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Ultrasound Approach to

Chronic Kidney Disease


and its Complications
Edited by
www.esciencecentral.org/ebooks

Dr. Luca Di Lullo

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Ultrasound Approach to Chronic Kidney


Disease and its Complications
Chapter: Chronic Kidney Disease
Edited by: Luca Di Lullo
Published Date: June 2014
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Chronic Kidney Disease


Bijin Thajudeen*
Assistant Professor, University of Arizona, Department of Nephrology, Tucson, USA
*Corresponding author: Bijin Thajudeen, Assistant Professor, University of Arizona, Department
of Nephrology, PO box 245022, Room 6325, 1501, North Campbell Ave, Tucson, AZ 85724,
USA, Tel: 5206266371; Fax: 5206262024; E-mail: bijint@email.arizona.edu, bijint@gmail.com

Introduction
Chronic kidney disease (CKD) is a pathophysiologic process characterized by progressive
loss of nephrons and function due to multiple etiologies and frequently leading to end stage
renal disease (ESRD). The incidence and prevalence of CKD are increasing every year all over
the world mainly driven by the ageing of the general population, rising incidence of obesity
as well as type 2 diabetes mellitus and improved survival from cancer as well as major
cardiovascular accidents. The clinical and public health importance of CKD is well established.
CKD in the long run progresses to ESRD and eventual need for renal replacement therapy.
It also predispose to increased risk of cardiovascular disease. This has impact not only on
the economy but also place a formidable effect on the mortality especially cardiovascular
mortality. Major causes of CKD include hypertension, diabetes mellitus, glomerulonephritis,
cystic kidney disease, urinary tract obstruction, interstitial nephritis, vesico-ureteric reflux,
nephrolithiasis and recurrent kidney infection. At the same time it is important to emphasize
that there is a natural physiological reduction in glomerular filtration rate (GFR) with aging
which behaves differently from the various etiologies mentioned above in terms of progression
of the disease. Although the renal prognosis is favorable in most patients who demonstrate
age related drop in GFR, even a modest reduction in GFR in this population is associated with
increased risk of cardiovascular morbidity and mortality [1].

Epidemiology of chronic kidney disease


CKD affects almost 1415% of the adult United States (U.S) population [2]. The prevalence
of CKD is highest in the elderly population especially those above the age of 65 years [3].
While the incidence and prevalence of CKD is increasing every year, not all patients with
CKD progress to ESRD. This is mostly because of the fact that a significant proportion of
patients with CKD die before reaching dialysis [4]. Currently almost 600000 people in U.S are
undergoing hemodialysis for ESRD [2].

Pathophysiology of Chronic Kidney Disease


The pathophysiology of CKD involves initiating mechanisms specific to the underlying
etiology as well as a set of progressive mechanisms viz, glomerulosclerosis and tubuloUltrasound Approach to Chronic Kidney Disease and its Complications
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interstitial fibrosis that are common consequences following long term reduction in renal mass,
irrespective of the etiology [5]. Structural and functional changes in surviving nephrons lead
to hypertrophy and hyper filtration of the surviving nephrons. This compensatory hypertrophy
mediated by vasoactive molecules, cytokines, growth factors and renin angiotensin axis
mediators eventually lead to intra-glomerular hypertension and accelerated sclerosis of
surviving nephrons. Raised intra-glomerular hypertension will lead to reduction of glomerular
permeability and filtration surface area resulting in decreased GFR [6] (Figure 1).
Initiating factors
Diabetes,
hypertension,
glomerulonephri
tis, gcystic
kidney disease

Figure 1: Stages of progression of glomerular injury following the initial insult.

In addition to glomerulosclerosis all forms of CKD are associated with tubulointerstitial


injury manifested by tubular dilatation and interstitial fibrosis. The degree of tubulointerstitial
disease is a better predictor of glomerular filtration rate decline and long term prognosis than
the severity of injury. The major hallmark of tubulointerstitial fibrosis is the progressive
accumulation of extracellular matrix (ECM). This expansion of the ECM is marked by
accumulation of mainly interstitial collagens and fibronectin (In normal kidney, the ECM is
composed of a variety of macromolecules including collagens, fibronectin, elastin, laminin,
proteoglycans and non-collagenous glycoproteins). In addition to expansion of ECM,
modification of proteins such as crosslinking of collagens may alter the mechanical properties
of the matrix and render it resistant to normal degradative process. Thus both increased
production and decreased turnover of ECM proteins contribute to matrix accumulation [5].
Other factors that play a role in the initiation and pathogenesis of fibrosis in CKD include [5]:
1) Upregulation of profibrotic factors such as transforming growth factor beta 1 (TGF-1),
platelet derived growth factor, fibroblast growth factor, osteopontin and endothelin.
2) Down regulation of anti-fibrotic factors like hepatocyte growth factor and bone
morphogenic protein.
3) Dysregulation of vasoactive factors with an increase in vasoconstrictors such as
angiotensin II, and a decrease in vasodilators such as nitric oxide (NO).
Ultrasound Approach to Chronic Kidney Disease and its Complications
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4) Microvascular injury and obliteration (due to hypoxia).
5) Disruption of normal homeostatic interactions between adjacent cell populations,
especially the one between tubular epithelial cells and interstitial fibroblasts.

Role of renin angiotensin-aldosterone system in CKD


The renin-angiotensin-aldosterone system (RAAS) plays a major role in maintaining the
blood volume and salt-water balance. It has effect on the blood pressure and tissue perfusion
through a number of multiple complex actions including vasoconstriction and sodium retention.
Despite its role in maintaining homeostasis, long-lasting stimulation of RAAS can lead to
development of kidney lesions and progression of CKD. An excess of angiotensin II increases
intraglomerular pressure by preferentially constricting the efferent arterioles, thus promoting
glomerular hypertension and protein trafficking through the glomerular basement membrane.
Additionally angiotensin II can stimulate aldosterone production which triggers the activation
of a cascade of profibrotic cytokines resulting in glomerular sclerosis and tubulointerstitial
fibrosis. Prorenin and renin can stimulate TGF-1 production via the activation of p42/p44
mitogen-activated protein kinase (p42/p44MAPK), which subsequently result in the upregulation of profibrotic and prothrombotic molecules, such as fibronectin, collagen-1, and
plasminogen activator inhibitor-1 (PAI-1) inducing renal fibrosis. A high prorenin level is also
associated with complications like microalbuminuria, and development of nephropathy
especially in diabetic patients [7,8].

Role of proteinuria in CKD


Proteinuria is an important risk factor for the progression of CKD. Increased protein
filtration results in excess reabsorption of filtered proteins by proximal tubular cells. The
reabsorbed proteins eventually leak into the renal tubular interstitium through focal breaks
in tubular basement membrane attracting macrophages. These macrophages can promote
tubulointerstitial fibrosis by release of proinflammatory mediators like endothelin, MCP and
RANTES) [9].

Role of sympathetic system in progression of chronic kidney disease


Hyperactivity of the sympathetic nervous system has been found to have considerable
adverse consequences on progression of CKD and cardiovascular disease. Sympathetic
activation aggravates hypertension and proteinuria, two important factors associated with
progression of CKD. Other consequences of sympathetic activation related to progression of
renal damage include accelerated atherosclerosis, vasoconstriction and proliferation of smooth
muscle cells as well as adventitial fibroblasts in the vessel wall [10].

Ischemic nephropathy and chronic kidney disease


Ischemic nephropathy is a common cause of renal disease especially in the elderly
population. It is defined by the gradual reduction of the GFR or a loss of renal parenchyma
resulting from vascular occlusion and not explained by other etiologies. The pathogenesis of
this disease involves not only the narrowing of the major renal artery due to atherosclerosis
but also renal microvascular disease. The role of microvascular disease is supported by the
fact that the severity of renal vascular disease on imaging has not been found to correlate with
the onset or progression or time to reach ESRD in patients with atherosclerotic renal vascular
disease. Microvascular involvement can result from vascular rarefaction within interstitium
Ultrasound Approach to Chronic Kidney Disease and its Complications
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(reduced number or length of peritubular capillaries), increased vascular wall to lumen ratio
and atheroembolic renal vascular disease. Induction of hypoxia secondary to these, results
in activation of renin-angiotensin system, growth factors, different cytokines and chemokines
playing a major role in the pathogenesis of ischemic nephropathy. Hypoxia additionally promotes
fibrosis by up regulating extracellular matrix production, suppressing turnover of collagen
and promoting epithelial-to mesenchymal transition. The other mechanisms responsible for
renal injury in ischemic nephropathy include aldosteronemediated damage, sympathetic
over activity, increased release of reactive oxygen species (ROS) and reduction in NO activity.
ROS increases renal vascular tone, sensitivity to vasoconstrictors and leads to endothelial
dysfunction. Similarly reduction of NO activity permits vasopressors like angiotensin II and
endothelin-1(ET-1) to dominate resulting in vasoconstriction and consequent reduction
in GFR. Prolonged periods of vasoconstriction and ischemia can also lead to permanent
structural changes in endothelium. Histology of ischemic nephropathy shows tubular atrophy,
glomerular collapse, irreversible glomerulosclerosis and interstitial fibrosis. Chronic ischemic
injury resulting from tubulointerstitial injury and loss of peritubular capillaries is the final
common pathway to ESRD [11,12].

Role of endothelial dysfunction in CKD


It is recognized that endothelial dysfunction takes place from the early stages of CKD and
play a role in the pathogenesis of CKD and cardiovascular disorders. Atherosclerotic lesions
in the arterial system are initiated by this functional disorder of the vascular endothelium.
Additionally endothelium has reduced capacity to generate nitric oxide in response to various
stimuli resulting in impaired endothelium-dependent vasorelaxation. Aging, smoking and
lifestyle-related diseases such as diabetes, hypertension and dyslipidemia contribute to the
development of endothelial dysfunction. In addition to these classical risk factors, novel factors
such as inflammation and oxidative stress are also thought to participate in the etiology and
pathogenesis of endothelial dysfunction in CKD patients [13,14].

Role of genetics in chronic kidney disease


Genetic disorders of kidney leading to CKD can be divided into diseases of monogenic
inheritance like polycystic kidney disease, focal segmental glomerulosclerosis (FSGS),
congenital nephrotic syndrome, Fabrys disease, Alport disease, nephronophthisis as well as
medullary cystic kidney disease and diseases of polygenic inheritance like diabetic nephropathy
and hypertensive nephropathy. Polycystic kidney disease (PKD) is the best-known and
most easily recognizable inherited kidney disease. There are mainly two genetic variants of
PKD-PKD1 and PKD2. Point mutations in the Alpha-actinin-4 (ACTN4), Transient Receptor
Potential Cation Channel Type 6 (TRPC6), and Inverted Formin 2 (INF2) genes can lead to
phenotypes characterized by injury to glomerular podocyte associated filtration barrier and
cause progressive deterioration in renal filtration function resulting in FSGS. Recent genomewide association studies have identified several genetic loci that may affect renal function.
UMOD gene is the most important among them which is strongly linked to effects on CKD and
GFR. The other major genetic locus associated with progression of kidney disease especially in
the African American population is the APOL-1(discussed elsewhere) [15-17].

Definition of Chronic Disease


Chronic kidney disease is defined as presence of following for three months or more [18].
Ultrasound Approach to Chronic Kidney Disease and its Complications
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1) Structural and functional abnormalities of the kidney (with or without reduction in the
GFR manifested by any of the following abnormalities.
a) Pathological abnormalities.
b) Clinical markers of renal damage in the form of proteinuria (more than 150 mg/gm
creatinine) or albuminuria (more than 30 mg/gm creatinine) or abnormalities of urine sediment.
c) Abnormal imaging studies (for example: polycystic kidneys or small hypo echoic kidneys
on ultrasound).
d) Tubular syndromes.
e) Kidney transplant recipient.
2) GFR less than 60 ml/min/1.73 m2 with or without kidney damage.

Staging of CKD
In 2002 national kidney foundation put forward staging of chronic kidney disease which
established the 5 stages based on estimation of GFR (G1 to G5) without regards to cause of
CKD. Staging of CKD helps in predicting the risk of cardiovascular disease and mortality. It
is important in monitoring dosage of medications cleared by kidneys and safety of diagnostic
tests as well as procedures which can damage kidneys. Staging is also important in terms of
promoting early referral to nephrologists and for kidney transplantation [18] (Table 1).
Stage

GFR

Description

Intervention
Confirm diagnosis,

G1

>90

normal GFR

G2

60-89

mild functional impairment

Retard progression.

G3a

45-59

moderate functional impairment

Confirm diagnosis, retard progression and treat secondary


complications.

G3b

30-44

Moderate to severe functional


impairment

Confirm diagnosis, retard progression and treat secondary


complications

G4

15-29

severe functional impairment

Prepare for renal replacement therapy, referral for transplantation

G5

<15

ESRD

Initiate renal replacement therapy

retard progression.

Table 1: Stages of CKD and interventions at each stage.

Methods of estimating GFR


There are several methods of estimating GFR. The most reliable markers of GFR estimation
include inulin clearance and use of radionuclides like iothalamate and iodohexol [19]. The
latter is considered as the gold standard for estimation of glomerular filtration rate. Both
these methods are useful only in the research setting and not in clinical practice. The
most commonly used methods for estimating GFR is based on creatinine. Creatinine is a
protein derived from metabolism of creatine in skeletal muscle and dietary meat intake. It
must be in a steady state to estimate GFR. Levels can be altered by medications interfering
with measurement (cephalosporin, ketone) or reduced secretion by medications (cimetidine,
Bactrim). It can also be altered by factors like variability in muscle mass (myasthenics, leg
amputees and paraplegics), presence of liver disease, age, sex, race and weight, chronic illness,
and consumption of cooked meat. An ideal estimation of GFR should incorporate all these
factors into account [20].
Ultrasound Approach to Chronic Kidney Disease and its Complications
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The various creatinine based formula for estimating GFR include
1) Modification of Diet in Renal Disease (MDRD) formula (takes into account age, gender
and race).
2) Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula (takes into
account age, gender and race).
3) Cockcroft-Gault (CG) equation (takes into account the age, weight and gender).
4) 24 hour urine estimation of creatinine clearance.
These formulas differ in both the estimates of CKD prevalence and ability to predict
consequences associated with CKD. The MDRD equation was found to be less accurate
than CKD-EPI in predicting risk for those with GFR more than 45-60 ml/min/1.73 m2 [19].
But at the same time CKD EPI was not superior in estimating GFR in the elderly or those
with extreme body mass. MDRD and CKD-EPI are more accurate in young compared to CG
equation. In terms of gender, CKD-EPI was most accurate in women whereas MDRD was most
accurate in men [19].
Estimation of GFR using serum creatinine has drawbacks. Creatinine does not fulfill
the criteria of an ideal marker for estimating GFR, since creatinine is excreted not only via
glomerular filtration but also via secretion in the proximal tubule. Moreover creatinine based
estimation of GFR is not validated in patients above the age of seventy years, children, pregnant
women, diabetics, Native Americans and Hispanics. Although creatinine clearance based on
24 hour urine collection is recommended in situations like extremes of age as well as body
size, severe malnutrition, disease of skeletal muscle, paraplegia or quadriplegia, vegetarian
diet, rapidly chang-ing kidney function, and calculation for adjustment of dosage of potentially
nephrotoxic drugs the main problem is the requirement for urine collection over 24 hours;
patients find this inconvenient and, therefore, collections are often inaccurate especially in
patients who are elderly and having cognitive impairment [19].
More recently cystatin C has been used for estimation of GFR. Cystatin C is involved in antigen
presentation, protein catabolism, tissue remodeling and pathogenesis of atherosclerosis. It is freely
filtered by glomerulus, reabsorbed and metabolized by proximal tubules and there is no urinary
excretion. Cystatin C has advantage over creatinine in conditions of decreased mass including older
adults, those with chronic diseases (such as heart failure, cirrhosis, AIDS) and in those without
established CKD and diabetics. In terms of assessing mortality risk, cystatin C maintains a linear
association across its entire distribution and is superior to creatinine based GFR and iothalamate
based GFR(Creatinine based glomerular filtration rate has a J-shaped relation with mortality with
only the lowest quintile of glomerular filtration rate associated with increased mortality risk). The
superiority of cystatin C GFR compared to iothalamate GFR in the assessment of all-cause and
cardiovascular mortality is due to two reasons; 1) Cystatin C has non-kidney influences that are
independent of GFR, which are associated with mortality risk. 2) The coefficient of variation of
measurement of iothalamate GFR is higher than that of cystatin C. The use of cystatin C also has
its own limitations. Among patients with a GFR <60 ml/min/ 1.73 m2, cystatin C offers only a
moderate gain over creatinine for approximating renal function. A combined serum cystatin C and
creatinine based formula is sometimes used in practice [19-21].
The different modalities of GFR estimation and advantages as well as disadvantages are
represented in Table 2
Ultrasound Approach to Chronic Kidney Disease and its Complications
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Method

Agent/agents used

Advantages

Disadvantages

Exogenous
substances.

Inulin, iohexol, chromium labeled


ethylenediamine tetraacetic acid
(Cr-EDTA), 131I-iothalamate, 99mTc
diethylenetriaminepentaacetic acid
(DTPA).

Precise and accurate (gold standard).

Costly, time consuming,


and labor-intensive.

Endogenous
substance

24 hour creatinine clearance.

Used for patients with highly abnormal muscle


mass or on vegetarian diet.

In accuracies due to
errors in urine collection.

(Creatinine).
Well suited for estimation of GFR changes during
pharmacotherapy.
Cockcroft-Gault equation.
Most accurate in men.
MDRD equation.

Most accurate in female and cases where GFR is


more than 60 ml/min/ m2.

CKD-EPI equation.

Endogenous
substance
(Cystatin C).

Cystatin C based GFR estimation.

Only suitable for adults,


slightly overestimates
GFR.

Less accurate in cases


where GFR is more
than 60 ml/min/m2 and
children.

Less accurate in elderly


and patients with
extremes of body mass.
No patient specific data required. More accurate
than creatinine based formula in diabetics and
elderly. Equally accurate in pediatric patients. Gives
better risk factor estimates for death and metabolic
abnormalities.

Levels can vary with age,


gender, ethnicity, body
mass index, diabetes and
inflammation.

Table 2: Different modalities of estimation of GFR with their advantages and disadvantages.

Role of proteinuria in the classification of CKD


Until recently proteinuria was not incorporated into the classification of CKD. It is already
known proteinuric patients with early stage CKD have higher risk for progression of renal
function than patients classified in more advanced stages of CKD but less proteinuria.
Additionally the presence of increased albuminuria especially in presence of CKD, involves a
manifold higher risk of unfavorable cardiovascular events well before they reach ESRD. Hence
recent classification of CKD incorporates proteinuria (Figure 2) [22].

Ultrasound Approach to Chronic Kidney Disease and its Complications


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Figure 2: Prognosis of CKD based on GFR and albuminuria categories. Red represents
the group with very high risk for adverse renal and cardiovascular outcomes; orange represents the group with high risk; yellow represents the group with moderately increased
risk; green represents the group with low risk.

Biomarkers in CKD
Effective CKD screening and management should ideally involve accurate, non-invasive
indicators that reflect the pathophysiologic mechanisms underlying CKD. Given the inherent
limitations of proteinuria assessments and GFR estimations, several potential novel biomarkers
that correlate with histopathological findings are actively being investigated for their utility in
determining the underlying renal pathological processes and in predicting CKD progression
prior to the development of overt clinical evidence of CKD. These include neutrophil gelatinaseassociated lipocalin (NGAL), asymmetric dimethylarginine (ADMA), and liver-type fatty acid
binding protein (L-FABP). NGAL is produced by neutrophils and various epithelial cell types,
including those composing the renal distal tubules. It has been shown as an early, sensitive
marker of acute kidney injury. Another promising biomarker for CKD is ADMA, which functions
as a nitric oxide synthase inhibitor reflecting endothelial function. ADMA levels have been
associated with faster progression to dialysis and death in individuals with CKD. Similarly,
L-FABP, a marker of proximal tubule integrity, has also been associated with progressive CKD.
In non-diabetic CKD patients, urinary L-FABP concentrations correlated with proteinuria as
well as serum creatinine levels in addition to progression of CKD [23].

Who should be screened for CKD?


According to Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, all individuals
with risk factors for CKD like history of diabetes, cardiovascular disease, hypertension,
hyperlipidemia, obesity, metabolic syndrome, smoking, HIV or hepatitis C virus infection,
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malignancy, family history of kidney disease and treatment with potentially nephrotoxic drugs
should be screened [16]. The Kidney Disease Improving Global Outcomes (KDIGO) Controversies
Conference suggested screening all patients over age 60 years [24]. The preferred screening
tests are urine albumin/creatinine ratio and serum creatinine (to calculate estimated GFR or
creatinine clearance) [25].

Clinical features of CKD


Clinical symptoms of CKD arise from accumulation of nitrogenous and non-nitrogenous
toxic substances. Urea the major nitrogenous toxic substance contributes to symptoms
including anorexia, malaise, vomiting and headache. Additional categories of nitrogenous toxic
substances include guanido compounds, urates, hippurates, phenol, benzoate and indoles.
Nitrogenous substances with molecular weight in the 500-12000 (so called middle molecules)
also accumulate in CKD. These middle molecules are believed to be associated with morbidity
and mortality. In addition a host of metabolic and endocrine abnormalities accompany CKD
which are represented in Table 3 [26].
Fluid and electrolyte abnormality

Hematologic abnormalities

Pulmonary abnormalities

Volume expansion and contraction

Anemia

Pulmonary edema

Hypernatremia and hyponatremia

Leucopenia

Uremic lung

Hyperkalemia and hypokalemia

Thrombocytopenia

Pleural effusion

Metabolic acidosis

Infection

Hyperphosphatemia

Platelet dysfunction

Hypocalcemia
Endocrine-metabolic abnormalities

Gastrointestinal abnormalities

Neuromuscular disturbances

Renal osteodystrophy

Anorexia

Fatigue

Adynamic bone disease

Nausea

Sleep disorders

Osteomalacia

Vomiting

Headache

Osteoporosis

Gastroenteritis

Asterexis

Impaired glucose tolerance

GI bleeding

Neuropathy

Hypoglycemia

Restless leg syndrome

Hyperuricemia

Myoclonus

Hypertriglyceridemia

Seizure

Low HDL cholesterol

Muscle cramps

Impaired growth and development

Myopathy

Infertility
Sexual dysfunction
Amyloidosis

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Dermatologic abnormalities

Cardiovascular abnormalities

Hyperpigmentation

Hypertension

Pruritus

Congestive heart failure

Ecchymosis

Pericarditis

Uremic frost

Cardiomyopathy
Atherosclerosis
Vascular calcification
Table 3: System wise representation of clinical features in CKD.

Risk Factors for CKD


Diabetes and CKD
Type 2 diabetes mellitus is the leading cause of CKD in developed countries and accounts for
45% of all cases of kidney failure [18]. Diabetic nephropathy complicates 30% of patients with
type 1 diabetes and 20% of patients with type 2 diabetes mellitus. Risk factors for prevalence
of CKD in diabetic patients include hyperglycemia, hypertension, proteinuria, smoking,
dyslipidemia and gene polymorphism affecting the renin angiotensin-aldosterone system [26].
Pathogenesis of nephropathy in diabetes mellitus progresses through various stages starting
from stage of hyperfiltration to microalbuminuria, macroalbuminuria, overt nephropathy and
ESRD. In the early stage there is hyperfiltration due to renal vasodilation [26]. The precise
mechanisms underlying diabetes associated glomerular hyperfiltration remain inconclusive,
but it is thought to be due to reduced delivery of salt to the macula densa, as a consequence of
increased proximal reabsorption of glucose and sodium, reducing afferent arteriolar resistance
leading to increased glomerular blood flow and GFR via attenuated tubuloglomerular
feedback. In addition, afferent vasodilation and efferent vasoconstriction due to circulating or
locally formed vasoactive factors (e.g. angiotensin II and endothelin) produced in response to
hyperglycemia or shear stress is also believed to contribute to the development of diabetesassociated glomerular hyperfiltration [27].

Hypertension and CKD


Hypertension is the most commonly treated chronic disease. It is a major risk factor for heart
disease, kidney failure and stroke. In relation to renal system, hypertension has been regarded
as a special condition since it is known to be both a cause and a consequence of renal damage.
The underlying pathophysiology of hypertensive nephropathy is related to the glomerular
ischemia resulting from afferent arteriolar narrowing. This arteriolar narrowing is mediated
by a myogenic contractile response to increased afferent arteriolar flow (due to hypertension)
and a tubuloglomerular feedback signal from the macula densa (resulting in auto regulation of
glomerular capillary pressure and flow). The histological lesion of hypertensive nephrosclerosis
is characterized by myointimal hyperplasia of interlobular and afferent arteriolar vessels,
hyaline arteriolosclerosis especially of the latter and wrinkling collapse of the glomerulus [28].

Race and CKD


Although the prevalence of early CKD is comparable across racial and ethnic groups in
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the United States, CKD progression to ESRD is far more rapid in African American compared
to White Americans. Moreover the onset of CKD is earlier in African Americans. Part of the
reason for these differences is that compared with whites, African Americans have higher rates
of diabetes and hypertension which is more severe. While diabetes accounts for nearly half of
new cases of kidney failure in African Americans, hypertension accounts for nearly a third.
This is compounded by the lower rate of blood pressure control in African Americans which
contribute to the more rapid progression of CKD to ESRD. The greater risk of proteinuria
in African Americans at any given level of higher blood pressure is thought to contribute
as well. High rates of low socioeconomic status, low health literacy, being underinsured or
uninsured, and lack of awareness of risk factors also contribute to the increased risk. A unique
genetic variation, originally linked to the MYH9 gene and now attributed to the APOL1 gene,
is another important factor associated with the rapid progression of non-diabetic ESRD in
African Americans ( details discussed elsewhere) [29].

Role of klotho and FGF 23 in CKD


Klotho is a protein present in various tissues including kidneys which functions as a humoral
factor exerting biologic functions like ion transport, anti-oxidation and anti-senescence.
Klotho functions as co-receptor for FGF23 which plays an important role in the homeostasis
of phosphorus. Its co receptor action amplifies and confers specificity of FGF23 action. Klotho
usually functions as a renoprotective factor especially against vascular calcification. Klotho
deficiency can be associated with elevated serum levels of FGF23 and phosphate predisposing
to vascular calcification [30].
FGF-23 is a phosphaturic peptide hormone derived from osteocytes and osteoblasts and
has multiple tissue effects influencing bone metabolism. The rise in FGF-23 corresponds to
decline in the number of intact nephrons as well as renal phosphate retention and appears
to precede the development of secondary hyperparathyroidism. Serum FGF-23 levels have
been reported to be persistently increased as early as stage 3 CKD and as CKD progresses, it
continues to increase with reduced responsiveness in late stages of CKD. FGF-23 elevation may
inhibit parathyroid hormone (PTH) mRNA activity, osteoblast differentiation, and bone matrix
maturation. Elevated FGF-23 levels are also associated with more rapid CKD progression to
ESRD, left ventricular hypertrophy, and premature mortality [30].

APOL 1 gene and CKD


Apolipoprotein L1 (APOL1) is the region on chromosome 22 containing the genes encoding
non-muscle myosin heavy chain 9 (MYH9) and it has been implicated in the increased risk
among African American patients of human immunodeficiency virus (HIV) nephropathy,
FSGS, CKD attributed to hypertension and ESRD not related to diabetes. Recent data suggest
that this risk is strongly associated with two common variants (G1 and G2) in the last exon of
APOL1 that confer resistance to lethal Trypanosoma brucei infections. The G1 and G2 variants
are common in populations of recent African descent but are very rare or absent in most other
populations. About 50 % of African Americans are carriers of at least one or the other allele;
1015 % is carriers of two alleles, whereas White Americans are carriers of neither. APOL1
cause autophagy in podocytes or cause renal vascular endothelial inflammation as a response
to the synthesis of dysfunctional HDL particle formation [31].

CKD and dyslipidemia


The dyslipidemia picture in CKD patients is characterized by low high-density lipoprotein
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(HDL), accumulation of small, dense highly atherogenic low-density lipoprotein (LDL), decreased
metabolism of chylomicrons as well as remnants of chylomicrons and reduced catabolism
of lipoprotein(a) [32]. This abnormal lipid metabolism facilitates glomerular, tubular and
interstitial injuries in the kidney [33]. The deposition of lipoprotein especially in glomerular
structures stimulates factors that excite inflammation and fibrogenesis [32]. Dyslipidemia also
leads to oxidative stress and inflammatory reactions which result in endothelial dysfunction
eventually leading to the development of arteriosclerosis and atherosclerosis in patients with
CKD [33].

Metabolic acidosis and CKD


Metabolic acidosis due to CKD has been associated with progressive deterioration of kidney
function in experimental animals and human beings. A typical diet of individuals living in
industrialized societies produces about 1 mEq of hydrogen ions (protons)/kilogram body
weight/day. This is mainly derived from the high acid-producing animal proteins. It is the
function of the kidney to eliminate the protons and regenerate the alkali. Dietary acid by itself
can augment kidney acidification through increased production of endothelin, aldosterone,
and angiotensin II. Although these agents can augment distal nephron acidification in the
short term, they might increase kidney inflammation and fibrosis over the longer term if
increased dietary acid intake is sustained. A U-shaped association was found between serum
bicarbonate concentration and all-cause mortality in CKD patients [34].

Cardiovascular risk factors associated with progression of CKD


A number of cardiovascular related risk factor associated with progression of CKD has
been studied. These include highest and lowest heart rate variability which predicted ESRD,
aortic stiffness measured by pulse wave velocity which showed independent association with
progression of CKD ( especially stage 3,4) and silent brain infarction which predicted CKD
progression [35-37].

Socioeconomic status and CKD


Low socioeconomic status (SES) is considered as an independent potential risk factor for
CKD [38]. SES can have direct and indirect effect on the progression of CKD [39]. Access
to nutrition, physical activity, health information and treatment are the major direct factors
influencing CKD whereas obesity, diabetes and hypertension are the important indirect factors
affecting CKD [38]. In United States low income additionally affects health care access, health
lifestyle choices which in turn increase the prevalence of CKD [39].

AKI and CKD


Acute kidney injury (AKI) is increasingly been recognized as a risk factor for development
and progression of CKD. Renal parenchymal injury sustained during episodes of AKI may lead
to permanent tubulointerstitial fibrosis and a reduction in the number of functioning nephrons.
Additionally, an episode of AKI may lead to permanent damage to the renal microvasculature,
and trigger inflammatory and fibrotic signaling pathways that predispose to future accelerated
declines in GFR. It has also been found that ischemic insult can result in persistent changes
at the gene transcription level in the kidneys of animals even after serum creatinine levels had
recovered. Each additional episode of AKI is associated with an independent and cumulative
increase in the risk for the development of CKD. This relation between AKI and progression
of CKD is independent of the underlying GFR which makes us think whether AKI is simply a
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marker or causal of progressive kidney disease. But at the same time its presence identifies
a high-risk population of patients likely to have progressive kidney disease. Determining a
history of AKI in CKD patients may be comparable to proteinuria especially in patients with
diabetes [40].

CKD and uric acid


The end product of purine metabolism, uric acid, is produced mainly by the liver, bowel
and peripheral tissues like muscles, endothelium and kidneys. Plasma urate is readily filtered
by the human glomerulus, but filtered uric acid is reabsorbed mainly by the selective urate
transport protein URAT1 in proximal convoluted tubules [41]. Hyperuricemia which is defined
as serum concentration of urate exceeding the solubility of urate in water (6.8 mg/day) may
result from uric acid overproduction, reduced excretion, or both. Uric acid can act as both
a risk factor and a biomarker for renal progression and/or cardiovascular outcomes among
patients with CKD. The mechanisms responsible for development of CKD in hyperuricemia
include:
1) Hyperuricemia leads to microvascular changes in the glomerular afferent arterioles
which induce the development of a glomerular arteriolopathy impairing renal autoregulation
and causing glomerular hypertension, eventually leading to glomerulosclerosis and interstitial
fibrosis.
2) Intraluminal uric acid crystals attaching to the epithelial renal cells in the collecting
ducts induce an acute inflammatory response.
3) Endothelial dysfunction 4) Activation of the renin angiotensin system. In addition to
CKD progression, increase in uric acid has been found to be associated with rise in all-cause
mortality, and cardiovascular mortality. There is a J-shaped mortality relationship for CKD
patients with higher and lower tertiles of serum uric acid [41,42].

Gender and CKD


There is role for gender in the progression of CKD. Most of the existing data regarding
potential sex differences suggest that women have lower risk of cardiovascular mortality,
all-cause mortality and progression to ESRD compared to men [43]. It has been postulated
that hormones play a role, with estrogen having a protective effect and testosterone having a
detrimental effect.

Smoking and CKD


Cigarette smoking is a risk factor for accelerated progression of renal disease and
cardiovascular disease in patients with diabetic nephropathy. Smoking, along with
hypertension and vascular disease, is a strong predictor of increased serum creatinine levels
in non-diabetic patients over the age of 65 years. It is also regarded as an independent risk
factor for renal failure in males with kidney diseases. It predisposes to vasoconstriction,
thromboembolism as well as vascular endothelial damage [44].

Obesity and CKD


Obesity is an important risk factor for genesis as well as progression of CKD. Development
of CKD and eventual ESRD in obesity is also mediated though risk factors including diabetes,
hypertension and other elements of the metabolic syndrome including body mass index (BMI).
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Although BMI is considered as an independent risk factor for progression of renal disease, it is
also known that patients with higher BMI on hemodialysis have better survival. In this context,
several studies have highlighted the importance of visceral or central obesity, rather than
BMI in the pathogenesis of incident CKD and increased cardiovascular risk in CKD patients.
Pathophysiology of obesity-related renal disease evolves in a sequence of stages beginning
with initial increase in GFR and intraglomerular capillary pressure, glomerular hypertrophy,
proteinuria and overt nephropathy. The mechanisms underlying obesity-related glomerular
hyperfiltration, is the increased sodium reabsorption by the proximal tubule or loop of Henle,
leading to tubuloglomerular feedback mediated reduction in afferent arteriolar resistance. This
tubuloglomerular feedback driven dilation of afferent arterioles and resultant impairment of
renal autoregulation, in turn, allows increases in blood pressure to be transmitted to the
glomerulus causing injury to glomerulus. This is especially important in individuals with
reduced nephron number. The higher preglomerular vasodilatation in this situation leads to
enhanced blood pressure transmission to glomerulus. Obesity also predisposes to increased
activation of the RAAS and renal sympathetic tone resulting in increased sodium reabsorption
exacerbating the renal hemodynamic changes associated with obesity [45,46].

Complications of CKD
Electrolyte abnormalities
The major electrolyte abnormalities seen in CKD patients are related to sodium and
potassium. Normal kidneys filter almost all of the sodium and reabsorb almost 99 percent
of the filtered sodium. With progressive deterioration in kidney function, the kidneys
compensate by increasing fractional excretion of sodium to maintain the sodium balance.
But in advanced renal disease states and in presence of disease process that tends to retain
sodium (glomerulonephritis) or excess dietary intake of sodium this compensation can be
offset resulting in a positive sodium balance state and attendant extracellular volume
expansion. This in turn contributes to hypertension and further damage to nephrons. Some
CKD patients on the other hand will have impairment in conserving sodium and water leading
to volume depletion especially in presence of extra renal cause for volume depletion (like
vomiting, diarrhea). Depletion of extracellular volume can in turn worsen the renal function.
Hyponatremia and hypernatremia seen in CKD is mainly due to impaired handling of free
water in relation to water intake [26].
Decline in renal function may not be necessarily accompanied by concomitant decline
in potassium excretion. The kidneys can efficiently handle potassium until late in CKD.
Additionally potassium excretion through gastrointestinal tract is augmented. But at the same
time hyperkalemia can be precipitated by a number of factors like increase dietary intake,
protein catabolism, hemolysis, hemorrhage, transfusion of stored red blood cells, metabolic
acidosis, exposure to medications like angiotensin converting enzyme inhibitors, angiotensin
receptor blocker, potassium sparing diuretics and NSAIDS. Sometimes impaired excretion of
potassium might be a feature of underlying disease responsible for CKD like hyporeninemic
hypoaldosteronism seen in diabetic nephropathy. Hypokalemia can also be occasionally seen
in relation to disorders where potassium wasting is part of the underlying disease process
like Fanconis syndrome, renal tubular acidosis and some hereditary and acquired forms of
tubulointerstitial diseases [26].

Vitamin D deficiency and CKD


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Vitamin D deficiency is very common among CKD patients. Possible explanations for this
high prevalence of nutritional vitamin D deficiency in patients are reduced sunlight exposure
(e.g., in the elderly, the sick, dark-skinned people, those who wear a veil for cultural reasons),
losses of vitamin Dbinding protein in proteinuric states [25 (OH) D is lost in the urine bound
to vitamin Dbinding protein] and a reduced endogenous synthesis of vitamin D from the skin
in the uremic state [47].

Anemia and CKD


Anemia is one of the major complications of CKD. It is also an independent modifiable
risk factor of cardiovascular and renal damage. Both deficiency and hyporesponsiveness to
erythropoietin contribute to anemia in CKD. The cause of erythropoietin deficiency in patients
with CKD is mainly due to the reduced renal mass with consequent depletion of the hormone.
Additionally there are various other explanations for erythropoietin deficiency in CKD:
1) Human erythropoietin (EPO) which is a 165-amino acid glycoprotein is mainly produced
by the liver during fetal life and by fibroblast-like peritubular interstitial cells (pericytes) in
the kidney in adulthood. In the progression of CKD, the EPO producing abilities of pericytes
are decreased (due to pericyte-myofibroblast transition) leading to the decreased production
of EPO. 2) Uremic toxins can induce deoxyribonucleic acid (DNA) methylation leading to
silencing of the EPO gene. 3) Defective hypoxic signaling leading to defective stimulation of
EPO synthesis [48,49].
Hyporesponsiveness to EPO is defined clinically as a requirement for high doses of EPO
in order to raise blood hemoglobin level in the absence of iron deficiency. It is believed to
represent impaired antiapoptotic action of EPO on proerythroblasts. Possible causes of this
EPO hyporesponsiveness include systemic inflammation, microvascular damage in the bone
marrow and deficiency as well as impaired utilization of iron [50].
Another major cause of anemia in CKD patients is iron deficiency. According to analyses
of the National Health and Nutrition Examination Survey IV, prevalence of iron deficiency
(both functional and absolute) is around 50% in patients with CKD. Absolute iron deficiency
is defined as a diminution of tissue iron stores demonstrated by a serum ferritin level <100
ng/ml or a transferrin saturation of <20%. Functional iron deficiency anemia is defined as
reduction in iron saturation in presence of adequate tissue iron (established by a serum ferritin
level 100 ng/ml). The latter is closely related to up regulation of inflammatory cytokines and
impaired tissue responsiveness to EPO, which inhibit iron transport from tissue stores to
erythroblasts [50].
Other causes of anemia in CKD include proteinuria and use of angiotensin-converting
enzyme (ACE) inhibitors. In CKD patients with nephrotic syndrome there is excretion
of transferrin and EPO which can predispose to anemia. The mechanisms responsible for
anemia with use of ACE inhibitors and angiotensin receptor blockers (ARB) include a direct
blockade of the proerythropoietic effects of angiotensin II on red cell precursors, degradation of
physiological inhibitors of hematopoiesis, and suppression of insulin-like growth factor 1 [50].
Anemia in turn can result in progression of renal failure. The mechanisms include renal
ischemia caused by reduced oxygen delivery due to low hemoglobin as well as heart failure
and increased renal sympathetic nerve activity. Renal medullary hypoxia resulting from
renal ischemia up regulates hypoxia-inducible factor-1 (a transcriptional regulator of the
erythropoietin gene) as well as heme oxygenase, nitric oxide synthases, extracellular matrix,
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and apoptosis genes. This up regulation results in induction of collagen gene expression in
renal fibroblasts, thereby increasing interstitial fibrosis. Additionally anemia can increase
sympathetic nerve activity, which leads to increased glomerular pressure and proteinuria
contributing to worsening of kidney function [48].

Cognitive impairment/frailty in CKD


Patients with CKD especially older adults with CKD face a high risk for cognitive
impairment, frailty and physical disability. Presence of frailty among CKD and among those
without CKD was associated with about a twofold higher risk for mortality. CKD shares risk
factors with cerebrovascular small vessel disease such that the development or progression
of CKD parallels the development of physical or cognitive impairment. Alternatively CKD is a
potential accelerant of decline in physical and cognitive functions through associated anemia,
mineral-bone disease, or inflammation [51].

Cardiovascular complications of CKD


Major cardiovascular complications of CKD include accelerated atherosclerosis,
sudden cardiac death, cardiac arrhythmias, vascular stiffness, vascular calcification, left
ventricular hypertrophy (LVH) and cardiac fibrosis. Accelerated atherosclerosis has close
association with impaired kidney function. Common risk factors associated with accelerated
atherosclerosis include dyslipidemia, hypertension, diabetes, acidbase imbalance, calcium
phosphate metabolism, anemia, high prevalence of vasoconstrictive agents like angiotensin
II, blood clotting factors, hyperhomocysteinemia and inflammatory factors. Elevated levels of
inflammatory mediators along with accumulation of asymmetric dimethylarginine, high levels
of homocysteine as well as raised levels of calcification promoters (e.g. osteopontin), diminished
levels of calcification inhibitors (e.g. feutin-A) and abnormal calciumphosphate metabolism
act as promoters of atherosclerosis. The other risk factors include cigarette smoking, male
gender, family history and lack of physical activity [52].
Common triggers for sudden cardiac death in patients with CKD include premature
atherosclerosis, cytokine-induced plaque instability and direct effect of inflammation on the
myocardium and the electrical conduction system. Ventricular arrhythmia due to inflammatory
involvement of electrical conduction system and myocardial ischemia is a common cause of
sudden cardiac death in patients with CKD. Fatal ventricular arrhythmias can also occur in
patients with CKD due to metabolic disorder (hyperphosphatemia and hyperparathyroidism),
electrolyte (potassium, pH) alterations, sympathetic overactivity, autonomic nerve dysfunction,
concomitant obstructive sleep apnea, acquired or hereditary QT interval prolongation, systolic
and/or diastolic dysfunction, acute volume overload and valvular calcification [52].
Increased arterial stiffness is an important factor associated with cardiovascular morbidity
as well as mortality and progression of kidney disease. Arterial stiffness is also associated
with abnormalities in microcirculation leading to poor wound healing and infection-related
deaths. The factors associated with arterial stiffness include matrix metalloproteinases
(MMP), advanced glycation end-products (AGE), endothelial dysfunction, RAAS and dietary
sodium. Increased MMP production promotes vascular stiffness by causing weakness of the
extracellular matrix (by enhancing collagen and elastin turnover). Accumulation of AGE leads
to modification of collagen making blood vessels stiffer and less susceptible to slow hydrolytic
degradation. Additionally glycation can also cause arterial stiffening through generation of
reactive oxygen species and nitric oxide deactivation. Endothelial dysfunction in CKD patients is
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characterized by impairment in endothelium dependent and independent vasodilatation which
usually is a reflection of the high oxidative stress. Risk factors like hypertension, diabetes and
the reduced clearance of uremic toxins, such as asymmetrical dimethylarginine (an effective
inhibitor of nitric oxide synthase) are risk factors associated with endothelial dysfunction.
Angiotensin II contributes to vascular stiffness by stimulating vascular smooth muscle cells
(VSMC) hypertrophy as well as proliferation and increasing the production of collagen as well
as MMP. Mechanisms of dietary sodium induced vascular stiffness include increase in VSMC
hypertrophy as well as tone, increase in collagen cross-linking and facilitation of aldosteroneinduced oxidative stress and inflammation [53].
In addition to vascular stiffness, vascular calcification (VC) also plays a major role in the
pathogenesis of cardiovascular disease in CKD patients. VC can either take place in the intima
or in the media of the vessel wall with former common in atherosclerosis and latter common
in arteriosclerosis. Key risk factors associated with progressive cardiovascular calcification
are age, diabetes, hyperphosphatemia, hypercalcemia, high intake of calcium (by calcium
containing phosphate binders), secondary hyperparathyroidism and inflammation. Other
risk factors associated with VC include osteoprotegerin, feutin-A, pyrophosphates, matrix Gla
protein, osteopontin, FGF 23 and bone morphogenic protein. Under the influence of these
factors the vascular tissue acquires bone cell characteristics resulting in deposition of calcium
in arterial walls. Calcification of blood vessels leads to arterial stiffening, increased pulse
pressure, decreased coronary perfusion and LVH. The high cardiovascular mortality seen in
uremic patients is directly related to the magnitude of vascular calcification (VC) [53,54].
The cardiovascular mortality in CKD patients is attributed to the traditional cardiovascular
risk factors (diabetes, hypertension, obesity and hypercholesterolemia), non-traditional risk
factors (such as hyperhomocysteinemia, abnormal lipoprotein levels and chronic inflammation
and oxidant stress). Some CKD patients are at an increased risk of mortality even with low
blood pressure and reduced cholesterol, which has been referred to as reverse epidemiology.
The mechanism involved includes malnutrition and vascular calcification. Abnormalities in
bone mineral disorder like hyperphosphatemia, PTH excess and vitamin D deficiency are
also associated with increased cardiovascular morbidity and mortality. Excess phosphate
influences cardiovascular risk by increasing PTH or decreasing 1,25-dihydroxyvitamin D3
levels. PTH excess has been implicated in cardiac fibrosis, impaired cardiac contractility,
impaired endothelial vasodilatory function and LVH. Lower levels of vitamin D may decrease
cardiac contractility, increase coronary calcification and up regulation of the renin-angiotensin
axis, resulting in the development of hypertension and LVH [55].
LVH and cardiac fibrosis are well described pathologies associated with CKD and ESRD.
They have major impact on morbidity and mortality of CKD and ESRD patients especially those
who have coexisting congestive heart failure and arrhythmias. The major factors determining
the extent of LVH include systemic arterial resistance, elevated systolic (and diastolic)
arterial blood pressure, and large vessel compliance which are closely related to the aortic
calcification seen in CKD and in ESRD. These afterload-related factors result in myocardial
cell thickening and concentric left ventricular remodeling. Preload-related factors related to
LVH include expansion of intravascular volume (salt and fluid loading) and anemia. These
latter factors result in myocardial cell lengthening and eccentric or asymmetric left ventricular
remodeling. Both afterload- and preload-related factors may operate independently or have
synergistic effects. Activation of the intracardiac renin-angiotensin system and aldosterone
are also involved in myocardial cell hypertrophy and fibrosis, independent of afterload.
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Hyperaldosteronemia, consequent to activation of renin-angiotensin system or through nonrenin-angiotensin system dependent factors, promotes cardiac fibrosis, perhaps through
generation of signals promoting profibrotic TGF production, deficiency of iron as well as
erythropoietin (with attendant anemia), carnitine deficiency, vitamin D deficiency (which can
activate the intracardiac renin-angiotensin system) elevated PTH, hypoalbuminemia and
albuminuria. Non-angiotensin IIdependent pathways like oxidative stress and xanthine
oxidase activation have also been implicated in LVH. LVH and myocardial fibrosis lead to
progressive impairment in contractility and stiffening of the myocardial wall, leading to systolic
and diastolic dysfunction and ultimately to dilated cardiomyopathy and diastolic and/or systolic
congestive heart failure. Intramyocardial fibrosis also leads to disturbances in the electrical
conduction system (through superimposition of high-resistance pathways for ventricular
electrical conductance and the encouragement of re-entry pathways of the heart) leading to
ventricular arrhythmogenesis (e.g. ventricular fibrillation). Additionally increased cardiac work
and oxygen consumption due to hypertrophy of myocardium can aggravate ischemic heart
disease from coronary atherosclerosis which in turn can aggravate the myocardial cell loss
and fibrosis [56].

CKD and cardiovascular disease markers


In patients with CKD the various markers of myocardial injury like troponin and N-terminal
pro-brain natriuretic peptide (NT-proBNP) should be interpreted with caution because of the
variation in levels depending on the level of renal function. The increased plasma NT-proBNP
levels is either related to the hemodynamic stimuli or may relate to anemia, obesity, cachexia,
impaired renal clearance of natriuretic peptides, despite similar hemodynamic stimuli. There
is conflicting reports in literature regarding the usage of NT-proBNP in patients with CKD and
heart failure. While some studies showed an inverse moderate, but significant, correlation
between GFR and NT-proBNP concentrations, others indicated that NT-proBNP is related to
presence and extent of cardiac pathology rather than impaired renal clearance. Based on these
the utility of using NT-proBNP for monitoring treatment in heart failure patients is uncertain.
On the other hand measurement of cardiac troponins in patients with CKD has been found
to have prognostic significance. Base-line measurement of cardiac troponin T is strongly
predictive of the risk of death or myocardial infarction [57,58].

CKD and infections


Infections are supposed to be a major factor responsible for the increased risk of morbidity
and mortality in patients with CKD. The susceptibility of CKD patients to infections results
from defective phagocytosis promoted by a variety of factors, including uremic toxins, iron
overload and anemia of renal disease. Risk factors associated with infection in CKD patients
include advanced malnutrition, age, diabetes, hypoalbuminemia, iron therapy, increased
intracellular calcium, and immunosuppressive therapy. CKD patients are also predisposed to
zinc, vitamin B6 (pyridoxine), vitamin C and folic acid deficiencies which can lead to alterations
in host defense. This alteration in the host defense function affects all cell lines of white
blood cells; polymorphonuclear cells, lymphocytes, and monocyte. Two proteins that have
been found to have association with increased risk of infection include leptin and resistin.
Leptin, which accumulates in CKD patients, plays a role in innate and acquired immunity by
regulating T lymphocyte responses, increasing secretion of several cytokines and by positively
modulating mononuclear cell survival by interfering with the apoptotic process. Resistin, a 12kDa protein expressed in inflammatory cells, impair polymorphonuclear leukocyte function in
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CKD patients [59,60].

CKD and bone mineral disorders


Disturbances of bone mineral metabolism and regulatory hormones may occur early in the
course of CKD, with changes occurring as early as stage 2 CKD, and progressing as kidney
function worsens [61]. The various bone mineral disorders associated with CKD include
decreased levels of 1,25-dihydroxy vitamin D as well as 25-hydroxy vitamin D, increased levels
of FGF-23 as well as PTH.
The elevation in PTH is due to reduction in calcium as well as 1, 25-dihydroxy vitamin D
and increase in phosphorus. In addition, as kidney function declines a corresponding decrease
in vitamin D receptors (VDR) and calcium-sensing receptors (CaSR) occurs in the parathyroid
glands making them less responsive to the actions of circulating vitamin D and calcium [62].
Reduced levels of 1,25-dihydroxy vitamin D seen in CKD patients is due to decreased
production of 1,25-dihydroxyvitamin D (calcitriol) resulting from a loss of functioning proximal
renal tubules and reduced activity of renal 1-alpha-hydroxylase. The combination of low
calcitriol and elevated PTH in CKD is now recognized as a cause of bone loss and a major
contributor to bone disease in CKD patients. 25-hydroxy vitamin D deficiency is also commonly
observed in CKD patients. The degree of decline in serum levels of 25-hydroxyvitamin D has
been found to be related directly with decreases in GFR, and indirectly with increases in PTH
and bone alkaline phosphatase. Hypovitaminosis D contributes to bone loss through decreased
intestinal calcium absorption, lowered bone formation, and increased osteoclastogenesis.
Hence 25-hydroxyvitamin D level should be measured in all patients at any stage of CKD [63].
Another major bone mineral disorder seen in CKD patients is hyperphosphatemia.
Phosphate homeostasis is primarily regulated by the kidney. Phosphate is filtered by the
renal glomerulus and 80% is then reabsorbed mostly by the proximal nephrons brush border
membrane type IIa sodium-phosphate co-transporter (NaP2a). Retention of phosphorus lead
to compensatory increases in FGF23 and PTH leading to decreased renal tubular reabsorption
of phosphate and increased urinary phosphate excretion (PTH increases urinary phosphate
excretion via cyclic-AMP dependent inhibition of NaP2a expression). Phosphate retention
can predispose to hypocalcemia by interfering with the kidneys ability to produce calcitriol
(creating a state of vitamin D deficiency and decreased intestinal absorption of calcium) and by
direct suppression of blood calcium which in turn can act directly on the parathyroid causing
elevated PTH. Hyperphosphatemia also has a direct effect on post-transcriptional increases in
PTH synthesis and secretion inducing parathyroid hyperplasia independent of low blood levels
of calcium or calcitriol [30,54].
The nature and type of bone disease that develops in CKD may vary among patients.
Four types of bone disease, as defined by quantitative bone histomorphometry, may be
encountered in patients with CKD: a) Increased bone turnover and resorption due to
secondary hyperparathyroidism with or without marrow fibrosis (osteitis fibrosa) b) Decreased
bone turnover and formation (termed adynamic bone) and c) Defective bone mineralization
(osteomalacia) and d) Osteoporosis [64].

Chronic kidney disease and role in activation of sympathetic system


CKD can activate the sympathetic system through its communication with the integrative
structures in the brain. Activation of sympathetic system in CKD patients can exert trophic
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effects on cardiac myocytes leading to LVH in patients with essential hypertension. Additionally
it can predispose to cardiac arrhythmias, which, in concert with the aforementioned factor, is
partly responsible for the high rate of sudden cardiac death in patients with CKD. Treatment
strategies targeting the inhibition of sympathetic nervous system should become an integral
part of the standard therapy in CKD to slow down the progression of renal failure and improve
cardio vascular prognosis in this high-risk patient group [65].

Coagulopathy in chronic kidney disease


Thrombotic events and coagulopathy are two major issues associated with CKD. Patients
with CKD have increased tendency for bleeding due to decreased activity of platelet factor
III, abnormal platelet aggregation and adhesiveness and impaired prothrombin consumption.
Hence use of medications like warfarin and aspirin can predispose those patients to high
risk of bleeding. CKD patients also have high predisposition to venous thromboembolism
(VTE) especially in presence of nephrotic syndrome. This is mostly related to the increase in
procoagulant markers, decreased endogenous anticoagulants, enhanced platelet activation as
well as aggregation and decreased activity of the fibrinolytic system. Other factors responsible
for increased procoagulant activity in CKD patients include increased levels of D-dimer,
C-reactive protein, fibrinogen, factor VII, factor VIII and von Willebrand factor [66].

Nutrition in CKD
The prevalence of protein energy wasting (PEW), a condition of loss of muscle and visceral
protein stores not entirely accounted for by inadequate nutrient intake increases progressively
as the renal function deteriorates. PEW appears to be the strongest predictor of survival in
CKD patients. Biochemical markers that are directly or indirectly linked to PEW and outcomes
include testosterone, leptin, visfatin, adiponectin, thyroid hormones, C-reactive protein and
interleukin 6 levels. Progressive increase in the levels of these factors with the decline of
GFR in CKD patients cause anorexia, induce resistance to growth hormone as well as insulin
like growth factor -I and increase energy expenditure. Additionally uremia-induced alterations
in protein metabolism and gastrointestinal tract dysfunction can result in poor nutritional
status, which in turn increases the risks of cardiovascular disease and infection [67,68].

Special Circumstances
Human immunodeficiency virus and CKD
The prevalence of impaired kidney function in human immunodeficiency virus (HIV) patients
can range between 2.4% and 10%. The majority of CKD cases in HIV infection are purportedly
due to HIV associated nephropathy (almost 50%). Other causes include pathologies resulting
from underlying coexisting diseases such as diabetes, hypertension, hepatitis C infection,
toxicity related to the medications used in the treatment of HIV which simultaneously
contribute to the development and progression of kidney disease in the setting of HIV infection.
Risk factors associated with development of CKD in these patients include intravenous drug
abuse (especially cocaine), family history of kidney disease, dyslipidemia and cigarette use.
The impact of CKD on mortality in HIV infected individuals is related to the severity of renal
dysfunction and insufficient use of highly active antiretroviral therapy and doses. Among the
HIV-positive individuals, proteinuria and impaired kidney function are associated with faster
progression to CKD and death. In agreement with the national kidney foundation, current
guidelines provided by the HIV Medicine Association of the IDSA advocate evaluation for both
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proteinuria and kidney dysfunction as CKD screening in HIV-infected individuals [69].
Because of lack of data, ideal method of estimation of GFR in the HIV patients is not clear.
Serum creatinine based estimated GFR among HIV infected persons may be particularly biased
due to altered metabolism; body mass abnormalities and exposure to multiple medications
known to affect renal tubular creatinine secretion. But at the same time until adequate
validation of these equations occurs in HIV infected patients, the re-expressed MDRD equation
should be the preferred GFR estimating equation used in this patient population, despite its
shortcomings, since it is the most widely accepted GFR estimating equation in clinical practice
and appears to be the most reliable of the available formulas studied thus far in HIV-positive
persons [69].

CKD in elderly
The prevalence of CKD is increasing in U.S elderly population especially those above the
age of 60 years [70]. Between 1988 and 1994 National Health and Nutrition Examination
Survey (NHANES) study and the 20032006 NHANES study, the prevalence of CKD in people
ages 60 and older increased from 18.8 to 24.5 percent. But at the same time, the prevalence
of CKD in people between the ages of 20 and 39 stayed consistently below 0.5 percent [4].
Although only a minority of elderly patients with CKD progress to ESRD, renal impairment
is associated with high cardiovascular mortality in this population. Renal impairment affects
the safety of many drugs used in older people. Most of the formulas used for estimating GFR
are not validated in elderly. It is unclear at this point which creatinine based formula is best
for GFR estimation in the elderly or in those with extremes of body mass. Cystatin C based
glomerular filtration rate estimation seems to be more accurate than any creatinine based
formula in elderly. A multidisciplinary care approach focusing especially on the cardiovascular
risk factor modification should be among the goals of treatment for this population [71].

Evaluation and Management of Patients with CKD


Care of CKD patients
Patients with CKD should receive multidisciplinary comprehensive clinical management by
kidney disease professionals for at least 6 months before requiring renal replacement therapy
(RRT). There is near-universal consensus that patients should be referred to a nephrologist
when glomerular filtration rate drops below 60 ml/min per 1.73 m2. Late referral results in
poor outcomes after dialysis initiation, increased mortality, higher hospitalization rates, lower
rate of renal transplantation and higher rate of dialysis catheter use at initiation of dialysis. In
addition to dietary instruction and modality education, recommended care includes counseling
on cardiovascular disease risk factors, management of blood pressure, screening for bone
and mineral disease of CKD and anemia, hepatitis B immunization and administration of
nephroprotective agents (renin-angiotensin system antagonists). Consensus guidelines also
emphasize placement of permanent dialysis access that is functional at the time of initiation, as
well as assessment and referral for preemptive transplantation, if possible. A multidisciplinary
team should include or have access to dietary counseling, education and counseling about
different RRT modalities, transplant options, vascular access surgery and ethical, psychological
as well as social care.

When to refer patients


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Referral to nephrology service should be considered in the following circumstances [24].
1) Acute kidney injury or abrupt sustained fall in glomerular filtration rate (GFR).
2) GFR <30 ml/min/1.73 m2.
3) A consistent finding of significant albuminuria (albumin-creatinine ratio 300 mg/g
creatinine [ 30 mg/mmol] or albumin excretion rate 300 mg/24 hours, approximately
equivalent to protein-creatinine ratio 500 mg/g creatinine [ 50 mg/mmol] or protein
excretion rate 500 mg/24 hours).
4) Rapid progression of CKD.
5) Presence of microscopic hematuria.
6) CKD and hypertension refractory to treatment with 4 or more antihypertensive agents.
7) Persistent abnormalities of serum potassium.
8) Recurrent or extensive nephrolithiasis.
9) Hereditary kidney disease.
10) Abnormal structural findings in kidney on imaging.
Effective management should include the following steps:
1) History, physical examination and laboratory studies to establish the diagnosis of CKD.
2) Modification of risk factors.
3) Treatment of complications.
4) Preparation for renal replacement therapy.
5) Patient education.

History and physical examination


A proper history taking in CKD should focus on the establishing the etiology of CKD.
This include history of diabetes, hypertension, systemic inflammatory disorders, nephron/
urolithiasis, metabolic diseases, exposure to drugs as well as toxins, exposure to intravenous
contrast, herbal medications (Chinese herb containing aristocholic acid), exposure to phosphate
containing enema and family history of renal diseases (polycystic kidney disease)and urologic
disorders. Drugs which are of particular importance are the NSAIDS, antimicrobials, ACE
inhibitors and lithium. In evaluating risk factors and complications ask about history of
smoking, drug abuse (mainly cocaine), uremia related symptoms like appetite, diet, nausea,
vomiting, and shortness of breath, edema, weight change, pruritus, skin rash, mental acuity
and activities of daily living. Physical examination should focus on blood pressure, fundoscopy
(hypertensive retinopathy and diabetic retinopathy), precordial examination (fourth heart
sound, murmurs, pericardial rub), abdomen (renal bruit, aortic bruit, palpable masses),
edema, peripheral pulses, central nervous system (asterixis, muscle weakness, neuropathy),
rectum (prostate size) and vagina (pelvic masses) [26].
Pertinent laboratory testing include tests to determine the stage and chronicity of the
disease (including complications of uremic syndrome) like plasma creatinine, estimated GFR,
urea, electrolytes (sodium, potassium, chloride, bicarbonate), calcium, phosphorus, alkaline
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phosphatase, PTH, 25-hydroxy vitamin D and hemoglobin. Urine analysis should include
urine dipstick (pH, specific gravity, blood, leucocyte esterase, nitrates, glucose and protein),
urine protein to urine creatinine ratio, urine albumin to creatinine ratio and urine microscopy
(dysmorphic red blood cells, white blood cells, white blood cell casts, red blood cell casts, broad
casts, cellular casts and granular casts). In certain situation a 24 hour urine collection may
be mandatory. Other tests depend on the necessity based on the history, physical examination
and abnormalities in above laboratory tests. This includes workup for collagen vascular
disease, vasculitis, plasma cell dyscrasias, viral hepatitis and HIV [26].
Most useful and commonly obtained imaging study is a simple ultrasound of renal
system. This can verify the presence of symmetric kidneys, estimate size of the kidneys,
assess echogenicity, corticomedullary differentiation as well as extent of intact cortex and
rule out renal masses as well as obstructive nephropathy. Presence of symmetric small
kidneys, increased echogenicity, loss of corticomedullary differentiation and thinning of cortex
are some of the signs of chronic kidney disease. Presence of large kidneys in the presence
of abnormal renal function indicates disorders like polycystic kidney disease; amyloidosis,
diabetes and HIV associated nephropathy. Presence of asymmetry in kidney size indicates
unilateral developmental abnormality, chronic unilateral obstruction or infection and chronic
renovascular disease. In cases where there is suspicion for renal vascular disease vascular
imaging such as renal duplex sonography of renal vessels, radionuclide scintigraphy or
magnetic resonance angiography should be strongly considered if revascularization is feasible.
Similarly a spiral computed tomography scan without contrast can pick up renal stone
disease. A voiding cystourethrography is indicated in the presence of history of enuresis or
family history of vesicoureteric reflux disease. In any case avoidance of intravenous contrast
exposure should be contemplated because of nephrotoxicity [26].
A renal biopsy is indicated in presence of near normal size kidneys without any changes
consistent with advanced structural damage of kidneys. It should also be considered in clinical
situations where there is absence of clear cut diagnosis by less invasive means and when there
is possibility of reversible underlying disease process. The extent of tubulointerstitial disease
on biopsy gives us the most reliable pathologic correlate indicating prognosis in a CKD patient
[26].
The information gathered from above should be put into the right perspective to establish
the diagnosis of CKD. Past medical records documenting serial measurements of plasma
creatinine, GFR and urine analysis can give an idea in terms of the duration of renal dysfunction.
In the absence of such information sometimes a urine analysis (presence of broad casts and
proteinuria), hyperphosphatemia, hypocalcemia, elevated PTH levels, radiologic evidence
of bone disease, normocytic normochromic anemia supported by imaging evidence of long
standing renal damage help in the diagnosis of CKD. Constellation of history, clinical findings,
laboratory and imaging tests can also facilitate the diagnosis of underlying disease process
(For example a 15-20 years history of type 1 diabetes mellitus, nephrotic range proteinuria
in the absence of hematuria and diabetic retinopathy favor a diagnosis of CKD from diabetic
nephropathy) [26].

Modification of Risk Factors


Treatment of hypertension
Effective antihypertensive treatment in CKD patients has clearly been shown to attenuate
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the worsening of renal function and to reduce proteinuria. At the same time progressively
lower blood pressures have been found to be associated with paradoxical increase in mortality
(so called J curve phenomenon) especially in diabetics and coronary artery disease patients [8].
The agents of choice in treatment of hypertension are the renin-angiotensin-aldosterone
(RAAS) blockers. Antihypertensive agents which specifically inhibit RAAS activity at various
levels exert antiproteinuric and renoprotective effects even beyond their systemic hemodynamic
effect on blood pressure [72]. These agents prevent progression of renal disease by ameliorating
intraglomerular hypertension as well as hypertrophy and consequently proteinuria [7]. Best
renal outcomes might be achieved in patients who have maximum reduction in proteinuria.
Even though ACE inhibitors and ARBs are equally effective in achieving this based on available
data, guidelines indicate ARBs as the preferred choice in type 2 diabetes mellitus patients, and
ACE inhibitors for type 1 diabetic as well as non-diabetic renal patients [8]. But at the same
time, despite the substantial use of ACE inhibitors and ARBs in the protection of CKD, large
fraction of CKD patients progressed to ESRD over time. This was attributed to the non ACEdependent angiotensin II formation pathways or counter regulatory supramaximal angiotensin
II production in the presence of angiotensin II type I receptor blockade (so called aldosterone
escape phenomenon). This results in incomplete blockade of the RAAS both under ACE
inhibitor or ARB treatment [7].
Although the concept of dual blockade was introduced to resolve this issue, trials using
dual blockade showed that on one hand there was reduction in proteinuria and on the other
hand use of dual agents resulted in hyperkalemia, hypotension and acute worsening of renal
function, especially in the subgroup with impaired renal function. Moreover it did not have any
impact on cardiovascular outcomes. Use of direct renin inhibitor with ACE inhibitor or ARB
entailed unfavorable outcomes [7]. Single agent high dose therapy came up with encouraging
results in terms of reduction in proteinuria which in turn can result in slowing of progression
of CKD [8]. The use of combined aldosterone receptor antagonist and ACE inhibitor /ARB did
not document any impact on renal function or survival but at the same time demonstrated
untoward effects including hyperkalemia when GFR was less than 30 ml/min/1.73 m2. But at
the same time the combination showed reduction in proteinuria [8].
Ambulatory blood pressure (particularly nighttime blood pressure) has been found to
be a significant and an independent predictor of renal function in both cross-sectional and
longitudinal studies. The other factors found to have association with impaired renal function
include elevated nighttime blood pressure, non-dipping and decreased circadian variation.
Additionally, the risk for micro-albuminuria was 70% lower in dippers (night/day blood
pressure ratio 0.90) compared with non-dippers which means that lowering nighttime blood
pressure in patients with CKD is associated with decreased urinary protein excretion and
improvement in renal function. Nighttime blood pressure also seems to be a good predictor of
adverse cardiovascular events in patients with hypertension and CKD [73].
The optimal goals of therapy and current guidelines (KDIGO) for treatment of blood pressure
are represented at the end of this chapter.

Control of diabetic renal disease


Since diabetes being the most common cause of renal disease progressing to ESRD, control
of diabetes should be given equal importance as management of hypertension. There has
been mixed findings in literature regarding the benefit of tight glycemic control and risk for
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renal disease progression. Beneficial effects of intensive glycemic control at reducing risk
of nephropathy and retinopathy has been demonstrated in both type 1 and type 2 diabetic
patients. Also there has been some data favoring delayed development of microalbuminuria
and overt proteinuria in these patients. But at the same time aggressive glycemic control was
also found to be associated with side effects like weight gain (leading to increased insulin
resistance) and severe hypoglycemia [74]. Hence current guidelines recommend achieving
glycosylated hemoglobin of around 7 [24].

Protein restriction
Protein restriction is an important intervention in preventing progression of CKD. Low
protein diet has been found to retard the decline of renal function and alleviate uremic
symptoms caused by the accumulation of urea, phosphorus, sulphates, and organic acids.
Low protein diet can lead to attenuated protein mediated hyperfiltration in progressive renal
injury. It can result in the reduction of sodium and phosphorus intakes and a low acidic
content favoring correction of several hormone and metabolic disorders responsible for uremic
symptoms. Moreover consuming low protein diet lower urea generation and therefore these
patients become less symptomatic and hence low protein diet may delay initiation of renal
replacement therapy especially in the elderly. However, long-term dietary restrictions expose
older individuals to inadequate protein-energy and micronutrient intake, which may cause a
deterioration of nutritional status. It can contribute to the development of sarcopenia, frailty,
and functional impairment, which eventually can result in the deterioration of quality of life
leading to deprivation, frustration, and social isolation. Hence it has been recommended that
protein restriction should be assisted by providing proteins of high biologic value, maintaining
sufficient caloric intake, maintaining adequate physical activity to prevent sarcopenia and
nutritional monitoring. Based on KDIGO guidelines, a moderate reduction of protein intake to
0.8 g/kg/day may be recommended in individuals with GFR less than 30 ml/min/m2 [24,75].

Treatment of dyslipidemia
The major modality of treatment of dyslipidemia in CKD patients is using statins. Its major
action is by reducing the level of LDL. In addition to role in improving lipid metabolism, statins
also have pleiotropic effects like anti-inflammatory and anti-oxidative actions. They reduce
inflammatory markers such as highly sensitive C-reactive protein and improve endothelial
function. Meta-analysis studies have shown beneficial role of anti-dyslipidemic drug therapy,
mostly using statins, in reducing proteinuria and deterioration of renal function. Improvement
in renal function and reduction in proteinuria as well as LDL cholesterol result in decrease
number of coronary events and revascularization. At the same time statins have been associated
with complications like rhabdomyolysis, liver dysfunction and diarrhea. Use of combination
of statins and ezitimibe (which inhibits cholesterol absorption in the jejunum) can reduce the
risk of adverse events associated with use of high dose statins and at the same time reduce
risk of cardiovascular events [33].

Treatment of metabolic acidosis


Since metabolic acidosis has been associated with renal injury and progression of kidney
disease, correction of acidosis might reduce this injury directly by ameliorating the acid
environment. Therefore, alkalization that reduces acid retention might be equivalent to drug
therapies that reduce kidney levels and effects of angiotensin II, endothelin, and aldosterone.
Short-term and long-term studies also show that bicarbonate therapy can reduce serum
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potassium, an outcome that can be beneficial in CKD patients who are at increased risk
of hyperkalemia, particularly in the later stages of CKD and in such patients taking ACE
inhibitors. Although there is data saying that bicarbonate supplementation in the form
of sodium bicarbonate will not elevate blood pressure or require increased dose of antihypertensive agents, higher alkali doses might cause sodium-water retention and affect blood
pressure control in patients with advanced renal failure. Sodium bicarbonate is contraindicated
in patients with metabolic or respiratory alkalosis and in those with hypocalcaemia in whom
alkalosis may induce tetany and hypokalemia. It should also be used with caution in patients
with chronic obstructive pulmonary disease, because alkalization can reduce the sensitivity of
the respiratory regulatory center. The National Kidney Foundation recommends 0.51.0 mEq
of NaHCO3/kg body weight in patients with bicarbonate less than 22 mmol/L [76].

Treatment of hyperuricemia
Targeting uric acid has also been found to have impact on the progression of CKD. The
most common agent used for this purpose in addition to diet restriction is allopurinol.
Allopurinol treatment resulted in a decrease of uric acid that was associated with improvement
of endothelial function, GFR and systolic blood pressure. The effect of allopurinol effect is
either due to reduction of uric acid per se or because of the antioxidant effect produced
when xanthine oxidase is inhibited. Similarly another xanthine oxidase inhibitor febuxostat
treatment protected against renal damage and progression of proteinuria, maintaining the
morphology of glomerular vessels and glomerular pressure independent of effect on uric acid
[77,78].

Treatment of Complications
Treatment of bone mineral disorders
Vitamin D has potent anti-proliferative, pro-differentiative, and immuno-modulating
activities modulated via vitamin D receptordependent genomic effects [44]. This seems to
provide the biologic basis for salutary effects of vitamin D receptor agonists (VDRA) in patients
with kidney disease. Use of oral VDRA is associated with significantly better survival, and
a lower risk of initiating dialysis. Inactive forms of supplementary vitamin D, ergocalciferol
(vitamin D2), and cholecalciferol (vitamin D3), significantly increase 25-hydroxy vitamin D
and 1,25-dihydroxy vitamin D levels in patients with stages 3 and 4 CKD. Markers of bone
formation, such as bone-specific alkaline phosphatase, will also be significantly reduced
by VDRA treatment. Although these supplements are generally considered ineffective for
PTH suppression in usual doses, in patients with stage 5 CKD (before or in those receiving
dialysis), they may prevent osteomalacia due to vitamin D deficiency. Hence depending on
the stage of kidney dysfunction, repletion of both inactive 25-hydroxy vitamin D and active
1,25-dihydroxy vitamin D is needed. In patients with stage 3 and 4 CKD and secondary
hyperparathyroidism, it is recommended to correct vitamin D deficiency with cholecalciferol
(vitamin D3). Supplementation of oral vitamin D should be done in patients who have 25hydroxy vitamin D levels less than 30 ng/ml. Use of calcitriol or VDRA is recommended only if
the PTH remains elevated inspite of correcting the vitamin D deficiency. Major side effects with
use of vitamin D include hypercalcemia, hyperphosphatemia and over suppression of PTH
leading to adynamic bone disease [62].
Treatment of secondary hyperparathyroidism is carried out with use of vitamin D
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supplementation, phosphate binders and calcimimetics (not FDA approved for non- dialysis
CKD patients). This might have beneficial effects for the vascular mineralization and mortality
in CKD, an effect that can be at least be partly mediated through the reduction of arterial
stiffness and arterial calcification [62].
Treatment of hyperphosphatemia includes dietary phosphate restriction and the use of
phosphate binders. This eventually will result in control of secondary hyperparathyroidism
with secondary lowering of FGF23. Lowering serum phosphorus also increases production
of calcitriol, which has a direct effect on the parathyroid glands to decrease PTH production
and secretion. The traditionally used phosphate binders include calcium based binders
like calcium acetate as well as non-calcium based binders like sevelamer carbonate and
lanthanum carbonate. Sevelamer can reduce FGF-23 levels irrespective of the changes in
serum phosphorus or 1,25-dihydroxyvitamin D [79].
KDIGO guidelines suggest measurement of serum total calcium, phosphorus, 25hydroxyvitamin D, PTH, and bone alkaline phosphatase as baseline values if patients are
diagnosed with stage 3 CKD (GFR 30-59 mL/min). Measurement of alkaline phosphatase
should be done on a regular basis since it is a readily available biochemical marker for assessing
bone formation in CKD and it is not excreted by the kidney. Although alkaline phosphatase
elevation in CKD likely reflects secondary hyperparathyroidism, it may also signify recent
fracture, hypovitaminosis D, osteomalacia, or other metabolic bone disorders. Increased levels
virtually exclude the presence of adynamic bone disease (ABD). But at the same time normal
alkaline phosphatase and normal to slightly elevated PTH levels in late CKD need to be viewed
with caution for possible ABD [80].
Bone mineral density (BMD) measurement may be done in stage 3 CKD (GFR30-59 mL/
min/m2), especially in patients with laboratory or other risk factors for osteoporosis. A DEXA
scan can assess fracture risk and bone loss over time in patients with stage 3-4 CKD. It can
also measure changes in bone mass following parathyroid surgery for hyperparathyroidism.
But at the same time it can be highly unreliable especially when GFR is less than 45 ml/min/
m2. The gold standard for the diagnosis and classification of CKD-MBD is the tetracycline
double-labeled bone biopsy (iliac crest biopsy) for histomorphometric analysis. Current KDIGO
guidelines do not recommend bone mineral density measurements for CKD but do suggest that
stages 3 to 5 CKD patients be measured for serum PTH or bone-specific alkaline phosphatase
to predict for low or high bone turnover [24]. Clinical practice guidelines (KDOQI) for bone
metabolism and disease in CKD are represented in Table 3.
CKD stage

Phosphorus (mg/dL)

Calcium( mg/dL)

PTH (pg/ml)

Stage 3

2.7-4.6

8.4-10.2

35-70

Stage 4

2.7-4.6

8.4-10.2

70-110

Stage 5

3.5-5.5

8.4-9.5

150-300

Table 3: Clinical practice guidelines (KDOQI) for bone metabolism and disease in CKD.

Treatment of anemia
Treatment of anemia in CKD includes correction of iron deficiency and erythropoietin
deficiency. The ideal goal of hemoglobin in patients with CKD is a matter of debate. The target
hemoglobin and threshold for use of erythropoietin is based on three major trials viz CHOIR,
CREATE and TREAT. In the CHOIR study the patients treated for the higher hemoglobin target
experienced a 34% increased risk of a composite cardiovascular endpoint compared to those
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treated for a lower hemoglobin target. In addition, quality of life did not differ between the
groups. In the CREATE study the composite cardiovascular endpoint did not differ between
the two groups. However, the risk of ESRD increased in the higher target group. In TREAT,
a large trial of 4038 patients with diabetes, CKD (GFR 20-60 mL/min/1.73 m2) and anemia,
participants were randomly assigned into receiving darbopoetin for a hemoglobin target of
13 g/dL, or matching placebo with rescue darbopoetin treatment below hemoglobin of 9 g/
dL. Even though there was a significant improvement in quality of life, the incidence of the
composite cardiovascular endpoint did not differ between the groups. At the same time a
doubling in the risk of stroke in the normal hemoglobin arm and increased cancer-related
mortality were observed. Based on the increased risk of adverse outcomes at higher hemoglobin
concentrations, the Food and Drug Administration (FDA) recommended more conservative
dosing guidelines for erythropoiesis stimulating agents (ESA) when used to treat anemia in
patients with CKD. On the same tune the KDIGO anemia guidelines also recommended that
for patients with CKD not on dialysis and anemia, ESA treatment should only be considered
when the hemoglobin level is < 10 g/dL and be individualized based on the rate of fall of
hemoglobin, prior response to iron therapy, the risk of needing a transfusion, the risks related
to ESA therapy, and the presence of symptoms attributable to anemia. In general, ESAs should
not be used to maintain a hemoglobin concentration > 11.5 g/dL in adult patients with CKD.
It is unclear whether the negative effects of complete correction of anemia are due primarily to
high hemoglobin levels per se, to excessive ESA doses, or to both. Higher doses of ESAs might
be associated with toxicities, which include erythropoietic and non-erythropoietic effects most
important being the increase in blood viscosity. Increased blood viscosity also predisposes
patients to increased vascular resistance and the development of hypertension [81,82].

Prevention of infection
Because of increased risk of infections seen in CKD patients it has been recommended to
take appropriate measures for prevention of infection. As part of this effort KDIGO has made
the following recommendations [24].
1) Annual vaccination with influenza vaccine, unless contraindicated.
2) CKD patients with GFR less than 30 and those at high risk of pneumococcal infection
(e.g., nephrotic syndrome, diabetes, or those receiving immunosuppression) receive vaccination
with polyvalent pneumococcal vaccine unless contraindicated. Additionally all adults with CKD
who have received pneumococcal vaccination should be offered revaccination within 5 years.
3) CKD patients who are at high risk of progression of CKD and have GFR <30 ml/min/1.73
m2 be immunized against hepatitis B and the response confirmed by appropriate serological
testing.
In addition to this early detection and treatment of urinary tract infection is also important
in preventing progression of CKD.

Dietary sodium restriction in CKD


Dietary sodium intake in CKD patients has been found to influence a number of uremia
related risk factors including oxidative stress, proteinuria, inflammation, and endothelial
cell damage. Additionally it has been found to increase blood pressure, cardiovascular risk
(independent of blood pressure changes), proteinuria and intraglomerular pressure and
decrease GFR. As sodium handling is primarily the role of the kidney those with CKD may have
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a reduced ability to excrete sodium, making them less able to compensate for the high sodium
load that is characteristic of the Western diet. Hence a diet low in sodium is essential for
better control of hypertension as well proteinuria and improvement in GFR and cardiovascular
outcomes. Current guidelines recommend salt restriction amounting to less than 90 mmol/
day (<2 gm/day) [83].

Medication use in CKD


The medical management of CKD patients involve complex and highly variable
pharmacotherapy, including frequent monitoring as well as evaluation to ensure optimal
pharmacotherapy and adherence to medication. A high number of prescribed medications, poor
medication adherence, and frequent dosage changes may contribute to drug-related morbidity
and related problems. Drug related side effects are very frequently reported in CKD patients
because of the complexity of dosing emanating from the changes in drug pharmacodynamics
and pharmacokinetics in the presence of CKD. NKF-KDOQI guidelines explicitly highlight
the need for regular medication reviews, including dosage adjustment, adverse drug event
detection, drug interaction detection, and therapeutic drug monitoring. One way of dealing
with this is by utilizing the service of a clinical pharmacist who can work with the physician
closely in outpatient clinics. A higher proportion of CKD patients achieve haemoglobin target,
increased medication knowledge, decreased hospitalisation rates, and an overall improvement
in the quality of life in such clinical pharmacist led programs [84].
Other interventions that can potentially prevent progression of renal disease include
immunosuppressive medications for autoimmune glomerular diseases, antibiotics for urinary
tract infections, removal of urinary stones, relief of obstruction, and cessation of toxic drugs,
avoidance of phosphate containing enema.

Monitoring in CKD
KDIGO guidelines for management of chronic kidney disease.

Proteinuria
a) During evaluation of CKD check for proteinuria using albumin to creatinine (ACR) ratio.
If ACR > 30 mg/g (>3 mg/mmol) on a random untimed urine, confirm it with a subsequent
early morning urine sample. If a more accurate estimate of albuminuria or total proteinuria
is required, measure albumin excretion rate or total protein excretion rate in a timed urine
sample.
b) Assess GFR and albuminuria at least annually in people with CKD. Assess GFR and
albuminuria more often for individuals at higher risk of progression (sustained decline in GFR
of more than 5 ml/min/1.73/m2/year), and/or where measurement will impact therapeutic
decisions.

Hypertension
a) For diabetic and non-diabetic adults with CKD and urine albumin excretion < 30
mg/24 hours (or urine ACR < 30 mg/g) start treatment for hypertension if blood pressure is
consistently more than 140 mmHg systolic or 90 mmHg diastolic.
b) For diabetic and non-diabetic adults with CKD and urine albumin excretion 30
mg/24 hours (or urine ACR 30 mg/g) start treatment for hypertension if blood pressure
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is consistently more than 130 mmHg systolic or 80 mmHg diastolic to achieve a goal blood
pressure of 130 mm Hg systolic and 80 mm Hg diastolic.
c) An ARB or ACE inhibitor can be used in diabetic adults with CKD and urine albumin
excretion 30300 mg/ 24 hours.
d) An ARB or ACE inhibitor should be used in both diabetic and non-diabetic adults with
CKD and urine albumin excretion > 300 mg/24 hours.

Dietary intervention/ Protein intake


a) Restrict protein intake to 0.8 g/kg/day in adults with diabetes or without diabetes and
GFR <30 ml/min/ 1.73 m2 with appropriate education.
b) High protein intake of > 1.3 g/kg/day in adults with CKD at risk of progression should
be avoided.
c) Dietary advice and information in the context of an education program, tailored to severity
of CKD and the need to intervene on salt, phosphate, potassium, and protein intake should be
provided where indicated.

Glycemic control
Target hemoglobin A1C to ~7.0% to prevent or delay progression of the micro vascular
complications of diabetes, including diabetic kidney disease.

Salt intake
Lower salt intake to <90 mmol (<2 g) per day of sodium in adults, unless contraindicated.

Metabolic acidosis
In the presence of CKD and serum bicarbonate concentrations <22 mmol/L, treatment
with oral bicarbonate supplementation can be given to maintain serum bicarbonate within the
normal range, unless contraindicated.

Miscellaneous interventions
a) Encourage people with CKD to undertake physical activity compatible with cardiovascular
health and tolerance (aiming for at least 30 minutes 5 times per week)
b) Encourage to achieve a healthy weight (body mass index of 20-25) based on exercise and
diet
c) Encourage to stop smoking.
d) Avoid use of phosphate enema
e) Refer for preemptive renal transplantation when the GFR is <20 ml/min/1.73 m2, and
when there is evidence of progressive and irreversible CKD over the preceding 612 months.
The following interventions should be avoided:
a) Perform bone mineral density testing routinely in those with GFR <45 ml/min/1.73 m2
as information may be misleading or unhelpful.
b) Prescribing bisphosphonate treatment in people with GFR <30 ml/min/1.73 m2 without
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a strong clinical rationale.
c) Use of gadolinium-containing contrast media in people with GFR <15 ml/min/1.73 m2
unless there is no alternative appropriate test. If there is need for using gadolinium in people
with GFR <30 ml/min/1.73 m2, a macrocyclic chelate preparation should be preferred.

Monitoring of laboratory tests


I. GFR
a) For GFR categories G1 &2, GFR can be tested annually if CKD is present in the absence
of microalbuminuria or 1-2 times per year if there is micro or macro albuminuria.
b) For GFR categories G3a & G3b, GFR should be tested at 1-3 times per year depending
on the severity of albuminuria.
c) For GFR categories G4 & G5, GFR should be tested at least 3-4 times per year depending
on the severity of albuminuria.
d) Assess GFR more often for individuals at higher risk of progression, and/or where
measurement will impact therapeutic decisions.
II. Metabolic bone disease and laboratory monitoring
a) For GFR categories G3a & G3b, serum calcium, phosphorus every 6-12 mos and PTH
based on baseline level and CKD progression.
b) For GFR categories G4, serum calcium, phosphorus every 3-6 mos and PTH every 6-12
months.
c) For GFR categories G5 (including dialysis), serum calcium, phosphorus every 1-3 mos
and PTH every 3-6 months.
III. Albuminuria
a) Assess Albuminuria at least annually irrespective of the stage of kidney disease.
b) Assess albuminuria more often for individuals at higher risk of progression, and/or
where measurement will impact therapeutic decisions.
IV. Hemoglobin
a) CKD and GFR categories G1 &2 when clinically indicated.
b) For GFR categories G3a & G3b: annually.
c) For GFR categories G4 &G5 twice per year.

Renal replacement therapy


Patients with CKD should be referred well in advance for placement of arteriovenous fistula
so that they will have mature fistula by the time they are on the point of initiation of renal
replacement therapy. This is preferably done at stage 4 when glomerular filtration rate (GFR)
is around 20 ml/min/1.73 m2. The decision to start dialysis treatment depends on the severity
of uremic symptoms. Clear indications for initiation of dialysis include pericarditis, progressive
neuropathy attributable to uremia, encephalopathy, muscle irritability, anorexia and nausea
attributable to uremia and that are not ameliorated by reasonable protein restriction, evidence
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of protein-energy malnutrition, and fluid and electrolyte imbalance refractory to conservative
treatment. Patients who have questionable history of compliance with conservative treatment
should be also considered for early initiation of dialysis treatment. The optimal timing of
initiation of dialysis based on absolute GFR is still not known at this point. Early initiation of
dialysis has not been found to be superior to late initiation based on available data [24,26].

Patient education
While conservative and supportive treatment is being carried out, simultaneous educational
program focusing on social psychological and physical preparation for transition to renal
replacement therapy should be initiated. This should include information regarding timing
of initiation of renal replacement therapy, various modalities of therapy available for dialysis.
Patients family should also be involved in the discussion especially of those who are planning
home hemodialysis, peritoneal dialysis and transplantation. The risk and benefits of each
dialysis modality and renal transplantation should be explained in detail. The potential
psychological impact that the patients could develop in this process should also be addressed
accordingly.

References
1. Nitta K, Okada K, Yanai M, Takahashi S (2013) Aging and chronic kidney disease. Kidney Blood Press Res 38: 109-120.
2. U.S. Renal Data System (2013) USRDS 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease
in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD.
3. Stevens LA, Li S, Wang C, Huang C, Becker BN (2010) Prevalence of CKD and comorbid illness in elderly patients in the United
States: results from the Kidney Early Evaluation Program (KEEP). Am J Kidney Dis 55: 23-33.
4. Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, et al. (2007) Prevalence of chronic kidney disease in the United States. JAMA
298: 2038-2047.
5. Norman J (2011) Fibrosis and progression of autosomal dominant polycystic kidney disease (ADPKD). Biochim Biophys Acta
1812: 1327-1336.
6. Rossert J, Fouqueray B, Boffa JJ (2003) Anemia management and the delay of chronic renal failure progression. J Am Soc Nephrol
14: 173-177.
7. Lizakowski S, Tylicki L, Rutkowski B (2013) Direct renin inhibition--a promising strategy for renal protection? Med Sci Monit 19:
451-457.
8. Viazzi F, Leoncini G, Pontremoli R (2013) Antihypertensive treatment and renal protection: the role of drugs inhibiting the reninangiotensin-aldosterone system. High Blood Press Cardiovasc Prev 20: 273-282.
9. Eddy AA (2004) Proteinuria and interstitial injury. Nephrol Dial Transplant 19: 277-281.
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41. Macas N, Goicoechea M, de Vinuesa MS, Verdalles U, Luo J (2013) Urate reduction and renal preservation: what is the evidence?
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42. Feig DI (2009) Uric acid: a novel mediator and marker of risk in chronic kidney disease? Curr Opin Nephrol Hypertens 18: 526-530.
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46. Maric-Bilkan C (2013) Obesity and diabetic kidney disease. Med Clin North Am 97: 59-74.
47. Agarwal R (2009) Vitamin D, proteinuria, diabetic nephropathy, and progression of CKD. Clin J Am Soc Nephrol 4: 1523-1528.
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49. Hung SC, Lin YP, Tarng DC (2014) Erythropoiesis-stimulating agents in chronic kidney disease: what have we learned in 25 years?
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50. Mehdi U, Toto RD (2009) Anemia, diabetes, and chronic kidney disease. Diabetes Care 32: 1320-1326.
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55. Covic A, Kothawala P, Bernal M, Robbins S, Chalian A et al. (2009) Systematic review of the evidence underlying the association
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56. Glassock RJ, Pecoits-Filho R, Barberato SH (2009) Left ventricular mass in chronic kidney disease and ESRD. Clin J Am Soc
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57. Iwanaga Y, Miyazaki S (2010) Heart failure, chronic kidney disease, and biomarkers--an integrated viewpoint--. Circ J 74: 12741282.
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61. Moranne O, Froissart M, Rossert J, Gauci C, Boffa JJ, et al. (2009) Timing of onset of CKD-related metabolic complications. J Am
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64. Martin KJ, Gonzlez EA (2007) Metabolic bone disease in chronic kidney disease. J Am Soc Nephrol 18: 875-885.
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67. Carrero JJ, Stenvinkel P, Cuppari L, Ikizler TA, Kalantar-Zadeh K, et al. (2013) Etiology of the protein-energy wasting syndrome in
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