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Nephrotic Syndrome

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Description: Nephrotic syndrome is a kidney disorder characterized by excessive protein loss in the urine, resulting in swelling, high cholesterol, and low blood protein levels.
Type: Nephrotic syndrome can be caused by several types, including congenital (present at birth) and acquired (developing later in life). The genetic transmission can vary:

1. **Congenital Nephrotic Syndrome:** Often inherited in an autosomal recessive manner. Key genetic mutations are found in genes like NPHS1 (nephrin) and NPHS2 (podocin).
2. **Other Genetic Forms:** Some forms of nephrotic syndrome can be inherited in an autosomal dominant manner, linked to mutations in specific genes such as WT1 (Wilms' tumor protein).

Overall, the genetic transmission of nephrotic syndrome depends on the specific genetic mutation involved.
Signs And Symptoms: Nephrotic syndrome is characterized by large amounts of proteinuria (>3.5 g per 1.73 m2 body surface area per day, or > 40 mg per square meter body surface area per hour in children), hypoalbuminemia (< 3.5 g/dl), hyperlipidaemia, and edema that begins in the face. Lipiduria (lipids in urine) can also occur, but is not essential for the diagnosis of nephrotic syndrome.
Hyperlipidaemia is caused by two factors:
Hypoproteinemia stimulates protein synthesis in the liver, resulting in the overproduction of lipoproteins.
Lipid catabolism is decreased due to lower levels of lipoprotein lipase, the main enzyme involved in lipoprotein breakdown. Cofactors, such as apolipoprotein C2 may also be lost by increased filtration of proteins.A few other characteristics seen in nephrotic syndrome are:

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 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 lunulaThe 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 (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.
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 are 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.
Prognosis: The prognosis for nephrotic syndrome under treatment is generally good although this depends on the underlying cause, the age of the person and their response to treatment. It is usually good in children, because minimal change disease responds very well to steroids and does not cause chronic kidney failure. Any relapses that occur become less frequent over time; the opposite occurs with mesangiocapillary glomerulonephritis, in which the kidney fails within three years of the disease developing, making dialysis necessary and subsequent kidney transplant. In addition children under the age of 5 generally have a poorer prognosis than prepubescents, as do adults older than 30 years of age as they have a greater risk of kidney failure.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).Without treatment nephrotic syndrome has a very bad prognosis especially rapidly progressing glomerulonephritis, which leads to acute kidney failure after a few months.
Onset: Nephrotic syndrome can have both acute and insidious onset, depending on the underlying cause. It may develop suddenly over days to weeks or progressively over a longer period. Common underlying causes include minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy. In children, minimal change disease is a frequent cause of acute onset nephrotic syndrome.
Prevalence: The prevalence of nephrotic syndrome varies depending on factors such as age, geography, and population studied. In children, it is estimated to affect about 2 to 7 per 100,000 annually, with a higher incidence in boys compared to girls. In adults, the prevalence is less well-studied but is considered lower than in children. Racial and ethnic disparities also exist, with higher rates observed in certain groups.
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.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%). 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. 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.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.The epidemiological data also reveals information regarding the most common way that symptoms develop in people with nephrotic syndrome: 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.
Intractability: Nephrotic syndrome itself is not necessarily intractable, but it can be challenging to manage. The prognosis depends on the underlying cause, the patient’s response to treatment, and whether there are complications such as infections or blood clots. Some cases respond well to treatment, which may include corticosteroids, immunosuppressants, and other medications to control symptoms, while others may have a more persistent or relapsing course.
Disease Severity: Nephrotic syndrome severity can vary widely depending on the underlying cause, response to treatment, and complications that arise. In severe cases, individuals may experience significant loss of protein in the urine, resulting in profound swelling (edema), high cholesterol levels, and increased risk of infections and blood clots. Early diagnosis and appropriate management are crucial to improve outcomes.
Healthcare Professionals: Disease Ontology ID - DOID:1184
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, but not larger macromolecules such as proteins.
In nephrotic syndrome, the glomeruli are affected by an inflammation or a hyalinization (the formation of a homogenous crystalline material within cells) that allows proteins such as albumin, antithrombin or the immunoglobulins to pass through the cell membrane and appear in urine.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.As a response to hypoproteinemia the liver commences a compensatory mechanism involving the synthesis of proteins, such as alpha-2 macroglobulin and lipoproteins. An increase in the latter can cause the hyperlipidemia associated with this syndrome.
Carrier Status: Nephrotic syndrome is not typically associated with a "carrier status" as it is not a single genetic disorder but rather a group of symptoms that can be caused by different underlying diseases, including both genetic and non-genetic conditions.
Mechanism: Nephrotic syndrome is a kidney disorder characterized by excessive protein loss in the urine, low blood protein levels, high cholesterol levels, and swelling. The mechanism of nephrotic syndrome involves damage to the glomeruli, the filtering units in the kidneys. This damage leads to increased protein permeability, resulting in proteinuria (protein loss in urine).

On a molecular level, nephrotic syndrome can involve several pathways:

1. **Podocyte Damage**: Podocytes are specialized cells in the glomeruli that play a crucial role in the filtration barrier. Damage to podocytes, due to genetic mutations, toxins, or immune responses, can disrupt the filtration mechanism, leading to proteinuria.

2. **Alteration in Slit Diaphragm Proteins**: The slit diaphragm, a structure between podocyte foot processes, contains proteins such as nephrin, podocin, and others. Mutations or dysfunction in these proteins can compromise the selective filtration barrier, allowing proteins to leak into the urine.

3. **Immune System Dysregulation**: Autoimmune diseases, such as lupus, can cause inflammation and damage to the glomeruli. Immune complexes and antibodies can target glomerular components, leading to increased permeability and protein loss.

4. **Cytokine Release**: Certain conditions can lead to the release of cytokines such as TNF-α and TGF-β, which can cause podocyte injury and disrupt the glomerular basement membrane.

5. **Proteinuria and Hypoalbuminemia**: The excessive loss of proteins, particularly albumin, in the urine leads to hypoalbuminemia. This decreases the oncotic pressure in the blood, resulting in fluid leakage into tissues and causing edema.

Understanding these molecular mechanisms is key to developing targeted therapies for different underlying causes of nephrotic syndrome.
Treatment: The treatment of nephrotic syndrome can be symptomatic or can directly address the injuries caused to the kidney.
Compassionate Use Treatment: Compassionate use treatment, also known as expanded access, allows patients with serious or life-threatening conditions to access investigational drugs or therapies that have not yet received FDA approval. For nephrotic syndrome, compassionate use treatment could include investigational drugs currently in clinical trials or those that have shown promise in earlier studies but are not yet widely available.

Off-label or experimental treatments for nephrotic syndrome may involve the use of medications approved for other conditions but not specifically for nephrotic syndrome. Examples include:

1. **Calcineurin Inhibitors (e.g., Tacrolimus, Cyclosporine)**: Primarily used to prevent organ transplant rejection but sometimes used off-label to treat refractory nephrotic syndrome.
2. **Rituximab**: An anti-CD20 monoclonal antibody typically used for certain cancers and autoimmune diseases, used off-label to treat difficult cases of nephrotic syndrome.
3. **Acthar Gel (Repository Corticotropin Injection)**: Originally approved for infantile spasms and multiple sclerosis, it has been used off-label for nephrotic syndrome.
4. **Cyclophosphamide**: An immunosuppressive drug used in various cancers and autoimmune disorders, sometimes employed off-label in severe or treatment-resistant nephrotic syndrome.

These treatments are generally considered when conventional therapies (such as corticosteroids and other immunosuppressive agents) are ineffective or cause intolerable side effects. Due to the complexity and potential risks, these treatments should be managed by healthcare professionals with expertise in nephrotic syndrome.
Lifestyle Recommendations: For nephrotic syndrome, some lifestyle recommendations include:

1. **Dietary Adjustments**:
- **Low Sodium Intake**: Reduce salt to help manage edema and high blood pressure.
- **Moderate Protein Intake**: Consult a dietitian for appropriate protein levels to avoid strain on kidneys.
- **Low-Fat Diet**: Reduce saturated fats to manage cholesterol levels.
- **Fluid Restriction**: If advised by a healthcare provider to manage fluid balance.

2. **Medications**: Adherence to prescribed medication regimens, such as diuretics, blood pressure medications, and cholesterol-lowering drugs.

3. **Regular Exercise**: Engage in moderate physical activity as tolerated to maintain overall health and weight management.

4. **Monitor Health**: Regular check-ups with a nephrologist to monitor kidney function and manage any complications.

5. **Avoid Nephrotoxic Substances**: Avoid medications and substances that can harm the kidneys, such as nonsteroidal anti-inflammatory drugs (NSAIDs).

6. **Quit Smoking**: Smoking cessation to improve overall cardiovascular health and reduce strain on the kidneys.

7. **Manage Underlying Conditions**: Control conditions like diabetes and hypertension that can exacerbate nephrotic syndrome.

Collaboration with healthcare providers to develop a personalized plan is essential for managing nephrotic syndrome effectively.
Medication: Nephrotic syndrome is typically treated with a combination of medications, depending on the underlying cause and the severity of the condition. Common medications include:

1. **Corticosteroids**: Prednisone is often used to reduce inflammation and proteinuria.
2. **Diuretics**: Medications like furosemide help reduce fluid buildup and swelling.
3. **ACE Inhibitors or ARBs**: These drugs, such as enalapril or losartan, help reduce protein loss in the urine and control blood pressure.
4. **Immunosuppressants**: Drugs like cyclophosphamide, cyclosporine, or tacrolimus may be used if corticosteroids are not effective or suitable.
5. **Statins**: These are often prescribed to manage high cholesterol levels associated with nephrotic syndrome.
6. **Anticoagulants**: Medications like warfarin may be administered to prevent blood clots, a risk in severe cases.

Always consult a healthcare provider for a treatment plan tailored to the individual's specific condition.
Repurposable Drugs: Current studies suggest some repurposable drugs for treating nephrotic syndrome include:

- **Rituximab**: Initially used for certain cancers and autoimmune diseases, it has shown efficacy in treating refractory nephrotic syndrome.
- **ACTH (Adrenocorticotropic hormone)**: Traditionally used in endocrine conditions, it has demonstrated potential in inducing remission in cases of nephrotic syndrome.
- **Mycophenolate mofetil (MMF)**: Originally an immunosuppressant for transplant patients, it has been effective in maintaining remission in nephrotic syndrome.

More research is needed to confirm these uses and determine long-term safety and efficacy.
Metabolites: Nephrotic syndrome is characterized by a specific set of metabolic abnormalities. Major metabolites affected include:

1. **Albumin**: There is a significant loss of albumin in the urine, leading to hypoalbuminemia.
2. **Lipoproteins**: Hyperlipidemia is common, with increased levels of cholesterol, triglycerides, and low-density lipoproteins (LDL).
3. **Proteinuria**: Excessive protein excretion in the urine, often exceeding 3.5 grams per day.
4. **Vitamin D**: Loss of Vitamin D-binding proteins in urine can result in vitamin D deficiency and its subsequent metabolic concerns.
5. **Electrolytes**: Altered levels of electrolytes such as sodium and potassium can occur due to protein loss and secondary kidney dysfunction.

Nan — No relevant information exists with this context.
Nutraceuticals: In the context of nephrotic syndrome, nutraceuticals are often discussed for their potential role in supporting overall kidney health and managing symptoms. Nutraceuticals like omega-3 fatty acids (found in fish oil), coenzyme Q10, and antioxidants such as vitamin E and selenium may help reduce inflammation and oxidative stress, potentially benefiting kidney function.

"Nan" could refer to "nanomedicine" or "nanotechnology," which is a cutting-edge field being explored for various health conditions, including nephrotic syndrome. Nanotechnology involves using nanoparticles to deliver drugs or therapeutic agents directly to targeted areas, potentially improving treatment efficacy and reducing side effects. While research is still ongoing, nanotechnology holds promise for advancing the treatment of kidney diseases, including nephrotic syndrome, by providing more precise and effective therapeutic options.
Peptides: Nephrotic syndrome is a kidney disorder characterized by excessive protein loss in the urine. Emerging research indicates that specific peptides and nanomedicines may play roles in diagnosing and treating the condition. Experimental treatments with peptide-based therapeutic agents are exploring mechanisms to reduce proteinuria and protect kidney function. In parallel, nanotechnology is being investigated for targeted drug delivery, potentially offering more effective treatments with fewer side effects. These areas are still under active research and are not yet widely adopted in clinical practice.