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Editor-in-Chief
Ajay K. Singh, MB, FRCP(UK)
Associate Professor of Medicine, Harvard Medical School
Director, Postgraduate Medical Education
Department of Medicine and Renal Division,
Brigham and Women’s Hospital
Chapter 6:
Chronic Kidney Disease
Ajay K. Singh, MB, FRCP
Daniel W. Coyne, MD
Contents
1. Introduction
3. Epidemiology of CKD
4. CKD Economics
12. References
Chronic kidney disease (CKD) is defined by the CKD is staged by using glomerular filtration rate
National Kidney Foundation as either: 1.) a (GFR) categories. The NKF-K-DOQI has classified
glomerular filtration rate (GFR) of <60 mL/min CKD into 5 stages (Table 1).1 The strengths of the
with or without kidney damage for 3 or more NKF K-DOQI classification are its simplicity and
months; or 2.) the presence of kidney damage for 3 its use of estimated GFR (eGFR) to classify CKD
or more months demonstrated by pathologic abnor- into different stages. Furthermore, the widespread
malities, markers of kidney damage (eg, blood or adoption of the classification has resulted in, per-
urine composition), or imaging tests.1 In the United haps for the first time, a uniform system understood
States, it is estimated that CKD affects 7%-10% of and applied worldwide. Indeed, the classification
the adult population, or 15 to 20 million individuals, serves as a useful starting point in evaluating a
although specific subgroups such as African-Ameri- patient with depressed GFR. It also provides the
cans and Hispanics are at especially high risk. impetus to either refer a patient to a nephrologist for
further work-up, or to identify a patient at higher
There is growing consensus on the importance of risk of developing cardiovascular complications.
using a prediction equation to estimate kidney func-
tion rather than relying on serum creatinine. Recent The major limitations of the NKF CKD classifica-
observational data has also emphasized the connec- tion are as follows. It stages the severity of kidney
tion between kidney disease and cardiovascular dis- disease on the basis of GFR without incorporating
ease (CVD), indicating the primary importance of other important parameters such as albuminuria.
CVD as a source of mortality among CKD patients. Two patients with similar GFR but with wide differ-
Also, the importance of CKD as a risk factor in ences in the degree of proteinuria at baseline are
patients with CVD has emerged. It has become evi- likely to have very different prognosis. The patient
dent that the level of kidney function as assessed by with high degree proteinuria is more likely to have a
either serum creatinine or estimated glomerular fil- worse prognosis. The NKF classification also
tration rate is a key factor in predicting survival after leaves unaddressed the significance of reduced GFR
an acute myocardial infarction (MI). From a thera- below 60 mL/min/1.73m2 in certain subgroups,
peutic standpoint, considerable progress has been such as the elderly, the undernourished, and mem-
made in demonstrating the critical role of the renal- bers of specific ethnic groups. For example, elderly
angiotensin system in mechanistically influencing individuals with reduced GFR may never develop
the progression of kidney disease. Angiotensin
blockade slows the progression of every stage of
CKD, whether CKD is caused by diabetes or not
(although the role of angiotensin blockade in retard-
ing the progression of specific disorders has not
Table 1
end-stage renal disease. Patients with congestive Using extrapolations from the NHANES study, it is
cardiac failure may have a low GFR because of estimated that approximately 19 million individuals
hemodynamic reasons but do not have any struc- in the United States have CKD.2,3 These estimations
tural evidence of kidney disease, and kidney func- provide a ballpark prevalence number because the
tion may normalize once the heart failure is treated. NHANES data relies on a single creatinine mea-
However, it is important to note that the use of NKF surement. As well, the NHANES White Sands labo-
CKD criteria may not apply to some racial groups ratory did not calibrate creatinine measurement with
since their GFR may be naturally lower than West- the Cleveland Clinic laboratory where the MDRD
ern levels as a consequence of smaller stature, lower predictive equation was generated.4 Thus, these
muscle mass, and vegetarianism. NHANES-based CKD prevalence estimates are
likely to be somewhat higher than the true figure.
Data on the prevalence of CKD in the developing The cost of medical care for patients with CKD is
world is quite limited.10-12 CKD in the developing high, and is reviewed in detail elsewhere.17 The
world suggests a prevalence of approximately average cost of care for a CKD patient is approxi-
5%-10% (Pakistan data is based on the Cockcroft- mately $1,300 per month compared to approxi-
Gault estimation of creatinine clearance and the mately $500 per month for a non-CKD patient.
estimate for CKD prevalence is 29%).12 This would This number is dwarfed by the cost of care for an
suggest that there are many millions of people ESRD patient—approximately $5000 each
among these that have CKD. However, it is impor- month. CKD patients consume a disproportion-
tant to be cautious in reaching this conclusion since ate share of health care resources.18 In 2002, the
the published studies, so far at least, have method- total cost of the ESRD program in the United
ologic limitations. These include the reliance on a States was $25.2 billion in 2002, an 11.5%
single creatinine as the measure of kidney function; increase from the previous year. Despite the cost
the lack of creatinine standardization against any of treatment of ESRD and improvements in the
international laboratory standard; and the absence quality of dialysis therapy, mortality and morbid-
of studies validating an estimating equation in a ity remains significant. In 2002, 71,006 ESRD
non-American population.13 patients died. Incidence and prevalence counts
for ESRD are expected to increase by 44% and
In the United States, there are notable racial differ- 85%, respectively, from 2000 to 2015 and inci-
ences in the epidemiology of CKD. This is reviewed dence and prevalence rates per million popula-
in detail elsewhere.14-16 African Americans, Pacific tion by 32% and 70%, respectively. Survival
Islanders, Latinos, and Native Indians have a higher probabilities for dialysis patients at 1, 2, 5 and 10
prevalence of CKD than Caucasians. African- years are approximately 80%, 67%, 40%, and
Americans are at especially high risk—a 3- to 4- 18%, respectively. Moreover, 50% of dialysis
fold higher risk than Caucasians. In particular, patients have three or more comorbid conditions,
African-Americans appear to have a higher preva- the mean number of hospital days per year is
lence of hypertensive kidney disease than Cau- approximately 14 per patient, and self-reported
casians (Table 3). quality of life is far lower in dialysis patients than
in the general population.
Table 3
Looming large over concerns about the current man- data suggests that decreased morbidity and mortality
agement of CKD are the issues of CKD under-recog- and lower costs are associated with early referral.
nition and late referral to nephrology.19 Under-recog- Indeed, patients referred late in the course of their
nition partly reflects the continued use of serum crea- kidney disease are more likely to have anemia and
tinine as a screening test for kidney disease. Since hypoalbuminemia, less likely to have been started
there is a nonlinear relationship between serum crea- on erythropoietin, and are less likely to have perma-
tinine and GFR20,21 and because women have lower nent AV access.
muscle mass than men, the problem of under-recog-
nition is particularly acute among women.3 Only
approximately 4% of women with moderate CKD
(GFR 15 to 59 mL/min/1.73m2) are aware that they
have CKD.
CVD is common in patients with all stages of kid- older age, diabetes mellitus, systolic hypertension,
ney disease (Table 4).25 Approximately 25% of and LVH are highly prevalent in CKD patients and
patients with mild to moderate CKD (stages 2 and 3) their relationship to CVD is the same regardless of
have evidence of left ventricular hypertrophy and CKD status. On the other hand, there appears to be
this increases to 40%-70% of patients by the time of what has been termed a reverse epidemiology for
end stage renal disease (stage 5 CKD). Patients with other factors, such as hypertension and LDL choles-
CKD also have a higher prevalence of congestive terol among dialysis patients. The increased risk at
heart failure (CHF). CHF represents a significant lower levels of blood pressure and cholesterol may
risk factor for mortality, especially when anemia is reflect confounding from cardiomyopathy and mal-
also present. A number of factors contribute to the nutrition, respectively, although this has not been
increased prevalence of CVD in patients with kid- proved.
ney disease.26 These can be divided into traditional
and nontraditional. The definition of traditional risk The role of nontraditional risk factors in influencing
factors are those factors that have been used to esti- CVD risk in CKD is more controversial. Observa-
mate the risk of developing symptomatic ischemic tional studies strongly suggest that factors such as
heart disease in the Framingham study (Table 5). proteinuria, hemoglobin level, inflammation, and
Traditional Framingham CVD risk factors, such as calcium-phosphorous abnormalities are important.
However, definitive evidence remains currently
lacking. Some of these nontraditional risk factors
are specific to kidney disease and worsen with pro-
gressive impairment of kidney function.27 It is likely
Table 4
GFR
GFR≤60 mL/min/1.73m2
In patients who are fast progressors (defined as a
GFR decline ≥4 mL/min/1.73 m2 per year)
Proteinuria
Anemia
Hypertension
Acidosis
Renal osteodystrophy
The justification for screening for CKD continues lines for CKD recommend that all individuals
to be debated.28 Because of the relatively low preva- should be assessed as part of routine health examina-
lence of CKD, screening of the general population tions to determine whether they are at increased risk
is unlikely to be cost effective. On the other hand, for developing CKD. Individuals at high risk for kid-
since kidney disease becomes symptomatic in the ney disease, particularly those with diabetes, hyper-
late stages of CKD, and since therapeutic strategies tension, or a family history for these conditions
such as angiotensin blockade and tighter blood and/or for kidney disease, should undergo formal
pressure control have been proven to be effective at testing. Such testing can be performed easily with a
earlier stages, detection of CKD early could poten- urinalysis, a first morning or a random “spot” urine
tially prevent ESRD in a significant proportion of sample for albumin or protein and creatinine assess-
patients. ment, and a serum creatinine level. The American
Diabetes Association (ADA) recommends that for
African Americans and Native Americans have a all type 2 diabetics at the time of diagnosis and all
higher risk of CKD than others (953 and 652 cases type 1 diabetics 5 years after initial diagnosis, an
per million in African Americans and Native Amer- evaluation for microalbuminuria should be per-
icans, respectively, compared to 237 per million formed.30 If the dipstick is positive for either red or
among Caucasians). Also, patients with diabetes white blood cells, a microscopic analysis should be
mellitus and hypertension and those with urine dip- performed of the urinary sediment.
stick positive for protein have a higher risk of devel-
oping CKD. Indeed, in a recent position paper
De Jong and Brenner recommend routine urine
albumin screening as a cost effective way of detect-
ing progressive CKD.29 The NKF-K/DOQI guide-
Table 5
Traditional Framingham CVD Risk Factors are Highly Prevalent in CKD Patients
Age Albuminuria
Male sex Abnormal calcium/phosphate metabolism
Diabetes Anemia
Hypertension Inflammation
Higher LDL cholesterol Oxidative stress
Lower HDL cholesterol
Smoking
Extracellular fluid volume overload
Physical inactivity
Menopause
Family history of CVD
LVH
Measurement of serum creatinine is currently the National Kidney Disease Education Program
most widely utilized measure for the assessment of (NKDEP) have recommended the use of actual
kidney function. However, the use of serum creati- GFR or, when this is unavailable, a prediction equa-
nine has several limitations31 (Table 6). Because cre- tion for estimating GFR.35 Since in most situations
atinine production is dependent on muscle mass, it direct measurement of GFR is not feasible, a pre-
needs to be interpreted cautiously among individu- diction equation to estimate GFR is the most practi-
als with low muscle mass, among females, and in cal and accurate method to assess kidney function.35
elderly patients. In patients with low muscle mass, The MDRD and Cockcroft-Gault equations are
the serum creatinine underestimates the degree of now the most popular prediction equations to assess
kidney function impairment, whereas among indi- GFR in adults.
viduals with large muscle mass (such as body-
builders) the serum creatinine overestimates actual Recently, an isotope dilution mass spectroscopy
GFR. Another source of inaccuracy is the effect of traceable (IDMS) MDRD equation (also known as
noncreatinine chromogens when the alkaline picrate the MDRD 3 equation) has been developed.34 In
assay (Jaffe reaction) for creatinine is utilized.32 essence this is a modified MDRD equation used
These factors include acetoacetate, cephalosporins, when creatinine values are generated from a labora-
and high concentrations of furosemide. Modern tory that has calibrated its creatinine measurement
versions of the Jaffe assay have reduced these to a set of creatinine standards. Until recently, one of
effects by adjusting temperature, assay con- the major limitations of using an estimated GFR
stituents, and various calibration settings. How- equation, such as the MDRD equation, was that
ever, in order to truly reduce the effect of non-crea- there was significant variability in the measurement
tine chromogens, alternative methods are neces- of serum creatinine that results in reduced accuracy
sary. These include an enzymatic creatinine assay, of the MDRD equation in the normal to slightly ele-
HPLC, or isotope dilution mass spectroscopy vated creatinine range (up to 1.5 mg/dL). This is
(IDMS). Furthermore, calibration of the serum cre- because assays in most laboratories are not cali-
atinine is important to reduce intra- and interlabora- brated to the alkaline picrate method used by the
tory variability.33,34 Cleveland Clinic laboratory during the conduct of
the MDRD study. Mass spectroscopy is the most
ideal method to obtain a “true” creatinine value and,
therefore, creatinine standardization using an IDMS
traceable panel for creatinine is now being recom-
Table 6
MDRD: “The Modification of Diet in Renal Dis- GFR can be calculated by the measurement of uri-
ease Study” GFR prediction equation was devel- nary or plasma clearances of isotopes or via images
oped in 1999.36 The equation is based on 1,628 non- produced from a gamma camera.38 There are 4 dif-
diabetic subjects, age 18-70, with renal insuffi- ferent agents that are used in clinical practice: [125
ciency. The formula utilizes urea, creatinine and I] iothalamate,51 Cr-ethylenediaminetetraacetic acid,
albumin as well as demographics of age, gender, 99m Tc-diethylenetriaminepentaacetic acid, and
and race (black or white). If race is unavailable and iohexol. These agents have been shown to correlate
white race is assumed, the GFR will be underesti- well with inulin clearance. They also have high pre-
mated by 18% if the patient is black. This equation cision in the setting of moderate to severe renal dys-
has been validated in American black and white function. Inulin clearance is the gold standard for
racial groups. It has also been validated in diabetics, measurement of actual GFR, since it is freely fil-
tered and neither secreted nor reabsorbed by the kid-
ney. However, it is not widely used in clinical prac-
tice largely for logistical reasons.38
Table 7
GFR Equations
Table 8
Cockcroft-Gault (CG): CrCl × BSA/1.73 m2
Advantages of the MDRD Over CG Equation
For men: CrCl = [(140-Age(yr)) xWeight (kg)]/
SCr x72
Direct comparison of the MDRD and the Cock-
For women: CrCl = ([(140 -Age) xWeight (kg)]/SCr x croft–Gault equation demonstrate the MDRD equation
72) x 0.85 to be superior for estimating GFR, particularly in the
range GFR < 60 mL/min/1.73m2
MDRD 1: GFR = 170 x [SCr]-0.999 x[Age]-0.176 x[0.762
if patient is female] x[1.18 if patient is black] x [BUN]- More widespread validation of MDRD than CG
0.170 x[Alb]0.318 (eg, in various populations).
MDRD(abbreviated): GFR = 186 x[SCr]-1.154 x [Age]-0.203 No requirement for additional information for MDRD
x[0.742 if patient is female] x [1.212 if patient is black] (eg, measurements of weight) beyond that already
collected by pathology laboratories.
As a clinical syndrome, CKD is characterized by symptomatic and may be severely disabled. In the
progressive decline in kidney function such that the early stages of CKD (stage 1 and 2), using the NKF
kidney’s ability to adequately excrete waste prod- K-DOQI CKD stages, patients may present simply
ucts and to contribute to the constancy of the body’s with an elevated serum creatinine and blood urea
homeostatic functions is severely impaired. Mild nitrogen (BUN) level but no symptoms. These indi-
CKD is asymptomatic; moderate CKD is frequently viduals are usually unaware that they have any
characterized by hypertension, anemia, and abnor- abnormalities in their kidney function, and usually
malities in mineral metabolism; whereas advanced fail to register on the “radar screen” of their
CKD is characterized by uremia. CKD may become internists. However, even at this early stage, insidi-
relentlessly progressive as the damage to function- ous effects on target organs may become manifest.
ing nephrons leads to a maladaptive response For example, patients may have mild to moderate
among the remaining nephrons. The progressive hypertension, mild anemia, left ventricular hyper-
decline in kidney function in individuals with CKD trophy, and subtle changes in bone structure due to
is variable and depends on both the cause of the renal osteodystrophy. As kidney function gradually
underlying insult and on patient-specific factors.42 declines further—with glomerular filtration rates
There is consensus that renal disease progression reaching less than 30 mL/min—early features of
rates are heterogeneous both between different eti- uremia become evident. These include worsening or
ologies and within the same etiology. Thus, patients more difficult to control hypertension, extracellular
with polycystic kidney disease (PKD) may progress volume expansion (manifest as edema and dysp-
more slowly than patients with diabetic nephropa- nea), hyperkalemia and acidosis, anemia, and cog-
thy; however, among patients with diabetic nitive, psychological and physical abnormalities.
nephropathy there are patients who progress fast Uremia reflects the accumulation of metabolic tox-
and others who progress hardly at all. Evidence ins, some characterized and others unknown, that
points to the importance of several factors in modu- influence the functioning of a variety of organ sys-
lating kidney progression.42 These include protein- tems. In this late stage, the need for renal replace-
uria, the presence of systemic hypertension, age, ment therapy is imminent and dialysis and/or trans-
gender, genetic factors, and smoking. plantation become inevitable in order to sustain life.
End stage renal disease is the term used to denote The indications for initiating renal replacement
CKD requiring renal replacement therapy (dialysis therapy include severe refractory abnormalities in
or transplantation). The incidence of ESRD in the biochemistry (severe hyperkalemia and acidosis),
United States is approximately 268 cases per mil- severe pulmonary edema, bleeding, metabolic
lion population per year. However, ESRD is over- encephalopathy, and the presence of pericarditis.
represented among African-Americans (829 per Subtler but no less important indications include
million population per year, as compared with 199 malnutrition and severe disability (marked tiredness
per million population per year among white Amer- and lethargy) (Table 10).
icans). The major causes of ESRD in the United
States are diabetes mellitus (44%), hypertension Life expectancy in patients with ESRD for a 49-
(30%), glomerular disease (15%), polycystic kidney year-old is, on average, approximately 7 years,
disease, and obstructive uropathy. Elsewhere in the lower than colon cancer and prostate cancer and
world, where the incidence of diabetes mellitus has one-quarter that of the general population. This
not reached epidemic proportions—for example in reduction in life expectancy is largely attributable to
Europe and parts of the developing world—chronic cardiovascular complications. Nearly 50% of all
glomerulonephritis (20%) and chronic reflux deaths in patients with ESRD are due to cardiovas-
nephropathy (25%) are the commonest causes cular causes.43 The risk is 17 times that of the gen-
of ESRD. eral population. Remarkably, this gap is largest in
young patients with end-stage renal disease. The
CKD is usually asymptomatic when there is mild risk factors for cardiovascular disease in individuals
impairment in kidney function, whereas when GFR with chronic renal failure include, but are not lim-
is markedly reduced the patient is usually clearly ited to, the magnitude of the calcium/phosphorous
The management of osteitis fibrosa is reviewed in Use of calcium further suppresses PTH by increas-
the NKF KDOQI guideline document.44 It is impor- ing serum calcium, but this may result in a chroni-
tant to emphasize that the measurement of calcium, cally positive calcium balance and contribute to vas-
phosphorus, and intact plasma parathyroid hormone cular calcification. Noncalcium based binders—
is important in all patients with a GFR less than 60 such as sevelamer HCl 800 mg TID or lanthanum
ml/min/1.73 m2. The frequency of these measure- carbonate 250 mg TID—offer effective phosphorus
Frequency of Measurement and Target Range for Intact PTH Based on CKD Stage
control without the dangers of calcium loading, but daily or 0.5 mcg thrice weekly and significantly
are substantially more expensive than calcium enhances intestinal absorption of calcium and phos-
based binders. Additionally, sevelamer can induce phorus. Hypercalcemia is common when doses
acidosis due to HCl release upon binding of phos- exceed 0.5 mcg per day.
phorus.
Vitamin D analogs were developed to reduce the
stimulation of intestinal calcium and phosphorus
absorption.48 Paricalcitol (Zemplar®) appears to have
Vitamin D and/or Vitamin D
A deficiency of both 25(OH)D and 1,25(OH)2D3 in randomized trials had an incidence of hypercal-
are common abnormalities in CKD patients. Both cemia and hyperphosphatemia similar to placebo.
may contribute to the development and progression Paricalcitol is usually started at 1 mcg daily or 2 mcg
of SHPT and/or associated osteomalacia and osteo- thrice weekly. Doxercalciferol (Hectorol®) is a pro-
porosis. Vitamin D stores are assessed by determi- hormone (1(OH)D2), and is metabolized constitu-
nation of serum 25(OH)D level, the stable liver tively by the liver to 1, 25(OH)2D2, an active form
metabolite of vitamin D. A normal level is >30 of vitamin D. Other metabolites of doxercalciferol
ng/ml, and lower levels should be supplemented. may also be formed and may account for the appar-
Most 25(OH)D circulates bound to D binding pro- ently lower incidence of hypercalcemia and hyper-
tein (DBP) and serum DBP may be greatly phosphatemia seen with this analog. Doxercalcif-
decreased in nephrotic syndrome due to heavy pro- erol is usually started at 1 mcg daily. (See Table 12
teinuria, making interpretation of the laboratory for recommended doses of ergocalciferol.)
results questionable. Nevertheless, restoration of
25(OH) D levels to normal is appropriate, although After three or more weeks on any form of the above
there is limited data that this lowers PTH. active vitamin D products, serum PTH should be
remeasured and the dose of the active D product
Treatment with vitamin D or one of its analogues is increased by 50%-100% if necessary to achieve
a key element in CKD management (Table 12). PTH suppression into the CKD stage specific target.
Active vitamin D analogs suppress PTH in a dose Adequate suppression of PTH should be balanced
dependent manner.48,49 One of these agents should be with maintenance of normal serum calcium (8.4 to
used whenever PTH is above the target range 10.2 mg/dL) and phosphorus (2.7 to 4.6 mg/dL).
despite vitamin D repletion and phosphorus control. Serum calcium and phosphorus should be measured
Doses are usually administered orally daily or thrice at least quarterly, and more frequently if calcitriol is
weekly, resulting in similar PTH suppression. Cal- used at a dose of 0.5 mcg per day or more.
citriol (Rocaltrol®) is typically begun at 0.25 mcg
Anemia is a common complication in CKD patients, RBC and Hb by 3. The RBC multiplied by 3 should
affecting approximately 40% of patients in stage 4 equal the Hb, and the Hb multiplied by 3 should
and 5 CKD (anemia defined herein as a Hb of <11 equal the Hct. Deviation from the calculated values
g/dL) (Table 13). Estimates suggest that almost suggests microcytosis, macrocytosis, or hypochro-
1,000,000 patients in the United States with CKD mia versus the presence of spherocytes (MCHC,
are anemic.52 Diabetes seems to be an additional risk >36). In patients suspected of CKD anemia, mea-
factor for anemia in CKD and more than 20% of dia- surement of an erythropoietin level (EPO) is not
betics with an eGFR of 30-59 mL/min/1.73 m2 are necessary. This is because a low normal or even a
anemic. The etiology of anemia in CKD is multifac- normal EPO level may suggest EPO deficiency. On
torial. While erythropoietin deficiency is the most the other hand, excluding the possibility of iron defi-
common cause (Tables 14, 15), iron deficiency, ciency is important. The diagnosis of iron deficiency
nutritional deficiencies (in vitamin B6 and B12), is made by demonstrating that the patient has a
occult blood loss and hyperparathyroidism are also transferrin saturation (TSAT) level of <20% and/or a
important causes. serum ferritin level of <100 ng/mL. While the gold
standard for iron deficiency is the absence of stain-
able iron in a bone marrow specimen, under most
circumstances a bone marrow evaluation is imprac-
Clinical Features and Diagnosis of CKD
Mild anemia (Hb levels >11 g/dL) is usually asymp- mia is helpful but not diagnostic. Every patient with
tomatic in CKD patients. By the time the Hb level is iron deficiency anemia should have a stool examina-
<10 g/dL, patients complain of tiredness and tion for occult blood. A positive result necessitates a
fatigue. Some patients may complain of a reduction careful search of the gastrointestinal tract to identify
in exercise capacity, well being, tiredness, and cold the site of bleeding. Unfortunately, a negative result
intolerance. Impairment in neurocognitive ability does not exclude gastrointestinal blood loss because
may be evident using formal tests but may be too bleeding can be intermittent and require several
subtle to detect by routine clinical evaluation. In examinations for detection. Also, less than 20-30
several observational studies, anemia increases the mL of blood in the stool per day may go undetected
risk of cardiovascular complications including left due to the insensitivity of the test.
ventricular hypertrophy, left ventricular dilatation,
and myocardial ischemia.53,54 From a diagnostic
standpoint, CKD anemia is characterized by normo-
cytic, normochromic hematologic indices. A rapid
than 10 mg/dL, and preferably when Hgb is 10 to 11 The 2002 NKF Anemia Update had recommended a
g/dL.51 For convenience reasons, less frequent dos- hemoglobin range of 11 to 12 g/dL.50 However, more
ing regimens are used in CKD than in dialysis recently, the NKF Anemia Update has recom-
patients.56-58 The initial dose of epoetin is usually mended that the target hemoglobin range should be
ized to the higher hemoglobin level did experience While several mechanisms may account for iron
improved quality of life. Indeed, several large ran- deficiency among dialysis patients (loss through the
domized controlled studies in both ESRD and pre- dialysis procedure, acute and chronic inflammation,
ESRD patients have either failed to demonstrate a and reduced oral absorption and reduced dietary
benefit of anemia correction, or have shown a trend intake), among predialysis CKD patients the most
towards worse outcomes such as cardiovascular dis- important reason appears to be reduced GI absorp-
ease or death. A recent meta-analysis concurs – tion (Table 16). The likeliest reason for this is a
increased risk with targeting a hemoglobin concen- block, through the action of hepcidin, in iron
tration of >12 g/dL in pre-dialysis and dialysis absorption through the intestinal iron transporter
patients. 58 In light of the evidence from interven- ferroportin.61 Hepcidin, a liver synthesized protein,
tional studies, as alluded to above, a recent boxed regulates ferroportin mediated iron absorption.
advisory from the Food and Drug Administration
(FDA) has recommended a Hgb target of High hepcidin levels result in reduced iron absorp-
10 to 12 g/dL. tion.62 Since hepcidin is excreted by the kidneys, it is
postulated that renal dysfunction results in progres-
Initiation of erythropoietic agents frequently con- sively higher levels of hepcidin and thus attenuated
sumes the patient’s iron stores, and the inflamma- iron absorption. CKD patients’ reduced dietary
tion present in CKD inhibits adequate intestinal iron intake, especially of foods high in iron, such as
absorption, resulting in iron deficiency. High levels meats and leafy vegetables, may further exacerbate
of C-reactive protein, a marker of inflammation, iron deficiency. It is estimated that approximately
have been associated with low iron absorption in 40% of patients with CKD have iron deficiency.63
patients on HD. As kidney disease progresses, iron deficiency
Table 16
Absolute iron deficiency TSAT <20% and serum Increased blood loss
serum ferritin <100 ng/mL Decreased iron
absorption
TSAT (calculated by the formula serum iron/total dose requirements have remained high despite IV
iron binding capacity x 100) and serum ferritin are iron, or no erythropoietic response has occurred (ie,
the primary measures used to assess patients’ iron Hgb level does not increase).
stores. Although neither has optimal sensitivity nor
specificity, they are inexpensive and widely avail- There are limitations to both the serum ferritin and
able. Tissue ferritin is a large protein molecule con- TSAT markers in accurately diagnosing iron defi-
tained within the reticuloendothelial system (RES), ciency.51,64-66 Serum ferritin is an acute-phase reac-
with iron at its core. Serum ferritin is ferritin that has tant, and levels are elevated in cases of inflamma-
leaked from tissues, and it is an indicator of tissue tion and infection, which are common in HD
iron stores. Most normal patients have serum fer- patients. Because iron is an acute-phase reactant,
ritin levels below 30 ng/mL; however, levels are TSAT levels also may be affected by inflammation
much higher in uremic patients. Transferrin is the or infection. In addition, because transferrin is pro-
body’s iron transport molecule, delivering iron duced primarily in the liver, hepatic disease can
from the RES to the bone marrow for erythro- reduce transferrin production. As a result, if trans-
poiesis. The TSAT represents the body’s circulating ferrin levels are low, the TSAT level may appear to
iron. According to the K/DOQI guidelines, a TSAT be normal in the presence of iron deficiency. TSAT
level <20% and a serum ferritin level <100 ng/mL levels also are affected by nutritional status. TSAT
represents iron deficiency, and a serum ferritin and serum ferritin levels may have greater diagnos-
level >500 ng/mL represents iron overload. How- tic utility for iron deficiency and iron overload when
ever, the 500 ng/mL level set by K/DOQI is opinion they are very low or very high, respectively.
based, not evidence based. Functional iron defi-
ciency and reticuloendothelial (RE) blockade may
Table 17
Half-life 40-60 h ~6 h ~1 h
The treatment of iron deficiency in CKD anemia is include an increased number of hypochromic red
reviewed extensively elsewhere.51,64-66 There is a lim- blood cells (percentage >10%), or a low reticulocute
ited role for oral iron in the treatment of iron defi- hemoglobin content (CHr <31 pg). Intravenous iron
ciency in patients with advanced CKD. Intravenous preparations include iron dextran (1000 mg IV as a
iron is recommended in these circumstances. Very single dose, with an initial test dose of 25 mg); ferric
little oral iron is absorbed and side effects of oral gluconate (initial dose 125 mg IV); or iron sucrose
iron may be quite considerable. A healthy individual (initial dose 100 to 200 mg IV). Iron dextrans have a
only absorbs about 1% of the total iron ingested in low but serious risk of anaphylactic reactions. Oral
an oral dose, while in CKD patients, impaired gas- iron therapy can be attempted in CKD. To maximize
trointestinal absorption can lead to even lower absorption, at least 200 mg of elemental iron should
absorption of iron. Side effects of oral iron include be consumed daily in divided doses taken between
constipation and gastrointestinal upset. meals. Oral iron salts may be bound by calcium-
based phosphorus binders and thus should be taken
Despite a clear rationale for intravenous iron ther- separately. Thyroid hormone supplements may also
apy, there continues to exist an underutilization of be bound by ferrous sulfate and therefore should be
these preparations. This is most likely because of taken separately.
expense, inconvenience of administration, and lim-
ited access to infusion facilities. There are 3 avail-
able forms of IV iron (ferric gluconate, iron sucrose,
Acidosis
and iron dextran); and there are 2 types of iron dex- Chronic metabolic acidosis begins to develop when
tran: INFeD® and Dexferrum®. Studies of mainte- eGFR falls below 40-50 mL/min, and most stage 4
nance IV iron therapy have demonstrated a consis- CKD patients have serum bicarbonate levels
tent improvement in erythropoiesis as measured by <22 meq/L.67,68 Unless patients have concomitant
decreased EPO requirements to maintain or renal tubular acidosis, the ensuing metabolic acido-
improve Hct levels. This improvement has been sis tends to be mild and easily treated. Even mild
seen with all 3 available forms of IV iron. The sig- metabolic acidosis results in increased resorption of
nificant decrease in EPO requirements in HD bone, weakening of bone structure, and can increase
patients may translate into substantial savings, the risk of fractures. Additionally, acidosis enhances
given the high cost of EPO therapy. protein catabolism and can contribute to malnutri-
tion in CKD. Treatment is usually started when
The IV irons differ based on their pharmacokinetic serum bicarbonate is persistently < 22 meg/L. One
profiles, which may have a potentially significant or two sodium bicarbonate tablets (650 mg, ~8 meq
impact on their safety profiles and bioavailability each) are usually administered TID to maintain
(Table 17). Among the IV irons, ferric gluconate has serum bicarbonate >22 meq/L. Use of citrate salts
the shortest elimination half-life (1 hour), approach- may increase the absorption of dietary aluminum in
ing the maximum rate of physiologic clearance by patients with CKD, and therefore should be
the RES. Ferric gluconate also has the largest avoided.
molecular size, reducing the risk of dialyzability.
All of the IV irons are delivered directly to the RES,
where they are stored as ferritin and turned over to
Dyslipidemia
transferrin. However, iron sucrose appears to have a Hypercholesterolemia is considered a major risk
dual method of turnover, with a portion of the iron factor and cause of atherosclerotic disease in the
complex being delivered directly to transferrin— general population; however, there is a lack of asso-
thereby raising the risk of transferrin oversaturation. ciation between this traditional risk factor and
atherosclerotic cardiovascular disease among dialy-
Iron stores should also be assessed periodically with sis patients, and limited data in patients with CKD.
evaluation of transferrin saturation and ferritin. If Multiple complex lipid abnormalities, known col-
transferrin saturation is <20% or ferritin is lectively as uremic dyslipidemia, are commonly
Table 18
Type of Kidney Disease Target Blood Preferred Agents for Other Agents to
Pressure CKD With or Without Reduce CVD Risk
(mmHg) Hypertension and Reach Blood
Pressure Target
Non-diabetic kidney disease with spot <130/80 ACE Inhibitor Diuretics preferred,
Up/Uc ratio ≥ 200 mg/g then BB or CCB
Disease in the kidney transplant <130/80 No preference CCB, Diuretic, BB, ACE
recipient inhibitor, ARB
There are three important elements to the manage- • Use of an ACE-I/ARB in patients with diabetic
ment of progression in CKD patients (Table 18): kidney disease, and use of ACE-I in non-diabetic
kidney disease with proteinuria (spot Up/Ucr
1. The use of angiotensin blockers to protect the ratio of ≥200 mg/g), to retard progression of kid-
kidney. Both landmark studies in animals by ney disease, irrespective of the presence of hyper-
Brenner and colleagues,74 as well as studies in tension.
humans, supports an independent role for
angiotensin blockade in renoprotection.75-77 ACE With regard to adjunctive anti-hypertensive
inhibitors (ACEi) or angiotensin receptor block- agents, the guidelines suggest diuretics followed
ers (ARB) can be used. It is important to titrate by either beta-blockers or calcium channel block-
the dose of ACEi or ARB to maximal levels using ers in diabetic kidney disease as well as in non-
reduction of proteinuria as the yardstick for effi- diabetic proteinuric kidney disease (spot Up/Ucr
cacy. Emerging evidence (from the COOPER- ratio of ≥200 mg/g). Diuretics are the preferred
ATE study)78 suggests a beneficial effect of using agent in patients with kidney disease in the
both ACEi and ARB in a synergistic strategy to absence of significant proteinuria, as defined by
reduce proteinuria and enhance renoprotection. In spot Up/Ucr ratio of <200 mg/g, followed by
addition, sodium restriction and diuretics in con- ACE-I, ARB, beta-blocker, or calcium channel
junction with ACE-I/ARB therapy increase their blocker. Finally, in recipients of renal allografts,
antiproteinuric effects and should be used in an the NKF-DOQI guidelines recommend calcium
adjunctive fashion. (ACE inhibitors or ARB are channel blockade, diuretic therapy, and beta
blockade, ACE-I or ARB.
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