1. APPROACH TO PROTENURIA Mehryar Mehrkash Pediatric Nephrologist 1

2. Protein Excretion 2 Normal range protenuria in children is : (≤4 mg/m 2 /hr ) or (<100 mg/m²/day ) or a total of 150 mg /day. Abnormal(4-40 mg/m 2 /hr) or (100< &<1000 mg/m²/day) Nephrotic(>40 mg/m 2 /h ) or ( >1 gr/m²/day ) In neonates, is higher, up to 300 mg/m²/day, because of reduced reabsorption of filtered proteins.

3. Abnormal Protein Excretion  Urinary protein excretion >100 mg/m²/day or 4 mg/m²/h is abnormal in children.  Nephrotic range proteinuria (heavy proteinuria) is Urinary protein > 40 mg/m²/hour or 1 g/m²/day > 50 mg/kg/day. 3

4. low urinary protein excretion 1. Restriction of the filtration of proteins across the glomerular capillary wall. 2. Reabsorption of freely filtered low molecular weight (LMW) proteins (< 25,000 Daltons) by the proximal tubule. 4

5. Mechanisms of protein excretion 1. Glomerular 2. Tubular 3. Overflow proteinuria 5

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10. Glomerular basal membrane 10

11. 11 tubule Normally, the larger proteins are excluded at the glomerular barrier. Smaller proteins can pass, but are mostly reabsorbed. Glomerular barrier

12. Glomerular Proteinuria Increased filtration of albumin across the glomerular capillary wall. Because of anatomical or functional (loss of anionic charge) lesions. Glomerular disease (MCD) Nonpathologic (fever, intensive exercise.. orthostatic or postural) 12

13. 13 tubule Large proteins are able to pass by the abnormal glomerular barrier.

14. Glomerular proteinuria Primary Minimal change disease Congenital nephrotic syndrome Focal segmental glomerular sclerosis IgA nephropathy (Berger's disease) Membranoproliferative glomerulonephritis Membranous nephropathy Alport syndrome 14

15. Tubular Proteinuria low molecular weight proteins such as β2- microglobulin, α1-microglobulin, and retinol-binding protein. These molecules filtered across the glomerulus and reabsorbed in the proximal tubule. Associated with other defects in proximal tubular. function( glycosuria,RTA 2, and phosphaturia). 15

16. 16 tubule Malfunctioning tubules unable to reabsorb the smaller proteins filtered at the glomerulus.

17. Tubular proteinuria Fanconi syndrome Heavy metal poisoning Acute tubular necrosis Tubulointerstitial nephritis Secondary to obstructive uropathy 17

18. Overflow Proteinuria Increased excretion of LMW proteins due to overproduction of a particular protein that exceeds tubular reabsorptive capacity. Primarily observed in adults with a plasma cell dyscrasia (multiple myeloma) Hemolysis,Rhabdomyolysis. 18

19. 19 tubule Filtered load of proteins exceeds the tubular reabsorption rate (similar to glucosuria in hyperglycemia )

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21. 21 tubule Filtered load of proteins exceeds the tubular reabsorption rate (similar to glucosuria in hyperglycemia )

22. Measurement of urinary protein The most common test Urine dipstick detect albumin. Sulfosalicylic acid test detects all proteins. Measure only the urine protein concentration. 22

23. Urine Dipstick  Measures albumin via a colorimetric reaction between albumin and tetrabromophenol blue producing different shades of green.  Dipstick testing will not detect LMW proteins. 23

24. Urinalysis Strips 24

25. Urinalysis Strips 25

26. Urinalysis Strips 26

27. Urinalysis Strips 27

28. Results Negative Trace : between 15 and 30 mg/dL 1+ : between 30 and 100 mg/dL 2+ : between 100 and 300 mg/dL 3+ : between 300 and 1000 mg/dL 4+ : >1000 mg/dL 28

29. False-Negative 29 Dilute urine (specific gravity <1005) Urinary protein is not albumin

30. False-Positive Highly concentrated urine ( SG >1025) Gross hematuria Urinary pH >7.0 Contaminated by antiseptic agents (chlorhexidine, benzalkonium chloride, hydrogen peroxide ) Phenazopyridine Iodinated radiocontrast 30

31. Quantitative Assessment Quantitative Assessment  Children with persistent dipstick-positive proteinuria must undergo a quantitative measurement of protein excretion (timed 24-hour urine collection). 31

32. Quantitative Assessment  Protein/cr ratio on a spot urine sample, in the first morning specimen.  The normal value is <0.2 in children greater than two years of age and <0.5 in infants and toddlers from 6 to 24 months. 32

33. Proteinuria in children presents in three ways 1. Transient or intermittent 2. Orthostatic 3. Persistent 33

34. Transient proteinuria Most common cause Fever, Exercise, Stress, Seizures, and Hypovolemia, or Exposure to extreme cold, act by altering renal hemodynamics. 34

35. Transient proteinuria Follow-up routinely Patient should have a repeat urinalysis on a first morning void in one year

36. Orthostatic Proteinuria Increased protein excretion in the upright position (to10-fold) which returns to normal in the supine position. Common cause of proteinuria, in adolescent boys. Generally <1 g/day. 36

37. Orthostatic Proteinuria  The disorder is uncommon over the age of 30 years.  The diagnosis by a negative dipstick on the first morning voided specimen. 37

38. Orthostatic Proteinuria A short period (15 to 20 minutes) of maximal exercise increased Pr/Cr ratios. It is wise to delay measurement, for a period of 24 hours after exercise. 38

39. Orthostatic Proteinuria A normal Pr/Cr ratio on the first morning void and dipstick-positive proteinuria on the second upright specimen indicate orthostatic proteinuria.. In transient or orthostatic proteinuria, repeat urinalysis on a first morning void in one year. 39

40. Orthostatic Proteinuria  Pathogenesis  Exaggeration normal response of transient increase protein in upright posture.  Subtle glomerular abnormalities.  Renal vein compression by aorta or superior mesenteric artery.

41. Prognosis  Benign condition, normal renal function after as long as 50 y of follow-up.  The proteinuria resolves spontaneously, being present 50 percent at 10 years and only 17 percent at 20 years. 41

42. Persistent Proteinuria Underlying renal disease 42  A positive dipstick for protein on a random U/A is. common in children aged 8-15 y (5 to 10%).  Only 0.1% of children have persistent proteinuria.

43. Persistent Proteinuria. In Glomerular and/or Parenchymal disease hematuria, red cell casts, pyuria, and/or lipiduria. RBC casts are pathognomonic for the GN. 43

44. Underlying disorder Primarily renal (glomerular and interstitial diseases) Secondary to a systemic process (infections, rheumatologic, immunologic). 44

45. EVALUATION OF PERSISTENT PROTEINURIA Examination or urine sediment CBC Renal function tests (blood urea nitrogen and creatinine) Serum electrolytes Cholesterol Albumin and total protein

46. History, physical examination History of febrile illness, intensive physical exercise or a seizure Change in urine volume or color Edema Increased BP Recent streptococcal infection Family history renal disease. hearing loss (underlying disease) 46

47. Approach If this initial evaluation is normal, the urine dipstick repeated on at least two additional specimens. If these tests are negative, the diagnosis is transient proteinuria. 47

48. Approach The simplest approach is to measure the Pr/Cr on a first morning void obtained at home. A normal Pr/Cr on the first morning void indicate Orthostatic proteinuria. Elevated Pr/Cr on both specimens indicate persistent proteinuria. 48

49. LABORATORY EVALUATION Single urine positive for protein Obtain: 1) first morning void Pr/Cr 2) UA in office Pr/Cr and UA normal Transient Proteinuria Pr/Cr normal, UA positive Orthostatic Proteinuria Both specimens abnormal Persistent Proteinuria

50. UTI Pyuria, bacteriuria, nitrites or leukocyte esterase with mild proteinuria. Proteinuria in UTI resolves with treatment of the infection. If the proteinuria persists after eradication of the infection, further work-up is indicated. 50

51. Asymptomatic Proteinuria Levels of protein excretion above the upper limits of normal for age No clinical manifestations such as edema, hematuria, oliguria, and hypertension

52. Asymptomatic Patients 52 With low-grade proteinuria (Pr/Cr 0.2-1.0) Periodic re-evaluation (every 4-6 m) Physical Exam BP U/A Cr Pr/Cr first morning urine

53. Management Avoid excessive restrictions in child’s lifestyle Dietary protein supplementation is of no benefit Salt restriction unnecessary (potentially dangerous) No indication for limitation of activity Regular follow-up

54. Symptomatic Child  General and nonspecific (fever, malaise, weight loss)  Specific (edema, HTN, renal insufficiency). 54

55. Laboratory Evaluation Renal function tests Serum electrolytes Cholesterol Albumin, total protein C3, C4, ANA, streptozyme testing, hepatitis B and C, HIV Renal ultrasound 55

56. Indications for renal biopsy  Close monitoring if urinary protein < 500 mg/m²/day before biopsy.  Assessment of BP, protein excretion, and renal function.  If any of these parameters shows evidence of progressive disease, a renal biopsy performed. 56

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58. Nephrotic syndrome 58

59. Nephrotic syndrome Heavy proteinuria (spot urine Pr/Cr ratio > 2 or than 50 mg/kg/d) Serum albumin < 3 g/dL Edema Hypercholesterolemia > 250mg 59

60. Pitting Edema 60

61. Pitting Edema 61

62. Pitting Edema 62

63. Mechanisms of glomerular injury Circulating nonimmune factors ( minimal change disease, primary FSGS). Circulating immune factors (MPGN, PSGN, lupus nephritis). Mutations in podocyte or slit diaphragm proteins (podocin, nephrin) in inherited forms of congenital, infantile, or glucocorticoid resistant nephrotic syndrome. 63

64. Classification Nephrotic Syndrome Primary : N.S in the absence of systemic disease. Secondary : N.S in the presence of systemic disease. Congenital and infantile : N.S < 1 y, primary or secondary (infection). 64

65. Clinical manifestation  Periorbital edema  The edema is gravity dependent  Over the day, periorbital edema decreases while edema of the lower extremities increases. 65

66. Severe periorbital edema 66

67. Marked Scrotal or Vulvar Edema 67

68. Anasarca  Generalized  Massive edema  Abdominal distension  Ascites 68