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Glomerular diseases are a leading caused of kidney failure. The three resident glomerular cell types respond differently to injury, which includes proliferation, hypertrophy, apoptosis and de-differentiation. Each leads to glomerular scarring, and a decline in renal function. Studies have shown that these events are critically controlled by cell cycle regulatory proteins, providing potential targets for the development of future therapeutics.
Glomerular protein droplets have been observed in human glomerular epithelial cells, peripolar cells and mesangial cells, particularly in the preeclamptic lesion. Although morphologically similar, their functional role is uncertain. Whilst previous electron microscopic studies have shown these droplets to be generally uniform in electron density, our immunoelectron microscopy study of 10 biopsies, one showing lesions of preeclampsia, and the remaining 9 showing different forms of glomerular disease, generally displayed two distinct patterns of electron density and immunolabelling, when using a less severe fixation regime. An electron dense inner core was strongly positive to anti-fibrinogen, whilst a less dense peripheral zone was positive to anti-IgM. All other immunoglobulins, C3c, and albumin showed a less specific immunolabelling pattern. Protein droplets were also observed in proximal tubules in 7 out of 10 biopsies. In droplets found in most tubular cells immunolabelling was not partitioned, the most prominent findings being diffuse labelling for fibrinogen and albumin. In most instances where glomerular droplets were found adjacent to intraglomerular deposits, the marker identified within the deposit could also be seen in either the core area or the peripheral zone of the droplets. These findings raise the possibility that these droplets may be involved in protein adsorption from the deposits through a damaged glomerular basement membrane.
Glomerular function was evaluated longitudinally over a 24- to 48-month period in 18 patients with diabetic glomerular disease (DGD) manifested by proteinuria. GFR was determined by iothalamate clearance at 4-month intervals. The patients were divided into two groups: Group 1 (N = 9) had subnephrotic proteinuria and an initially normal GFR of 91 +/- 8 mL/min. Group 2 (N = 9) had nephrotic-range proteinuria, and initial GFR was reduced to 53 +/- 5 mL/min. Serial GFR fluctuated over time in Group 1, but no trend towards hypofiltration was evident. In contrast, GFR declined linearly in Group 2 at 1.1 +/- 0.3 mL/min per month. The transglomerular sieving of uncharged dextrans of graded size was analyzed and initially revealed a uniform reduction in glomerular pore density and an enhancement of shuntlike pores. Pore density was initially reduced by 80% and declined further after 24 months in nephrotic Group 2; corresponding pore density in subnephrotic Group 1 was reduced by half but remained constant. Renal biopsy of four members of Group 1 revealed a 22% prevalence of global glomerulosclerosis. Remaining open glomeruli exhibited hypertrophy, excessive extracellular matrix, and deformation of epithelial podocytes. The latter abnormality appeared to be the predominant determinant of lowered ultrafiltration capacity. It was inferred that trials of therapy to attenuate the progression of DGD should be initiated at a functional level similar to that in subnephrotic Group 1. Because GFR is unlikely to decline over a 2- to 4-yr period, it is suggested that such trials be extended for longer periods. Alternatively, morphometric analysis of serial renal biopsies may shorten the time needed to demonstrate effective renoprotection in DGD.
Glomerular diseases are a diagnostic challenge. Early recognition and timely institution of appropriate treatment are critical to optimum outcome in many patients, especially those with rapidly progressive glomerulonephritis. The clinical presentations and laboratory data provide adequate presumptive diagnoses in some patients; however, renal biopsy evaluation is often required for a definitive diagnosis.
Glomerular subepithelial immune deposits are the hallmark of human membranous glomerulopathy, and of its corresponding experimental rat model, Heymann nephritis (HN). The pathogenesis of HN is now understood in some detail, and recent data on this issue are reviewed in this summary. Immune deposits in HN are caused by the interaction of certain epitopes on the nephritogenic antigen, the glycoprotein gp 330, which is a resident molecule of the clathrin coated pits of glomerular visceral epithelial cells, and specific anti-gp 330 IgG. This step is followed within minutes by detachment of the immune complexes and rapid and firm cross-linking to the glomerular basement membrane, thus preventing its endocytosis by the epithelial cells. Immune complexes accumulate locally to form large immune deposits by repeated cycles of antibody binding to newly synthetized gp 330 antigen, shedding and immobilization in the basement membrane. Also human kidneys contain a gp 330-related (but not identical) protein which appears to be not involved in the formation of immune deposits. However, recent data suggest that also in the human disease similar pathogenic mechanisms as in HN could be involved.
Glomerular cultures from mice have been established and the various cells associated with them observed microscopically by phase contrast time-lapse cinematography, after histological staining and ultrastructurally with the transmission and scanning electron microscope. The most common cell types were large 80-200 microns diameter irregular polyhedral cells appearing as flattened plate-like structures morphologically, possibly of epithelial origin. Smaller 70-100 microns diameter fusiform cells possibly derived from either endothelium or mesangium were also often seen. A third cell type, small 10-20 microns diameter circular, motile and actively phagocytic was especially noticeable in cultures of hybrid New Zealand Black/New Zealand White mice but was not present in appreciable numbers in control cultures from strains without renal disease. This third cell type appeared to have Fc receptors, stained positively with non-specific esterase and by indirect immunofluorescence with specific rabbit anti-mouse macrophage serum and had the morphological appearance of a macrophage by scanning and transmission electron microscopy. It is concluded that cells of macrophage origin are associated with the immune complex glomerulonephritis in these hybrid mice.
We compared the glomerular filtration rate (GFR) response to amino acids in patients with glomerular disease and polycystic kidney disease. The GFR response to infusion of amino acids (75 g/12 h), of dopamine (2 micrograms/kg per min), or their combination was evaluated in nine healthy probands and in patients with two types of renal diseases at various degrees of renal function: 15 patients with ADPKD and 11 patients with glomerular disease (IgA glomerulonephritis or diabetic nephropathy). Steady-state inulin infusion technique was used. In healthy subjects amino acids increased median C(in) in response to amino acids was not found in glomerular disease. In contrast in most ADPKD patients median C(in) increased after amino acids (+6.0 ml/min; range -4 to +68), (P less than 0.05). The response to amino acids was not modified by dopamine. The results demonstrate that amino acid-induced acute changes of glomerular filtration differ in polycystic kidney disease compared with glomerular disease. These observations may have implications with respect to mechanisms of progression.
The expression of CR-1 complement receptors on glomerular epithelial cells, was studied in 77 renal biopsies from patients with (74) or without (3) glomerular diseases, employing an anti-CR-1 monoclonal antibody, and an indirect immunoperoxidase technique. Four patterns of CR-1 expression were recognised: normal (18); generally decreased (6); focal/segmental partial loss (44); and complete loss (9). Normal expression was detected in all three biopsies with non-glomerular diseases, and in glomerular diseases with normal glomeruli on light microscopy, but also in several glomerulonephritic biopsies (13), including diffuse proliferative lupus nephritis (1 of 7) and idiopathic membranous nephritis (5 of 14). However, the majority of biopsies from patients with glomerular diseases showed abnormal CR-1 expression (59 of 74), most evident in proliferative biopsies (43 of 49), with or without crescent formation (respectively, 18 of 20 and 25 of 29). Complete loss of CR-1 expression was almost restricted to crescentic biopsies (8 of 9). The abnormal CR-1 expression was unrelated to the presence of capillary immune deposits of Ig or C. More intraglomerular monocytes, assessed by monoclonal antibodies, were encountered in glomerulonephritic biopsies with partial CR-1 loss (median 6.2, P less than 0.05) or complete loss (median 14, P less than 0.03), than in biopsies with normal receptor expression (median 1.4). Thus, changes in glomerular CR-1 expression are frequently seen in many glomerular diseases and are associated with glomerular proliferative changes and monocyte infiltration, but not with the presence of capillary immune deposits.(ABSTRACT TRUNCATED AT 250 WORDS)
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Fibrillar glomerular diseases are defined by the ultrastructural accumulation of glomerular extracellular microfibrils or microtubules. The deposits have compositions particular to specific diseases, and it is important to distinguish among these clinical pathologic entities and their differing clinical implications. Amyloidosis and immunotactoid glomerulopathy are two examples of fibrillar glomerular diseases. Amyloidosis is a systemic disease in which the fibrils stain with Congo red and contain various biochemically distinct proteins that identify diseases with differing prognostic and therapeutic implications. Immunotactoid glomerulopathy is a primary glomerular disease, and the deposits contain immunoglobulins that do not stain with Congo red. In contrast to amyloidosis, division of immunotactoid glomerulopathy based on the immunoglobulin content or ultrastructural appearance of the deposits has no clinical relevance.
Ultrastructural glomerular basement membrane changes are present in most hereditary glomerular diseases: thick and thin basement membrane with splitting of the lamina densa in Alport's syndrome, thin basement membrane in familial benign essential hematuria, and thick basement membrane with the presence of collagen-like fibrils in the nail-patella syndrome. They are useful markers for diagnosis. Moreover, their knowledge has set the problem of the primary biochemical defect in basement membrane metabolism accounting for morphological abnormalities and clinical disturbances. Further biochemical and immunochemical investigations are still required for a better understanding of hereditary glomerular diseases.
The clinical course of 123 pregnancies in 86 patients with biopsy-proven glomerular diseases have been studied. In 35 women the onset of nephropathy occurred during pregnancy. No complications were observed in more than half of the pregnancies. In the others, one third of the complications were obstetrical or fetal accidents, one third were renal manifestations (hypertension or deterioration of renal function) and one third were both causes. The lowest incidence of complications was observed in patients with membranous nephropathy and the highest in membranoproliferative glomerulonephritis patients. There were 6 spontaneous late abortion, 6 stillbirths and 5 neonatal deaths. 17 deliveries were preterm and 7 fetuses were small for gestational age. Hypertension appeared in 24 pregnancies, in 13 of which it was reversible and related to superimposed preeclampsia and in 11 it persisted after delivery (5 of these 11 pregnancies were in patients with IgA nephropathy). Renal function deteriorated in 10 cases during pregnancy. The deterioration was reversible in 6 and progressive in 4 (2 of whom had membranoproliferative glomerulonephritis). It is suggested that in most patients pregnancy does not change the natural history of glomerular disease.
AIMS: While Doppler ultrasonography is used commonly in various renal diseases, its clinical value in diagnosis of renal parenchymal diseases, especially glomerular diseases, remains controversial. We investigated whether Doppler ultrasonography in glomerular diseases could discriminate tubulointerstitial lesions, which correlated closely with long-term prognosis for renal function. METHODS: Sixty patients with primary or secondary glomerular diseases were examined by Doppler ultrasonography immediately before renal biopsy. The resistive index was calculated, as was the atrophic index (a newly proposed parameter defined as renal sinus length/renal length). These were compared with histologic changes in biopsy specimens. RESULTS: Receiver operator characteristic analysis showed a resistive index of 0.65 to be the optimal for discriminating tubulointerstitial changes with specificity of 100% and sensitivity of 57.1%. Tubulointerstitial injury scores were significantly higher in patients with resistive indices exceeding 0.65 than in patients with a lower value. An atrophic index of 0.70 was also shown to be optimal with specificity 100% and sensitivity 61.9%. In combination, the 2 indices showed improved sensitivity; when the patients were divided into groups where both resistive and atrophic indices were normal (respectively < or = 0.65 and < or = 0.70) or where either or both were high, sensitivity rose to 85.7%, while specificity remained 94.4%. CONCLUSIONS: In combination, the resistive and atrophic indices discriminated tubulointerstitial injury in glomerular diseases with high specificity and sensitivity.
The glomerular capillary is the most solicited renal component of the local and general systems of integration both under normal and pathological conditions. The alterative and reactive modifications of the glomerular capillary may be the expression of a systematic capillary disease of the initial involvement of ths structure of glomerular corpuscles. The sum of certain kind of lesions of the complex glomerular structure realizes diverse morphofunctional entities of proliferative, membranous, and sclerocicatricial glomerular diseases. The glomerular diseases, irrespective of their nature, induce changes in the balance of the intra-and internephronal relationships, realizing new vicious circles which amplify and maintain the tissular destructions.
Chronic glomerular diseases are the cause of 35 to 55% of end-stage renal failure, according to countries or regions. In France, the estimated annual incidence of nondiabetic glomerular nephropathies is 82 per million population. IgA deposits, membranous and minimal change glomerulopathies, and focal and segmental glomerulosclerosis are the most common; crescent proliferative glomerulonephritis has the worse prognosis. Combined patient and kidney survival varies from 24 to 62% according to histologic types. Their incidence remains relatively stable in contrast with the constant rise of type 2 diabetic nephropathy. Over the 90s, the annual incidence rate of renal replacement therapy for end-stage renal failure due to diabetes doubled in Europe, reaching 10 to 50 per million population according to the country in Europe, and 144 per million population in the United States.
BACKGROUND: Glomerular diseases may progress to end-stage renal failure via the development of glomerulosclerosis. Systemic hypertension and intraglomerular hypertension are important, although not the only, determinants of this process. Proteinuria (albuminuria) is a surrogate marker for glomerular damage and renal prognosis. EFFICACY OF ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS: In animal experiments and in controlled clinical studies, ACE inhibitors have proved to be effective in reducing proteinuria and in preventing glomerulosclerosis or progression to end-stage renal failure, possibly more than can be explained by their effects on blood pressure. EFFICACY OF CALCIUM CHANNEL BLOCKERS: In contrast to the uniform efficacy of ACE inhibitors, the effect of calcium channel blockers is less uniform. It depends on the model of renal damage used, the extent of the fall in systemic blood pressure and the type of calcium channel blocker used. Nevertheless, clinical studies have shown a reduction in proteinuria and at least an attenuation of progression with the use of long-acting calcium channel blockers. RATIONALE FOR THE COMBINATION OF ACE INHIBITORS AND CALCIUM CHANNEL BLOCKERS: If angiotensin II influences the progression of renal failure, as is universally accepted, then the combination of an ACE inhibitor (reducing the generation of angiotensin II) and a calcium channel blocker (reducing target-organ responsiveness to angiotensin II) appears a promising one. EVIDENCE FOR THE EFFECTIVENESS OF THIS COMBINATION: In animal experiments, co-administration of an ACE inhibitor and a calcium channel blocker caused a more marked reduction in glomerulosclerosis, and this was seen in the stroke-prone spontaneously hypertensive rat model even at non-antihypertensive doses. In human diabetic nephropathy at least, proteinuria (measured as a surrogate marker of the illness) was lowered more effectively by the combination of an ACE inhibitor and a calcium channel blocker than either drug used as monotherapy despite a similar fall in blood pressure.
Glomerular disease in the tropics differs considerably from that in temperate climates and between the developed and the developing world. The prevalence and pattern of glomerular disease in the tropics in turn varies widely in different geographic regions and is influenced by environmental, nutritional, and socioeconomic factors. Among the infective agents that have been identified as contributing to an increased prevalence of glomerular disease in the tropics are Plasmodium malaria, Schistsomiasis mansoni, Mycobacterium leprosy, and hepatitis B virus (HBV). A decline in the prevalence can only be expected with the eradication of infections. Accurate knowledge of the prevalence, histologic features, and causes is essential to achieve prevention and management of glomerular diseases in the tropics.
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