closely linked to obesity, accounts for approximately 90 per cent of all diabetes mellitus. Excess weight gain is also a major cause of essential hypertension, accounting for as much as 65 to 75 per cent of the risk for developing hypertension in adults. In addition to causing renal injury through diabetes and hypertension, obesity may have additive or synergistic effects to worsen renal function in patients with pre-existing kidney disease.
Effect of aging on the number of functional glomeruli
Injury to the Renal Vasculature as a Cause of Chronic Renal Failure
Many types of vascular lesions can lead to renal ischemia and death of kidney tissue. The most common of these are (1) atherosclerosis of the larger renal arteries, with progressive sclerotic constriction of the vessels; (2) fibromuscular hyperplasia of one or more of the large arteries, which also causes occlusion of the vessels; and (3) nephrosclerosis, caused by sclerotic lesions of the smaller arteries, arterioles, and glomeruli.
Atherosclerotic or hyperplastic lesions of the large arteries frequently affect one kidney more than the other and, therefore, cause unilaterally diminished kidney function. As discussed in Chapter 19, hypertension often occurs when the artery of one kidney is constricted while the artery of the other kidney is still normal, a condition analogous to "two-kidney" Goldblatt hypertension.
Benign nephrosclerosis, the most common form of kidney disease, is seen to at least some extent in about 70 per cent of postmortem examinations in people who die after the age of 60. This type of vascular lesion occurs in the smaller interlobular arteries and in the afferent arterioles of the kidney. It is believed to begin with leakage of plasma through the intimal membrane of these vessels. This causes fibrinoid deposits to develop in the medial layers of these vessels, followed by progressive thickening of the vessel wall that eventually constricts the vessels and, in some cases, occludes them. Because there is essentially no collateral circulation among the smaller renal arteries, occlusion of one or more of them causes destruction of a comparable number of nephrons. Therefore, much of the kidney tissue becomes replaced by small amounts of fibrous tissue. When sclerosis occurs in the glomeruli, the injury is referred to as glomerulosclerosis.
Nephrosclerosis and glomerulosclerosis occur to some extent in most people after the fourth decade of life, causing about a 10 per cent decrease in the number of functional nephrons each 10 years after age 40 (Figure 31-3). This loss of glomeruli and overall nephron function is reflected by a progressive decrease in both renal blood flow and GFR. Even in "normal" people, kidney plasma flow and GFR decrease by 40 to 50 per cent by age 80.
The frequency and severity of nephrosclerosis and glomerulosclerosis are greatly increased by concurrent hypertension or diabetes mellitus. In fact, diabetes mel-litus and hypertension are the two most important causes of end-stage renal disease, as discussed previously. Thus, benign nephrosclerosis in association with severe hypertension can lead to a rapidly progressing malignant nephrosclerosis. The characteristic histologi-cal features of malignant nephrosclerosis include large amounts of fibrinoid deposits in the arterioles and progressive thickening of the vessels, with severe ischemia occurring in the affected nephrons. For unknown reasons, the incidence of malignant nephrosclerosis and severe glomerulosclerosis is significantly higher in blacks than in whites of similar ages who have similar degrees of severity of hypertension or diabetes.
Injury to the Glomeruli as a Cause of Chronic Renal Failure— Glomerulonephritis
Chronic glomerulonephritis can be caused by several diseases that cause inflammation and damage to the capillary loops in the glomeruli of the kidneys. In contrast to the acute form of this disease, chronic glomeru-lonephritis is a slowly progressive disease that often leads to irreversible renal failure. It may be a primary kidney disease, following acute glomerulonephritis, or it may be secondary to systemic diseases, such as lupus erythematosus.
In most cases, chronic glomerulonephritis begins with accumulation of precipitated antigen-antibody complexes in the glomerular membrane. In contrast to acute glomerulonephritis, streptococcal infections account for only a small percentage of patients with the chronic form of glomerulonephritis. The results of the accumulation of antigen-antibody complex in the glomerular membranes are inflammation, progressive thickening of the membranes, and eventual invasion of the glomeruli by fibrous tissue. In the later stages of the disease, the glomerular capillary filtration coefficient becomes greatly reduced because of decreased numbers of filtering capillaries in the glomerular tufts and because of thickened glomerular membranes. In the final stages of the disease, many glomeruli are replaced by fibrous tissue and are, therefore, unable to filter fluid.
Injury to the Renal Interstitium as a Cause of Chronic Renal Failure— Pyelonephritis
Primary or secondary disease of the renal interstitium is referred to as interstitial nephritis. In general, this can result from vascular, glomerular, or tubular damage that destroys individual nephrons, or it can involve primary damage to the renal interstitium by poisons, drugs, and bacterial infections.
Renal interstitial injury caused by bacterial infection is called pyelonephritis. The infection can result from different types of bacteria but especially from Escherichia coli that originate from fecal contamination of the urinary tract. These bacteria reach the kidneys either by way of the blood stream or, more commonly, by ascension from the lower urinary tract by way of the ureters to the kidneys.
Although the normal bladder is able to clear bacteria readily, there are two general clinical conditions that may interfere with the normal flushing of bacteria from the bladder: (1) the inability of the bladder to empty completely, leaving residual urine in the bladder, and (2) the existence of obstruction of urine outflow. With impaired ability to flush bacteria from the bladder, the bacteria multiply and the bladder becomes inflamed, a condition termed cystitis. Once cystitis has occurred, it may remain localized without ascending to the kidney, or in some people, bacteria may reach the renal pelvis because of a pathological condition in which urine is propelled up one or both of the ureters during micturition. This condition is called vesicoureteral reflux and is due to the failure of the bladder wall to occlude the ureter during micturition; as a result, some of the urine is propelled upward toward the kidney, carrying with it bacteria that can reach the renal pelvis and renal medulla, where they can initiate the infection and inflammation associated with pyelonephritis.
Pyelonephritis begins in the renal medulla and therefore usually affects the function of the medulla more than it affects the cortex, at least in the initial stages. Because one of the primary functions of the medulla is to provide the countercurrent mechanism for concentrating urine, patients with pyelonephritis frequently have markedly impaired ability to concentrate the urine.
With long-standing pyelonephritis, invasion of the kidneys by bacteria not only causes damage to the renal medulla interstitium but also results in progressive damage of renal tubules, glomeruli, and other structures throughout the kidney. Consequently, large parts of functional renal tissue are lost, and chronic renal failure can develop.
Nephrotic Syndrome—Excretion of Protein in the Urine Because of Increased Glomerular Permeability
Many patients with kidney disease develop the nephrotic syndrome, which is characterized by loss of large quantities of plasma proteins into the urine. In some instances, this occurs without evidence of other major abnormalities of kidney function, but more often it is associated with some degree of renal failure.
The cause of the protein loss in the urine is increased permeability of the glomerular membrane. Therefore, any disease that increases the permeability of this membrane can cause the nephrotic syndrome. Such diseases include (1) chronic glomerulonephritis, which affects primarily the glomeruli and often causes greatly increased permeability of the glomerular membrane; (2) amyloidosis, which results from deposition of an abnormal proteinoid substance in the walls of the blood vessels and seriously damages the basement membrane of the glomeruli; and (3) minimal change nephrotic syndrome, which is associated with no major abnormality in the glomerular capillary membrane that can be detected with light microscopy. As discussed in Chapter 26, minimal change nephropathy has been found to be associated with loss of the negative charges that are normally present in the glomerular capillary basement membrane. Immunologic studies have also shown abnormal immune reactions in some cases, suggesting that the loss of the negative charges may have resulted from antibody attack on the membrane. Loss of normal negative charges in the basement membrane of the glomerular capillaries allows proteins, especially albumin, to pass through the glomerular membrane with ease because the negative charges in the basement membrane normally repel the negatively charged plasma proteins.
Minimal change nephropathy can occur in adults, but more frequently it occurs in children between the ages of 2 and 6 years. Increased permeability of the glomeru-lar capillary membrane occasionally allows as much as 40 grams of plasma protein loss into the urine each day, which is an extreme amount for a young child. Therefore, the child's plasma protein concentration often falls below 2 g/dl, and the colloid osmotic pressure falls from a normal value of 28 to less than 10 mm Hg. As a consequence of this low colloid osmotic pressure in the plasma, large amounts of fluid leak from the capillaries all over the body into most of the tissues, causing severe edema, as discussed in Chapter 25.
Loss of Functional Nephrons Requires the Surviving Nephrons to Excrete More Water and Solutes. It would be reasonable to suspect that decreasing the number of functional nephrons, which reduces the GFR, would also cause major decreases in renal excretion of water and solutes. Yet patients who have lost as much as 75 per cent of their nephrons are able to excrete normal amounts of water and electrolytes without serious accumulation of any of these in the body fluids. Further reduction in the number of nephrons, however, leads to electrolyte and fluid retention, and death usually ensues when the number of nephrons falls below 5 to 10 per cent of normal.
In contrast to the electrolytes, many of the waste products of metabolism, such as urea and creatinine, accumulate almost in proportion to the number of nephrons that have been destroyed. The reason for this
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