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1. Proteinuria in Adults: A Diagnostic Approach Dr.I.A.P.B.Illeperuma 15/07/2015

2. Bit of history….. Hippocrates (400 B.C.) described bubbles on the surface of the urine as indicating kidney disease and a long illness.

3. Physiology Although the glomerular filtration coefficient of albumin is small, the daily filtered load can be as much as 8 g. To prevent such massive losses of albumin, quantitative reabsorption along the proximal tubules is accomplished by “receptor”-mediated endocytosis Because of its size, albumin cannot leave the tubular lumen on the paracellular route across the tight junctions. Furthermore, albumin is not cleaved in the tubular lumen and therefore does not cross the apical membrane of the proximal tubular cell in the form of free amino acids Thus the only mechanism able to mediate albumin reabsorption is endocytosis.

4. Proteinuria The presence of abnormal quantities of protein in the urine, which may indicate damage to the kidneys. Normal urinary protein excretion - < 150mg/ 24 hours Of that 40% - Tamm – Horsfall proteins secreted by thick ascending limb of the loop of Henle 40% - Low molecular weight immunoglobulins (IgA), Urokinase , Peptide hormones 20% - Albumin Normal albumin excretion - < 30mg/ 24 hours

5. Proteinuria Microalbuminuria – Albumin excretion 30 – 300mg/ 24 hours Macroalbuminuria – Albumin excretion 300 – 3500mg/ 24 hours Nephrotic range proteinuria – Albumin excretion > 3500mg / 24h

6. Isaac Sarrabat 1600; Physician examining a urine flask. (US National Library of Medicine)

7. Detecting and Quantifying Proteinuria 1.Urine dipstick test Negative - Less than 10 mg per dL Trace - 10 to 20 mg per dL 1+ - 30 mg per dL 2+ - 100 mg per dL 3+ - 300 mg per dL 4+ - 1,000 mg per dL

8. Detecting and Quantifying Proteinuria 2. Sulfosalicylic acid (SSA) turbidity test The advantage of this easily performed test is its greater sensitivity for proteins such as Bence Jones An equal amount of 3 percent SSA is added to that specimen of urine The acidification causes precipitation of protein in the sample (seen as increasing turbidity), which is subjectively graded as trace,1+, 2+, 3+ or 4+

9. Detecting and Quantifying Proteinuria 3. Heat and Acetic Acid Test If turbidity develops add 1-2 drops of glacial acetic acid If turbidity is due to phosphate or carbonate precipitation, it will disappear with acetic acid Negative : No cloudiness Trace: Barely visible cloudiness. 1+ : Definite cloud without granular flocculation 2+ : Heavy and granular cloud without granular flocculation 3+ : Densed cloud with marked flocculation. 4+ : Thick curdy precipitation and coagulation

10. Detecting and Quantifying Proteinuria 4. 24 hour urine protein excretion 5. Urine protein creatinine ratio Determined in a random urine specimen while the person carries on normal activity Recent evidence indicates that the UPr/Cr ratio is more accurate than the 24-hour urine protein measurement. Fortunately, the ratio is about the same numerically as the number of grams of protein excreted in urine per day. Thus, a ratio of less than 0.2 is equivalent to 0.2 g of protein per day

11. Causes of proteinuria Benign Fever Strenuous exercise Acute illness Emotional stress Orthostatic proteinuria Due to increased renal blood flow

12. Causes of proteinuria False positives in dipstick testing Concentrated urine Alkaline urine (pH > 7) Gross hematuria Mucous Semen White cells

13. Pathological proteinuria Glomerular – Due to increased capillary permeability of glomerulus Glomerulonephritides – Primary or secondary Tubular – Due to decreased tubular reabsorption of filtered proteins Tubulo -interstitial diseases Overflow – Due to increased production of low molecular weight proteins Monoclonal gammopathies , Leukaemias , Lymphomas

14. Pathological proteinuria Glomerular Primary Minimal change disease Idiopathic membranous GN FSGS Membranoproliferative GN IgA nephropathy Secondary Diabetes Connective tissue disorders – Lupus nephritis Infection – Post streptococcal, Hep B Malignancy – Lymphoma, Lung cancer

15. Pathological proteinuria Tubular Hypertensive nephrosclerosis Uric acid nephropathy Heavy metals Sickle cell disease NSAIDS Hypersensitive interstitial nephritis Overflow Haemoglobinuria/ Myoglobinuria Myeloma Amyloidosis

16. Diagnostic Evaluation of Proteinuria When proteinuria is found on a dipstick urinalysis, the urinary sediment should be examined microscopically MICROSCOPIC FINDING PATHOLOGIC PROCESS Fatty casts, free fat or oval fat bodies Nephrotic range proteinuria (> 3.5 g per 24 hours) Leukocytes, leukocyte casts with bacteria Urinary tract infection Leukocytes, leukocyte casts without bacteria Renal interstitial disease Normal-shaped erythrocytes Suggestive of lower urinary tract lesion Dysmorphic erythrocytes Suggestive of upper urinary tract lesion Erythrocyte casts Glomerular disease Waxy, granular or cellular casts Advanced chronic renal disease Eosinophiluria* Suggestive of drug-induced acute interstitial nephritis Hyaline casts No renal disease; present with dehydration and with diuretic therapy * A Wright’s stain of the urine specimen is necessary to detect eosinophiluria

17. Diagnostic Evaluation of Proteinuria If urinary sediments are positive, investigate accordingly. Findings suggestive of infection on microscopic urinalysis mandate antibiotic treatment and then repeated dipstick testing If the results of microscopic urinalysis are inconclusive and the dipstick urinalysis shows trace to 2+ protein, the dipstick test should be repeated on a morning specimen at least twice during the next month If a subsequent dipstick test result is negative, the patient has transient proteinuria , which is not associated with increased morbidity and mortality, a specific follow-up is not indicated.

18. Diagnostic Evaluation of Proteinuria

19. ORTHOSTATIC PROTEINURIA This benign condition occurs in about 3 to 5 percent of adolescents and young adults which is characterized by increased protein excretion in the upright position but normal protein excretion when the patient is supine. To diagnose orthostatic proteinuria, split urine specimens are obtained for comparison. The first morning void is discarded and 16-hour daytime specimen is obtained with the patient performing normal activities and finishing the collection by voiding just before bedtime An eight-hour overnight specimen is then collected. The daytime specimen typically has an increased concentration of protein, with the nighttime specimen having a normal concentration.

20. ISOLATED PROTEINURIA A proteinuric patient with normal renal function, no evidence of systemic disease that might cause renal malfunction, normal urinary sediment and normal blood pressures is considered to have isolated proteinuria. Protein excretion is usually less than 2 g per day These patients have a 20 percent risk for renal insufficiency after 10 years and should be observed with blood pressure measurement, urinalysis and a creatinine clearance every six months

21. References American family physician online - Proteinuria in Adults: A Diagnostic Approach http://www.aafp.org/afp/2000/0915/p1333.html Medscape online - Proteinuria: Background, Pathophysiology, Etiology http://emedicine.medscape.com/article/238158-overview Harrisons Principles of Internal Medicine,18 th Edition

22. Thank you for your attention