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Journal of the American Society of Nephrology : JASN logoLink to Journal of the American Society of Nephrology : JASN
. 2013 Jul 5;24(10):1661–1667. doi: 10.1681/ASN.2012111118

Proteinuria and Rate of Change in Kidney Function in a Community-Based Population

Tanvir Chowdhury Turin *, Matthew James *,†, Pietro Ravani *,†, Marcello Tonelli ‡, Braden J Manns *,†, Robert Quinn *,†, Min Jun †, Scott Klarenbach ‡, Brenda R Hemmelgarn * ,‡,✉
PMCID: PMC3785273  PMID: 23833255

Abstract

Proteinuria identifies patients at risk for adverse clinical outcomes, but it is unclear whether proteinuria correlates with the rate of renal decline. We examined the association between proteinuria and rate of change in estimated GFR (eGFR) in a cohort of 638,150 adults from a province-wide registry in Alberta, Canada, who had a measure of proteinuria and three or more outpatient serum creatinine measurements over a period of ≥1 year. An adjusted sex-specific linear mixed-effects model was used to determine the rate of change in eGFR per year for patients with normal, mild, and heavy proteinuria, stratified by baseline kidney function (eGFR ≥90, 60–89.9, 45–59.9, 30–44.9, and 15–29.9 ml/min per 1.73 m2). In men, heavy proteinuria and a baseline eGFR of 45–59.9 ml/min per 1.73 m2 correlated with a change in eGFR of −2.16 (95% confidence interval [CI], −2.37 to −1.95) ml/min per 1.73 m2 per year, whereas mild proteinuria and a baseline eGFR of 30–44.9 ml/min per 1.73 m2 correlated with a change in eGFR of −0.51 (95% CI, −0.70 to −0.32) ml/min per 1.73 m2 per year. Similar trends were observed for female, elderly, and diabetic patients. Notably, normal protein levels and a lower baseline eGFR (15–29.9 ml/min per 1.73 m2) correlated with stable or improved renal function. In conclusion, our results suggest that proteinuria of increasing severity is associated with a faster rate of renal decline, regardless of baseline eGFR, and the combined effect should be considered in patients with CKD.

Reduced kidney function is a marker of adverse clinical outcomes.1,2 Emphasis has been placed on early detection and implementation of strategies to slow the diminution of kidney function, despite a limited understanding of the rate of change in kidney function and factors affecting progression. Although previous studies have examined progression of kidney function, these reports were predominantly based on selected patient populations (older adults) or involved a relatively small number of participants.3–6

The presence of proteinuria, a marker of kidney damage, identifies patients at increased risk of adverse clinical outcomes, including progression to ESRD.7–12 However, whether the effects of proteinuria on earlier signs of kidney damage, namely the rate of change in estimated GFR (eGFR), vary by baseline level of kidney function is less clear. A more detailed understanding of the relationship among proteinuria, kidney function, and progression of renal disease would permit the identification of those who are at greatest risk of a progressive decline in kidney function and aid in implementation of interventions to slow the progression or prevent the development of ESRD.

We sought to determine the association between proteinuria and rate of change in eGFR among a large cohort of individuals receiving routine care in a single Canadian province. We also evaluated whether the association between proteinuria and rate of change in eGFR varied by baseline level of kidney function, and among prespecified subgroups stratified by sex, age, and diabetic status.

Results

Participant Characteristics

A total of 638,150 participants had three or more outpatient serum creatinine measurements over a period >1 year. Of these participants, 612,776 (96.0%) had a urine dipstick measurement and 86,830 (13.6%) had a measurement of the albumin-to-creatinine ratio (ACR). Most participants had a baseline eGFR (ml/min per 1.73 m2 per year) of ≥90 (47.5%) and 89.9–60 (43.4%), whereas 6.4%, 2.0%, and 0.6% had a baseline eGFR of 45–59.9, 30–44.9, and 15–29.9, respectively. The median follow-up time was 4.4 years, during which a median of four serum creatinine measurements per patient were obtained. Among the participants, 7.7% had a follow-up of <2 years, 13.5% had a follow-up of <3 years, 18.6% had a follow-up of <4 years, and 60.1% had a follow-up of ≥4 years. As outlined in Table 1, participants without proteinuria were younger and more likely to be female. As the participants’ baseline urine protein deteriorated, the prevalence of diabetes, hypertension, and other comorbid conditions increased. Mild proteinuria was present in 7.1% of participants with proteinuria measured by urine dipstick and in 20.2% of participants with proteinuria measured by ACR. Participants who had their proteinuria measured by ACR were older, more likely to be male, and more likely to have diabetes and hypertension.

Table 1.

Demographic and clinical characteristics of participants, by level of kidney function or proteinuria

Characteristic Proteinuria Measured by Dipstick (n=612,776) Proteinuria Measured by ACR (n=86,830)
None (n=560,326) Mild (n=43,729) Heavy (n=8,711) None (n=64,680) Mild (n=17,536) Heavy (n=4,614)
Mean age (yr) ± SD 51.7±15.8 54.0±18.3 55.6±18.4 56.9±13.9 60.3±14.9 60.0±15.4
Mean eGFR (ml/min per 1.73 m2) ± SD 88.6±19.6 83.5±24.0 73.5±29.0 83.6±19.8 79.2±23.6 70.1±27.4
Female 60 51 42 47 44 40
Aboriginal 2 3 4 2 4 6
Diabetes 9 18 34 52 67 72
Hypertension 29 41 56 52 63 70
Cerebrovascular disease 2 4 7 3 5 6
PVD 1 3 5 2 4 6
CHF 2 5 9 3 7 10
Cancer 4 6 7 5 6 6
COPD 14 18 20 16 18 20
Dementia 1 2 3 1 1 1
Metastatic solid tumor 0 1 1 0 0 1
Myocardial infarction 2 4 6 4 6 8
Mild liver disease 1 1 2 1 1 2
Paralysis 0 1 1 0 1 1
PUD 2 3 3 3 3 3
Rheumatic disease 2 2 3 1 1 2
Socioeconomic status
 Pensioner 22 31 35 30 41 38
 Low 15 14 14 18 16 16
 Low with subsidy 3 5 6 4 4 7
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Unless otherwise noted, data are expressed as percentages. Totals do not always add to 100% because of rounding. Socioeconomic status was categorized as high (annual adjusted taxable family income ≥$39,250 CAD), low (annual adjusted taxable family income < $39,250 CAD), low with subsidy (receiving social assistance), and pensioners (age ≥65 years) according to government of Alberta health care insurance records. PVD, peripheral vascular disease; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; PUD, peptic ulcer disease.

Rate of Change in eGFR

The adjusted rates of change in eGFR (ml/min per 1.73 m2 per year) are shown in Figure 1 for men and Figure 2 for women. Within each stratum of eGFR, the rate of change in kidney function varied substantially according to presence and severity of proteinuria. After adjustment for sociodemographic characteristics and comorbidity, men with heavy proteinuria and baseline kidney function of 45–59.9 ml/min per 1.73 m2 had an annual rate of decline in eGFR of −2.16 (95% confidence interval [CI], −2.37 to −1.95) ml/min per 1.73 m2, whereas those with baseline kidney function of 30–44.9 ml/min per 1.73 m2 and mild proteinuria had an annual rate of change of −0.51 (95% CI, −0.70 to −0.32) ml/min per 1.73 m2. The trend was similar for women (Figure 2). However, the rate of decline among participants with heavy proteinuria was consistently greater for men than women, except for those in the lowest eGFR category (15–29.9 ml/min per 1.73 m2). Of note, among participants with a baseline eGFR of 15–29.9 ml/min per 1.73 m2, the rate of decline in kidney function was less pronounced across categories of proteinuria, although the trend of a greater rate of decline with increasing proteinuria persisted, as in other eGFR categories. Men with eGFR of 15–29.9 ml/min per 1.73 m2 and heavy proteinuria had an annual rate of change of −0.73 (95% CI, −1.00 to −0.45) ml/min per 1.73 m2. Results for women were similar.

Figure 1.

Figure 1.

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Rate of change in eGFR varied substantially across categories of proteinuria for men in every level of kidney function. Squares and horizontal bars represent the estimates and 95% CIs respectively for multivariate adusted rate of change in eGFR (ml/min per 1.73 m2 per year) of participants for various levels of kidney function status and proteinuria (measured by dipstick).

Figure 2.

Figure 2.

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Rate of change in eGFR varied substantially across categories of proteinuria for women in every level of kidney function. Squares and horizontal bars represent the estimates and 95% CIs respectively for multivariate adusted rate of change in eGFR (ml/min per 1.73 m2 per year) of participants for various levels of kidney function status and proteinuria (measured by dipstick).

Subgroup Analyses

Similar gradients in the rate of change in kidney function by level of proteinuria were observed when analyses were performed among the subset of 86,830 participants who had proteinuria estimated by urinary ACR measurements (Figures 3 and 4). Men with heavy proteinuria and baseline kidney function of 45–59.9 ml/min per 1.73 m2 had an adjusted annual rate of change in eGFR of −3.05 (95% CI, −3.40 to −2.71) ml/min per 1.73 m2, whereas those with baseline kidney function of 30–44.9 ml/min per 1.73 m2 and mild proteinuria had a rate of change of −0.63 (95% CI, −0.95 to −0.31) ml/min per 1.73 m2. Similar trends were observed for women (Figure 5). The rate of change in eGFR was greater with heavy proteinuria measured by ACR compared with that measured by dipstick proteinuria, within all eGFR strata and for both men and women.

Figure 3.

Figure 3.

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Rate of change in eGFR varied substantially across categories of proteinuria for men in every level of kidney function. Squares and horizontal bars represent the estimates and 95% CIs respectively for multivariate adusted rate of change in eGFR (ml/min per 1.73 m2 per year) of participants for various levels of kidney function status and proteinuria (measured by albumin to creatinine ratio).

Figure 4.

Figure 4.

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Rate of change in eGFR varied substantially across categories of proteinuria for men in every level of kidney function. Squares and horizontal bars represent the estimates and 95% CIs respectively for multivariate adusted rate of change in eGFR (ml/min per 1.73 m2 per year) of participants for various levels of kidney function status and proteinuria (measured by albumin to creatinine ratio).

Figure 5.

Figure 5.

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Overview of cohort formation.

We repeated analyses that further stratified by age. Findings among participants who were 65 years and older were similar to those of participants 18–64 years of age. Analysis of the subset of participants with a follow-up of 2 years or more showed similar results. Analyses stratified by presence and absence of diabetes mellitus revealed similar results, with proteinuria of increasing severity associated with a more rapid rate of decline in kidney function, across all levels of baseline kidney function. The adjusted annual rate of change in eGFR for diabetic men and women by proteinuria measured by ACR are shown in Supplemental Figures 1 and 2, respectively.

Discussion

In this population-based cohort, we observed that the rate of decline in kidney function within a given level of eGFR varied substantially according to the presence and severity of proteinuria. Persons with heavy proteinuria but without overtly abnormal eGFR had more rapid progression of kidney function than did those with moderately reduced eGFR but mild proteinuria. Within each strata of eGFR, patients with normal proteinuria experienced the lowest rate of decline in kidney function. Results were consistent for men and women, young and old, for patients with and without diabetes mellitus, and in further subgroup analyses in which proteinuria was measured by ACR and in patients with ≥2 years of follow-up.

Our study findings further emphasize the importance of considering proteinuria in classifying kidney function status.11–13 Our findings demonstrate that change in eGFR over time is relatively insensitive to assessment of kidney function alone but are highly dependent on the degree of underlying proteinuria. Although dipstick urinalysis has less favorable diagnostic properties compared with ACR for the assessment of proteinuria,14 dipstick urinalysis was the most common test used to measure proteinuria in our study population. Quantitative and semi-quantitative measurements of proteinuria, such as ACR, are preferable in the assessment of CKD,15 but dipstick urinalysis is considerably less expensive and easier to administer, and thus more widely used. Further, the consistency of the results for both urine dipstick and ACR assessment of proteinuria is reassuring.

Observations from prior studies suggest sex-specific differences in progression of CKD, pointing toward a higher rate of progression of kidney disease for men.3,16,17 On the contrary, Jafar et al.,18 in a patient-level meta-analysis of a pooled database of 11 randomized controlled trials, reported that progression of kidney disease in women was similar to that in men after correcting for baseline covariates. Similarly, in our study, we did not observe any definitive negative effect of male sex on the rate of change in eGFR.

We found that patients with normal proteinuria experienced relatively stable kidney function over time. Also, interestingly, patients with lower baseline levels of eGFR (15–29.9 mL/min per 1.73 m2) showed a trend toward stable or improved kidney function during the 4.4-year study period. Although CKD has traditionally been regarded as unremittingly progressive, our findings do not support those views and are similar to results from other recent studies. In a cohort of 3047 patients from a Norwegian clinical practice who had stage 3 CKD, Erikson and Ingebretsen reported that 27% of participants did not experience a decline in eGFR during a mean observation time of >4 years.3 Al-Aly et al. also reported that after a median observation period of 2.6 years, 38% of patients with stage 3 CKD maintained stable kidney function.19 In our study, a subset of participants with stage 3 and 4 CKD and normal proteinuria showed stable or improved kidney function.

Why would patients with lower levels of kidney function and normal or mild proteinuria experience relatively stable kidney function over time? We speculate that this may be related to several factors, including the closer follow-up and treatment that these patients receive because of their more severe kidney disease. Another factor that might be associated with this observed stable/improved kidney function is the statistical phenomenon of regression to mean, which would have the greatest effect on extreme values of eGFR. The phenomenon implies that if a variable is extreme on its first measurement, it will tend to be closer to the average on subsequent measurements,20,21 which is more likely to occur at higher levels of serum creatinine (and lower levels of eGFR). Also, the small number of participants in this group might have affected the analysis results. Importantly, however, our results add to those of prior studies by highlighting that stable kidney function, or improvements over time, occur in patients with normal proteinuria. These results identify the importance of proteinuria in predicting which patients with CKD are more likely to progress and which will have a more stable disease course.

Our study has several strengths, including the ability to study a large cohort of community-dwelling participants using multiple measurements of eGFR. We were also able to demonstrate the robustness of our results in several sensitivity analyses. However, several limitations due to the observational nature of this study also need to be considered. The cohort was limited to individuals who had at least three outpatient serum creatinine measurements over a period of at least 1 year and a measure of urinary protein. These assessments of creatinine or proteinuria were made for clinical purposes, and therefore do not include individuals who did not use medical services, which would affect the generalizability of our findings. We also did not have information on the physician who ordered the serum creatinine measurement or the indications. Because we used multiple serum creatinine measurements over time, laboratory drift over time may have influenced the study results. However, the effect of this potential laboratory drift is expected to be minimal because we calibrated measurements across time periods against a subset of healthy participants.22 Also, although we have estimated the rate of change in eGFR stratified by baseline kidney function categories, the estimation of the change in eGFR could have been affected by the baseline eGFR as a result of the statistical phenomenon of the relation between change and initial value. Although we adjusted for comorbid conditions, we could not adjust for BP control, cause of kidney disease, smoking habit, or lipid control, variables that may be associated with change in kidney function. Finally, we also could not adjust for drug use, such as use of blockers of the renin-angiotensin system, because this information is available for only a subset of the population in Alberta aged 65 years and older. Because the aim of this study was to illustrate the progression of kidney function over time in a community-based cohort, not to identify the predictors of progression, lack of information on these variables specifically would not change the overall interpretation of our study results.

In conclusion, we found that the rate of change in the kidney function associated with a given level of eGFR varies substantially according to the presence and severity of proteinuria. These findings further support information on both proteinuria and eGFR needs be considered together when identifying patients at higher rate of kidney function decline.

Concise Methods

Study Population

The Alberta Kidney Disease Network repository of laboratory data was used to create the study cohort.22 Eligible participants included adults in the province of Alberta, Canada, age 18 years or older who had at least three outpatient creatinine measurements over a period of at least 12 months in the period of May 2002 to March 2008 (Figure 5). To avoid episodes of acute renal failure, laboratory measurements associated with a hospital admission were not considered. Patients were excluded if they were treated with dialysis or a kidney transplant at baseline,23 or if the baseline eGFR was <15 ml/min per 1.73 m2.

Measurement of Kidney Function and Proteinuria

The eGFR for each participant was estimated using the CKD-Epidemiology Collaboration equation.24 Although data on race were not available from the data sources, <1% of the Alberta population is black.25 Thus, the population-level effect of eliminating race from the estimate of GFR was expected to be minimal. The first available eGFR was used to define the index (baseline) eGFR. All outpatient eGFR measurements until study end (December 31, 2009) were considered. The index eGFR (baseline kidney function) was categorized as ≥90, 60–89.9, 45–59.9, 30–44.9, and 15–29.9 ml/min per 1.73 m2.

Outpatient random spot urine dipstick and ACR measurements were used to estimate proteinuria. All outpatient urine dipstick and ACR measurements in the 6-month period around the index eGFR were used to establish baseline proteinuria. In the primary analysis, all patients with at least one urine dipstick measurement were included and proteinuria was categorized as normal (urine dipstick negative), mild (urine dipstick trace or 1+), or heavy (urine dipstick 2+).26 In sensitivity analyses, proteinuria based on ACR was used; the proteinuria categories were normal (ACR <30 mg/g), mild (ACR 30–300 mg/g), or heavy (ACR >300 mg/g).26

Covariates

Administrative data files of the provincial health ministry (Alberta Health) were used to define demographic characteristics and comorbid conditions. First Nations status was determined from the registry file; it was not possible to identify other race/ethnic groups, although >85% of the Alberta population is white.25 Socioeconomic status was categorized according to government records as high income (annual adjusted taxable family income ≥$39,250 CAD), low income (annual adjusted taxable family income <$39,250 CAD), low income with subsidy (receiving social assistance), and pensioners (≥65 years of age).27 Presence of diabetes mellitus and hypertension were identified from hospital discharge records and physician claims based on validated algorithms.28,29 Other comorbid conditions were identified from physician claims and hospitalization data using validated coding algorithms for the International Classification of Diseases, Ninth Revision, Clinical Modification, and International Classification of Diseases, Tenth Revision.30

Statistical Analyses

For the assessment of progression of kidney function across the eGFR and proteinuria levels, we determined the rate of change in eGFR in ml/min per 1.73 m2 per year, using a linear mixed-effects model regression analysis to model longitudinal change in the eGFR in association with kidney function and proteinuria categories. The mixed-effect model, with random intercepts and random slopes, estimates the rate of change in eGFR over time, taking into account the varying number and spacing of measurements of eGFR, as well as the variable follow-up for each patient. The analysis incorporated random-effects terms to account for patient and patient × time differences in the eGFR values. Covariates considered were age, sex, socioeconomic status, kidney function, proteinuria category, and comorbid conditions listed in Table 1. All variables were retained in the final model, and no criterion for removal of variables was applied.31 In addition, a term was incorporated into the model to assess interactive effects of eGFR level and proteinuria categories. Mixed-effects model assumptions, that random effects are linear and normally distributed, were examined using graphical diagnostics. Residuals were examined to ensure that they were normally distributed, and plots of residuals against predicted values and effects were examined to verify that nonlinear trends in the data were not present. We performed sex-stratified analysis because the preliminary analyses found evidence of a statistically significant interaction (P<0.01) between sex and progression of kidney function, as well as prior literature indicating that men show a more rapid decline in kidney function than women.16,32 Results are presented as the rate of change in eGFR per year.

The primary analysis was based on the cohort of participants with proteinuria defined from dipstick urinalysis. We undertook many sensitivity analyses to ensure the robustness of our results. We repeated all analyses with further stratification by age (18–64 and ≥65 years) and presence of diabetes mellitus, and among the subset of participants with a follow-up of 2 years or more. Finally, we repeated estimations for the subset of participants who had data for proteinuria based on urinary ACR. Statistical analyses were performed using SAS software, version 9.2 (SAS Institute Inc., Cary, NC) and Stata software, version 11.0 (Stata Corp., College Station, TX). The institutional review board of the University of Calgary approved the study. The institutional conjoint health research ethics review board approved the study and granted waiver of patient consent.

Supplementary Material

Supplemental Data
supp_24_10_1661__index.html (770B, html)

Acknowledgments

This study is based in part by data provided by Alberta Health and Alberta Health Services. The interpretation and conclusions are those of the researchers and do not represent the views of the government of Alberta. T.C.T. is supported by the Roy and Vi Baay Chair in Kidney Research. B.R.H., M.T., and B.J.M. are supported by AI-HS Salary Awards. B.R.H. is supported by the Roy and Vi Baay Chair in Kidney Research; M.T., by a Canada Research Chair; and M.J., by a KRESCENT new investigator award. M.J. is supported by an AIHS Fellowship Award.

Footnotes

Published online ahead of print. Publication date available at www.jasn.org.

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