Even Normal-Range Albuminuria May Increase Risk of CKD Progression, Kidney Failure

Ashish Verma, MD

Credit: Ashish Verma on LinkedIn

Moderate to severe albuminuria is widely recognized as a major risk factor for adverse kidney and cardiovascular outcomes, but findings from a recent study are calling attention to the prognostic value of albuminuria within the normoalbuminuric range for predicting the risk of chronic kidney disease (CKD) progression and eventual kidney failure.¹

Results published in Annals of Internal Medicine showed increasing albuminuria was linked to excess risk of CKD progression and kidney failure even in patients with normoalbuminuria, raising questions about the optimal timing of treatment initiation for reducing protein in urine and whether lowering albumin levels further could improve health outcomes.¹

Albuminuria is widely recognized as a significant risk factor for kidney damage and eventual failure, although urine albumin–creatinine ratio (UACR) <30 mg/g is generally considered to be normal and associated with minimal risk of kidney failure or having a cardiovascular event. Risk is thought to increase with UACR, although little is known about the true risk of complications in patients with normoalbuminuria.²

“Few studies have evaluated the risk gradient for CKD progression in persons with CKD and albuminuria less than 30 mg/g,” Ashish Verma, MD, assistant professor of medicine at Boston University School of Medicine, and colleagues wrote.¹ “Enhanced understanding of the risks associated with higher levels of albuminuria in the normoalbuminuric range may help change clinical thresholds to evaluate risk or to consider lowering albuminuria to levels less than 30 mg/g with newer kidney protective therapies in persons with CKD.”

To elucidate the association between albuminuria with adverse kidney outcomes in patients with CKD and normoalbuminuria, investigators leveraged data from patients enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study with UACR <30 mg/g. A multicenter, prospective, observational cohort study, CRIC was designed to investigate the risk factors for death, cardiovascular disease, and CKD progression in individuals with mild to severe CKD. It enrolled 3939 men and women 21 - 74 years of age between June 2003 and September 2008 across 7 clinical centers in the United States.¹

UACR measurements were available for 3791 CRIC participants at their baseline study visit. Of these, 2162 had a UACR of ≥ 30 mg/g and were thus excluded from the present analysis. The remaining 1629 participants were included. Among the cohort, the mean age was 60.2 (Standard deviation, 9.6) years, 52.0% of patients were female, and 54.3% identified as White. The median UACR was 6.9 mg/g (Interquartile range, 4.0-14.2 mg/g).¹

The primary exposure was baseline UACR, calculated as a spot urine albumin concentration divided by a spot urine creatinine concentration from 24-hour urine samples. The primary outcome was CKD progression, defined as the composite of a 50% decline in eGFR, or incident kidney failure, defined as the initiation of dialysis therapy or kidney transplantation, whichever came first. The secondary outcome was kidney failure. Participants were followed up until the occurrence of death, study withdrawal, loss to follow-up, or January 30, 2018.¹

Over a median follow-up of 9.8 years, 182 (11%) participants experienced CKD progression. The 10-year adjusted cumulative incidences of CKD progression were 8.7% (95% CI, 5.9%-11.6%) for UACR levels of 0 to < 5 mg/g, 11.5% (95% CI, 8.8%-14.3%) for 5 to < 15 mg/g, and 19.5% (95% CI, 15.4%-23.5%) for ≥ 15 mg/g. Investigators compared persons with UACR ≥ 15 mg/g to those with UACR 5 to < 15 mg/g and 0 to < 5 mg/g and found the absolute risk differences were 7.9% (95% CI, 3.0%-12.7%) and 10.7% (95% CI, 5.8%-15.6%), respectively.¹

The 10-year adjusted cumulative incidences of kidney failure were 3.8% (CI, 1.8% to 5.7%), 5.0% (95% CI, 3.3%-6.7%), and 10.1% (95% CI, 7.5%-12.8%) for persons who had UACRs of 0 to < 5 mg/g, 5 to < 15 mg/g, and ≥ 15 mg/g, respectively. For those who had UACRs of ≥ 15 mg/g compared with persons who had UACRs of 5 to < 15 mg/g and 0 to < 5 mg/g, the absolute risk differences were 5.1% (95% CI, 1.9%-8.3%) and 6.3% (95% CI, 3.0%-9.6%), respectively.¹

For both CKD progression and kidney failure, investigators pointed out the 10-year adjusted cumulative incidence increased linearly based on baseline UACR levels.¹

Investigators were careful to note several potential limitations to these findings. Specifically, they mentioned UACR was only measured at a single time point and baseline UACR was reflective of residual albuminuria on treatment because most of the cohort was already receiving an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). They further detailed their inability to account for the duration of ACEi or ARB use and the day-to-day variability of UACR.¹

Nonetheless, they concluded: “These findings underscore the need for future studies to determine the optimal threshold for initiating treatment with antiproteinuric agents and whether the further reduction in albuminuria may improve adverse clinical outcomes in persons with CKD who have normoalbuminuria.”

References:

1. ^{Verma A, Schmidt IM, Claudel S, et al. Association of Albuminuria With Chronic Kidney Disease Progression in Persons With Chronic Kidney Disease and Normoalbuminuria. Ann Intern Med. doi:10.7326/M23-2814}
2. ^{American College of Physicians. Even lower levels of albuminuria associated with increased risk for CKD progression and kidney failure. Newswise. March 27, 2024. Accessed April 9, 2024. https://www.newswise.com/articles/even-lower-levels-of-albuminuria-associated-with-increased-risk-for-ckd-progression-and-kidney-failure}
3. ^{National Kidney Foundation. Albuminuria (proteinuria). Accessed April 9, 2024. https://www.kidney.org/atoz/content/albuminuria}