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Saturday, September 23, 2017

Nephrotic Syndrome: Pathophysiology, Treatment, Complications, Differential Diagnoses

Today we will continue our discussion on nephrotic syndrome. In our previous article regarding nephrotic syndrome we have discussed the causes, prognosis, basic pathophysiology, and diagnostic investigations of nephrotic syndrome. In this article we will elaborate on the pathophysiology of nephrotic syndrome as well as discuss its differential diagnoses, complications and treatment.

Nephrotic Syndrome: Pathophysiology, Differential Diagnosis, Complications, Treatment

    Pathyphysiology of Nephrotic Syndrome 

    Nephrotic syndrome is caused by a derangement in glomerular capillary walls resulting in increased permeability to plasma proteins.

    The manifestations of the syndrome include:
    • Massive proteinuria, with the daily loss of 3.5 gm or more of protein (less in children)
    • Hypoalbuminemia, with plasma albumin levels less than 3 gm/dL 
    • Generalized edema (anasarca)
    • Hyperlipidemia and lipiduria
    • Microscopic hematuria
    • Hypertension
    Pathophysiology of Nephrotic Syndrome
    Pathophysiology of Nephrotic Syndrome

    Massive proteinuria and Hypoalbuminemia in Nephrotic Syndrome 

    The Glomerular Barrier (The glomerular capillary wall, with its endothelium, GBM, and visceral epithelial cells) acts as a size and charge barrier through which the plasma filtrate passes.
    Increased permeability resulting from either structural or physicochemical alterations in this barrier allows proteins to escape from the plasma (blood) into the urinary space, resulting in proteinuria.

    Heavy proteinuria depletes serum albumin levels at a rate beyond the compensatory synthetic capacity of the liver, resulting in hypoalbuminemia.

    Increased renal catabolism of filtered albumin also contributes to the hypoalbuminemia.

    Difference between Normal and Damaged Glomerular Barrier
    Difference between Normal and Damaged Glomerular Barrier

    What kind of proteins are excreted in Nephrotic Syndrome? 

    The largest proportion of protein lost in the urine is albumin, but globulins are also excreted in some diseases.

    The ratio of low- to high-molecular-weight proteins in the urine in various cases of nephrotic syndrome is a manifestation of the selectivity of proteinuria.

    What is highly and poorly selective proteinuria? 

    A highly selective proteinuria consists mostly of low-molecular-weight proteins (albumin, 70 kD, transferrin, 76 kD molecular weight), whereas a poorly selective proteinuria consists of higher molecular-weight globulins in addition to albumin.

    Highly selective proteinuria Poorly selective proteinuria
    Low molecular weight proteins

    • Albumin (70 kD) 
    • Transferrin (76 kD)
    High molecular weight proteins

    • Globulins

    And Albumin

    Generalized Edema 

    The generalized edema (anasarca) is a direct consequence of decreased intravascular colloid osmotic pressure. There is also sodium and water retention, which aggravates the edema. This seems to be due to several factors, including compensatory secretion of aldosterone, mediated by the hypovolemia-enhanced renin secretion, stimulation of the sympathetic system and a reduction in the secretion of natriuretic factors such as atrial peptides.

    What is the nature of edema in nephrotic syndrome? 

    Edema is characteristically soft and pitting, and is most marked in the periorbital regions and dependent portions of the body. If severe, it may also lead to pleural effusions and ascites.

    Hyperlipidemia in Nephrotic Syndrome 

    The genesis of the hyperlipidemia is complex.

    Most patients with nephrotic syndrome have increased blood levels of cholesterol, triglyceride, very-low-density lipoprotein, low-density lipoprotein, Lp(a) lipoprotein, and apoprotein, and there is a decrease in high-density lipoprotein concentration in some patients.

    These defects seem to be due to a combination of increased synthesis of lipoproteins in the liver, abnormal transport of circulating lipid particles, and decreased lipid catabolism.

    Lipiduria follows the hyperlipidemia, because lipoproteins also leak across the glomerular capillary wall. The lipid appears in the urine either as free fat or as oval fat bodies, representing lipoprotein resorbed by tubular epithelial cells and then shed along with injured tubular cells that have detached from the basement membrane.

    Complications of Nephrotic Syndrome 

    The complications are listed below:

    • Hypercoagulability leading to thrombotic and thromboembolic complications (especially renal vein thrombosis, also DVT) and pulmonary embolism. This occurs partly to loss of endogenous anticoagulants (e.g., antithrombin III) in the urine.
    • Infection such as pneumococcal infection (may cause peritonitis and septicemia), cellulitis, streptococcal infection, due to loss of immunoglobulin (IgG deficiency) complements in the urine.
    • Hyperlipidemia leading to atherosclerosis.
    • Acute Renal Failure.
    • May cause bilateral pleural effusion, pericardial effusion.
    • Loss of thyroxin binding globulin, that causes low FT3 and FT4 which leads to hypothyroidism.
    • Loss of transferrin and iron, resulting in iron deficiency anemia.
    • Loss of vitamin D binding protein, leading to osteomalacia.

    Complications of Nephrotic Syndrome
    Complications of Nephrotic Syndrome

    Brief Discussion of the Three Most Important Glomerulonephritis that cause Nephrotic Syndrome

    Membranous glomerulopathy 

    • It is a common cause of NS in adult, predominantly in males
    • It is mostly idiopathic
    • May be secondary to SLE, bronchial carcinoma, drugs (penicillamine), heavy metals like mercury, HBV, HCV
    • Renal vein thrombosis is a common complication
    • Renal biopsy shows thickening of glomerular basement membrane, increased matrix deposition and glomerulosclerosis
    • There is granular subepithelial IgG deposit
    • May progress to CKD
    • Response to steroid and other cytotoxic drugs is less.

    Minimal change nephropathy

    • Common in children, particularly male, but may occur in all ages, associated with atopy
    • On light microscopy, there is no abnormality
    • No immune deposit
    • On electron microscopy, there is fusion of podocyte foot process
    • Progress to renal failure is rare
    • Good response to steroid and cytotoxic drugs.

    Focal segmental glomerulosclerosis

    • Segmental scar in glomeruli, no acute inflammation, podocyte foot process fusion may be found. There is C3 and IgM deposition in the affected portions of glomerulus
    • Cause is unknown, but may be related to HIV, heroin misuse, morbid obesity, reflux nephropathy, also secondary to any other GN
    • Mostly present as idiopathic NS, may progress to renal failure, often resistant to steroid therapy and recurs after renal transplantation
    • There is massive proteinuria (usually non selective), hematuria, hypertension and renal impairment.

    Differential Diagnoses of Nephrotic Syndrome?

    The four following diseases are the differential diagnoses of nephrotic syndrome:

    • Acute glomerulonephritis
    • Congestive cardiac failure
    • Cirrhosis of the liver
    • Hypoproteinemia due to malnutrition or malabsorption.

    Differentiation between Nephrotic syndrome and its Differential Diagnoses

    Differential Diagnosis Differentiating Points
    Acute glomerulonephritis In AGN, there will be history of sore throat or skin lesion, no gross,or generalized edema. Also, there may be hypertension and hematuria. Proteinuria is usually mild, urine is smoky.
    Congestive cardiac failure The signs of CCF (engorged pulsatile neck vein, enlarged tender liver and dependent edema) will be absent in the patient. Usually, there is no generalized edema and no gross proteinuria in CCF.
    Cirrhosis of liver The patient will not exhibit any stigmata or signs of cirrhosis, or CLD. In cirrhosis usually there is only ascites but no generalized edema. Also, in cirrhosis, there is no generalized edema and no gross proteinuria.

    Treatment of Nephrotic Syndrome

    Treatment of Nephrotic Syndrome comprises of general treatment and type specific treatment.

    General treatment of Nephrotic Syndrome 

    1. Fluid restriction: depending on previous day’s output and patient’s edema status (average - 500 mL to 1000 mL/day). 
    2. Salt restriction. 
    3. High protein diet (2g/kg/day). In severe case, intravenous salt poor albumin may be given to diuretic resistant patients and those with oliguria and uremia in the absence of severe glomerular damage, e.g. in minimal change nephropathy. It helps in diuresis. Protein intake should be restricted in patient with impaired renal function. 
    4. Diuretics—loop diuretics (frusemide, bumetanide). If needed, potassium sparing diuretics (spironolactone) should be added. 
    5. ACE inhibitors and/or angiotensin II receptor antagonists are used in all types of GN (for their antiproteinuric properties. These drugs reduce proteinuria by lowering glomerular capillary filtration pressure).

    Specific Treatment of Nephrotic Syndrome according to cause 

    Minimal change disease

    • Prednisolone 60 mg/m2 body surface area (maximum 80 mg/day) is given for 4 to 6 weeks, followed by 40 mg/m2 every other day for a further 4 to 6 weeks. More than 95% responds (in children). Alternately, prednisolone 1mg/kg/day up to response (urine protein free) or 3 months followed by tapering the dose in next 3 months. 
    • If there is relapse after withdrawal of steroid, it should be given again with gradual withdrawal. Some patients may require low dose maintenance dose (5 to 10 mg/day) for 3 to 6 months. 
    • If there is frequent relapse or need high dose steroid or incomplete response to steroid then cyclophosphamide (2.0 mg/kg/day for 8 to 12 weeks) and mycophenolate mofetil with low dose steroid should be given. 

    Membranous glomerulopathy 

    • Inj. methylprednisolone 500 mg to 1000 mg iv for 3 days, followed by oral prednisolone 0.5 mg/kg/day for 27 days in 1st, 3rd and 5th months and Tab. cyclophosphamide 2 mg/kg/day or chlorambucil 0.2 mg/kg/day for 30 days in 2nd, 4th and 6th months. 
    • Chlorambucil (0.2 mg/kg/day in months 2, 4 and 6 alternating with oral prednisolone 0.4 mg/kg/day in months 1, 3 and 5) or cyclophosphamide (1.5 to 2.5 mg/kg/day for 6 to 12 months with 1 mg/kg/day of oral prednisolone on alternate days for the first 2 months) are equally effective. However, this treatment is reserved for patients with severe or prolonged nephrosis (proteinuria > 6 gm/day for > 6 months) or renal insufficiency and hypertension. 
    • Cyclosporine and mycophenolate mofetil with oral steroid may be used. 
    • Anti CD20 antibodies (rituximab) have been shown to improve renal function, reduce proteinuria and increase the serum albumin. 
    • Oral high dose corticosteroid and azathioprine are ineffective.

    Focal and segmental glomerulosclerosis

    • Symptomatic and supportive treatment. 
    • Steroid is effective in 40% cases. Tablet prednisolone 1 mg /kg /day for 3 months then tapered. Total duration of treatment at least about 6 months to 1 year. Most cases progress to renal failure. 
    • If no response—MMF 1 to 2 g/day or ciclosporine 5 to 6 mg/kg/ day for 3 months, and maintenances up to 15 months. 
    • Tacrolimus 0.05 mg/kg/day may be tried (occasionally effective). 
    • Renal transplantation can be done in renal failure, but may relapse after transplantation. 

    Mesangiocapillary or membrano-proliferative GN 

    • Only symptomatic and supportive treatment. 
    • No specific treatment. 
    • Aspirin may be given.

    Treatment of complication 

    • If infection: antibiotic is given. Pneumococcal vaccine is recommended. 
    • Venous thrombosis: to prevent, prolong bedrest should be avoided. Prophylactic heparin if immobile (enoxaparin may be given), followed by oral anticoagulant. 
    • For hyperlipidemia: statin may be added.

    That's all for today!
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    1 comment:

    1. Appreciating the commitment you put into your blog and in depth information you offer.
      It's good to come across a blog every once in a while that isn't the same unwanted rehashed material.
      Excellent read! I've saved your site and I'm adding your RSS feeds to my Google account.


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