Ageing Research Reviews 14 (2014) 65–80

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Ageing Research Reviews journal homepage: www.elsevier.com/locate/arr

Review

The aging kidney revisited: A systematic review Davide Bolignano a,∗ , Francesco Mattace-Raso b , Eric J.G. Sijbrands b , Carmine Zoccali a a b

CNR-IFC, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension of Reggio Calabria, Italy Department of Geriatric and Internal Medicine, Erasmus Medical Center of Rotterdam, The Netherlands

a r t i c l e

i n f o

Article history: Received 9 December 2013 Received in revised form 5 February 2014 Accepted 6 February 2014 Available online 15 February 2014 Keywords: Renal aging Renal senescence Chronic kidney disease Renal function decline Aging processes

a b s t r a c t As for the whole human body, the kidney undergoes age-related changes which translate in an inexorable and progressive decline in renal function. Renal aging is a multifactorial process where gender, race and genetic background and several key-mediators such as chronic inflammation, oxidative stress, the renin–angiotensin–aldosterone (RAAS) system, impairment in kidney repair capacities and background cardiovascular disease play a significant role. Features of the aging kidney include macroscopic and microscopic changes and important functional adaptations, none of which is pathognomonic of aging. The assessment of renal function in the framework of aging is problematic and the question whether renal aging should be considered as a physiological or pathological process remains a much debated issue. Although promising dietary and pharmacological approaches have been tested to retard aging processes or renal function decline in the elderly, proper lifestyle modifications, as those applicable to the general population, currently represent the most plausible approach to maintain kidney health. © 2014 Elsevier B.V. All rights reserved.

Contents 1. 2. 3. 4.

5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology of renal function decline with age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Issues with assessment of renal function in the elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Factors associated with renal aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Gender . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Race . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Oxidative stress and the nitric oxide system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Angiotensin-II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.6. Impairment in kidney repair ability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.7. Chronic inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.8. Cardiovascular disease and risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Structural and functional changes in the aging kidney . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Glomerular changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Tubulo-interstitial changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Vascular changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Endocrine changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.1. Renal autacoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.2. RAS system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.3. Erythropoietin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.4. Vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

66 66 66 68 68 68 68 70 70 71 71 71 72 72 73 73 73 74 74 74 74

∗ Corresponding author at: CNR-IFC, Istituto di Biomedicina, Epidemiologia Clinica e Fisiopatologia, delle Malattie Renali e dell’Ipertensione Arteriosa, c/o Euroline Via Vallone Petrara n. 55/57, 89124 Reggio Calabria, Italy. Tel.: +39 0965 397012; fax: +39 0965 26879. E-mail address: [email protected] (D. Bolignano). http://dx.doi.org/10.1016/j.arr.2014.02.003 1568-1637/© 2014 Elsevier B.V. All rights reserved.

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6. 7.

D. Bolignano et al. / Ageing Research Reviews 14 (2014) 65–80

Future perspectives for retarding renal aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Human lifespan has substantially increased over the last century and the projected increase of elderly people over the next two future decades is impressive. Persons aged 65 years or more were 420 million in 2000 (United, 2010). By 2030, the number of these individuals is expected to be 550–973 million (US Census Bureau, 2005). By that date, elderly people will account for approximately 20%, 24.8% and 33% of the global population in the US, China and Europe respectively, exceeding the number of children below 15 years (Centers for Disease Control and Prevention, 2006). The average age is now 76.5 years in economically developed- and 65.4 years in economically developing-countries. Population based studies documented that impaired renal function is common in the elderly. In the US population, renal dysfunction has a 15% prevalence in persons older than 70 years (Coresh et al., 2007). In the third National Health and Nutrition Examination Survey (NHANES III), 35% of the elderly population had stage 3 chronic kidney disease (CKD) (Coresh et al., 2003). The prevalence of the most severe CKD stage (stage 5 or end-stage kidney disease; ESKD) is age-dependent (Coresh et al., 2003; Kiberd and Clase, 2002). In the United States Renal Data System (USRDS) the prevalence of the age-stratum 65–74 years is 11% and 14% for those older than 75 years (National Institute of Health, 2009) and similar findings have been reported also in European cohorts (John et al., 2004; Jungers et al., 1996; Magnason et al., 2002). In this systematic review we describe the main anatomical and functional changes in the kidney associated with senescence and will provide updated information on the main molecular and biological pathways involved in renal aging. The criteria adopted for literature search and selection for this review are detailed in Fig. 1. 2. Epidemiology of renal function decline with age Changes in renal function associated with aging have been estimated in 9 cross-sectional and in 3 cohort studies. In these studies, the annual average GFR reduction ranged from 0.4 to 2.6 mL/min (Table 1). The cross-sectional nature of most of these analyses and the fact that four of them were performed in living kidney donors (Fehrman-Ekholm and Skeppholm, 2004; Poggio et al., 2009; Rule et al., 2004, 2010), a highly selected population where the absence of CKD and other co-morbidities is a pre-requisite for kidney donation, limits the generalizability of these findings and leaves open the question whether the decline in renal function is an inexorable process.

Fig. 1. Review criteria.

74 75 75 75

In studies based on inulin clearance performed in the fifties in a group of 70 men, including healthy volunteers but also hospitalized patients affected by hypertension, cancer, arteriosclerosis and various infective diseases, the GFR was by the 46% lower in the very old (90 years) as compared to the young people (Smith, 1951) and these findings were confirmed in a survey based on urea clearance (Davies and Shock, 1950). In the Baltimore Longitudinal Study of Aging (BLSA) (Lindeman et al., 1985), a longitudinal study based on serial creatinine clearance measurements in 254 men without kidney disease or hypertension, the average decline in GFR was 0.75 mL/min/year, an estimate very close to that described in a recent cross-sectional study in 1203 living kidney donors (0.63 mL/min/year) (Rule et al., 2010). In the Baltimore study, the rate of GFR loss was tripled (∼1.51 mL/min) in subjects aged 40–80 years as compared to subjects aged 20–39 years (0.26 mL/min). Similar observations were reported more recently in a longitudinal study in healthy Chinese people (Jiang et al., 2012). Both in the Baltimore (Lindeman et al., 1985) and in the Chinese (Jiang et al., 2012) study the GFR remained constant overtime in 36% and 44% of subjects respectively. In the Bronx longitudinal age study (Feinfeld et al., 1995, 1998) in very elderly subjects, just a small increase in serum creatinine occurred after 3 years in long term survivors and similar observations were reported in a subgroup of 31 subjects with mildly raised serum urea at baseline, suggesting that renal function decline may not be an obligatory consequence of the aging process. In a cross-sectional analysis of the BLSA study (Rowe et al., 1976a) focusing on 548 healthy subjects, creatinine clearance was 140 mL/min/1.73 m2 at age 30 to fall to 97 mL/min/1.73 m2 at age 80. In the inception cohort of the Nijmegen Biomedical Study (Wetzels et al., 2007), including 869 apparently healthy persons aged > 65 years, the annual GFR decline (as estimated by the MDRD185 formula) was approximately 0.4 mL/min/year. In a mixed population of adults aged ≥ 65 years including participants with major co-morbidities (CKD included), the InCHIANTI study, creatinine clearance estimated by the Cockcroft formula showed a 2.6 mL/min/year decline over a 3-year follow up (Lauretani et al., 2008). Overall, these studies clearly document that on average renal function declines overtime but also show that in about one third of elderly individuals the GFR remains remarkably constant. 3. Issues with assessment of renal function in the elderly Because sarcopenia and body weight loss reduce the daily generation of creatinine and creatinine levels are influenced by protein intake and hydration, these factors concur in making serum creatinine a suboptimal indicator of renal function in the elderly (Fliser, 2008). The reference range for creatinine considered as normal in the healthy young is inappropriately high in the elderly and serum values in the upper normal range may underlie early renal dysfunction (Kimmel et al., 1996). In 20 years old individuals a creatinine value of 1 mg/dL may correspond to an estimated GFR of 120 mL/min while the same value in 80 years-old persons might reflect an eGFR of 60 mL/min (Musso, 2002; Musso et al., 2009; Swedko et al., 2003). Traditional formulas for GFR estimation based on serum creatinine are notoriously unreliable in the elderly, particularly in the presence of multiple co-morbidities (Drusano et al., 1988; Fliser et al., 1997). In old subjects, GFR is systematically underestimated by the Cockcroft–Gault (CG) formula

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Table 1 Main studies on renal function decline with aging. Author

Year

Methods

Results

Davies and Shock (1950)

1950

- Linear 46% decline in mGFR from 123 (at the age of 30) to 65 (at the age of 89) mL/min/1.73 m2 .

Smith (1951)

1951

Rowe et al. (1976a)

1976

Lindeman et al. (1985)

1985

- Cross-sectional analysis of a miscellaneous population of 70 men aged 25–89 years including healthy subjects and hospitalized patients. - mGFR by inulin clearance. - Cross-sectional analysis of general population. - Renal function measured as urea clearance. - Cross-sectional analysis of an inception cohort of 548 men (aged 20–80 years) from the BLSA. - eGFR by creatinine clearance. - Prospective study of an inception cohort of 254 men (aged 20–80 years) without kidney disease from the BLSA followed over 5 to 14 years. - eGFR by creatinine clearance.

Feinfeld et al. (1995, 1998)

1995

Rule et al. (2004)

2004

Fehrman-Ekholm and Skeppholm (2004)

2004

Wetzels et al. (2007)

2007

Lauretani et al. (2008)

2008

Poggio et al. (2009)

2009

Rule et al. (2010)

2010

Jiang et al. (2012)

2012

- Prospective study of 141 very elderly subjects followed over 6 years. - Renal function assessed by BUN and serum creatinine. - Retrospective analysis of 365 potential living kidney donors. - mGFR by iothalamate clearance, eGFR by MDRD and Cockroft–Gault formulas. - Cross-sectional analysis of 52 elderly “healthy” persons aged 70–110 years. - mGFR by iothalamate, eGFR by Cockroft–Gault, MDRD and Walser formulas. - Cross-sectional study of an “healthy” inception cohort of 3732 subjects from the Nijmegen Biomedical Study, of whom 869 were elderly (age > 65 years). - eGFR by MDRD. - Cross-sectional and prospective analysis (3 years follow-up) of 931 adults (aged ≥ 65 years) from the InCHIANTI study. - eGFR by Cockroft–Gault formula. - Cross-sectional analysis of 1057 prospective kidney donors. - mGFR by iothalamate clearance. - Cross-sectional analysis of 1203 adult living kidney donors. - mGFR by iothalamate clearance, eGFR by MDRD and Cockroft–Gault formulas. - Prospective study of middle-aged and elderly 245 healthy individuals evaluated over a 5 years follow-up. - eGFR by creatinine clearance.

- Decrease in urea clearance from 100% at the age of 30 years to 55% at the age of 89 years. - Progressive linear decline (31%) in eGFR from 140 (at age 30) to 97 (at age 80) mL/min/1.73 m2 . - The mean decrease in eGFR was 0.75 mL/min/year. - Annual eGFR changes were different between the age class 20–39 (0.63 mL/min/year) and 40–80 (1.51 mL/min/year). - 36% of all subjects followed had no absolute decrease in renal function. - A small group of patients showed a statistically significant increase in creatinine clearance with age. - Small but significant decline in BUN and creatinine at 3 years, which persisted at 6 years. - Men at the age of 20 years had an estimated mean GFR of 129 mL/min that declined by 4.6 mL/min/decade. - Women at the age of 20 years had a mean GFR of 123 mL/min that declined by 7.1 mL/min/decade. - mGFR decreases by approximately 1.05 mL/min per year in very old persons.

- eGFR declined by 0.4 mL/min/year

- eGFR declined by 2.6 mL/min/year

- mGFR was reduced by 1.49 ± 0.61 mL/min/1.73 m2 per decade of testing. - Significant doubling in the rate of GFR decline in donors over age 45 as compared to younger donors. - Reduction in mGFR by 6.3 mL/min per decade

- eGFR decreased from 98.1 ± 15.6 to 90.4 ± 17.3 mL/min/1.73 m2 . - 43% of participants did not experience a decline in eGFR during follow-up.

BLSA, Baltimore Longitudinal Study of Aging; BUN, Blood Urea Nitrogen; eGFR: estimated glomerular filtration rate; mGFR, measured glomerular filtration rate; MDRD, modification of diet in renal disease (formula).

(Cockcroft and Gault, 1976; Fliser et al., 1999). The Modification of Diet in Renal Disease (MDRD) MDRD equation is generally considered more accurate than the CG to estimate GFR in old people (Levey et al., 2003). However, like the CG formula, the MDRD equation has not been specifically validated in the elderly and the discordance of estimates between these two formulas is such that the MDRD GFR may be by the 60% higher than the CGGFR in patients over 65 years (Berman and Hostetter, 2007). In a study involving 100 individuals aged 65–111 years no correlation was found between the two formulas (Wieczorowska-Tobis et al., 2006). In the elderly cohort of the InCHIANTI study, creatinine clearance 90 mL/min/1.73 m2 ). In this meta-analysis there was no effect modification by age on the cardiovascular risk associated with reduced GFR. In elderly individuals aged ≥75 years with GFR 45–59 mL/min/1.73 m2 the risk for end stage kidney disease was similar to that found in individuals aged 18–54 years with the same GFR, i.e. four times higher than that in individuals of the same age-categories and a GFR = 80 mL/min/1.73 m2 (Hallan et al., 2012). No classification system is perfect and clinical judgment is important, particularly around the diagnostic thresholds. Therefore, when evaluating the GFR in the elderly, clinicians should consider co-morbid conditions, life expectancy and the time-trajectory of GFR.

4. Factors associated with renal aging Renal senescence is a complex, multifactorial process characterized by anatomical and functional changes accumulating during life span. Several factors, spanning from the genetic background to chronic inflammation, exposure to chronic diseases and environmental factors generate a “multi-hit” scenario where the renal phenotype of elderly individuals shows high inter-individual variability (Figs. 2 and 3). 4.1. Gender In experimental models, male gender enhances the age-related decline in renal function (Baylis and Wilson, 1989; Reckelhoff et al., 1997b). Accelerated GFR loss in males is androgen-dependent (Reckelhoff et al., 1997b). Castration in mice limits reno-vascular aging (Tanaka et al., 1995) while therapy with estrogens may prevent this phenomenon (Maric et al., 2004). Studies of the effect of aging on renal function and anatomy abound but mechanistic knowledge on gender-dependent influence on this phenomenon is limited (Gandolfo et al., 2004). 4.2. Race Black race is an established risk factor for kidney dysfunction and for the risk of progression to end stage kidney failure (Derose et al., 2013; Peralta et al., 2013), particularly in diabetic patients (Krop et al., 1999). African descent is strongly associated with the risk of hypertensive nephrosclerosis (Marcantoni et al., 2002). 4.3. Genetics The genetic background plays a major role in renal senescence and genotypes exist which regulate the number of nephrons during life (Martin and Sheaff, 2007). Epigenetics – the process whereby neutral cells evolve into highly differentiated cells to constitute specialized tissues – has a prominent role in kidney aging.

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Fig. 3. Macroscopic and microscopic changes in the aging kidney and risk factors.

Regulatory genes and post-transcriptional processes, such as acetylation and methylation, are crucial for the control of the differentiation of kidney cells and for maintaining cell function during life span. In a rat model of normal aging (Wiggins et al., 2010), there is de novo glomerular expression of proteins which remains silenced in the young glomerulus. Accelerated renal aging including diffuse glomerulosclerosis and interstitial fibrosis occurs in differentiated podocytes after manipulation of methylation pathways (Lefevre et al., 2010). Fusion of foot processes and disorganization of foot structures in podocytes as well as proteinuria are hallmarks of aging kidneys in the rat and these alterations set the stage for glomerular rarefaction and functional decline. Spontaneous gene mutations in somatic and mitochondrial DNA accumulate with normal aging in kidney cells (Martin et al., 1996). Premature aging in the progeria syndrome is characterized by focal renal scarring, glomerulosclerosis, tubular atrophy and interstitial fibrosis and associates with mutations in genes involved in DNA repair, transcription and replication (Delahunt et al., 2000). Functional genomics studies showed that over 500 genes are differently expressed in human kidneys across age-strata encompassing neonate’s (8 weeks) and elderly’s kidneys (88 years). Kidneys of elderly individuals overexpress proteins involved in the immune response, inflammation, extracellular matrix synthesis and turnover while under-express genes involved in oxidative processes, lipid and glucose metabolism and collagen degradation (Melk et al., 2005a). In another study, more than 900 different agedependent genes were identified and the expression of these genes changed in parallel in the cortex and in the medulla (Rodwell et al., 2004). Genes that impact upon the aging process and influence

life span have been identified (Kwon et al., 2010). However, only some of these seem to be involved in kidney aging. The senescence marker protein (SMP) 30-knockout mouse displays accumulation of lipofuscin and electron-dense material and lysosomial enlargement in the proximal tubules, which are alterations peculiar to kidneys of elderly individuals (Yumura et al., 2006). Polymorphisms in the alpha-adducin gene predicted renal function decline in a population-based study in apparently healthy Chinese people (Lin et al., 2012). In vivo, senescent renal cells, particularly in the renal cortex, express high levels of cellular proliferation inhibitors, such as p16 and p27 (Chkhotua et al., 2003), and the expression of these proteins goes along with the severity of age-associated glomerulosclerosis, tubular damage and interstitial fibrosis (Melk et al., 2004). The target of rapamycin (TOR) is a highly conserved gene pathway modulating the influence of nutrients on life span (Kapahi and Zid, 2004). Selective TOR-inhibition dramatically increases life span and this effect is prevented by caloric restriction (Kapahi et al., 2010). TOR expression increases with age in rat kidneys, particularly so in mesangial cells, and the inhibition of this pathway by rapamycin attenuates the aging-related phenotype in this model (Zhuo et al., 2009). The sirtuins (SIRT), a gene family homolog of the Silent information regulator 2 (Sir2) gene (Michan and Sinclair, 2007), are also implicated in renal aging. Sir2, another highly conserved longevity gene, is implicated in nutrient-dependent changes in life span (Rogina and Helfand, 2004) as well as in the prevention of DNA damage (Herranz and Serrano, 2010). SIRT-6 knock-out rats are characterized by premature aging in various organ systems including the kidney (Mostoslavsky et al., 2006). SIRT-1

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over-expression promotes antifibrotic and antiapoptotic effects in renal interstitial cells and caloric restriction slows-down kidney aging by enhancing SIRT-1-mediated mitochondrial autophagy in mice (Kume et al., 2010). Klotho is perhaps the most powerful “aging-suppressor” gene (Kurosu et al., 2005). The Klotho knock-out mouse exhibits agingrelated diseases like atherosclerosis, osteoporosis, vascular and tissue calcifications and chronic kidney disease (Kuro-o et al., 1997) and genetic polymorphisms in the Klotho gene have been associated with altered life span (Arking et al., 2002), accelerated vascular disease (Arking et al., 2003) and osteopenia (Ogata et al., 2002). Klotho operates in concert with FGF-23 because the main receptor for this growth factor, the FGF receptor, is activated by FGF-23 only in the presence of Klotho in most tissues (Razzaque and Lanske, 2007). In the kidney, Klotho is predominantly expressed in the distal convolute tubule. Furthermore, Klotho exerts a series of potentially nephroprotective actions including: (1) reduction of oxidative stress via inhibition of the insulin/IGF1 signaling and induction of the manganese superoxide dismutase (Kuro-o, 2008); (2) fine-tuning of calcium-phosphorus homeostasis by down-regulation of vitamin-D synthesis and phosphaturia (Tsujikawa et al., 2003); (3) modulation of calcium channel activity in renal tubular cells (Chang et al., 2005); (4) regulation of endothelium-dependent vascular reactivity (Nagai et al., 2000). Sustained oxidative and metabolic stress (Nagai et al., 2000), angiotensin-II (AT-II) (Saito et al., 2003) and chronic kidney disease (Koh et al., 2001) down-regulate Klotho m-RNA expression. Transfection of the Klotho gene attenuates tubular–interstitial fibrosis and vascular wall thickening in renal vessels induced by chronic AT-II stimulation (Mitani et al., 2002). Thus, Klotho hypo-regulation might at least in part explain the link between renin–angiotensin system and renal senescence (see below). Telomeres, the nucleoprotein complexes located at the end of chromosomes which serve to prevent the fusion and degradation of chromosomes, are synthetized by the enzyme telomerase. Kidney cells do not express the enzyme telomerase (Melk, 2003). Therefore in these cells telomeres shorten progressively after each cell division, a process triggering cellular and organ senescence (Jiang et al., 2007). In the human kidney, telomeres shortening increases with age and is more rapid in the cortex (Melk et al., 2000). Telomerasedeficient mice show reduced glomerular, tubular and interstitial cell proliferative capacity and limited ability to recover after acute kidney injuries (Westhoff et al., 2010). MicroRNAs (miRNAs) are fundamental modulators of cell function which regulate important biological events like cell-differentiation and apoptosis. Global disruption of miRNAs in mice is associated with rapidly progressive chronic kidney disease (Harvey et al., 2008). However, studies of renal aging based on selective manipulation of the m-RNA system are lacking and the possibility of interfering with kidney senescence at m-RNA level is still little explored. 4.4. Oxidative stress and the nitric oxide system Free-radicals generation increases with lifespan (MendozaNunez et al., 2007). A substantial increase in kidney levels of oxidative stress markers like F2 isoprostanes, advanced glycosylation end-products (AGEs) and their receptors (RAGEs) occurs in the aging kidney (Reckelhoff et al., 1998). As to the AGE-RAGE system, it was found that aging also de-regulates kidney expression of AGE-R1, a receptor preventing AGEs-mediated injury (Lu et al., 2004). AGEs and circulating RAGEs are independently associated with decreased renal function and predict GFR decline in elderly community-dwelling women (Semba et al., 2009). In a secondary analysis of the BLSA cohort, serum levels of l-carboxymethyl-lysine (CML), one of the main AGE products, were independently associated with CKD and eGFR (Semba et al., 2010). AGEs promote

degradation of the hypoxia-inducible factor (HIF)-1␣, thereby limiting the response of renal cells to hypoxia. This phenomenon attenuates the secretion of EPO and the release of VEGF, a growth factor crucial for angiogenesis (Frenkel-Denkberg et al., 1999). AGEs and other oxidants reduce telomeres length and cell lifespan (see above) (Houben et al., 2008). Furthermore, AGEs are powerful inhibitors of Nitric oxide (NO)-synthase (NOS) activity in renal tubular cells (Long et al., 2005b; Verbeke et al., 2000). Reduced NO bioavailability plays a major role in the structural and functional adaptations of the aging kidney. NOs inhibition by l-NAME produces a stronger vasoconstriction in old than in young renal vessels (Hill et al., 1997; Tan et al., 1998), suggesting that endogenous NO production is of particular relevance for the control of renal circulation in aging animals. In aging rats, total body NO generation is reduced (Hill et al., 1997; Xiong et al., 2001), particularly so in the endothelium of peritubular capillaries (eNOS), suggesting that the tubular–interstitial ischemia and fibrosis typically associated with renal senescence is at least in part causally related to oxidative stress-mediated NOS inhibition (Thomas et al., 1998). Female aging rats show relatively conserved levels of eNOS in renal capillaries (Erdely et al., 2003) and neuronal (n)NOS in renal cortex (Baylis, 2009) as compared to aging male rats, a phenomenon depending on the stimulatory effects of estrogens on eNOS synthesis. Renal microvasculature is particularly sensitive to the vasodilator effect elicited by NO, a response fundamental for the control of renal blood flow and pressure-natriuresis (Granger and Alexander, 2000; Hill et al., 1997). The endogenous inhibitor of NOS Asymmetric dimethylarginine (ADMA) accumulates in aging rats (Xiong et al., 2001) and high ADMA appears to be involved in telomeres shortening (Scalera et al., 2004). In elderly patients, high ADMA is a strong predictor of death and cardiovascular events (Pizzarelli et al., 2013). Notably, this methyl-arginine may be an important effector of the age-related decrease of renal perfusion because high circulating ADMA levels go along with reduced renal perfusion in old people (Kielstein et al., 2003). Oxidative damage derives mainly from free radicals generated during metabolic processes at cell level. However, high dietary oxidant load with diet may contribute as well. Studies based on the ARIC cohort documented that subjects with scavenger receptors defects and high-fat diets develop atherosclerosis and severe impairment in kidney function (Muntner et al., 2000). In the rat, a diet enriched of antioxidants (such as vitamin-E) reduces kidney RAGEs and F2 isoprostanes levels and increases the GFR by the 50% (Reckelhoff et al., 1998). Similarly, caloric restriction in aging rats increases kidney levels of ceruloplasmin, a powerful anti-oxidant produced by parietal epithelial cells of the Bowman’s capsule in response to aging (Wiggins et al., 2006). Lipofuscin, a complex found in the cytosol of aging cells, is formed by freeradicals damaged proteins and fats. This complex, which is resistant to degradation, substantially impairs mithocondrial function (Jung et al., 2007). In rat models, lipofuscin accumulation in the kidney is linearly related with age and lipofuscin cell levels are 28-fold higher in very old as compared to very young rats (Melk et al., 2003). 4.5. Angiotensin-II Angiotensin II (AT-II) regulates a variety of biological functions within the kidney including vascular tone, aldosterone release, tubular sodium reabsorption and sympathetic nerve stimulation. In addition, this peptide has important effects on cell plasticity in the kidney because it induces fibroblast differentiation into myofibroblasts, vascular hypertrophy, mitogenesis and promotes the release of various cytokines and growth factors (such as TGF-␤1) (Basso et al., 2005). AT-II receptors with opposite vascular effect exist. Indeed, the angiotensin receptor-1 (ATR)-1 mediates vasoconstriction while ATR-2 promotes NO/cGMP-mediated vasodilatation (Riordan, 1995). In addition, ATRs stimulation by AT-II via the MAPK

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and ERK pathways leads to endothelial senescence and triggers endothelial and muscle cells apoptosis (Shan et al., 2008a,b). ATR-1 in the kidney are more abundant than ATR-2. During lifespan, the number of ATR-2 increases, which would favor renal vasodilation. However, due to the reduced renal flow and the attenuated NOmediated vasodilatation discussed before, in the elderly the renal response to angiotensin-II is a sustained vasoconstriction (Carey, 2007). Furthermore, ATR-1 stimulation promotes mithocondrial damage and reactive oxygen species production, both of which in turn trigger age-related vascular changes (Percy et al., 2008). In the ATR-1 knockout mice, oxidative stress is markedly reduced in the kidney and in the hearth and renal tubular cells show a higher number of mithocondria as compared to wild-type controls (Benigni et al., 2009). Of note, ATR-1 knockouts also outlive the wild-type controls by 26% and this increase in lifespan has been attributed to an up-regulation in the kidney of genes associated with survival (such as the sirtuin-3 or the NAMPT). Accordingly, ATR-blockade by selective inhibitors effectively improves renal function and vascular structure in aging rats (Basso et al., 2005). 4.6. Impairment in kidney repair ability Cell proliferation is crucial for normal tissue turnover and for tissue regeneration. In the adult kidney less than 1% of renal cells maintain proliferating potential and this fraction further declines with aging (Cardani and Zavanella, 2000). Such phenomenon is multifactorial in nature and it is often defined as “cellular senescence” to differentiate irreversible and specific morphofunctional changes associated with physiological cellular aging from other forms of cell cycle arrest. In aged mice kidneys, a clear age-dependent decline in the proliferative potential of proximal tubular cells occurs after ischemia/reperfusion injury (Schmitt and Cantley, 2008), a phenomenon secondary to modifications of various cell-cycle regulators and to enhancement of apoptosis. The cyclin-independent kinase (CDK) inhibitor p16INK4A , a powerful blocker of the cell-cycle, is up-regulated in epithelial and interstitial cells of aging mouse and in human kidneys as well (Melk, 2003; Melk et al., 2005b). Similarly p21, a CDK-inhibitor which induces proliferative arrest, apoptosis and cellular hypertrophy, increases with age in rats (Ding et al., 2001). Both p16INK4A and p21 promote renal tubular senescence by enhancing telomeres shortening (Melk et al., 2000) and by upregulating the activity of senescence-related enzymes, such as ␤-galactosidase (Melk, 2003). The Caspase family includes several cysteine protease involved in apoptosis induction (Zhang et al., 2003). Caspases 3,9 and the caspase-9 activator cytochrome-c are upregulated in the kidney of aging rodents (Qiao et al., 2005; Zhang et al., 2003) as it is the pro-apoptotic protein Bax (Schmitt and Cantley, 2008). Conversely, the expression of Bcl-2, a powerful apoptosis inhibitor, is reduced in renal tissue of aging rats (Schmitt and Cantley, 2008). Overall, multiple alterations in systems controlling apoptosis explain the very high apoptosis rate in aging kidneys (Qiao et al., 2005; Thomas et al., 1998). As previously alluded to, this pro-apoptotic pattern can be largely prevented by a low-calories diet adopted at young age (Lee et al., 2004). Growth factors are key players in kidney repair and an agedriven impairment in the pathways activated by these factors has been advocated to explain the inadequate regenerative capacity of the aging kidney (Karihaloo et al., 2005). The expression of factors promoting cell recruitment and cell proliferation such as the epidermal growth factor (EGF), the insulin-like growth factor (IGF)-1 and the vascular endothelial growth factor (VEGF), decline in an age-dependent fashion (Chou et al., 1997; Kang et al., 2001; Shurin et al., 2007) while the expression of pro-fibrotic factors like transforming growth factor (TGF)-␤ and integrin-linked kinase (ILK) increases (Ding et al., 2001; Li et al., 2004). A variety of other factors

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have been implicated in the impaired repair ability of senescent kidneys. The potential role of these factors in kidney aging was reviewed in detail elsewhere (Famulski and Halloran, 2005). 4.7. Chronic inflammation Chronic inflammation, which is characterized by a progressive accumulation of macrophages and lymphocytes in the kidney interstitium, may induce or potentiate renal aging (Mei and Zheng, 2009). The main pathways whereby chronic inflammation may promote renal senescence have been already previously described. These mechanisms include the induction of fibrosis by inflammatory cells via pro-fibrotic factors, such as IL-4, IL-13 and TGF-␤, which increase production of type I and type IV collagen (Ding et al., 2001); the enhancement of cell apoptosis and extra-cellular matrix deposition by inflammatory cytokines, such as IL-1, IL-6 and TNF␣ (Lim et al., 2012); the increase in oxidative stress via ROS and AGEs generation (Mendoza-Nunez et al., 2007); the alteration in stem and progenitor cells reproductive capacities with consequent impairment in kidney repair capacities (Famulski and Halloran, 2005). In addition, chronic inflammation accelerates renal aging by inducing cell senescence (Melk, 2003). Senescent cells, in turn, elicit inflammation by secreting high amounts of inflammatory factors, which leads to a vicious cycle enhancing fibrosis and parenchymal involution (Mei and Zheng, 2009). In chronic kidney disease and transplant patients, biochemical markers of cell senescence such as the cell-cycle inhibitor p16, are inversely correlated with renal function (Melk et al., 2009). 4.8. Cardiovascular disease and risk factors The age-related decline in renal function is amplified in subjects with pre-existing cardiovascular disease and/or risk factors. In a cohort study of 1456 elderly individuals, the components of the metabolic syndrome and insulin resistance predicted the risks of prevalent and incident CKD (Cheng et al., 2012). Hypertension, a classical age-dependent disease (Hajjar and Kotchen, 2003; Kotchen et al., 1982), associates with typical changes in renal structure and function (Duarte et al., 2011). High BP amplifies age-related vascular stiffness and atherosclerosis and vice versa (Tracy, 1999). Endothelial dysfunction, disturbed regulation of the renin–angiotensin system and increased sympathetic tone are critical factors at the hypertension-renal aging interface. Furthermore, due to age-related tubular–interstitial alterations, elderly subjects are salt-sensitive, i.e. predisposed to aggravation of renal damage by hypertension-dependent and independent mechanisms when exposed to excessive salt intake (Ohashi et al., 1987). In this respect, it is well documented that salt-restriction programs in the elderly allows better blood pressure control and improve clinical outcomes (He et al., 2013). Even though the causal nature of the link of aging with hypertension, arterial stiffness and renal dysfunction is reasonably well established, in the healthy elderly cohort of the BLSA study BP failed to predict the age-associated decline in creatinine clearance (Danziger et al., 1990) while carotid intima-media thickness had no prognostic value for renal function in a community cohort in China (Han et al., 2010). In the Italian Longitudinal Study on Aging (ILSA) cohort in 2981 subjects aged 65–84 years with normal renal function (Baggio et al., 2005), renal function loss as defined by an increase in serum creatinine >26.5 ␮mol/L associated with current smoking status (OR = 2.3; 95% CI = 1.0–5.3), fibrinogen levels > 3.5 g/L (OR = 2.2; 95% CI = 1.6–3.3), diabetes (OR = 1.8; 95% CI = 1.1–2.8) and systolic hypertension (OR = 1.6; 95% CI = 1.0–2.6). Similarly, in the Cardiovascular Health Study (Bleyer et al., 2000; Edwards et al., 2005) smoking, systolic blood pressure, internal carotid artery thickness and retinal microvascular abnormalities

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Table 2 Main functional changes of the aging kidney (see text). Glomerular • ↓GFR Tubular • Impaired sodium balance • Impaired fluid balance • ↑ Potassium retention • ↓ Capacity to dilute urines • ↓ Capacity to lower urine pH Vascular • ↓ ERPF (mostly in the cortex; conserved in the medullary) • ↓ Capacity to lower urine pH • ↑ Filtration fraction • ↑ Post-glomerular RVRs • Impaired vasodilatory responses Endocrine • ↓ Plasma RA and aldosterone • ↑ EPO (in the healthy elderly) • ↓ EPO response to anemia • ↓ Vit-D activation EPO, erythropoietin; ERPF, effective renal plasma flow; GFR, glomerular filtration rate; RA, renin activity; RVRs, reno-vascular resistances.

independently predicted renal function decline overtime. Similar findings were reported in two large community-based cohort studies (Chonchol et al., 2008; Shlipak et al., 2009) and in a recent study we briefly alluded to before (Jiang et al., 2012). The severity of systemic atherosclerosis has been indicated as one of the major determinants of age-related glomerulosclerosis and decline in renal function (Kasiske, 1987). 5. Structural and functional changes in the aging kidney The main anatomic and functional modifications which characterize the aging kidney are summarized in Fig. 3 and Table 2. Kidney mass progressively increases from birth to the fourth decade of life, peaking at 250–270 g (Zhou et al., 2008a) and gradually regresses thereafter at a 10% reduction rate per decade (Gourtsoyiannis et al., 1990; Long et al., 2005a; Tauchi et al., 1971) (Fig. 4). In the seventh and eighth decades, kidney mass is therefore at least 20–30% less than in the fourth decade (Rao and Wagner, 1972) and the reduction is more pronounced in the renal cortex than in the medulla (Gourtsoyiannis et al., 1990; Griffiths et al., 1976). As expected, kidney size follows the same temporal trend (Tauchi et al., 1971). In a series of 1957 potential kidney donors undergoing pre-donation renal imaging studies by computer tomography kidney aging was accompanied by parenchymal calcifications and

Fig. 4. Renal size (%) by age among 360 healthy adults. The size of the right kidney in the group aged 20–29 was considered as reference value. Redrawn from Gourtsoyiannis et al. (1990).

Fig. 5. Sclerosis scores by age group among 1.203 living kidney donors. Sclerosis score defined as: (1) any global glomerulosclerosis, (2) any tubular atrophy, (3) interstitial fibrosis >5% and (4) any arteriosclerosis. In the figure a score of 0 is azure, a score of 4 is deep blue and intermediate scores are on a blue scale. Width of each age group is proportional to the population sample. Redrawn from Rule et al. (2010).

by a rising prevalence of simple renal cysts (Lorenz et al., 2011). From a microscopic point of view, the aging kidney displays glomerular, vascular and tubular–interstitial changes of various type which we will discuss in some detail in the following paragraphs. 5.1. Glomerular changes The number of glomeruli in the adult kidney ranges from 330,000 to 1,100,000 (Nyengaard and Bendtsen, 1992). Race, gender and birth weight are the main determinants of glomerulogenesis. The number of functioning glomeruli decreases during life-time (Hoy et al., 2003; Nyengaard and Bendtsen, 1992) while the proportion of hyaline and sclerotic glomeruli increases (Kaplan et al., 1975; Kappel and Olsen, 1980; McLachlan et al., 1977; Rule et al., 2010) (Fig. 5). Glomerular obsolescence goes along with intrarenal arterial changes, particularly with intimal fibroplasia (Kasiske, 1987). In very old living kidney donors, the prevalence of glomerulosclerosis, which can be as high as 70% (Rule et al., 2010), can be predicted by the formula: (age/2)-10 (Smith et al., 1989). Sclerotic glomeruli prevail in the subcapsular cortical zone in the elderly (Newbold et al., 1992) and glomerulosclerosis purely attributable to aging is a multifactorial process which should be suspected when the renal interstitium shows scarce infiltration in the absence of changes characteristically seen in hypertensive and diabetic patients. Human podocytes are unable to undergo cell division and the number of these cells decreases with age (Smeets et al., 2009; Steffes et al., 2001). In aged rats, podocytes undergo hypertrophy which eventuates in apoptosis, podocytopenia and glomerulosclerosis (Wharram et al., 2005; Wiggins et al., 2005). Brenner hypothesis of renal aging holds that an altered control of glomerular hemodynamics increases glomerular plasma flow and intra-capillary pressure, leading to glomerulosclerosis (Brenner, 1983; Hill et al., 2003). Glomeruli spared from this process are hyper-perfused and hypertrophic and these functional adaptations may serve to maintain global glomerular filtration rate (Abdi et al., 1998; Li et al., 2002; Samuel et al., 2005; Tan et al., 2009). However, this process becomes “maladaptive” in the long term, because glomerular hyperperfusion goes along with glomerular hypertension (Brenner, 1983). Low glomerular density is a powerful predictor of renal function decline in patients with glomerulonephritides (Tsuboi et al., 2010, 2011). In elderly donors glomerular density is related in an inverse fashion to the proportion of sclerotic glomeruli (Rule et al., 2011). Glomerular basement membrane thickening is another

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typical feature of the aging glomeruli (Anderson and Brenner, 1986) as it is mesangial expansion (Musso and Oreopoulos, 2011). Direct shunts between afferent and efferent arterioles bypassing the glomerulal tuft in iuxta-medullary nephrons is an additional anatomo-pathological alteration commonly seen in kidneys of elderly subjects (Hoang et al., 2003; Musso and Oreopoulos, 2011). 5.2. Tubulo-interstitial changes The age-dependent decline in renal size and renal mass rests more on tubulo-interstitial changes than on glomerular or vascular changes (Bohle et al., 1987; Nath, 1992) and the same holds true for renal function (Bohle et al., 1987). As described for glomeruli, the overall number of tubules decreases with age (Lindeman and Goldman, 1986). Tubular length and volume are also markedly reduced and sparse areas of scarring, tubular atrophy and tubular diverticula are common in kidneys of elderly individuals (Kappel and Olsen, 1980; Laucks and McLachlan, 1981; Piepsz, 2001). Tubular diverticula localize mainly in the distal convolute tubule and in the collecting duct and may give rise to form simple renal cysts (Baert and Steg, 1977), an alteration observed in about a half of subjects ≥40 years (Tada et al., 1983). Tubular dilatation may be accompanied by accumulation of hyaline material and basement membrane thickening. When extended, this process may lead to a sort of “thyroidization” of the kidney, a common feature in end-stage kidney disease. Wrinkling and thickening of basement membrane and simplification of the tubular epithelium is frequently observed in old kidneys, while the so called “endocrine” transformation with thin basement membranes and numerous mitochondria is a relatively rare involution pattern (Lindeman and Goldman, 1986). Expanded interstitial volume, infiltration of mononuclear cells and diffuse areas of fibrosis are all hallmarks of the aging kidney (Martin and Sheaff, 2007). Excessive collagen deposition and structural changes in extracellular matrix, altered regulation of the expression of metalloproteinases and TGF-␤, activation of fibrosis- and hypoxia-related genes all concur to the pathogenesis of tubulo-interstitial fibrosis in aging kidneys (Abrass et al., 1995; Reckelhoff and Baylis, 1992; Ruiz-Torres et al., 1998; Tanaka et al., 2006). Alterations in tubular function go along with anatomical involvement. Enhanced proximal sodium reabsorption coupled to reduced distal fractional reabsorption allows maintenance of a normal sodium balance under steady-state conditions in the elderly (Fliser et al., 1997). However, this functional resetting limits the ability to conserve sodium in response to low salt intake and makes elderly people predisposed to volume depletion and acute kidney injury (Epstein and Hollenberg, 1976). Inadequate activation of the renin–angiotensin system and reduced aldosterone secretion (hyporeninemic hypoaldosteronism) play a leading role into this phenomenon (Crane and Harris, 1976) as well as in nocturnal natriuresis, another frequent alteration in old people (Baylis, 1993; Luft et al., 1987). On the other hand, aged individuals display also a relative inability to excrete sodium excess in response to salt load, a multifactorial alteration predisposing to salt retention, hypertension and cardiovascular congestion. Resistance to the natriuretic effect of atrial natriuretic peptide is a key step into this process (Ohashi et al., 1987). Alterations in tubular handling of electrolytes extend to potassium. Due to tubular atrophy and tubular–interstitial scarring, Na-K ATPase activity is reduced in the elderly, resulting in a high risk for hyperkalemia. Reduction in GFR, hyporeninemic–hypoaldosteronism, dehydration, metabolic acidosis, all enhance the tendency to hyperkalemia in the elderly and the administration of potassium-sparing drugs may precipitate serious clinical events in individuals harboring these risk

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factors (Perazella and Mahnensmith, 1997). The capacity of diluting and concentrating urine decreases with age in humans (Rowe et al., 1976b; Sands, 2003). Reduced expression of urea transporters in the inner medullary collecting ducts impairs the capacity of appropriately raising urine concentration in aged rats (Combet et al., 2003) which also show a down-regulation of vasopressin-2 receptors in the collecting duct and a reduced expression of the water-channels aquaporin 2 and 3 (Faull et al., 1993; Swenson et al., 1997; Tian et al., 2004). Nocturia, which is in part a consequence of a reduced concentrating ability, is a typical feature of old age (Kirkland et al., 1983; Rowe et al., 1976b). On the other hand, elderly people exhibit also impaired urine diluting capacity which expose them to an increased risk of hyponatremia after water load (Bengele et al., 1981; Zhou et al., 2008b). Even though the renal regulation of acid-base balance is globally conserved in the aging kidney (Frassetto et al., 1996), the capacity of generating ammonia is clearly impaired (Yamada et al., 1992). Elderly subjects are more prone than young individuals to develop acidosis in response to acid load (such as after a high-protein meal or in stress conditions which activate proteolysis) mainly because of the incapacity to increase ammonia and H+ synthesis (Adler et al., 1968; Agarwal and Cabebe, 1980; Luckey and Parsa, 2003). Impaired proton pump activity in the cortical collecting duct is a critical element in the deranged response to acid load in the elderly (Nakhoul et al., 1995; Yamada et al., 1992). Renal-dependent metabolic acidosis has been implicated in a constellation of alterations in the elderly including hypercalciuria, decreased citrate excretion, enhanced protein catabolism, muscle wasting, bone dissolution, cardiomyopathy and progression of CKD (Alpern, 1995).

5.3. Vascular changes Structural changes in renal vasculature are similar to those observed in vessels in other organ systems and include intimal and medial hypertrophy, arteriolosclerosis and overt atherosclerotic lesions (Hollenberg et al., 1974). Post-mortem angiograms and histology studies show increased irregularity and tortuosity of pre-glomerular vessels, direct shunts between afferent and efferent vessels (see above), wall thickening and narrowing of the vascular lumen of afferent arterioles (Davidson et al., 1969; Ljungqvist and Lagergren, 1962), an alteration mainly depending on vascular smooth muscle cells proliferation (Long et al., 2005a). In addition, micro-infarctions triggered by cholesterol emboli are often observed along with atherosclerosis of the aorta and renal arteries in elderly patients with diabetes and hypertension. Interlobular arteries in the elderly show fibro-intimal hyperplasia (Hollenberg et al., 1974), a feature typically observed in patients with chronic hypertension regardless of age. From adulthood to the age of 80 years, renal plasma flow (RPF) (Davies and Shock, 1950) and effective RPF (ERPF) exhibits a steady decline (Fliser et al., 1997). Reduction in RPF mainly occurs in the renal cortex while medullary flow is relatively well preserved (Hollenberg et al., 1974). Accordingly, the contribution of iuxtamedullary glomeruli to global GFR increases (Fliser et al., 1997). Due to an increase in post-glomerular renovascular resistances (RVR), the GFR is relatively better preserved than ERPF both in healthy elderly people and in elderly subjects with hypertension, heart failure and other cardiovascular co-morbidities (Fliser et al., 1997). Reduced ERPF has obvious causal links with structural changes in the renal vasculature, particularly at post-glomerular level (Hoang et al., 2003). Furthermore, the reno-vascular response to vasodilatory agents (Fuiano et al., 2001) and the sensitivity of renal arterioles to endogenous and exogenous vasoactive substances (Hill et al., 1997; Palmer, 2004; Zhang et al., 1997) is overtly altered in the elderly.

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5.4. Endocrine changes 5.4.1. Renal autacoids Autacoids, including prostaglandins, prostacyclins, thromboxanes and leukotrienes, are powerful endogenous vasoactive agents which also modulate platelet aggregation. The synthesis and the associated signaling transduction pathways of these complounds are altered by the aging process (Qian et al., 2012). Young and old rats fed at normal or low-salt diet, have comparable levels of PGE2 and PGF2-␣ in the renal interstitial fluid (Millatt and Siragy, 2000). However, PGF2-␣ production is reduced and PGE2 enhanced in old rats as compared to young rats after sodium overload (Millatt and Siragy, 2000). In human studies, PGF1-␣ production is agedependent while the synthesis of other prostaglandins (such as PGE2 and PGF2-␣) is in large part preserved in kidneys of elderly individuals (Hornych et al., 1991). A defect in prostaglandin modulation has been postulated to explain the altered adaptive capacity of the aging kidney to respond to sympathetic stimulation, such as that by mental stress (Castellani et al., 1998), particularly in elderly persons with isolated systolic hypertension (Castellani et al., 1999). On the other hand, the inhibition of prostaglandin synthesis produces similar functional derangements in healthy elderly and young subjects (Asokan et al., 1992).

5.4.2. RAS system Plasma renin activity (Noth et al., 1977; Tsunoda et al., 1986) and aldosterone (Skott et al., 1987) are about halved in elderly subjects, a phenomenon mainly due to limited synthesis and release of renin, particularly under stress conditions (Weidmann et al., 1978). As alluded to before, reduced activation of the renin–aldosterone system (RAS) contributes to the development of various fluid and electrolyte abnormalities and partly accounts for the higher risk of dehydration, hypernatremia and hyperkalaemia which characterize elderly persons.

5.4.3. Erythropoietin Circulating levels of erythropoietin (EPO) are higher in the healthy elderly as compared to younger individuals (Ershler et al., 2005). Increased EPO production in the elderly is interpreted as a counter regulatory mechanism aimed at preserving normal red blood cells mass in response to a higher turnover, as well as to EPO resistance. However, EPO levels are reduced in anemic elderly individuals, suggesting an impaired counter-regulatory response to low hemoglobin levels (Ferrucci et al., 2007). In a secondary analysis of the InCHIANTI study, old age went along with reduced EPO levels, anemia and impaired renal function (Ble et al., 2005).

5.4.4. Vitamin D Elderly people may develop vitamin D deficiency due to the impaired capacity of the aging kidney to convert 25-hydroxy vitamin-D to 1,25 dihydroxy vitamin-D (Gallagher et al., 2007b) but extra-renal factors, i.e. 25-OH-vitamin D availability, affect at least equally vitamin-D sufficiency in the elderly. In a cohort study in 168 elderly patients with various degree of renal impairment, reduced 25-OH-vitamin D levels were independent predictors of progression to dialysis and death in the long term (Ravani et al., 2009). In a secondary analysis of the BELFRAIL study, in individuals > 80 years with conserved renal function higher 25-OH-vitamin D levels associated with exposure to sunshine and with an active lifestyle (Van Pottelbergh et al., 2013) but not with renal function. CKD may worsen vitamin D deficiency in the elderly. Indeed in postmenopausal women, the presence of CKD predicts the risk for bone fractures while calcitriol supplements reduce the incidence of falls, a protective effect which may depend on improved muscle strength

promoted by up-regulation of vitamin D receptors (Gallagher et al., 2007a).

6. Future perspectives for retarding renal aging As briefly alluded to before, dietary interventions to retard systemic and kidney aging have been extensively studied in animal models. Isocaloric diets with low-AGE content reduce kidney and cardiovascular damage associated with age and extend lifespan in rat models (Cai et al., 2007). Furthermore, powerful anti-oxidants, such as the methylglyoxal, potentiate the protective effects of lowAGE diets (Cai et al., 2008). A diet enriched of antioxidants (such as vitamin-E), reduces kidney lipid peroxidation and accumulation of F2 isoprostanes and increases markedly the GFR (by 50%) in aging kidneys (Reckelhoff et al., 1998). Long-term administration of the NO precursor and ADMA antagonist l-arginine in aging rats ameliorates proteinuria and renal function (Reckelhoff et al., 1997a). It was hypothesized that the beneficial effects of the “Mediterranean” diet on general health and lifespan might depend on the very low content in AGEs and on the high content of anti-oxidants of this diet (Roman et al., 2008). Caloric restriction retards age-related structural changes in the kidney, including glomerulosclerosis, ischemic injury, vascular wall thickening and tubular–interstitial fibrosis (McKiernan et al., 2007). These beneficial effects associate with reduced expression of the matrix-metalloproteinase-7, kidney injury molecule-1 and claudin-7 (Chen et al., 2007), as well as with a reduction in renal lipid accumulation (Jiang et al., 2005), ceruloplasmin production (Wiggins et al., 2006) and apoptosis (Lee et al., 2004). In animal models of aging, such as the 24-months F344BN old rat, caloric restriction reduces aging-related proteinuria and extracellular matrix accumulation and these effects are apparently mediated by reduced expression of vascular endothelial growth factor (VEGF), plasminogen activator inhibitor (PAI)-1 and other connective tissue growth factors (Keenan et al., 2000). Caloric restriction also preserves renal SIRT-1 expression, a sensor of redox and energy state with antiapoptotic and antifibrotic effects which is considered as a main factor in the cytoprotective mechanisms which may retard kidney aging (see above). No studies documenting a beneficial effect of long-term, low-calories diets on renal function exist in humans. However, long term caloric restriction ameliorates hypertension and the metabolic profile and retards atherosclerosis (Walford et al., 2002) and the decline in diastolic function in humans (Meyer et al., 2006). Observations in the Nurses’ Health Study (Knight et al., 2003) would support the contention that low protein intake may limit age-related decline in renal function in humans. Indeed, in a subgroup of women with normal renal function, the estimated change in GFR attributable to excessive protein intake was 0.25 mL/min/1.73 m2 per 10-g increase in protein intake over a 11-year period. Salt intake is another important modifiable factor which may retard renal function decline, mainly because low salt diets improve blood pressure control (Hasegawa et al., 2012). In a small cohort of elderly hypertensive patients the average salt excretion and the baseline eGFR were the only independent predictors of renal function decline (Ohta et al., 2013). However, the observational nature of findings reporting a protective effect of low protein and sodium diets prevents causal interpretations and no recommendation for public health and clinical practice can be made on the basis of these data. Few drugs have been tested so far for retarding renal aging. In experimental studies, PPAR-␥ agonists limit parenchimal sclerosis, alleviate cell senescence and improve GFR and proteinuria (Benigni et al., 2006; Yang et al., 2009). Increased renal expression of Klotho and reduced oxidative stress have been proposed as potential mechanisms to explain improvements by PPAR-␥ agonists. Chronic

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treatment with angiotensin-converter enzyme inhibitors (ACEi) or ATR-blockers (ARBs) reduces age-related glomerulosclerosis, mesangial expansion, tubular–interstitial fibrosis and mononuclear cells infiltration along with renal mitochondria damage (de Cavanagh et al., 2003). Furthermore, selective ATR-1 blockade prevents renal damage by increasing NO bioavailability and by reducing oxidative stress in aged spontaneous hypertensive rats (Zhou et al., 2002). 7. Conclusions Aging has been defined as “the collection of changes that render human beings progressively more likely to die” (Medawar, 1952). This view implies the existence of an inexorable functional decline in biological systems in the whole organism. Whether aging is a disease or as the inevitable consequence of being human is a philosophical and a scientific question. Renal aging is a complex multifactorial process and ascertaining to what extent renal lesions in the elderly represent the life course exposure to chronic diseases or the local manifestation of systemic aging is tantalizing. Progress in genetics and proteomics provides promising new insights on renal aging. Proper lifestyle modifications, as those applicable to the general population, including the adoption of low-calories and lowAGEs diets with high content in anti-oxidants currently represent the most plausible approach to maintain kidney health. Acknowledgments This review was written as part of the project “Invecchiamento: innovazioni tecnologiche e molecolari per un miglioramento della salute nell’anziano” (PROGETTO BANDIERA 2012–2014). The project received funding by the Italian Ministry of Health. References United Nations World Population Prospects Report 2005–2010. US Census Bureau, 2005. International Database. Table 094. Mid-year Population, by Age and Sex. Abdi, R., Slakey, D., Kittur, D., Racusen, L.C., 1998. Heterogeneity of glomerular size in normal donor kidneys: impact of race. American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation 32, 43–46. Abrass, C.K., Adcox, M.J., Raugi, G.J., 1995. Aging-associated changes in renal extracellular matrix. American Journal of Pathology 146, 742–752. Adler, S., Lindeman, R.D., Yiengst, M.J., Beard, E., Shock, N.W., 1968. Effect of acute acid loading on urinary acid excretion by the aging human kidney. Journal of Laboratory and Clinical Medicine 72, 278–289. Agarwal, B.N., Cabebe, F.G., 1980. Renal acidification in elderly subjects. Nephron 26, 291–295. Alpern, R.J., 1995. Trade-offs in the adaptation to acidosis. Kidney International 47, 1205–1215. Alvarez-Gregori, J.A., Robles, N.R., Mena, C., Ardanuy, R., Jauregui, R., Macas-Nu Nunez, J.F., 2011. The value of a formula including haematocrit, blood urea and gender (HUGE) as a screening test for chronic renal insufficiency. Journal of Nutrition, Health and Aging 15, 480–484. Anderson, S., Brenner, B.M., 1986. Effects of aging on the renal glomerulus. American Journal of Medicine 80, 435–442. Arking, D.E., Becker, D.M., Yanek, L.R., Fallin, D., Judge, D.P., Moy, T.F., Becker, L.C., Dietz, H.C., 2003. KLOTHO allele status and the risk of early-onset occult coronary artery disease. American Journal of Human Genetics 72, 1154–1161. Arking, D.E., Krebsova, A., Macek Sr., M., Macek Jr., M., Arking, A., Mian, I.S., Fried, L., Hamosh, A., Dey, S., McIntosh, I., Dietz, H.C., 2002. Association of human aging with a functional variant of klotho. Proceedings of the National Academy of Sciences of the United States of America 99, 856–861. Asokan, A., Fancourt, G.J., Bennett, S.E., Castleden, C.M., 1992. Renal prostaglandins, effective renal plasma flow and glomerular filtration rate in healthy elderly subjects. Age and Ageing 21, 39–42. Baert, L., Steg, A., 1977. Is the diverticulum of the distal and collecting tubules a preliminary stage of the simple cyst in the adult? Journal of Urology 118, 707–710. Baggio, B., Budakovic, A., Perissinotto, E., Maggi, S., Cantaro, S., Enzi, G., Grigoletto, F., 2005. Atherosclerotic risk factors and renal function in the elderly: the role of hyperfibrinogenaemia and smoking. Results from the Italian Longitudinal Study on Ageing (ILSA). Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant Association – European Renal Association 20, 114–123.

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The aging kidney revisited: a systematic review.

As for the whole human body, the kidney undergoes age-related changes which translate in an inexorable and progressive decline in renal function. Rena...
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