eMedicine Specialties > Nephrology > Chronic Kidney Disease

Azotemia

Author: Moro O Salifu, MD, MPH, FACP, Associate Professor, Department of Internal Medicine, Chief, Division of Nephrology, Director of Nephrology Fellowship Program and Transplant Nephrology, State University of New York Downstate Medical Center
Coauthor(s): Onyekachi Ifudu, MD, Director of Inpatient Dialysis Services, Associate Professor, Department of Internal Medicine, State University of New York Health Science Center at Brooklyn
Contributor Information and Disclosures

Updated: Jul 27, 2009

Introduction

Background

Azotemia is an elevation of blood urea nitrogen (BUN) (reference range, 8-20 mg/dL) and serum creatinine (normal value, 0.7-1.4 mg/dL) levels. (See image below and Image 1.)

Urine formation by each nephron involves 3 main processes, as follows: filtration at the glomerular level, selective reabsorption from the filtrate passing along the renal tubules, and secretion by the cells of the tubules into this filtrate. Perturbation of any of these processes impairs the kidney's excretory function, resulting in azotemia.

The quantity of glomerular filtrate produced each minute by all nephrons in both kidneys is referred to as the glomerular filtration rate (GFR). Average GFR is about 125 mL/min (10% less for women) or 180 L/d. About 99% (178 L/d) is reabsorbed, and the rest (2 L/d) is excreted.

Measuring renal function

Radionuclide assessment of GFR is the criterion standard for measuring kidney function. However, because it is expensive and not widely available, serum creatinine concentration and creatinine clearance (CrCl) more commonly are used to estimate GFR.

An inverse relationship between serum creatinine and GFR exists. However, the serum creatinine and CrCl are not sensitive measures of kidney damage for 2 reasons. First, substantial renal damage can take place before any decrease in GFR occurs. Second, substantial decline in GFR may lead to only slight elevation in serum creatinine, as shown in Image 1. An elevation in serum creatinine is apparent only when the GFR falls to about 60-70 mL/min. This is due to compensatory hypertrophy and hyperfiltration of the remaining healthy nephrons.

Because creatinine normally is filtered as well as secreted into the renal tubules, the CrCl may cause the GFR to be substantially overestimated, especially as kidney failure progresses because of maximal tubular excretion. More accurate determinations of GFR require the use of inulin clearance or a radiolabeled compound, such as iothalamate. In practice, precise knowledge of the GFR is not required, and disease process usually can be monitored by the estimated GFR (eGFR) using different methods, as shown below. 

The CrCl is best calculated by obtaining a 24-hour collection for creatinine and volume and then using the following formula: CrCl (mL/min) = U/P X V where U is the 24-hour creatinine in mg/dL, P is the serum creatinine in mg/dL, and V is the 24-hour volume/1440 (number of min in 24 h). Using the 24-hour creatinine in grams and the serum creatinine in milligrams, CrCl (mL/min) = creatinine [g/d]/serum creatinine [mg/dL]) X 70. An adequate 24-hour collection usually reflects a creatinine generation of 15-20 mg/kg in women and 20-25 mg/kg in men. When 24-hour creatinine is measured, the adequacy of the collection must be established prior to calculation of the creatinine clearance.

Alternatively, a bedside formula (Cockroft and Gault) using the patient's serum creatinine, age, and lean weight (in kg) can be used to estimate the GFR, as follows: CrCl (mL/min) = (140 - age) X weight (kg) / (72 X serum creatinine) in mg/dL (X 0.85 for women).

Another formula was derived from data collected in a large study called the Modification of Diet in Renal Disease (MDRD). This formula is known as the MDRD formula, or the Levey formula. It is now widely accepted as more accurate than the Cockroft and Gault formula and is an alternative to radioisotope clearance. Because serum creatinine levels alone cannot detect earlier stages of chronic kidney disease (CKD), the MDRD formula also takes into account the patient's age and race. Although more accurate, it is much more difficult to calculate manually. However, software for estimating GFR by the MDRD formula is available for most pocket digital assistants (PDA) and can be found on the Internet.

Delanaye et al have argued that the MDRD formula is not applicable to all persons, such as healthy individuals and patients who are anorectic or obese.¹ It has therefore been argued that the formula should be applied with caution. 

Pathophysiology

There are 3 pathophysiologic states in azotemia, as follows: prerenal azotemia, intrarenal azotemia, and postrenal azotemia. 

Prerenal azotemia

Prerenal azotemia refers to elevation in BUN and creatinine levels because of problems in the systemic circulation that decrease flow to the kidneys. In prerenal azotemia, decrease in renal flow stimulates salt and water retention to restore volume and pressure. When volume or pressure is decreased, the baroreceptor reflexes located in the aortic arch and carotid sinuses are activated. This leads to sympathetic nerve activation, resulting in renal afferent arteriolar vasoconstriction and renin secretion through b ₁ -receptors. Constriction of the afferent arterioles causes a decrease in the intraglomerular pressure, reducing GFR proportionally. Renin converts angiotensin I to angiotensin II, which, in turn, stimulates aldosterone release. Increased aldosterone levels results in salt and water absorption in the distal collecting tubule.

A decrease in volume or pressure is a nonosmotic stimulus for antidiuretic hormone production in the hypothalamus, which exerts its effect in the medullary collecting duct for water reabsorption. Through unknown mechanisms, activation of the sympathetic nervous system leads to enhanced proximal tubular reabsorption of salt and water, as well as BUN, creatinine, calcium, uric acid, and bicarbonate. The net result of these 4 mechanisms of salt and water retention is decreased output and decreased urinary excretion of sodium (<20 mEq/L).

Intrarenal azotemia

Intrarenal azotemia, also known as acute renal failure (ARF), renal-renal azotemia, and acute kidney injury (AKI), refers to elevation in BUN and creatinine levels because of problems in the kidney itself. There are several definitions, including a rise in serum creatinine levels of about 30% from baseline or a sudden decline in output below 500 mL/d. If output is preserved, it is called nonoliguric ARF. If output falls below 500 mL/d, it is called oliguric ARF. Any form of ARF may be so severe to virtually stop formation, a condition called anuria (<100 mL/d).

The most common causes of nonoliguric ARF are acute tubular necrosis (ATN), aminoglycoside nephrotoxicity, lithium toxicity, or cisplatin nephrotoxicity. Tubular damage is less severe than in oliguric ARF. Normal output in nonoliguric ARF does not reflect normal GFR. Patients may still make 1440 mL/d of urine even when the GFR falls to about 1 mL/min because of decreased tubular reabsorption.

Some studies indicate that nonoliguric forms of ARF are associated with less morbidity and mortality than oliguric ARF. Uncontrolled studies also suggest that volume expansion, potent diuretic agents, and renal vasodilators can convert oliguric to nonoliguric ARF if administered early.

The pathophysiology of acute oliguric or nonoliguric ARF depends on the anatomical location of the injury. In ATN, epithelial damage leads to functional decline in the ability of the tubules to reabsorb salt, water, and other electrolytes. Excretion of acid and potassium also is impaired. In more severe ATN, the tubular lumen is filled with epithelial casts, causing intraluminal obstruction, resulting in the decline of GFR.

Acute interstitial nephritis is characterized by inflammation and edema, resulting in azotemia, hematuria, sterile pyuria, white cell casts with variable eosinophiluria, proteinuria, and hyaline casts. The net effect is a loss of urinary concentrating ability, with low osmolality (usually <500 mOsm/L), low specific gravity (<1.015), high urinary sodium (>40 mEq/L), and occasionally, hyperkalemia and renal tubular acidosis. However, in the presence of a superimposed prerenal azotemia, the specific gravity, osmolality, and sodium may be misleading.

Glomerulonephritis or vasculitis is suggested by the presence of hematuria, red cells, white cells, granular and cellular casts, and a variable degree of proteinuria. Nephrotic syndrome usually is not associated with active inflammation and often presents as proteinuria greater than 3.5 g/24 h.

Glomerular diseases may reduce GFR due to changes in basement membrane permeability and because of stimulation of the renin-aldosterone axis. Glomerular diseases often manifest as nephrotic or nephric syndrome. In nephrotic syndrome, the urinary sediment is inactive, and there is gross proteinuria (>3.5 g/d), hypoalbuminemia, hyperlipidemia, and edema. Azotemia and hypertension are uncommon initially, but their presence may indicate advanced disease. Some patients with nephrotic syndrome may present with ARF. Impairment of capillary circulation in the kidney due to edema (nephrosarca) and tubular obstruction from protein casts have been proposed as potential mechanisms for the development of ARF in patients with nephrotic syndrome.

In nephritic syndrome, the urinary sediment is active with white or red cell casts, granular casts, and azotemia. Proteinuria is less obvious, but increased salt and water retention in glomerulonephritis can lead to hypertension, edema formation, decreased output, low urinary excretion of sodium, and increased specific gravity.

Acute vascular diseases include vasculitis syndromes, malignant hypertension, scleroderma renal crisis, and thromboembolic disease, all of which cause renal hypoperfusion and ischemia leading to azotemia. Chronic vascular diseases are due to hypertensive benign nephrosclerosis, which has not been conclusively associated with end-stage renal disease and ischemic renal disease from bilateral renal artery stenosis.²

In bilateral renal artery stenosis, maintenance of adequate intraglomerular pressure for filtration greatly depends on efferent arteriolar vasoconstriction. Azotemia sets in when angiotensin-converting enzyme (ACE) inhibitors or angiotensin type 2 receptor blockers cause efferent arteriolar dilatation, thereby decreasing intraglomerular pressure and filtration. Therefore, converting enzyme inhibitors and receptor blockers are contraindicated in bilateral renal artery stenosis.

In addition to accumulation of urea creatinine and other waste products, a substantial reduction in GFR in CKD results in decreased production of erythropoietin (causing anemia) and vitamin D-3 (causing hypocalcemia, secondary hyperparathyroidism, hyperphosphatemia, and renal osteodystrophy); reduction in acid, potassium, salt, and water excretion (causing acidosis, hyperkalemia, hypertension, and edema); and platelet dysfunction, which leads to increased bleeding tendencies.

The syndrome associated with the signs and symptoms of accumulation of toxic waste products (uremic toxins) is termed uremia and often occurs at a GFR of about 10 mL/min. Some of the uremic toxins (ie, urea, creatinine, phenols, guanidines) have been identified, but none has been found responsible for all the manifestations of uremia.

Postrenal azotemia

Postrenal azotemia refers to elevation in BUN and creatinine levels because of obstruction in the collecting system. Obstruction to flow leads to a reversal of Starling forces responsible for glomerular filtration. Progressive bilateral obstruction causes hydronephrosis with an increase in the Bowman capsular hydrostatic pressure and tubular blockage resulting in progressive decline and ultimate cessation in glomerular filtration, azotemia, acidosis, fluid overload, and hyperkalemia.

Unilateral obstruction rarely causes azotemia. With relief of complete ureteral obstruction within 48 hours of onset, there is evidence that relatively complete recovery of GFR can be achieved within a week, while little or no further recovery occurs after 12 weeks. Complete or prolonged partial obstruction can lead to tubular atrophy and irreversible renal fibrosis. Hydronephrosis may be absent if obstruction is mild or acute or if the collecting system is encased by retroperitoneal tumor or fibrosis.

Frequency

United States

Considerable variability exists in reports about the incidence of hospital or community-acquired ARF. In one report, community-acquired ARF occurred in about 1% of all hospital admissions. Overall, ARF occurs in about 5% of all hospital admissions. However, differences exist in ARF occurring in the intensive care unit (about 15%) and in the coronary care unit (about 4%). In CKD, progressive azotemia leading to end-stage renal disease requiring dialysis or kidney transplantation occurs in a number of chronic diseases with frequencies for diabetes (36%), hypertension (24%), glomerulonephritis (15%), cystic kidney disease (4%), uncertain (5%), and all other known miscellaneous renal disorders (15%).

International

A report from Madrid evaluated 748 cases of ARF at 13 tertiary hospital centers. The most frequent causes were ATN (45%); prerenal (21%); acute or chronic renal failure, mostly due to ATN and prerenal disease (13%); urinary tract obstruction (10%); glomerulonephritis or vasculitis (4%); acute interstitial nephritis (2%); and atheroemboli (1%). Etiologies of CKD differ around the world. Diabetic nephropathy as a cause of CKD is on the rise in developed and developing countries.

Mortality/Morbidity

• Prognosis in ARF generally is poor and depends on the severity of the underlying disease and the number of failed organs. While mortality rate in simple ARF without other underlying disease is 7-23%, the mortality in the patient in the intensive care unit on mechanical ventilation is as high as 80%.
• The prognosis of patients with CKD depends on the etiology of the failure. Patients with diabetic kidney disease, hypertensive nephrosclerosis, and ischemic nephropathy (ie, large-vessel arterial occlusive disease) tend to have progressive azotemia resulting in end-stage renal disease. Different types of glomerulonephritis have major differences in prognosis, with some being quite benign and rarely progressing to end-stage renal disease, whereas others have rapid progression to end-stage renal disease within months. About 50% of patients with polycystic kidney disease progress to end-stage renal disease by the fifth or sixth decade of life.

Race

In the 2008 annual report of the United States Renal Data System (USRDS), more than 500,000 patients with end-stage renal disease were receiving dialysis or a kidney transplant in the United States. Racial distribution was reported as Asian/Pacific Islander (4.7%), black (32.0%), white (61.0%), American Indian (1.3%), and other/unknown (0.6%).

Sex

Of the patients reported in the 2008 annual report of the USRDS, male frequency is 56.0% and female frequency is 44.0%.

Age

Of the patients reported in the 2008 annual report of the USRDS, frequencies for patients aged 0-19 years is 1.5%; aged 20-44 years, 19.1%; aged 45-64 years, 44.0%; aged 65-74 years, 19.6%; and older than 75 years, 15.7%.

Clinical

History

It is necessary to quickly establish if azotemia is acute or chronic and whether it is due to prerenal, intrarenal, or postrenal causes. This is vital in initiating treatment and in preventing progression.

Clinical evaluation requires a thorough history, physical examination, and specific laboratory tests. Tests include serologies, urinalysis, and, if indicated, radiologic studies and kidney biopsy.

• Prerenal azotemia: History of diarrhea, vomiting, profound heat exhaustion, excessive sweat loss, concurrent illness that impairs patient's ability to eat and drink adequately, hemorrhage, liver disease, congestive heart failure, and polyuria (eg, caused by lithium intoxication, diuretics, diabetes, diabetes insipidus)
• Intrarenal azotemia
  • History of nocturia, polyuria, proteinuria, shock, and edema
  • Personal or family history of congenital or systemic diseases, especially diabetes, hypertension, systemic lupus erythematosus, other collagen vascular diseases, hepatitis B (HBV), hepatitis C (HCV), syphilis, multiple myeloma, and AIDS
  • Detailed medication history (looking for nephrotoxic medications, especially antibiotics, NSAIDs, ACE inhibitors, diuretics, and herbal remedies), chemical exposure, and intravenous drug abuse (exposure to HIV, HBV, and HCV infections)
• Postrenal azotemia: Renal colic, dysuria, frequency, hesitancy, urgency incontinence, pelvic malignancy or irradiation, and benign prostatic hypertrophy

Physical

Physical examination should be detailed but focused on signs of high diagnostic yield.

• Prerenal azotemia: Look for tachycardia; orthostatic hypotension (systolic BP drop of >20 mm Hg, diastolic BP drop of >10 mm Hg or more from the supine to standing position); hypotension; signs of dehydration, including dry mucous membranes, loss of skin turgor, and loss of axillary sweat; and signs of congestive heart failure or hepatic insufficiency.
• Intrarenal azotemia: Look for hypertension and its end organ effects, such as hypertensive retinopathy and left ventricular hypertrophy (apical impulse displaced lateral to midclavicular line), rash, joint swelling or tenderness, needle tracks, hearing abnormality, palpable kidneys, abdominal bruits, pericardial rub, and asterixis. The latter 2 signs are suggestive of uremia. The presence of uremic pericarditis requires immediate dialysis.
• Postrenal azotemia: A palpable bladder that is dull to percussion and a rectal or pelvic mass on digital examination is suggestive of postrenal azotemia (obstruction).

Causes

Causes are broadly classified as prerenal, intrarenal, and postrenal.

• Prerenal azotemia
  • Prerenal azotemia occurs as a result of impaired renal blood flow or decreased perfusion resulting from decreased blood volume, decreased cardiac output (congestive heart failure), decreased systemic vascular resistance, decreased effective arterial volume from sepsis or hepatorenal syndrome, and renal artery abnormalities.
  • It may be superimposed on a background of chronic renal failure.
  • Iatrogenic causes of prerenal azotemia, such as excessive diuresis and treatment with ACE inhibitors, should be ruled out.
• Intrarenal azotemia
  • Intrarenal azotemia occurs as a result of injury to the glomeruli, tubules, interstitium, or small vessels.
  • It may be acute oliguric, acute nonoliguric, or chronic.
  • The presence of systemic disease, nocturia, proteinuria, loss of urinary concentrating ability (low urine specific gravity), anemia, and hypocalcemia are suggestive of chronic intrarenal azotemia.
• Postrenal azotemia
  • Postrenal azotemia occurs when an obstruction to urine flow is present.
  • It is observed in bilateral ureteral obstruction from tumors or stones, retroperitoneal fibrosis, neurogenic bladder, and bladder neck obstruction from prostatic hypertrophy or carcinoma and posterior urethral valves.
  • It may be superimposed on a background of chronic renal failure.

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