**4. Pathophysiology**

In children with nephrotic syndrome facial or general edema, is the basic symptom due to accumulation of fluid in the interstitial compartment. In nephrotic syndrome the edema is usually causes disproportionate proteinuria, which leads to retention of sodium and water, hypoalbuminemia to recompense for intravascular volume depletion. The pathogenesis of edema can be well explained by analysis of the classic Starling equation, which explains the regulation of fluid movement across capillary walls [44].

Net filtration = LpS (Δ hydraulic pressure − Δ oncotic pressure).

$$=\text{LpS}\left[\left(\text{Pcap}-\text{Pif}\right)-\text{s}\left(\pi\text{cap}-\pi\text{if}\right)\right].$$

where:

Lp = the capillary permeability. S = the surface area of the capillary wall. Pcap = the capillary hydrostatic pressure. Pif = the interstitial fluid hydrostatic fluid pressure. s = the reflection coefficient for proteins (0 = complete permeability and 1 = complete impermeability). πcap = the capillary oncotic pressure. πif = the interstitial fluid oncotic pressure.

**59**

**Figure 2.**

*Causes and Pathophysiology of Nephrotic Syndrome in Childhood*

The formation of edema is prevented in healthy patients by a balance between forces favoring edema (capillary hydrostatic pressure [Pcap]) and those opposing it (capillary oncotic pressure [πcap]). The slight tendency toward fluid accumulation is counterbalanced by the lymphatics in the interstitial space. In nephrotic patients hypoalbuminemia results when the liver fails to synthesize the loss of albumin through urine. The hypoalbuminemia results leads to low down capillary oncotic pressure (πcap), which leads to relatively unopposed capillary hydrostatic pressure (Pcap) and subsequent edema formation. Relative intravascular volume reduction is due to edema formation the intravascular volume which triggers neurohumoral compensatory mechanisms. Which includes sympathetic nervous system (SNS), arginine vasopressin (AVP), and the renin angiotensin aldosterone system (RAAS), with

*Under fill hypothesis proposes the continuation of a reduced effective circulating blood volume in nephrotic* 

*syndrome. Pathophysiologic events leading to the formation of edema in nephrotic syndrome.*

*DOI: http://dx.doi.org/10.5772/intechopen.86825*

*Causes and Pathophysiology of Nephrotic Syndrome in Childhood DOI: http://dx.doi.org/10.5772/intechopen.86825*

*Renal Diseases*

**3.3 Defect in immunological system**

**4. Pathophysiology**

who actually transferred a soluble factor to their fetuses in utero [39], (3) decrease of repeated disease induced by treatment with protein A immunoadsorption due to presumed removal of circulating factors in the reappearance of FSGS in transplanted kidneys in patients with primary FSGS [40], and (4) FSGS recurrence in transplanted kidney patients serum injected in to the experimental animals leads to causing of enhanced glomerular permeability [32] serum of children with FSGS and recognized as components of apolipoproteins, from the suggestive of that an imbalance involving serum permeability factors and permeability inhibitors may have a pathogenic role in FSGS. Moreover, inhibitors of glomerular permeability have also been isolated [33].

For more than 30 years nephrotic syndrome may be because of abnormalities of the immune system has existed. Both the humoral and cellular immune responses are abnormal during relapse of nephrotic syndrome. Still, have a thought that relationship between the nephrotic syndrome and T lymphocyte function was first proposed by Shalhoub and his colleagues and concluded that abnormalities in cellular immune responses [36] proves for this includes (1) sensitivity of most forms of primary nephrotic syndrome to mycophenolate mofetil, corticosteroids, calcineurin inhibitors, and alkylating agents, these drugs all are inhibitors of T lymphocyte purpose, (2) mostly measles and malaria, diseases well-known to slow down the cellmediated immunity following remission of nephrotic syndrome, and (3) detection of Minimal-Change Nephrotic Syndrome (MCNS) as a paraneoplastic manifestation of lymphoreticular malignancies and other Hodgkin's disease. Latest reported cases have also suggested and vital role of the cell-mediated immune system in nephrotic syndrome, collectively with depressed cell-mediated immunity during relapses of MCNS alterations in T cell subsets during relapses and increased cell surface expression of IL-2 receptors on T cells, reflective of T cell activation [34, 41]. Additionally, a number of cytokines, released in part by T lymphocytes, have been recommended

to be erratically changed throughout nephrotic syndrome (NS) [42, 43].

Net filtration = LpS (Δ hydraulic pressure − Δ oncotic pressure).

s = the reflection coefficient for proteins (0 = complete permeability and

= LpS [(Pcap − Pif) − s(πcap − πif)].

Pif = the interstitial fluid hydrostatic fluid pressure.

Lp = the capillary permeability.

1 = complete impermeability).

πcap = the capillary oncotic pressure. πif = the interstitial fluid oncotic pressure.

S = the surface area of the capillary wall. Pcap = the capillary hydrostatic pressure.

In children with nephrotic syndrome facial or general edema, is the basic symptom due to accumulation of fluid in the interstitial compartment. In nephrotic syndrome the edema is usually causes disproportionate proteinuria, which leads to retention of sodium and water, hypoalbuminemia to recompense for intravascular volume depletion. The pathogenesis of edema can be well explained by analysis of the classic Starling equation, which explains the regulation of fluid movement across capillary walls [44].

**58**

where:

The formation of edema is prevented in healthy patients by a balance between forces favoring edema (capillary hydrostatic pressure [Pcap]) and those opposing it (capillary oncotic pressure [πcap]). The slight tendency toward fluid accumulation is counterbalanced by the lymphatics in the interstitial space. In nephrotic patients hypoalbuminemia results when the liver fails to synthesize the loss of albumin through urine. The hypoalbuminemia results leads to low down capillary oncotic pressure (πcap), which leads to relatively unopposed capillary hydrostatic pressure (Pcap) and subsequent edema formation. Relative intravascular volume reduction is due to edema formation the intravascular volume which triggers neurohumoral compensatory mechanisms. Which includes sympathetic nervous system (SNS), arginine vasopressin (AVP), and the renin angiotensin aldosterone system (RAAS), with

#### **Figure 2.**

*Under fill hypothesis proposes the continuation of a reduced effective circulating blood volume in nephrotic syndrome. Pathophysiologic events leading to the formation of edema in nephrotic syndrome.*

the net causes being sodium and water retention by the kidney. In the background of nephrotic syndrome, aortic arch, left ventricle, mechanoreceptors in the carotid sinus, and afferent arterioles in the glomeruli detect reduced pressure distension. This produce (1) SNS outflow increases from the central nervous system, (2) RAAS activation, and (3) nonosmotic release of AVP from the hypothalamus. These three changes lead to peripheral vasoconstriction (increased SNS and angiotensin II), sodium retention (angiotensin II, aldosterone, and increased SNS), and water retention.

As a result of these mechanisms, it is greatly accepted that patients with nephrotic syndrome have an excess of total body water and sodium. The condition of their intravascular volume is to some amount controvertible. Intravascular state in nephrotic is demonstrated by the following hypothesis: so-called overfill hypothesis and underfill hypothesis. The continuation of a reduced effective circulating blood volume in nephrotic syndrome is explained by underfill hypothesis (**Figure 2**). Due to activation of the RAAS with resultant of reduction in urinary sodium excretion and elevation of aldosterone levels, is most expectedly promoted by findings of low urine sodium in the presence of edema. The low urinary sodium [45] is due to reduction of atrial natriuretic peptide (ANP). Evidence, additionally for the underfill hypothesis includes betterment in sodium excretion with albumin infusion or head-out water immersion, and reduced cardiac output and increased vascular evaluated. It is possible that the overfilled state may be major in the chronic phase during which patients may have long-lasting sodium retention due to unrelenting low-grade hypoalbuminemia. But the underfilled state may be major in the acute setting in which excessive proteinuria causes rapid development of hypoalbuminemia and a gradual drop in plasma oncotic pressure.

Supposed to be intravascularly volume-expanded as different to degreeconstricted, founding whether a child is underfilled versus overfilled can be clinically important in the edema in children with nephrotic syndrome may be different. Depends upon the below urinary estimations comparison with elevated plasma vasopressin, renin, norepinephrine, aldosterone levels they are Single group has support to estimate the relative urinary potassium excretion [UK/(UK + UNa and)] absolute excretion of sodium (FENa) to elucidate the distinction. Nephrotic patients who are with high urinary potassium excretion (>60%) and a low FENa (<1%) would be probable to have a low intravascular load [46].

### **5. Conclusion**

Causes of nephrotic syndrome are also age reliant. The majority of the cases reported in the first 3 months of life is referred to as congenital nephrotic syndrome (CNS) and are because of genetic diseases. While there has been no efficient study of the etiology of nephrotic syndrome presenting in the rest of the first year of life (3–12 months), there are data telling that up to 40% of cases during this time may also be due to genetic causes. While it is extensively accepted that patients with nephrotic syndrome have an excess of total body sodium and water as a result of these remunerative mechanisms, the status of their intravascular volume is to some extent controversial. Nephrotic syndrome was a variety of disease processes with heavy proteinuria and hypoalbuminemia at its main symptoms. Although ongoing research hard work in the mechanism of disease, first-line therapy has stay over relatively unaffected for decades, and corticosteroids drugs are the basis of treatment Most children have MCNS, which come through a good prognosis; renal failure is uncommon in patients with MCNS. The manner of patients with nephrotic syndrome is changeable, but most patients will have periods of relapse and remission. Guidelines published by the American Academy of Pediatrics and the KDIGO can guide the pediatrician in the treatment of MCNS. There are alternative to corticosteroid therapy that has had

**61**

**Conflict of interest**

**Figure 3.**

*hypothesis.*

None declared.

**Notes/Thanks/Other declarations**

thankful to my colleagues for the completion of this work.

*Causes and Pathophysiology of Nephrotic Syndrome in Childhood*

success in induction and/or maintenance of reduction, although findings are conflicting, necessitating additional multicenter trials to contrast these medications head to head. Hypotheses concerning the mechanisms of proteinuria and the possible association of glomerular structure to the nephrotic syndrome are discussed (**Figure 3**).

*Pathophysiologic events leading to the formation of edema in nephrotic syndrome according to the overfill* 

I am very much thankful to Dr. Manish Kumar Thimmaraju for his guidance, kind help and constant encouragement during progress of my work. I am also very

*DOI: http://dx.doi.org/10.5772/intechopen.86825*

*Causes and Pathophysiology of Nephrotic Syndrome in Childhood DOI: http://dx.doi.org/10.5772/intechopen.86825*

#### **Figure 3.**

*Renal Diseases*

the net causes being sodium and water retention by the kidney. In the background of nephrotic syndrome, aortic arch, left ventricle, mechanoreceptors in the carotid sinus, and afferent arterioles in the glomeruli detect reduced pressure distension. This produce (1) SNS outflow increases from the central nervous system, (2) RAAS activation, and (3) nonosmotic release of AVP from the hypothalamus. These three changes lead to peripheral vasoconstriction (increased SNS and angiotensin II), sodium reten-

As a result of these mechanisms, it is greatly accepted that patients with nephrotic

tion (angiotensin II, aldosterone, and increased SNS), and water retention.

ment of hypoalbuminemia and a gradual drop in plasma oncotic pressure. Supposed to be intravascularly volume-expanded as different to degreeconstricted, founding whether a child is underfilled versus overfilled can be clinically important in the edema in children with nephrotic syndrome may be different. Depends upon the below urinary estimations comparison with elevated plasma vasopressin, renin, norepinephrine, aldosterone levels they are Single group has support to estimate the relative urinary potassium excretion [UK/(UK + UNa and)] absolute excretion of sodium (FENa) to elucidate the distinction. Nephrotic patients who are with high urinary potassium excretion (>60%) and a low FENa

(<1%) would be probable to have a low intravascular load [46].

Causes of nephrotic syndrome are also age reliant. The majority of the cases reported in the first 3 months of life is referred to as congenital nephrotic syndrome (CNS) and are because of genetic diseases. While there has been no efficient study of the etiology of nephrotic syndrome presenting in the rest of the first year of life (3–12 months), there are data telling that up to 40% of cases during this time may also be due to genetic causes. While it is extensively accepted that patients with nephrotic syndrome have an excess of total body sodium and water as a result of these remunerative mechanisms, the status of their intravascular volume is to some extent controversial. Nephrotic syndrome was a variety of disease processes with heavy proteinuria and hypoalbuminemia at its main symptoms. Although ongoing research hard work in the mechanism of disease, first-line therapy has stay over relatively unaffected for decades, and corticosteroids drugs are the basis of treatment Most children have MCNS, which come through a good prognosis; renal failure is uncommon in patients with MCNS. The manner of patients with nephrotic syndrome is changeable, but most patients will have periods of relapse and remission. Guidelines published by the American Academy of Pediatrics and the KDIGO can guide the pediatrician in the treatment of MCNS. There are alternative to corticosteroid therapy that has had

syndrome have an excess of total body water and sodium. The condition of their intravascular volume is to some amount controvertible. Intravascular state in nephrotic is demonstrated by the following hypothesis: so-called overfill hypothesis and underfill hypothesis. The continuation of a reduced effective circulating blood volume in nephrotic syndrome is explained by underfill hypothesis (**Figure 2**). Due to activation of the RAAS with resultant of reduction in urinary sodium excretion and elevation of aldosterone levels, is most expectedly promoted by findings of low urine sodium in the presence of edema. The low urinary sodium [45] is due to reduction of atrial natriuretic peptide (ANP). Evidence, additionally for the underfill hypothesis includes betterment in sodium excretion with albumin infusion or head-out water immersion, and reduced cardiac output and increased vascular evaluated. It is possible that the overfilled state may be major in the chronic phase during which patients may have long-lasting sodium retention due to unrelenting low-grade hypoalbuminemia. But the underfilled state may be major in the acute setting in which excessive proteinuria causes rapid develop-

**60**

**5. Conclusion**

*Pathophysiologic events leading to the formation of edema in nephrotic syndrome according to the overfill hypothesis.*

success in induction and/or maintenance of reduction, although findings are conflicting, necessitating additional multicenter trials to contrast these medications head to head. Hypotheses concerning the mechanisms of proteinuria and the possible association of glomerular structure to the nephrotic syndrome are discussed (**Figure 3**).

## **Conflict of interest**

None declared.

### **Notes/Thanks/Other declarations**

I am very much thankful to Dr. Manish Kumar Thimmaraju for his guidance, kind help and constant encouragement during progress of my work. I am also very thankful to my colleagues for the completion of this work.
