Independently and together, changes in estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) predict the risk of kidney and cardiovascular events and death in patients with type 2 diabetes, reports a study in a recent issue of CJASN.
“Our overall results suggest that a combined approach of determining clinically meaningful magnitudes of earlier change in both eGFR and UACR in type 2 diabetes may add substantial prognostic value to that associated with eGFR or albuminuria change alone,” concludes the report by John Chalmers, MD, PhD, of The George Institute for Global Health, University of New South Wales, Camperdown, Australia.
Based on 10-year follow-up data of nearly 9000 patients from an international randomized trial, the study suggests that assessing kidney function and albuminuria in combination might not only provide valuable information for risk stratification. “These are very simple and very good markers,” Chalmers said. “The combination should be a more potent predictor of major outcomes, especially renal outcomes, than either marker alone.”
“This paper is a nice addition to the research literature, because it monitors the effects of changes in both eGFR and UACR,” commented Kunihiro Matsushita, MD, PhD, of Johns Hopkins Bloomberg School of Public Health, Baltimore, and Director of the Chronic Kidney Disease Prognosis Consortium Data Coordinating Center.
“Although both markers have attracted attention in previous studies, this paper evaluates changes in both eGFR and UACR in the same patient population,” Matsushita added. “In terms of risk prediction, assessing changes in eGFR and UACR may provide additional information beyond the baseline values.”
Toshiaki Ohkuma, MD, PhD, of The George Institute, is lead author of the new report, on behalf of the ADVANCE Collaborative Group. Additional coauthors are Min Jun, Mark E. Cooper, Pavel Hamet, Stephen Harrap, Sophia Zoungas, Vlado Perkovic, and Mark Woodward (https://doi.org/10.2215/CJN.13391118).
Predicting DKD outcomes: Can eGFR plus UACR improve accuracy?
The researchers analyzed long-term follow-up data on participants with type 2 diabetes enrolled in the ADVANCE-ON (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation Observational) study. In that study, increases in UACR from baseline to 2 years were independently associated with an increased risk of major macrovascular events, major kidney events, or death from any cause.
Specifically, for patients with a 30% or greater increase in UACR, the hazard ratio (HR) for the primary outcome was 1.26, compared to patients with a minor change in albuminuria at 2 years. There was no reduction in risk for patients who had a decrease in UACR.
However, on analysis accounting for expected regression to the mean, the effects of a decrease in UACR become significant for the composite outcome, major cardiovascular events, and all-cause mortality, although not for major renal events. “Our results suggest that change in UACR may have important prognostic utility as a surrogate for clinically important outcomes in type 2 diabetes,” the ADVANCE-ON authors concluded (1).
The new analysis sought to address important unanswered questions: What is the prognostic impact of changes in kidney function in type 2 diabetes, and how does it relate to the predictive value of UACR? As reported in a 2004 study in JASN, nephrology has fewer randomized controlled trials providing evidence for clinical decision-making than any other internal medicine subspecialty (2).
One factor may be the slowly progressive nature of kidney disease. “We need surrogate outcomes for kidney failure, because there is very little symptomatic evidence of disease for a long time,” Chalmers said. “Often you don’t get to know kidney disease is present until the patient develops kidney failure.”
As a result, clinical trials of kidney disease use surrogate endpoints to enable studies of interventions for patients at earlier stages of kidney disease. An eGFR reduction of 40% or even 30% is now a widely used surrogate in kidney disease studies, while many studies—ADVANCE-ON among them—have evaluated change in proteinuria or albuminuria.
“There has been less interest in UACR, but this could be an important predictor as well,” Chalmers said. “Surprisingly, no one has looked at UACR and eGFR in combination.” The new analysis focused on whether the combined use of UACR and eGFR can improve accuracy in predicting major clinical outcomes, compared to either variable alone.
The study included 8766 (of 11,140) ADVANCE-ON participants with type 2 diabetes, enrolled from 215 centers in 20 countries, most in Asia or Europe. At enrollment, all were 55 years or older and at high risk of cardiovascular events.
Changes in eGFR and UACR were evaluated from baseline to 2 years. Both markers were categorized as a decrease of 40% or greater, an increase of 40% or greater, or a “minor change” of less than 40% in either direction. Ninety-three percent of patients had only a minor change in eGFR: 3% had a decrease while 4% had an increase.
Of the two predictors, changes in UACR were much more common: 29% of patients had a decrease, 34% had a minor change, and 37% had an increase. Only 108 patients—about 1%—had both a decrease in eGFR and an increase in UACR.
Over a median follow-up of 7.7 years, one or more primary outcome events occurred in 25% of patients. These included a major macrovascular event (fatal or nonfatal myocardial infarction or stroke or death from cardiovascular causes) in 16%, death from any cause in 16%, and major kidney event (renal replacement therapy or kidney death) in 1%.
On adjusted analysis, patients who had a 40% or greater decrease in eGFR from baseline to 2 years were at higher risk of the primary outcome: HR 1.58, compared to those with a minor change. For those with a 40% or greater increase in eGFR, the HR of 0.82 was not statistically significant.
Adjusted analysis also found a higher risk of the primary outcome among patients with a 40% or greater increase in UACR: HR 1.32. There was no significant reduction in risk for those with a 40% or greater decrease in UACR. “There was also a statistically significant trend for major macrovascular events alone, major kidney events alone, and all-cause mortality when considered alone,” the researchers write. Sensitivity analysis using a 30% cutoff for changes in eGFR and UACR showed a similar pattern.
The combination of decreased eGFR and increased UACR was associated with more than a twofold increase in risk of the primary outcome—HR 2.31—with evidence of an interaction between the two markers. The association was significant for all three components of the primary outcome, with HRs of 1.75 for major macrovascular events, 26.38 for major kidney events, and 3.70 for all-cause mortality.
The effects were similar on analysis using a 30% cutoff. The researchers add, “Furthermore, the addition of a combination of both change in eGFR and UACR, and their interaction term provided better prognostic information, when compared with adding any of the change individually.”
Implications for clinical monitoring and CKD surrogate outcomes
The ADVANCE-ON collaborators believe their findings have important implications for making the critical assessment of risk of cardiovascular and kidney outcomes in people with type 2 diabetes. They note that the improvements in prediction statistics were small, although statistically significant. “However,” they write, “we believe that even a modest improvement could be beneficial to prevent adverse events in these high-risk populations.”
The potential advantages of monitoring both UACR and eGFR may be especially important in primary care, where most people with type 2 diabetes are treated. “These are simple blood and urine tests that are easily monitored, if you happen to think about it,” Chalmers said. “But busy GPs see patients with such a wide variety of complaints, it’s difficult for them to track and document everything.
“That’s the sort of problem diabetes nurses and certified diabetes educators are so effective in managing. If patients have both rising UACR and falling eGFR, that’s a major signal of the need for increased attention to risk factors and therapy, or for referral to a nephrologist or diabetologist.”
Matsushita noted, “Current KDIGO guidelines recommend the use of both markers for monitoring individuals with chronic kidney disease. These findings should further encourage healthcare providers to follow guidelines for monitoring in patients with CKD, as well as other conditions including hypertension and diabetes.
“While the idea of using these markers in combination is not necessarily new, this study further supports attention to changes in eGFR and UACR together. Because both markers are independently related to outcomes, it’s important for healthcare professionals to pay attention to them.”
The ADVANCE-ON authors note some important limitations of their study, including the relatively low end stage kidney disease event rate: 0.2% per year. Strengths include the separate and combined assessment of associations with change in two clinically relevant markers, in a large and diverse population with long-term follow-up.
“There is also interest in looking at changes in kidney measures as surrogate endpoints of hard kidney endpoints,” said Matsushita. “The combination of increased albuminuria and decreased eGFR may be able to capture individuals who would develop hard kidney outcomes in the future.
“However, we need more data. The utility of the combined markers may be different for specific interventions—since, for example, we know the combination of ACEIs and ARBs can reduce albuminuria but may increase the risk of some adverse outcomes.”
In an accompanying editorial, Josef Coresh, MD, PhD, and Andrew S. Levey, MD, note that the findings “provide some support” for combined use of albuminuria and GFR, but raise several important questions that remain to be answered.
“[W]e believe that there is value in considering combinations of changes in albuminuria and GFR as surrogate end points for CKD progression,” Coresh and Levey conclude. “Subsequent studies should define when such risk prediction is clinically useful and how and when the combination of changes in ACR and eGFR can be used as an outcome for clinical trials.”
Chalmers agrees with the need for further research, especially in light of the relatively low number of ADVANCE-ON patients with major kidney events. “We need new studies with larger samples of patients with kidney disease and both rising UACR and falling eGFR.”
References
- 1.↑
Jun M , et al.. ADVANCE Collaborative Group. Changes in albuminuria and the risk of major clinical outcomes in diabetes: Results from ADVANCE-ON. Diabetes Care 2018; 41:163–170.
- 2.↑
Strippoli GF , Craig JC , Schena FP . The number, duality, and coverage of randomized controlled trials in nephrology. J Am Soc Nephrol 2004; 15:411–419.
