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 g/min in males and 1.1-21.9 g/min in females. Microalbuminuria is referred to as excretion of 30-300 mg/d or 20-200 g/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.

Recent studies
In a study of 225 proteinuric patients with diabetes mellitus type 2, Chiu et al investigated whether 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. Eighty-six percent of the study's patients were found to have coronary artery calcification, the degree of which, the authors determined, was associated with older age, white ethnicity, and being male. (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.[1]

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

Epidemiology
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 interstitium[2] 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 proteinmediated 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 urinaryto-creatinine ratios (UACRs) in persons with heart failure.[3] 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. In a study by Friedman et al, nondiabetic chronic kidney disease was found to occur in more than 3 million African Americans who have 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 similar risk for developing nondiabetic chronic kidney disease as European Americans.[4]

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.

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) o This is not indicative of significant underlying renal disease. o Proteinuria disappears upon repeat testing.

Orthostatic proteinuria (ie, tall thin adolescents or adults younger than 30 y, may be associated with severe lordosis) o Renal function is normal and proteinuria usually is less than 1 g/d. o Overnight urine collection shows normal protein excretion (ie, < 50 mg during 8h period). Persistent proteinuria due to extrarenal disease o 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. o 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: o Active urine sediment (dysmorphic red blood cells and red cell casts) o Hypoalbuminemia o Lipiduria o Edema o Abnormal renal function o Hyperlipidemia o 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) o Immunoglobulin A nephropathy o Membranoproliferative glomerulonephritis o Mesangial proliferative glomerulonephritis Primary glomerular diseases associated with bland urine sediment (nonproliferative glomerulonephritis) [5] o Membranous glomerulonephritis o Minimal-change disease o Primary focal segmental glomerulosclerosis (FSGS) o Fibrillary glomerulonephritis o Immunotactoid glomerulonephritis Secondary glomerular diseases associated with active urine sediment (proliferative glomerulonephritis, including rapidly progressive glomerulonephritis) o Anti-GBM disease o Renal vasculitis, including disease associated with antineutrophil cytoplasmic antibodies (ANCA) (eg, Wegener granulomatosis) [6] o Lupus nephritis o Cryoglobulinemia-associated glomerulonephritis o Bacterial endocarditis o Henoch-Schnlein purpura o 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) o Diabetic nephropathy o Amyloidosis o Hypertensive nephrosclerosis o Light-chain disease from multiple myeloma o Secondary focal glomerulosclerosis Secondary focal glomerulosclerosis may result from the following: o The healing phase of other glomerulonephritides o As a nonspecific result of reduced nephron mass from any cause, including nonglomerular diseases, such as reflux nephropathy o 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.

Laboratory Studies

To determine whether patients have transient proteinuria, perform the following: o Urinalysis and microscopic examination on at least 3 separate occasions [7, 8] o Albumin-to-creatinine or protein-to-creatinine ratio in random urine sample o Urinalysis on early morning sample, before patients are involved in physical activity To determine whether patients have orthostatic proteinuria, perform the following: o Urine microscopy o Split urine collection, daytime (7 am to 11 pm) and overnight (11 pm to 7 am) To determine whether proteinuria may be glomerular in origin, perform the following: o Urine microscopy o Urine collection (24 h) for quantification of albumin (or protein) excretion and creatinine clearance o Serum creatinine, albumin, cholesterol, and blood glucose determinations o If indicated, autoantibodies determinations, including antinuclear (ANA), antiDNA, complement levels, and cryoglobulins o If indicated, hepatitis B, hepatitis C, and HIV serologies o If indicated, urine and plasma protein electrophoresis

Imaging Studies

Renal ultrasound scan, if glomerular disease is being considered Chest x-ray, if indicated

Other Tests

Renal biopsy should be considered in adult patients with persistent proteinuria because the diagnostic and prognostic information yielded is likely to guide the choice of specific therapy (see Medical Care). o In children, most cases of nephrotic syndrome are due to steroid-sensitive minimal-change disease. In such cases, this is a reasonable assumption, and a trial of therapy should be given, reserving biopsy for unresponsive cases. o In adult patients who have isolated proteinuria of less than 1 g/d with no other indicators of renal disease, the renal prognosis is good and the need for specific treatment is unlikely. Most nephrologists would treat these patients with the nonspecific measures detailed in Medical Care and only proceed to biopsy if the degree of proteinuria increased or if the patient developed progressive renal decline.

Medical Care
Evaluation normally is conducted on an outpatient basis unless the patient develops a complication of severe nephrotic syndrome. All patients with evidence of glomerular disease or any reduction in renal function should be referred to a nephrologist.

Medical care can be considered as having 2 components as follows: o Nonspecific treatment that is applicable irrespective of the underlying cause, assuming the patient has no contraindications to the therapy o Specific treatment that depends on the underlying renal or nonrenal cause Nonspecific treatment o The degree of proteinuria depends on the integrity of the GCW (charge and size selectivity) and the intraglomerular pressure. Intraglomerular pressure is controlled by both the afferent arteriole, which transmits systemic blood pressure to the glomerulus, and the efferent arteriole. [9] o Normalization of systemic blood pressure in a patient with hypertension should result in a reduction in intraglomerular pressure and a fall in albuminuria. o Some vasodilatory antihypertensives (eg, hydralazine and nifedipine) dilate the afferent arteriole, which may attenuate the reduction in intraglomerular pressure despite the fall in arterial blood pressure. o As a consequence, these agents may not reduce proteinuria to the same degree, particularly if systemic blood pressure is not adequately reduced at the same time the afferent arteriole is dilated. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor antagonists (AT1-ra) reduce intraglomerular pressure by inhibiting angiotensinII-mediated efferent arteriolar vasoconstriction. o These groups of drugs have a proteinuria-reducing effect independent of their antihypertensive effect. o Other hemodynamic and nonhemodynamic effects of ACEIs may partly explain the renoprotective properties of this group of drugs, such as reduced breakdown

o o

o o

of bradykinin (an efferent arteriolar vasodilator), restoration of size and charge selectivity to the GCW, and reduced production of cytokines that promote glomerulosclerosis and fibrosis, such as TGF-beta. Target blood pressure is less than 125/75 mm Hg. The dose of ACEI should be increased as tolerated until this blood pressure is achieved. Normotensive patients with proteinuria also should be given ACEIs because low doses usually are well tolerated and do not usually cause symptomatic hypotension. Patients who develop adverse effects from ACEIs, such as cough, should be given an AT1-ra. Patients also may develop angioedema due to the increase in bradykinin levels that accompany the use of ACEIs. This adverse effect also warrants cessation of treatment. An AT1-ra may be used instead. Patients with mild hyperkalemia should receive dietary counseling. Those with significant hyperkalemia should have the medication immediately discontinued and should be administered a potassium-binding resin. Patients with edema should have salt and water restrictions (see Diet). Patients with fluid overload should be treated with diuretics. The use of diuretics in patients with nephrotic syndrome requires careful attention because patients may be refractory to normal doses of diuretics due to reduced delivery to the renal tubule (reduced albumin transport). Use a combination of diuretics acting at different sites of the nephron (eg, loop diuretic thiazide spironolactone). These patients, at the same time, may have intravascular volume depletion and, as a consequence, may be at risk of acute renal failure due to exacerbation of volume depletion. The routine use of albumin infusion combined with diuretics is not advocated in patients with nephrotic syndrome. Most patients diurese with a loop diuretic or a combination of diuretics. The addition of albumin may improve natriuresis in patients with refractory salt and water retention, but the potential benefits must be offset against cost and risks of albumin infusion, including the possibility of exacerbating fluid overload. No evidence-based recommendations are available for the treatment of hyperlipidemia associated with nephrotic syndrome, and, as such, this is a controversial topic. The lipid abnormalities in these patients usually are not responsive to dietary measures. In patients in whom proteinuria is reduced, by specific or nonspecific treatment, dyslipidemia usually improves. In patients with persistent proteinuria and lipid abnormalities, many nephrologists now treat the secondary lipid abnormalities, particularly if these patients have other risk factors for vascular disease. Unfortunately, patients with severe nephrotic syndrome frequently are only partially responsive to lipid-lowering agents (eg, statin group).[10] Recommendations on anticoagulation for patients with nephrotic syndrome also are not evidence-based and are equally controversial. Due to urinary losses associated with coagulation inhibitors, such as antithrombin III and protein S and C, these patients are hypercoagulable.

The risk of thrombosis appears highest in patients with membranous glomerulonephritis. Numerous case reports have been published pertaining to the development of renal vein thrombosis (usually presents as acute onset of gross hematuria and back pain) in patients with membranous glomerulonephritis. While some nephrologists advocate treating patients with Coumadin, most do not prophylactically anticoagulate these patients unless the patients have a second risk factor for venous thrombosis, such as immobility. Some nephrologists recommend the use of heparin (5000 U subcutaneously bid) as prophylactic anticoagulation in those patients with serum albumin levels of less than 2.5 mg/dL. o Patients with nephrotic syndrome are at increased risk of infection. The risk is greatest for bacterial infection (including spontaneous bacterial peritonitis) due to renal losses of immunoglobulin and complement components. No data, however, advocates the routine use of prophylactic antibiotics or immunoglobulin infusions. Specific treatment o This depends on the nature of the underlying glomerular injury and, in particular, whether or not the injury is immune mediated. o For details on specific treatment for the various glomerular diseases, see the relevant eMedicine articles.

Consultations

Nephrologist

Diet

Patients with nephrotic syndrome and fluid overload should have a salt-restricted diet. A "no-added-salt" diet usually is sufficient, although some patients may need restrictions of up to 40 mmol/d. Vegter et al found that for nondiabetic patients with chronic kidney disease, high dietary salt (>14 g daily) appeared to blunt the antiproteinuric effect of ACE inhibitor therapy and increase the risk for end-stage renal disease (ESRD), independent of blood pressure control.[11] The issue of dietary protein restrictions is controversial. o Evidence exists that indicates a protein restriction may slow down the rate of deterioration in the GFR in patients with glomerular diseases, including diabetic nephropathy. The presumed mechanism is a reduction in intraglomerular pressure. o However, concern exists that protein-restricted diets may increase the risk of protein malnutrition, and other methods of reducing intraglomerular pressure, such as the use of ACEIs, may be safer than protein restriction. o Most nephrologists recommend no restrictions or mild restriction in protein intake (0.8-1 g/kg/d). The role of cholesterol restriction is discussed in Medical Care.

Medication Summary

ACEIs are effective therapy for the reduction of proteinuria, regardless of whether it is associated with arterial hypertension.[12]

ACE inhibitors
Class Summary
Reduce intraglomerular pressure and may restore size and charge integrity to the GCW. They also reduce level of profibrotic cytokines. ACEIs reduce proteinuria and also reduce rate of deterioration of renal function in patients with diabetic and nondiabetic renal disease associated with proteinuria. View full drug information

Lisinopril (Zestril, Prinivil)

Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion. Target blood pressure is < 125/75 mm Hg in patients with proteinuria of > 1 g/d. Patients who develop a cough, angioedema, bronchospasm, or other hypersensitivity reactions after starting ACEIs should receive an angiotensin-receptor blocker. View full drug information

Ramipril (Altace)
Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion. View full drug information

Captopril (Capoten)
Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion. View full drug information

Enalapril (Vasotec)
Competitive inhibitor of ACE. Reduces angiotensin II levels, decreasing aldosterone secretion.

Angiotensin II receptor antagonists

Class Summary
Reduce intraglomerular pressure and may restore size and charge integrity to the GCW. They also reduce level of profibrotic cytokines. ACEIs reduce proteinuria and also reduce rate of deterioration of renal function in patients with diabetic and nondiabetic renal disease associated with proteinuria. View full drug information

Candesartan (Atacand)
Blocks vasoconstriction and aldosterone-secreting effects of angiotensin II. May induce more complete inhibition of renin-angiotensin system than ACE inhibitors, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema. Use in patients unable to tolerate ACE inhibitors.

Angiotensin II receptor blockers reduce blood pressure and proteinuria, protecting renal function and delaying onset of end-stage renal disease. View full drug information

Eprosartan (Teveten)
Nonpeptide angiotensin II receptor antagonist that blocks vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce more complete inhibition of renin-angiotensin system than ACE inhibitors, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors. Angiotensin II receptor blockers reduce blood pressure and proteinuria, protecting renal function and delaying onset of end-stage renal disease. View full drug information

Irbesartan (Avapro)
Blocks vasoconstrictor and aldosterone-secreting effects of angiotensin II at tissue receptor site. May induce more complete inhibition of renin-angiotensin system than ACE inhibitors, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema. View full drug information

Losartan (Cozaar)
Angiotensin II receptor antagonist that blocks the vasoconstrictor and aldosteronesecreting effects of angiotensin II. May induce a more complete inhibition of the reninangiotensin system than ACE inhibitors, does not affect the response to bradykinin, and is less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors. View full drug information

Olmesartan (Benicar)
Blocks vasoconstrictor effects of angiotensin II by selectively blocking binding of angiotensin II to AT-1 receptor in vascular smooth muscle. Action is independent of pathways for angiotensin II synthesis. View full drug information

Valsartan (Diovan)
Prodrug that produces direct antagonism of angiotensin II receptors. Displaces angiotensin II from AT1 receptor and may lower blood pressure by antagonizing AT1induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses. May induce more complete inhibition of renin-angiotensin system than ACE inhibitors, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema. For use in patients unable to tolerate ACE inhibitors.

Non-dihydropyridine calcium channel antagonists

Class Summary

May help reduce proteinuria. View full drug information

Diltiazem (Cardizem, Dilacor)

During depolarization, inhibits the influx of extracellular calcium across myocardial and vascular smooth muscle cell membranes. Serum calcium levels remain unchanged. The resultant decrease in intracellular calcium inhibits the contractile processes of myocardial smooth muscle cells, resulting in dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue. Decreases conduction velocity in AV node. Also increases refractory period via blockade of calcium influx. This, in turn, stops reentrant phenomenon. Decreases myocardial oxygen demand by reducing peripheral vascular resistance, reducing heart rate by slowing conduction through SA and AV nodes, and reducing LV inotropy. Slows AV nodal conduction time and prolongs AV nodal refractory period, which may convert SVT or slow the rate in atrial fibrillation. Also has vasodilator activity but may be less potent than other agents. Total peripheral resistance, systemic blood pressure, and afterload are decreased. Calcium channel blockers provide control of hypertension associated with less impairment of function of the ischemic kidney. Calcium channel blockers may have beneficial long-term effects, but this remains uncertain. Proteinuria reducing properties noted in patients with well-controlled hypertension.

Further Inpatient Care

Inpatient care is necessary only if the patient develops complications of severe nephrotic syndrome.

Further Outpatient Care

Patients may require regular follow-up care by a family physician, general internal medicine specialist, or nephrologist, depending on the cause and setting of proteinuria. Monitoring of proteinuria, the presence or absence of other indicators of renal disease, complications of nephrotic syndrome, treatment effectiveness, and adverse effects is required.

Transfer

If patients are not monitored by a nephrologist, transfer to a nephrologist is indicated if the patient develops proteinuria, any adverse prognostic markers (eg, rise in albumin excretion of > 1 g/d), or any worsening in renal function.

Complications

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

Prognosis

The prognosis depends on the cause, duration, and degree of proteinuria. Young adults with transient or orthostatic proteinuria have a benign prognosis. Patients with hypertension and microalbuminuria (or higher degrees of albuminuria) have a significantly increased risk of cardiovascular disease.