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“Normal” Urine Albumin to Creatinine Ratios Can Still Predict CV Risk

New evidence questions the idea of what is normal.

For several decades, the presence of microalbuminuria (urinary albumin/creatinine ratio [ACR] of 30-300 mg/G) has been used to indicate chronic kidney disease, supported by a low glomerular filtration rate (eGFR). It has also been used to predict progression of diabetes-related and non-diabetes related renal failure, and of cardiovascular disease (CVD) caused mortality.  Until recently, an ACR of less than 30 mg/G has been considered non-predictive for poor cardiovascular outcomes or progression of renal failure.  A newly published study in the Journal of the American Heart Association attempts to link “normal” ACR, coincident hypertension, and CVD mortality.

In a retrospective cohort of Korean patients who were part of a comprehensive health screening between 2002 and 2012, 37,091 subjects were evaluated for associations between low grade albuminuria (<30 mg/G) and coincident hypertension, coincident diabetes, and CVD mortality at follow-up, with a median follow time of 5.13 years.  All study subjects were further placed into four separate groups based on the degree of ACR as follows: Quartile 1 = ACR <3.4 mg/G, Quartile 2 = 3.4-4.7, Quartile 3 = 4.7-7.4, and Quartile 4  ≥7.4. The baseline characteristics of diabetes, obesity, and hypertension significantly increased across the quartiles as expected. Hazard ratios and confidence intervals across all subsets were estimated using Cox proportional hazards models.

In the cohort, there were 349 (0.9%) all-cause deaths noted during follow-up. Not surprisingly, there was a higher proportion of subjects with hypertension (41.8% vs 23.5%) and diabetes (17.2% vs 6.1%) when comparing those who died and those who did not. The investigators then demonstrated the link between baseline ACR and all-cause and CVD mortality by comparing across the quartiles, using Q1 as the base (HR=1). Comparing hazard ratios across Q2-Q4, it was shown that risk for all-cause mortality does indeed rise (HR 0.77-1.37). With CVD mortality in mind, hazard ratios also increased across the Q2-Q4 (HR 1.42-3.46). Associations between baseline ACR with coincident hypertension were also made, with a statistically significant connection with hypertension (highest HR 1.95, 95% CI 1.51-2.53), p<0.001 across the quartiles.  The highest HR for associated diabetes was 1.15 (95% CI 0.79-1.66), p=0.195 across the quartiles, but with no statistical significance.

The investigators suggested a relevant association between low-grade albuminuria and an increase in incident hypertension and CVD mortality over 10 years, suggesting a linear risk increase across the 0 to < 30 range of ACR, countering the notion that low-grade albuminuria was not linked to increased risk of CVD death. They go on to state that the presence of any albuminuria is a risk factor for vascular disease, increasing with the degree of albuminuria.

Caution must be taken when considering these claims. First, the period of follow-up (approximately five years) is rather short, and may undersell the overall mortality rate. Another, more important, consideration is the use of ACR of 0-3.4 mg/G, which includes subjects with no albuminuria, suggesting that even lack of urine albumin can predict CV death and hypertension, which, as a standalone marker, is highly unlikely. A control cohort of subjects without albuminuria would have been a better comparator. Finally, some of the reported HR values were less than 1, suggesting that some degrees of albuminuria may actually be protective against the undesired outcomes. Here, it is difficult to determine an association between low-grade ACR and CVD morbidity and mortality. As the authors state, a long-term multinational prospective controlled trial will be necessary to determine a true connection.

Practice Pearls:

  • Microalbuminuria remains an important predictor for cardiovascular morbidity and mortality.
  • While many patients with diabetes will go on to develop renal complications, there is no evidence in this study that microalbuminuria is a risk factor for diabetes.
  • Low grade microalbuminuria may indeed be indicative of increased cardiovascular risks, but multinational studies may be necessary to make a stronger association.

References:

Sung KC, Ryu S, Lee JY, Lee SH, Cheong E, Hyun YY, et al. Urine Albumin/Creatinine Ratio Below 30 mg/g is a Predictor of Incident Hypertension and Cardiovascular Mortality. J Am Heart Assoc. 2016;5(9). Epub 2016/09/13. doi: 10.1161/JAHA.116.003245. PubMed PMID: 27625343; PubMed Central PMCID: PMCPMC5079007.

Mark T. Lawrence, RPh, PharmD Candidate, University of Colorado-Denver, School of Pharmacy NTP