eMedicine Specialties > Nephrology > Glomerular Diseases

Proteinuria

Author: Edgar V Lerma, MD, Clinical Associate Professor of Medicine, Section of Nephrology, Department of Medicine, University of Illinois at Chicago College of Medicine; Consulting Staff, Associates in Nephrology, SC
Coauthor(s): Kevin McLaughlin, MB, ChB, MSc, PhD, Associate Professor, Department of Medicine, University of Calgary Faculty of Medicine, Calgary Health Region
Contributor Information and Disclosures

Updated: Aug 19, 2009

Introduction

Background

Plasma proteins are essential components of any living being. The kidneys play a major role in the retention of plasma proteins, and this is accomplished by the renal tubules through their reabsorption of such proteins as they pass through the glomerular filtration barrier. Normal urine protein excretion is up to 150 mg/d. Therefore, the detection of abnormal quantities or types of protein in the urine is considered an early sign of significant renal or systemic disease.

The detection of various types of proteins excreted in the urine has been extensively used in the assessment of renal diseases. The detection of low levels of albumin excretion (termed microalbuminuria) has been linked to the identification of the early stages of diabetic kidney disease.

Normally, the concentration of albumin in the urine is less than 5 mg/L. When expressed as an excretion rate (ie, urine albumin excretion rate [UAER]), this concentration averages 2.6-12.6 µg/min in males and 1.1-21.9 µg/min in females. Microalbuminuria is referred to as excretion of 30-300 mg/d or 20-200 µg/min of albumin, which, by routine dipstick screening methods, is too small to be detected.

To date, numerous assays have been developed to detect this range of concentration of albumin in the urine. However, most of these assays are limited by intraindividual variations, such as physical activity level, acute illnesses or fevers, menstruation, pregnancy, vaginal discharge, diet, blood pressure, volume status, degree of glycemic control, and urine collection method (eg, 24 h, overnight or timed, short-term). On average, albumin excretion is 25% higher during the day than overnight, with a day-to-day variation of 40%. Therefore, before a patient is classified as having microalbuminuria, at least 3 urine samples over a 6-month period that satisfy the above range criterion are recommended.

Pathophysiology

The presence of abnormal amounts or types of protein in the urine reflects the following:

• Systemic diseases that result in an inability of the kidneys to normally reabsorb the proteins through the renal tubules
• Overproduction of plasma proteins that are capable of passing through the normal glomerular basement membrane (GBM), as they enter the tubular fluid in amounts that exceed the capacity of the normal proximal tubule to reabsorb them
• A defective glomerular barrier that allows abnormal amounts of proteins of intermediate molecular weight to enter the Bowman space

Frequency

United States

Approximately 4% of males and 7% of females have proteinuria detected by a single routine dipstick test. The vast majority of these cases are due to transient proteinuria, which resolves spontaneously and does not represent significant underlying renal disease. Proteinuria is found upon repeat testing in 21% of males and 7% of females.

Mortality/Morbidity

• Filtration of albumin and nonalbumin proteins across the abnormal glomerular capillary wall (GCW) exposes mesangial cells and tubular cells to these proteins. Albumin and nonalbumin proteins are normally reabsorbed from the glomerular filtrate in the proximal convoluted tubule (PCT).
• Heavy proteinuria may exceed the capacity of lysosomes in the PCT cells to metabolize reabsorbed protein, and toxic enzymes may leak into the cells and the surrounding renal interstitium¹ as a consequence of lysosomal degranulation. Whether the nephrotoxic protein is albumin, nonalbumin protein, or both remains unclear. Other proteins, such as transferrin, complement components, and low-density lipoproteins, also appear to be directly toxic to tubular cells. Lipoproteins also appear to be toxic to mesangial cells and may contribute to the development of glomerular sclerosis. A consequence of protein-mediated cytotoxicity is the production of chemokines and cytokines that initiate an inflammatory response and ultimately lead to sclerosis and fibrosis.
• In addition to being a predictor of outcome in patients with renal disease, microalbuminuria also is a predictor of morbidity and mortality in patients who do not have evidence of significant renal disease. In patients with hypertension, the presence of microalbuminuria is correlated to the presence of left ventricular hypertrophy. In hypertensive patients and normotensive patients, the presence of microalbuminuria predicts an increased risk of cardiovascular morbidity and mortality.
  
  In a study of 2310 patients, Jackson et al examined the prognostic value of spot urinary-to-creatinine ratios (UACRs) in persons with heart failure.² The authors determined that compared with patients with normoalbuminuria, individuals with an increased UACR tended to be older, had higher rates of cardiovascular comorbidity and diabetes mellitus, and suffered from worse renal function. However, even after adjustment for variables such as renal function and diabetes, it was determined that an increased UACR was associated with a greater mortality risk. The authors concluded that elevated UACR has significant value as a prognostic indicator for patients with heart failure.

Race

Many causes of proteinuria are more common in African Americans and other groups.

• Diabetic nephropathy is more common in American Indians, African Americans, and Hispanics.
• The primary glomerular disorder, focal segmental glomerulosclerosis, also is more common in African Americans.
• In general, African Americans have a higher incidence and tend to have more rapid progression of glomerular diseases and, hence, proteinuria.

Sex

Most primary glomerular diseases associated with proteinuria (eg, membranous glomerulonephritis) and secondary renal diseases (eg, diabetic nephropathy) are more common in males than in females. As a result, persistent proteinuria is at least twice as common in males as in females.

Age

The incidence of hypertension and diabetes increases with age, and, as a consequence, the incidence of persistent proteinuria (and microalbuminuria) also increases with age.

Clinical

History

In most patients, proteinuria is asymptomatic and is detected upon screening, such as in patients with hypertension or diabetes, or at the time of an insurance medical examination.

Because proteinuria occurs frequently in the absence of serious underlying renal disease, considering the more common and benign causes of proteinuria first is important. Questions to be asked include the following:

• Is this transient proteinuria? This may be associated with physical exertion and fever.
• Is this orthostatic proteinuria? It typically is observed in tall thin adolescents or adults younger than 30 years. It may be associated with severe lordosis. Renal function is normal and albuminuria usually is less than 1 g/d.
• Is this due to a nonrenal disease (eg, severe cardiac failure, sleep apnea)? Renal function is normal and proteinuria usually is less than 1 g/d. Microalbuminuria frequently is observed in association with hypertension and the early stages of diabetic nephropathy.
• Are symptoms present that suggest nephrotic syndrome or significant glomerular disease?
• Have changes occurred in urine appearance (eg, red/smoky, frothy)? Did this occur in relation to an upper respiratory tract infection?
• Is edema (eg, ankle, periorbital, labial, scrotal) present?
• Has the patient ever been told his or her blood pressure is elevated?
• Has the patient ever been told his or her cholesterol is elevated?
• Is a history of multisystem disease or other cause of glomerular disease present?
• Is a past or family history of kidney disease (including pregnancy related) present?
• Does the patient have diabetes mellitus? For how long? Are eye diseases or other complications present?
• Is a family history of diabetes mellitus present? Does it include kidney disease?
• Is any chronic inflammatory disease (eg, systemic lupus erythematosus [SLE]) or rheumatoid arthritis present?
• Does the patient have any joint discomfort, skin rash, eye symptoms, or symptoms of Raynaud syndrome?
• Is the patient taking any medication, including over-the-counter or herbal remedies?
• Are any past health problems, such as jaundice, tuberculosis, malaria, syphilis, or endocarditis, present?
• Are any other systemic symptoms, such as fever, night sweats, weight loss, or bone pain, present?
• Does the patient have any risk factors for HIV or hepatitis?
• Are symptoms present that suggest complication(s) of nephrotic syndrome?
• Does the patient have any loin pain, abdominal pain, breathlessness, pleuritic chest pain, or rigors?

Physical

• Assess intravascular volume status by examining the jugular venous pulse (JVP), erect and supine pulse and blood pressure, and heart sounds.
• Assess extravascular volume status, looking for edema (eg, ankle, leg, scrotal, labial, pulmonary, periorbital), ascites, and pleural effusions.
• Examine for signs of systemic disease (eg, retinopathy, rash, joint swelling or deformity, stigmata of chronic liver disease, organomegaly, lymphadenopathy, cardiac murmurs).
• Examine for such complications as venous thrombosis or peritonitis.

Causes

• Transient proteinuria (ie, normal renal function, bland urine sediment, normal blood pressure, absence of significant edema, quantitative protein excretion of usually less than 1 g/d)
  • This is not indicative of significant underlying renal disease.
  • Proteinuria disappears upon repeat testing.
• Orthostatic proteinuria (ie, tall thin adolescents or adults younger than 30 y, may be associated with severe lordosis)
  • Renal function is normal and proteinuria usually is less than 1 g/d.
  • Overnight urine collection shows normal protein excretion (ie, <50 mg during 8-h period).
• Persistent proteinuria due to extrarenal disease
  • Renal function is normal, urine sediment is bland, blood pressure is normal, significant edema is absent, and quantitative albumin excretion usually is less than 500 mg/d.
  • This is not usually indicative of clinically progressive underlying renal disease.
• Persistent proteinuria in excess of 500 mg/d is more likely the result of significant glomerular disease, particularly when associated with the following:
  • Active urine sediment (dysmorphic red blood cells and red cell casts)
  • Hypoalbuminemia
  • Lipiduria
  • Edema
  • Abnormal renal function
  • Hyperlipidemia
  • Hypertension
• Causes of glomerular disease can be classified as primary (no evidence of extrarenal disease) or secondary (kidney involvement in a systemic disease) and then subdivided within these 2 groups based on the presence or absence of nephritic/active urine sediment. In some cases, identical renal pathology can occur in patients with primary and secondary diseases.
• Primary glomerular diseases associated with active urine sediment (proliferative glomerulonephritis)
  • Immunoglobulin A nephropathy
  • Membranoproliferative glomerulonephritis
  • Mesangial proliferative glomerulonephritis
• Primary glomerular diseases associated with bland urine sediment (nonproliferative glomerulonephritis)
  • Membranous glomerulonephritis³
  • Minimal-change disease
  • Primary focal segmental glomerulosclerosis (FSGS)
  • Fibrillary glomerulonephritis
  • Immunotactoid glomerulonephritis
• Secondary glomerular diseases associated with active urine sediment (proliferative glomerulonephritis, including rapidly progressive glomerulonephritis)
  • Anti-GBM disease
  • Renal vasculitis, including disease associated with antineutrophil cytoplasmic antibodies (ANCA) (eg, Wegener granulomatosis)
  • Lupus nephritis⁴
  • Cryoglobulinemia-associated glomerulonephritis
  • Bacterial endocarditis
  • Henoch-Schönlein purpura
  • Postinfectious glomerulonephritis
  • Hepatitis C disease (Renal lesion can be identical to that of primary membranoproliferative glomerulonephritis or that seen in patients with cryoglobulinemia.)
• Secondary glomerular diseases associated with bland urine sediment (nonproliferative glomerulonephritis)
  • Diabetic nephropathy
  • Amyloidosis
  • Hypertensive nephrosclerosis
  • Light-chain disease from multiple myeloma
  • Secondary focal glomerulosclerosis
• Secondary focal glomerulosclerosis may result from the following:
  • The healing phase of other glomerulonephritides
  • As a nonspecific result of reduced nephron mass from any cause, including nonglomerular diseases, such as reflux nephropathy
  • From other causes of glomerular hyperfiltration, such as hypertensive nephrosclerosis and obesity
• Unlike primary FSGS, secondary FSGS usually is gradual in onset and not usually associated with hypoalbuminemia or other manifestations of nephrotic syndrome, even in the presence of nephrotic-range proteinuria.

• Search for CME/CE on This Topic »

• Proteinuria (Pediatrics: General Medicine)
• Nephrotic Syndrome (Nephrology)
• Focal Segmental Glomerulosclerosis (Nephrology)
• Glomerulonephritis, Poststreptococcal (Nephrology)

• Proteinuria May Help Predict Outcomes in Chronic Kidney Disease
• Proteinuria Linked With Cerebral Microbleeds in Stroke, TIA Patients
• Hypertension, Proteinuria Early Complications of Cediranib Therapy

• GFR, Proteinuria and Circadian Blood Pressure
• Selective Cyclooxygenase-2 (COX-2) Inhibition Reduces Proteinuria in Renal Patients
• Proteinuria-Reducing Effects of Tonsillectomy Alone in IgA Nephropathy Recurring After Kidney Transplantation