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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].
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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
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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.
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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].
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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
Retard progression.
G3a
45-59
G3b
30-44
G4
15-29
G5
<15
ESRD
retard progression.
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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
Edited by: Luca Di Lullo
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Method
Agent/agents used
Advantages
Disadvantages
Exogenous
substances.
Endogenous
substance
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.
CKD-EPI equation.
Endogenous
substance
(Cystatin C).
Table 2: Different modalities of estimation of GFR with their advantages and disadvantages.
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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].
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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].
Hematologic abnormalities
Pulmonary abnormalities
Anemia
Pulmonary edema
Leucopenia
Uremic lung
Thrombocytopenia
Pleural effusion
Metabolic acidosis
Infection
Hyperphosphatemia
Platelet dysfunction
Hypocalcemia
Endocrine-metabolic abnormalities
Gastrointestinal abnormalities
Neuromuscular disturbances
Renal osteodystrophy
Anorexia
Fatigue
Nausea
Sleep disorders
Osteomalacia
Vomiting
Headache
Osteoporosis
Gastroenteritis
Asterexis
GI bleeding
Neuropathy
Hypoglycemia
Hyperuricemia
Myoclonus
Hypertriglyceridemia
Seizure
Muscle cramps
Myopathy
Infertility
Sexual dysfunction
Amyloidosis
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Dermatologic abnormalities
Cardiovascular abnormalities
Hyperpigmentation
Hypertension
Pruritus
Ecchymosis
Pericarditis
Uremic frost
Cardiomyopathy
Atherosclerosis
Vascular calcification
Table 3: System wise representation of clinical features in CKD.
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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].
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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].
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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].
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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].
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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].
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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].
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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].
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CKD patients [59,60].
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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].
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
Ultrasound Approach to Chronic Kidney Disease and its Complications
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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].
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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.
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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].
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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.
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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].
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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.
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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].
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.
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.
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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.
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