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Nephrotic syndrome is a rare disease, but why is it important?
Nephrotic syndrome is not a disease in itself but is an important feature of several kidney diseases.
The main characteristics are:
The key component is proteinuria which is due to a disorder of glomerular permselectivity. All other components are secondary to the protein leakage in the urine
A normal kidney has about 1.2 million nephrons
The glomerular structure has
The glomerular has two types of barriers: Size barrier and negative charge barrier
Usually, the glomerulus only lets small molecules such as sodium and water to pass through to urine
In Nephrotic syndrome, the glomeruli are damaged and become more permeable therefore letting plasma proteins to leak into urine. This causes proteinuria typically greater than 3.5 g/day
Nephrotic syndrome can be primary, being a disease specific to the kidneys, or it can be secondary, being a renal manifestation of a systemic general illness.
There is a need to rule out the possible causes before the disease as an idiopathic nephrotic syndrome by a good history taking and physical examinations together with laboratory investigations
Plasma protein larger than 70 nm is restricted from passing through the glomerular basement membrane by a charge – size-selective barrier.
Charge selective barrier -Polyanionic glycosaminoglycans, eg heparan sulfate in the glomerular basement membrane restrict the passage of small polyanionic plasma proteins (70-150 kd) such as albumin. There is a loss of charge selectivity in minimal change glomerulonephropathy.
In patients with FSGS, a plasma factor known as the Savin factor is produced by lymphocytes and increases glomerular basement membrane permeability.
Albumin is the main protein lost because it is the most common and is the smallest of the plasma proteins. When there is loss of charge selectivity like neutralization of the charges in minimal change glomerulonephropathy the albumin can leak out to urine causing hypoalbuminemia or low albumin levels in blood and albuminuria
Loss of albumin causes lowering of plasma oncotic pressure as a result, the extracellular fluid starts to seep out of the intravascular compartment causing hypovolemia. Hypovolemia leads to lowered kidney perfusion stimulating the activation of the Renin-angiotensin-aldosterone system.
RAAS system then enhances distal renal tubular sodium reabsorption. And since fluid cannot be held within the vascular compartment it leaks out to the tissues leading to development of pitting edema.
In severe cases, hypoalbuminemia can cause hypovolemia with pre-renal failure
This leads to loss of small-sized proteins in the urine such as immunoglobulins like IgG and factor B causing alternate pathway of complement activation to be compromised. This leads to low immunity to infections.
Proteinuria also causes loss of thyroxine-binding proteins, 25 OH cholecalciferol-binding globulin and transferrin leading to impaired iron transportation that causes iron deficiency anemia
Proteinuria also leads to loss of antithrombin III in the urine. Fibrinogen is a big molecule and not lost in urine therefore there are high levels of fibrinogen in serum
Higher levels of fibrinogen in serum causes hypercoagulation of blood. Thus nephrotic syndrome is a hypercoagulable status. The risk of thrombosis is increased by hyperviscosity of the blood.
There is also increased hepatic synthesis of cholesterol, triglycerides and lipoproteins known as Hyperlipidemia. There is also increased urinary loss of high-density lipoproteins (lipuria).
Long-standing proteinuria may cause interstitial disease
Hypoalbuminemia leads to low oncotic pressure in the intravascular compartment. This in turn causes a change in Starling equilibrium and extracellular fluids leaks from the intravascular compartment to the interstitial compartment.
Due to hypoalbuminemia resulting in low plasma oncotic pressure, hypovolemia develops that then stimulates the RAAS. More sodium is retained aggravating edema.
Therefore enhanced sodium reabsorption as feature of nephrotic kidney due to intrarenal mechanisms.
Edema in the common presentation. But may present with the following complication . Look for them !!!!!
Diagnostic studies for nephrotic syndrome may include the following:
Serum albumin is reduced markedly.
Urea, electrolytes and creatinine levels. sodium levels are low due to dilutional plus very high levels of lipids.
Pcr is raised at presentation.
Serologic studies for infection and immune abnormalities ie Heb B and C
Normal protein diet as per nutritional status of the patient.
High protein diet ↑ protein synthesis but ↑ albumin excretion rather than plasma albumin
Low salt diet. Use of salt during the preparation of food should be avoided in patients with edema. During remission, the child can take food with added salt
If obese due to steroids control calorie intake.
Loss of proteinuria produced by prednisolone and the subsequent diuresis usually occurs 7-14 days after initiating treatment in normal saline. There is need to manage edema before this period:
salt restriction- avoid using cooking salt in the food.
Furosemide (1-2mg/kg/day as BD dose) & spironolactone (2mg/kg/day in two divided doses) (spironolactone prevents hypokalemia. Should be started as soon as furosemide is commenced provided the patient not in renal failure.
Diuretics should not be given to a patient with hypovolemia)
No therapeutic tapping for ascites
Corticosteroids ie (prednisone), immunomodulators (cyclophosphamide), and cyclosporine are used to induce remission in nephrotic syndrome.
short-time treatment with Nifedipine or hydralazine. To either may add atenolol
Prevent thrombosis by mobilizing the patient.
These patients require psychological support
Give prophylactic a/b Pen V in patients with gross ascites, Septicemia or peritonitis
1st generation cephalosporins or cloxacillin or flucloxacillin
PLUS 3rd generation cephalosporins
In Hypovolemia, Albumin Infusion is indicated if hypovolemia is characterized by:
Give Albumin 1g/kg/day(OD or BD) over 4 hrs, give furosemide (1-2mg/kg ) 2 hrs after infusion.
Prednisolone 60mg/m2/day or 2mg/kg/day max 80mg/day for 4 WEEKS
ie Max wt 40kg, Max BSA 1.3
80% respond within 14 days
Classify nephrotic syndrome to:
2. Followed by Prednisolone 40mg/m2 on alternate days for a 28-day period.
3. Followed by Prednisolone 30mg/ m2 on alternate days for a 28-day period.
4. Followed by Prednisolone 20mg/ m2 on alternate days for a 28-day period.
5. Followed by Prednisolone 10mg/ m2 on alternate days for a 28-day period.
6. Followed by Prednisolone 5mg/ m2 on alternate days for a 28-day period. Then stop.
Remission :- urine protein 0/trace for 3days
Steroid resistance occurs when there is a failure to achieve remission despite of 4 weeks of prednisolone 2mg/kg/day.
Relapse:- urine dipstick 2+ or more on three consecutive days
OR protein 3-4+ plus edema.
Steroid dependence:- 2 consecutive relapse while on steroids or while tapering dose or within 14 days of its cessation.
Frequent relapser: Two or more relapses within 6 months of the initial response or four or more relapses within any 12 months period.
SSNS(steroid-sensitive nephrotic syndrome) is a Chronic disease but benign disorder
25% have single relapse
30% have occasional relapse
50% have cortical steroid dependency
It is unusual for the nephrotic syndrome to be active beyond puberty.
To test for urine protein at home or lab.
To seek medical help for proteinuria 2+ or more on 3 consecutive days
Side effects of steroids
During remission vaccinate
Ensure the child has received the second dose of measles vaccine after the routine one at 9 months, can be given as monovalent or trivalent vaccine (MMR), give at 15months of age or thereafter.
Hepatitis B vaccine – 3 doses
Hemophilus type b vaccine
Live attenuated vaccines can be given if the child is on low dose alternate-day prednisolone
Live attenuated vaccines should not be given concurrently with alkylating agents.
Among the vaccines mentioned above measles, MMR and chicken-pox vaccines are live attenuated vaccines.
Relapse on prednisolone dosage >0.5 mg/kg QOD plus one or more of the following:
Alkylating agents, cyclophosphamide or chlorambucil
In view of the benign nature of the illness, a permanent iatrogenic sequel is a matter of considerable concern benefits should outweigh the harm.
Uncommon condition – early referral to a nephrologist.
Primary doctor uncertain about the management of NS
Steroid resistant NS
Steroid dependent, relapse on prednisolone >1mg/kg QOD
History on unusually severe relapse; ARF, severe sepsis
Patients with indications for renal biopsy
Patients with indications for alternative treatment.