Proteinuria

Question 1

Normal protein handling

Answer 1

Glomerular protein filtration

• size and shape (>40 kDa retained; only small proteins e.g. retinol binding protein, beta-2 microglobulin)
• electrical charge (negative charge of membranes repels proteins)

Proximal tubular reabsorption
- most filtered proteins

==> normally <150 mg/day protein in urine

Question 2

Definition of Proteinuria

Answer 2

Proteinuria = >150 mg/day

Microalbuminuria = 30-300 mg/day but not detectable by conventional urine dipstick

Nephrotic syndrome = >3.5 g/day with hypoalbuminaemia, oedema, hyperlipidaemia

Question 3

Clinical significance of proteinuria

Answer 3

1. Sign of kidney damage
2. Direct pathogenic role in the progression of renal and CVS diseases

Assessment for:

• screening kidney damage
• marker for progressive renal dysfunction
• prognostic factor of CKD
• independent risk factor for CVS morbidity and mortality

Question 4

Classification of Proteinuria

Answer 4

Physiological

• transient
• orthostatic

Pathological

• overflow
• tubular
• glomerular

Question 5

Transient proteinuria causes

Answer 5

Causes:

• fever
• exercise
• concentrated spot urine e.g. early morning sample
• contamination e.g. from vagina

Question 6

Orthostatic proteinuria

Answer 6

Children and young adults, usually benign

• upright posture (absent when urine collected after sleep)

May indicate underlying renal disease and should be followed up 6-12 monthly

Question 7

Overflow proteinuria

Answer 7

Massive excretion of systemic low molecular weight protein

• light chains/ Bence Jones proteins (myeloma)
• myoglobin (rhabomyolysis, crush injury)
• haemoglobin (haemolysis)
• lysozyme (myelo-monocytic leukemia)

==> high load exceeds tubular reabsorption capacity

Question 8

Tubular proteinuria

Answer 8

Tubular dysfunction

• mainly cause low molecular weight proteinuria
  e. g. Retinol-binding protein, beta-2 microglobulin, lysozyme, light chains, haemoglobin, myoglobin

Causes:

• pyelonephritis
• ATN
• papillary necrosis e.g. analogies nephropathy
• heavy metal intoxications
• SLE
• Fanconi’s syndrome (also glucosuria, aminoaciduria, RTA)

Usually <3g/day

Question 9

Glomerular proteinuria

Answer 9

Most common form
Glomerular dysfunction = proteins >40 kDa can escape into urine

Classified as:

• selective proteinuria – only <100 kDa e.g. albumin, transferrin
• non-selective – range of different sized e.g. IgG also
• microalbuminuria

Causes:

• GN
• DM, HT
• Myeloma
• Amyloidosis
• SLE
• Drugs and toxins
• Pre-eclampsia

Question 10

Albuminuria

Answer 10

All levels of albumin that’s found in the urine
–> marker of kidney damage! (increased glomerular permeability)

Microalbuminuria
- urine albumin excretion 30-300 mg/day or excretion rate 20-200 mcg/min
==> greater than normal but NOT DETECTED BY URINE DIPSTICK

Question 11

3 categories of albuminuria

Answer 11

KDIGO guidelines
A1 = ACR < 3mg/mmol
A2 = ACR 3-30 mg/mmol
A3 = ACR >30 mg/mmol

A2 and A3 a/w significantly increased CVS risk even in patients with GFR >60

Cutoffs used in PWH (UACR)

• first void spot urine
• sex specific cut offs

Microalbuminuria

• men 2.5-25 mg/mmol
• women 3.5-35 mg/mmol

or 30-300 mg/day (24 hr)

Question 12

Clinical significance of microalbuminuria

Answer 12

Correlates with mortality in patients with DM and HT
Predicts development of nephropathy in DM
Treat promptly and adequately to prevent or postpone diabetic nephropathy

Treatment involves BP control, with ACEi and strict diabetic control

Question 13

Assessment of Proteinuria: choice of test, timing, patient variables

Answer 13

1. Choice of test
   - urine dipsticks for total protein or albumin
   - lab testing for urinary total protein, albumins or specific proteins
2. Time of urine collection
   - spot urine vs timed
   - random vs first morning void
3. Patient variables
   - should be free from UTI, fever, intense exercise within 24 hrs, menstruation
4. Reporting units
5. Interpretation

Question 14

Urine dipsticks: use, sensitivity, false positives and false negatives

Answer 14

SCREENING of proteinuria

• colour changes in presence of protein due to pH change
• intensity correlates with concentration

Detects albumin ==> GLOMERULAR PROTEINURIA

Sensitivity: 0.1 g/L (100 mg/L) of urine albumin –> NOT MICROALBUMINURIA
(have albumin specific dipsticks)

False positives:

• alkaline urine e.g. UTI
• pigmented urine
• concentrated urine
• drug/ chemical interference
• contamination with vaginal secretions
• egg white

False negatives:

• protein not albumin e.g. overflow proteiunuria
• urine too dilute

Question 15

Lab test for urinary proteins

Answer 15

UACR as surrogate of 24 hr urine
- 24 hr inconvenient, inaccurate collections

DM and HT – UACR
Myeloma – urine protein electrophoresis

Spot doesn’t mean random!!

• first morning urine preferred (least variable, best correlation; required for dx of orthostatic/exercise proteinuria)
• random urine acceptable if first morning not available
• utility improved by using ratio with Cr (standardise to urine concentration)

Question 16

**Overall values for proteinuria

Answer 16

uACR

• normal = <3 mg/mmol
• micro = 3-30
• macro = >30

24 hr urine albumin

• normal = <30 mg/day
• micro = 30-300 mg/day

24 hr urine protein

• normal = <150 mg/day
• nephrotic = >3.5 g.day

Question 17

Overall approach to proteinuria: initial investigations, diagnostic parameters, further investigations

Answer 17

Hx, PE

Ix

• RFT, total protein, albumin
• urine dipstick –> repeat if trace or 1+ (ensure no exercise, first morning void)
• diagnostic: albumin specific dipstick +ve, routine dipstick >1+, UACR >3mg/mmol

Further Ix

• 24 hr urine (confirm and assess severity)
• CrCl (estimate GFR)
• urine microscopy for casts, white cells, red cells, clue for dx of GN, ATN, pyelonephritis
• others based on suspicion (USG, biopsy, electrophoresis, myoglobin/Hb, HbA1c)

Question 18

When to refer to nephrologist?

Answer 18

eGFR <30 ml/min/1.73 m2
persistent significant albuminuria >30 mg/mmol
consistent decline in eGFR
haematuria with macroalbuminuria
CKD and HT that is hard to get to target despite 3 drugs

Any presentation of nephritis (oliguria, haematuria, acute HT, oedema)

Question 19

Nephrotic Syndrome classical features

Answer 19

Heavy proteinuria (>3.5 g/day)
Generalised oedema
Hypoalbuminaemia
Hyperlipidaemia

(RFT can be normal or abnormal!!)

Question 20

Causes of nephrotic syndrome

Answer 20

Renal disease

• minimal change disease
• membranous GN
• focal segmental GN
• membranoproliferative GN

Systemic disease

• DM
• amyloidosis
• myeloma
• SLE
• drugs e.g. gold, penicillamine

Question 21

Pathophysiology of Nephrotic syndrome

Answer 21

Heavy glomerular proteinuria

• -> hypoalbuminaemia
• -> decreased oncotic pressure –> oedema –> loss of fluid from intravascular compartment –> RAAS –> salt and water retention –> worsen oedema
• -> loss of anticoagulants e.g. anti-thrombin III could lead to thromboembolic disorders
• -> loss of Ig = IgG immunodeficiency

Loss of most proteins except very large e.g. lipoproteins

Liver increase protein synthesis in response to hypoproteinaemia

• -> can’t compensate fully for severe urine loss
• -> increased lipoproteins ==> hyperlipoproteinaemia

Question 22

Nephrotic Syndrome Ix

Answer 22

Serum electrolytes, Ur, Cr, total protein, albumin, lipid profile

24 hr urine protein
CrCl

Urine microscopy (casts)
Renal biopsy
Ix for systemic illness