Nephrotic syndrome

Nephrotic syndrome is a collection of

Treatment is directed at the underlying cause. Other efforts include managing high blood pressure, high blood cholesterol, and infection risk. A low-salt diet and limiting fluids are often recommended.[1] About 5 per 100,000 people are affected per year.^[3][4] The usual underlying cause varies between children and adults.^[4]

Signs and symptoms

Nephrotic syndrome is characterized by large amounts of

• The most common sign is
  excess fluid
  in the body due to serum hypoalbuminemia. Lower serum oncotic pressure causes fluid to accumulate in the interstitial tissues. Sodium and water retention aggravates the edema. This may take several forms:
  • Puffiness around the
    eyes
    , characteristically in the morning.
  • Pitting edema over the legs.
  • Fluid in the pleural cavity causing pleural effusion. More commonly associated with excess fluid is pulmonary edema.
  • Fluid in the peritoneal cavity causing ascites.
  • Generalized edema throughout the body known as anasarca.
• Most of the people with nephrotic syndrome are normotensive but hypertension (rarely) may also occur.
• Anaemia
  (iron resistant microcytic hypochromic type) may be present due to transferrin loss.
• Dyspnea may be present due to pleural effusion
  or due to diaphragmatic compression with ascites.
• Erythrocyte sedimentation rate is increased due to increased fibrinogen & other plasma contents.
• Some people may notice foamy or frothy
  haematuria or oliguria are uncommon, though these are seen commonly in nephritic syndrome
  .
• May have features of the underlying cause, such as the
  neuropathy associated with diabetes
  .
• Examination should also exclude other causes of gross edema—especially the
  cardiovascular and liver
  system.
• Muehrcke's nails; white lines (leukonychia) that extend all the way across the nail and lie parallel to the lunula^[7]

The main signs of nephrotic syndrome are:^[8]

• Proteinuria of greater than 3.5 g /24 h /1.73 m² (between 3 and 3.5 g/24 h /1.73 m² is considered to be proteinuria in the nephrotic range) or greater than 40 mg/h/m² in children.^[9][10] The ratio between urinary concentrations of albumin and creatinine can be used in the absence of a 24-hour urine test for total protein. This coefficient will be greater than 200–400 mg/mmol in nephrotic syndrome. This pronounced loss of proteins is due to an increase in glomerular permeability that allows proteins to pass into the urine instead of being retained in the blood. Under normal conditions a 24-hour urine sample should not exceed 80 milligrams or 10 milligrams per decilitre.^[11]
• protein synthesis
  in the liver is insufficient to increase the low blood protein levels.
• Edema is thought to be caused by two mechanisms. The first being hypoalbuminemia which lowers the oncotic pressure within vessels resulting in hypovolemia and subsequent activation of the renin–angiotensin system and thus retention of sodium and water (underfill hypothesis). Additionally, it is thought that urinary proteases (excreted as a result of significant proteinuria) cause a direct effect by activating the epithelial sodium channel (ENaC) on the principal cell that leads to the reabsorption of sodium and water (overfill hypothesis). Nephrotic syndrome edema initially appears in parts of the lower body (such as the legs) and in the eyelids. In the advanced stages it also extends to the pleural cavity and peritoneum (ascites) and can even develop into a generalized anasarca.
• apolipoprotein C2
  , may also be lost by increased filtration of proteins.
• antithrombin III
  in the blood due to its loss in urine.
• Lipiduria or loss of lipids in the urine is indicative of glomerular pathology due to an increase in the filtration of lipoproteins.^[14]

Complications

Nephrotic syndrome can be associated with a series of complications that can affect an individual's health and quality of life:^[15]

• Thromboembolic disorders: particularly those caused by a decrease in blood antithrombin III levels due to leakage. Antithrombin III counteracts the action of thrombin. Thrombosis usually occurs in the kidney veins although it can also occur in arteries. Treatment is with oral anticoagulants (not heparin as heparin acts via anti-thrombin 3 which is lost in the proteinuria so it will be ineffective.) Hypercoagulopathy due to extravasation of fluid from the blood vessels (edema) is also a risk for venous thrombosis.
• septicaemia. The most notable of the causative organisms are Streptococcus pneumoniae and Haemophilus influenzae
  .
• Spontaneous bacterial peritonitis can develop where there is ascites present. This is a frequent development in children but very rarely found in adults.^[16]
• Acute kidney failure due to hypovolemia: the loss of vascular fluid into the tissues (edema) produces a decreased blood supply to the kidneys that cause a loss of kidney function. Thus it is a tricky task to get rid of excess fluid in the body while maintaining circulatory euvolemia.
• dyspnoea
  .
• Hypothyroidism: deficiency of the thyroglobulin transport protein thyroxin (a glycoprotein that is rich in iodine and is found in the thyroid gland) due to decreased thyroid-binding globulin.
• Vitamin D deficiency can occur. Vitamin D binding protein is lost.
• Hypocalcaemia: lack of 25-hydroxycholecalciferol (the way that vitamin D is stored in the body). As vitamin D regulates the amount of calcium present in the blood, a decrease in its concentration will lead to a decrease in blood calcium levels. It may be significant enough to cause tetany
  . Hypocalcaemia may be relative; calcium levels should be adjusted based on the albumin level and ionized calcium levels should be checked.
• Microcytic
  anaemia: iron deficiency caused by the loss of ferritin
  (compound used to store iron in the body). It is iron-therapy resistant.
• Protein malnutrition: this occurs when the amount of protein that is lost in the urine is greater than that ingested, this leads to a negative nitrogen balance.^[17][18]
• Growth retardation: This can occur in cases of relapse or resistance to therapy. Causes of growth retardation are protein deficiency from the loss of protein in urine, anorexia
  (reduced protein intake), and steroid therapy (catabolism).
• Cushing's syndrome^[19]

Causes

Nephrotic syndrome has many causes and may either be the result of a glomerular disease that can be either limited to the kidney, called primary nephrotic syndrome (primary glomerulonephrosis), or a condition that affects the kidney and other parts of the body, called secondary nephrotic syndrome.^[20]

Primary glomerulonephrosis

Primary causes of nephrotic syndrome are usually described by their histology:^[21]

• Minimal change disease (MCD): is the most common cause of nephrotic syndrome in children. It owes its name to the fact that the nephrons appear normal when viewed with an optical microscope as the lesions are only visible using an electron microscope. Another symptom is pronounced proteinuria.
• Focal segmental glomerulosclerosis (FSGS): is the most common cause of nephrotic syndrome in adults.^[22] It is characterized by the appearance of tissue scarring in the glomeruli. The term focal is used as some of the glomeruli have scars, while others appear intact; the term segmental refers to the fact that only part of the glomerulus is damaged.
• Membranous glomerulonephritis (MGN): The inflammation of the glomerular membrane causes increased leaking in the kidney. It is not clear why this condition develops in most people, although an auto-immune mechanism is suspected.^[22]
• Membranoproliferative glomerulonephritis (MPGN): is the inflammation of the glomeruli along with the deposit of antibodies in their membranes, which makes filtration difficult.
• Rapidly progressive glomerulonephritis (RPGN): (Usually presents as a nephrotic syndrome) A person's glomeruli are present in a crescent moon shape. It is characterized clinically by a rapid decrease in the glomerular filtration rate (GFR) by at least 50% over a short period, usually from a few days to 3 months.^[23]

They are considered to be "diagnoses of exclusion", i.e. they are diagnosed only after secondary causes have been excluded.

Secondary glomerulonephrosis

Secondary causes of nephrotic syndrome have the same histologic patterns as the primary causes, though they may exhibit some differences suggesting a secondary cause, such as

• Diabetic nephropathy: is a complication that occurs in some diabetics. Excess blood sugar accumulates in the kidney causing them to become inflamed and unable to carry out their normal function. This leads to the leakage of proteins into the urine.
• Systemic lupus erythematosus: this autoimmune disease can affect a number of organs, among them the kidney, due to the deposit of immunocomplexes that are typical to this disease. The disease can also cause lupus nephritis
  .
• immune cells
  ) in the glomeruli can lead to nephrotic syndrome.
• Syphilis: kidney damage can occur during the secondary stage of this disease (between 2 and 8 weeks from onset).
• Hepatitis B: certain antigens present during hepatitis can accumulate in the kidneys and damage them.
• Sjögren's syndrome
  : this autoimmune disease causes the deposit of immunocomplexes in the glomeruli, causing them to become inflamed, this is the same mechanism as occurs in systemic lupus erythematosus.
• HIV: the virus's antigens provoke an obstruction in the glomerular capillary's lumen that alters normal kidney function.
• Amyloidosis: the deposit of amyloid substances (proteins with anomalous structures) in the glomeruli modifying their shape and function.
• Multiple myeloma: kidney impairment is caused by the accumulation and precipitation of light chains, which form casts in the distal tubules, resulting in kidney obstruction. In addition, myeloma light chains are also directly toxic on proximal kidney tubules, further adding to kidney dysfunction.
• Vasculitis: inflammation of the blood vessels at a glomerular level impedes the normal blood flow and damages the kidney.
• Cancer: as happens in myeloma, the invasion of the glomeruli by cancerous cells disturbs their normal functioning.
• Genetic disorders: congenital nephrotic syndrome is a rare genetic disorder in which the protein nephrin, a component of the glomerular filtration barrier, is altered.
• Drugs ( e.g. gold salts, penicillin, captopril):^[25] gold salts can cause a more or less important loss of proteins in urine as a consequence of metal accumulation. Penicillin is nephrotoxic in people with kidney failure and captopril can aggravate proteinuria.

By histologic pattern

Membranous nephropathy (MN)

• Sjögren's syndrome
• Systemic lupus erythematosus
  (SLE)
• Diabetes mellitus
• Sarcoidosis
• Drugs (such as corticosteroids, gold, intravenous heroin)
• Malignancy (cancer)
• Bacterial infections, e.g. leprosy & syphilis
• Protozoal infections, e.g. malaria

Focal segmental glomerulosclerosis (FSGS)^[26]

• Hypertensive nephrosclerosis
• HIV^[27]
• Obesity^[27]
• Kidney loss

Minimal change disease (MCD)^[26]

• Drugs, especially NSAIDs in the elderly
• Malignancy, especially
  Hodgkin's lymphoma
• Allergy
• Bee sting

Membranoproliferative Glomerulonephritis

• Hepatitis C

Genetics

Over 50 mutations are known to be associated with this condition.^[28][29]

Non-Genetic

There is no known genetic cause for idiopathic nephrotic syndrome. This is thought to be caused by a hitherto unknown circulating permeability factor that travels in the circulation to the podocyte within the glomerulus of the kidney. This circulating factor damages the podocyte which changes its structure. The podocytes are now less able to restrict urinary protein loss. Despite not knowing the specific indentity of the circulating factor, scientists are learning more about it. It is thought to be either T cell or B cell derived,^[30][31] hence why staroid treatment can be effective for some patients. There is also evidence that the circulating factor could be signalling via the PAR-1 receptro on the podocytes.^[32]

Pathophysiology

The kidney glomerulus filters the blood that arrives at the kidney. It is formed of capillaries with small pores that allow small molecules to pass through that have a molecular weight of less than 40,000 daltons,^[33] but not larger macromolecules such as proteins.

In nephrotic syndrome, the glomeruli are affected by an

Albumin is the main protein in the blood that is able to maintain an oncotic pressure, which prevents the leakage of fluid into the extracellular medium and the subsequent formation of edemas.^{[citation needed]}

As a response to hypoproteinemia the liver commences a compensatory mechanism involving the synthesis of proteins, such as

Along with obtaining a complete

A kidney biopsy may also be used as a more specific and invasive test method. A study of a sample's anatomical pathology may then allow the identification of the type of glomerulonephritis involved.^[35] However, this procedure is usually reserved for adults as the majority of children experience minimal change disease that has a remission rate of 95% with corticosteroids.^[37] A biopsy is usually only indicated for children that are corticosteroid resistant as the majority have focal and segmental glomeruloesclerosis.^[37]

Further investigations are indicated if the cause is not clear including analysis of

Classification

A broad classification of nephrotic syndrome based on underlying cause:

Nephrotic syndrome is often classified histologically:

Differential diagnosis

Some symptoms that are present in nephrotic syndrome, such as edema and proteinuria, also appear in other illnesses. Therefore, other pathologies need to be excluded in order to arrive at a definitive diagnosis.^[38]

• Edema: in addition to nephrotic syndrome there are two other disorders that often present with edema; these are
  NSAIDs, some antihypertensive drugs, the adrenal corticosteroids and sex hormones.^[41]

Acute fluid overload can cause edema in someone with kidney failure. These people are known to have kidney failure, and have either drunk too much or missed their dialysis. In addition, when Metastatic cancer spreads to the lungs or abdomen it causes effusions and fluid accumulation due to obstruction of lymphatic vessels and veins, as well as serous exudation.

• Proteinuria: the loss of proteins from the urine is caused by many pathological agents and infection by these agents has to be ruled out before it can be certain that a person has nephrotic syndrome.
  diabetes mellitus there is an association between increases in glycated hemoglobin levels and the appearance of proteinuria.^[43] Other causes are amyloidosis
  and certain other allergic and infectious diseases.

The treatment of nephrotic syndrome can be symptomatic or can directly address the injuries caused to the kidney.^[citation needed]

Symptomatic

The objective of this treatment is to treat the imbalances brought about by the illness:^[44] edema, hypoalbuminemia, hyperlipidaemia, hypercoagulability and infectious complications.

• Edema: a return to an unswollen state is the prime objective of this treatment of nephrotic syndrome. It is carried out through the combination of a number of recommendations:
  • Rest: depending on the seriousness of the edema and taking into account the risk of thrombosis caused by prolonged bed rest.^[45]
  • Medical nutrition therapy: based on a diet with the correct energy intake and balance of proteins that will be used in synthesis processes and not as a source of calories. A total of 35 kcal/kg body weight/day is normally recommended.^[46] This diet should also comply with two more requirements: the first is to not consume more than 1 g of protein/kg body weight/ day,^[46] as a greater amount could increase the degree of proteinuria and cause a negative nitrogen balance.^[18] People are usually recommended lean cuts of meat, fish, and poultry. The second guideline requires that the amount of water ingested is not greater than the level of diuresis. In order to facilitate this, the consumption of salt must also be controlled, as this contributes to water retention. It is advisable to restrict the ingestion of sodium to 1 or 2 g/day, which means that salt cannot be used in cooking and salty foods should also be avoided.^[47]
    Foods high in sodium include seasoning blends (garlic salt, Adobo, season salt, etc.) canned soups, canned vegetables containing salt, luncheon meats including turkey, ham, bologna, and salami, prepared foods, fast foods, soy sauce, ketchup, and salad dressings. On food labels, compare milligrams of sodium to calories per serving. Sodium should be less than or equal to calories per serving.
  • loop diuretics, such as furosemide). In severe cases of edema (or in cases with physiological repercussions, such as scrotal, preputial or urethral edema) or in people with one of a number of severe infections (such as sepsis or pleural effusion), the diuretics can be administered intravenously. This occurs where the risk from plasmatic expansion^[48]
    is considered greater than the risk of severe hypovolemia, which can be caused by the strong diuretic action of intravenous treatment. The procedure is the following:

• Hypoalbuminemia: is treated using the medical nutrition therapy described as a treatment for edema. It includes a moderate intake of foods rich in animal proteins.[49]
• Hyperlipidaemia: depending on the seriousness of the condition it can be treated with medical nutrition therapy as the only treatment or combined with drug therapy. The ingestion of cholesterol should be less than 300 mg/day,
  hypolipidaemic drugs may be necessary (these include statins, fibrates and resinous sequesters of bile acids).^[51]
• Thrombophilia: low molecular weight
  therapeutic range (between 2 and 3),^[54] it may be possible to suspend the LMWH while maintaining the OACs for at least 6 months.^[55]
• Infectious complications: an appropriate course of
  antibacterial
  drugs can be taken according to the infectious agent.

In addition to these key imbalances, vitamin D and calcium are also taken orally in case the alteration of vitamin D causes severe hypocalcaemia, this treatment has the goal of restoring physiological levels of calcium in the person.[56]

• Achieving better blood glucose level control if the person is diabetic.
• ACE inhibitors
  are the drug of choice. Independent of their blood pressure-lowering effect, they have been shown to decrease protein loss.

Kidney damage

The treatment of kidney damage may reverse or delay the progression of the disease.^[44] Kidney damage is treated by prescribing drugs:

• Corticosteroids: the result is a decrease in proteinuria and the risk of infection as well as a resolution of the edema.^[57] Prednisone is usually prescribed at a dose of 60 mg/m² of body surface area/day in a first treatment for 4–8 weeks. After this period the dose is reduced to 40 mg/m² for a further 4 weeks. People experiencing a relapse or children are treated with prednisolone 2 mg/kg/day until urine becomes negative for protein. Then, 1.5 mg/kg/day for 4 weeks. Frequent relapses treated by: cyclophosphamide or nitrogen mustard or cyclosporin or levamisole
  . People can respond to prednisone in a number of different ways:
  • People with Corticosteroid sensitive or early steroid-responder: the subject responds to the corticosteroids in the first 8 weeks of treatment. This is demonstrated by a strong diuresis and the disappearance of edemas, and also by a negative test for proteinuria in three urine samples taken during the night.
  • People with Corticosteroid resistance or late steroid-responder: the proteinuria persists after the 8-week treatment. The lack of response is indicative of the seriousness of the glomerular damage, which could develop into chronic kidney failure.
  • People with Corticosteroid intolerant: complications such as hypertension appear, and they gain a lot of weight and can develop aseptic or avascular necrosis of the hip or knee,^[58] cataracts and thrombotic phenomena and/or embolisms.
  • People with Corticosteroid dependent: proteinuria appears when the dose of corticosteroid is decreased or there is a relapse in the first two weeks after treatment is completed.

The susceptibility testing in vitro to glucocorticoids on the person's peripheral blood mononuclear cells is associated with the number of new cases of not optimal clinical responses: the most sensitive people in vitro have shown a higher number of cases of corticodependence, while the most resistant people in vitro showed a higher number of cases of ineffective therapy.^[59]

• alopecia. Complete blood count
  tests are carried out during the treatment in order to give advance warning of a possible infection.

Other causes such as focal segmental glomerulosclerosis frequently lead to end stage kidney disease. Factors associated with a poorer prognosis in these cases include level of proteinuria, blood pressure control and kidney function (GFR).^{[citation needed]}

Without treatment nephrotic syndrome has a very bad prognosis especially rapidly progressing glomerulonephritis, which leads to acute kidney failure after a few months.^{[citation needed]}

Epidemiology

Nephrotic syndrome can affect any age, although it is mainly found in adults with a ratio of adults to children of 26 to 1.^[62]

The syndrome presents in different ways in the two groups: the most frequent glomerulopathy in children is minimal change disease (66% of cases), followed by focal segmental glomerulosclerosis (8%) and mesangiocapillary glomerulonephritis (6%).^[24] In adults the most common disease is mesangiocapillary glomerulonephritis (30-40%), followed by focal and segmental glomeruloesclerosis (15-25%) and minimal change disease (20%). The latter usually presents as secondary and not primary as occurs in children. Its main cause is diabetic nephropathy.^[24] It usually presents in a person from their 40s or 50s. Of the glomerulonephritis cases, approximately 60% to 80% are primary, while the remainder are secondary.^[62]

There are also differences in epidemiology between the sexes, the disease is more common in men than in women by a ratio of 2 to 1.^[62]

The epidemiological data also reveals information regarding the most common way that symptoms develop in people with nephrotic syndrome:^[62] spontaneous remission occurs in up to 20% or 30% of cases during the first year of the illness. However, this improvement is not definitive as some 50% to 60% of people with Nephrotic syndrome die and/or develop chronic kidney failure 6 to 14 years after this remission. On the other hand, between 10% and 20% of people have continuous episodes of remissions and relapses without dying or jeopardizing their kidney. The main causes of death are cardiovascular, as a result of the chronicity of the syndrome, and thromboembolic accidents.

References