2 Overview of The Management of Chronic Kidney Disease in Adults

17/12/2010
Overview of the management of chro
Offic ial reprint from UpToDate

www.uptodate.com
2010 UpToDate
Overview of the management of chronic kidney disease in

adults
Authors
Theodore W Post, MD
Burton D Rose, MD
Section Editor
Gary C Curhan, MD, ScD
Last literature review version 18.3: Setembro 2010 |

2010
Deputy Editor
Alic e M Sheridan, MD
This topic last updated: Outubro 8,
INTRODUCTION All patients with renal disease (whether acute or chronic) should undergo an
assessment of renal func tion by estimating the glomerular filtration rate (GFR). This
measurement is used clinic ally to evaluate the degree of renal impairment, to follow the course
of the disease, and to assess the response to therapy. An attempt must also be made to obtain
a spec ific diagnosis. The first step in this process is a careful urinalysis. (See "Assessment of
kidney function: Serum c reatinine; BUN; and GFR" and "Diagnostic approach to the patient with
acute or chronic kidney disease" and "Urinalysis in the diagnosis of renal disease".)
An overview of the general issues involved in the management of the patient with chronic kidney
disease, including modalities to slow the rate of progression, will be presented here. The specific
therapy of patients with partic ular renal diseases is discussed separately in the appropriate topic
reviews.
NATURAL HISTORY OF RENAL DISEASE The initial injury to the kidney may result in a
variety of c linical manifestations, ranging from asymptomatic hematuria to renal failure requiring
dialysis. Many individuals fully rec over and subsequently suffer from little or no sequelae.
Poststreptococc al glomerulonephritis in c hildren, for example, most frequently has a long-term
benign prognosis. By comparison, some patients, such as those with lupus nephritis, experienc e
repeated and chronic insults to the renal parenchyma, thereby resulting in lasting damage.
Furthermore, others in whom the initial disease is either inactive or cured may still develop
progressive renal disease due to hemodynamic and other mechanisms.
In addition to variations in the ac tivity of the individual diseases, these different manifestations
are partly due to how the kidney responds to injury. The kidney is able to adapt to damage by
increasing the filtration rate in the remaining normal nephrons, a process called adaptive
hyperfiltration. As a result, the patient with mild renal insufficiency often has a normal or nearnormal serum creatinine concentration. Additional homeostatic mec hanisms (most frequently
occ urring within the renal tubules) permit the serum c oncentrations of sodium, potassium,
calc ium, and phosphorous and the total body water to also remain within the normal range,
particularly among those with mild to moderate renal failure. (See "Assessment of kidney
function: Serum creatinine; BUN; and GFR".)
Adaptive hyperfiltration, although initially benefic ial, appears to result in long-term damage to
the glomeruli of the remaining nephrons, which is manifest by proteinuria and progressive renal
insuffic ienc y. This process appears to be responsible for the development of renal failure among
those in whom the original illness is either inactive or c ured [1]. The institution of measures to
help prevent this process, suc h as antihypertensive therapy with an angiotensin c onverting
enzyme inhibitor or an angiotensin II receptor blocker, may slow progressive disease and even
preserve renal function. If these modalities are effective, the benefit is likely to be greatest if
begun before a great deal of irreversible scarring has occurred. (See "Secondary factors and
progression of chronic kidney disease".)
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The gradual decline in function in patients with c hronic kidney disease (CKD) is initially
asymptomatic . However, as previously mentioned, different signs and symptoms may be
observed with advanced renal dysfunction, inc luding volume overload, hyperkalemia, metabolic
acidosis, hypertension, anemia, and bone disease. The onset of end-stage renal disease results
in a constellation of signs and symptoms referred to as uremia.
Manifestations of the uremic state include anorexia, nausea, vomiting, pericarditis, peripheral
neuropathy, and central nervous system abnormalities (ranging from loss of c onc entration and
lethargy to seizures, coma, and death). No direct correlation exists between the absolute serum
levels of blood urea nitrogen (BUN) or creatinine, and the development of these symptoms. Some
patients have relatively low levels (eg, a BUN of 60 mg/dL [21.4 mmol/L] in an older patient) but
are markedly symptomatic, while others have marked elevations (eg, a BUN of 140 mg/dL [50
mmol/L]) but remain asymptomatic. To continue life, uremic patients require the institution of
renal replac ement therapy with hemodialysis, peritoneal dialysis, or renal transplantation. (See
"Uremic toxins".)
Not all individuals have progressive loss of kidney function. Some studies show a high rate of
progression, while others report relatively stable disease [2-4]. The rate of progression of
chronic kidney disease from one major stage to another varies based upon the underlying
disease, presence or absenc e of c omorbid conditions, treatments, soc ioec onomic status,
individual genetics, ethnicity, and other factors.
Using epidemiologic data, general estimates for the rate of transition from a GFR between 15 to
60 mL/min per 1.73 m2 to end stage disease may be approximately 1.5 percent per year, while
the rate of transition from a GFR above 60 to below 60 mL/min per 1.73 m2 may be
approximately 0.5 perc ent per year [5,6].
The combination of both a low GFR plus dipstick positive proteinuria, versus either parameter
alone, is assoc iated with a significantly inc reased risk of progressive renal disease. This was
shown in a retrospec tive study of the association between these measures and the 25 year
incidence of end-stage renal disease of middle aged men originally studied in the Multiple Risk
Fac tor Intervention Study (MRFIT) [7]. The presence of 1+ dipstick proteinuria, 2+ dipstick
proteinuria, estimated GFR less than 60 mL/min per 1.73m2, and a low GFR plus 2+ proteinuria
was associated with hazard ratios of 3.1, 15.7, 2.4, and 41, respec tively, for the development of
ESRD over a 25-year period.
DEFINITIONS AND CLASSIFICATION The definition and classification of c hronic kidney
disease may help identify affected patients, possibly resulting in the early institution of effec tive
therapy. To achieve this goal, guidelines were proposed from the National Kidney Foundation of
the United States through its Kidney Disease Outcomes Quality Initiative (K/DOQI) program [8].
These guidelines have been reviewed and accepted internationally [9-11].
The K/DOQI working group defined chronic kidney disease in adults as:
Evidence of structural or functional kidney abnormalities (abnormal urinalysis, imaging
studies, or histology) that persist for at least three months, with or without a decreased
GFR (as defined by a GFR of less than 60 mL/min per 1.73 m2). The most c ommon
manifestation of kidney damage is persistent albuminuria, inc luding mic roalbuminuria.
OR
Dec reased GFR, with or without evidence of kidney damage.
Based upon these definitions, the following is the rec ommended c lassific ation of chronic kidney
disease by stage [8,12-16] along with the estimated prevalenc e in adults in the United States of
eac h stage, as determined by a National Health and Nutrition Examination Survey (NHANES)
performed in 1999 to 2004 [15]:
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Stage 1 disease is defined by a normal GFR (greater than 90 mL/min per 1.73 m2) and
persistent albuminuria (5.7 percent of the total United States population)
Stage 2 disease is a GFR between 60 to 89 mL/min per 1.73 m2 and persistent albuminuria
(5.4 percent)
Stage 3 disease is a GFR between 30 and 59 mL/min per 1.73 m2 (5.4 perc ent)
Stage 4 disease is a GFR between 15 and 29 mL/min per 1.73 m2 (0.4 perc ent for stages 4
and 5)
Stage 5 disease is a GFR of less than 15 mL/min per 1.73 m2 or end-stage renal disease
(0.4 percent for stages 4 and 5)
Compared with 1988 to 1994, the overall prevalenc e of CKD stages 1 to 4 signific antly increased
in the period 1999 to 2004 (13.1 versus 10.0 percent) [16].
The GFR was estimated in this survey using the simplified or abbreviated Modific ation of Diet in
Renal Disease (MDRD) study equation [8,12]. For small c hanges in serum creatinine, which may
be clinically significant, the measurements are most reliable if performed in the same laboratory.
By comparison, changes in serum creatinine of 0.3 mg/dL measured in different laboratories may
represent variations in the assay rather than the GFR [17]. Because of this, there is an ongoing
effort to standardize serum creatinine measurements.
Websites are available to aid in the calc ulation of the GFR through different formulas. These
include: http://www.kidney.org/professionals/KDOQI/gfr_calculator.c fm and
nephron.com/mdrd/default.html
The K/DOQI guidelines c onsider a chronic estimated GFR (eGFR) of less than 60 mL/min per 1.73
m2 as a definition of c hronic kidney disease. We feel this is too restric tive because it will
miscategorize some patients with clear evidence of loss of renal function as not having chronic
kidney disease. As an example, a patient whose serum creatinine concentration inc reases (as
measured in the same laboratory) slowly on sequential measurements from 0.8 to 1.2 mg/dL (71
to 106 micromol/L) clearly has c hronic kidney disease even though the GFR may only have fallen
from 120 to 80 mL/min and the serum creatinine concentration still remains within the normal
range for the laboratory.
The K/DOQI guidelines have also suggested that microalbuminuria alone that persists for more
than three months falls within the definition of chronic kidney disease in patients without
diabetes. We do not agree that microalbuminuria without a reduction in GFR or some other
abnormality necessarily reflects renal disease. It c orrelates best with generalized endothelial
dysfunction and is clearly associated with an increase in cardiovascular risk. (See
"Mic roalbuminuria and cardiovascular disease".) The K/DOQI c linical practice guidelines for CKD,
as well as other K/DOQI guidelines, c an be accessed through the National Kidney Foundation's
web site at www.kidney.org/professionals/kdoqi/guidelines.cfm.
Some experts also feel that the presence of a low GFR alone should not necessarily be
considered a sign of progressive disease, particularly in older patients [18]. There are many
elderly patients who have substantial reduc tions in GFR who do not develop end-stage renal
disease in their lifetime [19]. Additional disc ussion related to the epidemiology of chronic kidney
disease and sc reening recommendations is presented separately. (See "Epidemiology of chronic
kidney disease and sc reening rec ommendations".)
ASSOCIATION WITH CARDIOVASCULAR DISEASE, END-STAGE RENAL DISEASE, AND
MORTALITY There is a large body of evidenc e that patients with CKD have a substantial
increase in cardiovascular risk that can be in part explained by an inc rease in traditional risk
fac tors such as hypertension, diabetes, and the metabolic syndrome. CKD alone is also an
independent risk factor for c ardiovascular disease. Among patients with CKD, the risk of death,
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particularly due to cardiovascular disease, is much higher than the risk of eventually requiring
dialysis. This is disc ussed separately. (See "Chronic kidney disease and c oronary heart disease".)
Close attention to the prevention and management of cardiovascular disease should occ ur
among patients identified with c hronic renal dysfunction [20]. As an example, the increased
intake of c alcium (which is c ommonly given to treat hyperphosphatemia and may result in a high
calc ium-phosphorus product) may enhanc e c oronary arterial calc ification. Although c ontroversial,
this is thought by some to be associated with the development of c oronary atherosc lerosis, and
is related to the presence and/or consequences of elevated serum phosphorus, c alcium, and
parathyroid hormone levels. (See 'Hyperphosphatemia' below and "Vasc ular calc ification in
chronic kidney disease".)
These and other observations have suggested that chronic kidney disease should be considered
a c oronary equivalent and that aggressive risk fac tor reduction should be part of standard
therapy of patients with chronic kidney disease. (See "Chronic kidney disease and coronary
heart disease".)
Patients with CKD are also at increased risk for the development of end-stage renal disease
(ESRD) as well as all-cause mortality. In some subsets of individuals with CKD, the risk of ESRD
exceeds the risk of mortality. As an example, in an analysis of the Afric an Americ an Study of
Kidney Disease and Hypertension (AASK), follow-up of 764 participants for over 11 years found
that the rate of ESRD significantly surpassed the rate of total mortality (3.9/100 patient-years
versus 2.2/100 patient-years, respec tively) [21].
ASSOCIATION WITH NON-CARDIOVASCULAR DISEASE Patients with CKD are at increased
risk for a variety of non-cardiovascular diseases, including infec tion and malignanc y [22-24].
Careful attention should be paid to preventive measures such as influenza and pneumoc occ al
immunization, and age-appropriate screening for malignanc y [25]. (See "Overview of preventive
medicine in adults".)
GENERAL MANAGEMENT OF CHRONIC KIDNEY DISEASE The general management of the
patient with chronic kidney disease involves the following issues [26]:
Treatment of reversible causes of renal dysfunc tion
Preventing or slowing the progression of renal disease
Treatment of the complications of renal dysfunction
Identification and adequate preparation of the patient in whom renal replac ement therapy
will be required
Reversible causes of renal dysfunction In addition to exacerbation of their original renal
disease, patients with chronic renal disease with a recent decrease in renal function may be
suffering from an underlying reversible process, which if identified and c orrected may result in
the recovery of function.
Decreased renal perfusion Hypovolemia (suc h as vomiting, diarrhea, diuretic use,
bleeding), hypotension (due to myocardial dysfunction or pericardial disease), infec tion (suc h as
sepsis), and the administration of drugs which lower the GFR (such as nonsteroidal
antiinflammatory drugs [NSAIDs] and ACE inhibitors) are c ommon causes of potentially reversible
dec lines in renal function.
The normal response to renal hypoperfusion is to lower the urine sodium c oncentration (less than
25 meq/L) and the frac tional excretion of sodium (less than 1 percent in patients with advanced
renal failure) to very low levels. However, the superimposition of a prerenal process among
patients with chronic kidney disease may not result in the expec ted low values sinc e the tubules
in the diseased kidney are unable to reabsorb sodium so efficiently. As a result, hypovolemia in
these patients should be diagnosed by the history and physical examination, inc luding the
presence of relative hypotension, a low jugular venous pressure, and poor skin turgor. In this
setting, a judicious trial of fluid repletion may result in the return of renal function to the
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previous baseline. (See "Fractional exc retion of sodium in acute kidney injury (acute renal
failure)".)
Administration of nephrotoxic drugs The administration of drugs or diagnostic agents
that adversely affect renal function are a frequent cause of worsening renal func tion. Among
patients with chronic kidney disease, common offenders inc lude aminoglycoside antibiotics
(partic ularly with unadjusted doses), nonsteroidal antiinflammatory drugs, and radiographic
contrast material, particularly in diabetic s. The administration of such drugs should therefore be
avoided or used with c aution in patients with underlying chronic kidney disease. (See
"Manifestations of and risk fac tors for aminoglycoside nephrotoxicity" and "NSAIDs: Acute kidney
injury (acute renal failure) and nephrotic syndrome" and "Pathogenesis, clinical features, and
diagnosis of contrast-induced nephropathy".)
Certain drugs also interfere with either c reatinine secretion or the assay used to measure the
serum creatinine. These inc lude cimetidine, trimethoprim, cefoxitin, and fluc ytosine. In these
settings, there will be no change in GFR; the c linical clue that this has occ urred is the absence
of a concurrent elevation in the blood urea nitrogen (BUN). (See "Drugs that elevate the serum
creatinine concentration".)
Urinary tract obstruction Urinary tract obstruc tion should always be c onsidered in the
patient with unexplained worsening renal function although, in the absenc e of prostatic disease,
it is muc h less common than decreased renal perfusion. Patients with slowly developing
obstruc tion typically have no changes in the urinalysis, no symptoms referable to the kidney,
and initially maintain their urine output. Given this lack of clinic al clues, renal ultrasonography is
often performed to exclude urinary tract obstruction in patients with an unexplained elevation in
the serum creatinine. (See "Diagnosis of urinary tract obstruction and hydronephrosis".)
Slowing the rate of progression Studies in experimental animals and humans suggest that
progression in chronic kidney disease may be due at least in part to secondary factors that are
unrelated to the activity of the initial disease. The major factors are thought to be
intraglomerular hypertension and glomerular hypertrophy (whic h are primarily responsible for the
adaptive hyperfiltration described above), leading to glomerular scarring (glomerulosc lerosis).
Additional c auses may include hyperlipidemia, metabolic acidosis, and tubulointerstitial disease.
(See "Secondary factors and progression of chronic kidney disease".)
The major histologic manifestation of hemodynamically-mediated renal injury is secondary focal
segmental glomerulosclerosis [27]. Thus, proteinuria typically oc curs in patients with progressive
chronic kidney disease, even in primary tubulointerstitial diseases suc h as reflux nephropathy.
Multiple studies in humans have been performed investigating the effec t of treating sec ondary
fac tors on the progression of renal disease. There is clear evidence in diabetic nephropathy and
nondiabetic c hronic kidney diseases that the administration of angiotensin converting enzyme
(ACE) inhibitors or angiotensin II receptor blockers (ARBs) slows the progression of chronic
kidney disease, with the greatest benefit in patients with higher degrees of proteinuria (figure
1) [28]. The possible efficac y of dietary protein restriction is less clear. (See "Antihypertensive
therapy and progression of nondiabetic c hronic kidney disease" and "Protein restric tion and
progression of chronic kidney disease".)
If these modalities are to be effective, the benefit is likely to be greatest if begun before a great
deal of irreversible scarring has occurred. Thus, protec tive therapy has the greatest impact if it
is initiated relatively early in the course, before the serum creatinine concentration exceeds 1.2
(106 micromol/L) and 1.5 mg/dL (133 micromol/L) in women and men, respectively, or the GFR is
less than 60 mL/min per 1.73 m2. At this point, most patients have already lost more than onehalf of their GFR. Waiting until the disease progresses further diminishes the likelihood of a
successful response.
The following recommendations are consistent with JNC 7 and the K/DOQI Clinical Practice
Guidelines on hypertension and antihypertensive agents in c hronic kidney disease [29-31].
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Aggressive goals are recommended for both proteinuria and blood pressure. Antihypertensive
therapy is given for both renal protection and c ardiovascular protection, since chronic kidney
disease is associated with a marked increased in cardiovascular risk. (See 'Association with
cardiovasc ular disease, end-stage renal disease, and mortality' above and "Chronic kidney
disease and coronary heart disease".)
A reduction in protein excretion to less than 500 to 1000 mg/day; recognizing the diffic ulty
of ac hieving suc h a goal in many patients, we recommend a minimum reduction of at least
60 percent of baseline values.
A reduction in blood pressure to less than 130/80 mmHg. However, evidence from the
Modific ation of Diet in Renal Disease study, the AASK trial, and a meta-analysis from the
ACE inhibition and Progressive Renal Disease (AIPRD) study group suggest that an even
lower systolic pressure may be more effective in slowing progressive renal disease in
patients with a spot urine total protein-to-c reatinine ratio 1000 mg/g (which represents
protein excretion of greater than 1000 mg/day) [28]. Caution is advised about lowering the
systolic blood pressure below 110 mmHg. (See "Measurement of urinary protein excretion".)
These aggressive goals will, in most patients, require therapy with multiple drugs. Our
rec ommendations concerning drug therapy are discussed separately. (See "Antihypertensive
therapy and progression of nondiabetic c hronic kidney disease".)
ACE inhibitors and ARBs can c ause a decline in renal function and a rise in plasma potassium that
typically occur soon after the onset of therapy. An elevation in serum creatinine of as much as
30 to 35 percent above baseline that stabilizes within the first two to four months of therapy is
considered ac ceptable and not a reason to discontinue therapy with these drugs [29,32].
However, a repeat plasma c reatinine and potassium should be measured within three to five
days. (See "Antihypertensive therapy and progression of nondiabetic c hronic kidney disease".)
In patients with nonproteinuric renal disease, most often a tubulointerstitial disease, none of the
above drugs has been shown to slow progression of the renal disease and therapy is limited to
blood pressure c ontrol.
Other therapeutic modalities also may offer some renal protec tion:
The optimal level of protein intake has also not been determined but it may be reasonable
to restrict intake to 0.8 to 1.0 g/kg per day of high biologic value protein, with the lower
value used in patients with progressive chronic kidney disease. Some recommend even
lower levels, such as 0.6 to 0.75 g/kg per day of high value protein, with c lose supervision
and dietary counseling [33]. (See "Protein restriction and progression of chronic kidney
disease".)
Both hyperlipidemia and metabolic acidosis should be treated, in part because there is
some evidenc e that they may enhance the rate of progression of the renal disease (see
below). (See "Statins and chronic kidney disease".)
Smoking cessation should be encouraged, with smoking stoppage being assoc iated with a
reduc ed rate of progression of c hronic kidney disease [34]. In an increasing number of
studies, smoking also appears to c orrelate with an enhanced risk of developing kidney
disease (primarily nephrosc lerosis) as well as increasing the rate of progression among
those with existing CKD [35].
Treatment of the complications of renal dysfunction A wide range of disorders may
develop as a consequence of the loss of renal func tion. These include disorders of fluid and
elec trolyte balance, suc h as volume overload, hyperkalemia, metabolic acidosis, and
hyperphosphatemia, as well as abnormalities related to hormonal or systemic dysfunction, suc h
as anorexia, nausea, vomiting, fatigue, hypertension, anemia, malnutrition, hyperlipidemia, and
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bone disease. Attention needs to be paid to all of these issues.

One recommended diet, including suggestions for protein, fat, mineral, water, and vitamin intake,
is presented in Tables 1 and 2 (table 1 and table 2). This should be modified based upon the
needs of the individual patient.
Volume overload Sodium and intravascular volume balance are usually maintained via
homeostatic mechanisms until the GFR falls below 10 to 15 mL/min. However, the patient with
mild to moderate c hronic kidney disease, despite being in relative volume balanc e, is less able to
respond to rapid infusions of sodium and is therefore prone to fluid overload.
Patients with chronic kidney disease and volume overload generally respond to the c ombination
of dietary sodium restriction and diuretic therapy, usually with a loop diuretic given daily. Some
investigators have also c laimed that limiting sodium intake may also help decrease progression of
chronic kidney disease by lowering intraglomerular pressure [36]. (See "Optimal dosage and side
effects of loop diuretic s" and "Treatment of refractory edema in adults".)
Hyperkalemia The ability to maintain potassium excretion at near normal levels is
generally maintained in patients with renal disease as long as both aldosterone secretion and
distal flow are maintained [37,38]. Thus, hyperkalemia generally develops in the patient who is
oliguric or who has an additional problem such as a high potassium diet, inc reased tissue
breakdown, or hypoaldosteronism (due in some cases to the administration of an ACE inhibitor or
ARB) [39]. Impaired cell uptake of potassium also may contribute to the development of
hyperkalemia in advanc ed c hronic kidney disease. (See "Causes of hyperkalemia".)
Hyperkalemia due to ACE inhibitor or ARB therapy is most likely to oc cur in patients in whom the
serum potassium concentration is elevated or in the high normal range prior to therapy. This is
discussed in detail separately. (See "Treatment and prevention of hyperkalemia".)
In addition to treating hyperkalemia, there are several measures that can help prevent
hyperkalemia in patients with chronic kidney disease. These include ingestion of a low potassium
diet (eg, less than 40 to 70 meq/day [1500 to 2700 mg/day]) and avoiding, if possible, the use
of drugs that raise the serum potassium c oncentration suc h as nonsteroidal antiinflammatory
drugs [40]. Nonselective beta-blockers make the postprandial rise in the serum potassium
concentration but do not produce persistent hyperkalemia. (See "Sympathetic ac tivity and
potassium balance" and "Patient information: Low potassium diet".)
Metabolic acidosis There is an increasing tendency to retain hydrogen ions among
patients with chronic kidney disease [41-43]. This can lead to a progressive metabolic acidosis
with the serum bicarbonate c onc entration tending to stabilize between 12 and 20 meq/L, and
rarely falling below 10 meq/L [42,44].
Previously, exogenous alkali was not usually given to treat the generally mild metabolic acidosis
(arterial pH generally above 7.25) in asymptomatic adults with chronic kidney disease. This was
primarily due to c onc erns related to the exacerbation of volume expansion and hypertension.
However, these concerns appear to be overstated.
There are three major reasons why treatment of the acidemia may be desirable in patients with
chronic kidney disease. (See "Pathogenesis and treatment of metabolic ac idosis in c hronic kidney
disease".)
Bic arbonate supplementation may slow the progression of chronic kidney disease [45].
Bone buffering of some of the excess hydrogen ions is associated with the release of
calcium and phosphate from bone, which can worsen the bone disease. (See 'Renal
osteodystrophy' below.)
Uremic acidosis c an increase skeletal muscle breakdown and diminish albumin synthesis,
leading to loss of lean body mass and musc le weakness. The administration of bic arbonate
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inc reases serum albumin and the lean body mass [45].
We rec ommend alkali therapy to maintain the serum bicarbonate conc entration above 23 meq/L
[45-50]. If alkali is given, sodium bic arbonate (in a daily dose of 0.5 to 1 meq/kg per day) is the
agent of choice. Sodium citrate (citrate is rapidly metabolized to bicarbonate) may be used in
patients who are unable to tolerate sodium bic arbonate, sinc e it does not produce the bloating
associated with bicarbonate therapy [47]. Sodium c itrate should be avoided in the rare patient
who may be taking aluminum-containing antacids since it markedly enhances intestinal aluminum
absorption [51,52].
The K/DOQI clinical practice guidelines for nutrition in CRF, as well as other K/DOQI guidelines,
can be acc essed through the National Kidney Foundation's web site at
www.kidney.org/professionals/kdoqi/guidelines.cfm.
Hyperphosphatemia A tendency toward phosphate retention begins early in renal
disease, due to the reduction in the filtered phosphate load. Although this problem is initially mild
with hyperphosphatemia being a relatively late event, phosphate retention is intimately related
to the common development of secondary hyperparathyroidism. (See "Pathogenesis of renal
osteodystrophy".)
From the viewpoint of calc ium and phosphate balance, the hypersec retion of parathyroid
hormone (PTH) is initially appropriate, since PTH can c orrect both hyperphosphatemia and
hypocalc emia. As a result, phosphate balance and a normal serum phosphate c onc entration are
generally maintained in patients with a GFR of greater than 30 mL/min [53]. The price paid is
secondary hyperparathyroidism and the development of renal osteodystrophy. (See
"Pathogenesis of renal osteodystrophy".)
Dietary phosphate restriction may limit the development of secondary hyperparathyroidism in
patients with chronic kidney disease. An intake of about 800 mg/day may be desirable and is
rec ommended by the K/DOQI guidelines in patients with elevated phosphate and/or PTH levels.
However, it c an be accomplished only by limiting protein intake which is not acc eptable to many
patients (even though it may provide some protec tion against progressive renal disease). (See
"Protein restric tion and progression of c hronic kidney disease".)
Once the GFR falls below 25 to 30 mL/min, the addition of oral phosphate binders are usually
required to prevent hyperphosphatemia [53,54]. The K/DOQI guidelines recommend that serum
phosphorus levels should be between 2.7 and 4.6 mg/dL (0.87 and 1.49 mmol/L) among patients
with stage 3 and 4 chronic kidney disease, and between 3.5 and 5.5 mg/dL (1.13 and 1.78
mmol/L) among those with end-stage renal disease (or stage 5 disease) [54]. The serum
calc ium-phosphorus product should also be maintained at <55 mg2/dL2. This is best ac hieved by
controlling serum levels of phosphorus within the target range. (See "Treatment of
hyperphosphatemia in c hronic kidney disease".)
One of the preferred agents to bind intestinal phosphate is calc ium salts, of which one of the
most widely used is c alcium carbonate. Another calc ium salt, calc ium acetate, may be a more
efficient phosphate binder than calcium c arbonate. In patients with stage 3 to 5 CKD, the
K/DOQI guidelines suggest that total elemental calcium intake (including both dietary calcium
intake and calcium-based phosphate binders) should not exceed 2,000 mg/day. Phosphate
binders are most effective if taken with meals to bind dietary phosphate.
Hypercalc emia is a c ommon c omplication of this regimen, partic ularly in patients also treated
with c alcitriol to protect against the development of renal osteodystrophy (see 'Renal
osteodystrophy' below). Thus, careful monitoring of the serum calcium concentration is
essential.
The nonabsorbable agent sevelamer, which contains neither calcium nor aluminum, is a cationic
polymer that binds phosphate through ion exchange. Sevelamer controls the serum phosphate
concentration without inducing hypercalc emia. It may be best used in patients who cannot
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tolerate c alcium-based phosphate binders (eg, due to hyperc alcemia or c onstipation) or have
persistent hyperphosphatemia. It may also be used in combination therapy with calciumcontaining antacids among those with serum phosphate levels consistently above target levels
despite single-agent binder therapy. (See "Treatment of hyperphosphatemia in chronic kidney
disease".)
Lanthanum, a rare earth element, also has significant phosphate binding properties. Although no
significant c linical adverse effects have yet been reported, the long-term safety of lanthanum,
particularly its possible effect on bone and other organs, remains unc lear. (See "Treatment of
hyperphosphatemia in c hronic kidney disease".)
Most other phosphate binders should be avoided:
Aluminum hydroxide, the previous standard, bec ause of the gradual induction of aluminum
toxicity
Magnesium-c ontaining antacids (such as magnesium hydroxide), because of the risk of
hypermagnesemia and the frequent development of diarrhea
Calc ium c itrate, since it markedly inc reases intestinal aluminum absorption
Unfortunately, all of the phosphate binders have a limited phosphorous binding capacity. Thus,
phosphate-binding compounds will be effective in lowering serum phosphorous levels only if the
dietary restrictions for phosphorus are continued simultaneously.
The increased intake of calcium may enhance c oronary arterial calc ification in this setting. This
is thought by some to be assoc iated with the development of c oronary atherosclerosis, and may
be related to the presence and/or consequenc es of elevated serum phosphorus, c alcium, and
parathyroid hormone levels. Detailed disc ussions of these issues, including specific K/DOQI
guidelines, can be found separately. (See "Vascular c alcific ation in c hronic kidney disease".) The
K/DOQI clinic al practic e guidelines for bone metabolism and disease in CKD, as well as other
K/DOQI guidelines, can be acc essed through the National Kidney Foundation's web site at
Renal osteodystrophy Changes in mineral metabolism and bone structure are an almost
universal finding with progressive chronic kidney disease [55]. The principal types of renal bone
disease include osteitis fibrosa, osteomalac ia, and adynamic bone disease. (See "Pathogenesis of
renal osteodystrophy".)
Osteitis fibrosa results from sec ondary hyperparathyroidism. Although an exact relationship is
unc lear, parathyroid hormone levels appear to increase when renal func tion decreases beyond a
certain threshold value, with evidence suggesting that hormone levels begin to rise when the
creatinine clearance is less than 40 to 70 mL/min [8,56].
To help guide preventive measures, parathyroid hormone levels should therefore be assessed
among suc h patients, as hormonal abnormalities are one of the earliest markers of abnormal bone
mineral metabolism with progressive chronic kidney disease. Prevention and/or treatment of
osteitis fibrosis in patients with predialysis c hronic kidney disease are primarily based upon
dietary phosphate restriction, the administration of oral phosphate binders, and the
administration of calc itriol (or vitamin D analogs) to directly suppress the secretion of
parathyroid hormone.
Calcitriol (1,25-dihydroxyvitamin D), the most active metabolite of vitamin D, is principally
synthesized in the kidney. Circulating c alcitriol levels begin to fall when the GFR is less than 40
mL/min and are typic ally markedly reduc ed in subjects with end-stage renal disease. In addition
to the loss of functioning renal mass, c alcitriol production is also reduc ed by phosphate
retention. (See "Pathogenesis of renal osteodystrophy".)
Calcimimetics are agents that allosterically increase the sensitivity of the c alcium-sensing
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rec eptor in the parathyroid gland to c alcium. The calcium-sensing receptor is the principal factor
regulating parathyroid gland parathyroid hormone secretion and hyperplasia. The separate target
offers the potential to suppress parathyroid hormone secretion by mec hanisms c omplementary
and potentially synergistic with vitamin D analogues that target the vitamin D receptor. Although
not approved for patients with CKD not yet on dialysis, cinacalcet, the only currently available
calc imimetic , is an emerging option in the treatment of secondary hyperparathyroidism in
predialysis patients with CKD.
Target serum levels for PTH as well as the approach to the management of this issue are
discussed separately. (See "Management of sec ondary hyperparathyroidism and mineral
metabolism abnormalities in adult predialysis patients with c hronic kidney disease".)
Hypertension Hypertension is present in approximately 80 to 85 percent of patients with
chronic kidney disease [57]. Treating hypertension can both slow the progression of proteinuric
CKD and reduce the rate of c ardiovascular complications. (See "Chronic kidney disease and
coronary heart disease", section on 'Blood pressure control' and "Hypertension in kidney
disease".)
The desired degree of blood pressure control c an usually be safely achieved with combined
therapy whic h usually begins with an ACE inhibitor or angiotensin II receptor blocker (also given
to slow disease progression as noted above) and a diuretic. Issues surrounding the treatment of
hypertension among patients with diabetic nephropathy are discussed in detail separately. (See
"Treatment of hypertension in patients with diabetes mellitus".)
Volume expansion, often in the absenc e of overt edema, contributes to the elevation in blood
pressure in most forms of chronic kidney disease. As a result, before other medic ations are
added, the dose of diuretic s should be increased until the blood pressure is normalized or the
patient has attained "dry weight" which, in the presence of persistent hypertension, is defined
as the weight at whic h further fluid loss will lead either to symptoms (fatigue, orthostatic
hypotension) or to decreased tissue perfusion as evidenc ed by an otherwise unexplained
elevation in the BUN and plasma creatinine c oncentration. (See "Hypertension in kidney
disease".)
A loop diuretic is rec ommended for the treatment of hypertension and edema in patients with
chronic kidney disease. The thiazide diuretics in conventional dosage become less effective as
monotherapy when the GFR falls below 20 mL/min. They do, however, produc e an additive effect
when administered with a loop diuretic for refrac tory edema. (See "Treatment of refrac tory
edema in adults".)
The optimal blood pressure in hypertensive patients with chronic kidney disease is uncertain. The
rate of loss of GFR appears to be more rapid when the mean arterial pressure remains at or
above 100 mmHg (whic h reflec ts a diastolic pressure of 80 to 85 mmHg in the absenc e of
systolic hypertension). To slow progression of chronic kidney disease, the optimal blood pressure
depends in part on the degree of proteinuria. (See "Antihypertensive therapy and progression of
nondiabetic c hronic kidney disease", section on 'Importance of proteinuria in predicting
response'.)
We rec ommend a blood pressure goal of less than 130/80 mmHg in patients with protein
excretion exc eeding 500 to 1000 mg/day, which is consistent with JNC 7 and the K/DOQI Clinical
Practice Guidelines on hypertension and antihypertensive agents in c hronic kidney disease
[29,30]. (See "Antihypertensive therapy and progression of nondiabetic c hronic kidney
disease" and 'Slowing the rate of progression' above.)
There is no clear evidence supporting a blood pressure goal less than 130/80 mmHg in patients
with protein excretion below 500 to 1000 mg/day. The data addressing this issue and our
rec ommendations are presented elsewhere. (See "Antihypertensive therapy and progression of
nondiabetic c hronic kidney disease", section on 'Nonproteinuric chronic kidney disease'.)
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Anemia The anemia of chronic kidney disease is, in most patients, normocytic and
normochromic, and is due primarily to reduced produc tion of erythropoietin by the kidney (a
presumed reflection of the reduction in functioning renal mass), and to shortened red cell
survival [58]. Anemia is a common feature in many patients with chronic kidney disease who do
not yet require dialysis, with anemia bec oming inc reasingly c ommon as glomerular filtration rates
(GFRs) decline below 60 mL/min per 1.73 m2 [59,60], partic ularly among diabetics [61]. As an
example, based upon over 15,000 partic ipants in the NHANES survey, the prevalence of anemia
(Hbg <12 g/dL in men and <11 g/dL in women) increased from 1 perc ent at an eGFR of 60
mL/min per 1.73 m2 to 9 percent at an eGFR of 30 mL/min per 1.73 m2 and to 33 to 67 percent
at an eGFR of 15 mL/min per 1.73 m2 [59]. (See "Erythropoietin for the anemia of chronic kidney
disease among predialysis and peritoneal dialysis patients".)
As stated in the 2006 K/DOQI guidelines, the evaluation of anemia in those with CKD should
begin when the Hgb level is less than 12 g/dL in females, and Hgb levels of less than 13.5 g/dL in
adult males [62]. These levels are based on the Hgb levels below the fifth perc entile for the
adult general population as noted in the NHANES database [63]. If untreated, the hematoc rit of
patients with advanced chronic kidney disease normally stabilizes at approximately 25 percent in
the absenc e of bleeding or hemolysis.
The anemia observed with chronic kidney disease is largely diagnosed by exc luding non-renal
causes of anemia in the patient with a suitably decreased GFR. The evaluation of patients should
therefore include red blood cell indices, absolute reticulocyte count, serum iron, total iron binding
capacity, percent transferrin saturation, serum ferritin, white blood cell count and differential,
platelet count, and testing for blood in stool. The content of hemoglobin in reticulocytes can
also be assessed. This work-up should be performed prior to administering epoetin alfa (EPO) or
darbepoetin alfa therapy. (See "Approach to the adult patient with anemia".)
Although primarily used in patients with end-stage renal disease, erythropoietic agents, such as
erythropoietin and darbepoetin alfa, also correc t the anemia in those with chronic kidney disease
who do not yet require dialysis. (See "Erythropoietin for the anemia of c hronic kidney disease
among predialysis and peritoneal dialysis patients".)
An erythropoietic agent should be given to the predialysis patient with CKD and anemia. We
suggest targeting Hgb levels in the range of 10 to 12 g/dL in predialysis patients with CKD. We
do not recommend maintaining Hgb levels above this level in predialysis patients being
administered an erythropoietic agent, since suc h levels have been associated with adverse
cardiovasc ular outc omes. In the patient with Hgb levels above 12 g/dL who is rec eiving an
erythropoietic agent, appropriate measures should be instituted, such as decreasing the dose of
the erythropoietic agent or inc reasing the dosing interval, to maintain Hgb levels in the range of
10 to 12 g/dL (see "Anemia of chronic kidney disease: Target hemoglobin/hematocrit for patients
treated with erythropoietic agents")
The erythropoietin dose should be approximately 50 to 100 U/kg per week. The 2006 guidelines
suggest that the initial erythropoietic agent dose and dose adjustment be given based upon the
initial and target hemoglobin level, the clinical setting, and the rate of increase of the
hemoglobin level [62].
Although erythropoietin has traditionally been given in two to three doses per week, it is
currently commonly given only once per week (or even less frequently). In prac tice, most
patients are dosed by unit dosing (eg, a vial), rather than on a U/kg basis. Thus, it would be
reasonable to begin most patients on 10,000 U subcutaneously once weekly. If necessary,
subsequent adjustments are made in interval and/or dose. Initially, to help detec t changes in
levels, weekly testing of the hemoglobin level is recommended. (See "Erythropoietin for the
anemia of c hronic kidney disease among predialysis and peritoneal dialysis patients".)
There is limited evidence suggesting that an increased mortality in predialysis patients may be
due to high erythropoietin doses. Thus, we suggest that the dose of epoetin alpha generally not
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exceed 20,000 units per week in CKD patients who are not on dialysis. (See "Anemia of chronic
kidney disease: Target hemoglobin/hematocrit for patients treated with erythropoietic agents".)
Darbepoetin alfa, another erythropoietic agent, is also indicated for the treatment of anemia
associated with chronic kidney disease. The three-fold longer half-life and greater biologic al
activity of darbepoetin alfa, c ompared with rec ombinant erythropoietin, enables this agent to
effectively maintain target hemoglobin levels with less frequent dosing. The infrequent
darbepoetin alfa dosing schedule of once weekly or once every two weeks, with the possibility of
monthly dosing in some patients, offers many potential benefits to both patients and caregivers.
The choic e of whether to use erythropoietin or darbepoetin alfa in a given patient is best
dec ided by the prac titioner. The key foc us should be on achieving the target hemoglobin, not
whic h hematopoietic stimulator to use. The recommended starting dose of darbepoetin alfa in
rec ombinant erythropoietin-naive patients with c hronic kidney disease is 0.45 mcg/kg
administered onc e weekly. Data in patients with chronic kidney disease who are not dialysis
dependent also demonstrate that darbepoetin alfa administered once every other week at a
dose of 60 mcg is an effec tive dosing strategy. Darbepoetin alfa can be given by either
intravenous or subcutaneous injec tion. (See "Darbepoetin alfa for the management of anemia in
chronic kidney disease".)
An adequate response to erythropoietin or darbepoetin alfa requires the maintenanc e of
sufficient iron stores, which usually requires the administration of either oral or intravenous iron
in patients with initially inadequate iron levels or in those being treated with erythropoietin. The
2006 K/DOQI guidelines defined low levels of iron tests among patients with predialysis CKD as
either serum ferritin <100 ng/mL or transferrin saturation (TSAT) <20 percent [62]. Such iron
indic es are common among predialysis CKD patients. Based on the NHANES data, for example,
approximately 60 and 70 percent of men and women, respec tively, with creatinine c learances
less than 60 mL/min would be defined as iron deficient [64].
We agree with the 2006 K/DOQI guidelines which suggest administering iron to maintain the
percent transferrin saturation 20 perc ent, and the serum ferritin level to be greater than 100
ng/mL [62]. If oral iron is given, we recommend that adults should receive a daily dose of
approximately 200 mg of elemental iron, usually as ferrous sulfate 325 mg three times daily (65
mg elemental iron per tablet). (See "Iron balance in predialysis, peritoneal dialysis, and home
hemodialysis patients" and "Use of iron preparations in hemodialysis patients".)
Dyslipidemia Abnormal lipid metabolism is common in patients with renal disease [65]. The
primary finding in chronic kidney disease is hypertriglyc eridemia with the total cholesterol
concentration usually being normal (perhaps due in part to malnutrition in some patients).
Patients with chronic kidney disease should be assessed for dyslipidemia, including a total
cholesterol, LDL, HDL, and triglycerides. The K/DOQI clinical practice guidelines for managing
dyslipidemias in CKD, as well as other K/DOQI guidelines, c an be accessed through the National
Kidney Foundation's web site at www.kidney.org/professionals/kdoqi/guidelines.cfm.
Among patients with CKD, the degree of hypertriglyceridemia that oc curs may not be sufficient
to significantly inc rease coronary risk, but other changes have been found that might c ontribute
to the ac celerated atherosclerosis commonly seen in end-stage renal disease. First, dietary
modification may be helpful for the hypertriglyc eridemia. Drug therapy in patients without renal
failure may be beneficial in selected patients with isolated marked hypertriglyc eridemia (serum
triglyc erides 500 mg/dL [5.65 mmol/L]) who have proven coronary disease, a strong family
history of CHD, or multiple c oexisting c ardiac risk factors. Whether this approac h is beneficial in
patients with renal failure is not known, but it should be considered. (See "Approac h to the
patient with hypertriglyc eridemia", section on 'Mild to moderate hypertriglyceridemia'.)
In the patient with hypercholesterolemia, a statin c an effectively and safely lower the plasma
cholesterol conc entration to or near acc eptable levels. A related issue is the goal LDLcholesterol level. Given evidence that mild to moderate degrees of chronic kidney disease are
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associated with an adverse c ardiovascular prognosis, c hronic kidney disease is considered a

coronary heart disease equivalent [66]. (See "Chronic kidney disease and coronary heart
disease".)
Thus, the goal LDL-c holesterol is similar to that in patients with CHD, which has been less than
100 mg/dL (2.6 mmol/L). However, subsequent data has led some experts to recommend a lower
goal of less than 70 mg/dL (1.8 mmol/L). A similar lipid-lowering goal, beginning with statin
therapy, should be administered to patients with chronic kidney disease. (See "Treatment of
lipids (inc luding hypercholesterolemia) in secondary prevention" and "Hyperlipidemia in nephrotic
syndrome" and "Chronic kidney disease and c oronary heart disease", section on 'Secondary
prevention'.)
Limited data suggest that lipid lowering may have an additional benefit in patients with chronic
kidney disease, whic h is slowing the rate of progression of the underlying renal disease. (See
"Sec ondary factors and progression of chronic kidney disease", sec tion on 'Hyperlipidemia' and
"Statins and chronic kidney disease".)
Sexual dysfunction Significant abnormalities in sexual and reproductive function are
frequently observed in patients with advanc ed renal disease. As an example, over 50 percent of
uremic men complain of symptoms that include erectile dysfunction, decreased libido, and
marked declines in the frequency of intercourse [67]; in addition, disturbances in menstruation
and fertility are c ommonly enc ountered in women with chronic kidney disease, usually leading to
amenorrhea by the time the patient reaches end-stage renal disease. (See "Sexual dysfunc tion
in uremic women" and "Sexual dysfunc tion in uremic men".)
An important c linical implication of these abnormalities is that pregnanc y which is carried to term
is uncommon in women with a plasma creatinine c onc entration of 3 mg/dL (265 mic romol/L) or
higher [68]. (See "Pregnancy in women with underlying renal disease".)
Treatment of complications of ESRD Onc e the patient has reached the stage of near endstage renal disease (GFR less than 15 mL/min), signs and symptoms related to uremia begin to
occ ur, such as malnutrition, anorexia, nausea, vomiting, fatigue, sexual dysfunction, platelet
dysfunction, pericarditis, and neuropathy.
Malnutrition Malnutrition is common in patients with advanced chronic renal disease
bec ause of a lower food intake (princ ipally due to anorexia), dec reased intestinal absorption and
digestion, and metabolic acidosis [69-71]. Among participants 60 years of age in the United
States Third National Health and Nutrition Examination Survey (NHANES), a GFR <30 mL/min was
independently associated with malnutrition (odds ratio of 3.6) [70]. Many additional studies have
shown a strong c orrelation between malnutrition and death in maintenance dialysis patients.
(See "Indications for initiation of dialysis in c hronic kidney disease".)
It is therefore desirable to monitor the nutritional status of patients with chronic kidney disease.
A low plasma concentration of albumin and/or c reatinine (whic h varies with musc le mass as well
as GFR) may be indic ative of malnutrition.
To best assess nutritional status, the serum albumin c oncentration and body weight should be
measured serially; these should be measured approximately every one to three months for those
with estimated GFRs <20 mL/min, and more frequently if necessary for those with GFRs 15
mL/min [50]. (See "Assessment of nutritional status in end-stage renal disease".)
The desire to maintain adequate nutrition among patients with chronic renal failure clearly
competes with attempts to slow the progression of renal dysfunction with the use of a low
protein diet. Although the benefits of slowing progressive c hronic kidney disease with marked
dietary protein restriction remain controversial, it is probably reasonable to restric t intake to 0.8
to 1.0 g/kg of high biologic value protein since this level of restriction avoids protein malnutrition
and may slow progressive disease. In addition, since symptoms and signs of uremic toxicity are
enhanced with high intakes of protein, it is reasonable to presc ribe this diet to all patients with a
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GFR below 20 mL/min per 1.73 m2 [72].

Overall, the diet of most patients with chronic kidney disease should provide approximately 30 to
35 kcal/kg per day [72]. One recommended diet, including suggestions for protein, fat, mineral,
water, and vitamin intake, is presented in the following tables (table 1 and table 2). The K/DOQI
clinical practic e guidelines for nutrition in CRF, as well as other K/DOQI guidelines, c an be
acc essed through the National Kidney Foundation's web site at
Uremic bleeding An inc reased tendenc y to bleeding is present in both ac ute and chronic
kidney disease. This appears to c orrelate most closely with prolongation of the bleeding time,
due primarily to impaired platelet function. (See "Platelet dysfunction in uremia".)
No spec ific therapy is required in asymptomatic patients. However, c orrection of the platelet
dysfunction is desirable in patients who are actively bleeding or who are about to undergo a
surgical or invasive proc edure (suc h as a renal biopsy). A number of different modalities can be
used in this setting, including the correction of anemia, the administration of
desmopressin (dDAVP), cryoprec ipitate, estrogen, and the initiation of dialysis. (See "Platelet
dysfunction in uremia".)
Pericarditis Advances in management have decreased the inc idence of peric arditis in
patients with chronic kidney disease, but this problem is still associated with signific ant morbidity
and occ asional mortality. (See "Pericarditis in renal failure".)
Fever, pleuritic c hest pain, and a peric ardial friction rub are the major presentations of uremic
pericarditis. One relatively c haracteristic feature of uremic pericarditis is that the
elec trocardiogram does not usually show the typical diffuse ST and T wave elevation,
presumably because this is a metabolic peric arditis and epicardial injury is unc ommon. Thus, the
finding of these abnormalities suggests some other cause for the pericarditis. The occurrence of
pericarditis in a patient with mild to moderate chronic kidney disease is another clue that the
renal disease is probably not responsible.
The development of otherwise unexplained pericarditis in a patient with advanced renal failure is
an indication to institute dialysis (providing there is no circ ulatory c ompromise or evidence of
impending tamponade) (see below). Most patients with uremic pericarditis respond rapidly to
dialysis with resolution of c hest pain as well as a decrease in the size of the peric ardial effusion.
(See "Pericarditis in renal failure".)
Uremic neuropathy Dysfunction of the central and peripheral nervous system, including
enc ephalopathy (impaired mental status progressing if untreated to seizures and coma),
polyneuropathy, and mononeuropathy are important c omplic ations of end-stage renal disease.
They have become much less common bec ause of the current tendency to earlier initiation of
dialysis.
Sensory dysfunctions, c haracterized by the restless leg or burning feet syndromes, are frequent
presentations of uremic neuropathy. These c omplic ations are usually absolute indications for the
initiation of dialysis. The extent of recovery from uremic neuropathy is directly related to the
degree and extent of dysfunction prior to the initiation of dialysis. (See "Uremic
polyneuropathy".)
Thyroid dysfunction The kidney normally plays an important role in the metabolism,
degradation, and excretion of several thyroid hormones. It is not surprising therefore that
impairment in kidney function leads to disturbed thyroid physiology. However, the overlap in
symptomatology between the uremic syndrome and hypothyroidism requires a c autious
interpretation of the tests of thyroid function.
It is usually possible in the individual patient with chronic kidney disease to assess thyroid status
acc urately by physical diagnosis and thyroid func tion testing. The disturbances that can occur
include low serum free and total T3 c onc entrations and normal reverse T3 and free T4
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concentrations. The serum thyrotropin (TSH) c onc entration is normal and most patients are
euthyroid. (See "Thyroid function in chronic kidney disease".)
PREPARATION FOR AND INITIATION OF RENAL REPLACEMENT THERAPY It is important to
identify patients who may eventually require renal replacement therapy since adequate
preparation can dec rease morbidity and perhaps mortality. Early identific ation enables dialysis to
be initiated at the optimal time with a functioning chronic acc ess and may also permit the
rec ruitment and evaluation of family members for the plac ement of a renal allograft prior to the
need for dialysis. In addition, the ability of the individual to psychologically ac cept the
requirement of life-long renal replacement therapy is often diminished if inadequate time has
elapsed between the time of rec ognition of end-stage renal disease and the initiation of dialysis.
Chronic kidney disease progresses at a variable rate due to differences in the clinic al course of
the underlying diseases (partic ularly between individuals) and the rec ognition that the natural
history of progressive renal disease can be altered by various therapeutic interventions,
particularly strict blood pressure control with an ACE inhibitor or ARB. (See 'Slowing the rate of
progression' above.) As a result, exac tly if and when a patient may require dialysis or renal
transplantation is unclear. In addition, some patients refuse renal replac ement therapy until the
onset of absolute indic ations, while others desire early initiation to avoid the complications of
severe chronic kidney disease, suc h as malnutrition.
Referral to nephrologists Patients with CKD should be referred to a nephrologist early in the
course of their disease, preferably before the plasma c reatinine conc entration exceeds 1.2 (106
micromol/L) and 1.5 mg/dL (133 micromol/L) in women and men, respectively, or the eGFR is less
than 60 mL/min per 1.73 m2. These subspecialists are trained to help c ounsel the patient in
choosing the optimal renal replac ement therapy and to manage the many issues associated with
chronic kidney disease [73]. Lower costs and/or dec reased morbidity and mortality may be
associated with early referral and care by subspecialists [74-84]. Reasons for later referral may
include disease spec ific factors, patient and physic ian dependent causes, and health care
system related fac tors [85]. (See "Late referral to nephrologists of patients with chronic kidney
disease".)
There are guidelines that advocate early sc reening for patients at risk of c hronic kidney disease.
The NKF-K/DOQI guidelines for CKD recommend that all individuals should be assessed, as part of
routine health examinations, to determine whether they are at increased risk for developing CKD.
The detec tion of patients with early disease may also facilitate proper care and early referral to
nephrologists. (See "Epidemiology of chronic kidney disease and sc reening rec ommendations".)
The K/DOQI clinical practice guidelines for CKD, as well as other K/DOQI guidelines, can be
acc essed through the National Kidney Foundation's web site at
An equally important component of early identification is institution of renoprotective therapy
(eg, ACE inhibitor, angiotensin II receptor blocker, and rigorous blood pressure control) as early
as possible after identifying the presenc e of progressive chronic kidney disease. Protec tive
therapy has the greatest impac t if it is initiated before the plasma creatinine c onc entration
exceeds 1.2 (106 mic romol/L) and 1.5 mg/dL (133 micromol/L) in women and men, respec tively,
or the eGFR is less than 60 mL/min per 1.73m2. At this point, most patients have already lost
more than one-half of their GFR. Waiting until the disease progresses further diminishes the
likelihood of a suc cessful response but still should be attempted. (See "Antihypertensive therapy
and progression of nondiabetic c hronic kidney disease" and 'Slowing the rate of
progression' above.)
Choice of renal replacement therapy Once it is determined that renal replac ement therapy
will eventually be required, the patient should be c ounseled to consider the advantages and
disadvantages of hemodialysis (in-center or at home), peritoneal dialysis (continuous or
intermittent modalities), and renal transplantation (living or deceased donor) [86]. The 2006
K/DOQI guidelines recommend that patients with a GFR less than 30 mL/min per 1.73 m2 should
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be educ ated concerning these issues [87].

Kidney transplantation is the treatment of choic e for end-stage renal disease. A successful
kidney transplant improves the quality of life and reduces the mortality risk for most patients,
when compared with maintenance dialysis. To fac ilitate early transplantation, a 2008 NKF/KDOQI
conference suggested early education and referral to a transplantation c enter plus the
identification of potential living donors [88].
However, not all patients are appropriate candidates for a kidney allograft because of absolute
and/or relative contraindications to this procedure or the subsequent required medications.
Referral to a transplant program should occur once renal replac ement therapy is thought to be
required within the next year [89]. (See "Patient survival after renal transplantation" and
"Evaluation of the potential renal transplant rec ipient".)
Living donor transplants, if available, have the additional advantage of being performed with
minimal delay, thereby permitting preemptive transplantation (transplantation prior to dialysis).
Such patients appear to have improved graft survival c ompared to those who undergo a period
of dialysis before transplantation [90]. (See "Dialysis issues prior to and after renal
transplantation" and "Risk fac tors for graft failure in kidney transplantation".)
For these individuals and for those who are suitable transplant recipients but must wait for an
available kidney, the choice between hemodialysis or peritoneal dialysis is influenc ed by a number
of considerations such as availability, convenienc e, comorbid conditions, home situation, age,
gender, and the ability to tolerate volume shifts. (See "Dialysis modality and patient
outc ome" and "Choosing a modality for c hronic peritoneal dialysis" and "Dialysis in diabetic
nephropathy".)
In the United States, the universal availability of renal replac ement therapy forces the
nephrologist to c onsider its application in every patient in whom it might be indicated. However,
the patient, particularly the elderly and terminally ill, may refuse dialysis, a choice whic h is
assuming more prominence as patients and physicians grapple with the increasing use of
advance directives, and the laudable goals of death with dignity and life with quality.
Nevertheless, not all nephrologists are willing to rec ommend no treatment, espec ially when
dialysis facilities are available with no need to ration therapy. These issues c an be a source of
conflict among physicians, patients, and their families. (See "Withdrawal from and withholding of
dialysis".)
Preparation for hemodialysis Hemodialysis requires a stable access to the bloodstream to
permit dialysis to be performed. (See "Overview of the hemodialysis apparatus".) The acc ess
should generally be placed in the nondominant upper extremity, because of the inc reased risk of
infection and more severe consequences of arterial steal syndrome with lower extremity grafts.
Venipuncture should therefore be restricted to the arm not c hosen for eventual ac cess
plac ement so that the veins in the other arm will be preserved.
There are three major types of vascular access for maintenanc e hemodialysis: primary
arteriovenous (AV) fistulas; synthetic arteriovenous fistulas (AV grafts); and double-lumen,
cuffed tunneled catheters. To facilitate placement of a permanent vascular ac cess, the 2008
Society for Vascular Surgery guidelines recommend that patients be referred to an access
surgeon when the patient has late stage 4 CKD, defined by an estimated GFR of less than 20 to
25 mL/min per 1.73 m2 [91]. (See "Chronic hemodialysis vascular ac cess: Types and
plac ement".)
Primary AV fistulas Primary AV fistulas are the preferred form of vascular access given
their signific antly higher long-term patenc y rates and lower rate of complications. Since a
primary AV fistula requires months to mature and is the acc ess of c hoic e, patients should be
referred for surgery to attempt access construction when it is estimated that the patient is
within one year of the anticipated need for dialysis as manifested by a GFR less than 25 mL/min,
a plasma c reatinine concentration greater than 4 mg/mL (354 micromol/L), or a rapid rate of
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progression. The 2006 K/DOQI guidelines recommend that a fistula be placed at least six months
prior to the anticipated start of hemodialysis [87].
Primary AV fistulas are typically c onstruc ted with an end-to-side vein-to-artery anastomosis of
the cephalic vein and the radial artery. These fistulas have good long-term patenc y and
infrequently develop infectious c omplic ations. A well constructed radial cephalic fistula that
functions for the first six months can be expected to function for up to 20 years.
The evaluation of non-maturing AV fistulas may require an assessment with procedures that
involve the administration of iodinated radiocontrast agents, thereby possibly resulting in
radiocontrast-induc ed nephropathy and required early dialysis. In one study of 65 endovascular
procedures among 34 patients with stage 4 CKD and nonmaturing AV fistulas, contrast-induc ed
nephropathy (25 percent increase in serum c reatinine conc entration) occ urred in only 5 percent
of patients at one week post-procedure and no one required acute dialysis [92]. The mean
contrast volume was small (mean of 7.8 mL per procedure).
The administration of gadolinium during magnetic resonance imaging has been linked to an often
severe disease called nephrogenic systemic fibrosis among patients with moderate to severe
renal disease, particularly those requiring dialysis. As a result, it is recommended that
gadolinium-based imaging be avoided, if possible, in patients with an eGFR less than 30 mL/min.
There is no consensus among experts c onc erning the decision to administer gadolinium among
patients with an eGFR between 30 and 60 mL/min. (See "Nephrogenic systemic
fibrosis/nephrogenic fibrosing dermopathy in advanced renal failure".)
Synthetic AV access (bridge grafts) AV fistulas c onstructed with synthetic material,
most commonly polytetrafluoroethylene (PTFE), provide excellent vascular ac cess in patients
who fail endogenous AV fistula placement. PTFE has good surgical handling c haracteristic s, and
grafts of this material usually mature in two weeks. Synthetic grafts have a higher long-term
complication rate (eg, infec tion, thrombosis) than primary fistulas. The 2006 K/DOQI guidelines
rec ommend that a synthetic graft be plac ed at least three to six weeks prior to the anticipated
start of hemodialysis [87].
Cuffed tunneled catheters These central venous catheters, which c an be used
immediately after placement, are primarily used as intermediate-duration vasc ular ac cess to
allow maturation of endogenous fistulas. They c an also provide acceptable long-term access in
patients who have exhausted all available sites. Nevertheless, these central venous catheters
are inferior to AV acc ess as long-term access, since they provide lower flows and have higher
rates of infec tion and other complications. (See "Acute hemodialysis vascular ac cess".)
Preparation for peritoneal dialysis Peritoneal dialysis c atheters, which are placed into the
abdominal cavity, can be used immediately after placement. However, to minimize the risk of
fluid leak, it is preferable to wait at least 10 to 14 days before beginning dialysis. If dialysis is
required less than 10 days following catheter plac ement, small volume exchanges performed in
the recumbent position c an be performed with little risk of leak. (See "Placement and
maintenance of the peritoneal dialysis catheter".)
Preparation for renal transplantation Preparation for renal transplantation, which principally
involves evaluation of the potential renal transplant recipient and/or the living donor, is
discussed in detail separately. Referral of patients with CKD to a transplant center should occ ur
when the GFR dec reases to less than 30 mL/min or, among diabetics, when the GFR is between
30 to 40 mL/min [93]. (See "Evaluation of the potential renal transplant recipient" and "Living
unrelated donors in renal transplantation".)
Indications for renal replacement therapy There are a number of clinical indications to
initiate dialysis in patients with chronic kidney disease (CKD). These inc lude [87,94,95]:
Pericarditis or pleuritis (urgent indic ation)
Progressive uremic enc ephalopathy or neuropathy, with signs such as confusion, asterixis,
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myoclonus, wrist or foot drop, or, in severe, c ases, seizures (urgent indication)
A c linically significant bleeding diathesis attributable to uremia (urgent indic ation)
Fluid overload refractory to diuretic s
Hypertension poorly responsive to antihypertensive medic ations
Persistent metabolic disturbanc es that are refractory to medic al therapy. These include
hyperkalemia, metabolic ac idosis, hyperc alcemia, hypocalcemia, and hyperphosphatemia.
Persistent nausea and vomiting
Evidence of malnutrition
Relative indications for the initiation of dialysis include decreased attentiveness and cognitive
tasking, depression, persistent pruritus or the restless leg syndrome.
We suggest that, among patients with progressive CKD, clinicians must be vigilant for the
presence of symptoms and/or signs of uremia and patients should also be fully informed of any
symptoms of uremia to be able to contact their physicians appropriately. Dialysis should be
considered based upon clinical factors plus the estimated GFR. Dialysis should be initiated in the
patient with symptoms and/or signs due to uremia.
Among asymptomatic patients with progressive CKD, the timing of initiation of dialysis is unclear
and there is no spec ific threshold GFR level that has been established for the initiation of
dialysis. To help avoid the onset of possible life-threatening complications of uremia, the
initiation of dialysis should be c onsidered in the asymptomatic patient with an extremely low GFR,
such as an estimated GFR of approximately 8 to 10 mL/min per 1.73 m2. However, some
clinicians may choose to closely monitor (weekly) asymptomatic patients with progressive CKD
even when the GFR is less than 8 to 10 mL/min per 1.73 m2, with the initiation of dialysis upon
the onset of uremic signs/symptoms. Nevertheless, as noted in the IDEAL trial, the vast majority
of patients are initiated on dialysis because of the onset of uremic symptoms at a GFR of
approximately 10 mL/min per 1.73 m2 or above [96]. All approac hes require close followup, early
nephrology referral, and adequate advanc e dialysis planning (including the presence of a
functioning peritoneal or vascular ac cess and referral for transplantation). A detailed disc ussion
of the IDEAL trial and indic ations for dialysis in the patient with CKD c an be found elsewhere.
(See "Indications for initiation of dialysis in c hronic kidney disease".)
The following are some of the more rec ent National and International Guidelines for the initiation
of dialysis, which were published before the results of the IDEAL trial were reported:
The 2006 National Kidney Foundation Dialysis Outcomes Quality Initiative (K/DOQI) for
peritoneal dialysis and hemodialysis adequac y published guidelines conc erning the initiation
of dialysis among patients with renal insuffic ienc y [87,95]. The work group suggested that
the benefits and risks of initiating renal replacement therapy should be considered in
patients with GFR less than 15 mL/min per 1.73 m2 (stage 5 c hronic kidney disease).
Initiation of dialysis prior to stage 5 chronic kidney disease may also be required in patients
with certain characteristics and/or complications, such as declining health due to the loss
of kidney function.
The 2005 European Best Prac tice Guidelines for peritoneal dialysis suggest that dialysis be
initiated before the GFR is less than 6 mL/min per 1.73 m2, with c onsideration of initiation
when the GFR is approximately 8 to 10 mL/min per 1.73 m2 [97].
INFORMATION FOR PATIENTS Educ ational materials on this topic are available for patients.
(See "Patient information: Low potassium diet".) We enc ourage you to print or e-mail this topic,
or to refer patients to our public web site www.uptodate.com/patients, whic h includes this and
other topics.
SUMMARY AND RECOMMENDATIONS There are a significant number of general issues
related to the management of patients with chronic kidney disease. These are discussed in the
following sections of this topic review:
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Natural history of c hronic kidney disease. (See 'Natural history of renal disease' above.)
The definition and classific ation of chronic kidney disease. (See 'Definitions and
classific ation' above.)
Association of chronic kidney disease with cardiovasc ular disease, end-stage renal
disease, infection, malignancy and mortality. (See 'Association with cardiovascular disease,
end-stage renal disease, and mortality' above and 'Assoc iation with non-cardiovascular
disease' above.)
Management of chronic kidney disease, which includes treatment of reversible causes of
renal dysfunction, preventing or slowing the progression of renal disease, treatment of the
complic ations of renal dysfunction, and the identific ation and adequate preparation of the
patient in whom renal replacement therapy will be required. (See 'General management of
chronic kidney disease' above and 'Preparation for and initiation of renal replac ement
therapy' above.)
Use of UpToDate is subjec t to the Subscription and License Agreement.

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20(Suppl 9):3.
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GRAPHICS
ACE inhibitor slows progression of diabetic
nephropathy
The effect of the administration of placebo or captopril to

patients with type 1 diabetes with overt proteinuria and a
plasma creatinine concentration equal to or greater than 1.5
mg/dL (132 mol/L). The likelihood of a doubling of the plasma
creatinine concentration (Pcr) was reduced by more than 50
percent in the captopril group. Data from Lewis, EJ, Hunsicker, LG,
Bain, RP, Rohde, RD, N Engl J Med 1993; 329:1456.
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Recommended dietary intake for chronic kidney and end-stage renal

disease patients*
Maintenance
hemodialysis
Chronic kidney disease

Protein
0.8 to 1.0 g/kg/day of high biological

value protein
>1.2 to 1.3 g/kg/day
Energy
35 kcal/kg/day; if the body weight is greater than 120 percent of

normal or the patient is greater than 60 years of age a lower
amount may be prescribed
Fat, percent of total

energy intake
30 to 40
30 to 40
Polyunsaturated-tosaturated ratio (fatty

acid ratio)
1.0:1.0
1.0:1.0
Carbohydrate
Balance of nonprotein calories
Total fiber, g/day
20 to 25
20 to 25
Minerals, range of intake

Sodium, mg/day
<2000
<2000
Potassium, meq/day
40 to 70
40 to 70
Phosphorus, mg/day
600 to 800
600 to 800
C alcium, mg/day
1400 to 1600
1400 to 1600
Magnesium, mg/day
200 to 300
200 to 300
Iron, mg/day
10 to 18
10 to 18
Zinc, mg/day
15
15
Up to 3000 as tolerated
Usually 750 to 1500
Water, mL/day
* The nutritional intake is adjusted based upon individual needs. This is particularly important
for the carbohydrate, lipid, and mineral contents of the diet.
GFR <70 mL/min/1.73 m2 with evidence for progression.
Some recommend 0.56 to 0.75 g/kg/day, with 0.35 g/kg/day of high biological value protein.
The protein intake is increased by 1.0 g/day of high biological value protein for each gram per
day of urinary protein loss. This is performed under close supervision and dietary counseling.
Phosphate binders often are also needed to maintain normal serum phosphorus levels.
10 mg/day for males and nonmenstruating females, 18 mg/day for menstruating females.
Data from:
1. Ahmed, K, Kopple, J. Nutritional management of renal disease. In: Primer on Kidney Diseases,
Greenberg, A (Ed). Academic Press, San Diego, CA, 1994, p. 289.
2. Ikizler, IA. Nutrition and kidney disease. In: Primer on Kidney Diseases, Greenberg, A (Ed).
Elsevier, Philadelphia, 2005, p. 496.
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Recommended vitamin intake for patients with chronic kidney and endstage renal disease
Chronic kidney
disease*
Vitamins
Maintenance
hemodialysis
Diets to be supplemented with the following quantities
Thiamin, mg/day
1.5
1.1-1.2
Riboflavin, mg/day
1.8
1.1-1.3
Pantothenic acid,
mg/day
Niacin, mg/day
20
14-16
Pyridoxine, mg/day
10
Vitamin B12, g/day
2.4
Vitamin C, mg/day
60
75-90
Folic acid mg, day
Vitamin A
No addition
No addition
Vitamin D
Vitamin E, IU/day
15
400-800
Vitamin K
None
None
The nutritional intake is adjusted based upon individual patient needs. * GFR <70
mL/min/1.73m2 w ith evidence for progression.
Vitamin D, given as calcitriol, is adjusted according to phosphate and calcium balance. Data
from:
1. Ahmed, K, Kopple, J. Nutritional management of renal disease. In: Primer on Kidney Diseases,
Greenberg, A (Ed). Academic Press, San Diego, CA, 1994, p. 289.
2. Tattersall, J, Martin-Malo, A, Pedrini, L, et al. European Best Practice Guidelines on
Haenodialysis. Nephrol Dial Transplant 2007; 22(Suppl 2):62.
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Overview of the management of chro

Offic ial reprint from UpToDate

Overview of the management of chronic kidney disease in

Last literature review version 18.3: Setembro 2010 |

This topic last updated: Outubro 8,

Overview of the management of chro

Overview of the management of chro

Overview of the management of chro

Overview of the management of chro

Overview of the management of chro

Overview of the management of chro

bone disease. Attention needs to be paid to all of these issues.

Overview of the management of chro

Overview of the management of chro

Overview of the management of chro

Overview of the management of chro

Overview of the management of chro

Overview of the management of chro

associated with an adverse c ardiovascular prognosis, c hronic kidney disease is considered a

Overview of the management of chro

GFR below 20 mL/min per 1.73 m2 [72].

Overview of the management of chro

Overview of the management of chro

be educ ated concerning these issues [87].

Overview of the management of chro

Overview of the management of chro

Overview of the management of chro

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Overview of the management of chro

Overview of the management of chro

Overview of the management of chro

Overview of the management of chro

Overview of the management of chro

The effect of the administration of placebo or captopril to

Overview of the management of chro

Recommended dietary intake for chronic kidney and end-stage renal

Chronic kidney disease

0.8 to 1.0 g/kg/day of high biological

>1.2 to 1.3 g/kg/day

35 kcal/kg/day; if the body weight is greater than 120 percent of

Fat, percent of total

Polyunsaturated-tosaturated ratio (fatty

Balance of nonprotein calories

Total fiber, g/day

Minerals, range of intake

Usually 750 to 1500

Overview of the management of chro

Diets to be supplemented with the following quantities

Vitamin B12, g/day

Folic acid mg, day

Overview of the management of chro

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