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Updates in Nephrotic Syndrome. Dr.Fathia Ahmed Abdel Magid Consultant Paediatrician. Nephrotic syndrome is a common manifestation of glomerular disease in children.

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slide1

Updates in Nephrotic Syndrome

Dr.Fathia Ahmed Abdel Magid

Consultant Paediatrician

slide2

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
slide3

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
slide4

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.

slide5

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.
slide6

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.
slide7

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.
slide8

Mechanisms of oedema

  • Hypoalbuminaemia causes ↓ in the plasma oncotic pressure and ↑ in the passage of fluid to the interstitial compartment.
  • Sodium reabsorption by the distal renal tubules is enhanced in the nephrotic state  ↑expansion of the extracellular fluid volume, further exacerbating oedema.
slide9

Clinical features and diagnosis

Patients with typical uncomplicated nephrotic syndrome require limited initial investigations.

slide12

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)
slide13

Atypical features of MCNS

  • Age <1 year or >12 years
  • Persistent hypertension
  • Gross haematuria
  • Renal impairment
  • ↓ plasma C3.
slide14

Blood pressure

Blood pressure readings should be interpreted with reference to appropriate centile charts.

slide15

Percentile Blood Pressure Readings for Children by Age and Height Percentile (mm Hg)

  • Girls
  • Age 5th 50th 95th
  • Percentile Percentile Percentile
  • 1 101/57 104/58 107/60
  • 6 108/71 111/73 114/75
  • 12 120/79 123/80 126/82
  • 126/83 129/84 132/86
  • -------------------------------------------------------
slide16

Boys

Age 5th 50th 95th

Percentile Percentile Percentile

1 98/55 102/53 106/59

6 109/72 114/74 117/76

12 119/79 123/81 127/83

17 132/85 136/87 140/89

slide17

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.
slide18

Patients with atypical features need further investigations e.g.

- ASO titre

- ANA

- Anti DS DNA antibodies

slide19
Management

General

The child’s condition remains stable  ↓ the risk of complications.

slide20

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.
slide21

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.
slide22

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.
slide23

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.

slide24
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.
slide25

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.
slide26

Standard definitions in monitoring of steroid sensitive nephrotic syndrome

Current Paediatrics , Volume 12 Number 7 December 2002

slide27

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.
slide28

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
slide29

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
slide30

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
slide31

Steroids – adverse effects (contd)

  • Pubertal delay
  • Adrenal suppression
  • Impaired glucose metabolism
  • Dyspepsia and peptic ulceration
  • Acute pancreatitis
  • Osteoporosis
  • Avascular osteonecrosis
  • Proximal myopathy
slide34

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:

slide35

(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)

slide36

Typical management strategy for steroid- sensitive nephrotic syndrome

  • 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
slide37

Frequent relapses

  • Maintenance prednisolone: 0.1-0.5 mg/kg on alternate days for up to 12 months.
  • Relapse on prednisolone>0.5 mg/kg on alternate days
  • Levamisole 2.5 mg/kg on alternate days for up to 12 months
  • 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.
slide38

Post-cyclophosphamide relapses

  • As in 2 and 3 above
  • 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.
slide39

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.
slide40

Levamisole (contd)

  • It may cause neutropenia. Therefore, a full blood count should be checked at 6 weeks, 12 weeks and every 3 months thereafter
slide41

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
slide42

The outcome of treatment of steroid sensitive nephrotic syndrome patients with levamisole (Lev) and cyclophosphamide(Cy)

Suleimania Children’s Hospital, Riyadh, K.S.A.

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

slide43

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
slide44

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.
slide45

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.
slide46

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.
slide47

Congenital Nephrotic Syndrome

  • 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.
  • In the 1st 6 months of life, causes include congenital infection and diffuse mesangeal sclerosis.
  • Nephrosis during the 2nd half of the 1st year is most commonly associated with idiopathic nephrotic syndrome or drugs.
  • Congenital nephrotic syndrome of the finish type is an autosomal recessive disease.
slide48

It is caused by mutations in the gene NPHs1 which is located in the 13.1 region of the long arm of chromosome 19.

  • This gene codes for a cell adhesion protein called Nephrin which is synthesized by podocytes.
  • All children with nephrotic syndrome in the 1st year of life should have a renal biopsy.
slide49

Clinical Features in 30 Children with Congenital Nephrotic Syndrome

Journal of Nephrology – Jordan University Hospital

slide50

OUTCOME IN 30 CHILDREN WITH CONGENITAL NEPHROTIC SYNDROME

Journal of Nephrology – Jordan University Hospital

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