Pathophysiology
The kidneys are located in the retroperineal space in the abdominal cavity. The primary functions of the kidneys are to regulate volume and osmolality, maintain proper electrolyte balance, excretion of metabolites, such as urea, creatine and drugs, and to regulate hormonal balance. The kidneys filter blood as it passes through the nephron of the kidney. Urine formation consists of three basic processes: glomerular filtration, tubular secretion, and tubular reabsorption
Each kidney contains about one million nephrons. Each nephron has a small blood vessel that brings in unfiltered blood, a glomerulus, which actively filtrates the blood to form urine. A tubule carries away filtered waste materials in the urine, and a small blood vessel returns filtered blood to the body. The primary waste products include urea, creatinine, and other metabolites.
Hormones in the kidney stimulate red blood cell production and regulate blood pressure. When there is a decrease flow through the glomerulus, a protein, renin, is released by the glomerular apparatus in the kidneys. Renin then produces angiotensin, the active form of which stimulates the adrenal gland to produce a hormone called aldosterone. Aldosterone affects sodium, potassium, total fluid in the body and blood pressure. Aldosterone causes the kidneys to hold onto more sodium, which leads to more water staying in the body. Potassium may decrease as the amount of aldosterone increases.
Nephrotic syndrome may occur when the filtering units (glomeruli) of the kidney are damaged. This damage allows protein to leak from the plasma into the urine in large amounts. Since the protein in the blood helps keep fluid in the bloodstream, the decrease in protein causes fluids to leak into tissue and produces edema. The hormonal stimulation can intensify these effects. Regardless of the etiology, once damage is done to the nephrons and glomerulus there is progressive decline of the filtration rate. Nephrotic syndrome can affect all age groups. In children, it is most common between ages 2 and 6. This disorder occurs slightly more often in males than females.
Potential Causes
Damage to the microvasculature of the glomerulus may be caused by many disorders but is most commonly caused by glomerulonephritis in adults and minimal change disease in children. Other causes include:
Diabetes
Strep infections
Skin infections
Systemic Infections such as HIV, hepatitis, mononucleosis, syphilis
Drugs such as NSAIDs, lithium, some antibiotics, bisphosphonate
Autoimmune disorders such as rheumatoid arthritis, lupus erythematosus
Genetic Disorders with mutations in B lymphocytes and T cells and sickle cell
Multiple myeloma
Cancers of the kidney or secondary cancers
Complication following renal transplantation
Idiopathic causes
All of these disorders may cause immune complexes (formed from antigen, antibodies, and other complements) to get trapped in the kidney filters. The glomeruli then become inflamed, which leads to ineffective kidney function with large loss of protein in the urine.
Symptoms
Primary symptomatology is reflective of the low serum protein levels, increased water retention and the ineffective absorption of electrolytes. People with nephrotic syndrome almost always experience edema. Leg swelling may be most noticeable after standing for long periods, and around the eyes in the morning. Eventually, the swelling in the legs may be there all the time. Symptoms and etiology of nephrotic syndrome are reflective of ineffective renal function.
Other signs and symptoms include:
Elevated urine protein levels
Fatigue and weakness
Swelling of feet, and abdomen
Loss of appetite
Increased weight from fluid retention
Frothy urine from high protein levels
Hypoalbuminemia (low serum albumin levels)
Orthostatic hypotension
Susceptibility to infectious diseases due to an impaired immune system
An increased risk of blood clots (thrombosis)
Muscle wasting (due to the loss of protein)
Malnourishment (due to poor absorption of vitamins and minerals)
Rashes and skin lesions
Weakening of the bones with low vitamin D, calcium and zinc levels
Abnormally low or abnormally high blood pressure
Hyperlipidemia – High cholesterol levels especially HDL and triglycerides
Seizures due to electrolyte imbalances
Kidney failure, from oliguria early to azotemia and acidosis
Albumin synthesis in the liver is increased in nephrotic syndrome, but it is not enough to compensate for losses in the urine. The loss of albumin leads to edema and also triggers cholesterol and lipoprotein synthesis in the liver. Hyperlipidemia is a classic feature of the nephrotic syndrome, rather than a mere complication.
Diagnosis
Whatever the underlying etiology, once the loss of nephrons and reduction of functional renal mass reaches a certain point; the remaining nephrons begin a process of irreversible sclerosis that leads to a progressive decline in the glomerular filtration rate (GFR).
Multiple blood tests will assist with the diagnosis and help find the underlying pathology. Blood chemistry tests such as comprehensive metabolic panel may show hyponatremia, hyperkalemia, and hypocalcemia. Blood urea nitrogen (BUN) and creatinine levels will be elevated.
Urine will be positive for large protein and may also be positive for blood and lipids. Along with a routine urinalysis, a 24 urine collection should be obtained. Urinary protein losses greater than 3-3.5 grams per day usually indicate nephrotic syndrome.
A kidney biopsy may be needed to find the cause and extent of the disorder. Absolute contraindications to renal biopsy include uncorrectable bleeding diathesis, severe hypertension, active renal or perirenal infection and skin infection at biopsy site. Biopsy is usually performed under CAT scan by a radiologist or urologist.
Additional tests to address the underlying cause may include:
Cholesterol and triglyceride levels
Glucose tolerance test
Hepatitis B and C antibodies
HIV test and syphilis serology
Treatment
Treatment usually consists of trying to find and manage the underlying cause of nephrotic syndrome. The goal of any treatment plan is to prevent complications and delay kidney damage for as long as possible. Treatment may be long term and the patient may develop chronic renal failure.
Keeping blood pressure at or below 130/80 mm Hg to delay kidney damage is the goal. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are the medicines most often used. ACE inhibitors and ARBs may also help decrease the amount of protein lost in the urine.
Glomerular integrity and inflammatory reduction are achieved with steroids. Corticosteroids and potent immune suppressant medications such as cyclosporine, cyclophosphamide, mycophenolate and rituximab have been used. Aphaeresis has been tried in patients who do not response to steroid treatment.
Loop diuretics, such as Furosemide, and fluid restriction is recommended for nephrotic syndrome but patients are at risk of hypotension with aggressive therapy and volume replacement with 3% saline IV’s may be needed. Dosage and frequency of diuretics should be titrated to blood pressure and reduction of fluid accumulation.
It has long been recognized that nephrotic syndrome is associated with an increased risk for thromboembolic complications, including deep venous thrombosis, renal vein thrombosis, and pulmonary embolism. Treatment therefore, must take into account the nature of the underlying disease, the severity of the nephrotic syndrome, preexisting thrombotic states, and the overall likelihood of serious bleeding events consequent to oral anticoagulation. Deep vein thrombosis is said to develop in approximately 15% of patients with the nephrotic syndrome.
Diet
Low protein diets are encouraged to decrease damage to the nephrons. Since albumin losses in nephrotic patients are due to increased catabolism, rather than a reduction in protein synthesis. A common recommendation is 0.6 to 1 grams of protein per kilogram of ideal body weight. Sodium is limited to 1-3 grams per day to reduce edema and hypertension. A diet low in saturated fat and cholesterol is recommended to reduce the risk of cardiovascular disease. Many clinicians recommend limiting cholesterol to less than 300 milligrams per day. Cholesterol-lowering drugs (Statins) can be used adjunctively if needed, but are not used in younger patient or those without risk factors for atherosclerotic disease and it is unknown if it benefits prognosis acutely.
Those with nephrotic syndrome are often low in B and D vitamins and zinc, and can benefit from supplements. Since a significant portion of serum calcium is protein-bound, it tends to be low when serum proteins are reduced. No modification is routinely needed for potassium, but potassium losses due to secondary hyperaldosteronism may require replacement.
The edema produced has a significant effect on daily activities. Cold compresses to reduce swelling in areas such as those of the eyes, upper cheeks and nose can be used. Gently massaging the swollen area will help stimulate blood circulation by reducing the edema. Wearing compression socks, sleeves and gloves enhances blood flow in the swollen area, and relieves the symptoms, Elevation of swollen hands or legs at a minimum of thirty minute intervals should be recommended to patients. The patient should be instructed to avoid hot baths and extreme temperatures which may exacerbate swelling. Chinese herbal therapies and alternative therapies can be employed in conjunction with the medical team. Green tea has been used as a diuretic in China for centuries; it may also be beneficial for high cholesterol and infections.
Prognosis is based on the return of renal functions and continued proteinuria. Nephrotic syndrome may persist for weeks to years and subsequent renal disease for a lifetime. Overall, it is important to maintain good health and nutrition and to ensure other medical conditions are treated promptly.
References:
Cheuck, Lanna. (2016). Renal Biopsy. Retrieved from http://emedicine.medscape.com/article/2093338-overview#showall.
Nephrotic Syndrome. Retrieved from https://www.kidney.org/atoz/content/nephrotic.
Russo, GE et. al. (2000). Nephrotic syndrome and plasmapheresis. The International Journal of Articficial Organs, 23, 111-113. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/10741806.
Swelling (Puffiness) and Chronic Kidney Disease. Retrieved from http://www.ckdstage.com/ckd-symptoms/17.html.
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