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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
Staging
The different stages of CKD form a continuum. The stages of CKD are classified as follows [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).
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:
Diagnosis
Laboratory studies
Laboratory studies used in the diagnosis of CKD can include the following:
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 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
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
Etiology
Causes of chronic kidney disease (CKD) 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)
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:
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.
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:
Differential Diagnoses
Alport Syndrome
Chronic Glomerulonephritis
Diabetic Nephropathy
Multiple Myeloma
Nephrolithiasis
Nephrosclerosis
Pemeriksaan Penunjang
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.
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
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
risk and life expectancy between older and younger patients may cause older patients to derive reduced
benefits from interventions to prevent ESRD.[55, 56]
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]
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]
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
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.
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: