Focal Segmental Lesions Research Articles

The nonspecificity of focal segmental glomerulosclerosis. The defining characteristics of primary focal glomerulosclerosis, mesangial proliferation, and minimal change.

We performed a detailed clinical review and pathologic analysis of the kidney biopsies of 134 children with nephrotic syndrome or asymptomatic proteinuria. This analysis challenges some of our concepts about the classification of conditions associated with these disorders. The presence of focal segmental sclerotic lesions does not define a unique disorder in childhood. Some children with such lesions will have unaffected glomeruli that are ultrastructurally completely normal. These patients, predominately black adolescents, present either with nephrotic syndrome or asymptomatic proteinuria. We classify this disorder as primary focal segmental glomerulosclerosis (FSGS) and have never found it to recur after transplantation. Most other children with FSGS have 1 of 2 specific glomerulopathies. Those with minimal change have generalized fusion of podocyte foot processes. Those with mesangial proliferation have similar foot process changes combined with mesangial expansion and proliferation and, frequently, thinning of the lamina densa and tubuloreticular inclusions. The presence of segmental lesions in these glomerulopathies appears to be nothing more than a marker of severity. Children with these glomerulopathies are generally younger white children, virtually all of whom have nephrotic syndrome. These disorders have a strong propensity to recur after transplantation. The presence of mesangial labeling of IgM or C1q has no significance in any of these 3 disorders. The classification of disorders associated with nephrotic syndrome or asymptomatic proteinuria must concentrate less on the presence or absence of focal sclerosis and more on the histologic appearance of the rest of the glomeruli.

Different clinicopathological types of segmental sclerosing glomerular lesions in adults

Renal biopsies and kidneys from 111 adult patients with segmental sclerosing glomerular lesions were put into different morphological groups by pathologists unaware of clinical findings. 'Overload changes' (n = 11) were large glomeruli with hilar lesions. Ten of these patients had reduced renal mass. In the 'glomerular tip lesion' (n = 10) there were changes at the tubular origin in otherwise normal glomeruli. All patients in this group had the nephrotic syndrome, completely responsive to steroids. 'Mesangial hypercellularity with diffuse segmental changes at the glomerular tip', corresponding to 'early classical focal segmental glomerulosclerosis' (n = 18), differed from the glomerular tip lesion in that glomeruli were larger and hypercellular. Most patients with this classification had the nephrotic syndrome, several were given additional immunosuppression, and less than half had complete remission. 'Diffuse multiple segmental lesions', corresponding to 'late classical focal segmental glomerulosclerosis' (n = 16), presented usually with the nephrotic syndrome, and most of these patients had no response to immunosuppression. Unlike most other groups, in 'focal segmental sclerosing lesions' (n = 56) there were genuinely focal lesions, not in every glomerulus. Most patients had asymptomatic proteinuria. Pathological study is able to classify segmental lesions that would often be grouped as 'focal segmental glomerulosclerosis' into types with different pathogenesis, clinical findings, appropriate treatment, response to treatment, and prognosis.

The Effects of Hyperfiltration on Serum Sickness Glomerulonephritis in Rats

The effects of hyperfiltration induced due to unilateral nephrectomy on immunologically induced glomerular injuries were studied. Glomerulonephritis was induced in rats by sensitizing them with egg albumin as an antigen. Unilateral nephrectomy did not affect the removal rate of the antigen from the glomeruli in the rats, but accelerated the rate of the glomerular injuries after cessation of the immunologically induced glomerular inflammation. The histopathological features were characterized by sclero-adhesive lesions with aneurysmal dilatation and hyalinosis of the glomerular capillaries. The parietal epithelial cells extended from the Bowman's capsule with matrices to cover the denuded basement membrane and formed adhesions. The neighboring capillaries collapsed, and the sclero-adhesive lesions progressed. These findings indicate that hyperfiltration at the capillary level did not accelerate the recovery from glomerulonephritis, but induced glomerular sclerosis with adhesions and deteriorated the trivial glomerular injuries to produce similar focal segmental lesions.

Glomerular hypertension and injury in desoxycorticosterone–salt rats on antihypertensive therapy

Uninephrectomized male Munich-Wistar rats received either weekly subcutaneous injections of vehicle and water for drinking; injections of desoxycorticosterone (DOC) and 1% saline (SALT) for drinking; or DOC and SALT with hydrochlorthiazide, hydralazine, reserpine and KCl added. All studies were performed six weeks after UNX. At that time, rats receiving DOC and SALT alone were hypertensive and had significantly more proteinuria and morphologic evidence of glomerular injury than rats given vehicle and tap water which were normotensive. Antihypertensive therapy normalized mean arterial pressure in DOC-SALT rats, but failed to prevent proteinuria, mesangial expansion or focal segmental glomerular lesions. Micropuncture studies revealed that glomerular capillary pressure was elevated in both untreated and treated DOC-SALT animals. We conclude that drugs which successfully reduce systemic blood pressure may fail to correct glomerular capillary hypertension in DOC-SALT rats. As persistence of intrarenal hypertension is associated with significant glomerular injury, normalization of glomerular capillary pressure rather than systemic arterial pressure is crucial to the prevention of glomerular injury in this model.

Mesangial proliferative glomerulonephritis. Natural history and effects of dextran sulfate.

We evaluated 246 cases having clinically primary chronic glomerulonephritis and histologically mesangial proliferative glomerulonephritis of varying degrees. 190 patients conservatively followed with serial measurements of GFR served as delineating the natural history. The remaining, randomly selected 56 subjects were treated with Dextran sulfate, a mild anticoagulant, for 7 to 56 months (average, 25.4). 55 cases underwent repeated renal biopsy at the mean interval of 3.3 years. It became evident clinically and morphologically that the severity of diffuse mesangial proliferation and the presence of focal and segmental lesions in more than 20% were two critical determinants of the natural history. All cases with mild mesangial proliferative alteration alone survived more than 10 years, but none of the patients with global sclerosis in more than 50% in the initial biopsy did. 10-year survival rates in mild, and moderate or greater mesangial proliferation with the focal-segmental lesions were 45.0% and 19.3%, respectively. In the treated group, renal function improved or was maintained, along with histologic confirmation in some, during the follow-up period. Moreover, the survival rate of subjects with global sclerosis in more than 50% ameliorated beyond the natural history. Thus, Dextran sulfate appeared promising for a possible suppression of the coagulatory process associated with the focal-segmental lesions.

Persistent renal damage following pre‐eclampsia: A renal biopsy study of 13 patients

Renal biopsy material was examined from 13 patients who had a history of pre-eclampsia and who were biopsied after delivery. The characteristic 'endotheliosis' associated with pre-eclampsia appeared to resolve at varying rates and was not seen in biopsies taken more than 1 month after delivery. Four of the biopsies showed residual focal segmental glomerular lesions which are described. Focal global glomerular sclerosis (eight biopsies), focal interstitial scarring (seven biopsies) and arteriolo-sclerosis (nine biopsies) were also identified. These findings support those earlier reports which indicated that pre-eclampsia is capable of producing persistent renal damage in a small but significant percentage of cases.

SCREENING SYSTEM: Screening for Asymptomatic Hematuria and Proteinuria in School Children ‐ Relationship between Clinical Laboratory Findings and Glomerular Pathology or Prognosis ‐

AbstractEarly morning urine is collected at home and urinalysis is performed at a clinical laboratory. Simple dipstick methods are used for the detection of proteinuria and hematuria. When the urine tests are positive, a second test is performed in the same manner. When the urine abnormalities are persistently encountered, urine sediments are checked under the microscope and diagnostic steps are taken to determine the cause of the urine abnormalities. A study of the diagnosis and prognosis of the asymptomatic proteinuria and hematuria detected by urine screening was performed with the collaboration of eight different hospitals. Correlations between renal pathology or prognosis and urinary findings or other laboratory data in 170 patients who had renal biospy were studied. Cases with asymptomatic hematuria without proteinuria tended to have a better prognosis, with the pathology of minor abnormality or focal segmental proliferative lesions. In cases with marked proteinuria and hematuria diffuse proliferative lesions including membranoproliferative glomerulonephritis (MPGN) were frequently observed. Renal pathology suggesting a poor prognosis was not uncommon in the cases with marked proteinuria and hematuria. The above observations were confirmed by a 5‐year follow‐up study in 141 cases.

IgA nephropathy — accumulated experience and current concepts

Primary IgA nephropathy is the most common form of glomerulonephritis in Australia. The condition presents in a variety of ways, but commonly with synpharyngitic hematuria, most often in young men in the third and fourth decades. The course of the disease is indolent but there is progression to renal failure in up to one quarter of cases. Renal biopsy morphology is variable but the essential immunofluorescence finding is diffuse mesangial IgA staining of greater intensity but often in association with other immunoglobulins. C3 is usually also present. Mesangial cellularity is increased in some two-thirds of cases, one third being of a minor focal or variable extent and one-third diffuse. Focal segmental lesions, hyaline nodules and vascular changes are frequent. Crescents are also often present. The etiology of the disease is uncertain but has been linked with HLA antigens, elevated serum IgA levels, IgA polymers, immune complexes and impaired T cell function. Secondary forms of mesangial IgA deposition occur with mucosal defects, hyperglobulinemia or impaired hepatobiliary clearance, and these may offer some insight into the immunopathogenesis of the primary disease.

Dense intramembranous deposit disease: New pathologic features

AbstractDense intramembranous deposit disease: New pathologic features. The pathologic and clinical features of 16 patients with dense intramembranous deposit disease are described. By light microscopy nine patients had membranoproliferative glomerulonephritis, five had focal segmental necrotizing glomerulonephritis with segmental epithelial crescents, four of whom also had a prominent tubulointerstitial nephritis, and two had focal segmental mesangial proliferative glomerulonephritis. The patients with membranoproliferative glomerulonephritis and one with focal segmental mesangial proliferative glomerulonephritis had easily recognizable dense intramembranous deposits by optical microscopy. The patients with focal segmental necrotizing glomerulonephritis and one with focal segmental mesangial proliferative glomerulonephritis did not have recognizable peripheral loop dense intramembranous deposits even under oil immersion. In patients with membranoproliferative glomerulonephritis ultrastructural examination revealed extensive capillary wall dense intramembranous deposits. Immunofluorescence revealed diffuse double linear staining along the capillary walls and “mesangial rings” of C3. In the patients with focal segmental necrotizing glomerulonephritis and one with focal segmental mesangial proliferative glomerulonephritis the immunofluorescence study suggested a diagnosis of dense intramembranous deposit disease because of the segmental double linear staining of the capillary walls and “mesangial rings” of C3, but the diagnosis was only established by fine structural analysis where occasional peripheral loop and prominent paramesangial basement membrane dense intramembranous deposits and mesangial nodular deposits were identified. Clinical features prior to biopsy included nephrotic syndrome in eight patients, an acute nephritic syndrome in six patients, and asymptomatic proteinuria and hematuria in two patients. Five of six patients with an acute nephritic presentation had focal segmental necrotizing glomerulonephritis. The acute renal insuificiency in these patients was transitory and appeared to be related to a prominent acute tubulointerstitial nephritis present in four of the biopsy specimens. Depressed serum C3 levels were present in patients with membranoproliferative glomerulonephritis; patients with focal segmental lesions were normocomplementemic. Because of the “atypical” light microscopic features in six of our patients, we support the suggestion that membranoproliferative glomerulonephritis, type II be replaced by the term ‘dense intramembranous deposit disease’ for this glomerulopathy with variable clinical and histologic features.Maladie des dépôts denses intramembraneux: Nouvelles caractéristiques pathologiques. Les caractéristiques pathologiques et cliniques de 16 malades avec une maladie des dépôts denses intramembraneux sont décrites. En microscopie optique, neuf malades avaient une glomérulonéphrite membrano-proliférative, cinq avaient une glomérulonéphrite nécrosante, focale et segmentaire avec des croissants épithéliaux segmentaires, quatre desquels avaient aussi une néphrite tubulo-interstitielle prédominante, et deux avaient une glomérulonéphrite focale, segmentaire, mésangiale. Les malades avec une glomérulonéphrite membrano-proliférative et un malade avec une glomérulonéphrite proliferative mésangiale segmentaire et focale avaient des dépôts denses intramembraneux facilement reconnaissables au microscope optique. Les malades avec une glomérulonéphrite segmentaire et focale nécrosante et le malade avec une glomérulonéphrite proliferative mésangiale segmentaire et focale n'avaient pas de dépôts denses intramembraneux reconnaissables dans les anses périphériques, même à l'immersion d'huile. Chez les malades avec une glomérulonéphrite membrano-proliférative, l'examen ultrastructural a révélé des dépôts denses intramembraneux étendus dans la paroi capillaire. L'immunofluorescence a révélé une coloration en double contour diffuse le long des parois capillaires et des “anneaux mésangiaux” de C3. Chez les malades avec une glomérulonéphrite nécrosante focale et segmentaire et chez celui avec une glomérulonéphrite proliférative mésangiale focale et segmentaire, l'étude en immunofluorescence a suggéré un diagnostic de maladie des dépôts denses intramembraneux en raison de la coloration en double contour segmentaire des parois capillaires et des “anneaux mésangiaux” de C3, mais le diagnostic n'a été établi uniquement que par une analyse structurale fine où des dépôts denses intramembraneux et des dépôts nodulaires mésangiaux occasionnels des anses périphériques et de la membrane basale paramésangiale étaient identifiés. Les caractéristiques cliniques avant la biopsie comprenaient un syndrome néphrotique chez huit malades, un syndrome néphritique aigu chez six malades, et une protéinurie asymptomatique et une hématurie chez deux malades. Cinq de six malades avec un tableau de néphrite aiguë avaient une glomérulonéphrite nécrosante segmentaire et fócale. L'insuffisance rénale aiguë chez ces malades était transitoire et est apparue reliée à une néphrite tubulo-interstitielle aiguë prédominante, présente sur quatre spécimens des biopsies. Des diminutions des niveaux de C3 sérique étaient présentes chez les malades avec une glomérulonéphrite membrano-proliférative; les malades avec des lésions segmentaires et focales étaient normo-complémentémiques. En raison des caractéristiques “atypiques” en microscopie optique chez six de nos cas, nous suggérons que la glomérulonéphrite membrano-proliférative de type II soit remplacée par le terme ‘maladie des dépôts denses intramembraneux’ pour cette glomérulopathie aux caractéristiques cliniques et histologiques variables.

Focal Glomerulosclerosis in Renal Allografts

Focal segmental and/or global sclerotic glomerular lesions with hyalinosis were noted in three allografts in association with the nephrotic syndrome (NS) and chronic rejection (CR). Similar lesions were absent in eight allografts with CR without NS. Previous reports have stressed the presence of this lesion in allografts with recurrence of the disease entity "idiopathic nephrotic syndrome with focal glomerulosclerosis". Both clinical and pathologic evidence suggest that recurrence was not a factor in the pathogenesis of the lesion in the three allografts with CR and NS. The presence of these lesions in failing allografts may represent the result of CR with associated NS rather than recurrence of the disease entity.

Focal segmental glomerulosclerosis

In this clinicopathologic study of 16 cases of focal segmental glomerulosclerosis, the median age at onset was 21 years. Sixty per cent had persistent microscopic hematuria, 88 per cent had the nephrotic syndrome, and all had steroid-resistant proteinuria. The clinical course was not affected by corticosteroid or immunosuppressive agents. Typical juxtamedullary focal segmental sclerotic lesions were found in 88 per cent of the initial renal biopsy specimens. The sclerotic glomerular lesions contained immunofluorescent deposits of immunoglobulin M (IgM), C′3 and C′4. Electron dense deposits were identified in the sclerotic glomerular segments. Because of the different morphologic and immunologic findings and the grave prognosis, focal segmentai glomerulosclerosis should be differentiated from lipoid nephrosis.

A study on focal glomerular lesions found in renal biopsies,.

Focal glomerular lesions were light microscopically found in 32 out of 436 renal biopsies by blind selection. Glomerular lesions in focal distribution are not an independent disease entity and may include a variety of diseases. They may be found in the early stage of some diseases which will progress to a diffuse lesion and also represent defective healing leaving persistent proteinuria or hematuria.The judgement of the presence of focal glomerular lesions should be based on the prominent changes such as nodular segmental mesangial proliferation, adhesions, segmental hyalinosis, organized crescent and localized necrosis. In a very strict sense there were almost no normal glomeruli at the level of electron microscopy. The result of quantitation of mesangial area and nuclear counts suggests that normal appearing glomeruli are not absolutely normal. Serial section study may disclose hidden segmental lesions.The clinical outcome of patients with focal segmental lesions is not simply favorable. Proteinuria or hematuria often perisisrs as long as 10 years or more; however, only a few cases fall into chronic renal failure.Historical background of this condition was also reviewed.