Review of Recent Literature


  • Michael J. Bloch MD,

    1. From the Department of Medicine, University of Nevada School of Medicine
    2. the Risk Reduction Center, Saint Mary’s Regional Medical Center, Reno, NV
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  • Jan N. Basile MD

    1. the Seinsheimer Cardiovascular Health Program, Division of General Internal Medicine/Geriatrics, Medical University of South Carolina
    2. the Ralph H. Johnson VA Medical Center, Charleston, SC
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Michael J. Bloch, MD, Risk Reduction Center, Saint Mary’s Regional Medical Center, 645 North Arlington Street, Suite 460, Reno, NV 89503

Existing Kidney Disease Classification Guideline Needs to Incorporate Degree of Proteinuria With Estimated Glomerular Filtration Rate to More Accurately Predict Cardiovascular and Renal Risk

Existing guidelines currently classify chronic kidney disease (CKD) into 5 stages, based almost exclusively on calculation of an estimated glomerular filtration rate (eGFR). Almost half of the 26 million Americans with CKD have stage 1 or stage 2 disease, in which the eGFR is either normal or nearly normal and CKD is defined by abnormalities detected in the urine or on renal imaging studies. Our evidence base for utilizing specific therapies and specific goals for those therapies to improve renal outcome in patients with CKD is based largely on the presence or absence of stage 3 CKD, defined as an eGFR <60 cc/min/1.73 m2 body surface area (BSA). Nowhere in the classification system is the degree of proteinuria taken into account, which may be problematic since renal functional decline and the degree of proteinuria do not always go hand-in-hand. In fact, proteinuria alone can be associated with worse cardiovascular (CV) and renal outcomes, and only 25% of Americans with proteinuria have overtly reduced eGFR (<60 mL/min/1.73 m2 BSA). Therefore, to better understand whether the current classification system may not identify individuals at higher risk for adverse CV and renal outcomes when eGFR is normal but proteinuria exists, investigators from Canada examined the association between reduced eGFR, increasing amounts of proteinuria, and adverse clinical outcomes. They hypothesized that patients with both reduced eGFR and proteinuria would be at higher risk for these outcomes than participants with one or neither of these characteristics.

A cohort of individuals 18 years or older, all of whom were covered by the Canadian government–sponsored health insurance program and received routine clinical care in the province of Alberta, were enrolled in this trial if they had at least one outpatient serum creatinine measurement and a measurement of proteinuria between May 1, 2002, and December 31, 2006. Patients were excluded if they had been treated with dialysis or had received a kidney transplant. The index or baseline eGFR for each patient, defined as the mean of all serum creatinine measurements taken within 6 months of the first creatinine measurement recorded, was estimated using the Modification of Diet in Renal Disease (MDRD) equation. Although ethnicity was not known for these individuals, the investigators went under the assumption that patients were not black (<1% of the Alberta population is black). Index eGFR was categorized as ≥60 mL/min/1.73 m2 BSA, 45 to 59.9 mL/min/1.73 m2 BSA, 30 to 44.9 mL/min/1.73 m2 BSA, or 15 to 29.9 mL/min/m2 BSA. Proteinuria was measured by urine dipstick and the albumin–creatinine ratio (ACR) was calculated based on a random outpatient spot urine measurement. In the primary analysis, all patients with at least one urine dipstick measurement were included, with proteinuria defined as normal (urine dipstick reading negative), mild (urine dipstick reading trace or 1+), or heavy (urine dipstick reading ≥2+). In the sensitivity analysis, based on the ACR, proteinuria was defined as normal (ACR <30 mg albumin/g creatinine), mild (ACR 30–300 mg albumin/g creatinine), or heavy (ACR >300 mg albumin/g creatinine). Demographic factors, socioeconomic factors, and medical history (diabetes, hypertension, and other comorbidities) were determined from the administrative data files of the provincial health ministry. Patients were followed up until study end (March 31, 2007). The primary outcome was all-cause mortality. Secondary outcomes were first hospitalization for acute myocardial infarction (MI), occurrence of end-stage renal disease (the date of registration for chronic dialysis or renal transplantation), and the occurrence of an outpatient serum creatinine measurement that was twice as high as the first creatinine measurement during the study period (corresponding to a 50% decline in renal function).

Of the 1,526,437 participants who had at least one outpatient serum creatinine measurement during the study period, 920,985 (60.3%) had at least one urine dipstick measurement and 102,701 (6.7%) had at least one ACR measurement. The majority (89%) in the primary analysis with proteinuria measurement by urine dipstick had an eGFR ≥60 mL/min/1.73 m2. During a median follow-up of 35 months, 27,959 participants (3%) died, 5772 (0.6%) were hospitalized for MI, 771 (0.08%) began chronic dialysis or received renal transplant, and 2514 (0.4%) experienced a doubling of serum creatinine. Within each stratum of eGFR, the presence of proteinuria markedly increased the risk of all 4 outcomes. Because proteinuria was such a strong predictor of risk, there was a wide variability in risk within each stratum of eGFR, depending on the presence or absence of proteinuria. For example, the adjusted mortality risk was >2-fold higher among those with heavy proteinuria and eGFR ≥60 mL/min/1.73 m2 BSA as compared with those with eGFR of 45 to 59.9 mL/min/1.73 m2 BSA and normal protein excretion (rate ratio, 2.5; 95% confidence interval [CI], 2.3–2.7). Significant interactions between eGFR and proteinuria were observed for death, initiation of renal replacement therapy, and doubling of serum creatinine, such that the additional risk of greater proteinuria was reduced at lower eGFR (all end points except MI statistically significant). The difference in risk associated with moderate or heavy proteinuria (as compared with those without proteinuria), however, appeared clinically relevant within every eGFR stratum for all 4 clinical outcomes.

Results were also consistent when analyses were restricted to the 102,701 participants who had ACR measurements performed. Risk increased progressively at levels of eGFR <60 mL/min/1.73 m2 as well as in those with mild or heavy albuminuria within all eGFR strata and for all 4 clinical outcomes. Because the current guideline for the classification of CKD describes eGFR between 60 and 90 mL/min/1.73 m2 BSA as “mildly reduced,” the investigators examined the prognostic value of proteinuria within this category (stage 2 CKD). A graded increase in the adjusted rate of all-cause mortality was seen with rates of 2.2 (95% CI, 2.1–2.3), 4.3 (95% CI, 4.1–4.6), and 5.1 (95% CI, 4.7–5.6) per 1000 person-years among those with no, mild, or heavy proteinuria, respectively (P for trend, <.001). Similar findings were seen for the outcomes of MI (rates, 1.0 [95% CI, 0.9–1.0], 1.4 [95% CI, 1.2–1.5], and 1.6 [95% CI, 1.2–1.9]; P for trend <.001); initiation of renal replacement therapy (rates, 0.02 [95% CI, 0.02–0.03], 0.04 [95% CI, 0.02–0.09] and 0.8 [95% CI, 0.5–1.3]; P for trend <.001); or doubling of serum creatinine (rates, 0.3 [95% CI, 0.3–0.4], 0.9 [95% CI, 0.7–1.1], and 2.8 [95% CI, 2.2–3.6]; P for trend <.001). When the analysis was stratified for age, findings were similar among those older compared with those younger than 65 years. In fact, the risk of all 4 clinical outcomes increased significantly in both age strata with declining eGFR (all P for trend <.001), as well as with increasing grades of proteinuria (all P for trend <.001).

The authors conclude that the risks of mortality, MI, and progression to kidney failure associated with a given level of eGFR are independently increased in patients with increasing levels of proteinuria. Future revisions of the classification system for CKD should incorporate information on proteinuria to more properly identify patients at CV and renal risk that use of eGFR alone may miss.—Hemmelgarn BR, Manns BJ, Lloyd A, et al. Relation between kidney function, proteinuria, and adverse outcomes. JAMA. 2010;303(5):423–429.


The current guidelines for the classification and staging of CKD from the National Kidney Foundation (NKF) are based on a strategy of stratifying similarly grouped individuals based on the severity of their renal disease in order to more easily identify those individuals who might benefit from specific therapies as well as earlier referral to a kidney specialist. This guideline certainly represents a major step forward in the identification and management of the renal and CV risk associated with CKD. Under the current NKF staging system outlined in the Table, CKD is defined as either an eGFR <60 mL/min/1.73 m2 or evidence of kidney damage such as abnormalities in blood tests, urine tests, or imaging studies. Under this paradigm, patients with albuminuria or proteinuria with an eGFR of at least 60 mL/min/1.73 m2 have only stage 1 or 2 CKD. Higher levels of CKD, which call for more aggressive therapy, require a further decrement in eGFR, with or without significant proteinuria. In patients with eGFR <60 mL/min/1.73 m2 (stage 3–5), the presence or absence of proteinuria does not change the stage of disease or the action recommended.

Table Table.   Stages of Chronic Kidney Disease: A Clinical Action Plan From the National Kidney Foundation
StageDescriptionGFR, mL/min per 1.73 m2Action
  1. Abbreviation: GFR, glomerular filtration rate.

1Kidney damage with normal GFR≥90Treatment of comorbid conditions; follow and prevent progression
2Kidney damage with mildly decreased GFR60–89Treatment of comorbid conditions; follow and prevent progression
3Moderately decreased GFR30–60Consider nephrology referral; identify and treat medical consequences
4Severely decreased GFR15–30Consider nephrology referral; treat medical consequences; preparation for renal replacement
5Kidney failure<15Consider renal replacement

In this large community-based cohort of adults undergoing laboratory testing in one Canadian province during a 5-year period, the prognosis associated with a given level of eGFR substantially varied with the presence and severity of proteinuria. In fact, patients with normal eGFR and heavy proteinuria had worse clinical outcomes than those with reduced eGFR but no proteinuria. These results remained consistent for two different measures of proteinuria and for several outcomes, including all-cause mortality, MI, and the need for renal replacement therapy, even after multivariable adjustment and several sensitivity analyses.

Certainly, this study does have some important limitations. These limitations include its observational nature, the fact that only those individuals that requested medical care and had a serum creatinine and urine measurement for protein were included, and the short 5-year follow-up for a disease that often takes many more years to develop and progress. In addition, there may have been important confounding variables that were not measured or included in the analysis. For example, there was no information on the degree of tobacco, alcohol, and blood pressure–lowering medication used. Of course, given the large sample size and consistency of the findings, it is unlikely that further adjustments for these covariates would have resulted in substantially different results.

These limitations aside, the findings of this important study infer that stratification to higher-risk groups (3–5) based solely on eGFR, as our current guidelines suggest, may not be an optimal strategy. For example, a patient with an eGFR of 80 mL/min/1.73 m2 BSA and 3+ proteinuria on urine dipstick or an ACR of 400 mg albumin/g creatinine would be assigned to stage 2 CKD under the current system even though, according to these data, the age-adjusted risk of death would be two times greater and risk of future renal replacement therapy 10 times higher than an age-adjusted patient with similar comorbidities and an eGFR of 50 mL/min/1.73 m2 (stage 3 CKD) but no evidence of proteinuria.

It appears that the risks of death, MI, and progression to kidney failure at any given level of eGFR are independently increased in those with concomitant proteinuria. Increased renal protein excretion, as evidenced by either a positive dipstick for urinary protein or an elevated urinary ACR, is evidence of significant kidney damage and a strong risk factor for progressive kidney disease and/or subsequent CVD events, even in nondiabetic and nonhypertensive persons. It is important to point out that the converse is also true. In patients both with and without proteinuria, a lower eGFR is also associated with increased risk.

Clearly, future guidelines should take into account both eGFR and proteinuria in risk stratification. Relying solely on eGFR to classify higher-risk patients, may overlook the substantial risk associated with proteinuria even in the setting of a relatively favorable eGFR and may lead clinicians to withhold important risk reduction strategies from these patients. Similarly, such a strategy does not recognize that in patients with lower eGFR the presence of proteinuria confers significant additional risk that should garnish the clinician’s attention. A revision to our guidelines is particularly important for the increasing number of patients who by our current paradigm have stage 3 CKD. This group likely includes a very wide range of CV and renal risk based on the wide range of included eGFR and the presence or absence of proteinuria, all of which are treated similarly according to our current guidelines. Future guidelines will need to further subdivide this group, both for treatment decisions and to define populations for studying specific interventions. While this may make the guideline more complicated for clinicians, it will at least produce consistency and more scientific validity.

Until we have further data and revisions to our guidelines, clinicians need to remain aware that the presence of clinically significant proteinuria, regardless of the stage of CKD, confers a higher risk of poor CV and renal outcomes and should be an indication for enhanced surveillance of renal function and aggressive cardiometabolic risk reduction, including strict BP control and use of an agent that blocks the renin-angiotensin-system if tolerated.