Nephritic syndrome

A few other characteristics seen in nephrotic syndrome are:

• The most common sign is excess fluid in the body due to the 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 urine, due to a lowering of the surface tension by the severe proteinuria. Actual urinary complaints such as haematuria or oliguria are uncommon, though these are seen commonly in nephritic syndrome.
• May have features of the underlying cause, such as the rash associated with systemic lupus erythematosus, or 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

The main signs of nephrotic syndrome are:

• A 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.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.
• A hypoalbuminemia of less than 2.5 g/dL,that exceeds the liver clearance level, that is, 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. Additionally, it is thought that albumin causes a direct effect on the epithelial sodium channel (ENaC) on the principal cell that leads to the reabsorption of sodium and water. 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.
• Hyperlipidaemia is caused by an increase in the synthesis of low and very low-density lipoproteins in the liver that are responsible for the transport of cholesterol and triglycerides. There is also an increase in the liver synthesis of cholesterol.
• Thrombophilia, or hypercoagulability, is a greater predisposition for the formation of blood clots that is caused by a decrease in the levels of 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.

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

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 antithrombin 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.

Infections: The increased susceptibility of people with nephrotic syndrome to infections can be a result of the leakage of immunoglobulins from the blood, the loss of proteins in general and the presence of oedematous fluid (which acts as a breeding ground for infections). The most common infection is peritonitis, followed by lung, skin and urinary infections, meningoencephalitis and in the most serious cases septicaemia. The most notable of the causative organisms are Streptococcus pneumoniae and Haemophilus influenzae.

Spontaneous bacterial peritonitis can develop where there are ascites present. This is a frequent development in children but very rarely found in adults.

Acute kidney failure due to hypovolemia: the loss of vascular fluid into the tissues (edema) produces a decreased blood supply to the kidneys that causes a loss of kidney function. Thus it is a tricky task to get rid of excess fluid in the body while maintaining circulatory euvolemia.

Pulmonary edema: the loss of proteins from blood plasma and the consequent fall in oncotic pressure causes an abnormal accumulation of liquid in the lungs causing hypoxia and dyspnoea.

Hypothyroidism: deficiency of the thyroglobulin transport protein thyroxine (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 hypochromic 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.

Growth retardation: 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

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.

Primary glomerulonephrosis

Primary causes of nephrotic syndrome are usually described by their histology:

• 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 a pronounced proteinuria.
• Focal segmental glomerulosclerosis (FSGS): is the most common cause of nephrotic syndrome in adults.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 suffers the damage.
• 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.
• 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 nephritic 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.

They are considered to be "diagnosis 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 difference suggesting a secondary cause, such as inclusion bodies.They are usually described by the underlying 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 immune complexes that are typical to this disease. The disease can also cause lupus nephritis.
• Sarcoidosis: This disease does not usually affect the kidney but, on occasions, the accumulation of inflammatory granulomas (collection of 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 immune complexes 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): 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

The treatment of nephrotic syndrome can be symptomatic or can directly address the injuries caused to the kidney.

Symptomatic

The objective of this treatment is to treat the imbalances brought about by the illness: edema, hypoalbuminemia, hyperlipidemia, 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.
• 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.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, as a greater amount could increase the degree of proteinuria and cause a negative nitrogen balance.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. 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.
• Medication: The pharmacological treatment of edema is based on diuretic medications (especially 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 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:

1. Analyse haemoglobin and haematocrit levels.
2. A solution of 25% albumin is used that is administered for only 4 hours in order to avoid pulmonary edema.
3. Haemoglobin and haematocrit levels are analysed again: if the haematocrit value is less than the initial value (a sign of correct expansion) the diuretics are administered for at least 30 minutes. If the haematocrit level is greater than the initial one this is a contraindication for the use of diuretics as they would increase said value.

It may be necessary to give a person potassium or require a change in dietary habits if the diuretic drug causes hypokalemia as a side effect.

• 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.
• 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, which will require a switch to foods that are low in saturated fats. Avoid saturated fats such as butter, cheese, fried foods, fatty cuts of red meat, egg yolks, and poultry skin. Increase unsaturated fat intake, including olive oil, canola oil, peanut butter, avocadoes, fish and nuts. In cases of severe hyperlipidaemia that are unresponsive to nutrition therapy the use of hypolipidemic drugs, may be necessary (these include statins, fibrates and resinous sequesters of bile acids).
• Thrombophilia: low molecular weight heparin (LMWH) may be appropriate for use as a prophylactic in some circumstances, such as in asymptomatic people that have no history of suffering from thromboembolism. When the thrombophilia is such that it leads to the formation of blood clots, heparin is given for at least 5 days along with oral anticoagulants (OAC). During this time and if the prothrombin time is within its therapeutic range (between 2 and 3), it may be possible to suspend the LMWH while maintaining the OACs for at least 6 months.
• 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 a severe hypocalcaemia, this treatment has the goal of restoring physiological levels of calcium in the person.

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