Focal glomerular sclerosis in the fawn-hooded rat.

We have examined the nature of focal glomerular sclerosis (FGS) in fawn-hooded (FH) rats. The fawn-hooded rat develops pathologic features similar to those observed in steroid-resistant focal glomerular sclerosis, ie, by light microscopy some of the glomeruli appear normal but others show areas of solidification confined to one or two lobules of the tuft. The pathogenesis of this disease is not well known and there is a great need for an animal model. In the FH animal, a marked difference in the development of the lesion was noted between male and female rats. Fifty percent of 4-month-old males had proteinuria in excess of 10 mg/day (none of the females had significant proteinuria), while all 12-month-old males had proteinuria in excess of 45 mg/day (female 12-month-old FH rats had mean proteinuria of 7 mg/day). At 6 months of age continuing through 12 months of age, male FH rats had mesangial deposits of IgG, IgM, and, occasionally, C3, demonstrable by immunofluorescence, whether or not FGS was present. Subepithelial electron-dense deposits were never seen by electron microscopy either at 6 of 12 months. Six-month-old animals frequently did not exhibit FGS. Instead, the glomerular epithelial cells, exhibited fusion of foot processes, vacuolization, and, in some areas, focal loss of the epithelial covering on the glomerular basement membrane (GBM). Six-month-old males with proteinuria exhibited focal loss of negative charge from all layers of the filtration barrier. The GBM from sclerotic glomeruli of 12-month-old rats was commonly denuded of epithelium. None of the animals in this study was uremic. FH rats demonstrated FGS associated with progressive glomerular epithelial cell injury.     

Ferritin deposition in the glomerular deposits of focal glomerular sclerosis in the rat

The glomerular lesions of focal sclerosis clinically associated with a steroid-resistant nephrotic syndrome, are of unknown origin. IgM and C3 deposits and electron dense material found in areas of sclerosis are not convincing evidence of an immune pathogenesis. These deposits have been studied in a rat model of focal sclerosis induced by uninephrectomy and repeated aminonucleoside administration. Sclerotic lesions closely resembling human disease developed in the remaining kidney. There was a severe progressive proteinuria. Seventy-eight days after initial aminonucleoside injection 65 per cent of glomeruli were sclerotic with IgM, IgG, C3 and fibrinogen deposits, and electron dense deposits by electron microscopy. To study macromolecule deposition in this model of focal sclerosis, ferritin uptake 4 and 24 h after intravenous ferritin given at 77 days was compared in focal sclerosis rats with control rats without sclerosis (uninephrectomy plus saline-only injections). In focal sclerosis rats sclerotic areas contained massive accumulations of ferritin. In unaffected segments of sclerotic glomeruli, and normal glomeruli of focal sclerosis rats, ferritin concentration was no different from controls. Abnormal ferritin trapping in areas of sclerosis suggests that the presence of IgM and C3 may be due to a similar mechanism, and is not indicative of an immune pathogenesis for focal sclerosis.     

Spontaneous glomerular sclerosis in aging Sprague-Dawley rats. II. Ultrastructural studies.

Increased protein filtration and work overload have been proposed to account for the development of glomerular sclerosis in old rats. Sprague-Dawley rat kidneys were examined ultrastructurally from birth through 24 months of age to further delineate pathogenetic factors. There was progressive thickening of all basement membranes with lamination, intramembranous pseudolinear deposits, and degeneration. The glomerular basement membrane (GBM) was 1300 A at birth and increased to 4800 A by 24 months of age. GBM thickening correlated very closely with age (r = 0.90, P less than 0.001), correlated roughly with mesangial sclerosis, but did not correlate at all with proteinuria. Obliteration of podocytes and degenerative changes in the cytoplasm occurred in all cell types and was present in both proteinuric and nonproteinuric rats. These findings suggest that the lesion of spontaneous glomerular sclerosis of aging rats results not from proteinuria but from the natural process of abiotrophic involution. Further, this lesion is but a more obvious indicator of the alterations occurring simultaneously in other portions of the kidney.     

Progressive passive Heymann nephritis in the rat

Progressive passive Heymann nephritis was produced in rats by simultaneous intravenous injections of heterologous antirat glomerular basement membrane antiserum and heterologous antirat kidney tubular fraction 3 antibody. The animals were killed at 16 weeks by which time approximately one-half of them were severely proteinuric. The glomeruli showed beaded immune deposits around the capillaries by immunofluorescence, and on electron microscopy osmiophilic deposits were noted in the subepithelial zones and within the glomerular basement membrane. The lesion resembled that of severe Heymann nephritis. gamma-Globulin eluted from the kidneys contained an autologous IgG that reacted with the brush border region of the renal proximal tubules of normal rats. This component was present in proteinuric and nonproteinuric animals. It is concluded that the progression results from the development of autoantibodies to the tubular nephritogenic antigen and the proteinuria is related to increasing deposition of immune complexes in the glomeruli.     

Focal segmental glomerular hyalinosis and/or sclerosis in rats with congenital unilateral hydronephrosis.

Focal segmental glomerular hyalinosis and/or sclerosis (FSHS) was observed in five Wistar-Imamichi rats with congenital unilateral hydronephrosis (CUH rats). Marked proteinuria (164.9 +/- 138.4 mg/day) was observed in the CUH rats. Immunoperoxidase staining for IgM, C3 and IgG was positive in the glomeruli, showing in a focal, segmental pattern that corresponded to the areas of FSHS seen by light microscopy. These glomerular findings were extremely similar to those of human focal glomerular sclerosis (FGS). FSHS was found to be common to both the hydronephrotic kidney and the contralateral kidney without hydronephrosis. Morphometry revealed that the glomerular area of the juxtamedullary glomeruli was greater than that of superficial glomeruli in control rats (11,037 micron2 vs. 6,847 microns2). On the other hand, glomerular hypertrophy was observed in non-sclerotic glomeruli of CUH rats (superficial glomeruli; 12,477-16,123 microns2, juxtamedullary glomeruli; 14,635-18,418 microns2). Also, a decreased in the number of glomeruli within the range 1.8-4.1 per unit area (1 mm2) was seen in CUH rats compared with control rats (mean 4.4). These results suggest that the increased rate of development of FSHS is based on hyperfiltration in the remaining functional nephrons.     

DAUNOMYCIN-INDUCED NEPHROPATHY IN RATS

A single intravenous injection of daunomycin into rats Induced severe glomerular injury with massive proteinuria. Mesangial thickening due to an increase in the matrix appeared as early as 5 weeks after injection. Focal and segmental glomerular tuft distortion developed by 10 weeks associated with a progressive mesangial change, which was accompanied by detachments of endothelial cells and podocytes from the glomerular basement membrane (GBM) resulting in obliteration of the affected tufts. After 20 weeks, the lesion ultimately progressed to cause diffuse and global glomerular obliteration. Scattered glomeruli also showed frank shrinkage with a mild obliterative change. By observing a number of isolated glomeruli in scanning electron microscopy, it was revealed that podocyte alterations were variable from case to case and foot processes remained discrete in some cases until 10 weeks, despite the presence of marked proteinuria. Anionic sites distributed throughout the GBM and on the surface of podocytes were usually preserved in proteinuric rats as far as evaluated by ruthenium red and colloidal iron stainings. Our results indicate that loss of foot processes and of glomerular anionic sites are not causative factors but consequences of proteinuria.     

Daunomycin-induced nephropathy in rats

A single intravenous injection of daunomycin into rats induced severe glomerular injury with massive proteinuria. Mesangial thickening due to an increase in the matrix appeared as early as 5 weeks after injection. Focal and segmental glomerular tuft distortion developed by 10 weeks associated with a progressive mesangial change, which was accompanied by detachments of endothelial cells and podocytes from the glomerular basement membrane (GBM) resulting in obliteration of the affected tufts. After 20 weeks, the lesion ultimately progressed to cause diffuse and global glomerular obliteration. Scattered glomeruli also showed frank shrinkage with a mild obliterative change. By observing a number of isolated glomeruli in scanning electron microscopy, it was revealed that podocyte alterations were variable from case to case and foot processes remained discrete in some cases until 10 weeks, despite the presence of marked proteinuria. Anionic sites distributed throughout the GBM and on the surface of podocytes were usually preserved in proteinuric rats as far as evaluated by ruthenium red and colloidal iron stainings. Our results indicate that loss of foot processes and of glomerular anionic sites are not causative factors but consequences of proteinuria.     

Mesangial glomerulonephropathy with deposition of IgG, IgM, and C3 induced by mercuric chloride: a new model.

A mesangial glomerulonephropathy, characterized by the deposition of rat IgG, IgM, and C3 in the glomerular mesangium, was produced in Wistar rats by a prolonged administration of mercuric chloride (HgCl2). The HgCl2 was dissolved in sterile distilled water (0.2 mg. per ml.), and a group of 15 male Wistar rats was given injections subcutaneously three times a week on alternate days at a dosage of 0.15 mg. per 100 gm. of body weight for 27 weeks. A control group of nine rats was given injections of distilled water only. Mesangial glomerulonephropathy developed in 12 of 15 rats injected with HgCl2 and was characterized by the following: (1) coarse granular and nodular deposition of rat IgG, IgM, and C3 in the mesangium of all glomeruli, (2) absence of staining for rat albumin, IgA, and fibrin, (3) presence of electron-dense deposits in the mesangium, (4) focal and segmental proliferation of the mesangial matrix, (5) interstitial inflammation, (6) tubular atrophy, and (7) deposition of periodic acid-Schiff-positive material in the medulla adjacent to the thin limbs of the loops of Henle. Glycosuria and a slight increase in proteinuria were observed transiently in some rats. The blood urea nitrogen levels were normal in all rats. Eluates from the kidneys with heavy mesangial deposits contained rat IgG. However, the eluted antibody failed to react with normal rat kidney tissue components. None of the above findings were present in the control rats. The study provides a model of a mesangial nephropathy that seems to be immunologically induced; however, the mechanism for the formation and deposition of the immune deposits containing rat IgG, IgM, and C3, and the nature of the antigen(s) have not been elucidated.     

Focal Segmental Glomerular Hyalinosis and/or Sclerosis in Rats with Congenital Unilateral Hydronephrosis

Focal segmental glomerular hyalinosis and/or sclerosis (FSHS) was observed in five Wistar-Imamichi rats with congenital unilateral hydronephrosis (CUH rats). Marked proteinuria (164.9+138.4mg/day) was observed in the CUH rats. Immunoperoxidase staining for IgM, C3 and IgG was positive in the glomerull, showing in a focal, segmental pattern that corresponded to the areas of FSHS seen by light microscopy. These glomerular findings were extremely similar to those of human focal glomerular sclerosis (FGS). FSHS was found to be common to both the hydronephrotic kidney and the contralateral kidney without hydronephrosis. Morphometry revealed that the glomerular area of the juxtamedullary glomeruli was greater than that of superficial glomeruli in control rats (11,037 μm² vs. 6,847 μm²). On the other hand, glomerular hypertrophy was observed in non-sclerotic glomeruli of CUH rats (superficial glomeruli; 12,477–16,123 μm², juxtamedullary glomeruli; 14,635–18,418 μm²). Also, a decreased in the number of glomeruli within the range 1.8-4.1 per unit area (1 mm²) was seen in CUH rats compared with control rats (mean 4.4). These results suggest that the increased rate of development of FSHS is based on hyperfiltration in the remaining functional nephrons. Acta Pathol Jpn 41: 653–660, 1991.     

Morphometric analysis of the glomerular capillary area--a comparison of minimal change nephrotic syndrome, focal glomerular sclerosis, and pre-eclampsia.

A morphometric analysis was performed to compare the capillary area in non-sclerotic glomeruli in focal glomerular sclerosis (FGS), pre-eclampsia with focal sclerotic change of the glomeruli, and minimal change nephrotic syndrome (MCNS). The mean and standard deviation of the capillary area was greater in FGS than in pre-eclampsia and MCNS. Tubulo-interstitial lesions, such as tubular atrophy, interstitial fibrosis, and lymphocytic infiltration, were more severe in FGS than in pre-eclampsia. The presence of tubulo-interstitial changes including tubular atrophy and interstitial fibrosis with lymphocytic infiltration is thought to be an important prognostic factor in pre-eclampsia as well as in FGS. Unequal dilatation of the glomerular capillaries in non-sclerotic glomeruli may be harmful to the glomeruli and may lead to the development of glomerular sclerosis.     

The mesangium in anti-Thy-1 nephritis. Influx of macrophages, mesangial cell hypercellularity, and macromolecular accumulation.

Mesangial pathology is a hallmark of focal and segmental glomerulosclerosis (FGS). In an immunologically mediated mesangial cell (MC) injury model, we analyzed the relationship between mesangial hypercellularity, increased macromolecular uptake by the mesangium, and long-term pathologic sequelae. A single injection of monoclonal anti-Thy-1 (AT) antibody induces MC apoptosis, extensive mesangiolysis, proteinuria, MC proliferation, and hypercellularity. Immunohistologic analysis indicated influx of ED 1-positive macrophages after 24 hours, which gradually subsiding thereafter. At day 12, hypercellularity was due to smooth musclelike MCs, and macrophagelike MCs were absent. Injection of iron dextran in nephritic rats indicated that mesangial uptake of iron correlated with mesangial hypercellularity, but was independent of proteinuria. Long-term studies showed no difference after 19 weeks in FGS between nephritic and control rats. In conclusion, although mesangiolysis is accompanied by influx of macrophages, a phase of smooth musclelike MC proliferation and increased macromolecular uptake, these pathologic events do not result in chronic mesangial pathology and FGS.     

Spontaneous hypertension and hypertensive renal disease in the fawn-hooded rat.

The fawn-hooded (FH) rat, a strain characterized by a platelet storage-pool disease, developed focal and segmental glomerulosclerosis at the age of 2-3 months (males) and approximately 6 months (females). Male animals died spontaneously at 11-13 months, and females at 15 months of age, both with overt malignant nephrosclerosis. During the first half year of life focal glomeruli showed depositions of IgG, IgA, IgM, C3 and fibrinogen in a segmental pattern and mainly in mesangial areas. Mesangial IgG and IgA were already demonstrable at the age of 5 weeks. On electron microscopy no electron-dense deposits suggestive of immune complexes were found. Mean arterial blood pressure in 5.5-month-old male FH rats was increased compared with that of matched Wistar rats. One-year-old FH rats had severe hypertension. The presumed relationship between the hypertension, the renal lesions and the blood platelet defect is discussed.     

Spontaneous hypertension and hypertensive renal disease in the fawn-hooded rat

The fawn-hooded (FH) rat, a strain characterized by a platelet storage-pool disease, developed focal and segmental glomerulosclerosis at the age of 2-3 months (males) and approximately 6 months (females). Male animals died spontaneously at 11-13 months, and females at 15 months of age, both with overt malignant nephrosclerosis. During the first half year of life focal glomeruli showed depositions of IgG, IgA, IgM, C3 and fibrinogen in a segmental pattern and mainly in mesangial areas. Mesangial IgG and IgA were already demonstrable at the age of 5 weeks. On electron microscopy no electron-dense deposits suggestive of immune complexes were found. Mean arterial blood pressure in 5.5-month-old male FH rats was increased compared with that of matched Wistar rats. One-year-old FH rats had severe hypertension. The presumed relationship between the hypertension, the renal lesions and the blood platelet defect is discussed.     

RETARDED MESANGIAL TRANSPORT AND ITS PATHOMORPHOLOGIC SEQUELAE IN HUMAN AND EXPERIMENTAL RENAL DISEASES

Human renal biopsy specimens (472 cases) from varied kidney diseases, especially minimal glomerular change group and other idiopathic glomerular diseases having nephrotic manifestation of mainly juvenile individuals, showed morphologic evidence of paraarterial deposits of afferent arterioles at the glomerular entrances in more than 50% of examined cases. Because these deposits were often accompanied with concomitant mesangial, intraarterial and subendothelial deposits of afferent arterioles, it was felt that retarded mesangial transport which is ordinarily associated with certain glomerular diseases might be an important factor to produce these particular paraarterial deposits. The referred deposits of minimal glomerular change group cases were thought to predispose the occurrence of focal sclerotic capillary lesions at the vascular poles of glomeruli. The experimental chronic nephrotic rats produced by daily administration of aminonucleoside of puromycin revealed mesangial dysfunction with increased uptake and retarded disposal of secondarily overloaded aggregated human gamma globulin at mesangial areas in glomeruli. Besides, the increased deposits of autologous serum proteins in mesangial areas and arteriolar walls were common findings in those rats, and these deposits were observed to be always preceded to the occurrence of segmental sclerotic changes of glomeruli, which were often associated in the later stage of this experiment. ACTA PATHOL. JPN. 33: 219∼236, 1983.     

Experimental proliferative glomerulonephritis in the cat.

A model of chronic serum sickness was used to induce immune-complex glomerulonephritis in seven experimental cats, by daily intravenous inoculation of an increasing dose (5 to 35 mg) of human serum albumin (HSA). At week four, two of the seven animals developed anterior uveitis. At week 23, two different animals developed the subcutaneous oedema characteristic of the nephrotic syndrome (NS), whilst the other five cats appeared clinically normal. The kidneys were examined at necropsy by light microscopy and by transmission electron microscopy. The glomeruli of four animals (three with both proteinuria and uraemia, and one with proteinuria only) showed morphological changes under light microscopy. The abnormalities suggested that a diffuse mesangial proliferative glomerulonephritis (GN) had been induced in three cats and diffuse membranoproliferative GN induced in another. Ultrastructural studies revealed electron-dense deposits (immune-complexes) in six of the seven cats. Two cats without glomerular abnormalities by light microscopy had mesangial deposits and three cats with mesangial proliferative GN had deposits at mesangial, subendothelial and/or subepithelial sites. The single cat with membranoproliferative GN had deposits at mesangial, subendothelial, subepithelial and intramembranous sites. Immunohistological examination (peroxidase-antiperoxidase technique) showed that HSA and immunoglobulin (IgG and IgM) were deposited in the glomeruli of these cats. Deposits were the most dense in cats with more severe renal lesions. Deposits of IgM were most abundant. An extensive cellular infiltrate, comprising macrophages, neutrophils and plasma cells, was observed only in the four animals which showed abnormalities in glomerular ultrastructure. The disease induced in these cats thus appears to differ from the membranous nephropathy previously described in the cat and bears a close resemblance to immune complex (IC) disease in man. In view of the relatively few specific animal models of IC-mediated proliferative GN, this model has potential for application to the study of human IC disease.     

A morphometric,biochemical and histochemical comparison of puromycin aminonucleoside and hyperalbuminaemic induced proteinurias in the female Wistar rat

Biochemical, immunological, histochemical and electron microscope morphometric techniques were used to monitor the changes in urinary protein composition, albumin clearance and glomerular ultrastructure induced in female Wistar rats following i.p. injection of puromycin aminonucleoside (PAN) or bovine albumin (BSA). BSA injected rats maintained a high degree of selectivity with albumin constituting 90 per cent. of the total protein excreted even when mean protein excretion was in the order of 500 mg/24 hr. A similar degree of selectivity was only evident in PAN nephrotic rats at low levels of proteinuria. Levels of 500 mg/24 hr only 57 per cent. of the total protein was albumin. These differences correlated well with the increased number of glomeruli from PAN nephrotics compared with hyperalbuminaemic rats which, at these high levels of proteinuria, had bare areas of glomerular basement membrane caused by epithelial cell detachment (88 and 7 per cent. respectively). Detailed electron microscope morphometric and immunohistochemical studies showed that there were also important quantitative differences in a number of superficially similar glomerular structural alterations. In PAN nephrotic rats all glomeruli showed very marked epithelial cell foot process loss and reduced staining with colloidal iron. In glomeruli from hyperalbuminaemic rats there was a wide variation in the extent of epithelial ceil foot process loss and reduced colloidal iron staining was only demonstrable in those glomeruli which had swollen epithelia containing large numbers of vacuoles and protein droplets. Similarly, while protein droplets were smaller and less numerous in glomeruli from PAN-injected rats, they were present in most glomeruli whereas their distribution was much more variable in glomeruli from BSA-injected rats. All the data collected therefore indicated that there were important differences in the types of proteinuria and glomerular ultrastructural damage present in PAN nephrotic and hyperalbuminaemic rats and suggested that their induction may have involved entirely different mechanisms. Evidence gathered from one experimental model should thus only be used with extreme caution to aid in interpretation of data obtained from the other.     

Focal and segmental glomerulosclerosis. Immunohistologic study of 20 renal biopsy specimens

To evaluate the deposition of immunoglobulins and complement and their relationship to sclerotic and nonsclerotic glomerular segments, immunoperoxidase without periodic acid-Schiff counterstain (IMP) and with periodic acid-Schiff counterstain (IMPAS) for IgG, IgA, IgM, and C3 was performed on cryostat-frozen sections using the direct method, along with routine light microscopy and electron microscopy, in a series of 20 renal biopsy specimens from 20 patients with the final diagnosis of focal and segmental glomerulosclerosis. Neither diffuse mesangial nor diffuse glomerular basement membrane deposits were detected by IMP, IMPAS, or electron microscopy. In 18 biopsy specimens, IMPAS demonstrated focal and segmental granular to globular deposits of IgM and/or C3 in sclerotic glomerular segments. In eight biopsy specimens, small granular deposits of IgM and/or C3 deposits were identified in optically normal glomeruli, suggesting that these deposits may precede segmental sclerosis.     

Glomerular epithelial cell structure and function in chronic proteinuria induced by homologous protein-load

The pathogenesis of glomerular scarring in proteinuric diseases is unknown, but glomerular epithelial cell (GEC) injury has been implied by the glomerular pathology seen in patients with focal segmental glomerular sclerosis and the nephrotic syndrome. We studied the effect of proteinuria on glomerular histology and GEC structure and function in rats made proteinuric for up to 8 weeks by the daily parenteral injection of homologous serum albumin. Proteinuria in the albumin-injected rats peaked at a mean level of 131 +/- 12 mg/24 hours (mean +/- SD) during the 1st week. It subsequently plateaued at 41 +/- 6 mg/24 hours but remained significantly greater than the saline-injected controls throughout the study. The albumin-injected rats developed slight but significant increases in blood pressure, serum albumin, plasma volume, and urine urea nitrogen compared to the saline injected controls. The serum creatinine was not different from controls. In the albumin-injected rats no glomerular scarring was observed after 8 weeks of proteinuria. The GEC developed albumin reabsorption droplets and signs of activity including increased numbers of organelles, vacuoles, and cytoplasmic hypertrophy, but there were no signs of irreversible GEC damage. The GEC foot processes were quantitated morphometrically, and there was no evidence of effacement after eight 4 or 8 weeks of proteinuria. GEC endocytic function, evaluated by the technique of protamine heparin aggregate disappearance, was not different from the saline injected controls. Proteinuria caused by the chronic administration of homologous serum albumin for 8 weeks is regularly associated with increased blood pressure, plasma volume, and serum albumin and ultrastructural changes in the GEC. These morphologic changes in the GEC apparently represent a normal response to proteinuria and are not evidence for irreversible cell damage. Despite their avid endocytosis of filtered plasma proteins, GEC endocytic function remains normal. These experimental results imply that glomerular sclerosis is not a consequence of proteinuria per se.     

Glomerulonephritis in congenital cytomegalic inclusion disease

Except for renal transplant recipients, glomerulonephritis has only very rarely been associated with renal cytomegalovirus (CMV) infection. The kidneys of five infants with congenital cytomegalic inclusion disease, including renal infection, were examined at autopsy. Two of the infants had glomerulonephritis. The younger, a 4-month-old female, had diffuse proliferative and necrotizing glomerulonephritis; virus was present in nuclei and cytoplasm of glomerular endothelial cells and, possibly, in leukocytes as well. There were no electron-dense deposits. The other infant, a 5-month-old male, had diffuse mesangial and focal segmental proliferative and sclerosing glomerulonephritis; electron-dense mesangial deposits were seen ultrastructurally. Three additional infants (a newborn male, a 2-day-old male, a 6-week-old female), all with CMV in tubules and one with a single glomerular inclusion, had only rare glomerular abnormalities, i.e., mesangial proliferation in less than 10 per cent of glomeruli (one infant) and segmental sclerosis in less than 1 per cent of glomeruli (all three infants). Thus, congenital renal CMV infection was associated with proliferative glomerulonephritis in the two infants who survived the longest. The three with shorter survival times had only minor glomerular alterations.     

Heterogeneous IgA glomerulonephropathy in liver cirrhosis

Kidney and liver sections were obtained from 75 consecutive autopsy cases with liver cirrhosis discovered at post-mortem. Mesangial IgA as the predominant immunoglobulin was found in 36% (27) cases, with accompanying IgM in 10, and IgG in three subjects. IgA deposits occurred more frequently in micronodular cirrhosis than in macronodular and mixed types. There was no direct correlation with alcoholism or HBs antigen-orcein positivity in livers. The IgA antigen-antibody complexes formed against infectious and/or dietary antigens may bypass the liver phagocytic system via collateral shunts and cause the mesangial IgA deposits. IgA-bearing plasma cells in the liver (80%) may also contribute to the deposits. In cases of liver cirrhosis, there was a variable glomerular morphology including normal appearance by light microscopy (32%), minor changes (38.7%), diffuse mesangial sclerosis (12%), diffuse mesangial cell proliferation, and infrequently membranous and diffuse proliferative glomerulonephritis with a 'lobular pattern'. Five (6.7%) cases showed focal and segmental mesangiolysis with glomerular aneurysms, probably caused by toxic and/or infective agents bypassing the liver reticuloendothelial phagocytic system and acting on the mesangium to cause rupture of anchor points and formation of capillary aneurysms. The cirrhotic glomerulonephropathy was usually clinically latent, but two biopsy cases with mesangiocapillary glomerulonephritis had developed a nephrotic syndrome.