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Saturday, September 23, 2017

Nephrotic Syndrome: Causes, Pathophysiology, Diagnostic Investigations, and Prognosis

In this article we will focus mainly on the definition of nephrotic syndrome, its causes, basic pathophysiology, prognosis and diagnostic investigations. We have another article for you which elaborates on the pathophysiology of nephrotic syndrome, its treatment, complications and differential diagnoses.

What Is Nephrotic Syndrome? 

Nephrotic syndrome is characterized by:

  • Hypoalbuminemia 
  • Massive proteinuria: >3.5 g proteinuria/day 
  • Dyslipidemia 
  • Salt and water retention, leading to generalized edema (anasarca)
  • Microscopic hematuria
  • Hypertension

If left undiagnosed or untreated, some of these syndromes will progressively damage enough glomeruli to cause a fall in GFR, producing renal failure.

Nephrotic Syndrome: Causes, Pathophysiology, Diagnostic Investigations, and Prognosis

    What Are the Causes of Nephrotic Syndrome?

    1. Primary renal disease—all types of glomerulonephritis (80%): 

    Nephrotic syndrome 
    • Minimal change glomerular disease (the most common in children) 
    • Congenital nephrotic syndrome 
    • Membranous GN (the most common in adult) 
    • Focal and segmental glomerulosclerosis 
    • IgA nephropathy. 
    Mixed Nephrotic/Nephritic syndrome
    • Mesangiocapillary glomerulonephritis 
    • Mesangial proliferative glomerulonephritis 

    2. Secondary Causes of Nephrotic Syndrome: 

    Nephrotic Syndrome
    • Diabetic nephropathy
    • Amyloidosis
    Mixed Nephrotic/Nephritic syndrome 
    • Collagen disease, mainly SLE, also rheumatoid arthritis (by amyloidosis)  
    • Drugs: penicillamine (common), captopril, gold, mercury 
    • Neoplastic: carcinoma (bronchial carcinoma), lymphoma 
    • Infection: malaria (quartan malaria), bacterial endocarditis, HBV, HCV, HIV, secondary syphilis, leprosy 
    • Allergies: bee stings, snake bite, anti-snake venom, pollens  
    • Cryoglobulinemic disease 
    • Henoch-Schonlein syndrome 
    • Idiopathic fibrillary glomerulopathy 
    • lmmunotactoid glomerulopathy 
    • Fibronectin glomerulonephropathy

    The incidences of the several causes of the nephrotic syndrome vary according to age and geography. In children younger than 17 years in North America, for example, nephrotic syndrome is almost always caused by a lesion primary to the kidney. In contrast, among adults, it is often associated with a systemic disease.

    The most frequent systemic causes of the nephrotic syndrome are diabetes, amyloidosis, and SLE.

    The most important of the primary glomerular lesions are minimal-change disease (most common in children), membranous glomerulopathy (most common in adults), and focal segmental glomerulosclerosis.

    Other less common causes of nephrotic syndrome include the various proliferative glomerulonephritides such as MPGN and IgA nephropathy.

    What Is the Most Common Cause of Nephrotic Syndrome in Children and Adult? 

    Most common cause of pediatric nephrotic syndrome is minimal change glomerulonephritis, and the most common cause of adult nephrotic syndrome is membranous glomerulonephritis. Focal segmental glomerulosclerosis occurs at all ages

    Basic Pathophysiology of Nephrotic Syndrome
    Basic Pathophysiology of Nephrotic Syndrome

    Patterns of Nephrotic Syndrome

    Nephrotic Syndrome Proteinuria Hematuria Vascular Injury
    Minimal change disease ++++
    Focal segmental glomerulosclerosis +++/++++ +
    Membranous glomerulonephritis ++++ +
    Diabetic nephropathy ++/++++ −/+
    AL and AA amyloidosis +++/++++ + +/++
    Light-chain deposition disease +++ +
    Fibrillary-immunotactoid disease +++/++++ + +
    Fabry’s disease + +

    Why Is There Proteinuria in Nephrotic Syndrome? 

    There is increased permeability of the glomerular capillary wall due to:
    1. Reduction of fixed negatively charged protein molecules in glomerular capillary wall which repel negatively charged protein molecules, allows proteins to pass through the pores 
    2. Damage to the glomerular barrier that leads to increase in the size and number of pores, allowing passage of larger molecules. 
    The glomerular barrier consists of:
    • Podocytes, 
    • Basement membrane, 
    • Fenestrated endothelium and 
    • Endothelial charge 
    The filtration slit between podocytes and normal podocyte architecture, and interdigitating podocyte foot processes are critical to maintaining a barrier to protein loss into the urinary space, as is a functional glomerular basement membrane and healthy capillary endothelium (and its charge).

    The Glomerular Barrier Structure
    The Normal Glomerular Barrier Structure

    Normal Vs Abnormal Podocytes

    Normal vs Abnormal Podocyte
    Normal vs Abnormal Podocyte

    A normal (left) and a proteinuric (right) glomerulus. A capillary loop shows normal glomerular morphology on the left with an epithelial cell with pseudopodia (foot processes). In the proteinuric diagram (right), there is fusion of the foot processes, which is characteristic of many diseases. 
    BM: basement membrane. MC: mesangial cell. MM: mesangial matrix.

    Why Is There Hypoalbuminemia in Nephrotic Syndrome? 

    Loss of urinary protein (largely albumin) of the order >3.5 g daily in an adult may lead to hypoalbuminemia. Normal dietary protein intake in the UK is around 70 g daily and the normal liver can synthesize albumin at a rate of 10-12 g daily. How, then, does a daily urinary protein loss of 3.5 g result in hypoalbuminemia? This can be partly explained by increased catabolism of reabsorbed protein, largely albumin, in the proximal tubules, even though the rate of albumin synthesis is increased.

    What Are the Lipid Abnormalities in Nephrotic Syndrome? What Are the Mechanisms of Dyslipidemia in Nephrotic Syndrome? 

    Lipid abnormalities are:
    • Hypercholesterolemia and hypertriglyceridemia
    • High LDL, VLDL and IDL
    • There is no change or low HDL. 
    The mechanisms of dyslipidemia are:
    • Increased synthesis of lipoproteins (such as apolipoprotein B, C-111 lipoprotein a) by the liver, secondary to hypoalbuminemia
    • Reduced renal clearance of triglyceride bearing lipoprotein (chylomicron and VLDL) in direct response to albuminuria. 
    Low-density lipoprotein (LDL) increases, partly due to upregulation of a liver serine protease, pro-protein convertase subtilisin kexin-9 (PCSK9), which causes internalization of LDL receptors. Very-low-density lipoprotein (VLDL) and/or intermediate-density lipoprotein (IDL) fractions increase, with no change (or a decrease) in HDL (the LDUHDL cholesterol ratio increases). There is also reduced clearance of the principal triglycerides bearing lipoprotein (chylomicrons and VLDL), as high plasma levels of free fatty acid (FFA) trigger release of appropriately sialylated angiopoietin-like 4 (Angptl4) protein from adipose tissue, heart and skeletal muscles, inhibiting lipoprotein lipase and resulting in hypertriglyceridemia. As a result, there is high rate of atherosclerosis.

    Why Generalized Edema Occurs in Nephrotic Syndrome? 

    Previously it was thought that reduction of albumin causes low plasma oncotic pressure, which causes to edema. But recent view is oncotic pressure is not changed in Nephrotic syndrome, edema is due to sodium retention in the extracellular compartment. Also, there is change in molecular barrier, which causes edema.

    What Are the Mechanisms of Renal Vein Thrombosis in Nephrotic Syndrome? 

    Mechanisms are as follows:
    1. In nephrotic syndrome, there is hypercoagulable state due to: 
      • Loss of inhibitors of coagulation in urine, such as antithrombin III, protein C and S, and loss of fibrinolytic factor (plasminogen).
      • Increase synthesis of clotting factors: factor V, VIII and fibrinogen.
      • Other factors: thrombocytosis and over diuresis resulting in dehydration, reduced renal blood flow and increased viscosity, prolonged bed ridden. 
    2. Also, there is hyperlipidemia, commonly high LDL, VLDL, cholesterol and triglyceride. So, there is more atherosclerosis. 
    These predispose to increased venous thrombosis that occurs specially in renal vein.

    Remember the following:
    • In nephrotic syndrome, if there is loin pain, hematuria and deterioration of renal function, it is highly suggestive of renal vein thrombosis. It is more common in membranous nephropaty, mesangiocapillary glomerulonephritis and amyloidosis.
    • To diagnose renal vein thrombosis, Doppler ultrasound, CT-Scan or MRI, sometimes renal angiogram (venous phase) may be done.
    • Treatment: anticoagulant heparin for 5 to 7 days, then warfarin for 3 to 6 months.

    What Is the Prognosis of Nephrotic Syndrome? 

    It depends on the type of Nephrotic syndrome:
    • Prognosis of minimal change disease in children is excellent. Remission and relapse may occur (common in children and less in adult). CKD does not occur.
    • In membranous nephropathy, one-third may remit spontaneously, one-third remain in nephrotic syndrome and one-third shows progressive loss of renal function.
    • In FSGS and Mesangiocapillary GN: prognosis is bad.
    • IgA nephropathy: course of the disease is indolent. ESRD occurs in 20 years.

    What Are the Lab Diagnostic Investigations in Nephrotic Syndrome? 

    Nephrotic syndrome diagnosis can be achieved by the following investigations:
    1. Urine R/E—Shows gross proteinuria. Red cells and red cell casts are absent (also, look for urine sugar to exclude diabetic nephropathy).
    2. 24 hours urinary total protein (more than 3.5 g/ 24 h is suggestive of nephritic syndrome).
    3. Serum total protein, serum albumin and A:G ratio (hypoalbuminemia).
    4. Serum lipid profile (high cholesterol and high TG may be present).
    5. Blood sugar, blood urea, serum creatinine, serum electrolytes should be done.
    6. USG of the whole abdomen to look for renal pathology.
    7. To find out causes: 
      • Blood sugar (to exclude diabetic nephropathy).
      • Chest X-ray (to exclude bronchial carcinoma, lymphoma. Also, to see bilateral pleural effusion, pericardial effusion).
      • ANA, Anti-dsDNA (if the history is suggestive of SLE)
      • P-ANCA and c-ANCA (if the history is suggestive of vasculitis)
      • HBsAg and anti HCV screening
      • Complement C3 and C4
      • Renal biopsy (to see the type of GN, whether minimal, membranous or membranoproliferative —this will guide for diagnosis, therapy and prognosis).

    That's all for today!
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