Porth's Essentials of Pathophysiology, 4e

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Disorders of Renal Function

C h a p t e r 2 5

Glomerular Lesions Associated with Systemic Disease

syndrome, there is nodular deposition of hyaline in the mesangial portion of the glomerulus. As the sclerotic process progresses in the diffuse and nodular forms of glomerulosclerosis, there is complete obliteration of the glomerulus, with impairment of renal function. Although the mechanisms of glomerular change in diabetes are uncertain, they are thought to repre- sent enhanced or defective synthesis of the glomeru- lar basement membrane and mesangial matrix with inappropriate incorporation of glucose into the non- cellular components of these glomerular structures. 20 Alternatively, hemodynamic changes that occur sec- ondary to elevated blood glucose levels may con- tribute to the initiation and progression of diabetic glomerulosclerosis. 4 It has been hypothesized that elevations in blood glucose produce an increase in GFR and glomerular pressure that leads to enlarge- ment of glomerular capillary pores by a mechanism that is, at least partly, mediated by angiotensin II. This enlargement results in an increase in the protein con- tent of the glomerular filtrate, which in turn requires increased endocytosis of the filtered proteins by tubu- lar endothelial cells, a process that ultimately leads to nephron destruction and progressive deterioration of renal function. The clinical manifestations of diabetic glomerulo- sclerosis are closely linked to those of diabetes. The increased GFR that occurs in persons with early altera- tions in renal function is associated with microalbu- minuria, defined as urinary albumin excretion of 30 to 300 mg in 24 hours. 5 Microalbuminuria is an impor- tant predictor of future diabetic nephropathies. 4,19 In many cases, these early changes in glomerular func- tion can be reversed by careful control of blood glu- cose levels (see Chapter 33). Inhibition of angiotensin by ACE inhibitors or ARBs has been shown to have a beneficial effect, possibly by reversing increased glo- merular pressure. Hypertension and cigarette smok- ing have been implicated in the progression of diabetic nephropathy. Thus, control of blood pressure (to levels of 130/80 mm Hg or less) and smoking cessation are recommended as primary and secondary prevention strategies in persons with diabetes.

Many systemic diseases (e.g., systemic lupus erythema- tosus, diabetes mellitus) are associated with glomerular injury. In some diseases the glomerular involvement may be the major clinical manifestation. Systemic Lupus Erythematosus Glomerulonephritis. Renal involvement is one of the most common compli- cations of SLE. 5,18 The pathogenesis of SLE (see Chapter 44) is uncertain, but appears to be related to dysregu- lated B-cell immunity with production of autoantibod- ies to a variety of nuclear, cytoplasmic, extracellular matrix, and cell membrane components. Most glomer- ular injury is triggered by the deposition of immune complexes within the glomerular wall. Immune com- plexes may derive from the circulation, develop locally, or both. The clinical manifestations of SLE glomerulonephri- tis, commonly referred to as lupus nephritis , depend on the site of immune complex–mediated injury. Immune complexes confined to the mesangium cause less inflammation than subendothelial immune complexes, which have greater exposure to inflammatory cells and mediators in the blood and therefore are more likely to produce inflammation. 5,18 Immune complexes may also localize in the renal interstitium, walls of inter- stitial vessels, and basement membranes, causing the tubulointerstitial inflammation that occurs in persons with SLE. 5 Because of the high risk for kidney disease, all per- sons with SLE should undergo routine urinalysis to monitor for the appearance of hematuria or proteinuria. If urinary abnormalities are noted, renal biopsy is often performed. Treatment depends on the extent of glomer- ular involvement. Oral corticosteroids and angiotensin- converting enzyme (ACE) inhibitors are the mainstays of treatment. Persons with more advanced disease may require treatment with immunosuppressive agents (e.g., intravenous cyclophosphamide or oral mycophenolate mofetil). Clinical trials using other immunosuppressant agents are ongoing. Diabetic Glomerulosclerosis. Diabetic nephropathy is a major cause of chronic kidney disease and the most common cause of kidney failure treated by renal replace- ment therapy in the United States. 4,5,19,20 It occurs in both type 1 and type 2 diabetes mellitus. The lesions of diabetic nephropathy most commonly involve the glomeruli and are associated with three glo- merular syndromes: nonnephrotic proteinuria, nephrotic syndrome, and chronic renal failure. Widespread thick- ening of the glomerular capillary basement membrane occurs in almost all persons with diabetes and can occur without evidence of proteinuria. This is followed by a diffuse increase in mesangial matrix, with mild prolif- eration of mesangial cells. As the disease progresses, the mesangial cells impinge on the capillary lumen, reduc- ing the surface area for glomerular filtration. In nodular glomerulosclerosis, also known as Kimmelstiel-Wilson

SUMMARY CONCEPTS

■■ Glomerulonephritis represents a group of kidney diseases that result from inflammation and injury of the glomerulus. It may occur as a primary condition in which the glomerular abnormality is the only disease present, or as a secondary condition in which the glomerular abnormality results from another disease, such as diabetes mellitus or SLE. Most cases of primary and many cases of secondary glomerular disease probably have an immune origin.

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