Nephrotic & Nephritic Syndrome
Nephrology, Pathology Related to Glomerular Injury
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The glomerulus is the filtration unit of the kidney. One kidney has approximately 1.2 million nephrons.
Glomerulopathies & Glomerulonephritis
Filtration Membrane – Main Components
There are three components of the filtration membrane.
1. Endothelial Cells
These are fenestrated cells (fenestrations within endothelial cells). Size of fenestration is 70-100nm.The endothelial cells are negatively charged.
2. Glomerular Basement Membrane:
This is a negatively charged membrane.
3. Epithelial Cells
These cells are also called podocytes, stick with the glomerular basement membrane. These podocytes are interdigitated forming filtration slits of around 20-30 mins. In some glomerular diseases, these podocytes detach and lead to increase in the permeability.
Barriers for Filtration
There are two barriers for filtration.
Size barrier does not let large sized molecules to pass through the filtration membrane and negative charges on components of filtration membrane repel negatively charged molecules (e.g. negatively charged plasma proteins).
In minimal change glomerulopathy these negative charges of membrane components are neutralized and a lot of albumin starts leaking out.
Types of Proteinuria
If there is a very small glomerular injury then smallest molecules start leaking into the urine e.g., albumin start appearing into urine (albuminuria). This is called selective proteinuria.
If there is moderate glomerular injury, filtration membrane becomes more permeable and relatively large molecules (globulin) also start leaking into urine with smaller molecules (albumin) causing globulinuria and albuminuria respectively.
This called non-selective proteinuria. Here proteinuria is lees than 3.5 gram/day.
In case of severe glomerular injury, filtration membrane becomes more and more leaky leading to proteinuria (albuminuria and globulinuria) more than 3.5gram/day.
Complications of Proteinuria
Loss of proteins occurs by two mechanisms.
Some proteins are leaked into urine leading to proteinuria.
Some proteins which are leaking down, many of them are taken up by cells of proximal convoluted tubules by pinocytic process and lots of proteins are catabolized there.
First liver compensates and maintains protein concentration but later when if fails to do then it leads to hypoproteinemia.
Edema due to hypoproteinemia.
Plasma proteins are responsible for maintaining oncotic pressure in circulatory system, so hypoproteinemia cause decrease in oncotic pressure, fluid moves to extra-cellular fluid and it leads to edema formation.
Edema of Renal Origin.
Normally in every tissue, from arterial end of capillaries fluid is leaking out adding to interstitial fluid due to increased hydrostatic pressure and less oncotic pressure at this end and on the venous end of capillaries fluid is constantly taken back due to increased oncotic pressure and less hydrostatic pressure at venous end of capillaries.
In patients with renal disease (glomerulopathy) proteinuria causes decrease in level of plasma proteins resulting in decreased oncotic pressure, causing more fluid to leak into interstitial space on arterial end and less fluid returning back to circulatory system on venous end of capillaries hence causing Edema due to glomerulopathy.
Due to accumulation of fluid in interstitial tissue, blood volume in circulatory system decreases leading to hypoperfusion of kidneys which activate rennin-angiotensin-aldosterone axis.
-Angiotensin-II causes vasoconstriction increasing hydrostatic pressure in capillaries and eventually edema is produced.
-Due to production of aldosterone there is more sodium and water retention leading to increase in blood volume which eventually increases hydrostatic pressure and causes edema.
When fluid moves to interstitial space, hemoconcentration occurs in the vessels which stimulate hypothalamus, resulting ADH production that promotes more retention of sodium and water which worsens the already produced edema.
Liver tries to compensate the protein loss, when liver is making more albumin and globulin then unfortunately it also makes more lipoproteins and patient develops hyperlipidemia.
In general, the levels of LDL, IDL, VLDL and triglycerides will go up and the level of HDL will go down.
This picture of dyslipidemia predisposes the patients to atherosclerosis, cardiac diseases and cerebrovascular accidents.
Due to severe hyperlipidemia, lipids also start appearing into urine, this is called lipiduria.
Proximal convoluted cells take in more lipids and will be loaded with fat globules making these cells dysfunctional and they start shedding down in urine as big fat globules; also known as fat oval bodies.
Pathology of Nephrotic Syndrome
Nephrotic syndrome is a clinicopathological condition which develops when there is significant damage to the glomeruli which leads to heavy proteinuria (>3.5g/day) and is associated with hypoproteinemia, generalized edema, hyperlipidemia and even lipiduria.
Nephrotic Range Proteinuria
Heavy proteinuria (>3.5g/day) leading to hypoproteinemia causing generalized edema, hyperlipidemia, lipiduria; good nephrologists will call it nephritic range proteinuria.
Sub-Nephrotic Range Proteinuria
When patient has proteinuria, but is not leading hypoproteinemia, generalized edema, hyperlipidemia, lipiduria. We call it Sub-nephrotic range proteinuria. It is less than 3.5 g/day.
Nephrotic Syndrome & Glomerular Injury
Nephrotic syndrome is just a clinical face of glomerular injury.
Due to slightest glomerular injury, the clinical picture will be selective proteinuria.
If moderate glomerular injury, it will cause non-selective proteinuria without generalized edemas, lipiduria and hyperlipidemia.
If severe glomerular injury, proteinuria becomes so heavy that turns the whole pathophysiological picture of patient into nephritic of patient into nephritic range proteinuria and we call patient is with nephritic syndrome
Other associations: with Nephrotic Syndrome
i) Iron Deficiency Anemia
Not only albumin leaks into urine but other very small proteins also leak into urine.
If patient has nephrotic syndrome for long time, patient will lose transfer of plasma protein responsible for iron binding, so iron will filter out and patient will develop Iron deficiency Anemia.
In nephrotic syndrome when other protein antithrombin-III (anticoagulant) leaks into urine, blood will become procoagulant and patient will develop thrombosis more readily. For example, renal vein thrombosis is common in patients with nephrotic syndrome.
In nephrotic syndrome, not only loss antithrombin-III promotes thrombogenesis but hyperlipidemia and hemoconcentration are also thrombogenic factors.
Immunoglobulins and lower molecular weight complements also leak into urine, so patient’s defense weakens and patients become more susceptible to infections (mostly develop pneumococcal infections)
iv) Frothy Urine
High protein in urine makes it frothy. It is a frequently encountered manifestation of nephrotic syndrome
Severe Glomerular Injury
If a patient has severe glomerular injury, it develops inflammatory lesion in glomeruli and as a result glomeruli get loaded with neutrophils and macrophages. In addition to albuminuria and globulinuria, hematuria also starts appearing.
Glomerular Origin Hematuria
Hematuria can be due to several reasons including glomerular origin. Glomerular origin hematuria is characterized by Dysmorphic changes of red blood cells in urine sample, (while leaking out, they become star shaped). that indicates serious damage in glomeruli.
Red Blood Cells Cast
When RBC’s leak in heavy numbers, they block lumen of the tubule as they held together by proteins, and these RBCs are pushed forward by the fluids behind these blockages, eventually these RBC’s are excreted out in the form of cylinder (as having cast of lumen) into the urine. When these groups of RBCs appear in urine as mentioned, we say patient is showing RBC cast.
With the progression (severity) of glomerular injury patients keep on developing more complication, first there was proteinuria and now it includes hematuria also.
Development of Oliguria
Normally during inflammation of glomeruli flow increases through the kidneys but when glomeruli are severely inflamed, they swell up and get loaded and clogged by the inflammatory cells and platelets accumulation. So, blood can’t pass through and glomerular filtration decreases. When total urine formation per 24 hours becomes less than 400 ml/24 hours, we say patient has developed oliguria due to reduced GFR.
Why Proteinuria is Less in Nephritic Syndrome?
Inflammatory glomerular injuries are so advanced that total glomerular filtration is reduced, thus lead to reduction in total amount of filtered proteins. That’s why in these cases albuminuria and globulinuria are comparatively less in nephritic syndrome.
When proteinuria is decreasing in Patient with nephritic syndrome, it is considered bad sign as decreased proteinuria is associated with hematuria and thus the condition gets worse.
Development of Azotemia
When GFR reduces, oliguria develops. Urea and creatinine will start accumulation in blood and patient will start developing azotemia.
Development of Hypertension
When blood flow through the kidneys is dangerously reduced then renin-angiotensin-aldosterone gets activated, resulting in retention of salt and water thus increasing vasoconstriction (due to angiotensin II), so patient develops hypertension.
Development of Nephritic Syndrome
When patient with nephrotic syndrome gets worse, develops hematuria (dysmorphic and RBC’s cast), azotemia with oliguria and hypertension, we can say patient has developed nephritic syndrome.
Recap of Glomerular Injuries
According to severity of injuries;
+Injury: Selective proteinuria.
++Injury: Non-selective proteinuria (it may be in sub-nephrotic range)
+++Injury: Heavy proteinuria (may be selective or non-selective) leads to nephritic syndrome.
++++Injury: There may be some degree of proteinuria, hypoproteinemia, edema but patient develop hematuria, oliguria with azotemia and hypertension.
+++++++++++++Injury: Very intense and so severe injury that produces multiple disruptions in the glomerular basement membrane where proteinuria, hematuria decrease but actually a lot of fibrin leak down and breakdown of this fibrin forms molecules which act as growth factor for epithelial cells, moreover fibrin attracts macrophages, and these macrophages, platelets derived growth factors and mesangial cells etc also start producing a lot of growth factors which cause proliferation of epithelial cells with macrophages and within few weeks whole urinary space is full of cells and they make cellular crescents.
This patient with cellular crescents will come with rapidly progressing loss of kidneys function, patient has all features of nephritic syndrome but urea and creatinine and other products are so much accumulated in blood that clinical features of renal failure become apparent i.e., potassium elevates and arrhythmia starts, uremic pericarditis, uremic enteropathies, uremic frost may develop. Some call it rapidly progressive glomerulopathy but clinically patient is developing acute renal failure.
What is Uremia?
When due to renal dysfunction blood chemistry is so much disturbed that sign and symptoms of renal failure appear, we say azotemia has converted into uremia.
Development of End-Stage Kidney Disease
Whatever the original cause of injury; patient may develop nephrotic or nephritic syndrome, if it is not controlled at time and it goes over the long time then in all chronic patients there is significant activation and accumulation of fibrocytes with fibroblasts, they start lying down collagen in glomeruli and glomeruli become hyalinized.
So, when glomeruli become hyalinized then lesions become irreversible, this progressive and irreversible damage to glomeruli eventually lead to chronic renal failure.
Here renal glomeruli are shrunken, hyalinized with atrophy of tubules.