Chronic Kidney Disease

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.

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.

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 (NSAIDs), cyclosporine, tacrolimus, trimethoprim/sulfamethoxazole, pentamidine, or (NSAIDs), cyclosporine, tacrolimus, trimethoprim/sulfamethoxazole, pentamidine, orangiotensin II receptor blockersangiotensin II receptor blockers may raise plasma potassium levels in patients with less advanced renal failure.

Abnormalities of calcium, phosphate, parathyroid hormone (PTH), and vitamin D metabolismvitamin D metabolism 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 (due to excessive parathyroid suppression) or osteomalacia. Calcitriol deficiency may cause osteopenia or osteomalacia.

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 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.

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.

Clinical Calculators

Creatinine Clearance (measured)

1. 1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024;105(4S):S117-S314. doi:10.1016/j.kint.2023.10.018

Moderate protein restriction (0.8 g/kg/day) among patients with estimated GFR (eGFR) < 60 mL/min/1.73 m² without nephrotic syndrome is recommended in patients without frailty, sarcopenia, or metabolic derangements. Severe (0.3 to 0.4 g/kg/day) protein restriction could be considered for motivated patients under the close supervision of a dietitian, to assure intake of adequate essential amino acids. Many uremic symptoms markedly lessen when protein catabolism and urea generation are reduced. Also, the 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 of protein has been prescribed should be closely followed by a dietitian.

Aim for a total dietary sodium intake of < 2 g/day, especially for patients with volume overload, elevated blood pressure, or heart failure.

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.

Dyslipidemia should be addressed. Dietary modification may be helpful for hypertriglyceridemia. Statins are effective for hypercholesterolemia. Fibric acid derivatives (clofibrate, gemfibrozil) may increase risk of should be addressed. Dietary modification may be helpful for hypertriglyceridemia. Statins are effective for hypercholesterolemia. Fibric acid derivatives (clofibrate, gemfibrozil) may increase risk ofrhabdomyolysis in patients with CKD, especially if taken with statin medications, whereas ezetimibe (which reduces cholesterol absorption) appears relatively safe. Correction of hypercholesterolemia is intended to reduce risk of cardiovascular disease, which is increased in patients with CKD (in patients with CKD, especially if taken with statin medications, whereas ezetimibe (which reduces cholesterol absorption) appears relatively safe. Correction of hypercholesterolemia is intended to reduce risk of cardiovascular disease, which is increased in patients with CKD (4).

Based on updated KDIGO (Kidney Disease Improving Global Outcomes) 2024 clinical practice guidelines (1), it is recommended that serum levels of calcium, phosphate, PTH, vitamin D 25-OH, and alkaline phosphatase activity be monitored beginning in CKD stage 3a. Frequency of monitoring depends on severity of CKD, magnitude of above abnormalities, and frequency of therapeutic interventions. Bone biopsy is the most definitive evaluation to determine the type of renal osteodystrophy. ), it is recommended that serum levels of calcium, phosphate, PTH, vitamin D 25-OH, and alkaline phosphatase activity be monitored beginning in CKD stage 3a. Frequency of monitoring depends on severity of CKD, magnitude of above abnormalities, and frequency of therapeutic interventions. Bone biopsy is the most definitive evaluation to determine the type of renal osteodystrophy.

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 [eg, calcium acetate] or non–calcium-containing [eg, sevelamer]) 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 . Additional intestinal phosphate binders (calcium-containing [eg, calcium acetate] or non–calcium-containing [eg, sevelamer]) may be necessary for adequate control of hyperphosphatemia, which has been associated with increased cardiovascular risk. Non–calcium-containing binders are preferred in patients withhypercalcemia, 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.

Vitamin D deficiencyVitamin D deficiency should be treated with cholecalciferol (vitamin D3) or ergocalciferol (vitamin D2) to target serum vitamin D 25-OH level approximately 30 to 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 deficiency, then an active vitamin D analog (eg, calcitriol) or a calcimimetic (for example, cinacalcet) is recommended. PTH levels are not corrected to normal because doing so risks precipitating adynamic bone disease.deficiency, then an active vitamin D analog (eg, calcitriol) or a calcimimetic (for example, cinacalcet) is recommended. PTH levels are not corrected to normal because doing so risks precipitating adynamic bone disease.

Restricted water intake is required only when serum sodium concentration is < 135 mmol/L (or mEq/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 or mEq/L) entails dietary restriction (including avoiding salt substitutes), correction of metabolic acidosis, and use of potassium-lowering diuretics (eg, furosemide) and gastrointestinal cation exchangers (eg, patiromer). (5.1 to 6 mmol/L or mEq/L) entails dietary restriction (including avoiding salt substitutes), correction of metabolic acidosis, and use of potassium-lowering diuretics (eg, furosemide) and gastrointestinal cation exchangers (eg, patiromer).Severe hyperkalemia (> 6 mmol/L or m/Eq/L) warrants urgent treatment.

Metabolic acidosis should be treated to bring serum bicarbonate to > 18 mmol/L to help reverse or slow muscle wasting, bone loss, and progression of CKD. Acidosis can be corrected with oral alkali sources such as sodium bicarbonate or an alkaline-ash diet (primarily fruits and vegetables). Sodium bicarbonate 1 to 2 g orally twice a day is given and the amount is increased gradually until bicarbonate concentration is > 18 mmol/L or until evidence of sodium overloading prevents further therapy. If the alkaline-ash diet is used, serum potassium is monitored because fruits and vegetables contain potassium (should be treated to bring serum bicarbonate to > 18 mmol/L to help reverse or slow muscle wasting, bone loss, and progression of CKD. Acidosis can be corrected with oral alkali sources such as sodium bicarbonate or an alkaline-ash diet (primarily fruits and vegetables). Sodium bicarbonate 1 to 2 g orally twice a day is given and the amount is increased gradually until bicarbonate concentration is > 18 mmol/L or until evidence of sodium overloading prevents further therapy. If the alkaline-ash diet is used, serum potassium is monitored because fruits and vegetables contain potassium (5).

Anemia is a common complication of moderate to advanced CKD (≥ stage 3) and, when hemoglobin is < 10g/dL, is treated with erythropoiesis-stimulating agents (ESA), such as recombinant human erythropoietin (eg, epoetin alfa). Due to risk of cardiovascular complications, including 10g/dL, is treated with erythropoiesis-stimulating agents (ESA), such as recombinant human erythropoietin (eg, epoetin alfa). Due to risk of cardiovascular complications, includingstroke, 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.

The bleeding tendency in CKD rarely needs treatment. Cryoprecipitate, red blood cell transfusions, desmopressin 0.3 to 0.4 mcg/kg (20 mcg maximum) in 20 mL of isotonic saline IV over 20 to 30 minutes, or conjugated estrogens 2.5 to 5 mg orally once a day help when needed. The effects of these treatments last 12 to 48 hours, except for conjugated estrogens, which may last for several days.The bleeding tendency in CKD rarely needs treatment. Cryoprecipitate, red blood cell transfusions, desmopressin 0.3 to 0.4 mcg/kg (20 mcg maximum) in 20 mL of isotonic saline IV over 20 to 30 minutes, or conjugated estrogens 2.5 to 5 mg orally once a day help when needed. The effects of these treatments last 12 to 48 hours, except for conjugated estrogens, which may last for several days.

Symptomatic heart failure is treated with

• Sodium restriction

• Diuretics

• Sometimes, dialysis

Loop diuretics such as furosemide usually are effective even when renal function is markedly reduced, although large doses may be needed. If left ventricular function is depressed, Loop diuretics such as furosemide usually are effective even when renal function is markedly reduced, although large doses may be needed. If left ventricular function is depressed,ACE inhibitors (or ARBs) and beta-blockers (carvedilol or metoprolol) should be used. Aldosterone receptor antagonists (eg, spironolactone) and sometimes sodium-glucose cotransporter-2 (SLGT2) inhibitors are recommended in patients with advanced stages of heart failure. Digoxin may be added, but the dosage must be reduced based on degree of renal function. (carvedilol or metoprolol) should be used. Aldosterone receptor antagonists (eg, spironolactone) and sometimes sodium-glucose cotransporter-2 (SLGT2) inhibitors are recommended in patients with advanced stages of heart failure. Digoxin may be added, but the dosage must be reduced based on degree of renal function.

Moderate or severe hypertension should be treated to avoid its deleterious effects on cardiac and renal function. Patients who do not respond to sodium restriction (1.5 g/day), should receive diuretics. Loop diuretics (eg, furosemide) may be combined with thiazide diuretics (eg, chlorthalidone, hydrochlorothiazide, metolazone) if hypertension or edema is not controlled. Even in renal failure, the combination of a thiazide diuretic with a loop diuretic is quite potent and must be used with caution to avoid overdiuresis. should be treated to avoid its deleterious effects on cardiac and renal function. Patients who do not respond to sodium restriction (1.5 g/day), should receive diuretics. Loop diuretics (eg, furosemide) may be combined with thiazide diuretics (eg, chlorthalidone, hydrochlorothiazide, metolazone) if hypertension or edema is not controlled. Even in renal failure, the combination of a thiazide diuretic with a loop diuretic is quite potent and must be used with caution to avoid overdiuresis.

Occasionally, dialysis may be required to control heart failure. If reduction of the volume of extracellular fluid does not control blood pressure, conventional antihypertensives (ACE inhibitors, ARBs, beta-blockers) are added. Azotemia may increase with such treatment and may be necessary for adequate control of heart failure and/or hypertension.

Renal excretion of medications is often impaired in patients with renal failure. Common medications that require revised dosing include penicillins, cephalosporins, aminoglycosides, fluoroquinolones, vancomycin, and digoxin. Renal excretion of medications is often impaired in patients with renal failure. Common medications that require revised dosing include penicillins, cephalosporins, aminoglycosides, fluoroquinolones, vancomycin, and digoxin.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 (6–8).

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/1.73m². They include nitrofurantoin and phenazopyridine. The MRI contrast agent gadolinium has been associated with the development of . They include nitrofurantoin and phenazopyridine. The MRI contrast agent gadolinium has been associated with the development ofnephrogenic 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 (8).

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.)

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.

1. 1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024;105(4S):S117-S314. doi:10.1016/j.kint.2023.10.018

2. 2. Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. . Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial.Lancet. 2008;372(9638):547-553. doi:10.1016/S0140-6736(08)61236-2

3. 3. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.  . Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 380(24):2295-2306, 2019. doi: 10.1056/NEJMoa1811744

4. 4. National Institute of Diabetes and Digestive and Kidney Diseases. Determining Drug Dosing in Adults with Chronic Kidney Disease. Accessed January 30, 2025.

5. 5.Goraya N, Simoni J, Jo CH, Wesson DE. A comparison of treating metabolic acidosis in CKD stage 4 hypertensive kidney disease with fruits and vegetables or sodium bicarbonate. . A comparison of treating metabolic acidosis in CKD stage 4 hypertensive kidney disease with fruits and vegetables or sodium bicarbonate.Clin J Am Soc Nephrol. 2013;8(3):371-381. doi:10.2215/CJN.02430312

6. 6. Munar MY, Singh HD. Drug dosing adjustments in patients with chronic kidney disease. Am Fam Physician. 75:1487-1496, 2007.

7. 7. 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

8. 8. ACR Committee on Drugs and Contrast Media. ACR Manual on Contrast Media. American College of Radiology. 2021. ISBN: 978-1-55903-012-0. Accessed January 30, 2025.