教学讲义2000.doc

教学讲义（2000）Nephrotic syndromeThe cardinal features of the nephritic syndrome include heavy proteinuria (defined as urine protein excretion over 3.5g/24 hours), hypoalbuminemia, edema and varying degrees of hyperlipidemia and lipiduria. The major causes of the nephritic syndrome are included as both primary glomerular disorders (minimal change, membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferatie glomerulonephritis, etc) and secondary disorders (diabetes mellitus, systemic lupus erythematosus, amyloidosis, etc). Pathogenesy of nephrotic syndromeThree structural elements in the glomerular capillary wall constitute the permselectivity barrier: endothelial cells separated by fenestrae, the glomerular basement membrane made up of a network of matrix proteins, and specialized epithelial cells(podocytes) connected to each other via an interdigitating network of slit diaphragms. Normally, proteins with the size of albumin (67KDa) and larger are excluded from filtration, a restriction that depends substantially on the integrity of the slit diaphragms. In the nephritic syndrome, adjacent podocytes appear fused together to assume a flattened rather than foot-like morphology. Abnormalities arising from podocyte proteins or circulating factors can alter the selective permeability barrier. Hypoalbuminemia is in part a consequence of urinary protein loss. It is also due to the catabolism of filtered albumin by the proximal tubule as well as to redistribution of albumin within the body. This in part accounts for the inexact relationship between urinary protein loss, the level of the serum albumin, and other secondary consequences of heavy albuminuria. Hyperlipidaemia in nephritic syndrome is characterized by raised serum cholesterol levels, and to a lesser extent hypertriglyceridemia. There is increased hepatic synthesis of low density lipoprotein, very low density lipoprotein and lipoprotein in response to hypoalbuminemia, and urinary loss of high density lipoprotein. In addition, enzymeic changes occur with abnormal lipid biosynthesis and degradation. Epidemiologic studies thus clearly define an increased risk of atherosclerotic complications in the nephrotic syndrome. Nephrotic patients often have a hypercoagulable state and are predisposed to deep vein thrombophlebitis, pulmonary emboli, and renal vein thrombosis. Contributing factors include increased hepatic synthesis of clotting factors (fibrinogen, factors II , V, VII, VIII, IX, X, XII, protein C), increased urinary loss of anticoagulants (antithrombin III), platelet abnormalities (thrombocytosis), hyperviscosity, hyperlipidemia, over-diuresis and immobilization. The mechanism of edema remains controversial. Proteinuria and hypoalbuminaemia lead to decreased intravascular oncotic pressure, resulting in the transudation of plasma water into the interstitial space. The reduced plasma volume in turn stimulates secondary sodium retention through activation of the rennin-angiotensin-aldosterone axis. However, these features are not universal. An alternative “overfill” theory suggests that defective tubular sodium excretion can lead to plasma volume expansion and suppression of rennin-angiotensin. The cause of sodium retention remains unknown, but maybe mediated by resistance to atrial natriuretic peptide. The resulting elevated plasma volume and reduced plasma oncotic pressure promote fluid transudation from blood to the interstitial space.Phathology types of nephrotic syndromeMINIMAL-CHANGE DISEASE Light Microscopy. The distinguishing feature is the paucity of glomerular alterations as seen by light microscopy. Increase in the overall cellularity of the mesangium is usually minor; but when it is more prominent, it may make a clear-cut distinction with mesangial proliferative glomerulonephritis. The epithelial cells may be enlarged with a more basophilic cytoplasm. Electron Microscopy. The electron microscope regularly detects abnormalities of the epithelial cells of the glomerular capillaries that are typical but not specific. Juxtaposition of the foot processes of the visceral epithelial cells and obliteration of the slit pore membrane complex are noted in most glomeruli and glomerular capillaries. The extent of this lesion correlates with the severity of reduction in GFR. Epithelial cell vacuolization and detachment from the underlying basement membrane may be present, although more commonly they occur in evolving or well-developed focal and segmental glomerulosclerosis. Microvillous transformation of the free surfaces of the epithelial cells is common. The GBM is usually of normal thickness, with minor and inconstant changes in fine structure. Immunofluorescence. Immunofluorescence findings are noteworthy for the lack of deposition of immunoglobulin and complement in glomeruli in most uncomplicated cases.MESANGIAL PROLIFERATIVE GLOMERULONEPHRITIS Light Microscopy. The glomeruli are characterized by definite but variable degrees of increase in cellularity of the mesangium, usually affecting all lobules of all glomeruli to an equal degree. Four or five nuclei may be seen per mesangial zone in mild forms and more than five nuclei in more severe forms. The capillary walls are thin and delicate and usually free of deposits. The capillary lumens are patent. In the uncomplicated variety, adhesions and segmenta sclerosis are lacking. Electron Microscopy. Ultrastructural studies have indicated that in up to 50% of the biopsy specimens, finely granular or homogeneous electron-dense deposits are identified in the mesangium. As noted previously, similar deposits may be seen in biopsies categorized as minimal-change lesions, even when immunofluorescence findings are negative.Immunofluorescence. A frequent although not invariable finding in this disorder is the presence of IgM deposits, primarily in the mesangium but also occasionally as small granularities, in the capillary walls. This feature has led some to use the more descriptive term IgM mesangial nephropathy. In many instances, C3 has been observed in a similar distribution, although not in all cases. IgG and IgA are variably present and usually with a lesser intensity than IgM and C3. FOCAL GLOMERULAR SCLEROSIS Light Microscopy. The light microscopic features that permit categorization as focal and segmental sclerosis are lesions affecting a variable minority of the glomeruli, often those in the deeper, juxtamedullary cortex. The unaffected glomeruli may appear normal by light microscopy or reveal diffuse mesangial proliferation. The individual glomerular lesion consists of a segmental sclerosis due to increased mesangial matrix and basement membrane. Electron Microscopy. By electron microscopy, most or all glomeruli show diffuse or segmental foot process alterations, especially if heavy proteinuria is present. Extensive foot process effacement is more likely to be seen in the idiopathic lesion. Diffuse mesangial cell hyperplasia may also be observed. Extensive mesangiolysis may be found to underlie the sclerotic lesion. Ballooning of the capillary wall and microaneurysms are commonly observed in this circumstance.Immunofluorescence. IgM, C1q, and C3 deposition may be seen in an irregular, granular, or nodular distribution in association with the focal sclerotic lesions seen by light microscopy. Unaffected glomeruli are usually negative but on occasion may contain variable amounts of IgM and C3 in a mesangial distribution or rarely in a segmental capillary wall distribution. MEMBRANOUS GLOMERULONEPHRITIS (Membranous Nephropathy)Light Microscopy. The typical and characteristic light microscopic feature of well-developed MGN is a diffuse and uniform thickening of the capillary wall, usually without any significant proliferation of endothelial, mesangial, or epithelial cells. Mild to moderate mesangial cell proliferation, especially when accompanied by parietal epithelial cell abnormalities and coexistent may indicate a worse prognosis. The capillary lumens are widely patent in early stages. Silver impregnation techniques may reveal the presence of spikes of argyrophilic material projecting outward toward the urinary space. In early or mild cases, the capillary wall may appear normal by light microscopy or may display numerous small round basement membrane vacuoles (best seen with silver impregnation stains) when sectioned tangentially. With progression of the lesions, the capillary wall becomes increasingly thickened and encroaches on the capillary lumen. The glomerulus therefore may acquire a rigid appearance. Electron Microscopy. The electron microscopic findings serve to clarify and amplify the changes seen by light microscopy and have important diagnostic and prognostic significance. Some workers have found a series of changes by electron microscopy that correspond to the stages of disease; others have not. In early cases (stage I), the GBM is normal in thickness and appearance, but small, discrete, subepithelial deposits of slightly greater electron density than the lamina densa appear at the level of the slit pore membrane. These deposits produce some distortion of the structure of the foot processes. In more advanced cases (stage II), projections of basement membrane like material corresponding to the silver-positive spikes seen by light microscopy are seen to develop between the enlarging deposits. This gives an irregular contour to the epithelial side of the GBM, which, however, remains of normal thickness. In time, the deposits become larger and more heterogeneous in size and distribution, and they may also vary in their degree of electron density. Spikes of GBM-like material may nearly encircle a deposit, giving a dome-like appearance (stage III). The foot processes are greatly distorted. Finally, the basement membrane like material encloses the deposit, which now has become less electron-dense, giving the capillary wall a thickened or Swiss cheese appearance (stage IV). These abnormalities have been well demonstrated by scanning electron microscopy of glomerular capillaries devoid of cells. With remission of proteinuria, the deposits become more lucent but usually do not disappear unless basement membrane alterations are initially minimal.Immunofluorescence. The immunofluorescence findings are typical and highly reproducible from case to case. IgG is nearly always present in a uniform granular distribution outlining all of the capillary loops but usually sparing the mesangium. Extensive mesangial deposits of immunoglobulins usually indicate an underlying disease, particularly SLE. Treatments of nephrotic syndromeThe optimal dose, schedule of administration, and total duration of steroid therapy have not yet been fully standardized and probably differ for children and adults with this disorder. The newly diagnosed child may be initially treated with oral prednisone or prednisolone, 60 mg/m2/d (equivalent to about 1.5 mg/kg/d in adults) but usually not more than 80 mg/d, given as a single daily dose. Such therapy results in the complete disappearance of abnormal proteinuria in more than 90% of patients within 4 weeks. At 4 to 6 weeks (or earlier, if remission occurs), therapy can be changed to 35 to 40 mg/m2 (about 0.9 mg/kg in adults) in a single dose every other morning (alternate-day schedule). This therapy may be continued for an additional 4 to 6 weeks, unless a remission occurs during the alternate-day therapy. Treatment is often continued for a full 6 weeks after a complete remission of proteinuria occurs. Too early or too abrupt withdrawal of steroids may result in a relapse, perhaps because of partial pituitary-adrenal suppression and relative adrenal insufficiency. Altered prednisone or prednisolone pharmacokinetics could play a role in responsiveness of patients to standard oral dosage regimens. Children who have persistent nephrotic syndrome after a full 8- to 12-week course of glucocorticoid therapy are commonly regarded as nonresponders or steroid-resistant patients. Renal biopsies in this group of patients frequently, although not invariably, demonstrate lesions other than those of minimal-change disease. Steroid resistance may also be acquired late in the cou