To the Editor:
In healthy individuals, the kidneys filter as much as 180 L of plasma to excrete toxins and maintain salt, water, and acid-base homeostasis without excreting >100 mg of protein daily.1 Proteinuria is a cardinal sign of kidney diseases that results from either excessive permeability of the glomerular filtration barrier to proteins or impaired tubular catabolism of filtered proteins.2 Clinical practice guidelines suggest a preference of urine albumin over urine protein excretion to screen for kidney damage in adults, but some nephrologists follow urinary protein levels longitudinally, particularly when laboratories do not report albuminuria levels above a certain threshold because of the “hook” effect.3,4 Although the urine albumin to urine protein ratio (UAPR) may have diagnostic potential to distinguish certain forms of kidney diseases, its value as a biomarker of kidney disease progression has not been studied in depth.5,6 To address this, we evaluated the prognostic value of UAPR, urine albumin-to-creatinine ratio (UACR), and urine protein-to-creatinine ratio (UPCR) in 338 individuals undergoing clinically indicated native kidney biopsy from the Boston Kidney Biopsy Cohort (BKBC) Study and 2,288 individuals with common forms of chronic kidney disease (CKD) from the Chronic Renal Insufficiency Cohort (CRIC) Study. Detailed information methods of this study are described in Item S1.
Baseline characteristics of the BKBC and CRIC Study participants by tertiles and quartiles of UAPR are in Tables S1 and S2, respectively. In BKBC, the mean age was 53 ± 17 years, mean estimated glomerular filtration rate (eGFR) was 54.7 ± 34.9 mL/min/1.73 m2, and median UAPR was 0.69 [0.55-0.77]. In CRIC, the mean age was 57.0 ± 11.2 years, mean eGFR was 41.9 ± 14.7 mL/min/1.73 m2, and median UAPR was 0.50 (0.33-0.67).
During a median follow-up time of 5.0 years, 90 participants progressed to kidney failure and 128 experienced kidney disease progression in BKBC. During a median follow-up time of 7.2 years, 964 participants progressed to kidney failure and 1,170 experienced kidney disease progression in CRIC. Table 1 shows the unadjusted and multivariable adjusted associations of UAPR with each outcome in BKBC and CRIC. After multivariable adjustment, each doubling of UAPR was associated with a 1.62- and 1.62-fold increased risk of kidney failure and kidney disease progression in BKBC, respectively. Similarly, in CRIC, each doubling of UAPR was associated with a 1.44- and 1.52-fold increased risk of kidney failure and kidney disease progression, respectively. These results were qualitatively unchanged after further adjustment for urine creatinine (Table S3). The magnitude of association between UAPR and adverse clinical outcomes was stronger in participants with glomerulopathies compared with nonglomerulopathies, but the directionality of the results were the same (Table S4). Table 2 shows the performance of the Kidney Failure Risk Equation (KFRE) to predict the 5-year risk of kidney failure that incorporated UACR, UPCR, and UAPR in separate models. The KFRE that included UAPR was not superior to the model that incorporated UACR or UPCR in either cohort. The KFRE model that used UACR statistically outperformed the KFRE model using UAPR in both cohorts. Further, the KFRE model using UPCR statistically outperformed the KFRE model using UAPR in the CRIC Study.
Table 1.
Associations of UAPR With Adverse Clinical Outcomes in the BKBC Study and CRIC Study.
| Events | Model 1 HR (95% CI) | Model 2 HR (95% CI) | Model 3 HR (95% CI) | Model 4 HR (95% CI) | |
|---|---|---|---|---|---|
| BKBC Study | |||||
| Kidney failure | |||||
| Continuous (per doubling) | 90 | 1.38 (1.00-1.90) | 1.46 (1.06-2.03) | 1.35 (0.97-1.88) | 1.62 (1.15-2.27) |
| Tertile 1 | 16 | Reference | Reference | Reference | Reference |
| Tertile 2 | 31 | 1.23 (0.67-2.25) | 1.48 (0.79-2.77) | 1.26 (0.63-2.53) | 1.85 (0.91-3.76) |
| Tertile 3 | 43 | 1.77 (1.00-3.15) | 1.97 (1.10-3.53) | 1.52 (0.78-2.95) | 2.67 (1.34-5.33) |
| Kidney disease progression (composite 40% eGFR decline/kidney failure) | |||||
| Continuous (per doubling) | 128 | 1.46 (1.10-1.93) | 1.50 (1.13-1.98) | 1.48 (1.10-2.00) | 1.62 (1.21-2.19) |
| Tertile 1 | 20 | Reference | Reference | Reference | Reference |
| Tertile 2 | 45 | 1.44 (0.85-2.45) | 1.64 (0.96-2.82) | 1.70 (0.93-3.11) | 2.14 (1.16-3.95) |
| Tertile 3 | 63 | 2.26 (1.36-3.74) | 2.39 (1.44-3.97) | 2.17 (1.21-3.89) | 2.83 (1.56-5.16) |
| CRIC Study | |||||
| Kidney failure | |||||
| Continuous (per doubling) | 964 | 1.84 (1.69-2.01) | 1.77 (1.62-1.93) | 1.61 (1.47-1.76) | 1.44 (1.31-1.59) |
| Quartile 1 | 107 | Reference | Reference | Reference | Reference |
| Quartile 2 | 216 | 2.42 (1.9-3.06) | 2.34 (1.85-2.95) | 2.00 (1.58-2.53) | 1.55 (1.22-1.97) |
| Quartile 3 | 300 | 3.76 (3.01-4.68) | 3.51 (2.81-4.38) | 2.7 (2.21-3.49) | 2.02 (1.61-2.54) |
| Quartile 4 | 341 | 4.96 (3.99-6.17) | 4.52 (3.62-5.63) | 3.53 (2.81-4.43) | 2.59 (2.06-3.26) |
| Kidney disease progression (Composite 50% eGFR decline/kidney failure) | |||||
| Continuous (per doubling) | 1170 | 1.87 (1.73-2.03) | 1.82 (1.68-1.97) | 1.66 (1.53-1.80) | 1.52 (1.40-1.65) |
| Quartile 1 | 142 | Reference | Reference | Reference | Reference |
| Quartile 2 | 279 | 2.65 (2.17-3.25) | 2.62 (2.14-3.21) | 2.30 (1.87-2.83) | 1.85 (1.50-2.28) |
| Quartile 3 | 356 | 3.84 (3.16-4.67) | 3.66 (3.00-4.46) | 2.89 (2.36-3.54) | 2.27 (1.85-2.78) |
| Quartile 4 | 393 | 5.16 (4.25-6.27) | 4.83 (3.97-5.89) | 3.81 (3.10-4.67) | 2.98 (2.42-3.66) |
Notes: In the BKBC Study, Model 1 is unadjusted; Model 2 stratifies by site and adjusts for age, sex, and race; Model 3 is Model 2 and further adjusts for clinicopathologic diagnosis; and Model 4 is Model 3 and further adjusts for eGFR.
In the CRIC Study, Model 1 is unadjusted; Model 2 stratifies by clinical sites and adjusts for age, sex, and race; Model 3 is Model 1 and further adjusts for smoking, BMI, systolic BP, diabetes, CVD, hemoglobin, serum albumin, and ACEi/ARB; and Model 4 is Model 2 and further adjusts for eGFR.
Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BMI, body mass index; CI, confidence interval; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate.
Table 2.
Prediction of the 5-Year Risk of Kidney Failure by KFRE Using Different Estimations of Proteinuria.
| UACR | UPCR | UAPR | |
|---|---|---|---|
| BKBC | |||
| C-statistic | 0.85 (0.81-0.88) | 0.83 (0.79-0.87) | 0.83 (0.79-0.87) |
| AIC | 661.9 | 686.1 | 679.6 |
| P for Comparison vs UAPR | 0.03 | 0.75 | |
| CRIC | |||
| C-statistic | 0.83 (0.81-0.84) | 0.83 (0.82-0.84) | 0.77 (0.76-0.79) |
| AIC | 12,666 | 12,640 | 13,160 |
| P for Comparison vs UAPR | <0.001 | <0.001 |
Notes: Kidney failure risk equation includes age, sex, eGFR, and proteinuria value.
Abbreviations: AIC, Akaike information criterion; KFRE, kidney failure risk equation.
Clinical practice guidelines recommend screening for and monitoring albuminuria to define and stage CKD.7 In addition, models require UACR to evaluate the risk of CKD progression.6 Our prior work demonstrated that UAPR may help distinguish tubulointerstitial diseases from other forms of kidney disease, which may be helpful in the initial diagnostic work-up of CKD.5 Although studies that compare the predictive value of UACR and UPCR demonstrated similar associations with progression to kidney failure, no prior studies evaluated the associations between UAPR and future kidney failure.8 In this study, we found strong consistent associations between higher UAPR and subsequent kidney failure in individuals with common and more diverse forms of kidney diseases. However, UAPR did not improve prediction for the 5-year risk of kidney failure and was outperformed by UACR in both cohorts. These results do not support the routine measurement of both urine albumin and urine protein in all individuals with CKD to estimate the risk of CKD progression. Our findings support prior efforts to estimate UACR from UPCR for assessment of kidney failure to facilitate a single measure that will reduce unnecessary costs and increase test availability.9
Strengths of our study are the inclusion of 2 large cohorts of individuals with established kidney disease that have simultaneous measurements of urine albumin, protein, and creatinine. Several limitations warrant consideration. We excluded individuals with low levels of proteinuria (<100 mg/g) because of low correlations between UACR and UPCR as previously reported.5 Our findings may thus not be generalizable to individuals with CKD who have minimal proteinuria. Because both BKBC and CRIC are cohorts that preceded the adoption of newer kidney protective therapies, we used the KFRE, which was validated in populations before approval of newer therapies. Although lower UAPR values may suggest lower risk of adverse clinical outcomes, this should not provide false reassurance about an individual’s subsequent risk of CKD progression, and our data suggest using UACR or UPCR in current risk prediction models.
In summary, UAPR was consistently associated with higher risks of kidney disease progression independent of several clinically relevant covariates in individuals undergoing a native kidney biopsy and individuals with common forms of CKD. However, UAPR did not improve prediction of kidney failure when compared with UACR and UPCR, suggesting simultaneous measurement of urine albumin and urine protein should not be routinely performed to assess the future risk of kidney failure.
Article Information
Authors’ Contributions
Study concept and design: RJ, AA, SSW, and AS; Statistical analysis: AS, AA, JL, and SSW. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved, including with documentation in the literature if appropriate.
Support
This work was supported by National Institutes of Health (NIH) grants R01DK093574 (SSW). AS is supported by NIH grants R01DK139321, R01HL180499, K23DK120811, U01AI163081, Kidney Precision Medicine Project Opportunity Pool grant under award U2CDK114886, and the American Society of Nephrology Carl W. Gottschalk Award.
Financial Disclosure
AS reports personal fees from Horizon Therapeutics PLC, Amgen, CVS Caremark, AstraZeneca, Bayer AG, and FNIH. The remaining authors declare that they have no relevant financial interests.
Peer Review
Received March 12, 2025. Evaluated by 2 external peer reviewers, with direct editorial input from an Associate Editor and the Editor-in-Chief. Accepted in revised form June 26, 2025.
Footnotes
Item S1. Supplementary methods.
Table S1. Baseline Characteristics of BKBC Study Participants.
Table S2. Baseline Characteristics of CRIC Study Participants.
Table S3. Associations of UAPR With Adverse Clinical Outcomes After Further Adjustment for Urine Creatinine in the BKBC Study and CRIC Study.
Table S4. Associations of UAPR With Adverse Clinical Outcomes Stratified by Glomerulopathy Status in the BKBC Study.
Supplementary Material
Item S1; Tables S1-S4.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Item S1; Tables S1-S4.