Evaluation and Management of Proteinuria. Negiin Pourafshar, MD University of Virginia Division of Nephrology

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1 Evaluation and Management of Proteinuria Negiin Pourafshar, MD University of Virginia Division of Nephrology

2 Case A 30-year-old man, is turned down for life insurance because of the presence of an unspecified amount of proteinuria. His past medical history is unremarkable, and he is not taking any medications. There is no history of diabetes or hypertension. His family history is negative for diabetes or renal diseases. Pt is a cigarette smoker but does not consume alcohol or use recreational drugs. He has no voiding symptoms or anything suggestive of a systemic infectious or inflammatory condition. Physical examination reveals a blood pressure of 125/76 mm Hg. Rest of physical exam is unremarkable. there is no edema, rash, lymphadenopathy or joint inflammation. Does Pt. have serious renal disease? What investigations are needed to determine the nature and severity of the proteinuria? Evaluation of asymptomatic hematuria and proteinuria in adult primary care CMAJ Feb 5;166(3):

3 Importance of Proteinuria Marker of kidney disease Insight into etiology of kidney disease (glomerulonephritis) Prognostic indicator for severity of disease Rose BD. Pathophysiology of Renal Disease, 2nd ed, McGraw-Hill, New York p.11.

4 Which of the following is the strongest independent predictor of progression of nondiabetic chronic kidney disease to ESRD? A. Age B. Sex C. Level of proteinuria at the time of diagnosis D. Diagnosis of underlying kidney disease E. Hemoglobin concentration

5 Proteinuria Glomerular proteinuria Tubular proteinuria Overflow proteinuria Post-renal proteinuria Carrol MF and Temte JL. Proteinuria in adults: a diagnostic approach. Am Fam Physician 2000; 62:1333.

6 Carrol MF and Temte JL. Proteinuria in adults: a diagnostic approach. Am Fam Physician 2000; 62:1333.

7 Physiology of Proteinuria Normal excretion is 150 mg per 24 hr 60% is filtered plasma protein 40% are glycoproteins IgA, uromodulin 500 to 1000 mg of albumin freely filtered by glomerulus Albumin is reabsorbed by proximal tubular cells Carrol MF and Temte JL. Proteinuria in adults: a diagnostic approach. Am Fam Physician 2000; 62:1333.

8 Evaluation of Proteinuria Albuminuria Detected by urine dipsticks Detects > mg/dl; almost always (+) if urine albumin > 30 mg/dl Microalbuminuria = mg/24 hr or µg/min Quantitative assays Sulfosalicylic method: Detects all proteins, sensitivity 5-10 mg/dl Constantiner M, Sehgal AR, Humbert L, et al. A dipstick protein and specific gravity algorithm accurately predicts pathological proteinuria. Am J Kidney Dis 2005; 45:833.

9 Methods for Measurement of Protein Dip for protein Protein to creatinine ratio 24 hr urine protein Dip Scale tr mg/dl mg/dl mg/dl mg/dl mg/dl Constantiner M, Sehgal AR, Humbert L, et al. A dipstick protein and specific gravity algorithm accurately predicts pathological proteinuria. Am J Kidney Dis 2005; 45:833.

10 Sulfosalicylic Acid Test

11 An 82 yo male referred for evaluation of increased albuminuria detected on a recent spot urine MAU/Cr ratio 33 mg/g on routine f/u for diet controlled DM type 2. He takes no medications other than occasional NSAIDS for osteoarthritis. His BP is 130/65 mmhg. BMI is 20 kg/m2. His physical exam is unremarkable. The serum Cr is 0.95 mg/dl, egfr 74. A CBC is normal. Hb A1C is 5.7%. The urine dipstick shows no protein or blood. The addition of sulfosalicylic acid yields no turbidity. Which of the following is the next MOST appropriate step in this patient s management? A. Start low dose ramipril B. Check the urine protein-to-cr ratio C. Measure or estimate 24 hr Cr excretion rate D. reduce protein intake to 0.8 g/kg E. Start metformin therapy

12 Protein-creatinine ratio to estimate protein excretion Ginsberg JM, Chang BS, Matarese RA, Garella S. N Engl J Med 1983; 309:1543.

13 Categories of Proteinuria <1 gm/24, normal renal function, benign sed Orthostatic proteinuria Idiopathic transient proteinuria Intermittent proteinuria Persistent isolated 1-3 gm/24 Mild glomerular disease Tubular dysfunction >3 gm/24 Glomerular disease Possibly severe tubular dysfunction Robinson RR. Isolated proteinuria in asymptomatic patients. Kidney Int 1980; 18:395.

14 Isolated Proteinuria Excessive amount of proteinuria discovered in the urine in asymptomatic healthy individuals No past history of renal problems Urine sediment is normal Renal imaging studies are normal Urine protein excretion is <2 g/day May be persistent or transient Robinson RR. Isolated proteinuria in asymptomatic patients. Kidney Int 1980; 18:395.

15 Benign Isolated Proteinuria Functional proteinuria Associated with high fever, illness, CHF, exposure to cold, stress Disappears after stress solves Consequence of change in renal hemodynamics Does not portend renal disease Poortmans JR. Postexercise proteinuria in humans. Facts and mechanisms. JAMA 1985; 253:236.

16 Benign Isolated Proteinuria Idiopathic transient proteinuria Common in children and young adults Seen in an isolated UA but resolves on subsequent UA s Considered part of normal physiology in young patients Does not portend renal disease Robinson RR. Isolated proteinuria in asymptomatic patients. Kidney Int 1980; 18:395.

17 Benign Isolated Proteinuria Intermittent proteinuria 50% of UA s show proteinuria Usually reflects subtle glomerular or tubulointerstitial abnormalities; renal biopsy usually normal Prognosis favorable; resolves after a few years Age < 30 does not portend renal disease; age > 30, need to follow patients in clinic Robinson RR. Isolated proteinuria in asymptomatic patients. Kidney Int 1980; 18:395.

18 Benign Isolated Proteinuria Orthostatic (Postural) Proteinuria Typically in individuals less than 30 years of age No proteinuria in the early morning (provided they have been recumbent overnight) and significant proteinuria after standing for a length of time. Generally follows a benign course, most individuals experience spontaneous resolution of proteinuria and no serious sequelae after many years of follow-up Springberg PD, Garrett LE Jr, Thompson AL Jr, et al. Fixed and reproducible orthostatic proteinuria: results of a 20-year follow-up study. Ann Intern Med 1982; 97:516.

19 Nephrotic Syndrome Heavy proteinuria (protein excretion greater than 3.5 g/24 hours in an adult), Hypoalbuminemia (less than 3 g/dl) Peripheral edema Hyperlipidemia and thrombotic disease may be present Praga M, Borstein B, Andres A, et al. Nephrotic proteinuria without hypoalbuminemia: clinical characteristics and response to angiotensin-converting enzyme inhibition. Am J Kidney Dis 1991; 17:330.

20 Frances Andrus, BA, Victoria Hospital, London, Ontario

21 Nephrology Syndrome: Etiology Primary Minimal change disease Focal segmental glomerulosclerosis Membranous glomerulonephritis Membranoproliferative glomerulonephritis Secondary Diabetic glomerulonephritis in a patient with nephrotic syndrome. Systemic lupus erythematosus. Sarcoidosis, Hepatitis B, HIV, Amyloidosis, Multiple myeloma, Cancer, Drugs ( e.g. gold salts, penicillin) Haas M, Meehan SM, Karrison TG, Spargo BH. Changing etiologies of unexplained adult nephrotic syndrome: a comparison of renal biopsy findings from and Am J Kidney Dis 1997; 30:621.

22 Nephrotic Syndrome The structural abnormality shared by all nephrotic conditions or diseases with heavy proteinuria, is diffuse simplification or fusion of foot processes of glomerular visceral epithelial cells

23 Minimal Change Disease Accounts for 90 percent of cases of the nephrotic syndrome in children under the age of 10 years, and more than 50 percent of cases in older children. It also may occur in adults as an idiopathic condition, in association with the use of nonsteroidal anti-inflammatory drugs (NSAIDS), or as a paraneoplastic effect of malignancy, most often Hodgkin lymphoma. Light microscopy in this disorder is either normal or reveals only mild mesangial cell proliferation The characteristic histologic finding in minimal change disease is diffuse effacement of the epithelial cell foot processes on electron microscopy. Braden GL, Mulhern JG, O'Shea MH, et al. Changing incidence of glomerular diseases in adults. Am J Kidney Dis 2000; 35:878

24 Membranous nephropathy Among the most common cause of primary nephrotic syndrome in adults. Many cases of idiopathic membranous nephropathy may be due to autoantibodies directed against the phospholipase A2 receptor found on podocytes. Secondary causes include hepatitis B antigenemia, autoimmune diseases, thyroiditis, carcinoma, and the use of certain drugs such as gold, penicillamine, captopril, and nonsteroidal anti-inflammatory drugs. Braden GL, Mulhern JG, O'Shea MH, et al. Changing incidence of glomerular diseases in adults. Am J Kidney Dis 2000; 35:878

25 Focal Segmental Glomerulosclerosis FSGS can present as an idiopathic syndrome (primary FSGS) or may be associated with HIV infection, reflux nephropathy, healed previous glomerular injury, or massive obesity. Patients with primary FSGS typically present with the acute onset of the nephrotic syndrome, whereas slowly increasing proteinuria and renal insufficiency over time are characteristic of the secondary disorders. Collapsing FSGS is a histologic variant that is usually but not always associated with HIV infection, bisphosphonate therapy, or systemic lupus erythematosus. D'Agati V. The many masks of focal segmental glomerulosclerosis. Kidney Int 1994; 46:1223.

26 Nephrotic Syndrome W/U Exclude secondary DM SLE Amyloid Infection malignancy Medications

27 Nephrotic Syndrome W/U P/E HTN Rash, Joint stiffness Lymphadenopathy Labs/imaging UA, 24 hr urine, urine protein/cr Renal US Complements, hepatitis, HIV, SPEP/UPEP, Light chains

28 Role of kidney biopsy

29 Management of Proteinuria Therapeutic interventions include Angiotensin-converting enzyme inhibitor therapy Dietary salt restriction: particularly important in hypertensive patients with proteinuria. Dietary protein restrictions: Moderate (0.8 g/kg body weight) restriction is recommended in proteinuric patients (data is mixed) W.F. Keane, G. Eknoyan Proteinuria, Albuminuria, Risk, Assessment, Detection, and Elimination (PARADE): A position paper of the National Kidney Foundation Am J Kidney Dis, 33 (1999), pp

30 Case revisited After being denied insurance, Pt sought the attention of his family physician, who confirmed the presence of persistent proteinuria, ranging from 1+ to 3+, by the dipstick test on several occasions, with no hematuria. Urine collection confirmed the excretion of 700 mg of protein daily, with normal creatinine clearance. The results of a complete blood count and biochemistry, including fasting glucose, were unremarkable. No structural abnormalities were revealed by ultrasonography. The physician was concerned about the degree of proteinuria but reassured by the lack of systemic disease and the normal creatinine clearance. The patient was referred to a nephrologist who performed some serologic tests for various secondary causes of proteinuria. Given the modest amount of protein excretion and the stable renal function, the nephrologist elected to forgo a renal biopsy and suggested management with annual timed testing of urine and serum creatinine levels. Evaluation of asymptomatic hematuria and proteinuria in adult primary care CMAJ Feb 5;166(3):

31 What can primary care provider do? Summary The discovery of asymptomatic proteinuria, is common in general practice. With a careful history-taking, physical examination and available laboratory testing, the primary care practitioner will be able to determine both the need and urgency for referral for further investigation and management. Proteinuria is often transient and benign in nature, but fixed proteinuria may represent serious kidney disease Evaluation of asymptomatic hematuria and proteinuria in adult primary care CMAJ Feb 5;166(3):

32 Nephrology Referral Evaluation of asymptomatic hematuria and proteinuria in adult primary care CMAJ Feb 5;166(3):

33 Nephrology Referral Please obtain preliminary evaluation Patient History and Physical Exam Serial measures of kidney function UA, Urine Protein/Cr or 24 hr urine protein Renal Ultrasound Screening serology (eg, hepatitis, antinuclear antibody, human immunodeficiency virus), and measurement of complement levels ASN NKEDP primary care provider

34 Thank You Questions?

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