Aging and Kidney Disease






  • Chapter Outline



  • STRUCTURAL CHANGES IN THE AGING KIDNEY, 727




    • Gross, 727



    • Microscopic, 727



    • Biologic Mediators and Potential Modulators of Age-Related Renal Fibrosis, 728




  • FUNCTIONAL CHANGES IN THE AGING KIDNEY, 735




    • Renal Plasma Flow, 735



    • Glomerular Filtration Rate, 736



    • Sodium Conservation, 737



    • Sodium Excretion, 738



    • Urinary Concentration, 739



    • Urinary Dilution, 740



    • Acid-Base Balance, 740



    • Potassium Balance, 741



    • Calcium Balance, 741



    • Phosphate Balance, 742




  • RENAL DISEASE IN THE AGING KIDNEY, 742




    • Disorders of Osmoregulation, 742



    • Acute Kidney Injury, 742



    • Hypertension, 744



    • Renovascular Disease, 746



    • Glomerular Disease, 746



    • Chronic Kidney Disease, 747



    • Renal Replacement Therapy, 747



    • Renal Transplantation, 748



    • Urinary Tract Infection, 749



    • Renal Cysts, 750



Though the kidneys undergo change in structure and function with age, they are remarkable in maintaining the internal milieu unless renal reserve is challenged. Older kidneys adapt less well and recover more slowly after acute ischemic injury, infections, exposure to toxins, or immunologic processes, or in the presence of other organ dysfunction. For example, transplanted kidneys from older healthy donors are more prone to allograft dysfunction than younger donor kidneys. In addition, subtle changes in function with age are associated with greater cardiovascular mortality in older adults. With growing numbers of aging adults and increased longevity, a greater number of elderly are more likely to experience chronic kidney disease and progress to end-stage kidney disease (ESKD). Renal failure is present or develops in an estimated 30% of older hospitalized adults. Therefore a careful study of the changes in kidney structure, function, and its ability to adapt to the short- and long-term physiologic changes with age becomes relevant to avoid unwanted outcomes in aging individuals.




Structural Changes in the Aging Kidney


Gross


Renal mass, size, weight, and volume decrease with normal aging. Kidney weight is found to decrease by as much as 15% to 20% with age, to 180 to 200 g (both kidneys) in those 90 years of age in comparison to 245 to 290 g in young adults, according to both radiologic and postmortem findings. These changes appear to be age appropriate in conjunction with a concurrent loss in body surface area.


Microscopic


A gross decrease in kidney size and weight is accompanied by microscopic findings of glomerulosclerosis and tubulointerstitial fibrosis. A greater number of sclerotic glomeruli are present in donor kidney biopsy specimens from patients older than 55 years. Intervening insults and comorbid conditions hasten the gradual and progressive senescence of the renal vasculature, glomeruli, tubules, and interstitium. Hypertension worsens sclerotic changes in the renal arteries. An increase in fibrointimal and medial sclerosis is present in cortical arteries of humans at age 70. Interlobular and arcuate arteries of older donor kidneys demonstrate greater arteriolosclerosis than younger healthy donor kidneys. By age 70, ischemic changes, including lobulation of the glomerular tuft, increased mesangial volume, and capillary collapse and obliteration, are present in the cortical nephrons. Little cellular response is evident, with hyaline deposition in the residual glomeruli ( Figure 24.1 ). Peritubular capillary density is decreased, offering a reason for the lower concentrations of pro-angiogenic vascular endothelial growth factors and increased expression of anti-angiogenic thrombospondin in aging rats. Basement membrane thickening and wrinkling in both glomeruli and tubules along with changes in the renal vasculature lead to progressive reduction and simplification of vascular channels, shunting blood from afferent to efferent arterioles of the juxtamedullary glomeruli. Intact arteriolar vasa rectae continue to deliver adequate blood flow to the renal medulla.




Figure 24.1


Histologic features of renal senescence.

A, Arteriohyalinosis. B, Fibrous intimal thickening. C, Glomerulosclerosis. D, Tubular atrophy. E, Lipofuscin pigment. F, Interstitial fibrosis.

(Courtesy Dr. Marjan Afrouzian, Edmonton, Alberta, Canada.)


As glomeruli sclerose, tubular atrophy follows, with a decrease in size and number. Tubules atrophy to form distal diverticula that may lead to early renal cysts frequently seen in older kidneys. Debris and bacterial accumulation in these structures may account for the increased incidence of infection in aging individuals.


Animal studies indicate that tubulointerstitial fibrosis may precede the development of focal glomerulosclerosis and tubular atrophy. Morphometry in aging mice suggests greater tubulointerstitial fibrosis in males than females. Aging rodents with accelerated apoptosis demonstrate interstitial inflammation with fibroblast activation. Immunostaining showing adhesive proteins osteopontin and intracellular adhesion molecule-1 (ICAM-1) as well as deposition of collagen IV are associated with focal tubular proliferation, myofibroblast activation, and macrophage infiltration in aged rat kidneys. The trigger for inflammation leading to focal glomerulosclerosis and tubular atrophy may be altered endothelial nitric oxide synthase (eNOS) expression in the presence of peritubular atrophy. Increased collagen-1 protein accumulation with age correlates with the extent of interstitial fibrosis, highlighting perhaps the importance of collagen-1 in age-associated interstitial fibrosis. Further molecular probing of aged kidneys reveals increased levels of the cell cycle inhibitor p16INK4a with age, glomerulosclerosis, and interstitial fibrosis. Because glomerulosclerosis can result from podocyte damage and loss, various mechanisms—adrenergic activation, increased free cytosolic calcium, low nitric oxide bioavailability, elevated endothelin-1 levels, and increases in oxidative stress and telomere shortening—are pathogenic processes that lead to podocyte dysfunction with subsequent age-related glomerulosclerosis. Critical telomere shortening, a marker of replicative senescence, is evident in aging renal cortical tissue. Telomere DNA repeats shorten with each cell replication, acting as a mitotic clock. However stress may also induce premature structural changes and lead to early senescence.


Biologic Mediators and Potential Modulators of Age-Related Renal Fibrosis


The finding that nearly a third of healthy elderly have little functional decline in renal clearance with age while two thirds show a gradual decline of renal function prompts the need to understand the factors mediating and modulating fibrosis ( Figure 24.2 ). Kidneys of aging animals have demonstrated changes in both level and function of various mediators of fibrosis, such as angiotensin II (Ang II), transforming growth factor-β (TGF-β), nitric oxide (NO), advanced glycosylation end products (AGEs), oxidative stress, inflammation, and lipids. Similarly, factors and processes have been identified that oppose fibrosis, such as Klotho, vitamin D and its receptor, the farnesoid X receptor (FXR), and autophagy. These may be potential and feasible targets for modulating progressive sclerosis in aging.




Figure 24.2


Factors that increase and decrease age-related renal glomerulosclerosis and tubulointerstitial fibrosis. AMPK, Adenosine monophosphate–activated protein kinase; FXR, farnesoid X receptor; mTOR, mammalian target of rapamycin; TGF-β, transforming growth factor-β.


Angiotensin II


Effects of Ang II on filtration, growth modulation, oxidative stress, apoptosis, and extracellular matrix accumulation influence the rate of glomerulosclerosis and tubulointerstitial fibrosis in kidney aging. Intraglomerular hypertension with efferent vasoconstriction in aging glomeruli increases sclerosis. Angiotensin-converting enzyme (ACE) inhibition in aged rats decreases intrarenal vascular resistance and intracapillary protein leak as well as postprandial hyperfiltration. An overall decrease in glomerulosclerosis is also observed in aged mice treated with ACE inhibitors (ACEIs) in comparison with untreated age- and sex-matched mice. Although measured renin and angiotensin levels seem not to decrease with age, intrarenal downregulation of renin messenger RNA (mRNA) and ACE levels occur in aged rats.


Profibrotic effects of Ang II—inducing TGF-β to promote collagen IV, promoting influx of monocytes/macrophages, stimulating mRNA and protein expression of the chemokine RANTES (regulated on activation, normal T cell expressed and secreted) in endothelial cells, and also inducing transcription of the pro-inflammatory chemokine monocyte chemoattractant protein-1 (MCP-1) via NO inhibition—are significantly reduced with ACEI treatment. Use of enalapril in aged rats showed marked reduction in tubulointerstitial fibrosis and smooth muscle actin in comparison with rats either treated with nifedipine or untreated, independent of blood pressure control. Matrix accumulation via Ang II’s effect on plasminogen activator inhibitor-1 (PAI-1) was also decreased with angiotensin antagonists, as were vascular sclerosis and collagen content. Ang II antagonists were found to prevent increases in age-related mitochondrial oxidants and dysfunction in aged rats. Furthermore, mouse Klotho gene transfer to Sprague-Dawley rats ameliorated Ang II–mediated renal damage.


Renal protective effects of ACEI and angiotensin receptor blockers (ARBs) in aging kidneys are mediated by many complementary mechanisms, including prevention of age-related increases in oxidative stress and glycation end products, and decreases in eNOS and Klotho. Furthermore, disruption of type 1 angiotensin II receptor (AT1R) in mice increases longevity and prevents cardiovascular and renal pathology mediated in part via increased oxidative stress and increased mitochondrial upregulation of survival genes nicotinamide phosphoribosyltransferase (Nampt) and Sirtuin 3 (Sirt3) in the kidney. Angiotensin II, via its diverse AT 1A receptor signaling pathways in the kidney and cardiovascular system, appears to play a crucial role in kidney aging, although data specific to humans have yet to be generated.


Transforming Growth Factor-β


TGF-β, an active modulator of tissue repair, is associated with age-related renal scarring. Gradual renal fibrosis with age likely results from normal and/or pathologic wound healing with tissue repair after injury. Persistent or repeated renal injury or insult may hasten tissue fibrosis. Various factors can stimulate TGF-β, including Ang II, abnormal glucose metabolism, platelet-derived growth factors (PDGFs), hypoxia, oxidative stress, mesangial stretch, and high AGE levels. TGF-β promotes gene transcription with matrix protein production and accumulation of collagens III, IV, and I, fibronectin, tenascin, osteonectin, osteopontin, thrombospondin, and matrix glycosaminoglycans, with subsequent glomerulosclerosis and tubulointerstitial fibrosis. Haplotype association mapping of genetic loci of chromosome 6 in aged mice reveals increased expression of Far2 in those mice that have increased mesangial matrix expansion. Overexpression of Far2 in mice mesangial cells leads to upregulation of PDGF and TGF-β. The renal interstitium in aged rats has increased TGF-β mRNA. Signaling by TGF-β and the protein SMAD3 adds to microRNA 21 (miR-21) production. Renal fibrosis secondary to injury depends on miR-21. MicroRNA-21 content is noted to be increased in the renal cortex of older mice than in that of both young and middle-aged mice, suggesting that age-specific regulation of matrix protein synthesis involves matrix protein–specific transcription and posttranscription mechanisms ( Figure 24.3 ). Angiotensin II inhibition downregulates TGF-β, resulting in decreased interstitial fibrosis. Although increased TGF-β expression may contribute in part to age-related sclerosis, direct evidence to implicate TGF-β needs further investigation. Decorin antisense oligonucleotides inhibit TGF-β expression and function and may provide better understanding of the role TGF-β plays in age-related sclerosis. The peptide hormone relaxin, produced by the prostate and the pregnant ovary, has antifibrotic properties. Use of relaxin in relaxin-deficient 12-month male knockout mice improved established interstitial fibrosis, glomerulosclerosis, and cortical thickening, with a decrease in collagen content via direct action on TGF-β–stimulated fibroblasts to decrease collagen I and III. Relaxin, via its primary receptor, RXFP1, and NO pathway, inhibits Smad2 phosphorylation. Smad2 inhibition prevents TGF-β signaling, which is responsible for myofibroblast differentiation as well as collagen and fibronectin production, thereby regulating matrix synthesis. Studies in relaxin knockout mice indicate that relaxin and castration may decrease the renal fibrosis seen with age.




Figure 24.3


Suggested pathway of microRNA’s effect on matrix protein and expansion in aged mice, including the products of genes Sprouty, Smad3, and ZEB2 . Col, Collagen; miR, micro-RNA; mRNA, messenger RNA;TGF-β, transforming growth factor-β.

(From Wolf G: Link between angiotensin II and TGF-beta in the kidney . Miner Electrolyte Metab . 24:174-180, 1998.)


Nitric Oxide


Although nitric oxide is found to moderate fibrosis, low NO levels in the aging renal vasculature is thought to mediate renal fibrosis with age. Vascular reactivity is an immediate response to nitric oxide, but its paracrine effects—to decrease fibrosis by inhibiting the nuclear factor κ light chain enhancer of activated B cells (NF-κB) family of transcription factors—can be important for the aging kidney. NF-κB promotes monocyte/macrophage influx in the presence of reactive oxygen species (ROS), with progression to injury and inflammation. Aging vessels have lower levels of NO. Oxidation stress also induces nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase)–mediated NO scavenging and NO depletion in aged kidneys. Peritubular capillaries of aged rats express less eNOS, a change that can lead to chronic tubulointerstitial ischemia and fibrosis. Treatment with dietary l -arginine supplementation in older rats improves renal plasma flow (RPF) and glomerular filtration (GFR) and decreases proteinuria and glomerulosclerosis. l -arginine supplementation also reduces kidney collagen and Nε-(carboxymethyl)lysine accumulation. Hypoxia, oxidative stress, increased dietary protein intake, insulin resistance, as well as increased angiotensin II activity are factors thought to decrease eNOS with age, so that use of angiotensin inhibitors and or dietary protein restriction seem to increase and normalize urinary NO excretion. Lower eNOS levels in males than in females are also thought to be the reason behind the sexual dimorphism seen in the aging kidney. Lower glomerular arginine transport is noted in male than in female rodents. Changes in estrogen and androgen activity may in part mediate the sex-dependent effects.


With aging, there is a noted decrease in eNOS phosphorylation and activity in endothelial cells from human umbilical veins. The eNOS phosphorylation induced at serine 1177 by Akt (protein kinase B) is critical in regulation of eNOS activity. Age-related decreases in eNOS activity are reversed by inhibition of (1) oxidative stress with use of α-lipoic acid, (2) the generation of ceramide levels, or (3) arginase. Studies examining endothelial cells from brachial arteries and peripheral veins from subjects with vascular endothelial dysfunction suggest that increased endothelin-1 activity and not decreased eNOS activity is more to blame for endothelial dysfunction with age.


Advanced Glycosylation End Products


Cross-links between proteins, lipids, and nucleic acids (AGEs) accumulate over time with age to produce vascular and tissue damage. Hyperglycemia accelerates the rate of end product accumulation and tissue damage. Glycated proteins decrease vascular elasticity, induce endothelial cell permeability, and increase monocyte chemotactic activity via AGE–receptor ligand binding, which stimulates activation of macrophages and secretion of cytokines and growth factors. Disturbance of NO-induced vascular endothelial vasodilation, thought to be secondary to chemical inactivation of endothelium-relaxing factor, occurs with endothelial and basement membrane AGE deposition. Diabetic patients display perturbations of the vascular endothelium similar to those in persons with age-related vasculopathy. Older animal kidneys demonstrate increased AGE and AGE receptor (RAGE) levels. Accumulation of AGEs in the kidney increases mesangial matrix, basement membrane thickening, and vascular permeability and induces PDGF and TGF-β, leading to glomerulosclerosis and tubulointerstitial fibrosis. Gradual age-related GFR loss—in addition to an increase in oxidative stress that modifies glycated proteins, as well as accumulation of N ε-(carboxymethyl)lysine—contributes to increased AGE and RAGE in aged kidneys. Furthermore, abnormal glucose metabolism with age-related insulin resistance adds to protein glycation. Lifelong consumption of AGE-enriched foods as well as smoking also increase AGE load and tissue accumulation.


The mesangial AGE receptor 1 (AGER1) has been shown to counter the proinflammatory mesangial cell response to AGE accumulation. Supersaturation and possible receptor downregulation under increased AGE burden may prevent AGER1 control. Studies in embryonic kidney cells indicate that AGER1 counteracts AGE-induced cellular oxidant stress via prevention of p66shc-dependent FKHRL1 phosphorylation, thus inactivating FKHRL1 and MnSOD suppression. P66shc knockout mice are protected against oxidative stress and oxidant-dependent injury, highlighting the importance of this pathway. AGER1 provides protection also against AGE-induced generation of ROS via NADPH. Mice eating low-AGE diet over time have lower RAGE and higher AGER1 levels ( Figure 24.4 ) and demonstrate less glomerulosclerosis and proteinuria ( Figure 24.5 ). Interestingly, AGER1 is suppressed in human subjects with chronic kidney disease. However, dietary decrease in AGE restores AGER1 levels.




Figure 24.4


Effect of a low-glycotoxin diet on levels of the advanced glycosylation end-product receptors AGER1 and RAGE.

Levels of the proteins AGER1 ( A ) and RAGE ( B ) were assessed in spleen tissues from mice consuming either a diet with normal high levels of advanced glycation end products (AGEs) (Reg AGE ) or a low-AGE diet (Low AGE ) ( n = 6 per group) at 4 and 24 months. AGER1 expression ( C ) in kidney and liver and RAGE expression ( D ) in kidney and liver of the same mouse groups were also assessed at 24 months by Western blotting and densitometric analysis. Data are shown as mean ± standard error for three independent experiments. *Statistically significant difference compared with 4-month Reg AGE at the P < 0.01 level. § Statistically significant difference compared with 24-month Reg AGE at the P < 0.01 level.

(From Cai W, et al: Reduced oxidant stress and extended lifespan in mice exposed to a low glycotoxin diet: association with increased AGER1 expression, Am J Pathol 170[6]:1893-1902, 2007.)



Figure 24.5


Effect of a low-glycotoxin diet on glomeruli and renal function in mice.

Morphology of renal cortex ( A ) with consumption of a diet containing normal high levels of advanced glycosylation end products (AGEs) (Reg AGE ), and ( B ) after consumption of a low-AGE diet (Low AGE ) ( n = 6 per group). (Periodic acid–Schiff stain, original magnification ×200.) C, Fractional mesangial volume (* P < 0.05) in Reg AGE versus Low AGE mice. D, Transforming growth factor-β (TGF-β) levels (* P < 0.05). E, Collagen type IV (Coll IV) messenger RNA (mRNA) levels (* P < 0.05). F, Albumin-to-creatinine ratio (* P < 0.05). Data are shown as mean ± standard error of triplicate values.

(From Cai W, et al: Reduced oxidant stress and extended lifespan in mice exposed to a low glycotoxin diet: association with increased AGER1 expression. Am J Pathol 170:1893-1902, 2007.)


Results of aminoguanidine treatment and calorie restriction in aged animals suggest some possible treatment options for AGE-mediated aging and sclerosis. Prolonged aminoguanidine treatment of aged rats and rabbits caused decreases in proteinuria and glomerulosclerosis in addition to age-related arterial stiffening and cardiac hypertrophy. Furthermore, AGE-associated changes in vascular permeability and abnormal vasodilatory responses to acetylcholine and nitroglycerin reversed with aminoguanidine treatment. Mononuclear cell activity was also prevented in aminoguanidine-treated animals. Similarly, 60% calorie restriction (CR) of the ad libitum diet of control rats decreased AGE burden with lowering of other glycated proteins, including Nε-(carboxymethyl)lysine and pentosidine, and increases life span. Even a 30% calorie restriction in comparison with control diet produced a decrease in AGE accumulation in the renal glomeruli and abdominal aorta. Therefore measures that can decrease AGE burden in aging individuals may be important in slowing age-related renal disease.


Oxidative Stress


Free radical generation and/or antioxidant enzyme deficiency leads to lipid peroxidation and oxidative stress, inducing tissue injury that can be seen with aging. High levels of oxidized amino acids in the urine of older rats signify higher levels of oxidized skeletal muscle proteins. Both thiobarbituric acid–reactive substances and levels of ROS are higher in aged kidneys and are associated with lipid peroxidative damage. Isoprostanes, AGE, and RAGE as well as heme oxygenase, other markers of oxidative stress, and lipid peroxidation are also increased in aged rats. Klotho gene expression in the distal inner medullary collecting duct (IMCD3) is reduced with oxidative stress in mouse cells, implying other possible reasons for renal aging. Use of a diet enriched in the antioxidant vitamin E in aged rats lowers markers of oxidative stress, decreases glomerulosclerosis, and improves RPF and GFR. ACEI use increases antioxidant enzyme activity and blocks TGF-β induction by ROS. Antioxidant taurine also blocks ROS in cultured mesangial cells. Tempol, a superoxide scavenger, restored the ability of ARBs to suppress oxygen consumption mediated via NO in renal cortical tissue. These findings suggest angiotensin antagonists and antioxidants as possible therapeutic options to decrease age-related renal scarring.


Calorie restriction also reduces age-related oxidative stress, suppressing activation of mitogen-activated protein kinase cellular signaling pathways. Calorie restriction also decreases mitochondrial lipid peroxidation and membrane damage with concomitant decrease in apoptosis. Thus dietary discrimination may be important in preventing age-associated renal sclerosis. Mitochondrial generation of ROS may also be contributing to age-associated diseases. In several genetic mouse models of longevity, including Ames and Snell dwarf mice, p66sch knockout mice, and mice heterozygous for insulin-like growth factor receptor, longer life span correlates with increased resistance to oxidative stress. Under-expression and over-expression of genes encoding for antioxidant enzymes show that superoxide dismutase 1 (copper-zinc superoxide dismutase or SOD1) knockout mice had decreased life span and greater oxidative stress. However transgenic SOD1 mice did not have a longer life span. Effects of superoxide dismutase deletion or over-expression in age-related renal disease continue to be of interest, given the possible therapeutic targets.


Calorie Restriction: Sirtuins, Adenosine Monophosphate–Activated Protein Kinase, Mammalian Target of Rapamycin, and Ribosomal Protein S6 Kinase 1A


Reducing calorie intake by 25% to 45% while maintaining intake of all essential nutrients increases longevity in many rodent strains as well as in fruit flies, worms, and yeasts. In addition, disease related to older age, including insulin resistance, atherosclerosis, oxidative damage, and immune dysfunction, are also decreased in calorie-restricted rhesus monkeys. Furthermore, mortality is decreased in these monkeys as the incidence of diabetes, cancer, cardiovascular disease, and brain atrophy lessens. A similar benefit is seen in human health, although the effect of longevity is yet to be reported. Rats and mice have also shown a decrease in age-related proteinuria and glomerulosclerosis with calorie restriction.


The potential mechanisms and proposed benefits of calorie restriction are numerous, including reduced body fat content, decreased metabolic rate, attenuation of oxidative stress and inflammation, modulation of mitochondrial function, and increases in sirtuin activity, and adenosine monophosphate (AMP)–activated protein kinase (AMPK) signaling, and decreases in mTOR (mammalian target of rapamycin) and S6K1 (ribosomal protein S6 kinase 1) signaling. Sir2 (silent information regulator 2), first identified in yeast, mediates nicotinamide adenine dinucleotide (NAD)–dependent histone deacetylase enzyme activity. At least seven mammalian homologs have been identified, sirtuins SIRT1 through SIRT7. Present in different subcellular compartments, these enzymes cause histone deacetylation, thereby controlling activity of various proteins and genes regulating cell survival, differentiation, and metabolism, DNA repair, inflammation, and longevity. Calorie restriction seems to increase SIRT1 activity in most tissues, including kidneys. Further support is seen in SIRT1 knockout mouse, which show resistance to effects of calorie restriction ; in contrast, SIRT1 transgenic mice show a phenotype similar to that of mice given a calorie-restricted diet. Mice treated with resveratrol, a synthetic activator of SIRT1, behave similarly to calorie-restricted mice, including being protected against age-related renal disease. Calorie restriction also increases SIRT1-induced FOXO3 (forkhead Box3) deacetylation, resulting in increases in Bnip3 (BCL2/adenovirus E1B 19 kDa protein–interacting protein3) and mitochondrial autophagy as well as prevention of age-dependent decreases in kidney function. Sirtuins thus have diverse physiologic functions extending beyond their important role in the process of aging.


A complex regulation of metabolic pathways in response to calorie restriction integrates the effects of the restriction on insulin release, AMPK, SIRT1, and FOXO activation as well as mTOR inhibition. Exercise and fasting have similar metabolic effects, regulating AMPK, SIRT1, peroxisome proliferator–activated receptor γ coactivator 1α (PGC-1α), and FOXO activity. Because aging is associated with decreased SIRT1 activity secondary to decreased systemic NAD + synthesis as well as reduced AMPK activity and mitochondrial biogenesis, these findings are very important. Thus activation of SIRT1 and AMPK activity holds promise for the prevention of age-related metabolic defects and disease.


In addition, SIRT1 deacetylates and positively regulates the oxysterol-activated nuclear receptor LXR (liver X receptor), which plays an important role in mediating reverse cholesterol efflux and inhibiting inflammation, adding further complexity to metabolic regulation. SIRT1 also deacetylates the bile acid–activated nuclear receptor FXR (farnesoid X receptor), a bile acid activated nuclear hormone receptor that plays an important role in inhibiting fatty acid synthesis mediated by sterol regulatory element binding protein-1 (SREBP-1) and also inflammation, oxidative stress, and fibrosis. Although the effects of LXR on renal disease and aging remain to be determined, LXR activation prevents progression of diabetic kidney disease. Activation of FXR using both natural and synthetic bile acid analogs modulates lipid metabolism, preventing development and progression of proteinuria in mouse models of type 2 diabetes mellitus, diet-induced obesity, and insulin resistance. Whether FXR agonists would have similar effects on aged rodent and human kidneys needs to be determined.


Studies also suggest potential important roles for mTOR and S6K1 in regulating mammalian life span. Treatment with rapamycin, an mTOR inhibitor, of older male and female mice extended their life span. In fact, long-lived Ames dwarf mice have reduced mTOR signaling. Mechanistic studies in yeast indicate that deletion or inhibition of TOR upregulates mitochondrial gene expression and prevents cellular accumulation of ROS. Deletion of S6K1, a component of the nutrient-responsive mTOR signaling pathway, results in longer life span and reductions in resistance to insulin and to diverse age-related pathologies. Intriguingly, S6K1-induced gene expression patterns are similar to those seen with calorie restriction and activation of AMPK.


Lipid Metabolism


Various studies have found altered expression of a number of transcriptional factors and nuclear hormone receptors regulating lipid metabolism in both chronic kidney disease (CKD) and aging. , Expression of both SREBP-1 and SREBP-2 is increased in the liver and adipose tissue of animal models of CKD. As master regulators of fatty acid, triglyceride, and cholesterol synthesis, these transcription factors are associated with increased serum lipid levels and insulin resistance. In addition, decreased peroxisome proliferator–activated receptor-α (PPARα) results in impaired fatty acid oxidation. These changes mimic those seen in kidneys of animals with nephritic syndrome and with aging.


Activity and expression of FXR are also decreased in livers of aging mice. FXR plays an important role in regulation of bile acid, fatty acid, cholesterol, and glucose metabolism in the liver and kidney. Decreased FXR activity may mediate increased SREBP-1 activity and decreased PPARα expression and activity in aging. Calorie restriction can prevent age-related changes in metabolic function, and studies indicate that it also prevents age-related increases in SREBP-1 expression and decreases in PPARα.


The expression of SIRT1 is increased with calorie restriction. Sirtuin analogs seem to replicate several beneficial effects of such restriction, including adipogenesis, insulin sensitivity and signaling, and lipid metabolism. Likewise, SIRT1 transgenic mice show phenotypes resembling the phenotype found in mice given calorie-restricted diets.


Experimental data in animals and observational data in humans suggest that dyslipidemia adds to the burden of disease progression in those with kidney disease. Low high-density lipoprotein (HDL) cholesterol levels in aging adults appear to be associated with a greater decline in GFR. This finding suggests that lipid lowering may be beneficial in those with CKD. Post hoc subgroup analysis of several prospective trials showed that subjects given 3-hydroxy-3 methylglutaryl-coenzyme A reductase (HMG-CoA) inhibitors (statins) had slower decrease in renal function and proteinuria than subjects not given statins. Pooled data from 3402 patients with CKD stage 3 from three large randomized double-blind trials comparing pravastatin 40 mg/day with placebo showed a 34% reduction in the slope of estimated GFR (eGFR), based on the Modification of Diet in Renal Disease (MDRD) study equation, with an absolute reduction of 0.22 mL/min/1.73 m 2 per year (95% confidence interval [CI] 0.07 to 0.37) in patients using statins in comparison with those given placebo. Meta-analysis of other randomized trials also noted a slower decline, by 1.2 mL/min/1.73 m 2 per year, and lower protein excretion in statin-treated subjects in comparison with subjects given placebo. Post hoc analysis in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, which involved 4719 patients with 5-year follow-up, showed that of the 1600 patients who had eGFR levels lower than 60 mL/min and mean age of 68 years, those who were randomly assigned to receive 80 mg daily of atorvastatin had an increase in eGFR of 3.46 ± 0.33 mL/min, compared with 1.42 ± 0.34 mL/min in the placebo group, independent of baseline function. A decrease in protein excretion has not been seen in all trials with statins. Favorable effects of statins on protein excretion were noted on meta-analysis when protein excretion was greater than 30 mg/day. However, statins might also exert their beneficial effects by suppressing inflammation and improving endothelial function and vessel stiffness. In the substudy of the Lescol Intervention Prevention Study, creatinine clearance as calculated with the Cockcroft-Gault equation remained stable for both fluvastatin-treated and placebo groups regardless of baseline renal function. Comparison of serum creatinine levels at baseline and end of treatment for pooled data of 10,000 patients using rosuvastatin (5-40 mg) in comparison with those using other statins and those receiving placebo for mean of 8 weeks showed no change in serum creatinine in either statin-treated or the placebo group. However, for those patients who continued to take rosuvastatin over 96 weeks, MDRD-estimated GFR either remained unchanged or increased but did not decrease from baseline. Post hoc analysis and meta-analysis randomized studies using statins on primary cardiovascular outcomes suggest either stability of GFR or possible improvement in renal function and/or proteinuria with treatment, but there are no primary prevention trials examining the effect of statins on the outcome of renal function in the elderly. Therefore, with no clear-cut evidence of the effectiveness of statins for primary renoprotection, use of these agents for renoprotection alone in the elderly remains premature.


Bile Acid Metabolism and the Farnesoid X Receptor


Studies in a long-lived dwarf mutant mouse, the little mouse ( Ghrhr lit/lit ), which does not secrete growth hormone (GH) and therefore has very low circulating levels of GH and insulin-like growth factor-1 (IGF-1), have identified a potential role for alterations in xenobiotic metabolism mediated by FXR in association with longevity in these mice. A possible role for bile acids as endocrine regulators of aging has also been found in Caenorhabditis elegans, in which bile acid–like steroids influence life span via the DAF-12 nuclear receptor. Although the age-related renal pathology in long-lived dwarf mutant mice has not been well studied, research involving diet-induced obesity in diabetic mice treated with FXR agonists indicates that these agents decrease proteinuria and glomerulosclerosis by modulating renal lipid metabolism, oxidative stress, inflammation, and fibrosis. Whether FXR can also modulate age-related renal disease remains to be determined.


Klotho


The Klotho gene can be identified as an “aging gene” that has multiple effects regulating the aging process, mineral metabolism, and other endocrine functions. Mice with defects in Klotho gene expression exhibit multiple aging-like phenotypes and die prematurely, whereas transgenic mice that overexpress the Klotho gene live longer than wild-type mice. The mechanisms of the anti-aging effects of Klotho are still being determined, but potential mechanisms include effects on antioxidative stress as well as modulation of insulin and IGF-1 signaling processes. Klotho is strongly expressed in the kidney and plays an important role in the regulation of fibroblast growth factor 23 signaling, phosphate transport activity, TRPV5 (transient receptor potential cation channel subfamily V member 5) activity, and ROMK1 (regulation of Kir 1.1 potassium channel) activity. Specific deletion of Klotho in the mouse kidney resulted in a phenotype similar to that observed in Klotho knockout mice, suggesting that the kidney may be a primary organ for Klotho ‘s effects. Studies suggest that Klotho protein may endogenously block Wnt/β-catenin signaling, which promotes fibrogenesis. Secreted Klotho suppressed myofibroblast activation, reduced matrix expression, and ameliorated renal fibrosis. Klotho inhibited expression of its target genes in tubular epithelial cells in addition to blocking Wnt-triggered activation and nuclear translocation of β-catenin. TGF-β 1 suppresses Klotho expression, with concomitant β-catenin activation; however, Klotho overexpression abrogates the fibrogenic effects of TGF-β1. Further, in vivo expression of secreted Klotho in both Adriamycin and ureteral obstruction mouse models of CKD inhibited the activation of renal β-catenin and expression of its target genes. Thus because Klotho is an antagonist of endogenous Wnt/β-catenin activity, its loss may contribute to kidney injury by removing the repression of pathogenic Wnt/β-catenin signaling.


Other studies also indicate that renal actions of Ang II are mediated via modulation of renal Klotho expression. In addition, the effects of the PPARγ agonists, including their beneficial effects in age-related renal disease, are mediated by regulation of intrarenal Klotho expression.


Autophagy


Phagolysosomal degradation of cytosolic debris, including organelles and proteins, known as autophagy, is noted to decrease with age. Accumulation of cellular waste leads to progressive cellular aging as seen from altered mitochondrial morphology and accumulation of age-related proteins such as SQSTM1 in kidneys of aging rats and mice. Renal tubular epithelial cells and podocytes process a high filtrate burden and therefore have an abundance of cellular cytoplasmic organelles, including mitochondria and endoplasmic reticulum, that are reprocessed via autophagy to maintain cellular integrity and conserve nutrient and energy. How this process prevents aging in podocytes and proximal tubular cells is becoming evident. Gene deletion of Atg5 gene in podocytes results in damaged mitochondrial debris and ubiquinated proteins in podocytes, leading to age-dependent albuminuria and glomerulosclerosis. Similarly Atg5 gene deletion in proximal renal tubular cells leads to accumulation of damaged mitochondria, ubiquinated proteins, and SQSTM1, thereby increasing proximal tubule cell apoptosis. Calorie restriction physiologically induces autophagy via SIRT1-mediated deacetylation of FOXO3/FOXO3A and continues to be investigated as a possible mechanism in the intervention to decrease renal aging ( Figure 24.6 ).




Figure 24.6


Autophagy in kidney aging.

In both podocytes and proximal tubular cells, autophagy maintains cellular and organelles homeostasis under both basal and stress conditions. Normal aging process or a deletion of Atg5 gene alters autophagy in podocytes and proximal tubular cells, leading to kidney aging. Calorie restriction prevents the progression of kidney aging in part through SIRT1 -dependent autophagy.

(From Huber TB, et al: Emerging role of autophagy in kidney function, diseases and aging. Autophagy 8:1009-1031, 2012; G 2012 Landes Bioscience.)




Functional Changes in the Aging Kidney


Renal Plasma Flow


Effective renal plasma flow decreases by 10% per decade in healthy aging adults, the rate of decline being greater in men than in women ( Figure 24.7 ). Cortical blood flow decreases in parallel with observed histologic changes but medullary blood flow remains preserved. A fractional decrease in the cardiac output to the kidneys in addition to structural changes in the vessels and vascular responsiveness are also thought to decrease renal blood flow. Use of potent vasodilators, such as intraarterial acetylcholine, intravenous pyrogen, and atrial natriuretic peptide (ANP), results in a blunted vasodilatory response in older individuals in comparison with the response in younger individuals. Similarly, although increases in GFR and RPF are seen with amino acid infusion and low-dose dopamine in healthy older subjects, the degree of vasodilation is less than in younger subjects. Higher levels of the eNOS inhibitor asymmetric dimethyl arginine (ADMA) are found with rising age, which has an inverse association with effective renal plasma flow rate (ERPF) in healthy and hypertensive elderly. Whether tubular cell senescence and the inability to degrade ADMA lead to higher levels of ADMA with aging is not clear. One study reported that an overexpression of dimethylaminohydrolase, the enzyme that hydrolyzes ADMA to dimethylamine and citrulline, in five of six nephrectomized rats ameliorated sclerotic glomerular changes. Cell senescence thus may contribute to the vascular changes in response seen with age.




Figure 24.7


Relationship between age and relative effective renal plasma flow (ERPF, in milliliters per minute per 1.73 m 2 body surface area [BSA]) in males ( A ) and females ( B ).

(From Berg UB: Differences in decline in GFR with age between males and females: reference data on clearances of inulin and PAH in potential kidney donors. Nephrol Dial Transplant 21:2577-2582, 2006.)


An imbalance in the vasodilatory and vasoconstrictive mediators can also alter intrarenal signaling and affect renal vasculature and RPF. NO production in isolated conduit arteries decreases with age, and levels of NOS and l -arginine are low. However, gene expression for substrate synthesis remains unaffected. Prostacyclin (prostaglandin I 2 [PGI 2 ]) is decreased in aging human vascular cells and older rat kidneys in comparison with vasoconstrictive thromboxane. Excretion of vasodilatory natriuretic hormones is also lower in older subjects. Forearm vasodilation in response to PGI 2 infusion was also lower in older than younger healthy individuals, a difference that appeared to be due to reduced contribution of endothelium-derived NO. Older and younger subjects have similar vasoconstrictive responses to intraarterial angiotensin infusion. Inhibition of angiotensin II–mediated vasoconstriction with ACEIs leads to less vasodilation in older individuals than in younger subjects. ACE inhibition also led to renal vasodilation in aged rats with an increase in RPF. Glycine infusion in older rats, however, causes a decreased vaso­dilation response. Competitive NO inhibition leads to increased vasoconstriction, increased vascular resistance, and decreased RPF in older than in younger rats. Maximal vasodilation was applied with dopamine and amino acid in young (27-37 years), middle-aged (44-74 years), and elderly (81-96 years) subjects; the increase in NO levels and RPF seen in young and middle-aged subjects did not occur in elderly subjects, who also had a reduction in renal functional reserve that paralleled the number of sclerotic glomeruli found in elderly kidney biopsy specimens. These findings suggest that in order to preserve renal plasma flow, the aged renal vasculature may be in a state of renal vasodilation to compensate for underlying glomerular sclerotic damage. Renal function is thereby maintained despite a decrease in renal functional reserve.


Glomerular Filtration Rate


A progressive decline in GFR is seen with aging, though the rate of change can vary depending on whether inulin, iothalamate, urea or creatinine clearance measurements are used. Annual decline in creatinine clearance averages 0.8 mL/min/1.73 m 2 , whereas iohexol clearance decreases by 1.0 mL/min/1.73 m 2 per year. Various factors, including race, gender, genetic variation, and underlying renal and cardiovascular risks, affect the rate of decline for a given individual. Some writers have suggested that healthy older men have a slightly faster rate of decline in renal function than healthy older women, although the difference is relatively small. However, when the rate is scaled to body surface area, women appear to show a slightly greater decline in GFR ( Figure 24.8 ). Elderly African American or Japanese individuals seem to have a higher rate of decline in renal function than white individuals. A longitudinal 5-year evaluation of baseline factors in healthy elderly subjects noted that higher eGFR at baseline, higher systolic blood pressures, higher low-density lipoprotein (LDL) cholesterol and lower transferrin levels were associated with a greater decline in eGFR. The presence of hypertension, impaired glucose tolerance, diabetes, systemic and/or renal atherosclerosis, and lipid abnormalities are associated with higher rate of GFR loss in the elderly. Higher pulse pressure, often seen in aging individuals and indicating increased arterial stiffness, correlates inversely with GFR. Older participants in a cardiovascular study who had evidence of systemic microvascular disease on retinal examination had a greater decrease in GFR over time.




Figure 24.8


Relations between glomerular filtration rate and age in all subjects.

A, In men; B, in women. Glomerular filtration rate (GFR) scaled to body surface area (BSA); broken and continuous lines are the least squares regressions fitted to data from age 30 to 40 years, respectively. The regression equations are from age 40 years. Note the more rapid age-dependent decline in GFR in women.

(Adapted from Esposito C, et al: Renal function and functional reserve in healthy elderly individuals. J Nephrol 20:617-625, 2007.)


In micropuncture studies, Ang II increases both preglomerular and efferent arteriolar resistances, decreases renal and glomerular plasma flow, and increases glomerular hydraulic pressure and filtration fraction in both young and old rats. However, Ang II infusion lowers single-nephron GFR and whole kidney GFR in older rats by decreasing single nephron ultrafiltration coefficient (SNKf), parameters that remain unchanged in younger rats. Ang II decreases SNKf likely by causing mesangial cell contraction and smaller filtration surface. These parameters can be estimated in recipients of transplanted kidneys from older and younger donors. In one study, the nonsclerotic glomeruli in transplants from deceased older donors actually had larger filtration surface and higher SNKf than those from young donors. Overall GFR was 32% lower, a difference that was attributable to a reduction in allograft ultrafiltration coefficient, which in turn was explained by a significantly lower number of functioning glomeruli than in organs from younger donors. In healthy volunteers who had not received transplants, similar results were found, except that SNKf was reduced in older individuals. Despite a linear decrease in RPF with age, the filtration fraction appears to be increased. This may be explained by a higher filtration fraction in juxtamedullary nephrons than cortical nephrons in light of relatively preserved medullary flow and decreased cortical RPF ( Figure 24.9 ). In summary, the age-related reduction in GFR may be explained by decreases in functioning nephrons, in RPF, and in SNKf at baseline, as well as a response to Ang II. This reduction is only partially ameliorated by the increase in filtration fraction and by an increase in SNKf that occurs in remnant glomeruli exclusively in a transplanted kidney.




Figure 24.9


Relationship between age and filtration fraction (FF, in percentage) in males ( A ) and females ( B ).

(From Berg UB: Differences in decline in GFR with age between males and females: reference data on clearances of inulin and PAH in potential kidney donors. Nephrol Dial Transplant 2:2577-2582, 2006.)


Although a gradual decrease in GFR is noted with age, a parallel increase in serum creatinine may not be evident because muscle mass also decreases with age, frequently leading to an overestimation of GFR. GFR estimation can therefore be tricky in the older patient. Steady-state 24-hour urine creatinine clearances depend on collected volume and diet. Appropriate collection times are cumbersome for the older individual. Clearance studies using a radionuclide such as technetium Tc 99m–labeled diethylenetriamine-pentaacetic acid, iothalamate, or iohexol are more accurate; the expense, radioactivity exposure, and/or test variability limit their use for routine GFR measurements. Formulas commonly used to calculate GFR either overestimate or underestimate actual GFR in older individuals. The MDRD study and Chronic Kidney Disease–Epidemiology Collaboration (CKD-EPI) equations may provide closer estimations of GFR than the Cockroft-Gault equation. Other endogenous markers of GFR, such as cystatin C, a cysteine proteinase inhibitor continuously produced by all nucleated cells that is freely filtered, internalized, and catabolized by proximal renal tubular cells, has been found to be comparable to the MDRD equation in estimating GFR in the elderly; however, body mass index may contribute to the discrepancies between cystatin-based and MDRD equation estimates of GFR. Comparison of the first MDRD equation (incoporating BUN, serum albumin, age, creatinie) MDRD1 and second MDRD equation (incorporating serum creatinine and age only) MDRD2, the 2009 CKD-EPI (creatinine) equation, and the 2012 CKD-EPI (creatinine[cr]–cystatin [cys]) equation for approximating GFR with GFR values measured by radionuclide studies in the elderly indicates that the CKD-EPI equations may be more accurate than the MDRD equations. Validation studies seem to confirm that CKD-EPI (cr) is comparable in estimating GFR in both the young and the elderly. In the healthy elderly patient, use of other factors, including the presence of albuminuria and other comorbid conditions, may be more helpful in determining the presence or absence of CKD than an estimation of GFR alone.


Sodium Conservation


Tubular efficiency in reabsorbing filtered sodium decreases with age. Healthy subjects more than 60 years old take nearly twice as long to decrease urine sodium as those 30 years and younger (31 hours vs. 17.6 hours, respectively) after the initiation of sodium restriction. This difference may be secondary to decreased distal tubular sodium reabsorption. Age-related interstitial scarring, fewer nephrons, and increased medullary blood flow leading to a greater solute burden per nephron may contribute to decreased tubular sodium reabsorption in the elderly. However, one study found that use of indomethacin to reduce medullary flow in older individuals did not decrease distal tubular sodium clearance, suggesting that increased medullary blood flow may not contribute to decreased sodium conservation in the elderly.


Changes in both levels and response of hormones regulating sodium conservation with age also influence sodium conservation. Plasma renin and aldosterone levels are lower in the healthy elderly. A 30% to 50% decrease in basal renin activity is found, although renin substrate levels remain normal. Maneuvers that increase renin activity, such as upright position, sodium restriction to 10 mEq/day, furosemide administration, and air jet stress, further amplify age-related differences in renin activity. Plasma renin levels both before and after hemorrhage were lower in 15-month-old rats than in 3-month-old rats, reflecting age-related differences in plasma renin even prior to the stress event. Renin mRNA abundance is downregulated and juxtamedullary single-nephron renin activity decreased in older rats. With sodium deprivation and a drop in mean arterial pressure, older rats demonstrate a blunted plasma renin activity with delayed decrease in urinary sodium excretion. Plasma renin substrate measurements in healthy older adults suggest decreased conversion of inactive to active renin.


Plasma aldosterone changes with age parallel the change in plasma renin activity with a 30% to 50% decrease in older adults. An intrinsic adrenal defect appears less likely because both aldosterone and cortisol responses to adrenocorticotropic hormone remain appropriate with age, suggesting a renin-angiotensin deficiency. The sluggish response to dietary sodium restriction seen in the elderly can be reproduced by ACE inhibition and blockade of the renin angiotensin aldosterone system (RAAS). With aldosterone infusion, tubular sensitivity to appropriate sodium reabsorption appears preserved in the elderly, further supporting an abnormal RAAS response to delayed sodium reabsorption in the elderly.


Sodium Excretion


Older individuals have a blunted natriuretic response to sodium or volume loading. Sodium excretion after a 2-liter saline load is slower and occurs relatively more during the night in subjects older than 40 years than gender-, size-, and race-matched younger control subjects ( Figure 24.10 ). Nocturia is more prevalent and evident in older individuals. The natriuretic response to saline loading normally decreases after uninephrectomy for kidney donation, and this decrease is greater in older kidney donors than in younger donors ( Figure 24.11 ).




Figure 24.10


Comparison of urinary sodium excretion in younger ( gold bars ) and older ( red bars ) subjects after administration of 2 L of intravenous normal saline. Numbers at the bottoms of bars are the number of subjects in each group.

(From Luft FC, et al: Effects of volume expansion and contraction in normotensive whites, blacks, and subjects of different ages, Circulation 59[4]:643-650, 1979.)



Figure 24.11


Influence of age at donation on change in natriuretic response to acute saline load in kidney donors after uninephrectomy. Red circles indicate normotensive.

(Adapted from Mimran A, et al: Aging and sodium homeostasis. Kidney Int Suppl 37:S107-S113, 1992.)


The tubule response to ANP, an important controller of sodium excretion, is decreased with aging. ANP induces hyperfiltration, inhibits luminal membrane sodium channels and reabsorption, and suppresses renin release via specific cell surface receptors on renal vasculature and tubular epithelium. ANP is rapidly degraded; however, selective blockade of degradative enzymes or clearance can prolong serum ANP half-life. Serum ANP levels are three to five times higher in healthy older adults than in younger adults. ANP levels rise in response to greater salt load and head-out water immersion in older subjects to a greater extent than in younger ones, although decreased salt intake results in similar ANP levels in the old and young. ANP secretion remains intact with aging, higher basal levels resulting from decreased metabolic clearance. An age-related decrease in GFR does not appear to contribute, because patients with CKD and low GFR do not have high ANP levels.


Decreased metabolic clearance of ANP in aged subjects also suggests the possibility of lower proximal brush border endopeptidase levels that break down ANP. This possibility is supported by the observation that endopeptidase inhibitors restored vagal reflex bradycardia in old rats to levels similar to those seen in young rats.


Some writers have proposed that higher ANP levels are a homeostatic response to reduced ANP renal sensitivity with age. In support of this idea, urinary sodium excretion reaches a plateau after a 2 ng/kg/min ANP infusion in older adults, whereas younger subjects continue to have increased urinary sodium excretion with incremental increases in ANP. Although cGMP and ANP levels are similar at baseline, low-dose ANP increases urinary excretion of cyclic guanosine monophosphate (cGMP) but not sodium in older subjects. This finding suggests that the problem is downstream of cGMP. ANP can suppress the RAAS and inhibit sodium reabsorption. Simultaneous measurements of plasma renin activity and plasma aldosterone concentration during ANP infusion imply that the natriuretic effects of ANP are different from those of RAAS suppression. Age seems to affect each ANP action differently.


Urinary Concentration


Older individuals are frequently unable to achieve maximal urinary concentrating capacity. A combination of processes leads to impairment of water reabsorption with aging. The presence of an intact osmoreceptor and volume receptor sensitivity to arginine vasopressin (AVP) release, in addition to an intact collecting tubule response to AVP under maximal medullary tonicity, is necessary for appropriate urinary concentration. A study found urinary osmolality to be lower in aged than in young rats and to persist after a 5-day water restriction, although plasma AVP levels increased equivalently in young and old rats. Both volume and osmotic stimulation of AVP remain intact with age, with actually enhanced osmoreceptor sensitivity for AVP in the elderly. A concentration defect remains after AVP infusion, suggesting an impaired AVP response. One study found that AVP receptor type 2 (V 2 R) mRNA expression decreased similarly in 8-week-old and 7-month-old rats at baseline and with dehydration. Although aquaporin-2 (AQP2) mRNA increased, the increase was smaller in older rats. In another study, no difference in V 2 R mRNA was seen between older and younger female nondehydrated WAG/Rij rats. Some investigators have noted lower V 2 R mRNA expression and decreased AQP2 protein levels in older than in younger hybrid F344/BN rats under baseline conditions. Previous studies in renal medullary cells from 6-month-old and 30-month-old mice found little difference in maximum AVP receptor binding, suggesting a post-receptor defect. Higher AVP levels are required to increase cyclic adenosine monophosphate (cAMP), because older animals have decreased cAMP levels.


Postreceptor guanine nucleotide–binding protein (G s protein) levels are also lower in older kidneys. Stimulation of G protein with cholera toxin and of adenylate cyclase with forskolin at the level of the catalytic unit and G protein interaction evoked a significantly reduced response in hydraulic conductivity of older rabbit collecting tubules, suggesting that the age-associated decrease in the cortical collecting tubule response to AVP may occur at the level of the G s catalytic subunit of adenylate cyclase. In the previously mentioned study in female WAG/Rij rats, however, expression of both AQP2 and AQP3 was markedly lower in older than in younger rats. AQP2 was noted to also redistribute into the intracellular compartment in the inner medulla and not in the renal cortex in the presence of low papillary osmolality and unchanged papillary cAMP in the older rats, suggesting that AQP2 and AQP3 expression may be independent of vasopressin-mediated cAMP accumulation. These data suggest that although vasopressin response appears to be preserved with age, the extent of this response may be affected by mechanistic factors, leading to actual aquaporin insertion and urinary concentration.


It has been proposed that older individuals have medullary “washout” on the basis of the observation that solute and osmolar clearances are increased and urine osmolality decreased after 12 hours of water deprivation. Evaluation of proximal and distal nephron clearance of sodium in comparison with free water clearance after water load followed by 0.45% saline load resulted in 29% lower distal tubular sodium reabsorption in older healthy versus younger healthy subjects, suggesting impaired distal sodium transport in the older subjects. Very old (31 months) rats have decreased Na-K-2CL cotransporter type 2 (NKCC2). However, renal cortical to medullary non-urea solute concentration and solute-free water clearance as a measure of loop salt transport (CH 2 O/GFR) in aged rats were not significantly different from those in younger rats at comparable rates of distal solute delivery; medullary washout is therefore less likely to be a contributing factor to the decrease in urinary concentrating ability with age.


Decreased urinary concentration with age may also be affected by reduced expression of urea transporters UT-A1 and UT-B1 in the renal medulla; one study found a decrease in papillary osmolality in senescent female WAG/Rij rats whether they received food restriction or ad libitum feeding. Other investigators report that papillary urea accumulation as well as urine osmolality and flow rates improved with upregulation of urea transporters when 1-desamino-8- d -rginine vasopressin (desmopressin; DDAVP) was given.


Urinary Dilution


Renal diluting capacity in the elderly may be affected by an underlying decrease in GFR with age as well as a decrease in distal sodium resorption. Maximum urinary dilution depends on appropriate solute extraction, adequate AVP suppression, and distal delivery of the filtered load. In one study, water loading of 20 mL/kg in healthy older adults resulted in excretion of only 41% of the water load over 2 hours, compared with excretion of 100% of the water load in young water-repleted individuals and 70% excretion of the water load in young water-depleted individuals; the lower excretion is partly attributable to an age-related decline in glomerular filtration. In another study, peak free water clearance after overnight fast and oral water loading of 20 mL/kg was 6 ± 0.6 mL/min in healthy elderly volunteers, compared with 10.1 ± 0.8 mL/min in young volunteers. However, total free water clearance over time was comparable in both older and younger groups in the two studies. Minimum urinary osmolality for subjects older than 70 years is 92 mOsm/kg H 2 O, compared with 52 mOsm/kg H 2 O in subjects younger than 40 years.


Acid-Base Balance


Acid-base homeostasis with usual daily acid or alkali intake remains well maintained in the elderly. Only during acid loading is the impaired ability to excrete an acid load evident. Although age-related decreases in renal mass and GFR contribute, endogenous acid production from acid diets can lower serum bicarbonate levels in older individuals. Healthy elderly demonstrated a lower net acid excretion capacity when compared in cross-sectional observational analysis with that of younger healthy adults. In the same group of elderly subjects, net acid excretion correlated positively with calcium and magnesium excretion. In older, cross-sectional studies, plasma bicarbonate and blood pH appear to decrease with age, concomitant with decreases in GFR ( Figure 24.12 ). There is a reciprocal increase in plasma chloride, as seen with renal tubular acidosis or early renal disease.




Figure 24.12


Relation between blood pH [(H + )b] and age ( A ) and between plasma bicarbonate concentration [(HCO 3 )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 equation: (H + )b = 0.045 × age + 37.2 (HCO 3 )p = –0.038 × age + 26.0.

(From Frassetto LA, et al: Effect of age on blood acid-base composition in adult humans: role of age-related renal functional decline. Am J Physiol 271:F1114-F1122, 1996.)


Ammonium excretion is found to decrease with age. Whereas ammonium excretion increased similarly with glutamine intake in both young and old in one study, ammonium loading resulted in lower ammonium excretion and inability to achieve minimal urine pH despite correction for GFR in older patients, suggesting a possible intrinsic tubular defect. Sodium-hydrogen exchanger activity, however, increased similarly in both older and younger rats, with phosphate transport also decreasing to the same extent in both groups.


Although the degree of acidosis observed in the elderly in these older studies is subtle, complications of chronic acidosis including bone demineralization and muscle wasting can be seen in the elderly. Higher protein intake results in endogenous acid production. In a population study in Pakistan, net endogenous acid production was reported to be higher in the elderly compared to younger cohorts owing to intake of protein rich foods. Increased dietary acid load would be expected to result in lower serum bicarbonate levels, which would be more evident in those over 40 years of age. This may not, however, be generalizable to populations elsewhere. Additionally, changes in net acid excretion can be seen in patients with small decreases in estimated GFR without overt changes in acid base parameters.


Muscle breakdown mediated by activation of the adenosine triphosphate (ATP)–dependent ubiquitin and proteasome pathway is induced by acidosis. Net acid excretion correlates positively with changes in parathyroid hormone (PTH) and urinary calcium excretion. Acidemia regulates calcium and alkali mobilization from bone and inhibits renal calcium reabsorption. Higher protein intake in Western diets, in conjunction with age-related impairment in acid excretion, negatively affects calcium balance and predisposes to osteoporosis, increased incidence of muscle wasting, and fractures despite normal bicarbonate levels. In one study, 24-hour net acid excretion in healthy elderly subjects also correlated with magnesuria irrespective of magnesium intake and when adjusted for potassium intake. In another, elderly men and women with increased potassium excretion, a marker of greater potassium intake due to consumption of potassium-rich alkaline fruits and vegetables, did not exhibit the mild metabolic acidosis noted with protein-rich diets, and this finding was associated with higher percentage of lean body mass. Bicarbonate supplementation in elderly patients with chronic kidney failure was reported to correct metabolic acidosis, improve serum albumin and prealbumin levels, and decrease whole-body protein degradation as evaluated by a decrease in normalized protein catabolic rate. Postmenopausal women were found to have improved nitrogen and calcium balance with potassium bicarbonate supplementation, which also was reported to have favorable effects on bone resorption and calcium excretion in older men and women. In a randomized double-blind placebo-controlled study of healthy elderly men and women, potassium citrate supplementation at both 60 and 90 mmol/day neutralized net acid excretion, with the further benefit of decreased 24-hour urinary calcium level even though calcium absorption was not affected.


Potassium Balance


Total-body potassium decreases with age as muscle mass declines, and this decrease is more evident in women. Lower plasma levels of renin and aldosterone could explain this decrease, with presence of relative hypoaldosteronism in the elderly. Potassium infusion results in decreased aldos­terone response in older individuals ( Figure 24.13 ). There is a relative decrease in fractional potassium excretion in relation to GFR in healthy older individuals. Aged rats given high-potassium diet demonstrate lower efficiency in potassium excretion. KCl infusion results in higher plasma potassium levels and inability to shift potassium into cells. After bilateral nephrectomy, sodium pump (Na + /K + -ATPase) activity is 38% lower in older than in younger rats with high-potassium feedings. Age, however, does not appear to affect insulin-mediated potassium uptake in humans. Exercise-induced increases in potassium levels in the elderly suggests an impaired β-adrenergic–induced increase in adenylate cyclase system resulting in decreased activity of the Na + /K + -ATPase pump in the skeletal muscle. Older individuals are more prone to development of hyporeninemic hypoaldosteronism (type 4 renal tubular acidosis) with abnormalities in both RAAS and renal acidification. Thus, medications that further impair long-term potassium adaptation, including RAAS inhibitors (ACEI, ARBs, heparin, calcineurin inhibitors, spironolactone, eplerenone), β-blockers, nonsteroidal antiinflammatory agents (NSAIDs), and sodium channel blockers (trimethoprim, pentamidine, amiloride, triamterene) can lead to significant hyperkalemia in the elderly and require close monitoring.




Figure 24.13


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 a lower aldosterone response ( P < 0.005) by analysis of variance.

(From Mulkerrin E, et al: Aldosterone responses to hyperkalemia in healthy elderly humans. J Am Soc Nephrol 6:1459-1462, 1995.)


Calcium Balance


Both renal calcium excretion and reabsorption in response to decreased or increased calcium intake are reported to be appropriate, as are the filtered load of calcium and proximal tubular calcium reabsorption per nephron, in both old and young rats. An age-related decrease in distal tubular epithelial calcium channel protein TRPV5 abundance is noted that corresponds to a decrease in TRPV5 mRNA and slight increases in 2-hour urine calcium excretion in older mice. It is possible that age-related deficiency in β-glucuronidase klotho is contributing to inadequate Na + -K + -ATPase sensing of low extracellular calcium. Healthy older males are found to have a higher calcium set point for PTH release as well as a greater number of parathyroid cells, not attributable to either lower ionized calcium or 1,25-hydroxyvitamin D levels. How the G protein–coupled calcium sensing receptor plays a role in this changed set point is yet to be clarified. However, fractional calcium excretion in the healthy older individuals with GFR values similar to those with stage 3 chronic kidney disease (CKD3) suggests greater calcium loss in those with CKD3.


Intestinal calcium reabsorption, however, is decreased with aging, in association with decreases in 1-α-hydroxylase activity and 1,25-dihydroxycholecalciferol (1,25[OH] 2 D 3 ) levels and increased basal PTH levels. Levels of vitamin D–dependent calcium-binding proteins also diminish with age in association with the change in intestinal calcium absorption. Although renal vitamin D production is lower with PTH stimulation, final concentrations of vitamin D are similar in both old and young. Urinary cAMP and fractional phosphorus levels also increase with PTH infusion as expected in both young and old, suggesting an intact renal response to PTH with aging.


Phosphate Balance


Intrinsic renal tubular capacity for phosphate reabsorption decreases with age. Older kidneys adapt less well to phosphate restriction. Intestinal phosphate absorption is also lower in the elderly. The lower maximal inorganic phosphate (Pi) transport capacity (TmPi) observed in older parathyroidectomized rats infused with graded levels of Pi suggests a significantly lower TmPi with age. Although TmPi decreased further with PTH infusion in these rats, the magnitude of the response was less with age.


Primary cultures of renal tubular cells from young and aged rats show a similar age-related impaired response in phosphate transport as seen in vivo studies. Decreases in maximum sodium-dependent phosphate transport velocity (Na/Pi cotransport) and the ability to adapt to low-phosphate culture media are found in cultured cells from older rats, accompanied by a decrease in type IIa Na/Pi cotransporter cortical mRNA levels and apical brush border membrane protein abundance.


Increase in membrane cholesterol content may further act to decrease Na/Pi cotransport with aging. In vitro cholesterol enrichment of isolated brush border membranes from young adult rats reproduces the age-related impairment in maximum velocity of Na/Pi cotransport activity. Direct changes in opossum kidney cell cholesterol content seem to affect Na/Pi cotransport activity by changing expression of the apical membrane type II Na/Pi cotransport protein. Thus, changes in membrane cholesterol content with age may contribute to changes in phosphate transport.


The effect of age-related changes in 1,25(OH) 2 D 3 metabolism on intestinal phosphate transport should be considered, given that vitamin D replacement improves renal and intestinal phosphate transport in vitamin D–deficient animals. Interestingly, changes in phosphate transport resulting from vitamin D administration parallel significant changes in brush border membrane lipid composition and fluidity. Thus, age-related effects of 1,25(OH) 2 D 3 may possibly be mediated by lipid-modulating properties that improve renal and intestinal transport of phosphate (and calcium).




Renal Disease in the Aging Kidney


Disorders of Osmoregulation


Hyponatremia


Hyponatremia can be a common finding in geriatric adults, given their enhanced osmotic AVP release and impaired ability to dilute urine. Many older ambulatory patients are also found to have an idiopathic form of the syndrome of inappropriate antidiuretic hormone. This predisposition to hyponatremia can be further exacerbated by medications that can affect AVP action or release (see Chapter 16 ). In addition, thiazide-type diuretics with distal tubular effects on solute reabsorption further impair urinary dilution in the elderly and can be implicated in nearly 20% to 30% of cases of hyponatremia. Aging-associated decreases in prostaglandin synthesis also inhibit water diuresis and increase susceptibility to hyponatremia with thiazide use. Acute or significant hyponatremia can manifest subtly as apathy, disorientation, lethargy, muscle cramps, anorexia, or nausea, which can progress to more devastating signs such as agitation, depressed deep tendon reflexes, pseudobulbar palsy, and seizures resulting from osmotic water shifts from the extracellular to the intracellular space. Thus early recognition with prompt appropriate therapy is indicated to avoid severe neurologic sequelae, including central pontine myelinolysis.


Hypernatremia


Both a concentrating defect and a decreased thirst response with aging predispose older individuals to dehydration and hypernatremia. Certainly the inability to access free water because of altered level of consciousness or immobility in the elderly can lead to a marked rise in serum sodium and osmolality, with associated mortality reported as high as 46% to 70%, particularly with sodium levels higher than 160 mEq/L. Medications that cloud sensorium and inhibit thirst, such as tranquilizers and sedatives, or that decrease AVP action in the renal tubules, such as lithium and demeclocycline, should be used with caution in older adults. In addition, osmotic diuretics, high-protein or high-glucose parenteral feedings, and bowel cathartics need to be used carefully in older adults to avoid dehydration. The presence of systemic illness, infection, fever, or neurologic impairment may add to impaired AVP secretion and increase the underlying predisposition for hypernatremia. Symptomatic severe cellular dehydration can be associated with obtundation, stupor, coma, seizures, and death. Thus, particular care in use of medications and medication review are necessary in the older debilitated patient to avoid hypernatremia.


Acute Kidney Injury


Susceptibility to both ischemic and nephrotoxic acute kidney injury (AKI), as well as time for recovery from injury, increases with age. Acute kidney injury is 3.5 times more prevalent in those older than 70 years and is associated with greater morbidity and mortality in older hospitalized patients. An estimated 28% of those older than 65 years are unlikely to recover kidney function after AKI.


Renal artery occlusion in older rats produced a larger increase in renal vascular resistance and a greater fall in glomerular filtration, and it took these rats longer to recover from ischemic injury than younger rats. Renal cortical slices from aged rats that were exposed to anoxia were less able to take up paraaminohippurate and tetraethylammonium than renal cortical slices from younger rats. Reduced antioxidant potential and increased oxidative stress predisposed older rats to more severe reperfusion injury. Expression of candidate genes, including claudin-7 ( Cldn7), kidney injury molecule-1 ( Kim-1 ), and matrix metalloproteinase ( MMP-7 ), was increased during ischemic injury in slices of kidney from older rats in comparison with younger rats; interestingly, gene expression was attenuated in calorie-restricted older rats. Hemoglobin infusion to induce heme protein nephrotoxic injury to older rats resulted in significantly greater increase in blood urea nitrogen and creatinine as well as histologic evidence of acute tubular necrosis with tubular cast formation in older (16 months) mice but not in younger (6 months) mice. Older mice failed to increase protective heme oxygenase 2 (HO-2) mRNA but did increase the nephrotoxic cytokine interleukin-6 (IL-6) 30-fold, compared with a 10-fold increase in younger rats.


Transcriptomic analysis of murine kidney tissue in experimental AKI suggested that tumor necrosis factor–like weak inducer of apoptosis (TWEAK) activation of its receptor, fibroblast growth factor–inducible 14 (Fn14), via secretion of chemokine CXCL16 decreased both mRNA and protein expression of the anti-aging hormone Klotho. Klotho reduction persisted after recovery from nephrotoxic injury and may add to the progression of CKD, which is more common in the elderly after AKI. In addition, critical telomere shortening with increased cell cycle inhibitor p21 and greater numbers of apoptotic cells in relation to significantly reduced tubular, glomerular, and interstitial cell proliferative capacity were noted in older telomerase-deficient mice in comparison with younger mice. Evaluation of renal progenitor cells with bromodeoxyuridine before and after ischemia reperfusion noted decreases in progenitor cells with age, with no significant difference in the ratio of label retaining cell division after injury among rats tested of different ages. Higher numbers of renal progenitor cells were noted in cells co-cultured with human umbilical vein endothelial cells (HUVECs) than in cells cultured without HUVECs, suggesting that tubular regeneration with age may be affected by access to surrounding peritubular capillary network. Proximal tubular cells also failed to induce autophagy during ischemic stress, and this feature seemed to correlate with the development of age-related AKI. Data also show more decreased autophagy in older than in younger mice after ischemic and nephrotoxic injury.


Thus, decreased regenerative capacity in relation to injury appears to add to prolonged recovery from AKI with age.


Data from older humans reflect similar findings. Euvolemic older men consuming a constant sodium diet have higher renal vascular resistance with a blunted response to orthostatic change. Also, unlike younger adults, older adults are unable to improve medullary oxygenation with water diuresis ( Figure 24.14 ). In patients without kidney dysfunction who underwent cardiopulmonary bypass, postoperative excretion of kidney-specific proteins ( N -acetyl-β-glucosaminidase, α 1 -microglobulin, π-glutathione-S-transferase, α-glutathione-S-transferase) and fractional sodium excretion were higher in the older patients than in the younger patients. Similarly, increasing donor age significantly correlated with higher expression of the enzyme poly (ADP-ribose) polymerase 1 (PARP-1) in kidney biopsy specimens from aged donors, suggesting a greater susceptibility to cold ischemia and ischemia reperfusion in older kidneys.




Figure 24.14


Comparison of changes in R 2 * (1/sec) in response to water load in nine young and nine elderly subjects.

R 2 * reflects the apparent spin-spin relaxation of deoxygenated hemoglobin by magnetic resonance and is equal to the slope or equivalent to the concentration of deoxyhemoglobin or blood oxygen pressure (P o 2 ) or tissue P o 2. Because blood P o 2 is thought to be in rapid equilibrium with tissue P o 2 , changes in blood oxygen level–dependent magnetic resonance imaging signal intensity, or R 2 *, should reflect changes in the P o 2 of the tissue. Blue bars indicate medulla; red bars indicate cortex. Bar heights represent mean values with standard error indicated. NS, Not significant. *Statistically significant at the P < 0.01 level.

(From Prasad PV, Epstein FH: Changes in renal medullary pO 2 during water diuresis as evaluated by blood oxygenation level–dependent magnetic resonance imaging: effects of aging and cyclooxygenase inhibition, Kidney Int 55:294-298, 1999.)


Multifactorial and iatrogenic insults, whether prerenal, intrinsic, or postrenal, that lead to AKI are poorly tolerated as age increases and renal reserve decreases. The common presence of comorbid diabetes, hypertension, heart failure, liver disease, or malignancies in older individuals adds to the poor tolerability of an acute renal insult. Generalized atherosclerosis in older patients predisposes to renal ischemic events and spontaneous or procedure-related cholesterol renal atheroemboli. In addition, acute vasculitis and rapidly progressive glomerulonephritis can be devastating in older individuals.


Approximately half of the AKI events in the elderly result from prerenal processes. Vomiting, diarrhea, bleeding, and use of excessive diuretics are common causes of dehydration and volume depletion in this population. Impaired thirst, decreased urinary concentration ability, and diminished sodium conservation capacity predispose to these processes. Blunted autoregulation, decreased RPF, and reduced renal reserve in the older kidney allow volume changes to be less well tolerated. Renal hypoperfusion from decreased cardiac output, sepsis, and use of medications that interfere with renal autoregulatory mechanisms, such as angiotensin antagonists (ACEIs, ARBs) and prostaglandin inhibitors (NSAIDs), can cause and exacerbate prerenal processes, leading to AKI in older adults. NSAID use increases the risk of AKI in those 65 years and older by 58%. Because tubular defects in older individuals may lead to a higher urine sodium excretion despite underlying hypoperfusion, the usual renal indices used to differentiate prerenal from intrinsic causes—urine sodium excretion, fractional sodium excretion, and urine osmolality—need careful interpretation in the elderly. Although prerenal processes are often reversible with careful volume management, discontinuation of the exacerbating factor, or improvement in cardiac output, the evolution from prerenal azotemia to acute tubular necrosis (ATN) occurs more commonly in older (23%) than younger (15%) patients.


Intrinsic AKI results in acute structural insults that prolong recovery of renal clearance in the elderly. ATN from ischemic and nephrotoxic tubular injury affects approximately 50% of hospitalized older patients with intrinsic AKI. Lower levels of the NO substrate, l -arginine, in the elderly are associated with decreased NO synthesis in aging vasculature and higher ADMA levels, impairing vasodilation and predisposing older kidneys to ischemia. Data from aged rats support these findings. Feeding l -arginine to older rats prior to renal artery occlusion improved GFR, RFP, and renal vascular resistance (RVR), whereas administration of the NO inhibitor l -NAME ( N G -nitro- l -arginine methyl ester) abolished these effects. With an increase in eNOS mRNA and protein, NO availability was improved when RhoA protein activation was partially inhibited by statins. This increases NO availability therefore renal vasoconstriction and significantly attenuates ischemic lesions in older animals with ischemic acute renal failure, suggesting the vulnerability of aging kidneys to AKI.


Hypotension, either before or after surgery, sepsis, and nephrotoxins are poorly tolerated by aging kidneys and are major culprits in hospital-acquired AKI in the elderly. A prospective evaluation of all patients admitted to one hospital over a 12-month period, of whom 4176 were older than 60 years, noted that the incidence of treatment-related in-hospital AKI in the elderly was 1.4%. Nephrotoxins contributed to AKI in 66% of the elderly patients, sepsis and hypotension in 45.7%, contrast-induced nephropathy in 16.9%, and postoperative renal failure in 25.4%, with various combinations of these factors leading to AKI. Sepsis, oliguria, and hypotension were independent predictors of poor outcome in this older population.


Both decreased clearance and tubular changes in older kidneys predispose to the toxic effects of antibiotics, chemotherapeutics, and diagnostic agents such as those using iodinated contrast. Therefore careful estimation of renal clearance is crucial in the elderly prior to antibiotic and chemotherapy dosing with continued close monitoring and drug dose adjustment as necessary. Drug-induced interstitial nephritis is more common in the elderly, particularly with commonly used drugs such as penicillins and proton pump inhibitors. Careful assessment of renal clearance should be considered before infusion of contrast agents in the elderly. Use of concurrent medications such as NSAIDs, ACEIs, and ARBs as well as metformin for underlying comorbidities in the elderly should be carefully evaluated and appropriately discontinued before an intravenous injection of a contrast agent. Whenever possible, diuretic agents should also be discontinued several days prior to contrast agent injection in the elderly to prevent an added prerenal process. Furthermore, intravenous saline infusion should be considered to avoid prerenal process in the elderly before and after contrast infusion. Dose and duration of saline infusion should be individualized through clinical evaluation of volume status and other underlying comorbidities for each elderly patient.


Atheroembolic AKI is of greater risk in elderly patients who have generalized atherosclerosis, particularly with intraarterial cannulation and the use of anticoagulation. In one study, approximately 7.1% of renal biopsy specimens obtained for acute kidney failure in patients older than 60 years were found to have atheroemboli. Subtle increases in blood urea nitrogen and creatinine with or without complaints of dysuria, hesitancy, or dribbling should prompt an evaluation for underlying urinary tract obstruction. Careful investigation for urogenital tumors, pelvic prolapse, and papillary sloughing, as well as medication review for anticholinergic drugs, sedatives and hypnotics, narcotic and opioid analgesics, antipsychotics, and histamine-1 receptor antagonists, should be considered, with prompt urologic intervention as necessary.


AKI also increases the risk of ESKD in the elderly. In a cohort of nearly 234,000 Medicare beneficiaries 67 years and older discharged from the hospital, the incidence of AKI was 3.1%, and ESKD developed in 5.3 per 1000. Therefore early recognition of a greater susceptibility of elderly patients to AKI is crucial, with the aim of preventing the disease by avoiding nephrotoxic medications and interventions that increase the risk. Early nephrology referral and management are prudent if these exposures cannot be avoided.


Although aging individuals have both greater risks for AKI and prolonged recovery from it, therapeutic intervention should not be based on age alone, because factors other than age can contribute to overall survival in the elderly. Response to dialysis therapy for AKI in the elderly is frequently good, providing relief of uremic symptoms and complications such as volume overload, bleeding, disorientation, catabolic state, and electrolyte disturbances. Therefore, as in any patient, it is important to consider the overall assessment of the elderly patient in the decision about renal replacement therapy (RRT), including illness severity, comorbidities, and projected cognitive and/or physical recovery in addition to patient and family wishes.


Hypertension


Hypertension leading to kidney disease is a common problem in the elderly in most developed nations. NHANES data from 1999 to 2004 indicate the presence of hypertension in 67% of U.S. adults 60 years and older. Overall there is a progressive increase in the incidence of coronary disease, stroke, and cardiovascular mortality as blood pressure rises above 115 mm Hg systolic/75 mm Hg diastolic, with some notable differences in risk based on age and underlying comorbid conditions. Between the ages of 40 and 69 years, a 20–mm Hg systolic blood pressure (SBP) change is associated with a twofold difference in the death rates from ischemic heart disease and other vascular causes, with an even greater difference noted in the stroke death rate. As age increases, SBP and pulse pressure become better predictors of cardiovascular disease (CVD). Elastic senescence, altered extracellular matrix cross-linking, and calcium deposition lead to fibrotic changes with medial elastocalcinosis and stiffness in the larger elastic aging vasculature, which decrease vascular capacitance and propagation of the pulse wave velocity, clinically evident as widened pulse pressure. Impaired endothelial function and relaxation from low NO production with age are also noted to increase vascular stiffness. With greater arterial stiffness in aging as diastolic blood pressure (DBP) decreases and pulse pressure increases, studies suggest that evaluating a combination of parameters such as SBP + DBP or pulse pressure + mean arterial pressure may be more useful in predicting mortality outcomes. Isolated systolic hypertension (ISH), with SBP more than 160 mm Hg and DBP less than 90 mm Hg, is evident in nearly 75% of U.S. hypertensive elderly patients. Although hypertension independently increases the risk of ESKD, elevated SBP appears to be associated with greater risk of ESKD. ISH is a strong independent risk factor for a decline in kidney function in older individuals ( Figure 24.15 ).




Figure 24.15


Adjusted relative risk of a decline in kidney function according to quartiles of blood pressure (BP) component in 2181 participants in the Systolic Hypertension in the Elderly Program (SHEP). CI, confidence interval; DBP, diastolic blood pressure; MAP, mean arterial pressure; PP, pulse pressure; SBP, systolic blood pressure.

(From Young JH, et al: Blood pressure and decline in kidney function: findings from the Systolic Hypertension in the Elderly Program (SHEP). J Am Soc Nephrol 13:2776-2782, 2002.)


Measurement of blood pressure in the elderly should follow standard guidelines in the American Heart Association recommendations, although standing blood pressure should also be measured periodically in the elderly, given the increased risk for postural hypotension. A thorough examination to assess underlying causes and end-organ involvement, including laboratory evaluation of renal function (serum creatinine level or eGFR), is important in those elderly diagnosed with hypertension. Although treatment of elevated blood pressure in the elderly, including those older than 80 years, is clearly beneficial, the goal of SBP less than 140 mm Hg that was developed for the general population needs to be adjusted for those with ISH and for patients 80 years and older. Blood pressure therapy that decreases DBP to 60 mm Hg or less in the elderly with ISH can impair tissue perfusion, increase cardiovascular risk, and reduce survival. Thus SBP goals should not be reached at the expense of excessive DBP reduction. The intention-to-treat Hypertension in the Very Elderly Trial (HYVET) supports a target blood pressure of 150/80 mm Hg in patients 80 years or older, reporting a 21% reduction in all-cause mortality and a marked reduction in other cardiovascular morbidity, such as stroke and heart failure. The Eighth Joint National Committee (JNC8) guidelines, based on a review of a number of randomized trials—including HYVET, the Systolic Hypertension in Europe Trial (Sys-Euro), the Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients (JATOS), the Valsartan in Elderly Isolated Systolic Hypertension (VALISH) Study, and the usual versus tight control of systolic blood pressure in non-diabetic patients with hypertension trial (CARDIO-SIS)—recommend blood pressure goals of less than 150/90 mm Hg for people older than 60 years.


Lifestyle modification with appropriate dietary salt restriction, exercise, and weight loss when necessary remains the primary treatment, with medications added as required and tailored to each patient. Various medications have been used and are tolerated in the elderly, including chlorthalidone, hydrochlorothiazide, ACEIs, ARBs, and calcium channel blockers. These drugs should be initiated at lower dosages and titrated carefully, with awareness of the greater risk of postural and postprandial hypertension in the elderly given the exaggerated response in those with ISH. In a random sample of individuals 75 years or older, SBP was found to drop by more than 50% with the rise from a supine to a standing position. The total prevalence of orthostatic hypotension was 34% in this cohort, which emphasizes the need to monitor and initiate antihypertensive therapy carefully in the elderly. Furthermore, given that many elderly persons are taking a variety of medications, it is important to be wary of drug-drug interactions, which may either potentiate antihypertensive therapy, as do the α 1 -blockers frequently used to treat benign prostatic hypertrophy, or inhibit antihypertensive therapy, as do the NSAIDs frequently used to manage antiinflammatory processes in the elderly.


Renovascular Disease


Renovascular disease is an important cause of resistant hypertension and progressive renal insufficiency, often manifesting in the elderly as part of a generalized atherosclerotic process rather than an isolated syndrome. USRDS data report incidence and prevalence rates of 1.3% and 0.7% respectively of ESKD in those diagnosed with atherosclerotic renovascular disease (ARVD). The prevalence of renovascular disease has been estimated to be 6.8% in unselected community-dwelling African American and white men and women older than 65 years. Angiographically determined stenosis of 75% or greater in the renal arteries is more likely to progress to occlusion. Unexplained progressive azotemia, worsening or new-onset hypertension, and/or development of AKI with antihypertensive therapy should raise suspicion of renovascular disease in an elderly patient. These signs may be more evident when ACEIs and ARBs are used. Patients also may experience recurrent episodes of acute (flash) pulmonary edema or otherwise unexplained heart failure. Patients with ARVD are at increased risk of death from CVD ; therefore, aggressive control of atherosclerotic risk factors is recommended. Screening and diagnostic tests should be performed in patients with moderate to high probability of ARVD (see Chapter 48 for complete discussion).


Treatment options for hemodynamically significant lesions, including medical therapy with antihypertensive drugs, revascularization with angioplasty with or without stenting, and surgery, should be individualized for each patient with consideration of the benefits and risks of each procedure. A randomized trial comparing endovascular revascularization plus medical therapy with medical therapy alone in 806 older patients with ARVD found no clinical benefit for revascularization when the end points of renal function, blood pressure, time to renal and cardiovascular events, and mortality were assessed over 34 months of follow-up. Serious complications associated with revascularization occurred in 23 patients, including two deaths and three amputations of toes or limbs. A later study comparing stenting and medical therapy for atherosclerotic renal artery stenosis similarly determined that renal artery stenting did not confer a significant benefit with respect to the prevention of clinical events when added to comprehensive, multifactorial medical therapy in people with atherosclerotic renal artery stenosis and hypertension or CKD.


Revascularization also carries the risk of atheroemboli, although the reported incidence is low. There is no evidence that revascularization improves any outcomes in asymptomatic patients.


Glomerular Disease


Renal biopsy findings in the elderly suggest that acute and chronic glomerular disease is common in this patient population. As in younger patients, AKI and/or nephrotic syndrome often is the reason for renal biopsy in the elderly.


Nephritic presentations with acute or rapidly progressive renal failure can be devastating in the elderly. Several small case series suggest that pauci-immune glomerulonephritis (GN) is more common in older adults more than 60 years of age. Greater age is associated with increased risk of death from therapy as well as from all causes in older patients with pauci-immune GN. Of the pauci-immune GN biopsy specimens evaluated at a large referral center, 79% of cases were noted in those older than 60 years. Although fewer cases of anti–glomerular basement membrane GN and immune complex crescentic GN were noted in these reports, diagnostic workup for these processes must be included. Similarly, although the incidence of postinfectious or poststreptococcal diffuse proliferative GN has decreased in most developed nations, the disease is becoming more evident in the elderly in underdeveloped regions and in those elderly living in poor socioeconomic or debilitating conditions. Therefore a careful history should be taken to identify possible exposure, and a history and/or physical examination findings suggesting the possibility of infection should prompt early diagnosis and supportive treatment in the elderly.


Paraproteinemia, particularly multiple myeloma, can also manifest as AKI in the elderly with or without overt hypercalcemia. Thus quantification of urine protein, serum free monoclonal light-chain analysis immunoelectrophoresis, and immunofixation can be important early on, particularly if the cause of AKI remains unclear. A test result positive for monoclonal proteins should also be followed by further evaluation for the presence of amyloidosis or light-chain deposition disease. In addition, minimal change disease can manifest as AKI in the elderly with significant proteinuria and hypertension. Renal biopsy findings frequently suggest acute tubular injury in the presence of minimal change disease, but the cause remains speculative.


Primary glomerular diseases appear to be more prevalent in the elderly than secondary diseases, although diabetic glomerulopathy may be underrepresented because biopsies often are not performed in cases of presumed diabetic renal disease. Relative frequencies of various glomerular diseases are different in older and younger patients. Membranous nephropathy is the most common histologic finding in numerous case series, with 36% of 317 renal biopsy specimens from patients older than 60 years showing nephrotic syndrome. Anti-PLA2R antibodies may be detected by ELISA in 75% of patients with idiopathic membranous nephropathy with higher levels associated with both greater chance of partial or complete remission as well as greater risk for decreased renal function on follow-up.


Minimal change disease (11%) and amyloidosis (10.7%) also were noted and were more frequent than other diagnoses in this large series. In the very elderly (≥80 years), focal sclerosis from hypertension and hypertensive nephrosclerosis seemed to be more prevalent, followed by immunoglobulin A and membranous nephropathy.


Nephrotic syndrome can coexist with or precede malignancy in up to 30% of elderly diagnosed with malignancy. An immune response to tumor antigens is considered the possible pathologic cause. Solid tumors of the lung, breast, colon or rectum, kidney, and stomach have been commonly reported in association with membranous lesions in renal biopsy specimens, with resolution of the nephrosis after tumor treatment. The presence of anti–phospholipase A 2 receptor (PLA 2 R) antibodies may be helpful in differentiating idiopathic from secondary malignancy–associated membranous nephropathy. Minimal change lesions in renal biopsy specimens have also been noted in conjunction with Hodgkin’s and non-Hodgkin’s lymphoma in the elderly. Given this association, a thorough history taking, physical examination, and basic screening to rule out a secondary malignant cause should be considered in elderly patients with new-onset nephrosis.


Retrospective studies and meta-analysis of randomized trials as well as pooled analysis of randomized prospective and case series suggest that use of steroids alone for the treatment of membranous lesions has little impact on the rate of renal functional decline in the elderly, although the incidence of CKD is noted to be greater in the elderly, likely owing to decreased functional reserve. Although treatment with steroids and cytotoxic agents may lead to partial or complete remission, individual risk/benefit assessment is important given the high risk of infection in the elderly. Case series of minimal change lesions in the elderly suggest that such lesions may respond to steroid use alone; however, the response to both steroids and cytotoxic agents is less than for younger patients. Older patients with minimal change disease seem to experience relapse less frequently and have more stable remissions after cyclophosphamide treatment.


Evaluation for primary and secondary amyloidosis should be included in the elderly patient presenting with nephrotic syndrome; Congo red staining of renal or other tissue signifies the presence of amyloid fibrils, confirming the diagnosis. In a small number of elderly patients, generalized global sclerosis can also manifest as nephrotic proteinuria caused by undiagnosed processes that lead to renal scarring, with hypertension hastening this process.


Based on limited data, recommendations for treatment of glomerular diseases are to select and tailor therapy for the elderly using the same criteria as for younger individuals. Treatment with medications requires cautious dosing and careful follow-up because drug metabolism and renal excretion are altered in the elderly, raising the risk of drug toxicity.


Chronic Kidney Disease


CKD increases in prevalence with age and heralds a poor outcome. Recognized as a global public health problem, CKD with eGFR less than 60 mL/min/1.73 m 2 is present in approximately 38% of U.S. adults 70 years and older. CKD in the elderly is associated with a greater risk of kidney failure and CVD, including ischemic stroke and death. A high risk for all-cause and CVD mortality has been described in community-dwelling elderly individuals with CKD, particularly those with an eGFR of less than 45 mL/min/1.73 m 2 and in men. Frailty is also more prevalent among older patients with CKD than among those with normal renal function, and cognitive impairment increases in older CKD patients independently of other confounding factors, although the full extent of the burden of CKD in the elderly is yet to be known.


AKI can hasten the progression of CKD secondary to medical disease such as diabetes, hypertension, chronic GN, and renovascular and obstructive nephropathy. In addition, prolonged use of analgesics, frequently seen in the elderly, may be associated with papillary necrosis and progression to CKD. Similarly, decompensated medical illness can result from gradual CKD progression even though frank uremic symptoms are absent. Older individuals may experience episodes of volume overload and symptoms of heart failure, gastrointestinal bleeding, hypertension, or gradual confusion that indicate progression of renal loss. Interestingly, the most common cause of death in elderly patients with CKD is CVD rather than the progression of kidney disease to kidney failure, whereas in patients younger than 65, renal replacement is more common.


Therefore, cardiovascular risk management remains important in elderly patients with CKD. Estimates of renal function from serum creatinine levels alone may be inadequate in the elderly, given the changes in muscle mass with age. Although the accuracy of available formulas for estimating GFR in the elderly continues to be investigated, the MDRD and CKD-EPI equations may be useful. Validation studies suggest comparable accuracy for the CKD-EPI (cr) equation in both young and elderly patients.


Renal Replacement Therapy


A significant number of elderly diagnosed with ESKD initiate RRT. The number of octogenarians and nonagenarians starting dialysis has nearly doubled, rising from 7054 persons in 1996 to 13,577 persons in 2003, with the 2013 report of initiation of dialysis in a centenerian. In a retrospective analysis of patient survival among those older than 75 years who had stage 5 CKD, the 1- and 2-year survival rates were 84% and 76%, respectively, in the group receiving dialysis compared with 68% and 47%, respectively, in the group treated conservatively. This survival advantage was lost in patients with multiple comorbid conditions, particularly in those with ischemic heart disease. In-center hemodialysis is the modality of choice for 96% of those older than 75 years. Approximately 19% of the elderly undergo peritoneal dialysis. Although no clear modality advantage exists in the elderly, some studies suggest a higher mortality in elderly patients receiving peritoneal dialysis, particularly in those with diabetes. For either modality, overall survival for the elderly is shorter than that for younger patients, as would be expected. Thus, the choice between hemodialysis and peritoneal dialysis should remain individualized in the elderly, with consideration given to medical and psychosocial factors.


For maintenance hemodialysis, an arteriovenous fistula (AVF) is the preferred access, particularly in the elderly, because it is associated with a lower incidence of infectious complications. Concern for fistula maturation is not unique to older patients, and thus age should not be a limiting factor in AVF creation given the equivalent procedural and fistula survival rates in younger and older patients. Factors limiting fistula creation such as significant vascular disease and cardiovascular instability may be more prevalent in the elderly. Retrospective analysis or United States Renal Data System (USRDS) data adjusted for vascular disease, diabetes, nutritional status, gender, and race suggest little difference in mortality benefit between AVF and arteriovenous graft (AVG) placement. The prevalence of central venous catheter use for maintenance hemodialysis is reported to be as high as 24% in Europe and 28% in North America. Although AVF remains an optimal choice for hemodialysis access in the elderly, AVG and central venous catheters continue to be prevalent access options in the elderly. Similarly, peritoneal dialysis may be an option for elderly patients who experience hemodynamic instability during hemodialysis. There is little difference between older and younger patients in the likelihood of technique failure, number of peritonitis episodes, and types of infections, and fewer peritoneal catheter replacements are actually required in older patients.


RRT in the elderly patient heralds important problems requiring careful medical management. Clearance levels of numerous concurrent medications required for comorbid conditions in the elderly change with ESKD and dialysis. Elderly patients undergoing dialysis may be more prone to hypoglycemia because of prolonged insulin clearance, poor intake, and decreased sympathetic response due to other medications. Therefore, close monitoring of medications and careful attention to detect subtle changes in the clinical condition of the elderly patient undergoing dialysis are essential. Despite limited survival of some patients, many elderly patients have a high quality of life while undergoing dialysis, and they should not be denied treatment on the basis of chronologic age alone. On the other hand, among 3702 nursing home residents in the United States for whom dialysis treatment was started between June 1998 and October 2000, initiation of dialysis was associated with a substantial and sustained decline in functional status. Prospective data from the Australian and New Zealand Dialysis and Transplant Registry show that patients 75 years or older at dialysis initiation with median follow-up between 2 and 3 years have a 1.24 hazard ratio for death for every 5-year increase in age. The presence of low body mass index (<18.5), the number of comorbidities, and late referral added further to higher mortality in this population. Dialysis should not be used only to prolong the dying process. Symptom relief and maintenance of independence should be considered the main goals of treatment.


Renal Transplantation


Age alone does not necessarily preclude candidacy for renal transplantation for those medically eligible. As the subset of older patients with ESKD grows, there is a shift toward older renal transplant candidates while kidney allocation remains skewed toward younger recipients. The 2013 Scientific Registry of Transplant Recipients reports that approximately 40% of all candidates waiting for transplant are between 50 and 64 years old and 18% are 65 years or older. In 2011, 60% of kidney transplant recipients were older than 50 years, of whom 18% were older than 65 years. The proportion of older patients receiving kidney transplants in relation to the number of older patients wait-listed to receive transplants are similar to the proportion of younger recipients of kidney transplants compared with younger wait-listed patients. Although younger transplant recipients experience a higher number of healthy life-years, older patients undergoing transplantation have a significant survival advantage over those remaining on dialysis. The overall risk of death is 41% lower for older kidney transplant recipients than for wait-listed candidates, with survival advantage also noted for recipients of extended criteria donor (ECD) kidneys.


In one study, patients 60 years and older who did not undergo transplantation had an overall 2.54 times higher adjusted risk of death than patients of the same age who did receive transplants, regardless of the type of graft; when data were stratified by donor graft type, risk of death was 3.78 times higher for patients receiving non-ECD donor grafts and 2.31 times higher for those receiving ECD grafts. Allograft type affects recipient survival in recipients 65 years and older, with 2009 registry data suggesting better survival rates for living donor grafts than for both deceased non-ECD grafts and deceased ECD donor grafts ( Table 24.1 ) at 3 months, 1 year, and 5 years. Allograft survival is similarly excellent after 3 months, 1 year, and 5 years for recipients 65 years and older, with living donor allografts faring best, followed by deceased non-ECD grafts and deceased ECD grafts (see Table 24.1 ).


Feb 6, 2019 | Posted by in NEPHROLOGY | Comments Off on Aging and Kidney Disease
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