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Overview of the management of chronic kidney disease

in adults
Author: Mark Rosenberg, MD
Section Editor: Gary C Curhan, MD, ScD
Deputy Editor: Shveta Motwani, MD, MMSc, FASN

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2021. | This topic last updated: Nov 12, 2020.

INTRODUCTION

All patients with kidney disease (whether acute or chronic) should undergo an assessment of
kidney function by estimating the glomerular filtration rate (GFR) from the serum creatinine.
This measurement is used clinically to evaluate the degree of kidney impairment, to follow the
course of the disease, and to assess the response to therapy. An attempt must also be made to
obtain a specific diagnosis. The first step in this process is a careful urinalysis, looking for
proteinuria, hematuria, and cellular casts. Further evaluation may include quantification of
proteinuria, kidney ultrasound, referral to a nephrologist, and a kidney biopsy. Nephrology
referral is especially indicated when there is a rapid decline in kidney function, an elevated
albumin-to-creatinine ratio (>300 mg/g), or urinary red blood cell casts. (See "Assessment of
kidney function" and "Diagnostic approach to adult patients with subacute kidney injury in an
outpatient setting" and "Urinalysis in the diagnosis of kidney disease".)

An overview of the general issues involved in the management of the patient with chronic
kidney disease (CKD), including modalities to slow the rate of progression, will be presented
here. The specific therapy of patients with particular kidney diseases is discussed separately in
the appropriate topic reviews.

NATURAL HISTORY OF KIDNEY DISEASE

The initial injury to the kidney may result in a variety of clinical manifestations, ranging from
asymptomatic hematuria to kidney failure requiring dialysis. Many individuals fully recover and
subsequently suffer from little or no sequelae. Poststreptococcal glomerulonephritis in
children, for example, most frequently has a long-term benign prognosis. By comparison, some
patients, such as those with lupus nephritis, experience repeated and chronic insults to the
kidney, thereby resulting in lasting damage. Furthermore, others in whom the initial disease is
either inactive or cured may still develop progressive kidney disease due to hemodynamic and
other mechanisms.

In addition to variations in the activity 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 kidney insufficiency often has a normal or near-
normal serum creatinine concentration. Additional homeostatic mechanisms (most frequently
occurring within the renal tubules) permit the serum concentrations of sodium, potassium,
calcium, and phosphorous and the total body water to also remain within the normal range,
particularly among those with mild to moderate kidney failure. (See "Assessment of kidney
function".)

Adaptive hyperfiltration, although initially beneficial, appears to result in long-term damage to

the glomeruli of the remaining nephrons, which is manifest by proteinuria and progressive
kidney failure. This process appears to be responsible for the development of kidney failure
among those in whom the original illness is either inactive or cured [1]. Estimates of single
nephron glomerular filtration rate (SNGFR) in humans support hyperfiltration as a relevant
pathophysiologic mechanism [2]. An elevated SNGFR was associated with risk factors for
progression, including obesity, a family history of end-stage kidney disease (ESKD), and a
greater degree of glomerulosclerosis and arteriosclerosis, suggesting compensation in
remaining nephrons to maintain total GFR. The institution of measures to help prevent this
process, such as antihypertensive therapy with an angiotensin-converting enzyme (ACE)
inhibitor or an angiotensin II receptor blocker (ARB), and sodium-glucose cotransporter-2
(SGLT2) inhibitors, may slow progressive disease and even preserve kidney function [3]. 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".)

The gradual decline in function in patients with CKD is initially asymptomatic. However, different
signs and symptoms may be observed with advanced kidney failure, including volume overload,
hyperkalemia, metabolic acidosis, hypertension, anemia, and mineral and bone disorders
(MBDs). The onset of ESKD 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 concentration 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 kidney replacement therapy with hemodialysis, peritoneal dialysis, or kidney
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 [4-6]. The rate of progression of CKD
from one major stage to another varies based upon the underlying disease, presence or
absence of comorbid conditions, treatments, socioeconomic status, individual genetics,
ethnicity, and other factors. Episodes of acute kidney injury (AKI) may cause more rapid
progression to ESKD in individual patients. (See "Kidney and patient outcomes after acute
kidney injury in adults".)

Using epidemiologic data, general estimates for the rate of transition from an estimated GFR
(eGFR) between 15 to 60 mL/min/1.73 m2 to end-stage disease may be approximately 1.5
percent per year, while the rate of transition from an eGFR >60 to <60 mL/min/1.73 m2 is
approximately 0.5 percent per year [7,8].

The combination of both a low eGFR plus dipstick-positive proteinuria versus either parameter
alone is associated with a significantly increased risk of progressive kidney disease. This was
shown in a retrospective study of the association between these measures and the 25-year
incidence of ESKD of middle-aged men originally studied in the Multiple Risk Factor
Intervention Study (MRFIT) [9]. The presence of 1+ dipstick proteinuria, 2+ dipstick proteinuria,
eGFR <60 mL/min/1.73 m2, and a low eGFR plus 2+ proteinuria was associated with hazard
ratios of 3.1, 15.7, 2.4, and 41, respectively, for the development of ESKD over a 25-year period.

DEFINITION AND CLASSIFICATION

CKD is defined as the presence of kidney damage (usually detected as urinary albumin
excretion of ≥30 mg/day or equivalent) or decreased kidney function (defined as estimated
glomerular filtration rate [eGFR] <60 mL/min/1.73 m2) for three or more months, irrespective
of the cause. The persistence of the damage or decreased function for at least three months is
necessary to distinguish CKD from acute kidney disease (AKI).

Classification, or staging, of CKD provides a guide to management, including stratification of

risk for progression and complications of CKD. Risk stratification is used to inform appropriate
treatments and the intensity of monitoring and patient education. We agree with the 2012
Kidney Disease: Improving Global Outcomes (KDIGO) guidelines that state that, among patients
who are diagnosed using the criteria described above, staging of CKD should be done
according to the following ( table 1) [10]:

● Cause of disease
● Six categories of eGFR (G stages)
● Three categories of albuminuria (A stages)

Staging patients with CKD according to cause, eGFR, and albuminuria enhances risk
stratification for the major complications of CKD ( figure 1 and figure 2). As seen in these
figures, increasing albuminuria is associated with a higher risk of adverse events at every level
of eGFR.

A more detailed discussion of the definition and classification of CKD is provided separately.
(See "Definition and staging of chronic kidney disease in adults".)

ASSOCIATION WITH CARDIOVASCULAR DISEASE, END-STAGE KIDNEY

DISEASE, AND MORTALITY

There is a large body of evidence that patients with CKD have a substantial increase in
cardiovascular risk that can be in part explained by an increase in traditional risk factors such as
hypertension, diabetes, and the metabolic syndrome. CKD alone is also an independent risk
factor for cardiovascular disease. Among patients with CKD, the risk of death, particularly due
to cardiovascular disease, is much higher than the risk of eventually requiring dialysis. This is
discussed separately. (See "Chronic kidney disease and coronary heart disease".)

Close attention to the prevention and management of cardiovascular disease should occur
among patients identified with CKD [11]. As an example, the increased intake of calcium (which
is commonly given to treat hyperphosphatemia and may result in a high calcium-phosphorus
product) may enhance coronary arterial calcification. Although controversial, this is thought by
some to be associated with the development of coronary atherosclerosis and is related to the
presence and/or consequences of elevated serum phosphorus, calcium, and parathyroid
hormone (PTH) levels. (See 'Mineral and bone disorders (MBD)' below and "Vascular calcification
in chronic kidney disease".)

These and other observations have suggested that CKD should be considered a coronary
equivalent and that aggressive risk factor reduction should be part of standard therapy of
patients with CKD. (See "Chronic kidney disease and coronary heart disease", section on 'CKD as
a CHD risk equivalent' and "Chronic kidney disease and coronary heart disease", section on
'Reduction of CHD risk in patients with CKD'.)

Patients with CKD are also at increased risk for the development of end-stage kidney disease
(ESKD) as well as all-cause mortality. The competing risks of cardiovascular and ESKD vary
depending on the population of patients studied and factors such as age, proteinuria, and type
of kidney disease. (See "Chronic kidney disease and coronary heart disease", section on
'Competing risks of cardiovascular and end-stage kidney disease'.)

GENERAL MANAGEMENT OF CHRONIC KIDNEY DISEASE

The general management of the patient with CKD involves the following issues [12]:

● Treatment of reversible causes of kidney failure

● Preventing or slowing the progression of kidney disease
● Treatment of the complications of kidney failure
● Adjusting drug doses when appropriate for the level of estimated glomerular filtration rate
(eGFR)
● Identification and adequate preparation of the patient in whom kidney replacement
therapy will be required

Reversible causes of kidney failure — In addition to exacerbation of their original kidney

disease, patients with CKD with a recent decrease in kidney function may be suffering from an
underlying reversible process, which, if identified and corrected, may result in the recovery of
function.

Decreased renal perfusion — Hypovolemia (such as vomiting, diarrhea, diuretic use,

bleeding), hypotension (due to myocardial dysfunction or pericardial disease), infection (such as
sepsis), and the administration of drugs which lower the eGFR (such as nonsteroidal
antiinflammatory drugs [NSAIDs] and angiotensin-converting enzyme [ACE] inhibitors or
angiotensin receptor blockers [ARBs]) are common causes of potentially reversible declines in
kidney function.
In patient with CKD, hypovolemia should be diagnosed by history and physical examination
rather than the urine sodium or fractional excretion of sodium. The normal response to renal
hypoperfusion is to lower the urine sodium concentration (<25 mEq/L) and the fractional
excretion of sodium (<1 percent in patients with advanced kidney failure) to very low levels.
However, the superimposition of a prerenal process among patients with CKD may not result in
the expected low values, since the tubules in the diseased kidney are unable to reabsorb
sodium so efficiently. If hypovolemia is suspected, a judicious trial of fluid repletion may result
in the return of kidney function to the previous baseline. (See "Fractional excretion of sodium,
urea, and other molecules in acute kidney injury".)

Administration of nephrotoxic drugs — The administration of drugs or diagnostic agents

that adversely affect kidney function is a frequent cause of worsening kidney function. Among
patients with CKD, common offenders include aminoglycoside antibiotics (particularly with
unadjusted doses), NSAIDs, and radiographic contrast material. The administration of such
drugs should therefore be avoided or used with caution in patients with underlying CKD. (See
"Manifestations of and risk factors for aminoglycoside nephrotoxicity" and "NSAIDs: Acute
kidney injury (acute renal failure)" and "Contrast-associated and contrast-induced acute kidney
injury: Clinical features, diagnosis, and management".)

Certain drugs also interfere with either creatinine secretion or the assay used to measure the
serum creatinine. These include cimetidine, trimethoprim, cefoxitin, and flucytosine. In these
settings, there will be no change in the true GFR; the clinical clue that this may have occurred 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 obstruction should always be considered in the

patient with unexplained worsening kidney function, although, in the absence of prostatic
disease, it is much less common than decreased renal perfusion. Patients with slowly
developing obstruction typically have no changes in the urinalysis, no symptoms referable to
the kidney, and initially maintain their urine output. Given this lack of clinical clues, renal
ultrasonography is often performed to exclude urinary tract obstruction in patients with an
unexplained elevation in the serum creatinine. (See "Clinical manifestations and diagnosis of
urinary tract obstruction and hydronephrosis".)

Blood pressure control — Overall, the best evidence supports the following points (see
"Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults",
section on 'Effect of goal blood pressure on progression of CKD'):
 ● More intensive versus less intensive blood pressure lowering reduces the risk of end-stage
kidney disease (ESKD) in patients with proteinuric chronic kidney disease (CKD), but not in
patients with nonproteinuric CKD.

● However, more intensive blood pressure lowering may reduce mortality in patients with
CKD (whether they have proteinuria or not), even though there is no benefit on kidney
endpoints among patients without proteinuria. The mortality benefit from aggressive blood
pressure lowering is most evident when patients are followed over the long term (ie, during
post-trial follow-up), although an early reduction in mortality was noted in the Systolic
Pressure Intervention Trial (SPRINT).

Hypertension is present in approximately 80 to 85 percent of patients with CKD [13]. Treating

hypertension can both slow the progression of proteinuric CKD and reduce the rate of
cardiovascular complications. (See "Chronic kidney disease and coronary heart disease", section
on 'Blood pressure control' and "Overview of hypertension in acute and chronic kidney
disease".)

The choice of antihypertensive therapy in patients with nondiabetic and diabetic CKD is
discussed separately. (See "Antihypertensive therapy and progression of nondiabetic chronic
kidney disease in adults" and "Treatment of hypertension in patients with diabetes mellitus".)

Patients with CKD are frequently hypervolemic and will require diuretic therapy to attain goal
blood pressure. The choice of diuretic is presented elsewhere. In patients with advanced CKD
and refractory edema, both loop diuretics and thiazide diuretics may be needed. (See "Thiazides
versus loop diuretics in the treatment of hypertension", section on 'Patients with chronic kidney
disease' and "Overview of hypertension in acute and chronic kidney disease" and "Causes and
treatment of refractory edema in adults".)

The optimal blood pressure in hypertensive patients with CKD and its impact on the
progression of CKD is presented at length elsewhere ( table 2). (See "Goal blood pressure in
adults with hypertension", section on 'Patients with chronic kidney disease'.)

Slowing the rate of progression — Studies in experimental animals and humans suggest that
progression in CKD 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 (which are primarily responsible for the adaptive hyperfiltration
described above), leading to glomerular scarring (glomerulosclerosis). Additional causes may
include systemic hypertension, 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 [14]. Thus, proteinuria typically is present in patients with
progressive CKD, even in primary tubulointerstitial diseases such as reflux nephropathy.

Treating the underlying cause — Treatment of the underlying cause of CKD may halt or
reduce the rate of its progression. The diagnostic evaluation of a patient with CKD to identify
the cause is presented in detail separately. (See "Chronic kidney disease (newly identified):
Clinical presentation and diagnostic approach in adults".)

Details of treatment of the underlying cause of CKD (by cause) are detailed elsewhere. As
examples:

● Autosomal dominant polycystic kidney disease (See "Autosomal dominant polycystic kidney
disease (ADPKD): Treatment".)

● Diabetic kidney disease (See "Treatment of diabetic kidney disease".)

● Obesity (See "Overweight and obesity in adults: Health consequences", section on 'Chronic
kidney disease' and "Obesity in adults: Overview of management".)

● Glomerular disease (See "Treatment and prognosis of IgA nephropathy" and

"Membranoproliferative glomerulonephritis: Treatment and prognosis" and "Anti-GBM
(Goodpasture) disease: Treatment and prognosis" and "Membranous nephropathy:
Treatment and prognosis" and "Focal segmental glomerulosclerosis: Treatment of primary
focal segmental glomerulosclerosis", section on 'Treatment'.)

● Viral infections (See "Kidney disease associated with hepatitis B virus infection", section on
'Treatment' and "Overview of renal disease associated with hepatitis C virus infection",
section on 'Treatment' and "HIV-associated nephropathy (HIVAN)", section on 'Overview of
medical therapy'.)

● Hematological disorders (See "Renal amyloidosis", section on 'Response to therapy' and

"Kidney disease in multiple myeloma and other monoclonal gammopathies: Treatment and
prognosis", section on 'Patients with chronic kidney disease'.)

● Cardiac or hepatic disorders (See "Cardiorenal syndrome: Prognosis and treatment",

section on 'Management' and "Hepatorenal syndrome", section on 'Treatment'.)

Additional therapies in proteinuric patients — Therapy to slow the rate of progression in

proteinuric patients with CKD, independent of treatment of the underlying disease, is centered
on treating with an ACE inhibitor or ARB and attaining the blood pressure goal. In addition,
such patients may benefit from treatment with sodium-glucose cotransporter 2 (SGLT2)
inhibitors.

● ACE inhibitors or ARBs – Patients with proteinuric CKD should attain specific goals related
to a reduction in urinary protein excretion to slow the rate of progression. Proteinuria goals
and the use of ACE inhibitors or ARBs in such patients are discussed elsewhere. (See
"Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults"
and "Treatment of hypertension in patients with diabetes mellitus".)

In contrast to their renoprotective effects in proteinuric CKD, angiotensin inhibitors do not

appear to be more beneficial than other antihypertensive agents in patients with
nonproteinuric CKD. Recommendations for antihypertensive treatment in patients with
nonproteinuric CKD are discussed elsewhere. (See "Overview of hypertension in acute and
chronic kidney disease", section on 'Sequence of antihypertensive therapy in
nonproteinuric CKD'.)

When used in patients with CKD, common side effects of angiotensin inhibition include a
mild to moderate reduction in GFR and hyperkalemia. The decline in GFR occurs soon after
the initiation of therapy or after an increase in dose. Hyperkalemia can occur soon after the
initiation of therapy or later, if CKD is progressive. (See "Major side effects of angiotensin-
converting enzyme inhibitors and angiotensin II receptor blockers".)

● SGLT2 inhibitors – Patients who have proteinuric CKD (with or without diabetes) may
benefit from treatment with SGLT2 inhibitors. While the majority of trials demonstrating
kidney protective benefits have been performed in proteinuric patients with diabetic kidney
disease, there are data to suggest that these benefits also extend to nondiabetic
proteinuric patients [15,16].

SGLT2 inhibitors act by blocking reabsorption of glucose in the proximal tubule through
SGLT2, which lowers the renal glucose threshold and leads to substantial glycosuria. SGLT2
inhibitors have additional effects on the kidney, and, given their weak glucose-lowering
effect, these effects are likely independent of glycemic control. By blocking the co-
transporter, they reduce sodium reabsorption. The resulting natriuresis reduces
intravascular volume and blood pressure, but it also increases the delivery of sodium to the
macula densa. Increased sodium delivery to the macula densa normalizes
tubuloglomerular feedback and thereby reduces intraglomerular pressure (ie, reduces
glomerular hyperfiltration) through constriction of the abnormally dilated afferent arteriole
[15]. This decrease in glomerular hyperfiltration can, hypothetically, slow the rate of
progression of kidney disease (see "Diabetic kidney disease: Pathogenesis and
 epidemiology", section on 'Glomerular hyperfiltration'). A range of additional mechanisms
may explain the benefits of SGLT2 inhibitors on kidney disease progression [16].

The data in support of treatment with SGLT2 inhibitors among nondiabetic patients come
from the Dapaglifozin and Prevention of Adverse Outcomes in Chronic Kidney Disease
(DAPA-CKD) trial [17]. In this trial, 4304 individuals with eGFR 25 to 75 mL/min/1.73 m2 and
urinary albumin to creatinine ratio of 200 to 5000 mg/g were randomly assigned to
dapaglifozin (10 mg daily) or placebo. Approximately one-third of the participants did not
have diabetes, of which a large majority had CKD due to either chronic glomerulonephritis
or hypertensive nephrosclerosis [18]. At a median follow-up of 2.4 years, dapaglifozin
reduced all-cause mortality (4.7 versus 6.8 percent), incidence of ESKD (5.1 versus 7.5
percent), and the risk of 50 percent or greater decline in eGFR (5.2 versus 9.3 percent). The
beneficial effect of dapaglifozin was similar in patients with and without diabetes.

Other targets for renal protection — Other therapeutic modalities also may offer some
renal protection:

● Protein restriction − Protein restriction may slow the progression of CKD, although the
optimal level and type of protein intake have not been determined. This issue is discussed
elsewhere. (See "Dietary recommendations for patients with nondialysis chronic kidney
disease".)

● Smoking cessation − Stopping smoking is associated with a slower rate of progression of

CKD [19]. In an increasing number of studies, smoking also appears to correlate with an
enhanced risk of developing kidney disease (primarily nephrosclerosis) as well as increasing
the rate of progression among those with existing CKD [20].

● Treatment of chronic metabolic acidosis with supplemental bicarbonate may slow the
progression to end-stage kidney disease (ESKD). (See "Pathogenesis, consequences, and
treatment of metabolic acidosis in chronic kidney disease", section on 'Slowing of CKD
progression'.)

● Glycemic control – Control of blood glucose can slow the development of albuminuria, the
progression of microalbuminuria to overt proteinuria, and GFR loss in diabetic patients.
Treatment with sodium-glucose cotransporter 2 (SGLT-2) inhibitors may reduce the risk of
kidney disease progression in patients with type 2 diabetes [3]. (See "Sodium-glucose co-
transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus",
section on 'Microvascular outcomes' and "Treatment of diabetic kidney disease".)
Treatment of the complications of kidney failure — A wide range of disorders may develop
as a consequence of the loss of kidney function. These include disorders of fluid and electrolyte
balance, such as volume overload, hyperkalemia, metabolic acidosis, and hyperphosphatemia,
as well as abnormalities related to hormonal or systemic dysfunction, such as anorexia, nausea,
vomiting, fatigue, hypertension, anemia, malnutrition, hyperlipidemia, and bone disease.
Attention needs to be paid to all of these issues.

One recommended diet, including suggestions for protein, fat, mineral, and water, is presented
( table 3). 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 eGFR falls below 10 to 15 mL/min/1.73 m2. However, the
patient with mild to moderate CKD, despite being in relative volume balance, is less able to
respond to rapid intake of sodium and is therefore prone to fluid overload.

Patients with CKD and volume overload generally respond to the combination of dietary sodium
restriction and diuretic therapy, usually with a loop diuretic given daily. Some investigators have
claimed that limiting sodium intake may also help decrease progression of CKD by lowering
intraglomerular pressure [21]. We agree with the 2012 Kidney Disease: Improving Global
Outcomes (KDIGO) guidelines that, among all adults with CKD, sodium intake should be
restricted to <2 g/day unless contraindicated [10]. (See "Loop diuretics: Dosing and major side
effects" and "Causes and treatment of refractory edema in adults".)

Hyperkalemia — The ability to maintain potassium excretion at near-normal levels is

generally maintained in patients with kidney disease as long as both aldosterone secretion and
distal flow are maintained [22,23]. Thus, hyperkalemia generally develops in the patient who is
oliguric or who has an additional problem such as a high-potassium diet, increased tissue
breakdown, or hypoaldosteronism (due in some cases to the administration of an ACE inhibitor
or ARB) [24]. Impaired cell uptake of potassium also may contribute to the development of
hyperkalemia in advanced CKD. (See "Causes and evaluation of hyperkalemia in adults".)

Hyperkalemia due to ACE inhibitor or ARB therapy is most likely to occur 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
adults".)

There are several measures that may help prevent hyperkalemia in patients with CKD. These
include ingestion of a low-potassium diet (eg, <40 to 70 mEq/day [1500 to 2700 mg/day]) and
avoiding, if possible, the use of drugs that raise the serum potassium concentration, such as
NSAIDs [25]. Nonselective beta blockers may result in a postprandial rise in the serum
potassium concentration but do not cause persistent hyperkalemia. (See "Causes and
evaluation of hyperkalemia in adults", section on 'Beta blockers' and "Patient education: Low-
potassium diet (Beyond the Basics)".)

Metabolic acidosis — There is an increasing tendency to retain hydrogen ions among

patients with CKD [26-28]. This can lead to a progressive metabolic acidosis, with the serum
bicarbonate concentration tending to stabilize between 12 and 20 mEq/L and rarely falling
below 10 mEq/L [27,29]. The treatment of metabolic acidosis in CKD patients is discussed
elsewhere. Metabolic acidosis may be treated with bicarbonate supplementation. Bicarbonate
supplementation requires careful monitoring of volume status because bicarbonate is
administered with sodium. (See "Pathogenesis, consequences, and treatment of metabolic
acidosis in chronic kidney disease", section on 'Treatment of metabolic acidosis in CKD'.)

Mineral and bone disorders (MBD) — Hyperphosphatemia is a common complication of

CKD. A tendency toward phosphate retention begins early in kidney 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 "Overview of chronic kidney
disease-mineral and bone disorder (CKD-MBD)".)

From the viewpoint of calcium and phosphate balance, the hypersecretion of parathyroid
hormone (PTH) is initially appropriate since PTH can correct both hyperphosphatemia and
hypocalcemia. As a result, phosphate balance and a normal serum phosphate concentration are
generally maintained in patients with an eGFR of >30 mL/min/1.73 m2 [30]. The price paid is
secondary hyperparathyroidism and the development of renal osteodystrophy. (See "Overview
of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

Dietary phosphate restriction and oral phosphate binders may limit the development of
secondary hyperparathyroidism in patients with CKD ( table 4A-B). Our approach, including
the choice of phosphate binder, is discussed elsewhere. (See "Management of
hyperphosphatemia in adults with chronic kidney disease", section on 'Nondialysis chronic
kidney disease patients'.)

The increased intake of calcium may enhance coronary arterial calcification in this setting. This
is thought by some to be associated with the development of coronary atherosclerosis and may
be related to the presence and/or consequences of elevated serum phosphorus, calcium, and
PTH levels. Detailed discussions of these issues, including specific KDIGO guidelines, can be
found separately (see "Vascular calcification in chronic kidney disease"). The KDIGO clinical
practice guidelines for MBD in CKD, as well as other KDIGO guidelines, can be accessed through
the KDIGO website.

Changes in bone structure are an almost universal finding with progressive CKD [31]. The
principal types of renal bone disease include osteitis fibrosa, osteomalacia, and adynamic bone
disease. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

Osteitis fibrosa results from secondary hyperparathyroidism. Although an exact relationship is

unclear, PTH levels appear to increase when kidney function decreases beyond a certain
threshold value, with evidence suggesting that hormone levels begin to rise when the
creatinine clearance is <40 to 70 mL/min [32,33].

To help guide preventive measures, PTH levels should therefore be assessed among such
patients as hormonal abnormalities are one of the earliest markers of abnormal mineral and
bone metabolism with progressive CKD. Prevention and/or treatment of osteitis fibrosis in
patients with predialysis CKD are primarily based upon dietary phosphate restriction, the
administration of oral phosphate binders, and the administration of calcitriol (or vitamin D
analogs) to directly suppress the secretion of PTH.

Circulating calcitriol (1,25-dihydroxyvitamin D), the most active metabolite of vitamin D, is

principally synthesized in the kidney. Circulating calcitriol levels begin to fall when the eGFR is
<40 mL/min/1.73 m2 and are typically markedly reduced in patients with ESKD. In addition to
the loss of functioning renal mass, calcitriol production is also reduced by phosphate retention.
(See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

Calcimimetics are agents that allosterically increase the sensitivity of the calcium-sensing
receptor in the parathyroid gland to calcium. The calcium-sensing receptor is the principal
factor regulating parathyroid gland PTH secretion and hyperplasia. The separate target offers
the potential to suppress PTH secretion by mechanisms complementary and potentially
synergistic with vitamin D analogs that target the vitamin D receptor. Although not approved
for patients with CKD not yet on dialysis, cinacalcet, the only currently available calcimimetic, 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 secondary hyperparathyroidism in adult nondialysis
patients with chronic kidney disease".)

Hypertension — Hypertension is present in approximately 80 to 85 percent of patients with

CKD [13]. It can be a cause or consequence of CKD. Important aspects of hypertension in CKD
patients are discussed above. (See 'Blood pressure control' above.)

Anemia — The anemia of CKD is, in most patients, normocytic and normochromic and is due
primarily to reduced production of erythropoietin by the kidney (a presumed reflection of the
reduction in functioning renal mass) and to shortened red cell survival [34]. Anemia is a
common feature in many patients with CKD who do not yet require dialysis, with anemia
becoming increasingly common as eGFRs decline below 60 mL/min/1.73 m2 [35,36], particularly
among diabetics [37]. As an example, based upon over 15,000 participants in the National
Health and Nutrition Examination Survey (NHANES), the prevalence of anemia (hemoglobin [Hb]
<12 g/dL in men and <11 g/dL in women) increased from 1 percent at an eGFR of 60
mL/min/1.73 m2 to 9 percent at an eGFR of 30 mL/min/1.73 m2 and to 33 to 67 percent at an
eGFR of 15 mL/min/1.73 m2 [35]. (See "Treatment of anemia in nondialysis chronic kidney
disease".)

The 2012 KDIGO guidelines suggest that, among patients who do not have anemia, the Hb
concentration should be checked when it is clinically indicated and at least yearly among all
patients with stage 3 CKD (ie, eGFR 30 to 59 mL/min/1.73 m2), at least every six months among
patients with stage 4 to 5 CKD (ie, eGFR ≤29 mL/min/1.73 m2), and at least every three months
among patients who are on dialysis [10,38]. Among patients who are known to have anemia
and are not treated with erythropoiesis-stimulating agents (ESAs), Hb should be checked when
it is clinically indicated and at least every three months among patients with stage 3 to 5 (ie,
eGFR ≤59 mL/min/1.73 m2) who are not on hemodialysis (including patients who are on
peritoneal dialysis); patients on hemodialysis should be monitored monthly. (See "Definition
and staging of chronic kidney disease in adults", section on 'Staging of CKD'.)

As stated in the 2012 KDIGO guidelines, the evaluation of anemia in those with CKD should
begin when the Hb level is <12 g/dL in females and <13 g/dL in adult males [10,38]. These
values are consistent with the World Health Organization (WHO) definition of anemia [39]. If
untreated, the Hb level of patients with advanced CKD normally stabilizes at approximately 8
g/dL in the absence of bleeding or hemolysis.

The anemia observed with CKD is largely diagnosed by excluding nonrenal causes of anemia in
the patient with a suitably decreased eGFR. 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, B12 and folate concentrations if the mean corpuscular volume (MCV) is increased, and
testing for blood in stool. This work-up should be performed prior to administering ESA
therapy. (See "Diagnostic approach to anemia in adults".)
Evaluating the adequacy of iron stores in patients with CKD and issues relating to iron therapy
in such patients are presented elsewhere. (See "Diagnosis of iron deficiency in chronic kidney
disease" and "Treatment of iron deficiency in hemodialysis patients" and "Treatment of iron
deficiency in nondialysis chronic kidney disease (CKD) patients".)

Although primarily used in patients with ESKD, ESAs such as erythropoietin and darbepoetin
alfa also correct the anemia in those with CKD who do not yet require dialysis. (See "Treatment
of anemia in nondialysis chronic kidney disease".)

The use of ESAs for the treatment of anemia in patients with CKD, including the 2012 KDIGO
guideline recommendations, is discussed in detail separately. (See "Treatment of anemia in
hemodialysis patients".)

Dyslipidemia — Abnormal lipid metabolism is common in patients with kidney disease [40].

The primary finding in CKD is hypertriglyceridemia, with the total cholesterol concentration
usually being normal (perhaps due in part to malnutrition in some patients). All CKD patients
should be evaluated and potentially treated for dyslipidemia. (See "Lipid management in
patients with nondialysis chronic kidney disease", section on 'Treatment' and "Secondary
prevention of cardiovascular disease in end-stage renal disease (dialysis)", section on 'Lipid
modification' and "Kidney transplantation in adults: Lipid abnormalities after kidney
transplantation", section on 'Treatment'.)

Follow-up testing may be performed among patients who are age <50 years who are not
already on a statin in order to assess cardiovascular risk and the need for statin therapy. Follow-
up evaluation may also be performed to assess adherence to statin treatment, if there is a
change in the modality of kidney replacement therapy, or if there is concern about new
secondary causes of dyslipidemia (such as nephrotic syndrome, hypothyroidism, diabetes,
excessive alcohol consumption, or liver disease).

Among patients with CKD, the degree of hypertriglyceridemia that occurs may not be sufficient
to significantly increase coronary risk, but other changes have been found that might
contribute to the accelerated atherosclerosis commonly seen in ESKD. The treatment of
hypertriglyceridemia in CKD patients, including the 2013 KDIGO recommendations, is discussed
elsewhere. (See "Lipid management in patients with nondialysis chronic kidney disease", section
on 'Hypertriglyceridemia' and "Secondary prevention of cardiovascular disease in end-stage
renal disease (dialysis)", section on 'Hypertriglyceridemia' and "Kidney transplantation in adults:
Lipid abnormalities after kidney transplantation", section on 'Treatment'.)

In the patient with hypercholesterolemia, a statin with or without ezetimibe can effectively and
safely lower the plasma cholesterol concentration to or near acceptable levels. Given evidence
that mild to moderate degrees of CKD are associated with an adverse cardiovascular prognosis,
CKD is considered a coronary heart disease equivalent [41]. (See "Chronic kidney disease and
coronary heart disease".)

The goal low-density lipoprotein cholesterol (LDL-C) is discussed elsewhere. (See "Lipid
management in patients with nondialysis chronic kidney disease", section on 'Treatment'.)

Although some studies suggested that lipid lowering with statins could reduce proteinuria and
slow progression of kidney disease, subsequent large trials found no beneficial effect on kidney
outcomes [42-46]; therefore, statin therapy is not useful solely for renal protection.

Sexual dysfunction — Significant abnormalities in sexual and reproductive function are

frequently observed in patients with advanced kidney disease. As an example, >50 percent of
uremic men complain of symptoms that include erectile dysfunction, decreased libido, and
marked declines in the frequency of intercourse [47]; in addition, disturbances in menstruation
and fertility are commonly encountered in women with CKD, usually leading to amenorrhea by
the time the patient reaches ESKD. (See "Epidemiology and etiologies of male sexual
dysfunction".)

An important clinical implication of these abnormalities is that pregnancy that is carried to term
is uncommon in women with a plasma creatinine concentration of ≥3 mg/dL (265 micromol/L)
[48]. (See "Pregnancy in women with nondialysis chronic kidney disease".)

Treatment of complications of end-stage kidney disease — Once the patient has reached the
stage of near ESKD (eGFR <15 mL/min/1.73 m2), signs and symptoms related to uremia begin to
occur, such as malnutrition, anorexia, nausea, vomiting, fatigue, sexual dysfunction, platelet
dysfunction, pericarditis, and neuropathy.

Malnutrition — Malnutrition is common in patients with advanced CKD because of a lower

food intake (principally due to anorexia), decreased intestinal absorption and digestion, and
metabolic acidosis [49-51]. Among participants age ≥60 years in the United States Third
NHANES, an eGFR <30 mL/min/1.73 m2 was independently associated with malnutrition (odds
ratio [OR] 3.6) [50]. Many additional studies have shown a strong correlation between
malnutrition and death in maintenance dialysis patients. (See "Indications for initiation of
dialysis in chronic kidney disease".)

It is therefore desirable to monitor the nutritional status of patients with CKD. A low plasma
concentration of albumin may be indicative of malnutrition. To best assess nutritional status,
the serum albumin concentration and body weight should be measured serially; these should
be measured approximately every one to three months for those with eGFRs <20 mL/min/1.73
m2 and more frequently, if necessary, for those with eGFRs ≤15 mL/min/1.73 m2 [52]. (See
"Assessment of nutritional status in hemodialysis patients".)

The desire to maintain adequate nutrition among patients with CKD clearly competes with
attempts to slow the progression of kidney failure with the use of a low-protein diet. This issue
is discussed elsewhere. (See "Dietary recommendations for patients with nondialysis chronic
kidney disease".)

Overall, the diet of most patients with CKD should provide approximately 30 to 35 kcal/kg per
day [53]. One recommended diet, including suggestions for protein, fat, mineral, and water, is
presented in the table ( table 3). The Kidney Disease Outcomes Quality Initiative (KDOQI)
clinical practice guidelines for nutrition in CKD, as well as other KDOQI guidelines, can be
accessed through the National Kidney Foundation's website.

Uremic bleeding — An increased tendency to bleeding is present in patients with CKD. This
appears to correlate most closely with prolongation of the bleeding time due primarily to
impaired platelet function. (See "Platelet dysfunction in uremia".)

No specific therapy is required in asymptomatic patients. However, correction of the platelet

dysfunction is desirable in patients who are actively bleeding or who are about to undergo a
surgical or invasive procedure (such as a kidney biopsy). A number of different modalities can
be used in this setting, including the correction of anemia, the administration of desmopressin
(DDAVP), cryoprecipitate, estrogen, and the initiation of dialysis. (See "Platelet dysfunction in
uremia".)

Pericarditis — Advances in management have decreased the incidence of pericarditis in

patients with CKD, but this problem is still associated with significant morbidity and occasional
mortality.

Fever, pleuritic chest pain, and a pericardial friction rub are the major presentations of uremic
pericarditis. One relatively characteristic feature of uremic pericarditis is that the
electrocardiogram does not usually show the typical diffuse ST and T wave elevation,
presumably because this is a metabolic pericarditis, and epicardial injury is uncommon. Thus,
the finding of these abnormalities suggests some other cause for the pericarditis. The
occurrence of pericarditis in a patient with mild to moderate CKD is another clue that the kidney
disease is probably not responsible.

The development of otherwise unexplained pericarditis in a patient with advanced kidney

failure is an indication to institute dialysis (providing there is no circulatory compromise or
evidence of impending tamponade) (see below). Most patients with uremic pericarditis respond
rapidly to dialysis, with resolution of chest pain as well as a decrease in the size of the
pericardial effusion.

Uremic neuropathy — Dysfunction of the central and peripheral nervous system including

encephalopathy (impaired mental status progressing, if untreated, to seizures and coma),
polyneuropathy, and mononeuropathy are important complications of ESKD. They have become
much less common because of the tendency to earlier initiation of dialysis.

Sensory dysfunctions, characterized by the restless leg or burning feet syndromes, are frequent
presentations of uremic neuropathy. These complications 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 cautious
interpretation of the tests of thyroid function.

It is usually possible in the individual patient with CKD to assess thyroid status accurately by
physical diagnosis and thyroid function testing. The disturbances that can occur include low
serum-free and total T3 concentrations and normal reverse T3 and free T4 concentrations. The
serum thyrotropin (TSH) concentration is normal, and most patients are euthyroid. (See
"Thyroid function in chronic kidney disease".)

Infection and vaccination — Patients with CKD are at increased risk for infection [54-56]. The
risk of bacterial infection (particularly pulmonary and genitourinary) increases with the decline
in kidney function [55,57]. In one study, compared with an eGFR ≥90 mL/min/1.73 m2, eGFRs
between 60 to 89, 45 to 59, and 15 to 44 mL/min/1.73 were associated with 16, 37, and 64
percent greater risks of all-cause infection related hospitalization, respectively [55].

Careful attention should be paid to preventive measures such as influenza and pneumococcal
immunization [58,59].

We agree with the following 2012 KDIGO guidelines [10]:

● Adults with all stages of CKD should be offered annual vaccination with influenza virus
unless contraindicated.
 ● Adults with stage 4 and 5 CKD who are at high risk of progression of CKD should be
immunized against hepatitis B and the response confirmed by immunologic testing.

● Adults with CKD stages 4 and 5 should be vaccinated with polyvalent pneumococcal vaccine
unless contraindicated. Patients who have received pneumococcal vaccination should be
offered revaccination within five years.

The United States Advisory Committee on Immunization Practices (ACIP) has recommended two
forms of pneumococcal vaccine, including pneumococcal polysaccharide vaccine (PPSV23
[Pneumovax or Pnu-Immune]) and the 13-valent conjugate pneumococcal vaccine (PCV13
[Prevnar 13]) for individuals aged ≥19 years with an immunocompromising condition, including
CKD [60]. Specific recommendations regarding the schedule of administration of both vaccines
are discussed elsewhere. (See "Pneumococcal vaccination in adults", section on 'Initial
vaccination'.)

Other — A comprehensive study of a patient with CKD or end-stage kidney disease (ESKD)
should include examination of the external eye and direct ophthalmoscopy. Advanced kidney
disease of any etiology induces eye findings that signal the need for initiation or intensification
of therapy. These include conjunctival erythema (which may be noted when high plasma
phosphate levels induce corneal and conjunctival precipitation of calcium pyrophosphate) [61-
63].

Profound uremia may rarely be complicated by transient cortical blindness; this is termed
uremic amaurosis, which occurs in association with preserved pupillary contraction on light
exposure and normal funduscopic findings. This abnormality clears within 24 to 48 hours of
initiating dialytic therapy [64].

REFERRAL TO NEPHROLOGISTS

Patients with CKD should be referred to a nephrologist when the estimated glomerular
filtration rate (eGFR) is <30 mL/min/1.73 m2 in order to discuss and potentially plan for kidney
replacement therapy. There is less consensus about referral for patients with higher eGFRs. This
issue and other indications for referral to a nephrologist are discussed elsewhere. (See
"Definition and staging of chronic kidney disease in adults", section on 'Referral to a specialist'.)

Lower costs and/or decreased morbidity and mortality may be associated with early referral
and care by nephrologists [65-75].
In most studies, referral to the nephrologist is considered late if it is within one to six months of
the requirement for kidney replacement therapy [76]. Such late referrals are extremely common
in the United States [77-79]. In various studies, 25 to 50 percent of patients beginning chronic
kidney replacement therapy in the United States required dialysis within one month of their first
nephrology visit [77,78,80]; in addition, 22 to 49 percent of patients were first seen by a
nephrologist less than four months prior to the initiation of dialysis [77,81]. Disturbingly, some
patients received no medical care at all [82].

Similar patterns relating to late referral have been reported from other parts of the world [83-
85]. The proportion of dialysis patients who required dialysis within one month of the first visit
to a nephrologist ranged from 25 percent in Paris, France [83] to 58 percent in Sao Paulo, Brazil
[84]. The prevalence of late referral can also have significant regional variation within a country;
in the larger cities of Australia, the proportion of patients referred within three months of
needing to start dialysis ranged from 14 to 44 percent [86].

Causes of late referral — Late referral to the nephrologist can be due to unavoidable causes,
the referral biases of clinicians, patient factors, socioeconomic status of the patient, and/or the
structure of the healthcare system(s) within a certain country [86-88].

Unavoidable causes — Unavoidable causes of late referral include end-stage kidney disease

(ESKD) that follows acute kidney injury (AKI), "asymptomatic" kidney failure only presenting at
an advanced stage, or a patient's refusal to seek help until symptoms occur.

Patients may resist referral to a nephrologist for a variety of reasons, including patient denial
regarding the presence of kidney failure, lack of appropriate understanding of their condition,
fear of dialysis procedures, fear of cost, distance from treatment center, or the desire to remain
with the local clinician. The frequency of unavoidable late referral ranges from 12 to 60 percent
[81,83,89,90].

Referral biases of clinicians — There are clear differences among clinicians in the rate of
referral of patients with CKD to a nephrologist [91]. Several factors might influence nephrology
referral decisions by clinicians, including:

● Lack of training about guidelines regarding timing or indications for referral [78].

● Poor communication between referring clinicians and specialists, which has been
implicated as a factor that adversely affects the quality and cost of patient care [78,92-94].

● Economic factors, including fear of losing patients and the loss of income from office visits,
hospitalizations, or tests. In addition, nephrologists may subsequently refer patients to
 other specialists for nonrenal issues that can be handled by primary clinicians.

Structure of the health care system — In most developing countries, patients have limited
access to medical care, commonly resulting in the need for emergency dialysis upon
presentation to the nephrologist. Unfortunately, this type of presentation is also common in
developed countries such as the United States, where many patients have no direct, insured
access to medical care [95].

The structural and economic constraints imposed upon referring clinicians by health care
organizations may also dictate the frequency and timing of referral to the nephrologist:

● In the United Kingdom and Canada, and within certain health plans in the United States, a
patient may be seen by a nephrologist only after referral from a primary care physician
(PCP). Referrals from such physicians may be limited by some of the factors previously
mentioned.

● Pressure to contain costs by avoiding subspecialty referral is a policy promoted by some

health maintenance organizations (HMOs) in the United States.

Subsequently, certain payers have developed disease management organizations, which offer a
continuum of care beginning with diseases that cause kidney failure through the requirement
for kidney replacement therapy, and have placed the nephrologist at the center of the patient-
care team [96]. This development could potentially reverse earlier trends and channel patients
to the nephrologist in larger numbers and in a more timely manner.

Patient factors — Socioeconomic patient characteristics are also associated with late

referral in some studies. This was illustrated in a review of 460 patients starting dialysis over a
four-year period, of whom 46, 37, and 17 percent presented less than one month, one to three
months, and more than three months prior to initiating dialysis [88]. Those presenting at less
than one month were more likely to be alcoholic (34 percent), substance abusers (37 percent),
and homeless or unemployed (28 percent) compared with 10 percent or fewer among those
presenting at more than three months.

Consequences of late referral — The clinical and economic consequences of late referral to

the nephrologist have mostly been described from uncontrolled or retrospective studies.
Comparison of study results is further hindered by differences in definition of early and late
referral and duration of follow-up.

Metabolic and hematologic findings — Patients referred late to the nephrologist invariably

present with biochemical indices of severe uremia and an imminent need for dialysis [80-84,97].
In most studies addressing this, compared with patients referred early, patients referred late
also have a significantly greater degree of acidosis, anemia, hypocalcemia, hypoalbuminemia,
and hyperphosphatemia.

As an example, in a study examining the predialysis care of 135 patients with CKD, compared
with early referral, those referred late (referred less than four months before the initiation of
dialysis) had a higher prevalence of hypoalbuminemia (80 versus 56 percent) and a hematocrit
of less than 28 percent (55 versus 33 percent) [81].

Advanced metabolic abnormalities at the time of initiation of dialysis reflect suboptimal care of
progressive CKD; this possibly contributes to the high morbidity and costs of initiation of
dialysis.

Hospitalization and cost — The delayed referral of patients with CKD is associated with a
greater likelihood of prolonged hospitalization around the time of initiation of dialysis, as well
as with higher costs [73,98]. This was best shown in a 2007 meta-analysis of eight studies
consisting of 3220 patients in which number of days in hospital was significantly higher for late-
versus early-referral patients (25 versus 14 days, respectively) [73].

Late-referral patients are also hospitalized more frequently for the initiation of dialysis
[73,78,82,83,89,99,100]. These adverse associations are probably due in part to a greater
prevalence of uremic complications and other serious illnesses, such as uncontrolled
hypertension and pulmonary edema. In addition, vascular access placement and the
management of complications related to this aspect of dialysis care are a frequent cause of
hospitalization and a large component of the cost of care [77,101,102].

Despite the pressure to control health care costs by avoiding hospitalization, a large proportion
of patients with ESKD in the United States are hospitalized for initiation of dialysis [82,103]. This
may in part be due to late referral, but perceptions of nephrologists that dialysis should be
initiated in the hospital setting, as well as regional regulations requiring a first dialysis to be at
an inpatient facility, may also have contributed. Multidisciplinary patient education and follow-
up programs may decrease the likelihood of hospitalization for initiation of dialysis and lower
the frequency of emergency initiation and time spent in hospital during the first month of
dialysis [99].

Selection of dialysis modality, emergent first dialysis, and permanent access — Early

referral to the nephrologist enables discussion of the preferred mode of kidney replacement
therapy to suit the patient's lifestyle and timely placement of a permanent dialysis access. An
informed decision on dialysis modality made under nonemergency circumstances reduces the
likelihood of a subsequent change in dialysis modality [80,89]. Furthermore, patients referred
late are less likely to receive a kidney transplant [104].

The majority of patients referred to the nephrologist in a timely manner tend to have a
functioning permanent access at the start of dialysis compared with only a small minority of
late referrals [81,82,84,85,89,105-107]. One study evaluated the clinical characteristics of 139
patients who, prior to the initiation of dialysis, received medical care provided by a nephrologist
or a generalist or no medical care [82]. Compared with the group cared for by generalists,
patients treated by nephrologists were significantly less likely to have required a temporary
venous catheter for the first dialysis (36 versus 89 percent). The late referral of patients has
therefore resulted in a large number of dialysis patients without permanent vascular access at
the time of initiation of dialysis. (See "Central catheters for acute and chronic hemodialysis
access and their management".)

Late referrals may also affect the choice of chronic hemodialysis access. (See "Approach to the
patient needing vascular access for chronic hemodialysis".)

Loss of kidney function and rehabilitation — Late referral to a nephrologist may not

permit the timely institution of therapy aimed at decreasing the rate of loss of kidney function.
Early institution of an angiotensin-converting enzyme (ACE) inhibitor and other renoprotective
therapy such as strict blood pressure and glycemic control has its greatest impact when started
early [108]. The potential benefits of appropriate care were illustrated in a study of 726 patients
newly referred to nephrology; the rate of decline in GFR decreased substantially from 5.4
mL/min/1.73 m2 per year during the five years prior to nephrology referral to a decline of 0.35
mL/min/1.73 m2 per year during the five years after nephrology referral [109]. Protective
therapy appears to have the greatest impact if it is initiated before the plasma creatinine
concentration exceeds 1.5 to 2 mg/dL (132 to 176 micromol/L) or GFR is less than 60
mL/min/1.73 m2 [110]. Waiting until the disease progresses further diminishes the likelihood of
a successful response. (See "Antihypertensive therapy and progression of nondiabetic chronic
kidney disease in adults" and "Dietary recommendations for patients with nondialysis chronic
kidney disease" and "Treatment of diabetic kidney disease".)

Timely referral also permits the enrollment of patients into a multidisciplinary program that
addresses the physical, logistic, social, emotional, and vocational problems encountered during
life on dialysis. Participation in such predialysis educational programs has been associated with
higher employment rates and delay in the need for initiation of kidney replacement therapy
[111].
 Mortality — A large number of studies have examined the association between timing of
nephrology referral and deaths subsequent to initiation of dialysis, particularly during the first
year of dialysis. To best assess this association, a 2007 meta-analysis evaluated this correlation
among 20 studies that included over 12,000 patients [73]. Compared with early referral, late
referral was associated with a significantly increased risk of all-cause mortality (risk ratio [RR]
1.99, 95% CI 1.66-2.39) and one-year mortality (RR 2.08, 95% CI 1.31-3.31). However, significant
heterogeneity was noted. Similar findings were noted in subsequent studies [98,112,113] and
did not seem to vary with the cause of kidney disease (diabetic versus nondiabetic kidney
disease) or whether patients were older [113]. The positive impact of nephrology care on
mortality was confirmed in a retrospective cohort study of 39,031 patients in the Department of
Veteran's Health Affairs system [74]. Patients with multiple nephrology visits during the year
had a substantially lower mortality compared with patients who were not seen by a
nephrologist or seen only once by a nephrologist, with adjusted hazard ratios of 0.80, 0.68, and
0.40 for two, three, and four nephrology visits, respectively.

Studies relating to mortality may suffer from lead-time bias. In general, such bias may be
observed with early diagnosis and/or early initiation of treatment of a condition, resulting in the
patient being expected to live longer from the time of diagnosis and/or initiation of treatment.

Future studies relating to the timing of initiation of dialysis may consider the effect of lead-time
bias by adjusting for the estimated duration of time the patient would have remained off
dialysis, which could be predicted using an estimated rate of decline of kidney function.

Co-management with primary care provider — Co-management of the patient with the

primary care provider is a common strategy at early stages of CKD. Institution of renoprotective
therapy (eg, ACE inhibitor, angiotensin receptor blocker [ARB], and rigorous blood pressure
control) should be done as early as possible after identifying the presence of progressive CKD.
Protective therapy has the greatest impact if it is initiated before the plasma creatinine
concentration exceeds 1.2 (106 micromol/L) and 1.5 mg/dL (133 micromol/L) in women and
men, respectively, or when the eGFR is <60 mL/min/1.73 m2. At this point, most patients have
already lost more than one-half of their eGFR. Waiting until the disease progresses further
diminishes the likelihood of a successful response but still should be attempted. (See
"Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and
'Slowing the rate of progression' above.)

Multidisciplinary chronic kidney disease clinic — The optimal medical care of CKD patients
may be best provided by a team of health care professionals who practice at a single site (ie, a
CKD clinic), following the principles of the chronic disease model of care [114]. Such CKD clinics
focus on guideline-driven nephrology care, management of comorbidities, lifestyle
modification, and patient education in order to optimize patient outcomes. Observational and
nonrandomized prospective studies have suggested that, compared with standard nephrology
care, patients who attend a multidisciplinary CKD clinic have fewer hospitalizations, are more
likely to have an arterial-venous fistula rather than graft or catheter, are more likely to start
dialysis as an outpatient, are more likely to adhere to established CKD anemia or mineral and
bone disease (MBD) goals, and may have improved survival [99,115-118].

Care management programs — The benefits of an outpatient care management program

were demonstrated in a randomized, controlled trial that included 130 patients with GFR <30
mL/min/1.73 m2 [119]. Patients were assigned to either standard care or to a "Healthy
Transitions Program," which utilized nurse care managers supported by a protocol-driven
informatics system that provided daily reports that identified incomplete process steps for each
patient. Discussion and decision regarding kidney replacement modality (KRT) was identified as
a critical process step, as were discussions regarding dietary education, medication
reconciliation, and home safety.

The overall hospitalization rate was lower with the Healthy Transitions Program compared with
a control standard care group (0.61 versus 0.92 per year, respectively), a result driven by a few
patients with multiple hospitalizations in the control group. The most frequent cause of
hospitalization was volume overload. Peritoneal dialysis was the initial KRT in more patients in
the Healthy Transitions group compared with control (23 versus 3 percent, respectively).
Hemodialysis was started without hospitalization in more patients in the Healthy Transitions
group compared with control (58 versus 23 percent). Catheters were less common in the
Healthy Transitions group compared with control (37 versus 69 percent respectively). Despite
the small sample size, these data suggest better outcomes with a protocol-defined care
management program.

The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) CKD guidelines suggest
management of CKD patients in a multidisciplinary setting, with access to dietary counseling,
kidney replacement therapies, transplant options, vascular access surgery, and ethical,
psychological and social care [120].

PREPARATION FOR AND INITIATION OF KIDNEY REPLACEMENT THERAPY

It is important to identify patients who may eventually require kidney replacement therapy
since adequate preparation can decrease morbidity and perhaps mortality. Early identification
enables dialysis to be initiated at the optimal time with a functioning chronic access and may
also permit the recruitment and evaluation of family members for the placement of a renal
allograft prior to the need for dialysis. In addition, the ability of the individual to psychologically
accept the requirement of lifelong kidney replacement therapy is often diminished if
inadequate time has elapsed between the time of recognition of end-stage kidney disease
(ESKD) and the initiation of dialysis.

CKD progresses at a variable rate due to differences in the clinical course of the underlying
diseases (particularly between individuals) and the recognition that the natural history of
progressive kidney disease can be altered by various therapeutic interventions, particularly
strict blood pressure control with an angiotensin-converting enzyme (ACE) inhibitor or
angiotensin receptor blocker (ARB) (see 'Slowing the rate of progression' above). As a result,
exactly if and when a patient may require dialysis or kidney transplantation is unclear. In
addition, some patients refuse kidney replacement therapy until the onset of absolute
indications, while others desire early initiation to avoid the complications of severe CKD, such as
malnutrition.

Choice of kidney replacement therapy — Once it is determined that kidney replacement

therapy will eventually be medically indicated, the patient should be counseled to consider the
advantages and disadvantages of hemodialysis (in-center or at home), peritoneal dialysis
(continuous or intermittent modalities), and kidney transplantation (living or deceased donor)
[121,122]. The option of conservative management should also be discussed among patients
who are unwilling or unable to undergo kidney replacement therapy. The 2015 Kidney Disease
Outcomes Quality Initiative (KDOQI) guidelines recommend that patients with an estimated
glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 should be educated concerning these
issues [123].

Kidney transplantation is the treatment of choice for ESKD. A successful kidney transplant
improves the quality of life and reduces the mortality risk for most patients when compared
with maintenance dialysis. To facilitate early transplantation, a 2008 National Kidney Foundation
(NKF)-KDOQI conference suggested early education and referral to a transplantation center
plus the identification of potential living donors [124].

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.
(See "Kidney transplantation in adults: Patient survival after kidney transplantation" and "Kidney
transplantation in adults: Evaluation of the potential kidney transplant recipient".)

Living-donor transplants, if available, have the additional advantage of being performed with
minimal delay, thereby permitting pre-emptive transplantation (transplantation prior to
dialysis). Such patients appear to have improved graft survival compared with those who
undergo a period of dialysis before transplantation [125]. (See "Kidney transplantation in adults:
Dialysis issues prior to and after kidney transplantation" and "Kidney transplantation in adults:
Risk factors for graft failure".)

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 influenced by a
number of considerations such as availability, convenience, comorbid conditions, home
situation, age, gender, and the ability to tolerate volume shifts. (See "Dialysis modality and
patient outcome" and "Evaluating patients for chronic peritoneal dialysis and selection of
modality".)

In the United States, the universal availability of kidney replacement therapy forces the
nephrologist to consider its application in every patient in whom it might be indicated.
However, the patient, particularly older adults and terminally ill, may decline kidney
replacement therapy, a choice which is assuming more prominence as patients and clinicians
grapple with the increasing use of advance directives and the laudable goals of death with
dignity and life with quality. We agree with the 2012 Kidney Disease: Improving Global
Outcomes (KDIGO) guidelines that conservative management of ESKD should be an option for
such patients [120]. (See 'Conservative management of end-stage kidney disease' below and
"Kidney palliative care: Withdrawal 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 access
should generally be placed in the nondominant upper extremity because of the increased risk
of infection and more severe consequences of arterial steal syndrome with lower extremity
grafts. Venipuncture should therefore be restricted to the arm not chosen for eventual access
placement so that the veins in the other arm will be preserved.

There are three major types of vascular access for maintenance hemodialysis: primary
arteriovenous (AV) fistulas, AV grafts, and tunneled hemodialysis catheters. To facilitate
placement of a permanent vascular access, we agree with the 2008 Society for Vascular Surgery
(SVS) guidelines that recommend referral to an access surgeon when the patient has late stage
4 CKD, defined by an eGFR of <20 to 25 mL/min/1.73 m2 [126]. (See "Approach to the patient
needing vascular access for chronic hemodialysis".)

Arteriovenous fistulas — AV fistulas are the preferred form of vascular access given their
significantly higher long-term patency rates and lower rate of complications. Since an AV fistula
requires months to mature and is the access of choice, 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 an eGFR <25 mL/min/1.73 m2, a plasma
creatinine concentration >4 mg/mL (354 micromol/L), or a rapid rate of progression. The 2006
KDOQI guidelines recommend that a fistula be placed at least six months prior to the
anticipated start of hemodialysis [122]. (See "Arteriovenous fistula creation for hemodialysis and
its complications", section on 'Timing of AV fistula creation'.)

There are several types of AV fistulas, each of which is typically constructed with an end-to-side
vein-to-artery anastomosis. The type chosen is based upon clinical evaluation and vascular
mapping. AV fistulas have good long-term patency and infrequently develop infectious
complications. A well-constructed radial cephalic fistula that functions for the first six months
can be expected to function for up to 20 years. (See "Patient evaluation prior to placement of
hemodialysis arteriovenous access" and "Arteriovenous fistula creation for hemodialysis and its
complications", section on 'Types by anatomic location' and "Arteriovenous fistula creation for
hemodialysis and its complications", section on 'Fistula creation'.)

The patient should be instructed in the care of the fistula. Such care includes routinely checking
for a thrill and notifying the nephrologist if this is not present. The arm that has the fistula
should not be used for blood drawing or for blood pressure checks. Patients should avoid
sleeping on the access arm, avoid tight clothing on the access, and not carry anything that
weighs more than 5 pounds with that arm. In addition, the fistula should be regularly examined
by a clinician. (See "Overview of hemodialysis arteriovenous fistula maintenance and
thrombosis prevention".)

Arteriovenous grafts — AV grafts are constructed by interposing a graft between an artery

and vein, most commonly polytetrafluoroethylene (PTFE). AV grafts can provide excellent
vascular access in patients who have inadequate vascular anatomy to support an AV fistula.
PTFE has good surgical handling characteristics, and grafts of this material can usually be used
two weeks after placement. However, AV grafts have a higher long-term complication rate (eg,
infection, thrombosis) compared with primary fistulas. The 2006 KDOQI guidelines recommend
that a synthetic graft be placed at least three to six weeks prior to the anticipated start of
hemodialysis [122]. (See "Arteriovenous graft creation for hemodialysis and its complications",
section on 'Timing of AV graft creation'.)

As for a fistula, the patient should be instructed in the care of the AV graft. Such care includes
routinely checking for a thrill and notifying the nephrologist if this is not present. The arm that
has the graft should not be used for blood drawing or for blood pressure checks. Patients
should avoid sleeping on the access arm, avoid tight clothing on the access, and not carry
anything that weighs more than 5 pounds with that arm. The graft should be regularly
examined by a clinician. (See "Overview of hemodialysis arteriovenous graft maintenance and
thrombosis prevention".)

Tunneled hemodialysis catheters — Following placement, typically in the right internal

jugular vein, tunneled hemodialysis catheters can be used immediately. (See "Central catheters
for acute and chronic hemodialysis access and their management".)

Tunneled hemodialysis catheters are primarily used as intermediate-duration vascular access

during maturation of AV fistulas. They can also provide acceptable long-term access in patients
with contraindications to AV access or those who have exhausted all available sites.
Nevertheless, tunneled hemodialysis catheters are inferior to AV access as long-term access
since they provide lower flows and have higher rates of infection and other complications. (See
"Approach to the patient needing vascular access for chronic hemodialysis".)

Preparation for peritoneal dialysis — Peritoneal dialysis catheters, which are placed into the
abdominal cavity, can be used immediately after placement [127]. 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 placement, small volume exchanges performed in
the recumbent position can be performed with little risk of leak. (See "Placement and
maintenance of the peritoneal dialysis catheter", section on 'Post-placement catheter care'.)

Preparation for kidney transplantation — Preparation for kidney transplantation, which

principally involves evaluation of the potential kidney transplant recipient and the living donor,
is discussed in detail separately. (See "Kidney transplantation in adults: Evaluation of the
potential kidney transplant recipient" and "Kidney transplantation in adults: Living unrelated
donors".)

Many patients, however, may not even be referred for evaluation for transplantation. Among
426,489 patients who started dialysis between 2005 and 2009, 12.5 percent had reportedly not
been assessed for transplantation [128].

A number of studies have shown that women, African Americans, Hispanics, Native Americans,
patients dialyzed in for-profit centers, and patients without private insurance are less likely to
report having been assessed for transplantation, placed on a waitlist, or transplanted [128-138].

A living-donor kidney transplant program in which a home-based education approach is added

to conventional, standard, clinic-based transplant may enhance kidney donation among African
Americans. In a randomized study, this combined approach, compared with a clinic-alone
education, resulted in significantly more living-donor inquires (77 versus 52 percent), living-
donor evaluations (48 versus 17 percent), and eventual kidney transplantation (45 versus 14
percent) in African Americans [139].

In the United States, patients with higher education levels may have an advantage in obtaining
kidney transplantation. In a study of 3245 incident dialysis patients, those with college degrees
were approximately three times more likely than high school graduates to be waitlisted or
undergo kidney transplantation [140]. Although these results must be confirmed, it appears
that education level contributes to the disparity in transplant referrals and operations [141].

Indications for kidney replacement therapy — There are a number of clinical indications to

initiate dialysis in patients with CKD. These are discussed in detail elsewhere. (See "Indications
for initiation of dialysis in chronic kidney disease".)

These include [122,142,143]:

● Pericarditis or pleuritis (urgent indication).

● Progressive uremic encephalopathy or neuropathy, with signs such as confusion, asterixis,

myoclonus, wrist or foot drop, or, in severe, cases, seizures (urgent indication).

● A clinically significant bleeding diathesis attributable to uremia (urgent indication).

● Fluid overload refractory to diuretics.

● Hypertension poorly responsive to antihypertensive medications.

● Persistent metabolic disturbances that are refractory to medical therapy. These include
hyperkalemia, hyponatremia, metabolic acidosis, hypercalcemia, 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 clinicians appropriately. Dialysis should be
considered based upon clinical factors plus the eGFR. 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 specific threshold eGFR level that has been established for the initiation
of dialysis. To help avoid the onset of possible life-threatening complications of uremia, dialysis
should be initiated in the asymptomatic patient with an extremely low eGFR, such as an eGFR of
approximately 8 to 10 mL/min/1.73 m2. However, some clinicians may choose to closely monitor
(weekly) asymptomatic patients with progressive CKD, even when the eGFR is less than 8 to 10
mL/min/1.73 m2, with the initiation of dialysis upon the onset of uremic signs/symptoms. The
Initiating Dialysis Early and Late (IDEAL) study failed to demonstrate a difference between
planned "early" and planned "late" dialysis initiation, although a limitation of this study was that
patients crossed over between the two groups [144].The 2012 KDIGO guidelines suggest that
dialysis be initiated when there are signs or symptoms attributable to kidney failure (such as
serositis, acid-base or electrolyte disorders not easily corrected medically, pruritus); an inability
to control volume status or blood pressure; a progressive deterioration in nutritional status that
is refractory to dietary interventions; or cognitive impairment [10]. The 2012 KDIGO guidelines
state that such signs and symptoms often but not invariably occur when the eGFR is between 5
and 10 mL/min/1.73 m2.

All approaches require close follow-up, early nephrology referral, and adequate advanced
dialysis planning (including the presence of a functioning peritoneal or vascular access and
referral for transplantation). A detailed discussion of the indications for dialysis in the patient
with CKD can be found elsewhere. (See "Indications for initiation of dialysis in chronic kidney
disease".)

CONSERVATIVE MANAGEMENT OF END-STAGE KIDNEY DISEASE

Patients may elect to withhold dialysis [145-147]. We agree with the 2012 Kidney Disease:
Improving Global Outcomes (KDIGO) guidelines that conservative management of end-stage
kidney disease (ESKD) should be an option for all patients who decide not to pursue kidney
replacement therapy [120]. Conservative care includes the management of symptoms, advance-
care planning, and provision of appropriate palliative care. (See "Kidney palliative care:
Conservative kidney management" and "Kidney palliative care: Withdrawal of dialysis" and
"Kidney palliative care: Principles, benefits, and core components".)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Chronic kidney disease
in adults".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Chronic kidney disease (The Basics)" and "Patient
education: Peritoneal dialysis (The Basics)" and "Patient education: Dialysis and diet (The
Basics)" and "Patient education: Bone problems caused by kidney disease (The Basics)" and
"Patient education: Medicines for chronic kidney disease (The Basics)")

● Beyond the Basics topics (see "Patient education: Chronic kidney disease (Beyond the
Basics)" and "Patient education: Dialysis or kidney transplantation — which is right for me?
(Beyond the Basics)" and "Patient education: Hemodialysis (Beyond the Basics)" and
"Patient education: Peritoneal dialysis (Beyond the Basics)" and "Patient education: Protein
in the urine (proteinuria) (Beyond the Basics)" and "Patient education: Split urine collection
for orthostatic proteinuria (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● Chronic kidney disease (CKD) is defined as the presence of kidney damage (usually detected
as urinary albumin excretion of 30 mg/day or more, or equivalent) or decreased kidney
function (defined as an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2) for
three or more months, irrespective of the cause. The persistence of the damage or
decreased function for at least three months is necessary to distinguish CKD from acute
kidney disease. Classification, or staging, of CKD provides a guide to management. (See
'Definition and classification' above.)
● CKD is associated with a higher risk of cardiovascular disease, end-stage kidney disease
(ESKD), infection, malignancy, and mortality. (See 'Association with cardiovascular disease,
end-stage kidney disease, and mortality' above and 'Infection and vaccination' above.)

● The management of CKD includes treatment of reversible causes of kidney dysfunction and
preventing or slowing the progression of kidney disease. (See 'Reversible causes of kidney
failure' above and 'Slowing the rate of progression' above.)

● Complications of the loss of kidney function include disorders of fluid and electrolyte
balance, such as volume overload, hyperkalemia, metabolic acidosis, and
hyperphosphatemia, as well as abnormalities related to hormonal or systemic dysfunction,
such as anorexia, nausea, vomiting, fatigue, hypertension, anemia, malnutrition,
hyperlipidemia, and bone disease. Attention needs to be paid to all of these issues. (See
'Treatment of the complications of kidney failure' above.)

● Patients with CKD should be referred to a nephrologist when eGFR is <30 mL/min/1.73 m2
in order to discuss and potentially plan for kidney replacement therapy. Co-management of
the patient with the primary care provider is a common strategy at early stages of CKD, The
optimal medical care of later-stage CKD patients may be best provided by a team of
healthcare professionals who practice at a single site (ie, a CKD clinic), following the
principles of the chronic disease model of care. (See 'Referral to nephrologists' above.)

● It is important to identify patients who may eventually require kidney replacement therapy
since adequate preparation can decrease morbidity and perhaps mortality. Such patients
should be counseled to consider the advantages and disadvantages of hemodialysis (in-
center or at home), peritoneal dialysis (continuous or intermittent modalities), and kidney
transplantation (living or deceased donor). The option of conservative management should
also be discussed among patients who are unwilling or unable to undergo kidney
replacement therapy. Early referral to a surgeon for evaluation and establishment of
arteriovenous (AV) access is needed for patients choosing hemodialysis. (See 'Preparation
for and initiation of kidney replacement therapy' above and 'Conservative management of
end-stage kidney disease' above.)

● Clinical indications to initiate dialysis in patients with CKD include (see 'Indications for
kidney replacement therapy' above and "Indications for initiation of dialysis in chronic
kidney disease"):

• Pericarditis or pleuritis (urgent indication).

 • Progressive uremic encephalopathy or neuropathy, with signs such as confusion,
asterixis, myoclonus, wrist or foot drop, or, in severe, cases, seizures (urgent
indication).

• A clinically significant bleeding diathesis attributable to uremia (urgent indication).

• Fluid overload refractory to diuretics.

• Hypertension poorly responsive to antihypertensive medications.

• Persistent metabolic disturbances that are refractory to medical therapy. These include
hyperkalemia, hyponatremia, metabolic acidosis, hypercalcemia, hypocalcemia, and
hyperphosphatemia.

• Persistent nausea and vomiting.

• Evidence of malnutrition.

• Relative indications include decreased attentiveness and cognitive tasking, depression,

persistent pruritus, or the restless leg syndrome.

● Conservative management of ESKD should be an option for all patients who decide not to
pursue kidney replacement therapy. Conservative care includes the management of
symptoms, advance-care planning, and provision of appropriate palliative care. (See
'Conservative management of end-stage kidney disease' above and "Kidney palliative care:
Withdrawal of dialysis" and "Kidney palliative care: Principles, benefits, and core
components".)

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1):S1.
Topic 7172 Version 48.0
GRAPHICS

Chronic kidney disease classification based upon glomerular filtration rate and albuminuria

GFR

GFR stages (mL/min/1.73 Terms

m 2)
G1 ≥90 Normal or high

G2 60 to 89 Mildly decreased

G3a 45 to 59 Mildly to moderately decreased

G3b 30 to 44 Moderately to severely decreased

G4 15 to 29 Severely decreased

G5 <15 Kidney failure (add D if treated by dialysis)

Albuminuria AER

Terms
stages (mg/day)
A1 <30 Normal to mildly increased (may be subdivided for risk prediction)

A2 30 to 300 Moderately increased

A3 >300 Severely increased (may be subdivided into nephrotic and nonnephrotic for differential
diagnosis, management, and risk prediction)

The cause of CKD is also included in the KDIGO revised classification but is not included in this table.

GFR: glomerular filtration rate; AER: albumin excretion rate; CKD: chronic kidney disease; KDIGO: Kidney Disease Improving Global
Outcomes.

Data from:

1. KDIGO. Summary of recommendation statements. Kidney Int 2013; 3 (Suppl):5.

2. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.
Am J Kidney Dis 2002; 39 (Suppl 1):S1.

Graphic 70597 Version 17.0

Relative risks of major complications of chronic kidney disease based
upon categorical meta-analysis

Summary of categorical meta-analysis (adjusted relative risk) for general population cohorts with
ACR. Mortality is reported for general population cohorts assessing albuminuria as urine ACR.
Kidney outcomes are reported for general population cohorts assessing albuminuria as either
urine ACR or dipstick. eGFR and albuminuria are expressed as categorical variables. All results are
adjusted for covariates and compared with the Ref. Each cell represents a pooled RR from a meta-
analysis; bold numbers indicate statistical significance at p<0.05. Incidence rates per 1000
person-years for the reference cells are 7.0 for all-cause mortality, 4.5 for CVD mortality, 0.04 for
kidney failure, 0.98 for AKI, and 2.02 for kidney disease progression. Absolute risk can be
computed by multiplying the RRs in each cell by the incidence rate in the reference cell. Colors
reflect the ranking of adjusted RR. The point estimates for each cell were ranked from 1 to 28 (the
lowest RR having rank number 1, and the highest number 28). The categories with rank numbers
1 through 8 are green; rank numbers 9 through 14 are yellow; rank numbers 15 through 21 are
orange; and trank numbers 22 through 28 are colored red. (For the outcome of kidney disease
progression, two cells with RR of 1.0 are also green, leaving fewer cells as orange.)

RR: relative risk; ACR: albumin creatinine ratio; eGFR: estimated glomerular filtration rate; Ref: reference
cell; ESRD: end-stage renal disease; AKI: acute kidney injury; CKD: chronic kidney disease; CVD:
cardiovascular disease.

* Dipstick included (-, ±, +, ≥++).

Reprinted by permission from Macmillan Publishers Ltd: Levey AS, de Jong PE, Coresh J, et al. The definition,
classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int
2010; 80:17. Copyright © 2010.

Graphic 68921 Version 9.0

Relative risks of major complications of chronic kidney disease based upon a continuous
meta-analysis

Summary of continuous meta-analysis (adjusted RR) for general population cohorts with ACR. Mortality is reported for
general population cohorts assessing albuminuria as urine ACR. Kidney outcomes are reported for general population
cohorts assessing albuminuria as either urine ACR or dipstick. eGFR is expressed as a continuous variable. The three
lines represent urine ACR of <30 mg/g or dipstick negative and trace (blue), urine ACR 30-299 mg/g or dipstick 1+
positive (green), and urine ACR >300 mg/g or dipstick >2+ positive (red). All results are adjusted for covariates and
compared with reference point of eGFR of 95 mL/min per 1.73 m 2 and ACR of <30 mg/g or dipstick negative (diamond).
Each point represents the pooled RR from a meta-analysis. Solid circles indicate statistical significance compared with
the reference point (p<0.05); triangles indicate non-significance. Red arrows indicate eGFR of 60 mL/min per 1.73 m 2,
threshold value of eGFR for the current definition of CKD.

CKD: chronic kidney disease; ACR: albumin creatinine ratio; HR: hazard ratio; eGFR: estimated glomerular filtration rate; RR:
relative risk.

Reprinted by Permission from Macmillan Publishers Ltd: Levey AS, de Jong PE, Coresh J, et al. The definition, classification, and
prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int 2010; 80:17. Copyright © 2010.

Graphic 58089 Version 6.0

Goal blood pressure according to baseline risk for cardiovascular disease and method of
measuring blood pressure

Routine/conventional office
Unattended AOBPM, daytime
blood pressure (manual
  ABPM, or home blood
measurement with stethoscope
pressure ¶
or oscillometric device)*

Higher-risk population Δ

Known ASCVD ◊ 125 to 130/<80 120 to 125/<80

Heart failure
Diabetes mellitus
Chronic kidney disease
Age ≥65 years §
Calculated 10-year risk of ASCVD
event ≥10% ¥

Lower-risk ‡

None of the above risk factors 130 to 139/<90 125 to 135/<90

All target ranges presented above are in mmHg.

On average, blood pressure readings are 5 to 10 mmHg lower with digital, unattended, or out-of-office methods of
measurement (ie, AOBPM, daytime ABPM, home blood pressure) than with routine/standard methods of office
measurement (ie, manual auscultatory or oscillometric measurement), presumably due to the "white coat effect." However,
it is critical to realize that this average difference in blood pressures according to the methodology of measurement applies
to the population and not the individual. Some patients do not experience a white coat effect, and, therefore, there is some
uncertainty in setting goals that are specific to the method of measurement.
When treating to these goals, a patient may (inadvertently) attain a blood pressure below the given target. Provided the
patient does not develop symptoms, side effects, or adverse events as a result of the treatment regimen, then reducing or
withdrawing antihypertensive medications is unnecessary.
Less aggressive goals than those presented in the table may be appropriate for specific groups of patients, including those
with postural hypotension, the frail older adult patient, and those with side effects to multiple antihypertensive medications.

AOBPM: automated oscillometric blood pressure monitoring; ABPM: ambulatory blood pressure monitoring; ASCVD: atherosclerotic
cardiovascular disease; ACC/AHA: American College of Cardiology/American Heart Association.

* Office blood pressure must be performed adequately in order to use such measurements to manage patients. Critical to an adequate
office assessment of blood pressure are proper patient positioning (eg, seated in a chair, feet flat on the floor, arm supported, remove
clothing covering the location of cuff placement) and proper technique (eg, calibrated device, proper-sized cuff). The average of multiple
measurements should be used for management. Refer to UpToDate topics on measurement of blood pressure. Office readings should
not be used to manage blood pressure unless it is performed adequately.

¶ Home blood pressure, like office blood pressure, must be performed adequately in order for the measurements to be used to manage
patients. First, the accuracy of the home blood pressure device must be verified in the clinician's office. Second, the clinician should verify
that the cuff and bladder that the patient will use are the appropriate size. Third, patients should measure their pressure after several
minutes of rest and while seated in a chair (back supported and feet flat on the floor) with their arm supported (eg, resting on a table).
Fourth, the blood pressure should be measured at different times per day and over multiple days. The average value of these multiple
measurements is used for management. Home blood pressure readings should not be used to manage blood pressure unless it is
performed adequately and in conjunction with office blood pressure or ambulatory blood pressure.

Δ The level of evidence supporting the lower goal in higher-risk individuals is stronger for some risk groups (eg, patients with known
coronary heart disease, patients with a calculated 10-year risk ≥15%, chronic kidney disease) than for other risk groups (eg, patients with
diabetes, patients with a prior stroke). Refer to UpToDate topics on goal blood pressure for a discussion of the evidence.

◊ Prior history of coronary heart disease (acute coronary syndrome or stable angina), prior stroke or transient ischemic attack, prior
history of peripheral artery disease.

§ In older adults with severe frailty, dementia, and/or a limited life expectancy, or in patients who are nonambulatory or institutionalized
(eg, reside in a skilled nursing facility), we individualize goals and share decision-making with the patient, relatives, and caretakers,
rather than targeting one of the blood pressure goals in the table.

¥ The 2013 ACC/AHA cardiovascular risk assessment calculator should be used to estimate 10-year cardiovascular disease risk.

‡ In the large subgroup of patients who have an initial (pretreatment) blood pressure ≥140/≥90 mmHg, but who do not have any of the
other listed cardiovascular risk factors, some experts would set a more aggressive blood pressure goal of <130/<80 mmHg rather than
those presented in the table. This more aggressive goal would likely reduce the chance of developing severe hypertension and
ultimately lower the relative risk of cardiovascular events in these lower-risk patients over the long term. However, the absolute benefit
of more aggressive blood pressure lowering in these patients is comparatively small, and a lower goal would require more intensive
pharmacologic therapy and corresponding side effects.

Graphic 117101 Version 3.0

Recommended dietary intake for chronic kidney and end-stage renal disease patients*

  Chronic kidney disease ¶ Maintenance hemodialysis

Protein 0.8 to 1.0 g/kg/day Δ of high biological >1.2 to 1.3 g/kg/day
value protein

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-to-saturated ratio (fatty 1.0:1.0 1.0:1.0

acid ratio)

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 ◊
Calcium, 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

Water, mL/day Up to 3000 as tolerated Usually 750 to 1500

* 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 m 2 with evidence for progression.

Δ 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 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.

Graphic 71336 Version 6.0

Table 20. Phosphorus content of protein-containing foods

Data from: US Department of Agriculture, Agricultural Research Service 2001. USDA Nutrient
Database for Standard Reference, Release 14.Edit Source

Graphic 79877 Version 7.0

Table 20. Phosphorus content of protein-containing foods (cont'd)

A common way to determine a dietary phosphorus limit is to use an average of 10 to 12

mg/g of protein (multiply protein goal times 10 to 12 mg phosphorus). Thus, for a 70 kg
individual requiring 84 g of protein, the phosphorus range is 840 to 1008 mg.

Considering all common sources of protein, the average phosphorus content per gram of
protein is 17.8. If all diary products, nuts, beans, and seeds are eliminated, but meats and
tofu are considered, the average phosphorus content per gram of protein is 10.3.

FF: fast food; Tb: tablespoon.

Data from: US Department of Agriculture, Agricultural Research Service 2001. USDA Nutrient Database
for Standard Reference, Release 14.

Graphic 56081 Version 9.0

Contributor Disclosures
Mark Rosenberg, MD Nothing to disclose Gary C Curhan, MD, ScD Employment: OM1 Inc [Healthcare
data analytics company] - No relevant conflict on topic. Equity Ownership/Stock Options: Allena
Pharmaceuticals [Oxalate]; OM1 Inc [Healthcare data analytics company]. Grant/Research/Clinical Trial
Support: Decibel Therapeutics [Hearing loss, tinnitus]; GlaxoSmithKline [Shingles]. Shveta Motwani, MD,
MMSc, FASN Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

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