Kidney Aging and Diseases

Human kidney function declines with age, reflecting both normal processes and the cumulative impact of comorbid diseases such as hypertension and diabetes. It is crucial to recognize the decline in kidney function in older adults because poor kidney function compromises drug metabolism and may lead to kidney failure. On average, a single human kidney reaches its maximum size during the fourth decade of life. Kidney mass declines by approximately 10% per decade thereafter, with the major decline in mass localized to the cortical or outer layer of the kidney. Normal aging processes play a role in diabetic and hypertensive kidney disease; however, these changes occur at a faster rate in patients with these conditions.

Progressive arteriole hyalinosis, tubulointerstitial fibrosis, and glomerulosclerosis reduce the mass of an aging kidney. Several important vascular changes occur in the aging kidney where the arterioles of the kidney undergo sclerotic changes. Although these changes are seen in individuals with normal blood pressure, they are worse in hypertensive individuals. Often, the arteriolar changes are seen in association with glomerulosclerosis in the outer part of the kidney. The aging kidney also develops evidence of injury to the tubules. The tubule is the portion of the nephron located distal to the glomerulus and proximal to the collecting ducts. Tubular damage is concentrated in the outer medulla and the medullary rays, the part of the kidney most dependent on capillary blood flow. The interstitium or matrix portion of this region may have a high concentration of invading monocytes and macrophages, reflecting inflammatory processes and subsequent decline in kidney function. Transforming growth factor-β (TGF-B), an inflammation-activating factor, is prevalent in this area of the kidney. In addition to vascular and tubular changes, the kidney develops glomerulosclerosis, or “scarring,” of the glomerular capillary bed at the beginning of the nephron. Glomerulosclerosis is a prominent anatomical change seen with the aging kidney. Although glomerulosclerosis is a rare finding in younger individuals, it becomes more common with age. Studies show that less than 5% of glomeruli are sclerotic in individuals under 40 years of age. The percentage of sclerotic glomeruli increases to between 10% and 30% by 70 years of age.

Although a number of experimental approaches have been used to study the anatomical changes associated with aging, the most valuable has been the “remnant kidney model” that involves the removal of one kidney and a large fraction of the other kidney from an animal test subject. Using this approach, the influence of reduced nephron mass has been studied. The increase in kidney intracapillary pressure seen in the remnant kidney model sets in motion a cascade of events also seen in normal bilateral aging kidneys. There is an immediate increase in RNA synthesis, followed by an increase in DNA synthesis. Mesangial cells multiply, epithelial cells hypertrophy, epithelial [Page 314]foot processes increase in number, and glomerular capillary length increases. Growth factors increase in activity, although the primary events and the exact cellular mechanisms are not fully understood. Growth factors such as angiotensin II (AII) and TGF-B have been proposed as primary mediators of the anatomical and cellular changes seen. As more nephrons are lost to this process, the remaining nephrons compensate. Compensation leads to hypertrophy, which in turn leads to increased damage and sclerosis.

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