AKI is a major postoperative complication of cardiac surgery. Even a mild rise in creatinine as small as 0.3 mg/dl (26.5 μmol/L) (AKI Stage I) in this setting is associated with increased morbidity and mortality.19
Our study demonstrates that pre-operative albuminuria (UACR) is independently associated with development of AKI even after consideration of several important pre-operative characteristics. Furthermore, dipstick proteinuria is also an independent predictor for the development of stage I AKI. Finally, pre-operative UACR is also independently associated with in-hospital dialysis, ICU length of stay, and in-hospital length of stay. Both UACR and dipstick proteinuria have better prognostic ability for AKI in patients with estimated GFR ≥45 mL/min per 1.73 m2
than patients with estimated GFR ≤ 45 mL/min per 1.73 m2
and those undergoing elective surgery.
Our study builds upon the results of Huang et al,10
demonstrating that pre-operative proteinuria is an independent risk factor for the development of cardiac surgery associated AKI. In their study involving patients undergoing cardiac surgery, urine dipstick defined as mild (trace to 1+), had adjusted odds ratio (OR) of 1.66 for the development of AKI (95% CI 1.09 to 2.52), and or heavy proteinuria (2+ to 4+) had an adjusted OR of 2.30 (95% CI 1.35 to 3.90). Our study extends Huang’s observations by incorporating UACR for categorization and analyses. Our results are similar to the non-surgical setting where Grams et al7
demonstrated UACR is associated with AKI in a graded fashion in a community-based population. We confirmed that low grade albuminuria (UACR < 30 mg/g), which generally is not considered pathological, was independently associated with the risk for AKI.
Several clinical risk-scoring systems have been developed and validated to predict the risk of AKI in cardiac surgery. The majority consider severe AKI as the endpoint (requiring acute renal replacement therapy).12,13
However, a few studies developed models for predicting milder forms of AKI.21,22
Regardless, all the clinical risk scoring systems, except for one,21
solely utilized pre-operative serum creatinine or GFR to define chronic kidney disease. None of the studies examined the added value of albuminuria or proteinuria to predict AKI in cardiac surgery. In this multi-center cohort study of patients undergoing cardiac surgery, we found that both pre-operative UACR and dipstick proteinuria add to pre-operative risk stratification for AKI.
These risk-assessment tools are used both to allow individual patients and surgeons to balance the risks and benefits of cardiac surgery and to monitor the quality of care and outcomes of cardiac surgery. Cardiac surgery outcomes are widely monitored, thus even mild improvements to help risk adjust for adverse outcomes could have great clinical and research importance by choosing alternative procedures (e.g., percutaneous coronary revascularization or valve repair) and selection of a high-risk cohort for enrollment into randomized controlled trials. Therefore, if pre-operative proteinuria can be validated further as a relevant marker for improving risk assessment for AKI or other adverse outcomes after cardiac surgery, then it could be of value to individual patients, clinicians, hospitals and trialists.
It has been postulated that proteinuria represents endothelial dysfunction or may injure the kidney itself. There is a body of evidence which describes proteinuria as toxic to the tubules. This can result in significant tubulointerstitial injury and progression of renal disease independent of the cause of proteinuria in chronic kidney disease. Filtered albumin when taken up by renal tubular cells via receptor mediated endocytosis can trigger expression of a series of pro-inflammatory molecules like monocyte chemotactic protein-1 (MCP-1), osteopontin, regulated upon activation normal T cell expressed and secreted (RANTES), endothelin-1.10
Also, low molecular weight proteinuria can exacerbate acute ischemic injury in experimental animals.22
It is possible that patients with albuminuria have some degree of altered functional renal reserve due to the above mentioned factors and are more prone to ischemic injury during cardiac surgery.23
We found effect modification by two clinical variables: surgery status and pre-operative estimated GFR. Specifically, the relationship between the degree of pre-operative proteinuria and risk for AKI was stronger in those undergoing elective surgery and those who had higher pre-operative estimated GFR but was weak or abolished in those undergoing urgent surgery and those with estimated GFR < 45 ml/min/m2
. These findings are not surprising. In patients who are already at much higher risk for AKI (urgent surgery and profoundly decreased baseline estimated GFR), it is unlikely that additional parameters will provide more information for the risk of outcomes. However, in patients with lower pre-operative risk, a measure of kidney injury, such as proteinuria, may provide additional benefit for risk stratification. For example, in those with GFR > 60 and no albuminuria, the rate of AKI was 24%. In contrast, the rate of AKI in those with GFR 30–44 was 38%. Thus, since the background or baseline risk of AKI is already higher in those with low GFR, it is more difficult to demonstrate higher risk in association with another predictor variable, in this case albuminuria. These findings are very similar to the findings by Tonelli et al.11
where the value of albuminuria to risk-stratify for the outcomes of end stage renal disease (ESRD) and all-cause mortality was greatest in those with higher baseline estimated GFR.
The strengths of this study are that it is a multicenter cohort study involving six large academic centers in North America, and representative of contemporaneous surgical practice. Furthermore, unlike previous studies8,9,10
proteinuria was measured both by UACR and dipstick at the bedside, thus we were able to compare the two methodologies of assessment of proteinuria with the outcomes. However, there are some limitations to our study. The majority of the patients in our cohort experienced only mild AKI (Acute Kidney Injury Network stage I). The number of patients with stage II AKI (or worse) was much lower, which may have limited our ability to observe a stable independent relationship between albuminuria and more severe AKI. However, the distribution of severity of AKI reflects the current epidemiology of AKI in cardiac surgery in the modern era in North America. In addition, despite the multi-center design of our study, two-thirds of participants were male and over 90% were white. The ability for the models to correctly classify patients as AKI or non-AKI using pre-operative variables was only modest, with an AUC of 0.7. Thus, additional factors such as intra-and post-operative events also influence the ultimate risk for AKI. Finally, the amount of proteinuria by dipstick can be influenced by urine concentration.
In conclusion, our results indicate that pre-operative proteinuria, both by UACR and urine dipstick, is an independent predictor for the risk of developing stage I AKI in cardiac surgery. UACR is also an independent predictor of other important outcomes, including dialysis and length of stay. However, with consideration of the cost differential between the two tests (approximately 40 cents per patient for dipstick and $130 per patient for UACR), dipstick proteinuria may be a more cost-effective method to screen patients prior to surgery, as it still improved risk classification by 24%. This implies that the number needed to screen via UACR to correctly classify one patient prior to surgery is 14, at a total cost of $1820. Future studies will need to determine whether the additional precision at the expense of increased costs is worth pursuing and then translates into improved clinical outcomes. We propose that these, widely available, and potentially bedside tests can be used as an aid in assessing risk for poor outcomes in patients undergoing cardiac surgery.