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Dr.Fathia Ahmed Abdel Magid
Consultant Paediatrician
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Nephrotic syndrome is a common manifestation of glomerular disease in children.
Develops when an abnormality of glomerular permeability results in heavy proteinuria, hypoalbuminaemia and generalized oedema
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Defining features of nephrotic syndrome
Early morning urine protein/creatinine ratio > 200 mg/mmol.
This is equivalent to the classical definition of protein excretion > 40 mg/m2/hr.
Hypoalbuminaemia = plasma albumin concentration < 25 gm/L.
Oedema
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Histological diagnosis in children presenting with nephrotic syndrome
1) Minimal change disease (80%) : more frequent in males (3:2)
Age at presentation : 2-6 yrs.
Incidence of MCNS in the UK is 2-4/100000 in Caucasian children and is six times higher in children of Asian origin.
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Aetiology and Pathogenesis of MCNS
Remain incompletely defined
Abnormality of the negatively charged residues in the glomerular basement membrane, which normally limit the filtration of anionic plasma, proteins e.g. albumin.
There is a recognized association with atopic disease and other evidence suggests that the glomerular abnormality may be induced by a soluble mediator derived from T lymphocytes.
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Renal biopsy
No significant abnormality on light microscopy or immunofluorescent staining.
Electron microscopy demonstrates effacement of the foot processes of the visceral glomerular epithelial cells (podocytes). A non-specific morphological change seen in most proteinuric disorders.
MCNS responds to corticosteroid therapy and is associated with a favourable long term outcome. However, at least, 70% of patients will experience a chronic, relapsing or remitting course.
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2) Focal segmental glomerulosclerosis and mesangiocapillary glomerulonephritis account for the remaining 20% of cases of nephrotic syndrome in childhood.
Compared to MCNS, these conditions tend to occur in older children.
The majority of patients do not enter remission with standard initial steroid therapy and the prognosis is poorer.
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Mechanisms of oedema
1)Hypoalbuminaemia causes ↓ in the plasma oncotic pressure and ↑ in the passage of fluid to the interstitial compartment.
2)Sodium reabsorption by the distal renal tubules is enhanced in the nephrotic state ↑expansion of the extracellular fluid volume, further exacerbating oedema.
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Clinical features and diagnosis
Patients with typical uncomplicated nephrotic syndrome require limited initial investigations.
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Suggested first line investigations in nephrotic syndrome
Urine dipstick analysis (protein, blood)
Early-morning urine protein/creatinine ratio
Urine microscopy and culture
Plasma albumin, creatinine and electrolytes
Full blood count
Complement C3 and C4 levels
Varicella zoster antibody titres
Hepatitis serology (Types B and C)
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Atypical features of MCNS
• Age <1 year or >12 years
• Persistent hypertension
• Gross haematuria
• Renal impairment
• ↓ plasma C3.
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Blood pressure
Blood pressure readings should be interpreted with reference to appropriate centile charts.
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Percentile Blood Pressure Readings for Children by Age and Height Percentile (mm Hg)
Girls
Age 5th 50th 95th
(Y) Percentile Percentile Percentile
1 101/57 104/58 107/60
6 108/71 111/73 114/75
12 120/79 123/80 126/82
17 126/83 129/84 132/86
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BoysAge 5th 50th 95th Percentile Percentile Percentile
1 98/55 102/53 106/596 109/72 114/74 117/7612 119/79 123/81 127/8317 132/85 136/87 140/89
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• Children with MCNS are usually normotensive.
• Hypotension is a sign of severe hyponatraemia and demands urgent attention.
• Blood pressure >95th centile for age, sex and height requires careful evaluation.
• Hypertension may be present in hypovolaemic children because of compensatory systemic vasoconstriction.
• Hypertension in the absence of hypovolaemia is an atypical feature which needs further assessment.
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Patients with atypical features need further investigations e.g.
- ASO titre
- ANA
- Anti DS DNA antibodies
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Management
General
The child’s condition remains stable ↓ the risk of complications.
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Use of albumin solutions
Many specialist centres use infusions of 20% albumin solution together with diuretics to relieve severe oedema in cases refractory to other management. However, this is not recommended for general use. The acute osmotic effect of the concentrated albumin solution may mobilize large quantities of ECF into the intravascular compartment causing rapid circulatory volume expansion and acute left ventricular failure.
There is no indication for the use of 20% albumin solely to raise low plasma albumin levels.
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Prophylactic antibiotics
Urinary losses of immunoglobulin and complement render these children susceptible to bacterial infections e.g. peritonitis, septicaemia and cellulitis.
However, some centres use prophylactic antibiotics for children with severe oedema - oral phenoxymethyl penicillin.
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Immunization
Mobilization
Diet
Information for parents
Corticosteroid therapy
60 mg/m2/day of prednisolone not exceeding a maximum of 80 mg/day for one month.
The 2nd month 40 mg/m2 on alternate day.
A longer therapy of 3 months’ duration has been advocated by a working group of the German Society of Paediatric Nephrology.
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A metaanalysis of six trials compared two months of prednisolone with 3 months or more. It showed that the longer duration significantly ↓ the risk of relapse at 12-24 months without an increase in adverse effects. The number of patients who became frequent relapsers and the mean relapse/patient/year were also significantly reduced.
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• The modified ISKDC regimen consist of prednisolone 60mg/m2 (maximum of 80mg) given daily for 28 days followed by prednisolone 40 mg/m2 given on alternate days, for a total of 14 doses over 28 days given as a single dose.
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The term: steroid sensitive nephrotic syndrome, is used for patients with minimal change nephrotic syndrome who respond to empirical corticosteroid therapy without an underlying histological diagnosis being confirmed and also includes a small number of children with underlying non-minimal change histology.
The term: steroid resistant nephrotic syndrome refers to those patients who do not respond to a standard initial course of prednisolone.
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Standard definitions in monitoring of steroid sensitive nephrotic syndrome
Remission
Relapse
Frequently relapsing nephrotic syndrome
Steroid-dependent nephrotic syndrome
Urine protein dipstick (albustix) reading 0 or trace for three consecutive days
Albustix reading 2+ or more, for three consecutive days, having previously been in remission
Two or more relapses within 6 months of initial response or four or more relapses within a 12-month period
Two consecutive relapses occurring during corticosteroid treatment or within 14 days after its cessation.
Current Paediatrics , Volume 12 Number 7 December 2002
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Management of relapses
Relapses can be expected in at least, 70-80 % of SSNS patients.
Patients who relapse frequently in the 1st 6 months after initial steroid response, are at the highest risk of continuing to relapse frequently over the subsequent 18 months period.
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Relapses should be treated only after a period of 3-5 days of proteinuria.
The standard relapse regimen consist of prednisolone 60 mg/m2 until urinary remission; followed by prednisolone 40 mg/m2 on alternate day, for 14 doses.
50% of SSNS patients will follow a frequently relapsing or steroid dependent course
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Maintenance Prednisolone
In frequent relapsers, a longer course of alternate day steroid is given to patients with no evidence of steroid adverse effects.
After remission, the dose is gradually tapered to a dose in the range, 0.1–0.5 mg/kg on alternate days, for 6-12 months.
Patients on maintenance prednisolone should be seen at least, every 3 months, for side effects
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Some potential adverse effects of therapeutic corticosteroid
Susceptibility to infection
Mood and behavioural disturbance
Increased appetite
Weight gain and obesity
Cushingnoid appearance
Acne
Hirsutism
Cutaneous striae
Posterior subcapsular cataracts
Hypertension
Growth suppresion
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Steroids – adverse effects (contd)
Pubertal delay
Adrenal suppression
Impaired glucose metabolism
Dyspepsia and peptic ulceration
Acute pancreatitis
Osteoporosis
Avascular osteonecrosis
Proximal myopathy
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Alternative Therapies
Indications for alternative immunomodulatory therapy in SSNS
1. Relapse while taking prednisolone >1 mg/kg on alternate days.
2. Relapse while taking prednisolone >0.5 mg/kg on alternate days, plus one or more of the following:
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(a) Unacceptable adverse effects of corticosteroid therapy
(b) High risk of adverse steroid effects (e.g. boys approaching puberty; diabetic children)
(c) Unusually severe relapses (hypovolaemia; thrombosis, severe sepsis; acute renal failure)
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Typical management strategy for steroid- sensitive nephrotic syndrome
1.Initial episode
Prednisolone 60 mg/m2 daily for 28 days, followed by prednisolone 40 mg/m2 on alternate days, for 14 doses over 28 days.
2. First two relapses
Prednisolone 60mg/m2 daily until remission, followed by prednisolone 40 mg/m2 on alternate days, for 14 doses over 28 days
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3.Frequent relapses
Maintenance prednisolone: 0.1-0.5 mg/kg on alternate days for up to 12 months.
4.Relapse on prednisolone >0.5 mg/kg on alternate days
Levamisole 2.5 mg/kg on alternate days for up to 12 months
4.Relapse on prednisolone > 1 mg/kg on alternate days or relapse on prednisolone > 0.5 mg/kg on alternate days plus adverse steroid effects/other risk factors.
Cyclophosphamide 3 mg/kg daily for 8 weeks.
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6.Post-cyclophosphamide relapses
As in 2 and 3 above
7.Relapse on prednisolone > 0.5 mg/kg on alternate days.
Cyclosporin 2.5 mg/kg per dose, given twice per day for up to 12 months.
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Levamisole
• Has a weak steroid sparing action
• Following induction of remission with prednisolone, levamisole can be started at a dose of 2.5 mg o.d on alternate days; then prednisolone can be tapered or discontinued.
• It is continued for a period of 12 months after a successful remission.
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Levamisole (contd)
• It may cause neutropenia. Therefore, a full blood count should be checked at 6 weeks, 12 weeks and every 3 months thereafter
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Alkylating agents 1. Cyclophosphamide • It has the ability to induce long term remission or
cause a reduction in relapse frequency.• Dose is 3 mg/kg for an 8-week course.• Frequent relapsers have a better outcome than
those who are steroid dependent.• 70% of patients with frequently relapsing SSNS
will remain in remission after 2 years, compared
with only 25% of children with steroid dependant NS.
• Side effects include, bone marrow suppression, neutropenia, alopecia, haemorrhagic cystitis,
gonadal toxicity (> male), malignancy.2. Cyclosporin
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The outcome of treatment of steroid sensitive nephrotic syndrome patients with levamisole (Lev) and
cyclophosphamide(Cy)
Suleimania Children’s Hospital, Riyadh, K.S.A.Diagnosis
Patients received Lev
Patients with SR after Lev
Mean duration of Lev therapy (months)
Mean duration of SR after Lev (months)
Patients received Cy
Patients SR after Cy (months)
Mean duration of SR after Cy (months)
FRNS 11 4 6.9 19.5 7 4 24.8
SDNS 13 7 9.5 8.5 6 4 14
Total 24 11(46%)
8.2 14 13 8(61.5% )
19.4
SR: Sustained remission, FRNS: frequently relapsing nephrotic syndrome, SDNS: steroid dependent nephrotic patients.
Source: Saudi Journal of Kidney Diseases and Transplantation
Volume 14 Number 2; June 2003
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Indications for referral of nephrotic patients to a paediatric nephrologist
• Atypical features at initial presentation
• Acute complications
• Steroid-resistant nephrotic syndrome
• Frequent relapses or steroid dependency in
steroid-sensitive nephrotic syndrome
• Adverse effects of corticosteroid therapy and
consideration of alternative medication
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Nephrotic syndrome - Acute complications
Hypovolaemia
Infection
Thrombosis
Urinary losses of antithrombin III, raised plasma fibrinogen concentration and hypovolaemia contribute to a risk of vascular thrombosis in nephrotic syndrome.
Avoid blood sampling from the femoral vessels.
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Long term prognosis of SSNS
Is generally good
The rate of relapse will decrease over the course of several years till entering long term remission before adulthood.
Up to 20% of patients continue to have relapses till the 2nd decade of life.
After a 5-year interval of remission, approximately 20% of patients will relapse within the subsequent 5 years.
However, if a 10-year remission has been achieved, the risk of subsequent relapse is very small.
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NS - Mortality
Mortality rate which is about 1.7-2% is mainly due to the acute
complications e.g. sepsis, vascular thrombosis, etc.
Mortality nowadays is thought to be lower.
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Congenital Nephrotic Syndrome
1. It is an uncommon disorder that may be caused by several diseases. These may be inherited, sporadic, acquired, or part of a general malformation syndrome.
2. In the 1st 6 months of life, causes include congenital infection and diffuse mesangeal sclerosis.
3.Nephrosis during the 2nd half of the 1st year is most commonly associated with idiopathic nephrotic syndrome or drugs.
4.Congenital nephrotic syndrome of the finish type is an autosomal recessive disease.
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5.It is caused by mutations in the gene NPHs1 which is located in the 13.1 region of the long arm of chromosome 19.
6.This gene codes for a cell adhesion protein called Nephrin which is synthesized by podocytes.
7.All children with nephrotic syndrome in the 1st year of life should have a renal biopsy.
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Family history
consanguinity
Finnish ancestry
Thrombotic events
Psychomotor delay
Prematurity
Failure to thrive
Serious bacterial infections (925 episodes)
Peritonitis
Sepsis
Pneumonia
Urinary tract infection
Cellulitis
Associated abnormalities
microcephaly
24/30
0
4
23/28
24/30
26/30
4
11
4
4
2
5
80
0
13
82
80
87
Clinical Features in 30 Children with Congenital Nephrotic Syndrome
Journal of Nephrology – Jordan University Hospital
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End-stage renal failure
Peritoneal dialysis
Hypertension
Death
Lost to follow-up
17/30
5/17
8/30
27/30
3/30
OUTCOME IN 30 CHILDREN WITH CONGENITAL NEPHROTIC SYNDROME
Journal of Nephrology – Jordan University Hospital
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