Renal physiology and pathophysiology of aging.
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Adult↗
Biomedical subjects
R D Lindeman
Publications and source records attributed to R D Lindeman.
Assessment of renal function in the old. Special considerations.
The most important clinical renal function to monitor with age is glomerular filtration rate (GFR), as all other changes in renal function tend to parallel changes in GFR. The serum creatinine and creatinine clearance have become the clinical tests most frequently used to measure GFR. The creatinine clearance decreases at a rate approximately 1% per year after age 40 years. Mean serum creatinine values, however, fail to increase with age because creatinine production, which is dependent on muscle mass, falls at nearly the same rate as the renal clearance of creatinine. Serum creatinine concentrations must be interpreted with this in mind when used to determine or modify dosages of drugs cleared totally, for example, the aminoglycoside antibiotics, or partially, for example, digoxin, by the kidney.
Adult↗
Low blood glutathione levels in healthy aging adults.
The objective of this investigation was to test the hypothesis that blood glutathione levels are lower in aging human subjects as previously found in blood and tissues of standard rodent models of aging. Thus a study was conducted with 39 men and 130 women, 20 to 94 years old, who were selected by the criteria of being ambulatory, healthy, and free from diabetes mellitus, thyroid disease, anemias, and cancer. The reference group was comprised of the 20- to 39-year-old subjects, whose blood glutathione levels were 547 +/- 53.5 micrograms/10(10) erythrocytes (mean +/- SD) for 40 individuals and defined the reference range (95% confidence limits) of 440 to 654. Based on the 440 micrograms/10(10) erythrocyte cutoff, the incidence of low blood glutathione content in the older subjects increased significantly, particularly in the 60- to 79-year-old group. Their glutathione levels were 452 +/- 86.8 micrograms/10(10) erythrocytes, 17% lower than the reference group (p < 0.001). These findings demonstrate an increased incidence of low glutathione levels in apparently healthy elderly subjects, who thus may be at risk because of a decreased capacity to maintain many metabolic and detoxification reactions mediated by glutathione.
Adult↗
Overview: renal physiology and pathophysiology of aging.
Cross-sectional studies in humans have suggested that there is a progressive decline of renal function with age after 40 years. The decline in various functions (eg, tubular maximums, concentrating and diluting abilities, and acidification) tend to parallel the decreases in glomerular filtration rate (GFR) and renal blood (plasma) flow (RPF). Recent observations from the Baltimore Longitudinal Study of Aging suggest that not all individuals follow this pattern, and that, indeed, many show no decline and some even an increase in their renal function over time. Whether the observed decreases in renal function with aging are the results of intervening pathologic processes, eg, immunologic, infectious, and toxic injury and ischemia, or can be related to hyperperfusion and hyperfiltration with resultant glomerulosclerosis, or to some other relentless involutional process, remains unclear. The purpose of this report is to review the descriptive studies documenting the changes in renal morphology and physiology with age and to discuss what is known about mechanisms involved in these losses of renal substance and function.
Aging↗
Trace minerals and the kidney: an overview.
The deviations from normal health produced by abnormalities in trace mineral metabolism in patients with renal disease and renal disorders produced by deficiencies or excesses of these trace minerals serve as the focus for this symposium on trace minerals and the kidney. Zinc, the trace mineral of most interest of the nephrologist, and aluminum, the nonessential (toxic) trace element of most interest, are treated in separate reviews. Iron, copper, selenium, and silicon (essential trace elements) and cadmium, lead, mercury, and lithium (nonessential or toxic elements) are covered in this review.
Humans↗
Hypertension and the kidney.
The purpose of this study was to confirm, using longitudinal observations in a normal population, that the rate of decline in renal function (creatinine clearance) is inversely correlated with blood pressure. The negative regression coefficients plotting individual rates of decline over time (Bcr) against mean blood pressures (MBP) were highly significant (p less than 0.001) for all subjects and subjects in category 3 (normals). Although the Bcr also decreases significantly with age and MBP increases with age suggesting this might be an age effect, a multiple regression analysis shows that both MBP and age as independent variables exert statistically significant effects on Bcr, the dependent variable.
Adult↗
Anatomic and physiologic age changes in the kidney.
Cross-sectional studies of renal function in man indicate there is a progressive decline with age after the age of 40 years. The blood vessels, glomeruli, tubules and interstitium are all potential sites of primary involvement in the aging process as well as for renal disease. Regardless of the anatomic structure initially affected, most chronic renal conditions evolve with destruction of the entire nephron. Whether the observed decrease in renal function associated with aging is the result of intervening pathologic processes, e.g. ischemia (vascular obliteration) or infection, or is the result of a more insidious involutional process, it has generated much discussion but few answers. The purpose of this report is to review the descriptive studies documenting the changes in renal morphology and physiology with age and to focus on what is known about the mechanisms involved in these losses of renal substances and function.
Adolescent↗
Magnesium deficiency inhibits biosynthesis of blood glutathione and tumor growth in the rat.
Previously we found that blood glutathione (GSH) levels increase in response to tumor growth in the rat and that this increase is not prevented with zinc deficiency. We also found that zinc deficiency which inhibited tumor growth did not prevent this increase in blood GSH. Therefore, the objectives of this study were to determine the effects of another nutritional modification, namely magnesium deficiency, on blood GSH status and on tumor growth. Magnesium was selected because it is an obligatory cofactor in GSH synthesis and in all biosynthetic reactions involving ATP. To this end, magnesium- and zinc-deficient rats with and without tumors were compared to pair-fed control rats with and without tumors. After 32 days of depletion, the rats were killed, and blood samples were analyzed for nonprotein sulfhydryls (SH) and specifically for GSH. The key finding was that in magnesium-deficient rats with or without tumors, blood GSH levels were low and SH levels were normal indicating a decrease in GSH biosynthesis. In contrast, zinc deficiency affected SH and GSH in parallel. Thus, these two deficiencies must act by different mechanisms. The zinc data verified our earlier results obtained with a different tumor type and rat strain, for blood GSH levels increased in tumor-bearing rats fed control diets, and zinc deficiency did not prevent this increase. Depletion of magnesium or zinc was equally effective in inhibiting tumor growth. These results provide in vivo evidence of a magnesium requirement for GSH biosynthesis in rat erythrocytes. Further, the results suggest that magnesium deficiency may inhibit tumor growth by limiting GSH synthesis from SH precursors.
Animals↗
The aging kidney.
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Acid-Base Equilibrium↗
Chronic renal failure and magnesium metabolism.
A number of factors affect the concentration and distribution of magnesium in patients with chronic renal failure (CRF). Poor nutritional intake, impaired absorption from the intestine, vomiting, diarrhea, the use of diuretics and acidosis may result in a negative balance. More commonly, accumulation of magnesium may be the consequence of reduced renal excretion. Magnesium concentrations are increased in serum and red cells in CRF patients. Bone concentrations and total body magnesium also appear to be increased; muscle magnesium does not appear to be increased. Use of magnesium hydroxide-containing antacids as phosphate binders in patients with CRF was largely discontinued 2 decades ago after reports described increases in serum magnesium concentrations to toxic levels. More recently, the undesirable effects of aluminum-containing phosphate binders (encephalopathy, osteomalacia) have led several investigators to report favorable experiences using low concentrations of magnesium in dialysate and a combination of magnesium and aluminum-containing antacids, as phosphate binders, while closely monitoring serum magnesium concentrations.
Antacids↗
Longitudinal studies on the rate of decline in renal function with age.
Serial creatinine clearances (5 to 14 studies) were obtained for 446 normal volunteers in the Baltimore Longitudinal Study of Aging followed between 1958 and 1981. When those subjects with possible renal or urinary tract disease and subjects on diuretics and antihypertensives were removed from the study, leaving a group of 254 "normal" subjects, the mean decrease in creatinine clearance was 0.75 ml/min/year. The slopes of the creatinine clearance vs. time fell into a normal (Gaussian) distribution around this mean. One third of all subjects followed had no absolute decrease in renal function (positive slope of creatinine clearance vs. time) and there was a small group of patients who showed a statistically significant increase (P less than 0.05) in creatinine clearance with age.
Adult↗
Association between blood pressure and the rate of decline in renal function with age.
A significant negative correlation (P less than 0.0001) exists between the mean blood pressure (MBP) and the rate of decline in creatinine clearance with time in years (BCr) in 446 subjects in the Baltimore Longitudinal Study on Aging (BLSA) followed serially on five or more visits over a period of 8 or more years. Even when the 118 subjects with possible renal and/or urinary tract pathology (category 1) and 74 subjects treated with diuretic and/or antihypertensive agents (category 2) were not included, this relationship remained in the 254 "normal" (category 3) subjects. Since both MBP and negativity of the BCr tend to increase with age, multiple regression analyses using both MBP and age as independent variables were performed to determine their respective influences on BCr. Both MBP and age significantly influenced BCr. When those subjects with hypertension (mean MBP greater than 107 mm Hg) were not included, however, the inverse relationship between MBP and BCr is lost, suggesting that an accelerated loss of renal function is observed primarily because of the impact exerted by individuals with blood pressures in the hypertensive range.
Adult↗
Inhibition of tumor growth by magnesium depletion of rats.
In earlier studies tumor growth was inhibited in rats that first were made magnesium-deficient and subsequently implanted with tumors. The objective of this study was to determine if the reverse sequence is also effective. Namely, is tumor growth inhibited if tumors first are established and then a magnesium deficiency imposed? Rats with palpable mammary adenocarcinomas, or with sham implants were pair-fed either a control or magnesium-deficient diet for 32 days. Rats were then killed and tumors, plasma and several tissues analyzed. In tumors from magnesium-depleted rats, growth was inhibited 46%, magnesium concentration decreased 40% and necrosis was 50% greater. Magnesium depletion alone resulted in a 66% decrease in magnesium and a 29% increase in copper in plasma. Also, depletion caused a decrease in heart zinc and increase in kidney copper concentrations. As a result of tumor growth alone, concentrations of zinc in plasma decreased 40% and copper increased 37%. Rats with tumors also had decreased sodium and increased potassium levels in plasma. To our knowledge this is the first demonstration that the growth of an established tumor can be retarded solely by dietary magnesium depletion and thus may be significant for the nutritional management of tumor patients.
Animal Nutritional Physiological Phenomena↗
Inhibition of tumor growth by zinc depletion of rats.
Tumors grow less rapidly when implanted into zinc-deficient rats. The objective of this study was to determine if tumor growth is also inhibited when tumors first are established and then a zinc depletion initiated. Therefore, rats with palpable mammary adenocarcinomas or with sham implants were pair-fed either a control or zinc-deficient diet for 32 days. Rats were then killed and tumors, plasma and several tissues analyzed. In three separate experiments tumor growth was inhibited 32, 35 and 35%, respectively. The extent of tumor necrosis and tumor zinc concentration were not different between control and deficient groups. However, there was a significant positive correlation between tumor zinc concentration and percent viable tumor tissue in both groups. Although zinc depletion in tumor-bearing rats resulted in a 10% loss of carcass weight, there was little effect on liver, kidney and heart weights. As a result of depletion alone, zinc concentrations decreased only in plasma and kidney. As a result of tumor growth alone, concentrations of liver zinc increased and kidney copper decreased. In plasma of tumor-bearing rats, levels of zinc decreased 40% while copper and magnesium increased 50 and 13%, respectively. To our knowledge, this is the first demonstration that growth of established tumors can be retarded solely by dietary zinc depletion.
Animal Nutritional Physiological Phenomena↗
Red blood cell and serum selenium concentrations as influenced by age and selected diseases.
Red blood cell and serum selenium concentrations were investigated to determine normal concentrations for our geographic area and if potential differences existed in patients with selected diagnoses (hepatic, renal, malignant, and chronic diseases). Selenium was quantified in samples of red blood cells, serum and urine by neutron activation analysis. The results were analyzed by comparing 1) pooled data from all ages for each disease with normal values, and 2) normal values with age-matched patients in each disease category. Decreases in red blood cell selenium concentrations (P less than 0.05) occurred in normal subjects over 60 years of age without concurrent significant decreases in serum selenium. Although differential results were noted in age-matched groups, overall results showed that decreased concentrations of selenium in both red cells and in serum occurred with alcoholic cirrhosis, malignancies, and chronic renal failure (P less than 0.025). Red blood cell selenium concentrations also were decreased in patients with stable chronic disease. Decreased serum selenium concentrations were positively correlated with albumin concentrations in patients with cirrhosis. There was no correlation between serum selenium and bilirubin concentrations in patients with liver disease or between serum selenium and creatinine concentrations in patients with chronic renal failure whose urinary excretion of selenium was far below control levels.
Adult↗
Mineral metabolism in the aging and the aged.
With the development of accurate and precise techniques for quantifying sodium, potassium, calcium, and magnesium concentrations, a vast literature has been generated indicating that deficits and excesses of these cations in the body create many clinical challenges for the physician. Iron has received its share of attention as the most abundant trace metal in the body, primarily being utilized in the formation of hemoglobin. Zinc is the next most abundant trace element in the body, and evaluation of its role in the biochemistry and pathophysiology of disease is now stimulating a great deal of interest. Deficiencies of the other trace metals also are receiving increasing attention as attempts to evaluate their importance in human nutrition are being made. Studies were not considered reliable until technological advances made it possible, by atomic absorption spectroscopy, neutron activation analysis, and other techniques, to quantify these trace elements accurately and precisely.
Aged↗
A specific dietary zinc requirement for the growth of Walker 256/M1 tumor in the rat.
To determine the specific effect of zinc status on the growth of Walker 256/M1 carcinosarcomas young male rats were pair-fed either a control or zinc-deficient diet for 14 days, were implanted with tumors and killed 7 days later. Half of the deficient rats were repleted with zinc for the 7 days after tumor implantation. In deficient rats, tumor weights were decreased 70% (p less than 0.005), tumor necrosis was 3-fold greater (p less than 0.05) and tumor zinc concentrations were decreased 23 to 37% (p less than 0.005). A specific zinc effect was observed by a 2-fold increase in tumor weights in repleted rats (p less than 0.05) with marked decreases in tumor necrosis (p less than 0.05) and 29 to 84% increases in tumor zinc concentrations (p less than 0.005). Since there were no decreases in organ weights of zinc-deficient animals and no correlation between final tumor weights and postimplant changes in carcass weights, the results indicate a specific inhibitory effect of zinc deficiency independent of a nonspecific malnutrition.
Animals↗
Effect of zinc deficiency on blood glutathione levels.
The specific effect of zinc deficiency on blood glutathione (GSH) concentrations has not been clearly demonstrated, for earlier results could have been due to differences in dietary intake. To clarify this, we determined blood GSH concentrations over a 17-day period in young, mature rats fed a zinc-deficient diet and compared them with pair-fed controls. Glutathione concentrations based on hemoglobin content increased in both groups but a different rates. After 17 days, the GSH levels increased 20% in deficient rats and 29% in control rats (P less than 0.005). The GSH levels in deficient rats were 11% lower than in controls by 10 days (P less than 0.025) and remained significantly lower thereafter. These results indicate that the decrease in blood GSH levels was a specific result of zinc deficiency.
Animals↗