PROTEINURIA

THE CHILD WITH PROTEINURIA

&
NEPHROTIC SYNDROME
 Learning Objectives
At the end of this session you should be able to:
• Define proteinuria
p
• Understand the pathophysiologic mechanisms and
age differences
• Distinguish between pathological and non-
pathological proteinuria
• Assess and evaluate proteinuria in a clinical
situation
 Definition
• Presence of protein in urine
• Normal proteinuria
• Significant proteinuria
 Epidemiology
• Prevalence depends on how proteinuria
defined
• 2-3% of children in 3 consecutive samples –
10 mg/dl
• At least one episode of proteinuria in 11%
school age children
school-age
• Increases with age
 Pathophysiology
• Albumin and smaller molecular weight
pproteins are filtered byy the gglomerular
capillaries
• 95% of filtered proteins reabsorbed by
proximal tubules
• Children excrete up to 100 mg/m2 of protein
daily
 Pathophysiology
• Increased in newborns, adolescents and
adults
• Protein excretion increased by
Any condition that raises intraglomerular
capillary pressure
Glomerular disease
Tubular disorders
Benign condition of orthostatic proteinuria
 Classification
Non-pathological (non- Pathological
nephrotic) (nephrotic)
• Vigorous exercise • Glomerular leaks
• Febrile illness • Failed tubular
• Orthostatic reapsorption
• Accidental trauma • Inflammation of
• UTI interstitium
• CC
CCF
 Classification
(Pathological)
• Nephrotic syndrome 10 and 20
• Glomerulonephritides
• HUS
• H
Hypertension
i
• Diabetes
• Hyperfiltration 20 to nephron loss
 Classification
(Tubular)
• Acute tubular necrosis
• Antibiotic induced
• Interstitial nephritis
• H
Heavy metall poisoning
i i (lead,
(l d gold,
ld
mercury)
• Inherited – cystinosis, Wilson disease,
aminoacidurias
 Classification
• Pre-glomerular – increased filtration
• Glomerular – increased glomerular
permeability
• Post-glomerular
Post glomerular – tubular and intersitial
 Classification
• Transient
• Persistent
• Intermittent (orthostatic)
 Clinical Presentation

• Incidental finding
P th l i l or non-pathological?
Pathological th l i l?
• Peripheral oedema
What would be the differential
g
diagnosis?
• Anasarca
Assessment of proteinuria
 Assessment - Qualitative
Urine Dipstick 3% Sulphosalicylic acid
• False +: concentrated,, (SSA)
alkaline urine, • False +: conc. urine,
contamination with penicillin,
chlorhexidine,
hl h idi sulphonamides,
l h id
benzalkonium cephalosporins,
• False
F l -: dilute
dil t urine
i contrast agents
• False -: dilute urine
Assessment - Semiquantitative
Spot urine protein to creatinine ratio
Normal </
</= 0.2
02
Minimal proteinuria 0.2 – 0.5
M d
Moderate proteinuria
i i 0.505–2
Nephrotic range > 2
 Assessment - Quantitative
12 – 24 hour urine collection and assessment
 Assessment
What is significant proteinuria?
• 1+ on 2 or more consecutive urine samples
• 2+
• Urine
U i protein/creatinine
i / i i > 0.2
02
• 4-39 mg/m2/hr in 12-24 hour collection
 Assessment
Nephrotic Range Proteinuria
• Urine protein/creatinine > 2.0
20
• > 40 mg/m2/hr in 12-24 hour collection
• > 0.05g/kg/day
0 05 /k /d in i 24 hr
h collection
ll i
Evaluation of Proteinuria
Non-pathological or pathological?
 Evaluation
Non-pathological
• Contamination – e.g.
e g vaginal secretions
• False + test
• O h
Orthostatic
i proteinuria
i i – repeat 3
consecutive days supine & ambulant urine
• Transient or intermittent
 Evaluation
Pathological
• Associated haematuria – always
• Persistent proteinuria – sometimes
• Nephrotic
N h i range proteinuriai i
 Evaluation - History
• ANC and birth hx • Hx – joint pains or
• Neonatal problems – swelling, skin rashes
sepsis,
i shock,
h k UAC,
UAC UVC • Hx
H – previous
i UTIs,
UTI
• Swelling – periorbital, urinary abnormalities,
pedal, abdomen haematuria
• Recent illness – • Hx – ↑BP or weight
pharyngitis, impetigo, changes
f b il illness
febrile ill • Hx – SCD,
SC DM,
• Recent athletic event transfusions
• FH – renal disease
 Evaluation - Examination
• Growth parameters • Skin – rash of
• Blood ppressure impetigo, HSP
determination • Joint – swelling,
• Assess for oedema tenderness
• Abdomen – ascites,
organomegaly
 Evaluation - Investigations
• Rule out Orthostatic proteinuria
• Urine microscopy – spun/unspun samples
• Spot urine protein / creatinine
• 24 hhour urine
i proteini & creatinine
i i
• Hb, electrophoresis
Evaluation-Further Investigations
• ASTO, ANF, VDRL, C3, Hepatitis B s
antigen,
g , HTLV1,, HIV
• Renal ultrasound
• Renal glucoheptonate scan
• MCUG
• Renal biopsy
 Evaluation – Biopsy Indications
• Nephritis
• Atypical nephrotic syndrome
• Renal failure
• F il
Failure to thrive
h i – systemici illness
ill
• Increasing proteinuria on follow-up
• Family hx of chronic nephritis / renal failure
 Summary
You should now be able to:
• Define proteinuria
p
• Understand the pathophysiologic
mechanisms and ageg differences
• Distinguish between pathological and non-
ppathological
g proteinuria
p
• Assess and evaluate proteinuria in a clinical
situation
 Case report
A 3-year-old child presented with ‘flu-like’
symptoms 4 weeks ago. Subsequently mom
noticed that his eyes were swollen on
waking 2-weeks ago. He saw his GP who
prescribed
ib d eye drops
d for
f allergy.
ll This
Thi week, k
there was progressive swelling of his feet
and then abdomen
abdomen. Today he presented to
Casualty with diarrhoea and intermittent
abdominal pain.
Nephrotic
p Syndrome
y

A Primary Care Approach

 Learning Objectives
At the end of the session you should be able to:
p
• Define nephrotic syndrome
y
• Understand the pathophysiologic mechanisms in
its genesis
• Distinguish minimal change nephrotic syndrome
(MCNS) from other forms in childhood
• Identify and manage the problems associated with
MCNS
 Definition
Proteinuria
• > 50 mg/kg/d; > 40 mg/m2/hr
• Protein/creatinine > 2.0
• 4+
4 proteinuria
i i on at least
l 5 consecutive
i
urines
Hypoalbuminemia
• < 25 g/l
g
 Definition
Oedema
Hypercholesterolemia
Hypertriglyceridemia
 Epidemiology
• 2-3 / 100,000 children per year in USA
• 16 / 100
100,000
000 children – cumulative
prevalence
• 90% - primary
• 2/3 of cases present before 5 years
• M/F ratio is 2:1 in childhood; sexes equally
affected in adolescence
 Classification - Primary
• Minimal change NS
g
• Focal segmental gglomerulosclerosis
• Diffuse proliferative GN
g proliferative
Mesangial p GN
Membranoproliferative GN
Cresentic GN
• Membranous nephropathy
• Congenital NS
 Classification - Secondary
• Infection : post Strep, • Inflammatory: JRA
Hepatitis B, congenital • Systemic disorders:
and 20 syphilis, HIV, SCD, DM
HTLV1, varicella, • Drugs: gold, D-
SBE VP shunt
SBE, sh nt inf.,
inf penicillamine
penicillamine,
malaria captopril, mercury
• Autoimmune: SLE,
SLE • Neoplasia:
p Hodgkin’s
g
HSP, IgA nephropathy lymphoma
vasculitides • Heredity: Alport’s
 Pathophysiology - NS
Proteinuria
• Increased permeability of glomerular capillary
wall
ll
• Alteration of electrostatic properties of the
glomerular filtration barrier
• Loss of neg. charged glycoproteins within
capillary
p y wall
• Protein loss > 2 g/24 hr
• Mainlyy albumin;; variable selectivityy
 Pathophysiology - NS
Hypoalbuminemia – loss of primarily albumin
Oedema
• Occurs when serum alb < 25 g/l
q
• Disequilibrium of Starling’s
g forces within the
tissue capillaries
• ↓p plasma oncotic ppressure ⇒ ↑ transudation ⇒
oedema ⇒ ↓ intravascular volume ⇒ RAA
system activated ⇒ Na and water retention
 Pathophysiology - NS
Hypercholesterolemia &
Hypertriglyceridemia
yp gy
• ↑ hepatic synthesis of↓ lipids and
lipoproteins
• ↓ catabolism owing to ↓ plasma levels of
lipoprotein lipase
• ↓ transport of lipids to adipose tissue
 Primary NS - Etiology
Genetics
• No established links
• ↑ frequency of HLA-B12 in children with
steroid sensitive NS
• Familial cases of MCNS documented
 Primary NS - Etiology
Immunology
• Mediation by modulation of the immune system
suggestedd by
b
Use of ‘immunosuppressive drugs’ in control
of condition
Association of MCNS with T-lymphocyte
disorders ((e.g.
g HD))
Remission with natural measles infection
Induction of pprolonged
g remission with
cytotoxic drugs e.g. cyclophosphamide
 Primary NS - MCNS
• Accounts for 80-85% of • No macroscopic
NS in childhood haematuria
• Age
A off onset: 11-66 years • No ↑ BP or CCF
• M:F – 2:1 • Neg for 20 cause
• Highly selective
• Oedema insiduous proteinuria
• May have preceding URTI • Normal renal function
• Anorexia,, abd. ppain,, • C3, Hb normal
diarrhoea common • Usually responsive to
steroids
• Renal biopsy – retraction
of foot processes on EM
 MCNS - Evaluation
• Establish the diagnosis and the severity of
NS
• Elucidate the cause
• Treatment – general and specific
 MCNS - Investigations
• Hb, Hb electrophoresis
• BUN,, creatinine,, electrolytes,
y , calcium,,
phosphate, serum albumin, globulin, TGs
• C3,, ASTO,, ANF,, VDRL,, Hep p B s Ag,
g, HIV,,
HTLV1
• Renal biopsy
py
For those presenting with atypical
features;; and steroid resistant NS
 MCNS – Treatment - General
• Fluids – maintenance for est. dry weight
• Sodium – 2 mEq/k/d
• Normal protein and potassium
• D il weights
Daily i h
• Accurate intake/output charting
• BP 4 hourly
• Adjustments for renal failure
 MCNS – Treatment - General
Oedema control - diuretics
• Mild
spironolactone 3-5 mg/kg/d; may add
chlorothiazide 10-40 mg/kg/d
• Moderate
M d t / severe
Anasarca, pre-renal failure with oliguria,
abdominal pain
Salt-poor albumin (25%) 1g/kg followed
byy frusemide 1-2 mg/kg
g g
MCNS – Treatment - General
EDUCATION – ongoing during admission and
continuing into ambulatory period
No live vaccines while on immuno-modulating
agents
Risks associated with exposure to varicella
infection
 MCNS – Treatment - Specific
Induction of remission
• Prednisone – 2 mg/kg/d
g g (60( mg/m g 2/d)) –
divided tid for 28 days (or till remision for
relapses)
Maintenance of remission
• Prednisone – 2 mg/kg/d
g g (60( mg/m g 2/d)) as
single dose alternate day for 28 days; then
taper over 2-3 months
 MCNS - Progress
• Remission - trace / negative proteinuria for 3-5
consecutive days
• Relapse
l - >/=
/ 2+ proteinuria
i i for
f 5 consecutive
i
days or on any day with oedema
• Frequent relapse - >/= 2 relapses in 6 months
• Steroid resistance – no remission with high dose
dailyy prednisone
p after 28 days
y
Use of immunosuppressive agents –
cyclophosphamide, chlorambucil, more
aggressive steroid regimes, levamisole
 MCNS - Complications
Infection
• Cellulitis,
Cellulitis peritonitis,
peritonitis bacteremia
• Organisms – Strep. pneumoniae, E. coli, H.
influenzae Pseudomonas,
influenzae, Pseudomonas Klebsiella
• Contributing factors - ↓ levels of Igs, loss of
transferrin,
f i impaired
i i d opsonization,
i i steroids id
Acute renal failure
 MCNS - Complications
Thromboembolic complications
e g renal vein thrombosis - ↑ plasma
e.g.
fibrinogen levels – hypercoagulable state;
cofactors VV, VIII ↑; ↓ levels of inhibitors of
coagulation in plasma (antithrombin III loss
in urine); platelets ↑; resultant
hyperviscosity of plasma
 MCNS - Complications
Calcium and vitamin D metabolism altered
• ↓ in total serum Ca and ionized Ca
• Vit D-binding protein is low
• ↓ levels of vit D metabolite – 25 HVD
• ↓ Ca absorption from GIT
Malnutrition
• Overall state of negative nitrogen balance;
enhanced pprotein catabolism
 MCNS - Complications
• Complications of steroid therapy
 Prognosis
• Good for MCNS
 Summary
You should now be able to:
p
• Define nephrotic syndrome
y
• Understand the pathophysiologic mechanisms in
its genesis
• Distinguish minimal change nephrotic syndrome
(MCNS) from other forms in childhood
• Identify and manage the problems associated with
MCNS