Chronic Kidney Disease

Practice Essentials
Chronic kidney disease (CKD)or chronic renal failure (CRF), as it was historically termedis a term that
encompasses all degrees of decreased renal function, from damagedat risk through mild, moderate, and
severe chronic kidney failure. There is a rising incidence and prevalence of kidney failure, with poor
outcomes and high cost

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.

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.

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

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 (QIDSSR[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.

Diagnostic Considerations
Chronic kidney disease (CKD) can have a variety of different presentations 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

Pemeriksaan Penunjang

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 equationcould 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 m 2. 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/1.73m 2, but in a 70-kg man aged
80 years, that same value represents an estimated GFR of 58 mL/min/1.73m 2. Thus, in a 70-kg, 80-yearold 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 springloaded 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.

Treatment

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 antiinflammatory 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-tocreatinine 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 largepopulation 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 noncalciumcontaining 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 -Dglucosaminidase, 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]