Predictive Value of Three Methods of Proteinuria Measurement in CKD Patients

Proteinuria is a marker of kidney damage, a risk factor for progression of chronic kidney disease (CKD) in patients with CKD, and a risk factor for cardiovascular events and mortality in patients with and without diabetes mellitus. The previously established gold standard for precise measurements of proteinuria is the timed 24-hour protein excretion. However, due to the inconvenience and inaccuracies associated with the 24-hour measurement, major clinical practice guidelines now recommend using a spot urine albumin-to-creatinine ratio (UACR) as first-line model in evaluating proteinuria for the diagnosis of CKD and monitoring response to treatment.

It is unclear which measure of proteinuria is most predictive of renal events in stable CKD patients. Tracey Ying, MD, and colleagues recently conducted a single-center longitudinal prospective study to examine the relationship between the three most common laboratory-based measurements of proteinuria (spot urine protein-to-creatinine ratio [UPCR], UACR, and 24-hour total protein excretion) and clinical outcomes over 5 years. The study was conducted at a tertiary care hospital in Sydney, Australia.

The researchers sought to test the hypothesis that UPCR and UACR are non-inferior to 24-hour total protein excretion in predicting clinical progression and outcomes for patients with CKD. The primary outcome of interest was a composite of death, end-stage renal disease (ESRD), or >30% decline in estimated glomerular filtration rate (eGFR). Secondary outcomes included each component of the composite outcome. Results of the study were reported in BMC Nephrology [doi.org/10.1186/s12882-018-0853-1].

At baseline in 2008-2010, 270 CKD and kidney transplant patients were enrolled in the study. Patients were instructed to perform a 24-hour collection and to collect multiple spot untimed urine samples over the 24-hour period. Baseline UPCR and UACR measurements were obtained from the morning (not first void) samples. The fresh specimens were returned to the hospital at the end of the 24-hour collection period and analysis in the hospital’s laboratory occurred within 48 hours. Of the 270 patients enrolled at baseline, 144 provided all three measurements of proteinuria and had follow-up data available; those 144 patients were included in the present study.

Mean age of the study cohort was 54 years and 58.4% were male. The most common cause of CKD was glomerulonephritis (37.5%), followed by hypertension (21.5%), and diabetic nephropathy (11.8%). Forty-two patients (29.2%) had a functioning kidney transplant at the time of study recruitment. Eighty-one participants were Caucasian (56.3%), 35 (24.3%) were Mediterranean, and 22 (15.3%) were Asian.

Median baseline eGFR, measured by the CKD-Epidemiology Collaboration equation, was 44 mL/min/1.73 m2. Of the 144 study participants, 34.7% (n=50) had microalbuminuria (3-30 mg/mmol) and 54.9% (n=70) had macroalbuminuria (>30 mg/mmol), Eighteen patients (12.5%) had nephrotic-range proteinuria (>3 g of protein excretion over 24 hours). Median protein excretion as measured by UPCR, UACR, and 24-hour protein excretion were 0.06 g/mmol, 41.9 mg/mmol, and 0.6 g/day, respectively.

Patients were followed for a mean duration of 5 years (range, 4.4-6 years). During the follow-up period, 85 patients (59%) met the primary composite outcome, including 23 patients (16%) who died.

Results of univariable analysis of log UPCR, UACR, and 24-hour protein excretion demonstrated strong evidence of association with the primary composite outcome. Following adjustment for age, eGFR, hypertension, and diabetes mellitus status, the association remained highly significant: (log-UPCR adjusted hazard ratio [HR], 1.31, 95% confidence interval [CI], 1.18-1.63, P=.001; log-UACR adjusted HR, 1.27; 95% CI, 1.11-1.23, P<.001; and log-24-hour protein excretion adjusted HR, 1.43; 95% CI, 1.20-1.78, P<.001).

In multivariable analysis, the predictive power for the primary outcome of all three baseline measures of proteinuria was similar, as was the model’s goodness-of-fit (Harrell’s C statistic with 95% CI: UPCR, 0.74 [0.69-0.81]; UACR, 0.75 [0.69-0.81]; 24-hour protein excretion, 0.75 [0.69-0.81]; and Akaike information criterion: UPCR, 671; UACR, 668; and 24-Hour protein excretion, 665).

For secondary outcomes, there was no significant association between any of the proteinuria measures and death alone. UACR and 24-hour protein excretion demonstrated marginally better association with ESRD and >30% decline in eGFR, respectively.

There were some study limitations cited by the authors, including the single-center design, the small sample size, and the majority of participants being white males. Strengths noted were the prospective design with very low numbers of loss to follow-up, limiting analysis to fresh samples, and using a standardized urine collection procedure.

“In conclusion, our study supports the current clinical practice of collecting spot UCAR or UPCR for prognostic information in patients with stable CKD with non-nephrotic range proteinuria. All three measures of proteinuria were similarly predictive of hard clinical outcomes over 5 years, defined as a composite of death, ESRD, and >30% decline in eGFR. The evidence is less certain when we consider each outcome individually. In a bid to assess the utility of UACR or UPCR as surrogate measures of hard outcomes, future research should focus on whether changes in the quantity of proteinuria over time in response to treatment or natural history is predictive of a similar change in the risk of hard outcomes,” the researchers said.

Takeaway Points

  1. A prospective longitudinal cohort study was conducted in Australia to test the hypothesis that spot urine protein-to-creatinine ratio, and spot urine to creatinine-to-creatinine ratio are non-inferior to 24-hour total protein excretion as predictors for clinical progression and outcomes for patients with chronic kidney disease (CKD).
  2. The primary outcome of interest was a composite of death, end-stage renal disease, or >30% decline in estimated glomerular filtration rate.
  3. Al three measures were predictive of the primary composite outcome; which measure best predicted the outcomes individually was less certain.