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Overview of heavy proteinuria and the nephrotic syndrome

Overview of heavy proteinuria and the nephrotic syndrome
Authors:
Ellie Kelepouris, MD, FAHA
Brad H Rovin, MD
Section Editor:
Richard J Glassock, MD, MACP
Deputy Editor:
Albert Q Lam, MD
Literature review current through: Dec 2022. | This topic last updated: Sep 14, 2022.

INTRODUCTION — Diseases of the glomerulus can result in two different urinary and clinical patterns: nephritic and nephrotic. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)

Nephritic – Disorders resulting in a nephritic sediment are generally associated with inflammatory lesions of the glomeruli on light microscopy. These lesions can be focal or diffuse. In focal lesions (focal glomerulonephritis), the urinalysis reveals red cells (which often have a dysmorphic appearance), occasionally red cell casts, and mild proteinuria (usually less than 1.5 g/day). These patients often present with asymptomatic hematuria and proteinuria discovered on routine examination or, occasionally, with episodes of gross hematuria. Diffuse lesions (diffuse glomerulonephritis) occur in more advanced disease, which usually presents with heavy proteinuria (which may be in the nephrotic range), edema, hypertension, and kidney function impairment. The urinalysis in diffuse glomerulonephritis is similar to that in focal disease.

Nephrotic – The nephrotic sediment is associated with heavy proteinuria and lipiduria, but few cells or casts, and is typically considered bland. The term "nephrotic syndrome" refers to a distinct constellation of clinical and laboratory features of kidney disease. It is specifically defined by the presence of heavy proteinuria (protein excretion greater than 3.5 g/24 hours), hypoalbuminemia (less than 3.5 g/dL), and peripheral edema. Hyperlipidemia and thrombotic disease are also frequently observed.

Isolated heavy proteinuria without edema or other features of the nephrotic syndrome is suggestive of a glomerulopathy (with the same etiologies as the nephrotic syndrome) but is not necessarily associated with the multiple clinical and management problems characteristic of the nephrotic syndrome. This is an important clinical distinction because heavy proteinuria in patients without edema or hypoalbuminemia is more likely to be due to secondary focal segmental glomerulosclerosis (FSGS) (due, for example, to diabetes) [1].

This topic review will provide an overview of heavy proteinuria and the nephrotic syndrome, with emphasis on those disorders with a nephrotic as opposed to a nephritic presentation. More specific issues relating to complications of the nephrotic syndrome are presented elsewhere:

(See "Pathophysiology and treatment of edema in adults with the nephrotic syndrome".)

(See "Hypercoagulability in nephrotic syndrome".)

(See "Endocrine dysfunction in the nephrotic syndrome".)

(See "Lipid abnormalities in nephrotic syndrome".)

(See "Acute kidney injury (AKI) in minimal change disease and other forms of nephrotic syndrome".)

The individual disorders that cause the nephrotic syndrome are discussed in detail in separate topic reviews. Readers will be referred to these individual topics where appropriate.

ETIOLOGY — Heavy proteinuria with or without the nephrotic syndrome may occur in association with a wide variety of primary and systemic diseases. Minimal change disease is the predominant cause in children. In adults, approximately 30 percent have a systemic disease such as diabetes mellitus, amyloidosis, or systemic lupus erythematosus; the remaining cases are usually due to primary kidney disorders such as minimal change disease, focal segmental glomerulosclerosis (FSGS), and membranous nephropathy [2-9]. Amyloidosis is another common cause of the nephrotic syndrome, particularly among older adults. The nephrotic syndrome can also develop in patients with postinfectious and infection-associated glomerulonephritis, glomerulonephritis with a membranoproliferative pattern of injury, and immunoglobulin A (IgA) nephropathy. However, these individuals typically have a "nephritic" type of urinalysis with hematuria and cellular (including red cell) casts as a prominent feature. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)

The etiology of nephrotic syndrome varies by race, ethnicity, and geographic region:

In a single center study of 3275 native kidney biopsies performed in northern India between 2006 and 2016, there were 1974 cases of the nephrotic syndrome [10]. Minimal change disease was the most common cause (22.4 percent), followed by membranous nephropathy (22.4 percent) and FSGS (21.5 percent).

In another study of over 34,000 patients who underwent a native kidney biopsy in central China between 2009 and 2018, among the 17,938 biopsies in patients with the nephrotic syndrome, 38 percent had a diagnosis of membranous nephropathy, 20 percent had minimal change disease, 11 percent had IgA nephropathy, 6 percent had lupus nephritis, and only 3.4 percent had FSGS [11]. Similar findings were reported in another large biopsy series from northeast China [12].

In a study of a diverse population of 2501 patients from California who had primary glomerulopathy identified on native kidney biopsy, the most common lesion was FSGS (40 percent), followed by membranous nephropathy (13 percent), minimal change disease (11 percent), and IgA nephropathy (10 percent) [13]. Over the 12 years between 2000 and 2011, the case rates of FSGS and IgA nephropathy increased, while the rates of membranous nephropathy and minimal change disease remained stable. Other studies have also suggested that the prevalence of FSGS appears to be increasing worldwide [14].

Minimal change disease — Minimal change disease (also called nil disease or lipoid nephrosis) accounts for 90 percent of cases of the nephrotic syndrome in children under the age of 10 years, and more than 50 percent of cases in older children. It also may occur in adults as an idiopathic condition, in association with the use of nonsteroidal antiinflammatory drugs (NSAIDs), or as a paraneoplastic effect of malignancy, most often Hodgkin lymphoma. (See "Minimal change disease: Etiology, clinical features, and diagnosis in adults".)

The terms "minimal change" and "nil disease" reflect the observation that light microscopy in this disorder is either normal or reveals only mild mesangial cell proliferation (picture 1). Immunofluorescence and light microscopy typically show no evidence of immune complex deposition. The characteristic histologic finding in minimal change disease is diffuse effacement of the epithelial cell foot processes on electron microscopy.

Focal segmental glomerulosclerosis — Focal segmental glomerulosclerosis (FSGS) is among the most common lesions found to underlie the idiopathic nephrotic syndrome in adults, accounting for 39 percent of all cases in the United States and over 50 percent of cases among Black patients. FSGS is not a single disease but a specific histologic pattern of kidney injury that is characterized on light microscopy by the presence in some but not all glomeruli (hence the name focal) of segmental areas of mesangial collapse and sclerosis [15]. FSGS can present as an idiopathic syndrome (primary FSGS) or may be associated with HIV infection, reflux nephropathy, healed previous glomerular injury, or massive obesity.

Diagnostic issues — There are three important diagnostic concerns in FSGS:

Sampling error

Distinguishing primary and secondary FSGS

Identifying FSGS associated with collapsing glomerulopathy

Sampling error can easily lead to misclassification of a patient with FSGS as having minimal change disease. Clinical features that are more common in FSGS are hematuria, hypertension, and decreased kidney function. There is, however, substantial overlap in these features. In addition to careful review of the kidney biopsy, glucocorticoid resistance in a patient considered to have minimal change disease should raise suspicion about FSGS. (See "Minimal change disease: Etiology, clinical features, and diagnosis in adults".)

Primary FSGS is a disorder of the podocyte (a podocytopathy); congenital forms also exist. In addition, as noted above, FSGS can occur as a secondary response to nephron loss (as is reflux nephropathy) or previous glomerular injury. Differentiating primary and secondary FSGS has important therapeutic implications. The former sometimes responds to immunosuppressive agents such as glucocorticoids while secondary disease is best treated with modalities aimed at lowering the intraglomerular pressure, such as angiotensin-converting enzyme (ACE) inhibitors, and addressing the underlying cause of the secondary FSGS, if it can be identified (eg, weight reduction in patients with obesity). (See "Focal segmental glomerulosclerosis: Genetic causes" and "Focal segmental glomerulosclerosis: Pathogenesis" and "Focal segmental glomerulosclerosis: Treatment and prognosis".)

The distinction between primary and secondary FSGS can sometimes be made from the history (such as one of the disorders associated with secondary disease) and the rate of onset and degree of proteinuria. Patients with primary FSGS typically present with the acute onset of the nephrotic syndrome and diffuse podocyte foot process effacement, whereas slowly increasing proteinuria, kidney function impairment over time, and segmental podocyte foot process effacement are characteristic of the secondary disorders. The proteinuria in secondary FSGS is often non-nephrotic; even when protein excretion exceeds 3 to 4 g/day, both hypoalbuminemia and edema are unusual. (See "Focal segmental glomerulosclerosis: Epidemiology, classification, clinical features, and diagnosis", section on 'Clinical features'.)

Collapsing FSGS is a histologic variant that can be associated with HIV infection, bisphosphonate therapy, or systemic lupus erythematosus. Two major features distinguish it from primary FSGS: a tendency toward collapse and sclerosis of the entire glomerular tuft, rather than segmental injury; and often severe tubular injury with proliferative microcyst formation and tubular degeneration (picture 2A-B). These patients often have rapidly progressive kidney failure. (See "HIV-associated nephropathy (HIVAN)" and "Collapsing focal segmental glomerulosclerosis not associated with HIV infection".)

Membranous nephropathy — Membranous nephropathy is the leading cause of primary nephrotic syndrome in White adults. It is characterized by basement membrane thickening with little or no cellular proliferation or infiltration, and the presence of electron dense deposits across the glomerular basement membrane (picture 3A-F). (See "Membranous nephropathy: Clinical manifestations and diagnosis" and "Membranous nephropathy: Clinical manifestations and diagnosis", section on 'Pathology'.)

Membranous nephropathy is most often a primary (idiopathic) disorder in adults and a secondary disorder in children. Most cases of primary membranous nephropathy are due to autoantibodies directed against the phospholipase A2 receptor (PLA2R) found on podocytes. A number of other antigens have been found to be associated with membranous nephropathy, and, in some cases, circulating autoantibodies have been identified [16]. Secondary causes include hepatitis B antigenemia, autoimmune diseases (eg, systemic lupus erythematosus), thyroiditis, carcinoma, and the use of certain drugs such as NSAIDs, penicillamine, gold, and captopril. The underlying malignancy in presumed tumor-induced membranous nephropathy usually has been diagnosed but may not always be clinically apparent at the time that proteinuria is discovered. (See "Membranous nephropathy: Pathogenesis and etiology", section on 'Phospholipase A2 receptor' and "Membranous nephropathy: Pathogenesis and etiology", section on 'Secondary MN'.)

Amyloidosis — Amyloidosis accounts for 4 to 17 percent of cases of seemingly idiopathic nephrotic syndrome, with an increased frequency observed among older individuals [2,3]. There are two major types of renal amyloidosis: AL or primary amyloid, which is a light chain dyscrasia in which fragments of monoclonal light chains form the amyloid fibrils; and AA or secondary amyloidosis, in which the acute phase reactant serum amyloid A forms the amyloid fibrils. AA amyloid is associated with a chronic inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, or chronic osteomyelitis. More recently, through the use of laser capture microdissection of glomeruli from kidney biopsies followed by proteomic analysis of the tissue, several additional forms of renal amyloidosis have been identified [17]. (See "Renal amyloidosis".)

The diagnosis is suspected by a history of a chronic inflammatory disease or, with primary disease, detection of a monoclonal paraprotein in the serum or urine. Diagnosis should be confirmed, if possible, using specific identification of the amyloid protein with mass spectrometry of the biopsy tissue [17]. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis" and "Causes and diagnosis of AA amyloidosis and relation to rheumatic diseases".)

PATHOPHYSIOLOGY

Proteinuria — There are three basic types of proteinuria: glomerular, tubular, and overflow. (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults".)

In the nephrotic syndrome, protein loss is due to glomerular proteinuria, characterized by increased filtration of macromolecules across the glomerular capillary wall. Electrical potential differences generated by transglomerular flow may modulate the flux of macromolecules across the glomerular capillary wall [18], although other theories exist for the mechanism of glomerular proteinuria.

The podocyte appears to be the major target of injury in diseases that cause idiopathic nephrotic syndrome in adults and children (membranous nephropathy, minimal change disease, and focal segmental glomerulosclerosis [FSGS]), as illustrated by the following observations:

The common ultrastructural phenotype seen in these diseases is podocyte foot process effacement, slit diaphragm disruption, and a relative or absolute depletion of podocytes [19-21].

Hereditary podocyte injury (eg, in patients with congenital nephrotic syndrome) is due to mutations of podocyte proteins that are important in the maintenance of the slit diaphragm such as nephrin and podocin, or mutations in proteins that affect the integrity of the podocyte cytoskeleton such as alpha-actinin-4 [21]. (See "Congenital and infantile nephrotic syndrome".)

Adult-onset primary membranous nephropathy and FSGS may be due to autoantibodies to podocyte antigens or circulating factors that affect the podocyte. The engagement or activation of these podocyte proteins alters the arrangement of the slit diaphragm or podocyte cytoskeleton. (See "Membranous nephropathy: Pathogenesis and etiology", section on 'Pathogenesis'.)

In patients with nephrotic syndrome, albumin is the principal urinary protein, but other plasma proteins including clotting inhibitors, transferrin, immunoglobulins, and hormone carrying proteins such as vitamin D-binding protein may be lost as well. (See "Hypercoagulability in nephrotic syndrome" and "Endocrine dysfunction in the nephrotic syndrome" and "Lipid abnormalities in nephrotic syndrome".)

Hypoalbuminemia — The mechanism of hypoalbuminemia in patients with the nephrotic syndrome is not completely understood. Most of albumin loss is due to urinary excretion [22,23]. However, at the same level of albumin loss, patients with the nephrotic syndrome have a plasma albumin concentration that is approximately 1 g/dL (10 g/L) lower than patients treated with continuous ambulatory peritoneal dialysis, in which there is significant albumin loss in the dialysate (figure 1). One proposed explanation is that, in patients with nephrotic syndrome, a substantial fraction of the filtered albumin is taken up by and catabolized in the proximal tubular cells, resulting in a much greater degree of albumin loss than estimated from the rate of albumin excretion, although this hypothesis is controversial [22,23].

Hepatic albumin synthesis does increase in response to the albumin loss. This effect is mediated by an increase in hepatic albumin gene expression [24] stimulated in part by the low oncotic pressure [25]. Hypoalbuminemia may also lead to the release of an as yet unidentified circulating factor that contributes to the elevation in hepatic albumin synthesis [26]. The low oncotic pressure has a second clinically important effect: it increases hepatic lipoprotein synthesis, which plays an important role in the development of hyperlipidemia. (See 'Hyperlipidemia and lipiduria' below and "Lipid abnormalities in nephrotic syndrome".)

It remains unclear why, in a patient excreting 4 to 6 g of protein per day, the liver is usually unable to sufficiently increase albumin synthesis to normalize the plasma albumin concentration. There are patients with nephrotic-range proteinuria who have little or no hypoalbuminemia; these patients are more likely to have one of the secondary forms of FSGS (such as reflux nephropathy) rather than one of the primary nephrotic disorders such as membranous nephropathy, primary FSGS, or minimal change disease [1]. One contributory factor may be the release of cytokines in the latter conditions; tumor necrosis factor and interleukin-1, for example, directly suppress hepatic albumin synthesis [27].

Edema — Two mechanisms have been proposed to explain the occurrence of edema in the nephrotic syndrome. In some patients, marked hypoalbuminemia leads to egress of fluid into the interstitial space by producing a decrease in plasma oncotic pressure. In most patients however, there is a parallel fall in the interstitial protein concentration and little change in the transcapillary oncotic pressure gradient (figure 2). In the latter patients, edema appears to be the consequence of primary renal sodium retention in the collecting tubules (figure 3) mediated through the epithelial sodium channel and the basolateral Na-K-ATPase (figure 4) [28]. The lack of major arterial underfilling has important implications for diuretic therapy since the excess fluid can usually be removed without inducing volume depletion. (See "Pathophysiology and treatment of edema in adults with the nephrotic syndrome".)

Hyperlipidemia and lipiduria — The two most common lipid abnormalities in the nephrotic syndrome are hypercholesterolemia and hypertriglyceridemia. Decreased plasma oncotic pressure appears to stimulate hepatic lipoprotein synthesis resulting in hypercholesterolemia. Diminished clearance may also play a role in the development of hypercholesterolemia. Impaired metabolism is primarily responsible for nephrotic hypertriglyceridemia. (See "Lipid abnormalities in nephrotic syndrome".)

Lipiduria is usually present in the nephrotic syndrome. Urinary lipid may be present in the sediment, entrapped in casts (fatty casts), enclosed by the plasma membrane of degenerative epithelial cells (oval fat bodies), or free in the urine. Under polarized light, the fat droplets have the appearance of a Maltese cross (picture 4A-B). (See "Urinalysis in the diagnosis of kidney disease", section on 'Urinary lipids'.)

COMPLICATIONS — Proteinuria and edema are the principal clinical manifestations of the nephrotic syndrome. Interstitial fluid tends to accumulate in dependent areas where tissue turgor is low. Thus, periorbital edema upon awakening in the morning and pedal edema are common. Edema is often accompanied by serous effusions when it becomes generalized and massive (anasarca).

Less well appreciated manifestations of the nephrotic syndrome include protein malnutrition, hypovolemia, acute kidney injury, urinary loss of hormones, hyperlipidemia and the potential for accelerated atherosclerosis, a tendency to venous or arterial thrombosis, and increased susceptibility to infection [29].

Protein malnutrition — A loss in lean body mass with negative nitrogen balance often occurs in patients with marked proteinuria, although it may be masked by weight gain due to concurrently increasing edema. Protein malnutrition may be compounded by gastrointestinal symptoms of anorexia and vomiting which are secondary to edema of the gastrointestinal tract.

Hypovolemia — Symptomatic hypovolemia can occur in patients with the nephrotic syndrome, often as a result of overdiuresis in those with a serum albumin less than 1.5 g/dL. Occasional untreated children show signs of volume depletion thought to be due to severe hypoalbuminemia causing fluid movement into the interstitium.

Acute kidney injury — Acute kidney injury can develop in some patients with the nephrotic syndrome, particularly in those with profound proteinuria and hypoalbuminemia [30]. The mechanism is not understood; several factors including hypovolemia, interstitial edema, ischemic tubular injury, and the use of nonsteroidal antiinflammatory drugs (NSAIDs) have been suggested. (See "Acute kidney injury (AKI) in minimal change disease and other forms of nephrotic syndrome".)

Two other major settings are collapsing focal segmental glomerulosclerosis, in which the tubular injury is thought to play an important role, and crescentic glomerulonephritis superimposed upon membranous nephropathy, in which the urine sediment becomes active. (See "Collapsing focal segmental glomerulosclerosis not associated with HIV infection" and "Membranous nephropathy: Pathogenesis and etiology", section on 'Crescentic glomerulonephritis'.)

Thromboembolism — Patients with the nephrotic syndrome have an increased incidence (10 to 40 percent of patients) of arterial and venous thrombosis (particularly deep vein and renal vein thrombosis) and pulmonary emboli. Cerebral vein thrombosis has also been rarely reported. The mechanism of the hypercoagulability is not completely understood. (See "Hypercoagulability in nephrotic syndrome".)

Renal vein thrombosis is found disproportionately in patients with membranous nephropathy, particularly those excreting more than 10 g of protein per day [31]. It can present acutely or, much more commonly, in an indolent manner. The acute presentation includes flank pain, gross hematuria, and a decline in kidney function. Most patients are asymptomatic, and the diagnosis of renal vein thrombosis is suspected only when pulmonary thromboembolism develops. (See "Renal vein thrombosis in adults".)

Infection — Patients with the nephrotic syndrome are susceptible to infection, which was the leading cause of death in children with the nephrotic syndrome before antibiotics became available. Infectious complications of nephrotic syndrome include recurrent respiratory tract infections, urinary tract infections, peritonitis, and sepsis, particularly with encapsulated bacteria such as Streptococcus pneumonia. All patients should receive pneumococcal vaccinations. (See "Pneumococcal vaccination in adults".)

Patients with nephrotic syndrome can develop hypogammaglobulinemia due to protein loss, as well as depressed cellular immunity due to loss of vitamin D and other serum factors [29]. Hypogammaglobulinemia may be severe with total immunoglobulin G (IgG) less than 200 mg/dL. Treatment with immunosuppressive drugs, such as glucocorticoids, further increases the risk of infection. (See "Complications of nephrotic syndrome in children", section on 'Infection'.)

Other complications — Proximal tubular dysfunction has been noted in some patients with the nephrotic syndrome, often in association with advanced disease. This can result in glucosuria, aminoaciduria, phosphaturia, bicarbonaturia, and vitamin D deficiency (ie, Fanconi syndrome). A decrease in thyroxine-binding globulins can cause marked changes in various thyroid function tests although patients are clinically euthyroid. Anemia, perhaps due to the urinary loss or impaired synthesis of erythropoietin, has also been described in a few patients [32-34]. (See "Endocrine dysfunction in the nephrotic syndrome".)

DIAGNOSIS

Assessment of proteinuria — Protein excretion can be measured on a 24-hour urine collection, with the normal value being less than 150 mg/day. Patients excreting more than 3.5 g/day are considered to have nephrotic-range proteinuria.

There is an alternative to the 24-hour urine collection: calculating the total protein-to-creatinine ratio (mg/mg) on a random urine specimen [35]. This ratio correlates closely with daily protein excretion in g/1.73 m2 of body surface area. Thus, a ratio of 4.9 (as with respective urinary protein and creatinine concentrations of 210 and 43 mg/dL) represents daily protein excretion of approximately 4.9 g/1.73 m2 (calculator 1). There are limitations to estimating proteinuria from a random urine specimen, particularly in patients whose daily creatinine generation varies substantially from 1000 mg. We prefer to obtain a 24-hour urine collection in most patients during the initial evaluation of proteinuria. (See "Patient education: Collection of a 24-hour urine specimen (Beyond the Basics)" and "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults".)

Once it has been determined that the patient has heavy proteinuria, the etiology may be suggested from the history and physical examination. This is particularly true for patients who have a systemic disease such as diabetes mellitus, systemic lupus erythematosus, HIV infection, or have been taking drugs such as nonsteroidal antiinflammatory drugs (NSAIDs), interferons, bisphosphonates, lithium, gold, or penicillamine. In most cases, however, kidney biopsy is required to establish the diagnosis.

Serologic studies — A number of serologic studies often are obtained in the evaluation of patients with the nephrotic syndrome depending upon clinical setting, including antinuclear antibodies (ANA), complement (C3/C4 and total hemolytic complement), serum protein electrophoresis and immunofixation and serum free light chains, syphilis serology, hepatitis B and hepatitis C serologies, and the measurement of cryoglobulins. The value of all of these tests on a routine basis is uncertain; such tests may be best ordered as suggested by the clinical presentation of the patient [36]. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)

Although serologic tests and hypocomplementemia can suggest the diagnosis of systemic lupus erythematosus, kidney biopsy is still indicated to determine the type of disease that is present. (See "Lupus nephritis: Diagnosis and classification".)

Kidney biopsy — Kidney biopsy is the gold standard procedure for determining the cause of proteinuria. Pediatric nephrologists often use an initial empiric trial of glucocorticoids because of the high incidence of minimal change disease. Most adult nephrologists, however, feel that biopsy is indicated to confirm the diagnosis, to offer prognosis, and to inform management decisions. In one study of 28 adults with nephrotic-range proteinuria, for example, knowledge of the histology altered management in 24 (86 percent). (See "The kidney biopsy".)

TREATMENT — This section will review the general management issues in patients with nephrotic syndrome (ie, proteinuria, edema, hyperlipidemia, and hypercoagulability).

Disease-specific therapy in patients with one of the major causes of primary nephrotic syndrome is discussed separately:

(See "Membranous nephropathy: Treatment and prognosis".)

(See "Focal segmental glomerulosclerosis: Treatment and prognosis".)

(See "Minimal change disease: Treatment in adults".)

(See "Treatment of idiopathic nephrotic syndrome in children".)

(See "Renal amyloidosis".)

(See "IgA nephropathy: Treatment and prognosis".)

Proteinuria — In the absence of specific therapy directed against the underlying disease, efforts to lower intraglomerular pressure should be undertaken. This often decreases protein excretion and slows the rate of disease progression. This is usually achieved by the administration of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blockers (ARBs). Potentially adverse effects of these agents include an acute decline in glomerular filtration rate and hyperkalemia; serum creatinine and potassium levels should be measured during the initiation and titration of these drugs. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers".)

Patients who have chronic kidney disease and proteinuria (with or without diabetes) may also benefit from treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors. (See "Overview of the management of chronic kidney disease in adults", section on 'Patients with proteinuria'.)

Although protein restriction also may slow disease progression, the evidence is unclear and this modality is not usually used in nephrotic patients because of the heavy protein losses. (See "Dietary recommendations for patients with nondialysis chronic kidney disease".)

Edema — Peripheral edema and ascites is due to primary renal sodium retention in most patients and should be treated with dietary sodium restriction (to approximately 2 g of sodium per day) and diuretics. Edema should be reversed slowly to prevent acute hypovolemia. (See "Pathophysiology and treatment of edema in adults with the nephrotic syndrome" and "Patient education: Low-sodium diet (Beyond the Basics)".)

Loop diuretics are usually required. There generally is a lesser natriuresis than seen in normal patients because of hypoalbuminemia (causing decreased delivery of protein bound drug to the kidney) and albuminuria (binding the drug within the tubular lumen). For these reasons, the diuretic dose often has to be increased. Addition of diuretics that act on different nephron segments may also be useful. An important guide for the evaluation of diuretic therapy is serial measurement of body weight. (See "General principles of the treatment of edema in adults" and "Causes and treatment of refractory edema in adults".)

Hyperlipidemia — The lipid abnormalities induced by the nephrotic syndrome reverse with resolution of the disease, as with glucocorticoid therapy in minimal change disease. The optimal treatment of patients with persistent nephrosis is uncertain. Dietary modification is generally of little benefit. Lipid-lowering therapy may be indicated for selected patients, such as those with persistent nephrotic syndrome and hyperlipidemia despite treatment of the underlying kidney disorder. (See "Lipid abnormalities in nephrotic syndrome".)

Hypercoagulability — There is a relatively high incidence of arterial and venous thromboemboli among patients with the nephrotic syndrome; however, this seems to be particularly prevalent in those with membranous nephropathy. If thrombosis occurs, it is typically treated with heparin followed by warfarin for as long as the patient remains nephrotic. The issue of routine prophylactic anticoagulation in patients with nephrotic syndrome is discussed elsewhere. (See "Hypercoagulability in nephrotic syndrome", section on 'Prevention of thromboembolism'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Protein in the urine (proteinuria) (Beyond the Basics)" and "Patient education: The nephrotic syndrome (Beyond the Basics)" and "Patient education: Low-sodium diet (Beyond the Basics)")

SUMMARY

General principles – The nephrotic syndrome is defined by the presence of heavy proteinuria (protein excretion greater than 3.5 g/24 hours in an adult), hypoalbuminemia (less than 3 g/dL), and peripheral edema. Hyperlipidemia and thrombotic disease may be present. (See 'Introduction' above.)

Etiology – The predominant cause of the nephrotic syndrome in children is minimal change disease. Approximately 30 percent of adults with the nephrotic syndrome have a systemic disease such as diabetes mellitus, amyloidosis, or systemic lupus erythematosus; the remaining cases are usually due to primary disorders including minimal change disease, focal segmental glomerulosclerosis (FSGS), and membranous nephropathy. Heavy proteinuria in patients without edema or hypoalbuminemia is more likely to be due to secondary FSGS. (See 'Etiology' above.)

Pathophysiology – Proteinuria is due to increased filtration of macromolecules across the glomerular capillary wall. Albumin is the principal urinary protein, but other plasma proteins including clotting inhibitors, transferrin, and hormone carrying proteins such as vitamin D-binding protein may be lost as well. (See 'Proteinuria' above.)

Complications – Proteinuria and edema are the principal clinical manifestations of the nephrotic syndrome. Other manifestations include protein malnutrition, hypovolemia, acute kidney failure, urinary loss of hormones, hyperlipidemia and the potential for accelerated atherosclerosis, a tendency to venous and/or arterial thromboses and pulmonary embolism, and increased susceptibility to infection. (See 'Complications' above.)

Diagnosis – The etiology of heavy proteinuria may be suggested from the history and physical examination. In most adults, however, a kidney biopsy is required to establish the diagnosis. (See 'Diagnosis' above.)

Treatment – Treatment includes the administration of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blockers (ARBs) to lower intraglomerular pressure, and dietary sodium restriction and loop diuretics to slowly reduce edema. The lipid abnormalities induced by the nephrotic syndrome usually reverse with resolution of the disease, but lipid-lowering therapy may be indicated in selected patients. Arterial and venous thromboemboli are typically treated with heparin followed by warfarin for as long as the patient remains nephrotic. Patients with primary (idiopathic) nephrotic syndrome often receive immunosuppressive therapy. (See 'Treatment' above.)

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Topic 3084 Version 30.0

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