with cirrhosis: case report and review of the literature.

A case of Pasteurella multocida septicemia and peritonitis in a patient with cirrhosis is reported and the literature reviewed. Patients with cirrhosis and exposure to domestic animals are at risk for this infection. Initial empiric therapy of spontaneous bacterial peritonitis in such patients should include a penicillin to which this organism is usually susceptible.

Circulating immune complexes in patients with uncomplicated group A streptococcal pharyngitis and patients with acute poststreptococcal glomerulonephritis.

To investigate the role of circulating immune complexes (CIC) in the pathogenesis of acute poststreptococcal glomerulonephritis (AGN), sera were obtained serially from 13 patients with biopsy-proven AGN, 16 patients with group A streptococcal infection, and 20 age- and sex-matched controls. Samples were analysed for Clq-binding activity (Clq-BA), levels of IgG, IgA, IgM, C3 and C4, and antibody titres to streptococcal enzymes. Significant elevation of Clq-BA was observed in 11 patients (84.5%) with AGN and 7 patients (44%) with streptococcal infection alone. The data suggest that CIC do not necessarily cause glomerular damage, but rather represent a systemic inflammatory response in patients with group A streptococcal infection.

Cellular immunity in systemic lupus erythematosus as evidenced in vitro by leucocyte migration inhibition tests.

A leucocyte migration inhibition test was performed on 26 patients with systemic lupus erythematosus (SLE) and on 35 control subjects using three different antigens, fetal calf thymus DNA, baker's yeast RNA, and calf thymus extractable nuclear antigen (ENA). Leucocyte migration was inhibited by DNA in 17 out of 26 SLE patients (65-3%), and in only 2 of the 35 controls (5-7%). When RNA or ENA was added none of the patients or controls showed inhibition. In SLE patients migration inhibition by DNA was significantly correlated with the presence of proteinuria and/or granular casts in urinary sediment. When the migration inhibition test was positive, immunofluorescence verified active histology of the glomeruli obtained by a percutaneous renal biopsy.

Epidemic glomerulonephritis in Maracaibo. Evidence for progression to chronicity.

In 1968 an outbreak of 348 cases of acute poststreptococcal glomerulonephritis (AGN) was observed in Maracaibo, Venezuela. During the year, the epidemic had three peaks of incidence. Districts with better sanitation showed a lower incidence of disease than those with less adequate facilities. Endemic cases occur every year. Lowering of serum complement activity was observed in 96% and hypertension in 90% of the patients. The mortality rate in the acute phase during the epidemic was 1.31%. A history of antecedent infection was found in 39% of the cases. 70% of these infections were in the upper respiratory tract. During 1973-74, 120 of the patients (19 adults and 101 children) were reexamined. All but one had been completely asymptomatic. Sixteen patients (13.3%) had one or more of the following abnormalities (group A): low CCr, microscopic hematuria, proteinuria of 1 g/day or more and hypertension. One hundred and four patients (86.7%) were normal by all clinical and laboratory parameters tested (group B). The incidence of persisting disease, as judged by biochemical findings, was significantly higher (P less than .01) in adults (36.7%) than in children (8.9%). Percutaneous renal biopsies from 7 patients of group A, and 8 patients from group B, were studied by light microscopy and immune histology. All biopsies from group A patients had evidence of advanced glomerular disease by light microscopy and by immune histology. Seven biopsies from group B patients were also abnormal showing mild changes with corresponding immunologic findings. Only in one patient was the biopsy completely normal. Our studies indicate that significant numbers of patients progress towards chronicity after epidemic, poststreptococcal AGN. Such progression is more common in adults than in children.

A hitherto unknown streptococcal antigen and its probable relation to acute poststreptococcal glomerulonephritis.

In the initial phase of acute poststreptococcal glomerulonephritis (AGN), antigenic sites not covered by specific antibody can be demonstrated in the glomeruli. These sites are on the endothelial side of the glomerular basement membrane and in the mesangial matrix. The antigen is contained in a water-soluble fraction of nephritogenic streptococci. It can be highly purified by column chromatography or acrylamide electrophoresis. This antigen against which the patient develops specific antibodies is contained and immunologically identical in all nephriotogenic streptococci examined so far irrespective of their M or T protein. It is not identical with any known streptococcal extracellular product. When antibodies are produced in rabbits against this streptococcal antigen they localize on kidney biopsies, obtained early during the disease from patients with AGN in an identical way as does the labelled antibody of the serum of patients wiht AGN. This antigen may be suited as a vaccine for the prevention of AGN.

Demonstration of antigenic sites in glomeruli of patients with acute poststreptococcal glomerulonephritis by immunofluorescein and immunoferritin technics.

The presence and localization of antigenic sites in glomeruli of 14 patients with acute poststreptococcal glomerulonephritis (AGN) were studied by immunofluorescein and immunoferritin technics. Labeled IgG fractions from the same patients were used for the identification of antigenic sites. The staining capacity of these IgG fractions depended on the time when sera were obtained. Staining was minimal during the first week, and increased up to the fourth or fifth week. Glomeruli, however, stained only when renal tissue was obtained during the early phase of the disease. Precise localization of antigenic sites was determined with ferritin-conjugated patients' IgG. Segmental deposition of ferritin was observed in the mesangial matrix and on the endothelial side of the glomerular basement membrane. Subepithelial electron-dense deposits contained no or very few ferritin particles. In contrast, ferritin-conjugated antihuman IgG was distributed diffusely in the mesangial matrix, on the endothelial side of the basement membrane and in subepithelial deposits. These findings suggest that, during the early stage of acute poststreptococcal glomerulonephritis, free antigen is present in the glomeruli of patients with this disease.

Relationship of nervous tissue transketolase to the neuropathy in chronic uremia.

Patients with chronic uremia develop neurologic defects which are similar to the demyelinating lesions seen in thiamine deficiency. The present study describes inhibitory effects of uremic material on nervous tissue transketolase, a thiamine-dependent enzyme of the pentose phosphate pathway which has been reported to have functional importance in the metabolism of myelinated nervous structures. Transketolase activity (TKA) of normal human brain and spinal cord was measured by the conversion of ribose-5-phosphate (R5P) to sedoheptulose-7-phosphate (S7P). TKA was significantly inhibited by plasma, cerebrospinal fluid and low molecular weight dialysate fractions obtained from patients with uremic neuropathy, but not by samples from normal subjects. The specific effect on transketolase by uremic material was established by showing suppressed formation of S7P from R5P also in the presence of excess cofactor thiamine pyrophosphate and of the other substrate xylulose-5-phosphate. Uremic plasma likewise inhibited a partially purified transketolase preparation from bakers' yeast.31 of 35 chronic uremic patients with inhibition values between 10 and 84% before or during the early phase of intermittent hemodialysis had evidence of neuropathy. Data of clinical grading of the neurologic deficits and values of motor nerve conduction velocity revealed a correlation between the extent of uremic neuropathy and the degree of nervous tissue transketolase inhibition. Hemodialysis markedly reduced the inhibitory effects of the patients' plasma and the data indicate that uremic patients who received effective long-term dialysis treatment show a parallel decline of transketolase inhibition and uremic neuropathy.The findings demonstrate that in patients with chronic renal failure, low molecular weight factors accumulate and inhibit nervous tissue transketolase. This biochemical defect-uncorrectable by thiamine but reversible by dialysis-may interfere with the metabolism of myelin-supporting cells, and/or of the axonal metabolism of medullated structures, and may thus contribute to the degeneration of myelinated nerves seen with uremic neuropathy.