Approximately 15 kg of protein are filtered through the healthy adult kidney each day, with less than 150 mg excreted [2,5,8]. Proteinuria is generally defined as urinary protein excretion of more than 150 mg/day (10–20 mg/dL) [9]. The presence of proteinuria is considered the hallmark of renal disease. Moderately increased albuminuria (microalbuminuria) is defined as the excretion of 30–300 mg/day of albumin protein and can be a sign of early renal disease, particularly in patients with diabetes [9,10]. Severely increased albuminuria (macroalbuminuria) describes albumin excretion rates of more than 300 mg/day. This finding indicates more advanced renal disease [9].

Although isolated proteinuria is not necessarily associated with excess morbidity and mortality, it can be a sign of serious systemic disease. In the United States, diabetes is the leading cause of end-stage renal disease (ESRD), followed by hypertension [12]. In both type 1 and type 2 diabetes, microalbuminuria is often the first sign of deteriorating renal function [7]. As kidney function declines, microalbuminuria becomes full-fledged proteinuria. ESRD has a yearly mortality rate of approximately 15% and currently affects more than808,500 patients in the United States alone [13]. Proteinuria can also be a sign of nephrotic syndrome, which carries a high risk of morbidity and mortality.

Patients with proteinuria range from healthy young adults with functional proteinuria related to prolonged exercise to seriously ill diabetic patients with nephrotic syndrome. Therefore, all individuals presenting for primary care should be screened for proteinuria by routine dipstick testing. Especially important is the routine screening of pregnant women. Proteinuria before 20 to 24 weeks' gestation indicates likely glomerulonephritis, whereas proteinuria after 24 weeks' gestation is usually a sign of pre-eclampsia [6].

After proteinuria has been identified, unless the cause is readily identified (e.g., pre-eclampsia, nephrotic syndrome, diabetes), the urine should be tested for Bence Jones proteins; if present, Bence Jones proteins suggest multiple myeloma [2]. In addition, a full blood chemistry panel with fasting blood glucose, a lipid profile, urine culture and sensitivity, and complete blood count (CBC) with differential are indicated. Further evaluation of persistent proteinuria usually includes determination of 24-hour urinary protein excretion or spot urinary protein/creatinine ratio, microscopic examination of urinary sediment, urinary protein electrophoresis, and additional assessment of renal function [10,17].

Another important consideration is whether the proteinuria is persistent or transient [2]. Transient proteinuria secondary to an identifiable cause (e.g., exercise, fever, congestive heart failure) in an otherwise healthy patient may be classified as functional proteinuria and does not require further testing or evaluation [2,8]. Persistent proteinuria that cannot be classified as functional proteinuria requires further investigation, beginning with a 24-hour measurement of urine protein and creatinine clearance to determine the urinary protein excretion and the protein/creatinine ratio [5,17]. If the excretion rate is 3.5 g/day or more, the patient by definition has nephrotic syndrome, which is usually accompanied by hypoalbuminemia, hyperlipidemia, and edema [5,9]. Nephrotic syndrome requires a nephrologist's evaluation [9,17]. Systemic diseases that affect the kidneys are secondary causes of nephrotic syndrome. Diabetes is the leading secondary cause of nephrotic syndrome and accounts for more than 50% of all cases [2,18].

Another important consideration is whether the proteinuria is persistent or transient [2]. Transient proteinuria secondary to an identifiable cause (e.g., exercise, fever, congestive heart failure) in an otherwise healthy patient may be classified as functional proteinuria and does not require further testing or evaluation [2,8]. Persistent proteinuria that cannot be classified as functional proteinuria requires further investigation, beginning with a 24-hour measurement of urine protein and creatinine clearance to determine the urinary protein excretion and the protein/creatinine ratio [5,17]. If the excretion rate is 3.5 g/day or more, the patient by definition has nephrotic syndrome, which is usually accompanied by hypoalbuminemia, hyperlipidemia, and edema [5,9]. Nephrotic syndrome requires a nephrologist's evaluation [9,17]. Systemic diseases that affect the kidneys are secondary causes of nephrotic syndrome. Diabetes is the leading secondary cause of nephrotic syndrome and accounts for more than 50% of all cases [2,18].

If the 24-hour urinary protein excretion rate is less than 3.5 g/day, patients should be classified by their level of renal function (i.e., normal or abnormal). Proteinuria in the presence of normal renal function is referred to as isolated proteinuria. In these patients, the next step is to determine whether the proteinuria is orthostatic or nonorthostatic [2]. Urinary protein excretion can increase after prolonged standing, so three early-morning voids should be checked for protein. If all the results are negative, a diagnosis of orthostatic proteinuria can be made, and no further diagnostic tests are necessary [2]. However, these patients may benefit from referral to a renal specialist, as the condition is poorly understood, although generally benign and self-limited [2,8,17].

Medications to decrease proteinuria may be prescribed. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) have been found to reduce proteinuria, most likely by decreasing intraglomerular pressure [2,9,19,20]. Additionally, ACE inhibitors reduce the rate of deterioration of renal function in patients with diabetic and nondiabetic renal disease associated with proteinuria. ARBs protect renal function and delay the onset of ESRD [9]. Calcium channel antagonists (e.g., diltiazem, nifedipine) may help to reduce proteinuria [9].

Patients most commonly notice edema as the first symptom of nephrotic syndrome [1]. Peripheral and facial edema, weight gain (from fluid retention), and abdominal ascites may be present. Most symptoms are the result of hypoalbuminemia. While patients may only notice the presence of edema, hypoalbuminemia has effects on many systems [18]. Complications can include impaired renal function, increased platelet aggregation, hyperlipidemia, increased drug toxicity, and abnormalities in blood volume [1,21].

Pre-eclampsia is defined as proteinuria greater than or equal to 300 mg in a 24-hour urine specimen, a protein/creatinine ratio of 0.3 mg/dL or higher, or a urine dipstick protein of 1+ and hypertension (systolic blood pressure greater than 140 mm Hg or diastolic blood pressure greater than 90 mm Hg) after 20 weeks' gestation in a woman who was normotensive before 20 weeks' gestation [30,31]. Higher rates of proteinuria are indicative of more severe disease [31]. Pre-eclampsia affects 2% to 6% of all pregnancies and is a leading cause of maternal death [30,31]. The global incidence of pre-eclampsia has been estimated at 5% to 14% of all pregnancies [31]. Risk factors include advanced maternal age (older than 35 years), pre-existing hypertension or renal disease, obesity, diabetes, urinary tract infection, and multiple pregnancy. All patients should be screened for pre-eclampsia and treated immediately [1,31]. The only cure is delivery, and worsening pre-eclampsia may necessitate early delivery [31]. Up to 16% of all eclamptic seizures actually occur more than 48 hours after delivery, so clinicians should be alert to symptoms of impending eclampsia, including headache, visual disturbances, abdominal pain, and increasing edema.

Hematuria is generally defined as more than three red blood cells (RBCs) per high-powered field (HPF) [32]. Transient hematuria is hematuria that occurs on one occasion, whereas persistent hematuria is present on two or more consecutive tests [2,10]. Exercise-induced hematuria in healthy young adults is not associated with any known morbidity or mortality, but both transient and persistent hematuria can be signs of serious disease (Table 3).

Hematuria is generally defined as more than three red blood cells (RBCs) per high-powered field (HPF) [32]. Transient hematuria is hematuria that occurs on one occasion, whereas persistent hematuria is present on two or more consecutive tests [2,10]. Exercise-induced hematuria in healthy young adults is not associated with any known morbidity or mortality, but both transient and persistent hematuria can be signs of serious disease (Table 3).

Hematuria is often accompanied by clinically significant symptoms or by abnormalities in the urinalysis that can aid in identifying the source of bleeding. The patient's age, gender, and level of physical activity should always be considered. A high level of exercise is considered a risk factor, and long-distance runners have been documented to have rates of hematuria as high as 18% [6]. Hematuria with pyuria suggests an infectious process, whereas colicky flank pain suggests pain originating from a ureter [6]. A prostatic or urethral source is likely when bleeding occurs only at the beginning or end of micturition [5,25]. The combination of hemoptysis, acute renal failure, and hematuria is highly suggestive of Goodpasture syndrome, a rare autoimmune disease affecting the lungs and kidneys [38]. Glomerulonephritis is signified by hematuria accompanied by edema, hypertension, and a sore throat or skin infection, although many patients do not report any recent signs or symptoms of infection [37,39,40].

Causes of hematuria can be categorized as glomerular, renal (i.e., nonglomerular), or urologic. Glomerular hematuria is typically associated with significant proteinuria, erythrocyte casts, and dysmorphic RBCs [40]. However, 20% of patients with biopsy-proven glomerulonephritis present with hematuria alone [10]. Immunoglobulin A nephropathy (Berger disease) is the most common cause of glomerular hematuria [10,40]. Nonglomerular or renal hematuria is due to tubulointerstitial, renovascular, or metabolic disorders. There is often co-existing proteinuria but no dysmorphic RBCs or erythrocyte casts [40]. The evaluation of glomerular and nonglomerular hematuria requires an assessment of renal function and 24-hour urine or spot urinary protein/creatinine ratio. Urologic causes of nonglomerular hematuria include tumors, calculi, and infections. This etiology is distinguished from other types of hematuria by the absence of proteinuria, dysmorphic RBCs, and erythrocyte casts [40]. Up to 20% of older patients with gross hematuria have a urinary tract malignancy, so a full workup, including cystoscopy and imaging of the upper urinary tract, should be completed in patients with hematuria of suspected urologic origin [10]. Despite this recommendation, studies have found that only 18% of patients presenting with hematuria undergo proper evaluation. African American patients are less likely than white patients to undergo any aspect of evaluation, and women are less likely to be referred to a urologist than men [43,44].

Isolated, transient hematuria and hematuria related to a urinary tract infection do not require urology consultation. However, referral to a renal or urology specialist is indicated to evaluate other causes of hematuria. Patients with large amounts of frank hematuria, severe flank pain suggestive of renal calculi, unstable vital signs, signs of urologic obstruction, or acute renal failure should be referred for urgent evaluation and possible hospitalization.

Nephritic syndrome, not to be confused with nephrotic syndrome, is an inflammation of the kidneys that causes damage to the podocytes, one of the structures in the glomeruli [53]. The damage causes holes in the podocytes large enough for RBCs to pass through, resulting in hematuria. Nephritic syndrome often results in proteinuria, but usually at rates lower than those seen in nephrotic syndrome. In addition, the presence of RBCs differentiates nephritic syndrome from nephrotic syndrome (proteinuria in the absence hematuria). One of the most common causes of nephritic syndrome in adults is systemic lupus erythematosus (SLE) [53].

Early detection of lupus nephritis should begin with frequent outpatient visits for all lupus patients (including those with no current symptoms) and dipstick analysis of urine at all patient visits, with special emphasis on patients with known risk factors for development of lupus nephritis and patients at increased risk for ESRD [55]. Race may be one of these risk factors. SLE is most common in African American and Hispanic individuals; severe lupus nephritis is more common in African American and Asian patients than in any other ethnic group [54,55]. Other risk factors for progression of lupus nephritis include genetic predisposition, lower socioeconomic status, elevated serum creatinine, and failure to achieve remission. Early detection is associated with improved outcomes and may help to provide better access to available treatments [55].

While mild lupus with arthritis symptoms may be treated with NSAIDs or hydroxychloroquine, lupus nephritis is life-threatening and demands a rapid response. Referral to a rheumatologist is essential. Unfortunately, high-dose corticosteroid treatment often results in multiple side effects, and patient adherence may suffer as a result. Patients may experience weight gain, steroid-induced diabetes, osteoporosis, cataracts, and psychiatric side effects including mania, psychosis, and depression.