Brenner and Rector's The Kidney, 8th ed.

CHAPTER 21. Aging and Kidney Disease

Devasmita Choudhury   Moshe Levi

  

 

Structural Changes, 681

  

 

Gross and Microscopic, 681

  

 

Mediators and Potential Modulators of Age-Associated Renal Fibrosis, 682

  

 

Angiotensin II, 682

  

 

TGF-b, 683

  

 

Nitric Oxide, 684

  

 

Advanced Glycosylation End Products, 684

  

 

Oxidative Stress, 684

  

 

Lipids, 685

  

 

Functional Changes, 685

  

 

Renal Plasma Flow, 685

  

 

Glomerular Filtration Rate, 686

  

 

Sodium Conservation, 687

  

 

Sodium Excretion, 687

  

 

Urinary Concentration, 688

  

 

Urinary Dilution, 689

  

 

Acid-Base Balance, 689

  

 

Potassium Balance, 690

  

 

Calcium Balance, 690

  

 

Phosphate Balance, 691

  

 

Osmolar Disorders, 691

  

 

Aging and Renal Disease, 692

  

 

Acute Renal Failure, 692

  

 

Renovascular Disease, 693

Structural and functional changes associated with biologic aging in the kidney are most evident in the presence of significant physiological and pathophysiological perturbations. Despite aging, the kidney functions to maintain appropriate internal milieu until renal reserve is challenged. Older kidneys seem to adapt less well and recover more slowly in the presence of intervening infections, immunologic processes, exposure to drugs and toxins, or other organ failure. This can be seen with healthy donor kidneys from those older than 55 years of age, which are more likely to fail from chronic allograft nephropathy than younger donor kidneys. [1] [2] [3] [4] [5] With a growing older adult population (>65 years), expected to be 54 million by year 2010,[6] and five times greater prevalence of end stage renal disease (ESRD)[7] added to the independent risk of renal failure[6] contributing to mortality, basic knowledge of anatomic, physiologic, and pathologic physiologic changes associated with renal aging may be helpful to avoid disastrous outcomes in the elderly. Renal senescence can now be probed with molecular technology to better understand basic mechanisms such that newer interventions can be entertained to prevent loss of renal function in the elderly. The goal of this chapter then is to provide current understanding of the effect of aging on renal function and disease.

STRUCTURAL CHANGES

Gross and Microscopic

With advancing age, there is a decrease in renal mass as well as weight, size, and volume as noted by radiographic[8] and postmortem studies. Kidney weights of 250 gm to 270 gm in young adulthood decrease over years to 200 gm by the ninth decade. When adjusted for concurrent decrease in body surface area with aging, this decrease may be age appropriate.

Variable sclerotic changes in the walls of the larger renal vessels can be made worse by hypertension.[9] Changes in the aging intrarenal vasculature however can occur, independent of hypertension and other renal diseases. Increased arteriosclerosis of interlobular and arcuate arteries can be seen in older healthy donor kidney biopsies in comparison to younger donors. Sections of human cortical arteries from age 6 to 70 years reveal progressive arterionephrosclerosis with increased fibrointima and medial sclerosis.[10]

Underlying glomerulosclerosis and tubulointerstitial fibrosis may lead to the decrease in renal size and weight noted. Histology reveals a 30% to 50% decrease in cortical glomerular number by age 70 from ischemic changes. There is loss of glomerular tuft lobulation, increased mesangial volume, and capillary collapse with obliteration in the obsolescent glomeruli. There are hyaline deposits in residual glomeruli and Bowman space with little cellular response. Fibrous intimal thickening, medial sclerosis, as well as hyalinosis of both arteries and arterioles is seen ( Fig. 21-1 ). [10] [11] [12] Both glomerular and peritubular capillary density is decreased.[13] This may be explained by decreased concentration in proangiogenic vascular endothelial growth factor as well as increased expression of antiangiogenic factor, thrombospondin-1 as demonstrated in aging rats.[13] These changes in addition to basement mem-brane wrinkling and thickening of both glomeruli and tubules lead to progressive reduction and simplification of vascular channels. [14] [15] Blood flow is then shunted from afferent to efferent arterioles of the juxtamedullary glomeruli, favoring the renal medulla. The arteriolar Vera rectae remain intact to provide adequate blood flow to the medulla.

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FIGURE 21-1  Glomerular and arteriolar types. A, A normal glomerulus and its associated afferent arteriole (arrow) without hyaline deposits. B, A hypertrophic glomerulus, which although not particularly large in this plane of section, demonstrates the massive dilatation of hilar capillary and its first branches. Peripheral capillaries are dilated and a channel (arrowhead) leading to the efferent arteriole is also dilated. The dilated afferent arteriole (arrow) shows a massive nonobstructive hyaline deposit. C, A focal segmental glomerulosclerosis (FSGS)-type glomerulus shows mesangial increase and sclerosis with capsular adhesions, particularly at hilus (arrowheads). Its associated afferent arteriole (arrow) shows nonobstructive deposits. D, An ischemic glomerulus shows collapsing capillary loops with resulting small capillary lumens. Its afferent arteriole (arrow) is without deposits. All were stained with periodic acid-Schiff.[250]  (Reprinted with permission from Hill GS, Heudes D, Bariety J: Morphometric study of arterioles and glomeruli in the aging kidney suggests focal loss of autoregulation. Kidney Int 63:1027–1036, 2003.)

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Renal tubules, lessening in size and number, atrophy to form distal diverticula. These outpouchings may signify formation of early renal cysts as seen in aging kidneys.[16] Collection of debris and bacteria in these structures may then lead to infection and possible pyelonephritis.

Tubulointerstitial fibrosis characterizes the aging renal extracellular matrix and may precede development of focal glomerulosclerosis and tubular atrophy. [17] [18] Studies from aging rodents suggest that tubulointerstitial fibrosis may be the result of an active process with associated interstitial inflammation, fibroblast activation, and accelerated apoptosis.[19] The presence of focal tubular proliferation, myofibroblast activation, macrophage infiltration, and increased immunostaining for adhesive proteins osteopontin and intracellular adhesion molecule-1 (ICAM-1) as well as collagen IV deposition are found in aging rat kidneys. Peritubular capillary ischemia and injury with altered endothelial nitric oxide expression (eNOS) is believed to trigger this inflammatory process with subsequent development of focal glomerulosclerosis or tubular atrophy.[20] Collagen-1 protein accumulation increased with age and correlated with the extent of interstitial fibrosis when renal tissue from autopsies was examined. [20] [21] Therefore collagen-1 may be an important component of age-associated interstitial fibrosis.

Histological changes may reflect changes at the molecular level. Cell cycle inhibitor, p16INK4a, inversely correlates with cell cycle replication, and is increased with both age and glomerulosclerosis and tubulointerstitial fibrosis.[22]Interestingly telomere length also appears to shorten in an age-dependent fashion in the renal cortex faster than the renal medulla. Telomere DNA repeats is thought to act as mitotic clocks for reflecting replicative senescence of the cell. Critical telomere shortening is seen in the renal cortex in aging. However rodent studies indicate that environmental stresses may contribute more to renal senescence than telomere shortening.[23]

MEDIATORS AND POTENTIAL MODULATORS OF AGE-ASSOCIATED RENAL FIBROSIS

Mediators associated with renal fibrosis ( Fig. 21-2 ) such as angiotensin II, transforming growth factor-β (TGF-β), nitric oxide (NO), advanced glycosylation end products (AGE), oxidative stress, and lipids are also evident in kidneys of aging animals and may be targets for modulating progression of sclerosis. Longitudinal studies in healthy elderly indicate that up to one third of individuals have little functional change in creatinine clearance whereas two thirds show decline in function.[24] Thus it is possible that various factors hasten sclerosis in some more than others. The ability to modify these factors may result then in preventing progressive age-related decline in renal function.

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FIGURE 21-2  Factor associated with the pathogenesis of age-related glomerulosclerosis and tubulointerstitial fibrosis. TGF-b, transforming growth factor-β.

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Angiotensin II

Diverse biologic effects of angiotensin II on the kidney including proximal tubular transport of sodium and water,[25] glomerular and tubular growth, [26] [27] [28] decreased nitric oxide (NO) synthesis,[29] immunomodulation, growth factor induction, and accumulation of extracellular matrix proteins can affect glomerulosclerosis and tubulointerstitial fibrosis. Hemodynamic effects of angiotensin II in aging nephrons maintain filtration pressure with preferential efferent arteriolar vasoconstriction. This effect however is also implicated with inducing intraglomerular hypertension and subsequent glomerular damage.[30] With use of angiotensin converting enzyme inhibitors (ACEIs) in aged rats, there is decrease intra renal vascular resistance (RVR) and intracapillary pressure, which decreases protein leak in aging rodents.[31] Chronic ACEI use decreases postprandial hyperfiltration, thus decreasing filtered load.[32] Glomerular capillary size selectivity or change in the distribution of negative charge within the glomerular barrier may also be affected with ACEI. [31] [33] ACEI-treated aged mice are noted to have a decrease in glomerular area, mesangial area, and overall total decrease in glomerulosclerosis in comparison to age-matched and sex-matched untreated mice ( Fig. 21-3 ). [33] [34] [35] [36] [37] It is interesting to note that although systemic changes in renin and angiotensin converting enzymes may not be evident with aging, there is intrarenal downregulation of renin mRNA and angiotensin converting enzyme level with aging.[38]

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FIGURE 21-3  Effects of angiotensin converting enzyme on renal aging. Enalapril administered to drinking water in aging mice. Group A (n=16), B (n=17), C (n=16), D (n=10). * * P < 0.01, Group A, B, C compared with D. * P < 0.001, Group A, B, C compared with D.  (Figure drawn from data from Ferder L, Inserra F, Romano L, et al: Decreased glomerulosclerosis in aging by angiotensin-converting enzyme inhibitors. J Am Soc Nephrol 5:1147–1152, 1994.)

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Nonhemodynamic growth effects of angiotensin II stimulate profibrotic cytokines. Angiotensin II induces synthesis and autocrine action of TGF-β to stimulate collagen IV transcription in the medullary collecting tubule. [39] [40]Angiotensin II also promotes monocyte-macrophage influx, stimulates mRNA and protein expression of the chemokine RANTES in endothelial cells, and inhibits NO.[41] NO inhibition leads to transcription of the proinflammatory chemokine, monocyte chemoattractant protein-1 (MCP-1). Tubulointerstitial fibrosis and a smooth muscle cell actin was significantly reduced when ACEI enalapril-treated aged rats were compared with either calcium channel blocker nifedipine-treated aged rats or untreated aged rats despite similar blood pressure control.[42]

Another nonhemodynamic effect of angiotensin II in the aged kidney may be matrix accumulation by stimulating plasminogen activator inhibitor-1 (PAI-1) from the endothelium.[43] Increased PAI-1 levels inhibit tissue plasminogen activator and urokinase-plasminogen activator and leads to decreased proteolysis and fibrinolysis with increased matrix accumulation.[44] Angiotensin antagonist treated rats had regression of age-related glomerular and vascular sclerosis with decrease in collagen content.[45] Use of angiotensin II antagonists also prevented age-associated decrease in mitochondrial energy production by lessening the age-related increases in mitochondrial oxidants.[46]

The klotho gene that is primarily expressed in the kidney and its protein product are associated with suppression of premature aging and arteriosclerosis. Angiotensin II appears to downregulate this gene expression. Mouse klotho gene transfer, via adenovirus vector into male Sprague-Dawley rats, ameliorated angiotensin II-mediated renal morphologic damage. Also klotho mRNA downregulation was reversed with the angiotensin II receptor blocker losartan but not by use of other antipressor agents such as hydralazine.[47] Taken together, these animal data suggest benefits of angiotensin II antagonism in elderly with age-related renal functional decline although conclusive data in humans is lacking.

TGF-β

Renal fibrosis seen with aging may be the result of normal or pathologic tissue repair or both. Response to injury is wound healing and tissue repair. Persistent injury or insult may lead to tissue fibrosis. TGF-b, an active modulator of tissue repair, is associated with the structural changes of renal scarring as seen in the aging kidney. A number of factors can stimulate TGF-β including increased angiotensin II activity, abnormal glucose metabolism, platelet-derived growth factors, hypoxic or oxidative stress, mesangial stretch, and increased levels of advanced glycosylation end products (AGE). TGF-β induces gene transcription and production of matrix proteins collagen III, IV, I, fibronectin, tenascin, osteonectin, osteopontin, thrombospondin, and matrix glycosaminoglycans.[48] In addition, TGF-β inhibits collagenase and metalloproteinase (MMP) inhibitors.[49] The net result is accumulation of extracellular matrix proteins with subsequent glomerulosclerosis and tubulointerstitial nephritis. [49] [50] [51] [52] TGF-β mRNA is increased in the renal interstitium of aged rats. [18] [53] Down-regulation of TGF-β via angiotensin II antagonism results in decreased interstitial fibrosis.[53] Although increased expression of TGF-β may in part mediate age-related sclerosis, direct evidence is not available. Identification and use of antisense oligonucleotides inhibiting TGF-β expression, or function such as decorin may provide better understanding of the role TGF-b plays in aging sclerosis and prevention. Recently identified functions of relaxin, a peptide hormone produced by the pregnant ovary and prostate, include antifibrotic properties. Via direct actions on TGF-b-stimulated fibroblasts to decrease collagen 1 and 3, treatment with relaxin of relaxin-deficient 12-month-old male knockout mice improved established interstitial fibrosis, glomerulosclerosis, and cortical thickening with a decrease in collagen content.[54] Future studies may further clarify the clinical use of this peptide in aging renal sclerosis.

Nitric Oxide

The role of nitric oxide goes beyond affecting vascular reactivity. NO acts to decrease fibrosis by inhibiting the family of transcription factors NF-kB, which in the presence of reactive oxygen intermediates stimulates MCP-1 and promotes influx of monocyte-macrophages leading to inflammation and injury. [55] [56] However, in the aging vasculature, levels of nitric oxide are decreased as seen in urinary excretion of stable NO oxidation products (nitrites and nitrates) in aged rats. [57] [58] Oxidant stress may also induce NADPH oxidase-mediated NO scavenging and NO depletion in aged kidneys.[59] In addition there is decreased expression of eNOS in peritu-bular capillaries of aged rats.[19] This can lead to chronic tubulointerstitial ischemia and fibrosis. L-arginine dietary supplementation in aging rats improves renal plasma flow (RPF) and glomerular filtration rate (GFR) and decreases proteinuria and glomerulosclerosis.[60] Supplementation with L-arginine also significantly decreases kidney collagen and N-e-(carboxymethyl) lysine accumulation.[61] Suspected factors imposing on the age-related decrease in eNOS are increased angiotensin II activity, increased AGE levels, hypoxia, oxidative stress, and dietary protein intake. [58] [62] [63] [64] [65] Angiotensin II antagonists and or dietary protein restriction is associated with significant increases and normalization of urinary NO excretion.[58]

Advanced Glycosylation End Products

Cross links of glycosylated proteins, lipids, and nucleic acids (AGE) slowly accumulate and produce damage to the vascular and renal tissue with aging. [66] [67] In the presence of hyperglycemia, these end products accumulate more rapidly and accelerate tissue damage.[68] These glycated proteins decrease vascular elasticity, induce endothelial cell permeability, and increase monocyte chemotactic activity via AGE-receptor ligand binding, which stimulates macrophage activation and secretion of cytokines and growth factors. AGE accumulation in the vascular endothelium and basement membrane results in defective NO vasodilation, possibly due to chemical inactivation of endothelium-derived relaxing factor. [69] [70] [71] [72] Similar perturbations of the vascular endothelium are evident in diabetic patients and those with age-related vasculopathy. Both biochemical assays and histochemical studies have demonstrated increased levels of AGE and AGE-receptor (RAGE) in aged kidneys of animals.[66] AGE deposition in the kidney is associated with increased mesangial matrix, increased basement thickening, increased vascular permeability, and induction of platelet-derived growth factor and TGF-b, resulting in glomerulosclerosis and tubulointerstitial fibrosis.[69] Several factors contribute to AGE and RAGE accumulation including age-related decline in GFR and increased oxidative stress causing oxidative modifications of glycated proteins and accumulation of N-e-(carboxymethyl) lysine. With age-related insulin resistance there is abnormal glucose metabolism and glycation of proteins. Recent studies also suggest that lifelong AGE-enriched food consumption and smoking can lead to increased AGE loads and increased AGE accumulation in tissues. [73] [74]

Although mesangial cell response to AGE/RAGE interaction are increased in the kidney in the presence of hyperglycemia and oxidative stress, a newly identified mesangial cell receptor, AGE-R1, may act to counterregulate the proinflammatory mesangial cell response to increased AGE. Supersaturation and possible receptor downregulation, under increased AGE burden, may prevent appropriate opposing regulatory control of this receptor.[75] In addition, whether aging itself affects mesangial cell receptor expression or activity must be understood. Intuitively then, mechanisms that can increase AGE-R1 antioxidant mesangial receptor activity may be future targets in decreasing AGE-associated tissue changes seen with aging kidneys.

Studies using long-term aminoguanidine treatment in aged rats and rabbits, show marked decreased in glomerulosclerosis and proteinuria,[76] as well as a decrease in age-related arterial stiffening and cardiac hypertrophy.[77]Furthermore, AGE-associated changes in vascular permeability, and abnormal vasodilation to acetylcholine and nitroglycerin were reversed in aminoguanidine-treated animals.[78] In addition, mononuclear cell migration activity was prevented in these animals.

Calorie restriction also seems to decrease the burden of AGE and other glycated proteins including N-e-(carboxymethyl) lysine and pentosidine in rats restricted to 60% of the ad libitum dietary intake of control rats with improved life span. [79] [80] AGE content in renal glomeruli and abdominal aorta of lean 30-month-old rats restricted to even 30% caloric intake was decreased compared to ad libitum control similar aged rats[81] ( Fig. 21-4 ). Future studies may delineate the role of decreasing the burden of AGE in aging individuals.

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FIGURE 21-4  Immunolocalization of advanced glycosylation end products (AGE) in the renal cortex of 10-month-old (A) and 30-month-old (B) female WAG/Rij rats fed ad libitum and 30-month-old animals food restricted by 30% (C) age localized predominantly in extracellular matrix. Increased AGE accumulation was evident in tubular basement membranes, mesangial matrix, glomerular basement membranes, and Bowman capsule between 10-month-old and 30-month-old rats fed ad libitum. Such accumulation was mostly prevented in food-restricted animals. Magnification ×350.  (Reprinted with permission from Teillet L, Verbeke P, Gouraud S, et al: Food restriction prevents advanced glycation end product accumulation and retards kidney aging in lean rats. J Am Soc Nephrol 11:1488–1497, 2000.)

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Oxidative Stress

Tissue injury in aging can occur from free radical production and or antioxidant enzyme deficiency with subsequent lipid peroxidation and oxidative stress. [82] [83] [84] [85] Increased urinary oxidized amino acid levels in aged rats indicate the presence of increased oxidized skeletal muscle proteins.[86] Aged kidneys indicate the presence of increased levels of reactive oxygen species and thiobarbiturate acid reactive substances (TBARS), substances associated with lipid oxidative damage.[87] In addition, other markers of oxidative stress and lipid peroxidation such as isoprostanes, AGE, RAGE, increased heme oxygenase, are also noted in aged rats.[88] Experimental studies evaluating oxidant stress on klotho gene expression in mouse medullary IMCD3 cells show reduced klotho expression[89] suggesting another possible mechanism toward renal aging. When an antioxidant vitamin E-enriched diet is fed to aged rats, markers of oxidative stress are lessened, with improvements noted in renal plasma flow (RPF), glomerular filtration rate (GFR), as well as decreased glomerulosclerosis.[88] Studies indicate that ACEI can increase antioxidant enzyme activity and block TGF-β induction by reactive oxygen species. [90] [91] In addition the anti-oxidant taurine also blocks reactive oxygen species in cultured mesangial cells.[92] A superoxide scavenger, tempol, restored the NO-mediated response of angiotensin II receptor blocker to suppress oxygen consumption in renal cortical tissue.[59] These findings suggest the possibility of both angiotensin II antagonists and anti-oxidants as potential therapeutic options in the future. Furthermore, calorie restriction is also noted to decrease age-related oxidant stress via suppressing activation of mitogen activated protein kinase (MAPK) cellular signaling pathways, as well as mitochondrial lipid peroxidation, and membrane damage with decrease in apoptosis [93] [94] suggesting perhaps the need for dietary discrimination in the prevention of age-associated renal sclerosis.

Lipids

Cholesterol accumulation in the kidney occurs with aging and may contribute to the progression of glomerulosclerosis and proteinuria. [95] [96] Sterol regulatory element binding proteins 1 and 2 (SREBP-1 and SREBP-2), key regulators of fatty acid and cholesterol synthesis, are associated with increased synthesis and renal accumulation of triglyceride and cholesterol in aged rats.[96] In addition, serum leptin levels are also increased in aging.[96] The presence of oxidative stress and increases in AGE level in aging may further contribute to increased levels of modified low density lipoproteins (LDL), lipoprotein (a). [97] [98] [99] Associated with increased free oxygen radical formation, increased expression of growth factors such as platelet-derived growth factor and TGF-b, inhibition of NO synthesis, migration and adherence of monocytes, and growth of mesangial and vascular cells, these lipids can add to the pathogenic role of aging-related renal disease progression. Calorie restriction in aging rats have shown not only decreases in extracellular matrix accumulation and expression of growth factors, but also significant decreases in renal nuclear SREBP-1 and SREBP-2 abundance and renal triglyceride and cholesterol accumulation.[96]

Similar changes of glomerulosclerosis and tubulointerstitial fibrosis occur from lipo-oxidative stress with high cholesterol feeding in type 2 diabetic rats.[100] When treated with 3–hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor for 12 months, streptozotocin-induced diabetic rats decrease urine albumin excretion and glomerular volume compared with untreated rats.[101] Both diabetic and nondiabetic patients treated long term with HMG-CoA reductase inhibitors and or peroxisome proliferator activated receptor-α (PPAR-α) agonists seem to decrease proteinuria and partially preserve GFR. [102] [103] [104] Further studies defining their role in the prevention of age-related renal changes in humans must be done.

FUNCTIONAL CHANGES

Renal Plasma Flow

Changes in renal plasma flow as measured by paraaminohippurate clearance note a 10% decrease per decade increase from the third to ninth decade.[105] Xenon washout scans demonstrate a preferential decrease in cortical blood flow with medullary flow preserved, paralleling the histological changes observed with aging. Although changes in cardiac output may possibly be contributing the decrease in RPF, there seems to be a small but definite decrease in the renal fraction of the cardiac output. [106] [107] Changes in anatomic and vascular responsiveness seen with aging may explain this decrease.

When vasodilation is assessed in elderly healthy subjects with infusion intra-arterial acetylcholine, or intravenous infusion of pyrogen or atria natriuretic peptide (ANP), vascular response is altered.[108] Older subject have a blunted response in comparison to younger counterparts. This is also noted with infusion of amino acids, where RPF is unchanged whereas filtration fraction (FF) increases with increases in GFR.[109] With the addition of dopamine and amino acid, older subjects increase RPF and GFR although the response is less in older subjects than younger subjects ( Fig. 21-5 ).[9]

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FIGURE 21-5  Percent changes in renal plasma flow (RPF), glomerular filtration rate (GFR), filtration fraction (FF), and renal vascular resistance (RVR) in younger (blue bars) and older (red bars) subjects (P < 0.05 for the difference in changes between the two groups).  (Reprinted from Fuiano G, Sund S, Mazza G, et al: Renal hemodynamic response to maximal vasodilating stimulus in healthy older subjects. Kidney Int 59:1052–1058, 2001.)

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Abnormal intrarenal signaling in the older subjects may lead to impaired vasorelaxation.[110] Stimulation of the renal sympathetic system results in exaggerated vasoconstriction. [111] [112] Mediators of vasorelaxation, such as vasodilatory prostacyclin (PGI2) are decreased in aged human vascular cells and aged rat kidneys compared with vasoconstrictive thromboxanes. [113] [114] Older subjects also excrete less vasodilatory natriuretic prostaglandins. With inhibition of angiotensin II, vasodilation appears to be exaggerated or preserved. [115] [116] RPF increases significantly in aged rats.[117] This allows for speculation for possibly a greater role for angiotensin II-mediated vasoconstriction in the aging renal vessels; however, intra-arterial angiotensin infusion leads to similar vasoconstrictive responses in both young and older human subjects. With preserved vasoconstriction and blunted vasodilation, it is possible that the aged kidney remains in a state of renal vasodilation to compensate for underlying sclerotic damage.

Similar changes with intravenous glycine infusion are observed in aged rats that histologically correlate with progressive glomerulosclerosis.[118] With competitive inhibition of endothelium-derived relaxing factor, NO, there is a sig-nificant increase in vasoconstriction, increased RVR, and decreased RPF in aged rats versus younger rats.[119] Micropuncture demonstrates no age-associated changes in magnitude of pressor or vasoconstriction with angiotensin II infusion in rats. Both pre-glomerular and efferent arteriolar resistances increase whereas RPF and glomerular plasma flow decrease accompanied by a rise in glomerular hydraulic pressure gradient and increased filtration fraction in both young and older rats. Single nephron GFR (SNGFR) and GFR are lower in older rats with noted decrease in glomerular capillary ultrafiltration coefficient (Kf), with no change in these parameters in the younger rats. Angiotensin II-mediated glomerular mesangial cell contraction and decrease in Kf likely translates to decreased filtration surface.[120] Studies in healthy transplant donors suggest that a drop in Kf with age may be the function of both underlying structural changes lowering single nephron Kf and a decrease in the number of functioning glomeruli.[105]

Despite a linear decrease in RPF, filtration fraction increases with age.[105] Preserved medullary flow in relation to decreased cortical flow may allow for a higher juxtamedullary FF than cortical nephrons.

Glomerular Filtration Rate

Changes in GFR can be expected with gradual renal senescence. Factors including race, gender, genetic variation, and underlying risk factors for renal disease all contribute to the rate of GFR decline in the elderly. Increased arterial stiffness, as reflected by elevated pulse pressure in older individuals, also appears to inversely correlate with age-related loss in GFR.[121] Retinal microvascular abnormalities indicative of systemic microvascular disease in elderly participants of the Cardiovascular Health Study are associated with greater decline in GFR.[122]

Methodological variations differ in gauging the rate of change. A decrease in urea clearance was noted in the late 1930s and confirmed with noted decreases in inulin, creatinine, and iothalamate clearances with increasing age.[105]Iohexol clearances indicate a drop of 1.0 ml/min/1.73 m2 per year.[123] Despite normal protein intake, the decrease in inulin clearance in older subjects without renal disease is less than younger controls. Creatinine clearance drops from 0.8 ml/min/1.73 m2 per year from age 40 to age 80 years in healthy elderly subjects.[124] However, a parallel rise in serum creatinine is not seen because muscle mass concomitantly decreases with age. Clinically this translates to an overestimation of GFR in older patients when using serum creatinine alone to assess medication dosing or renal risk to the aged kidney for ischemic, toxic, or metabolic events. Commonly used formulas ( Table 21-1 ) to estimate GFR frequently overestimate or underestimate GFR in the older subjects ( Fig. 21-6 ). [6] [125] [126] The GFR formula derived from the Modification of Diet in Renal Disease (MDRD) study appears to more closely proximate GFR changes in aged subjects.[126] Newer markers such as serum 2-(alpha-mannopyranosyl)-L-tryptophan (MTP)[127] and cystatin C are being considered for estimating GFR. Cystatin C, an endogenous cysteine proteinase with a constant rate of production by nucleated cells, freely filtered, reabsorbed, and catabolized, but not secreted by the renal tubules is being evaluated more closely for accuracy in predicting GFR in the elderly.[128]Future widespread availability of this marker may increase its applicability in estimating GFR in the elderly.


TABLE 21-1   -- Commonly Used Formulas to Estimate Glomerular Flow Rate (GFR)

1. Creatinine clearance (mL/min/1.73 m2) = (1.33 - 0.64) × age[*]

2.000494

3. GFR = 170 × [Pcr]-0.999 × [age]-0.0176 × [0.762 if patient is female] × [1.180 if patient is black] × [SUN]-0.0170 × [alb]+0.318

Formula 1 from Rowe JW, Andrew R, Tobin JD, et al: Age-adjusted standards for creatinine clearance. Ann Intern Med 84:567–569, 1976. Formula 2 from Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41, 1976. Formula 3 from Levey AS, Bosch J, Lewis JB, et al: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Ann Intern Med 130:461–470, 1999.

*

15% less in females.

 

 

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FIGURE 21-6  Percentiles of glomerular filtration rate (GFR) and Cockcroft-Gault creatinine clearance (CCr) by age, plotted on the same graph as data from 1950 on inulin clearance in healthy men by Davies and Shock (J Clin Invest 29:496, 1950). Percentiles are calculated using a fourth-order polynomial weighted quantile regression. The solid line shows a polynomial regression to the inulin data. Dashed lines without symbols show the fifth and ninety-fifth percentiles for GFT estimates.  (Reprinted from Coresh J, Astor BC, Greene T, et al: Prevalence of chronic kidney disease and decreased kidney function in the US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 41:1–12, 2003.)

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Routine 24-hour creatinine clearance to estimate GRF may be cumbersome with measurement precision dependent on the volume collected, diet, and other factors. Radionuclide clearances with technetium 99m-labelled diethylenetriamine-pentacetic acid (99mTc-DTPA)125-iothalamte or radiocontrast clearance with single injection iohexol x-ray fluorescence analysis can also be done.[129] However expense, radioactivity exposure, and test availability may be limiting factors.

Although some studies suggest a bias toward slower decline with being female, the role of gender with declining GFR in the elderly population is not yet clear. Genetic variance and race seem however to suggest a greater loss of GFR in aging African Americans and those of Japanese origin than whites. [130] [131] The presence of hypertension, [132] [133] and other risk factors including glucose intolerance,[134] frank diabetes, systemic or renal atherosclerosis, and abnormal lipid metabolism add to a greater rate of GFR decline in the elderly.

Sodium Conservation

Tubular efficiency in conserving filtered sodium declines with aging. This is seen with sodium restriction in older healthy subjects who take twice as long to decrease urinary sodium excretion in comparison to younger subjects under similar conditions. Subjects ≥60 years take almost 31 hours to decrease urinary sodium compared with 17.6 hours in those ≥30 years old.[135] Distal sodium conservation may be diminished ( Fig. 21-7 ).[136] Age-related changes in interstitial scarring, decreased nephron number, and increased medullary flow likely increase solute load per nephron as observed in patients with chronic renal failure.

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FIGURE 21-7  Response of urinary sodium excretion to restriction of sodium intake in normal humans. The mean half-time (t1/2) for eight subjects older than 60 years was 30.9 ± 2.8 hours, exceeding the mean t1/2 of 17.6 ± 0.7 hours for subjects younger than 25 years of age (P < 0.01). When younger subjects were separated by geographic area, the mean t1/2 for the Texas group (>17.9 ± 0.7 hours) was similar to that of the New England group (>15.6 ± 1.4 hours; P < 0.3).  (Reprinted from Macias Nunez JF, Garcia Iglesias C, Bondia Roman A, et al: Renal handling of sodium in old people: A functional study. Age Ageing 7:178–181, 1978.)

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In addition, both levels and responses to hormones that regulate tubular sodium reabsorption change with aging. Concentration of plasma renin and aldosterone are decreased in aging healthy elderly subjects. A 30% to 50% lower basal renin activity is noted despite normal levels of renin substrate. Maneuvers such as upright position, 10 meq/day sodium intake, furosemide administration, and air jet stress that stimulate renin secretion further amplifies age-related differences in plasma renin activity. [137] [138] Decreased juxtamedullary single nephron renin content,[139] down-regulation of renin mRNA abundance, and decreased renal angiotensin converting enzyme levels and decreased type-1 angiotensin receptor mRNA are found in aged rats. [38] [140] Both pre and post hemorrhage plasma renin content are decreased in 15-month-old rats in comparison to 3-month-old rats.[38] Sodium deprivation with a resultant fall in mean arterial pressure revealed a blunted response to plasma renin activity with delayed fall in urinary sodium excretion.[141] Normal aging adults have decreased conversion of inactive to active renin when plasma renin substrate is measured.[142]

Plasma aldosterone also decreases in parallel with aging with a fall of 30% to 50% seen in older adults versus younger counterparts. Because infusion of adrenocorticotropic hormone produces an appropriate aldosterone and cortisol response, aldosterone deficiency with aging is more likely related to a renin-angiotensin deficiency and not an intrinsic adrenal defect.[143] Interestingly the sluggish response to dietary sodium restriction can be reproduced by ACE inhibition and blocking of the renin-angiotensin-aldosterone system (RAAS).[144] Tubular sensitivity to aldosterone infusion appears appropriate with increased sodium reabsorption noted, lending further support to an abnormal RAAS response as an important factor leading to delayed sodium conservation with aging.

Sodium Excretion

Tubular natriuretic capacity is also blunted with aging. This is seen with sodium loading or volume expansion in healthy elderly. [145] [146] A 2 liter saline load is excreted much slower with a greater amount excreted overnight in adults over 40 years of age than gender-, size-, and race-matched younger adults. [130] [147] This circadian variation in sodium excretion with older adults may add to the higher frequency of nocturia seen in this population.

Studies implicate a diminished response to atrial natriuretic peptide (ANP), an important factor in the control of sodium excretion. ANP via specific cell surface receptors on the renal microvasculature and tubular epithelium induces hyperfiltration, inhibits luminal membrane sodium channels and reabsorption, and suppresses renin release. Released from atrial myocytes in response to atrial stretch, ANP is rapidly degraded but serum half-life can be prolonged with selective blockade of degradative enzymes or clearance receptors.[148] Healthy older adults have elevated basal levels three to five times those of healthy young adults. [149] [150] Stimulation of ANP with increased salt load, head-out body water immersion leads to higher levels in older versus younger individuals.[151] Decreased salt intake results in similar ANP levels in old and young adults. This suggests intact ANP release with aging. However, higher basal levels may be a result of decreased metabolic clearance with aging. [152] [153] A decrease in GFR with aging may not be the etiology, given that patients with chronic kidney disease and low GFR do not have high ANP levels.[154] However, endopeptidases, degradative enzymes in the renal proximal brush border, which degrade ANP, may be decreased with aging. Rats with reduced renal mass when infused with endopeptidase inhibitors, phosphoramidon, have increased urinary cGMP (ANP second messenger) and urinary salt excretion.[155] Similarly renal endopeptidase inhibition by candoxatril in class II New York Heart Association congestive heart failure patients significantly increased ANP and cGMP levels as well as urinary sodium excretion without changes in renal hemodynamics.[156] Metabolic clearance of low level ANP infusate is decreased in older compared with younger subjects.[152]

Some investigators propose that higher ANP levels may be homeostatic to reduced renal sensitivity with aging. [145] [146] A blunted response to incremental increases in ANP infusion is seen with older adults who do not continue to increase urinary sodium beyond 2 ng/kg/min, whereas younger subjects have progressive increase in their urinary sodium excretion with increased ANP infusion ( Fig. 21-8 ).[145] Baseline cGMP and ANP second messenger levels may not change with age. Although cGMP[157] increases with low-dose ile-ANP administration, increased urinary sodium is not seen in older subjects.[152] This suggests a possible post-cGMP problem.

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FIGURE 21-8  Urinary sodium excretion (UnaV) with a low-salt diet (in basal condition and during infusion of atrial natriuretic factor (ANF)) and with a high-salt diet in young (group 1), middle age (group 2), and elderly (group 3) subjects. The columns represent means and the bars SE. °P < 0.05 versus other steps and low-salt diet, *P < 0.01 versus low-salt diet.  (Reprinted from Leosco D, Ferrara N, Landino P, et al: Effects of age on the role of atrial natriuretic factor in renal adaptation to physiologic variations of dietary salt intake. J Am Soc Nephrol 7:1045–1051, 1996.)

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Simultaneous measurements in plasma renin and aldosterone during ANP infusion notes that natriuretic properties of ANP is different from that of inhibiting sodium reabsorption via suppression of RAAS. Each property of ANP appears to be influenced differently by age. [145] [152]

Urinary Concentration

The ability to maximize urinary concentration is diminished with aging ( Fig. 21-9 ). [124] [158] Appropriate urinary concentration under hyperosmolar and water-deprived conditions depends on intact osmoreceptor and volume receptor sensitivity of arginine vasopressin (AVP) release in addition to an intact collecting tubule response to AVP under maximum medullary tonicity. With aging, a combination of processes appears to impair water conservation.

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FIGURE 21-9  Age-related changes in urine osmolality (A) and urine volume (B) after mild water restriction. Urine osmolality and volume in the water restricted rats were expressed s a percentage of the non dehydrated rats of each age group. Values are expressed as means ± SE (n=12; *P < 0.05 compared with 3-month-old rats, **P < 0.05 compared with 3-month-old and 10-month-old rats).  (Reprinted from Tian Y, Serino R, Verbalis JG: Downregulation of renal vasopressin V2 receptor and aquaporin-2 expression parallels age-associated defects in urine concentration. Am J Physiol Renal Physiol 287:F797–805, 2004.)

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Both volume pressure and osmotic stimulation of AVP release is intact in the elderly with osmoreceptor AVP sensitivity enhanced. [159] [160] Basal circulating AVP levels are also increased after 24 hours of water deprivation in older adults. [161] [162] Intrarenal resistance to AVP infusion in healthy older adults is suspected given that decreased concentrating capacity is not corrected with AVP infusion.[163] A medullary “washout” is suggested with increased medullary blood flow in the aged kidney, increased solute excretion and osmolar clearance as well as decreased urine osmolality in elderly healthy subjects deprived of water for 12 hours overnight.[124] Water diuresis in older adults demonstrates decreased sodium chloride transport in the ascending loop of Henle.[164] Studies in aged rats however suggest AVP resistance in the collecting tubules. Solute free water formation after 40 hours dehydration and exogenous AVP is normal; however, solute free water reabsorption is impaired. Solute content in the inner medulla is identical in young and older rats. This suggests intact ascending limb solute transport but diminished collecting tubule water transport.[165]

Investigation of collecting tubule response to AVP suggests no change in receptor number or affinity for AVP.[166] However, greater amounts of AVP are required to increase cAMP, which is decreased in older animals. [167] [168]Post receptor guanine nucleotide-binding protein (Gs) is also decreased in aging kidneys.[169] Stimulation of the G proteins with cholera toxin and using forskolin to stimulate adenylate cyclase at the level of the catalytic unit and G protein interaction resulted in significantly lower adenylate cyclase stimulation from older rabbit cortical collecting tubule (CCT).[170] Thus an inadequate AVP response in the CCT in aging may be located to the level of interaction of Gs catalytic subunit of adenylate cyclase.

Evaluation of collecting duct water channel activity in older rats is notable for decreased expression of aquaporin-2 (AQP-2)[158] ( Fig. 21-10 ) and aquaporin-3 (AQP-3) in medullary collecting duct of older rats compared to younger rats whereas papillary cAMP content was not different.[171] V2 mRNA abundance is also decreased in aged rats under baseline conditions despite equivalent plasma AVP concentration as in young rats.[158] Furthermore, V2 receptors on basolateral membranes in dehydrated older and younger rats have similar levels of downregulation.[172] This in part may explain the low water permeability in the inner medullary collecting duct and decreased urinary concentration seen with aging.

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FIGURE 21-10  Immunohistolocalization of AQP2 under baseline conditions. AQP2 staining in both the inner medulla (top) and cortex (bottom) is less intense in 24-month-old rats compared with 3-month-old F344BN rats. Staining of the apical membrane is specifically reduced by visual inspection, particularly in the inner medulla (original magnification ×400).  (Reprinted with permission from Tian Y, Serino R, Verbalis JG: Downregulation of renal vasopressin V2 receptor and aquaporin-2 expression parallels age-associated defects in urine concentration. Am J Physiol Renal Physiol 287:F797–805, 2004.)

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Decreased urea transporters, UT-A1 and UT-B-1, expres-sion is also seen in the renal medulla of older rats with decrease papillary osmolality whether food restricted on ad libitum diet.[173] Deamino-8-D arginine vasopressin (DDAVP) infusion improved papillary urea accumulation and improved urine osmolality and flow rates with up-regulation of urea transporters.[174] These data suggest another mechanism by which urinary concentration may be affected in aging kidneys.

Urinary Dilution

An impairment in urinary diluting capacity is seen with aging when older individuals undergo water diuresis.[175] The minimum osmolality reached in subjects older than 70 years is 92 mOsm/kgH2O compared with 52 mOsm/kgH2O in subjects younger than 40 years. Oral water loading of 20 ml/kg plus overnight fast from fluids in older versus younger adults results in free water clearance of 6.0 ± 0.6 ml/min in the elderly compared to 10.1 ± 0.8 ml/min in the young. Various factors including appropriate solute extraction, adequate AVP suppression must occur with the distally delivered filtered load. Although a decline in GFR may be contributing, solute free water clearance is decreased despite correction for GFR.[175] Other factors including appropriate AVP suppression or solute extraction (or both) in the ascending loop need further clarification.

Acid-Base Balance

Although homeostatic acid base balance is maintained in the elderly, acid loading reveals an impaired ability to excrete the acid load. Age-associated loss of renal mass and decrease in GFR may be contributing. Constant endogenous acid production from a steady-state acid diet leads to worsening of a low-grade metabolic acidosis with age. Changes in both blood pH and plasma HCO3 correlate with changes in GFR with age ( Fig. 21-11 ). A reciprocal increase in plasma chloride concentration as noted with early renal disease or renal tubular acidosis is seen.[176] Ammonia excretion appears to account for less of the total acid excretion in older adults than younger adults. With glutamine intake, ammonium excretion increased in equal amounts and with the same rapidity in both older and younger subjects.[177] However, ammonium loading in older patients resulted in reduced ammonium excretion with inability to reach minimal urinary pH despite correction for GFR[178] suggesting a possible intrinsic tubular defect. This is confirmed by animal studies of ammonium loading. Sodium-hydrogen exchanger activity, a major regulator of proximal tubular transport was similarly enhanced in young and aged rages. Phosphate transport was reduced to the same extent in both groups.[179] Thus impaired ammonium excretion may mediate the age-related renal impairment to metabolic acidosis.

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FIGURE 21-11  Relation between blood pH ((H+)b) and age (A), and between plasma bicarbonate concentration ((HCO3-)p) and age (B), in normal adult humans (n=64). Each data point represents the mean steady-state value in a subject eating a constant diet. Regression equations: (H+)b=0.045 × age + 37.2 (HCO3-)p=-0.038 × age + 26.0.  (Reprinted from Frassetto LA, Morris RC, Jr, Sebastian A: Effect of age on blood acid-base composition in adult humans: Role of age-related renal functional decline. Am J Physiol 271:F1114–1122, 1996.)

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The subtle degree of metabolic acidosis that exists in the elderly is not associated with laboratory abnormalities in serum bicarbonate or pH. However, bone demineralization and muscle wasting, complications of chronic metabolic acidosis, are common in the elderly. Increased protein intake increases endogenous acid production. Underlying metabolic acidosis regulated calcium and alkali mobilization from bone and inhibits renal calcium reabsorption. Acidosis-induced enhanced muscle breakdown is medicated by activation of an ATP-dependent ubiquitin and proteasome pathway.[180] In industrialized nations, increased protein intake in the elderly in conjunction with aging and impaired acid excretion, may be associated with negative calcium balance, osteoporosis, and increased incidence of fractures and muscle wasting despite eubicarbonatemia.[181] Studies in postmenopausal women have noted improved nitrogen and calcium balance with potassium bicarbonate supplementation.[182] Whether bicarbonate supplementation should be recommended as an intervention in the elderly to prevent complications of subtle acidosis remains to be determined.

Potassium Balance

Total body potassium decreases with advancing age and loss of muscle mass and is more pronounced in women than men. Plasma renin and aldosterone levels parallel this decrease.[183] As a result, a relative hypoaldosteronism predisposes the elderly to hyperkalemia. Potassium infusion results in a blunted aldosterone response in the elderly ( Fig. 21-12 ).[184] Potassium excretion on high potassium diet was less efficient in older rats. The rise in plasma potassium was also higher when KCL infusion was given. Bilateral nephrectomy and high k feeding along with KCL infusion, revealed inability of the older rats to decrease serum potassium. Sodium-potassium exchange pump (Na+-K+ ATPase) activity was decreased by 38% in the medulla of the older rats.[185] No effect of aging was noted with insulin-mediated potassium uptake in humans.[186] Exercise-mediated potassium increase in the elderly suggest an impaired β-adrenergic-induced increase in the adenylate cyclase system yielding a decreased activity of the Na+K+ ATPase pump in skeletal muscle.[187]

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FIGURE 21-12  Serum potassium and aldosterone levels before, during, and after infusion of potassium chloride (0.05 mEq/kg body weight over 45 minutes) in six healthy young and six healthy elderly men. Changes in serum potassium levels were similar, but elderly subjects have lower aldosterone responses (P < 0.005) by analysis of variance.  (Reprinted from Mulkerrin E, Epstein FH, Clark BA: Aldosterone responses to hyperkalemia in healthy elderly humans. J Am Soc Nephrol 6:1459–1462, 1995.)

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Defect in renal acidification and also of the RAAS in the elderly may contribute to the increased incidence of type 4 renal tubular acidosis (RTA) or syndrome of hyporeninemic hypoaldosteronism in this population. Given problems with chronic potassium adaptation with aging, medications inhibiting the RAAS including ACEIs, heparin, cyclosporine, tacrolimus, β-blockers, spirolactone, and NSAIDs can increase the risk of hyperkalemia in older adults. In addition, sodium channel blockers such as trimethoprim, pentamidine, amiloride, and triamterene can add to the underlying defects in potassium excretion in the elderly.

Calcium Balance

Calcium reabsorption in the renal tubules is unaffected with aging though calcium metabolism is impaired. Both reabsorption and excretion of calcium is appropriate in aged rats under conditions of either decreased or increased dietary calcium.[188] The absolute filtered load and proximal reabsorption of calcium per nephron is unaffected between young and aged rats.[189]

Intestinal calcium reabsorption is decreased with aging and correlates with decrease 1-a-hydroxlase activity, decreased 1.25-dihydroxy-cholecalciferol (1,25(OH)2D3), and increased basal parathyroid hormone (PTH) levels. The 1,25(OH)2D3—dependent calcium binding protein declines with age in parallel with the age-related drop in calcium absorption. [188] [190] PTH infusion stimulated less renal 1,25(OH)2D3 production in healthy elderly although final concentrations were not different between the older and younger groups. Urinary cAMP and fractional phosphorus excretion also increased similarly in both groups, suggesting that the renal response to PTH infusion is intact with aging.[191] However, calcium regulation of PTH release may be altered with aging shown by calcium gluconate infusion and sodium ethylenediamene tetraacetic acid (NaEDTA) infusion in relation to PTH response. Serum concentration of PTH reflects an increase in both the set point for calcium and the number of parathyroid cells. It is not clear if the G protein-coupled calcium-sensing receptor (CaSR), which alters the set point for PTH seen in primary and secondary uremic hyperparathyroidism, plays a role in the increase in the set point for PTH release seen with aging.[192]

Phosphate Balance

Metabolic balance and clearance studies in humans and rats reveal an age-related decrease in intrinsic capacity of renal tubules to reabsorb phosphate. [192] [193] Renal adaptation to a low phosphate diet is impaired with age. [95] [194]In addition, there is an age-related decrement in intestinal phosphate absorption. Maximum inorganic phosphate (Pi) transport capacity (TmPi) assessed in parathyroidectomized aged rats infused with graded levels of Pi shows a significant drop in TmPi with age. Parathyroid hormone infusion in these rats reveals an appropriate further drop in TmPi; however, the magnitude of the response decreased with age.[193]

A similar age-related impairment in phosphate transport has also been demonstrated in primary cultures of renal tubule cells from young and adult rats.[195] In agreement with the in vivo studies,[194] there is a decrease in maximum velocity of sodium-dependent phosphate transport (Na/Pi cotransport) and decreased ability to adapt to low-phosphate culture media in renal tubular cells cultured from old rats compared with young adult rats. This is accompanied by a decrease in type IIa Na/Pi cotransporter cortical mRNA level and apical brush border membrane protein abundance in aged rats.[196]

An additional factor that may play a role in the decrease in Na/Pi cotransport is the age-related increase in membrane cholesterol content.[197] In vitro cholesterol enrichment of isolated brush border membranes of young adult rats reproduces the age-related impairment in Vmax of Na/Pi cotransport activity.[197] Direct changes in opossum kidney cell cholesterol content appears to affect Na/Pi cotransport activity by changing expression of the apical membrane type II Na/Pi cotransport protein.[198] Thus changes in membrane cholesterol content with aging may play a role in phosphate transport.

The role of vitamin D (1,25(OH)2D3) metabolism with aging and its effect on intestinal phosphate transport must be considered given that vitamin D-deficient animals improve both renal and intestinal phosphate transport when given vitamin D replacement. [199] [200] [201] The changes in phosphate transport associated with vitamin D parallel significant changes in brush border membrane lipid composition and fluidity.[202] This suggests that 1,25(OH)2D3 may possibly act via lipid modulating effects on the aged to improve renal and intestinal transport of phosphate (and calcium).

Osmolar Disorders

Hyponatremia

Hyponatremia is a common finding in geriatric patients with the greatest prevalence in chronic care facilities. Enhanced osmotic AVP release and impaired diluting capacity predisposes the elderly to a higher incidence of hyponatremia.[203] The idiopathic form of syndrome of anti-diuretic hormone secretion can be easily found among many older ambulatory clinic patients.[204] Thiazide diuretic use in older adults further impairs an already present dilution defect and is implicated in 20% to 30% of the cases of hyponatremia.[205] Deficient prostaglandin synthesis with aging may increase thiazide susceptibility to hyponatremia as water diuresis is impaired with inhibition of prostaglandin synthesis.[205] Other common medications including sulfonylureas, chlorpropramide, tolbutamide, or NSAIDs potentiate peripheral AVP action and can be synergistic in decreasing water excretion. Medications that lead to a nonosmotic release of AVP or potentiation of AVP action on the renal tubules by medications can also worsen or exacerbate hyponatremia in the elderly and should be used carefully ( Table 21-2 ).


TABLE 21-2   -- Mechanisms by which Drugs Can Lead to Impaired Water Metabolism

Inhibit AVP Release

Inhibit Peripheral Action of AVP

Potentiate AVP Release

Potentiate Peripheral Action of AVP

Fluphenazine

Lithium

Nicotine

Tolbutamide

Haloperidol

Colchicine

Vincristine

Chlorpropamide

Promethazine

Vinblastine

Histamine

Nonsteroidal anti-inflammatory drugs

Morphine (low doses)

Demeclocycline

Morphine (high doses)

 

Alcohol

Glyburide

Epinephrine

 

Carbamazepine

Methoxyflurane

Cyclophosphamide

 

Norepinephrine

Acetohexamide

Angiotensin

 

Cisplatinum

Propoxyphene

Bradykinin

 

Clonidine

Loop diuretics

 

 

Glucocorticoids

 

 

 

 

AVP, arginine vasopressin.

 

 

 

Significant or acute hyponatremia frequently leads to a myriad of signs and symptoms including apathy, disorientation, lethargy, muscle cramps, anorexia, nausea, agitation, depressed tendon reflexes, pseudobulbar palsy, and seizures. This results from an osmotic shift of water from the extracellular to the intracellular space. Prompt recognition and appropriate initiation of therapy is necessary to avoid severe neurological sequelae including central pontine myelinolysis.

Hypernatremia

Susceptibility to hypernatremia is common for the elderly with impaired renal concentrating and sodium conserving ability. Thirst followed by fluid intake usually defends against hypernatremia and free water loss. However, the thirst mechanism is frequently decreased in the elderly. In addition, altered levels of consciousness or immobility often prevent geriatric patient's access to free water replacement. Significant hypernatremia can be lethal in some cases with mortality as high as 46% to 70%.[206] Acute increases in serum sodium concentrations more than 160 mEq/l is associated with a 75% mortality rate.

Medications that can cloud the sensorium (e.g., sedatives, tranquilizers) and inhibit thirst or further inhibit AVP action in the renal tubules such as lithium or demeclocycline should be given with caution. Use of osmotic diuretics, parenteral high protein or glucose feedings, and bowel cathartics must be monitored carefully. Geriatric patients with systemic illnesses, infections, dementia, fevers, or neurological disorders that impair AVP release are at high risk for dehydration and hypernatremia. Cellular dehydration can lead to severe obtundation, stupor, coma, seizures, and death. Therefore cautious review and monitoring of electrolytes and medications in older particularly debilitated patients is necessary.

AGING AND RENAL DISEASE

Acute Renal Failure

With aging, susceptibility to acute renal failure (ARF) is greater. Prospective studies note ARF to be 3.5 times more common over age 70 years.[207] Underlying prevalence of systemic diseases in older patients of atherosclerosis, hypertension, diabetes, heart failure, and malignancy precludes increased medical and surgical interventions further exacerbating common causes of ARF. Cholesterol embolization to the kidney, both spontaneous and post procedure, occurs more commonly in those with generalized atherosclerosis. Acute vasculitis and rapidly progressive glomerulonephritis can lead to significant morbidity and cannot be overlooked as the number of older adults increase.

Vomiting, diarrhea, overzealous use of diuretics, bleeding, medication, and/or sepsis- induced renal hypoperfusion or low cardiac output lead to 50% prevalence of pre-renal azotemia in the elderly. [207] [208] Impaired urinary concentra-tion, thirst, and sodium conservation likely contribute to greater susceptibility. In addition, impaired autoregulation, decreased RPF, and renal reserve make the aging kidney more vulnerable to acute changes in volume. Medications such as prostaglandin inhibitors (NSAIDs), angiotensin antagonists (ACEIs and ARBs), and α-adrenergic blockers frequently necessary for rheumatologic, cardiovascular, or genitourinary disorders in the elderly can further compromise renal vasoregulatory mechanisms. Careful volume management, drug discontinuation, and improvement in cardiac output often lead to renal recovery.

Although prerenal azotemia is frequently reversible, some instances can lead to acute tubular necrosis (ATN). Evolution to ATN is more common in older than younger patients (23% versus 15%, respectively).[209] Moreover traditional indices to distinguish prerenal process from other intrinsic renal etiologies such as fractional sodium excretion (FeNa) should be carefully interpreted in the elderly. Despite volume depletion, older patients may not have the capacity to conserve adequate tubular sodium to achieve a FeNa less than 1. Thus an elevated FeNa from preexisting tubular defects may be present despite underlying hypoperfusion.[210]

Surgical complications account for 30% of ARF in the elderly. Hypotension pre or post surgery, postoperative fluid losses from gastrointestinal drainage, dysarrhythmias, and myocardial infarction are common postsurgical complications leading to ARF in older patients.

Septic complications during hospitalization also account for one third of ARF prevalence in the elderly. Endotoxin-mediated renal vasoconstriction from gram negative sepsis increases susceptibility for ATN. Associated multi-organ failure or peri-operative sepsis increases catabolic demands, which carry a poor prognosis in the elderly. [211] [212] [213] Hemodynamic instability, along with the need for complicated nephrotoxic antibiotic regimens such as use of aminoglycosides or amphoteracin, can prolong renal dysfunction. Biochemical and tubular alterations with aging may enhance toxic effects of antibiotics. Age is a well-known risk factor for aminoglycoside-induced nephrotoxicity.[214] Thus, careful dosing and monitoring of antibiotics is necessary in the elderly. Bedside estimates of GFR using creatinine-based formulas may be helpful (see Table 21-1 ). Use of serum creatinine alone may be highly unreliable.

Various common infections such as staphylococci, streptococci, legionella, cytomegalovirus, human immunodeficiency virus, as well as common antibiotics, β-lactams, sulfonamides, and numerous other medications lead to interstitial inflammation and nephritis.[215] Activated macrophages during tubulointerstitial inflammation release degradative enzymes resulting in injury to intact basement membranes, which can hamper regeneration of tubular segments. Loss of functioning nephrons, with failure of the remaining nephrons to compensate, results in a fall in GFR.[215] An atypical presentation of acute interstitial nephritis can be seen with NSAIDs and angiotensin II antagonists presenting as nephrotic proteinuria only with or without pyuria. Renal biopsy lesions are of minimal change or membranous pathology with NSAIDs,[216] particularly propionic acid derivatives, and membranous lesions with the ACEI captopril.

Acute and prolonged vasoconstriction from radiocontrast infusion can significantly impair renal function in the elderly.[217] An acute reversible rise in serum creatinine within 1 to 4 days after contrast injection can be attributed to the contrast dye. The osmotic load delivered to the macula densa may trigger tubuloglomerular feedback with renin release and drop in GFR.[218]

Experimental studies in aging rodents indicated a greater propensity for ischemic and toxic ARF. [219] [220] Renal artery occlusion leads to a more severe decline and slower recovery of renal function in older versus younger rats.[221] [222] Changes in renal hemodynamics with aging rats may be more at play than underlying glomerulosclerosis. Older rats increase renal vascular resistance (RVR) with renal artery clamping to a greater extent than younger rats. Euvolemic men on a constant sodium diet also have increased RVR with blunted response to orthostatic change.[223] A predisposition to hypoxic renal injury in older adults is demonstrated by inability to improve medullary oxygenation with water diuresis as in younger adults.[224] Older cardiopulmonary bypass patients without acute renal failure also have greater excretion of kidney specific proteins (N-acetyl-b-glucosaminadase, alpha-1-microglobulin, glutathione transferase-pi (GST-pi), glutathione-alpha (GST-alpha)) as well as higher fractional sodium excretion post surgery to pre surgery in comparison to similar younger patients.[225] Oxygen free radicals can be generated during hemodynamically mediated ischemic ARF.[226] Infusion of a free radical scavenger, superoxide dismutase, markedly improves renal hemodynamics in ischemic aged rats ( Fig. 21-13 ).[221]

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FIGURE 21-13  Change in glomerular filtration rate (GFR) in aged (18-month-old) rats measured under basal conditions (CON) 1 day after acute renal failure (ARF); with super oxide dismutase infusion 1 day after ARF (ARF + SOD); and with pretreatment with L-arginine and ARF (ARF + ARG).  (Redrawn from Sabbatini M, Sansone G, Uccello F, et al: Functional versus structural changes in the pathophysiology of acute ischemic renal failure in aging rats. Kidney Int 45:1355–1361, 1994.)

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The role of nitric oxide (NO) in aging vasculature may have a pronounced role in maintaining renal perfusion. Intrarenal levels of NO and acetylcholine-induced vasodilation are reduced in aging rodent kidneys.[227] NO production from isolated conduit arteries also decreases with aging. [228] [229] [230] L-arginine, NO synthase substrate, levels are low in both aged rats and aging humans. [230] [231] However, gene expression regulating substrate synthesis does not appear to be affected with aging.[232] Urinary nitrate, nitrite and cGMP, a marker for NO production was lower in healthy aged subjects despite a fall in blood pressure while on a low sodium diet, suggesting age-dependent decrease in clearance.[233] It is possible that renal endothelial NO production is maximized in normal aging to maintain stable renal function. This may explain the blunted vasodilator response observed in the elderly. NO measurements in face of renal ischemia have yet to be done in humans.

L-arginine feeding prior to renal occlusion results in significant improvements in GFR and RPF with decreased RVR in older rats. When NOS inhibitor, L-NAME was given to these rats, these hemodynamic changes were abolished.[221] Whether higher protein intake affected these results is unclear as protein restricted aged rats maintain urinary excretion of nitrate and nitrite similar to controls.[58] L-arginine supplementation in drinking water of aged animals appears to limit structural changes in the aging glomerular basement membrane. [60] [61] Whether beneficial effects of low-protein diet on age-related glomerulosclerosis is in some way related to NO is not yet clear. Recent studies of ischemic acute renal failure in aged and young rats with suggest improved NO availability with increase in eNOS mRNA and protein in older animals via partial inhibition of RhoA protein activation, decreasing renal vasoconstriction and significantly attenuating ischemic lesions.[234]

NOS inhibitor, N (G), N (G′)-asymmetric dimethylarginine (ADMA) is significantly elevated in aged rats compared to younger control rats despite similar levels of L-arginine.[235] ADMA levels are also increased with age in humans.[236] Increased ADMA levels can then decrease NO synthesis in endothelial cells thus impairing endothelium-dependent vasodilation[235] predisposing the aged kidney to ischemia. High ADMA levels with increased RVR and decreased effective renal plasma flow are noted in healthy older adults in comparison to younger adults. Even greater ADMA levels are noted in hypertensive elderly suggesting that endogenous NOS inhibition may be important in decreased renal perfusion and increased blood pressure seen with aging.[237]

Biochemical and metabolic alterations of aging tubular cells may also make aged kidneys more prone to ischemic injury. Renal cortical slices of older rats exposed to anoxia have impaired uptake of paraaminohippurate and tetraethylammonium in comparison to younger rats.[220]

Atheroembolic renal disease can be a complication after intra-arterial cannulation in elderly with generalized atherosclerosis. Spontaneous cholesterol embolization may also occur[233]; however, cholesterol embolization is more common after manipulation of the arterial vasculature for radiographic or surgical intervention such as carotid, coronary, renal or abdominal angiography; aortic surgery; percutaneous transluminal angioplasty of coronary or renal arteries. Embolization of cholesterol plaques can also be triggered by the use of anticoagulants and or fibrinolytic agents.[238] Renal failure is frequently progressive and irreversible and not necessarily associated with other systemic symptoms findings of purpura, livido reticularis of the abdominal and lumbar wall and or lower extremities, Hollenhorst plaques with retinal ischemia, gastrointestinal bleeding, pancreatitis, myocardial infarc-tion, cerebral infarction, and distal ischemic necrosis of the toes. Laboratory clues of low complement, eosinophilia, and eosinophiluria may not necessarily be present. Therapy remains primarily supportive with necessary avoidance or clear procedural and or anticoagulation benefits and risks outlined.

Acute renal failure from urethral or ureteral obstruction can present with either complaints of dysuria, hesitancy, dribbling, incontinence, or as only a rise in blood urea nitrogen and serum creatinine. Prostatic hypertrophy, either benign or malignant, strictures, uroepithelial malignancies, pelvic tumors of the uterus or cervix can present commonly in the form of acute renal failure in the elderly.[239] Retroperitoneal fibrosis, metastatic tumors, and lymphomas may also result in ureteral obstruction and loss of renal function in the elderly. Medications such as anticholinergic agents, central nervous system inhibition leading to bladder detrusor muscle overactivity in elderly patients with cerebrovascular accident, Parkinson disease, and Alzheimer disease can lead to bladder outlet obstruction with subsequent renal failure. Similarly, detrusor underactivity from injury to nerves supplying the bladder or autonomic neuropathy as seen in diabetes or chronic alcoholism also leads to outlet bladder obstruction. Prolapse of pelvic structures in post menopausal women with atrophy of supporting tissues under low estrogen levels can also lead to obstructive nephropathy. Prolonged obstruction can result frequently in irreversible renal loss. Therefore prompt medication review and evaluation including post void residual, noncontrast renal imaging with ultrasonography, CT, or MRI scan with urologic evaluation for decompression may be necessary in older individuals presenting with acute renal failure.

Although older individuals face both greater risk[207] and require longer time to recover from acute renal failure,[240] age alone does not determine the survival of patients with acute renal failure and should not be used as a discriminating factor in therapeutic decisions concerning ARF. [211] [241] [242] Most of the older patients respond well to treatment of ARF with dialysis if necessary to alleviate uremic symptoms and complications of ARF such as volume overload, bleeding, disorientation, catabolic state, and electrolyte disturbances.

Renovascular Disease

Renovascular atherosclerotic disease leads to hypertension and progressive ischemic renal failure with ESRD in up to 15% of patients. Prevalence of renovascular disease over age 65 years is estimated at 6.8%.[243] Lesions in the renal arteries leading to stenosis, as well as complex intrarenal vascular lesions and atheromatous embolization represent the spectrum of this disease in the elderly.[244] New onset or sudden worsening of underlying hypertension or renal failure in those with generalized atherosclerosis should bring attention to this disease. An underlying angiographic stenosis in the renal arteries of 75% or greater usually leads to eventual occlusion with loss of GFR.[245]Azotemic patients with high-grade stenosis in a solitary kidney or unilateral renal artery occlusion and contralateral stenosis are at greatest risk for renal failure.[246] Bilateral renal artery stenosis is associated with a crude mortality of 45% at 5 years.[247]

Smoking is noted to be an independent risk factor and predictor in the progression of both macrovascular and microvascular renal disease and renal artery stenosis in the elderly.[248] In the Cardiovascular Health Study cohort, a multivariate “best fit” model adjusted for gender, race, weight, age, and baseline serum creatinine of nondiabetic patients >65 years suggests that the number of cigarettes smoked daily is independently associated with an increase in serum creatinine.[249] Smoking increases epinephrine and norepinephrine release in addition to interfering with both endothelial metabolism of prostacyclin, thromboxane A2 as well as vascular response to acetylcholine, NO, and endothelin-1 (ET-1). ET-1, a potent vasoconstrictor with mitogenic and atherogenic activity on vascular smooth muscle, may be important in mediating renal arteriolar thickening. ET-1 levels are increased in active smokers and the protein is up-regulated in healthy aging rodents. [250] [251]

Diagnosis of clinically significant renovascular disease involves a combination of both functional and radiological evaluations. An increase in serum creatinine with use of angiotensin II antagonists (ACEI or ARB) may provide a clinical clue to the presence of functional stenoses in bilateral renovascular disease or unilateral atherosclerotic stenosis in a solitary functional kidney.[252] Angiotensin II antagonism interferes with necessary efferent autoregulatory vasoconstriction, which maintains GFR despite decreased renal perfusion from renal artery stenosis. Renal scintigraphy with technetium 99m-labelled diethylenetriamine-pentacetic acid (99mTc-DTPA) or technetium-mercaptoacetythiglycine (99-Tc-Mag3) before and after ACEI administration can be useful to increase clinical suspicion for a significant functional unilateral renal artery stenosis. [253] [254] Duplex ultrasound scanning of renal arteries is used in some centers with reliability to provide both noninvasive imaging of stenoses and data on blood flow velocity to determine stenosis significance.[255] Recently imaging with magnetic resonance angiography is being used to visualize stenosis anatomy. CO2 angiography is also useful to evaluate anatomy in the presence of decreased GFR. Contrast angiography remains the gold standard with visualization of the renal and intrarenal vasculature because lesions in distal renal branches and microvasculature can also lead to hypertension and ischemic renal failure.[256]

Arterial manipulation of diffuse atherosclerotic vessels can lead to irreversible and often progressive renal failure that occurs 1 to 4 weeks after arterial manipulation and is often secondary to cholesterol embolization with or without systemic manifestations. Cholesterol crystals lodge in arteries with diameters of 100 mm to 200 mm or smaller, including glomerular tufts.[257] Biconvex clefts with surrounding inflammation are seen on renal biopsy as the lipid material dissolves during tissue fixation. Management is supportive with blood pressure control, avoidance of other nephrotoxic insults, and anticoagulation.

Percutaneous transluminal angioplasty (PTA) or surgical revascularization can be considered when technically feasible to preserve renal function and improve blood pressure control in patients with significant atherosclerotic renovascular disease. The presence of collateral circulation in some may protect renal parenchymal ischemia despite progressive occlusive disease.[258] Although reversibility of renal failure is noted with angioplasty or surgical revascularization (or both) of renal artery stenosis by some, a creatinine ≥2.5 mg/dL may predict poorer outcome including no improvement in blood pressure, need for dialysis, and death seen within months after a technically successful PTA. [259] [260] Lesions amenable to angioplasty are more commonly unilateral, nonostial, and technically feasible to approach. Repeat angioplasty may be necessary in at least 20% of patients. Surgical revascularization is recommended for ostial, bilateral lesions or those completely occluded. Predictors of poor outcome are initial serum creatinine ≥3.2 mg/dl, need for surgical repair, and high-grade unilateral stenosis. Bilateral renal artery repair and unchanged or improved post operative response are favorable outcomes after surgical repair.[261]

Acute Glomerulonephritis

Rapidly progressive glomerulonephritis (RPGN) generally characterizes acute glomerulonephritis in the elderly. A rapid decline in renal function associated with active nephritic urine sediment (hematuria, pyuria, red blood cell casts, and moderate to severe proteinuria) with histological findings of more than 50% glomerular crescents is seen. An immune pathogenesis is most likely though direct evidence may not be always be evident. RPGN immune histology can broadly be categorized into 3 types: type 1—presence of anti-glomerular antibodies; type 2—with granular immune deposits; type 3—with no immune deposits seen; however, circulating anti-neutrophilic cytoplasmic antibodies may be present. The latter two immune processes are more prevalent in the elderly. [262] [263] In a case series biopsy of 115 older patients, 19 patients were noted to have RPGN. Of these 19 patients, 9 patients had granular IgG deposits, 6 had no immune deposits found on histology, and 3 patients were noted to have antiglomerular basement membrane antibodies.[264] Other case series have suggested pauci-immune crescentic glomerulonephritis as the most common form of acute glomerulonephritis in adults over age 60 years presenting with acute renal failure. [265] [266] Renal prognosis of RPGN in the elderly is poor. Risks and benefits of treatment with pulse steroids, cyclophosphamide, and/or plasmapheresis must be individualized in the elderly given medication side effects.

Poststreptococcal diffuse proliferative glomerulonephritis usually occurs in association with streptococcal infections of the throat and skin. Incidence in patients older than 55 years is as high as 22.6%.[267] Supportive renal management is usually recommended with an expected generally favorable renal outcome.

Chronic Glomerulonephritis

Nephrotic proteinuria and nephrotic syndrome often lead to renal biopsy in the elderly. Both registry and collected case series data from different countries reveal idiopathic membranous nephropathy as the most common histological finding followed by minimal change pathology ( Table 21-3 ). [264] [268] [269] [270] [271] [272] [273] [274] [275] [276] [277] Nephrotic syndrome may coexist or precede a malignancy in the elderly in up to 20% of patients. The association between membranous lesions and malignancy is presumed to be mediated in part via immune response to tumor associated antigens.[278] Solid tumors of lung, colon, rectum, kidney, breast, and stomach have most commonly been associated with membranous lesions on biopsy. Minimal change pathology has also been associated with both Hodgkin and non-Hodgkin lymphoma in the elderly. A higher risk of renal failure, more severe proteinuria, and lower albumin level is also found in the elderly with minimal change than in younger patients.[279] Given a greater predisposition to underlying malignancy in the elderly, a thorough history, physical examination, and basic screening for underlying malignancy should be done in elderly presenting with nephrotic syndrome.


TABLE 21-3   -- Histologic Lesions in 545 Elderly Patients with Primary Nephrotic Syndrome

Authors

Minimal Change

Membranous Glomerulonephritis

Mesangial Proliferative Glomerulonephritis

Membranoproliferative Glomerulonephritis

Glomerulosclerosis

Chronic Glomerulonephritis

Fawcett et al., 1971

6

5

4

16

5

Huriet et al., 1975

4

2

6

Moorthy and Zimmerman, 1980

9

15

7

2

1

Ishimuto et al., 1981

1

6

2

7

Lustig et al., 1982

2

16

2

3

Zech et al., 1982

19

31

2

4

3

Kingswood et al., 1984

2

16

11

3

Murphy et al., 1987

2

2

2

Sato et al., 1987

7

30

12

7

1

Johnston et al., 1992

35

116

18

5

Ozono et al., 1994

6

26

8

Shin et al., 2001

14

27

8

6

1

Total

107 (19%)

292 (54%)

50 (9%)

48 (9%)

39 (7%)

9 (2%)

 

 

 

Prednisone therapy alone for membranous lesions did not affect the rate of renal function loss when compared younger patients; however, the incidence of chronic renal failure was greater in the elderly, possibly from a decreased functional reserve. Treatment with prednisone and cytotoxic agents may induce partial or complete remission; however, use of these agents in the elderly must be carefully and individually considered given risks of infection. Steroid use alone may have a more favorable response in elderly with minimal change disease. [280] [281]

Other common causes of nephrosis in the elderly include systemic amyloidosis both primary and secondary to paraproteinemic processes. Approximately 40% to 68% patients with primary amyloidosis present with paraproteinemia. Serum and urine electrophoresis should be checked in elderly presenting with unexplained nephrotic syndrome. Abnormal test findings should prompt a bone marrow biopsy to rule out multiple myeloma. Although abdominal fat pad aspiration examined with Congo red stain may be useful in some hands to diagnose primary amyloidosis, renal biopsy is often done to confirm in this diagnosis. Kidney biopsy specimens in older adults presenting with unexplained nephrotic syndrome should routinely be stained with Congo red and examined under electron microscopy for amyloid fibrils. Treatment with Melphalan and prednisone may delay the progression to ESRD.

A small percentage of elderly patients presenting with nephrotic syndrome have a generalized glomerulosclerosis on biopsy. Because filtration fraction is greater in the juxtamedullary glomeruli of the elderly, these may be more affected. Immunofluorescence staining is notable for IgM and third complement component, C3. This pathology is frequently seen as the end result of other glomerulopathies and secondary to advanced systemic diseases including hypertension, as hyperfiltration hastens the sclerotic process. Glomerular enlargement and segmental sclerosis may be adaptive. Interestingly, renal histology in healthy aging rats is similar to human glomerulosclerosis.

Chronic Renal Failure

Progression of underlying medical diseases common with increasing age frequently leads to chronic renal failure with aging. Approximately 6.6 million elderly people have GFR <60 ml/min/1.73 m2 per NHANES III data.[282] The presence of longstanding diabetes, hypertension, chronic glomerulonephritis, atherosclerotic ischemic renovascular disease, and obstructive uropathy are prevalent diagnoses associated with chronic renal failure in the elderly. Furthermore, the level of GFR is an independent risk for de novo cardiovascular disease and all-cause mortality in individuals over 65 years of age.[283] Decompensating medical illness can sometimes herald renal failure progression rather than frank uremia. Volume overload with symptoms of heart failure, gastrointestinal bleeding, hypertension, and gradual confusion can be presenting signs in older individuals approaching renal loss. Actual renal reserve may be underestimated by laboratory serum creatinine measurements given gradual loss of muscle mass in the elderly.

Renal Replacement Therapy

Age alone does not preclude renal replacement therapy. Elderly patients without other major organ dysfunction seem to adjust and tolerate dialysis fairly well. Approximately 55% of the current ESRD population is older than 60 years of age. [284] [285] [286] Although longevity is less than younger ESRD patients, life expectancy on dialysis for the older population is not significantly reduced. Octogenarians on hemodialysis are found to have 24-month median survival.[287] Older patients on shorter treatment schedules are more likely to die from increased risk for silent ischemia during hypotensive episodes, more common with shorter treatments. [288] [289] Chronic ambulatory peritoneal dialysis (CAPD) can be an alternative to hemodialysis particularly for those with hemodynamic instability on hemodialysis. [285] [290] Differences in the number of episodes of peritonitis, or type of organism, or likelihood of technique failure are not significant between younger and older patients. Catheter replacement is in fact less likely in the older than younger patients. [290] [291]

Neither dialysis mode, peritoneal nor hemodialysis, is clearly demonstrated to be superior to the other in the elderly. [292] [293] [294] Evaluation of CMS data suggest that older patients, particularly patients with diabetes may have lower relative risk of death on hemodialysis than peritoneal dialysis.[295] Dialysis modality should be individualized in the elderly taking into consideration underlying medical and psychosocial factors. Patients with widespread vascular disease or inability to maintain vascular access or those with hemodynamic instability during hemodialysis may benefit from peritoneal dialysis. Hemodialysis may be more appropriate for deconditioned patients or those with a precarious home situation that prevents adequate self care dialysis. Socialization during in-center hemodialysis may be important for lonely or depressed elderly patients. Co-morbidity of malnutrition, malignancy, infection, vascular disease, and withdrawal from dialysis contribute to ESRD mortality in the elderly.

Renal Transplantation

Medically eligible elderly patients can undergo successful renal transplantation. Age alone generally is not exclusion for renal transplantation in the elderly. [296] [297] Donor age is more significant in determining delayed graft function than recipient age ( Fig. 21-14 ).[4] Analytic decision models for quality-adjusted life expectancy for selected elderly patients younger than 70 years and with few co-morbidities project 1.1 years of life expectancy gain with transplantation.[298] Patients over 60 years of age matched for demographics and co-morbidities with anticipated 80% or more 5-year survival who have undergone rigorous pre-transplant screening have increased survival advantage over ESRD patients on dialysis. Preoperative 1-, 3-, and 5-year survival was 98%, 95%, and 90% respectively for elderly transplant patients compared to 92%, 62%, and 27% respectively for elderly dialysis patients.[299] Post-transplant 1-year patient survival and allograft survival rates are similar between young and elderly patients. Cardiovascular and infection related patient mortality is major reasons for allograft loss after transplantation in older individuals. [297] [300] Age seems to be an independent risk for infection-associated death in the elderly transplant patient.[301] Acute rejection episodes are also noted to be fewer in older individuals.[302] Thus mortality risk given biologic age and co-morbidities must be carefully considered when considering renal transplantation in the elderly.

000022

000519

FIGURE 21-14  Effect of donor age on delayed graft function (DGF) of first transplants (1996–2000).  (Reprinted from Cecka JM: The UNOS renal transplant registry. Clin Transpl:1–18, 2001.)

000519

 

 

Urinary Tract Infection

Urinary tract infection is quite common in the older population. Numerous factors contribute to increased prevalence. Altered bladder function, immune senescence and decreased defenses, changes in pelvic musculature, prostate size and concomitant illnesses such as cerebrovascular accident or dementia can lead to poor hygiene, impaired mobility, and neurogenic as well as obstructive bladder dysfunction. Lower prostatic secretions in elderly men predispose to lower urinary tract infections. Prostatic microcalculi can harbor bacteria and provide nidus for prostatic infections. Decreased estrogen levels in postmenopausal women change pH of vaginal secretions leading to vaginal colonization of bacteria and cystitis. Intravaginal estrogen may prevent recurrent urinary tract infection in these women.

Prevalence of asymptomatic bacteriuria can range from 20% in older men to 25% in both men and women living in extended care facilities. Thirty percent to 50% of older hospitalized patients also have bacteriuria. Creatinine clearance is decreased in older patients with bacteriuria compared with nonbacteriuric older individuals. Although the mechanism is not clear, chronic pyelonephritis and glomerulosclerosis may contribute. Underlying predisposing illness leading to chronic bacteriuria frequently leads to decreased survival as treatment for asymptomatic bacteriuria does not result in improved survival.[303] As treatment failure and relapse is high,[304] treatment for asymptomatic bacteriuria in the elderly is not necessary in the absence of renal or urologic abnormalities. Given the possibility of resistant bacterial strains, use of long-term suppressive antibiotic therapy must be determined.

Acquired Renal Cysts

Number of simple renal cysts increase with age. Incidental cysts are being detected with increased frequency as abdominal imaging procedures for other diagnostic purposes are done. Microdissection of the distal renal tubule in adults and those older than 50 years reveals greater ectasia, diverticula, and microscopic cysts in comparison to 20-year- olds. These findings morphologically lead to larger cysts with age. Postmortem studies reveal at lease one cyst in at least 50% of older patients. Sonographic evidence suggest a 22% prevalence for acquired cysts in subjects ≥70 years of age, with 0% prevalence in the 15- to 29-year age group.[305] Acquired cysts are usually painless, simple, and asymptomatic. With bleeding into the cyst, or cyst infection, there may be associated lumbar pain, hematuria. Associated renin-dependent hypertension can also be present. Cysts with smooth clear walls, fluid-filled without internal echoes, usually require no further follow-up. Cysts filled with debris and or internal echoes, thick walls, or occurring in association with a possible renal mass are considered to be complicated acquired cysts. Complicated cysts must be followed carefully with further investigation with cyst puncture, angiography, or surgical exploration as indicated.

Acknowledgments

The authors thank Masuma Hussain and the Library and Medical Media staff at the Dallas VA Medical Center with expert help with obtaining the references, creating the endnote library, and preparing the figures.

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