Proteinuria and Microalbuminuria Optimum Re 2015 Charlotte A

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

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

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

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.

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

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

Normal Values Serum creatinine 0. 5 -1. 50 mg/d. L (44 -132 umol/L) Urine Creatinine 10 -300 mg/d. L Urine Total Protein 0 -30 mg/d. L (0. 3 g/L) Protein Creatinine Ratio (PCR) 0 -200 mg/g creatinine (0 -. 20 gm/gm) 24 hr. Protein 30 -150 mg/24 hr (0. 03 -0. 15 g/24 hr) GFR >90 ml/min/1. 73 m 2 (1. 5 m. L/sec/1. 73 m 2) �= SI Units

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

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

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

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

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

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.

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

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

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

“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

Formula Calculation: Protein (mg/d. L) Creatinine (mg/d. L) x 1000 mg/g

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

Microalbumin The “Mini-Me” of Albuminuria

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

Disorders Associated with Microalbuminuria Renal: § § § Diabetes mellitus Nephrotoxic drugs Bence Jones proteinuria Myoglobinuria Hemoglobinuria

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

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.

“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

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)

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

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