Management of New-Onset Proteinuria in the Ambulatory Care Setting Akinlolu Ojo, MD, PhD, MBA
Urine dipstick 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
This presentation will cover the following topics Working definition of proteinuria (and albuminuria) Risk factors, frequency and clinical profile of patients presenting with proteinuria How and who should be screened for proteinuria Managing patients with proteinuria
Transient proteinuria Epidemiology 4% of men 7% of women Causes Fever Urinary tract infection Systemic infection Exercise Decompensated Congestive Heart Failure Renovascular hypertension Poor glycemic control
Components of the normal nephron
Types of proteinuria Overflow proteinuria: Capacity to reabsorb normally filtered protein in proximal tubules over whelmed due to overproduction e.g. light chains, hemoglobinuria and myoglobinuria Tubular proteinuria: Decreased reabsorption of filtered proteins by tubules due to tubulointerstitial damage, usually <2 gm/day Glomerular proteinuria: Microalbuminuria to overt proteinuria can exceed >3.5 gm/day
Types of proteinuria Type Etiology Main protein excreted in urine Test (spot urine) Glomerular Glomerular diseases; Diabetic Nephropathy; hemodynamic, tubulointerstitial disease, systemic inflammation Albumin Dipstick if >300mg/d Protein:creatinine ratio Tubular Tubulointerstitial disease Retinol binding proteins, amino acids, B2-microglobulins, Ig light chains Dipstick Proteinuria Electrophoresis Overflow Myeloma, Monoclonal gammopathies Low molecular weight proteins (Ig) Dipstick Proteinuria Electrophoresis
Definition of proteinuria Microalbuminuria refers to albumin excretion above the normal range but below the level of detection by tests for total protein. Protenuria refers albuminuria or increased urinary excretion of albumin, increased urinary excretion of other specific proteins, and increased excretion of total urine protein.
Definition of proteinuria Albumin Total Protein Parameter Normal <30 24-hour Urine (mg/day) Microalbuminuria 30-300 Albuminuria >300 ACR (mg/g) <17 (men) <25 (women) 17-250 (men) 25-355 (women) >250 (men) >355 (women) 24-Hour urine mg/day) <300 <200 Proteinuria NA NA >300 >200 NA NA PCR (mg/g) NA=Not Applicable; ACR=Albumin to Creatinine Ratio; PCR=Protein to Creatinine Ratio National Kidney Foundation. Available at: http://www.kidney.org/professionals/kdoqi/guidelines_ckd. Adapted with permission. NA NA
Frequency of proteinuria in the U.S. Test Threshold value Total # of adults (in millions) % of all US adults Increased urinary ratio of albumin/creatinine Proteinuria Microalbuminuria >30 mg/gm 20.2 11.7 >300mg/24h 18.3 10.6 30-300 mg/24h 1.9 1.1 Keane WF, Eknoyan G. Am J Kidney Dis. 1999;33(5):1004-1010
Testing for proteinuria Method Indication Comment Routine dipstick Spot Protein:Cr Screening for overt proteinuria Quantification of proteinuria Not sensitive for microalbuminuria. Not recommended Simple. Less sensitive than 24-hr urine. Useful for monitoring Spot Albumin:Cr Screening for microalbuminuria $3-11/test. Recommended
Measurement of urinary protein excretion by spot PCR ratio and 24-hr urine collection PCR = protein to creatinine ratio Ginsberg JM. S. N Engl J Med 1983; 309:1543
Testing for proteinuria Dipstick: Gives green color, does not check for light chains 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
Urine dipstick for proteinuria: False Tests Results False positive IV iodinated radiocontrast Wait for 24 hours False Negative Light chain proteins B2-microglobulins Dilute urine
Orthostatic or postural proteinuria Less than 1g/day Age <30 years 2-5% of adolescents Resolves with recumbency Empty bladder 2 hours after lying down Check first void urine Check last void urine before recumbency First void after 8-hr recumbency should be < 50mg
Exercise-induced transient proteinuria Vigorous exercise Usually less than 1g/day but can exceed 3g/day Resolves with exercise holiday (few days)
Progression of renal disease according to level of proteinuria GFR decline (ml/min/yr) 0-2 -4-6 -8-10 -12 <0.25 0.25-0.5 0.5-1.0 >1.0 Amount of urine protein (g/day) Adapted from Adler et al. Kidney Int 51:1908-1919, 1997
8192 64.5 Adjusted HR 1 2 4 8 Adjusted HR 16 Proteinuria and prognosis Outcomes Summary of Mortality: All cause & CVD Relative Risks Kidney: ESRD, AKI, Progression Exposure from egfr Continuous MDRD + Albuminuria (UACR, Dip, PCR) Meta-Analysis All models adjusted All-Cause Mortality 15 30 45 60 75 90 105 120 egfr, ml/min/1.73m^2 End Stage Renal Disease Acute Kidney Injury CKD Prognosis Consortium, Kidney Int, 2011
Adjusted HR Adjusted HR 1 2 4 8 justed HR 2 4 8 Adjusted HR 2 4 8 Adjusted HR justed HR 2 4 8 16 1 2 4 8 16 16 16 16.5 1 4 16 64 Adjusted Adjusted OR HR Adjusted OR 2561024 8192.5.5. Meta-Analysis Proteinuria and Lower egfr 15 30 45 60 75 90 105 120 egfr, ml/min/1.73m^2 Greater Renal Risk 15 1530304545606075759090105 105120 120 egfr, egfr, ml/min/1.73m^2 End Acute Stage Kidney Renal Injury Disease Acute Progressive Kidney CKD Injury.5 1 4 16 64 of mary of ks Summary of ve Risks Relative Risks <30 mg/g rom s from 15 15 30 45 60 75 90 105 120 egfr, ml/min/1.73m^2.5 16 64 256.5 1 4 16 64 1 4 All-Cause Mortality Cardiovascular M All-Cause Mortality Cardiov All-Cause Mortality >30 300 mg/g 15 15 30 30 45 45 60 6075759090105 105120 120 egfr, ml/min/1.73m^2 >300 mg/g CKD Prognosis Consortium. Lancet, 2010 & Kidney Int, 2011
Microalbuminuria compared to traditional risk factors for ischemic heart disease Relative Risk 3 2.5 N=2,085; 10 year follow-up 2 1.5 1 0.5 Borch-Johnsen K, et al. Arterioscler Thromb Vasc Biol. 1999;19(8):1992-1997.
Progression of microalbuminuria to overt cardiovascular and renal Disease Microalbuminuria Overt Proteinuria Doubling of Creatinine CV Events Death End-Stage Renal Disease
Management of persistent proteinuria Rule out orthostatic proteinuria Referral to nephrologist indicated Microscopic hematuria Presence of systemic disease ( e.g. SLE, vasculitis) Unexplained proteinuria greater than 1g/day = PCR >1000mg/g (e.g. no diabetic nephropathy) Abnormal renal function
Use of ACEI and ARB (RAAS Blocking Agents) One agent reduces proteinuria by 40% Two agents combined reduces proteinuria by 60-70% but should be limited to selected patients In early diabetic nephropathy with microalbuminuria, remission of proteinuria can occur with ACEI or ARB
ONTARGET Whether there is benefit to adding an ARB to an ACEI Randomized approx. 26,000 hypertensive patients with CAD, PVD, CVA or advanced DM Three arms: Ramipril 10 mg Telmisartan 80 mg Ramipril 10 mg plus Telmisartan 80 mg
ONTARGET and TRANSCEND Study Design and End points High-risk patients with previous vascular event or DM with target-organ damage but controlled BP and no HF Tolerate ACEI Yes No 3-week run-in ONTARGET N=25,620 3-week run-in TRANSCEND N=5,776 Telmisartan 80 mg n=7800 Ramipril 10 mg n=7800 Telmisartan 80 mg + Ramipril 10 mg n=7800 Telmisartan 80 mg n=3000 Placebo n=3000 Follow-up of 3.5 to 5.5 years Primary outcome Composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for CHF N=25,260 Am Heart J. 2004;148:52-61 (A).
Combining ACEIs and ARBs for high risk patients ONTARGET Renal Analysis Telmisartan/ramipril was associated with a higher incidence of the primary composite endpoint (death, doubling of serum creatinine or dialysis) than ramipril monotherapy The incidence of renal impairment and reduction in egfr were also greater with combination therapy Incidence of primary composite outcome (%) * 15 14.5 13.4 13.5 Incidence of renal impairment (%) 15 * 13.5 Change from baseline in egfr (ml/min/1.73 m²) 0 n=8542 n=8576 n=8502 10 10 10.6 10.2 2 2.8 5 0 n=8542 n=8576 n=8502 Telmisartan 80 mg Ramipril 10 mg Telmisartan/ramipril 80/10 mg Yusuf S, et al. N Engl J Med 2008;358:1547-59 *p<0.001, **p<0.0001 vs ramipril monotherapy egfr, estimated glomerular filtration rate 5 0 n=8542 n=8576 n=8502 4 6 4.1 ** 6.1 ** Mann J, et al. 2008
Transient proteinuria Epidemiology 4% of men 7% of women Causes Fever Urinary tract infection Systemic infection Exercise Decompensated Congestive heart failure Renovascular hypertension Poor glycemic control
Key points: Proteinuria Common incidental laboratory finding Powerful prognostic indicator for CKD progression and cardiovascular events High risk patients should be screened routinely for proteinuria Treatment almost always include ACEI or ARB Transient proteinuria is a common cause of unnecessary diagnostic work-up