nephrotic syndrome

proteinurea
?10% of children aged 8-12 years have +ve test for Protienurea.
?Ways of detection of Protienurea.
?1-Dipstick, qualitative assessment of protein excretion, primarily for albumin and less sensitive for others types of protein(LMW, Bense Jones , gamma globulin),trase(10-20mg/dl), +=30, ++(100), +++=(300) , ++++=1000-2000mg/dl.
?False +ve 1-grosse haemeturia
? 2-contamination with antiseptic
? 3- urine PH greater than 7
? 4- phenozopyridne medication
? 5- high concentrated urine(sp.gravity more than 1.015)
?False –ve 1- diluted urine(sp.gravity less than 1.005)
? 2- other than albumin
2-Timed 12-24H urine collection for protein
Normally 150mg/day, or 4mg/m2/day
Abnormal=4-40mg/m2/hr
Nephrotic range more than 3.5g/day or more than 40mg/m2/hr
3- URINARY PROTIE/ URINARY CREATINNE (upro/ucre)
Normally less than 0.5 in child less than 2year and less than 0.2 in child more than 2year
More than 3 suggest nephrotic
Nephrotic syndrome
Nephrotic syndrome
?prevalense 2-3/100000
?Disease of children (15 fold than adult)
?
?hr)or urinary protein 24g/kg/1/hr(or ²mg/m40 above proteinuria.1(mg/dl)/creatinine(mg/dl)ratio of 2.0 or more ;alternative units-ratio more than 0.2mg/micromole
?g/dl2.5(serum albumin less than Hypoalbuminamia. 2
?Oedema .3
?
?(serum cholesterol over Hypercholesterolemia .4The primary abnormality is protein urea . mmol/l5.25mg/dl,200
?others features are secondary to this, others chara .findings include
?.Hypocalcaemia(ionized fraction normal),below 9.0mg/dl
?.Hyponatremia(below 135mmol/l
?.Hypercoagulabity
Etiology
?90% Idiopathic( MCNS, related to glomerular diseases like membranous nephropathy, membranoprolefretive)
? ,10%secondary(systemic diseases such as systemic lupus erythematosus, Henoch-Schonlein purpura, malignancy (lymphoma and leukemia), and infections (hepatitis, HIV, and malaria)
?85%minimal change disease nephrotic syndrome(MCNS)
?Most common type ,affect younger children (2-5),and more in boys(until the puberty),it is thought to be due to defective electrostatic glomerular barrier (due to circulating lymphokine).
?An associated defect is proliferation of a T- cell subclass.MCNS characteristically shows fusion of epithelial foot process on electron microscopy
?Clinically , hypertension and haemeturia occur in 10% and in about 95%steroid responder
?10%Focal segmental G.sclerosis ,histolegically,there is mesangial proliferation, increase in matrices, and segmental sclerosis,20% steroid responder and may lead to end stage renal failure
?5%Mesangial proliferative deffuse mesangial l cell proliferation, increase in matrice, 50% steroid responder .
Pathophysiology
?Increase permeability of glomerular capillary wall lead to massive protein urea and hypoalbuminemia.
?The cause still unknown,in MGNS , there is possible T- cell defect,
?In focal segmental sclerosis, plasma factor, perhaps prodused by lymphokines may responsible for increase in capillary wall permeability
?protein urea?hypoalbumin??oncotic pressure?shifting of fluid from intravascular spase to the interstitial compartment???intravascular volume ??renal perfution?activate Renin-Angiotensen-Aldosteron system?stimulate tubuler reabsorption of NA+ alsoADH lead to reabsorption of water ?Odem
This theory not apply to all patients with nephrotic syndrome, however, because some patients actually have increase intravascular volume with diminished levels of rennin and aldosteron.Therefore, other factors, including primary renal avidity for sodium and water, may be involved in the formation of odema in some patients with nephrotic syndrome.
?Hyperlipidemia (cholesterol and trigyceride) is due to
?1- Hypoalbuminamia may stimulate hepatic synthesis of lipoprotein
?2- loss of lipoprotein lipase in urine which is responsible for degradation of lipoptotien.
Minimal change disease nephrotic syndrome(MCNS)
?Clinical feature
?Most common age (2-6),reported as early as 6months of age
?The initial episode and subsequent relapse may flow minor infection, occasionally related to insect bite.
?Mild edema noted around the eye and then to lower extremity ,may be misdiagnosed as allergic disorders. with time edema become generalized with ascites, pleural effusion and genital edema
?Anorexia, irritability, abdominal pain, diarrhea are common
?Hypertension and grosse hematuria are uncommon
?D.DX
?Hepatic failure, congestive heart failure, acute or chronic GN, protein malnutrition , protein
Diagnosis
?Any child with NS should probably have the following tests
? URINE
?1-proteinin urine 3+ or 4+(1+=10-20mg/dl,2+=100mg/dl,3+=300mg/dl,4+=1000-2000mg/dl)or proteinuria above 40 mg/m²/hr(or 1g/kg/24hr)or urinary protein (mg/dl)/creatinine(mg/dl)ratio of 2.0 or more ;alternative units-ratio more than 0.2mg/micromole
?2- cellular cast which do not to occur in INS but may well occur in other glomerlonephropathies(note that halyine or waxy casts are common in INS
?3- micro .RBC in 10-20%.
BLOOD
1- Urea , creatinin and electrolytes(renal function usually normal in INS(10-20%increase in BUN); may be abnormal in other glomerlonephropathies
2- Albumin(less than2.5g/dl) and total serum protien
3- increase Serum cholesterol and triglyceride
4 Serum complement level C3,C4(low with mesangial proliferative ,SLE., normal in INS)
5- Hepatitis B and C serology (Hep B is associated with membranous nephritis, Hep C is associated with mesangial proliferative.
6- Anti-nuculer antibody(ANA), Anti-double stranded .
Renal biopsy
?not required in most patients, and should be reserved for those very atypical feature. There is probably NO indication for biopsy before commencing non-steroid agents if the child completely responsive to prednisolone (protein urea absent in the past 3 days).so indicated in the following
? 1- Age before 1year and above 8years
? 2- Macroscopically hematuria
? 3- Persistent hypertension and microscopically
? hematuria
? 4-Abnormal levels of complements
? 5- Elevated serum creatinin level
?Definitions in NS
?Remission=urinary protein excretion less than 4mg/ m²/hour or trace of protein in urine dipstick, or urinary protein (mg/dl)/creatinine(mg/dl)ratio of0.2 mg/dl for 3 consecutive days
?Relapse=recurrence of protein urea defined in INS 3-4+dipstick +edema.
?Frequent relapser=2 or more relapse in the first 6months of initial response OR more than 4 relapse in 12months
?Corticosteroid dependence=2 consecutive relapse while on steroid (every other day) or within 2 weeks of ceasing steroid
?Corticosteroid resistance =failed response after 8weeks of 2mg/kg/day
Treatment
Diuretics
mild to moderate edema may be managed as outpatients , low-sodium diet , oral diuretics????
severe symptomatic edema, including large pleural effusions, ascites, or severe genital edema, should be hospitalized. In addition to sodium restriction, fluid restriction may be necessary if the child is hyponatremic
. A swollen scrotum may be elevated with pillows to enhance the removal of fluid by gravity. Diuresis may be augmented by administration of furosemide (1–2 mg/kg/dose IV q 12 hr).
Albumin
IV administration of 25% human albumin (0.5 g/kg/dose q 6–12 hr administered over 1–2 hr) followed by furosemide (1–2 mg/kg/dose IV) is often necessary when fluid restriction and parenteral diuretics are not effective.
Such therapy mandates close monitoring of volume status, serum electrolyte balance, and renal function. Symptomatic volume overload, with hypertension and heart failure, is a potential complication of parenteral albumin therapy, particularly with rapid infusions.
Prednisone
In children with presumed MCNS, prednisone should be administered (after confirming a negative PPD test and administering the polyvalent pneumococcal vaccine) at a dose of 60 mg/m2/day (2mg/kg)(maximum daily dose, 80 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.
After the initial 6-wk course, the prednisone dose should be tapered to 40 mg/m2/day(1.5mg/kg) 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(5mg /week). 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. While planning the duration of steroid therapy, the side effects of prolonged corticosteroid administration must be kept in mind
Many children with nephrotic syndrome experience at least 1 relapse (3-4+ proteinuria plus edema). Although relapse rates of 60-80% have been noted in the past, the relapse rate in children treated with longer initial steroid courses may be as low as 30-40%.
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 4-8 wk.
Other agents, cytotoxic drugs(CLAIM)
C cyclophosphamide(CPA:2-3mg/kg for 8-12weeks),Chlorambucil 0.2mg/kg for 8-12 weeks), Cyclosporine(CSA:2.5mg/kg12hourly for 12months
L levamisole(2.5mg/kg daily for 6-12 months)
A angiotensin-converting enzyme ACE inhibitors
I immunization with pnuemoccocal vaccine
M mycopgenolate mofetil 25mg/kg /day for 1year
CPA has significant side effect ,short term=bone morrow suppretion.risk of viral infections such as varicella,measles)long term (gonadal toxicity and risk of malignancy)
CAS can cause nephrotoxicoty, hypertention,gingival hypertrophy and hirsutism
Levemisole cause enhanced celluler immune response in certain conditions with depressed immune function, and may help to maintain remission in steroid-dependent INS(neutropenia,rarly vasculitis,liver toxicity,convulsion )
?ACE inhibitor reduce glomerular hyperfilteration (hypotension and cough)
?Immunization, heptavalent conjugate(7vPCV) in children less than 5years and polysaccharide pnuemoccocal vaccine (PPV23) 5YEARS AND OLDER
?mycopgenolate mofetil used in lopus type
?ALL the above medications are indicated in the following
?1- steroid resistant type
?2- steroid dependent type(only if side effect are unacceptable)
?3- frequent relapse with hypertension or thrombosis
?4- unacceptable steroid side effect(weight gain, cushnoid facies
Antibiotics
Some unite treat all episodes of relaps with prophylactic daily penicillin to ovoid pnuemoccocal infection. Others not, some use third generation cephalosporin ,however the use of prophylactic antibiotic during relapse remain controversial
Immunization
Live viral vaccine should be avoided in patient taking steroid or other immune suppressive drug. pnuemoccocal vaccine is recommended and annual influenza vaccine
Hypertension
Minority, treated by nifedipine and beta blocker
Diet
-
No added salt, no fluid restriction unless in very edematous and diuretics is required ,high biological value protein.
In hospital management
-
Fluid balance chart, twice daily weight, 4-horly chart of vital sings.
Activity
No need for bed rest or restriction of activity
Complications of NS
?Infection -1
? More with encapsulated bacteria(pnuemoccocal, haemphilus ) including spontaneous bacterial peritonitis (SBP) , cellulites, UTI,pneumonia due to many factors
? •urinary loss of immunoglobulin
? •loss of B factor of alternate activation path.
? •loss of transferring
? •alter T- cell function
? •steroid and other immune suppressive therapy
? •mechanical factors such as edema and ascitis
? •malnutrition
? The occurrence of (SBP)is 2-6%and this risk is further increased by decrease mesenteric blood flow and increase coagulability causing micro infarction
?The (SBP) need high index of suspicion because the clinical signs some times are masked by the steroid (blood culture, peritoneal fluid culture then prompt antibiotic)
Thromboembolism -
2
?NS associated with Hypercoagulabity (2-5%) state due to
? Due to increase prothrombotic activity(fibrinogen, thrombocytosis, haemoconcetration and relative immobilization ) and decrease fibrnolytic factor(loss of antithombin III, and protien C, S), prophylactic anticoagulant not recommended unless they have previous thromboembolic event.
?Over use of diuretics, and use of indwelling catheter should be restricted.
Prognosis
?Majority of child with steroid responsive NS had repeated relapse with time, decrease relapse specially if not getting relapse in the 1st 6months
?not lead to NS steroid responsive chronic renal failure, and not hereditary, normal sterility in absence of prolonged use of cyclophosphomide)
?child during remission no need for testing of Protienurea.
?poor prognosis Steroid resistant NS end stage renal failure dialysis and renal transplant(30-50% getting the same disease)
3- Other complications
Site effect of drugs (steroid),
(cytotoxic drugs)
Secondary NS
10%
1-drugs(pencillamine, gold
2- membranoprolefretive NS
3-PSGN, LOPUS, HSP
4- infection malaria, Hepatitis B,C, HIV
5- Malignancy H. lymphoma.
Congenital NS
?In the 1st 3month most common type
?Finnish type autosomal recessive ,increase alpha feto protein, large placenta, marked edema, prematurely, RDA, separation of cranial suture
?Lead to end stage renal disease, no value of steroid or cytotoxic
?ACE inhibitor, endomethacine, unilateral nephrectomy
?Other form is due to infection(TORCH).