Azotemia

Azotemia is an elevation of blood urea nitrogen (BUN) and serum creatinine levels. The reference range for BUN is 8-20 mg/dL. Reference ranges for serum creatinine vary slightly by age and sex: in adults, the normal range is 0.5-1.1 mg/dL (44-97 μmol/L) in women and 0.6-1.2 mg/dL (53-106 μmol/L) in men.

Each human kidney contains approximately 1 million functional units, nephrons, which are primarily involved in urine formation. Urine formation ensures that the body eliminates the final waste products of metabolism and excess water in an attempt to maintain a constant internal environment (homeostasis). 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
• 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). On average, the GFR is about 125 mL/min (10% less for women), or 180 L/day. About 99% of the filtrate (178 L/day) is reabsorbed, and the rest (2 L/day) is excreted.

Measurement of kidney function

Radionuclide assessment of the GFR is the best available test for measuring kidney function. However, this test is expensive and not widely available, and as a result, serum creatinine concentration, creatinine clearance (CrCl) and estimating equations for GFR (eGFR) more commonly are used to estimate GFR.

An inverse relation between serum creatinine and the GFR exists; however, serum creatinine and CrCl are not sensitive measures of kidney damage, for 2 reasons. First, substantial kidney damage can take place before any decrease in the GFR occurs. Second, a substantial decline in the GFR may lead to only a slight elevation in serum creatinine (see the image below). Because of compensatory hypertrophy and hyperfiltration of the remaining healthy nephrons, an elevation in serum creatinine is apparent only when the GFR falls to about 60-70 mL/min.

Because creatinine normally is filtered as well as secreted into the renal tubules, 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 (eg, iothalamate). In practice, precise knowledge of the GFR is not required, and the disease process usually can be adequately monitored by using the estimated GFR (eGFR), which may be obtained with a number of different methods.

CrCl is best calculated by obtaining a 24-hour urine collection for creatinine and volume and then using the following formula:

CrCl (mL/min) = U/P × V

where U is the urine creatinine in mg/dL, P is the serum creatinine in mg/dL, and V is the 24-hour volume divided by 1440 (the number of minutes in 24 hours). See also the CrCl from 24h Urine calculator. 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. 24-hr creatinine clearance measurements have largely been replaced by estimating equations described below.

Alternatively, several formulas are available for estimating GFR. The Cockcroft-Gault formula, a bedside formula that uses the patient’s serum creatinine (mg/dL), age (y), and lean weight (kg), is as follows:

CrCl (mL/min) = [(140 – age) × weight]/(72 × serum creatinine)

For women, the result of the equation is multiplied by 0.85.

An online calculator for the Cockcroft-Gault formula is available. Although the Cockcroft-Gault formula is rarely used in clinical practice, it is still the preferred formula used in clinical trials that require kidney function assessment, due to its longevity and its use in many drug trials.

Another formula was derived from data collected in the Modification of Diet in Renal Disease (MDRD) study. The MDRD formula, also called the Levey formula, became widely accepted as more accurate than the Cockcroft and Gault formula; see the MDRD eGFR and MDRD eGFR (6 Variable) calculators.

Both formulas have limitations: the Cockcroft-Gault formula is simple to use but overestimates the GFR by 10-15% because creatinine is both filtered and secreted. The MDRD formula is much more complex and has been found to underestimate GFR by 6.2% in patients with chronic kidney disease (CKD) and by 29% in healthy persons.[1] Furthermore the MDRD formula overstimated eGFR by a factor of 21% in Black CKD patients resulting in delayed referrals of Black patients for needed renal care.

A third formula, the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation, is based on the same four variables as the MDRD Study formula but uses a 2-slope “spline” to model the relationship between estimated GFR and serum creatinine, and a different relationship for age, sex, and race. See the eGFR using CKD-EPI calculator. The National Kidney Foundation (NKF) recommended using the CKD-EPI equation to estimate GFR[2] until recently, when researchers noted that although the CKD-EPI equation performed much better than MDRD, it still overestimated the eGFR in Black patients, although to a lesser extent (by 16%), which would also lead to delayed referral of Black patients for renal care.

As a result, a new formula was developed in 2023, the CKD-EPI Refit equation; see the eGFR calculator without race eGFR calculator. The CKD EPI-Refit equation does not include race, thereby eliminating the health disparity issue.[3] Inputs for the eGFR calculator without race are the patient's serum creatinine level, age, and gender. Users have the option to input cystatin C level rather than creatinine level, to get a cystatin C-based eGFR. Cystatin C–based eGFR estimates perform better than creatinine-based eGFR estimates because cystatin C is produced by all nucleated cells and thereby has a better steady state than creatinine, which is produced by muscles alone, so levels can fluctuate based on muscle mass. However, cystatin C assays are expensive and not for routine use. For clinical use, the creatinine-based eGFR estimate without race is the current standard.

There are three pathophysiologic states in azotemia, as follows:

• Prerenal azotemia
• Intrarenal azotemia
• Postrenal azotemia

Prerenal azotemia

Prerenal azotemia refers to elevations in BUN and creatinine levels resulting from problems in the systemic circulation that decrease blood flow to the kidneys. The decreased renal flow stimulates salt and water retention to restore volume and pressure.

Decreases in blood volume or pressure activate the baroreceptor reflexes located in the aortic arch and carotid sinuses. This leads to sympathetic nerve activation, resulting in renal afferent arteriolar vasoconstriction and renin secretion through β1 receptors. Constriction of the afferent arterioles causes a decrease in intraglomerular pressure, which reduces the GFR proportionally. Reduction in renal blood flow results in the generation of renin, which converts angiotensinogen to angiotensin I. Angiotensin-converting enzyme then converts angiotensin I to angiotensin II, which, in turn, stimulates aldosterone release. The increase in aldosterone levels results in salt and water absorption in the distal collecting tubule.

A decrease in volume or pressure is a nonosmotic stimulus for hypothalamic production of antidiuretic hormone, 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 those 4 mechanisms of salt and water retention is decreased urine output and decreased urinary excretion of sodium (< 20 mEq/L).

Intrarenal azotemia

Intrarenal azotemia, also known as acute kidney injury (AKI), renal-renal azotemia, and (in the past) acute renal failure (ARF), refers to elevations in BUN and creatinine resulting from problems in the kidney itself. Definitions of AKI include a rise in serum creatinine levels of about 30% from baseline or a sudden decline in output below 500 mL/day. If output is preserved, AKI is nonoliguric; if output falls below 500 mL/day, AKI is oliguric. Any form of AKI may be so severe that it virtually stops urine formation; this condition is called anuria (< 100 mL/day).

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

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

The pathophysiology of acute oliguric or nonoliguric AKI depends on the anatomic 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 is also impaired. In more severe ATN, the tubular lumen is filled with epithelial casts, causing intraluminal obstruction and resulting in a declining GFR.

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

Glomerulonephritis or vasculitis is suggested by the presence of hematuria, red blood cells (RBCs), WBCs, 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 by changing basement membrane permeability and stimulating the renin-aldosterone axis. Such diseases often manifest as nephrotic or nephritic syndrome.

In nephrotic syndrome, the urinary sediment is inactive, and there is gross proteinuria (> 3.5 g/day), 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 AKI. Impairment of capillary circulation in the kidney due to edema (nephrosarca) and tubular obstruction from protein casts, as well as decreased effective circulating volume, have been proposed as potential mechanisms for the development of AKI in patients with nephrotic syndrome.

In nephritic syndrome the urinary sediment is active, with WBC or RBC casts, and granular casts, and azotemia is present. 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 include hypertensive benign nephrosclerosis, which has not been conclusively associated with end-stage renal disease (ESRD), and ischemic renal disease from bilateral renal artery stenosis.[4]

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 II receptor blockers (ARBs) cause efferent arteriolar dilatation, thereby decreasing intraglomerular pressure and filtration. Therefore, ACE inhibitors and ARBs 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 the following:

• 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)

• Platelet dysfunction (leading 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 (eg, urea, creatinine, phenols, and guanidines) have been identified, but none have been found responsible for all the manifestations of uremia.

Postrenal azotemia

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

Unilateral obstruction rarely causes azotemia. There is evidence that if complete ureteral obstruction is relieved within 48 hours of onset, relatively complete recovery of GFR can be achieved within a week; 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.

Prerenal azotemia occurs as a consequence 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,[5] or renal artery abnormalities. It may be superimposed on a background of chronic kidney disease. Iatrogenic factors, such as excessive diuresis and treatment with ACE inhibitors, should be ruled out.

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. Systemic disease, nocturia, proteinuria, loss of urinary concentrating ability (low urine specific gravity), anemia, and hypocalcemia are suggestive of chronic intrarenal 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 kidney disease.

United States statistics

The reported incidence of hospital or community-acquired AKI varies considerably. In one report, community-acquired AKI occurred in about 1% of all hospital admissions. Overall, AKI occurs in about 5% of all hospital admissions. However, differences exist between the incidence of AKI occurring in the intensive care unit (ICU; about 15%) and that in the coronary care unit (CCU; about 4%).[6]

In CKD, progressive azotemia leading to ESRD necessitating dialysis or kidney transplantation occurs in a number of chronic diseases, including the following:

• Diabetes (36%)
• Hypertension (24%)
• Glomerulonephritis (15%)
• Cystic kidney disease (4%)
• Other known miscellaneous kidney disorders (15%)

International statistics

In a report from Madrid that evaluated 748 cases of AKI at 13 tertiary hospital centers, conditions included the following[7] :

• ATN (45%)
• Prerenal (21%)
• AKI or CKD, mostly due to ATN and prerenal disease (13%)
• Urinary tract obstruction (10%)
• Glomerulonephritis or vasculitis (4%)
• Acute interstitial nephritis (2%)
• Atheroemboli (1%)

A study of the epidemiology of community-acquired AKI in eastern India in 1983–95 versus 1996–2008 found that the incidence rate rose from 1.95 to 4.14 per 1000 hospital admissions. In addition, the etiology of AKI shifted: the incidences of obstetric, surgical, and diarrheal AKI decreased significantly, whereas those of AKI associated with malaria, sepsis, nephrotoxic drugs, and liver disease increased.[8]

Etiologies of CKD differ around the world. Diabetic nephropathy as a cause of CKD is on the rise in developed and developing countries.

Age-, sex-, and race-related demographics

According to the 2022 annual report of the United States Renal Data System (USRDS), rates of hospitalization with AKI in older adults (events per 1000 person-years) were highest in patients age 85 years and older (132.8, versus 73.2 in those age 75-84), in men (75.5, 52.6 in women), and in Blacks (114.5, vs 58.9 in Whites). The USRDS reported that in 2017-March 2020, 14.0% of the US adult population had CKD, and that at the end of 2020 there were 807,920 prevalent cases of ESRD in the US.[9] Prevalence by race/ethnicity was as follows:

• Black: 6306 cases per million population (pmp)
• Native American: 3478 cases pmp
• Hispanic: 3378 cases pmp
• Asian: 2350 cases pmp
• White: 1475 cases pmp

The prognosis for patients with AKI generally is poor and depends on the severity of the underlying disease and the number of failed organs. Whereas mortality in patients with simple AKI without other underlying disease is 7-23%, that in ICU patients on mechanical ventilation is as high as 80%.

The prognosis of CKD depends on the etiology. Patients with diabetic kidney disease, hypertensive nephrosclerosis, and ischemic nephropathy (ie, large-vessel arterial occlusive disease) tend to have progressive azotemia resulting in ESRD. Different types of glomerulonephritis have major differences in prognosis: some are quite benign and rarely progress to ESRD, whereas others progress to ESRD within months. About 50% of patients with polycystic kidney disease progress to ESRD by the fifth or sixth decade of life.

The clinician must 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 (including serologies, urinalysis, and, if indicated, radiologic studies and kidney biopsy; see Workup).

Patients with prerenal azotemia commonly have a history of one or more of the following:

• Diarrhea
• Vomiting
• Profound heat exhaustion
• Excessive sweat loss
• Concurrent illness that impairs the ability to eat and drink adequately
• Hemorrhage
• Liver disease
• Congestive heart failure
• Polyuria (eg, caused by lithium intoxication, diuretics, diabetes, or diabetes insipidus)

Patients with intrarenal azotemia may have a history of nocturia, polyuria, proteinuria, shock, and edema. They may have a personal or family history of congenital or systemic diseases, especially diabetes, hypertension, systemic lupus erythematosus (SLE), other collagen vascular diseases, hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, syphilis, multiple myeloma, or HIV infection.

Obtain a detailed medication history, looking for nephrotoxic medications (especially antibiotics, nonsteroidal anti-inflammatory drugs [NSAIDs], angiotensin-converting enzyme [ACE] inhibitors, diuretics, and herbal remedies), chemical exposure, and intravenous (IV) drug abuse (which increases risk for HIV, HBV, and HCV infections).

Patients with postrenal azotemia frequently have a history of renal colic, dysuria, frequency, hesitancy, urgency, incontinence, pelvic malignancy, irradiation, or benign prostatic hyperplasia.

Physical examination should be detailed but should focus on signs that have a high diagnostic yield.

In suspected prerenal azotemia, look for the following:

• Tachycardia
• Orthostatic hypotension (systolic blood pressure drop greater than 20 mm Hg or diastolic drop greater than 10 mm Hg from supine to standing)
• Hypotension
• Signs of dehydration, including dry mucous membranes, loss of skin turgor, and loss of axillary sweat
• Signs of congestive heart failure
• Signs of hepatic insufficiency

In suspected 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 last 2 signs are suggestive of uremia. Patients with uremic pericarditis require immediate dialysis.

Postrenal azotemia (obstruction) is suggested by a palpable bladder that is dull to percussion and the presence of a rectal or pelvic mass on digital examination.

For the initial evaluation, obtain a complete blood count (CBC), a biochemical profile, urinalysis, and urine electrolyte concentrations. In addition to establishing the presence of systemic disease, these tests may reveal clues to the origin of the azotemia. Diagnostic indices are commonly used to differentiate prerenal azotemia from intrarenal or postrenal azotemia (see in the image below).

Prerenal azotemia

In prerenal azotemia, hemoconcentration results in elevation of the hematocrit and total protein/albumin, calcium, bicarbonate, and uric acid levels from baseline values. Urinary findings include the following:

• Oliguria (urine volume <  500 mL/day) or anuria (<  100 mL/day)
• High specific gravity (> 1.015)
• Normal sediment
• Low sodium (<  20 mEq/L; fractional excretion of sodium [FENa] <  1%)

When volume depletion is predominant, exaggerated proximal tubular reabsorption results in azotemia, hypernatremia, and elevated levels of calcium, uric acid, and bicarbonate, whereas hemoconcentration results in elevation of total protein, albumin, and hematocrit levels from baselines. Patients with hypoperfusion due to decreased cardiac output or effective arterial volume is present, patients exhibit edema, hyponatremia, and hypoalbuminemia. Hematocrit and calcium, uric acid, and bicarbonate levels vary widely. These patients often are critically ill.

The FENa has traditionally been used to differentiate prerenal azotemia from ATN. An FENa below 1% suggests a prerenal cause (eg, volume depletion), whereas an FENa above 2% suggests acute tubular necrosis (ATN). Because the FENa is based on the fact that sodium reabsorption is enhanced in the setting of volume depletion, active use of diuretics may elevate the FENa even when volume depletion is present, yielding misleading values.

Alternatives to the FENa in this setting include the fractional excretion of urea or urea nitrogen (FEUrea) and the fractional excretion of uric acid (FEUA); excretion of urea and uric acid excretion is not influenced by diuretics. An FEUrea below 35% or an FEUA below 9-10 % suggests a prerenal etiology of acute kidney injury (AKI), whereas an FEUrea above 50% or an FEUA above 10-12 % suggests acute tubular necrosis (ATN).[10]

Intrarenal azotemia

On blood studies, findings that may suggest intrarenal azotemia include the following:

• Anemia
• Thrombocytopenia
• Hypocalcemia
• High–anion gap metabolic acidosis
• Plasma BUN–creatinine ratio <  20

On urine studies, findings that may suggest intrarenal azotemia include the following:

• Low specific gravity (< 1.015)
• Active sediment (see Pathophysiology)
• High sodium (> 40 mEq/L; FENa > 5%)
• Low osmolality

In patients with long-standing chronic kidney disease (CKD), renal ultrasonography usually shows small, contracted kidneys. However, normal-sized or large kidneys may be seen in CKD from some causes, such as HIV nephropathy, diabetes, and renal amyloidosis. The renal sonogram usually is diagnostic for patients with polycystic kidney disease. In patients with active urinary sediment, progressive azotemia, proteinuria, or normal-sized kidneys on ultrasonography, a kidney biopsy should be considered. Consultation with a nephrologist is imperative in all such patients.

Postrenal azotemia

Urinary indices in postrenal azotemia due to complete bilateral obstruction are usually nondiagnostic. The prima facie finding here is anuria, occasionally accompanied by hypertension. Urine output still may be present if overflow (in bladder outlet obstruction) or partial ureteral obstruction is present.

A Foley catheter should be inserted as part of the initial evaluation to rule out obstruction below the bladder outlet. Unilateral ureteral obstruction rarely leads to azotemia; it occurs acutely (as a result of obstruction from calculi, papillary necrosis, or hematoma), producing renal colic, or may be chronic and asymptomatic, producing hydronephrosis.

Bilateral partial obstruction may be associated with azotemia in the presence of normal urine output. When patients are subjected to maneuvers that increase urinary flow (eg, diuretic renography or perfusion pressure flow studies), they may exhibit an increase in size or pressure of the collecting system or experience pain.

In addition to azotemia, polyuria due to loss of concentrating ability and type 1 renal tubular acidosis, with hyperkalemia, hypercalcemia from a metastatic pelvic tumor, and elevated prostate-specific antigen (PSA) levels, may be clues to postrenal azotemia. Hydronephrosis in the absence of hydroureter may be seen in early (<  3 days) obstruction, retroperitoneal process, or partial obstruction.

Renal ultrasonography (see below) is the test of choice for ruling out obstructive uropathy. If the renal sonogram is equivocal, a furosemide (Lasix) washout scan (see Radionuclide Studies) should be performed.

Renal ultrasonography is the most commonly used renal imaging study because of its ease of use and broad applicability for the following purposes[11] :

• Determination of kidney size and echogenicity, which is important when considering kidney biopsy; small echogenic kidneys (<  9 cm) may suggest scarring from advanced renal disease, whereas normal or large kidneys with smooth contours may indicate a potentially reversible process

• Differentiation of cystic lesions from solid lesions

• Diagnosis of urinary tract obstruction (for which it is the test of choice)

• Detection of kidney stones

Doppler renal ultrasonography can be used to evaluate renal vascular flow (eg, for identification of renal vein thrombosis, renal infarction, or renal artery stenosis).

Computed tomography (CT)[12] is complementary to ultrasonography, especially when the diagnosis is uncertain. Contrast nephrotoxicity should be weighed against the benefits. CT is used for the following purposes:

• Differentiation of neoplastic lesions from simple cysts (in most cases)
• Radiologic diagnosis of renal stone disease, including radiolucent stones
• Evaluation and staging of renal cell carcinoma
• Diagnosis of renal vein thrombosis
• Diagnosis of polycystic kidney disease; it is more sensitive than ultrasonography for this task, particularly in younger patients

Knipp et al describe successful use of a technique for computed tomographic angiography (CTA) of the abdomen and pelvis in azotemic patients that uses a reduced iodinated contrast volume and low kilovolt (peak) [80-kV(p)] with iterative reconstruction. Their retrospective study in 103 patients with end-stage renal disease found that this technique allows for satisfactory abdominal/pelvic CTA with a 50% reduction in contrast volume and a 43% mean radiation dose reduction, compared with a standard 120-kV(p) CTA protocol.[13]

Magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA) is used only when CT and ultrasonography are nondiagnostic. These modalities are standard for diagnosis of renal vein thrombosis and are also used in the evaluation of renal cell carcinoma and renal artery stenosis or vasculitis.

If symptoms suggest nephrolithiasis, a plain film of the abdomen is performed to screen for presence of a radiopaque stone. Calcium-containing, struvite, and cystine stones can be identified, but radiolucent ones, such as uric acid stones, will be missed.

Intravenous pyelography (IVP) can provide detailed information concerning calyceal anatomy and the size and shape of the kidney. It is extremely useful for detecting renal stones. IVP is the preferred technique for evaluation and diagnosis of certain structural disorders (eg, chronic pyelonephritis, medullary sponge kidney, and papillary necrosis). It can provide data on the degree of obstruction. The risk of contrast nephrotoxicity should be weighed against the benefits of making a diagnosis that will not change management.

Retrograde or anterograde pyelography is of limited usefulness now that renal ultrasonography is more widely available. It may be used in patients with a high index of suspicion for hydronephrosis in whom sonograms appear normal, such as those with retroperitoneal fibrosis.

Renal arteriography is used in polyarteritis nodosa and renal artery stenosis to demonstrate multiple aneurysms or stenoses. Because of the availability of procedures that do not require contrast material (eg, ultrasonography, MRI, and MRA) and thus do not carry a risk of contrast nephrotoxicity, this test is less commonly used than it once was.

Renal venography is the standard for diagnosis of renal vein thrombosis. However, it poses a risk of contrast nephrotoxicity.

Technetium-99m dimercaptosuccinic acid (99mTc DMSA) is heavily distributed within the renal parenchyma at first pass and so is best for detecting renal parenchymal scarring.

Technetium diethylenetriamine pentaacetic acid (99mTc DTPA) is heavily filtered at first pass and therefore is best for qualitative assessment of kidney function (filtration and excretion). Because it is heavily filtered, it is most sensitive in detecting urine leaks after kidney transplantation. For the same reason, it is also used concomitantly with a furosemide washout scan (see below) for assessing functional obstruction of the collecting system.

Mercaptoacetyltriglycine (MAG3) is evenly distributed at first pass in the kidney and so is best for qualitative assessment of perfusion, filtration, and excretion. It is the preferred test for assessing those 3 aspects of function after kidney transplantation. It can be used with furosemide to detect urine leaks or functional obstruction, though 99mTc DTPA scanning remains the test of choice for these conditions. Voiding cystourethrography can be performed with a radionuclide study to detect vesicoureteral reflux.

In a furosemide washout scan, the renal scan usually is performed first. Then, if needed, the furosemide washout is done after the radionuclide has accumulated in the collecting system. Furosemide is used as a part of the renogram to separate nonobstructive hydronephrosis from obstructive hydronephrosis. If there is no obstruction, furosemide-induced flow containing little or no radionuclide will fill the collecting system, washing out radionuclide-containing urine. If obstruction is present, the radionuclide is not washed out as quickly.

The half-life or clearance of the radioisotope is plotted on a curve. A half-life shorter than 10 minutes is considered normal, one longer than 20 minutes is considered obstruction, and one of 10 to 20 minutes is subject to further interpretation.

Conditions that can make it difficult to interpret the furosemide washout curve include a megaureter or pelvis that accepts a large bolus of urine and poor kidney function. In patients with a megaureter, it can be difficult to determine when the renal pelvis is full, and in patients with kidney disease, the onset of furosemide action may be delayed. To overcome the problem of poor kidney function or relative hypovolemia if a patient has been fasting, the patient should be well hydrated with intravenous (IV) fluids before the study.

The test also is operator dependent, in that the furosemide should be administered at a time when the renal pelvis is believed to be full. A full bladder also delays washout of isotope. Therefore, the patient’s bladder must be catheterized before the study can be performed.

When glomerulonephritis, vasculitis, and (occasionally) interstitial nephritis are suspected, kidney biopsy is indicated to establish the correct diagnosis and guide therapy. The following are common indications for kidney biopsy:

• Isolated glomerular proteinuria or hematuria
• Nephrotic syndrome
• Acute nephritic syndrome
• Unexplained acute or subacute kidney injury

Percutaneous kidney biopsy is associated with potential complications. Severe bleeding causing hypotension occurs in 1-2% of patients. Bleeding necessitating transfusion occurs in about 0.1-0.3% of patients. Bleeding complications can be minimized by performing pre-procedure coagulation studies: bleeding time, prothrombin time (PT), activated partial thromboplastin time (aPTT), and platelet count.

Nonsteroidal anti-inflammatory drugs (NSAIDs) should be stopped at least 1 week before a scheduled elective biopsy. Patients on warfarin should be started on heparin at least 3 days before kidney biopsy. Patients who are taking heparin for other reasons should stop the drug for at least 1 day.

Contraindications for percutaneous kidney biopsy include the following:

• Uncorrectable bleeding diathesis
• Small kidneys
• Severe hypertension
• Multiple bilateral cysts or renal tumor
• Hydronephrosis
• Active renal or perirenal infection
• Uncooperative patient

Percutaneous biopsy may be performed in selected patients with a solitary kidney because of the generally low risk of bleeding. Open biopsy may be performed if a percutaneous attempt is either unsuccessful or contraindicated and if the benefits of diagnosis outweigh the risks. When percutaneous biopsy is contraindicated but a diagnosis is necessary, a transvenous transjugular renal core biopsy can be performed.[14] With this approach, bleeding occurs intravascularly, thereby reducing the risk of hematoma.

Prerenal azotemia

If volume depletion is due to free water loss, the serum sodium is often elevated by 10 mEq/L from baseline. The amount of fluid replacement in liters—that is, the free water deficit—can be estimated from serum sodium (mg/dL) and patient weight (kg) as follows:

[(Na/140) – 1] × 0.5 × weight

The volume of fluid to be administered is equal to the sum of the free-water deficit and daily maintenance fluids. Fifty percent of this total volume should be administered in the first 24 hours, and a new calculation should be performed at 24 hours based on new laboratory results.

Maintenance fluid can be roughly estimated at 1.5-2 L/day; however, it can also be estimated from caloric intake since 1 kCal requires 1 mL of water in the metabolic process. Normal caloric intake is about 30 Kcal/kg (low catabolic state requires < 30 kCal/kg and high catabolic state requires > 40 kCal/kg). A 70-Kg person at normal caloric intake requires 2100 Kcal/day or 2.1 L of fluid intake. This volume should be added to the free-water deficit and administered as noted above.

Alternatively, the total free water deficit is usually quite close to the sum of 50% free-water deficit and daily maintenance fluids. Therefore, for all practical purposes, the total free-water deficit can be administered intravenously in 24 hours.

The fluid to be administered should consist of hypotonic solutions such as 0.5% saline or 5% dextrose in water (D5W). Alert patients should be encouraged to drink as much free water as they can tolerate; otherwise, free water can be administered via a nasogastric tube.

Serum sodium should be measured every 6-8 hours, and fluid replacement should be adjusted to avoid a precipitous decline in the serum sodium. To prevent brain edema, the rate of decrease in serum sodium should be no more than 0.7 mEq/h (17 mEq/24 h).

Volume depletion due to blood loss requires IV saline and transfusion to maintain pressure (as well as interventions to halt further loss).

Diarrhea often causes isotonic volume loss that necessitates replacement with normal saline. Normal–anion gap metabolic acidosis occurring with diarrhea warrants infusion of bicarbonate in half-normal saline.

Diuretic-induced volume depletion, especially in the elderly, manifests as dehydration, hyponatremia,[15] and, occasionally, hypokalemia. The treatment of choice consists of normal saline infusion and correction of hypokalemia.

Decreased cardiac output requires optimization of cardiac performance through careful use of the following:

• Diuretics
• An angiotensin-converting enzyme (ACE) inhibitor
• Beta-blockers
• Nitrates
• Positive inotropic agents (including dobutamine)
• When indicated, specific therapy for the cause of impaired cardiac function

When ACE inhibitors are contraindicated because of hyperkalemia, the combination of nitrates and hydralazine offers an alternative. Because these patients tend to have risk factors for macrovascular disease, the diagnosis of ischemic nephropathy or atheroembolic disease should be entertained when kidney function continues to worsen despite optimization of cardiac function.

Reduced effective arterial volume due to systemic shunting can result from sepsis or liver failure. Severe edema, hyponatremia, and hypoalbuminemia often pose management problems. Decreased oncotic pressure, increased vascular permeability, and exaggerated salt and water retention shift the Starling forces toward formation of interstitial fluid. Effective treatment of sepsis with antibiotics and of hypotension with dopamine and norepinephrine is mandated. Crystalloid replacement can be tried, but it often leads to more edema.

In severely hypoalbuminemic patients, salt-poor albumin infusion may be undertaken, but there is no conclusive evidence of benefit from this therapy.

Adequate nutrition and effective treatment of sepsis may improve oncotic pressure and normalize vascular permeability, thereby decreasing the systemic shunting. The net result is improved renal perfusion, decreased salt and water retention, improved urinary output, and reduced edema. In hepatorenal syndrome (HRS), the average survival is 1-2 weeks; however, there is evidence that the kidneys will recover with early liver transplantation. Occasionally, kidney dysfunction is advanced, necessitating replacement therapy.

Intrarenal azotemia

Acute kidney injury

For ischemic or nephrotoxic acute tubular necrosis (ATN) due to shock (hypovolemic, cardiogenic, septic), the initial approach is to restore volume and pressure (with fluid replacement and vasopressors, respectively) and to withdraw any nephrotoxic drugs.[16] If the patient becomes oliguric or anuric from shock, volume in the form of crystalloids should be aggressively administered in boluses (eg, 300 mL every 2 hours, rather than 150 mL every hour). Bolus infusion leads to acute intravascular volume expansion, release of atrial natriuretic peptide from the heart, increased renal blood flow, and natriuresis, all of which favor recovery from ATN compared with slow intravenous hydration.

If at least 2 L of fluids have been administered in a relatively short period (approximately 12 hours) with no improvement in urine output, a trial of high-dose intravenous furosemide (100-160 mg) can be tried, prior to preparation for renal replacement. This approach, called “tank and blast” in shock, also known as "Furosemide Stress Test",[17] is clinically useful. In one small study, hemodynamic and renal support with a continuous infusion of noradrenaline (0.06-0.12 μg/kg/min) and furosemide (10-30 mg/hr) induced polyuria and reversed ATN to nonoliguric acute kidney injury (AKI) in 11 of 14 cancer patients who had severe sepsis and multiorgan dysfunction syndrome.[18] If the patient does not respond to this approach within 6 hours, dialysis or continuous renal replacement therapy should be considered as soon as possible.

If the patient responds by restoration of urine output to greater than 30 mL/h, continue the appropriate amounts of intravenous fluids, vasopressors, and as-needed diuretics to maintain the desired fluid balance (negative, positive, or match intake to output).

This approach is not indicated in nonshock patients with AKI. Nonshock patients with AKI require maintenance fluids, if needed, and avoidance of nephrotoxicity.

In both scenarios, early initiation of renal replacement therapy if azotemia sets in provides a better prognosis than late initiation.

Albumin can be administered in combination with high-dose furosemide to enhance the diuretic effect of furosemide. The use of albumin in this context is not for volume expansion; rather, it allows more furosemide to be bound to albumin for delivery to the organic anion transporter in the kidney, thereby enabling more furosemide to enter the tubule than would otherwise do so.

Although this approach is widely used, research on the combination of albumin and a loop diuretic has principally been on its use for improving diuretic-resistant edema in patients with nephrotic syndrome.[19] Other therapies that have not been conclusively shown to be beneficial are renal-dose dopamine and synthetic atrial natriuretic peptide.

The kidney failure phase usually lasts 7-21 days if the primary insult can be corrected. Postischemic polyuria can be seen in the recovery phase and represents an attempt to excrete excess water and solute. Saline may be replaced (75% of output) as a maintenance fluid, owing to salt wasting during this phase, and to allow the patient to lose excess water retained while the patient was oliguric. Hypokalemia may result from the saline diuresis, so potassium should be replaced. Recovery is marked by the return of blood urea nitrogen (BUN) and creatinine levels to near-baseline values.

Acute interstitial nephritis is managed by withdrawing the offending nephrotoxin and avoiding further nephrotoxic exposure and dehydration. The creatinine level begins to improve within 3-5 days. Kidney biopsy may be indicated if kidney function is severely decreased or azotemia is not improving.

Once the diagnosis is confirmed, a trial of oral prednisone (starting at 1 mg/kg/day and tapering over 6 weeks) or IV pulse methylprednisolone (1 g for 3 days) in severe cases may be considered. If the patient is a poor candidate for biopsy but the diagnosis is strongly suspected, therapy should be started.

Contrast-induced azotemia, which typically becomes evident 3-5 days after exposure, is best prevented by adequate hydration with half-normal saline at 1 mL/kg/h 12 hours before contrast administration and the use of smaller amounts of contrast. Clearly explain the risks of such procedures to the patient.

The benefits of N-acetylcysteine (NAC) and sodium bicarbonate for prevention of contrast-induced azotemia are still being debated.[20, 21, 22] A systematic review and meta-analysis of prevention strategies found that the greatest clinically and statistically significant reduction in contrast-induced nephropathy occurred with NAC in patients receiving low-osmolar contrast media (compared with IV saline) and with statins plus NAC (compared with NAC alone).[23]

The Prevention of Serious Adverse Events Following Angiography (PRESERVE) trial, which included 5177 patients at high risk for renal complications who were undergoing angiography, found no benefit of IV sodium bicarbonate over IV saline or of oral acetylcysteine over placebo. Outcomes measured included the prevention of death, need for dialysis, or persistent decline in kidney function at 90 days, as well as the prevention of contrast-associated AKI.[24]

Chronic kidney disease

It is important that patients with chronic kidney disease (CKD) be referred early to a nephrologist for the management of complications and for the transition to renal replacement therapy (ie, hemodialysis, peritoneal dialysis, renal transplantation). There is some evidence that early referral of patients with CKD improves short-term outcome.

Disease progression can be slowed by means of various maneuvers, such as aggressive control of diabetes, hypertension, and proteinuria; dietary protein and phosphate restriction; and specific therapies for some of the glomerular diseases, such as lupus nephritis. Anemia, hyperphosphatemia, acidosis, and hypocalcemia should be aggressively managed before renal replacement therapy.

Postrenal azotemia

Relief of the obstruction is the mainstay of therapy for postrenal azotemia. In anuria, bladder catheterization is mandatory to rule out bladder neck obstruction, whereas in progressive azotemia, catheterization should be done after the patient has voided to determine the postvoid residual volume. A postvoid residual volume of 100 mL or more suggests obstructive uropathy, and the cause should be further investigated.

If hydronephrosis is due to ureteral obstruction, unilateral or bilateral stenting or percutaneous nephrostomy is performed. Recovery of kidney function takes 7-10 days, but kidney function may be severely impaired, necessitating dialysis until such time as partial recovery is adequate for withdrawal of dialysis.

Up to 500-1000 mL/min of postobstructive polyuria can be seen with relief of obstruction. This is an appropriate response and represents an attempt to excrete the excess fluid accumulated during the period of obstruction.

Because of salt wasting during this phase, dehydration and hypokalemia are likely. Thus, two thirds of the urine output should be replaced with half-normal saline and potassium chloride if the patient is hypokalemic. Close monitoring is indicated to prevent hypotension and prerenal azotemia.

Matching the hourly urine output with IV replacement fluid is not recommended, because the excess water retained during the period of obstruction cannot be offloaded if hourly urine output is matched.

The goals of therapy are to increase renal perfusion and to maintain urine output. Drugs used in the management of patients with azotemia include diuretics, adrenergic agents, plasma volume expanders, and corticosteroids. Specific therapies for various systemic conditions affecting the kidney are discussed in other articles.

Class Summary

Diuretics are used to induce urine output in acute tubular necrosis (ATN) and to treat edema and hypertension. They increase urine excretion by inhibiting sodium and chloride reabsorption at different sites in the nephron.

Furosemide (Lasix)

Furosemide is the drug of choice as a diuretic. It inhibits sodium chloride reabsorption in the thick ascending limb of the loop of Henle.

Hydrochlorothiazide (Microzide)

Hydrochlorothiazide (HCTZ) acts on the distal nephron to impair sodium reabsorption, enhancing sodium excretion. It has been in use for more than 40 years and is generally an important agent for the treatment of essential hypertension.

Chlorothiazide (Diuril)

Chlorothiazide inhibits the reabsorption of sodium in distal tubules, causing increased excretion of sodium and water, as well as of potassium and hydrogen ions.

Metolazone (Zaroxolyn)

Metolazone is given as an adjunct to furosemide in severe edematous states or when furosemide alone does not achieve adequate diuresis. It increases excretion of sodium, water, potassium, and hydrogen ions by inhibiting reabsorption of sodium in distal tubules. Metolazone may be more effective in the setting of impaired renal function.

Class Summary

Plasma volume expanders increase plasma oncotic pressure and mobilize fluid from the interstitial space into the intravascular space in hypoalbuminemic patients. They enhance delivery of furosemide to distal tubule.

Albumin (Albuminar, Plasbumin, Albutein)

Albumin is supplied as a 5% solution in 250 mL or a 25% solution in 50 mL. The choice between the 2 formulations is based on whether patient requires additional fluid replacement. Albumin is not used for nutritional supplementation; thus, attempts should be made to improve patient's nutrition.

Class Summary

Corticosteroids are potent anti-inflammatory agents and immunosuppressants. They suppress humoral and cellular response to tissue injury, thereby reducing inflammation.

Prednisone

Prednisone is commonly used for many forms of glomerulonephritis and interstitial nephritis. Once the diagnosis is confirmed, a trial of oral prednisone (starting at 1 mg/kg/day and tapering over 6 weeks) may be considered.

Prednisolone (Orapred, Pediapred, Millipred)

Corticosteroids act as potent inhibitors of inflammation. They may cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to their modification of the immune response of the body. Once the diagnosis is confirmed, a trial of oral prednisolone (starting at 1 mg/kg/day and tapering over 6 weeks) may be considered.

Methylprednisolone (Medrol, Solu-Medrol, Depo-Medrol)

Methylprednisolone decreases inflammation by suppressing the migration of PMNs and reversing increased capillary permeability. In severe cases, a trial of intravenous pulse methylprednisolone (1 g for 3 days) may be considered once the diagnosis is confirmed.

Class Summary

Adrenergic agents stimulate vasodilation of the renal vasculature and enhance perfusion.

Dopamine

Above a critical dose (renal dose), dopamine becomes a potent vasoconstrictor. Renal-dose dopamine is used widely, but a clear benefit has not been established.