Because kidney failure commonly develops over a long period of time, researchers designing and conducting randomized trials in nephrology face specific challenges; studies that seek to examine effects on the outcome of kidney failure require substantial follow-up time.
Previous kidney trials have used changes in estimated glomerular filtration rate (eGFR) and albuminuria separately as alternative outcomes. However, there are few data available on the utility of combining change in albuminuria and change in eGFR as a surrogate for progression to kidney failure. Brendon L. Neuen, MBBS (Hons.), MSc, and colleagues conducted a study to test the hypothesis that combined changes in urinary albumin-creatinine ratio (UACR) and eGFR would predict advanced kidney disease more accurately than either measurement alone. Results of the study were reported in the American Journal of Kidney Diseases [2021;78(3):350-360].
The primary outcome of the observational cohort study was advanced CKD, defined as sustained eGFR <30 mL/min/1.73 m2. Secondary outcomes were kidney failure, cardiovascular disease, and all-cause mortality. Study participants were primary care patients gathered from the Clinical Practice Research Datalink in the United Kingdom between 2000 and 2015. Exposures were changes in UACR and eGFR (categorized as ≥30% increase, stable, or ≥30% decrease), alone and in combination, over a 3-year period.
A total of 91,319 individuals had paired UACR and eGFR assessments over an approximate 3-year esposure window. Mean interval times between UACR and eGFR assessments were 8 days at the beginning of the exposure ascertainment period and 3 days at the end of the exposure ascertainment period. Mean age of the cohort was 65.0 years, 43.4% (n=39,613) were women, and 77.7% (n=70,957) had diabetes.
Mean eGFR at baseline was 72.6 mL/min/1.73 m2, and median UACR was 9.7 mg/g. Median follow-up was 2.9 years. During follow-up, 2541 participants progressed to advanced CKD and kidney failure occurred in 379 participants. A total of 7185 developed cardiovascular disease and 9853 died.
Over the 3-year exposure window, 20.0% of participants (n=18,238) experienced a ≥30% decrease in UACR, 52.6% (n=48,008) had a stable UACR, and 27.5% (n=25,073) experienced a ≥30% increase in UACR. Four point six percent of participants (n=4246) experienced a 30% increase in eGFR, 90.3% (n=82,477) had stable eGFR, and 5.0% (n=4596) experienced a ≥30% decrease in eGFR.
Those in the group with greater increases in UACR were more likely to be older and to have a lower baseline eGFR and UACR, a history of cardiovascular disease, and more use of renin-angiotensin system (RAS) blockade and other antihypertensive medication (all P<.001). Those with greater decreases in eGFR were older, had higher baseline UACR and blood pressure, and were more likely to have a history of cardiovascular disease and greater use of RAS blockade and other antihypertensive medications (all P<.001).
There was an association between increases in UACR and greater risks of advanced CKD and kidney failure. Compared with those with stable UACR, the hazard ratios (HRs) for a ≥30% increase in UACR were 1.78 (95% confidence interval [CI], 1.59-1.98) for advanced CKD and 4.16 (95% CI, 2.74-6.32) for kidney failure. There were also associations between reductions in UACR and a decreased risk of kidney outcomes: the HRs for a ≥30% decrease in UACR were 0.77 (95% CI, 0.68-0.87) for advanced CKD and 0.46 (95% CI, 0.26-0.84) for kidney failure. There were associations between increases and decreases in UACR and greater and lesser risk of cardiovascular disease and all-cause mortality, respectively; the magnitude of those associations was smaller than those for kidney outcomes.
There were strong associations between decreases in eGFR and the risk of advanced CKD and kidney failure. The HRs for a ≥30% decrease in eGFR for advanced CKD and kidney failure were 7.53 (95% CI, 6.70-8.445) and 5.09 (95% CI, 3.27-7.92), respectively. Increases in eGFR were associated with substantially lower risk of advanced CKD and kidney failure. Decreases in eGFR were associated with a risk for cardiovascular disease and all-cause mortality that was lower than the risk for kidney outcomes. There were no associations between increases in eGFR and lower risk of cardiovascular disease. Both increases and decreases in eGFR were associated with greater risk of all-cause mortality.
Compared with participants with stable UACR and eGFR, there was an association between a combined increase in UACR and eGFR and increased risk of kidney, cardiovascular, and mortality outcomes. The magnitude of the association was greatest for kidney outcomes. Compared with participants with stable values, the HR for a combined increase in UACR and a decrease in eGFR for advanced CKD was 15.15 (95% CI, 12.43-18.46). The corresponding HR for kidney failure was 16.68 (95% CI, 7.80-35.69).
Combined changes in UACR and eGFR improved the discrimination of advanced CKD better than either alone; the magnitude of the improvement was greater when change in eGFR was added. Combined exposure changes also improved discrimination for kidney failure better than either alone. Combined changes in UACR and eGFR also provided statistically significant improvements in discrimination for cardiovascular disease and all-cause mortality; the changes were of smaller magnitude than those for kidney outcomes.
Limitations to the study cited by the authors included possible selection bias, the relatively small proportion of participants without diabetes, and very few kidney failure events.
In summary, the researchers said, “In a large-scale general population, the combination of increased UACR and decreased eGFR was strongly associated with risk of advanced CKD. Further assessment of combined changes in UACR and eGFR as an alternative outcome for kidney failure in trials of CKD progression is warranted.”
- Results of an observational cohort study to test the hypothesis that combined changes in urinary albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) predict advanced kidney disease better than either alone.
- There was a strong association between an increase in UACR and a decrease in eGFR with the risk of advanced chronic kidney disease.
- The combination of changes in UACR and eGFR predicted kidney outcomes better than either alone.