1.

Introduction

The age of the Polish population is gradually increasing; in 2011, there was 19.2% of
people over the age of 60 years, and this number is estimated to exceed 25% in 2020.1 In
this group, the number of persons old er than 80 years is growing most rapidly.
Similar ly, the prevalence of hypertension is rising with age, reaching 76% in the age
group of 65 year olds and older,2 but it decreases slightly after the age of 80 years. The
results of the recently completed HYVET study provide the evidence that some oc
togenarians can benefit from proper blood pres sure (BP) lowering.3 During the last
decade, BP control has improved significantly, but it is still far from optimal or even
satisfactory. Considering the above data, a decision was made to develop specific
guidelines on the management of hyper tension in the elderly.(Tomasik et al. 2013)

Epideomiology

With this growth, there has been a rise in the prevalence of CKD in the elderly.The
National Health and Examination Nutrition Survey (NHANES) observed an increase in
the prevalence of CKD from 10.3% in 1988 to 13.1% in 2004. Over 48% of those with
CKD stages 3 to 5 were 70 years of age or older. This rise in CKD was attributed to
diabetes mellitus, obesity, and hyper- tension, which are commonly associated with
aging. There is also a decline in adaptive capacity, an increase in apoptosis and changes
in gene expression with aging that result in fibrosis and inflammation. (Schlanger et al.
2015)

The kidneys

Renal mass is approximately 50 g at birth, peaks at 400 g during the fourth decade and
then gradually decreases to about 300 g by the ninth decade. Loss of renal mass is
primarily cortical with relative sparing of the medulla, and correlates with the reduction
in body surface area. With diminished glomerular lobulation and sclerosis of the
glomeruli, there is reduced surface area available for filtration, contributing to an age-
related decline in glomerular filtration rate (GFR). Glomerular basement membrane
permeability increases, with a secondary increase in microalbuminuria and proteinuria.
This occurs even in the absence of diabetes mellitus, hypertension and chronic kidney
disease.

After the age of 30 years, renal blood flow declines progressively at a rate of 10% per
decade. A greater proportion of the decline in renal blood flow occurs in the cortex, with
a relative increase in blood flow to the juxtamedullary region. In the ageing population,
the ability to vasodilate the afferent renal artery to increase renal plasma flow and GFR is
impaired. This largely results from an imbalance between vasodilatory and vasocon-
strictive influences in ageing kidneys.

Age-related changes in structure and renal haemodynamics (Table 1) compromise the

ability of the kidney to adapt to acute ischaemia and heighten susceptibility to acute
kidney injury, including normotensive ischaemic nephropathy. It also sets the stage for
progressive chronic kidney disease.

Davies and Shock e in a classic cross-sectional inulin clear- ance study e demonstrated
that GFR decreases by about 8 ml/ minute/1.73 m2 per decade from the fourth decade
onwards.1 There is wide inter-individual variability in the age-related fall in estimated
GFR, further amplified by the presence of vascular and renal disease.

Creatinine clearance is influenced by nutritional status, protein intake, muscle mass, body
weight, gender and ethnicity.2 As people age, muscle mass is reduced and daily urinary
creatinine excretion decreases, accompanied by an age-related reduction in creatinine
clearance. This means that interpretation of estimated GFR needs to be accompanied by a
clinical assessment of muscle mass.

The combined effect of these changes is that declining GFR in older patients is
accompanied by lower rises in serum creatinine than would occur in younger patients.
(Jackson 2016)

The elderly are the most rapidly growing demographic subset of world population. Not
only does the prevalence of hypertension increase with age, but elderly patients also have
increased prevalence of co-morbidities like coronary artery disease, congestive heart fail-
ure, chronic renal impairment, stroke and cognitive decline. Managing hypertension in
elderly patients represents a therapeutic challenge for physicians and till recently the
overall benefits of treating these patients remained unclear. The following review focuses
on salient features of hypertension in the elderly population along with reappraisal of
blood pressure management principles in this population. (Kapoor & Kapoor 2013)

Estimates suggest that in a century the majority of babies born in 2000, in developed
countries, such as USA or France, will have an incredibly increased lifespan (about 100
years) (Christensen et al., 2009), and new demands in geriatric healthcare appear, with a
special focus on obesity, cancer and cardiovascular disease. Therefore, understanding the
aging process and the functional decline of organic systems, such as the renal system is
essential.

Aging is a universal degenerative process that affects many systems and organs and has
increasing interest in several medical research fields. The causes and consequences of
aging are not fully clarified but some modifications seem to be unanimous, such as the
declining ability to respond to stress, e.g., oxidative injury (i.e., extrinsic senescence), the
resulting homeostatic imbalance and the increased risk of disease which will inevitably
end in death. It is also believed that telomere shortening with each replication event (i.e.,
intrinsic senescence) is implicated in cellular aging (Itahana et al., 2004). Age-related
changes lead to a functional decline of several organs, including the kidney.

Two important issues in aging, namely in the renal aging, are the genetic background and
the molecular features. Referring to gender, it has been proved that renal function is more
affected in male animals and that a limitation in androgen production has a positive effect
in vascular age-related changes of the kidney (Gandolfo et al., 2004). Recently, renewed
attention has been drawn to aging-associated genes. One of these genes, klotho, is
particularly significant in calcium and phosphorus homeostasis, inhibiting vitamin D
synthesis. Angiotensin II (see further for a detailed discussion) plays a role in klotho
expression down- regulation in chronic renal failure; in fact, in vivo klotho gene transfer
by an adenovirus vector was shown to defend against renal deterioration induced by Ang
II and has been proposed (Mitani et al., 2002) as a novel therapeutic possibility for
hypertensive renal damage. PPAR-g was also recently implicated in klotho regulation, as
troglitazone (improvement of insulin sensitivity) increased klotho expression through
PPAR-g activation (Zhang et al., 2008). It has also been proven the anti-aging effect of
this gene in mice overexpressing klotho (extended life by some mechanisms, such as,
oxidant stress resistance) (Torres et al., 2007). Furthermore, particular genotypic and
racial features are taken into consideration as some studies report the increased
susceptibility for hypertensive nephrosclerosis of African-Amer- icans (Marcantoni et al.,
2002).

An interesting molecular perspective in kidney aging is given by Famulski et al. In this

comprehensive review the authors discuss the importance of the ATM/p53/p21 and
Ras/p38/p16 pathways in the overall cellular senescence, the significance of epigenetic
factors (e.g., the beneficial effect of caloric restriction) and conclude that p16 INK4a
remains the best marker of chronological age in the kidney, as an increase in p16INK4a
expression was observed with aging, particularly in the renal cortex (Famulski and
Halloran, 2005). Percy et al. discuss cellular age-dependant modifications in the kidney
and provide an updated insight on oxidative stress. The authors highlight some of the
points already discussed and analyze the mitochondrial influence in renal aging (Percy et
al., 2008).

The epidemiological relevance of the aging factor in renal disorders is significant: Coresh
et al. report that 11% of people older than 65 years old, without any significant
comorbidity (e.g., diabetes), had a 60% reduction in glomerular filtration rate (GFR) (i.e.,
stage 3 or worse chronic kidney disease (CKD)), when compared to healthy younger
individuals and that approximately 25% of all 70 years old and older Americans had
moderate to severe decrease of the kidney function (Coresh et al., 2003; Hansberry et al.,
2005).

The aim of this review is to discuss the role of hypertension and angiogenesis in renal
aging, to analyze the changes that occur in the kidney during the aging processes, to
examine the importance of certain mechanisms and molecular agents and to provide
insight on possible future diagnostic tests and therapeutic agents in this context.

2. Changes in the aging kidney

Kidney weight gradually decreases with age, with a 10% mass reduction per decade
observed from the 5th decade on (Long et al., 2005a; Razzaque, 2007). Other
modifications relating kidney and aging will be summarized in relation to the 3 major
renal components: blood vessels, glomeruli and tubulointerstitium. A more
comprehensive insight will be given to the impairment of renal blood vessels and to the
major role of hypertension and angiogenesis. Firstly, we shall focus in age-related
modifications that give rise to a set of disruptions, including the decrease of renal blood
flow and the reduction of GFR.

One of the most prominent aging effects is the 3040% decrease of creatinine clearence
in individuals over the age of 80. Furthermore, the prevalence of microalbumuria
increases and blunted renin responses, reduced conversion of 25-hydroxyvita- min D to
1,25-dihydroxyvitamin D and reduced erythropoietin production appear among some
endocrine disruptions (Zhou et al., 2008). The severity of primary renal diseases in
elderly individuals is amplified by systemic and metabolic disorders, including
hypertension, diabetes and amyloidosis. Also, the immune response becomes weaker and
the risk of infection higher, leading to the appearance of infectious pathologies. In
addition, tumors of the kidney and renal pelvis become more common, which can
possibly be explained by the loss of cell cycle control with cell senescence (Lakatta,
1993; Ferder et al., 2003; Long et al., 2005a; Martin and Sheaff, 2007).

2.1. Glomerular changes

As the kidney becomes older, the declining number of functional glomeruli is coupled
with focal and segmental glomerulosclerosis. Even though the causes of sclerosis are not
clear, ischemia, immunological disorders and other insults seem to play a role.
Additionally, there is glomerular basement membrane thickening and wrinkling
associated with loss of capillary loops and mesangial matrix expansion, which may be an
outcome of the imbalance between formation and removal of extracellular matrix (Long
et al., 2005a; Silva, 2005a; Martin and Sheaff, 2007) (Fig. 1).

Latter disorders may arise in the glomerulus as a consequence of the referred age related
modifications, such as membranous glomerulonephritis (almost three times more frequent
in the elderly) and crescentic glomerulonephritis (four times more prevalent in the
elderly). On the other hand, there is a decrease in IgA nephopathy incidence in the elderly
(Kingswood et al., 1984; Silva, 2005a).

2.2. Tubulointerstitial changes

In aging, along with the kidney mass reduction, there are other important macroscopic
findings, like scarring and cyst formation that appear to be highly influenced by
tubulointerstitial changes (Laucks and McLachlan, 1981; Piepsz, 2001). Central
modifications occur in tubulointerstitial areas, with dilatation and atrophy of many
tubules, associated with basement membrane thickening and flattening of the tubular
epithelium. There is also an increase of the interstitial volume, interstitial fibrosis and
invasion by infiltrating mononuclear cells (Ferder et al., 2003; Martin and Sheaff, 2007).
These interstitial alterations can be explained by increased collagen deposition, up-
regulation of extracellular matrix-related genes (e.g., TGF-b gene), reduction of tubular
metalloproteinases and increased production of proinflamatory and profibrogenic
molecules (Razzaque, 2007). Moreover, it is important to highlight the role of advanced
glycation end-products (AGEs), which strongly participate in diabetic nephropathy by
stimulating extracellular matrix synthesis. It has been reported that AGE-R1, an AGE
receptor that inhibits AGE-mediated injury, is down-regulated in aging (Lu et al., 2004).
As tubular-interstitial changes become more severe, significant functional consequences
appear, namely: impairment of sodium balance and overall disruption of the ion transport
system, which explains the reduced ability to concentrate urine, dehydratation, nocturnal
polyruria and decreased drug excretion (Martin and Sheaff, 2007).

2.3. Vascular changes

In aging, modifications of the renal blood vessels are major predictors of kidney
dysfunction, as they precede and implicate decreased blood flow, renal damage,
tubulointersticial disease and ultimate loss of GFR. A central modification is the
thickening of preglomerular arterioles, mainly caused by the proliferation of vascular
smooth muscle cells (VSMC); this is generally accompa- nied by hyalinosis (i.e., a
histopathological feature defined as the deposition of homogeneous acidophilic
substances with glassy appearance, which result in a degenerative process) (Long et al.,
2005a). This modification is frequently referred in the literature as hyaline
arteriolosclerosis (Fig. 1) (Olson, 2003) and as Silva evidences, the term means
thickening of the artery wall as well as narrowing of the vascular lumen along with
hyalinosis (Silva, 2005a). Despite the uncertain etiology of this vascular finding, this is
still very common in hypertensive and diabetic patients. Other changes have been
reported, such as the establishment of deleterious shunts between afferent and efferent
arterioles

leading the blood flow to bypass glomeruli (Long et al., 2005a). A common finding in
renal biopsies of elderly and/or hypertensive individuals is fibrosis of the intimal layer of
the interlobular arteries, the so-called intimal fibroplasia (Silva, 2005a). The cause of
intimal fibroplasia remains to be clarified, namely its possible relation to hypertension or
aging. However, this is a clinical feature of hypertensive nephropathy (Martin and Sheaff,
2007) and is considered to be omnipresent in every elderly individual (Silva, 2005a).
Intimal fibroplasia has also a heterogenic distribution, causing dispersed focal ischemia
of the nephrons. These modifica- tions are also associated with blood vessel stiffening
during the aging process (see further in Section 3). In addition, macrovascular
disturbances have been reported, such as micro-infarction caused by cholesterol emboli
together with parenchymal scarring (Martin and Sheaff, 2007).

To further understand the vascular changes of the aging kidney, we need to analyze the
hemodynamic and molecular mechanisms responsible for the modulation of the vascular
tone. Endothelial cells (ECs) are fundamental in this discussion, as they have important
homeostatic functions, namely: separation of the intravascular and interstitial
compartments, inflammatory and thrombogenic intermediation, angiogenesis modulation
(i.e., vascular remodeling), synthetic and metabolic role and vasomo- tion control (i.e.,
vasodilation and vasoconstriction balance) (ORiordan et al., 2005). In aging,
vasodilatory capacity is depressed with loss of sensitivity to vasodilators, such as nitric
oxide (NO), endothelial-derived hyperpolarizing factor (EDHF) and prostacy- clin. On
the other hand, vasoconstriction is increased and vasoconstrictors, such as angiotensin II
(Ang II) and endothelin- 1, become more influent (Barton, 2005; Long et al., 2005a).
These disturbances are explained by an age-related endothelial dysfunc- tion. It should be
pointed out that the contracting and relaxing factors released by the vascular endothelium
exert their actions mainly in VSMC. The following description should be completed with
the discussion in Sections 3 and 4.

2.4. Nitric oxide (NO)

NO is a well-known mediator of acetylcholine (Ach)-induced vasodilation and is

considered to be our main endogenous vasodilator. NO is synthesized from the precursor
L-arginine by nitric oxide synthase (NOS) and its activity is inhibited by superoxide
anion, O2 (in a reaction that ends with the formation of citotoxic peroxynitrite) and by the
NOS endogenous inhibitor, the asymmetric dimethylarginine (ADMA) (Ignarro, 1996)
(Fig. 2).

NO causes relaxation of the vascular smooth muscle by a sequence of events (i.e.,

increased guanylate cyclase, which drives an increase in cyclic guanosine
monophosphate, cGMP-concentration) that results in a decrease of intracellular calcium
concentration (Ignarro, 1996). In a very elegant study in aging rats by Long et al.
(2005b), reduced levels of NO were documented by measurement of nitrites and nitrates
in serum samples and in the kidney cortex, which is consistent with other studies
reporting the same loss of NO function in aging animals. Interestingly, the authors found
higher protein levels of endothelial NOS (eNOS) in the renal cortex of aged rats.
However, this is not a common finding and other studies have accounted for lower
protein levels of eNOS and neuronal NOS (nNOS) (Thomas et al., 1998; Erdely et al.,
2003), while inducible NOS (iNOS) was reported to be up-regulated in aging rats.
Barton, reviewing recent literature in this matter, discussed the impairment of anti-
aggregation and anti-inflammatory functions of NO with aging as the corruptive isoform
of NOS, NOS2, increases, along with NADPH oxidase activity and O2 concentration
(Barton, 2005). L-Arginine is either sustained or decreased in aging animals.
Additionally, females seem to have a more protected renal NO system, which can be
explained by their increased levels of nNOS in the renal cortex, the decreased levels of
circulating NO antagonists and the positive effect of estrogen on NO production (Baylis,
2009). With aging, the lower NO activity is paired with disrupted vasodilatation, causing
diminished blood flow and renal damage, which is also consistent with hypertensive
injury.

2.5. Asymmetric dimethylarginine (ADMA)

ADMA is a competitive endogenous inhibitor of NOS and has been considered, along
with hyperhomocysteinemia and AGE, one of the novel major factors involved in EC
dysfunction (ORiordan et al., 2005). Kielstein et al. reported an age-related increase of
ADMA levels and a positive relationship of ADMA levels with high blood pressure and
renovascular resistance, causing decreased renal perfusion (Kielstein et al., 2003a,b).
When using L-argine analog N-nitro-L-arginine methyl ester (L-NAME) to mimic
ADMA activity, vasoconstriction increased due to the diminished NO availability,
secondary to NOS inhibition (Fig. 2). Increased activity of ADMA in elderly individuals
appears, therefore, to be a feature of age-related impairment of the kidney, especially
associated with hypertensive nephropathy. Dimethylarginine dimethylaminohy- drolase
(DDAH) is an enzyme responsible to the degradation of approximately 80% of ADMA
and was found to be decreased in typically age-associated conditions such as
hypercholesterolemia and insulin resistance (Cooke, 2000).

2.6. Endothelial-derived hyperpolarizing factor (EDHF)

EDHF is an unidentified mediator of Ach and probably bradykinin vasodilation (i.e.,

hyperpolarization by calcium-in- duced potassium channels) that induces relaxation of
the vascular smooth muscle via unknown mechanisms, with epoxyeico- satrienoic acid
(EET) and potassium ions-dependent pathways being the most convincing candidates.

EDHF seems to be more important in vasodilation of resistance arteries than of large

conduit arteries, where NO may play the leading role (Feletou and Vanhoutte, 2006).

Several studies, in human and rat arteries, demonstrated (Fujii et al., 1993; Urakami-
Harasawa et al., 1997) that vasodilatation mediated by EDHF appears to be decreased
with aging.

Additionally, Bussemaker et al. (2003) reported complete loss of EDHF-mediated

relaxation in renal arteries of aging spontaneously hypertensive rats and Long et al.
(2005b) using the isolated perfused kidney model in which NO and prostaglandins
responses were previously inhibited, addressed diminished EDHF action in the renal
vasculature of aging rats.

The present evidence suggests a disruption in EDHF response in renal vascular aging,
which could possibly contribute to impaired vasodilatation and EC dysfunction.

2.7. Angiotensin II (Ang II)

Ang II is the end-product of angiotensin I conversion by the angiotensin converting

enzyme (ACE) and the most important effector of the reninangiotensinaldosterone
system.

Ang II action results in several effects, including: renal fibroblast differentiation into
myofibroblasts, enhanced vasoconstriction, TGF-b stimulation, aldosterone release,
tubular sodium reabsorp- tion, sympathetic nervous stimulation, oxidative stress,
mitogen- esis promotion, chemokines and osteopontic inducement and vascular
hypertrophy.

Ang II action is mediated by Ang type I (AT1) and Ang type II (AT2) receptors. Despite
the identical affinity of Ang II to both receptors, AT1 is more abundant then AT2 during
lifespan and therefore is the main responsible for the mediation of the overall Ang II
action (Carey and Siragy, 2003; Long et al., 2005a).

It seems clear that Ang II-related vascular damage has a leading role in aging, namely in
the development of high mean blood pressure and in the consequent decreased renal
perfusion.
This assumption is supported by studies reporting the mild protective effect of ACE
inhibitors and the strong protective effect of AT1 receptor antagonists (Mogensen, 2002),
as well as the combination of both treatments in CKD (more prevalent in the elderly)
(Toto and Palmer, 2008).

Ang II blockers were also shown to improve renal function and structure in aging mice
and rats (Basso et al., 2005).

Despite the fact that the molecular basis of Ang II action in renal aging remains unclear,
important steps are being taken, as Shang et al. noted in the Ang II-induced endothelial
cellular senescence through ERK and MAPK pathways (Shan et al., 2008a) and in the
importance of apoptosis in vascular endothelium with aging (Shan et al., 2008b).

The dynamics of angiotensin receptors is also very relevant in aging (Carey, 2007). It is
generally accepted that AT1 receptor mediates Ang II vasoconstriction and AT2 receptor
is responsible for Ang II-induced vasodilatation through stimulation of the cascade
bradykinin/NO/cGMP.

However, AT2 receptor expression is altered along the lifespan of an individual as it

appears to be increased in aging, where AT2 receptor-mediated responses shift to
vasoconstriction, by diminished flow and NO- vasodilatation.

Additionally, AT2 receptor expression, in aging, occurs fundamentally in VSMC and not
in EC (Carey, 2007).

Long et al. (2005a) also discuss this matter and propose that increased responsiveness to
Ang II in the aging kidney might be explained by differential expression of Ang II
receptors, i.e., increased expression of both Ang II receptors with aging, causing
enhanced vasoconstriction.

3. Hypertension

3.1. Definition

Hypertension (HT) defined as a blood pressure over 140/ 90 mm Hg is frequently

encountered in elderly individuals and is an important risk factor for cardiovascular
morbidity and mortality in them.

Due to an overall longer life expec- tancy, elderly patients, especially those older than 80
years, currently represent the fastest growing stratum of society. It is estimated that by
2050, approximately one-fifth of the world population will be older than 80 years.1

Due to the age associated increased prevalence of HT, most of the elderly are
hypertensive. Data from the Framingham Heart Study demonstrated that 90% of those
who were normotensive at age 55 developed HT and nearly two-thirds of males and
three-fourths of females develop HT by 70 years of age.2,3
Management of HT in elderly patients is complex and challenging because of existent co-
morbidities and concerns related to drug dosages and resultant adverse effects, often
leading to poor blood pressure control. Moreover till recently, evidence based data on
management of HT, (especially in those older than 80 years) was lacking since most trials
had not exclusively studied patients in this age group. (Kapoor & Kapoor 2013)

According to a WHO (2002) report, hypertension may affect 1 billion individuals, cause
approximately 7.1 million deaths each year and be responsible for 4.5% of the global
disease burden.

The influence of hypertension in the progression of several pathologic conditions is also

highlighted by WHO that acknowledges hypertension to play a major etiologic role in
the development of cerebrovascular disease, ischemic heart disease and cardiac and renal
failure. The definition of hypertension has also been a point of disagreement: the
Writing Group of the American Society of Hypertension rejected a simplified
classification based on blood pressure values and characterized hypertension as a
progressive cardiovascular syndrome with several causes that end in functional/structural
modifications of the heart and vascular system; this new definition comprises the
presence or absence of risk factors, early disease markers, target-organ damage and the
sub-clinical character of hypertension (Giles, May 1418, 2005). In addition, the term
hypertension was claimed by the European Society of Hypertension (ESH) as
incomplete but it was preserved in ESH Guidelines due to its practical character (Mancia
et al., 2007). Nevertheless, a globally accepted definition of hypertension is demanded.
Therefore, several guidelines have been published in 2003 (special attention should be
regarded to JNC 7) (Chobanian et al., 2003), discussing management aspects of
hypertension and a more up to date review from the European Society of Cardiology
(ESC) was published in 2007. Hypertension can be defined as the level of blood pressure
at which the institution of therapy reduces blood pressure-related morbidity and mortality
and is frequently referred as a chronically elevated high blood pressure. ESC Guidelines
recommend a classification of blood pressure in optimal, normal, high normal
(prehypertension), hypertension (grades 1, 2 and 3) and isolated systolic hypertension
(more frequent in the elderly) (Graham et al., 2007) (Table 1).

Going further into the assessment of hypertension risk, 2003 WHO/ISH Guidelines took
into consideration some of the crucial factors in our review, specifically age (i.e., males >
55 years and females > 65 years) and kidney determinants (i.e., microalbumi- nuria and
renal disease) among others (Whitworth, 2003). With no doubt we can affirm that
hypertension is an emerging condition in several disorders and it is strongly associated
with aging and declined renal function. In this matter Hajjar et al. (2006) address a 90%
lifetime chance of developing hypertension for middle-age and elderly people, being
dysfunction of the aging kidney a participating vehicle.

3.2. Hypertension and aging kidney modifications

In the aging kidney, vascular changes have an important role in the overall damage, as we
described earlier. Thus, significant consequences, such as hypertension, appear and act to
reinforce the vascular changes. It has been previously proven that arterial thickness leads
to hypertension (an increase of 1 mm in arterial thickness leads to a 1.6 mmHg rise in the
mean blood pressure) (Silva, 2005b), and on the other hand, hypertension increases
arterial thickness (e.g., VSMC proliferation) through hemodynamic mechanisms.
Whether hypertension is the cause or the conse- quence of these changes is still an
unresolved question. However, it seems clear that hypertension amplifies age-related
vascular changes (despite the fact that some studies report no or minimal vascular
changes on kidney biopsies of hypertensive patients) (Tracy, 1999).

This concept can be applied to the general damage of the aging kidney, mainly because
hypertension is strongly associated with kidney disease. Keller et al. (2003) and Hughson
et al. (2003) reported a considerable decrease in the nephron number of hypertensive
patients and the relation between low birth weight and increased predisposition to
develop hypertension (possibly due to maternal malnutrition in pregnancy); these
elements appear to be major predictors of hypertension and seem to be consistent with the
Barker hypothesis (Barker et al., 1990). Furthermore, if we had to choose a singular
important factor for the development of kidney disease, hypertension would be a solid
choice and the anti-hipertensive treatment would be a reasonable measure in this context
(Klahr et al., 1994). Nevertheless, the mechanisms underlying the association
hypertension-aging kid- ney are still not clarified. Ritz et al. (2003), in their update,
proposed 5 mechanisms involved in the onset of the increased renal blood pressure,
namely: higher renal perfusion pressure required for sodium excretion; impairment of
reninangiotensin system activation; increased sympathetic tone (despite an unchanged
GFR); disrupted vasodilatation dependent on EC; age-related stiffening of central
arteries.

3.2.1. Pressure-natriuresis and the reninangiotensin system

The idea that blood pressure regulation is highly controlled in the kidney was worldwide
postulated by several studies of Guyton (1991). In this matter, special attention was given
to the renin angiotensin system and to the pressure-natriuresis mechanism (renal
function curve). The concept of pressure-natriuresis consisted in increased excretion
of sodium and water by the kidney, in response to an elevation of the renal perfusion
pressure. This mechanism was described as an influent compensatory system: if the renal
function was preserved, an elevation of the blood pressure would activate the pressure-
natriuresis mecha- nism, which would trigger sodium and water excretion and eventually
set blood pressure to normal. However, a disturbance in this sequence of events would
rearrange the relationship of blood pressure-natriuresis. For instance, if excretion function
is dimin- ished, increase of blood pressure would occur as a result and a chronic
condition could emerge (i.e., hypertension) (Guyton, 1987; Hall, 2003). We described
tubular-interstitial changes with age and reported that in the aging process impairment
of sodium balance and overall disruption of the ion transport system befalls. Thus, we
could hypothesize that the pressure-natriuresis mechanism is impaired in the aging
kidney and that higher perfusion pressures are required to excrete an identical sodium
charge, leading to the development of hypertension (Fig. 3). Pressure-natriuresis has also
a critical interaction with the reninangitensin system (RAS). Stimulation of the RAS
stimulates sodium re-absorption and conservation of water and is often associated with
the systemic detrimental compensatory elevation of blood pressure. Interest- ingly, a dual
regulation of the circulating and intrarenal RAS occurs with aging. Plasma RAS
components (mainly renin and Ang II) are decreased in older animals as a consequence of
elevated BP. On the other hand, there is evidence of increased tubular renin concentration
and Ang II responsiveness that point out to a particular intrarenal regulation (Kobori et
al., 2007). In order to explain this difference we could propose a thesis similar to the one
from Guyton: as the afferent preglomerular arterioles become thicker and the vascular
lumen becomes narrow, baroreceptors of the aging kidney detect underprefusion of
glomeruli, stimulating renin production, which results in the elevation of the blood
pressure to the right when Ang II is increased, reinforcing the idea that when RAS is
activated the arterial pressure tends to rise in order to maintain a similar diuresis (Figs. 3
and 4). The central nervous system (CNS) was also implicated in this mechanism, mainly
through the glial angiotensinogen (ASrAogen) and the autonomic nervous system (see
below). Diz (2008), in a recent work, provides interesting data about the potential
beneficial blockage of ASrAogen by lipophilic RAS blockers.

3.2.2. The sympathetic system

Another contributor to the shifting of the pressure-natriuresis curve to the right is the
sympathetic nervous system overactivity. The sympathetic system is a major element
involved in the regulation of arterial pressure and the co-participation of this system and
the kidney in the development of hypertension has become largely discussed (Grisk and
Rettig, 2004). Despite some recent data suggesting that renal sympathetic nerves do not
contribute to hypertension (Burke et al., 2008), we cannot ignore the increased
sympathetic tone in renal disease and aging. Studies by Converse, using
microneurography in pre-dialysis patients, strengthen the idea that renal disease is firmly
related to increase of the sympathetic nerve activity (SNA) (Augustyniak et al., 2002).
Hypertensive damage of different organs has been correlated to a long-term high
sympathetic tone, which appears to increase renin production in the impaired kidney and
to amplify the trophic effects of Ang II by a-adrenergic stimulation on cardiac muscle and
VSMC (Augustyniak et al., 2002). The positive association between aging and
sympathetic activity has also been clearly demonstrated. Esler et al. (2002) reported an
increase of norepinephrine turnover in suprabulbar subcortical brain areas with aging and
a positive correlation between this turnover and SNA. The authors also found a 49.7%
increase of norepinephrine concentration with aging and a moderate extension of the
renal norepinephrine spillover. However, the effect of aging on renal norepinephrine
spillover rate is not statistically significant, which might indicate a minor role of aging in
the regulation of the renal sympathetic outflow. Nevertheless, a 40% increase of this
spillover was in fact observed in older man (Esler et al., 2002). Thus, we can speculate
about a particular mediation of norepinephrine in the increase of renal SNA with aging
(by stimulation of intrarenal chemoreceptors and baroreceptors) (Ritz et al., 2003) and its
possible relevant role in the development of hypertension. Furthermore, it has been
proven that renal norepinephrine spillover is strongly related to plasma renin activity
overflow in hypertensive rabbits, as a consequence of the relationship between
hypertension and deficient retention of norepinephrine in renal nerves (Burke et al.,
2007).
3.2.3. Endothelial cell (EC) dysfunction

Hypertension has also been related to vascular tone modifica- tions, essentially to
disrupted vasodilatation and enhanced vasoconstriction. EC dysfunction appears to be the
underlying syndrome (ORiordan et al., 2005) of these vasomotor modifica- tions and
the main agents probably involved in decreased vasodilation are NO, ADMA and EDHF.
Furthermore, renovascular vasoconstriction is accentuated with aging by higher levels of
contracting factors, such as Ang II and endothelin. A complex cross- talk between these
factors and their direct actions during aging, lead to increased blood pressure and,
eventually, establishment of hypertension. The mentioned factors are also therapeutic
targets in hypertensive patients with renal dysfunction (Ohishi et al., 2007). A more
detailed description in this matter was done earlier in our review (see Section 2.3).

3.2.4. Arterial stiffening

It was already discussed the close association between vascular changes and increased
blood pressure. Yet, the role of central arteries modifications in renal aging was not
specifically consid- ered. Several studies report a considerable increase of arterial
stiffness with age (especially from the age of 55) and a more significant stiffening of
large arteries contrasting with milder stiffening of muscular arteries (Benetos et al.,
2002). The clinical consequences of central artery stiffness include: systolic blood
pressure elevation (intrinsically associated with isolated systolic hypertension in the
elderly), raised pulse pressure, left ventricular hypertrophy and decreased coronary
perfusion (Covic et al., 2005). The rigidity of central arteries is associated with reduced
compliance and consequent early wave reflections, i.e., pulse wave pressure (PWV)
index (a frequently used method to evaluate clinical consequences of arterial stiffness) is
increased in situations of pronounced arterial stiffness. Blacher et al. addressed increased
mortality risk for end-stage renal patients with elevated PWV, which is representative of
the strong relationship between renal dysfunction and the age-related arterial stiffness
(Blacher et al., 2003). Nevertheless, PWV increase with age can be less prominent if
there is appropriate management of other risk factors of hypertension, such as high salt
intake (Avolio, 1995). The underlying mechanisms that switch on the progressive
arterial stiffening (mainly, central arteries like aorta) are well discussed by Gusbeth-
Tatomir and Covic (2007). The authors propose various factors to the inception of these
vascular changes, including: increased collagen synthesis coupled with deficient elastin
production (which can be due to matrix metalloproteinases activation and AGE
accumulation), thickening of intima/media layers along with VSMC proliferation and
intima invasion by macrophages (Gusbeth-Tatomir and Covic, 2007). Arterial stiffness is
becoming a classical predictor of the cardiovascular burden in elderly individuals with
kidney dysfunction. Additionally, hyper- tension has been strongly associated with
arterial stiffening and the anti-hypertensive treatment implicated in the improvement of
arterial compliance and in the decrease of renal damaging with aging.

(Leite-moreira et al. 2011)

Prevention and nonpharmacological treatment

The guidelines give precise recommenda tions about lifestyle modification, which are
lightly different in elderly patients compared with the general population with
hypertension.

Weight loss For elderly people younger than 75 years, the recommended body mass in
dex (BMI) should be kept within the range of 22 to 25 kg/m2. The lower threshold is thus
set up slightly higher than for younger adults. For hypertensive seniors older than 75
years, and definitely for those older than 80 years, the ac ceptable upper limit of the
BMI is increased to 2728 kg/m2. Such recommendations stem from the fact that slight
overweight might be beneficial in the elderly and might help prevent the frailty
syndrome, which is particularly dangerous at this age. The 2013 ESH/ESC guidelines for
the man agement of hypertension indicate a worse prognosis following weight loss in
the elderly. There fore, weight stabilization in this group of patients seems to be more
important than weight reduc tion.14 Moreover, reliable studies demonstrating the
benefits from dietary or pharmacologically supported weight reduction were conducted
on younger patients.(Tomasik et al. 2013)

dietary approach Diet of elderly hypertensive patients should be well balanced and fit
patients preferences to secure the normal functioning of the gastrointestinal tract and the
optimal nutri tional value. Basic caloric demand is at the level of 20 to 25 kcal/kg of the
desired body mass. A balanced diet should contain a lot of fruit and vege tables,
especially those rich in potassium.20,21 Excessive consumption of sweet fruit, rich in
sim ple carbohydrates, should be avoided.

salt reduction The guidelines recommend the re duction of salt intake below 5 g (or 85
mmol) NaCl per day. This should be reached by avoiding processed food and salt. Fresh
food and steam cooking should be encouraged. The recommen dation to limit salt
consumption also in elder ly patients is strongly supported by the results of the TONE
study.22 However, clinicians should be aware of the risk of hyponatremia, especially in
patients treated with thiazides and selective serotonin reuptake inhibitors or
carbamazepine (SIDAH syndrome). Also, one may need to con sider the quality of life
of elderly people depend ing on individual dietary habits.

Alcohol intake Alcohol intake should be reduced to less than 20 g/d for men and 10 g/d
for wom en. Since participants of the studies demonstrat ing a beneficial effect of
limited alcohol intake on BP reduction were usually younger adults, this recommendation
is based mostly on experts consensus.

Physical exercises Exercise training is beneficial for BP lowering but its role in very
elderly or frail patients has not been studied.23 Regular aerobic exercise at the level of
60% to 75% of the max imum heart rate for 20 to 45 minutes per day

should be recommended. However, in the elderly, because of frequent comorbidities and

function al limitations, the advice concerning the exercise should be adapted to the
preferences and capa bilities of patients and caregivers. In individuals after myocardial
infarction, an exercise program should be preceded by stress electrocardiography to
assess the exercise tolerance level.

smoking cessation Smoking cessation, although it does not lower BP, is beneficial
irrespective of age,24 and all elderly hypertensive smokers should be encouraged to quit.
The 5A strategy (ask, as sess, advice, assist, arrange) as well as nicotine replacement or
pharmacological therapy are ap plicable to help patients quit smoking. (Tomasik et al.
2013)

Pharmacotherapy recommendations

General considerations There is good evidence from randomized trials that adequate
control of hyper tension in the elderly population can reduce cardiovascular events and
mortality.25 On the other hand, such studies were performed in thorough ly selected
patients and, moreover, the registries and retrospective analyses of the randomized trials
showed risks related to abrupt and intense BP lowering in some elderly patients.
Similarly, epidemiological prospective studies demonstrated the presence of the J curve
relationship between BP and mortality, dementia, or falls in feeble el derly patients.

The basic principles of pharmacotherapy initiation in uncomplicated hypertension in the

el derly, recommended by the presented guidelines, are similar to those in younger
patients.12 Thera py should begin with 1 drug and the doses should be increased, or the
second or third agent should be added, if the first one is ineffective. Drug toler ance
should be carefully monitored. If the initial drug is not a diuretic, it should be added. The
pre ferred drugs are long acting antihypertensive medications, administered once
daily, which con tribute to better BP control and improve coopera tion with the
patient. If the BP exceeds the target by over 20/10 mmHg, treatment may begin with 2
drugs at small doses. The treatment of older hy pertensive patients with compelling
indications requires individualization of therapy and is de scribed in the next section of
this article.

The normalization of BP level should be slow er (rather in months than in weeks)

among el derly patients, and the tolerance of treatment should be monitored.12 The
initial doses should always be reduced by about one third or a half be cause the
process of aging changes the pharma cokinetics and pharmacodynamics of drugs and
increases the probability of adverse drug reac tions. The baroreceptor function
decreases dur ing aging and elderly patients have poor toler ance of a sudden drop in
BP, which may cause falls and reduce blood flow in the brain, heart, or kidneys.26
Caution is recommended in dis abled patients over 80 years of age with comor bidity,
for whom we have little information about

the benefits of antihypertensive therapy because such patients were not included in
randomized treatment trials.27

drug choice The first line drug treatment may include, as a single drug or in
combination, an angiotensin converting enzyme inhibitor (ACEI), an angiotensin
receptor blocker (ARB), a long acting calcium channel blocker (CCB), and thiazide or
thiazide like diuretics.12,13 blockers should not be used as first line therapy with
out compelling indications. Thiazide like diuret ics followed by an ACEI should be
considered as a first line therapy for fit hypertensive patients older than 80 years.

diuretics Thiazide type diuretics are useful first line agents in the treatment of
hyperten sion in elderly patients as a low renin patient group. In the elderly, a starting
dose of 12.5 mg and a maximum dose of 50.0 mg of hydrochlo rothiazide (or its
equivalent) are recommend ed.28 It has not been confirmed that low dose thiazides
used as a first line therapy are worse than first line high dose thiazides or first line
ACEIs and CCBs.29 However, recent data have shown that the antihypertensive efficacy
of hy drochlorothiazide in very low doses, as measured in head to head studies by
ABPM, is inferior to that of all other drug classes.30 Thiazide like di uretics
(chlorthalidone, indapamide) seem to be more effective in elderly hypertensive patients.
They not only have long half life but also have been proved to be effective in reducing
BP, im proving cardiovascular outcomes, and increas ing life expectancy.3,31-34

Angiotensin converting enzyme inhibitors ACEIs were originally indicated for the
treatment of essential hypertension and, by implication, for the prevention of
cardiovascular, cerebrovascu lar, and renal complications of hypertension. Currently,
they are indicated for the treatment of pa tients at high risk for coronary artery disease,
af ter myocardial infarction, with dilated cardiomyopathy, heart failure, or with chronic
kidney dis ease.35 ACEIs also reduce the risk of major vascular events in old
hypertensive patients.32,36 Apart from high BP control, the reninangiotensin sys tem
(RAS) blockade may play a direct role in reducing the risk of Alzheimers dementia and
cog nitive decline in older patients.37 There is evidence of positive association between
use of ACEIs and multiple functional beneficial effects on muscle function and exercise
capacity.37,38

Angiotensin receptor blockers ARBs and ACEIs are equally important in the treatment of
hyperten sion. ARBs are typically used as an alternative to ACEIs, primarily in elderly
patients, because they do not tolerate the side effects of ACEIs.40 Howev er, it was also
reported that ACEIs were more ef fective than ARBs in reducing cardiovascular and
cerebrovascular morbidity and mortality in aged

patients with hypertension. Moreover, the use of ARBs does not affect muscle function in
this patient group.

Calcium channel blockers CCBs reduce BP across all patient groups, regardless of sex,
age, race ethnicity, and dietary sodium intake.42 Comparative randomized trials
indicated that dihy dropyridine CCBs can prevent all major types of cardiovascular
disease, except heart failure (for which an ACEI or diuretic is superior). 32,43 CCBs in
the elderly hypertensive population have also been shown to prevent dementia.44,45
 blockers blockers should not be used as the first choice to start treatment in elderly
hy pertensive patients without strong indications. There are data that show blockers
to be inferi or to diuretics and other antihypertensive med ications with regard to all
clinical outcomes and preventing cardiovascular events in older pa tients.46,47 There
are still comorbid conditions in which blockers need to be considered for anti
hypertensive therapy in the elderly, such as cor onary artery disease, postmyocardial
infarction, heart failure, and arrhythmias.

Combination therapy The majority of elderly pa tients with hypertension require dual
antihy pertensive therapy or even triple antihyperten sive therapy to control BP. The
preferred combi nations are an ACEI and a diuretic; an ARB and a diuretic; an ACEI or
an ARB; and a dihydropyr idine CCB.4 8 , 4 9 Spironolactone could be useful in
addition to the combination of a CCB, RAS in hibitor, and/or thiazide or thiazide like
diuretic, in the case of resistant hypertension.50 The dual inhibition with ACEI and ARB
is ineffective and is associated with a significantly increased risk of adverse events such
as syncope, hypotension, and renal dysfunction.51,52

To decrease cardiovascular morbidity and mor tality, it is crucial to improve BP control

in elderly patients. The reasons for lower efficacy of antihy pertensive treatment in
elderly patients are com plex.53 However, combination therapy in the treat ment of
hypertension may improve both BP and tolerability.5 4 , 5 5

Conclusions

Proper hypertension control is crucial in the care of elderly patients. In Poland, the
quality of care provided to hypertensive pa tients, particularly older ones, is largely
unsatisfactory. This is mainly reflected by the lack of specific quality improvement
tools, which can as sist professionals in achieving better outcomes of care. We believe
that the publication and im plementation of the Polish guidelines on hyper tension
management in the elderly will be an im portant step in continuous quality
improvement. The guidelines allow to identify the major prob lems in the care of
elderly patients with hyper tension, to enhance cooperation between family doctors and
specialists in other areas, including geriatrics, and to facilitate the planning of care. For
octogenarians, due to comorbidities and dis abilities, comprehensive geriatric
assessment is recommended. Much more effort is needed in Po land to reduce the risk
and burden of cardiovas cular diseaseas, also in elderly patients. (Tomasik et al. 2013)

HTN GUIDELINES

Since the inception of the Joint National Committee guidelines on HTN, the National
Heart, Lung, and Blood Institute (NHLBI) has sanctioned these publications. However,
the last-sanc- tioned HTN guideline by the NHLBI was the Seventh Report of the Joint
National Committee (JNC 7), published in 2003. The writing panel for the JNC 8
guideline was appointed in 2008; however, in 2013 the NHLBI transferred the HTN
guide- line development to the American Heart Association and the American College of
Cardiology (AHA/ACC) (Gibbons 2013). The original JNC 8 writing panel published its
recommen- dations in December 2013, acknowledging that it was not sanctioned or
endorsed by the NHLBI (James 2014). In addition, the American Society of
Hypertension/International Society of Hypertension (ASH/ISH) published guidelines in
December 2013; some of these recommendations differ from those of the JNC 8 writing
panel (Weber 2014). The official ACC/AHA guide- lines for HTN management, which
are intended to replace the last NHLBI guidelines, are expected in 2016.

The JNC 7 guidelines classified blood pressure as follows: nor- mal (SBP less than 120
mm Hg and DBP less than 80 mm Hg), pre-HTN (SBP 120139 mm Hg or DBP 8089
mm Hg), stage 1 HTN (SBP 140159 mm Hg or DBP 9099 mm Hg), or stage 2 HTN
(SBP 160 mm Hg or higher or DBP 100 mm Hg or higher) (Chobanian 2003). Table 1-1
compares blood pressure goals for different populations among various international
guidelines, including several U.S. guidelines, the Canadian Hypertension Education
Program, and the European Society of Hypertension/ European Society of Cardiology
(ESH/ESC) guidelines. (Mcconnell et al. 2016)

HTN Guideline Controversy

Although the various HTN guidelines differ, one controversial issue in these guidelines is
the age that the blood pressure goal should be increased to less than 150/90 mm Hg for
older adult patients. Published data are limited on the benefits of achieving a target blood
pressure of less than 140/90 mm Hg in older adult patients. For patients 60 years and
older, the JNC 8 panel rec- ommends initiating treatment to achieve a goal blood pressure
of less than 150/90 mm Hg (James 2014). The age chosen by the JNC 8 writing panel for
a less aggressive blood pressure tar- get is 20 years younger than the age defined as older
adults, 80 years and older, in the 2013 ASH/ISH, Canadian Hypertension Education
Program, ESH/ESC, and ACC/AHA/ASH guidelines, which target a blood pressure goal
of less than 150/90 mm Hg .The JNC 8 panel authors cited the VALISH and JATOS
stud- ies as evidence for setting a goal SBP of higher than 140 mm Hg in patients older
than 60 years. Neither the VALISH nor the JATOS study showed any difference between
strict control (SBP of less than 140 mm Hg) and more modest control (SBP less than 150
mm Hg for VALISH; SBP less than 160 mm Hg for JATOS) (Ogihara 2010; JATOS
2008). However, both trials were underpowered to determine whether strict control was
superior to less stringent targets. Of interest, the authors of the JATOS trial noted that
strict treatment may decrease CVD risk in patients younger than 75 (JATOS 2008). A
minority of the JNC 8 writing panel published a report stating that there was no con-
sensus on the age at which to increase the blood pressure goal in older adults. This report
stated that the evidence supporting raising the target from 140 mm Hg to 150 mm Hg in
people 60 or older was insufficient and inconsistent (Wright 2014). (Mcconnell et al.
2016)

The HYVET trial assessed various CV end points in 3845 patients 80 years and older
(mean age 83) with an SBP of 160 mm Hg or greater treated with indapamide versus pla-
cebo. Perindopril or matching placebo was added to achieve a target blood pressure of
150/80 mm Hg. After 1.8 years, the mean SBP was 143.5 mm Hg in the treatment group
and 158.5 mm Hg in the placebo group. The treated group had a 30% reduction in the
rate of fatal or nonfatal stroke (95% CI, -1 to 51; p=0.06), a 39% reduction in the rate of
death from stroke (95%

CI, 162; p=0.05), and a 21% reduction in the rate of death from any cause (95% CI, 4
35; p=0.02) compared with the pla- cebo group (Beckett 2008). This study supports
increasing the blood pressure goal for patients older than 80 to less than 150/90 mm Hg
because lowering blood pressure below this level decreased both death and stroke.

What is Considered Hypertension

in the Older Person?Fewer than half of the guidelines gave an explicit definition of
hypertension for older populations. For guidelines that did define hypertension, there was
consensus that a higher BP reading was less acceptable in younger patients than in older
patients; however, there was some variation in the systolic BP considered to represent
hypertension in older populations. The major- ity of guidelines that defined hypertension
in older persons considered a BP reading of 140/90 mm Hg consistent with hypertension.
Only two guidelines differed, with the ASH/ISH and EG guidelines specify- ing a slightly
higher BP of 150/90 mm Hg. These differences in the definitions of hypertension did not
appear to be related to the age of the populations included.

Specific Treatment Recommendations

BP Targets for Initiation of Therapy. Around half of the guidelines did not provide
explicit guidance in terms of BP control for commencement of treatment in older persons.
For guidelines that did specify initiation targets, there was variation in the BP levels at
which treatment should be considered for older persons. While most of the guidelines
considered therapy initiation in terms of systolic BP, four guidelines (the 2014 American
Eighth Joint National Committee panel guideline [JNC 8], NICE, ASH/ISH, and JSH)
provided specific recom- mendations in terms of diastolic BP. In general, treat- ment
initiation targets were higher than those recommended for nonelderly populations. Only
the JNC 8 discussed the uncertainty regarding the evidence for initiation of management
in patients older than 80 years.

Management and Pharmacotherapy for Uncomplicated Hypertension in Older Persons.

While all the guidelines discussed lifestyle modification as first-line management for
nonelderly populations, only the JSH discussed implementing lifestyle modification
specifically in the elderly. In terms of pharmacotherapy, the Canadian Hypertension
Education Project (CHEP) guideline did not make any specific recommendations for the
man- agement of uncomplicated hypertension in older per- sons. Both the United
Kingdom NICE guideline and the Taiwanese guideline explicitly stated first-line pharma-
cotherapy for persons older than 80 years should be the same as that for those aged 55 to
80 years, while the remainder provided specific recommendations for initi- ation of
therapy for uncomplicated hypertension in older populations. Some variation was found
in the choice of agent. Thiazide diuretics (and thiazide-like diuretics) and calcium
channel blockers (CCB) were recommended as first-line therapy for the elderly in most
guidelines; however, a number of guidelines further specified that the dihydropyridine
CCBs were preferred for older persons. Angiotensin-converting enzyme (ACE) inhibitors
and angiotensin receptor blockers (ARBs) were also proposed as equally effective first-
line therapy in a number of guidelines (Table).

Although the majority of guidelines provided guid- ance regarding first-line agents for
older populations, some guidance was also provided regarding agents that should not be
considered in the elderly. The CHEP, Saudi Arabian (SHMS), and EG guidelines
explicitly stated that b-blockers should not be considered in elderly patients, and the
Taiwanese guidelines recom- mend that atenolol, in particular, should not be used for
patients 60 years and older.

Awareness of treatment tolerability or increased likelihood of adverse effects in older

persons with hypertension were mentioned in a number of guidelines with respect to
using pharmacotherapy in older persons. Most guidelines recommended dose adjustment
if phar- macotherapy was not tolerated. The ESC guideline recommends consideration of
treatment tolerability when treating either frail older persons or those older than 80 years.
The Latin American (LA) guidelines recommend that antihypertensive medications be
initi- ated at low doses and then adjusted every 4 to 6 weeks after evaluating side effects,
while the EG and JSH guidelines recommended starting at lower doses and avoidance of
centrally acting agents. Only the SHMS and CHEP guidelines specifically mentioned an
increased risk of orthostatic hypertension and falls with antihypertensive use in older
persons.

Treatment Targets. Most guidelines, with the exception of the South African (SAHS) and
the Australian (HF) guidelines, gave explicit BP targets for managing hyper- tension in
older populations. In all of the guidelines where explicit targets were given, higher targets
were specified for older persons than for nonelderly populations.

Approximately half of the guidelines (n=6) recom- mended a treatment target for older
persons of <150 mm Hg, while five guidelines supported treatment targets of 140 mm Hg
(Table). Treatment target recommendations did not appear related to age, with half of the
guidelines recommending the higher target were aimed at patients aged 65 years and
older, while the remaining half were targeting those aged 80 years and older. Likewise, of
those with a target of 140/ 90 mm Hg, two were recommendations for patients aged 65
years and older, one for patients aged 75 years and older, and two for patients 80 years
and older. Three guidelines (the 2014 JSH guideline, the 2011 NICE guidelines, and the
2015 Taiwanese guideline) Recommended different treatment targets for different age
groups proposing targets. The JSH guideline rec- ommends systolic targets of 140 mm
Hg for older populations aged 65 years and younger, and the higher target of 150 mm Hg
for populations aged 75 years and older. The NICE guideline and the Taiwanese
guideline both propose the lower target for those younger than 80 years and the higher
target for those older than 80. With the exception of the Japanese guideline, all of the
guidelines recommending treatment targets of <140 mm Hg were published prior to
2012.

(Alhawassi et al. 2015)

Kidney Volume. Ultrasound and especially, CT are the tools that allow fairly accurate
assessment of the kidney size with aging. Two decades ago, Emamian and col- leagues43
used ultrasound in a sample of more than 600 adult volunteers and showed that larger
kidney volumes correlated with younger age, height, weight, and total body surface area.
In another contemporary study using CT scan in 360 patients with no kidney disease,
authors found that in both genders, parenchymal thickness of a kidney declined 10% per
older decade of age.44 A decline in kidney dimensions with age was replicated in a more
recent study with a large sample size of 1040 asymptom- atic patients.45 Furthermore, in
a cohort of more than 1000 patients, Bax and colleagues46 demonstrated that
concomitant atherosclerosis accelerated the age-related decline of kidney size.
Conversely, a recent study that used 224 healthy potential transplant donors aged ,65
years, showed that kidney parenchymal volume correlated directly with body size and
male gender, but not with age.47 In a larger cohort of 1344 potential kidney donors that
included healthy individuals aged 18 to 75 years, kidney volume was relatively stable
through 50 years of age and then started to decrease after this age.9 This study also found
that the reason for a relatively constant kidney volume with aging through 50 years of age
was the canceling effects of a declining cortical vol- ume, whereas medullary volumes
increased with age (Fig 2). This trend changed after the age of 50 years, when cortical
volume continued to decline in both men and women, whereas medullary volume
declined only in women and remained relatively stable in men. Finally, it is possible that
age-related increase in kidney sinus fat may also be the reason for obscured decline in
total kidney volume with aging in studies that do not adequately distinguish the kidney
parenchyma from non- parenchymal regions when assessing kidney dimen- sions.43,44

The volume-losing lesions of GSG with atrophy of corre- sponding tubules

(nephrosclerosis) would explain this age-related decline in kidney cortical volume.
Likewise, compensatory hypertrophy of NSG and their attached tu- bules may help
maintain kidney parenchymal volum with aging, at least until beyond middle
age.24,32,34,35 In particular, hypertrophy of tubules that make up the medullary volume
and attach to juxtamedullary glomeruli may explain the initial rise in medullary volume
to compensate for sclerosis and atrophy of superficial nephrons in the cortex.49 The more
accelerated loss of total kidney volume after about 50 years of age9,50,51 is consistent
with the hypertrophy of remaining functional nephrons no longer adequately
compensating for volume loss from nephrosclerosis.

(Denic et al. 2016)