- Author: Edgar V Lerma, MD, FACP, FASN, FAHA, FASH, FNLA, FNKF; Chief Editor: Vecihi Batuman, MD, FACP, FASN more...
Normal urinary protein excretion is <150 mg/24 hour, with majority consisting of secreted proteins such as Tamm-Horsfall protein. Daily albumin excretion in a normal person is <30 mg.
Proteinuria can occur in various forms and at different levels of severity. It can be classified on the basis of the amount of protein (nephrotic or non-nephrotic), the type of protein (albuminuria or low molecular weight proteinuria), or the underlying pathological damage (glomerular vs non-glomerular). Most cases of proteinuria can be classified as tubular, overflow, or glomerular.
Tubular proteinuria occurs most commonly in disease processes affecting the tubulo-interstitial component of the kidney. It comprises low molecular proteins such as beta-2 microglobulin, which in normal conditions are completely reabsorbed by proximal tubules. The amount of proteinuria is <2 g and dipstick may be negative.
Overflow proteinuria is most commonly associated with increased production of abnormal low molecular weight proteins (eg, light chains in multiple myeloma, myoglobin in rhabdomyolysis) that exceeds the reabsorption capacity of the tubules, leading to spilling of the protein into the urine. These low molecular proteins can be toxic to the tubules and can cause acute kidney injury.
Glomerular proteinuria can be categorized according to whether pathological damage of the glomerulus is present. Types in which the patient has no pathological damage to the glomerulus include transient and orthostatic proteinuria.
Transient proteinuria occurs in patients with normal renal function, bland urine sediment, and normal blood pressure. The quantitative protein excretion is less than 1 g/day. The proteinuria is not indicative of significant underlying renal disease; it may be precipitated by high fever or heavy exercise, and it disappears upon repeat testing.
Orthostatic proteinuria is diagnosed if the patient has no proteinuria in early morning samples but has low-grade proteinuria at the end of the day. It usually occurs in tall, thin adolescents or adults younger than 30 years (and may be associated with severe lordosis). Patients have normal renal function and proteinuria usually is less than 1 g/day with no hematuria.
Glomerular proteinuria associated with pathological damage to the glomerulus is categorized by protein quantity. In non-nephrotic proteinuria, the amount of proteinuria is <3.5 g/24 h and is persistent. These patients require close follow-up and may need a kidney biopsy if they have abnormal urine microscopy results and/or impairment of kidney function.
Nephrotic-range proteinuria is defined as >3.5 g of proteinuria on a spot urine protein–to-creatinine ratio. This finding denotes significant glomerular disease and requires a kidney biopsy for diagnosis and management.
Accompanying findings in patients with glomerular damage may include the following: (see Workup):
Active urine sediment - Dysmorphic red blood cells and red cell casts
Abnormal renal function
Plasma proteins are essential components of any living being. The kidneys play a major role in the retention of plasma proteins, using renal tubules to reabsorb them as the proteins pass through the glomerular filtration barrier. Normal urine protein excretion is up to 150 mg/day. Therefore, the detection of abnormal quantities or types of protein in the urine is considered an early sign of significant renal or systemic disease. (See Pathophysiology and Etiology.)
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, excretion of albumin in the urine is less than 30 mg per day. 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 the excretion of 30-300 mg of albumin daily or 20-200 µg of albumin per minute. (See Workup, Treatment, and Medication.)
Complications of proteinuria include the following (see Prognosis):
Pulmonary edema due to fluid overload
Acute renal failure due to intravascular depletion
Increased risk of bacterial infection, including spontaneous bacterial peritonitis
Increased risk of arterial and venous thrombosis, including renal vein thrombosis
Increased risk of cardiovascular disease
The glomerulus provides a charge- and size-selective barrier to albumin. The small amount of albumin and non-albumin protein that is filtered is very well reabsorbed in the proximal convoluted tubule (PCT). Damage to this intricate selectivity to albumin has detrimental effects and contributes to sclerosis.
Podocytes are the terminally differentiated epithelial cells of the glomerulus. Crosstalk among podocytes, mesangium, and endothelium maintains the normal filtration barrier. As all three are interlinked, damage to any one of them affects the functioning of the others.
Endothelium activation and loss of selectivity leads to prolonged exposure of podocytes to proteins. This result in the activation of renin-angiotensin in podocytes and alteration of size selectivity. Damage to podocytes in turns leads to decrease in vascular endothelial growth factor (VEGF) required for endothelial fenestrae formation . 
The filtration of proteins across the abnormal glomerular capillary wall (GCW) exposes mesangial and tubular cells to these proteins. Mesangial cells lie close to capillary lumen and play an important role in glomerular hemodynamics and immune complex clearance. However, cytokine generation with podocyte damage can lead to mesangial cell activation and proliferation . 
The protein-mediated cytotoxicity causes endothelial damage, with podocyte loss leading to the production of chemokines and cytokines that initiate an inflammatory response. The end point is sclerosis and fibrosis of the glomerulus . 
The presence of abnormal amounts or types of protein in the urine may reflect any of 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) and that consequently 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
Causes of glomerular disease can be classified as primary (no evidence of extrarenal disease) or secondary (kidney involvement in a systemic disease) and can then subdivided within these two groups on the basis of the presence or absence of nephritic/active urine sediment. In some cases, however, primary and secondary diseases can produce identical renal pathology.
Primary glomerular diseases associated with active urine sediment (proliferative glomerulonephritis) include the following
Immunoglobulin A (IgA) nephropathy
Mesangial proliferative glomerulonephritis
Primary glomerular diseases associated with bland urine sediment (nonproliferative glomerulonephritis) include the following:
Membranous glomerulonephritis 
Secondary glomerular diseases associated with active urine sediment (proliferative glomerulonephritis, including rapidly progressive glomerulonephritis) include the following:
Renal vasculitis - Including disease associated with antineutrophil cytoplasmic antibodies (ANCAs), such as granulomatosis with polyangiitis (formerly known as Wegener granulomatosis)
Lupus nephritis 
Secondary glomerular diseases associated with bland urine sediment (nonproliferative glomerulonephritis) include the following:
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 focal segmental glomerulosclerosis, the secondary type usually is gradual in onset and is not usually associated with hypoalbuminemia or other manifestations of nephrotic syndrome, even in the presence of nephrotic-range proteinuria.
MPGN is usually a pattern of injury seen on light microscopy. The current classification divides MPGN further into immunoglobulin- and complement-positive MPGN versus complement-positive MPGN. The latter is due to dysregulation of complement pathway and includes C3 glomerulonephritis and dense-deposit disease.
Occurrence in the United States
In the third National Health and Nutrition examination Survey (NHANES III), the prevalence of microalbuminuria in the US population was found to be 6.1% in males and 9.7 % in females. The prevalence of microalbuminuria was 28.8% in persons with diabetes, 16.0% in those with hypertension, and 5.1% in those without diabetes, hypertension, cardiovascular disease, or elevated serum creatinine levels. The prevalence of proteinuria starts increasing at 40 years of age. Also, 3.3 % of the US adult population was found to have persistent albuminuria with a normal estimated glomerular filtration rate (eGFR).
According to the NHANES III survey, the prevalence of microalbuminuria is greater in non-Hispanic blacks and Mexican Americans aged 40 to 79 years compared with age-matched non-Hispanic whites. Similar results were found in the NHANES survey from 2006, where even after adjusting for covariates and medication use, racial and ethnic minorities with and without diabetes had greater odds of albuminuria compared with whites without diabetes. The results were similar when the comparison was made in patients with eGFR < 60 mL/min.[9, 10]
Many causes of proteinuria are particularly common in African Americans and certain other groups. The primary glomerular disorder, focal segmental glomerulosclerosis, has a higher incidence as well as a worse prognosis in African Americans.
In a study by Friedman et al, nondiabetic chronic kidney disease was found to occur in more than 3 million African Americans who had genetic variants in both copies of APOL1, increasing their risk for hypertension-attributable end-stage renal disease and focal segmental glomerulosclerosis. However, African Americans without the risk genotype appear to have a risk similar to that of European Americans for developing nondiabetic chronic kidney disease.
Sex- and age-related demographics
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.
The incidence of hypertension and diabetes increases with age. In consequence, the incidence of persistent proteinuria (and microalbuminuria) also increases with age.
The prognosis for patients with proteinuria depends on the cause, duration, and degree of the proteinuria. Young adults with transient or orthostatic proteinuria have a benign prognosis, while patients with hypertension and microalbuminuria (or higher degrees of albuminuria) have a significantly increased risk of cardiovascular disease.
Proteinuria has been associated with progression of kidney disease, increased atherosclerosis, and left ventricular abnormalities indirectly contributing to cardiovascular morbidity and mortality. 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 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.
Cardiovascular outcomes and proteinuria
In a study of 2310 patients, Jackson et al concluded that spot urinary albumin-to-creatinine ratios (UACRs) have significant prognostic value in persons with heart failure. These authors determined that, compared with patients with normoalbuminuria, those with an elevated UACR tended to be older, had higher rates of cardiovascular comorbidity and diabetes mellitus, and suffered from worse renal function. 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.
In the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) population study, the incidence of myocardial infarction was higher in patients with microalbuminuria than in those with normal urinary albumin levels. In a study by Rein et al, albuminuria was an important predictor of cardiovascular mortality even after adjusting for conventional risk factors. Analysis of 1208 hypertensive, normoalbuminuric patients with type 2 diabetes from the BENEDICT trial also showed increased cardiovascular problems with any degree of measurable urinary albumin.
Results from a study by Chiu et al of 225 proteinuric patients with type 2 diabetes mellitus indicated that vascular calcification, which can be particularly severe in nondialyzed patients with coexisting proteinuria and diabetes, is a prognostic indicator in early-stage type 2 diabetic nephropathy.
In the study, 86% of patients were found to have coronary artery calcification, the degree of which was associated with older age, white ethnicity, and male sex. Fifty-four patients died during the follow-up period, which averaged 39 months.Univariate and multivariate analyses indicated that the degree of coronary artery calcification was, in relation to the calcification's severity, an independent predictor of all-cause mortality in the study's patients, with a 2.5-fold greater mortality risk found in subjects with a calcification score in the highest quartile. 
A study of 3939 subjects enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study, a prospective observational cohort, found that proteinuria and albuminuria are better predictors of stroke risk in patients with chronic kidney disease than estimated glomerular filtration rate. In patients with albuminuria, treatment with renin-angiotensin blockers did not decrease stroke risk.
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