Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia, nocturia, lassitude, fatigue, pruritus, decreased mental acuity, muscle twitches and cramps, water retention, undernutrition, peripheral neuropathies, and seizures. Diagnosis is based on laboratory testing of renal function, sometimes followed by renal biopsy. Treatment is primarily directed at the underlying condition but includes fluid and electrolyte management, blood pressure control, treatment of anemia, various types of dialysis, and kidney transplantation.
Prevalence of CKD (defined as estimated glomerular filtration rate [eGFR] <60 mL/min/1.73m2 or urinary albumin to creatinine ratio [ACR] ≥30 mg/g) among adults in the United States from 2017 through March 2020 was estimated to be 14.0% (1).
General reference
1. United States Renal Data System (USRDS): CKD in the general population. Accessed August 18, 2023.
Etiology of Chronic Kidney Disease
Chronic kidney disease may result from any cause of renal dysfunction of sufficient magnitude (see table Major Causes of Chronic Kidney Disease).
The most common causes in the United States in order of prevalence are
Various primary and secondary glomerulopathies
Metabolic syndrome, in which hypertension and type 2 diabetes are present, is a large and growing cause of renal damage.
Pathophysiology of Chronic Kidney Disease
Chronic kidney disease (CKD) is initially described as diminished renal reserve or renal insufficiency, which may progress to renal failure (end-stage kidney disease). Initially, as renal tissue loses function, there are few noticeable abnormalities because the remaining tissue increases its performance (renal functional adaptation).
Decreased renal function interferes with the kidneys’ ability to maintain fluid and electrolyte homeostasis. The ability to concentrate urine declines early and is followed by decreases in ability to excrete excess phosphate, acid, and potassium. When renal failure is advanced (glomerular filtration rate [GFR] ≤ 15 mL/min/1.73 m2), the ability to effectively dilute or concentrate urine is lost; thus, urine osmolality is usually fixed at about 300 to 320 mOsm/kg, close to that of plasma (275 to 295 mOsm/kg), and urinary volume does not respond readily to variations in water intake.
Creatinine and urea
Plasma concentrations of creatinine and urea (which are highly dependent on glomerular filtration) begin a hyperbolic rise as GFR diminishes. These changes are minimal early on. When the GFR falls below 15 mL/min/1.73 m2 (normal > 90 mL/min/1.73 m2), creatinine and urea levels are high and are usually associated with systemic manifestations (uremia). Urea and creatinine are not major contributors to the uremic symptoms; they are markers for many other substances (some not yet well-defined) that cause the symptoms.
Sodium and water
Despite a diminishing GFR, sodium and water balance is well-maintained by increased fractional excretion of sodium in urine and a normal response to thirst. Thus, the plasma sodium concentration is typically normal, and hypervolemia is infrequent unless dietary intake of sodium or water is very restricted or excessive. Heart failure can occur due to sodium and water overload, particularly in patients with decreased cardiac reserve.
Potassium
For substances whose secretion is controlled mainly through distal nephron secretion (eg, potassium), renal adaptation usually maintains plasma levels at normal until renal failure is advanced or dietary potassium intake is excessive. Potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, beta-blockers, nonsteroidal anti-inflammatory drugs may raise plasma potassium levels in patients with less advanced renal failure.
Calcium and phosphate
Abnormalities of calcium, phosphate, parathyroid hormone (PTH), and can occur, as can renal osteodystrophy. Decreased renal production of calcitriol (1,25(OH)2D, the active vitamin D hormone) contributes to hypocalcemia. Decreased renal excretion of phosphate results in hyperphosphatemia. Secondary hyperparathyroidism is common and can develop in renal failure before abnormalities in calcium or phosphate concentrations occur. For this reason, monitoring PTH in patients with moderate CKD, even before hyperphosphatemia occurs, has been recommended.
Renal osteodystrophy (abnormal bone mineralization resulting from hyperparathyroidism, calcitriol deficiency, elevated serum phosphate, or low or normal serum calcium) usually takes the form of increased bone turnover due to hyperparathyroid bone disease (osteitis fibrosa) but can also involve decreased bone turnover due to adynamic bone disease (with increased parathyroid suppression) or osteomalacia. Calcitriol deficiency may cause osteopenia or osteomalacia.
pH and bicarbonate
Moderate metabolic acidosis (plasma bicarbonate content 15 to 20 mmol/L) is characteristic. Acidosis causes muscle wasting due to protein catabolism, bone loss due to bone buffering of acid, and accelerated progression of kidney disease.
Anemia
Anemia is characteristic of moderate to advanced CKD (≥ stage 3). The anemia of CKD is normochromic-normocytic, with a hematocrit of 20 to 30% (35 to 40% in patients with polycystic kidney disease). It is usually caused by deficient erythropoietin production due to a reduction of functional renal mass (see page Anemias Caused by Deficient Erythropoiesis). Other causes include deficiencies of iron, folate, and vitamin B12.
Symptoms and Signs of Chronic Kidney Disease
Patients with mildly diminished renal reserve are asymptomatic. Even patients with mild to moderate renal insufficiency may have no symptoms despite elevated blood urea nitrogen (BUN) and creatinine. Nocturia is often noted, principally due to failure to concentrate the urine. Lassitude, fatigue, anorexia, and decreased mental acuity often are the earliest manifestations of uremia.
With more severe renal disease (eg, estimated glomerular filtration rate [eGFR] < 15 mL/min/1.73 m2), neuromuscular symptoms may be present, including coarse muscular twitches, peripheral sensory and motor neuropathies, muscle cramps, hyperreflexia, restless legs syndrome, and seizures (usually the result of hypertensive or metabolic encephalopathy).
Anorexia, nausea, vomiting, weight loss, stomatitis, and an unpleasant taste in the mouth are almost uniformly present. The skin may be yellow-brown and/or dry. Occasionally, urea from sweat crystallizes on the skin (uremic frost). Pruritus may be especially uncomfortable. Undernutrition leading to generalized tissue wasting is a prominent feature of chronic uremia.
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In advanced CKD, pericarditis and gastrointestinal ulceration and bleeding may occur. Hypertension is present in > 80% of patients with advanced CKD and is usually related to hypervolemia. Heart failure caused by hypertension or coronary artery disease and renal retention of sodium and water may lead to dependent edema and/or dyspnea.
Diagnosis of Chronic Kidney Disease
Electrolytes, blood urea nitrogen (BUN), creatinine, phosphate, calcium, complete blood count (CBC)
Urinalysis (including urinary sediment examination)
Quantitative urine protein (24-hour urine protein collection or spot urine protein to creatinine ratio)
Ultrasonography
Sometimes renal biopsy
Chronic kidney disease (CKD) is usually first suspected when serum creatinine rises. The initial step is to determine whether the renal failure is acute, chronic, or acute superimposed on chronic (ie, an acute disease that further compromises renal function in a patient with CKD—see table Distinguishing Acute Kidney Injury From Chronic Kidney Disease). The cause of renal failure is also determined. Sometimes determining the duration of renal failure helps determine the cause; sometimes it is easier to determine the cause than the duration, and determining the cause helps determine the duration.
Testing includes urinalysis with examination of the urinary sediment, electrolytes, urea nitrogen, creatinine, phosphate, calcium, and CBC. Sometimes specific serologic tests are needed to determine the cause. Distinguishing acute kidney injury from CKD is most helped by a recent rapid rise in serum creatinine or abnormalities in the urinalysis. Urinalysis findings depend on the nature of the underlying disorder, but broad (> 3 white blood cell diameters wide) or especially waxy (highly refractile) casts often are prominent in advanced renal failure of any cause.
An ultrasound examination of the kidneys is usually helpful in evaluating for obstructive uropathy and in distinguishing acute kidney injury from CKD based on kidney size. Except in certain conditions (see table Distinguishing Acute Kidney Injury From Chronic Kidney Disease), patients with CKD have small shrunken kidneys (usually < 10 cm in length) with thinned, hyperechoic cortex. Obtaining a precise diagnosis becomes increasingly difficult as renal function reaches values close to those of end-stage kidney disease. The definitive diagnostic tool is renal biopsy, but it is not recommended when ultrasonography indicates small, fibrotic kidneys; high procedural risk outweighs low diagnostic yield.
Stages of chronic kidney disease
Staging CKD is a way of quantifying its severity. CKD has been classified into 5 stages.
Stage 1: Normal GFR (≥ 90 mL/min/1.73 m2) plus either persistent albuminuria or known structural or hereditary renal disease
Stage 2: GFR 60 to 89 mL/min/1.73 m2
Stage 3a: 45 to 59 mL/min/1.73 m2
Stage 3b: 30 to 44 mL/min/1.73 m2
Stage 4: GFR 15 to 29 mL/min/1.73 m2
Stage 5: GFR < 15 mL/min/1.73 m2
GFR (in mL/min/1.73 m2) in CKD can be estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI 2021) creatinine equation:
,
where
Scr = standardized serum creatinine in mg/dL
κ = 0.7 (females) or 0.9 (males)
α = -0.241 (female) or -0.302 (male)
min(Scr/κ, 1) = minimum of Scr/κ or 1.0
max(Scr/κ, 1) = maximum of Scr/κ or 1.0
Age (years)
In contrast to prior versions, the most recent equation does not adjust for race, so as to reduce racial inequities in CKD diagnosis and thus treatment. Alternatively, GFR can be estimated using timed (most commonly 24-hour) urine creatinine clearance that includes measured serum and urine creatinine; this equation tends to overestimate GFR by 10 to 20%. It is used when serum creatinine assessment may not be as accurate (eg, in patients who are sedentary, very obese, or very thin). Serum cystatin C is an alternative endogenous GFR marker used as a confirmatory test in people with nonrenal factors affecting serum creatinine level (eg, extremely high or low muscle mass, exogenous creatine intake, amputations or neuromuscular diseases, and high protein or exclusively plant-based diets). GFR is calculated using CKD-EPI cystatin C equation.
The CKD-EPI 2021 formula is more accurate than the Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault formulas, particularly for patients with a GFR near normal values. The CKD-EPI equation yields fewer falsely positive results indicating chronic kidney disease and predicts outcome better than the other formulas.
Treatment of Chronic Kidney Disease
Control of underlying disorders
Possible restriction of dietary protein, phosphate, and potassium
Treatment of anemia
Treatment of contributing comorbidities (eg, heart failure, diabetes mellitus, nephrolithiasis, prostatic hypertrophy)
Doses of all medications adjusted as needed
Maintaining sodium bicarbonate level in the normal range (23–29 mmol/L)
Dialysis for severely decreased glomerular filtration rate (GFR) if symptoms and signs not adequately managed by medical interventions
Underlying disorders and contributory factors must be controlled. In particular, controlling hyperglycemia in patients with diabetic nephropathy and controlling hypertension in all patients substantially slows deterioration of GFR.
For hypertension, some guidelines suggest a target BP of < 140/90 mm Hg, the American Heart Association recommends 130/80, and some authors continue to recommend about 125 to 130/ <proteinuria more. Sodium-glucose cotransporter-2 (SGLT2) inhibitors delay progression of proteinuric CKD in patients with or without diabetes, although these medications are contraindicated in patients with type 1 diabetes mellitus (1, 2).
Activity need not be restricted, although fatigue and lassitude usually limit a patient’s capacity for exercise.
Pruritus may respond to dietary phosphate restriction and phosphate binders if serum phosphate is elevated.
Nutrition
Severe protein restriction in renal disease is controversial. However, moderate protein restriction (0.8 g/kg/day) among patients with estimated GFR (eGFR) < 60 mL/min/1.73 m2 without nephrotic syndrome is safe and easy for most patients to tolerate. Some experts recommend 0.6 g/kg/day for patients with diabetes and for patients without diabetes if GFR is < 25 mL/min/1.73 m2. Many uremic symptoms markedly lessen when protein catabolism and urea generation are reduced. Also, rate of progression of CKD may slow down. Sufficient carbohydrate and fat are given to meet energy requirements and prevent ketosis. Patients for whom < 0.8 g/kg/day has been prescribed should be closely followed by a dietitian.
Because dietary restrictions may reduce necessary vitamin intake, patients should take a multivitamin containing water-soluble vitamins. Administration of vitamins A and E is unnecessary. Vitamins D2 (ergocalciferol) or D3 (cholecalciferol) are not given routinely but are used based on blood levels of vitamin D 25-OH and PTH.
Mineral and bone disorders
Based on updated KDIGO (Kidney Disease Improving Global Outcomes) 2017 clinical practice guidelines (3
Hyperphosphatemia should be treated with
Dietary phosphate restriction
Phosphate binders
Phosphate restriction to 0.8 to 1 g/day of dietary intake is typically sufficient to normalize serum phosphate level in patients with eGFR < 60 mL/min/1.73 m2. Additional intestinal phosphate binders (calcium-containing or non–calcium-containing) may be necessary for adequate control of hyperphosphatemia, which has been associated with increased cardiovascular risk. Non–calcium-containing binders are preferred in patients with hypercalcemia, suspected adynamic bone disease, or evidence of vascular calcification on imaging. If calcium-containing binders are prescribed, then the total dietary and medication sources of calcium should not exceed 2000 mg/day in patients with eGFR < 60 mL/min/1.73 m2.
should be treated with cholecalciferol (vitamin D3) or ergocalciferol (vitamin D2) to target serum vitamin D 25-OH level approximately 30-50 ng/mL, as long as there is no hyperphosphatemia or hypercalcemia.
The optimal level of PTH in patients with CKD stages 3a to 5 not on dialysis is not known. However, if PTH levels are progressively rising or are markedly elevated (above 9 times the upper limit of normal for the assay), despite treatment of hyperphosphatemia and vitamin D
Fluid and electrolytes
Restricted water intake is required only when serum sodium concentration is < 135 mmol/L or there is heart failure or severe edema.
Sodium restriction of < 2 g/day is recommended for CKD patients with eGFR < 60 mL/m/1.73 m2 who have hypertension, volume overload, or proteinuria.
Potassium restriction is individualized based on serum level, eGFR, dietary customs, and use of medications that increase potassium levels (eg, ACE, ARBs, or potassium-sparing diuretics). Typically, potassium restriction is not needed with eGFR >30 mL/min/1.73 m2. Treatment of mild to moderate hyperkalemia (5.1 to 6 mmol/L) entails dietary restriction (including avoiding salt substitutes), correction of metabolic acidosis, and use of potassium-lowering diuretics and gastrointestinal cation exchangers. Severe hyperkalemia (> 6 mmol/L) warrants urgent treatment.
Anemia and coagulation disorders
Anemia is a common complication of moderate to advanced CKD (≥ stage 3) and, when <stroke, thrombosis, and death, the lowest dose of these agents needed to keep the Hb between 10 and 11 g/dL is used.
Because of increased iron utilization with stimulated erythropoiesis, iron stores must be replaced, often requiring parenteral iron. Iron concentrations, iron-binding capacity, and ferritin concentrations should be followed closely. Target transferrin saturation (TSAT), calculated by dividing serum iron by total iron binding capacity and multiplying by 100%, should be > 20%. Target ferritin in patients not on dialysis is>100 ng/mL. Transfusion should not be done unless anemia is severe (Hb < 8 g/dL) or causes symptoms.
Heart failure
Symptomatic heart failure is treated with
Sodium restriction
Sometimes, dialysis
ACE inhibitors (or ARBs) and beta-blockers
Moderate or severe hypertension
Occasionally, dialysis may be required to control heart failure. If reduction of the volume of extracellular fluid does not control blood pressure, conventional antihypertensives are added. Azotemia may increase with such treatment and may be necessary for adequate control of heart failure and/or hypertension.
Medications
Hemodialysis reduces the serum concentrations of some medications, which should be supplemented after hemodialysis. It is strongly recommended that physicians consult a reference on drug dosing in renal failure before prescribing medications to these very vulnerable patients (4, 5, 6).
Most experts recommend avoiding NSAIDs (nonsteroidal anti-inflammatory drugs) in patients with CKD because they may worsen renal function, exacerbate hypertension, and precipitate electrolyte disturbances.
Certain medications should be avoided entirely in patients with chronic kidney disease with eGFR < 60 mL/min/1.73m2nephrogenic systemic fibrosis in patients with estimated GFR < 30 mL/min/1.73m2 in the past. More recently, class II gadolinium agents are considered safer and preferred when gadolinium is indicated for patients with eGFR <30 or on dialysis (7).
Dialysis
Dialysis is usually initiated at the onset of either of the following:
Uremic symptoms (eg, anorexia, nausea, vomiting, weight loss, pericarditis, pleuritis)
Difficulty controlling fluid overload, hyperkalemia, or acidosis with medications and lifestyle interventions
These problems typically occur when the estimated GFR reaches ≤ 10 mL/min in a patient without diabetes or ≤ 15 mL/min in a patient with diabetes; patients whose estimated GFR values are near these values should be closely monitored so that these signs and symptoms are recognized early. Dialysis is best anticipated so that preparations can be made and urgent insertion of a hemodialysis catheter can be avoided. Such preparations usually begin when the patient is in early to mid stage 4 CKD; preparation allows time for patient education, selection of the type of dialysis, and timely creation of an arteriovenous fistula or placement of a peritoneal dialysis catheter. (For dialysis preparation, see Hemodialysis.)
Pearls & Pitfalls
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Transplantation
If a living kidney donor is available, better long-term outcomes occur when a patient receives the transplanted kidney early, even before beginning dialysis. Patients who are transplant candidates but have no living donor should be placed on the waiting list of their regional transplant center early because wait times may exceed several years in many regions of the United States.
Treatment references
1. Perkovic V, Jardine MJ, Neal B, et alN Engl J Med 380(24):2295-2306, 2019. doi: 10.1056/NEJMoa1811744
2. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et alN Engl J Med 383(15):1436-1446, 2020. doi: 10.1056/NEJMoa2024816
3. KDIGO 2017 Clinical Practice Guidelines for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD) Kidney Int Suppl 7(1):1-59, 2017.
4. Determining Drug Dosing in Adults with Chronic Kidney Disease.
5. Munar MY, Singh HD: Drug dosing adjustments in patients with chronic kidney disease. Am Fam Physician 75:1487-1496, 2007.
6. Matzke GR, Aronoff GR, Atkinson AJ, et al: Drug dosing consideration in patients with acute and chronic kidney disease—a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 80:1122–1137, 2011. doi:10.1038/ki.2011.322
7. ACR Committee on Drugs and Contrast Media: ACR Manual on Contrast Media. American College of Radiology. 2021. ISBN: 978-1-55903-012-0
Prognosis for Chronic Kidney Disease
Progression of chronic kidney disease (CKD) is predicted in most cases by the degree of proteinuria. (See the Kidney Failure Risk Equation.) Patients with nephrotic-range proteinuria (> 3 g/24 h or urine protein/creatinine ratio > 3) usually have a poorer prognosis and progress to renal failure more rapidly. Progression may occur even if the underlying disorder is not active. In patients with urine protein < 1.5 g/24 h, progression usually occurs more slowly if at all. Hypertension, acidosis, and hyperparathyroidism are associated with more rapid progression as well.
Key Points
Common causes of chronic kidney disease (CKD) in the United States are diabetic nephropathy (the most common), hypertensive nephrosclerosis, glomerulopathies, and metabolic syndrome.
Effects of CKD can include hypocalcemia, hyperphosphatemia, metabolic acidosis, anemia, secondary hyperparathyroidism, and renal osteodystrophy.
Distinguish CKD from acute kidney injury based on history, clinical findings, routine laboratory tests, and ultrasonography.
Control underlying disorders (eg, diabetes) and BP levels (usually with an ACE inhibitor or ARB).
Treat patients with proteinuric CKD with an ACE inhibitor or ARB, plus an SGLT2 inhibitor.
Treat heart failure, anemia, and other complications.
Educate patients with advanced CKD on treatment options (dialysis, kidney transplantation, or palliative care) early, to allow adequate time for planning.
Initiate dialysis for patients with severely decreased eGFR when signs and symptoms are inadequately controlled with medications and lifestyle interventions.
