Alfred J. Fish

The glomerular mesangium: I. Kinetic studies of macromolecular uptake in normal and nephrotic rats

This study was designed to define quantitatively the function of the rat glomerular mesangium in the uptake and processing of intravenously administered protein macromolecules (radiolabeled aggregated human IgG, AHIgG-(125)I), to relate this function to that of the general reticuloendothelial system, and to examine the effects of increased glomerular permeability to protein on the mesangial cell system.Mesangial localization of human IgG as demonstrated by immunofluorescent microscopy showed good correlation with concentrations of AHIgG-(125)I in preparations of isolated glomeruli. In normal rats the concentrations of AHIgG-(125)I in glomeruli were similar to those of lung, liver, and spleen and demonstrated a rapid decrease with increasing time intervals after aggregate administration. In rats given aminonucleoside of puromycin a marked increase in mesangial uptake of aggregates was found while studies of nephrotic lungs, liver, spleen, and blood showed no such differences. Glomerular levels of AHIgG-(125)I in aminonucleoside animals could not be correlated with the quantity of proteinuria. Nephrotic and control animals given unaggregated human IgG showed little glomerular localization by immunofluorescent microscopy; no difference in the concentration of this protein in nephrotic as compared to control glomerular isolates was found.Thus, the mesangium in normal animals functions in a manner analogous to that of the general reticuloendothelial system. In nephrotic rats the mesangial uptake of macromolecules is makedly increased, a finding not observed in other tissues.

Nephritogenic antigen determinants in epidermal and renal basement membranes of kindreds with Alport-type familial nephritis.

We probed epidermal basement membranes (EBM) of acid-urea denatured skin from members of kindreds with Alport-type familial nephritis (FN) for the presence of antigens reactive with Goodpasture sera (GPS) and serum (FNS) from an Alport patient who developed anti-glomerular basement membrane (GBM) nephritis in a renal allograft. By immunoblotting, GPS reacted primarily with the 28,000 molecular weight (mol wt) monomer but also the 24,000 mol wt and 26,000 mol wt monomers of the noncollagenous globular domain (NC1) of type IV collagen from normal human GBM, while FNS identified only the 26,000-mol wt monomer. FNS reacted with EBM of 12 controls and nine unaffected male kindred members but not EBM of eight affected males. Five affected females exhibited interrupted reactivity of FNS with EBM. GPS showed variable reactivity with EBM and was not discriminating with respect to Alport-type FN. FNS did not stain renal basement members of five affected males. However, the EBM, tubular basement membrane, and Bowmans capsules of affected males contained antigens reactive with GPS. These immunochemical studies suggest that the FNS antigen is distinct from Goodpasture antigen(s). The expression of FNS antigen located on the NC1 domain of type IV collagen is altered in basement membranes of patients with Alport-type FN, and the distribution of this antigenic anomaly within kindreds suggests X-linked dominant transmission of a defective gene.

Systemic lupus erythematosus within the first two decades of life

Forty-nine patients with systemic lupus erythematosus (SLE) during childhood and adolescence presenting over a period of 17 years were followed during treatment with prednisone and azathioprine. The average period of follow-up was 5.7 years. Detailed analyses of clinical parameters of renal function and sequential changes in glomerular abnormalities by percutaneous renal biopsy are reported. Therapy was directed towards normalizing the results of urinalysis and renal function, eliminating proteinuria and maintaining normal serology (normal serum complement and negative antiDNA titers). The 10 year survival of the entire group was 86 per cent. A survival of 73 per cent and 87 per cent over this interval in patients with diffuse and focal proliferative lupus nephritis, respectively, was achieved. The major cause of mortality in this series was infection. It appears that intensive observation and monitoring of serologic parameters in SLE, along with aggressive steroid and immunosuppressive therapy, lead to a prognosis in SLE more favorable than previously reported.

Alport familial nephritis. Absence of 28 kilodalton non-collagenous monomers of type IV collagen in glomerular basement membrane.

Alport-type familial nephritis (FN), a genetic disorder, results in progressive renal insufficiency and sensorineural hearing loss. Immunochemical and biochemical analyses of the non-collagenous (NC1) domain of type IV collagen isolated from the glomerular basement membranes (GBM) of three males with this disease demonstrate absence of the normally occurring 28-kilodalton (kD) NC1 monomers, but persistence of the 26- and 24-kD monomeric subunits derived from alpha 1 and 2 (both type IV) collagen chains, respectively.

Pregnancy and systemic lupus erythematosus

Eleven patients with 18 pregnancies occurring during the course of systemic lupus erythematosus (SLE) were reviewed. Ten had long-standing lupus glomerulonephritis and a single patient developed glomerulonephritis during pregnancy. Patients were divided into those without (Group A) and those with (Group B) clinical evidence of renal disease or active SLE at conception. In Group A there were 10 pregnancies in five patients; all pregnancies were uncomplicated, except for mild superimposed pre-eclampsia in two, and all resulted in term delivery. Eight pregnancies in six patients occurred in Group B; four pregnancies were complicated by severe (2) or mild (1) superimposed pre-eclampsia and the onset of glomerulonephritis (1), resulting in three premature deliveries and a spontaneous abortion. The remaining four pregnancies were uncomplicated but resulted in one term delivery, one elective abortion, and two spontaneous abortions. None of the patients developed either renal failure or a rapidly progressive course following pregnancy.

Avascular necrosis of bone in systemic lupus erythematosus

A skeletal radiologic survey was performed on 35 patients with systemic lupus erythematosus (SLE) to determine the prevalence of avascular necrosis of bone. Fourteen patients had avascular necrosis of a total of 31 bones. Eight of nine symptomatic sites were in the femoral head or condyles. The most frequently involved area was the femoral condyle, followed in order of frequency by the femoral head, talus, capitulum of the elbow, metatarsals, and the patella. No difference was found in the age of onset of SLE, the duration of prednisone and azathioprine therapy, or the average annual dose of prednisone between patients with and without bone disease. It appears that the development of avascular necrosis of bone may results from interference with the blood supply to the bone due to corticosteriod-induced vascular changes andlor from the vasculitic component of blood vessel alteration in SLE.

The immunohistology of glomerular antigens. IV. Laminin, a defined noncollagen basement membrane glycoprotein.

Abstract This study describes the detailed immunohistologic localization of laminin, a defined noncollagen basement membrane glycoprotein and its relationship to fibronectin and the antigens localized by the Goodpasture antibody (GPaGBM) and heterologous anti-GBM antibody (RaGBM) in normal human kidney. The bilaminar GBM staining pattern for laminin reveals an outer epithelial line continuous with Bowmans capsule and the TBM and an inner subendothelial line continuous with the mesangium and vascular smooth muscle wall. This suggests a previously unrecognized role for the mesangial cell in the normal structure of the peripheral GBM. Fibronectin, predominantly mesangial, also has a weak localization in the subendothelial space, but no epithelial component. These defined glycoprotein antigens differ from those localized by GP antibody and RaGBM. The role of noncollagen glycoproteins in the maintenance of GBM filtration barrier remains to be elucidated. The adhesive or repulsive properties of molecules such as fibronectin may be required for the maintenance of normal glomerular cellular relationships.

Absence of Goodpasture's Antigen in Male Patients With Familial Nephritis

The presence of Goodpastures (GP) antigen in the glomerular basement membrane (GBM) of the kidney was evaluated by indirect immunofluorescence in nine patients with familial nephritis from five kindreds. The GP antigen was not detected in seven males but was present in an affected sister and mother, an unaffected brother, and 13 normal controls. The specificity of this finding in affected males is supported by the persistence of other GBM antigens identified by monoclonal antibodies. The lack of GP antigen in affected males and its persistence in related females with the disease suggests a possible X-linked dominant mode of inheritance. We propose that the absence of GP antigen leads to severe disease in the male, whereas its presence in related females is associated with mild disease.

Epidemic acute glomerulonephritis associated with type 49 streptococcal pyoderma: II. Correlative study of light, immunofluorescent and electron microscopic findings

Abstract We have investigated the pathologic alterations in kidney biopsy specimens from twenty-seven patients with suspected acute poststreptococcal glomerulonephritis (AGN) occurring during an epidemic of this disease on the Indian Reservation at Red Lake, Minnesota in 1966. This epidemic of AGN was associated with introduction once again of type 49 beta hemolytic streptococcal infection in this population. Light microscopic evidence of proliferative AGN was found in twenty-one of the twenty-seven patients. Immunofluorescent microscopic study of the renal biopsy material revealed that discrete nodular deposits of IgG and β 1 C (beta-1-C globulin of complement), which are the characteristic immunopathologic lesion of sporadic AGN, were observed in six patients. In fourteen patients a different pathologic alteration consisting of the deposition of β 1 C alone focally in an interrupted fashion along the glomerular basement membrane was observed. By electron microscopy discrete electron-dense deposits were present on the epithelial side of the glomerular basement membrane and in some instances in a subendothelial location. In this study it has been possible for the first time to investigate a large group of patients encompassing the entire clinical spectrum of AGN and to correlate the light, immunofluorescent and electron microscopic findings with the bacteriologic and serum complement data.

The Immunohistopathology of Glomerular Antigens THE GLOMERULAR BASEMENT MEMBRANE, COLLAGEN, AND ACTOMYOSIN ANTIGENS IN NORMAL AND DISEASED KIDNEYS

The immunofluorescent localization of antisera to human glomerular basement membrane (GBM), collagen, and smooth muscle actomyosin was examined in 15 specimens of normal renal tissue and 98 specimens from patients with renal disease. The anti-GBM and anticollagen antisera normally localize to GBM, while antiactomyosin localizes to the mesangium. Diabetic nephropathy revealed a striking expansion of mesangial material reacting with antiactomyosin. In contrast, the expanded mesangium in membranoproliferative glomerulonephritis did not react with antiactomyosin, and the GBM localization of anti-GBM and anticollagen sera was similarly lost. The thickened GBM in diabetes mellitus and membranous nephropathy reacted with anti-GBM and anticollagen, but with accentuation of staining on the inner aspect of the GBM. In proliferative glomerulonephritis there was a moderate increase in the distribution of actomyosin. Glomerular sclerosis and hyalinization in all diseases studied was accompanied by a loss of immunofluorescent staining for all glomerular antigens, including collagen.