THOROUGH CRITICAL

APPRAISAL

JNEPHROL 2011; 24( 01

1- 10

):

DOI:10.5301/JN.2010.2030

Epidemiology and pathophysiology of left

ventricular abnormalities in chronic kidney
disease: a review
Giovanni Cerasola 1, Emilio Nardi 1,
Alessandro Palermo 1, Giuseppe Mul
1
,
Santina Cottone 2

Chair of Internal Medicine, Department of Internal

Medicine, Cardiovascular and Renal Diseases,
University of Palermo, Palermo - Italy*
2
Chair of Nephrology, Department of Internal Medicine,
Cardiovascular and Renal Diseases, University of
Palermo, Palermo - Italy*
1

* Excellence Centre of the European Society

of Hy p ertension
Departmen

t of

and
Renal

ABSTRACT

of heart failure and with mortality; impairment of

diastolic function in patients with CKD may occur
very early, even in the absence of LVH. Early detection of LVH and LV dysfunction in CKD could yield
an improvement in the adverse cardiovascular outcomes of CKD patients.

Introduction: Cardiovascular diseases are highly

prev- alent in patients with chronic kidney disease
(CKD), and represent the major hazard for mortality
in this population. Anomalies of left ventricular (LV)
structure and function are very frequent too among
CKD pa- tients, and show a negative impact on
Key words: Cardiovascular disease, Chronic kidney
cardiovascular prognosis.
disease, Hypertension, Left ventricular hypertrophy
Methods: We searched PubMed for manuscripts regarding left ventricular hypertrophy (LVH) in CKD.
Definition of LVH was different according to different
studies.
BACKGROUND: CARDIOVASCULAR DISEASES
Results: In patients with end-stage renal disease, the
IN CHRONIC KIDNEY DISEASE
prevalence of LVH is higher than 70%. Studies in patients with less advanced CKD have reported increasing prevalence of LVH along with declining renal funcThe burden of cardiovascular (CV) diseases in patients
tion. However, there is relatively wide heterogeneity in
with chronic kidney disease (CKD) has been a topic of
the prevalence of LVH in different studies, according
great in- terest in the medical literature in the last 10
to the characteristics of the population studied, the
years. There
is increasing knowledge of the
method chosen to estimate glomerular filtration rate
epidemiology of CKD and the related CV morbidity and
and the definition of LVH.
mortality, and it is now well- established that CV diseases
Conclusions: Hypertension, alterations of fluid and
are the leading cause of death for patients with CKD (1, 2).
electrolyte balance and anemia are identified as the
CKD represents today an important public health problem,
major determinants of LVH in CKD. However, beyond
since the incidence of end-stage renal disease (ESRD) rehemodynamic factors, other factors, such as an inapquiring renal replacement treatment (RRT) is growing, with
propriate activation of the renin-angiotensin-aldosincreasingly higher costs (3, 4). However, this topic
terone system, oxidative stress, inflammation and
collagen and muscle cell growth factors may have a
received scant attention until the late 1990s. In 1998, a
relevant role. LV diastolic dysfunction is also very frefamous paper by Foley, Parfrey and Sarnak (5),
quent among CKD patients and is associated with
2011 Societ Italiana di Nefrologia - ISSN 1121-8428
1
risk

highlighted the fact that patients with CKD, especially

those with ESRD requiring RRT by dialysis, should be
considered to be in the highest

2011 Societ Italiana di Nefrologia - ISSN 1121-8428

JNEPHROL 2011; 24( 01 ):

risk group for CV events. Moreover, since the

prevalence of early stages of CKD is estimated to be
100-fold greater than the prevalence of ESRD (6), it is
timely to remark that the majority of patients with CKD die
before ever reaching ESRD; thus, for patients with a
reduced glomerular fi
rate (GFR), the risk of a fatal CV event is much higher than
the risk to develop ESRD (7). Data from epidemiologic studies have confirmed that even a moderate reduction in
kidney function is associated with a signifi increase of CV
risk, and that the level of kidney function itself is an
independent predictor of CV outcome and all-cause
mortality (8-10).
Although patients with CKD manifest a high prevalence
of traditional CV risk factors, this does not fully account for
the burden of CV diseases in CKD, and an adequate
pharmaco- logic treatment of these traditional CV risk
factors does not necessarily lead to better CV outcome
(11). Other factors, which are typical of the CKD condition,
such as secondary hyperparathyroidism and the related
alterations of mineral metabolism, are associated with
enhanced CV damage and mortality (12-15).
Traditional CV risk factors, however, play a central role. Hypertension, often together with diabetes, is today the fi
cause of CKD (3, 4). Hypertension in itself represents
a powerful risk factor for CV diseases in CKD and is
almost invariably present in patients with renal failure.
Obversely, the prevalence of CKD is high among
hypertensive patients (16-18). Sodium retention and
activation of the renin-angio- tensin system have been
considered the most important mechanisms involved in
the elevation of blood pressure in subjects with kidney
disease (19). Sympathetic nervous sys- tem activation also
plays a role. Plasma catecholamine con- centrations are
elevated, and increased sympathetic nerve traffi has
been demonstrated in renal failure (20-23).
Hypertension also plays a major role in cardiac damage
in CKD via left ventricular hypertrophy (LVH) induction
(24). As in other populations (25, 26), in CKD patients the
presence of LVH is predictive of a worse CV prognosis
(27-30).

STUDIES OF LEFT VENTRICULAR HYPERTROPHY IN CHRONIC KIDNEY DISEASE

Anomalies of left ventricular (LV) structure and function
are very frequent among CKD patients (31-34). Many
data are available about patients with advanced renal
dysfunction. Among patients with ESRD, nearly 15% have
systolic dys- function, nearly 40% have heart failure and
more than 70% have LVH (35, 36). The association

1- 10

between less advanced renal dysfunction and LVH has

been less studied until the late 1990s. Successively,
several papers appeared in the literature and showed that
in nonuremic CKD patients, the

Cerasola et al: Left ventricular abnormalities in

CKD

prevalence of LVH is high, ranging from 34% to 78% in

the different studies, with increasing prevalence with
declining renal function (31, 33, 36, 37).
However, the relatively wide heterogeneity in the
prevalence of LVH in different studies (Tab. I) can be
attributed to several differences with regard to the
characteristics of the popula- tion studied (age, RRT or
earlier stage of CKD, prevalence of hypertension and
prevalence of CV diseases), the method chosen to
estimate GFR, the cutoff of GFR used to enroll the
patients and, last but not least, the definition of LVH; in
this regard, it is noteworthy that in some studies no
definition of LVH has been provided (28, 36).
A study by Tucker et al (33) evaluated LVH and
ambulatory blood pressure (BP) in 85 CKD patients free
of diabetes and CV diseases. Mean age was 49 years
and mean creatinine clearance (40) was 39 ml/min. LV
mass (LVM) was deter- mined by the American Society
of Echocardiography (ASE) cube formula (41), and
indexed by body surface area (LVMI). LVH was defi
as LVMI >131 g/m2 in men and >100
g/m2 in women. The prevalence of LVH was 16% in
patients with creatinine clearance (CrCl) >30 ml/min
and 38% in those with CrCl <30 ml/min. Both concentric
and eccentric hyper- trophy were more prevalent with
decreasing renal function. After multiple stepwise
regression analysis, the variables independently

associated with LVM were male sex, body mass index,

ambulatory systolic BP and hemoglobin (33). In a study by
Levin et al (36), 318 patients with CKD were enrolled to
evaluate the variables associated with LV growth after a 1year follow-up period. Mean age was 57 years; GFR
was estimated by Cockcroft-Gault equation (42), and its
mean value for the whole population was <40 ml/min.
Thirty-nine percent of the patients had CV diseases at
the time of enrollment. Of the patients studied, 34% had
LVH, the prevalence of which increased with declining renal
func- tion, becoming nearly 70% in the subgroup with
ESRD. After the 1-year follow-up period, systolic BP and
the reduction of hemoglobin concentration were the
independent predic- tors of LVM increase. Of the patients
with LVH at the end of follow-up, 65% had eccentric
hypertrophy. Given the great- er prevalence of eccentric
changes and the independent relationship between
hemoglobin and LV growth (although mean hemoglobin
was 12.8 g/dL), the authors emphasized the importance of
relative anemia in this population. Of note is the fact that in
this study the prevalence of hypertension is not reported,
and no defi
of LVH is provided.
A study by Stack and Saran (28) evaluated 2,257 patients
with ESRD at the start of dialysis. Mean age was 58 years,
and mean GFR (estimated by Modification of Diet in Renal
Disease [MDRD] Study equation (43)) was <8 ml/min.
Among different covariates, hypertension, diabetes,
tobacco use,

low serum albumin and higher calcium and parathyroid

hormone were the factors independently associated with
LVH. After 2 years of follow-up, the presence of LVH
was associated with lower survival. This study involved a
very wide group of subjects of different ethnic groups
(white, black, Asian, Native Americans and other), but,
apart from the above-mentioned results which are in
agreement with other studies, it showed an extremely
low prevalence of LVH (particularly in such subjects
having ESRD): 16.4%. It is not possible to adequately
discuss why in this study the prevalence of LVH was so
much lower than in other stud- ies, because LVH is not
defined by the authors. Moreover, it is noteworthy that no
echocardiographic data are reported in the paper.
A study by Paoletti et al (37) evaluated the prevalence
of LVH in 244 patients with CKD, free of diabetes and
coronary

artery disease; the prevalence of hypertension was 66%.

GFR was estimated by Cockcroft-Gault equation (42). An
in- dependent association between LVM and ambulatory
pulse pressure was demonstrated. LVM was indexed by
body sur- face area (LVMI) and LVH was defi
as LVMI
>134 g/m2 in men and >110 g/m2 in women. The overall
prevalence of LVH was 74%, and was increasingly higher
with declin- ing renal function: 51% in stage 1-2 CKD,
71% in stage 3,
and 80% and 84% in stages 4 and 5, respectively. Further,
a greater prevalence of concentric geometry was found in
patients with more advanced renal dysfunction. The fact
that in this study the prevalence of LVH was so much
higher than in other studies, has been discussed by
Agarwal (44). In their reply, Paoletti et al (45) recalculated
LVM using the ASE-cube formula (41) instead of the
Penn-cube formula (46). Although slightly reduced, the
prevalence of LVH in this

TABLE I
ESTIMATED PREVALENCE OF LEFT VENTRICULAR HYPERTROPHY (LVH) IN PATIENTS WITH CHRONIC
KIDNEY DISEASE IN SOME DIFFERENT STUDIES

Author

Year of
publication

Number
of patients

LVH prevalence
GFR

Definition of LVH

LVMI >131
g/m2
in men
and >100 g/m2
in women

Mean

39
ml/min

Method to
estimate GFR

Creatinine
clearance

Tucker et al (33)

1997

85

16%-38%

Levin et al (36)
ml/min

1999

318

34%

Not defined

<40

Cockcroft-Gault
equation

Stack and Saran (28)

2002

2,257

16.4%

Not defined

<8 ml/min

MDRD equation

36 ml/min

Cockcroft-Gault
equation

Paoletti et al (37)

2005

244

74%

LVMI >134
g/m2
in men
and >110 g/m2
in women

LVMH2.7 >49.2
g/m in men and >46.7
2.7

Peterson et al (38)

2007

599

69.4%

g/m2.7

in women
44 ml/min/1.73 m2

Equation by Lewis et al (39)

Nardi et al (31)

2009

293

47.1%

LVMI >125
g/m2
in men
and >110 g/m2
in women

39 ml/min/1.73 m2

Cockcroft-Gault
equation

GFR = glomerular filtration rate; LVH = left ventricular hypertrophy; LVMI = left ventricular mass indexed by body surface area;
MDRD = Modification of Diet in Renal Disease.

Fig. 1 - Prevalence of patterns of left ventricular hypertrophy (LVH) in patients with essential hypertension and normal
renal function, and in hypertensives with chronic kidney disease (CKD).

study, regardless of the stage of CKD, remained substantially higher than in the rest of the literature (45).
In the African American Study of Kidney Disease (AASK)
(38), the prevalence and the correlates of LVH were
evaluated in 599 nondiabetic hypertensive African
Americans. Mean age was 60 years, and mean GFR was
44 ml/min per 1.73 m2. Of note is the fact that in this
study, GFR was estimated by means of a different
equation developed from baseline data in the AASK trial
(39). LVM was indexed by height el- evated to a power of
2.7 (LVMH2.7) (47) and LVH was defi
as LVMH2.7 >49.2 g/m2.7 in men and >46.7 g/m2.7 in women.
The variables independently associated with LVH, the
global prevalence of which was 69.4%, were daytime and
night- time ambulatory BP, GFR and younger age (38).
A recent study by our group (31) evaluated the prevalence
of LVH and LV geometry in a group of 293 hypertensive

Fig. 2 - Prevalence of inappropriate left ventricular mass

(iLVM) in patients with essential hypertension and normal renal function, and in hypertensives with chronic kidney disease (CKD).

patients with stage 2-5 CKD and free of CV diseases,

and in 289 patients with essential hypertension and normal renal function. Mean age was 59 years, mean GFR
(estimated by Cockcroft-Gault equation (42) corrected
by body surface area) was 39 ml/min per 1.73 m2 for the
whole CKD group. Prevalence of diabetes was 30% in
both groups studied. LVH was defi
as LVMI >125 g/
m2 in men and >110 g/m2 in women. In our CKD patients,
the overall prevalence of LVH was 47.1%. We observed
increasingly greater prevalence of LVH with declining renal function, and, as expected, the prevalence of LVH was
>70% in patients with stage 5 CKD (31). After multiple
regression analysis, the variables independently associated with LVMI were GFR, hemoglobin, diastolic BP and
age. An interesting fi
in our study was that in CKD

patients, the increase of LVM was, in many cases,

the result of the simultaneous increase of LV
diameters and wall thicknesses. In fact, we found that
the prevalence of mixed LVH (31) was higher in CKD
patients than in es- sential hypertensives (Fig. 1). We
also observed that LV wall thicknesses and diameters
were increasingly greater with lessening renal function,
and that in stage 5 CKD a very pronounced LV growth
takes place, largely due to a further significant increase
of wall thicknesses, rather than of LV diameter (31).
Further, we evaluated the prevalence of inappropriate
LVM (iLVM). According to some authors (48), iLVM is
con- sidered as the value of LV mass exceeding the
amount needed to adapt to stroke work for a given
individuals sex and body size: iLVM is defined as an
excess of >28% from the value predicted by means of
an equation including BP, stroke volume, height2.7 and

sex. Recently, the presence of iLVM has shown a

negative impact on CV prognosis of hypertensive patients
(49). In our study, the prevalence of iLVM was 52.6% for
the whole CKD group and 30.5% in essential
hypertensive patients with normal renal function (Fig. 2),
and was increasingly higher with lessening renal
function: 38% in stage 2, 47.5% in stage 3, 51.35% in
stage 4 and 80.7% in stage 5 CKD.
Another recent study by our group (50) analyzed the relationship between LVM and mild-moderate reduction of kidney function in a group of 455 nondiabetic hypertensive patients, free of CV diseases, all with GFR >30 ml/min per
1.73 m2, selected among the 1,856 participants in the
Renal Dys- function in Hypertension (REDHY) Study (17).
Mean age was 48 years. LVH was defi
as LVMI 125
g/m2 or LVMH2.7

51 g/m2.7. GFR was estimated by 4 different methods:

CrCl (40), Cockcroft-Gault (42), MDRD (43) and Mayo
Clinic equa- tions (51). Independently of the method
chosen to estimate GFR, we found a progressive
increase of LVH prevalence with decreasing renal
function, and an inverse association between GFR and
LVM, independent of potential confound- ers such as, in
particular, 24-hour BP load (50).

PATHOPHYSIOLOGY OF LEFT VENTRICULAR

HYPERTROPHY IN CHRONIC KIDNEY DISEASE
Although the pathogenesis of LVH in CKD is considered
to be multifactorial, hypertension, alterations of fluid and
electrolyte balance and anemia are identified as the major
determinants of LV growth in CKD and ESRD patients
(28, 29, 33-35, 52-55).
From an hemodynamic view, LVH is primarily an adaptive remodeling process, compensating for an increase in
cardiac work, which may be schematically due to volume
and/or pressure overload. Schematically, pressure overload caused, for example, by hypertension or aortic
stenosis leads to concentric hypertrophy, while volume
overload caused, for example, by anemia, volume overload or (in patients on hemodialysis) the presence of an
arteriovenous fi leads to the development of eccentric hypertrophy (52).
However, both patterns of LVH are frequent among patients with CKD, and often a mixed pattern characterized
by the increase of both diameters and wall thicknesses,
can be recognized. This mixed pattern of LVH was indeed
frequently found in our recent study (31) (Fig. 1). Further,
along with the worsening of renal dysfunction, instead of a
trend toward an eccentric ventricle, attributable to volume
overload, we found a very high prevalence of concentric
and mixed LVH, due to increase of wall thicknesses (31).
To our knowledge, the literature data to date do not offer
an explanation for this fi
Among hemodynamic factors, another frequent feature of
pa- tients with CKD is increased arterial stiffness, which has
been associated with LVH as well as with CV mortality (5658).
However, beyond hemodynamic factors, other factors, such
as an inappropriate activation of the renin-angiotensin-aldosterone system, oxidative stress, infl
(59-63)
and the hyperactivation of collagen and muscle cell growth
factors may have a relevant role in LV growth in CKD.
It could be hypothesized that in cases of advanced
renal dysfunction, the clearance of some growth factors
could be impaired. The carboxy-terminal propeptide of
collagen type I (PICP) or cardiotrophyn-1 (CT-1), which

are involved in the development of LVH in hypertensive

heart disease (64, 65),

could play a role. However, renal function seems not to

in- fluence PICP clearance, which depends on hepatic
function (66), while to our knowledge a role for an
impaired clearance of CT-1 cannot be excluded. In a
recent study by our group (62), PICP and CT-1
concentrations were higher in CKD pa- tients than in
hypertensives with normal renal function, and were
higher in CKD patients with LVH than in those without it.
However, after multiple regression analysis, systolic BP
and the inflammation marker C-reactive protein were
the only independent correlates of LVMI (59).
Further, evidence indicates that sodium/potassium ATPase inhibitors may be involved in the pathogenesis
of LVH in CKD (67, 68). Recently, some attention has
been focused on fibroblast growth factor-23 (FGF-23).
FGF-23 is a recently discovered hormone, secreted by
osteo- blasts and osteocytes, that helps maintain
normal serum phosphate concentrations in CKD by
stimulating
urinary
phosphate
excretion
and
decreasing dietary phosphorus absorption through
inhibition of 1,25-dihydroxyvitamin D synthesis (69). In
CKD patients, an independent relation- ship between
FGF-23 and LVH (particularly concentric LVH) has
been found in 2 very recent studies (70, 71). It can be
hypothesized that at the markedly elevated concentrations which FGF-23 reaches in CKD patients, it
can nonselectively bind to FGF receptors normally

activated by other factors, thus inducing enhanced fi

osis.
In patients with renal failure, increased myocardial fi osis
has been demonstrated either in post mortem analysis or
by means of endomyocardial biopsies (72-74). Increased
myo- cardial fi osis presumably contributes to myocardial
isch- emia due to the reduction in capillary density and
coronary reserve (73). Recently, even subclinical renal
damage has been associated with impaired coronary fl
reserve (75). Further, increased myocardial fibrosis has a
central role in the alterations of diastolic function (Fig. 3).

LEFT VENTRICULAR DIASTOLIC FUNCTION IN

CHRONIC KIDNEY DISEASE
LV diastolic dysfunction is very frequent among CKD patients and may be associated with the subsequent development of heart failure and with mortality (76); it has been also
reported that in ESRD patients, diastolic function deteriorates in parallel with the progression of LVH (77). LV
diastolic dysfunction has been found also in CKD patients
with LVH not undergoing dialysis (78). In patients with
heart failure, the presence of CKD is associated with
worse diastolic function, intracardiac conduction and
prognosis (79, 80); the negative impact on CV outcome
seems to be stronger in patients with diastolic heart failure
(80).

Fig. 3 - Possible mechanisms connecting chronic kidney disease, inflammation and left ventricular hypertrophy (LVH).
CRP = C-reactive protein; CT1 = cardiotrophyn-1; NADPH =
nicotinamide adenine dinucleotide phosphate; NO = nitric
ox- ide; PICP = carboxy-terminal propeptide of collagen
type I; ROS = reactive oxygen species.

Fig. 4 - Early diastolic myocardial velocity (Em) according

to the stages of renal dysfunction in 293 hypertensives with
chronic kidney disease (CKD); *p=0.0001, stage 3 vs. stage 2;
**p=0.0001, stage 5 vs. stage 4.

However, impairment of diastolic function in patients with

CKD may occur very early, even in the absence of LVH.
This has been focused in a recent study by our group (32).
Briefl , we evaluated diastolic function by means of both
mitral in- flow assessment and tissue Doppler imaging
(TDI), in 156 hypertensive patients, with and without CKD.
Patients with CV diseases or LVH were excluded from the
study. The group with CKD (mean GFR 37 ml/min) had
signifi
worse dia- stolic function. Further, multiple
regression analysis demon- strated an independent
relationship between renal function and diastolic function

(32). In another recent study by our group (31), which

involved 293 hypertensive patients with stage 2-5 CKD,
free of CV diseases, early diastolic myocar- dial velocity (Em)
evaluated by TDI was lower with lessening renal function,
having very low values in stage 5 CKD (Fig. 4), although all
patients were free from heart failure.
Although conventional mitral infl assessment has become
the main tool in assessing diastolic function in daily practice,
preload dependency of fl patterns constitutes the major
limitation of the technique to assess either ventricular relaxation or fi pressures separately (81, 82). An interesting

feature of Em measured by TDI is its relative preload independence. Consequently, Em remains reduced even in
those stages of diastolic dysfunction characterized by
increased preload compensation. Moreover, Em has been
demonstrat- ed to be inversely related to the degree of fi
osis in isch- emic as well as in normal myocardial
segments (83).

CONCLUSIONS
CV diseases are highly prevalent in patients with CKD, and
represent the major hazard for mortality in this population.
Anomalies of LV structure and function are very frequent
too among CKD patients, and show a negative impact on
CV prognosis.
Early detection of LVH and LV dysfunction is recommended, as early and aggressive treatment can yield
an improvement in the adverse CV outcomes of CKD
patients. Furthermore, treatment of major determinants
of LV growth in CKD, such as hypertension and anemia, should be of benefit. It has been demonstrated in
hypertensive patients that echocardiographic finding of
LVH regression may have positive prognostic relevance
(84-87).
On the other hand, studies regarding the effect of
treatment of anemia on LV growth in CKD patients have
reached con- flicting results (88-92).
However, it is timely to remark that, despite the established
evidence that CKD patients are exposed to a very high CV
risk, they are often undertreated in clinical practice. In this
regard, in a large cohort of more than 130,000 elderly patients, it has been demonstrated that patients with renal
insufficiency were less likely to receive appropriate cardioprotective treatments (93).

Financial support: No financial support.

11.

Conflict of interest statement: None declared.

12.

Address for correspondence:

Prof. Giovanni Cerasola
Via del Vespro 129
IT-90127 Palermo, Italy
medint@unipa.it

13.

14.

15.

REFERENCES
Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic
kidney disease in the United States. JAMA. 2007;298:20382047.
2. Hostetter TH. Chronic kidney disease predicts cardiovascular disease. N Engl J Med. 2004;351:1344-1346.
3. US Renal Data System. USRD 2006 annual data report.
Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2006.
4. Centers for Disease Control and Prevention (CDC). Prevalence of chronic kidney disease and associated risk factors
United States, 1999-2004. MMWR Morb Mortal Wkly Rep.
2007;56:161-165.
5. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of
cardiovascular disease in chronic renal disease. Am J
Kidney Dis. 1998;32(Suppl 3):S112-S119.
6. Thorp ML, Eastman L, Smith DH, Johnson ES. Managing the burden of chronic kidney disease. Dis Manag.
2006;9:115-121.
7. Shulman NB, Ford CE, Hall WD, et al. Prognostic value of
serum creatinine and effect of treatment of hypertension on
renal function: results from the Hypertension Detection and
Follow-up Program. The Hypertension Detection and Followup Program Cooperative Group. Hypertension. 1989;13(5
Suppl):I80-93.
8. Manjunath G, Tighiouart H, Ibrahim H, et al. Level of kidney
function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J Am Coll Cardiol. 2003;41:47-55.
9. Manjunath G, Tighiouart H, Coresh J, et al. Level of kidney
function as a risk factor for cardiovascular outcomes in the
elderly. Kidney Int. 2003;63:1121-1129.
10. Henry RM, Kostense PJ, Bos G, et al. Mild renal
insufficiency is associated with increased cardiovascular
mortality: The Hoorn Study. Kidney Int. 2002;62:1402-1407.

16.

1.

17.

18.

19.

20.

21.

22.

23.

24.

25.

Fellstrom BC, Jardine AJ, Schmieder RE, et al. Rosuvastatin

and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009;360:1395-1407.
Ganesh SK, Stack AG, Levin NW, Hulbert-Shearon T, Port
FK. Association of elevated serum PO(4), Ca x PO(4)
product, and parathyroid hormone with cardiac mortality risk
in chronic he- modialysis patients. J Am Soc Nephrol.
2001;12:2131-2138.
Goodman WG, Goldin J, Kuizon BD, et al. Coronaryartery calcifi
in young adults with end-stage renal
disease who are undergoing dialysis. N Engl J Med.
2000;342:1478-1483.
Raggi P, Boulay A, Chasan-Taber S, et al. Cardiac calcification in adult hemodialysis patients: a link between end-stage
renal disease and cardiovascular disease? J Am Coll
Cardiol. 2002;39:695-701.
Young EW, Albert JM, Satayathum S, et al. Predictors
and consequences of altered mineral metabolism: the Dialysis Outcomes and Practice Patterns Study. Kidney Int.
2005;67:1179-1187.
Coresh J, Byrd-Holt D, Astor BC, et al. Chronic kidney disease awareness, prevalence, and trends among U.S. adults,
1999 to 2000. J Am Soc Nephrol. 2005;16:180-188.
Cerasola G, Mul G, Cottone S, Nardi E, Cusimano P. Hypertension, microalbuminuria and renal dysfunction. The
REDHY (REnal Dysfunction in HYpertension) study. J Nephrol. 2008;21:368-373.
Cerasola G, Mul G, Nardi E, et al. Clinical correlates of renal dysfunction in hypertensive patients without cardiovascular complications: the REDHY study. J Hum Hypertens.
2010;24:44-50.
Guyton AC, Coleman TG, Wilcox CS. Quantitative analysis
of the pathophysiology of hypertension. J Am Soc Nephrol.
1999;10:2248-2249.
Converse RL Jr, Jacobsen TN, Toto RD, et al. Sympathetic
overactivity in patients with chronic renal failure. N Engl J
Med. 1992;327:1912-1918.
Zoccali C, Mallamaci F, Tripepi G, et al. Norepinephrine and
concentric hypertrophy in patients with end-stage renal disease. Hypertension. 2002;40:41-46.
Neumann J, Ligtenberg G, Klein II, Koomans HA, Blankestijn
PJ. Sympathetic hyperactivity in chronic kidney disease:
pathogenesis, clinical relevance, and treatment. Kidney Int.
2004;65:1568-1576.
Schiffrin EL, Lipman ML, Mann JF. Chronic kidney disease: effects on the cardiovascular system. Circulation.
2007;116:85-97.
Locatelli F, Bommer J, London GM, et al. Cardiovascular
dis- ease determinants in chronic renal failure: clinical
approach and treatment. Nephrol Dial Transplant.
2001;16:459-468.
Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP.
Prognostic implications of echocardiographically determined

left ventricular mass in the Framingham Heart Study. N

Engl J Med. 1990;322:1561-1566.

26. Sundstrom J, Lind L, Arnlov J, Zethelius B, Andrn B, Lithell

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

HO. Echocardiographic and electrocardiographic diagnoses

of left ventricular hypertrophy predict mortality independently of each other in a population of elderly men. Circulation.
2001;103:2346-2351.
Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC,
Barre PE. The prognostic importance of left ventricular
geometry in uremic cardiomyopathy. J Am Soc Nephrol.
1995;5:2024-2031.
Stack AG, Saran R. Clinical correlates and mortality impact
of left ventricular hypertrophy among new ESRD patients in
the United States. Am J Kidney Dis. 2002;40:1202-1210.
Foley RN, Parfrey PS, Kent GM, Harnett JD, Murray DC,
Barre PE. Serial change in echocardiographic parameters
and cardiac failure in end-stage renal disease. J Am Soc
Nephrol. 2000;11:912-916.
Tsioufis C, Vezali E, Tsiachris D, et al. Left ventricular hypertrophy versus chronic kidney disease as predictors of cardiovascular events in hypertension: a Greek 6-year-follow-up
study. J Hypertens. 2009;27:744-752.
Nardi E, Palermo A, Mul G, Cusimano P, Cottone S, Cerasola G. Left ventricular hypertrophy and geometry in hypertensive patients with chronic kidney disease. J Hypertens.
2009;27:633-641.
Nardi E, Cottone S, Mul G, Palermo A, Cusimano P,
Ceraso- la G. Influence of chronic renal insufficiency on left
ventricu- lar diastolic function in hypertensives without left
ventricular hypertrophy. J Nephrol. 2007;20:320-328.
Tucker B, Fabbian F, Giles M, Thuraisingham C, Raine
AE, Baker LR. Left ventricular hypertrophy and ambulatory
blood pressure monitoring in chronic renal failure.
Nephrol Dial Transplant. 1997;12:724-728.
McGill RL, Biederman RW, Getts RT, et al. Cardiac magnetic resonance imaging in hemodialysis patients. J Nephrol.
2009;22:367-372.
Foley RN, Parfrey PS, Harnett JD, et al. Clinical and ecocardiographic disease in patients starting end stage renal disease therapy. Kidney Int. 1995;47:186-192.
Levin A, Thompson C, Ethier J, et al. Left ventricular mass
index increase in early renal disease: impact in decline in
haemoglobin. Am J Kidney Dis. 1999;34:125-134.
Paoletti E, Bellino D, Casottana P, Rolla D, Cannella G.
Left ventricular hypertrophy in nondiabetic predialysis CKD.
Am J Kidney Dis. 2005;46:320-327.
Peterson GE, de Backer T, Gabriel A, et al. Prevalence and
correlates of left ventricular hypertrophy in the African American Study of Kidney Disease Cohort Study. Hypertension.
2007;50:1033-1039.
Lewis J, Agodoa L, Cheek D, et al. comparison of crosssectional renal function measurements in African Americans
with hypertensive nephrosclerosis and of primary formulas to estimate glomerular filtration rate. Am J Kidney Dis.
2001;38:744-753.
Rose BD. Clinical assessment of renal function. In: Rose
BD,

41.

42.
43.

44.
45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.
56.

ed. Pathophysiology of renal disease. 2nd ed. New York:

McGraw-Hill; 1987:1-23.
Devereux RB, Alonso DR, Lutas EM, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to
necropsy findings. Am J Cardiol. 1986;57:450-458.
Cockcroft DW, Gault MH. Prediction of creatinine clearance
from serum creatinine. Nephron. 1976;16:31-41.
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth
D. A more accurate method to estimate glomerular filtration
rate from serum creatinine: a new prediction equation. Ann
Intern Med. 1999;130:461-470.
Agarwal R. Prevalence of left ventricular hypertrophy: some
alternate thoughts. Am J Kidney Dis. 2005;46:1148.
Paoletti E, Cassottana P, Cannella G. Prevalence of left ventricular hypertrophy: some alternate thoughts. In reply. Am J
Kidney Dis. 2005;46:1148-1149.
Devereaux RB, Reichek N. Echocardiographic determination
of left ventricular mass in man: Anatomic validation of the
method. Circulation. 1977;55:613-618.
De Simone G, Daniels SR, Devereux RB, et al. Left ventricular mass and body size in normotensive children and adults:
assessment of allometric relations and the impact of overweight. J Am Coll Cardiol. 1992;20:1251-1260.
De Simone G, Devereux RB, Kimball TR, et al. Interaction
between body size and cardiac workload. Influence on left
ventricular mass during body growth and adulthood. Hypertension. 1998;31:1077-1082.
Muiesan ML, Salvetti M, Paini A, et al. Inappropriate left ventricular mass changes during treatment adversely affects
cardiovascular prognosis in hypertensive patients. Hypertension. 2007;49:1077-1083.
Cerasola G, Nardi E, Mul G, et al. Left ventricular mass in
hypertensive patients with mild-to-moderate reduction of renal function. Nephrology. 2010;15:203-210.
Rule AD, Larson TS, Bergstrahl EJ, Slezak JM, Jacobsen
SJ, Cosio FG. Using serum creatinine to estimate
glomerular fil- tration rate: accuracy in good health and in
chronic kidney disease. Ann Intern Med. 2004;141:929-937.
Middleton RJ, Parfrey PS, Foley RN. Left ventricular hypertrophy in the renal patient. J Am Soc Nephrol.
2001;12:1079-1084.
Harnett JD, Kent GM, Barre PE, Taylor R, Parfrey PS. Risk
factors for the development of left ventricular hypertrophy
in a prospectively followed cohort of dialysis patients. J
Am Soc Nephrol. 1994;4:1486-1490.
London G. Pathophysiology of cardiovascular damage
in the early renal population. Nephrol Dial Transplant.
2001;16(Suppl 2):3-6.
Sarnak MJ. Cardiovascular complications in chronic kidney
disease. Am J Kidney Dis. 2003;41(Suppl 5):S11-S17.
Henry RM, Kamp O, Kostense PJ, et al. Mild renal insufficiency is associated with increased left ventricular mass in
men, but not in women: an arterial stiffness-related phenom-

enon The Hoorn Study. Kidney Int. 2005;68:673-679.

57. Wang MC, Tsai WC, Chen JY, Cheng MF, Huang JJ.
Arterial stiffness correlated with cardiac remodelling in
patients with chronic kidney disease. Nephrology.
2007;12:591-597.
58. Fukuta H, Ohte N, Mukai S, et al. Relationship between
renal function, aortic stiffness and left ventricular function in patients with coronary artery disease. Circ J.
2009;73:1740-1745.
59. Cottone S, Nardi E, Mul G, et al. Association between
biomark- ers of infl and left ventricular hypertrophy in
moderate chronic kidney disease. Clin Nephrol. 2007;67:209216.
60. Cottone S, Mul G, Nardi E, et al. C-reactive protein and
intercellular adhesion molecule-1 are stronger predictors of
oxidant stress than blood pressure in established hypertension. J Hypertens. 2007;25:423-428.
61. Cottone S, Lorito MC, Riccobene R, et al. Oxidative stress,
inflammation and cardiovascular disease in chronic renal
fail- ure. J Nephrol. 2008;21:175-179.
62. Cottone S, Mul G, Guarneri M, et al. Endothelin-1 and F2isoprostane relate to and predict renal dysfunction in hypertensive patients. Nephrol Dial Transplant. 2009;24:497-503.
63. Ayerden Ebin F, Ebina H, Derici U, et al. The relationship
between adiponectin levels and proinflammatory cytokines
and left ventricular mass in dialysis patients. J Nephrol.
2009;22:216-223.
64. Lopez B, Gonzalez A, Varo N, Laviades C, Querejeta R,
Diez
J. Biochemical assessment of myocardial fibrosis in hypertensive heart disease. Hypertension. 2001;38:1222-1226.
65. Lopez B, Gonzalez A, Lsarte JJ, et al. Is plasma cardiotrophin-1 a marker of hypertensive heart disease? J Hypertens.
2005;23:625-632.
66. Smedsrd B, Melkko J, Risteli L, Risteli J. Circulating C-terminal propeptide of type I procollagen is cleared mainly via
a mannose receptor in the liver endothelial cells. Biochem J.
1990;271:345-350.
67. Kennedy DJ, Vetteth S, Periyasamy SM, et al. Central role
for the cardiotonic steroid marinobufagenin in the pathogenesis of experimental uremic cardiomyopathy. Hypertension.
2006;47:488-495.
68. Stella P, Manunta P, Mallamaci F, et al. Endogenous
oua- bain and cardiomyopathy in dialysis patients. J Intern
Med. 2008;263:274-280.
69. Gutierrez O, Isakova T, Rhee E, et al. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol.
2005;16:2205-2215.
70. Gutirrez OM, Januzzi JL, Isakova T, et al. Fibroblast growth
factor-23 and left ventricular hypertrophy in chronic kidney
disease. Circulation. 2009;119:2545-2552.
71. Mirza M, Larsson A, Melhus H, Lind L, Larsson T. Serum intact FGF-23 associate with left ventricular mass, hypertro-

phy and geometry in an elderly population. Atherosclerosis

2009;207:546-551.

72. Mall G, Huther W, Schneider J, Lundin P, Ritz E. Diffuse

in- termyocardiocytic fibrosis in uraemic patients. Nephrol
Dial Transplant. 1990;5:39-44.
73. Amann
K,
Breitbach
M,
Ritz
E,
Mall
G.
Myocyte/capillary mismatch in the heart of uremic
patients. J Am Soc Nephrol. 1998;9:1018-1022.
74. Aoki J, Ikari Y, Nakajima H, et al. Clinical and
pathologic characteristics of dilated cardiomyopathy in
hemodialysis patients. Kidney Int. 2005;67:333-340.
75. Bezante GP, Viazzi F, Leoncini G, et al. Coronary flow
reserve is impaired in hypertensive patients with
subclinical renal damage. Am J Hypertens. 2009;22:191196.
76. London GM. Left ventricular alteration and end-stage
renal disease. Nephrol Dial Transplant. 2002;17:29-36.
77. Fathi R, Isbel N, Haluska B, Case C, Johnson DW,
Marwick TH. Correlates of subclinical left ventricular
dysfunction in ESRD. Am J Kidney Dis. 2003;41:10161025.
78. Miyazato J, Horio T, Takiuchi S, et al. Left ventricular
diastolic dysfunction in patients with chronic renal failure:
impact of diabetes mellitus. Diabet Med. 2005;22:730736.
79. Bruch C, Rothenburger M, Gotzmann M, et al. Chronic
kid- ney disease in patients with chronic heart failure:
impact on intracardiac conduction, diastolic function and
prognosis. Int J Cardiol. 2007;118:375-380.
80. Ahmed A, Rich M, Sanders P, et al. Chronic kidney
dis- ease associated mortality in diastolic versus

81.

82.

83.

84.

85.

86.

87.

systolic heart failure: a propensity matched study. Am J

Cardiol. 2007;99:393-398.
Oh JK, Appleton CP, Hatle LK, Nishimura RA, Seward
JB, Tajik AJ. The noninvasive assessment of left ventricular
dia- stolic function with two-dimensional and Doppler
echocar- diography. J Am Soc Echocardiogr. 1997;10:246292.
Choong CY, Herrmann HC, Weyman AE, Fifer MA. Preload dependence of Doppler-derived indexes of left ventricular diastolic function in humans. J Am Coll Cardiol.
1987;10:800-808.
Shan K, Bick RJ, Poindexter BJ, et al. Relation of tissue
Dop- pler derived myocardial velocities to myocardial
structure and beta-adrenergic receptor density in humans.
J Am Coll Cardiol. 2000;36:891-896.
Verdecchia P, Schillaci G, Borgioni C, et al. Prognostic
signifi- cance of serial changes in left ventricular mass in
essential hypertension. Circulation. 1998;97:48-54.
Devereux RB, Wathcell K, Gerdts E, et al. Prognostic significance of left ventricular mass change during treatment of
hypertension. JAMA. 2004;292:2350-2356.
Verdecchia P, Angeli F, Borgioni C, et al. Changes in
cardio- vascular risk by reduction of left ventricular mass in
hyperten- sion: a meta-analysis. Am J Hypertens.
2003;16:895-899.
Pierdomenico SD, Lapenna D, Cuccurullo F. Regression of
echocardiographic left ventricular hypertrophy after 2 years
of therapy reduces cardiovascular risk in patients with essential hypertension. Am J Hypertens. 2008;21:464-470.

88. Roger SD, McMahon LP, Clarkson A, et al. Effects of

early and late intervention with epoetin alpha on left
ventricular mass among patients with chronic kidney
disease (stage 3 or 4): results of a randomized clinical trial.
J Am Soc Nephrol. 2004;15:148-156.
89. Levin A, Djurdjev O, Thompson C, et al. Canadian randomized trial of hemoglobin maintenance to prevent or delay left
ventricular mass growth in patients with CKD. Am J Kidney
Dis. 2005;46:799-811.
90. Dreke TB, Locatelli F, Clyne N, et al; CREATE Investigators.
Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355:2071-2084.
91. Ritz E, Laville M, Bilious RW, et al. Target level of
hemoglobin correction in patients with diabetes and CKD:
primary results of the Anemia Correction in Diabetes
(ACORD) Study. Am J Kidney Dis. 2007;49:194-207.

92. Cianciaruso B, Ravani P, Barrett BJ, Levin A; for the

ITA- EPO-7 Investigators. Italian randomized trial of
hemoglobin maintenance to prevent or delay left ventricular
hypertrophy in chronic kidney disease. J Nephrol.
2008;21:861-870.
93. Shlipak MG, Heidenreich PA, Noguchi H, Chertow GM,
Browner WS, McClellean MB. Association of renal insufficiency with treatment and outcomes after myocardial infarction in elderly patients. Ann Intern Med. 2002;137:555-562.

Received: January 11, 2010

Revised: February 10, 2010
Accepted: February 10, 2010