Chronic kidney disease (CKD) is diagnosed when there is evidence of kidney damage for more than 3 mo (urine albumin >30 mg/g creatinine, hematuria, or parenchymal abnormalities) and/or decreased kidney function (glomerular filtration rate [GFR] <60 ml/min per 1.73 m².¹ Advanced CKD, when GFR is <30 ml/min per 1.73 m², is characterized by accumulation of metabolic waste products in the blood, electrolyte abnormalities, mineral and bone disorders, and anemia. The pathophysiology of CKD and its manifestations are summarized in Table 1.

The 2012 Kidney Disease: International Global Outcomes classifies CKD with a C-G-A format: Cause (etiology), GFR (G1 to G5), and albuminuria (A1 to A3) by urine albumin-to-creatinine ratio. This format is recommended when documenting and discussing CKD. Fig. E1 depicts how CKD prognosis worsens with either increasing levels of albuminuria or declining GFR.

CKD

Chronic renal failure (CRF)

Chronic renal insufficiency (CRI)

Chronic renal disease (CRD)

• In the U.S., 37 million adults are estimated to have CKD, and approximately 90% do not know that they have diminished kidney function.² One in three U.S. adults is at risk for CKD.^2,3
• Total Medicare spending on CKD and ESRD patients exceeds $120 billion US. Accompanying chronic diseases such as diabetes and heart failure compound the cost of caring for these individuals, and CKD is considered a “cost multiplier,” accounting for 25% of Medicare expenditures. Spending per patient-year for patients with all three chronic conditions of CKD, diabetes, and heart failure was more than twice as high ($40,516) as for patients with only CKD.³
• CKD will be the fifth highest cause of years of life lose world wide by 2040.^3a
• Kidney transplantation represents the best option for kidney replacement therapy, offering greater longevity and quality of life while having the lowest overall cost. Mortality is significantly lower (48.9 per 1000) versus those on dialysis (160.8 per 1000).²

• Most patients with early CKD have no or few symptoms on physical exam
• Skin pallor, ecchymosis
• Sleep disorder
• Hypertension, edema, jugular venous distension
• Leg cramps, restless legs, peripheral neuropathy
• Emotional lability, depression, decreased cognitive function
• Uremic frost, odor, and fetor in severe cases
• Clinical presentation varies with the degree of kidney disease and its underlying etiology. Common symptoms are generalized fatigue, nausea, anorexia, pruritus, sleep disturbance, smell and taste disturbances, hiccoughs, and seizures

• Diabetes mellitus
• Hypertension
• Glomerular disease
• Failed kidney transplant
• Interstitial nephritis (e.g., drug hypersensitivity, analgesic nephropathy)
• Obstructive nephropathies (e.g., nephrolithiasis, prostatic disease)
• Congenital disease (e.g., Alport syndrome, polycystic kidney disease)
• Vascular diseases (renal artery stenosis, hypertensive nephrosclerosis)
• Autoimmune disorders
• Acute kidney injury (AKI)

• Ultrasound: Evaluation for sagittal length, echogenicity, and anatomical abnormalities including causes of obstructive uropathy.
• Kidney biopsy: Greatest diagnostic determination for AKI of unknown etiology and albuminuric disorders; generally, not performed when kidneys are small (<8.5-9.0 cm in length) or if CKD is advanced.
• Table 3 provides a summary of a practical approach for detection and management of CKD.

• Blood urea nitrogen (BUN) and serum creatinine: Serum creatinine is used to determine eGFR via multivariable (creatinine, age, sex) prediction equations normalized to a body surface area of 1.73 m². eGFR calculators are available online (www.kidney.org/kls/professionals/gfr_calculator.cfm). The preferred eGFR equation is the new race-free eGFR 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI).⁴
• Urinalysis: Biochemical identification of albumin and/or blood. Microscopy may demonstrate formed elements, including red blood cells, white blood cells, casts, and crystals.
• Serum chemistry: Sodium, potassium (elevated), chloride, and total carbon dioxide (primarily low bicarbonate), calcium (low), phosphorus (elevated), glucose (elevated), and uric acid (elevated).
• Urinary protein excretion. A urine total protein-to-creatinine ratio >1000 mg/g creatinine or albumin-to-creatinine ratio of >500 mg/g creatinine generally indicates glomerular disease because tubular proteinuria is usually less than this threshold.¹
• Special studies: Serum and urine immunoelectrophoresis (multiple myeloma), serum free light chains (monoclonal gammopathy of renal significance), antinuclear antibody (i.e., systemic lupus erythematosus), and other serological tests for determination of etiology of glomerular disorders.¹
• Cystatin C: A small protein biomarker used for determination of glomerular filtration. It is used to estimate GFR when a serum creatinine-based eGFR determination is less accurate, i.e., HIV or malnutrition, or if a more precise eGFR is required.⁴ The European Kidney Function Consortium (EKFC) EKFC eGFRcys equation, which has the same mathematical form as the EKFC eGFRcr equation but has a scaling factor for cystatin C that does not differ according to race or sex, has been reported to improve the accuracy of GFR assessment over that of commonly used equations.^4a

• Ultrasound of kidneys and bladder for kidney length measurements (normal, 10 to 12 cm based on height) and to rule out cause of obstructive uropathy
• Plain radiographs of the aorta and extremities ordered for other reasons may reveal vascular and extraskeletal calcification

The Kidney Disease: Improving Global Outcomes organization recommends lowering protein intake in adults with CKD to 0.8 g/kg per day and eGFR below 30 ml/min per 1.73 m², whereas high protein intake (>1.3 g/kg per day) should be avoided in adults with CKD at risk of progression. Table 5 describes nutritional recommendations for patients with CKD.¹

• Referral to a dietitian for medical nutritional therapy for patients with eGFR <50 ml/min per 1.73 m² is recommended and is a Medicare-covered service.
• Dietary restriction of sodium (∼100 mmol/day), potassium (≤60 mmol/day), and phosphorus (<800 mg/day). Potassium restriction is recommended for those with or at risk for hyperkalemia only.
• Blood pressure: Current guidelines from the American College of Cardiology/American Heart Association and the National Kidney Foundation Kidney Disease Outcomes Quality Initiative recommend a goal blood pressure of <130/<80 mm Hg for diabetic and nondiabetic CKD.
• Contrast-enhanced magnetic resonance imaging (MRI): Gadolinium-based contrast media (GBCM) with group II agents should not be withheld regardless of renal function if MRI is deemed medically necessary.
• Medications: Reviewed for potential toxicity and dosages adjusted based on eGFR.
• Resistance exercise training can preserve lean body mass and improve nutritional status and muscle function in patients with moderate CKD.
• Avoid iodinated radiocontrast media for eGFR <30 ml/min per 1.73 m². Prophylactic intravenous volume expansion with sodium chloride or sodium bicarbonate before dye exposure is equally effective and is usually recommended when eGFR <45 ml/min per 1.73 m².
• Smoking cessation.
• Nephrology referral: Late or delayed evaluation of patients with CKD is associated with greater burden and severity of comorbid disease and CKD complications, increased risk of hospitalization, reduced access to patient-centric home dialysis and kidney transplant, and reduced survival.⁵ Criteria for referral are listed in Table 6.
• Referral for kidney transplantation evaluation should be considered for patients with eGFR <20 ml/min per 1.73 m², unless absolute contraindications are present (e.g., malignancy within the past year).

• Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs) reduce cardiovascular risk and slow progression of CKD. Combining ACEI and ARB agents is not recommended because of increased risks of hyperkalemia and AKI. Elevation of serum creatinine 30% or more higher than baseline serum creatinine within 3 mo of initiating ACEI or ARB therapy is generally tolerated without complication(s) and does not indicate parenchymal injury or the need to dose adjust or discontinue drug therapy.
• In 2019, the U.S. FDA approved canagliflozin, a sodium-glucose cotransporter (SGLT-2) inhibitor, the first novel treatment for type 2 diabetic kidney disease (DKD) in nearly 18 yr. Canagliflozin was effective in the CREDENCE clinical trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation), which showed that canagliflozin achieved its primary end point compared with placebo and reduced the renal-specific composite of progression to ESRD, doubling of serum creatinine, and renal or cardiovascular death. Canagliflozin had been previously shown to reduce the decline in eGFR and albuminuria in DKD. Another SGLT-2 inhibitor, dapagliflozin, substantially reduced the rate of progression of CKD and frequency of ESRD in patients with and without diabetes in the DAPA-CKD trial (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease). Glucagon-like peptide 1 receptor agonists (GLP-1 RA) have shown similar improvements in cardiovascular and kidney outcomes in patients with type 2 diabetes; however, the renal end points were secondary outcomes. The SGLT-2 inhibitor class has been recommended especially for CKD patients with heart failure, as salt and water loss occur from glucosuria. GLP-1 RAs are especially recommended for atherosclerotic cardiovascular disease. The addition of chlorthalidone for CKD patients with difficult-to-treat hypertension may reduce blood pressure and proteinuria.^6,7
• Erythropoiesis-stimulating agents (ESAs), such as epoetin alfa and beta and darbepoetin alfa, are administered to reduce the need for transfusions in CKD patients with anemia. A target hemoglobin of 9 to 11 g/dl is reasonable to avoid premature and excessive ESA use. Higher hemoglobin values have been associated with adverse cardiovascular events. Iron sufficiency should be present, defined as transferrin saturation >20% and ferritin >100 ng/ml before ESA therapy is initiated.¹
• Optimal diuretic therapy should be prescribed for edema or cardiopulmonary congestion, although it has not shown mortality benefit in CKD.
• ACEIs or ARBs retard progression of CKD and lower blood pressure but cause short-term reductions of GFR and increase serum potassium.
• Treat metabolic acidosis with oral sodium bicarbonate to attain a goal serum HCO₃ level of approximately 22 to 26 mmol/L.¹
• Statin, or a combination of statin and ezetimibe, is recommended in adults ≥50 yr with eGFRs <60 ml/min per 1.73 m². Lipid management focuses on absolute risk for coronary events, and there are no target cholesterol levels without any effect on GFR trajectory.
• Therapy of mineral and bone disease in patients with CKD targets normal serum calcium and phosphorus levels. Calcitriol and vitamin D analogs are generally reserved for patients at CKD stages G4 to G5 and severe, progressive hyperparathyroidism (see chapter).
• Dietary phosphate restriction is recommended for nearly all CKD patients. For additional management of hyperphosphatemia, phosphate-binders are recommended. Calcium-based phosphate binders, although inexpensive, should be restricted if total serum calcium is >10.2 mg/dl or if serum phosphorus exceeds 6.0 mg/dl. Sevelamer carbonate and lanthanum carbonate are effective as phosphate binders but are more expensive. Two iron-based phosphate-binding agents, sucroferric oxyhydroxide and ferric citrate, are effective phosphate-binders.⁸
• Uremic pruritus: Difelikefalin, a selective agonist of kappa opioid receptors, reduces itch intensity in hemodialysis patients.⁹
• The U.S. Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices recommends pneumococcal vaccination of individuals >19 yr at time of CKD diagnosis in sequence with both 13-valent strain and 23-valent strain vaccines. An annual influenza vaccination for all persons aged ≥6 mo who do not have a contraindication is recommended. Individuals at high risk of progression of CKD with eGFRs <30 ml/min per 1.73 m² should be immunized against hepatitis B to ensure seroconversion.¹⁰
• Initiation of dialysis: Early initiation of dialysis at eGFR 10 to 15 ml/min per 1.73 m² does not enhance survival compared with a symptom-driven strategy for initiation of dialysis at eGFR <8 to 10 ml/min per 1.73 m².
  1. Urgent indications: Uremic pericarditis, neuropathy, neuromuscular abnormalities, congestive heart failure, hyperkalemia, or seizure.
  2. Other indications: GFR 10 to 15 ml/min per 1.73 m² with progressive anorexia, weight loss, anuria, disordered sleep, pruritus, uncontrolled fluid gain with hypertension, and signs of heart failure.
  3. Nearly 4 million people worldwide currently rely on some form of dialysis for treatment of ESRD. Peritoneal dialysis accounts for approximately 11% of patients undergoing dialysis overall.

• Prognosis is influenced by CKD stage and burden of comorbid illness. Factors affecting renal dysfunction in long-term survivors are summarized in Table 7. Late nephrology referral or no referral to a nephrologist within 6 to 12 mo before a diagnosis of ESRD is established is associated with greater morbidity and mortality. Despite recommendations for early referral, nearly two thirds of CKD patients are referred late, and a majority of patients do not realize they live with CKD.
• Choosing Wisely is an American Board of Internal Medicine Foundation initiative (https://www.choosingwisely.org/societies/american-society-of-nephrology/) that promotes conversations between clinicians and patients by helping patients choose evidence-based care that avoids wasteful or unnecessary medical tests, treatments, and procedures.
• Genetic susceptibility for CKD is prominent in African Americans. Two high-risk alleles of apolipoprotein L1 predict more rapid CKD progression independent of diabetes, race, and lipid and nonlipid factors. Approximately 14% of African Americans have two risk alleles, and 38% have one risk allele.
• Kidney transplantation in selected patients improves survival. Whereas the 2-yr kidney graft survival rate for living-related donor transplantations is >80%, the 2-yr graft survival rate for cadaveric donor transplantation is approximately 70%.