Comprehensive Analysis of Nephrotic Syndrome: Causes, Treatment, and Emerging Therapies

Introduction to Nephrotic Syndrome

Nephrotic syndrome is an illness characterized by excessive protein loss in the urine, low levels of albumin in the blood, high cholesterol levels, and swelling, which is predominantly in the legs, ankles, and around the eyes. In the case of nephrotic syndrome, there is a direct relationship with underlying kidney disease due to damage that affects the glomeruli tiny filtering units inside the kidney- resulting in leakage of protein, mostly albumin, into the urine.
Nephrotic syndrome can present in any age group but is especially prevalent among children, mostly between the ages of 2 and 6. While idiopathic in etiology, it is a common complication of glomerular diseases or systemic disorders such as diabetes, lupus, or infections.

Nephrotic Syndrome Pathophysiology
Nephrotic syndrome pathophysiology centers on the glomerular filtration barrier located in the kidneys. This barrier filters blood, letting water and small solutes pass through while retaining large proteins such as albumin. With nephrotic syndrome, damage to the podocytes, the cells lining the glomeruli or the glomerular basement membrane, breaches this filtration barrier, and proteins leak into the urine through a series of physiological breakdowns.
Nephrotic syndrome is characterized by a hallmark proteinuria that has a whole chain of downstream effects. Albumin is the main protein in the blood, and upon its loss, the oncotic pressure declines, and water penetrates into adjacent tissues and results in edema. The attempt of the body to balance the low albumin is to boost the production of cholesterol and lipoproteins leading to hyperlipidemia. In due course, chronic loss of proteins can result in wasting of muscles, fatigue, and immunosuppression.
The causes of nephrotic syndrome range widely. In children, the primary cause is minimal change disease, where the glomeruli are normal microscopically but not functioning normally. In adults, nephrotic syndrome more commonly relates to focal segmental glomerulosclerosis, membranous nephropathy, or systemic diseases like diabetic nephropathy or lupus nephritis.

Symptoms and Diagnosis of Nephrotic Syndrome
Patients suffering from nephrotic syndrome can present with swelling in the legs, ankles, feet, and around the eyes-especially in the morning. Edema can be much more generalized and may extend to the abdomen (ascites) or the general body surface (anasarca). The other symptoms include frothy urine due to elevated levels of protein, tiredness, weight gain due to edema, and infections owing to urinary loss of immunoglobulins.
Diagnosis is mainly by urinalysis, showing significant amounts of proteinuria, usually above 3.5 grams per day. Blood tests often reveal low levels of albumin and elevated cholesterol, as well as other laboratory signs of kidney disease; for example, elevations of creatinine. In a significant proportion of adults with nephrotic syndrome, a kidney biopsy often is needed to diagnose the cause; in both children and adults, it provides an important means of distinguishing among various diseases affecting the glomeruli, including minimal change disease, FSGS, or membranous nephropathy.

Current Treatments for Nephrotic Syndrome
The goal in the management of nephrotic syndrome would be controlling symptoms, reducing proteinuria, and treating the cause of glomerular damage. There are different treatment approaches depending on whether the nephrotic syndrome is primary, due to intrinsic kidney disease, or secondary to other systemic diseases such as diabetes or lupus.
Corticosteroids represent the first-line treatment of minimal change disease, which is usually highly responsive to steroids. These children are commonly treated with prednisone for weeks or months and enter into complete remission during this time. In steroid-resistant cases, primarily in adults or within conditions such as FSGS, however, patients need stronger immunosuppressive therapies. Such drugs include cyclophosphamide, mycophenolate mofetil, or calcineurin inhibitors such as cyclosporine or tacrolimus.
Other treatments, such as rituximab, a monoclonal antibody against B-cells, may be added in secondary cases of nephrotic syndrome caused by an autoimmune disease, like lupus. In membranous nephropathy, treatment advances with rituximab and belimumab, that inhibit B-cell activation, are yet to show some promise in reducing proteinuria and slowing the evolution of the disease.
The management of nephrotic syndrome also requires supportive treatment. ACE inhibitors or ARBs like lisinopril or losartan are used to manage hypertension and minimize proteinuria. Diuretics like furosemide can diminish edema through enhanced fluid excretion; however, statins may be prescribed for the treatment of hyperlipidemia.

Complications of Nephrotic Syndrome
Left uncontrolled, nephrotic syndrome can result in severe complications stemming from the original cause of kidney disease and secondary effects of protein loss. One of the common complications of this syndrome is AKI, or acute kidney injury, where there is a sharp and severe loss of function of the kidneys, especially in cases accompanied by high-grade proteinuria and fluid loss. Other complications may lead to CKD, though some of them may eventually progress to ESRD, which requires dialysis or kidney transplantation to control.
Since the loss of immunoglobulins in the urine increases a patient's chances of getting infections, especially in the form of pneumonia, peritonitis, and sepsis, loss of anticoagulant proteins in the urine is another complication of nephrotic syndrome that raises the risk for DVT, pulmonary embolism, and other clotting disorders.
Another common complication is hyperlipidemia, which elevates the risk for cardiovascular disease. Patients with chronic nephrotic syndrome are at an increased risk for heart disease and stroke and should have aggressive lipid-lowering therapy and lifestyle changes.
 

New Treatments and Future Perspective
A deeper understanding of the molecular events of nephrotic syndrome has paved the way for more targeted therapies beyond the use of corticosteroids and broad immunosuppressive therapy. For example, monoclonal antibodies such as rituximab have established potential in the treatment of FSGS, among others, by selectively targeting immune pathways involved in glomerular injury.
A newer treatment, particularly in steroid-resistant nephrotic syndrome, is ACTH (Adrenocorticotropic hormone). Actually used for the treatment of childhood nephrotic syndrome years ago, recent studies have shown ACTH to be not only immunomodulatory but anti-inflammatory, which can help decrease proteinuria in adult patients.
Beyond monoclonal antibodies, further research into complement inhibition continues to be pursued in such diseases as membranous nephropathy and IgA nephropathy, where the complement system plays a part in the pathogenesis of the disease. Complement cascade inhibitors, including eculizumab, are currently under investigation in active clinical trials in those settings.
Researchers are also exploring gene therapy for genetic forms of nephrotic syndrome, especially in relation to mutations in genes such as NPHS1 that encode nephrin and cause congenital nephrotic syndrome. While these gene therapies are still very embryonic in their development, they may hold promise in principle to correct the underlying genetic disorder causing the glomerular injury permanently.
Finally, biomarker research is an area of critical development, aimed at discovering very early markers of nephrotic syndrome progression. Some urinary CD80 and circulating suPAR (soluble urokinase plasminogen activator receptor) promise to predict how likely it is to respond to the treatment and in cases of relapse of such conditions as FSGS and minimal change disease.