1. Optimum Re 2015 Charlotte A. Lee, M.D., FLMI, DBIM Proteinuria and Microalbuminuria

2. General Considerations Evidence now suggests that proteinuria has implications for all- cause mortality and cardiovascular outcomes at a general population level, not only in individuals with chronic kidney disease (CKD).

3. Risk of Proteinuria Cardiovascular risk appears to be increased even at levels of urinary protein excretion that are not considered to be pathological.* Increasing albuminuria is associated with a graded increase in risk. + *Hillege HL, Janssen WM, Bak AA, et al. Prevend Study Group Microalbuminuria is common, also in a nondiabetic, nonhypertensive population, and an independent indicator of cardiovascular risk factors and cardiovascular morbidity. J Intern Med. 2001;249(6):519–526 + Wachtell K, Ibsen H, Olsen MH, et al. Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study. Ann Intern Med. 2003;139(11):901–906

4. Risk of Proteinuria A 2010 meta-analysis of studies totaling 48,000 participants reported that the presence of microalbuminuria was associated with a future stroke risk 90% greater than that of normoalbuminuric individuals.* *Lee M, Saver JL, Chang KH, Liao HW, Chang SC, Ovbiagele B. Impact of microalbuminuria on incident stroke: a meta-analysis. Stroke. 2010;41(11):2625–2631.

5. PREVEND Study Prevention of Renal and Vascular Endstage Disease Studied over 40,000 individuals Found that a 2-fold increase the ACR (albumin-creatinine ratio) causes a 30% increase in cardiovascular mortality Hillege HL, Fidler V, Diercks GF, et al. Prevention of Renal and Vascular End Stage Disease (PREVEND) Study Group Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation. 2002;106(14):1777–1782

6. HOPE Study Heart Outcomes Prevention Evaluation Found that proteinuria was associated with adverse outcome independently of traditional cardiovascular risk factors. Gerstein HC, Mann JF, Yi Q, et al. HOPE Study Investigators Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA. 2001;286(4):421–426

7. Normal Values Serum creatinine 0.5-1.50 mg/dL (44-132 umol/L) Urine Creatinine 10-300 mg/dL Urine Total Protein 0-30 mg/dL (0.3 g/L) Protein Creatinine Ratio (PCR) 0-200mg/g creatinine (0-.20gm/gm) 24 hr. Protein 30-150 mg/24 hr (0.03-0.15g/24 hr) GFR >90 ml/min/1.73m 2 (1.5 mL/sec/1.73m 2 ) = SI Units

8. Proteinuria Normally always present in small amounts, less than 150 mg/24 hr Standard laboratory testing includes all proteins, such as albumin, globulins, peptides, any protein-containing sediment or inclusions Up to 30% of all urine protein is albumin

9. Tamm-Hosfall Protein A mucoprotein produced by the ascending limb of the loop of Henle that is a normal constituent of urine and is the major constituent of urinary casts

10. Incidental Causes of Proteinuria: Bacteria Spermatozoa WBC’s (UTI) Blood (even if no RBC’s but “heme positive”) Vaginal secretions Cellular debris Pregnancy Fever

11. Rate of urinary protein excretion may vary with: Alcohol intake Diet Hydration levels Time of day Heavy exercise Fever Reliability of the “HOS” (Home Office Specimen, UA, Urinalysis)

12. 24 hr. Urine Protein vs. Spot Collection 24 hr. collection—Inconvenient 24 hr. collection—Often unreliable due to inadequate collection Spot urine is accurate regardless of age and sex Spot urine is inexpensive and adapts to lab automation

13. Why use the PCR instead of Total Protein? Based on the fact that there is a normal acceptable range of protein excretion and there is a normal daily range of creatinine excretion over time in a given individual.

14. Urine Creatinine Based on the premise that urine creatinine (by-product of muscle metabolism) production is constant and can be used as a measure of urine concentration

15. Urine Creatinine Normal Daily Excretion 12-24 mg/kg/day in females 16-26 mg/kg/day in males Example: 135 (61kg) woman excretes ~723 —1464 mg/day ( Average = ~1000mg/day )

16. Varying Laboratory Reporting of the Normal PCR: 0-.2 mg(protein)/mg(creatinine)* 0-20 mg/dl + 0-200 mg/gm* 0-200 mcg/mg + SI units * Insurance Laboratories

17. “Spot” Urine (HOS) vs. 24-hr. collection Normal = 0-200 mg/g creatinine Estimation of 24-hr. urinary protein excretion based on calculation of the protein/creatinine ratio

18. Formula Calculation: Protein (mg/dL) Creatinine (mg/dL) x 1000 mg/g

19. Comparative Values Normal protein excretion: <150mg/24 hr. PCR of 200mg/gm is roughly 300 mg/24 hr., hence the reason for 200mg/gm being the upper limit of normal.

20. Microalbumin The “Mini-Me” of Albuminuria

21. MA—Normal Values 0-3 mg/dL (0-30 mg/L) 30-300 mg/24 hr. 0-30 mg/gm creatinine

22. Disorders Associated with Microalbuminuria Renal:  Diabetes mellitus  Nephrotoxic drugs  Bence Jones proteinuria  Myoglobinuria  Hemoglobinuria

23. Disorders Associated with Microalbuminuria Non-Renal: Atherosclerosis Lipid abnormalities Insulin resistance Hypertension Myocardial infarction

24. Microalbumin  Strokes, myocardial infarctions and peripheral vascular disease are 2 to 10 times more frequent in diabetics than non-diabetics.* *Schmitz A., et al. “Microalbuminuria: A major risk factor in non-insulin dependent diabetics. A 10 year follow-up study of 503 patients.” Diabetic Med 1988; 5:126-34.

25. “Persistent or increasing microalbuminuria indicates early diabetic nephropathy and represents a twenty-fold greater risk for the development of clinically overt renal disease in patients with IDDM and NIDDM.” Bennett, et al. Ad Hoc Committee, Council on D.M., National Kidney Foundation, 1995

26. Effect of ACE Inhibitors Lowering of blood pressure by lowering arteriolar resistance by inhibiting angiotensin I→ angiotensin II Decrease the degradation of bradykinin (a vasodilator)

27. ACE Inhibitors Aid excretion of sodium (natriuresis) Reduce the progression of diabetic nephropathy (and thus proteinuria) independently from the blood pressure-lowering effect

28. Underwriting Application When reflexed from elevated glucose, fructosamine, or glycohemoglobin: 33% >3mg/dL (>30 mg/L)* 67% 0-3 mg/dL (0-30 mg/L) *Likely to be at greater risk of complications