NEPHROTIC SYNDROME

•	Definition.
•	Causes.
•	Minimal change nephrotic syndrome.
•	Approach.
•	Investigations.
•	Management

Definition of Nephrotic Syndrome

1.	Proteinuria: above 40 mg/m2/hr (or 1g/kg/24hr), or urinary protein (mg/dL) / creatinine (mg/dL) ratio of 2.0 or more.

2.	Hypoalbuminaemia: serum albumin less than 25 g/L.

3.	Hypercholesterolaemia.

4.	Edema:

a.	Nephrotic:

i.	proteinuria leads to decreased plasma oncotic pressure, decreased plasma volume and increased interstitial volume.

ii.	BP is normal.

iii.	hypovolaemic state: restriction of fluids and diuretics would precipitate ARF.

b.	Nephritic:

i.	decreased GFR leads to sodium retention and increased plasma and interstitial volume.

ii.	BP is elevated.

iii.	hypervolaemic state: restrict fluids and diuretics.

Causes

1.	Primary Glomerulonephritis ( 90% )

Type of GN	Child	Adult	
Minimal change nephrotic syndrome (MCNS)	76%	23%	
Focal & segmental glomerusclerosis (FSGS)	8%	12%	
Membranoproliferative GN (MPGN)	8%	7%	
Diffuse proliferative GN	2%	-	
Mesangial proliferative GN	2%	27%	
Membranous GN	2%	28%	
Focal / global glomerosclerosis	2%	-	

2.	Secondary GN ( 10% )

a.	Infections: SBE, malaria.

b.	Drugs: heavy metals, penicillamine.

c.	Autoimmune diseases: SLE, Henoch Schonlein pupura.

d.	Hereditory nephritis: Alport’s.

e.	Metabolic disorders: diabetes mellitus.

f.	Allergic: bee sting, immunization of atopic child.

g.	Neoplasia: leukaemias, nephroblastoma, Hodgkins lymphoma.

h.	Vascular diseases.

3.	Prevalence

a.	90% of NS in children are due to primary GN:

i.	of this, 76% is due to MCNS.

ii.	of the remaining primary GN, FSGS is the most common and important because it can cause CRF.

b.	10% of NS in children are due to secondary GN:

i.	of this, SLE is the most important cause.

ii.	secondary GN must be excluded first because the treatment and progress differs.

c.	It is important to differentiate between MCNS and non-MCNS because it influences:

i.	need for biopsy: not needed in MCNS.

ii.	initial treatment: steroids for MCNS.

iii.	prognosis: good if MCNS.

4.	Focal segmental glomerulosclerosis

a.	Presentation is similar to MCNS but with steroid resistance. 

b.	Renal biopsy shows segmental sclerosis or hyalinosis with other glomeruli completely sclerosed or normal.

c.	Immunofuorescence shows IgM and IgG in the affected segmental lesions.

d.	The majority of children with this lesion are resistant to steroids, cyclophosphamide and cyclosporin.

e.	Approximately 60% progress to end stage renal failure over 10 years.

f.	It has a 30% recurrence risk in a transplanted kidney and in some cases plasmapheresis is beneficial.

5.	Acute nephritis is defined as:

a.	Haematuria.

b.	Proteinuria.

c.	Edema.

d.	Hypertension.

e.	Renal insufficiency.

6.	Causes of acute nephritis:

a.	Post-infectious glomerulonephritis.

b.	Henoch-Schonlein purpura.

c.	IgA nephropathy.

d.	Alport’s syndrome.

e.	Lupus erythematous.

7.	Alport’s syndrome.

e.	Lupus erythematous.

7.	Post-streptococcal glomerulonephritis

a.	This disorder follows 2 – 3 weeks after group A haemolytic streptococcal throat or skin infection.

b.	Circulating antigen-antibody complexes form in the blood and deposit in glomeruli with activation of the complement system.

c.	The pathological features consists of proliferation of mesangial and endothelial cells with neutrophil inflitration.

d.	Usual presentation is a child of school age, with macroscopic haematuria, edema or headache, lassitude, fever and loin pain.

e.	Management:

i.	mild hypertension: frusemide 2 – 4 mg/kg/day.

ii.	oral penicillin for 10 days to eradicate any existing streptococcal infection.

f.	Complications:

i.	hypertensive encephalopathy.

ii.	left ventricular failure.

iii.	acute renal failure.

8.	Henoch-Schonlein purpura

a.	A vasculitic illness involving small vessels in the skin, large joints and GI tract.

b.	Preceded by upper respiratory tract infection in 30 – 50% of patients.

c.	These children present with a petechial or purpuric rash, abdominal pain and arthritis.

d.	A mild nephritis is seen in 50 – 70% of cases, manifest usually by microscopic haematuria and proteinuria.

e.	Renal histology shows a proliferative glomerulonephritis with IgA in the mesangium.

f.	The prognosis is good with less than 5% developing CRF.

9.	IgA disease (Berger’s)

a.	Present in 50% of children who have recurrent episodes of macroscopic haematuria.

b.	The episodes of haematuria often occur simultaneously with intercurrent viral infections and flank pain.

c.	Very few children develop CRF as the disorder is more common in adults.

10.	Alport’s syndrome

a.	Inherited as an X-linked dominant or autosomal dominant condition.

b.	Males are affected more severely than females.

c.	In males this disorder presents in the first 10 years of life with haematuria and proteinuria.

d.	Renal failure develops in the teenage years.

e.	High tone nerve deafness and eye abnormalities are other features of the syndrome.

11.	Lupus erythematous

a.	SLE in childhood is seen more in females in the later childhood years.

b.	Facial rash, arthritis and fever are common presenting symptoms.

c.	Renal biopsy is indicated if haematuria and proteinuria are present.

d.	Serum C3 complement is usually low.

e.	The type of glomerulonephritis can vary from a mild focal proliferative GN to a diffuse crescentic GN with associated membranous features.

f.	The treatment includes prednisolone, azathioprine, cyclophosphamide and plasmapheresis.

12.	Haemolytic uraemic syndrome (HUS)

a.	Characterized by a triad of:

i.	microangiopathic haemolytic anaemia.

ii.	thrombocytopenia.

iii.	acute renal insufficiency.

b.	It is a major cause of ARF in childhood.

c.	Classification:

i.	diarrhoea associated (D+) HUS.

ii.	atypical or sporadic form, diarrhoea negative (D -) HUS.

d.	Clinical features:

i.	more common under age of 3 years.

ii.	usually it follows a mild gastroenteritis, but the diarrhoea is often blood-stained.

iii.	over the next few days, the child becomes pale, oliguric and unwell.

e.	Investigations:

i.	examination of the blood film shows fragmented red blood cells and thrombocytopenia.

ii.	urinalysis reveals haematuria and proteinuria.

iii.	serum creatinine is usually elevated.

iv.	hypertension is often severe.

f.	Primary injury of HUS is swelling of endothelial cells in arterioles and widening of the subendothelial space with fibrin deposition.

g.	Dialysis is often necessary in the management of ARF.

Minimal Change Nephrotic Syndrome

1.	Introduction

a.	MCNS tends to affect younger children (2 – 5 years), and more often boys.

b.	It is associated with loss in the urine of low molecular weight anionic proteins, e.g. albumin.

c.	The vast majority of children with MCNS respond to corticosteroids – ‘steroid-sensitive nephrotic syndrome’.

2.	Etiology

a.	Caused by an alteration in the glomerular anionic status.

b.	Sensitized lymphocytes secrete a number of lymphokines that alter the normal negatively charged sialoproteins on the glomerular basement membrane.

c.	Loss of membrane negative charge allows anionic proteins to leak across the basement membrane into Bowman’s space.

d.	Light microscopy shows normal glomeruli but in some cases a mild increase in mesangial cells and mesangial matrix may occur.

3.	Clinical features

a.	Age of onset: 1 – 10 years.

b.	Generalized edema.

c.	No gross haematuria; 30% have microscopic haematuria. 

d.	No hypertension (can be hypertensive if on steroids).

4.	Biochemical features

a.	Normal renal function in remission; may be hypovolaemic in acute phase leading to ARF.

b.	Normal C3 levels: if low, suspect SLE, post-streptococccal GN, MPGN.

c.	Highly selective proteinuria:

i.	selective protein index (SPI): clearance of IgG / transferrin.

ii.	in MCNS, protein lost is low molecular weight protein (albumin + transferrin); high molecular weight protein (IgG) is retained.

iii.	therefore in MCNS, SPI < 0.1.

5.	Patients with the above clinical and biochemical criteria are presumed to have MCNS and are treated accordingly with steroids.

6.	Indications for Renal biopsy

a.	Atypical presentation:

i.	age > 10 years or < 1 year.

ii.	gross / persistent haematuria.

iii.	hypertension.

iv.	uraemia in the absence of hypovolaemia.

v.	persistently low C3.

vi.	poorly selective proteinuria.

b.	Steroid resistance: 50% probably not MCNS.

c.	Use of cytotoxic drugs: when frequent relapses / steroid dependency causes unacceptable steroidal toxicity, biopsy would be a pre-requisite to confirm MCNS before initiating cytotoxic therapy.

7.	Complications

a.	Infections:

i.	children with MCNS have increased susceptibility to infection with encapsulated bacteria, e.g. Pneumococcus, Haemophilus, E.coli.

ii.	look out for peritonitis, cellulitis and urinary tract infection.

iii.	this is due to urinary loss of immunoglobulin, transferrin, fluid accumulation, steroid therapy and hyperlipidaemia inhibiting lymphocyte function.

b.	Thrombosis and embolism:

i.	MCNS can be associated with hypercoagulability due to increase in plasma fibrinogen and clotting factors V and VII and decrease in plasma antithrombin III.

ii.	this leads to increased risk of major vessel thrombosis; most commonly this involves renal veins, or sagittal sinuses.

iii.	the likelihood is further increased by any co-existing illnesses leading to fluid loss, and haemoconcentration, from vomiting or diarrhoea.

c.	Hypovolaemic shock leading to ARF.

d.	Hyperlipidaemia: atherosclerosis and long-term complications.

e.	Impaired growth because of chronic malnutrition and steroid therapy.

f.	Hypocalcaemia: loss of vitamin D-binding protein in the urine leading to bone demineralization in the long term.

g.	End-stage renal failure:

i.	only a small minority of children with MCNS develop ESRF.

ii.	the group most likely to do so have steroid-resistant FSGS.

iii.	rarely children who were initially steroid-responsive become steroid-resistant and progress to ESRF.

h.	Complications of steroid / cytotoxic therapy.

History

1.	Presenting complaint:

a.	Reason for current admission.

b.	Age: 2 – 5 (range 1 – 10); nephritic (5 – 15).

2.	Current symptoms

a.	General health:

i.	anorexia.

ii.	weight gain.

iii.	lethargy.

iv.	poor height gain.

b.	Edema:

i.	extent: periorbital, ankle swelling, ascites.

ii.	onset and progression.

c.	Hypovolaemia:

i.	giddiness.

ii.	oliguria.

iii.	palpitations.

d.	Urinary symptoms:

i.	frothy urine.

ii.	oliguria.

iii.	haematuria.

3.	Exclusion of concomitant nephritic syndrome / ARF / CRF

a.	Urinary symptoms:

i.	haematuria: nephritic.

ii.	oliguria / anuria: ARF.

iii.	polyuria / nocturia: CRF.

b.	Features of nephrotic syndrome:

i.	preceding URTI / insect bites in the lower limb, usually 3 weeks prior to onset of symptoms.

ii.	hypertensive encephalopathy: headache, nausea and vomiting, blurring of vision.

c.	Features of ARF and CRF.

4.	Assess secondary etiologies

a.	SLE: rash, arthralgia, fever.

b.	HSP: lower limb rash, arthralgia, abdominal pain, haematuria.

c.	Drug ingestion, bee sting. 

5.	Assess for complications of MCNS.

6.	Family history of renal disease / CRF.

7.	Recurrence

a.	Initial diagnosis:

i.	when.

ii.	where.

iii.	presenting symptoms.

iv.	initial investigations.

v.	established etiology.

vi.	initial treatment.

b.	Hospital course:

i.	number of episodes per year: usual precipitants and treatment.

ii.	number of hospitalizations.

iii.	presenting symptoms.

iv.	sequence of complications.

v.	management.

vi.	modalities: renal biopsy, dialysis for RF, cytotoxic drug treatment.

c.	Management:

i.	diet.

ii.	medications.

iii.	present treatment in hospital.

iv.	usual management at home.

v.	home urine testing.

vi.	usual follow-up.

d.	Medications:

i.	steroid treatment and its response.

ii.	addition of cytotoxic drugs.

iii.	sequence of prior drugs used.

iv.	side effects.

v.	compliance.

vi.	future treatment plans.

e.	Social history:

i.	impact on child: amount of school missed, body image.

ii.	impact on family: finance, psychological.

iii.	social supports.

Clinical Examination

1.	Causes of edema:

a.	Renal: nephrotic syndrome, CRF.

b.	Liver: CLD.

c.	Cardiac: CCF.

d.	Bowel: IBD, CF.

e.	Nutrition: protein calorie malnutrition.

f.	Local causes: lymphadenopathy.

2.	General observation

a.	Position patient: standing.

b.	Periorbital edema.

c.	Pale sallow complexion: CRF.

d.	Jaundice: CLD.

e.	Cushingoid: steroids for GN.

f.	Nutritional status.

g.	Spider naevi: CLD.

h.	Tachypnoea: CCF, CRF.

I.	Rickets: osteodystrophy.

j.	Ascites: inspect from side as well.

k.	Kyphoscoliosis: osteodystrophy.

l.	Buttock purpura: HSP.

3.	Request:

a.	BP: CRF, various GNs.

b.	Urinalysis: proteinuria with GNs.

c.	Weight chart.

d.	Stool chart: IBD.

4.	Demonstrate distribution of edema:

a.	Ankle edema: press over the anterior tibiae for 1 minute.

b.	Ascites: shifting dullness, fluid thrill.

c.	Sacral edema: press over sacrum for 1 minute.

d.	Pleural effusion: percuss the posterior chest wall.

e.	Periorbital edema.

f.	Scrotal edema. 

5.	Upper limbs

a.	Clubbing: CLD, IBD.

b.	Leukonychia: CLD.

c.	Rapid pulse: CCF.

d.	Palmar crease pallor: CRF.

e.	Palmar erythema: CLD.

f.	Wrist flaring: osteodystrophy.

g.	Spider naevi: CLD.

h.	Muscle bulk and subcutaneous fat: poor in CRF, CLD.

6.	Head and neck

a.	Raised JVP: CCF.

b.	Face: 

i.	moon-face, hirsute: steroids.

ii.	malar flush: SLE.

c.	Eyes:

i.	scleral icterus: CLD.

ii.	conjunctival pallor: CRF.

d.	Mouth: uraemic foetor in CRF.

e.	Tongue: glossitis in nutritional deficiency.

7.	Chest:

a.	Palpate for:

i.	rib rosary: osteodystrophy.

ii.	cardiomegaly: CCF, CRF.

b.	Auscultate for:

i.	flow murmur: CCF.

ii.	gallop rhythm: CCF.

iii.	crepitations: CCF.

8.	Abdomen

a.	Palpate:

i.	hepatomegaly: CCF, CLD.

ii.	splenomegaly: CLD.

iii.	nephromegaly: polycystic disease, hydronephrosis.

b.	Demonstrate ascites.

c.	Inspect:

i.	buttock purpura: HSP.

ii.	perianal disease: IBD.

9.	Assess for complications.

INVESTIGATIONS

1.	Confirm nephrotic syndrome

a.	Urine protein levels:

i.	 > 2 + proteins for 3 consecutive days via dipstick.

ii.	24 hr urinary total protein: > 3g / 1.73m2 / day.

b.	Serum albumin < 25 g/L (N: 40 – 52).

c.	Serum cholesterol: increased (N: 2.6 – 6.7 mmol/L).

d.	Serum triglycerides: increased (N: 0.2 – 1.6 mmol/L).

2.	Assess predictors of MCNS

a.	Renal function (usually normal in MCNS):

i.	urea.

ii.	creatinine.

iii.	total urine volume.

iv.	creatinine clearance.

b.	UFEME for haematuria.

c.	Complement levels: low with MCGN, SLE; normal in MCNS).

d.	Selective protein index:

i.	N ratio: 0.1 – 0.2

ii.	MCNS < 0.1

3.	Exclude a secondary cause

a.	ANA: SLE.

b.	ESR: raised in low albumin, autoimmune disease.

c.	Blood sugar level, HbA1c.

d.	Hepatitis B and C serology: hepatitis B is associated with membranous nephritis, hepatitis C is associated with MCGN.

e.	Renal biopsy.

4.	Assess complications

a.	Full blood count:

i.	Hb: polycythaemia.

ii.	TW: infection.

iii.	platelets: low in AI conditions.

b.	CXR: chest infection, pleural effusion.

c.	UFEME + urine culture for UTI.

MANAGEMENT

1.	Acute management

a.	Admit child. Confirm diagnosis and assess patient’s condition.

b.	Resuscitate if necessary:

c.	Albumin replacement: give 20% IV albumin 1g/kg together with frusemide over 12 hours to replace lost albumin.

d.	Indications for albumin replacement:

i.	severe edema.

ii.	severe hypovolaemia.

iii.	U&E imbalance.

e.	Rest in bed and prop-up if necessary.

f.	Monitor progress and response via a nephrotic chart:

i.	input / output chart.

ii.	weight gain / loss.

iii.	urine protein.

2.	General management

a.	Diet:

i.	salt restriction only if edematous, once in remission, no need for restriction.

ii.	fluid.

iii.	calories: low calorie, no refined sugar and no fat diet.

b.	Diuretics + albumin to push interstitial fluid into blood and then fluid from blood into urine.

c.	Monitor progress and response via nephrotic chart.

d.	Maintain steroid therapy.

3.	Specific management

a.	Steroid therapy.

b.	Immunosuppressive therapy.

c.	Antibiotics: treat episodes of remission with prophylactic daily penicillin to avoid pneumococcal infection.

d.	Immunization: 

i.	live viral vaccines should be avoided.

ii.	pneumococcal vaccine is recommended because of the increased risk of streptococcal infection.

4.	Steroid therapy

a.	Principle: high dose for long duration.

b.	Efficacy:

i.	steroids do not alter the prognosis of nephrotic syndrome.

ii.	does not prevent patient to be a frequent relapser.

iii.	only shorten period of each relapse to prevent complications.

c.	Regimen: prednisolone 2 mg/kg/day for 4 weeks, then decrease dose to 1.5 mg/kg alternate-daily for the next 4 weeks.

d.	IV methylprednisolone used for steroid-resistant NS, usually due to FSGS.

e.	Response to steroids:

i.	initial response to steroids is the most important prognostic factor.

ii.	93% of MCNS respond to steroid therapy, steroid resistant defined as no recovery after 1month.

iii.	of the 93%, 36% are non-relapsers – no further action needed.

iv.	18% are infrequent relapsers: reccurrence of edema and not of proteinuria.

v.	39% are frequent relapsers and steroid-dependent: > 2 relapses in past 6 months – maintenance steroid therapy indicated.

f.	Complications of steroids:

i.	distribution of body fat: moon-face, buffalo-hump, truncal obesity, proximal myopathy.

ii.	hyperglycaemia and glycosuria.

iii.	osteoporosis and avascular necrosis of femoral head.

iv.	sodium and water retention: hypertension, edema and cardiac failure.

v.	suppression of inflammatory and immune responses leading to increased susceptibility to infections.

vi.	posterior subcapsular cataracts.

vii.	GIT: dyspepsia, peptic ulceration.

viii.	stunting of growth.

ix.	hirsutism and menstrual disturbances.

4.	Immunosuppressive therapy

a.	Indications: unacceptable steroid toxicity leading to uncontrolled hypertension, severe DM, severe growth retardation and psychosis.

b.	If indicated, renal biopsy is required to confirm MCNS.

c.	Drugs used and side effects:

i.	cyclosporin A: nephrotoxicity, hypertension, gingival hyperplasia and hirsutism.

ii.	cyclophosphamide: bone marrow suppression, gonadal toxicity, haemorrhagic cystitis, alopecia, bladder fibrosis and secondary malignancy.

5.	Long term considerations and follow-up

a.	Diet.

b.	Activity.

c.	Home monitoring:

i.	teach parents use of dipstick.

ii.	always check in the morning after waking up and when there is some complication.

d.	Immunization: no immunization for at least 6 months to a year after last steroid dose.

e.	Assess response to therapy and steroid toxicity.