Author Contributions: Dr Grams had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Acquisition, analysis, or interpretation of data: Chen, Grams.

Drafting of the manuscript: Chen.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Grams.

Administrative, technical, or material support: Chen, Knicely.

Supervision: Grams.

Additional Contributions: We thank Andrew S. Levey, MD, Tufts Medical Center, and Natalie Daya, MS, Johns Hopkins University, for helpful input on the manuscript (uncompensated).

Chronic kidney disease (CKD) is the 16th leading cause of years of life lost worldwide. Appropriate screening, diagnosis, and management by primary care clinicians are necessary to prevent adverse CKD-associated outcomes, including cardiovascular disease, end-stage kidney disease, and death.

Defined as a persistent abnormality in kidney structure or function (eg, glomerular filtration rate [GFR] Open in a separate windowFigure 1.Considerations for Diagnosis, Staging, and Referral of Patients With Chronic Kidney Disease

a Other imaging modalities or urine studies may also be considered.

b A variety of scores are available, eg, https://kidneyfailurerisk.com/.

Once a diagnosis of CKD has been made, the next step is to determine staging, which is based on GFR, albuminuria, and cause of CKD (Figure 2).5 Staging of GFR is classified as G1 (GFR ≥90 mL/min/1.73 m2), G2 (GFR 60–89 mL/min/1.73 m2), G3a (45–59 mL/min/1.73 m2), G3b (30–44 mL/min/1.73 m2), G4 (15–29 mL/min/1.73 m2), and G5 (Open in a separate windowFigure 2.Definition and Prognosis of Chronic Kidney Disease by GFR and Albuminuria Categories, KDIGO 2012

GFR indicates glomerular filtration rate; KDIGO, Kidney Disease Improving Global Outcomes. Categories are grouped by risk of progression, which includes chronic kidney disease progression, defined by a decline in GFR category (accompanied by a ≥25% decrease in estimated GFR from baseline) or sustained decline in estimated GFR greater than 5 mL/min/1.73 m2 per year. Green indicates low risk (if no other markers of kidney disease and no CKD); yellow, moderately increased risk; orange: high risk; and red, very high risk. Reproduced with permission from Kidney International Supplements.5

Albuminuria should ideally be quantified by a urine ACR. Albuminuria staging is classified as A1 (urine ACR 300 mg/g).5 Guidelines recommend the use of urine ACR to stage CKD rather than urine protein-to-creatinine ratio because assays for the former are more likely to be standardized and have better precision at lower values of albuminuria.5,33 The most precise measurements come from a first morning sample or 24-hour collection, as there is high biological variability in urine albumin excretion over the course of the day.5,34,35 Random samples, however, are also acceptable in initial screening.5 Compared with urine protein-to-creatinine ratio, urine ACR is believed to be a more sensitive and specific marker of glomerular pathology5 since some urine proteins such as uromodulin are present (and may even be protective) in normal physiology.36–38 If tubular or overflow proteinuria is suspected, then urine protein electrophoresis or testing for the specific protein can be pursued (eg, immunoglobulin heavy and light chains, α1-microglobulin, and β2-microglobulin).5 Imaging by kidney ultrasound to assess morphology and to rule out urinary obstruction should be considered in all patients diagnosed as having CKD.5

Cause of CKD can be difficult to discern but is generally classified by the presence or absence of systemic disease and the location of anatomic abnormality. Examples of systemic disease include diabetes, autoimmune disorders, chronic infection, malignancy, and genetic disorders in which the kidney is not the only organ affected. Anatomic locations are divided into glomerular, tubulointerstitial, vascular, and cystic/congenital diseases.5 Determining the cause of CKD may have important implications on prognosis and treatment. For example, polycystic kidney disease may progress to ESKD faster than other causes and often requires evaluation for extrarenal manifestations and consideration of specific therapies such as tolvaptan, a vasopressin V2 receptor antagonist that slows decline in GFR.39,40 Patients with unexplained causes of CKD should be referred to a nephrologist.

Given that most patients with CKD are asymptomatic, screening may be important to early detection of disease.18 The National Kidney Foundation has developed a kidney profile test that includes measuring both serum creatinine for estimating GFR and urine ACR.41 A risk-based approach to screening is suggested by many clinical practice guidelines, with screening recommended in those older than 60 years or with a history of diabetes or hypertension.18–20 Screening should also be considered in those with clinical risk factors, including autoimmune disease, obesity, kidney stones, recurrent urinary tract infections, reduced kidney mass, exposure to certain medications such as NSAIDs or lithium, and prior episodes of acute kidney injury, among others (Box).9,18,42–45 However, no randomized clinical trials have demonstrated that screening asymptomatic patients for CKD improves outcomes.

Diabetes

Hypertension

Autoimmune diseases

Systemic infections (eg, HIV, hepatitis B virus, hepatitis C virus)

Nephrotoxic medications (eg, nonsteroidal anti-inflammatory drugs, herbal remedies, lithium)

Recurrent urinary tract infections

Kidney stones

Urinary tract obstruction

Malignancy

Obesity

Reduced kidney mass (eg, nephrectomy, low birth weight)

History of acute kidney injury

Smoking

Intravenous drug use (eg, heroin, cocaine)

Family history of kidney disease

Age >60 years

Nonwhite race

Low income

Low education

APOL1 risk alleles

Sickle cell trait and disease

Polycystic kidney disease

Alport syndrome

Congenital anomalies of the kidney and urinary tract

Other familial causes

There are several sociodemographic factors that contribute to increased risk of CKD, including nonwhite race, low education, low income, and food insecurity.18,43,46 Compared with whites, African Americans and Pacific Islanders have a substantially greater risk of ESKD.47 This is in part due to an increased prevalence of hypertension, diabetes, and obesity.11 However, genetic factors likely also contribute. More specifically, risk alleles in the gene encoding apolipoprotein L1 (APOL1) may increase risk of kidney disease in a recessive genetic manner7,8: individuals with 2 APOL1 risk alleles (present in approximately 13% of African Americans) have a 2-fold risk of CKD progression and up to a 29-fold risk of specific CKD etiologies (eg, focal-segmental glomerulosclerosis and HIV-associated nephropathy) compared with those with 0 or 1 risk allele.11,44,45,48,49 Sickle cell trait (present in approximately 8% of African Americans) has also been associated with an increased risk of kidney disease. Compared with noncarriers, individuals with sickle cell trait have a 1.8-fold odds of incident CKD, 1.3-fold odds of eGFR decline greater than 3 mL/min/1.73 m2, and 1.9-fold odds of albuminuria.9

The prevalence of cardiovascular disease is markedly higher among individuals with CKD compared with those without CKD. For example, in a Medicare 5% sample, 65% of the 175 840 adults aged 66 years or older with CKD had cardiovascular disease compared with 32% of the 1 086 232 without CKD.47 Moreover, presence of CKD is associated with worse cardiovascular outcomes. For example, in the same population, the presence of CKD was associated with lower 2-year survival in people with coronary artery disease (77% vs 87%), acute myocardial infarction (69% vs 82%), heart failure (65% vs 76%), atrial fibrillation (70% vs 83%), and cerebrovascular accident/transient ischemic attack (73% vs 83%).47

Therefore, a major component of CKD management is reduction of cardiovascular risk. It is recommended that patients aged 50 years or older with CKD be treated with a low- to moderate-dose statin regardless of low-density lipoprotein cholesterol level.50–52 Smoking cessation should also be encouraged.5,53 Both the Eighth Joint National Committee (JNC 8) and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines have recommended goal systolic and diastolic blood pressures of less than 140 mm Hg and less than 90 mm Hg, respectively, among adults with CKD based on expert opinion.5,54 The KDIGO guidelines further recommend that adults with urine ACR of at least 30 mg per 24 hours (or equivalent) have systolic and diastolic blood pressures maintained below 130 mm Hg and 80 mm Hg, respectively.5 More recently, the Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that among individuals with increased risk of cardiovascular disease but without diabetes, more intensive blood pressure control (goal systolic blood pressure

Screening, Monitoring, and Management of the Complications of Chronic Kidney Disease (CKD)