1. Nephrotic Syndrome By
Dr. Athal Humo

2. Nephrotic Syndrome
Nephrotic syndrome, is a manifestation of glomerular disease. Characterized by:
Heavy proteinuria (Nephrotic range proteinuria is defined protein excretion of > 40 mg/m2/hr or a first morning protein : creatinine ratio of >2-3 : 1).
Hypoalbuminemia(serum albumin <2.5 g/dL)
Edema.
Hyperlipidemia (serum cholesterol >250 mg/dL).
The annual incidence is 2-3 cases per 100,000 children per year.

3. Etiology:
Most children with nephrotic syndrome have a form of primary or idiopathic nephrotic syndrome. Glomerular lesions associated with idiopathic nephrotic syndrome include:
minimal change disease (the most common).
focal segmental glomerulosclerosis.
membranoproliferative glomerulonephritis.
membranous nephropathy.
diffuse mesangial proliferation

4. Nephrotic syndrome may also be secondary to systemic diseases such as:
Infections (hepatitis, HIV, malaria, toxoplasmosis)
Drugs (gold, penicillamine, NSAI, Interferon)
Immunologic or allergic disorders(bee sting, food allergens)
Associated with malignant disease(Lymphoma & Leukemia)
A number of hereditary proteinuria syndromes are caused by mutations in genes that encode critical protein components of the glomerular filtration apparatus such as:
Finnish-type congenital nephrotic syndrome
Denys-Drash syndrome

5. Pathophysiology:
For understanding pathophysiology of NS should know the Normal Glomerular barrier & Function.
One of the kidney’s most important functions is filtration of the blood by glomeruli, allowing excretion of fluid and waste products, while retaining all blood cells and the majority of blood proteins within the bloodstream.
Glomerular filter acts via two phenomenon size selectivity and charge selectivity.
Each glomerulus is composed of numerous capillaries which have evolved to permit ultrafiltration of the fluid that eventually forms urine. The capillary walls are composed of :
an inner endothelial cell cytoplasm, with pores known as ‘fenestrations’.
GBM.
external, epithelial cell (podocytes), the epithelial cells are large, with specialized cytoplasmic extensions known as foot processes, which firmly anchor them to the GBM. The adjacent foot processes do not come into contact with each other and are separated by ~40 nm wide spaces known as filtration slits. These slits are bridged by a continuous membrane-like structure known as the slit diaphragm

6. Glomerular Filtration Membrane

8. Size Selective Barrier
Size selectivity:
under normal conditions, molecules greater than 42 Å in diameter are unable to cross the filtration barrier.
Size Selective Barrier

9. Charge selectivity:
In addition to molecular size, molecular charge has also been shown to influence the clearance of macromolecules from the glomerular capillary.
Electrical charge is an important determining factor for the passage of protein molecules through the glomerular filtration barrier. Several reports have indicated a reduction in the negative charge of the GBM in nephrotic syndrome
This has led to the concept that the passage of anionic molecules such as plasma proteins is actively hindered by the anionic surface charge of the glomerular filter

10. Charge selective barrier

11. Negative charge is thought to retard filtration of anionic molecules (red) such as albumin, facilitate filtration of cationic molecules (green), and have little impact on neutral molecules (yellow).

12. Glomerular Filtration Membrane charge & size selective barrier

13. Pathophysiology in NS:
Protienuria
Edema
Hyper
lipidemia
Hypo
albuminemia

14. Proteinuria:
The underlying abnormality in nephrotic syndrome is an increased permeability of the glomerular capillary wall, which leads to massive proteinuria.
In idiopathic NS found that it is associated with complex disturbances in the immune system, especially T cell–mediated immunity which lead to :
Extensive effacement of podocyte foot processes (the hallmark of idiopathic nephrotic syndrome) suggests a vital role for the podocyte, which is normally prevent passage of large molecule as albumin.
loss of the glomerular basement membrane sialoproteins, which leads to a loss of the normal negative charge responsible for the increase in capillary wall permeability.(normally prevent passage of anionic molecules as albumin)
In focal segmental glomerulosclerosis, a plasma factor, probably produced by a subset of activated lymphocytes, may be responsible for the increase in capillary wall permeability.

15. Changes to capillary endothelial cells, GBM, or podocytes, which normally filter serum protein selectively by size and charge.
Glomerular Proteinuria develops when there is alteration in either charge selectivity and size selectivity

17. Hypoalbuminemia
Massive proteinuria that results leads to a decline in serum proteins, especially albumin.

18. Edema:
Although the mechanism of edema formation in nephrotic syndrome is incompletely understood, it seems likely that in most instances, massive urinary protein loss leads to hypoalbuminemia, which causes a decrease in plasma oncotic pressure and transudation of fluid from the intravascular compartment to the interstitial space. The reduction in intravascular volume decreases renal perfusion pressure, activating the renin-angiotensin-aldosterone system, which stimulates tubular reabsorption of sodium. The reduced intravascular volume also stimulates the release of antidiuretic hormone, which enhances the reabsorption of water in the collecting duct.
This theory does not apply to all patients with nephrotic syndrome because some patients actually have increased intravascular volume with diminished plasma levels of renin and aldosterone. Therefore, other factors, including primary renal avidity for sodium and water, may be involved in the formation of edema in some patients with nephrotic syndrome.

19. Hyperlipidemia:
In the nephrotic state, serum lipid levels (cholesterol, triglycerides) are elevated for 2 reasons:
Hypoalbuminemia stimulates generalized hepatic protein synthesis, including synthesis of lipoproteins. This is also why a number of coagulation factors are increased, increasing the risk of thrombosis.
In addition, lipid catabolism is diminished as a result of reduced plasma levels of lipoprotein lipase related to increased urinary losses of this enzyme.

20. Idiopathic Nephrotic Syndrome

21. Idiopathic Nephrotic Syndrome
Approximately 90% of children with nephrotic syndrome have idiopathic nephrotic syndrome. Idiopathic nephrotic syndrome is associated with primary glomerular disease without evidence of a specific systemic cause.

22. Pathology
Idiopathic nephrotic syndrome includes multiple histologic types:
minimal change disease: about 85% of total cases of nephrotic syndrome in children, 95% are steroid responsive .
mesangial proliferation: 50% are steroid responsive .
focal segmental glomerulosclerosis: only 20% are steroid responsive, the disease is often progressive, ultimately involving all glomeruli, and ultimately leads to end-stage renal disease in most patients.
membranous nephropathy.
membranoproliferative glomerulonephritis

23. Clinical Manifestations
The idiopathic nephrotic syndrome is more common in boys than in girls (2 : 1).
Most commonly appears between the ages of 2 and 6 yr. However, it has been reported as early as 6 mo of age and throughout adulthood.
MCNS is present in 85-90% of patients <6 yr of age. In contrast, only 20-30% of adolescents who present for the first time with nephrotic syndrome have MCNS. The more common cause of idiopathic nephrotic syndrome in this older age group is FSGS.
The initial episode of INS, as well as subsequent relapses, usually follows minor infections and, uncommonly, reactions to insect bites, bee stings, or poison ivy.

24. A diagnosis other than MCNS should be considered in:
Children usually present with mild edema, which is initially noted around the eyes and in the lower extremities.
Nephrotic syndrome can initially be misdiagnosed as an allergic disorder because of the periorbital swelling that decreases throughout the day. With time, the edema becomes generalized, with the development of ascites, pleural effusions, and genital edema.
Anorexia, irritability, abdominal pain, and diarrhea are common. Important features of minimal change idiopathic nephrotic syndrome are the absence of hypertension and gross hematuria (previously termed nephritic features).
A diagnosis other than MCNS should be considered in:
children <1 yr of age.
a positive family history of nephrotic syndrome.
presence of extrarenal findings (e.g., arthritis, rash, anemia).
hypertension or pulmonary edema.
acute or chronic renal insufficiency.
gross hematuria.

26. Differential Diagnosis
The differential diagnosis of the child with marked edema includes:
protein-losing enteropathy.
hepatic failure.
heart failure.
acute or chronic glomerulonephritis.
protein malnutrition.

27. Diagnosis Urinalysis :
Proteinuria: 3+ or 4+
Urinary protein excretion exceeds 40 mg/m2/hr.
A spot urine protein: creatinine ratio exceeds 2.0.
Microscopic hematuria is present in 20%.
Serum creatinine value is usually normal, but it may be abnormally elevated if there is diminished renal perfusion from contraction of the intravascular volume.
Serum albumin level is <2.5 g/dL.
Serum cholesterol and triglyceride levels are elevated.
Serum complement levels are normal.

28. Renal biopsy: if there is atypical feature( suggest other than MCNS):
Gross hematuria.
Hypertension.
Renal insufficiency.
Hypocomplementemia.
Age <1 yr or >8 yr.

29. Treatment
Children with their first episode of nephrotic syndrome and mild to moderate edema may be managed as outpatients.
The pathophysiology and treatment of nephrotic syndrome must be carefully reviewed with the family to enhance understanding of their child's disease. The child's parents must be able to recognize the signs and symptoms of the complications of the disease and its treatment and must be taught how to use and interpret the results of urinary dipstick testing for protein.
Children with nephrotic syndrome should attend school and participate in physical activities as tolerated.
Low sodium diet until remission.
Oral diuretics used with cautious if needed because the risk of thromboembolic complication.

30. Indication for hospitalization:
Children with severe symptomatic edema, including:
Large pleural effusions.
Ascites.
Severe genital edema.

31. Treatment in hospital:
Sodium restriction.
Fluid restriction may be necessary if the child is hyponatremic.
A swollen scrotum may be elevated with pillows to enhance fluid removal by gravity.
Diuresis may be augmented by the administration of loop diuretics (furosemide), orally or intravenously, with caution.
IV administration of 25% albumin (  g albumin/kg), as a slow infusion followed by furosemide (1-2 mg/kg/dose IV) is sometimes necessary when a patient has significant generalized edema with evidence of intravascular volume depletion (e.g., hemoconcentration). Such therapy mandates close monitoring of volume status, blood pressure, serum electrolyte balance, and renal function. Symptomatic volume overload, with hypertension, heart failure, and pulmonary edema is a potential complication of parenteral albumin therapy, particularly when administered as rapid infusions.

32. Children with typical feature suggestive MCNS, prednisone is started without need for biopsy.
prednisone should be administered at a dose of 60 mg/m2/day or 2 mg/kg/day (maximum daily dose, 60 mg) in a single daily dose for 4-6 consecutive wk.
An initial 6-wk course of daily steroid treatment leads to a significantly lower relapse rate than previously recommended shorter courses of daily therapy.
About 80-90% of children respond to steroid therapy (clinical remission, diuresis, and urine trace or negative for protein for 3 consecutive days) within 3 wk. The vast majority of children who respond to prednisone therapy do so within the first 5 wk of treatment.

33. After the initial 6-wk course, the prednisone dose should be tapered to 40 mg/m2/day given every other day as a single daily dose for at least 4 wk.
The alternate-day dose is then slowly tapered and discontinued over the next 1-2 mo.
There is evidence that both an increased dose of steroids and a prolonged duration of therapy are important factors in reducing the risk of relapse, but the frequency of SE is higher.
Children who continue to have proteinuria (2+ or greater) after 8 wk of steroid therapy are considered steroid resistant, and a diagnostic renal biopsy should be performed.

34. Relapse
Many children with nephrotic syndrome experience at least 1 relapse (3-4+ proteinuria plus edema). Although relapse rates decrease after treated with longer initial steroid courses.
Relapses should be treated with 60 mg/m2/day (80 mg daily max) in a single am dose until the child enters remission (urine trace or negative for protein for 3 consecutive days). The prednisone dose is then changed to alternate-day dosing as noted with initial therapy, and gradually tapered over 1-2month.
Patients who respond well to prednisone therapy but relapse ≥4 times in a 12-mo period are termed frequent relapsers.

35. A subset of patients relapse while on alternate-day steroid therapy or within 28 days of completing a successful course of prednisone therapy. Such patients are termed steroid dependent.
Children who fail to respond to prednisone therapy within 8 wk of therapy are termed steroid resistant. Steroid-resistant nephrotic syndrome is usually caused by FSGS (80%), MCNS, or mesangial proliferative glomerulonephritis.

36. Alternative therapies
Steroid-dependent patients, frequent relapsers, and steroid-resistant patients are candidates for alternative therapies, particularly if the child has severe corticosteroid toxicity (cushingoid appearance, hypertension, cataracts, and/or growth failure).
Cyclophosphamide
Cyclosporine or tacrolimus
Mycophenolate
Levamisole
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II blockers may be helpful as adjunct therapy to reduce proteinuria in steroid-resistant patients.

37. Complications
Infection: is a major complication of nephrotic syndrome. Children in relapse have increased susceptibility to bacterial infections because of:
urinary losses of immunoglobulins and properdin factor B.
defective cell-mediated immunity.
their immunosuppressive therapy.
Malnutrition.
edema or ascites acting as a potential culture medium.

38. Spontaneous bacterial peritonitis is a common infection
Spontaneous bacterial peritonitis is a common infection. Although Streptococcus pneumoniae is the most common organism causing peritonitis, gram-negative bacteria such as Escherichia coli may also be encountered. Because fever & physical finding may be minimal in presence of steroid therapy, the patient's caregivers should be counseled to seek medical attention if the child appears ill, has a fever, or complains of persistent abdominal pain. A high index of suspicion for bacterial peritonitis, prompt evaluation (including cultures of blood and peritoneal fluid), and early initiation of antibiotic therapy are critical.
Sepsis.
Pneumonia.
Cellulitis.
Urinary tract infections.

39. The incidence of this complication in children is 2-5%.
Thromboembolic events:
The incidence of this complication in children is 2-5%.
Both arterial and venous thromboses may be seen, including renal vein thrombosis, pulmonary embolus, sagittal sinus thrombosis, and thrombosis of indwelling arterial and venous catheters.
The risk of thrombosis is related to:
Increased prothrombotic factors (fibrinogen, thrombocytosis, hemoconcentration, relative immobilization).
Decreased fibrinolytic factors (urinary losses of antithrombin III, proteins C and S).
Prophylactic anticoagulation is not recommended in children unless a previous thromboembolic event has occurred.
To minimize the risk of thromboembolic complications, aggressive use of diuretics and the use of indwelling catheters should be avoided if possible.

40. Prognosis Steroid-responsive nephrotic syndrome:
Most children with steroid-responsive nephrotic syndrome have repeated relapses, which generally decrease in frequency as the child grows older.
Although there is no proven way to predict an individual child's course, children who respond rapidly to steroids and those who have no relapses during the first 6 mo after diagnosis are likely to follow an infrequently relapsing course.
It is important to indicate to the family that the child with steroid- responsive nephrotic syndrome is unlikely to develop chronic kidney disease, that the disease is rarely hereditary, and that the child (in the absence of prolonged cyclophosphamide therapy) will remain fertile.
To minimize the psychologic effects of the condition and its therapy, children with idiopathic nephritic syndrome should not be considered chronically ill and should participate in all age-appropriate childhood activities and maintain an unrestricted diet when in remission.

41. Steroid-resistant nephrotic syndrome:
Children with steroid-resistant nephrotic syndrome, most often caused by FSGS, generally have a much poorer prognosis.
These children develop progressive renal insufficiency, ultimately leading to end-stage renal disease requiring dialysis or kidney transplantation.
Recurrent nephrotic syndrome develops in 30-50% of transplant recipients with FSGS.

42. The difference between APGN & NS

43. THANKS