A Simple Urine Test Detects Rapid Kidney Function Decline

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A simple and inexpensive urine test that can be routinely performed in family physicians’ offices can help identify individuals who are silently experiencing rapid kidney function decline (RKFD), according to new research. The test could help save lives because RKFD predicts cardiovascular morbidity and mortality, but serial assessment of kidney function by measuring estimated GFR (eGFR) is not cost effective for the general population.

“Our new strategy using a simple urine dipstick allows clinicians to follow fewer patients with serial eGFR assessments to identify those with rapid kidney function decline,” said William Clark, MD, of the University of Western Ontario and London Health Sciences Centre, in London, Ontario, Canada, who was the lead author of the Journal of the American Society of Nephrology (JASN) study. “This strategy enables earlier identification of many patients with rapid kidney function decline in the general population and will potentially provide an opportunity to introduce therapy to reduce cardiovascular mortality and end stage kidney failure in this asymptomatic subgroup,” he added.

Detecting kidney decline

For the approximately 60 million people globally who have chronic kidney disease, early detection and treatment are crucial for preventing kidney failure and cardiovascular complications. Unfortunately, individuals with chronic kidney disease often do not experience symptoms until later stages of the disease. In particular, patients with RKFD are at increased risk for cardiovascular disease and mortality, even when they have only mildly reduced kidney function at baseline.

Although serial monitoring of kidney function in the general population would likely catch such silently progressing disease early, it is too expensive. Similarly, screening for proteinuria to prevent ESRD is not cost effective unless it is directed at high-risk populations.

To date, no studies have investigated the clinical utility of combining risk-factor assessment with routine screening tests to identify those at highest risk for RKFD who would benefit the most from serial eGFR assessment and early intervention.

To conduct such an investigation, Clark and his colleagues designed a prospective cohort study to identify the risk factors for RKFD and to evaluate the ability of routine screening tests for urine protein to improve the efficiency of detecting the condition across a broad range of eGFR values.

A simple test

The investigators monitored 2574 participants in a community-based clinic for an average of 7 years. They found that dipstick proteinuria (a urinary protein concentration of ≥1 g/L) had better diagnostic utility for identifying patients at risk for RKFD than did albuminuria (albumin:creatinine ratio of >2.0 mg/mmol if male or >2.8 mg/mmol if female). Although more participants were identified with albuminuria (n = 253), fewer developed RKFD (6 percent) in comparison with those identified at various thresholds of dipstick protein. Among the participants who developed RKFD,12 percent had trace or above protein; 33 percent, ≥1 g/L protein; and 40 percent, ≥3 g/L protein.

Overall, 2.5 percent of participants in the study had a urinary protein concentration of ≥1 g/L at the start of the study. If all of them were followed up with serial monitoring of kidney function, one case of RKFD would be identified for every 2.6 patients who were monitored. This decreased to 2.3 among those with cardiovascular disease, diabetes, or hypertension or who were 60 or older.

The test correctly identified whether or not individuals had RKFD in 90.8 percent of participants, mislabeled 1.5 percent as having the condition, and missed 7.7 percent who were later identified as having the condition. Among those with cardiovascular disease, diabetes, or hypertension or who were age 60 or older, the probability of identifying RKFD from serial kidney function measurements increased from 13 percent to 44 percent after the incorporation of a positive dipstick test result. Although albuminuria had greater sensitivity, particularly among persons with diabetes, a higher false-positive rate resulted in a greater number to follow up.

“This novel strategy, although not identifying all with RKFD, addresses the shortcomings of many prior studies by changing the focus from static eGFR assessment among those with eGFR below 60 mL/min per 1.73 m2 to dynamic assessment of those with eGFR above and below 60 mL/min per 1.73 m2,” Clark said.

He added that strategies that focus on identifying progressive renal disease in individuals with eGFR below 60 mL/min per 1.73 m2 identify patients later in their disease. This analysis focused on all adults, including those with eGFR above 60 mL/min per 1.73 m2, whose conditions may otherwise go undetected and yet are likely to experience greater therapeutic benefit if the disorder is identified at an earlier stage. More than 80 percent of those with RKFD in the study cohort had an eGFR above 60 mL/min per 1.73 m2.

“The paper by Clark et al is a major step forward in the ongoing search for a practical and universal Renal Risk Score that can be used to predict the likelihood of progressive renal failure and eventual end stage renal disease in subjects within the general population, in a fashion similar to the Framingham Risk Score for cardiovascular risk assessment,” said Richard Glassock, MD, who was not involved with the research and is professor emeritus at the David Geffen School of Medicine at UCLA in Los Angeles.

Next steps

The techniques described in this study should not be difficult to incorporate into the clinic, but Hiddo Lambers Heerspink, PharmD, PhD, of the University Medical Center Groningen in the Netherlands, noted that confirmation of the approach in other independent cohorts is needed before the strategy can be implemented.

“How and whom to screen for kidney disease remains an unanswered question,” said Catherine Clase, MB, FRCPC, of McMaster University in Hamilton, Ontario, Canada. “There is now little doubt that further research into screening strategies for kidney disease should, as the authors suggest, incorporate both measurement of urine protein and dynamic assessment of clearance. Dipstick proteinuria looks very attractive as a metric for assessment of proteinuria.”

Early treatment may be warranted for those who are found to have RKFD as determined by the techniques in this study, but future research is needed to assess the impact and cost effectiveness of different follow-up strategies.

“The next and much more difficult step will be show that early intervention in subjects with high Renal Risk Scores but without marked proteinuria or moderately depressed eGFR actually prevents progression and avoids end-stage renal disease,” said Glassock.