Proteinuria, albuminuria, risk, assessment, detection, elimination (PARADE): A position paper of the National Kidney Foundation

SPECIAL REPORT

Proteinuria, Albuminuria, Risk, Assessment, Detection, Elimination (PARADE): A Position Paper of the National Kidney Foundation William F. Keane, MD, and Garabed Eknoyan, MD, for the Committee* INDEX WORDS: Proteinuria, albuminuria, cardiovascular disease, renal disease, diabetes mellitus, hypertension, progression.

PREAMBLE

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ONSIDERABLE evidence, accrued over the past decade, indicates that the presence of even relatively small amounts of protein or albumin in the urine is an important early sign of kidney disease and is a strong predictor of an increased risk for cardiovascular mortality and morbidity in certain high-risk groups within the general population. The early detection of proteinuria/albuminuria and institution of appropriate therapy has been shown to slow the progression of kidney disease. Similarly, the presence of abnormal quantities of protein in the urine identifies those who are at increased risk for myocardial infarction and stroke, and intensive management of such risk factors as high blood pressure and abnormal lipids may be of great benefit to these high-risk individuals. To make this information more available to the profession and the public, the National Kidney Foundation (NKF) convened a conference titled ‘‘Proteinuria, Albuminuria, Risk, Assessment, Detection and Elimination’’ (PARADE), in Nashville, Tennessee, on March 25 and 26, 1998. Three separate panels of experts and invited participants addressed issues related to proteinuria as a risk factor for cardiovascular disease, proteinuria as a mediator and marker of progressive kidney disease, and persistent massive proteinuria as the inciting factor that leads to the nephrotic syndrome. The initial expert recommendations that were developed for the evaluation

*See page 1009 for a list of Committee members. Received and accepted as submitted January 29, 1999. Address reprint requests to Kerry Willis, PhD, National Kidney Foundation, 30 E 33rd St, New York, NY 10016. E-mail: [email protected]

娀 1999 by the National Kidney Foundation, Inc. 0272-6386/99/3305-0033$3.00/0

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and management of adults with proteinuria were presented at four Town Hall meetings in Minneapolis, Minnesota; San Antonio, Texas; Memphis, Tennessee; and Washington, DC, for additional input, comment, or further modification. These revised recommendations were submitted for review by the Scientific Advisory Board of the NKF and adopted as a position paper by the Board of Directors of the NKF at its meeting in Philadelphia on October 23, 1998. They will be submitted for review and comment to appropriate federal, medical, and public organizations before wider dissemination. In due course, a structured review of the subject will be necessary to develop guidelines. Specific recommendations for children and adolescents are in preparation. BACKGROUND

Increased urinary protein or albumin excretion (microalbuminuria) is a cardinal sign and an independent risk factor or predictor for the outcome of both kidney and cardiovascular disease (Table 1 gives definitions and indications for testing). Proteinuria may be detected as part of a routine examination or in association with other signs and symptoms of generalized or systemic illness. Occasionally, proteinuria/microalbuminuria may be transient, for example, as a result of upright position (postural proteinuria), and such findings are frequently benign. It is also recognized that a number of other clinical events can transiently increase urinary protein excretion (eg, exercise, fever, sleep apnea, or congestive heart failure), and these factors should be considered in the evaluation of the patient. However, small amounts of persistent proteinuria or microalbuminuria in any adult suggest not only the existence of renal disease, but also an increased risk for myocardial infarction and stroke.

American Journal of Kidney Diseases, Vol 33, No 5 (May), 1999: pp 1004-1010

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Indications

⬍30 mg urinary albumin/g urine creatinine on first morning urine. Albumin excretion is normally ⬍30 mg/24h or 20 µ/g/min Routine screening for protein- ⱕ ‘‘Trace’’ (ⱕ10 mg/dL) in a uria concentrated (sp gr ⱖ1.020) urine specimen

Spot albumin/creatinine ratio Assess risk of glomerulopfor microalbuminuria athy in diabetics Assess cardiovascular risk in hypertensives Routine urinalysis Dipstick testing

Normal Range

Comment

Therapy should be intensified in diabetics and hypertensives with onset of sustained microalbuminuria

False-positive test can occur if urine is very alkaline (pH ⬎8.0) or very concentrated (sp gr ⬎1.025) ‘‘Spot’’ urine protein/creatiQuantitation of proteinuria ⬍200 mg urine protein/g Simplest method to quantinine ratio urine creatinine tate proteinuria. Less accurate than measuring 24-hour proteinuria 24-hour urine for protein and Quantitation of proteinuria (as ⬍150 mg/24 h* in docuMore accurate than ‘‘spot’’ creatinine well as dietary Na, K, promented 24-hour collection† analysis. Assesses key tein, and creatinine cleardietary parameters and ances) creatinine clearance. Inconvenient for patient *Some methods have a higher range of normal. †In a urine specimen analyzed for 24-hour excretion rates, the creatinine content of the urine specimen should be measured to determine whether the specimen is truly a 24-hour collection. In adults younger than age 60 years, amount of creatinine expected in a 24-hour specimen can be estimated as follows: females, 15 to 20 mg/kg ideal body weight; males, 20 to 25 mg/kg ideal body weight. By age 80, the expected 24-hour urine creatinine is about 10 mg/kg ideal body weight in both males and females.

Testing for Proteinuria If proteinuria is detected on any evaluation of the urine, dipstick urinalysis should be repeated on at least one additional sample (first morning specimen is optimal to avoid postural proteinuria) within the next 3 months to confirm the persistence of proteinuria. In this setting, even the presence of 1⫹ reading of the dipstick must be considered potentially abnormal. If one subsequent dipstick temporally spaced by at least 1 to 2 weeks confirms the presence of proteinuria (1⫹ or greater), an attempt should then be made to quantify the amount of proteinuria (see below). Testing for Albuminuria Specific measurement of albumin in the urine (microalbuminuria) is a more accurate measurement than routine urinalysis dipstick in assessing the degree of albuminuria. The presence of microalbuminuria has been shown to be a sensitive indicator of kidney disease in patients with diabetes mellitus and in patients with hypertension. Increased urine albumin excretion appears be-

fore other measurable changes in renal function and is a marker of small blood vessel disease in the kidney and heart. Therefore, it is critical to accurately determine the presence and amount of albumin in the urine. The routine urinalysis dipstick is insensitive to albuminuria, being positive only when urinary albumin concentration reaches 30 mg/dL or greater. Levels of albumin excretion below the sensitivity of the dipstick have been referred to as microalbuminuria. Microalbuminuria is defined as urine albumin excretion between 30 and 300 mg/24 h. In diabetic patients, albuminuria greater than 300 mg/24 h is regarded as overt proteinuria. To simplify testing, a first voided, clean-catch (spot) urine can be analyzed for its albumin (mg) to creatinine (g) ratio. A ratio (albumin/creatinine) greater than 30 is considered abnormal. Microalbuminuria can be measured by various specific antibody methods or by specific urinary albumin dipsticks. Confirmation of this abnormality should be sought in one additional urine sample within the next 3 months (a first voided morning specimen is preferable). If microalbu-

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minuria is confirmed on subsequent testing, an attempt should be made to quantify the amount of albumin that is excreted in the urine. Quantification of Urinary Protein or Albumin Excretion This should be done by one of the following: ● 24-hour urine collection is the standard method (adequacy of collection should be documented by measurement of creatinine content) for analysis of urinary protein or albumin (Table 1). ● Clean, mid-stream, ‘‘spot’’ urine for measurement of protein or albumin-to-creatinine ratio is also a satisfactory method to quantitate albuminuria. The collection of a ‘‘spot’’ urine is more convenient for the patient than collecting a 24-hour urine specimen. Because of variations in 24-hour protein excretion and vagaries in collection, the ratio of a spot urine content of protein or albumin (mg) to creatinine (g) obtained under standardized conditions (first voided, morning, clean mid-stream sample) is recommended. The albumin/creatinine ratio of a ‘‘spot’’ urine usually accurately predicts the 24-hour urine excretion. Independent of proteinuria, an elevated level of serum creatinine is also an important indicator of patients at risk for progressive renal disease. When proteinuria coexists with any increase in serum creatinine (⬎1.4 mg/dL in men or ⬎1.2 mg/dL in women) or hypertension (⬎140/90 mm Hg), patients are at higher risk for loss of kidney function. In this setting, appropriate evaluations and interventions must be promptly initiated. Consultation with a nephrologist is an essential part of developing an appropriate care plan for all such patients, because therapeutic strategies are available to minimize the rate of loss of renal function. It has been clearly demonstrated that early consultation and co-management with nephrology services can reduce the cost of patient care and improve the long-term survival of those patients who ultimately require dialysis. Under any circumstance, all patients in whom persistent proteinuria or microalbuminuria is confirmed (two positive tests over a 3-month interval) should have further evaluation, including nephrology consultation. Before referral, it is ideal that the initial assessment by a primary care

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provider include a complete history, physical examination, careful assessment of blood pressure, a complete blood count, blood chemistries (eg, glucose, blood urea nitrogen, serum creatinine, albumin, and electrolytes), routine urinalysis, and quantification of urinary albumin/protein excretion. PROTEINURIA AND CARDIOVASCULAR DISEASE

The presence of small quantities of albumin in the urine (microalbuminuria) in high-risk individuals (diabetic, obese, hypertensive, family history of cardiovascular or renal disease) is now recognized as an independent risk factor or predictor of cardiovascular disease (heart attack, stroke). Microalbuminuria itself does not cause cardiovascular disease. Rather, its presence signals and identifies those individuals who will need more intensive therapy and closer followup. Thus, these patients require a more thorough assessment and intensive therapy for known cardiovascular risk factors (Figs 1, 2). Clinical situations in which albuminuria may be associated with increased adverse cardiovascular and renal events include: Diabetes mellitus Hypertension Central obesity Advanced age African Americans Hispanics Native Americans Pacific Islanders A family history of cardiovascular or renal disease The prevalence of microalbuminuria in hypertensive individuals ranges from 7% to 40%, depending on age, race, and ethnicity. The prevalence of microalbuminuria in patients with diabetes mellitus ranges from 30% to 40%. PROTEINURIA AND PROGRESSIVE KIDNEY DISEASE

In a variety of studies, proteinuria has been identified as an important and independent risk factor for the progression of renal disease. The magnitude of proteinuria is also directly correlated with risk for end-stage renal disease and the rate of progression to renal failure. The greater

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Fig 1.

Evaluation of proteinuria in the asymptomatic, healthy population.

the magnitude of proteinuria, the faster is the loss of renal function. In addition, at any given level of proteinuria, the higher the blood pressure, the more detrimental is the effect of proteinuria on progression to renal failure. This adverse association of proteinuria with loss of kidney function is especially prominent in patients with diabetes mellitus, in patients with greater than 1 g urinary protein/24 h, as well as in proteinuric renal allograft patients. Reduction in the amount of

Fig 2.

proteinuria with an angiotensin-converting enzyme inhibitor has been shown to slow the rate of loss of renal function independent of large decreases in arterial pressure. These clinical studies, together with experimental studies, support the notion that proteinuria itself is a cause of progressive kidney damage. They also suggest that the reduction of proteinuria may be used as a indicator of a therapeutic response. Therapeutic interventions that have been shown

Evaluation of proteinuria/albuminuria in patients at risk for cardiovascular and/or renal disease.

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to reduce proteinuria and slow the progression of renal disease include: ● Blood pressure control: The goal is a sitting blood pressure of less than 130/85; 125/75 mm Hg is preferable. ● Angiotensin-converting enzyme inhibitor therapy: Therapy with an angiotensin II receptor antagonist is recommended in those patients who are intolerant of angiotensinconverting enzyme inhibitors. ● Dietary salt restriction: A high-salt diet can override the antiproteinuric effects of angiotensin-converting enzyme inhibitors. Salt restriction is particularly important in hypertensive patients with proteinuria. ● Dietary protein restrictions: Moderate (0.8 g/kg body weight) restriction is recommended in proteinuric patients to assist in reducing the degree of proteinuria and probably reduce the rate of progression of renal disease. PROTEINURIA IN THE NEPHROTIC SYNDROME

Although the detrimental effects of proteinuria begin at relatively modest levels of protein excretion, the urinary loss of massive amounts of protein presents a special problem. Massive proteinuria (nephrotic-range proteinuria) is defined in the adult patient when urinary excretion is greater than 3 g protein/24 h and in children when urinary protein excretion exceeds 1 g/m2 body surface area/24 h. Most of these individuals will manifest 3⫹ to 4⫹ proteinuria by urinary dipstick measurements. Although edema may accompany this presentation, serum albumin can be within the normal range. Nephrotic-range proteinuria can occur in elderly individuals, in whom it may suggest an occult malignancy, amyloidosis, or undiagnosed diabetes mellitus. The nephrotic syndrome is defined as persistent nephrotic-range proteinuria and reduced serum albumin. These individuals develop several metabolic consequences that deserve special attention, including massive edema, hyperlipidemia, hypercoaguability, muscle wasting, hypocalcemia, and vitamin D deficiency. Additionally, they are prone to develop infectious problems that may lead to overwhelming sepsis and death. Reducing proteinuria in individuals with nephrotic-range proteinuria is important to slow

progressive loss of renal function as well as to decrease the risks associated with cardiovascular disease, such as elevated blood pressure and hyperlipidemia. All patients with the nephrotic syndrome or nephrotic-range proteinuria should be referred immediately to a nephrologist for implementation of a comprehensive diagnostic and management plan. NEPHROLOGY REFERRAL AND FOLLOW-UP

Patients with persistent proteinuria will benefit from consultation with a nephrologist. Nephrology evaluation of the patient with persistent proteinuria is likely to include estimation of glomerular filtration rate (eg, creatinine clearance), urine microscopic evaluation, renal ultrasound, serological testing for systemic disorders that can cause proteinuria (eg, hepatitis, antinuclear antibody, human immunodeficiency virus), and measurement of complement levels. A diagnostic kidney biopsy may be required for patients who have proteinuria (⬎1 g/24 h). The presence of systemic illness, hematuria, hypocomplementemia, reduced renal function, or hypertension in a proteinuric patient also may indicate the need for a renal biopsy. The histopathologic interpretation of the renal biopsy specimen should be performed by a competent nephropathologist. The nephrologist is usually expected to refer the patient back to their primary care physician with a detailed report of the findings and plan of treatment. Subsequent management of patients with persistent proteinuria and progressive renal disease should be performed jointly between the primary care physician and the nephrologist, because pharmacological treatments and immunosuppressive therapies (when needed) are complex in these patients. Thus, to ensure optimal patient outcomes, the health care team must work in close collaboration to achieve the maximal benefit to the patient. Because patients with proteinuria are at high risk for progression to end-stage renal failure, follow-up for proteinuric patients should be regular (eg, at least every 3 to 4 months) and include monitoring of proteinuria (eg, protein:creatinine ratio), dietary compliance (urine urea and sodium), assessment of blood pressure, measurement of serum albumin and serum cholesterol, and estimation of kidney function (eg, serum

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creatinine). Reduction in urinary protein excretion (eg, at least 40% to 50%) with the intent of achieving remission of proteinuria must be an important therapeutic goal. In addition, blood pressure levels of 125/70 mm Hg or lower to 130/75 mm Hg, if tolerated by the patient, should be the goal of therapy. Reduction of dietary protein and sodium intake and risk reduction management of other known cardiovascular risks (eg, smoking, lipids) are important for achieving optimal patient care. NKF PARADE COMMITTEE ● Co-Chairs:

Garabed Eknoyan, MD William F. Keane, MD ● Microalbuminuria and Cardiovascular Disease

Committee Members: Richard Grimm, MD, and Ronald Portman, MD—Co-Chairs Bruce Culleton, MD, John M. Flack, MD, MPH, James Sowers, MD ● Proteinuria and Progression of Renal Disease

Committee Members: Lee Hebert, MD, and Ronald Hogg, MD—CoChairs Lawrence Agodoa, MD, Allison Eddy, MD, Lawrence Hunsicker, MD, Bertram Kasiske, MD, Shaul Massry, MD, Dawn Milliner, MD, Giuseppe Remuzzi, MD ● Proteinuria and Nephrotic Syndrome

Committee Members: Julie Ingelfinger, MD, and George Kaysen, MD—Co-Chairs Gerald Appel, MD, Richard Glassock, MD, Robert Toto, MD ● Active Participants:

Hanna Abboud, MD, Sergio Acchiardo, MD, George Bakris, MD, Eileen Brewer, MD, Connie Breach Cranford, MS, RD, Mark Eberhardt, PhD, Frederick Kaskel, MD, Raynard Kington, MD, Saulo Klahr, MD, Bobbie Knotek, RD, Joel Kopple, MD, Vicki Lawson, MSW, Kevin Lemley, MD, William

Mitch, MD, Robert Nelson, MD, Anton Schoolwerth, MD, Gerald Schulman, MD, Gary Striker, MD, Christopher Wilcox, MD, Mark Williams, MD, James Winchester, MD SELECTED BIBLIOGRAPHY Bennett PH, Haffner S, Kasiske BL, Keane WF, Mogensen CE, Parving H-H, Steffes MW, Striker GE: Screening and management of microalbuminuria in patients with diabetes mellitus: Recommendations to the Scientific Advisory Board of the National Kidney Foundation from an Ad Hoc Committee of the Council on Diabetes Mellitus of the National Kidney Foundation. Am J Kidney Dis 25:107-112, 1995 Giatras I, Lau J, Levey AS: Effect of angiotensinconverting enzyme inhibitors on the progression of nondiabetic renal disease: A meta-analysis of randomized trials. Angiotensin-Converting-Enzyme Inhibition and Progressive Renal Disease Study Group. Ann Intern Med 127:337-345, 1997 Grimm RH, Svendsen KH, Kasiske B, Keane WF, Wahi MM: Proteinuria is a risk factor for mortality over 10 years of follow-up. MRFIT Research Group. Multiple Risk Factor Intervention Trial. Kidney Int 63:S10-S14, 1997 (suppl 63) Haffner SM, Stern MP, Gruber MK, Hazuda HP, Mitchell BD, Patterson JK: Microalbuminuria: Potential marker for increased cardiovascular risk factors in nondiabetic subjects? Arteriosclerosis 10:727-731, 1990 Heeg JE, de Jong PE, van der Hem GK, de Zeeuw D: Efficacy and variability of the antiproteinuric effect of ACE inhibition by lisinopril. Kidney Int 36:272-279, 1989 Hohage H, Kleyer U, Bruckner D, August C, Zidek W, Spieker C: Influence of proteinuria on long-term transplant survival in kidney transplant recipients. Nephron 75:160165, 1997 Hunsicker LG, Adler S, Caggiula A, England BK, Greene T, Kusek JW, Rogers NL, Teschan PE: Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study. Kidney Int 51:1908-1919, 1997 Kannel WB, Stampfer MJ, Castelli WP, Verter J: The prognostic significance of proteinuria: The Framingham Study. Am Heart J 108:1347-1352, 1984 Kasiske BL, Kalil RSN, Ma JZ, Liao M, Keane WF: Effect of antihypertensive therapy on the kidney in patients with diabetes: A meta-regression analysis. Ann Intern Med 118:129-138, 1993 Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW, Striker G: The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med 330:877-884, 1994 Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy: The Collaborative Study Group. N Engl J Med 329:1456-1462, 1993 Maschio G, Alberti D, Janin G, Locatellli F, Mann JFE, Motolese M, Ponticelli C, Ritz E, Zucchelli P, AngiotensinConverting-Enzyme Inhibition in Progressive Renal Insufficiency Group: Effect of the angiotensin-converting-enzyme

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inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 334:939-945, 1996 Massy ZA, Guijarro C, Wiederkehr MR, Ma JZ, Kasiske BL: Chronic renal allograft rejection: Immunologic and nonimmunologic risk factors. Kidney Int 49:518-524, 1996 Navis G, de Jong P, Donker AJ, van der Hem GK, de Zeeuw D: Diuretic effects of angiotensin-converting enzyme inhibition: Comparison of low and liberal sodium diet in hypertensive patients. J Cardiovasc Pharmacol 9:743-748, 1987 Navis G, de Jong PE, Donker AJ, van der Hem GK, de Zeeuw D: Moderate sodium restriction in hypertensive subjects: Renal effects of ACE-inhibition. Kidney Int 31:815819, 1987 Peddi VR, Dean DE, Hariharan S, Cavallo T, Schroeder TJ, First MR: Proteinuria following renal transplantation: Correlation with histopathology and outcome. Transplant Proc 29:101-103, 1997 Pedrini MT, Levey AS, Lau J, Chalmers TC, Wang PH: The effect of dietary protein restriction on the progression of

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diabetic and nondiabetic renal diseases: A meta-analysis. Ann Intern Med 124:627-632, 1996 Peterson JC, Adler S, Burkart JM, Greene T, Hebert LA, Hunsicker LG, King AJ, Klahr S, Massry SG, Seifter JL: Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Intern Med 123:754-762, 1995 The GISEN Group (Gruppo Italiano de Studi Epidemiologici in Nefrologia): Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 349:1857-1863, 1997 Samuelsson O, Wilhelmsen L, Elmfeldt D, Pennert K, Wedel H, Wikstrand J, Berglund G: Predictors of cardiovascular morbidity in treated hypertension: Results from the primary prevention trial in Goteborg, Sweden. J Hypertens 3:167-176, 1985 The Sixth Report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 157:2413-2446, 1997