approach to nephrotic syndrome

1. Approach to a case of
Nephrotic Syndrome
Dr Sandeep Kumar Garg
MD DM
Nephrologist, Dialysis Expert
Renal transplant physician
Fellow in critical care medicine
NUTEMA HOSPITAL
Meerut

3. Proteinuria and Nephrotic syndrome
 Definitions
 Physiology
 Physiological proteinuria
 Classification of proteinuria
 Urine dipstick
 Investigation of proteinuria
 Nephrotic syndrome

4. Definitions
 Proteinuria
 Urine protein excretion > 150mg/day
 Microalbuminuria
 Urine [albumin] > 30mg/day but not detectable
by urine dipstick
 Nephrotic syndrome
 Urine protein excretion > 3.5g/day (with
hypoalbuminaemia, oedema and
hyperlipidaemia)

5. Normal physiology
 Protein filtration through the glomerulus is
dependent on the protein size, shape and
electrical charge

6. Normal physiology
 Protein charge
 At physiological pH, most proteins are
negatively charged
 Since the basement membranes are also
negatively charged, most proteins are
retained

7. Normal physiology
 Protein size
 Proteins greater than 40kDa are almost
completely retained
 Thus, only small proteins, e.g. retinol-binding
protein, ß2 microglobulin, passes into the
ultrafiltrate

8. Normal physiology
 However, most of the filtered proteins are
reabsorbed by the proximal tubules.
 Consequently, very little plasma protein
appears in the urine
 Normally < 150mg/24hours

9. “Physiological” proteinuria
 In some non-pathological situations, a
higher than normal urine protein level is
found:
 A concentrated spot urine
 Exercise
 Orthostatic proteinuria
 Contamination e.g. from vagina

10. Proteinuria

11. Classification
 Tubular proteinuria
 Tubular dysfunction
 Overflow proteinuria
 Glomerular proteinuria
 Selective proteinuria
 Non-selective proteinuria
 microalbuminuria

12. Tubular proteinuria
 This occurs when glomerular function is
intact, but protein is lost to the urine either
because of:
 Tubular dysfunction
 Overflow

13. Tubular proteinuria
 Tubular dysfunction
 The tubules are damaged and cannot function
properly
 Therefore, the small MW proteins that are
normally filtered are not reabsorbed by the
tubules
 The small MW proteins include: retinol-
binding protein, ß2 microglobulin, lysozyme,
light chains, haemoglobin, myoglobin

14. Tubular proteinuria
 Tubular dysfunction
 Pyelonephritis
 Acute tubular necrosis
 Papillary necrosis e.g. analgesic nephropathy
 Heavy metal poisoning
 SLE
 Fanconi’s syndrome

15. Tubular proteinuria
 Overflow proteinuria
 Occurs when the concentration of one of the
small MW proteins is so high that the filtered
load exceeds the tubular reabsorptive
capacity
 Thus, the excess filtered load appears in the
urine

16. Tubular proteinuria
 Overflow proteinuria
 Bence Jones proteinuria
 Myoglobinuria
 Haemoglobinuria

17. Glomerular proteinuria
 When there is glomerular dysfunction,
proteins > 40kDa can escape into the
urine
 The most common form of proteinuria

18. Glomerular proteinuria
 Selective proteinuria
 Non-selective proteinuria
 Microalbuminuria

19. Glomerular proteinuria
 Selective proteinuria
 If only intermediate-sized (< 100kDa) proteins
(albumin, transferrin), leaks through the
glomerulus, this is termed selective
proteinuria

20. Glomerular proteinuria
 Non-selective proteinuria
 When a range of different sized proteins leak
through including larger proteins (IgG), this is
termed non-selective proteinuria

21. Glomerular proteinuria
 Selectivity
 The measurement of the selectivity of
proteinuria used to be popular, however,
this has been replaced by renal biopsy
and electron microscopy

22. Glomerular proteinuria
 Causes
 Glomerulonephritis
 Diabetes mellitus
 Multiple myeloma
 Amyloidosis
 SLE
 Pre-eclampsia
 Penicillamine, gold

23. Glomerular proteinuria
 Microalbuminuria
 Urine albumin concentrations which are
greater than normal but not detectable by
urine dipstick

24. Microalbuminuria
 Normal urine protein: 150mg/day
 About 15-20 mg of the normal urine
protein is albumin
 Urine dipsticks detects urine albumin
>300mg/day

25. Microalbuminuria
 Therefore, microalbuminuria is defined as:
 Urine albumin excretion 30-300mg/day
Or
 Urine albumin excretion rate 20-
200ug/min.

26. Microalbuminuria
 Microalbuminuria is not detectable by
dipsticks
 Therefore, a 24hr or 12 hr urine collection
is required

27. Microalbuminuria
 Clinical significance:
 Correlates with mortality in diabetics and
hypertensives
 Predicts the development of nephropathy in
Type 1 and Type 2 diabetes

28. Microalbuminuria
 Treatment:
 Good BP control, especially by ACE-inhibitors
And
 Good diabetic control
 Postpones the development of diabetic
nephropathy

29. Urine dipstick
 Commonly used for screening of
proteinuria
 Is a plastic strip impregnated with a pH
indicator which changes colour in the
presence of proteins, due to a pH change

30. Urine dipstick
 The intensity of the colour correlates with
the concentration of protein in the urine
 Mainly detects albumin, and therefore
glomerular proteinuria
 Sensitivity: 0.1g/l

31. Urine dipstick
 False positives:
 When urine is alkaline (some UTI)
 The urine is pigmented (haematuria)
 The urine is concentrated
 Drug / chemical interference (chlorhexidine)
 Contamination with vaginal secretions
 Addition of egg white

32. Urine dipstick
 False negatives:
 The protein is not albumin
 The urine is dilute

33. Approach to proteinuria
 Proteinuria usually presents:
 Incidentally upon urine dipstick testing
Or
 When a patient presents with a condition
which is associated with proteinuria

34. Approach to proteinuria
 Clinical history
 Physical examination
 Initial investigation
 Further investigation

35. Clinical history
 Incidental finding
 Evidence of renal disease
 Evidence of systemic illness
 Family history of renal disease
 Medications being taken

36. Initial investigation
 Renal function
 Urine dipstick
 Determine the amount of protein detected

37. Initial investigation
 If renal function is normal
and
 If protein is trace or 1+
and
 There is no significant clinical history
then
 Repeat testing

38. Initial investigation
 When urine dipstick is repeated, ask the
patient to:
 Refrain from exercise for few hours
 Collect early morning urine to exclude
orthostatic proteinuria

39. Initial investigation
 If the findings are negative upon repeat
testing, then the initial positive result may
be due to a transient proteinuria (e.g.
fever, exercise)
Or
 A false positive

40. Further investigation
 Further investigation is needed if:
 Still positive upon repeat testing
 Positive clinical history
 Abnormal renal function
 Initial urine protein is > 1+

41. Further investigation
 24 hour urine protein excretion
 Creatinine and creatinine clearance
 Urine microscopy
 Other relevant tests dependent on the
provisional diagnosis

42. 24 hour urine protein excretion
 Gives a more accurate assessment of the
severity of the proteinuria
 > 150mg/24 hour = proteinuria
 > 3.5 g/24 hour (with associated features)
= nephrotic syndrome
 For estimation of 24hr urine albumin if
suspect microalbuminuria

43. Creatinine and creatinine clearance
 And estimation of GFR
 Assesses severity of renal dysfunction

44. Urine microscopy
 To look for casts, white cells and red cells
 May be a clue to the diagnosis of
glomerulonephritis, pyelonephritis, tubular
damage

45. Other tests
 Renal ultrasound if suspect renal disease
 Renal biopsy if suspect glomerular
disease
 Plasma and urine electrophoresis if
suspect multiple myeloma with Bence
Jones proteinuria
 Urine for myoglobin / haemoglobin
 HbA1c to assess diabetic control

46. Nephrotic syndrome
 Definition
 Causes
 Pathophysiology

47. Nephrotic syndrome
 Definition
 Heavy proteinuria (>3.5g/day)
 Generalised oedema
 Hypoalbuminaemia
 Hyperlipidaemia
 (renal function tests can be normal or
abnormal)

48. Nephrotic syndrome - causes
 Renal disease
 Minimal change disease
 Membranous glomerulonephritis
 Focal segmental glomerulonephritis
 Membranoproliferative glomerulonephritis

49. Nephrotic syndrome - causes
 Systemic disease
 Diabetes mellitis
 Amyloidosis
 Multiple myeloma
 SLE
 Drugs: gold, penicillamine

50. Nephrotic syndrome
 The above causes result in glomerular
proteinuria
 Heavy urinary loss of proteins, including
albumin, results in hypoalbuminaemia

51. Nephrotic syndrome
 Reduced blood albumin level results in
decreased intravascular oncotic pressure,
thus oedema develops
 Loss of fluid from the intravascular
compartment, causes activation of RAS,
which stimulates salt and water retention
and thus, worsens the oedema

52. Nephrotic syndrome
 Most proteins are lost to the urine, except
the very large proteins, e.g. lipoprotein
 Due to hypoproteinaemia, the liver
increases rate of protein synthesis

53. Nephrotic syndrome
 For most proteins, the increased hepatic
synthesis cannot fully compensate for the
severe urine loss
 But for lipoproteins, since it is retained and
in addition to the increased hepatic
synthesis, hyperlipoproteinaemia results

54. Nephrotic syndrome
 As for the loss of other proteins, there is
loss of anti-coagulants such as
antithrombin III, and thus nephrotic
syndrome could be complicated by
thromboembolic disorders, such as renal
vein thrombosis

55. Nephrotic syndrome
 There is also loss of immunoglobulins, and
thus, immunodeficiency of IgG may result

56. Investigation of Nephrotic syndrome
 Serum electrolytes, protein and lipid profile
 Serum urea and creatinine
 24hr urine protein excretion
 Creatinine clearance
 Urine microscopy
 Renal biopsy
 Investigation for systemic illness

57. Investigation of Nephrotic syndrome
 Exception to renal biopsy:
 Children presenting with nephrotic syndrome
are most commonly due to minimal change
disease
 Readily responds to steroid
 Therefore, give empirical steroid treatment
 Preform renal biopsy when no reponse to
steroid treatment

58. Proteinuria
 Must know:
 Definitions
 Significance of microalbuminuria
 Approach to investigation
 Dipsticks
 Pathophysiology of nephrotic syndrome

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68. Thanks