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com/contents/etiology-clinical-manifestations-and-diagnosis-of-nephrotic-syndrome-inchildrenINTRODUCTION The nephrotic syndrome is caused by renal diseases that increase the permeability across the
glomerular filtration barrier. It is classically characterized by four clinical features, but the first two are used diagnostically because the last two may not be seen in all patients: Nephrotic range proteinuria Urinary protein excretion greater than 50 mg/kg per day Hypoalbuminemia Serum albumin concentration less than 3 g/dL (30 g/L) Edema Hyperlipidemia

The etiology, clinical manifestations, and diagnosis of nephrotic syndrome in children are reviewed here. The complications and treatment of idiopathic childhood nephrotic syndrome and specific renal diseases that present as nephrotic syndrome in children are discussed separately. (See "Complications of idiopathic nephrotic syndrome in children" and "Treatment of idiopathic nephrotic syndrome in children" and "Etiology, clinical features, and diagnosis of minimal change disease in adults" and "Congenital and infantile nephrotic syndrome" and "Epidemiology, classification, and pathogenesis of focal segmental glomerulosclerosis".) PATHOGENESIS Two issues are important in the pathogenesis of nephrotic syndrome: the mechanisms of glomerular injury and proteinuria. Mechanisms of glomerular injury A variety of different, disease-specific mechanisms have been described in the nephrotic syndrome: Circulating factors in minimal change disease and primary focal segmental glomerulosclerosis. (See 'Idiopathic nephrotic syndrome' below.) Circulating immune factors in disorders, such as membranoproliferative glomerulonephritis, poststreptococcal glomerulonephritis, and lupus nephritis. (See"Mechanisms of immune injury of the glomerulus".) Mutations in podocyte or slit diaphragm proteins (eg, CD2AP, podocin, and nephrin) in inherited forms of congenital, infantile, or glucocorticoid resistant nephrotic syndrome. (See "Congenital and infantile nephrotic syndrome" and "Steroidresistant idiopathic nephrotic syndrome in children", section on 'Genetic mutations'.)

Mechanisms of proteinuria The mechanisms of proteinuria in patients with nephrotic syndrome is discussed in detail elsewhere but will be briefly reviewed here. (See"Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on 'Glomerular proteinuria'.) The proteinuria in glomerular disease is due to increased filtration of macromolecules (such as albumin) across the glomerular capillary wall. The latter consists of three components: the fenestrated endothelial cell, the glomerular basement membrane (GBM), and the epithelial cell foot processes. The pores between the foot processes are closed by a thin membrane called the slit diaphragm (picture 1). The filtration of macromolecules across the glomerular capillary wall is normally restricted by two mechanisms: charge-selectivity and size-selectivity. The endothelial cells and the GBM have a net negative charge due to polyanions such as heparan sulfate proteoglycans. This creates a charge barrier to the filtration of large anions such as albumin. In comparison, circulating IgG is predominantly neutral or cationic, and its filtration is not limited by charge. In minimal change disease, the most common cause of nephrotic syndrome in children, there is a loss of anionic charge that is not accompanied by any structural damage or change to the glomerular filtration unit observed by light microscopy (picture 2). However, electron microscopy demonstrates epithelial podocyte effacement (picture 3). (See "Etiology, clinical features, and diagnosis of minimal change disease in adults", section on 'Pathogenesis'.) The glomerular capillary wall is size-selective, having functional pores of an approximate radius of 40 to 45 (the radius of albumin is roughly 36 ). These pores appear to be located throughout the GBM and across the GBM at the slit diaphragms between the adjacent epithelial cell foot processes. In comparison, the width of the endothelial cell fenestrae is much larger (375 to 400 ); as a result, the endothelial cell is not part of the size barrier to macromolecule filtration. In glomerular diseases other than minimal change disease, structural injury seen by light microscopy results in an increase in the number of large pores in the GBM (figure 1). This structural damage allows movement of normally restricted proteins of varying sizes (including large neutral proteins, such as IgG) across the filtration barrier. CLASSIFICATION In this discussion, children with nephrotic syndrome are classified based upon whether or not there are signs of systemic disease. We use the following classification system: Primary nephrotic syndrome, which refers to nephrotic syndrome in the absence of an identifiable systemic disease. Within this category are patients with idiopathic nephrotic syndrome, who have no glomerular inflammation on renal biopsy, and patients with primary glomerulonephritis, who have an active sediment and glomerular inflammation on renal biopsy.

Secondary nephrotic syndrome, which refers to nephrotic syndrome in the presence of an identifiable systemic disease. Congenital and infantile nephrotic syndrome, which occur in children less than one year of age and can be either secondary (mostly due to infection) or primary. Two-thirds of nephrotic syndrome cases that occur during the first year of life and as many as 85 percent of cases that occur during the first three months of life have a genetic basis and a poor outcome [1]. These disorders are discussed separately. (See "Congenital and infantile nephrotic syndrome".)

Primary nephrotic syndrome Primary nephrotic syndrome is defined as nephrotic syndrome in the absence of systemic disease with a reported incidence of 1.5 per 100,000 children per year [2]. Within this category are two subgroups: Disorders without glomerular inflammation on renal biopsy. Included in this group are idiopathic nephrotic syndrome and some cases of membranous nephropathy, which are discussed elsewhere. (See "Causes and diagnosis of membranous nephropathy".) Nephritic disorders associated with an active urine sediment (red cells and cellular casts) and the presence of glomerular inflammation on renal biopsy. Included in this group are membranoproliferative glomerulonephritis and IgA nephropathy, which are discussed separately. (See "Clinical presentation, classification, and causes of membranoproliferative glomerulonephritis" and "Clinical presentation and diagnosis of IgA nephropathy" and "Evaluation of a child with glomerular disease", section on 'Glomerulonephritis'.)

Idiopathic nephrotic syndrome Idiopathic nephrotic syndrome is the most common form of childhood nephrotic syndrome, representing more than 90 percent of cases between 1 and 10 years of age and 50 percent after 10 years of age [3]. Idiopathic nephrotic syndrome is defined by the association of the clinical features of nephrotic syndrome with renal biopsy findings of diffuse foot process effacement on electron microscopy and minimal changes (called minimal change disease [MCD]), primary focal segmental glomerulosclerosis (FSGS), or mesangial proliferation on light microscopy. It is unclear whether these three light microscopic patterns represent separate disorders or are a spectrum of a single disease process [4]. (See "Etiology, clinical features, and diagnosis of minimal change disease in adults" and"Epidemiology, classification, and pathogenesis of focal segmental glomerulosclerosis" and "Minimal change variants: Mesangial proliferation; IgM nephropathy; C1q nephropathy".) Most patients have histologic findings of MCD. The vast majority of patients with MCD (>90 percent) respond to steroid therapy [5]. MCD can be clinically differentiated from those with other causes of nephrotic syndrome. This was illustrated in a classic study from the International Study of Kidney Disease in Children (ISKDC) of 521 children (age range 12 weeks to 16 years of age) who presented with primary nephrotic syndrome. The study was conducted in 24 centers in North America, Europe, and Asia between 1967 and 1974 [3]. Renal biopsies were obtained in all children. Multivariate analysis demonstrated that clinical findings at presentation accurately differentiated children with MCD from those with other glomerular pathology [3]. These findings included: Age younger than six years of age Absence of hypertension Absence of hematuria by Addis count Normal complement levels Normal renal function

One exception to the age criterion is onset of nephrotic syndrome in the first year of life, particularly the first three months of life, which is much more likely to be due to a gene mutation and to be resistant to glucocorticoids [1]. Based upon these observations, an initial trial of steroid therapy is generally administered to children who are likely to have MCD based upon clinical diagnosis, thereby avoiding renal biopsy. (See 'Initial therapy versus renal biopsy' below.) Patients with idiopathic nephrotic syndrome are further classified based upon their response to empiric steroid therapy. (See "Treatment of idiopathic nephrotic syndrome in children".) Steroid-responsive nephrotic syndrome The majority of children with idiopathic nephrotic syndrome are steroidresponsive (also referred to as steroid-sensitive nephrotic syndrome). In these patients, the most likely histologic lesion is MCD, although some patients with FSGS will also respond to steroid therapy [5]. Patients who are steroid-responsive have a favorable long-term outcome with a very low risk of chronic renal disease. Steroid-resistant nephrotic syndrome Approximately 20 percent of all children with idiopathic nephrotic syndrome will not respond to steroid therapy. The response rate is better in younger children, who are much more likely to have MCD. In an ISKDC study, only about 10 percent of children less than 10 years of age failed to respond to steroids [5]. Patients with steroid resistant nephrotic syndrome have a worse prognosis as renal survival rate in Caucasian children is approximately 50 percent at 10 years and even worse in children with African or Hispanic ethnicity [5-7]. Some children with steroid-resistant nephrotic syndrome have genetic mutations of podocyte proteins,

including NPHS2, NPHS1, and WT1 genes. (See "Steroid-resistant idiopathic nephrotic syndrome in children", section on 'Genetic mutations'.) Secondary nephrotic syndrome Secondary nephrotic syndrome is defined as nephrotic syndrome associated with systemic diseases or is secondary to another process that causes glomerular injury. Within this category are the same two subgroups as in primary nephrotic syndrome: Disorders without glomerular inflammation on renal biopsy. Included in this group are some cases of membranous nephropathy (eg, due to lupus, penicillamine), secondary focal segmental glomerulosclerosis due to nephron loss resulting from renal scarring or hypoplasia, and, rarely, disorders such as amyloidosis. (See"Causes and diagnosis of membranous nephropathy" and "Epidemiology, classification, and pathogenesis of focal segmental glomerulosclerosis", section on 'Secondary FSGS'.) Nephritic disorders associated with an active urine sediment (red cells and cellular casts) and the presence of glomerular inflammation on renal biopsy. A variety of disorders are included in this group.

Postinfectious glomerulonephritis and infective endocarditis. (See "Poststreptococcal glomerulonephritis" and "Renal disease in the setting of infective endocarditis or an infected ventriculoatrial shunt".) Systemic lupus erythematosus. (See "Diagnosis and classification of renal disease in systemic lupus erythematosus".) Vasculitides, such as Henoch-Schnlein purpura (IgA vasculitis), and, rarely, in granulomatosis with polyangiitis (formerly referred to as Wegeners granulomatosis) and microscopic polyang iitis. (See "Renal manifestations of HenochSchnlein purpura (IgA vasculitis)" and "Clinical manifestations and diagnosis of granulomatosis with polyangiitis (Wegener's) and microscopic polyangiitis".) Other causes include sickle cell disease, which is usually associated with secondary focal segmental glomerulosclerosis, Alport syndrome, and hemolytic uremic syndrome. (See "Renal manifestations of sickle cell disease" and "Genetics, pathogenesis, and pathology of hereditary nephritis (Alport syndrome)".) ETIOLOGY Minimal change disease (MCD) is the most commonly seen histopathology of childhood nephrotic syndrome. In the previously mentioned ISKDC study of 521 children who presented with nephrotic syndrome without systemic disease between 1967 and 1974, the following findings were made based upon renal biopsy [3]: Minimal change disease (MCD) 77 percent Membranoproliferative glomerulonephritis (MPGN) 8 percent Focal segmental glomerulosclerosis (FSGS) 7 percent Proliferative glomerulonephritis 2 percent Mesangial proliferation 2 percent Focal and global glomerulosclerosis 2 percent Membranous glomerulonephropathy 2 percent

Eighty percent of patients with MCD and 50 percent of patients with FSGS presented before six years of age. In contrast, none of the 39 patients with MPGN presented before six years of age. Subsequent studies have demonstrated an increasing prevalence of FSGS [8,9]. Whether this is due to a true increase in prevalence or is a result of improved detection of the histologic changes consistent with FSGS on renal biopsy is unknown. Since the diagnosis of FSGS is made by the detection of one or more glomeruli with segmental glomerulosclerosis, one cannot be certain that a patient with an initial diagnosis of MCD does not actually have FSGS that was missed because of sampling error. In addition, advances in molecular genetics of glomerular diseases have shown single gene defects that affect glomerular basement membrane formation and/or glomerular podocyte differentiation and function are responsible for many cases of steroid-resistant nephrotic syndrome in children. (See "Steroid-resistant idiopathic nephrotic syndrome in children", section on 'Genetic mutations'.) CLINICAL MANIFESTATIONS Primary nephrotic syndrome is more common in younger children, particularly those less than six years of age [2,3,10]. There is an increased incidence of nephrotic syndrome in family members when compared to the general population [11,12]. In affected siblings, nephrotic syndrome usually presents at the same age with the same histopathology and outcome [12]. Childhood nephrotic syndrome generally presents with edema and often occurs after an inciting event, such as an upper respiratory infection or an insect bite. Two major factors have been thought to be responsible for edema. Sodium retention directly induced by the renal disease, which is most common. Arterial underfilling as the low plasma oncotic pressure leads to plasma volume depletion and stimulation of the reninangiotensin-aldosterone system with renal sodium retention under the influence of aldosterone [13].

Primary sodium retention is a result of increased sodium reabsorption in the collecting duct of the nephrotic kidney due to an uncontrolled activation of the epithelial sodium channels (ENaC) [14].

This issue is discussed in detail separately. (See "Pathophysiology and treatment of edema in patients with the nephrotic syndrome", section on 'Underfilling versus renal sodium retention' and "Pathophysiology and treatment of edema in patients with the nephrotic syndrome", section on 'Varying mechanisms in childhood minimal change disease'.) Edema increases gradually and becomes detectable when fluid retention exceeds 3 to 5 percent of body weight. Typically, periorbital edema is noted first and is often misdiagnosed as a manifestation of allergy. The edema is gravity dependent, and thus, over the day, periorbital edema decreases while edema of the lower extremities increases. In the reclining position, edema localizes to the back and sacral area. Other dependent areas that can become edematous include the scrotum, penis, or labia. The affected edematous areas are white, soft, and pitting. Some patients develop anasarca (ie, generalized and massive edema) with marked peripheral edema, abdominal distension resulting from ascites, marked scrotal or vulvar edema, and severe periorbital edema resulting in swollen shut eyelids. Despite the marked increase in extracellular fluid volume, some children with nephrotic syndrome, primarily those with MCD, present with or develop signs of a decrease in effective circulating volume, such as tachycardia, peripheral vasoconstriction, oliguria, decreased glomerular filtration rate, elevation of plasma renin aldosterone, and norepinephrine [13]. In such children, a further insult such as diuretic therapy, sepsis, or diarrhea can lead to hypotension and rarely shock [15]. A variety of other manifestations can occur. (See "Complications of idiopathic nephrotic syndrome in children".) Umbilical or inguinal hernias. Abdominal pain due to rapid fluid accumulation or peritonitis. Dyspnea, which is most often due to respiratory compromise from pleural effusions or marked ascites. Infrequently, respiratory symptoms may be due to pneumonia or, rarely, pulmonary embolus due to the hypercoagulable state associated with the nephrotic syndrome. Nonspecific complaints, including headache, irritability, malaise, and fatigue are common at presentation.

The likelihood of hypertension varies with the underlying cause of nephrotic syndrome [3]. Hypertension is common in patients with glomerulosclerosis or glomerulonephritis, but is infrequent in patients with idiopathic nephrotic syndrome. Gross hematuria is most often seen in patients with glomerulonephritis (eg, postinfectious glomerulonephritis or membranoproliferative glomerulonephritis). In contrast, gross hematuria is rare in idiopathic nephrotic syndrome, although microscopic hematuria is seen in 20 percent of cases [3]. (See 'Urinalysis' below.) DIAGNOSIS The diagnosis of nephrotic syndrome is made by fulfilling the following two defining characteristics: Urinary protein excretion greater than 50 mg/kg per day Hypoalbuminemia

Although, edema is generally the presenting sign of nephrotic syndrome, the diagnosis is confirmed by the presence of nephrotic range proteinuria and hypoalbuminemia. Clinical and laboratory findings can also be used to diagnosis specific diseases that present as nephrotic syndrome. In particular, clinical findings are highly predictive of idiopathic nephritic syndrome [3] and are used to make the diagnosis initiate steroid therapy without renal biopsy. (See 'Initial therapy versus renal biopsy' below.) Our approach is consistent with the following initial evaluation of nephrotic syndrome developed by the Children's Nephrotic Syndrome Consensus Conference, which included pediatric nephrologists from the southeast and midwest sections of the United States [16]. Urinalysis First morning void to measure urinary protein to creatinine ratio Blood tests, including electrolytes, creatinine, blood urea nitrogen, cholesterol, albumin, and C3 Other blood tests include antinuclear antibody level for patients 10 years of age or with signs of systemic lupus erythematosus, and serology for hepatitis B, C, and HIV in high-risk populations Renal biopsy for children 12 years of age

Urine tests Urine protein excretion Nephrotic range proteinuria in children is defined as urinary protein excretion greater than 50 mg/kg per day or 40 mg/m2 per hour. Quantitative measurement of protein excretion is based upon a timed 24-hour urine collection.

However, it is difficult to obtain accurately timed urine collections in young children. An alternative method of quantitative assessment of urine protein excretion is measurement of the total protein/creatinine ratio on a spot urine sample (calculator 1). The ratio that is indicative of nephrotic range proteinuria is greater than 3 mgprotein/mg creatinine (300 mg protein/mmol creatinine). (See "Evaluation of proteinuria in children", section on 'Quantitative assessment'.) Urinalysis The urinary dipstick measures albumin concentration via a colorimetric reaction between albumin and tetrabromophenol blue. It measures protein concentration rather than the rate of protein excretion and, therefore, cannot be used to make the diagnosis of nephrotic syndrome. However, in most patients with nephrotic syndrome, the urinary dipstick demonstrates a high albumin concentration (3+ to 4+, 300 to >1000 mg/dL). Thus, it is often used as a screening test while awaiting confirmation by quantitative protein excretion studies. Patients with idiopathic nephrotic syndrome have a relatively inactive urine sediment (ie, oval fat bodies and hyaline casts but few red cells and no red cell or other cellular casts). Hematuria is commonly seen in patients with glomerulonephritis but does occur in focal segmental sclerosis (FSGS) and, less often, minimal change disease (MCD). This was illustrated in the previously mentioned ISKDC study of 521 children who presented with primary nephrotic syndrome [3]. Hematuria was reported in 59 percent of patients with membranoproliferative glomerulonephritis, 49 percent of those with FSGS, and 23 percent with MCD. Blood tests Serum proteins Hypoalbuminemia is one of the criteria that defines nephrotic syndrome. The serum albumin is typically below 3 g/dL (30 g/L) and can be as low as 1 g/dL (10 g/L). (See "Overview of heavy proteinuria and the nephrotic syndrome", section on 'Hypoalbuminemia'.) Although serum albumin is reduced, total globulins are relatively preserved in patients with idiopathic nephrotic syndrome with either normal or slightly decreased serum alpha-1 globulin concentrations and increased alpha-2 and beta globulin. Gamma globulin concentrations vary depending upon the underlying disease. As examples, serum IgG is reduced in patients with MCD and is elevated in those with systemic lupus erythematous (SLE). Lipids Hyperlipidemia is a characteristic feature of nephrotic syndrome. Serum total cholesterol, triglycerides, and total lipids are elevated. The increase in cholesterol is inversely correlated to the serum albumin concentration. (See "Lipid abnormalities in nephrotic syndrome".) Estimation of GFR In stable patients, the glomerular filtration rate (GFR) is estimated from the serum creatinine. The serum creatinine is elevated in 30 to 40 percent of patients with MCD at presentation, due at least in part to hypovolemia [3,13]. Other studies Complete blood count Hemoglobin and hematocrit may be increased in children with nephrotic syndrome, particularly MCD, as a result of plasma volume contraction. Thrombocytosis is common and platelet counts may reach 500,000 to 1 million counts/microL. Hemoconcentration and thrombocytosis may contribute to hypercoagulability and thrombotic complications. (See "Complications of idiopathic nephrotic syndrome in children", section on 'Thromboembolism'.) Complement studies Serum complement testing can be useful in the diagnosis of a specific renal or systemic disease that presents with nephrotic syndrome. Low C3 levels are typically seen in patients with membranoproliferative glomerulonephritis (MPGN) and postinfectious glomerulonephritis, while both low C3 and C4 are seen in patients with lupus nephritis. Serum complement is normal in patients with idiopathic nephrotic syndrome [3]. (See "Clinical presentation, classification, and causes of membranoproliferative glomerulonephritis" and "Poststreptococcal glomerulonephritis" and "Diagnosis and classification of renal disease in systemic lupus erythematosus".) Electrolytes Hyponatremia can be present, due to decreased free water excretion resulting from hypovolemic stimulation of the release of antidiuretic hormone (ADH).

Initial therapy versus renal biopsy A presumptive diagnosis of minimal change disease (MCD) can be made based upon clinical findings. In a multivariate analysis of 521 patients with nephrotic syndrome from the ISKDC, the following findings were predictive of MCD [3]: Age younger than six years of age Absence of hypertension Absence of hematuria by Addis count Normal complement levels Normal renal function

In addition, over 90 percent of patients with MCD will respond to steroid therapy within eight weeks [5]. (See "Treatment of idiopathic nephrotic syndrome in children".)

Because of these two observations, steroid therapy can be initiated in patients with a high probability of having steroid responsive idiopathic nephrotic syndrome without confirmation of the diagnosis by renal biopsy. Empiric steroid therapy can be given to patients who fulfill all of the following criteria; renal biopsy is performed before initiation of therapy in other patients. Age older than 1 year and less than 10 years of age None of the following clinical findings are present: hypertension, gross hematuria, and a marked elevation in serum creatinine Normal complement levels

Using this approach, invasive renal biopsy can be avoided in 80 percent of children between 1 and 10 years of age who present with nephrotic syndrome [5]. Patients with steroid-responsive nephrotic syndrome typically have a favorable outcome. (See "Treatment of idiopathic nephrotic syndrome in children".) DIFFERENTIAL DIAGNOSIS Because children with nephrotic syndrome initially present with edema, the other causes of childhood edema need to be considered in the differential diagnosis (table 1). Nephrotic syndrome is distinguished from these causes of edema by the presence of nephrotic range proteinuria >50 mg/kg per day and hypoalbuminemia <3 g/dL (30 g/L). (See "Pathophysiology and etiology of edema in children".) Heart failure Other causes of hypoalbuminemia, such as protein losing enteropathy or protein malnutrition (kwashiorkor). Hypoalbuminemia is also present in children with cirrhosis but the main cause of fluid retention is portal hypertension. (See "Pathogenesis of ascites in patients with cirrhosis".) Increased capillary permeability due to an allergic reaction or hereditary angioedema. The edema in this setting is typically focal.

INTRODUCTION AND TERMINOLOGY Diseases of the glomerulus can result in three different urinary and clinical patterns: focal nephritic; diffuse nephritic; and nephrotic. (See "Differential diagnosis and evaluation of glomerular disease".) Focal nephritic Disorders resulting in a focal nephritic sediment are generally associated with inflammatory lesions in less than one-half of glomeruli on light microscopy. The urinalysis reveals red cells (which often have a dysmorphic appearance), occasionally red cell casts, and mild proteinuria (usually less than 1.5g/day). The findings of more advanced disease are usually absent, such as heavy proteinuria, edema, hypertension, and renal insufficiency. These patients often present with asymptomatic hematuria and proteinuria discovered on routine examination or, occasionally, with episodes of gross hematuria. Diffuse nephritic The urinalysis in diffuse glomerulonephritis is similar to focal disease, but heavy proteinuria (which may be in the nephrotic range), edema, hypertension, and/or renal insufficiency may be observed. Diffuse glomerulonephritis affects most or all of the glomeruli. Nephrotic The nephrotic sediment is associated with heavy proteinuria and lipiduria, but few cells or casts. The term nephrotic syndrome refers to a distinct constellation of clinical and laboratory features of renal disease. It is specifically defined by the presence of heavy proteinuria (protein excretion greater than 3.5 g/24hours), hypoalbuminemia (less than 3.0 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 (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 presentation (ie, bland rather than active urine sediment). More specific issues relating to complications of the nephrotic syndrome are presented elsewhere. (See "Pathophysiology and treatment of edema in patients with the nephrotic syndrome" and "Renal vein thrombosis and hypercoagulable state in nephrotic syndrome" and "Endocrine dysfunction in the nephrotic syndrome" and "Lipid abnormalities in nephrotic syndrome" and "Acute kidney injury (acute renal failure) 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 renal disorders such as minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy [2-9]. (See "Differential diagnosis and evaluation of glomerular disease".)

The frequency of the different forms of nephropathy underlying the nephrotic syndrome in adults was evaluated in a Spanish glomerulonephritis registry of 2000 patients biopsied between the years 1994 and 2001 [2]. Among patients between 15 and 65 years of age, the most common causes of nephrotic syndrome were membranous nephropathy (24 percent), minimal change disease (16 percent), lupus (14 percent), focal segmental glomerulosclerosis (12 percent), membranoproliferative glomerulonephritis (7 percent), amyloidosis (6 percent), and IgA nephropathy (6 percent). A similar distribution was observed among the 725 elderly individuals (age greater than 65 years) except for an increased prevalence of amyloidosis (17 percent) and a decreased prevalence of lupus (1 percent). The relative frequency of the different disorders has varied over time in some series as illustrated by the following observations: A study of 233 renal biopsies performed between 1995 and 1997 at the University of Chicago in adults with nephrotic syndrome (in the absence of an obvious underlying disease such as diabetes mellitus or lupus) found the major causes to be membranous nephropathy and focal segmental glomerulosclerosis (33 and 35 percent, respectively), minimal change disease (15 percent), and amyloidosis (4 percent overall, but 10 percent in patients over age 44) [3]. Focal segmental glomerulosclerosis accounted for more than 50 percent of cases of nephrotic syndrome in black individuals. The frequency of focal segmental glomerulosclerosis was much lower (15 percent) among biopsies for nephrotic syndrome performed at the same institution between 1976 and 1979. The increased prevalence of focal segmental glomerulosclerosis in the 1995 to 1997 series was observed in both black and white individuals. Similar findings were noted in a report from Springfield, Massachusetts, which compared renal biopsies at a single center that were performed in two time periods: 1975-1979 and 1990-1994 [4]. Over time, the relative frequency of membranous nephropathy fell from 38 to 15 percent, while the frequency of focal segmental glomerulosclerosis increased from 14 to 25 percent overall; this increase was primarily seen in black and Hispanic patients. The relative incidence of focal segmental glomerulosclerosis also appears to have increased in Brazil [7]. The increase in FSGS is not restricted to black populations. A retrospective analysis of the patterns of glomerular disease a in predominantly white cohort from Minnesota showed a 13-fold increase in FSGS and no change in membranous nephropathy frequency between 1994 and 2003 compared with the interval between 1974 and 1983 [10]. Nephrotic proteinuria was present in 80 percent of the patients with FSGS.

The nephrotic syndrome can also develop in patients with postinfectious glomerulonephritis, membranoproliferative glomerulonephritis, and 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 'Introduction and terminology'above and "Differential diagnosis and evaluation of glomerular disease".) 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, 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 "Etiology, clinical features, and diagnosis of minimal change disease 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 1A-B). 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 lesion found to underlie the idiopathic nephrotic syndrome in adults, accounting for 35 percent of all cases in the United States and over 50 percent of cases among blacks. FSGS 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 (picture 2A-B) [11]. 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. (See"Epidemiology, classification, and pathogenesis of focal segmental glomerulosclerosis".) 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 renal function. There is, however, substantial overlap in these features. In addition to careful review of the renal biopsy, steroid-resistance in a patient considered to have minimal change disease should raise suspicion about FSGS. (See "Etiology, clinical features, and diagnosis of minimal change disease in adults".)

Primary FSGS is an epithelial cell disorder that may be related etiologically to minimal change disease; congenital forms also exist. (See "Epidemiology, classification, and pathogenesis of focal segmental glomerulosclerosis".) 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 corticosteroids, while secondary disease is best treated with modalities aimed at lowering the intraglomerular pressure, such as angiotensin converting enzyme inhibitors. (See "Treatment of primary focal segmental glomerulosclerosis".) The distinction between primary and secondary FSGS can usually 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, whereas slowly increasing proteinuria and renal insufficiency over time are characteristic of the secondary disorders. The proteinuria in secondary FSGS is often nonnephrotic; even when protein excretion exceeds 3 to 4 g/day, both hypoalbuminemia and edema are unusual. Collapsing FSGS is a histologic variant that is usually but not always 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 3A-B). These patients often have rapidly progressive renal failure and optimal therapy is uncertain. (See "HIVassociated nephropathy (HIVAN)" and "Collapsing focal segmental glomerulosclerosis not associated with HIV infection".) Membranous nephropathy Membranous nephropathy is among the most common cause of primary nephrotic syndrome in 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 4A-F). (See "Causes and diagnosis of membranous nephropathy", section on 'Pathology'.) Membranous nephropathy is most often a primary (idiopathic) disorder in adults and a secondary disorder in children. Many cases of idiopathic membranous nephropathy may be due to autoantibodies directed against the phospholipase A2 receptor found on podocytes. Secondary causes include hepatitis B antigenemia, autoimmune diseases, thyroiditis, carcinoma, and the use of certain drugs such as gold, penicillamine, captopril, and nonsteroidal antiinflammatory drugs. The malignancy in presumed tumor-induced membranous nephropathy has usually been diagnosed or is clinically apparent at the time the proteinuria is discovered. (See "Causes and diagnosis of membranous nephropathy", section on 'Phospholipase A2 receptor' and "Causes and diagnosis of membranous nephropathy" and "Causes and diagnosis of membranous nephropathy", section on 'Malignancy'.) Amyloidosis As previously noted above, 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 or osteomyelitis. (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. (See"Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis (primary amyloidosis)" and "Causes and diagnosis of secondary (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 [12], 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 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 [13-15]. 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 [15]. (See"Congenital and infantile nephrotic syndrome".) Adult onset idiopathic membranous nephropathy and focal segmental glomerulosclerosis may be due to autoantibodies to podocyte antigens, circulating factors like soluble urokinase-type plasminogen activator receptor that active podocyte integrins, or circulating factors like cytokines or microbial products that may induce podocyte CD80. The engagement or activation of these podocyte proteins alters the arrangement of the slit diaphragm or podocyte cytoskeleton. (See "Causes and

diagnosis of membranous nephropathy", section on 'Pathogenesis' and "Epidemiology, classification, and pathogenesis of focal segmental glomerulosclerosis", 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 "Renal vein thrombosis and hypercoagulable state in nephrotic syndrome" and"Endocrine dysfunction in the nephrotic syndrome" and "Lipid abnormalities in nephrotic syndrome".) Hypoalbuminemia The mechanism of hypoalbuminemia in nephrotic patients is not completely understood. Most of albumin loss is due to urinary excretion [16,17]. 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 [16,17]. Hepatic albumin synthesis does increase in response to the albumin loss. This effect is mediated by an increase in hepatic albumin gene expression [18] stimulated in part by the low oncotic pressure [19]. Hypoalbuminemia may also lead to the release of an as yet unidentified circulating factor that contributes to the elevation in hepatic albumin synthesis [20]. 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 or 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 focal segmental glomerulosclerosis (such as reflux nephropathy) rather than one of the primary nephrotic disorders such as membranous nephropathy 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 [21]. (See "Epidemiology, classification, and pathogenesis of focal segmental glomerulosclerosis", section on 'Distinguishing between primary and secondary FSGS'.) 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) [22]. 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 patients 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 5A-B). (See"Urinalysis in the diagnosis of kidney disease", section on 'The assessment of lipiduria'.) 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 [23]. 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 nephrotic patients, often as a result of over diuresis 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 older adults with minimal change disease and profound hypoalbuminemia [24]. The mechanism is not understood; several factors including

hypovolemia, interstitial edema, ischemic tubular injury, and the use of nonsteroidal antiinflammatory drugs have been suggested. (See "Acute kidney injury (acute renal failure) in minimal change disease and other forms of nephrotic syndrome".) Two other major settings are collapsing focal 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 "Causes and diagnosis of membranous nephropathy".) 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 "Renal vein thrombosis and hypercoagulable state 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. It can present acutely or, much more commonly, in an indolent manner. The acute presentation includes flank pain, gross hematuria, and a decline in renal function. Most patients are asymptomatic, and the diagnosis of renal vein thrombosis is suspected only when pulmonary thromboembolism develops. (See "Renal vein thrombosis and hypercoagulable state in nephrotic syndrome", section on 'Renal vein thrombosis'.) 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. Pneumococcal infections, are particularly common, and all patients should receive pneumococcal vaccinations. (See "Pneumococcal vaccination in adults".) The mechanism of the impairment of normal defense mechanisms is not well understood; low levels of immunoglobulin G due to urinary loss may play a role. (See"Complications of idiopathic nephrotic syndrome in children", section on 'Infection'.) Miscellaneous 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 (all features of a proximal renal tubular acidosis). 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 [25-27]. (See "Endocrine dysfunction in the nephrotic syndrome".) DIAGNOSIS 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/dayare considered to have nephrotic-range proteinuria. There is an alternative to the cumbersome 24-hour urine collection: calculating the total protein-to-creatinine ratio (mg/mg) on a random urine specimen [28]. 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 information: 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, interferons, bisphosphonates, lithium, gold, or penicillamine. In most cases, however, renal biopsy is required to establish the diagnosis. A review of the findings suggesting that a diabetic patient might have a different form of renal disease is available in a separate topic review. (See "Overview of diabetic nephropathy", section on 'Nondiabetic renal disease'.) 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 free light chains and urine protein electrophoresis and immunofixation, 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 [29]. (See "Differential diagnosis and evaluation of glomerular disease", section on 'Laboratory testing in patients with suspected glomerular disease'.) Although serologic tests and hypocomplementemia can establish the diagnosis of systemic lupus erythematosus, renal biopsy is still indicated to determine the type of disease that is present. (See "Diagnosis and classification of renal disease in systemic lupus erythematosus".) Renal biopsy Renal biopsy is the standard procedure for determining the cause of proteinuria. Pediatric nephrologists often use an initial empiric trial of steroids because of the high incidence of minimal change disease. Most adult nephrologists, however, feel that biopsy is indicated when the etiology of persistent nephrotic range proteinuria is in doubt in order to determine 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 "Indications for and complications of renal biopsy".) Percutaneous renal biopsy is generally contraindicated in the following settings:

Uncorrectable bleeding diathesis Small kidneys which are generally indicative of chronic irreversible disease Severe hypertension, which cannot be controlled with antihypertensive medications Multiple, bilateral cysts or a renal tumor Hydronephrosis Active renal or perirenal infection An uncooperative patient

There are also several relative contraindications (eg, solitary kidney). (See "Indications for and complications of renal biopsy", section on 'Relative contraindications'.) TREATMENT This section will review the general management issues in patients with nephrotic syndrome (ie, proteinuria, edema, hyperlipidemia, and hypercoagulability). Immunosuppressive therapy in patients with one of the major causes of idiopathic nephrotic syndrome is discussed separately. (See "Treatment of idiopathic membranous nephropathy" and "Treatment of primary focal segmental glomerulosclerosis" and "Treatment of minimal change disease in adults" and "Treatment of idiopathic nephrotic syndrome in children" and "Renal amyloidosis" and "Treatment and prognosis of IgA nephropathy".) Proteinuria In the absence of specific therapy directed against the underlying disease, efforts to lower intraglomerular pressure, which may be manifested as a reduction in protein excretion, may slow the rate of disease progression. This is usually achieved by the administration of an angiotensin converting enzyme inhibitor or angiotensin receptor blockers. 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".) 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 "Protein restriction and progression of 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 patients with the nephrotic syndrome" and "Patient information: Lowsodium 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 "Treatment of refractory edema in adults".) Hyperlipidemia The lipid abnormalities induced by the nephrotic syndrome reverse with resolution of the disease, as with corticosteroid therapy in minimal change disease. The optimal treatment of patients with persistent nephrosis is uncertain. Dietary modification is generally of little benefit. Most patients are initially treated with an HMG CoA reductase inhibitor (statin). (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 "Renal vein thrombosis and hypercoagulable state in nephrotic syndrome".)http://www.uptodate.com/contents/overview-of-heavy-proteinuria-and-the-nephrotic-syndrome#H9

Symptoms

In children, facial swelling is a common presenting feature, with periorbital oedema often being the first evidence that something is wrong; oedema may progress to involve the whole body. Adults tend to present with peripheral oedema affecting the ankles and legs, which may progress to involve the whole body. Some patients may notice frothiness of their urine. Hypercoagulability may manifest as venous or arterial thrombosis - eg, deep vein thrombosis, myocardial infarction. Recurrent infections and/or general fatigue, lethargy, poor appetite, weakness or episodic abdominal pain may cause presentation to a doctor.

Signs
Clinical signs of nephrotic syndrome include:[1]

Oedema (oedema of dependent parts or generalised oedema are the main clinical findings): periorbital oedema (facial oedema may be found in children), lower limb oedema, oedema of the genitals, ascites. Tiredness. Leukonychia. Breathlessness: pleural effusion (occasionally, severely hypoalbuminaemic cases may have pleural effusions or ascites), fluid overload (high jugular venous pressure), acute kidney injury (acute renal failure). Breathlessness with chest pain: pulmonary embolism, myocardial infarction. Dyslipidaemia: eruptive xanthomata, xanthelasmata.

Complications
Complications of nephrotic syndrome include: Decreased resistance to infections, due to urinary immunoglobulin loss. Increased risk of arterial and venous thrombosis, due to loss of antithrombin III and plasminogen in the urine, combined with an increase in hepatic synthesis of clotting factors. Adults with membranous nephropathy are at particular risk.[11] Acute kidney injury may rarely occur as a spontaneous complication of nephrotic syndrome. Acute kidney injury may also be caused by excessive diuresis, interstitial nephritis due to use of diuretics or NSAIDs, sepsis or renal vein thrombosis.[1] Chronic kidney disease may occur as a result of an underlying cause - eg, amyloidosis or diabetes.[1] Increased risk of osteitis fibrosa cystica and osteomalacia due to loss of vitamin D-binding protein and its complexes in the urine, through a combination of calcium malabsorption and secondary hyperparathyroidism. http://www.patient.co.uk/doctor/nephrotic-syndrome-pro
Nephrotic syndrome, or nephrosis, is defined by the presence of nephrotic-range proteinuria, edema, hyperlipidemia, and hypoalbuminemia. While nephrotic-range proteinuria in adults is characterized by protein excretion of 3.5 g or more per day, in children it is defined as protein excretion of more than 40 mg/m2/h or a first-morning urine protein/creatinine of 2-3 mg/mg creatinine or greater.

Essential update: New guidelines from KDIGO

The Kidney Disease: Improving Global Outcomes (KDIGO) group released new guidelines that address management of steroidsensitive nephrotic syndrome in children aged 118 years.[1] Highlights of these new guidelines include: Definition of nephrotic syndrome: edema, urine protein:creatinine ratio 2000 mg/g; urine protein 300 mg/dL, dipstick urine protein 3+, hypoalbuminemia 2.5 mg/L. Initial treatment: Oral prednisone, starting as a daily dose of 60 mg/m2/day or 2 mg/kg/day (maximum, 60 mg/day) for 46 weeks. After 46 weeks, switch to 40 mg/m2 or 1.5 mg/kg (maximum, 40 mg) on alternate days for 2 5 months with tapering, with a minimum total duration of treatment of 12 weeks. Treatment of infrequent relapse (1 relapse in 6 months or 1 3 relapses in 12 months): Administer initial treatment dose (60 mg/m2/day or 2 mg/kg/day) until urinary protein is negative for 3 days. After urine is negative for protein for 3 days, change prednisone to 40 mg/m2 or 1.5 mg/kg (maximum, 40 mg) on alternate days for 4 weeks, then stop or taper dose. Treatment of frequent relapse (2 relapses in 6 months or 4 relapses in 12 months): Continue infrequent relapse treatment for 3 months at lowest dose to maintain remission or use corticosteroid-sparing agents, including alkylating agents, levamisole, calcineurin inhibitors, mycophenolate mofetil.

Signs and symptoms

Pitting edema is the presenting symptom in about 95% of children with nephrotic syndrome. It is typically found in the lower extremities, face and periorbital regions, scrotum or labia, and abdomen (ascites). Other signs and symptoms of nephrotic syndrome may include the following: Respiratory tract infection - A history of a respiratory tract infection immediately preceding the onset of nephrotic syndrome is frequent Allergy - Approximately 30% of children with nephrotic syndrome have a history of allergy [2] Macrohematuria Symptoms of infection - Such as fever, lethargy, irritability, or abdominal pain due to sepsis or peritonitis Hypotension and signs of shock - Can be present in children presenting with sepsis Respiratory distress - Due to either massive ascites and thoracic compression or frank pulmonary edema, effusions, or both Tachypnea - To compensate for mechanical restriction to breathing Seizure - Due to cerebral thrombosis

Anorexia Irritability Fatigue Abdominal discomfort Diarrhea Hypertension See Clinical Presentation for more detail.

Diagnosis
In order to establish the presence of nephrotic syndrome, laboratory tests should confirm the existence of (1) nephrotic-range proteinuria, (2) hypoalbuminemia, and (3) hyperlipidemia. Therefore, initial laboratory testing should include the following: Urinalysis Urine protein quantification Serum albumin Lipid panel The following tests should be performed to determine whether the nephrotic syndrome is idiopathic or secondary and, if INS has been determined, whether signs of chronic kidney disease, kidney insufficiency, or other signs exclude the possibility of minimal change nephrotic syndrome (MCNS): Complete blood count (CBC) Metabolic panel - levels of serum electrolytes, calcium, phosphorus, and ionized calcium, as well as of blood urea nitrogen (BUN) and creatinine Testing for HIV Testing for hepatitis B and C Complement studies (C3, C4) Antinuclear antibody (ANA), antidouble-stranded DNA antibody (in selected patients) Other tests and procedures in selected patients can include the following: Genetic studies Kidney ultrasonography Chest radiography Mantoux test Kidney biopsy See Workup for more detail.

Management
Corticosteroids If kidney biopsy is not initially indicated, a trial of corticosteroids is the first step in the treatment of INS. Diuretics Loop diuretics, such as furosemide (starting at 1-2 mg/kg/d), may improve edema. Metolazone may be beneficial in combination with furosemide for resistant edema. Antihypertensive agents Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) can reduce hypertension and may also contribute to reducing proteinuria. However, ACE inhibitors and ARBs can cause birth defects, so adolescent women who are taking these agents must be counseled regarding use of birth control, and pregnancy testing should be considered before starting these agents. Calcium channel blockers and beta blockers may also be used as first-line agents for hypertension. Alkylating agents Alkylating agents (eg, cyclophosphamide [CYP], chlorambucil, nitrogen mustard) offer the benefit of possible sustained remission after a defined course of treatment, although with the possible risk of infertility and other side effects. Calcineurin inhibitors Calcineurin inhibitors (eg, cyclosporin A [CSA], tacrolimus [TAC]) are steroid-sparing agents that can also be used in children who fail to respond to, or who subsequently relapse after, treatment with CYP, or in children whose families object to the use of CYP.

Home monitoring Home monitoring of urine protein and fluid status is an important aspect of management. All patients and parents should be trained to monitor first morning urine proteins at home with urine dipstick. Urine testing at home is also useful in monitoring response (or nonresponse) to steroid treatment. See Treatment and Medication for more detail.

Image library
Schematic drawing of the glomerular barrier. Podo = podocytes; GBM = glomerular basement membrane; Endo = fenestrated endothelial cells; ESL = endothelial cell surface layer (often referred to as the glycocalyx). Primary urine is formed through the filtration of plasma fluid across the glomerular barrier (arrows); in humans, the glomerular filtration rate (GFR) is 125 mL/min. The plasma flow rate (Qp) is close to 700 mL/min, with the filtration fraction being 20%. The concentration of albumin in serum is 40 g/L, while the estimated concentration of albumin in primary urine is 4 mg/L, or 0.1% of its concentration in plasma. Reproduced from Haraldsson et al, Physiol Rev 88: 451-487, 2008, and by permission of the American Physiological Society (www.the-aps.org).

Background
Pediatric nephrotic syndrome, also known as nephrosis, is defined by the presence of nephrotic-range proteinuria, edema, hyperlipidemia, and hypoalbuminemia. Nephrotic-range proteinuria in adults is characterized by protein excretion of 3.5 g or more per day. However, because of the great range of body sizes in children, the pediatric definition of nephrotic-range proteinuria is more cumbersome. Nephrotic-range proteinuria in children is protein excretion of more than 40 mg/m 2/h. Because 24-hour urine collections are potentially unreliable and burdensome, especially in young children, many pediatric nephrologists instead rely on a single, firstmorning urine sample to quantify protein excretion by the ratio of protein to creatinine. [3] The use of a first-morning urine sample eliminates the contribution of potentially nonpathological orthostatic proteinuria, which might otherwise falsely elevate the protein level in a urine sample collected while a patient is active during the day. A urine protein/creatinine value of more than 2-3 mg/mg indicates nephrotic range proteinuria and correlates with results from 24-hour urine collection. Nephrotic syndrome is a constellation of clinical findings that is the result of massive renal losses of protein. Thus, nephrotic syndrome is not a disease itself, but the manifestation of many different glomerular diseases. These diseases might be acute and transient, such as postinfectious glomerulonephritis, or chronic and progressive, such as focal segmental glomerulosclerosis (FSGS). Still other diseases might be relapsing and remitting, such as minimal change nephrotic syndrome (MCNS). The glomerular diseases that cause nephrotic syndrome generally can be divided into primary and secondary etiologies. Primary nephrotic syndrome (PNS), also known as idiopathic nephrotic syndrome (INS), is associated with glomerular diseases intrinsic to the kidney and not related to systemic causes. The subcategories of INS are based on histological descriptions, but clinical-pathological correlations have been made. A wide variety of glomerular lesions can be seen in INS. These include MCNS, focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), membranoproliferative glomerulonephritis (MPGN), C3 glomerulonephritis (C3GN), IgA nephropathy, diffuse mesangial proliferation, and others. By definition, secondary nephrotic syndrome refers to an etiology extrinsic to the kidney. Secondary causes of nephrotic syndrome include (1) autoimmune and vasculitic diseases, such as Henoch-Schnlein purpura (HSP), systemic lupus erythematosus, and antineutrophil cytoplasmic antibody (ANCA)associated vasculitis; (2) infectious diseases, such as congenital syphilis, malaria, human immunodeficiency virus (HIV), and hepatitis B and C; (3) malignancy; (4) environmental and drug exposure, such as heroin and mercury; and (5) systemic diseases such as diabetes mellitus, among many other causes (see Etiology). Nephrotic syndrome may also be caused by genetic abnormalities. Infantile NS (presenting before age 3 mo) and congenital NS (presenting at age 4-12 mo) have been associated with defects in the nephrin gene ( NPHS1), phospholipase C epsilon 1 gene (PLCE1), and the Wilms tumor suppressor gene ( WT1). Mutations in the podocin gene (NPHS2) are associated with a familial, autosomalrecessive form of FSGS. Mutations in the -actinin-4 gene (ACTN4) and the gene TRPC6are associated with autosomal-dominant forms of familial FSGS. Additionally, other genetic syndromes have been associated with nephrotic syndrome, such as nail-patella syndrome, Pierson syndrome, Schimke immuno-osseous dysplasia, and others. (See Pathophysiology and Etiology.) INS is divided into steroid-sensitive (SSNS) and steroid-resistant nephrotic syndrome (SRNS) because response to steroids has a high correlation with histological subtype and prognosis. The landmark study of nephrotic syndrome in children, the International Study of Kidney Disease in Children (ISKDC), found that the vast majority of preadolescent children with INS had MCNS on kidney biopsy.[4,

5]

Whereas 90% of children with MCNS responded to corticosteroid treatment with remission of their nephrotic syndrome, only 20% of children with FSGS responded to steroids. This article focuses on INS, primarily SSNS (which primarily consists of MCNS). The treatment and prognosis of SRNS (primarily FSGS in children) is briefly discussed. (see Treatment). The discussion of congenital and secondary nephrotic syndrome is beyond the scope of this article.

Pathophysiology
Proteinuria and hypoalbuminemia
Immune system The hallmark of INS is massive proteinuria, leading to decreased circulating albumin levels. The initiating event that produces proteinuria remains unknown. However, strong evidence suggests that INS, at least in part, has an immune pathogenesis. The effect of glucocorticoids on inducing remission in INS implicates the immune system, and particularly T-lymphocytes, in the pathogenesis of the condition. Glucocorticoids, primarily acting through the nuclear factor kappaB (NF-B) transcription pathway, have a variety of effects, including inhibiting cytokine production and inhibiting T-cell production and proliferation. A variety of studies provide further evidence of the role of T-cells in INS. Patients with INS in remission have alterations in the NFB pathway compared with healthy control subjects. NF-B transcription is up-regulated in relapse of INS compared with remission. Additionally, nephrotic syndrome has been reported in patients with Hodgkin lymphoma, a T-cell disease. Other observations in INS include altered thymic regulation of T-cell differentiation and alterations in T-cell subsets in INS patients compared with healthy controls. In addition to T-cells, the recent reports of remission in INS after treatment with rituximab, an anti-CD20 monoclonal antibody that results in complete depletion of B lymphocytes, implicate a role for B cells in the pathogenesis of INS. A circulating factor may play a role in the development of proteinuria in INS. This can be demonstrated by the rapid development of proteinuria in recurrence of nephrotic syndrome after kidney transplantation, the improvement in nephrotic syndrome in such patients after treatment with plasmapheresis, and the experimental induction of proteinuria in animals by plasma from patients with INS.[6] The nature of this circulating factor is not known. Various cytokines and molecules have been implicated, including the following[7] : Interleukin (IL)2, IL-4, IL-12, IL-13, IL-15, IL-18 IL-2 receptor Interferon- Tumor growth factor (TGF)- Vascular permeability factor Nuclear factor (NF)-B Tumor necrosis factor (TNF)- Recently, investigators have found high circulating levels of soluble urokinase receptor (suPAR) in children and adults with FSGS. Treatment of FSGS with immunosuppressive medications led to lower levels of suPAR, and a decline in suPAR levels over 26 weeks of treatment was associated with reduction in proteinuria. Interestingly, suPAR levels were higher in patients with familial FSGS and those with podocin mutations (see below). suPAR might act as a glomerular permeability factor. [8] The association of allergic responses with nephrotic syndrome also illustrates the role of the immune system in INS. Nephrotic syndrome has been reported to occur after allergic reactions to bee stings, fungi, poison ivy, ragweed, house dust, jellyfish stings and cat fur. Food allergy might play a role in relapses of INS; a reduced-antigenic diet was associated with improved proteinuria and complete remission in one study.[9] Additionally, INS is 3-4 times more likely in children with human leukocyte antigen (HLA)-DR7. Steroid sensitive INS has also been associated with HLA-B8 and theDQB1 gene of HAL-DQW2. A greater incidence of INS is also observed in children with atopy and HLA-B12.[10] Podocyte biology and genetics Perhaps the most exciting development in recent years in understanding the pathophysiology of nephrotic syndrome has occurred in the area of podocyte biology (see the image below).

Schematic drawing of the glomerular barrier. Podo = podocytes; GBM = glomerular basement membrane; Endo = fenestrated endothelial cells; ESL = endothelial cell surface layer (often referred to as the glycocalyx). Primary urine is formed through the filtration of plasma fluid across the glomerular barrier (arrows); in humans, the glomerular filtration rate (GFR) is 125 mL/min. The plasma flow rate (Qp) is close to 700 mL/min, with the filtration fraction being

20%. The concentration of albumin in serum is 40 g/L, while the estimated concentration of albumin in primary urine is 4 mg/L, or 0.1% of its concentration in plasma. Reproduced from Haraldsson et al, Physiol Rev 88: 451-487, 2008, and by permission of the American Physiological Society (www.the-aps.org).

The glomerular filtration barrier consists of the fenestrated capillary endothelium, the extracellular basement membrane, and the intercalated podocyte foot processes, connected by 35-45 nm slit diaphragms. Nephrotic syndrome is associated with the biopsy finding of fusion (effacement) of podocyte foot processes. This effacement of the podocytes long was thought to be a secondary phenomenon of nephrotic syndrome. However, theories have shifted toward the podocyte as playing a primary role in the development of proteinuria. The understanding of the pathophysiology of proteinuria in renal diseases has greatly expanded with insights into the molecular biology of the podocyte. Various forms of INS have been described with genetic mutations, such as those associated with the following [11, 12] : Slit-diaphragm and podocyte cytoskeleton -NPHS1, NPHS2, TRCP6, CD2AP, ACTN4, INF2, MYH9, MYO1E Phospholipases and second-messenger systems - PLCE1 Glomerular basement membrane -LAMB2 Transcription factors -WT1, LMX1B Lysosomal proteins -SCARB2 Mitochondrial proteins -COQ2 DNA-nucleosome restructuring mediator -SMARCAL1 Nephrin is a transmembrane protein that is a major structural element of the slit diaphragm and is encoded by the NPHS1 gene on chromosome 19. Mutations in the NPHS1 gene are responsible for autosomal recessive, congenital nephrotic syndrome of the Finnish type (FNS). FNS is characterized by massive proteinuria in the first year of life (usually within the first 3 mo) and progression to end-stage kidney disease within the first decade of life, although milder forms of the disease have been described. [11] Mutations inNPHS1 are usually associated with congenital nephrotic syndrome, but Philipe and colleagues have described NPHS1 mutations in children aged 6 months to 8 years with later-onset SRNS.[13] Santin has described NPHS1 mutations in patients with later childhood onset as well as adult-onset SRNS.[14] Podocin is another podocyte protein that interacts with nephrin and CD2AP and is integral to the assembly of the slit diaphragm. Podocin is encoded by the NPHS2gene on chromosome 1. Mutations in the NPHS2 gene were originally described in patients with autosomal recessive, steroid-resistant INS with FSGS on biopsy. Podocin mutations account for approximately 45-55% of familial and 8-20% of sporadic cases of SRNS.[11] -Actinin-4, encoded by the gene ACTN4 on chromosome 19, cross-links actin filaments of the podocyte cytoskeleton and anchors them to the glomerular basement membrane. The TRPC6 gene on chromosome 11 encodes for a calcium channel associated with the slit diaphragm.[11] Disruptions in either ACTN4 orTRPC6 are associated with autosomal dominant forms of FSGS.[10] CD2AP, which codes for a podocyte protein that associates with podocin and nephrin, has been associated with the development of nephrotic syndrome in animal models. However, the role it plays in human nephrotic syndrome is unclear. Various case reports have demonstrated heterozygous mutations inCD2AP in patients with nephrotic syndrome and FSGS. One report describes a single patient with a homozygous mutation in CD2AP and early onset of nephrotic syndrome with FSGS and diffuse mesangial sclerosis. [11] Because African Americans have a 3- to 4-fold higher risk of end-stage kidney disease compared with persons of European ancestry, genetic studies have sought to explain this higher propensity to kidney disease. In 2008, a strong association was found in African Americans between idiopathic and HIV-related FSGS, as well as hypertensive end-stage kidney disease, and mutations in the nonmuscle myosin heavy chain 9 (MYH9). Nonmuscle MYH9 is a podocyte protein that binds to the podocyte actin cytoskeleton to perform intracellular motor functions.[15] However, more recent studies have demonstrated that the increased risk of kidney disease previously ascribed to MYH9 was, in fact, more strongly associated with variations in the neighboring apolipoprotein L1 (APOL1) gene. Interestingly, theseAPOL1 variations, which are more common in African Americans but absent in whites, are able to lyse trypanosomes and may confer resistance to African sleeping sickness (Trypanosoma brucei rhodesiense infection).[16] Another nonmuscle myosin gene, MYO1E, was recently reported to be associated with FSGS in children. Mutation of the MYO1E gene led to disruption of the podocyte cytoskeleton.[17] Other genetic forms of nephrotic syndrome continue to shed light on the pathogenesis of INS. Mutations in the developmental regulatory gene WT1 are associated with forms of congenital nephrotic syndrome associated with male pseudohermaphroditism, Wilms tumor (Denys-Drash syndrome), andgonadoblastoma (Frasier syndrome). Mutations in phospholipase C epsilon 1 (PLCE1), a cytoplasmic enzyme required for podocyte maturation, have been associated with as many as 28% of cases of congenital nephrotic syndrome due to isolated (nonsyndromic) diffuse mesangial sclerosis. Nail-patella

syndrome, a disorder characterized by skeletal and nail dysplasia as well as nephrotic syndrome, is caused by mutations in the LMX1Bgene, which regulates expression of type IV collagen and the podocyte proteins nephrin, podocin, and CD2AP. [18] Pierson syndrome, characterized by microcoria, abnormal lens shape, cataracts, blindness, severe neurological deficits, congenital nephrotic syndrome and progressive kidney failure, is caused by a mutation in the LAMB2 gene that codes for laminin b2, which is found in glomerular basement membrane, retina, lens and neuromuscular synapses. [11] Other rare forms of nephrotic syndrome have been associated with mutations in SCARB2, which codes for a lysosomal protein; disruption of this gene causes a syndrome of myoclonus epilepsy and glomerulosclerosis. Alterations in the mitochondrial protein coded by the gene COQ2 are associated with a syndrome of encephalopathy and nephropathy. Finally, mutations in the DNAnucleosome restructuring mediator SMARCAL1 cause Schimke immuno-osseous dysplasia, a syndrome characterized by spondyloepiphyseal dysplasia (SED) resulting in disproportionate short stature, nephropathy, and T-cell deficiency.[12] The role of alterations in the slit diaphragm in MCNS has not been elucidated. Podocin appears to be expressed normally in MCNS but decreased in FSGS. Mutations in nephrin and podocin do not at this time appear to play a role in steroid-sensitive nephrotic syndrome. However, acquired alterations in slit diaphragm architecture might play a role in INS apart from actual mutations in the genes encoding podocyte proteins. Various authors have reported changes in expression and distribution of nephrin in MCNS. Coward et al demonstrated that nephrotic plasma induces translocation of the slit diaphragm proteins nephrin, podocin, and CD2AP away from the plasma membrane into the cytoplasm of the podocyte. [19] These authors also demonstrated the normal plasma might contain factors that maintain the integrity of slit diaphragm architecture and that the lack of certain factors (rather than the presence of an abnormal circulating factor) might be responsible for alterations in the podocyte architecture and development of INS. Thus, in addition to the traditional immunological theories of INS pathogenesis, it has become clear in recent years that INS is a podocytopathy. Podocytes also possess glucocorticoid receptors, which can lead to stabilization of the podocyte cytoskeleton and inhibit apoptosis. Cyclosporine, another important treatment for INS, can act directly on the podocyte by inhibiting phosphorylation of the podocyte protein synaptopodin, which plays an important role in the maintenance of the glomerular basement membrane. [6] Apart from the podocyte and slit diaphragm, alterations in the glomerular basement membrane also likely play a role in the proteinuria of nephrotic syndrome. In INS, the glomerular capillary permeability to albumin is selectively increased, and this increase in filtered load overcomes the modest ability of the tubules to reabsorb protein. In its normal state, the glomerular basement membrane is negatively charged because of the presence of various polyanions along this surface, such as heparan sulfate, chondroitin sulfate, and sialic acid. This negative charge acts as a deterrent to filtration of negatively charged proteins, such as albumin. Experimental models in which the negative charges are removed from the basement membrane show an increase in albuminuria. Children with MCNS have been reported to have decreased anionic charges in the glomerular basement membrane.[18]

Edema
The classical explanation for edema formation is a decrease in plasma oncotic pressure, as a consequence of low serum albumin levels, causing an extravasation of plasma water into the interstitial space. The resulting contraction in plasma volume (PV) leads to stimulation of the renin-angiotensin-aldosterone axis and antidiuretic hormone. The resultant retention of sodium and water by the renal tubules contributes to the extension and maintenance of edema. While the classical model of edema (also known as the "underfill hypothesis") seems logical, certain clinical and experimental observations do not completely support this traditional concept. First, the PV has not always been found to be decreased and, in fact, in most adults, measurements of PV have shown it to be increased. Only in young children with MCNS have most (but not all) studies demonstrated a reduced PV. Additionally, most studies have failed to document elevated levels of renin, angiotensin, or aldosterone, even during times of avid sodium retention. Active sodium reabsorption also continues despite actions that should suppress renin effects (eg, as albumin infusion or angiotensin-converting enzyme [ACE] inhibitor administration). Coupled with these discrepancies is the fact that, in the steroid-responsive nephrotic, diuresis usually begins before plasma albumin has significantly increased and before plasma oncotic pressure has changed. Some investigators have demonstrated a blunted responsiveness to atrial natriuretic peptide (ANP) despite higher-than-normal circulating plasma levels of ANP.[20] Another model of edema formation, the "overfill hypothesis," postulates a primary defect in renal sodium handling. A primary increase in renal sodium reabsorption leads to net salt and water retention and subsequent hypertension. ANP might play a role is this mechanism; studies have shown an impaired response to ANP in nephrotic syndrome. This ANP resistance, in part, might be caused by overactive efferent sympathetic nervous activity, as well as enhanced tubular breakdown of cyclic guanosine monophosphate.

Other mechanisms that contribute to a primary increase in renal sodium retention include overactivity of the Na + -K+ -ATPase and renal epithelial sodium channel (RENaC) in the cortical collecting duct and shift of the Na +/H+ exchanger NHE3 from the inactive to active pools in the proximal tubule.[20] A more recent theory of edema formation posits that massive proteinuria leads to tubulointerstitial inflammation and release of local vasoconstrictors and inhibition of vasodilation. This leads to a reduction in single-nephron glomerular filtration rate and sodium and water retention.[20] Thus, the precise cause of the edema and its persistence is uncertain. A complex interplay of various physiologic factors, such as the following, probably contribute: Decreased oncotic pressure Increased activity of aldosterone and vasopressin Diminished atrial natriuretic hormone Activities of various cytokines and physical factors within the vasa recti

Hyperlipidemia
INS is accompanied by disordered lipid metabolism. Apolipoprotein (apo)-Bcontaining lipoproteins are elevated, including verylow-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoproteins (LDL), and lipoprotein(a), with resultant increases in total cholesterol and LDL-cholesterol. The level of high-density lipoprotein (HDL) cholesterol is normal or low. Elevations in triglyceride levels occur with severe hypoalbuminemia. The traditional explanation for hyperlipidemia in INS was the increased synthesis of lipoproteins that accompany increased hepatic albumin synthesis due to hypoalbuminemia. However, serum cholesterol levels have been shown to be independent of albumin synthesis rates. Decreased plasma oncotic pressure may play a role in increased hepatic lipoprotein synthesis, as demonstrated by the reduction of hyperlipidemia in patients with INS receiving either albumin or dextran infusions. Also contributing to the dyslipidemia of INS are abnormalities in regulatory enzymes, such as lecithin-cholesterol acyltransferase, lipoprotein lipase, and cholesterol ester transfer protein.[20, 21]

Thrombosis
Patients with nephrotic syndrome are at increased risk for thrombosis. The incidence rate of thromboembolic complications (TEC) is about 25% in adults with nephrotic syndrome. The risk of TEC varies with the underlying disease. Infants with congenital nephrotic syndrome have an incidence of TEC of about 10%. The risk of thrombosis increases throughout childhood, and adolescents are at higher risk than younger children after the first year of life. The risk of TEC also is greater in secondary compared with primary nephrotic syndrome. Children with membranous nephropathy and nephrotic syndrome are at high risk of TEC, with an incidence of approximately 25%.[22] One study found the subclinical rate of pulmonary embolism in children with nephrotic syndrome to be 28% using scintigraphic pulmonary ventilation and perfusion studies. [23] The risk of TEC is greatest earlier in the course of nephrotic syndrome. The median time from diagnosis of nephrotic syndrome to TEC was found to be 70 days in a recent study. Other studies have shown that the majority of TEC occur within the first 3 months of diagnosis.[22] Renal vein thrombosis, deep vein thrombosis, and pulmonary embolism (PE) are the most frequently encountered TEC in children. Other venous sites of thrombosis include the superior sagittal sinus, other cerebral venous sites, and the inferior vena cava. Arterial thrombosis, although less common than venous TEC, can occur and has been reported at the axillary, subclavian, femoral, coronary, and mesenteric arteries.[24] Nephrotic syndrome is a hypercoagulable state. The increased risk of thrombosis can be attributed to 2 basic mechanisms: (1) urine losses of antithrombotic proteins and (2) increased synthesis of prothrombotic factors. [25] Abnormalities described in INS include decreased antithrombotic factors and increased synthesis of pro-thrombotic factors. Decreased antithrombotic factors include the following: Antithrombin III Proteins C and S (conflicting data) Increased synthesis of prothrombotic factors include the following: Increased platelet number, platelet activation and aggregation Elevation in levels of factors V, VIII, von Willebrand factor, 2 -plasmin inhibitor, plasminogen activator inhibitor 1, and fibrinogen Increased activities of tissue plasminogen activator and plasminogen activator inhibitor-1

These abnormalities in hemostatic factors, combined with potential hypovolemia, immobility, and increased incidence of infection, lead to a hypercoagulable state in INS.[2, 26]

Infection
Patients with INS are at increased risk of infection. Peritonitis and sepsis are the most common and serious infections. Peritonitis occurs at a rate of approximately 2-6% and may be accompanied by sepsis or bacteremia. The predominant bacterial causes are Streptococcus pneumoniae and Gram-negative enteric organisms such as Escherichia coli.[27] Various infections can also occur, including meningitis, cellulitis, viral infections, and others. Varicella is a particular concern in immunosuppressed patients and can be lethal. Prompt recognition and treatment with acyclovir (or postexposure prophylaxis with varicella-zoster immune globulin [VZIG]) is essential. Routine childhood varicella immunization has alleviated some of the concern regarding this complication. Infection, viral or bacterial, can trigger relapse of INS and further complicate the course of the condition. Risk of infection may be increased in INS because of low immunoglobulin (Ig)G levels, which do not appear to be the result of urinary losses. Instead, low IgG levels seem to be the result of impaired synthesis, again pointing to a primary disorder in lymphocyte regulation in INS. Additionally, increased urinary losses of factor B are noted. This is a cofactor of C3b in the alternative pathway of complement, which plays an important role in the opsonization of encapsulated organisms such as S pneumoniae. Impaired T-cell function may also be present in INS, which contributes to the susceptibility to infection. Finally, the medications used to treat INS, such as corticosteroids and alkylating agents, further suppress the immune system and increase the risk of infection.[2]

Acute kidney failure

Acute kidney failure (AKF) is a rare complication of INS, occurring in about 0.8% of cases. [28] Causes include the following[28] : Rapid progression of underlying disease (nephrotic syndrome other than MCNS, secondary nephrotic syndrome) Bilateral renal vein thrombosis Acute interstitial nephritis (AIN) due to drug therapy (eg, antibiotics, nonsteroidal anti-inflammatory agents [NSAIDs], diuretics) Acute tubular necrosis (ATN) due to hypovolemia or sepsis Use of ACE inhibitors or angiotensin II receptor blockers (ARBs) in conjunction with volume depletion can also precipitate AKF.

Etiology
Causes of INS include the following: MCNS FSGS MPGN Membranous glomerulonephritis (MGN) C3 glomerulonephritis IgA nephropathy Idiopathic crescentic glomerulonephritis Causes of genetic or congenital nephrotic syndrome include the following: Finnish-type congenital nephrotic syndrome ( NPHS1, nephrin) Denys-Drash syndrome (WT1) Frasier syndrome (WT1) Diffuse mesangial sclerosis (WT1, PLCE1) Autosomal recessive, familial FSGS (NPHS2, podocin) Autosomal dominant, familial FSGS (ACTN4, -actinin-4; TRPC6) Nail-patella syndrome (LMX1B) Pierson syndrome (LAMB2) Schimke immuno-osseous dysplasia (SMARCAL1) Galloway-Mowat syndrome Oculocerebrorenal (Lowe) syndrome Infections that can cause secondary nephrotic syndrome include the following: Congenital syphilis, toxoplasmosis, cytomegalovirus, rubella Hepatitis B and C HIV/acquired immunodeficiency syndrome (AIDS)

Malaria Drugs that can cause secondary nephrotic syndrome include the following: Penicillamine Gold Nonsteroidal anti-inflammatory drugs (NSAIDs) Interferon Mercury Heroin Pamidronate Lithium Systemic diseases that can cause secondary nephrotic syndrome include the following: Systemic lupus erythematosus Malignancy - Lymphoma, leukemia Vasculitis -Wegener granulomatosis (granulomatosis with polyangiitis), Churg-Strauss syndrome (eosinophilic granulomatosis with polyangiitis),polyarteritis nodosa, microscopic polyangiitis, Henoch-Schnlein purpura (HSP) Immune-complexmediated - Poststreptococcal (postinfectious) glomerulonephritis

Epidemiology
In the United States, the reported annual incidence rate of nephrotic syndrome is 2-7 cases per 100,000 children younger than 16 years. The cumulative prevalence rate is approximately 16 cases per 100,000 individuals. [29] The ISKDC found that 76.6% of children with INS had MCNS on kidney biopsy findings, with 7% of cases associated with FSGS on biopsy findings. [4, 30] A study from New Zealand found the incidence of nephrotic syndrome to be almost 20 cases per million children under age 15 years.[31] In specific populations, such as those of Finnish or Mennonite origin, congenital nephrotic syndrome may occur in 1 in 10,000 or 1 in 500 births, respectively.[32] Some studies have suggested a change in the histology of INS over the past few decades, although the overall incidence of INS has remained stable. The frequency of FSGS associated with INS appears to be increasing. A review of the literature suggested a 2-fold increase in the incidence of FSGS in recent decades.[33] However, another study found no evidence of an increasing incidence of FSGS.[34]

Race-, sex, and age-related demographics

Black and Hispanic children appear to have an increased risk of steroid-resistant nephrotic syndrome and FSGS.[34, 35] An increased incidence of INS is reported in Asian children, (6 times the rate seen in European children). An increased incidence of INS is also seen in Indian, Japanese, and Southwest Asian children. Primary, SSNS is rare in Africa, where nephrotic syndrome is more likely to be secondary or steroid-resistant. These variations in ethnic and geographic distribution of INS underscore the genetic and environmental influences in the development of PNS.[2] In children younger than 8 years at onset, the ratio of males to females varies from 2:1 to 3:2 in various studies. In older children, adolescents, and adults, the male-to-female prevalence is approximately equal. ISKDC data indicate that 66% of patients with either MCNS or FSGS are male, whereas 65% of individuals with MPGN are female. Of patients with MCNS, 70% are younger than 5 years. Only 20-30% of adolescents with INS have MCNS on biopsy findings. In the first year of life, genetic forms of INS and secondary nephrotic syndrome due to congenital infection predominate. [29]

Prognosis
Since the introduction of corticosteroids, the overall mortality of INS has decreased dramatically from over 50% to approximately 25%. Despite the improvement in survival, INS is usually a chronic, relapsing disease and most patients experience some degree of morbidity, including the following: Hospitalization, in some instances Frequent monitoring both by parents and by physician Administration of medications associated with significant adverse events A high rate of recurrence (relapses in >60% of patients) The potential for progression to chronic kidney failure and end-stage kidney failure (ESKD) Additionally, INS is associated with an increased risk of multiple complications, including edema, infection, thrombosis, hyperlipidemia, acute kidney failure, and possible increased risk of cardiovascular disease. The prognosis varies, depending on whether the nephrotic syndrome is steroid responsive or steroid resistant.

Steroid-responsive nephrotic syndrome

Patients who remain responsive to steroids with remission of proteinuria, even with frequent relapses, generally have a good prognosis. The ISKDC found that in 93% of children with INS who responded to steroids, kidney biopsy revealed MCNS. [5]In contrast, 75% of patients who did not initially respond to steroids had histology other than MCNS. About 90% of children with MCNS (but only 20% of children with focal segmental glomerulosclerosis [FSGS]) achieve remission after the initial course of steroid treatment. Despite the generally favorable prognosis in patients who respond to steroids, the ISKDC reported a 60% rate of subsequent relapses, which can lead to complications, increased morbidity, and decreased quality of life. [5] A longer course of initial steroid treatment (12 wk rather than the original ISKDC protocol of 8 wk) may reduce the rate of subsequent relapse to 36%, [36] which still represents a large number of patients who undergo repeated courses of immunosuppression, with possible hospitalizations, edema, infections, medication side effects, and other comorbidities. A long-term study of 398 children with INS found that the percentage of children who became free of relapses during the course of their disease rose from 44% one year after diagnosis to 69% at 5 years and 84% 10 years after diagnosis. [29, 37]Although most children with INS who respond to steroids achieve long-term remission, relapses may continue into adulthood. Older studies suggested that more than 90% of children achieve long-term remission without further relapses by puberty. However, this has recently been challenged by surveys indicating a rate of relapse during adulthood as high as 27-42%. In a retrospective study, Vivarelli et al reported that the length of time between initiation of steroid treatment and syndrome remission is an early prognostic indicator for children with INS.[38] In study patients who did not suffer relapse or who relapsed infrequently, the median time from treatment onset to remission was less than 7 days. In patients who had frequent relapses or who developed steroiddependent nephrotic syndrome, the median time to remission was more than 7 days. A study of 42 adult patients with a history of childhood INS found that 33% of patients continued to relapse into adulthood. Fortunately, overall morbidity (eg, bone disease, infections, malignancies, cardiovascular complications) remained low, and patients had normal adult height, body mass index (BMI), and kidney function. Predictors of adult relapse included the number of relapses during childhood and the use of immunosuppressant medications other than steroids (ie, cyclosporine, chlorambucil, cyclophosphamide).[39]

Steroid-resistant nephrotic syndrome

Approximately 10% of patients overall with INS do not respond to an initial trial of steroids (2% of patients with MCNS do not respond to steroids). Additionally, about 1-3% of patients who initially do respond to steroids later become resistant to treatment ("late non-responders").[2] Most patients who do not achieve remission of proteinuria with steroids have kidney biopsy findings other than MCNS. The most common diagnosis in these patients is FSGS. More than 60% of patients with nephrotic syndrome and FSGS who fail to achieve remission with any treatment progress to end-stage kidney disease (ESKD). In contrast, only 15% progression to ESKD is observed in patients with FSGS who achieve remission by any treatment.[40] Gipson et al reported a 90% lower risk of progression to ESKD in patients with INS who achieved remission. [41] Thus, patients with steroid-resistant INS have a good prognosis if remission of proteinuria can be achieved by other medications. Failure to respond to treatment (ie, failure to achieve remission) and kidney insufficiency at presentation are predictors of poor outcome and progression to ESKD.[42]

General complications
Complications are discussed in detail in previous sections (see Pathophysiology and History). Complications of INS include: Edema Hyperlipidemia Thrombosis (renal vein thrombosis, deep vein thrombosis, and pulmonary embolism are the most frequently encountered TEC in children. Other venous sites of thrombosis include the superior sagittal sinus, other cerebral venous sites, and the inferior vena cava.) Infection (spontaneous bacterial peritonitis, sepsis, cellulitis) Acute kidney failure Medication adverse effects (steroids, diuretics, albumin, steroid-sparing agents). (see Side-effects of drug therapy under Treatment)

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History
Edema is the presenting symptom in about 95% of children with nephrotic syndrome. Early on, the edema is intermittent and insidious, and its presence may not be appreciated. A common story is for the child to present to a primary care practitioner repeatedly for periorbital edema, which is ascribed to "allergies" until the edema progresses. Edema usually appears first in areas of low tissue resistance (eg, the periorbital, scrotal, and labial regions). It can progress rapidly or slowly. Ultimately, it becomes generalized and can be massive (anasarca). The edema is pitting and typically dependent in nature, being more noticeable in the face in the morning and predominantly in lower extremities later in the day. A history of a respiratory tract infection immediately preceding the onset of nephrotic syndrome is frequent, but the relevance to causation is uncertain. Upper respiratory infections, otitis media, and other infections are often associated with relapses of idiopathic nephrotic syndrome (INS) as well. Approximately 30% of children have a history of allergy. A hypersensitivity event, such as a reaction to bee sting or poison ivy, has been reported to precede the onset of INS in some cases. [2] Children with nephrotic syndrome occasionally present with gross hematuria. The frequency of macrohematuria depends on the histological subtype of nephrotic syndrome. It is more common in patients with membranoproliferative glomerulonephritis (MPGN) than in other causes, but its frequency in minimal change nephrotic syndrome (MCNS) has been reported to be as high as 3-4% of cases. Statistically, a higher percentage of patients with focal segmental glomerulosclerosis (FSGS) have microhematuria than those with MCNS, but this is not helpful in differentiating between types of nephrotic syndrome in the individual patient. Given the risk of thrombosis in INS, renal vein thrombosis must be considered in patients with significant hematuria. Rarely, a child can present with other symptoms secondary to thrombosis, such as seizure caused by cerebral thrombosis. A child might be brought to medical attention for symptoms of infection, such as fever, lethargy, irritability, or abdominal pain due to sepsis or peritonitis. Peritonitis can be mistaken for appendicitis or other cause of acute abdomen unless the child's proteinuria and edema are appreciated. Anorexia, irritability, fatigue, abdominal discomfort, and diarrhea are common. GI distress can be caused by ascites, bowel wall edema, or both. Respiratory distress can occur, due to either massive ascites and thoracic compression or frank pulmonary edema, effusions, or both. Except in rare cases of familial INS, no significant family history of kidney disease or INS is usually noted. Children are typically healthy prior to onset of INS and, except for the history of allergy and atopy noted above, do not usually have a significant past medical history related to INS.

Physical Examination
The most common clinical finding is edema. The edema is pitting and is typically found in the lower extremities, face and periorbital regions, scrotum or labia, and abdomen (ascites). In those children with marked ascites, mechanical restriction to breathing may be present, and the child may manifest compensatory tachypnea. Pulmonary edema and effusions can also cause respiratory distress. Hypertension can be present and is more common in children with FSGS and MPGN rather than MCNS. Physical findings can also be present due to complications of INS. Abdominal tenderness might indicate peritonitis. Hypotension and signs of shock can be present in children presenting with sepsis. Thrombosis can cause various findings, including tachypnea and respiratory distress (pulmonary thrombosis/embolism), hematuria (renal vein thrombosis), and seizure (cerebral thrombosis).

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Description
Nephrotic syndrome is characterized by high protein excretion, peripheral edema, and metabolic abnormalities Consists of clinical and laboratory abnormalities common to several primary and secondary kidney diseases, each characterized by increased permeability of the glomerular capillary wall to circulating plasma proteins, particularly albumin Presents with edema, hypoalbuminemia, and massive proteinuria (3.5 g/24 h or greater), hypertension, and hyponatremia Hyperlipidemia, lipiduria, and hypercoagulability are typically also present The most common primary cause in children is minimal change glomerulopathy; in adults, it is idiopathic membranous glomerulopathy A significant proportion of adults who show signs of nephrotic syndrome have a related systemic disease, such as diabetic glomerulosclerosis, amyloidosis, lupus erythematosus, or HIV nephropathy

Synonyms

Immediate action
Order immediate blood tests, including sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, creatinine, albumin, spot urine protein, and albumin-to-creatinine ratio, to assess the degree of proteinuria Chest radiography to rule out pulmonary edema Order more advanced blood tests, such as hepatitis A, B, and C; cytoplasmic antineutrophil cytoplasmic antibody (C-ANCA); perinuclear antineutrophil cytoplasmic antibody (P-ANCA); lupus antibody; HIV; and complement levels Insert intravenous lines and access for volume status; if the patient is volume overloaded, start treatment with powerful loop diuretics, such as furosemide Most of the time, patients can be treated with medication alone and do not require dialysis In patients with severe fluid retention, treatment may have to be given in the intensive care unit, with frequent monitoring of electrolytes

Urgent action
Urgently refer or admit patients with acute kidney injury or rapidly deteriorating renal function Urgently refer or admit patients with nephrotic crisis (as evidenced by massive edema, anorexia, vomiting, pleural effusions, muscle wasting, and pulmonary emboli)

Key points
A rapid diagnostic and confirmatory test for nephrotic-range proteinuria is the random urine protein-to-creatinine ratio, which gives a fairly close estimate of 24-hour urine collection. It is calculated as urinary protein in milligrams divided by urinary creatinine in mg, multiplied by 1000 in males and by 800 in females. The result of this calculation is expressed in grams of protein per day. This test can also be used as an outpatient guide to the therapy The most common cause of nephrotic syndrome in children and young adults is minimal change disease, which has an excellent prognosis with steroid therapy, and in fact a trial of steroids can be used as a diagnostic test The most common and benign form of nephrotic syndrome in adults is membranous glomerulonephritis, which has a fair prognosis if treated properly Always perform a kidney biopsy if the patient has no contraindications, such as a bleeding diathesis or advanced renal failure; this is the gold standard for the correct diagnosis and the best guide to therapy. Do not hesitate to repeat biopsy if the response is not as expected or if the patient's condition worsens

Background

Cardinal features
Nephrotic syndrome with proteinuria, hypoalbuminemia, and edema results from either a primary glomerular disorder (idiopathic nephrotic syndrome) or is a manifestation of systemic disease (in 30%-50% of cases in adults) Renal biopsy in idiopathic nephrotic syndrome in adults usually shows 1 of 4 pathologic entities: membranous glomerulonephropathy (30%-40% of idiopathic cases), focal segmental glomerulosclerosis (FSGS) (20%-30%), minimal change disease (10%-15%), or membranoproliferative glomerulonephritis (10%-20%) Minimal change disease accounts for more than 80% of all cases of nephrotic syndrome in children younger than 10 years of age but only 10% to 15% of primary cases in adults Most common associated multisystem diseases are diabetes mellitus (by far the most common),systemic lupus erythematosus and other collagen vascular diseases, and primary or secondaryamyloidosis, especially in older patients HIV infection is associated with a specific HIV-nephropathy Proteinuria in nephrotic syndrome is due to increased permeability of the glomerular basement membrane to albumin and arises in response to alterations in both the size and charge barriers of the glomerular filtration apparatus. Albumin is the predominant protein excreted Hypoalbuminemia seems to be due to failure of hepatic synthesis of albumin to compensate for the albumin lost in urine. Release of cytokines may also suppress hepatic albumin synthesis Edema: Plasma oncotic pressure decreases because of proteinuria and a decrease in serum albumin concentration. This causes fluid to move from the vascular to the interstitial fluid compartment, initiating a series of pathophysiologic events that result in renal sodium retention and generalized edema. Edema may be massive and widely distributed, and it may vary with posture. Facial and upper-limb edema are characteristic and particularly obvious after recumbency. Transudative ascites and pleural effusions are often seen Hyperlipidemia and lipiduria: An increase in serum cholesterol and phospholipid levels and lipiduria are typically components of the nephrotic syndrome. This is due to increased hepatic synthesis, which may be triggered by the decrease in plasma oncotic pressure Other metabolic derangements: Many patients with nephrotic syndrome have a hypercoagulable state, possibly due to urinary loss of antithrombin III and decreased activity of proteins S and C. Loss of vitamin D-binding globulin may result in vitamin D deficiency,

hypocalcemia, osteomalacia, and secondary hyperparathyroidism. Loss of immunoglobulins may result in impaired immunity and increased rates of infections. Depletion of transferrin may result in iron-deficiency anemia

Causes
Common causes
Most commonly, nephrotic syndrome is primary or idiopathic. Minimal change glomerulopathy: Accounts for 80% of cases of nephrotic syndrome in children younger than 10 years, approximately 50% of cases in older children, and 10% to 15% of cases in adults No cause is found in most patients. Disease is immunologically mediated and related to abnormal T-cell function rather than immunecomplex deposition Patients usually present with full-blown pure nephrotic syndrome Hypertension and microscopic hematuria are uncommon, but one of these may occur in 20% to 30% of patients Renal impairment and acute kidney injury can occur but are rare Severe edema, ascites, and pleural effusions may occur Spontaneous remission may occur in rare cases, but it is seldom justified to leave the patient untreated, because persistent nephrotic syndrome causes significant morbidity and mortality The risk of relapse decreases with time, and relapse is often precipitated by a minor upper respiratory tract infection Nonsteroidal anti-inflammatory drugs (NSAIDs) may cause minimal change disease in adults. This medication history needs to be elicited during examination Focal segmental glomerulosclerosis: Important entity associated with primary nephrotic syndrome in adults and children; forms part of a spectrum that ranges from minimal change to steroid-resistant FSGS Its incidence seems to be increasing, particularly in African American males but also in the white population Primary FSGS accounts for 10% to 15% of cases of nephrotic syndrome in children and as many as 35% of cases in adults May be idiopathic or secondary to a systemic disease, such as reflux nephropathy or HIV Poor prognosis with high rate of progression to end-stage renal disease (more than 80% untreated cases) Presents with proteinuria, often full-blown nephrotic syndrome, impaired or deteriorating renal function, and hypertension in 30% to 50% of patients. Proteinuria is unselective Spontaneous remission is rare Secondary FSGS is the final result of many different causes of glomerular injury: late-stage focal glomerulonephritis, renal dysplasia, reflux nephropathy, surgical loss of renal mass, sickle cell disease, obesity, cyanotic heart disease, heroin abuse, HIV nephropathy, or aging. Prognosis is determined by the underlying condition Mutation in several genes encoding the podocyte protein have been identified as a possible cause of FSGS Membranous nephropathy: Most common clinicopathologic entity associated with idiopathic nephrotic syndrome in adults May be primary or secondary to a wide range of diseases. Its pathogenesis is unknown, and treatment is controversial 80% of patients present with nephrotic syndrome, and the remainder present with lesser degrees of proteinuria. Occasionally, patients may present with acute kidney injury as a complication of nephrotic syndrome Up to 50% of patients are hypertensive at presentation Membranoproliferative glomerulonephritis: Group of immune complex diseases: type 1 (mesangiocapillary glomerulonephritis); type 2 (dense deposit disease), with characteristic histologic appearance that may be idiopathic or caused by another disease ( eg, hepatitis C or cryoglobulinemia) Both types usually present with mixed nephrotic and nephritic syndrome; urine sediment contains nephritic components, such as hematuria and erythrocyte casts, as well as evidence of lipiduria (oval fat bodies) associated with nephrotic-range proteinuria Hypertension is common Up to 30% of patients present with rapidly deteriorating renal function Slow progression to end-stage renal disease is the usual course Spontaneous remission is rare Secondary causes:

Diabetic glomerulosclerosis due to both type 1 and type 2 diabetes mellitus is the most common systemic disease causing nephrotic syndrome Systemic lupus erythematosus with renal involvement may occasionally present with nephrotic syndrome and the morphology of membranous glomerulopathy on renal biopsy Amyloid causes proteinuria, nephrotic syndrome, and progressive renal failure Myeloma may present initially with nephrotic syndrome associated with secondary amyloid

Rare causes
Syphilis Sickle cell disease Hepatitis B Malaria Cancer (carcinomas and lymphomas) Reflux nephropathy NSAIDs

Contributory or predisposing factors

Minimal change disease: Although usually idiopathic, may also be caused by mercury or lead exposure; Hodgkin disease; cancer; drugs, such as NSAIDs or sulfasalazine and its derivatives; food allergies; infectious mononucleosis; and HIV infection Focal segmental glomerulosclerosis: 20% to 30% of patients have underlying disease Hypertension Reflux nephropathy Sleep apnea Membranous nephropathy: Tumors (15% of cases; proportion increases with age) Drugs, especially gold and penicillamine Infection: hepatitis B, syphilis, malaria Systemic lupus erythematosus Sickle cell disease Membranoproliferative glomerulonephritis: Systemic lupus erythematosus Mixed essential cryoglobulinemia Cryoglobulinemia secondary to chronic infection, including hepatitis C, subacute bacterial endocarditis, HIV Homozygous for sickle cell Intravenous drug abuse Partial lipodystrophy Cancer and chronic lymphocytic leukemia

Epidemiology
Incidence and prevalence

Incidence
Children: 2 per 100,000 persons per year Adults: 3 to 4 per 100,000 persons per year

Demographics

Age
Minimal change disease accounts for more than 80% of all cases of nephrotic syndrome in children younger than 10 years but only 10% to 15% of primary cases in adults.

Gender
Minimal change disease: boys are affected twice as frequently as girls, but the gender ratio is equal in adults.

Race
FSGS is the predominant cause of nephrotic syndrome in African Americans.

Genetics
Familial renal diseases, such as Alport syndrome, nail-patella syndrome, and congenital nephrotic syndrome, may cause nephrotic syndrome Reflux nephropathy has a strong familial component and may cause renal failure with nephrotic syndrome

https://www.clinicalkey.com/topics/nephrology/nephrotic-syndrome.html#677302

What conditions are associated with childhood nephrotic syndrome?

Minimal Change Disease The condition most commonly associated with childhood nephrotic syndrome is minimal change disease. Doctors do not know what causes it. The condition is called minimal change disease because children with this form of the nephrotic syndrome have normal or nearly normal appearing kidney biopsies. If a child is diagnosed with minimal change disease, the doctor will probably prescribe prednisone, which belongs to a class of drugs called corticosteroids. Prednisone stops the movement of protein from the blood into the urine, but it does have side effects that the doctor will explain. Following the doctor's directions exactly is essential to protect the child's health. The doctor may also prescribe another type of drug called a diuretic, which reduces the swelling by helping the child urinate more frequently. When protein is no longer present in the urine, the doctor will begin to reduce the dosage of prednisone. This process takes several weeks. Some children never get sick again, but most experience a relapse, developing swelling and protein in the urine again, usually following a viral illness. However, as long as the child continues to respond to prednisone and the urine becomes protein free, the child has an excellent long-term outlook without kidney damage. Children who relapse frequently, or who seem to be dependent on prednisone or have side effects from it, may be given a second type of drug called a cytotoxic agent. The agents most frequently used are cyclophosphamide and chlorambucil. After reducing protein in the urine with prednisone, the doctor may prescribe the cyclophosphamide or chlorambucil for 8 to 12 weeks. Alternatively, cyclosporine, a drug also used in transplant patients, may be given. Treatment with cyclosporine frequently continues over an extended period. In recent years, doctors have explored the use of mycophenolate mofetil (MMF) instead of cytotoxic agents for children who relapse frequently. MMF is an immunosuppressant used to treat autoimmune diseases and to keep the body from rejecting a transplanted organ. MMF has not been tested for treating minimal change disease in large clinical trials, but doctors report promising results with small numbers of patients. MMF has milder side effects than cytotoxic agents, but taking immunosuppressants can raise the risk of infection and other diseases. The good news is that most children outgrow minimal change disease by their late teens with no permanent damage to their kidneys. Focal Segmental Glomerulosclerosis (FSGS) and Membranoproliferative Glomerulonephritis (MPGN) In about 20 percent of children with nephrotic syndrome, a kidney biopsy reveals scarring or deposits in the glomeruli. The two most common diseases that damage these tiny blood-filtering units are FSGS and MPGN. Because prednisone is less effective in treating these diseases than it is in treating minimal change disease, the doctor may use additional therapies, including cytotoxic agents. Recent experience with another class of drugs called ACE inhibitors, usually used to treat high blood pressure, indicates these drugs can help decrease the amount of protein leaking into the urine and keep the kidneys from being damaged in children with FSGS or MPGN. Congenital Nephropathy Rarely, a child may be born with congenital nephropathy, a condition that causes nephrotic syndrome. The most common form of this condition is congenital nephropathy of the Finnish type (CNF), inherited as an autosomal recessive trait-meaning the gene for CNF must be inherited from both parents. Another condition that causes nephrotic syndrome in the first months of life is diffuse mesangial sclerosis (DMS). The pattern of inheritance for DMS is not as clearly understood as the pattern for CNF, although the condition does appear to be genetic. Since medicines have little effect on congenital nephropathy, transplantation is usually required by the second or third year of life, when the child has grown enough to receive a kidney. To keep the child healthy, the doctor may recommend infusions of the protein albumin to make up for the protein lost in urine and prescribe a diuretic to help eliminate the extra fluid that causes swelling. The child's immune system may be weakened, so antibiotics should be given at the first sign of infection. Congenital nephropathy can disturb thyroid activity, so the child may need the substitute hormone thyroxine to promote growth and help bones mature. Some children with congenital nephropathy have excessive blood clotting, or thrombosis, which must be treated with a blood thinner like warfarin. A child with congenital nephropathy may need tube feedings to ensure proper nutrition. In some cases, the diseased kidneys may need to be removed to eliminate proteinuria. Dialysis will then be required to replace kidney function until the child's body is big enough to receive a transplanted kidney. Peritoneal dialysis is preferable to hemodialysis for young children. In peritoneal dialysis, a catheter is surgically placed in the abdomen and then used to introduce a solution into the abdominal cavity, or peritoneum. The solution draws wastes and extra fluid from the bloodstream. After a few hours, the solution is drained and replaced

with a fresh supply. The drained solution carries the wastes and extra fluid out of the body.

http://kidney.niddk.nih.gov/kudiseases/pubs/childkidneydiseases/nephrotic_syndrom/ II. PATHOPHYSIOLOGY A. ANATOMY AND PHYSIOLOGY OF THE KIDNEYS The kidneys are remarkable organs. Each is smaller than a persons fist, but in a single day the two organs process approximately 1700 L of blood and combine its waste products into approximately 1.5 L of urine. As part of their function, the kidneys filter physiologically essential substances, such as sodium (Na+) and potassium (K+) ions, from the blood and selectively reabsorb those substances that are needed to maintain the normal composition of internal body fluids. Substances that are not needed or are in excess of those needed for this purpose pass into the urine. In regulating the volume and composition of body fluids, the kidneys perform excretory and endocrine functions. The renin-angiotensin mechanism participates in the regulation of blood pressure and the maintenance of circulating blood volume, and erythropoietin stimulates red blood cell production. Gross Structure and Location The kidneys are paired, bean-shaped organs that lie outside the peritoneal cavity in the back of the upper abdomen, one on each side of the vertebral column at the level of the 12th thoracic to 3rd lumbar vertebrae. The right kidney normally is situated lower than the left, presumably because of the position of the liver. In the adult, each kidney is approximately 10 to 12 cm long, 5 to 6 cm wide, and 2.5 cm deep, and weighs approximately 113 to 170 g (What about in children?). The medial border of the kidney is indented by a deep fissure called the hilus. It is here that blood vessels and nerves enter and leave the kidney. The ureters, which connect the kidneys with the bladder, also enter the kidney at the hilus. The kidney is a multilobular structure, composed of up to 18 lobes (what about how many in children?). Each lobe is composed of nephrons, which are the functional units of the kidney. Each nephron has a glomerulus that filters the blood and a system of tubular structures that selectively reabsorb material from the filtrate back into the blood and secrete materials from the blood into the filtrate as urine is being formed. On longitudinal section, a kidney can be divided into an outer cortex and an inner medulla. The cortex, which is reddish-brown, contains the glomeruli and convoluted tubules of the nephron and blood vessels. The medulla consists of lightcolored, cone-shaped massesthe renal pyramidsthat are divided by the columns of the cortex (i.e., columns of Bertin) that extend into the medulla. Each pyramid, topped by a region of cortex, forms a lobe of the kidney. The apices of the pyramids form the papillae (i.e., 8 to 18 per kidney, corresponding to the number of lobes), which are perforated by the openings of the collecting ducts. The renal pelvis is a wide, funnel-shaped structure at the upper end of the ureter. It is made up of the calyces or cuplike structures that drain the upper and lower halves of the kidney.

The kidney is sheathed in a fibrous external capsule and surrounded by a mass of fatty connective tissue, especially at its ends and borders. The adipose tissue protects the kidney from mechanical blows and assists, together with the attached blood vessels and fascia, in holding the kidney in place. Although the kidneys are relatively well protected, they may be bruised by blows to the loin or by compression between the lower ribs and the ileum. Because the kidneys are located outside the peritoneal cavity, injury and rupture do not produce the same threat of peritoneal involvement as that of other organs such as the liver or spleen. Renal Blood Supply Each kidney is supplied by a single renal artery that arises on either side of the aorta. As the renal artery approaches the kidney, it divides into five segmental arteries that enter the hilus of the kidney. In the kidney, each segmental artery branches into several lobular arteries that supply the upper, middle, and lower parts of the kidney. The lobular arteries further subdivide to form the interlobular arteries at the level of the corticomedullary junction. These arteries give off branches, the arcuate arteries, that arch across the top of the pyramids. Small intralobular arteries radiate from the arcuate arteries to supply the cortex of the kidney. The afferent arterioles that supply the glomeruli arise from the intralobular arteries. Although nearly all the blood flow to the kidneys passes through the cortex, less than 10% is directed to the medulla and only approximately 1% goes to the papillae. Under conditions of decreased perfusion or increased sympathetic nervous system stimulation, blood flow is redistributed away from the cortex toward the medulla. This redistribution of blood flow decreases glomerular filtration while maintaining the urine concentrating ability of the kidneys, a factor that is important during conditions such as shock.

The Nephron Each kidney is composed of more than 1 million tiny, closely packed functional units called nephrons. Each nephron consists of a glomerulus, where blood is filtered, and a proximal convoluted tubule, loop of Henle, distal convoluted tubule, and collecting duct, where water, electrolytes, and other substances needed to

maintain the constancy of the internal environment are reabsorbed into the bloodstream while other, unneeded materials are secreted into the tubular filtrate for elimination.

Nephrons can be roughly grouped into two categories. Approximately 85% of the nephrons originate in the superficial part of the cortex and are called cortical nephrons. They have short, thick loops of Henle that penetrate only a short distance into the medulla. The remaining 15% are called juxtamedullary nephrons. They originate deeper in the cortex and have longer and thinner loops of Henle that penetrate the entire length of the medulla. The juxtamedullary nephrons are largely concerned with urine concentration.

The nephrons are supplied by two capillary systems, the glomerulus and the peritubular capillary network. The glomerulus is a unique, high-pressure capillary filtration system located between two arterioles, the afferent and the efferent arterioles. Because the arterioles are high resistance vessels and the afferent arteriole has a larger diameter than the efferent arteriole, the blood pressure in the glomerulus is extraordinarily high for a capillary bed and easily forces fluid and solutes out of the blood into the glomerular capillary along its entire length. The peritubular capillaries originate from the efferent arteriole. They are low-pressure vessels that are adapted for reabsorption rather than filtration. These capillaries surround all portions of the tubules, an arrangement that permits rapid movement of solutes and water between the fluid in the tubular lumen and the blood in the capillaries. In the deepest part of the renal cortex, the efferent arterioles serving the juxtaglomerular glomeruli also continue into long, thin-walled looping vessels called the vasa recta. The vasa recta accompany the long loops of Henle in the medullary portion of the kidney to assist in exchange of substances flowing in and out of that portion of the kidney. The peritubular capillaries rejoin to form the venous channels by which blood leaves the kidneys and empties into the inferior vena cava.

The Glomerulus The glomerulus consists of a compact tuft of capillaries encased in a thin, double-walled capsule called Bowmans capsule. Blood flows into the glomerular capillaries from the afferent arteriole and flows out of the glomerular capillaries into the efferent arteriole, which leads into the peritubular capillaries. Fluid and particles from the blood are filtered through the capillary membrane into a fluid-filled space in Bowmans capsule, called Bowmans space. The portion of the blood that is filtered into the capsule space is called the filtrate. The mass of capillaries and its surrounding epithelial capsule are collectively referred to as the renal corpuscle. The glomerular capillary membrane is composed of three layers: the capillary endothelial layer, the basement membrane, and the single-celled capsular epithelial layer. The endothelial layer lines the glomerulus and interfaces with blood as it moves through the capillary. This layer contains many small perforations, called fenestrations. The epithelial layer that covers the glomerulus is continuous with the epithelium that lines Bowmans capsule. The cells of the epithelial layer have unusual octopus-like structures that possess a large number of extensions, or foot processes (i.e., podocytes), which are embedded in the basement membrane. These foot processes form slit pores through which the glomerular filtrate passes. The basement membrane consists of a homogeneous acellular meshwork of collagen fibers, glycoproteins, and mucopolysaccharides. Because the endothelial and epithelial layers of the glomerular capillary have porous structures, the basement membrane determines the permeability of the glomerular capillary membrane. The spaces between the fibers that make up the basement membrane represent the pores of a filter and determine the size-dependent permeability barrier of the glomerulus. The size of the pores in the basement membrane normally prevents red blood cells and plasma proteins from passing through the glomerular membrane into the filtrate. There is evidence that the epithelium plays a major role in producing the basement membrane components, and the epithelial cells probably are active in forming new basement membrane material throughout life. Alterations in the structure and function of the glomerular basement membrane are responsible for the leakage of proteins and blood cells into the filtrate that occurs in many forms of glomerular disease. Another important component of the glomerulus is the mesangium. In some areas, the capillary endothelium and the basement membrane do not completely surround each capillary. Instead, the mesangial cells, which lie between the capillary tufts, provide support for the glomerulus in these areas. The mesangial cells produce an intercellular substance similar to that of the basement membrane. This substance covers the endothelial cells where they are not covered by basement membrane. The mesangial cells possess (or can develop) phagocytic properties and remove macromolecular materials that enter the intercapillary spaces. Mesangial cells also exhibit contractile properties in response to neurohumoral substances and are thought to contribute to the regulation of blood flow through the glomerulus. In normal glomeruli, the mesangial area is narrow and contains only a small number of cells. Mesangial hyperplasia and increased mesangial matrix occur in a number of glomerular diseases.

Structures of the Glomerulus

Cross-section of the glomerular membrane, showing the position of the endothelium , basement membrane, and epithelial foot processes

Position of the Mesangial cells in relation to the capillary loops and Bowmans capsule Tubular Components of the Nephron The nephron tubule is divided into four segments: a highly coiled segment called the proximal convoluted tubule, which drains Bowmans capsule; a thin, looped structure called the loop of Henle; a distal coiled portion called the distal convoluted tubule; and the final segment, called the collecting tubule, which joins with several tubules to collect the filtrate. The filtrate passes through each of these segments before reaching the pelvis of the kidney. The proximal tubule is a highly coiled structure that dips toward the renal pelvis to become the descending limb of the loop of Henle. The ascending loop of Henle returns to the region of the renal corpuscle, where it becomes the distal tubule. The distal convoluted tubule, which begins at the juxtaglomerular complex, is divided into two segments: the diluting segment and the late distal tubule. The late distal tubule fuses with the collecting tubule. Like the distal tubule, the collecting duct is divided into two segments: the cortical collecting tubule and the inner medullary collecting tubule. Throughout its course, the tubule is composed of a single layer of epithelial cells resting on a basement membrane. The structure of the epithelial cells varies with tubular function. The cells of the proximal tubule have a fine, villous structure that increases the surface area for reabsorption; they also are rich in mitochondria, which support active transport processes. The epithelial layer of the thin segment of the loop of Henle has few mitochondria, indicating minimal metabolic activity and reabsorptive function. Urine Formation

Urine formation involves the filtration of blood by the glomerulus to form an ultrafiltrate of urine and the tubular reabsorption of electrolytes and nutrients needed to maintain the constancy of the internal environment while eliminating waste materials. Glomerular Filtration Urine formation begins with the filtration of essentially protein-free plasma through the glomerular capillaries into Bowmans space. The movement of fluid through the glomerular capillaries is determined by the same factors (i.e., capillary filtration pressure, colloidal osmotic pressure, and capillary permeability) that affect fluid movement through other capillaries in the body. The glomerular filtrate has a chemical composition similar to plasma, but it contains almost no proteins because large molecules do not readily cross the glomerular wall. Approximately 125 mL of filtrate is formed each minute. This is called the glomerular filtration rate (GFR). This rate can vary from a few milliliters per minute to as high as 200 mL/minute. The location of the glomerulus between two arterioles allows for maintenance of a high-pressure filtration system. The capillary filtration pressure (approximately 60 mm Hg) in the glomerulus is approximately two to three times higher than that of other capillary beds in the body. The filtration pressure and the GFR are regulated by the constriction and relaxation of the afferent and efferent arterioles. Constriction of the efferent arteriole increases resistance to outflow from the glomeruli and increases the glomerular pressure and the GFR. Constriction of the afferent arteriole causes a reduction in the renal blood flow, glomerular filtration pressure, and GFR. The afferent and the efferent arterioles are innervated by the sympathetic nervous system and are sensitive to vasoactive hormones, such as angiotensin II, as well. During periods of stron sympathetic stimulation, such as shock, constriction of the afferent arteriole causes a marked decrease in renal blood flow and thus glomerular filtration pressure. Consequently, urine output can fall almost to zero. Tubular Reabsorption and Secretion From Bowmans capsule, the filtrate moves into the tubular segments of nephron. In its movement through the lumen tubular segments, the glomerular filtrate is considerably by the tubular transport of water Tubular transport can result in reabsorption substances from the tubular fluid into the capillaries or secretion of substances into the fluid from the blood in the peritubular The basic mechanisms of transport tubular epithelial cell membrane are similar other cell membranes in the body and include passive transport mechanisms. Water and urea are passively along concentration gradients. Sodium, K+, (Cl), calcium (Ca++), and phosphate ions, as well as urate, glucose, and amino reabsorbed using primary or secondary active mechanisms to move across the tubular Some substances, such as hydrogen, and urate ions, are secreted into the tubular Under normal conditions, only approximately 125 mL of glomerular filtrate that is formed is excreted in the urine. The other 124 mL is in the tubules. This means that the average urine is approximately 60 mL/hour.

glomerular the of the changed and solutes. of peritubular tubular capillaries. across the to those of active and absorbed chloride (PO4) acids are transport membrane. potassium, fluids. 1 mL of the each minute reabsorbed output of

Renal tubular cells have two membrane surfaces through which substances must pass as they are reabsorbed the tubular fluid. The outside membrane adjacent to the interstitial fluid is called the basolateral membrane, and the side that is contact with the tubular lumen and tubular is called the luminal membrane. In most substances move from the tubular filtrate tubular cell along a concentration gradient, they require facilitated transport or carrier systems to move across the basolateral membrane into the interstitial fluid, where are absorbed into the peritubular capillaries.

from that lies in filtrate cases, into the but

they

The bulk of energy used by the kidney is for active sodium transport transport depends on the energy-dependent Na+/K+-adenosine triphosphatase (ATPase) pump on the basolateral side of renal tubular cells. The pump maintains a low intracellular sodium concentration that facilitates the downhill (i.e., from a higher to lower concentration) movement of sodium from the filtrate across the luminal membrane. Cotransport uses a carrier system in which the downhill movement of one substance such as sodium is coupled to the uphill movement (i.e., from a lower to higher concentration) of another substance such as glucose or an amino acid. A few substances, such as the hydrogen (H+) ion, are secreted into the tubule using countertransport, in which the movement of one substance, such as sodium, enables the movement of a second substance in the opposite direction.

Proximal Tubule. Approximately 65% of all reabsorptive and secretory processes that occur in the tubular system take place in the proximal tubule. There is almost complete reabsorption of nutritionally important substances, such as glucose, amino acids, lactate, and water-soluble vitamins. Electrolytes, such as Na+, K+, Cl, and bicarbonate (HCO3), are 65% to 80% reabsorbed. As these solutes move into the tubular cells, their concentration in the tubular lumen decreases, providing a concentration gradient for the osmotic reabsorption of water and urea. The proximal tubule is highly permeable to water, and the osmotic movement of water occurs so rapidly that the concentration difference of solutes on either side of the membrane seldom is more than a few milliosmoles. Many substances, such as glucose, are freely filtered in the glomerulus and reabsorbed by energy-dependent cotransport carrier mechanisms. The maximum amount of substance that these transport systems can reabsorb per unit time is called the transport maximum. The transport maximum is related to the number of carrier proteins that are available for transport and usually is sufficient to ensure that all of a filtered substance such as glucose can be reabsorbed rather than being eliminated in the urine. The plasma level at which the substance appears in the urine is called the renal threshold. Under some circumstances, the amount of substance filtered in the glomerulus exceeds the transport maximum. For example, when the blood glucose level is elevated in uncontrolled diabetes mellitus, the amount that is filtered in the glomerulus often exceeds the transport maximum (approximately 320 mg/minute), and glucose spills into the urine. In addition to reabsorbing solutes and water, cells in the proximal tubule also secrete organic cations and anions into the urine filtrate (see Figs. 30-6 and 30-8). Many of these organic anions and cations are end products of metabolism (e.g., urate, oxalate) that circulate in the plasma. The proximal tubule also secretes exogenous organic compounds such as penicillin, aspirin, and morphine. Many of these compounds can be bound to plasma proteins and are not freely filtered in the glomerulus. Therefore, excretion by filtration alone eliminates only a small portion of these potentially toxic substances from the body. The Loop of Henle. The loop of Henle plays an important role in controlling the concentration of the urine. It does this by establishing a high concentration of osmotically active particles in the interstitium surrounding the medullary collecting tubules where the antidiuretic hormone exerts its effects. The loop of Henle is divided into three segments: the thin descending segment, the thin ascending segment, and thick ascending segment. The loop of Henle, taken as a whole, always reabsorbs more sodium and chloride than water. This is in contrast to the proximal tubule, which reabsorbs sodium and water in equal proportions. The thin descending limb is highly permeable to water and moderately permeable to urea, sodium, and other ions. As the urine filtrate moves down the descending limb, water moves out of the filtrate into the surrounding interstitium. Thus, the osmolality of the filtrate reaches its highest point at the elbow of the loop of Henle. In contrast to the descending limb, the ascending limb of the loop of Henle is impermeable to water. In this segment, solutes are reabsorbed, but water cannot follow and remains in the filtrate; as a result, the tubular filtrate becomes more and more dilute, often reaching an osmolality of 100 mOsm/kg of H2O as it enters the distal convoluted tubule, compared with the 285 mOsm/kg of H2O in plasma. This allows for excretion of free water from the body. For this reason, it is often called the diluting segment.

The thick segment of the loop of Henle begins in the ascending limb where the epithelial cells become thickened. As with the thin ascending limb, this segment is impermeable to water. The thick segment contains a Na+/K+/2Cl cotransport system. This system involves the cotransport of a positively charged Na+ and a positively charged K+ ion accompanied by two negatively charged Cl ions. The gradient for the operation of this cotransport system is provided by the basolateral Na+/K+-ATPase pump, which maintains a low intracellular sodium concentration. Approximately 20% to 25% of the filtered load of sodium, potassium, and chloride is reabsorbed in the thick loop of Henle. Movement of these ions out of the tubule leads to the development of a transmembrane potential that favors the passive reabsorption of small divalent cations such as calcium and magnesium. The thick ascending loop of Henle is the site of the powerful loop diuretics (e.g., furosemide [Lasix]), which exert their action by inhibiting the Na+/ K+/2Cl cotransporters.

Distal and Collecting Tubules. Like the thick ascending loop of Henle, the distal convoluted tubule is relatively impermeable to water, and reabsorption of sodium chloride from this segment further dilutes the tubular fluid. Sodium reabsorption occurs through a Na+/Cl cotransport mechanism. Approximately 5% of filtered sodium chloride is reabsorbed in this section of the tubule. Unlike the thick ascending loop of Henle, neither Ca++ nor Mg++ is passively absorbed in this segment of the tubule. Instead, Ca++ ions are actively reabsorbed in a process that is largely regulated by parathyroid hormone and possibly by vitamin D. The thiazide diuretics exert their action by inhibiting sodium chloride reabsorption in this segment of the renal tubules. The late distal tubule and the cortical collecting tubule constitute the site where aldosterone exerts its action on sodium reabsorption and potassium secretion and elimination. Although responsible for only 2% to 5% of sodium chloride reabsorption, this site is largely responsible for determining the final sodium concentration of the urine. The late distal tubule with the cortical collecting tubule also is the major site for regulation of potassium excretion by the kidney. When the body is confronted with a potassium excess, as occurs with a diet high in potassium content, the amount of potassium secreted at this site may exceed the amount filtered in the glomerulus. The mechanism for sodium reabsorption and potassium secretion in this section of the nephron is distinct from other tubular segments. This tubular segment is composed of two types of cells, the intercalated cells, where potassium is reabsorbed and hydrogen is secreted, and the principal cells, where aldosterone exerts its action. The secretion of H+ ions into the tubular fluid by the intercalated cells is accompanied by the reabsorption of HCO3 ions. The intercalated cells can also reabsorb K+ ions. The principal cells reabsorb Na+ and facilitate the movement of K+ into the urine filtrate. Under the influence of aldosterone, sodium moves from the urine filtrate into principal cells; from there, it moves into the surrounding interstitial fluid and peritubular capillaries. Potassium moves from the peritubular capillaries into the principal cells and then into the urine filtrate. Regulation of Urine Concentration The ability of the kidney to respond to changes in the osmolality of the extracellular fluids by producing either a concentrated or dilute urine depends on the establishment of a high concentration of osmotically active particles (approximately 1200 mOsm/kg of H2O) in the interstitium of the kidney medulla and the action of the antidiuretic hormone (ADH) in regulating the water permeability of the surrounding medullary collecting tubules. In approximately one fifth of the juxtamedullary nephrons, the loops of Henle and special hairpin-shaped capillaries called the vasa recta descend into the medullary portion of the kidney, forming a countercurrent system that controls water and solute movement so that water is kept out of the area surrounding the tubule and solutes are retained. The term countercurrent refers to a flow of fluids in opposite directions in adjacent structures. In this case, there is an exchange of solutes between the adjacent descending and ascending loops of Henle and between the ascending and descending sections of the vasa recta. Because of these exchange processes, a high concentration of osmotically active particles (approximately 1200 mOsm/kg of H2O) collects in the interstitium of the kidney medulla. The presence of these osmotically active particles in the interstitium surrounding the medullary collecting tubules facilitates the ADH-mediated reabsorption of water. ADH assists

in maintenance of the extracellular fluid volume by controlling the permeability of the medullary collecting tubules. Osmoreceptors in the hypothalamus sense an increase in osmolality of extracellular fluids and stimulate the release of ADH from the posterior pituitary gland. In exerting its effect, ADH, also known as vasopressin, binds to receptors on the basolateral side of the tubular cells. Binding of ADH to the vasopressin receptors causes water channels, known as aquaporin-2 channels, to move into the luminal side of the tubular cell membrane, producing a marked increase in water permeability. At the basolateral side of the membrane, water exits the tubular cell into the hyperosmotic interstitium of the medullary area, where it enters the peritubular capillaries for return to the vascular system. The aquaporin-2 channels are thought to have a critical role in inherited and acquired disorders of water reabsorption by the kidney (e.g., diabetes insipidus). Regulation of Renal Blood Flow In the adult, the kidneys are perfused with 1000 to 1300 mL of blood per minute, or 20% to 25% of the cardiac output. This large blood flow is mainly needed to ensure a sufficient GFR for the removal of waste products from the blood, rather than for the metabolic needs of the kidney. Feedback mechanisms, both intrinsic (e.g., autoregulation, local hormones) and extrinsic (e.g., sympathetic nervous system, blood-borne hormones), normally keep blood flow and GFR constant despite changes in arterial blood pressure. Neural and Humoral Control Mechanisms The kidney is richly innervated by the sympathetic nervous system. Increased sympathetic activity causes constriction of the afferent and efferent arterioles and thus a decrease in renal blood flow. Intense sympathetic stimulation such as occurs in shock and trauma can produce marked decreases in renal blood flow and GFR, even to the extent of causing blood flow to cease altogether. Several humoral substances, including angiotensin II, ADH, and the endothelins, produce vasoconstriction of renal vessels. The endothelins are a group of peptides released from damaged endothelial cells in the kidney and other tissues. Although not thought to be an important regulator of renal blood flow during everyday activities, endothelin I may play a role in reduction of blood flow in conditions such as postischemic acute renal failure. Other substances such as dopamine, nitric oxide, and prostaglandins ( i.e., E2 and I2) produce vasodilation. Nitric oxide, a vasodilator produced by the vascular endothelium, appears to be important in preventing excessive vasoconstriction of renal blood vessels and allowing normal excretion of sodium and water. Prostaglandins are a group of mediators of cell function that are produced locally and exert their effects locally. Although prostaglandins do not appear to be of major importance in regulating renal blood flow and GFR under normal conditions, they may protect the kidneys against the vasoconstricting effects of sympathetic stimulation and angiotensin II. Nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit prostaglandin synthesis may cause reduction in renal blood flow and GFR under certain conditions. Autoregulatory Mechanisms The constancy of renal blood flow is maintained by a process called autoregulation. Normally, autoregulation of blood flow is designed to maintain blood flow at a level consistent with the metabolic needs of the tissues. In the kidney, autoregulation of blood flow also must allow for precise regulation of solute and water excretion. For autoregulation to occur, the resistance to blood flow through the kidneys must be varied in direct proportion to the arterial pressure. The exact mechanisms responsible for the intrarenal regulation of blood flow are unclear. One of the proposed mechanisms is a direct effect on vascular smooth muscle that causes the blood vessels to relax when there is an increase in blood pressure, and to constrict when there is a decrease in pressure. A second proposed mechanism is the juxtaglomerular complex. The Juxtaglomerular Complex. The juxtaglomerular complex is thought to represent a feedback control system that links changes in the GFR with renal blood flow. The juxtaglomerular complex is located at the site where the distal tubule extends back to the glomerulus and then passes between the afferent and efferent arterioles. The distal tubular site that is nearest the glomerulus is characterized by densely nucleated cells called the macula densa. In the adjacent afferent arteriole, the smooth muscle cells of the media are modified as special secretory cells called juxtaglomerular cells. These cells contain granules of inactive renin, an enzyme

that functions in the conversion of angiotensinogen to angiotensin. Renin functions by means of angiotensin II to produce vasoconstriction of the efferent arteriole as a means of preventing large decreases in the GFR. Angiotensin II also increases sodium reabsorption indirectly by stimulating aldosterone secretion from the adrenal gland, and directly by increasing sodium reabsorption by the proximal tubule cells. Because of its location between the afferent and efferent arterioles, the juxtaglomerular complex is thought to play an essential feedback role in linking the level of arterial blood pressure and renal blood flow to the GFR and the composition of the distal tubular fluid. It is thought to monitor the systemic arterial blood pressure by sensing the stretch of the afferent arteriole and the concentration of sodium chloride in the tubular filtrate as it passes through the macula densa. This information is then used in determining how much renin should be released to keep the arterial blood pressure within its normal range and maintain a relatively constant GFR. Studies suggest that a decrease in the GFR slows the flow rate of the urine filtrate in the ascending loop of Henle, thereby increasing sodium and chloride reabsorption. This, in turn, decreases the delivery of sodium chloride to the macula densa. The decrease in delivery of sodium chloride to the macula densa has two effects: it decreases resistance in the afferent arterioles, which raises glomerular filtration pressure, and it increases the release of renin from the juxtaglomerular cells. The renin from these cells functions as an enzyme to convert angiotensinogen to angiotensin I, which is converted to angiotensin II. Finally, angiotensin II acts to constrict the efferent arteriole as a means of producing a further increase in the glomerular filtration pressure and thereby returning the GFR toward a more normal range.

Effect of Increased Protein and Glucose Load Even though renal blood flow and glomerular filtration are relatively stable under most conditions, two conditions can increase renal blood flow and glomerular filtration. These are an increased amount of protein in the diet and an increase in blood glucose. With ingestion of a high-protein diet, renal blood flow increases 20% to 30% within 1 to 2 hours. Although the exact mechanism for this increase is uncertain, it is thought to be related to the fact that amino acids and sodium are absorbed together in the proximal tubule (secondary active transport). As a result, delivery of sodium to the macula densa is decreased, which elicits an increase in renal blood flow through the juxtaglomerular complex feedback mechanism. The resultant increase in blood flow and GFR allows sodium excretion to be maintained at a near-normal level while increasing the excretion of the waste products of protein metabolism, such as urea. The same mechanism is thought to explain the large increases in renal blood flow and GFR that occur with high blood glucose levels in persons with uncontrolled diabetes mellitus. Elimination Functions of the Kidney

The functions of the kidney focus on elimination of water, waste products, excess electrolytes, and unwanted substances from the blood. Blood tests can provide valuable information about the kidneys ability to remove metabolic wastes and maintain the bloods normal electrolyte and pH composition. As renal function declines, there is an increase in serum levels of substances such urea, creatinine, phosphate, and potassium. Renal Clearance Renal clearance is the volume of plasma that is completely cleared each minute of any substance that finds its way into the urine. It is determined by the ability of the substance to be filtered in the glomeruli and the capacity of the renal tubules to reabsorb or secrete the substance. Every substance has its own clearance rate, the units of which are always volume of plasma per unit time. It can be determined by measuring the amount of a substance that is excreted in the urine (i.e., urine concentration urine flow rate in milliliters per minute) and dividing by its plasma concentration. Inulin, a large polysaccharide, is freely filtered in the glomeruli and neither reabsorbed nor secreted by the tubular cells. After intravenous injection, the amount that appears in the urine is equal to the amount that is filtered in the glomeruli (i.e., the clearance rate is equal to the GFR). Because of these properties, inulin can be used as a laboratory measure of the GFR. Some substances, such as urea, are freely filtered in the glomeruli, but the volume that is cleared from the plasma is less than the GFR, indicating that at least some of the substance is being reabsorbed. At normal plasma levels, glucose has a clearance of zero because it is reabsorbed in the tubules and none appears in the urine. Regulation of Sodium and Potassium Elimination Elimination of sodium and potassium is regulated by the GFR and by humoral agents that control their reabsorption. Aldosterone functions in the regulation of sodium and potassium elimination. Atrial natriuretic peptide (ANP) contributes to the regulation of sodium elimination. Sodium reabsorption in the distal tubule and collecting duct is highly variable and depends on the presence of aldosterone, a hormone secreted by the adrenal gland. In the presence of aldosterone, almost all the sodium in the distal tubular fluid is reabsorbed, and the urine essentially becomes sodium free. In the absence of aldosterone, virtually no sodium is reabsorbed from the distal tubule. The remarkable ability of the distal tubular and collecting duct cells to alter sodium reabsorption in relation to changes in aldosterone allows the kidneys to excrete urine with sodium levels that range from a few tenths of a gram to 40 g per day. Like sodium, potassium is freely filtered in the glomerulus, but unlike sodium, potassium is reabsorbed from and secreted into the tubular fluid. The secretion of potassium into the tubular fluid occurs in the distal tubule and, like that of sodium, is regulated by aldosterone. Only approximately 70 mEq of potassium is delivered to the distal tubule each day, but the average person consumes this much and more potassium in the diet. Excess potassium that is not filtered in the glomerulus and delivered to the collecting tubule therefore must be secreted (i.e., transported from the blood) into the tubular fluid for elimination from the body. In the absence of aldosterone, potassium secretion becomes minimal. In these circumstances, potassium reabsorption exceeds secretion, and blood levels of potassium increase. Atrial natriuretic peptide, discovered in 1981, is a hormone believed to have an important role in salt and water excretion by the kidney. It is synthesized in muscle cells of the atria of the heart and released when the atria are stretched. The actions of ANP include vasodilation of the afferent and efferent arterioles, which results in an increase in renal blood flow and glomerular filtration rate. ANP inhibits aldosterone secretion by the adrenal gland and sodium reabsorption from the collecting tubules through its action on aldosterone and through direct action on the tubular cells. It also inhibits ADH release from the posterior pituitary gland, thereby increasing excretion of water by the kidneys. ANP also has vasodilator properties. Whether these effects are sufficient to produce long-term changes in blood pressure is uncertain. Regulation of pH The kidneys regulate body pH by conserving base bicarbonate and eliminating hydrogen ions (H+). Neither the blood buffer systems nor the respiratory control mechanisms for carbon dioxide elimination can eliminate hydrogen ions from the body. This is accomplished by the kidneys. Virtually all the hydrogen ions excreted in the urine are secreted into the tubular fluid by means of tubular secretory mechanisms. The lowest tubular fluid pH that can be achieved is 4.4 to 4.5. The ability of the kidneys to excrete hydrogen ions depends on buffers in the urine that combine with the hydrogen ion. The three major urine buffers are bicarbonate (HCO3 ), phosphate (HPO4=), and ammonia (NH3). Bicarbonate ions, which are present in the urine filtrate, combine with hydrogen ions that have been secreted into the tubular fluid; this results in the formation of carbon dioxide and water. The carbon dioxide is then absorbed into the tubular cells and bicarbonate is

regenerated. The phosphate ion is a metabolic end product that is filtered into the tubular fluid; it combines with a secreted hydrogen ion and is not reabsorbed. Ammonia is synthesized in tubular cells by deamination of the amino acid glutamine; it diffuses into the tubular fluid and combines with the hydrogen ion. An important aspect of this buffer system is that the deamination process increases whenever the bodys hydrogen ion concentration remains elevated for 1 to 2 days. pH-Dependent Elimination of Organic Ions The proximal tubule actively secretes large amounts of different organic anions. Foreign anions ( e.g., salicylates, penicillin) and endogenously produced anions ( e.g., bile acids, uric acid) are actively secreted into the tubular fluid. Most of the anions that are secreted use the same transport system, allowing the kidneys to rid the body of many different drugs and environmental agents. Because the same transport system is shared by different anions, there is competition for transport such that elevated levels of one substance tend to inhibit the secretion of other anions. The proximal tubules also possess an active transport system for organic cations that is analogous to that for organic ions. Uric Acid Elimination Uric acid is a product of purine metabolism. Excessively high blood levels (i.e., hyperuricemia) can cause gout, and excessive urine levels can cause kidney stones. Uric acid is freely filtered in the glomerulus and is reabsorbed and secreted into the proximal tubules. Uric acid is one of the anions that use the previously described anion transport system in the proximal tubule. Tubular reabsorption normally exceeds secretion, and the net effect is removal of uric acid from the filtrate. Although the rate of reabsorption exceeds secretion, the secretory process is homeostatically controlled to maintain a constant plasma level. Many persons with elevated uric acid levels secrete less uric acid than do persons with normal uric acid levels. Uric acid uses the same transport systems as other anions, such as aspirin, sulfinpyrazone, and probenecid. Small doses of aspirin compete with uric acid for secretion into the tubular fluid and reduce uric acid secretion, and large doses compete with uric acid for reabsorption and increase uric acid excretion in the urine. Because of its effect on uric acid secretion, aspirin is not recommended for treatment of gouty arthritis. Thiazide and loop diuretics ( i.e., furosemide and ethacrynic acid) also can cause hyperuricemia and gouty arthritis, presumably through a decrease in extracellular fluid volume and enhanced uric acid reabsorption. Urea Elimination Urea is an end product of protein metabolism. The normal adult produces 25 to 30 g/day; the quantity rises when a highprotein diet is consumed, when there is excessive tissue breakdown, or in the presence of gastrointestinal bleeding. With gastrointestinal bleeding, the blood proteins are broken down to form ammonia in the intestine; the ammonia is then absorbed into the portal circulation and converted to urea by the liver before being released into the bloodstream. The kidneys, in their role as regulators of blood urea nitrogen (BUN) levels, filter urea in the glomeruli and then reabsorb it in the tubules. This enables maintenance of a normal BUN, which is in the range of 8 to 25 mg/dL (2.9 to 8.9 mmol/L). During periods of dehydration, the blood volume and GFR drop, and BUN levels increase. The renal tubules are permeable to urea, which means that the longer the tubular fluid remains in the kidneys, the greater is the reabsorption of urea into the blood. Only small amounts of urea are reabsorbed into the blood when the GFR is high, but relatively large amounts of urea are returned to the blood when the GFR is reduced. Drug Elimination Many drugs are eliminated in the urine. These drugs are selectively filtered in the glomerulus and reabsorbed or secreted into the tubular fluid. Only drugs that are not bound to plasma proteins are filtered in the glomerulus and therefore able to be eliminated by the kidneys. Many drugs are weak acids or weak bases and are present in the renal tubular fluid partly as water-soluble ions and partly as nonionized lipid-soluble molecules. The nonionized lipid-soluble form of a drug diffuses more readily through the lipid membrane of the tubule and then back into the bloodstream, whereas the water-soluble ionized form remains in the urine filtrate. The ratio of ionized to nonionized drug depends on the pH of the urine. For example, aspirin is highly ionized in alkaline urine and in this form is rapidly excreted in the urine. Aspirin is largely nonionized in acid urine and is reabsorbed rather than excreted. Alkaline or acid diuresis may be used to increase elimination of drugs in the urine, particularly in situations of drug overdose.

Endocrine Functions of the Kidney In addition to their function in regulating body fluids and electrolytes, the kidneys function as an endocrine organ in that they produce chemical mediators that travel through the blood to distant sites where they exert their actions. The kidneys participate in control of blood pressure through the reninangiotensinaldosterone mechanism, in calcium metabolism by activating vitamin D, and in regulating red blood cell production through the synthesis of erythropoietin. The Renin-Angiotensin-Aldosterone Mechanism The renin-angiotensin-aldosterone mechanism plays an important part in short- and long-term regulation of blood pressure. Renin is an enzyme that is synthesized and stored in the juxtaglomerular cells of the kidney. This enzyme is thought to be released in response to a decrease in renal blood flow or a change in the composition of the distal tubular fluid, or as the result of sympathetic nervous system stimulation. Renin itself has no direct effect on blood pressure. Rather, it acts enzymatically to convert a circulating plasma protein called angiotensinogen to angiotensin I. Angiotensin I, which has few vasoconstrictor properties, leaves the kidneys and enters the circulation; as it is circulated through the lungs, angiotensinconverting enzyme catalyzes the conversion of angiotensin I to angiotensin II. Angiotensin II is a potent vasoconstrictor, and it acts directly on the kidneys to decrease salt and water excretion. Both mechanisms have relatively short periods of action. Angiotensin II also stimulates aldosterone secretion by the adrenal gland. Aldosterone acts on the distal tubule to increase sodium reabsorption and exerts a longer-term effect on the maintenance of blood pressure. Renin also functions via angiotensin II to produce constriction of the efferent arteriole as a means of preventing a serious decrease in glomerular filtration pressure. Erythropoietin Erythropoietin is a polypeptide hormone that regulates the differentiation of red blood cells in the bone marrow. Between 89% and 95% of erythropoietin is formed in the kidneys. The synthesis of erythropoietin is stimulated by tissue hypoxia, which may be brought about by anemia, residence at high altitudes, or impaired oxygenation of tissues due to cardiac or pulmonary disease. Persons with endstage kidney disease often are anemic because of an inability of the kidneys to produce erythropoietin. This anemia usually is managed by the administration of a recombinant erythropoietin (epoetin alfa) produced through DNA technology, to stimulate erythropoiesis. Vitamin D Activation of vitamin D occurs in the kidneys. Vitamin D increases calcium absorption from the gastrointestinal tract and helps to regulate calcium deposition in bone. It also has a weak stimulatory effect on renal calcium absorption. Although vitamin D is not synthesized and released from an endocrine gland, it often is considered as a hormone because of its pathway of molecular activation and mechanism of action. Vitamin D exists in two forms: natural vitamin D (cholecalciferol), produced in the skin from ultraviolet irradiation, and synthetic vitamin D (ergocalciferol), derived from irradiation of ergosterol. The active form of vitamin D is 1,25-dihydroxycholecalciferol. Cholecalciferol and ergocalciferol must undergo chemical transformation to become active: first to 25-hydroxycholecalciferol in the liver and then to 1,25-dihydroxycholecalciferol in the kidneys. Persons with end-stage renal disease are unable to transform vitamin D to its active form and may require pharmacologic preparations of the active vitamin (calcitriol) for maintaining mineralization of their bones.

CAPILLARY FLUID EXCHANGE Movement of fluid between the vascular compartment and the interstitial fluid compartment surrounding the body cells occurs at the capillary level. The direction and amount of fluid that flows across the capillary wall are determined by: (1) the hydrostatic pressure of the two compartments, (2) the colloidal osmotic pressures of the two compartments, and (3) the removal of excess fluid and osmotically active particles from the interstitial spaces by the lymphatic system.

 Hydrostatic Pressure. The hydrostatic pressure is the pushing force exerted by a fluid. Inside the capillaries, the hydrostatic pressure is the same as the capillary filtration pressure, about 30 mm Hg at the arterial end and 10 mm Hg at the venous end. The interstitial fluid pressure is the force of fluid in the interstitial spaces pushing against the outside of the capillary wall. Evidence suggests that the interstitial pressure is slightly negative (3 mm Hg), contributing to the outward movement of fluid from the capillary.

Colloidal Osmotic Pressure. The colloidal osmotic pressure is the pulling force created by the presence of evenly dispersed particles, such as the plasma proteins, that cannot pass through the pores of the capillary membrane. The capillary colloidal osmotic pressure is normally about 28 mm Hg throughout the length of the capillary bed. The interstitial colloidal osmotic pressure (about 8 mm Hg) represents the pulling pressure exerted by the small amounts of plasma proteins that leak through the pores of the capillary wall into the interstitial spaces. The capillary colloidal osmotic pressure, which is greater than both the hydrostatic pressure at the venous end of the capillary and the interstitial colloidal osmotic pressure, is largely responsible for the movement of fluid back into the capillary.

Lymph Drainage. The lymphatic system represents an accessory system by which fluid can be returned to the circulatory system. Normally the forces moving fluid out of the capillary into the interstitium are greater than those returning fluid to the capillary. Any excess fluids and osmotically active plasma proteins that may have leaked into the interstitium are picked up by vessels of the lymphatic system and returned to the circulation. Without the function of the lymphatic system, excessive amounts of fluid would accumulate in the interstitial spaces.

Edema Edema can be defined as palpable swelling produced by expansion of the interstitial fluid volume. Edema does not become evident until the interstitial volume has been increased by 2.5 to 3 L.3 The physiologic mechanisms that contribute to edema formation include factors that (1) increase the capillary filtration pressure, (2) decrease the capillary colloidal osmotic pressure, (3) increase capillary permeability, or (4) produce obstruction to lymph flow. Increased Capillary Filtration Pressure. As the capillary filtration pressure rises, the movement of vascular fluid into the interstitial spaces increases. Among the factors that increase capillary pressure are (1) increased arterial pressure or decreased resistance to flow through the precapillary sphincters, (2) an increase in venous pressure or increased resistance to outflow at the postcapillary sphincter, and (3) capillary distention due to increased vascular volume. Edema can be either localized or generalized. The localized edema that occurs with urticaria (i.e., hives) or other allergic or inflammatory conditions results from the release of histamine and other inflammatory mediators that cause dilation of the precapillary sphincters and arterioles that supply the swollen lesions. Thrombophlebitis obstructs venous flow, producing an elevation of venous pressure and edema of the affected part, usually one of the lower extremities. Generalized edema (termed anasarca) is generally the result of increased vascular volume. The swelling of hands and feet that occurs in healthy persons during hot weather is an example of edema that is caused by the vasodilation of superficial blood vessels along with sodium and water retention. Generalized edema is common in conditions such as congestive heart failure that produce fluid retention and venous congestion. In right-sided heart failure, blood dams up throughout the entire venous system, causing organ congestion and edema of the dependent extremities. Because of the effects of gravity, edema resulting from increased capillary pressure commonly causes fluid to accumulate in the dependent parts of the body, a condition referred to as dependent edema. For example, edema of the ankles and feet becomes more pronounced during prolonged periods of standing. Decreased Capillary Colloidal Osmotic Pressure. Plasma proteins exert the osmotic force needed to pull fluid back into the capillary from the tissue spaces. The plasma proteins constitute a mixture of proteins, including albumin, globulins, and fibrinogen. Albumin, the smallest of the plasma proteins, has a molecular weight of 69,000; globulins have molecular weights of approximately 140,000; and fibrinogen has a molecular weight of 400,000. Because of its lower molecular weight, 1 g of albumin has approximately twice as many osmotically active molecules as 1 g of globulin and almost six times as many osmotically active molecules as 1 g of fibrinogen. Also, the concentration of albumin (approximately 4.5 g/dL) is greater than that of the globulins (2.5 g/dL) and fibrinogen (0.3 mg/dL). Edema due to decreased capillary colloidal osmotic pressure usually is the result of inadequate production or abnormal loss of plasma proteins, mainly albumin. The plasma proteins are synthesized in the

liver. In persons with severe liver failure, the impaired synthesis of albumin results in a decrease in colloidal osmotic pressure. In starvation and malnutrition, edema develops because there is a lack of amino acids for plasma protein synthesis. The most common site of plasma protein loss is the kidney. In kidney diseases such as glomerulonephritis, the glomerular capillaries become permeable to the plasma proteins, particularly albumin, which is the smallest of the proteins. When this happens, large amounts of albumin are filtered out of the blood and lost in the urine. An excessive loss of plasma proteins also occurs when large areas of skin are injured or destroyed. Edema is a common problem during the early stages of a burn, resulting from capillary injury and loss of plasma proteins. Because the plasma proteins are evenly distributed throughout the body and are not affected by the force of gravity, edema due to a decrease in capillary colloidal osmotic pressure tends to affect tissues in nondependent as well as dependent parts of the body. There is swelling of the face as well as the legs and feet. Increased Capillary Permeability. When the capillary pores become enlarged or the integrity of the capillary wall is damaged, capillary permeability is increased. When this occurs, plasma proteins and other osmotically active particles leak into the interstitial spaces, increasing the tissue colloidal osmotic pressure and thereby contributing to the accumulation of interstitial fluid. Among the conditions that increase capillary permeability are burn injury, capillary congestion, inflammation, and immune responses. Obstruction of Lymph Flow. Osmotically active plasma proteins and other large particles that cannot be reabsorbed through the pores in the capillary membrane rely on the lymphatic system for movement back into the circulatory system. Edema due to impaired lymph flow is commonly referred to as lymphedema. Malignant involvement of lymph structures and removal of lymph nodes at the time of cancer surgery are common causes of lymphedema. Another cause of lymphedema is infection and trauma involving the lymphatic channels and lymph nodes. B. READINGS Background Nephrotic syndrome is kidney disease with proteinuria, hypoalbuminemia, and edema. Nephrotic-range proteinuria is 3 grams per day or more. On a single spot urine collection, it is 2 g of protein per gram of urine creatinine. There are many specific causes of nephrotic syndrome. These include kidney diseases such as minimalchange nephropathy, focal glomerulosclerosis, and membranous nephropathy. Nephrotic syndrome can also result from systemic diseases that affect other organs in addition to the kidneys, such as diabetes, amyloidosis, and lupus erythematosus. Nephrotic syndrome may affect adults and children, of both sexes and of any race. It may occur in typical form, or in association with nephritic syndrome. The latter connotes glomerular inflammation, with hematuria and impaired kidney function. Classification Nephrotic syndrome can be primary, being a disease specific to the kidneys, or it can be secondary, being a renal manifestation of a systemic general illness. In all cases, injury to glomeruli is an essential feature. Primary causes of nephrotic syndrome include the following, in approximate order of frequency:

Minimal-change nephropathy Focal glomerulosclerosis Membranous nephropathy

Hereditary nephropathies

Secondary causes include the following, again in order of approximate frequency:

Diabetes mellitus Lupus erythematosus Amyloidosis and paraproteinemias Viral infections (eg, hepatitis B, hepatitis C, human immunodeficiency virus [HIV] ) Preeclampsia

see the Medscape Reference article Pediatric Nephrotic Syndrome. From a therapeutic perspective, nephrotic syndrome may be classified as steroid sensitive, steroid resistant, steroid dependent, or frequently relapsing. Corticosteroids (prednisone), cyclophosphamide, and cyclosporine are used to induce remission in nephrotic syndrome. Diuretics are used to reduce edema. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers are administered to reduce proteinuria. (See Treatment and Medication.) Pathophysiology In a healthy individual, less than 0.1% of plasma albumin may traverse the glomerular filtration barrier.[2] Controversy exists regarding the sieving of albumin across the glomerular permeability barrier. On the basis of studies in experimental animals, it has been proposed that there is ongoing albumin passage into the urine, in many grams per day, with equivalent substantial tubular uptake of albumin, the result being that the urine has 80 mg per day or less of daily albumin.[3] However, studies of humans with tubular transport defects suggest that the glomerular urinary space albumin concentration is 3.5 mg/L.[4] With this concentration, and a normal daily glomerular filtration rate (GFR) of 150 liters, one would expect no more than 525 mg per day of albumin in the final urine. Amounts above that level point to glomerular disease. The glomerular capillaries are lined by a fenestrated endothelium that sits on the glomerular basement membrane, which in turn is covered by glomerular epithelium, or podocytes, which envelops the capillaries with cellular extensions called foot processes. In between the foot processes are the filtration slits. These 3 structuresthe fenestrated endothelium, glomerular basement membrane, and glomerular epitheliumare the glomerular filtration barrier. A schematic drawing of the glomerular barrier is provided in the image below. Schematic drawing of the glomerular barrier. Podo = podocytes; GBM = glomerular basement membrane; Endo = fenestrated endothelial cells; ESL = endothelial cell surface layer (often referred to as the glycocalyx). Primary urine is formed through the filtration of plasma fluid across the glomerular barrier (arrows); in humans, the glomerular filtration rate (GFR) is 125 mL/min. The plasma flow rate (Qp) is close to 700 mL/min, with the filtration fraction being 20%. The concentration of albumin in serum is 40 g/L, while the estimated concentration of albumin in primary urine is 4 mg/L, or 0.1% of its concentration in plasma. Reproduced from Haraldsson et al, Physiol Rev 88: 451-487, 2008, and by permission of the American Physiological Society (www.the-aps.org). Filtration of plasma water and solutes is extracellular and occurs through the endothelial fenestrae and filtration slits. The importance of the podocytes and the filtration slits is shown by genetic diseases. Thus, in congenital

nephrotic syndrome of the Finnish type, the gene for nephrin, a protein of the filtration slit, is mutated, leading to nephrotic syndrome in infancy . Similarly, podocin, a protein of the podocytes, may be abnormal in a number of children with steroid-resistant focal glomerulosclerosis. The glomerular structural changes that may cause proteinuria are damage to the endothelial surface, the glomerular basement membrane, or the podocytes. One or more of these mechanisms may be seen in any one type of nephrotic syndrome. Albuminuria alone may occur, or, with greater injury, leakage of all plasma proteins, (ie, proteinuria) may take place. Proteinuria that is more than 85% albumin is selective proteinuria. Albumin has a net negative charge, and it is proposed that loss of glomerular membrane negative charges could be important in causing albuminuria. Nonselective proteinuria, being a glomerular leakage of all plasma proteins, would not involve changes in glomerular net charge but rather a generalized defect in permeability. This construct does not permit clear-cut separation of causes of proteinuria, except in minimal-change nephropathy, in which proteinuria is selective. Pathogenesis of edema An increase in glomerular permeability leads to albuminuria and eventually to hypoalbuminemia. In turn, hypoalbuminemia lowers the plasma colloid osmotic pressure, causing greater transcapillary filtration of water throughout the body and thus the development of edema. Capillary hydrostatic pressure and the gradient of plasma to interstitial fluid oncotic pressure determine the movement of fluid from the vascular compartment to the interstitium. The oncotic pressure is mainly determined by the protein content. The flux of water across the capillary wall can be expressed by the following formula: Qw = K ([Pc - Pi] - [pp - pi] In this formula, Qw is net flux of water, K is the capillary filtration coefficient, Pc is capillary hydrostatic pressure, and Pi is the interstitial fluid hydrostatic pressure, while pp is the plasma oncotic pressure, and pi is the interstitial fluid oncotic pressure. With a high enough capillary hydrostatic pressure or a low enough intravascular oncotic pressure, the amount of fluid filtered exceeds the maximal lymphatic flow, and edema occurs. In patients with nephrotic syndrome, this causes a reduction in plasma volume, with a secondary increase of sodium and water retention by the kidneys. An alternative hypothesis is that a condition of renal sodium retention occurs because of the proteinuria, but this is not related to intravascular volume or to serum protein concentration. The evidence supporting this so-called overfill hypothesis includes the facts that (1) sodium retention is observed even before the serum albumin level starts falling and (2) intravascular volume is normal or even increased in most patients with nephrotic syndrome. This could occur if intraluminal protein directly stimulated renal epithelial sodium reabsorption.[5] A third possible mechanism is an enhanced peripheral capillary permeability to albumin, as shown by radioisotopic technique in human studies of 60 patients with nephrotic syndrome.[6] This would then lead to increased tissue oncotic pressure and fluid retention in the peripheral tissues. Metabolic consequences of proteinuria Metabolic consequences of the nephrotic syndrome include the following:

Infection Hyperlipidemia and atherosclerosis Hypocalcemia and bone abnormalities

Hypercoagulability Hypovolemia

Acute renal failure may indicate an underlying glomerulonephritis but is more often precipitated by hypovolemia or sepsis. Edema of the kidneys that causes a pressure-mediated reduction in the GFR has also been hypothesized. Hypertension related to fluid retention and reduced kidney function may occur. Failure to thrive may develop in patients with chronic edema, including ascites and pleural effusion. Failure to thrive may be caused by anorexia, hypoproteinemia, increased protein catabolism, or frequent infectious complications. Edema of the gut may cause defective absorption, leading to chronic malnutrition. Infection Infection is a major concern in nephrotic syndrome; patients have an increased susceptibility to infection with Streptococcus pneumoniae, Haemophilus influenzae, Escherichia coli, and other gram-negative organisms. Varicella infection is also common. The most common infectious complications are bacterial sepsis, cellulitis, pneumonia, and peritonitis. Proposed explanations include the following:

Urinary immunoglobulin losses Edema fluid acting as a culture medium Protein deficiency Decreased bactericidal activity of the leukocytes Immunosuppressive therapy Decreased perfusion of the spleen caused by hypovolemia Urinary loss of a complement factor (properdin factor B) that opsonizes certain bacteria

Hyperlipidemia and atherosclerosis Hyperlipidemia may be considered a typical feature of the nephrotic syndrome, rather than a mere complication. It is related to the hypoproteinemia and low serum oncotic pressure of nephrotic syndrome, which then leads to reactive hepatic protein synthesis, including of lipoproteins.[7] In addition, reduced plasma levels of lipoprotein lipase results in diminution of lipid catabolism. Some of the elevated serum lipoproteins are filtered at the glomerulus, leading to lipiduria and the classical findings of oval fat bodies and fatty casts in the urine sediment. Atherosclerotic vascular disease appears to occur in greater frequency in persons with nephrotic syndrome than in healthy persons of the same age. Curry and Roberts showed that the frequency and extent of coronary artery disease stenoses were greater in patients with nephrotic syndrome than in nonnephrotic control subjects.[8] When their study was published, in 1977, lipid-lowering treatments were less widely used than they are today. Accordingly, the average highest serum total cholesterol in this series was over 400 mg/dL. That is in the range of serum cholesterol seen in familial hypercholesterolemia, a disease that predisposes individuals to myocardial infarction. Hypocalcemia

Hypocalcemia is common in the nephrotic syndrome, but rather than being a true hypocalcemia, it is usually caused by a low serum albumin level. Nonetheless, low bone density and abnormal bone histology are reported in association with nephrotic syndrome. This could be caused by urinary losses of vitamin Dbinding proteins, with consequent hypovitaminosis D and, as a result, reduced intestinal calcium absorption.[9] Tessitore et al reported that when the GFR was normal, persons with the nephrotic syndrome had no consistent calcium or bony abnormalities.[10] Yet in that same study, when the GFR was reduced, bone mineralization defects were found by biopsy. A later study found osteomalacia on bone biopsy in over half of adults who had longstanding nephrotic syndrome but whose GFR was preserved.[9] A further complication derives from therapies, especially prednisone use. Low bone mass may be found in relation to cumulative steroid dose.[11] This subject remains controversial; as reported by Leonard et al, intermittent corticosteroid treatment of childhood steroid-sensitive nephrotic syndrome does not appear to be associated with bone mineral deficits.[12] It is possible that long duration of either the nephrotic syndrome or treatments for it are the important risk factors for bone disease in these patients. Hypercoagulability Venous thrombosis and pulmonary embolism are well-known complications of the nephrotic syndrome. Hypercoagulability in these cases appears to derive from urinary loss of anticoagulant proteins, such as antithrombin III and plasminogen, along with the simultaneous increase in clotting factors, especially factors I, VII, VIII, and X. A study by Mahmoodi et al of almost 300 patients with nephrotic syndrome confirmed that venous thromboembolism (VTE) was almost 10 times higher in these persons than in the normal population (1% vs 0.10.2%).[13] Moreover, that risk appeared especially elevated during the first 6 months of nephrotic syndrome, being at almost 10%. This high incidence may justify the routine use of preventive anticoagulation treatment during the first 6 months of a persistent nephrotic syndrome. Mahmoodi's study also showed an increased risk of arterial thrombotic events, including coronary and cerebrovascular ones, in nephrotic syndrome. Unlike the risk of VTE, which was related to proteinuria, this arterial risk was related to usual risk factors for arterial disease, such as hypertension, diabetes, smoking, and reduced GFR. Hypovolemia Hypovolemia occurs when hypoalbuminemia decreases the plasma oncotic pressure, resulting in a loss of plasma water into the interstitium and causing a decrease in circulating blood volume. Hypovolemia is generally observed only when the patient's serum albumin level is less than 1.5 g/dL. Symptoms include vomiting, abdominal pain, and diarrhea. The signs include cold hands and feet, delayed capillary filling, oliguria, and tachycardia. Hypotension is a late feature. Etiology Common primary causes of nephrotic syndrome include kidney diseases such as minimal-change nephropathy, membranous nephropathy, and focal glomerulosclerosis. Secondary causes include systemic diseases such as diabetes mellitus, lupus erythematosus, and amyloidosis. Congenital and hereditary focal glomerulosclerosis may result from mutations of genes that code for podocyte proteins, including nephrin, podocin, or the cation channel 6 protein. Nephrotic syndrome can result from drugs of abuse, such as heroin. Nephrotic-range proteinuria occurring in the third trimester of pregnancy is the classical finding of preeclampsia. In that condition, also known as toxemia, hypertension develops as well. It may occur de novo or it may be superimposed on another chronic kidney disease. In the latter case, there will have been preexisting proteinuria that will have worsened during pregnancy.

Medication can cause nephrotic syndrome. This includes the very infrequent occurrence of minimal-change nephropathy with NSAID use, and the occurrence of membranous nephropathy with the administration of gold and penicillamine, which are older drugs used for rheumatic diseases; there have also been reports of focal glomerulosclerosis in association with intravenous bisphosphonates. Lithium and interferon therapy also are implicated in focal glomerulosclerosis of the collapsing type. Nephrotic-range proteinuria could occur with the use of anticancer agents, such as bevacizumab, that inhibit vascular endothelial growth factor (VEGF).[14] However, the clinical picture of this complication is of a thrombotic microangiopathy rather than of nephrotic syndrome per se. The association of membranous nephropathy with cancer is a clinical dilemma. This association presumably results from immune complex injury to the glomerulus caused by cancer antigens. While there are about 6000 new cases of membranous nephropathy per year in the United States, there are 1.5 million new cases of nonskin cancer. Therefore, from the oncologists standpoint, the problem of paraneoplastic membranous nephropathy is trivial. Nonetheless, a carefully performed analysis from France suggested that the cancer rate in persons with membranous nephropathy is approximately 10-fold higher than it is in the general population, especially in individuals over age 65 years.[15] In that study, 50% of membranous nephropathy cases were diagnosed before the diagnosis of cancer. Thus, in some patients with membranous nephropathy, one should consider the possibility of an undiagnosed cancer. Epidemiology United States statistics The figure below shows the incidence per million population of important causes of nephrotic syndrome. Diabetic nephropathy with nephrotic syndrome is most common, at an estimated rate of at least 50 cases per million population. That is an underestimation, however, since the rate of end-stage renal disease from diabetes has reached 100 cases per million population in some Western countries. In children, nephrotic syndrome may occur at a rate of 20 cases per million children.[16] Incidence of important causes of nephrotic syndrome, in number per million population. The left panel shows systemic causes, and the right panel lists primary renal diseases that can cause nephrotic syndrome. fgs = focal glomerulosclerosis, MN = membranous nephropathy, min change = minimal-change nephropathy. Data are in part from Swaminathan et al and Bergesio et al. International statistics Biopsy studies in children with nephrotic syndrome have shown similar types of histology in India and Turkey, compared with what one would expect in Western countries.[17, 18] In Pakistani adults with nephrotic syndrome, the spectrum of histologies of kidney biopsies has been found to be similar to that seen in western countries.[19] In parts of Africa and the Middle East (eg, Egypt), glomerular disease may be associated with urogenital schistosomal infection.[20] However, so-called "tropical nephrotic syndrome" (eg, from parasitic diseases such as schistosomiasis or malaria) may not be a true entity. Doe et al reviewed causes of nephrotic syndrome in African children and found no evidence for a dominating role of steroid-resistant tropical glomerulopathies; rather, kidney biopsy most often showed typical histologic findings (focal and segmental glomerulosclerosis and minimal change disease).[21] The connection of nephrotic syndrome to quartan malaria is not well-established. Indeed, Pakasa and Sumaili call attention to the apparent decline of parasite-associated nephrotic syndrome in the Congo.[22, 23] It is possible

that the perceived association between nephrotic syndrome and parasitic infections was coincidental, as supported by the ongoing and probably increasing occurrence of chronic kidney disease in the Congo.[23] Race-, sex-, and age-related demographics Because diabetes is major cause of nephrotic syndrome, American Indians, Hispanics, and African Americans have a higher incidence of nephrotic syndrome than do white persons. HIV nephropathy is a complication of HIV infection that is unusual in whites; it is seen with greater frequency in African Americans. [24] Focal glomerulosclerosis appears to be overrepresented in African-American children, as compared with white children, as a cause of nephrotic syndrome.[25] There is a male predominance in the occurrence of nephrotic syndrome, as there is for chronic kidney disease in general. This male overrepresentation is also seen in paraneoplastic membranous nephropathy. [15] However, lupus nephritis affects mostly women. The image below shows typical ages at which a given cause of nephrotic syndrome may occur. It does not show every possible cause of nephrotic syndrome, such as lupus nephritis, which typically affects young black women. The ages shown are averages. A schema of the average patient ages associated with various common forms of nephrotic syndrome.