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Am Fam Physician. 2011;84(10):1138-1148

Author disclosure: No relevant financial affiliations to disclose.

Chronic kidney disease affects an estimated 27 million adults in the United States, and is associated with significantly increased risk of cardiovascular disease and stroke. Patients should be assessed annually to determine whether they are at increased risk of developing chronic kidney disease based on clinical and sociodemographic factors. Diabetes mellitus, hypertension, and older age are the primary risk factors that warrant screening. Other risk factors include cardiovascular disease, family history of chronic kidney disease, and ethnic and racial minority status. Serum creatinine levels can be used to estimate the glomerular filtration rate, and spot urine testing can detect proteinuria. After the diagnosis of chronic kidney disease is made, staging based on estimated glomerular filtration rate determines prognosis, evaluation, and management. Further evaluation should focus on the specific type of kidney disease and on identifying complications related to the disease stage. Patients should be assessed for risk factors leading to the further loss of kidney function and cardiovascular disease. Patients with estimated glomerular filtration rates less than 30 mL per minute per 1.73 m2, significant proteinuria, or rapid loss of kidney function should be referred to a nephrologist for further evaluation and management.

Chronic kidney disease (CKD) affects an estimated 27 million adults in the United States and is associated with increased mortality, morbidity, and health care costs.1,2 CKD is also associated with significantly increased risks of cardiovascular disease3 and stroke.4 The incidence and prevalence of CKD among U.S. adults have increased dramatically since 1991.5 More than 500,000 Americans were treated for end-stage renal disease in 2007.6 The increases are partly explained by the increasing prevalence of diabetes mellitus and hypertension, the leading risk factors for CKD. Awareness of CKD among patients has modestly increased in recent years, but remains low. According to the 2003–2004 National Health and Nutrition Examination Survey, less than 5 percent of patients with stage 1 or 2 CKD and less than 10 percent with stage 3 reported having been diagnosed with CKD; only 45 percent of patients with stage 4 were aware of their condition.7 Although clinical laboratories report estimated glomerular filtration rate (GFR) directly to physicians, CKD recognition remains low.8 In 2002, the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative published practice guidelines to help primary care physicians identify patients with early CKD and improve health outcomes.9

Clinical recommendationEvidence ratingReferences
Physicians should screen at-risk populations for CKD using serum creatinine levels and random urine testing for albuminuria.C9, 11, 12, 15
Adults with cardiovascular disease should be screened for CKD.C13
The Chronic Kidney Disease Epidemiology Collaboration formula is more accurate than the Modification of Diet in Renal Disease equation or the Cockcroft-Gault equation, and should be used to estimate GFR.C19, 21
Acetaminophen is the analgesic of choice for short-term treatment of mild to moderate pain in patients with stage 3 to 5 CKD.C33
Nephrology consultation is indicated when the estimated GFR is less than 30 mL per minute per 1.73 m2.C9

CKD is defined by the presence of structural or functional abnormalities of the kidney with or without an accompanying reduction in GFR. Persons with CKD may have one or more of the following: pathologic abnormalities, markers of kidney damage (i.e., imaging abnormalities and abnormalities in serum or urine, including proteinuria and abnormal urinary sediment), or GFR less than 60 mL per minute per 1.73 m2 for at least three months. If the duration of the abnormality is unknown, the possibility of acute kidney injury should be considered and appropriate evaluation performed for reversible causes. Most persons who have received kidney transplants are considered to have CKD.

Detection of CKD


Annual CKD screening is recommended by the American Diabetes Association,10 by the National Kidney Foundation for patients at risk,9,11 by the Joint National Committee on Hypertension12 for patients with diabetes and hypertension, and by the American Heart Association for patients with cardiovascular disease.13 The U.S. Preventive Services Task Force has not examined the evidence or made recommendations for screening. Cardiovascular disease, a family history of CKD, and ethnic or racial minority status do not significantly increase the risk of CKD in adults older than 60 who have diabetes and hypertension.14 Risk factors are listed in Table 1.9

Autoimmune disease
Diabetes mellitus
Exposure to certain chemicals and environmental conditions (e.g., lead, cadmium, arsenic, mercury, uranium)
Exposure to certain drugs (Table 625)
Family history of CKD
Low birth weight
Low income or education
Lower urinary tract obstruction
Minority status (e.g., blacks, American Indians, Asians, Pacific Islanders)
Older age
Recovery from acute kidney injury
Reduction in kidney mass
Systemic infections
Urinary tract infections


CKD is typically detected by measuring serum creatinine levels to calculate the GFR and by measuring the urinary albumin/creatinine ratio to detect proteinuria.15 Although the most common causes of CKD are diabetes and hypertension (Table 29,16 ), the disease can be caused by many other conditions. Urinalysis can detect signs of glomerulonephritis, tubulointerstitial disease, vasculitis, hereditary nephritis, and lupus nephritis; however, it is not routinely recommended in otherwise healthy patients.

Disease typeEtiology and examplesPrevalence among patients with end-stage renal disease in 2010 (%)
Diabetic kidney diseaseType 2 diabetes mellitus32.5
Type 1 diabetes mellitus5.7
Nondiabetic kidney disease
Vascular diseasesHypertension, ischemic renal disease24.8
Glomerular diseasesPrimary: lupus nephritis, vasculitis, membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, immunoglobulin A nephropathy 18
Secondary: infections (e.g., hepatitis B and C, human immunodeficiency virus–associated bacterial endocarditis), amyloidosis, heroin use, malignancy (e.g., leukemia, Hodgkin lymphoma, carcinoma)
Cystic diseasesPolycystic kidney disease7
Tubulointerstitial diseaseUrinary tract infections, nephrolithiasis, obstruction, sarcoidosis, multiple myeloma, drug toxicity (e.g., proton pump inhibitors, lithium, nonsteroidal anti-inflammatory drugs)3.8


The GFR is the best measure of kidney function. Normal GFR varies by age, sex, and body size. GFR is approximately 120 to 130 mL per minute per 1.73 m2 in young adults, and decreases by an average of 1 mL per minute per 1.73 m2 per year after 30 years of age.9 A GFR less than 60 mL per minute per 1.73 m2 represents a loss of at least one-half of normal kidney function; below this level, there is an increased prevalence of CKD complications.

Creatinine clearance is used to estimate the GFR. Because creatinine is filtered and secreted by the proximal tubules, the creatinine clearance exceeds the GFR. Generation of creatinine is determined by muscle mass and diet, whereas tubular secretion could be decreased by the use of medications such as trimethoprim and cimetidine (Tagamet).

The serum creatinine level is an insensitive marker of GFR early in the course of CKD. A 33 percent decrease in GFR may raise the creatinine level from 0.8 to only 1.2 mg per dL (70.72 to 106.08 μmol per L). If the prior creatinine level is not known, this decrease in GFR may go unrecognized. When estimated GFR is suspected to be inaccurate—for example, in patients with severe malnutrition or paraplegia—a 24-hour urine collection should be performed to evaluate creatinine clearance.

Three equations are typically used to estimate GFR: the Cockcroft-Gault equation,17 the Modification of Diet in Renal Disease (MDRD) equation,18 and the more accurate Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)19 formula (Table 3).1719 The Cockcroft-Gault equation systematically overestimates GFR. The MDRD is reasonably accurate in patients with CKD, but it underestimates GFR when it is greater than 60 mL per minute per 1.73 m2, and it may misidentify persons with normal kidney function as having CKD. The MDRD can also be affected by fluctuations in creatinine production and fluid balance; it gives falsely elevated estimated GFRs in malnourished and overhydrated patients and falsely decreased GFRs due to increased serum creatinine levels in patients taking trimethoprim and cimetidine.20 The CKD-EPI formula provides better GFR estimation in patients with reduced and normal kidney function.19 In a recent study, the CKD-EPI was found to be the most accurate formula in estimating GFR.21

EquationVariablesAvailable at
Chronic Kidney Disease Epidemiology CollaborationAge, sex, race, serum creatinine levelNational Kidney Foundation
Web site:
Nephron Information Center
Web site:
Cockcroft-GaultAge, weight, sex, serum creatinine levelNephron Information Center
Web site:
Modification of Diet in Renal DiseaseAge; sex; race; and serum urea, nitrogen, albumin, and creatinine levelsNational Kidney Disease Education Program
Web site:
Nephron Information Center
Web site:

Markers of Kidney Damage


Proteinuria refers to increased excretion of any urinary protein, including albumin and other serum proteins (tubular proteins). A normal urinary protein/creatinine ratio is less than 200 mg per g; proteinuria is a predictor of total mortality and CKD progression, and can help determine the type of CKD. A normal urinary albumin/creatinine ratio is less than 30 mg per g. Patients with albumin/creatinine ratios of 30 to 300 mg per g are classified as having microalbuminuria, and those with ratios greater than 300 mg per g are classified as having macroalbuminuria.10,11

Urine dipstick testing is insensitive for the measurement of small amounts of albumin and is not recommended for CKD screening in patients at risk. This test is positive when a large amount (greater than 500 to 1,000 mg per day) of protein is excreted. Patients with positive urine dipstick results should repeat the test in the absence of urinary tract infection, ketosis, and hypovolemia. If the second result is positive, the urinary protein/creatinine ratio should be obtained within three months. Persistent proteinuria can be diagnosed by two positive protein/creatinine ratios one to two weeks apart.9 Diabetes, the leading cause of nephrotic syndrome in the United States, is diagnosed when the protein/creatinine ratio is greater than 3,000 mg (3.0 g) per g.


Albumin is a sensitive marker of CKD caused by diabetes, hypertension, and glomerular diseases. Microalbuminuria was the most common abnormality associated with the diagnosis of stages 1 and 2 CKD in the National Health and Nutrition Examination Survey.5 Microalbuminuria is an inherent part of the diabetes disease process but also can be present with nonrenal conditions (e.g., obesity, inflammation, cancer).22 Microalbuminuria may indicate increased vascular permeability rather than kidney injury.23

Patients with diabetes and microalbuminuria who progress to macroalbuminuria are more likely to progress to end-stage renal disease. Diabetic kidney disease can be diagnosed based on the urinary albumin/creatinine ratio, duration of diabetes, and presence of diabetic retinopathy (Table 4).11 When albuminuria reaches the range of macroalbuminuria, albumin becomes the dominant urinary protein, and the advantage of measuring albuminuria over proteinuria is generally lost.9 Two out of three abnormal readings are required to confirm persistent albuminuria (Figure 1).9,15,24

Screening initiation
At the time of diagnosis of type 2 diabetes mellitus
Five years after diagnosis of type 1 diabetes mellitus
Screening frequency
Diagnostic criteria
Microalbuminuria in patients who have had type 1 diabetes for more than 10 years
Microalbuminuria in the presence of diabetic retinopathy
Clinical findings that should prompt consideration of other causes
Absence of albuminuria in patients with stage 3 to 5 chronic kidney disease
Absence of diabetic retinopathy
Active urinary sediment (cells or casts)
Low GFR at the time of diagnosis
More than 30 percent reduction in GFR within two to three months after initiation of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker
Rapidly decreasing GFR (more than 4 mL per minute per 1.73 m2 per year)
Rapidly increasing proteinuria or nephrotic syndrome
Refractory hypertension
Signs or symptoms of other systemic disease


Other markers of kidney damage include hematuria, cellular casts, serum markers, and imaging abnormalities. Clinical judgment based on the assessment of CKD risk factors should be used to determine if measurement of other markers of kidney damage is indicated.

CKD Staging

Staging is an important step for determining the prognosis, evaluation, and management of CKD. Staging is based on the level of estimated GFR, irrespective of diagnosis (Table 5).9 Markers of kidney damage are required for stages 1 and 2. Using the current classification system, nearly 50 percent of U.S. adults older than 70 years have stage 3 CKD, and most have no evidence of albuminuria.5 Older patients with stage 3 CKD without proteinuria and stable creatinine levels on repeat testing at three to six months are unlikely to progress to end-stage renal disease and do not have increased mortality risk. Physicians may choose to defer further evaluation in such patients, avoid the use of nephrotoxic medications (Table 625 ), and adjust the dosages of those that are excreted by the kidneys20 (Table 79,26 ).

StageDescriptionEstimated GFR (mL per minute per 1.73 m2 )Action plan
1Kidney damage* with normal or increased GFR≥ 90Diagnose and treat CKD, treat comorbid conditions, slow progression of CKD, reduce cardiovascular risk
2Kidney damage* with mildly decreased GFR60 to 89Estimate progression
3Moderately decreased GFR30 to 59Evaluate and treat complications
4Severely decreased GFR15 to 29Prepare for kidney transplant
5Kidney failure< 15 (or dialysis)Kidney transplant if uremia present
DrugMechanism of kidney injury
Acyclovir (Zovirax)Acute interstitial nephritis, crystal nephropathy
AminoglycosidesTubular cell toxicity
Amphotericin BTubular cell toxicity
Chinese herbal preparations containing aristolochic acidChronic interstitial nephritis
Contrast mediaRenal ischemia
LithiumChronic interstitial nephritis
Nonsteroidal anti-inflammatory drugsAcute and chronic interstitial nephritis, impaired glomerular hemodynamics
Phenytoin (Dilantin)Acute interstitial nephritis
SulfonamidesAcute interstitial nephritis, crystal nephropathy
VancomycinAcute interstitial nephritis
Zoledronic acid (Zometa)Tubular cell toxicity
MedicationDosage adjustment based on GFR (mL per minute per 1.73 m2 )*
> 5010 to 50< 10
Acyclovir (Zovirax; oral)100%100%200 mg every 12 hours
Allopurinol (Zyloprim)75%50%25%
AmoxicillinEvery 8 hoursEvery 8 to 12 hoursEvery 24 hours
Amoxicillin/clavulanate (Augmentin)Every 12 hoursEstimated GFR 10 to 30 mL per minute per 1.73 m2: every 12 hours Every 24 hours
Estimated GFR < 30 mL per minute per 1.73 m2: do not use 875-mg/125-mg tablets
Atenolol (Tenormin)100%50%25%
CefazolinEvery 8 hoursEvery 12 hours50% every 24 to 48 hours
Cephalexin (Keflex)Every 8 hoursEvery 8 to 12 hoursEvery 12 to 24 hours
Ciprofloxacin (Cipro)100%50 to 75%50%
Clarithromycin (Biaxin)100%50 to 100%50%
Famotidine (Pepcid)50%25%10%
Fluconazole (Diflucan)100%50%50%
Gabapentin (Neurontin)Estimated GFR 30 to 60 mL per minute per 1.73 m2: 200 to 700 mg twice daily
Estimated GFR 16 to 29 mL per minute per 1.73 m2: 200 to 700 mg daily
Estimated GFR ≤ 15 mL per minute per 1.73 m2: 100 to 300 mg daily
Levofloxacin (Levaquin)100%Estimated GFR 20 to 49 mL per minute per 1.73 m2: 500- to 750-mg initial dose, then 250 to 750 mg every 24 to 48 hours
Estimated GFR 10 to 19 mL per minute per 1.73 m2: 500-mg initial dose, then 250 to 500 mg every 48 hours
Metformin (Glucophage)Avoid if serum creatinine level is greater than 1.5 mg per dL (132.60 μmol per L) in men or greater than 1.4 mg per dL (123.76 μmol per L) in women, and in patients older than 80 years
Metoclopramide (Reglan)100%75%50%
Ranitidine (Zantac)75%50%25%
Rosuvastatin (Crestor)GFR < 30 mL per minute per 1.73 m2: 5 mg per day initially; 10 mg per day maximum
Simvastatin (Zocor)GFR < 30 mL per minute per 1.73 m2: 5 mg per day initially
Thiazide diuretics100%100%Avoid
Valacyclovir (Valtrex)100%Every 12 to 24 hours500 mg every 24 hours

CKD staging does not include risk-modifying parameters such as degree of albuminuria, age, sex, and cardiovascular risk factors. Revised guidelines, currently under development, will address those issues.

Evaluation of CKD

A thorough initial investigation includes determining the etiology and type of CKD and evaluating for comorbidities. The patient and family histories, physical examination, and blood pressure and weight measurements are the most valuable parts of the CKD evaluation (Table 8).9,27,28 Laboratory tests should include measurement of serum electrolytes and glucose, and a fasting lipid panel. Urinalysis should be performed to evaluate urinary sediment and the urinary albumin/creatinine or protein/creatinine ratio9 (Table 99,11,29 ). Additional testing may be required to identify rare causes of CKD. Renal ultrasonography is recommended to evaluate kidney size and assess for possible structural abnormalities.9

Examination componentDiagnostic cluesFindings suggestive of CKD risks and etiology
Review of systemsRecent infectionsPoststreptococcal glomerulonephritis
Risk factors for sexually transmitted diseaseHIV infection, hepatitis B or C
Skin rash or arthritisAutoimmune disease (e.g., systemic lupus erythematosus, cryoglobulinemia)
Symptoms during urinationUrinary tract infection, obstruction, or stone
Medical historyDiabetes mellitus (5 to 10 years' duration)Microalbuminuria with evidence of retinopathy and elevated BP
Diabetes (10 to 15 years' duration)Albuminuria, retinopathy, hypertension
HypertensionSevere BP elevation, often with target organ damage
Family history of kidney diseaseMales and females are affected equally in every generationAutosomal dominant polycystic kidney disease
Males in every generation are affectedSex-linked recessive disease (e.g., Alport syndrome)
Less frequent than every generationAutosomal recessive polycystic kidney disease
Physical examinationAbdominal findingsBruit (renal artery stenosis, fibromuscular dysplasia), flank pain, distended bladder
Cardiovascular findingsHeart failure, ventricular hypertrophy
Carotid bruitCarotid artery disease
Decreased peripheral pulsesPeripheral vascular disease
General findingsCushingoid appearance, edema
Increased BP and weightHypertension, obesity
Musculoskeletal findingsArthritis, synovitis
Ophthalmoscopic findingsHypertensive or diabetic retinal disease
Skin changesRash and skin changes in autoimmune disease or neurofibromatosis
Laboratory testsAbnormal serum and urine protein electrophoresisMultiple myeloma, amyloidosis, light-chain deposition disease
Decreased serum complement levels C3 and C4Poststreptococcal glomerulonephritis, membranoproliferative glomerulonephritis, lupus nephritis, cryoglobulinemia
EosinophiluriaAtheroembolic disease, tubulointerstitial disease
Positive antiglomerular basement membrane antibody testGoodpasture syndrome, antiglomerular basement membrane–associated rapidly progressive glomerulonephritis
Positive antineutrophil cytoplasmic antibody testWegener granulomatosis, microscopic polyangiitis, pauci-immune rapidly progressive glomerulonephritis
Positive antinuclear antibody testLupus nephritis
Positive cryoglobulin testCryoglobulinemia
Positive hepatitis B serologyMembranous nephropathy, membranoproliferative nephritis
Positive hepatitis C serologyMixed cryoglobulinemia, membranoproliferative glomerulonephritis, membranous nephropathy
Positive HIV serologyFocal and segmental glomerulosclerosis
UltrasonographyDoppler ultrasonographyMay be useful in investigation of venous thrombosis, less so in arterial stenosis
General findingsMay show nephrocalcinosis, discrete stones, hydronephrosis, cysts,* or masses
Increased echogenicityMay indicate cystic disease or medical renal disease
Large kidneysGenerally indicate tumors, infiltrating diseases, or diseases causing nephrotic syndrome
Size disparities and scarringSuggest vascular, urologic, or tubulointerstitial diseases due to stones or infection
Small hyperechoic kidneysGenerally indicate CKD
Associated kidney diseasePredominant abnormality on urinalysis
ACR or PCR (mg per g creatinine)RBCsRBC casts*WBCsWBC castsTubular cellsGranular casts
Cystic kidney diseasePCR 200 to 1,000+
Diabetic kidney disease, earlier stagesACR 30 to 300
Diabetic kidney disease, later stagesACR > 300 or PCR > 500 to 1,000
Hereditary nephritis or disease of small vessels (microangiopathy)PCR < 1,000+++
Hypertensive diseasePCR 200 to 1,000
Noninflammatory glomerular disease (minimal change disease, focal segmental glomerulosclerosis, associated with neoplasm)PCR > 1,000
Proliferative glomerulonephritis (systemic lupus erythematosus, vasculitis, infections) or hereditary nephritisPCR > 500++±±
Tubulointerstitial nephritisPCR 200 to 1,000±++

Cardiovascular disease risk assessment—especially smoking status and lipid levels—is important because death is more likely than progression to dialysis in any stage of CKD.9 Electrocardiography is recommended to identify left ventricular hypertrophy.

Patients with an estimated GFR of less than 60 mL per minute per 1.73 m2 require further evaluation to assess for complications. Evaluation for anemia is recommended in women with hemoglobin levels less than 12 g per dL (120 g per L) and in men with levels less than 13.5 g per dL (135 g per L), in addition to nutritional assessment and evaluation for bone disease (Table 10).9,30,31

Clinical findingCKD stageParameters to assessFrequency of evaluation
AnemiaAllComplete blood count with differential; reticulocyte count; iron, ferritin, and transferrin levelsOnce per year (more frequently if abnormal)
Malnutrition3 to 5Weight, serum albumin level, dietary historyEvery 6 to 12 months in stage 3; every 1 to 3 months in stages 4 and 5
Metabolic bone disease3 to 5Alkaline phosphatase levelOnce in stage 3; every 12 months in stages 4 and 5
Calcium and phosphorus levelsEvery 6 to 12 months in stage 3; every 3 to 6 months in stage 4; every 1 to 3 months in stage 5
Consider duel energy x-ray absorptiometryNo routine testing
25-hydroxyvitamin D levelOnce, then as indicated
Parathyroid hormone levelOnce, then as indicated in stage 3; every 6 to 12 months in stage 4; every 3 to 6 months in stage 5
Neuropathy3 to 5Paresthesias, mental status, sleep disturbances (e.g., restless legs syndrome); consider sleep study and nerve conduction studyAs indicated
Reduced level of functioning and well-being3 to 5Health literacy assessment, social support, standardized self-administered instruments (e.g., Dartmouth-Northern New England Primary Care Cooperative Information Project charts, Duke Health Profile, 36-item Medical Outcomes Study [SF-36], Kidney Disease Quality of Life scale)Once, then as indicated

Short-term risks of GFR reduction (e.g., volume depletion, urinary tract obstruction, use of nephrotoxic agents) require immediate recognition to prevent irreversible deterioration of renal function. High cumulative exposure to nonsteroidal anti-inflammatory drugs is associated with rapid progression of CKD.32 Acetaminophen is the analgesic of choice for short-term treatment of mild to moderate pain in patients with stage 3 to 5 CKD.33 Nonsteroidal anti-inflammatory drugs may be used in patients with stage 3 CKD for short-term therapy with regular renal function monitoring.33

Indications for Nephrology Referral

Nephrology consultation is indicated when the estimated GFR is less than 30 mL per minute per 1.73 m2, or earlier if necessary (Table 11).9,15 Partnership between primary care physicians and nephrologists is key to successful CKD management. The National Kidney Foundation's suggested multidisciplinary clinical action plan for CKD is available at

Acute, complex, or severe cardiovascular disease
Anemia of CKD
Bone and mineral disorder of CKD
Difficult to manage adverse effects of medications
Hyperkalemia (potassium level > 5.5 mEq per L [5.50 mmol per L] despite treatment)
Refractory proteinuria (urinary protein/creatinine ratio > 500 to 1,000 mg per g or urinary albumin/creatinine ratio > 300 mg per g)
Resistant hypertension (target blood pressure not achieved with use of at least three antihypertensive drugs)
Stage 4 CKD (estimated GFR < 30 mL per minute per 1.73 m2)
Unexplained decrease in estimated GFR > 30 percent over four months

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