Testing for Chronic Kidney Disease: A Position Statement From the National Kidney Foundation

Proteinuria 

Proteinuria refers to increased excretion of any urinary protein, including albumin and other serum proteins, and proteins synthesized by the tubule (Tamm-Horsfall protein) or in the lower urinary tract. Albuminuria refers to increased excretion of albumin only. In this article, we refer to testing for proteinuria as tests for detection of proteinuria, including tests for albumin only. We refer to testing for albuminuria as tests for detection of albumin only.

Healthy individuals usually excrete a small amount of protein in the urine. Persistently increased protein excretion is usually a marker of kidney damage. The specific proteins excreted depend upon the type of kidney disease. Increased excretion of albumin is a sensitive and specific marker for CKD due to diabetes, hypertension, and glomerular diseases. Increased excretion of nonalbumin proteins in the absence of albumin occurs in some tubulointerstitial diseases associated with defective reabsorption of filtered, low molecular weight proteins. These diseases are more common in children than adults; therefore, in adults, tests for albumin are preferred because they are more sensitive and specific for the common causes of CKD. In children, tests for total urine protein are preferred, except in children with diabetes, in whom testing for albumin is preferred.

There are many options for measurement of total protein and albumin.5 The most commonly used tests measure total protein (including albumin) or albumin alone. Tests for albuminuria have higher sensitivity and specificity for kidney disease due to diabetes, hypertension, and glomerular diseases than tests for total protein but are more expensive. Assays for total protein and albumin vary across laboratories, which makes it difficult to compare results across laboratories and to determine the normal range. Assays for albumin can be standardized, but there is no “gold standard” for total urine protein, since the composition of urine protein varies among individuals.

In addition, there are multiple methods of urine collection. The 24-hour collection has been regarded as the gold standard but is difficult to implement in routine practice. Measurement of albumin or total protein concentration in a spot sample avoids the need for collection of a timed urine specimen but is affected by the state of hydration. Factoring the concentration of albumin or total protein by urine creatinine concentration (the ratio of albumin-creatinine or total protein-creatinine) eliminates this source of variation but is also affected by urine creatinine excretion rate. Some authors have suggested sex-specific thresholds for the definition of abnormal results to account for differences between men and women in creatinine excretion.9 There are also important differences according to age and race. Table 6 shows the thresholds for the definition of albuminuria and proteinuria according to collection method and sex where appropriate.5 In both adults and children, measurement of the ratio of albumin-creatinine or total protein-creatinine in a spot urine sample is recommended.5

Table 6. Definitions of Proteinuria and Albuminuria

	Urine Collection Method	Normal	Microalbuminuria	Macroalbuminuria or Clinical Proteinuria
	Total Protein
	24-hour excretion (varies with method)	<300mg/d	NA	>300mg/d
	Spot urine dipstick	<30mg/dL	NA	>30mg/dL
	Spot urine protein-creatinine ratio (varies with method)	<200mg/g	NA	>200mg/g
	Albumin
	24-hour excretion	<30mg/d	30-300 mg/d	>300mg/d
	Spot urine albumin-specific dipstick	<3mg/dL	>3 mg/dL	NA
	Spot urine albumin-creatinine ratio (varies by sex⁎)	<17mg/g(men)	17-250 mg/g (men)	>250mg/g(men)
		<25mg/g(women)	25-355 mg/g (women)	>355mg/g(women)

Abbreviation: NA, not applicable. Adapted from National Kidney Foundation KDOQI Clinical Practice Guidelines for CKD.5

⁎ Sex-specific cut-off values are from a single study. Use of the same cut-off value for men and women leads to higher values of prevalence for women than men. Current recommendations from the American Diabetes Association define cut-off values for spot urine albumin-creatinine ratio for microalbuminuria and albuminuria as 30 mg/g and 300 mg/g, respectively, without regard to sex.

Both total protein and albumin excretion can be increased transiently due to a number of factors, including urinary tract infection, hemodynamic stress (exercise, fever, and congestive heart failure) and transient metabolic perturbations (ketosis and hyperglycemia), which emphasizes the importance of repeated testing to confirm the diagnosis of CKD. Thus, to confirm persistence of proteinuria, 2 of 3 abnormal readings are required over a minimum of 3 months.6 Figure 1 shows the algorithm for sequential use of tests in adults and children.22

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Figure 1. Algorithm for the evaluation for proteinuria. Adapted with permission from Molitch et al.22

Proteinuria provides important information for evaluation and management of CKD in addition to being a marker for its identification (Table 7).23 Proteinuria is a clue to the cause of CKD (Table 5). Diabetes and other glomerular diseases are associated with higher levels of proteinuria than hypertension and other vascular diseases, tubulointerstitial diseases, or cystic diseases. In addition, regardless of cause of CKD, proteinuria is an important prognostic factor for kidney disease progression and is an indication for use of specific antihypertensive agents (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) to slow progression. Indeed, low levels of albumin (microalbuminuria) are associated with the same relative risk of progression to increased total protein (clinical proteinuria) in patients with and without diabetes.24 Some have hypothesized that proteinuria is a surrogate outcome for kidney disease progression and a target for therapy. Finally, very low levels of albuminuria (below the level defined as microalbuminuria) are associated with increased risk for cardiovascular disease.13

Table 7. Importance of Proteinuria in Chronic Kidney Disease

	Interpretation	Explanation
	1. Marker of kidney damage	Spot urine albumin-creatinine ratio >30 mg/g or spot urine total protein-creatinine ratio >200 mg/g for ≥3 months indicates CKD.
	2. Clue to the type (diagnosis) of CKD	Spot urine total protein-creatinine ratio >500-1,000 mg/g suggests diabetic kidney disease, glomerular diseases, or transplant glomerulopathy.
	3. Risk factor for adverse outcomes	Higher proteinuria predicts faster progression of kidney disease and increased risk of CVD.
	4. Effect modifier for interventions	Strict blood pressure control and ACE inhibitors or ARB are more effective in slowing kidney disease progression in patients with higher baseline proteinuria.
	5. Hypothesized surrogate outcome and target for interventions	If a decline in proteinuria is validated as a surrogate marker for interventions to slow kidney disease progression, then reducing proteinuria would be a goal of therapy.

Abbreviations: CKD, chronic kidney disease; CVD, cardiovascular disease; ACE inhibitors, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers. Adapted from the National Kidney Foundation KDOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in CKD.23

Other Markers of Kidney Damage 

Clinical judgment should determine the utility of testing for other markers of kidney damage for detection of CKD, such as imaging studies, other urine or serum markers, or biopsy of the kidney.5 For example, people with family history of polycystic kidney disease should undergo ultrasound examination to detect the presence of cysts, and people with a family history of Alport syndrome should have a urinalysis to detect hematuria. Consultation with a nephrologist is recommended if there are questions about the most appropriate tests for detection of specific diseases other than those mentioned here.

Testing for the Level of Kidney Function: GFR Estimating Equations 

GFR is considered the best overall measure of kidney function. Measurement of GFR is cumbersome and expensive, however, and is not usually performed in routine clinical practice; therefore, serum levels of endogenous filtration markers, such as creatinine, have traditionally been used to estimate GFR. Serum creatinine is limited because of variation among laboratories in assays and because its level is also affected by physiologic processes other than GFR, including generation (largely dependent on muscle mass and meat intake), proximal tubular secretion, and extrarenal elimination.15 Estimating equations incorporate creatinine in association with age, sex, race, and body size as surrogates for creatinine generation. One commonly used equation to estimate GFR, the Modification of Diet in Renal Disease (MDRD) Study equation, was developed in patients with CKD and has been re-expressed for use with standardized serum creatinine assay (Table 8).21, 25, 26, 27 The MDRD Study equation has now been evaluated in numerous populations, including African Americans, Europeans, and Asians, diabetic and nondiabetic patients with and without kidney disease, kidney transplant recipients, and potential kidney donors. These studies have shown that in American or European populations, the MDRD Study equation has reasonable accuracy in nonhospitalized patients known to have CKD, regardless of diagnosis.28 It is likely that the MDRD Study equation will not perform as well in other populations due to differences in diet or muscle mass. Two recent evaluations of the MDRD Study equation in China and Japan showed conflicting results, with the first study showing an underestimation of the measured GFR, and the second showing an overestimation.29, 30 It is not known whether these conflicting results are due to differences in creatinine assay, differences in GFR measurement procedures, or differences among populations in creatinine generation.

Table 8. Glomerular Filtration Rate Estimating Equations

	1. The original MDRD Study equation25, 26:
	GFR = 186 × Scr−1.154 × age−0.203 × 1.212 [if black] × 0.742 [if female]
	2. The “re-expressed” MDRD Study equation21 for standardized serum creatinine:
	GFR = 175 × standardized Scr−1.154 × age−0.203 × 1.212 [if black] × 0.742 [if female]
	3. Cockcroft–Gault equation27:
	Ccr = (140−age) × weight × 0.85 [if female] × 1.73/(72 Scr × BSA)

Note: Age is expressed in years; weight is expressed in kilograms; body surface area is calculated as W 0.425 × H 0.725 × 0.007184 /1.73 m2. To convert serum creatinine in mg/dL to μmol/L, multiply by 88.4. Abbreviations: MDRD, Modification of Diet in Renal Disease; Scr, serum creatinine; Ccr, creatinine clearance; BSA, body surface area.

In all populations studied so far, the MDRD Study equation has been reported to have lower accuracy in populations without kidney disease than in patients with CKD, such as young patients with type 1 diabetes without microalbuminuria or people undergoing evaluation for kidney donation.31, 32, 33 There are several possible explanations for decreased accuracy of higher GFR estimates, including (1) interlaboratory variation in the calibration of serum creatinine assay, which has a larger effect at higher GFR levels34; (2) greater biologic variation and errors in measurement of GFR at higher range of GFR; and (3) limitations of applying an equation developed in people with CKD to a population predominantly without CKD.15 The limitations discussed above are relevant for all GFR estimating equations.

The MDRD Study equation has not yet been validated in children (age less than 18 years), pregnant women, adults older than 85 years, or in some racial or ethnic subgroups in the United States, such as Asians, Native Americans, and Hispanics. Furthermore, effects of diet and medications on serum creatinine are not accounted for in the MDRD Study equation.35

Many studies have compared the performance of the MDRD Study and the Cockcroft-Gault equations (Table 8). In some of these studies, the MDRD Study equation was more accurate than the Cockcroft-Gault equation. Other studies demonstrated similar performance. The Cockcroft-Gault equation appears to be less accurate than the MDRD Study equation specifically in older and obese people.15 The Cockcroft-Gault equation has not been re-expressed for use with standardized serum creatinine assays. With planned standardization of the serum creatinine assay, GFR estimates based on the Cockcroft-Gault equation will likely routinely overestimate measured GFR and become less useful.36

Interpretation of CKD Tests 

Persistent proteinuria or reduction in GFR to below 60 mL/min/1.73 m2 (1.0 mL/s/1.73 m2) is defined as CKD. The lesser accuracy of current estimating equations at higher levels of GFR may make it difficult to interpret GFR estimates near 60 mL/min/1.73m2 (1.0 mL/s/1.73 m2) in some people. In this range, interpretation of GFR estimates depends on the results of tests for markers of kidney damage and the clinical context (Table 9). Patients with proteinuria have CKD even if GFR estimates are 60 mL/min/1.73 m2 (1.0 mL/s/1.73 m2) or greater. Patients without markers of kidney damage and with GFR estimates of 60 mL/min/1.73 m2 (1.0 mL/s/1.73 m2) or greater are unlikely to have CKD. There will be some uncertainty for patients without markers of kidney damage and with GFR estimates just below 60 mL/min/1.73 m2 (1.0 mL/s/1.73 m2). Some patients will have measured GFR less than 60 mL/min/1.73 m2 (1.0 mL/s/1.73 m2) and would therefore have CKD (a “true-positive” test result). Others may have a measured GFR above 60 mL/min/1.73 m2 (1.0 mL/s/1.73 m2) and therefore would not have CKD (a false-positive test result). Clinical interpretation and decision-making will depend on the patient’s risk for CKD. An estimated GFR of less than 60 mL/min/1.73 m2 (1.0 mL/s/1.73 m2) is more likely to be a true-positive result in a patient at increased risk for CKD (ie, a patient with hypertension, diabetes, cardiovascular disease, or a family history of CKD) than in a patient not at increased risk. Current guidelines recommend routine CKD testing in patients at increased risk for CKD. Restricting routine testing to patients at increased risk for CKD is likely to reduce false-positive results and enable more efficient use of resources.5, 6, 15, 37 In patients at increased risk for CKD and with an estimated GFR less than 60 mL/min/1.73 m2 (1.0 mL/s/1.73 m2), it is appropriate for clinicians to proceed with the CKD clinical action plan (Table 3). In patients not at increased risk for CKD and with an estimated GFR less than 60 mL/min/1.73 m2 (1.0 mL/s/1.73 m2), clinicians may decide to defer further evaluation for CKD. Nonetheless, it may be prudent to monitor estimated GFR more frequently, adjust the dosage of medications that are excreted by the kidney, and avoid medications toxic to the kidney.

Table 9. Interpretation of Chronic Kidney Disease Testing

	Marker of Kidney Damage	GFR	CKD	What to do?
	+	<60	Y	Action Plan
	+	≥60	Y	Action Plan
	−	<60	Y	Action Plan⁎
	−	≥60	N

Abbreviations: GFR, glomerular filtration rate; CKD, chronic kidney disease.

⁎ Because of bias in the MDRD Study equation in non-CKD populations, some individuals with normal measured GFR may have GFR estimates just below 60. Individual decision-making is required.

Clinical Action Plan for CKD 

CKD can be identified in most people using the 2 simple tests described above; however, the evaluation and management should be individualized according to the cause and type (pathology) of kidney disease, severity, rate of progression, and comorbid conditions. Individualized care should begin with a clinical action plan tailored to the stage of disease (Table 3). Thorough evaluation of CKD includes assessment of its severity, markers of kidney damage, cause, and complications.

Referral to Nephrologists 

Patients with CKD stage 4 should be referred to a nephrologist for co-management with their primary care physician or other specialists.5 Late nephrology referral before dialysis initiation is associated with increased morbidity and mortality.20, 38 It is thought that early planning for kidney replacement therapy and increased attention to CKD complications and cardiovascular disease risk factors may improve overall health care status; however, there are many other reasons for consultation with a nephrologist earlier in the course of disease (Table 10), such as uncertainty in diagnosis or treatment, total urine protein greater than 1 g/d, rapid GFR decline (>30% within 4 months without explanation), and difficult to control hypertension or hyperkalemia.23 In general, consultation should be sought if the clinical action cannot be prepared, or if the prescribed evaluation or the recommended treatment cannot be carried out.5 Nephrology referral may not always be appropriate for patients with terminal illnesses such as severe heart failure, liver failure, or metastatic cancer in whom care is focused on palliation with no plans for kidney replacement therapy.

Table 10. Recommendations for Referral to Specialists⁎ for Consultation and Co-Management of Chronic Kidney Disease

	Indication	Specialist
	Evaluation and management of CKD, as described in KDOQI CKD Clinical Action Plan	Kidney disease specialist (C); other specialists as appropriate (C)
	GFR <30 mL/min/1.73m2	Kidney disease specialist (B)
	Spot urine total protein-creatinine ratio >500-1000 mg/g	Kidney disease specialist (C)
	Increased risk for progression of kidney disease†	Kidney disease specialist (C)
	GFR decline >30% within 4 months without explanation	Kidney disease specialist (C)
	Hyperkalemia (serum potassium concentration >5.5 mEq/L) despite treatment	Kidney disease specialist (C)
	Resistant hypertension	Kidney disease or hypertension specialist (C)
	Difficult-to-manage drug complications	Kidney disease or hypertension specialist (C)
	Acute presentations of CVD	Cardiovascular disease specialist (C)
	Complex or severe chronic CVD conditions	Cardiovascular disease specialist (C)
	Age <18	Pediatric kidney disease specialist (C)

Note: Letters in parenthesis denote strength of recommendations. To convert GFR in mL/min/1.73m2 to mL/s/1.73m2, multiply by 0.01667; serum potassium levels expressed in mEq/L and mmol/L are equivalent. Abbreviations: CKD, chronic kidney disease; KDOQI, kidney disease outcome quality initiative; GFR, glomerular filtration rate; CVD, cardiovascular disease. Adapted from the National Kidney Foundation KDOQI Clinical Practice Guidelines on Hypertension of Antihypertensive Agents in CKD.23

⁎ Availability of specialists may vary, depending on location. † Defined as “fast” GFR decline (>4 mL/min/1.73 m2 per year) or risk factors for fast GFR decline. Short-term decline in GFR up to 30% may be seen after initiation of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and does not require referral to specialists in the absences of other indications.