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Drugs & Diseases > Nephrology

Chronic Kidney Disease

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Updated: Jul 25, 2016

Author: Pradeep Arora, MD; Chief Editor: Vecihi Batuman, MD, FASN more...

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Practice Essentials
Chronic kidney disease (CKD)or chronic renal failure (CRF), as it was historically termed
is a term that encompasses all degrees of decreased renal function, from damagedat risk
through mild, moderate, and severe chronic kidney failure. CKD is a worldwide public health
problem. In the United States, there is a rising incidence and prevalence of kidney failure,
with poor outcomes and high cost (see Epidemiology).
CKD is more prevalent in the elderly population. However, while younger patients with
CKD typically experience progressive loss of kidney function, 30%% of patients over 65
years of age with CKD have stable disease. [1]

CKD is associated with an increased risk of cardiovascular disease and chronic renal failure.
Kidney disease is the ninth leading cause of death in the United States.

The Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney
Foundation (NKF) established a definition and classification of CKD in 2002. [3] The KDOQI
and the international guideline group Kidney Disease Improving Global Outcomes (KDIGO)
have subsequently updated these guidelines. [4, 5] These guidelines have allowed better
communication among physicians and have facilitated intervention at the different stages of
the disease.

The guidelines define CKD as either kidney damage or a decreased glomerular filtration rate
(GFR) of less than 60 mL/min/1.73 m2 for at least 3 months. Whatever the underlying
etiology, once the loss of nephrons and reduction of functional renal mass reaches a certain
point, the remaining nephrons begin a process of irreversible sclerosis that leads to a
progressive decline in the GFR.

Hyperparathyroidism is one of the pathologic manifestations of CKD. See the image below.

Calciphylaxis due to secondary

hyperparathyroidism.

Staging

The different stages of CKD form a continuum. The stages of CKD are classified as follows [5]
:

Stage 1: Kidney damage with normal or increased GFR (>90 mL/min/1.73 m 2)

Stage 2: Mild reduction in GFR (60-89 mL/min/1.73 m 2)

Stage 3a: Moderate reduction in GFR (45-59 mL/min/1.73 m 2)

Stage 3b: Moderate reduction in GFR (30-44 mL/min/1.73 m 2)

 Stage 4: Severe reduction in GFR (15-29 mL/min/1.73 m 2)

Stage 5: Kidney failure (GFR <15 mL/min/1.73 m 2 or dialysis)

In stage 1 and stage 2 CKD, reduced GFR alone does not clinch the diagnosis, because the
GFR may in fact be normal or borderline normal. In such cases, the presence of one or more
of the following markers of kidney damage can establish the diagnosis [5] :

Albuminuria (albumin excretion >30 mg/24 hr or albumin:creatinine ratio >30 mg/g [>3
mg/mmol])
Urine sediment abnormalities

Electrolyte and other abnormalities due to tubular disorders

Histologic abnormalities

Structural abnormalities detected by imaging

History of kidney transplantation in such cases

Hypertension is a frequent sign of CKD but should not by itself be considered a marker of it,
because elevated blood pressure is also common among people without CKD.

In an update of its CKD classification system, the NKF advised that GFR and albuminuria
levels be used together, rather than separately, to improve prognostic accuracy in the
assessment of CKD. [4, 5] More specifically, the guidelines recommended the inclusion of
estimated GFR and albuminuria levels when evaluating risks for overall mortality,
cardiovascular disease, end-stage kidney failure, acute kidney injury, and the progression of
CKD. Referral to a kidney specialist was recommended for patients with a very low GFR
(<15 mL/min/1.73 m) or very high albuminuria (>300 mg/24 h). [4, 5]

Patients with stages 1-3 CKD are frequently asymptomatic. Clinical manifestations resulting
from low kidney function typically appear in stages 4-5 (see Presentation).

Signs and symptoms

Patients with CKD stages 1-3 are generally asymptomatic. Typically, it is not until stages 4-5
(GFR <30 mL/min/1.73 m) that endocrine/metabolic derangements or disturbances in water
or electrolyte balance become clinically manifest.

Signs of metabolic acidosis in stage 5 CKD include the following:

Protein-energy malnutrition
Loss of lean body mass

Muscle weakness

Signs of alterations in the way the kidneys are handling salt and water in stage 5 include the
following:

Peripheral edema
Pulmonary edema
 Hypertension

Anemia in CKD is associated with the following:

Fatigue
Reduced exercise capacity

Impaired cognitive and immune function

Reduced quality of life

Development of cardiovascular disease

New onset of heart failure or the development of more severe heart failure

Increased cardiovascular mortality

Other manifestations of uremia in end-stage renal disease (ESRD), many of which are more
likely in patients who are being inadequately dialyzed, include the following:

Pericarditis: Can be complicated by cardiac tamponade, possibly resulting in death if

unrecognized
Encephalopathy: Can progress to coma and death

Peripheral neuropathy, usually asymptomatic

Restless leg syndrome

Gastrointestinal symptoms: Anorexia, nausea, vomiting, diarrhea

Skin manifestations: Dry skin, pruritus, ecchymosis

Fatigue, increased somnolence, failure to thrive

Malnutrition

Erectile dysfunction, decreased libido, amenorrhea

Platelet dysfunction with tendency to bleed

Screen adult patients with CKD for depressive symptoms; self-report scales at initiation of
dialysis therapy reveal that 45% of these patients have such symptoms, albeit with a somatic
emphasis.

See Clinical Presentation for more detail.

Diagnosis

Laboratory studies

Laboratory studies used in the diagnosis of CKD can include the following:

Complete blood count (CBC)

Basic metabolic panel
 Urinalysis

Serum albumin levels: Patients may have hypoalbuminemia due to malnutrition, urinary
protein loss, or chronic inflammation

Lipid profile: Patients with CKD have an increased risk of cardiovascular disease

Evidence of renal bone disease can be derived from the following tests:

Serum calcium and phosphate

25-hydroxyvitamin D

Alkaline phosphatase

Intact parathyroid hormone (PTH) levels

In certain cases, the following tests may also be ordered as part of the evaluation of patients
with CKD:

Serum and urine protein electrophoresis and free light chains: Screen for a monoclonal
protein possibly representing multiple myeloma
Antinuclear antibodies (ANA), double-stranded DNA antibody levels: Screen for systemic
lupus erythematosus

Serum complement levels: Results may be depressed with some glomerulonephritides

Cytoplasmic and perinuclear pattern antineutrophil cytoplasmic antibody (C-ANCA and P-

ANCA) levels: Positive findings are helpful in the diagnosis of granulomatosis with polyangiitis
(Wegener granulomatosis); P-ANCA is also helpful in the diagnosis of microscopic polyangiitis

Antiglomerular basement membrane (anti-GBM) antibodies: Presence is highly suggestive

of underlying Goodpasture syndrome

Hepatitis B and C, human immunodeficiency virus (HIV), Venereal Disease Research

Laboratory (VDRL) serology: Conditions associated with some glomerulonephritides

Imaging studies

Imaging studies that can be used in the diagnosis of CKD include the following:

Renal ultrasonography: Useful to screen for hydronephrosis, which may not be observed in
early obstruction or dehydrated patients; or for involvement of the retroperitoneum with
fibrosis, tumor, or diffuse adenopathy; small, echogenic kidneys are observed in advanced
renal failure
Retrograde pyelography: Useful in cases with high suspicion for obstruction despite negative
renal ultrasonograms, as well as for diagnosing renal stones

Computed tomography (CT) scanning: Useful to better define renal masses and cysts usually
noted on ultrasonograms; also the most sensitive test for identifying renal stones

Magnetic resonance imaging (MRI): Useful in patients who require a CT scan but who cannot
receive intravenous contrast; reliable in the diagnosis of renal vein thrombosis
 Renal radionuclide scanning: Useful to screen for renal artery stenosis when performed with
captopril administration; also quantitates the renal contribution to the GFR

Biopsy

Percutaneous renal biopsy is generally indicated when renal impairment and/or proteinuria
approaching the nephrotic range are present and the diagnosis is unclear after appropriate
workup.

See Workup for more detail.

Management

Early diagnosis and treatment of the underlying cause and/or institution of secondary
preventive measures is imperative in patients with CKD. These may slow, or possibly halt,
progression of the disease.The medical care of patients with CKD should focus on the
following:

Delaying or halting the progression of CKD: Treatment of the underlying condition, if

possible, is indicated
Diagnosing and treating the pathologic manifestations of CKD

Timely planning for long-term renal replacement therapy

The pathologic manifestations of CKD should be treated as follows:

Anemia: When the hemoglobin level is below 10 g/dL, treat with erythropoiesis-stimulating
agents (ESAs), which include epoetin alfa and darbepoetin alfa after iron saturation and
ferritin levels are at acceptable levels
Hyperphosphatemia: Treat with dietary phosphate binders and dietary phosphate restriction

Hypocalcemia: Treat with calcium supplements with or without calcitriol

Hyperparathyroidism: Treat with calcitriol or vitamin D analogues or calcimimetics

Volume overload: Treat with loop diuretics or ultrafiltration

Metabolic acidosis: Treat with oral alkali supplementation

Uremic manifestations: Treat with long-term renal replacement therapy (hemodialysis,

peritoneal dialysis, or renal transplantation)

Indications for renal replacement therapy include the following:

Severe metabolic acidosis

Hyperkalemia

Pericarditis

Encephalopathy

Intractable volume overload

 Failure to thrive and malnutrition

Peripheral neuropathy

Intractable gastrointestinal symptoms

In asymptomatic patients, a GFR of 5-9 mL/min/1.73 m, [2] irrespective of the cause of the
CKD or the presence or absence of other comorbidities

The National Kidney Foundations Kidney Disease Outcomes Quality Initiative (KDOQI)
issued a Clinical Practice Guideline for Nutrition in Chronic Renal Failure, as well as a
revision of recommendations for Nutrition in Children with Chronic Kidney Disease.

See Treatment and Medication for more detail.

For a discussion of CKD in children, click here.

Pathophysiology
A normal kidney contains approximately 1 million nephrons, each of which contributes to the
total glomerular filtration rate (GFR). In the face of renal injury (regardless of the etiology),
the kidney has an innate ability to maintain GFR, despite progressive destruction of nephrons,
as the remaining healthy nephrons manifest hyperfiltration and compensatory hypertrophy.
This nephron adaptability allows for continued normal clearance of plasma solutes. Plasma
levels of substances such as urea and creatinine start to show measurable increases only after
total GFR has decreased to 50%.

The plasma creatinine value will approximately double with a 50% reduction in GFR. For
example, a rise in plasma creatinine from a baseline value of 0.6 mg/dL to 1.2 mg/dL in a
patient, although still within the adult reference range, actually represents a loss of 50% of
functioning nephron mass.

The hyperfiltration and hypertrophy of residual nephrons, although beneficial for the reasons
noted, has been hypothesized to represent a major cause of progressive renal dysfunction. The
increased glomerular capillary pressure may damage the capillaries, leading initially to
secondary focal and segmental glomerulosclerosis (FSGS) and eventually to global
glomerulosclerosis. This hypothesis is supported by studies of five-sixths nephrectomized
rats, which develop lesions identical to those observed in humans with chronic kidney disease
(CKD).

Factors other than the underlying disease process and glomerular hypertension that may cause
progressive renal injury include the following:

Systemic hypertension
Nephrotoxins (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], intravenous contrast
media)

Decreased perfusion (eg, from severe dehydration or episodes of shock)

Proteinuria (in addition to being a marker of CKD)

 Hyperlipidemia

Hyperphosphatemia with calcium phosphate deposition

Smoking

Uncontrolled diabetes

Thaker et al found a strong association between episodes of acute kidney injury (AKI) and
cumulative risk for the development of advanced CKD in multiple hospitalized patients with
diabetes mellitus. [6] Any AKI versus no AKI was a risk factor for stage 4 CKD, and each
additional AKI episode doubled that risk. [6]

Findings from the Atherosclerosis Risk in Communities (ARIC) Study, a prospective

observational cohort, suggest that inflammation and hemostasis are antecedent pathways for
CKD. [7] This study used data from 1787 cases of CKD that developed between 1987 and
2004.

Childhood renal function and CKD in children

In children, the GFR increases with age and is calculated with specific equations that are
different than those for adults. Adjusted for body surface area, the GFR reaches adult levels
by age 2-3 years.

Aspects of pediatric kidney function and the measure of creatinine are informative not only
for children but also for adults. For example, it is important to realize that creatinine is
derived from muscle and, therefore, that children and smaller individuals have lower
creatinine levels independent of the GFR. Consequently, laboratory reports that do not supply
appropriate pediatric normal ranges are misleading. The same is true for individuals who
have low muscle mass for other reasons, such as malnutrition, cachexia, or amputation.

Another important note for childhood CKD is that physicians caring for children must be
aware of normal blood pressure levels by age, sex, and height. Prompt recognition of
hypertension at any age is important, because it may be caused by primary renal disease.

Fortunately, CKD during childhood is rare and is usually the result of congenital defects, such
as posterior urethral valves or dysplastic kidney malformations. Another common cause is
FSGS. Genetic kidney diseases are also frequently manifested in childhood CKD. Advances
in pediatric nephrology have enabled great leaps in survival for pediatric CKD and end-stage
renal disease (ESRD), including for children who need dialysis or transplantation.

Aging and renal function

The biologic process of aging initiates various structural and functional changes within the
kidney. [8, 9] Renal mass progressively declines with advancing age, and glomerulosclerosis
leads to a decrease in renal weight. Histologic examination is notable for a decrease in
glomerular number of as much as 30-50% by age 70 years. The GFR peaks during the third
decade of life at approximately 120 mL/min/1.73 m2; it then undergoes an annual mean
decline of approximately 1 mL/min/y/1.73 m2, reaching a mean value of 70 mL/min/1.73 m2
at age 70 years.
Ischemic obsolescence of cortical glomeruli is predominant, with relative sparing of the renal
medulla. Juxtamedullary glomeruli see a shunting of blood from afferent to efferent
arterioles, resulting in redistribution of blood flow favoring the renal medulla. These
anatomic and functional changes in renal vasculature appear to contribute to an age-related
decrease in renal blood flow.

Renal hemodynamic measurements in aged humans and animals suggest that altered
functional response of the renal vasculature may be an underlying factor in diminished renal
blood flow and increased filtration noted with progressive renal aging. The vasodilatory
response is blunted in the elderly when compared to younger patients.

However, the vasoconstrictor response to intrarenal angiotensin is identical in young and

older human subjects. A blunted vasodilatory capacity with appropriate vasoconstrictor
response may indicate that the aged kidney is in a state of vasodilatation to compensate for
the underlying sclerotic damage.

Given the histologic evidence for nephronal senescence with age, a decline in the GFR is
expected. However, a wide variation in the rate of GFR decline is reported because of
measurement methods, race, gender, genetic variance, and other risk factors for renal
dysfunction.

Genetics

Most cases of CKD are acquired rather than inherited, although CKD in a child is more likely
to have a genetic or inherited cause. Well-described genetic syndromes associated with CKD
include autosomal dominant polycystic kidney disease (ADPKD) and Alport syndrome.
Other examples of specific single-gene or few-gene mutations associated with CKD include
Dent disease, nephronophthisis, and atypical hemolytic uremic syndrome (HUS).

APOL1 gene

More recently, researchers have begun to identify genetic contributions to increased risk for
development or progression of CKD. Friedman et al found that more than 3 million black
persons with genetic variants in both copies of apolipoprotein L1 (APOL1) are at higher risk
for hypertension-attributable ESRD and FSGS. In contrast, black individuals without the risk
genotype and European Americans appear to have similar risk for developing nondiabetic
CKD. [10]

FGF-23 gene

Circulating levels of the phosphate-regulating hormone fibroblast growth factor 23 (FGF-23)

are affected by variants in the FGF23 gene. Isakova et al reported that elevated FGF-23
levels are an independent risk factor for ESRD in patients who have fairly well-preserved
kidney function (stages 2-4) and for mortality across the scope of CKD. [11]

Single-nucleotide polymorphisms

A review of 16 single-nucleotide polymorphisms (SNPs) that had been associated with

variation in GFR found that development of albuminuria was associated mostly with an SNP
in the SHROOM3 gene. [12] Even accounting for this variant, however, there is evidence that
some unknown genetic variant influences the development of albuminuria in CKD. This
study also suggests a separate genetic influence on development of albuminuria versus
reduction in GFR. [12]

A genome-wide association study (GWAS) that included over 130,000 patients found 6 SNPs
associated with reduced GFR, located in or near MPPED2, DDX1, SLC47A1, CDK12,
CASP9, and INO80. [13] The SNP in SLC47A1 was associated with decreased GFR in
nondiabetic individuals, whereas SNPs located in the DNAJC16 and CDK12 genes were
associated with decreased GFR in individuals younger than 65 years. [13]

Immune-system and RAS genes

A number of genes have been associated with the development of ESRD. Many of these
genes involve aspects of the immune system (eg, CCR3, IL1RN, IL4). [14]

Unsurprisingly, polymorphisms in genes involving the renin-angiotensin system (RAS) have

also been implicated in predisposition to CKD. One study found that patients with CKD were
significantly more likely to have the A2350G polymorphism in the ACE gene, which encodes
the angiotensin-converting enzyme (ACE). [15] They were also more likely to have the C573T
polymorphism in the AGTR1 gene, which encodes the angiotensin II type 1 receptor. [15]

Hyperkalemia

The ability to maintain potassium excretion at near-normal levels is generally maintained in

CKD, as long as aldosterone secretion and distal flow are maintained. Another defense
against potassium retention in patients with CKD is increased potassium excretion in the
gastrointestinal tract, which also is under control of aldosterone.

Hyperkalemia usually does not develop until the GFR falls to less than 20-25 mL/min/1.73
m, at which point the kidneys have decreased ability to excrete potassium. Hyperkalemia can
be observed sooner in patients who ingest a potassium-rich diet or have low serum
aldosterone levels. Common sources of low aldosterone levels are diabetes mellitus and the
use of ACE inhibitors, NSAIDs, or beta-blockers.

Hyperkalemia in CKD can be aggravated by an extracellular shift of potassium, such as

occurs in the setting of acidemia or from lack of insulin.

Hypokalemia

Hypokalemia is uncommon but can develop in patients with very poor intake of potassium,
gastrointestinal or urinary loss of potassium, or diarrhea or in patients who use diuretics.

Metabolic acidosis

Metabolic acidosis often is a mixture of normal anion gap and increased anion gap; the latter
is observed generally with stage 5 CKD but with the anion gap generally not higher than 20
mEq/L. In CKD, the kidneys are unable to produce enough ammonia in the proximal tubules
to excrete the endogenous acid into the urine in the form of ammonium. In stage 5 CKD,
accumulation of phosphates, sulfates, and other organic anions are the cause of the increase in
anion gap.
Metabolic acidosis has been shown to have deleterious effects on protein balance, leading to
the following:

Negative nitrogen balance

Increased protein degradation

Increased essential amino acid oxidation

Reduced albumin synthesis

Lack of adaptation to a low-protein diet

Hence, metabolic acidosis is associated with protein-energy malnutrition, loss of lean body
mass, and muscle weakness. The mechanism for reducing protein may include effects on
adenosine triphosphate (ATP)dependent ubiquitin proteasomes and increased activity of
branched-chain keto acid dehydrogenases.

Metabolic acidosis also leads to an increase in fibrosis and rapid progression of kidney
disease, by causing an increase in ammoniagenesis to enhance hydrogen excretion.

In addition, metabolic acidosis is a factor in the development of renal osteodystrophy,

because bone acts as a buffer for excess acid, with resultant loss of mineral. Acidosis may
interfere with vitamin D metabolism, and patients who are persistently more acidotic are
more likely to have osteomalacia or low-turnover bone disease.

Salt- and water-handling abnormalities

Salt and water handling by the kidney is altered in CKD. Extracellular volume expansion and
total-body volume overload results from failure of sodium and free-water excretion. This
generally becomes clinically manifested when the GFR falls to less than 10-15 mL/min/1.73
m, when compensatory mechanisms have become exhausted.

As kidney function declines further, sodium retention and extracellular volume expansion
lead to peripheral edema and, not uncommonly, pulmonary edema and hypertension. At a
higher GFR, excess sodium and water intake could result in a similar picture if the ingested
amounts of sodium and water exceed the available potential for compensatory excretion.

Tubulointerstitial renal diseases represent the minority of cases of CKD. However, it is

important to note that such diseases often cause fluid loss rather than overload. Thus, despite
moderate or severe reductions in GFR, tubulointerstitial renal diseases may manifest first as
polyuria and volume depletion, with inability to concentrate the urine. These symptoms may
be subtle and require close attention to be recognized. Volume overload occurs only when
GFR reduction becomes very severe.

Anemia

Normochromic normocytic anemia principally develops from decreased renal synthesis of

erythropoietin, the hormone responsible for bone marrow stimulation for red blood cell
(RBC) production. The anemia starts early in the course of the disease and becomes more
severe as, with the shrinking availability of viable renal mass, the GFR progressively
decreases.
Using data from the National Health and Nutrition Examination Survey (NHANES), Stauffer
and Fan found that anemia was twice as prevalent in people with CKD (15.4%) as in the
general population (7.6%). The prevalence of anemia increased with stage of CKD, from
8.4% at stage 1 to 53.4% at stage 5. [16]

No reticulocyte response occurs. RBC survival is decreased, and bleeding tendency is

increased from the uremia-induced platelet dysfunction. Other causes of anemia in CKD
include the following:

Chronic blood loss: Uremia-induced platelet dysfunction enhances bleeding tendency

Secondary hyperparathyroidism

Inflammation

Nutritional deficiency

Accumulation of inhibitors of erythropoiesis

Bone disease

Renal bone disease is a common complication of CKD. It results in skeletal complications

(eg, abnormality of bone turnover, mineralization, linear growth) and extraskeletal
complications (eg, vascular or soft-tissue calcification).

Different types of bone disease occur with CKD, as follows:

High-turnover bone disease from high parathyroid hormone (PTH) levels

Low-turnover bone disease (adynamic bone disease)

Defective mineralization (osteomalacia)

Mixed disease

Beta-2-microglobulinassociated bone disease

Bone disease in children is similar but occurs during growth. Therefore, children with CKD
are at risk for short stature, bone curvature, and poor mineralization (renal rickets is the
equivalent term for adult osteomalacia).

CKDmineral and bone disorder (CKD-MBD) involves biochemical abnormalities related to

bone metabolism. CKD-MBD may result from alteration in levels of serum phosphorus,
PTH, vitamin D, and alkaline phosphatase.

Secondary hyperparathyroidism develops in CKD because of the following factors:

Hyperphosphatemia
Hypocalcemia

Decreased renal synthesis of 1,25-dihydroxycholecalciferol (1,25-dihydroxyvitamin D, or

calcitriol)
 Intrinsic alteration in the parathyroid glands, which gives rise to increased PTH secretion and
increased parathyroid growth

Skeletal resistance to PTH

Calcium and calcitriol are primary feedback inhibitors; hyperphosphatemia is a stimulus to

PTH synthesis and secretion.

Hyperphosphatemia and hypocalcemia

Phosphate retention begins in early CKD; when the GFR falls, less phosphate is filtered and
excreted, but because of increased PTH secretion, which increases renal excretion, serum
levels do not rise initially. As the GFR falls toward CKD stages 4-5, hyperphosphatemia
develops from the inability of the kidneys to excrete the excess dietary intake.

Hyperphosphatemia suppresses the renal hydroxylation of inactive 25-hydroxyvitamin D to

calcitriol, so serum calcitriol levels are low when the GFR is less than 30 mL/min/1.73 m.
Increased phosphate concentration also effects PTH concentration by its direct effect on the
parathyroid glands (posttranscriptional effect).

Hypocalcemia develops primarily from decreased intestinal calcium absorption because of

low plasma calcitriol levels. It also possibly results from increased calcium-phosphate
binding, caused by elevated serum phosphate levels.

Increased PTH secretion

Low serum calcitriol levels, hypocalcemia, and hyperphosphatemia have all been
demonstrated to independently trigger PTH synthesis and secretion. As these stimuli persist
in CKD, particularly in the more advanced stages, PTH secretion becomes maladaptive, and
the parathyroid glands, which initially hypertrophy, become hyperplastic. The persistently
elevated PTH levels exacerbate hyperphosphatemia from bone resorption of phosphate.

Skeletal manifestations

If serum levels of PTH remain elevated, a high bone turnover lesion, known as osteitis
fibrosa, develops. This is one of several bone lesions, which as a group are commonly known
as renal osteodystrophy and which develop in patients with severe CKD. Osteitis fibrosa is
common in patients with ESRD.

The prevalence of adynamic bone disease in the United States has increased, and it has been
described before the initiation of dialysis in some cases. The pathogenesis of adynamic bone
disease is not well defined, but several factors may contribute, including high calcium load,
use of vitamin D sterols, increasing age, previous corticosteroid therapy, peritoneal dialysis,
and increased level of N-terminally truncated PTH fragments.

Low-turnover osteomalacia in the setting of CKD is associated with aluminum accumulation.

It is markedly less common than high-turnover bone disease.

Another form of bone disease is dialysis-related amyloidosis, which is now uncommon in the
era of improved dialysis membranes. This condition occurs from beta-2-microglobulin
accumulation in patients who have required chronic dialysis for at least 8-10 years. It
manifests with cysts at the ends of long bones.

Etiology
Causes of chronic kidney disease (CKD) include the following:

Diabetic kidney disease

Hypertension

Vascular disease

Glomerular disease (primary or secondary)

Cystic kidney diseases

Tubulointerstitial disease

Urinary tract obstruction or dysfunction

Recurrent kidney stone disease

Congenital (birth) defects of the kidney or bladder

Unrecovered acute kidney injury

Vascular diseases that can cause CKD include the following:

Renal artery stenosis

Cytoplasmic pattern antineutrophil cytoplasmic antibody (C-ANCA)positive and perinuclear
pattern antineutrophil cytoplasmic antibody (P-ANCA)positive vasculitides

ANCA-negative vasculitides

Atheroemboli

Hypertensive nephrosclerosis

Renal vein thrombosis

Primary glomerular diseases include the following:

Membranous nephropathy
Alport syndrome

Immunoglobulin A (IgA) nephropathy

Focal and segmental glomerulosclerosis (FSGS)

Minimal change disease

Membranoproliferative glomerulonephritis (MPGN)

Complement-related diseases (eg, atypical hemolytic-uremic syndrome [HUS], dense deposit

disease)
 Rapidly progressive (crescentic) glomerulonephritis

Secondary causes of glomerular disease include the following:

Diabetes mellitus
Systemic lupus erythematosus

Rheumatoid arthritis

Mixed connective tissue disease

Scleroderma

Wegener granulomatosis

Mixed cryoglobulinemia

Endocarditis

Hepatitis B and C

Syphilis

Human immunodeficiency virus (HIV)

Parasitic infection

Heroin use

Gold

Penicillamine

Amyloidosis

Light-chain deposition disease

Neoplasia

Thrombotic thrombocytopenic purpura (TTP)

Shiga-toxin or Streptococcus pneumoniae related HUS

Henoch-Schnlein purpura

Reflux nephropathy

Causes of tubulointerstitial disease include the following:

Drugs (eg, sulfonamides, allopurinol)

Infection (viral, bacterial, parasitic)

Sjgren syndrome

Tubulointerstitial nephritis and uveitis (TINU) syndrome

Chronic hypokalemia
 Chronic hypercalcemia

Sarcoidosis

Multiple myeloma cast nephropathy

Heavy metals

Radiation nephritis

Polycystic kidneys

Cystinosis and other inherited diseases

Urinary tract obstruction may result from any of the following:

Benign prostatic hypertrophy

Urolithiasis (kidney stones)

Urethral stricture

Tumors

Neurogenic bladder

Congenital (birth) defects of the kidney or bladder

Retroperitoneal fibrosis

Epidemiology
In the United States, the National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) reports that one in 10 American adults has some level of chronic kidney disease
(CKD). [17] Kidney disease is the ninth leading cause of death in the United States. [18]

According to the NIDDK, the incidence of recognized CKD in people aged 20-64 years in the
United States rose only slightly from 2000 2008 and remains less than 0.5%. [17] In contrast,
the incidence of recognized CKD in people aged 65 years or older more than doubled
between 2000 and 2008, from approximately 1.8% to approximately 4.3%. [17]

The US prevalence of CKD increases dramatically with age (4% at age 29-39 y; 47% at age
>70 y), with the most rapid growth in people aged 60 years or older. In the National Health
and Nutrition Examination Survey (NHANES) study, the prevalence of stage 3 CKD in this
age group rose from 18.8% during the years 1988 1994 to 24.5% during the years 2003
2006. During the same period, the prevalence of CKD in people aged 20-39 years remained
consistently below 0.5%. [17]

According to 1999 2004 NHANES data, the estimated prevalence of CKD by stage was as
follows [19] :

Stage 1: 5.7%
Stage 2: 5.4%
 Stage 3: 5.4%

Stage 4: 0.4%

Stage 5: 0.4%

The US incidence of end-stage renal disease (ESRD) rose steadily from 1980-2001, but the
rate subsequently leveled off at approximately 350 per 1 million population. [17] However, the
percentage of patients older than 65 years has been the most rapidly growing segment of the
ESRD population, having increased from 5% to 37% of this group. [17]

The US Surgeon Generals latest report on 10-year national objectives for improving the
health of all Americans, Healthy People 2020, contains a chapter focused on CKD. For 2020,
Healthy People lays out 14 objectives concerning reduction of the US incidence, morbidity,
mortality, and health costs of CKD. Reducing renal failure will require additional public
health efforts, including effective preventive strategies and early detection and treatment of
CKD.

A systematic review and meta-analysis of observational studies estimating CKD prevalence

in general populations worldwide found a consistent estimated global CKD prevalence of 11-
13%. The majority of cases are stage 3. [20]

Race-related demographics

Although CKD affects all races, the incidence rate of ESRD among blacks in the United
States is nearly 4 times that for whites. [17] Choi et al found that rates of ESRD among black
patients exceeded those among white patients at all levels of baseline estimated glomerular
filtration rate (GFR). [21] Risk of ESRD among black patients was highest at an estimated GFR
of 45-59 mL/min/1.73 m2, as was the risk of mortality.

Schold et al found that among black kidney transplant recipients, rates of graft loss and acute
rejection were higher than in white recipients, especially among younger patients. [22] Hicks et
al looked at the connection between black patients with the sickle cell trait and their increased
risk for kidney disease; the study found that sickle cell trait was not associated with diabetic
or nondiabetic ESRD in a large sample of black patients. [23]

Important differences also exist in the frequency of specific causes of CKD among different
races. In the Chronic Kidney Disease in Children (CKiD) Study, for example, glomerular
disease was much more common among nonwhite persons. [24] Overall, FSGS in particular is
more common among Hispanic Americans and black persons, as is the risk of nephropathy
with diabetes or with hypertension; in contrast, IgA nephropathy is rare in black individuals
and more common among those with Asian ancestry. [25]

Sex- related demographics

In NHANES, the distribution of estimated GFRs for the stages of CKD was similar in both
sexes. In the United States Renal Data System (USRDS) 2011 Annual Data Report, however,
the incident rate of ESRD cases at the initiation of hemodialysis in 2009 was higher for
males, with 415.1 per million population compared with 256.6 for females. [26]
CKD in children is somewhat more common in boys, because posterior urethral valves, the
most common birth defect leading to CKD, occur only in boys. Importantly, many individuals
with congenital kidney disease such as dysplasia or hypoplasia do not clinically manifest
CKD or ESRD until adulthood.

Prognosis
Patients with chronic kidney disease (CKD) generally experience progressive loss of kidney
function and are at risk for end-stage renal disease (ESRD). The rate of progression depends
on age, the underlying diagnosis, the success of implementation of secondary preventive
measures, and the individual patient. Timely initiation of chronic renal replacement therapy is
imperative to prevent the uremic complications of CKD that can lead to significant morbidity
and death.

Tangri et al developed and validated a model in adult patients that uses routine laboratory
results to predict progression from CKD (stages 3-5) to kidney failure. [27] They reported that
lower estimated glomerular filtration rate (GFR), higher albuminuria, younger age, and male
sex pointed to a faster progression of kidney failure. Also, a lower serum albumin, calcium,
and bicarbonate level and a higher serum phosphate level were found to predict an elevated
risk of kidney failure. [27]

Hospitalization

Unadjusted rates of hospitalization in the CKD population, reflecting its total disease burden,
are 3-5 times higher than those of patients without CKD. [26] After adjustment for gender, prior
hospitalizations, and comorbidity, rates for patients with CKD are 1.4 times higher. Rates of
hospitalization for cardiovascular disease and bacterial infection are particularly elevated. [26]

Dialysis

In the United States, hemodialysis and peritoneal dialysis patients average 2 hospital
admissions per year; patients who have a renal transplant average 1 hospital admission per
year. Additionally, patients with ESRD who undergo renal transplantation survive longer than
those on long-term dialysis. [28]

Hemodialysis performed 6 times per week significantly increased the risk of vascular access
complications compared with a conventional 3-day regimen in one study. [29, 30] Of 125 patients
who received hemodialysis 6 days per week, 48 experienced the composite primary endpoint
event of vascular repair, loss, or related hospitalization, compared with only 29 of the 120
patients undergoing conventional treatment. Results indicated that overall risk for a first
access event was 76% higher with daily hemodialysis than with the conventional regimen. [29,
30]

Mortality

The mortality rates associated with CKD are striking. After adjustment for age, gender, race,
comorbidity, and prior hospitalizations, mortality in patients with CKD in 2009 was 56%
greater than that in patients without CKD. [26] For patients with stages 4-5 CKD, the adjusted
mortality rate is 76% greater.
Mortality rates are consistently higher for men than for women, and for black persons than
for white individuals and patients of other races. For Medicare CKD patients aged 66 years
and older, deaths per 1000 patient-years in 2009 were 75 for white patients and 83 for black
patients. [26]

The highest mortality rate is within the first 6 months of initiating dialysis. Mortality then
tends to improve over the next 6 months, before increasing gradually over the next 4 years.
The 5-year survival rate for a patient undergoing long-term dialysis in the United States is
approximately 35%, and approximately 25% in patients with diabetes.

A study by Sens found that the risk of mortality was elevated in patients with ESRD and
congestive heart failure who received peritoneal dialysis compared with those who received
hemodialysis. [31] Median survival time was 20.4 months in patients receiving peritoneal
dialysis versus 36.7 months in the hemodialysis group.

At every age, patients with ESRD on dialysis have significantly increased mortality when
compared with nondialysis patients and individuals without kidney disease. At age 60 years, a
healthy person can expect to live for more than 20 years, whereas the life expectancy of a
patient aged 60 years who is starting hemodialysis is closer to 4 years. Among patients aged
65 years or older who have ESRD, mortality rates are 6 times higher than in the general
population. [26]

The most common cause of sudden death in patients with ESRD is hyperkalemia, which
often follows missed dialysis or dietary indiscretion. The most common cause of death
overall in the dialysis population is cardiovascular disease; cardiovascular mortality is 10-20
times higher in dialysis patients than in the general population. [32]

The morbidity and mortality of dialysis patients is much higher in the United States than in
most other countries, which is probably a consequence of selection bias. Because of liberal
criteria for receiving government-funded dialysis in the United States and the use of rationing
(medical and economic) in most other countries, US patients receiving dialysis are on the
average older and sicker than those in other countries.

In the National Health and Nutrition Examination Survey (NHANES) III prevalence study,
hypoalbuminemia (a marker of protein-energy malnutrition and a powerful predictive marker
of mortality in dialysis patients, as well as in the general population) was independently
associated with low bicarbonate, as well as with the inflammatory marker C-reactive protein.
A study by Raphael et al suggests that higher serum bicarbonate levels are associated with
better survival and renal outcomes in African Americans. [33]

A study by Navaneethan et al found a connection between low levels of 25-hydroxyvitamin D

(25[OH]D) and all-cause mortality in patients with nondialysis CKD. [34] Adjusted risk of
mortality was 33% higher in patients whose 25(OH)D levels were below 15 ng/mL.

Morbidity and mortality among children with CKD and ESRD are much lower than among
adults with these conditions, but they are strikingly higher than for healthy children. As with
adults, the risk is highest among dialysis patients; consequently, transplantation is the
preferred treatment for pediatric patients with ESRD.

Sexual and reproductive issues

Puberty is often delayed among males and females with significant CKD. Female patients
with advanced CKD commonly develop menstrual irregularities. Women with ESRD are
typically amenorrheic and infertile. However, pregnancy can occur and can be associated
with accelerated renal decline, including in women with a kidney transplant. In advanced
CKD and ESRD, pregnancy is associated with markedly decreased fetal survival.

Vitamin D

Many patients with CKD have low circulating levels of 25(OH)D. A study of 1099 patients
(mostly men) with advanced CKD found that the lowest tertile of 1,25(OH)(2)D (< 15
pg/mL) was associated with death and initiation of long-term dialysis therapy compared with
the highest tertile (>22 pg/mL). [35] A retrospective cohort study in 12,763 nondialysis-
dependent patients with CKD found that 25(OH)D levels below 15 ng/mL were associated
independently with all-cause mortality. [36]

Patient Education
Patients with chronic kidney disease (CKD) should be educated about the following:

Importance of avoiding factors leading to increased progression (see Etiology)

Natural disease progression

Prescribed medications (highlighting their potential benefits and adverse effects)

Avoidance of nephrotoxins

Diet (see Diet)

Renal replacement modalities, including peritoneal dialysis, hemodialysis, and

transplantation

Timely placement of vascular access for hemodialysis

Women of childbearing age who have end-stage renal disease (ESRD) should be counseled
that although their fertility is greatly reduced, pregnancy can occur and is associated with
higher risk than in women who do not have renal disease. In addition, many medications used
to treat CKD are potentially teratogenic; in particular, women taking angiotensin-converting
enzyme (ACE) inhibitors and certain immunosuppressive treatments require clear counseling.

Clinical Presentation

Contributor Information and Disclosures

Author

Pradeep Arora, MD Assistant Professor of Medicine, University of Buffalo State University

of New York School of Medicine and Biomedical Sciences; Attending Nephrologist, Veterans
Affairs Western New York Healthcare System

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FASN Huberwald Professor of Medicine, Section of Nephrology-

Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast
Louisiana Veterans Health Care System

Vecihi Batuman, MD, FASN is a member of the following medical societies: American
College of Physicians, American Society of Hypertension, American Society of Nephrology,
International Society of Nephrology, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Acknowledgements

George R Aronoff, MD Director, Professor, Departments of Internal Medicine and

Pharmacology, Section of Nephrology, Kidney Disease Program, University of Louisville
School of Medicine

George R Aronoff, MD is a member of the following medical societies: American Federation

for Medical Research, American Society of Nephrology, Kentucky Medical Association, and
National Kidney Foundation

Disclosure: Nothing to disclose.

Laura Lyngby Mulloy, DO, FACP Professor of Medicine, Chief, Section of Nephrology,
Hypertension, and Transplantation Medicine, Glover/Mealing Eminent Scholar Chair in
Immunology, Medical College of Georgia

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska

Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Mauro Verrelli, MD, FRCP(C), FACP Assistant Professor, Department of Medicine,

Section of Nephrology, University of Manitoba, Canada

Disclosure: Nothing to disclose.

Sections Chronic Kidney Disease

Overview

o Practice Essentials

o Pathophysiology

o Etiology

o Epidemiology
 o Prognosis

o Patient Education

Presentation

DDx

Workup

Treatment

Medication

References

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News & Perspective

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Use of Clinical Decision Support to Improve Primary Care Identification and Management of
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Chronic Kidney Disease

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Updated: Jul 25, 2016

Author: Pradeep Arora, MD; Chief Editor: Vecihi Batuman, MD, FASN more...

Sections

o

Practice Essentials
Chronic kidney disease (CKD)or chronic renal failure (CRF), as it was historically termed
is a term that encompasses all degrees of decreased renal function, from damagedat risk
through mild, moderate, and severe chronic kidney failure. CKD is a worldwide public health
problem. In the United States, there is a rising incidence and prevalence of kidney failure,
with poor outcomes and high cost (see Epidemiology).

CKD is more prevalent in the elderly population. However, while younger patients with
CKD typically experience progressive loss of kidney function, 30%% of patients over 65
years of age with CKD have stable disease. [1]

CKD is associated with an increased risk of cardiovascular disease and chronic renal failure.
Kidney disease is the ninth leading cause of death in the United States.

The Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney
Foundation (NKF) established a definition and classification of CKD in 2002. [3] The KDOQI
and the international guideline group Kidney Disease Improving Global Outcomes (KDIGO)
have subsequently updated these guidelines. [4, 5] These guidelines have allowed better
communication among physicians and have facilitated intervention at the different stages of
the disease.

The guidelines define CKD as either kidney damage or a decreased glomerular filtration rate
(GFR) of less than 60 mL/min/1.73 m2 for at least 3 months. Whatever the underlying
etiology, once the loss of nephrons and reduction of functional renal mass reaches a certain
point, the remaining nephrons begin a process of irreversible sclerosis that leads to a
progressive decline in the GFR.

Hyperparathyroidism is one of the pathologic manifestations of CKD. See the image below.
 Calciphylaxis due to secondary
hyperparathyroidism.

Staging

The different stages of CKD form a continuum. The stages of CKD are classified as follows [5]
:

Stage 1: Kidney damage with normal or increased GFR (>90 mL/min/1.73 m 2)

Stage 2: Mild reduction in GFR (60-89 mL/min/1.73 m 2)

Stage 3a: Moderate reduction in GFR (45-59 mL/min/1.73 m 2)

Stage 3b: Moderate reduction in GFR (30-44 mL/min/1.73 m 2)

Stage 4: Severe reduction in GFR (15-29 mL/min/1.73 m 2)

Stage 5: Kidney failure (GFR <15 mL/min/1.73 m 2 or dialysis)

In stage 1 and stage 2 CKD, reduced GFR alone does not clinch the diagnosis, because the
GFR may in fact be normal or borderline normal. In such cases, the presence of one or more
of the following markers of kidney damage can establish the diagnosis [5] :

Albuminuria (albumin excretion >30 mg/24 hr or albumin:creatinine ratio >30 mg/g [>3
mg/mmol])
Urine sediment abnormalities

Electrolyte and other abnormalities due to tubular disorders

Histologic abnormalities

Structural abnormalities detected by imaging

History of kidney transplantation in such cases

Hypertension is a frequent sign of CKD but should not by itself be considered a marker of it,
because elevated blood pressure is also common among people without CKD.
In an update of its CKD classification system, the NKF advised that GFR and albuminuria
levels be used together, rather than separately, to improve prognostic accuracy in the
assessment of CKD. [4, 5] More specifically, the guidelines recommended the inclusion of
estimated GFR and albuminuria levels when evaluating risks for overall mortality,
cardiovascular disease, end-stage kidney failure, acute kidney injury, and the progression of
CKD. Referral to a kidney specialist was recommended for patients with a very low GFR
(<15 mL/min/1.73 m) or very high albuminuria (>300 mg/24 h). [4, 5]

Patients with stages 1-3 CKD are frequently asymptomatic. Clinical manifestations resulting
from low kidney function typically appear in stages 4-5 (see Presentation).

Signs and symptoms

Patients with CKD stages 1-3 are generally asymptomatic. Typically, it is not until stages 4-5
(GFR <30 mL/min/1.73 m) that endocrine/metabolic derangements or disturbances in water
or electrolyte balance become clinically manifest.

Signs of metabolic acidosis in stage 5 CKD include the following:

Protein-energy malnutrition
Loss of lean body mass

Muscle weakness

Signs of alterations in the way the kidneys are handling salt and water in stage 5 include the
following:

Peripheral edema
Pulmonary edema

Hypertension

Anemia in CKD is associated with the following:

Fatigue
Reduced exercise capacity

Impaired cognitive and immune function

Reduced quality of life

Development of cardiovascular disease

New onset of heart failure or the development of more severe heart failure

Increased cardiovascular mortality

Other manifestations of uremia in end-stage renal disease (ESRD), many of which are more
likely in patients who are being inadequately dialyzed, include the following:

Pericarditis: Can be complicated by cardiac tamponade, possibly resulting in death if

unrecognized
 Encephalopathy: Can progress to coma and death

Peripheral neuropathy, usually asymptomatic

Restless leg syndrome

Gastrointestinal symptoms: Anorexia, nausea, vomiting, diarrhea

Skin manifestations: Dry skin, pruritus, ecchymosis

Fatigue, increased somnolence, failure to thrive

Malnutrition

Erectile dysfunction, decreased libido, amenorrhea

Platelet dysfunction with tendency to bleed

Screen adult patients with CKD for depressive symptoms; self-report scales at initiation of
dialysis therapy reveal that 45% of these patients have such symptoms, albeit with a somatic
emphasis.

See Clinical Presentation for more detail.

Diagnosis

Laboratory studies

Laboratory studies used in the diagnosis of CKD can include the following:

Complete blood count (CBC)

Basic metabolic panel

Urinalysis

Serum albumin levels: Patients may have hypoalbuminemia due to malnutrition, urinary
protein loss, or chronic inflammation

Lipid profile: Patients with CKD have an increased risk of cardiovascular disease

Evidence of renal bone disease can be derived from the following tests:

Serum calcium and phosphate

25-hydroxyvitamin D

Alkaline phosphatase

Intact parathyroid hormone (PTH) levels

In certain cases, the following tests may also be ordered as part of the evaluation of patients
with CKD:

Serum and urine protein electrophoresis and free light chains: Screen for a monoclonal
protein possibly representing multiple myeloma
 Antinuclear antibodies (ANA), double-stranded DNA antibody levels: Screen for systemic
lupus erythematosus

Serum complement levels: Results may be depressed with some glomerulonephritides

Cytoplasmic and perinuclear pattern antineutrophil cytoplasmic antibody (C-ANCA and P-

ANCA) levels: Positive findings are helpful in the diagnosis of granulomatosis with polyangiitis
(Wegener granulomatosis); P-ANCA is also helpful in the diagnosis of microscopic polyangiitis

Antiglomerular basement membrane (anti-GBM) antibodies: Presence is highly suggestive

of underlying Goodpasture syndrome

Hepatitis B and C, human immunodeficiency virus (HIV), Venereal Disease Research

Laboratory (VDRL) serology: Conditions associated with some glomerulonephritides

Imaging studies

Imaging studies that can be used in the diagnosis of CKD include the following:

Renal ultrasonography: Useful to screen for hydronephrosis, which may not be observed in
early obstruction or dehydrated patients; or for involvement of the retroperitoneum with
fibrosis, tumor, or diffuse adenopathy; small, echogenic kidneys are observed in advanced
renal failure
Retrograde pyelography: Useful in cases with high suspicion for obstruction despite negative
renal ultrasonograms, as well as for diagnosing renal stones

Computed tomography (CT) scanning: Useful to better define renal masses and cysts usually
noted on ultrasonograms; also the most sensitive test for identifying renal stones

Magnetic resonance imaging (MRI): Useful in patients who require a CT scan but who cannot
receive intravenous contrast; reliable in the diagnosis of renal vein thrombosis

Renal radionuclide scanning: Useful to screen for renal artery stenosis when performed with
captopril administration; also quantitates the renal contribution to the GFR

Biopsy

Percutaneous renal biopsy is generally indicated when renal impairment and/or proteinuria
approaching the nephrotic range are present and the diagnosis is unclear after appropriate
workup.

See Workup for more detail.

Management

Early diagnosis and treatment of the underlying cause and/or institution of secondary
preventive measures is imperative in patients with CKD. These may slow, or possibly halt,
progression of the disease.The medical care of patients with CKD should focus on the
following:

Delaying or halting the progression of CKD: Treatment of the underlying condition, if

possible, is indicated
 Diagnosing and treating the pathologic manifestations of CKD

Timely planning for long-term renal replacement therapy

The pathologic manifestations of CKD should be treated as follows:

Anemia: When the hemoglobin level is below 10 g/dL, treat with erythropoiesis-stimulating
agents (ESAs), which include epoetin alfa and darbepoetin alfa after iron saturation and
ferritin levels are at acceptable levels
Hyperphosphatemia: Treat with dietary phosphate binders and dietary phosphate restriction

Hypocalcemia: Treat with calcium supplements with or without calcitriol

Hyperparathyroidism: Treat with calcitriol or vitamin D analogues or calcimimetics

Volume overload: Treat with loop diuretics or ultrafiltration

Metabolic acidosis: Treat with oral alkali supplementation

Uremic manifestations: Treat with long-term renal replacement therapy (hemodialysis,

peritoneal dialysis, or renal transplantation)

Indications for renal replacement therapy include the following:

Severe metabolic acidosis

Hyperkalemia

Pericarditis

Encephalopathy

Intractable volume overload

Failure to thrive and malnutrition

Peripheral neuropathy

Intractable gastrointestinal symptoms

In asymptomatic patients, a GFR of 5-9 mL/min/1.73 m, [2] irrespective of the cause of the
CKD or the presence or absence of other comorbidities

The National Kidney Foundations Kidney Disease Outcomes Quality Initiative (KDOQI)
issued a Clinical Practice Guideline for Nutrition in Chronic Renal Failure, as well as a
revision of recommendations for Nutrition in Children with Chronic Kidney Disease.

See Treatment and Medication for more detail.

For a discussion of CKD in children, click here.

Pathophysiology
A normal kidney contains approximately 1 million nephrons, each of which contributes to the
total glomerular filtration rate (GFR). In the face of renal injury (regardless of the etiology),
the kidney has an innate ability to maintain GFR, despite progressive destruction of nephrons,
as the remaining healthy nephrons manifest hyperfiltration and compensatory hypertrophy.
This nephron adaptability allows for continued normal clearance of plasma solutes. Plasma
levels of substances such as urea and creatinine start to show measurable increases only after
total GFR has decreased to 50%.

The plasma creatinine value will approximately double with a 50% reduction in GFR. For
example, a rise in plasma creatinine from a baseline value of 0.6 mg/dL to 1.2 mg/dL in a
patient, although still within the adult reference range, actually represents a loss of 50% of
functioning nephron mass.

The hyperfiltration and hypertrophy of residual nephrons, although beneficial for the reasons
noted, has been hypothesized to represent a major cause of progressive renal dysfunction. The
increased glomerular capillary pressure may damage the capillaries, leading initially to
secondary focal and segmental glomerulosclerosis (FSGS) and eventually to global
glomerulosclerosis. This hypothesis is supported by studies of five-sixths nephrectomized
rats, which develop lesions identical to those observed in humans with chronic kidney disease
(CKD).

Factors other than the underlying disease process and glomerular hypertension that may cause
progressive renal injury include the following:

Systemic hypertension
Nephrotoxins (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], intravenous contrast
media)

Decreased perfusion (eg, from severe dehydration or episodes of shock)

Proteinuria (in addition to being a marker of CKD)

Hyperlipidemia

Hyperphosphatemia with calcium phosphate deposition

Smoking

Uncontrolled diabetes

Thaker et al found a strong association between episodes of acute kidney injury (AKI) and
cumulative risk for the development of advanced CKD in multiple hospitalized patients with
diabetes mellitus. [6] Any AKI versus no AKI was a risk factor for stage 4 CKD, and each
additional AKI episode doubled that risk. [6]

Findings from the Atherosclerosis Risk in Communities (ARIC) Study, a prospective

observational cohort, suggest that inflammation and hemostasis are antecedent pathways for
CKD. [7] This study used data from 1787 cases of CKD that developed between 1987 and
2004.

Childhood renal function and CKD in children

In children, the GFR increases with age and is calculated with specific equations that are
different than those for adults. Adjusted for body surface area, the GFR reaches adult levels
by age 2-3 years.

Aspects of pediatric kidney function and the measure of creatinine are informative not only
for children but also for adults. For example, it is important to realize that creatinine is
derived from muscle and, therefore, that children and smaller individuals have lower
creatinine levels independent of the GFR. Consequently, laboratory reports that do not supply
appropriate pediatric normal ranges are misleading. The same is true for individuals who
have low muscle mass for other reasons, such as malnutrition, cachexia, or amputation.

Another important note for childhood CKD is that physicians caring for children must be
aware of normal blood pressure levels by age, sex, and height. Prompt recognition of
hypertension at any age is important, because it may be caused by primary renal disease.

Fortunately, CKD during childhood is rare and is usually the result of congenital defects, such
as posterior urethral valves or dysplastic kidney malformations. Another common cause is
FSGS. Genetic kidney diseases are also frequently manifested in childhood CKD. Advances
in pediatric nephrology have enabled great leaps in survival for pediatric CKD and end-stage
renal disease (ESRD), including for children who need dialysis or transplantation.

Aging and renal function

The biologic process of aging initiates various structural and functional changes within the
kidney. [8, 9] Renal mass progressively declines with advancing age, and glomerulosclerosis
leads to a decrease in renal weight. Histologic examination is notable for a decrease in
glomerular number of as much as 30-50% by age 70 years. The GFR peaks during the third
decade of life at approximately 120 mL/min/1.73 m2; it then undergoes an annual mean
decline of approximately 1 mL/min/y/1.73 m2, reaching a mean value of 70 mL/min/1.73 m2
at age 70 years.

Ischemic obsolescence of cortical glomeruli is predominant, with relative sparing of the renal
medulla. Juxtamedullary glomeruli see a shunting of blood from afferent to efferent
arterioles, resulting in redistribution of blood flow favoring the renal medulla. These
anatomic and functional changes in renal vasculature appear to contribute to an age-related
decrease in renal blood flow.

Renal hemodynamic measurements in aged humans and animals suggest that altered
functional response of the renal vasculature may be an underlying factor in diminished renal
blood flow and increased filtration noted with progressive renal aging. The vasodilatory
response is blunted in the elderly when compared to younger patients.

However, the vasoconstrictor response to intrarenal angiotensin is identical in young and

older human subjects. A blunted vasodilatory capacity with appropriate vasoconstrictor
response may indicate that the aged kidney is in a state of vasodilatation to compensate for
the underlying sclerotic damage.

Given the histologic evidence for nephronal senescence with age, a decline in the GFR is
expected. However, a wide variation in the rate of GFR decline is reported because of
measurement methods, race, gender, genetic variance, and other risk factors for renal
dysfunction.

Genetics

Most cases of CKD are acquired rather than inherited, although CKD in a child is more likely
to have a genetic or inherited cause. Well-described genetic syndromes associated with CKD
include autosomal dominant polycystic kidney disease (ADPKD) and Alport syndrome.
Other examples of specific single-gene or few-gene mutations associated with CKD include
Dent disease, nephronophthisis, and atypical hemolytic uremic syndrome (HUS).

APOL1 gene

More recently, researchers have begun to identify genetic contributions to increased risk for
development or progression of CKD. Friedman et al found that more than 3 million black
persons with genetic variants in both copies of apolipoprotein L1 (APOL1) are at higher risk
for hypertension-attributable ESRD and FSGS. In contrast, black individuals without the risk
genotype and European Americans appear to have similar risk for developing nondiabetic
CKD. [10]

FGF-23 gene

Circulating levels of the phosphate-regulating hormone fibroblast growth factor 23 (FGF-23)

are affected by variants in the FGF23 gene. Isakova et al reported that elevated FGF-23
levels are an independent risk factor for ESRD in patients who have fairly well-preserved
kidney function (stages 2-4) and for mortality across the scope of CKD. [11]

Single-nucleotide polymorphisms

A review of 16 single-nucleotide polymorphisms (SNPs) that had been associated with

variation in GFR found that development of albuminuria was associated mostly with an SNP
in the SHROOM3 gene. [12] Even accounting for this variant, however, there is evidence that
some unknown genetic variant influences the development of albuminuria in CKD. This
study also suggests a separate genetic influence on development of albuminuria versus
reduction in GFR. [12]

A genome-wide association study (GWAS) that included over 130,000 patients found 6 SNPs
associated with reduced GFR, located in or near MPPED2, DDX1, SLC47A1, CDK12,
CASP9, and INO80. [13] The SNP in SLC47A1 was associated with decreased GFR in
nondiabetic individuals, whereas SNPs located in the DNAJC16 and CDK12 genes were
associated with decreased GFR in individuals younger than 65 years. [13]

Immune-system and RAS genes

A number of genes have been associated with the development of ESRD. Many of these
genes involve aspects of the immune system (eg, CCR3, IL1RN, IL4). [14]

Unsurprisingly, polymorphisms in genes involving the renin-angiotensin system (RAS) have

also been implicated in predisposition to CKD. One study found that patients with CKD were
significantly more likely to have the A2350G polymorphism in the ACE gene, which encodes
the angiotensin-converting enzyme (ACE). [15] They were also more likely to have the C573T
polymorphism in the AGTR1 gene, which encodes the angiotensin II type 1 receptor. [15]

Hyperkalemia

The ability to maintain potassium excretion at near-normal levels is generally maintained in

CKD, as long as aldosterone secretion and distal flow are maintained. Another defense
against potassium retention in patients with CKD is increased potassium excretion in the
gastrointestinal tract, which also is under control of aldosterone.

Hyperkalemia usually does not develop until the GFR falls to less than 20-25 mL/min/1.73
m, at which point the kidneys have decreased ability to excrete potassium. Hyperkalemia can
be observed sooner in patients who ingest a potassium-rich diet or have low serum
aldosterone levels. Common sources of low aldosterone levels are diabetes mellitus and the
use of ACE inhibitors, NSAIDs, or beta-blockers.

Hyperkalemia in CKD can be aggravated by an extracellular shift of potassium, such as

occurs in the setting of acidemia or from lack of insulin.

Hypokalemia

Hypokalemia is uncommon but can develop in patients with very poor intake of potassium,
gastrointestinal or urinary loss of potassium, or diarrhea or in patients who use diuretics.

Metabolic acidosis

Metabolic acidosis often is a mixture of normal anion gap and increased anion gap; the latter
is observed generally with stage 5 CKD but with the anion gap generally not higher than 20
mEq/L. In CKD, the kidneys are unable to produce enough ammonia in the proximal tubules
to excrete the endogenous acid into the urine in the form of ammonium. In stage 5 CKD,
accumulation of phosphates, sulfates, and other organic anions are the cause of the increase in
anion gap.

Metabolic acidosis has been shown to have deleterious effects on protein balance, leading to
the following:

Negative nitrogen balance

Increased protein degradation

Increased essential amino acid oxidation

Reduced albumin synthesis

Lack of adaptation to a low-protein diet

Hence, metabolic acidosis is associated with protein-energy malnutrition, loss of lean body
mass, and muscle weakness. The mechanism for reducing protein may include effects on
adenosine triphosphate (ATP)dependent ubiquitin proteasomes and increased activity of
branched-chain keto acid dehydrogenases.
Metabolic acidosis also leads to an increase in fibrosis and rapid progression of kidney
disease, by causing an increase in ammoniagenesis to enhance hydrogen excretion.

In addition, metabolic acidosis is a factor in the development of renal osteodystrophy,

because bone acts as a buffer for excess acid, with resultant loss of mineral. Acidosis may
interfere with vitamin D metabolism, and patients who are persistently more acidotic are
more likely to have osteomalacia or low-turnover bone disease.

Salt- and water-handling abnormalities

Salt and water handling by the kidney is altered in CKD. Extracellular volume expansion and
total-body volume overload results from failure of sodium and free-water excretion. This
generally becomes clinically manifested when the GFR falls to less than 10-15 mL/min/1.73
m, when compensatory mechanisms have become exhausted.

As kidney function declines further, sodium retention and extracellular volume expansion
lead to peripheral edema and, not uncommonly, pulmonary edema and hypertension. At a
higher GFR, excess sodium and water intake could result in a similar picture if the ingested
amounts of sodium and water exceed the available potential for compensatory excretion.

Tubulointerstitial renal diseases represent the minority of cases of CKD. However, it is

important to note that such diseases often cause fluid loss rather than overload. Thus, despite
moderate or severe reductions in GFR, tubulointerstitial renal diseases may manifest first as
polyuria and volume depletion, with inability to concentrate the urine. These symptoms may
be subtle and require close attention to be recognized. Volume overload occurs only when
GFR reduction becomes very severe.

Anemia

Normochromic normocytic anemia principally develops from decreased renal synthesis of

erythropoietin, the hormone responsible for bone marrow stimulation for red blood cell
(RBC) production. The anemia starts early in the course of the disease and becomes more
severe as, with the shrinking availability of viable renal mass, the GFR progressively
decreases.

Using data from the National Health and Nutrition Examination Survey (NHANES), Stauffer
and Fan found that anemia was twice as prevalent in people with CKD (15.4%) as in the
general population (7.6%). The prevalence of anemia increased with stage of CKD, from
8.4% at stage 1 to 53.4% at stage 5. [16]

No reticulocyte response occurs. RBC survival is decreased, and bleeding tendency is

increased from the uremia-induced platelet dysfunction. Other causes of anemia in CKD
include the following:

Chronic blood loss: Uremia-induced platelet dysfunction enhances bleeding tendency

Secondary hyperparathyroidism

Inflammation

Nutritional deficiency
 Accumulation of inhibitors of erythropoiesis

Bone disease

Renal bone disease is a common complication of CKD. It results in skeletal complications

(eg, abnormality of bone turnover, mineralization, linear growth) and extraskeletal
complications (eg, vascular or soft-tissue calcification).

Different types of bone disease occur with CKD, as follows:

High-turnover bone disease from high parathyroid hormone (PTH) levels

Low-turnover bone disease (adynamic bone disease)

Defective mineralization (osteomalacia)

Mixed disease

Beta-2-microglobulinassociated bone disease

Bone disease in children is similar but occurs during growth. Therefore, children with CKD
are at risk for short stature, bone curvature, and poor mineralization (renal rickets is the
equivalent term for adult osteomalacia).

CKDmineral and bone disorder (CKD-MBD) involves biochemical abnormalities related to

bone metabolism. CKD-MBD may result from alteration in levels of serum phosphorus,
PTH, vitamin D, and alkaline phosphatase.

Secondary hyperparathyroidism develops in CKD because of the following factors:

Hyperphosphatemia
Hypocalcemia

Decreased renal synthesis of 1,25-dihydroxycholecalciferol (1,25-dihydroxyvitamin D, or

calcitriol)

Intrinsic alteration in the parathyroid glands, which gives rise to increased PTH secretion and
increased parathyroid growth

Skeletal resistance to PTH

Calcium and calcitriol are primary feedback inhibitors; hyperphosphatemia is a stimulus to

PTH synthesis and secretion.

Hyperphosphatemia and hypocalcemia

Phosphate retention begins in early CKD; when the GFR falls, less phosphate is filtered and
excreted, but because of increased PTH secretion, which increases renal excretion, serum
levels do not rise initially. As the GFR falls toward CKD stages 4-5, hyperphosphatemia
develops from the inability of the kidneys to excrete the excess dietary intake.

Hyperphosphatemia suppresses the renal hydroxylation of inactive 25-hydroxyvitamin D to

calcitriol, so serum calcitriol levels are low when the GFR is less than 30 mL/min/1.73 m.
Increased phosphate concentration also effects PTH concentration by its direct effect on the
parathyroid glands (posttranscriptional effect).

Hypocalcemia develops primarily from decreased intestinal calcium absorption because of

low plasma calcitriol levels. It also possibly results from increased calcium-phosphate
binding, caused by elevated serum phosphate levels.

Increased PTH secretion

Low serum calcitriol levels, hypocalcemia, and hyperphosphatemia have all been
demonstrated to independently trigger PTH synthesis and secretion. As these stimuli persist
in CKD, particularly in the more advanced stages, PTH secretion becomes maladaptive, and
the parathyroid glands, which initially hypertrophy, become hyperplastic. The persistently
elevated PTH levels exacerbate hyperphosphatemia from bone resorption of phosphate.

Skeletal manifestations

If serum levels of PTH remain elevated, a high bone turnover lesion, known as osteitis
fibrosa, develops. This is one of several bone lesions, which as a group are commonly known
as renal osteodystrophy and which develop in patients with severe CKD. Osteitis fibrosa is
common in patients with ESRD.

The prevalence of adynamic bone disease in the United States has increased, and it has been
described before the initiation of dialysis in some cases. The pathogenesis of adynamic bone
disease is not well defined, but several factors may contribute, including high calcium load,
use of vitamin D sterols, increasing age, previous corticosteroid therapy, peritoneal dialysis,
and increased level of N-terminally truncated PTH fragments.

Low-turnover osteomalacia in the setting of CKD is associated with aluminum accumulation.

It is markedly less common than high-turnover bone disease.

Another form of bone disease is dialysis-related amyloidosis, which is now uncommon in the
era of improved dialysis membranes. This condition occurs from beta-2-microglobulin
accumulation in patients who have required chronic dialysis for at least 8-10 years. It
manifests with cysts at the ends of long bones.

Etiology
Causes of chronic kidney disease (CKD) include the following:

Diabetic kidney disease

Hypertension

Vascular disease

Glomerular disease (primary or secondary)

Cystic kidney diseases

Tubulointerstitial disease
 Urinary tract obstruction or dysfunction

Recurrent kidney stone disease

Congenital (birth) defects of the kidney or bladder

Unrecovered acute kidney injury

Vascular diseases that can cause CKD include the following:

Renal artery stenosis

Cytoplasmic pattern antineutrophil cytoplasmic antibody (C-ANCA)positive and perinuclear
pattern antineutrophil cytoplasmic antibody (P-ANCA)positive vasculitides

ANCA-negative vasculitides

Atheroemboli

Hypertensive nephrosclerosis

Renal vein thrombosis

Primary glomerular diseases include the following:

Membranous nephropathy
Alport syndrome

Immunoglobulin A (IgA) nephropathy

Focal and segmental glomerulosclerosis (FSGS)

Minimal change disease

Membranoproliferative glomerulonephritis (MPGN)

Complement-related diseases (eg, atypical hemolytic-uremic syndrome [HUS], dense deposit

disease)

Rapidly progressive (crescentic) glomerulonephritis

Secondary causes of glomerular disease include the following:

Diabetes mellitus
Systemic lupus erythematosus

Rheumatoid arthritis

Mixed connective tissue disease

Scleroderma

Wegener granulomatosis

Mixed cryoglobulinemia

Endocarditis
 Hepatitis B and C

Syphilis

Human immunodeficiency virus (HIV)

Parasitic infection

Heroin use

Gold

Penicillamine

Amyloidosis

Light-chain deposition disease

Neoplasia

Thrombotic thrombocytopenic purpura (TTP)

Shiga-toxin or Streptococcus pneumoniae related HUS

Henoch-Schnlein purpura

Reflux nephropathy

Causes of tubulointerstitial disease include the following:

Drugs (eg, sulfonamides, allopurinol)

Infection (viral, bacterial, parasitic)

Sjgren syndrome

Tubulointerstitial nephritis and uveitis (TINU) syndrome

Chronic hypokalemia

Chronic hypercalcemia

Sarcoidosis

Multiple myeloma cast nephropathy

Heavy metals

Radiation nephritis

Polycystic kidneys

Cystinosis and other inherited diseases

Urinary tract obstruction may result from any of the following:

Benign prostatic hypertrophy

Urolithiasis (kidney stones)
 Urethral stricture

Tumors

Neurogenic bladder

Congenital (birth) defects of the kidney or bladder

Retroperitoneal fibrosis

Epidemiology
In the United States, the National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) reports that one in 10 American adults has some level of chronic kidney disease
(CKD). [17] Kidney disease is the ninth leading cause of death in the United States. [18]

According to the NIDDK, the incidence of recognized CKD in people aged 20-64 years in the
United States rose only slightly from 2000 2008 and remains less than 0.5%. [17] In contrast,
the incidence of recognized CKD in people aged 65 years or older more than doubled
between 2000 and 2008, from approximately 1.8% to approximately 4.3%. [17]

The US prevalence of CKD increases dramatically with age (4% at age 29-39 y; 47% at age
>70 y), with the most rapid growth in people aged 60 years or older. In the National Health
and Nutrition Examination Survey (NHANES) study, the prevalence of stage 3 CKD in this
age group rose from 18.8% during the years 1988 1994 to 24.5% during the years 2003
2006. During the same period, the prevalence of CKD in people aged 20-39 years remained
consistently below 0.5%. [17]

According to 1999 2004 NHANES data, the estimated prevalence of CKD by stage was as
follows [19] :

Stage 1: 5.7%
Stage 2: 5.4%

Stage 3: 5.4%

Stage 4: 0.4%

Stage 5: 0.4%

The US incidence of end-stage renal disease (ESRD) rose steadily from 1980-2001, but the
rate subsequently leveled off at approximately 350 per 1 million population. [17] However, the
percentage of patients older than 65 years has been the most rapidly growing segment of the
ESRD population, having increased from 5% to 37% of this group. [17]

The US Surgeon Generals latest report on 10-year national objectives for improving the
health of all Americans, Healthy People 2020, contains a chapter focused on CKD. For 2020,
Healthy People lays out 14 objectives concerning reduction of the US incidence, morbidity,
mortality, and health costs of CKD. Reducing renal failure will require additional public
health efforts, including effective preventive strategies and early detection and treatment of
CKD.
A systematic review and meta-analysis of observational studies estimating CKD prevalence
in general populations worldwide found a consistent estimated global CKD prevalence of 11-
13%. The majority of cases are stage 3. [20]

Race-related demographics

Although CKD affects all races, the incidence rate of ESRD among blacks in the United
States is nearly 4 times that for whites. [17] Choi et al found that rates of ESRD among black
patients exceeded those among white patients at all levels of baseline estimated glomerular
filtration rate (GFR). [21] Risk of ESRD among black patients was highest at an estimated GFR
of 45-59 mL/min/1.73 m2, as was the risk of mortality.

Schold et al found that among black kidney transplant recipients, rates of graft loss and acute
rejection were higher than in white recipients, especially among younger patients. [22] Hicks et
al looked at the connection between black patients with the sickle cell trait and their increased
risk for kidney disease; the study found that sickle cell trait was not associated with diabetic
or nondiabetic ESRD in a large sample of black patients. [23]

Important differences also exist in the frequency of specific causes of CKD among different
races. In the Chronic Kidney Disease in Children (CKiD) Study, for example, glomerular
disease was much more common among nonwhite persons. [24] Overall, FSGS in particular is
more common among Hispanic Americans and black persons, as is the risk of nephropathy
with diabetes or with hypertension; in contrast, IgA nephropathy is rare in black individuals
and more common among those with Asian ancestry. [25]

Sex- related demographics

In NHANES, the distribution of estimated GFRs for the stages of CKD was similar in both
sexes. In the United States Renal Data System (USRDS) 2011 Annual Data Report, however,
the incident rate of ESRD cases at the initiation of hemodialysis in 2009 was higher for
males, with 415.1 per million population compared with 256.6 for females. [26]

CKD in children is somewhat more common in boys, because posterior urethral valves, the
most common birth defect leading to CKD, occur only in boys. Importantly, many individuals
with congenital kidney disease such as dysplasia or hypoplasia do not clinically manifest
CKD or ESRD until adulthood.

Prognosis
Patients with chronic kidney disease (CKD) generally experience progressive loss of kidney
function and are at risk for end-stage renal disease (ESRD). The rate of progression depends
on age, the underlying diagnosis, the success of implementation of secondary preventive
measures, and the individual patient. Timely initiation of chronic renal replacement therapy is
imperative to prevent the uremic complications of CKD that can lead to significant morbidity
and death.

Tangri et al developed and validated a model in adult patients that uses routine laboratory
results to predict progression from CKD (stages 3-5) to kidney failure. [27] They reported that
lower estimated glomerular filtration rate (GFR), higher albuminuria, younger age, and male
sex pointed to a faster progression of kidney failure. Also, a lower serum albumin, calcium,
and bicarbonate level and a higher serum phosphate level were found to predict an elevated
risk of kidney failure. [27]

Hospitalization

Unadjusted rates of hospitalization in the CKD population, reflecting its total disease burden,
are 3-5 times higher than those of patients without CKD. [26] After adjustment for gender, prior
hospitalizations, and comorbidity, rates for patients with CKD are 1.4 times higher. Rates of
hospitalization for cardiovascular disease and bacterial infection are particularly elevated. [26]

Dialysis

In the United States, hemodialysis and peritoneal dialysis patients average 2 hospital
admissions per year; patients who have a renal transplant average 1 hospital admission per
year. Additionally, patients with ESRD who undergo renal transplantation survive longer than
those on long-term dialysis. [28]

Hemodialysis performed 6 times per week significantly increased the risk of vascular access
complications compared with a conventional 3-day regimen in one study. [29, 30] Of 125 patients
who received hemodialysis 6 days per week, 48 experienced the composite primary endpoint
event of vascular repair, loss, or related hospitalization, compared with only 29 of the 120
patients undergoing conventional treatment. Results indicated that overall risk for a first
access event was 76% higher with daily hemodialysis than with the conventional regimen. [29,
30]

Mortality

The mortality rates associated with CKD are striking. After adjustment for age, gender, race,
comorbidity, and prior hospitalizations, mortality in patients with CKD in 2009 was 56%
greater than that in patients without CKD. [26] For patients with stages 4-5 CKD, the adjusted
mortality rate is 76% greater.

Mortality rates are consistently higher for men than for women, and for black persons than
for white individuals and patients of other races. For Medicare CKD patients aged 66 years
and older, deaths per 1000 patient-years in 2009 were 75 for white patients and 83 for black
patients. [26]

The highest mortality rate is within the first 6 months of initiating dialysis. Mortality then
tends to improve over the next 6 months, before increasing gradually over the next 4 years.
The 5-year survival rate for a patient undergoing long-term dialysis in the United States is
approximately 35%, and approximately 25% in patients with diabetes.

A study by Sens found that the risk of mortality was elevated in patients with ESRD and
congestive heart failure who received peritoneal dialysis compared with those who received
hemodialysis. [31] Median survival time was 20.4 months in patients receiving peritoneal
dialysis versus 36.7 months in the hemodialysis group.

At every age, patients with ESRD on dialysis have significantly increased mortality when
compared with nondialysis patients and individuals without kidney disease. At age 60 years, a
healthy person can expect to live for more than 20 years, whereas the life expectancy of a
patient aged 60 years who is starting hemodialysis is closer to 4 years. Among patients aged
65 years or older who have ESRD, mortality rates are 6 times higher than in the general
population. [26]

The most common cause of sudden death in patients with ESRD is hyperkalemia, which
often follows missed dialysis or dietary indiscretion. The most common cause of death
overall in the dialysis population is cardiovascular disease; cardiovascular mortality is 10-20
times higher in dialysis patients than in the general population. [32]

The morbidity and mortality of dialysis patients is much higher in the United States than in
most other countries, which is probably a consequence of selection bias. Because of liberal
criteria for receiving government-funded dialysis in the United States and the use of rationing
(medical and economic) in most other countries, US patients receiving dialysis are on the
average older and sicker than those in other countries.

In the National Health and Nutrition Examination Survey (NHANES) III prevalence study,
hypoalbuminemia (a marker of protein-energy malnutrition and a powerful predictive marker
of mortality in dialysis patients, as well as in the general population) was independently
associated with low bicarbonate, as well as with the inflammatory marker C-reactive protein.
A study by Raphael et al suggests that higher serum bicarbonate levels are associated with
better survival and renal outcomes in African Americans. [33]

A study by Navaneethan et al found a connection between low levels of 25-hydroxyvitamin D

(25[OH]D) and all-cause mortality in patients with nondialysis CKD. [34] Adjusted risk of
mortality was 33% higher in patients whose 25(OH)D levels were below 15 ng/mL.

Morbidity and mortality among children with CKD and ESRD are much lower than among
adults with these conditions, but they are strikingly higher than for healthy children. As with
adults, the risk is highest among dialysis patients; consequently, transplantation is the
preferred treatment for pediatric patients with ESRD.

Sexual and reproductive issues

Puberty is often delayed among males and females with significant CKD. Female patients
with advanced CKD commonly develop menstrual irregularities. Women with ESRD are
typically amenorrheic and infertile. However, pregnancy can occur and can be associated
with accelerated renal decline, including in women with a kidney transplant. In advanced
CKD and ESRD, pregnancy is associated with markedly decreased fetal survival.

Vitamin D

Many patients with CKD have low circulating levels of 25(OH)D. A study of 1099 patients
(mostly men) with advanced CKD found that the lowest tertile of 1,25(OH)(2)D (< 15
pg/mL) was associated with death and initiation of long-term dialysis therapy compared with
the highest tertile (>22 pg/mL). [35] A retrospective cohort study in 12,763 nondialysis-
dependent patients with CKD found that 25(OH)D levels below 15 ng/mL were associated
independently with all-cause mortality. [36]
Patient Education
Patients with chronic kidney disease (CKD) should be educated about the following:

Importance of avoiding factors leading to increased progression (see Etiology)

Natural disease progression

Prescribed medications (highlighting their potential benefits and adverse effects)

Avoidance of nephrotoxins

Diet (see Diet)

Renal replacement modalities, including peritoneal dialysis, hemodialysis, and

transplantation

Timely placement of vascular access for hemodialysis

Women of childbearing age who have end-stage renal disease (ESRD) should be counseled
that although their fertility is greatly reduced, pregnancy can occur and is associated with
higher risk than in women who do not have renal disease. In addition, many medications used
to treat CKD are potentially teratogenic; in particular, women taking angiotensin-converting
enzyme (ACE) inhibitors and certain immunosuppressive treatments require clear counseling.

History
Patients with chronic kidney disease (CKD) stages 1-3 (glomerular filtration rate [GFR] >30
mL/min/1.73 m) are frequently asymptomatic; in terms of possible negative symptoms
related simply to the reduction in GFR, they do not experience clinically evident disturbances
in water or electrolyte balance or endocrine/metabolic derangements.

Generally, these disturbances become clinically manifest with CKD stages 4-5 (GFR <30
mL/min/1.73 m). Patients with tubulointerstitial disease, cystic diseases, nephrotic
syndrome, and other conditions associated with positive symptoms (eg, polyuria,
hematuria, edema) are more likely to develop signs of disease at earlier stages.

Uremic manifestations in patients with CKD stage 5 are believed to be primarily secondary to
an accumulation of multiple toxins, the full spectrum and identity of which is generally not
known. Metabolic acidosis in stage 5 may manifest as protein-energy malnutrition, loss of
lean body mass, and muscle weakness. Altered salt and water handling by the kidney in CKD
can cause peripheral edema and, not uncommonly, pulmonary edema and hypertension.

Anemia, which in CKD develops primarily as a result of decreased renal synthesis of

erythropoietin, manifests as fatigue, reduced exercise capacity, impaired cognitive and
immune function, and reduced quality of life. Anemia is also associated with the development
of cardiovascular disease, the new onset of heart failure, the development of more severe
heart failure, and increased cardiovascular mortality.

Other manifestations of uremia in end-stage renal disease (ESRD), many of which are more
likely in patients who are inadequately dialyzed, include the following:
 Pericarditis: Can be complicated by cardiac tamponade, possibly resulting in death
Encephalopathy: Can progress to coma and death

Peripheral neuropathy

Restless leg syndrome

Gastrointestinal symptoms: Anorexia, nausea, vomiting, diarrhea

Skin manifestations: Dry skin, pruritus, ecchymosis

Fatigue, increased somnolence, failure to thrive

Malnutrition

Erectile dysfunction, decreased libido, amenorrhea

Platelet dysfunction with tendency to bleed

Physical Examination
A careful physical examination is imperative. It may reveal findings characteristic of the
condition that is underlying chronic kidney disease (CKD) (eg, lupus, severe arteriosclerosis,
hypertension) or its complications (eg, anemia, bleeding diathesis, pericarditis). However, the
lack of findings on physical examination does not exclude kidney disease. In fact, CKD is
frequently clinically silent, so screening of patients without signs or symptoms at routine
health visits is important.

Screening for depression

Forty-five percent of adult patients with CKD have depressive symptoms at initiation of
dialysis therapy, as assessed using self-report scales. However, these scales may emphasize
somatic symptomsspecifically, sleep disturbance, fatigue, and anorexiathat can coexist
with chronic disease symptoms.

Hedayati et al reported that the 16-item Quick Inventory of Depressive Symptomatology-Self

Report (QIDS-SR[16]) and the Beck Depression Inventory (BDI) are effective screening
tools and that scores of 10 and 11, respectively, were the best cutoff scores for identification
of a major depressive episode in their study's patient population. [37] The study compared the
BDI and QIDS-SR(16) with a gold-standard structured psychiatric interview in 272 patients
with CKD stages 2-5 who had not been treated with dialysis.

depending on the stage of the disease and its cause, as well as patient factors such as age. A
detailed history and physical examination is essential. In addition to routine laboratory
studies, the workup should include calculation of the estimated glomerular filtration rate
(GFR), measurement of albumin levels, and acquisition of radiologic studies. The differential
diagnosis for CKD includes the following conditions, as well as the disorders listed in the
next section:

Systemic lupus erythematosus (SLE)

Renal Artery Stenosis
 Urinary Tract Obstruction

Granulomatosis with Polyangiitis (Wegener Granulomatosis)

Differential Diagnoses
Acute Kidney Injury
Alport Syndrome

Antiglomerular Basement Membrane Disease

Chronic Glomerulonephritis

Diabetic Nephropathy

Multiple Myeloma

Nephrolithiasis

Nephrosclerosis

Rapidly Progressive Glomerulonephritis

Approach Considerations
Testing in patients with chronic kidney disease (CKD) typically includes a complete blood
count (CBC), basic metabolic panel, and urinalysis, with calculation of renal function.
Normochromic normocytic anemia is commonly seen in CKD. Other underlying causes of
anemia should be ruled out.

The blood urea nitrogen (BUN) and serum creatinine levels will be elevated in patients with
CKD. Hyperkalemia or low bicarbonate levels may be present. Serum albumin levels may
also be measured, as patients may have hypoalbuminemia as a result of urinary protein loss or
malnutrition. A lipid profile should be performed in all patients with CKD because of their
risk of cardiovascular disease.

Serum phosphate, 25-hydroxyvitamin D, alkaline phosphatase, and intact parathyroid

hormone (PTH) levels are obtained to look for evidence of renal bone disease. Renal
ultrasonography and other imaging studies may be indicated.

Measurement of serum cystatin-C levels is gaining a greater role in the estimation of kidney
function. [38] Cystatin-C is a small protein that is expressed in all nucleated cells, produced at a
constant rate, and freely filtered by the glomerulus; it is not secreted but is instead reabsorbed
by tubular epithelial cells and catabolized, so it does not return to the bloodstream. These
properties make it a valuable endogenous marker of renal function. [39] A study that used
cystatin C instead of creatinine to estimate glomerular filtration rate (GFR) concluded that
cystatin Cbased GFR equations outperform creatinine-based formula in obese CKD patients,
especially those with a body mass index (BMI) 35 kg/m2 and in obese women. [40]

In certain cases, the following tests may be ordered as part of the evaluation of patients with
CKD:

Serum and urine protein electrophoresis, serum and urine free light chains: Screen for a
monoclonal protein possibly representing multiple myeloma
Antinuclear antibodies (ANA), double-stranded DNA antibody levels: Screen for systemic
lupus erythematosus

Serum complement levels: Results may be depressed with some glomerulonephritides

Cytoplasmic and perinuclear pattern antineutrophil cytoplasmic antibody (C-ANCA and P-

ANCA) levels: Positive findings are helpful in the diagnosis of granulomatosis with polyangiitis
(Wegener granulomatosis); a positive P-ANCA result is also helpful in the diagnosis of
microscopic polyangiitis

Antiglomerular basement membrane (anti-GBM) antibodies: Their presence is highly

suggestive of underlying Goodpasture syndrome

Hepatitis B and C, human immunodeficiency virus (HIV), Venereal Disease Research

Laboratory (VDRL) serology: These conditions are associated with some
glomerulonephritides

Imaging studies and consideration of bladder function studies: These evaluate for possible
obstruction and other urologic abnormalities

Screening

New evidence-based recommendations from the American College of Physicians (ACP)

regarding the screening, monitoring, and treatment of adults with stage 1-3 CKD recommend
against CKD screening for asymptomatic adults with no risk factors for kidney disease. The
ACPs position, however, has been disputed by the American Society of Nephrology (ASN).
[41, 42, 43]

The ACP recommendations, issued in October 2013, are as follows [41, 43] :

Asymptomatic adults without risk factors for CKD should not be screened for the disease
(Grade: weak recommendation, low-quality evidence)
Adults with or without diabetes who are currently taking an angiotensin-converting enzyme
(ACE) inhibitor or an angiotensin II-receptor blocker (ARB) should not be tested for
proteinuria (Grade: weak recommendation, low-quality evidence)

In treating patients with hypertension and stage 1-3 CKD, clinicians should select
pharmacologic therapy that includes either an ACE inhibitor (moderate-quality evidence) or
an ARB (high-quality evidence) (Grade: strong recommendation)
 Elevated low-density lipoprotein levels in patients with stage 1-3 CKD should be managed
with statin therapy (Grade: strong recommendation, moderate-quality evidence)

The ASN, however, in response to the ACP recommendations, released a statement strongly
advocating CKD screening even in patients without risk factors for CKD. The ASN pointed
out that early CKD is usually asymptomatic and that catching and treating it early may slow
its development. [42]

The nephrology society also disagreed with the ACPs recommendation against testing for
proteinuria, whether or not diabetes is present, in adults taking an ACE inhibitor or an ARB,
emphasizing the importance of renal health assessment in adults on antihypertensive
medication. [42]

The See Kidney Disease (SeeKD) targeted screening project identified a high proportion of
individuals with risk factors for CKD and a high prevalence of unrecognized CKD.
Participants with at least one risk factor for CKD (eg, diabetes, hypertension, vascular
disease, family history of kidney problems) received a point-of-care creatinine measurement.
Of the 5194 participants screened, 18.8% had unrecognized CKD (estimated [eGFR] <60
ml/min/1.73 m2); 13.8% had stage 3a CKD (eGFR 45-60 ml/min/1.73 m2). [44]

Urinalysis

In adult patients who are not at elevated risk for CKD, screening with total protein can be
done with a standard urine dipstick, according to guidelines from the National Kidney
Foundations Kidney Disease Outcomes Quality Initiative (KDOQI). If the dipstick test is
positive (1+ or greater), patients should undergo testing for confirmation of proteinuria. [45]

Although 24-hour urine collection for total protein and creatinine clearance (CrCl) can be
performed, spot urine collection for total proteinto-creatinine (P/C) ratio allows reliable
approximation (extrapolation) of total 24-hour urinary protein excretion. In children,
teenagers, and young adults in particular, a first morning urine specimen is preferable to a
random specimen, as so-called orthostatic proteinuria (considered benign) can be excluded.

Patients with a P/C ratio above 200 mg/mg should undergo a full diagnostic evaluation. [45] A
value of greater than 300-350 mg/mg is within the nephrotic range.

For screening patients at elevated risk, the KDOQI recommends using an albumin-specific
dipstick; this is because albuminuria is a more sensitive marker than total protein for CKD
from diabetes, hypertension, and glomerular diseases. A positive dipstick test should be
followed by calculation of the albumin-to-creatinine ratio, with a ratio greater than 30 mg/mg
followed by a full diagnostic evaluation. [45]

For monitoring proteinuria in adults with CKD, the KDOQI recommends measuring the P/C
ratio in spot urine samples, using the albumin-to-creatinine ratio. However, a total P/C ratio is
acceptable if the albumin-to-creatinine ratio is high (>500 to 1000 mg/g). [45]

Dipstick proteinuria may suggest a glomerular or tubulointerstitial problem. The urine

sediment finding of red blood cells (RBCs) and RBC casts suggests proliferative
glomerulonephritis. Pyuria and/or white blood cell casts suggest interstitial nephritis
(particularly if eosinophiluria is present) or urinary tract infection.
Renal Function Formulas
The Cockcroft-Gault formula for estimating creatinine clearance (CrCl) should be used
routinely as a simple means to provide a reliable approximation of residual renal function in
all patients with CKD. The formulas are as follows:

CrCl (male) = ([140-age] weight in kg)/(serum creatinine 72)

CrCl (female) = CrCl (male) 0.85

Alternatively, the Modification of Diet in Renal Disease (MDRD) Study equation could be
used to calculate the glomerular filtration rate (GFR). This equation does not require a
patient's weight. [46]

However, the MDRD underestimates the measured GFR at levels above 60 mL/min/1.73 m2.
Stevens et al found that the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
equation is more accurate than the MDRD Study equation overall and across most subgroups
and that it can report estimated GFRs that are at or above 60 mL/min/1.73 m2. [47]

However, a study by Silveiro et al found that both the CKD-EPI and MDRD equations
underestimated GFR in patients with type 2 diabetes. [48] The measured GFR was 103 23
mL/min/1.73 m, the CKD-EPI GFR was 83 15 mL/min/1.73 m, and the MDRD GFR was
78 17 mL/min/1.73 m. Accuracy was 67% for the CKD-EPI equation and 64% for the
MDRD equation. [48]

Renal function calculation in pediatric patients

GFR in children is calculated using the Schwartz formula (see Chronic Kidney Disease in
Children). Because this formula may currently overestimate GFR, likely due to a change in
methods used to measure creatinine, Schwartz et al have proposed an updated equation that
includes cystatin C. [49] However, the majority of dosing guidelines for medication adjustments
due to reduced GFR use the original Schwartz equations.

Renal function calculation in elderly patients

Age is an important consideration with respect to estimated GFR. In a 70-kg man aged 25
years, a serum creatinine value of 1.2 mg/dL represents an estimated GFR of 74
mL/min/1.73m2, but in a 70-kg man aged 80 years, that same value represents an estimated
GFR of 58 mL/min/1.73m2. Thus, in a 70-kg, 80-year-old man, a serum creatinine of 2 mg/dL
actually represents severe renal impairment, with an estimated GFR of 32 mL/min/1.73 m2 as
measured by the MDRD equation.

Therefore, in elderly patients an estimated GFR must be determined using a formula such as
the MDRD equation, which includes age as a variable. This will allow appropriate drug
dosing adjustments to be made and nephrotoxins to be avoided in patients who have more
extensive CKD than would be suggested by the serum creatinine value alone.

Renal Ultrasonography
Renal ultrasonography is useful to screen for hydronephrosis, which may not be observed in
early obstruction, or involvement of the retroperitoneum with fibrosis, tumor, or diffuse
adenopathy. Small, echogenic kidneys are observed in advanced renal failure.

In contrast, kidneys usually are normal in size in advanced diabetic nephropathy, in which
affected kidneys are initially enlarged from hyperfiltration. Structural abnormalities, such as
those indicative of polycystic kidneys, also may be observed on ultrasonograms.

Renal ultrasonography is the initial imaging modality of choice for children. However,
radiologists must have specific training to be able to recognize abnormal kidney size or
development in pediatric patients.

Radiography
A retrograde pyelogram may be indicated if a high index of clinical suspicion for obstruction
exists despite a negative finding on renal ultrasonography. Intravenous pyelography is not
commonly performed, because of the potential for renal toxicity from the intravenous
contrast; however, this procedure is often used to diagnose renal stones.

Plain abdominal radiography is particularly useful to look for radio-opaque stones or

nephrocalcinosis, while a voiding cystourethrogram (VCUG) is the criterion standard for
diagnosis of vesicoureteral reflux.

CT, MRI, and Radionuclide Scans

Computed tomography (CT) scanning can better define renal masses and cysts usually noted
on ultrasonography. Also, CT scanning is the most sensitive test for identifying renal stones.
Intravenous (IV) contrastenhanced CT scans should be avoided in patients with renal
impairment to avoid acute renal failure; this risk significantly increases in patients with
moderate to severe CKD. Dehydration also markedly increases this risk.

Magnetic resonance imaging (MRI) is very useful in patients who would otherwise undergo a
CT scan but who cannot receive IV contrast. This imaging modality is reliable in the
diagnosis of renal vein thrombosis, as are CT scanning and renal venography.

Magnetic resonance angiography (MRA) is becoming more useful for the diagnosis of renal
artery stenosis, although renal arteriography remains the criterion standard. However, MRI
contrast is problematic in patients with existing chronic kidney disease (CKD) because they
have a low, but potentially fatal, risk of developing nephrogenic systemic fibrosis.

A renal radionuclide scan can be used to screen for renal artery stenosis when performed with
captopril administration; it also quantitates differential renal contribution to total glomerular
filtration rate (GFR). However, radionuclide scans are unreliable in patients with a GFR of
less than 30 mL/min/1.73 m.

Renal Biopsy
Percutaneous renal biopsy is performed most often with ultrasonographic guidance and the
use of a spring-loaded or other semi-automated needle. This procedure is generally indicated
when renal impairment and/or proteinuria approaching the nephrotic range are present and
the diagnosis is unclear after an appropriate workup.

Biopsies are also indicated to guide management in already-diagnosed conditions, such as

lupus, in which the prognosis is highly dependent on the degree of kidney involvement.
Biopsy is not usually indicated when renal ultrasonography reveals small, echogenic kidneys
on ultrasonography, because this finding represents severe scarring and chronic, irreversible
injury.

The most common complication of this procedure is bleeding, which can be life-threatening
in a minority of cases. Surgical open renal biopsy can be considered when the risk of renal
bleeding is felt to be great, occasionally with solitary kidneys, or when percutaneous biopsy
is technically difficult to perform.

Renal histology in CKD reveals findings compatible with the underlying primary renal
diagnosis. In some cases, a biopsy may show nonspecific changes, with the exact diagnosis
remaining in doubt.

Approach Considerations
Early diagnosis and treatment of the underlying cause and/or the institution of secondary
preventive measures are imperative in patients with chronic kidney disease (CKD). These
steps may delay, or possibly halt, progression of the disease. Early referral to a nephrologist is
of extreme importance.

The medical care of patients with CKD should focus on the following:

Delaying or halting the progression of CKD

Diagnosing and treating the pathologic manifestations of CKD

Timely planning for long-term renal replacement therapy

In February 2014, the Canadian Society of Nephrology released new guidelines that
recommend delaying dialysis in CKD patients without symptoms until their estimated
glomerular filtration rate (eGFR) drops to 6 mL/min/1.73 m2 or until the first onset of a
clinical indication (which includes symptoms of uremia, fluid overload, and refractory
hyperkalemia or acidemia). [50, 51] Close monitoring should begin when eGFR reaches 15
mL/min/1.73 m2. Additional factors that may affect dialysis initiation include patient
education and modality selection, the severity of existing uremic symptoms, and the rate of
renal function decline. [50, 51]

Patients with CKD acutely presenting with indications for dialytic therapy should be
transferred to a hospital center where acute dialysis can be performed.

The National Kidney Foundations Kidney Disease Outcomes Quality Initiative (KDOQI) has
issued several clinical practice guidelines for managing all stages of CKD and related
complications in adults.
Delaying or Halting Progression of Chronic Kidney
Disease
Measures indicated to delay or halt the progression of chronic kidney disease (CKD) are as
follows:

Treatment of the underlying condition if possible

Aggressive blood pressure control to target values per current guidelines

Treatment of hyperlipidemia to target levels per current guidelines

Aggressive glycemic control per the American Diabetes Association (ADA) recommendations
(target hemoglobin A1c [HbA1C] < 7%)

Avoidance of nephrotoxins, including intravenous (IV) radiocontrast media, nonsteroidal anti-

inflammatory agents (NSAIDs), and aminoglycosides

Use of renin-angiotensin system (RAS) blockers among patients with diabetic kidney disease
(DKD) and proteinuria

Use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers

(ARBs) in patients with proteinuria

A prospective cohort study indicated that in patients with advanced CKD and stable
hypertension, antihypertensive treatment with ACEIs or ARBs reduces the likelihood of long-
term dialysis and lowers the mortality risk as well. [52, 53, 54]

The study involved 28,497 predialysis patients with advanced CKD, hypertension, and
anemia. Based on a median follow-up period of 7 months, the investigators found that in
those patients who were treated with ACEIs or ARBs, the need for long-term dialysis was 6%
lower than in patients who were not treated with these drugs, with the composite outcome of
long-term dialysis or death also being 6% lower.

The rate of hyperkalemia-associated hospitalization was higher in the ACEI/ARB patients,

but no significant increase was found in hyperkalemia-related predialysis mortality.

In a retrospective simulation study to determine the effectiveness of angiotensin-converting

enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in preventing ESRD
in older patients with CKD, researchers found that these treatments had only marginal
benefit. Among over 370,000 patients aged 70 years and above with CKD, the number
needed to treat (NNT) to prevent 1 case of ESRD was more than 100 for most patients (even
with an exposure time of >10 y). In younger patients, the researchers found that the NNT
ranged from 9-25. The investigators suggested that differences in baseline risk and life
expectancy between older and younger patients may cause older patients to derive reduced
benefits from interventions to prevent ESRD. [55, 56]

Blood pressure control

Aggressive blood pressure control can help to delay the decline in renal function in patients
with CKD. The Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure (JNC VII) and the National Kidney Foundations Kidney
Disease Outcomes Quality Initiative (KDOQI) suggest a target blood pressure of less than
130/80 mm Hg.

Systolic blood pressure (SBP) control is considered more important than diastolic blood
pressure control. However, SBP is also considered difficult to control in elderly patients with
CKD.

In a diverse, community-based study by Peralta et al, high SBP appeared to account for most
of the risk of progression to end-stage renal disease (ESRD). [57] The risk began at an SBP of
140 mm Hg, as opposed to the current recommended goal of less than 130 mm Hg. The
highest risk was found among patients with an SBP of at least 150 mm Hg. These researchers
concluded that to improve blood pressure control in CKD, treatment approaches that lower
SBP may be required. [57]

Use ACEIs or ARBs as tolerated, with close monitoring for renal deterioration and for
hyperkalemia. With every dose change, serum creatinine levels need to be monitored. If
serum creatinine levels increase more than 30% from baseline after adding RAS blockers,
RAS blockers should be stopped. Avoid these agents in advanced patients with renal failure,
bilateral renal artery stenosis, or renal artery stenosis in a solitary kidney.

The time of day at which patients take antihypertensive medications can affect circadian
patterns of blood pressure, and this may translate into an effect on clinical outcome. Hermida
et al reported, after a median follow-up of 5.4 years, that hypertensive patients with CKD
who took at least 1 of their antihypertensive medications at bedtime had an adjusted risk for
total cardiovascular events that was approximately one third that of patients who took all of
their medications upon awakening. [58]

Management of protein

Data support the use of ACEIs or ARBs in diabetic kidney disease with or without
proteinuria. However, in nondiabetic kidney disease, these agents are effective in retarding
the progression of disease among patients with proteinuria of more than 500 mg/day.

In the Modification of Diet in Renal Disease (MDRD) Study, dietary protein restriction (0.58
g/kg/day, versus a usual-protein diet of 1.3 g/kg/day) did not significantly affect the mean
change in glomerular filtration rate (GFR) over 3 years. Secondary analyses, however,
suggested that a low-protein diet may slow the GFR decline in patients with the most rapidly
declining GFR and reduce proteinuria. [59] A meta-analysis by Kasiske et al suggested that
dietary protein restriction retards the rate of renal function decline, but the magnitude of the
effect is relatively weak. [60]

National Kidney Foundation (NKF) guidelines advise that if a patient is started on protein
restriction, the physician needs to closely monitor the patient's nutritional status. [45]
Predialysis low serum albumin is associated with a poor outcome among dialysis patients.
Protein restriction is not recommended in pediatric patients with CKD.

Vitamin D supplementation
Paricalcitol (Zemplar), a synthetic vitamin D analogue, is approved by the US Food and Drug
Administration (FDA) for the prevention and treatment of secondary hyperparathyroidism
associated with CKD stage 5. However, a meta-analysis has found that paricalcitol also can
safely reduce protein excretion in patients with CKD stages 2-5. Whether paricalcitol can
slow the development of ESRD or reduce mortality is not yet known. [61]

In a prospective, controlled study, daily vitamin D supplementation decreased albuminuria in

patients with stage 3-4 chronic kidney disease (CKD) who had low vitamin D levels and high
parathyroid hormone (PTH) levels. The study population was composed of 50 CKD patients
with hyperparathyroidism who were given 666 IU of oral cholecalciferol daily and 51 CKD
patients without hyperparathyroidism who acted as controls. [62, 63]

At 6 months, cholecalciferol supplementation led to a mean increase in vitamin D (25(OH)D)

levels of 53%. Urinary albumin-to-creatinine ratio decreased, from 284 to 167 mg/g, without
alterations in other factors that could affect proteinuria. Control patients showed no change.

Changes in 25(OH)D levels were significantly and inversely associated with those in the
urinary albumin-to-creatinine ratio , supporting a possible antiproteinuric effect of vitamin D
receptor activation. Treated patients also had a mean drop of 13.8% in PTH, with a mild rise
in phosphate and calcium-phosphate product. There was no change in controls. [62, 63]

Nephrotoxins

A study by Plantinga et al found that a great number of individuals with CKD may be
unaware of their disease and thus may be at risk for further kidney injury through use of
NSAIDs. [64] Persons who knew that they had CKD were less likely to use NSAIDs,
suggesting that primary care physicians should be involved in communication regarding the
risks of NSAIDs. [64]

Encourage smoking cessation, as smokers tend to reach ESRD earlier than nonsmokers. A
large-population Norwegian study found that smoking cessation decreased the risk for future
onset of kidney failureespecially in men, who tended to be heavier smokers than women in
this cross-section. [65]

Subclinical hypothyroidism

In a study of 113 patients with CKD stages 2-4 and subclinical hypothyroidism, thyroid
hormone replacement therapy (THRT) with L-thyroxine delayed the rate of decline in kidney
function to end-stage renal disease (ESRD). [66, 67] On average, before patients were treated
with THRT, their estimated GFR declined by 4.31 0.51 mL/min per 1.73 m2 each year;
following treatment, the estimated GFR decline slowed to 1.08 0.36 mL/min per 1.73 m2
each year. [66, 67]

Based on the slope of the decline in estimated GFR prior to THRT, linear regression analysis
predicted that 53 of the 113 patients (46.9%) would reach stage 5 CKDwhere they would
require dialysis or a kidney transplantwithin 10 years. However, using the altered slope of
the decline of estimated GFR after patients received therapy, it was estimated that only 10
patients (8.8%) would reach this outcome in 10 years. Thus, THRT delayed reaching stage 5
CKD in 43 of the predicted 53 patients (81%). [66, 67]
Treating Pathologic Manifestations of Chronic Kidney
Disease
Treat these pathologic manifestations of chronic kidney disease (CKD) as follows:

Anemia: When the hemoglobin level is below 10 g/dL, treat with an erythropoiesis-
stimulating agent (ESA) such as epoetin alfa or darbepoetin alfa (previously, peginesatide was
also considered an option for anemia in CKD, but this agent was withdrawn from the market
in February 2013 due to serious hypersensitivity reactions [68] ); caution should be exercised in
patients with malignancy
Hyperphosphatemia: Treat with dietary phosphate binders and dietary phosphate restriction

Hypocalcemia: Treat with calcium supplements with or without calcitriol

Hyperparathyroidism: Treat with calcitriol, vitamin D analogues, or calcimimetics

Volume overload: Treat with loop diuretics or ultrafiltration

Metabolic acidosis: Treat with oral alkali supplementation

Uremic manifestations: Treat with long-term renal replacement therapy (hemodialysis,

peritoneal dialysis, or renal transplantation)

Cardiovascular complications: Treat as appropriate

Growth failure in children: Treat with growth hormone

Anemia treatment

With erythropoietin treatment, the goal is a hemoglobin level of 10-12 g/dL, as normalization
of hemoglobin in patients with CKD stages 4-5 has been associated with an increased risk of
adverse outcomes. Before starting erythropoietin, patients should have their iron stores
checked. The aim is to keep iron saturation at 30-50% and ferritin at 200-500 ng/mL.

A study by Shurraw et al showed that in people with nonhemodialysis-dependent CKD, a

hemoglobin A1c (HbA1c) level higher than 9% is associated with worse clinical outcomes.
Lower levels of HbA1c also seemed to be associated with excess mortality. Appropriate and
timely control of the HbA1c level in people with diabetes mellitus and CKD may be more
important than previously realized, but findings also suggest that intensive glycemic control
may lead to increased mortality. [69]

Management of mineral and bone disorder

Treatment of abnormal mineral homeostasis in patients with CKD includes the following [70] :

Lowering high serum phosphorus levels

Maintaining serum calcium levels

Lowering serum parathyroid hormone levels

Providing osteoporosis prophylaxis

The Kidney Disease: Improving Global Outcomes (KDIGO) Implementation Task Force
published guidelines on the management of CKDmineral and bone disorder in 2009. [70] An
update of the guidelines is currently in progress. The guidelines, which were issued after the
quality and the depth of evidence, when available, were weighed, propose a common-sense
approach to the evaluation and treatment of mineral and bone disorder in different stages of
CKD. London et al summarized the best evidence and the KDIGO recommendations on this
topic. [71]

Management of hyperphosphatemia

Definitive evidence on the benefit of lowering phosphate levels in CKD is lacking, and
guideline recommendations vary. KDIGO guidelines recommend maintaining serum
phosphate levels within the normal range in stages 3-5 CKD and lowering levels toward
normal in stage 5D. [70] United Kingdom National Institute for Health and Clinical Excellence
(NICE) guidelines provide recommendations only for stages 4, 5, and 5d. [72]

Restricting dietary phosphate is one strategy for correcting hyperphosphatemia. However,

because of its complexity and challenges, diet control by iself is insufficient and unreliable
for keeping phosphate concentrations within the recommended range. Consequently, the use
of phosphate binders (eg, calcium acetate, sevelamer carbonate, lanthanum carbonate) has
been proposed as a means of reducing elevated phosphorus levels in patients with CKD. [73]
Unfortunately, calculation of the cost-effectiveness of the various agents is complicated. [74]

KDIGO guidelines suggest that the choice of phosphate-binding agent for the treatment of
hyperphosphatemia take into account CKD stage, presence of other components of CKD
mineral and bone disorder, concomitant therapies, and side-effect profile. [70] For adult
patients, NICE guidelines recommend calcium acetate as the first-line phosphate binder to
control serum phosphate, in addition to dietary management. [72] For full discussion of
management, see Hyperphosphatemia.

Block et al reported that in patients with CKD who have normal or near-normal serum
phosphorus levels, these agents significantly reduce serum and urinary phosphorus and
discourage secondary hyperparathyroidism progression. The investigators also reported,
however, that phosphate binders encourage vascular calcification. [75]

These results are in contrast to those reported in previous experimental findings in animals
with CKD and in human clinical trials, in which the use of phosphate binders did not reduce
elevated phosphorus levels or decrease the progression to secondary hyperparathyroidism.
Moreover, the effect of calcification is different among patients taking calcium-containing
phosphate binders relative to those taking noncalcium-containing phosphate binders.

Furthermore, no randomized, controlled trials have shown improved mortality in dialysis

patients who were treated with phosphate binders, activated vitamin D, or cinacalcet to
manage moderate to severe hyperparathyroidism.

Management of metabolic acidosis

The evidence for the benefits and risks of correcting metabolic acidosis is very limited, with
no randomized, controlled trials in patients who are not yet in ESRD, none in children, and
only 3 small trials in dialysis patients. These trials suggest that there may be some beneficial
effects on protein and bone metabolism, but the studies were underpowered and so did not
provide robust evidence. Experts recommend alkali therapy to maintain the serum
bicarbonate concentration above 22 mEq/L.

De Brito-Ashurst et al found that patients with CKD who receive bicarbonate

supplementation show a slower decline in renal function. [76] In this study, 134 adult patients
with CKD (ie, creatinine clearance [CrCl], 15-30 mL/min/1.73 m2; serum bicarbonate, 16-20
mmol/L) were randomly assigned to receive oral sodium bicarbonate supplementation or
standard care for 2 years. A slower decline in CrCl was observed in the bicarbonate group
(1.88 mL/min/1.73 m2) than in the control group (5.93 mL/min/1.73 m2). [76]

Patients in the bicarbonate group were also less likely to experience rapid disease progression
(9%) than were members of the control group (45%), and fewer patients who received
bicarbonate supplementation developed ESRD than did controls (6.5% vs 33%, respectively).
[76]
In addition, nutritional parameters improved with bicarbonate supplementation.

Management of cardiovascular risks

Guidelines issued in December 2013 by the Kidney Disease: Improving Global Outcomes
(KDIGO) workgroup recommend wider statin use among patients with CKD. Specific
recommendations include the following [77, 78] :

Adults aged 50 years or above with an estimated glomerular filtration rate (GFR) of less than
60 mL/min/1.73 m 2 who are not being treated with long-term dialysis or kidney
transplantation should be treated with a statin or a statin plus ezetimibe
Treatment with statins or statin/ezetimibe should not be initiated in adults with dialysis-
dependent CKD

Patients already being treated with a statin at the time of dialysis should continue

Adult kidney transplant patients should be treated with a statin because of an increased risk
for coronary events

Adults aged 18-49 years with an estimated GFR of less than 60 mL/min/1.73 m 2 who are not
being treated with dialysis or kidney transplantation should be treated with statins if they
have coronary disease, diabetes, prior ischemic stroke, or an estimated 10-year incidence of
coronary death or nonfatal myocardial infarction exceeding 10%

Low-density lipoprotein cholesterol is an insufficient test for cardiovascular risk in individuals

with CKD, and adults with newly diagnosed CKD should undergo lipid profile testing

Adults aged 50 years or older with CKD and an estimated GFR of 60 mL/min/1.73 m2 or
higher should be treated with a statin

Renal Replacement Therapy

Indications for renal replacement therapy in patients with chronic kidney disease (CKD)
include the following:

Severe metabolic acidosis

Hyperkalemia
 Pericarditis

Encephalopathy

Intractable volume overload

Failure to thrive and malnutrition

Peripheral neuropathy

Intractable gastrointestinal symptoms

In asymptomatic adult patients, a glomerular filtration rate (GFR) of 5-9 mL/min/1.73 m, [2]
irrespective of the cause of the CKD or the presence of absence of other comorbidities

Timely planning for long-term renal replacement therapy

Consider the following:

Early patient education regarding natural disease progression, different dialytic modalities,
renal transplantation, and option to refuse or discontinue chronic dialysis
Timely placement of permanent vascular access (arrange for surgical creation of primary
arteriovenous fistula, if possible, and preferably at least 6 mo in advance of the anticipated
date of dialysis for patients in whom transplantation is not imminent)

Timely elective peritoneal dialysis catheter insertion

Timely referral for renal transplantation

Diet
Protein restriction

Protein restriction early in chronic kidney disease (CKD) as a means to delay a decline in the
glomerular filtration rate (GFR) is controversial; however, as the patient approaches CKD
stage 5, this strategy is recommended in adults (but not in children) to delay the onset of
uremic symptoms.

Piccoli and colleagues observe that the choice of low-protein diets is extremely wide, and that
moderate protein restriction may be feasible in the context of several traditional diets, such as
the Mediterranean diet, which also address other therapeutic goals in CKD. However, these
authors note that diet is deeply rooted in personal preferences and social habits, so the best
compliance is probably obtained by personalization and comprehensive counseling. [79]

Patients with CKD who already are predisposed to becoming malnourished are at higher risk
for malnutrition with overly aggressive protein restriction. Malnutrition is a well-established
predictor of increased morbidity and mortality in the population with end-stage renal disease
(ESRD) and must be avoided if possible.

Salt restriction
Reduction in salt intake may slow the progression of diabetic CKD, at least in part by
lowering blood pressure. A meta-analysis found that dietary salt reduction significantly
reduced blood pressure in type 1 and type 2 diabetes, with results comparable to those of
single-drug therapy. [80] This finding is consistent with other evidence relating salt intake to
blood pressure and albuminuria in hypertensive and normotensive patients. The dietary
sodium recommendation for the general population in public health guidelines is less than 5-6
g daily.

Children and adults with tubulointerstitial diseases may experience salt wasting, and salt
restriction would not usually be required in that situation.

A randomized, controlled trial by Slagman et al found that moderate dietary sodium reduction
(approximately 2500 mg/day of Na+ or 6 g/day of NaCl) added to angiotensin-converting
enzyme (ACE) inhibition compared with dual blockade (ACE inhibitor [ACEI] and
angiotensin receptor blocker [ARB]) was more effective in reducing proteinuria and blood
pressure in nondiabetic patients with modest CKD. Furthermore, a low-sodium diet added to
dual blockade therapy yielded additional reductions in blood pressure and proteinuria . [81]

Vegter et al found that among patients with CKD but without diabetes, a high dietary salt
intake (>14 g/day) interfered with the antiproteinuric effect of ACEI therapy and increased
the risk for ESRD. [82] The risk was independent of blood pressure control.

Other dietary restrictions

The following dietary restrictions may also be indicated:

Phosphate restriction starting early in CKD

Potassium restriction

Sodium and water restriction as needed to avoid volume overload

Fruits and vegetables

A study by Goraya et al showed that increasing the amount of alkali-inducing fruits and
vegetables in the diet may help to reduce kidney injury. [83] In this report, 30 days of a diet that
included fruits and vegetables, in amounts calculated to reduce dietary acid by half, resulted
in decreased urinary albumin, N-acetyl -D-glucosaminidase, and transforming growth factor
in patients with moderately reduced estimated GFR as a result of hypertensive nephropathy.
[83]

Nutritional guidelines

The National Kidney Foundations Kidney Disease Outcomes Quality Initiative (KDOQI)
issued a clinical practice guideline for Nutrition in Chronic Renal Failure, as well as a 2008
revision of recommendations for Nutrition in Children with CKD. For adult patients on
maintenance dialysis, the KDOQI guidelines recommend routine assessment of the following
nutritional parameters:

Predialysis or stabilized serum albumin: Monthly

 Percentage of usual postdialysis (hemodialysis) or postdrain (peritoneal dialysis) body
weight: Monthly

Percentage of standard (National Health and Examination Survey II [NHANES II]) body weight:
Every 4 months

Subjective global assessment: Every 6 months

Dietary interview and/or diet diary: Every 6 months

Protein Equivalent of Total Nitrogen Appearance normalized to body weight (nPNA): Monthly
with hemodialysis; every 3-4 months with peritoneal dialysis

Consultations and Long-Term Monitoring

Consultations for the management of patients with chronic kidney disease (CKD) may
include the following:

Early nephrology referral (decreases morbidity and mortality)

Renal dietitian

Surgery for permanent vascular access or for peritoneal catheter placement

Referral to renal transplant center

Patients with CKD should be referred to a nephrologist early in the course of their disease
and have continued nephrologic follow-up until initiation of chronic renal replacement
therapy, during dialysis, and after kidney transplantation. Moreover, a multidisciplinary
approach to care, including involvement of the nephrologist, primary care physician, renal
dietitian, nurse, and social worker, should be initiated early in the course of CKD, with close
patient follow-up.

Patients should be monitored for obstructive sleep apnea (OSA), which occurs with increased
frequency in patients receiving dialysis. Sakaguchi et al also found a high incidence (65%) of
OSA in Japanese patients with nondialysis CKD, with the OSA being moderate or severe in
about one third of the patients who had it. [84] The study also found that a decreased
glomerular filtration rate (GFR) was associated with an increased risk of OSA. [84]

Medication Summary
In chronic kidney disease (CKD), doses and dosing intervals of drugs that are excreted or
metabolized renally should be adjusted according to the residual glomerular filtration rate
(GFR). Some drugs are contraindicated in moderate to severe renal impairment because of
potentially serious effects from drug or metabolite accumulation. Routine consultation of the
appropriate references should be undertaken when prescribing any new drug to a patient with
CKD.

For patients undergoing dialysis, it is extremely important to carefully check dosing guides or
monitor levels when possible. These modalities differ in their clearance of drugs.
Hospitalized patients undergoing other types of continuous renal replacement therapy also
require close monitoring. An experienced clinical pharmacist can be invaluable in assisting to
design individualized dosing regimens.

Treatments for the pathologic manifestations of CKD include the following:

Hyperphosphatemia: Dietary phosphate binders and dietary phosphate restriction

Hypocalcemia: Calcium supplements and possibly calcitriol

Hyperparathyroidism: Calcitriol or vitamin D analogues

Anemia: Iron replacement therapy and erythropoiesis-stimulating agents

Calcium Salts
Class Summary

Dietary phosphate binders promote the binding of phosphate in the gastrointestinal tract to
reduce hyperphosphatemia.

Calcium acetate (PhosLo, Eliphos, Phoslyra)

View full drug information

Calcium acetate is used for the treatment of hyperphosphatemia in end-stage renal disease
(ESRD). It combines with dietary phosphorus to form insoluble calcium phosphate, which is
excreted in feces.

Calcium carbonate (Caltrate 600, Tums)

View full drug information

Calcium carbonate is used for the treatment of hyperphosphatemia, normalizing phosphate

concentrations in patients with CKD. It can also be used as a calcium supplement in these
patients.

Calcium carbonate combines with dietary phosphate to form insoluble calcium phosphate,
which is excreted in feces. It is marketed in a variety of dosage forms and is relatively
inexpensive.

Vitamin D Analogues
Class Summary

Vitamin D analogues are recommended in patients with CKD stages 3-5 who are not on
dialysis and in whom the serum parathyroid hormone (PTH) level is elevated or has been
persistently rising. Vitamin D increases the absorption of calcium in the intestines and helps
to prevent secretion of calcium in the kidneys. By increasing calcium levels in serum, it helps
to decrease phosphate and PTH levels, as well as bone resorption.
Calcitriol (Rocaltrol, Calcijex, Vectical)

View full drug information

Calcitriol (1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin D3), the potent active

metabolite of vitamin D, can be used to suppress PTH production and secretion in secondary
hyperparathyroidism. In addition, calcitriol can alleviate hypocalcemia in CKD by increasing
intestinal calcium absorption and helping to prevent secretion of calcium in the kidneys.

Doxercalciferol (Hectorol)

View full drug information

Doxercalciferol is a vitamin D analogue (1-alpha-hydroxyergocalciferol) that does not require

activation by the kidneys. It is metabolized to the active form of vitamin D. Doxercalciferol is
indicated for the treatment of secondary hyperparathyroidism in patients with CKD.

Paricalcitol (Zemplar)

View full drug information

Paricalcitol is a synthetic vitamin D analogue that binds and activates vitamin D receptors in
the kidneys, parathyroid glands, intestines, and bones. It is used for the prevention and
treatment of secondary hyperparathyroidism associated with CKD stages 3-4 and stage 5
patients on hemodialysis or peritoneal dialysis. It reduces PTH levels, improves calcium and
phosphorus homeostasis, and stimulates bone mineralization.

Calcifediol (Rayaldee)

View full drug information

Extended-release formulation of calcifediol (25-hydroxyvitamin D3), a prohormone of the

active form of vitamin D3. Calcifediol is converted to calcitriol by CYP27B1, also called 1-
alpha hydroxylase, primarily in the kidney. Calcitriol binds to the vitamin D receptor in target
tissues and activates vitamin D responsive pathways that result in increased intestinal
absorption of calcium and phosphorus and reduced parathyroid hormone synthesis. It is
indicated for secondary hyperparathyroidism associated with vitamin D insufficiency in
patients with stage 3 or 4 chronic kidney disease (CKD) and serum total 25-hydroxyvitamin
D levels <30 ng/mL.

PO4 Scavengers
Class Summary

Dietary phosphate binders promote the binding of phosphate in the gastrointestinal tract to
reduce hyperphosphatemia.

Lanthanum carbonate (Fosrenol)

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Lanthanum carbonate is a noncalcium, nonaluminum phosphate binder indicated for the

reduction of high phosphorus levels in patients with stage 5 kidney disease. It dissociates into
ions in the upper gastrointestinal tract, and these ions directly bind to dietary phosphate,
forming insoluble lanthanum phosphate complexes. It therefore inhibits phosphorus
absorption.

Sevelamer (Renagel, Renvela)

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Sevelamer is indicated for the reduction of serum phosphorus levels in patients with CKD on
hemodialysis. This agent binds dietary phosphate in the intestine, thus inhibiting its
absorption. In patients on hemodialysis, sevelamer treatment results in fewer hypercalcemic
episodes than does calcium acetate therapy.

Sucroferric oxyhydroxide (Velphoro)

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Sucroferric oxyhydroxide is an iron-based, calcium-free phosphate binder. When it is taken

with meals, dietary phosphate is adsorbed in the GI tract and eliminated in the feces. It is
indicated for control of serum phosphorus levels in patients with chronic kidney disease on
hemodialysis.

Hematopoietic Growth Factors

Class Summary

Growth factors are used to treat anemia of CKD by stimulating red blood cell (RBC)
production.

Epoetin alfa (Epogen, Procrit)

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Epoetin alfa stimulates the division and differentiation of committed erythroid progenitor
cells. It induces the release of reticulocytes from the bone marrow into the bloodstream.

Darbepoetin (Aranesp)

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Darbepoetin is an erythropoiesis-stimulating protein closely related to erythropoietin, a

primary growth factor produced in the kidney that stimulates the development of erythroid
progenitor cells. Its mechanism of action is similar to that of endogenous erythropoietin,
which interacts with stem cells to increase red cell production.
Darbepoetin contains 5 N-linked oligosaccharide chains, whereas epoetin alfa contains 3 such
chains. Darbepoetin has a longer half-life than epoetin alfa and may be administered weekly
or biweekly.

Iron Products
Class Summary

Iron salts are nutritionally essential inorganic substances used to treat anemia.

Ferrous sulfate (Feosol, Fer-In-Sol, Slow FE, Fer-iron, MyKidz Iron 10)

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Ferrous sulfate is used as a building block for hemoglobin synthesis in patients with anemia
of CKD who are being treated with erythropoietin.

Iron dextran complex (Dexferrum, INFed)

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Iron dextran is used to treat microcytic, hypochromic anemia resulting from iron deficiency,
and to replenish iron stores in individuals on erythropoietin therapy, when oral administration
is infeasible or ineffective. A 0.5-mL (0.25 mL in children) test dose should be administered
prior to starting therapy. This agent is available as 50 mg iron/mL (as dextran).

Iron sucrose (Venofer)

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Iron sucrose is used to treat iron deficiency anemia (in conjunction with erythropoietin) in
patients with dialysis- and nondialysis-dependent CKD. Iron deficiency in these patients is
caused by blood loss during the dialysis procedure, increased erythropoiesis, and insufficient
absorption of iron from the gastrointestinal tract. There is a lower incidence of anaphylaxis
with iron sucrose than with other parenteral iron products.

Ferric gluconate (Ferrlecit, Nulecit)

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Ferric gluconate replaces the iron found in hemoglobin, myoglobin, and specific enzyme
systems, allowing transportation of oxygen via hemoglobin.

Ferumoxytol (Feraheme)

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Ferumoxytol is indicated for iron replacement in adults with CKD who have iron deficiency
anemia. Iron is released from an iron-carbohydrate complex in reticuloendothelial system
macrophages. The released iron is transported into storage pools or plasma transferrin, which
allows the iron to be incorporated into hemoglobin.

Ferric pyrophosphate (Triferic)

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Contains iron in the form of soluble ferric pyrophosphate citrate that is added to
hemodialysate solution and administered to patients by transfer across the dialyzer
membrane. Iron delivered into the circulation binds to transferrin for transport to erythroid
precursor cells to be incorporated into hemoglobin.

Ferric carboxymaltose (Injectafer)

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Ferric carboxymaltose is a non-dextran IV colloidal iron hydroxide in complex with

carboxymaltose, a carbohydrate polymer that releases iron. It is indicated for iron deficiency
anemia (IDA) in adults who have intolerance or an unsatisfactory response to oral iron. It is
also indicated for IDA in adults with nondialysis- dependent chronic kidney disease.

Metabolic & Endocrine, Other

Class Summary

A calcimimetic mimics calcium at the parathyroid hormone (PTH) receptor and reduces PTH
levels. Cinacalcet is the only drug in this class.

Cinacalcet (Sensipar)

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Cinacalcet directly lowers intact PTH levels by increasing the sensitivity to extracellular
calcium of calcium-sensing receptors on chief cells of the parathyroid glands. It also results
in a concomitant decrease in serum calcium. It is indicated for secondary
hyperparathyroidism in patients with CKD on dialysis.