Original ArticlesAcute Kidney Injury

Association of Preoperative Urinary Uromodulin with AKI after Cardiac Surgery

Pranav S. Garimella, Bertrand L. Jaber, Hocine Tighiouart, Orfeas Liangos, Michael R. Bennett, Prasad Devarajan, Tarek M. El-Achkar and Mark J. Sarnak
CJASN January 2017, 12 (1) 10-18; DOI: https://doi.org/10.2215/CJN.02520316

Abstract

Background and objectives AKI is a serious complication after cardiac surgery. Although high urinary concentrations of the tubular protein uromodulin, a marker of tubular health, are associated with less AKI in animal models, its relationship in humans is unknown.

Design, setting, participants, & measurements A post hoc analysis of a prospective cohort study of 218 adults undergoing on–pump cardiac surgery between 2004 and 2011 was conducted. Multivariable logistic and linear regression analyses were used to evaluate the associations of preoperative urinary uromodulin-to-creatinine ratio with postoperative AKI (defined as a rise in serum creatinine of >0.3 mg/dl or >1.5 times baseline); severe AKI (doubling of creatinine or need for dialysis) and peak postoperative serum creatinine over the first 72 hours.

Results Mean age was 68 years, 27% were women, 95% were white, and the median uromodulin-to-creatinine ratio was 10.0 μg/g. AKI developed in 64 (29%) patients. Lower urinary uromodulin-to-creatinine ratio was associated with higher odds for AKI (odds ratio, 1.49 per 1-SD lower uromodulin; 95% confidence interval, 1.04 to 2.13), which was marginally attenuated after multivariable adjustment (odds ratio, 1.43; 95% confidence interval, 0.99 to 2.07). The lowest uromodulin-to-creatinine ratio quartile was also associated with higher odds for AKI relative to the highest quartile (odds ratio, 2.94; 95% confidence interval, 1.19 to 7.26), which was slightly attenuated after multivariable adjustment (odds ratio, 2.43; 95% confidence interval, 0.91 to 6.48). A uromodulin-to-creatinine ratio below the median was associated with higher adjusted odds for severe AKI, although this did not reach statistical significance (odds ratio, 4.03; 95% confidence interval, 0.87 to 18.70). Each 1-SD lower uromodulin-to-creatinine ratio was associated with a higher adjusted mean peak serum creatinine (0.07 mg/dl per SD; 95% confidence interval, 0.02 to 0.13).

Conclusions Lower uromodulin-to-creatinine ratio is associated with higher odds of AKI and higher peak serum creatinine after cardiac surgery. Additional studies are needed to confirm these preliminary results.

Introduction

AKI is a serious complication of on–pump cardiac surgery (1,2) and it is largely believed that the culprit lesion is acute tubular necrosis (3). Current preoperative assessment of kidney function is limited to measures of the glomerular axis, namely eGFR and urinary albumin-to-creatinine ratio (ACR). Although a number of tubular injury biomarkers have been evaluated to diagnose early AKI in the postoperative setting (4), preoperative tubular function assessment is not part of routine care.

Uromodulin is a 95-kD glycoprotein synthesized by the thick ascending limb of the loop of Henle and early distal convoluted tubule (5). It is the most abundant urinary protein in healthy adults (20–70 mg/d). In vitro studies suggest that uromodulin binds pathogenic bacteria, prevents stone formation, and assists in excretion of uric acid (6–8). Urinary uromodulin positively correlates with eGFR, volume status, and tubular function in the general population (9,10). We have previously shown that higher urinary concentrations of uromodulin are associated with a lower risk of decline in eGFR and mortality (11).

Data suggest that Umod gene knockout mice lacking uromodulin are more susceptible to ischemia-reperfusion kidney injury (12) and more likely to experience tubular inflammation and necrosis, especially in the S3 segment of the proximal tubule. This is also the most common site of tubular injury in humans. To our knowledge, no studies have evaluated whether urinary uromodulin concentrations are associated with risk of AKI in humans. In this study, we evaluated whether urinary uromodulin associates with the risk of AKI in adults undergoing on–pump cardiac surgery.

Materials and Methods

Design and Participants

We performed a post hoc analysis of a cohort of patients undergoing on–pump cardiac surgery at three tertiary care academic centers (Tufts Medical Center, St. Elizabeth’s Medical Center, and University of Massachusetts Medical Center, Worcester, MA) between 2004 and 2011. The aim of the parent study was to evaluate genetic risk factors for AKI after cardiac surgery (13,14). Consecutive adults (≥18 years of age) scheduled to undergo on–pump cardiac surgery were eligible for enrollment. Written informed consent was obtained from study participants or next of kin. The institutional review board of each participating center approved the study protocol.

Data and Sample Collection

Urine samples were freshly collected before surgery, kept on ice, and centrifuged within 30 minutes to remove insoluble elements. The supernatant was treated with a protease inhibitor cocktail tablet (Complete Mini; Roche Diagnostics, Indianapolis, IN) to prevent biomarker degradation by urinary proteases. Urinary aliquots were stored at −80°C and not thawed before this study.

Exposure Variable

Uromodulin was assayed in urine using a commercially available ELISA kit (MD Bioproducts, St. Paul, MN). The colorimetric sandwich immunoassay uses a polyclonal antibody against human uromodulin as the capture antibody and a biotinylated polyclonal antibody against human uromodulin as the detection antibody. Absorbance was read on a Bio-Rad Benchmark Plus Plate Reader (Bio-Rad, Hercules, CA) at 450 nm, with correction at 620 nm. Uromodulin concentration was calculated from a standard curve generated with a four–parameter logistic regression. Data for each run were calculated from a set of eight standards (created by serial dilution) using a cubic regression curve fit. Curve R values below 0.9 were rejected, and the assay was repeated. The correlation coefficient for the assay run was 1.00. The interassay coefficient of variation was 5.02%. The minimum detectable concentration as reported by the manufacturer was 0.75 ng/ml. No measured values in our cohort were below the detectable limit. To account for urine dilution, uromodulin was indexed to urinary creatinine, and the resulting uromodulin-to-creatinine ratio was expressed as micrograms per gram (15).

Outcome Variable

Serum creatinine was assayed using the modified Jaffe method. We defined AKI as a rise in serum creatinine of at least >0.3 mg/dl or >1.5 times the preoperative value during the first 72 hours after surgery as previously reported (16–18). This definition differs slightly from the Kidney Disease Improving Global Outcomes (KDIGO) criteria, requiring the serum creatinine rise to occur within 48 hours (19). Given the possibility of hemodilution associated with cardiac surgery, we anticipated an early postoperative decline in serum creatinine concentration in some patients and a delay in achieving the KDIGO criterion threshold for diagnosing AKI over the first 48 hours (20,21). We, therefore, adopted a 72-hour window for the rise in the serum creatinine. Severe AKI was defined as at least the doubling of the serum creatinine or the need for RRT. Urine output was only collected at 24-hour intervals, and thus precluded its use in identifying patients with AKI (19). Peak serum creatinine was defined as the highest value recorded over the first 72 hours after surgery.

Covariates

Patient characteristics included age, sex, history of diabetes (including the use of at least one oral antidiabetic drug or insulin), heart failure as defined by the Society of Thoracic Surgeons (22), left ventricular ejection fraction assessed by echocardiography, chronic obstructive pulmonary disease (COPD), peripheral vascular disease (PVD), preoperative eGFR calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (23), and urine ACR. Surgical parameters of interest included type of surgery (coronary artery bypass graft surgery, valvular surgery, or both) and elective versus emergent surgery (i.e., immediately after cardiac catheterization). To account for the possibility of sample degradation over time, we also adjusted for storage time in our final models.

Statistical Analyses

We used descriptive statistics to compare the characteristics of the cohort by quartiles of uromodulin-to-creatinine ratio. Continuous variables were described as means (with SDs) or medians (with 25th and 75th percentiles) as appropriate. Categorical variables were expressed as frequencies (with percentages). Normally distributed continuous variables were compared using ANOVA, and non–normally distributed variables were evaluated using the Kruskal–Wallis test. Categorical variables were compared using the chi-squared test and the Fisher exact test as appropriate.

To evaluate the association of preoperative uromodulin-to-creatinine ratio with the development of postoperative AKI, we used univariate and multivariable logistic regression analyses. We first included demographic variables (age and sex; model 1), and then, diabetes, heart failure, left ventricular ejection fraction, eGFR, type and elective nature of the cardiac surgery, and urine ACR were added (model 2) (24–27). The effect estimates are displayed as odds ratios (ORs; per 1 SD lower or across quartiles) with the corresponding 95% confidence intervals (95% CIs). Given that the majority of patients were white, we accounted for the quasicomplete separation seen in our logistic models using the penalized likelihood method proposed by Firth (28). We evaluated the interaction between CKD status (defined as eGFR<60 ml/min per 1.73 m2) and the need for nonelective surgery with uromodulin-to-creatinine ratio with AKI. In a sensitivity analysis, we adjusted for additional confounders, including COPD, PVD, prior radiocontrast use, cardiopulmonary bypass time, and urine sample storage time. In additional sensitivity analyses, we also evaluated the association between raw (not indexed to creatinine) uromodulin concentration and AKI.

We used restricted cubic splines in the rms package in R (29) to explore the functional relationship between the uromodulin-to-creatinine ratio and peak serum creatinine. We used the default number and location of knots along the distribution of uromodulin-to-creatinine ratio quantiles 5%, 35%, 65%, and 95% with the following values of uromodulin: 2.11, 6.03, 17.32, and 44.77 μg/g, respectively. Multivariable linear regression analyses were then used to examine the association of the preoperative uromodulin-to-creatinine ratio with peak postoperative serum creatinine after adjustment for the same confounders. Among patients who developed AKI, we compared the mean (SD) serum creatinine values across quartiles at different time points (preoperative, 24, 48, and 72 hours postoperatively) using trend P values, which were calculated using the P value from the Spearman rank correlation of the ordered quartiles and serum creatinine. All analyses were performed using SAS, version 9.3 (SAS Institute Inc., Cary, NC), and a two–sided P value <0.05 was considered statistically significant.

Results

Of the 274 patients enrolled in the original study, urine samples were available for 254 participants. After excluding patients with missing urine creatinine (n=36), our final sample included 218 patients. Other than eGFR, which was higher (78 versus 72 ml/min per 1.73 m2), there were no statistically significant differences in the baseline characteristics between the excluded and included cohorts (Supplemental Table 1). The mean age was 68 years, 27% were women, 95% were white, and the mean (SD) eGFR was 71.9 (19.3) ml/min per 1.73 m2. The median urinary uromodulin-to-creatinine ratio was 10.0 μg/g (interquartile range, 4.2–22.8). Except for higher proportions of women in the third and fourth quartiles, there were no differences in the patient characteristics across quartiles (P>0.05 for all) (Table 1).

View this table:
Table 1.

Characteristics of the total cohort according to urinary uromodulin-to-creatinine ratio quartiles

Of the 218 patients in our study cohort, AKI developed in 64 (29%). Of these 64 patients, 20 (37%) were in the first quartile of uromodulin-to-creatinine ratio, 18 (33%) were in the second quartile, 17 (31%) were in the third quartile, and nine (17%) were in the fourth quartile (trend P=0.02) (Table 2). Patients developing AKI were older, had a greater prevalence of heart failure, and had lower eGFR and lower uromodulin-to-creatinine ratio (Supplemental Table 2). They were also more likely to have cardiac valve surgery and longer cardiopulmonary bypass time. In unadjusted models, lower uromodulin-to-creatinine ratio was associated with higher odds for AKI (OR, 1.49 per 1 SD lower; 95% CI, 1.04 to 2.13; P=0.03), which remained significant after adjustment for model 1 variables (OR, 1.53; 95% CI, 1.06 to 2.20; P=0.02). After further adjustment (model 2), the association between uromodulin-to-creatinine ratio and AKI was marginally attenuated (OR, 1.43; 95% CI, 0.99 to 2.07; P=0.06) (Table 2). A sensitivity analysis that included further adjustment for COPD, PVD, prior radiocontrast use, bypass perfusion time, and urine sample storage time did not significantly alter the results (OR, 1.43; 95% CI, 0.99 to 2.08; P=0.06). Compared with patients in the fourth uromodulin-to-creatinine ratio quartile, those in the first quartile had a threefold higher odds for AKI after adjustment for model 1 variables (OR, 2.98; 95% CI, 1.19 to 7.46; P=0.02) (Table 2), although this was modestly attenuated and failed to reach statistical significance after adjusting for model 2 variables (OR, 2.43; 95% CI, 0.91 to 6.48; P=0.06). Only eight patients developed severe AKI, with three requiring dialysis. Of these, seven were in the first and second uromodulin-to-creatinine ratio quartiles, and none were in the fourth quartile. Although each 1-SD lower uromodulin-to-creatinine ratio was associated with two times greater adjusted odds for severe AKI or need for dialysis in adjusted models, this did not reach statistical significance (OR, 2.03; 95% CI, 0.80 to 5.17; P=0.14). Because of few severe AKI events, we compared the odds of AKI in persons with above– and below–median uromodulin-to-creatinine ratio. After adjusting for variable in model 2, compared with persons with uromodulin-to-creatinine levels above the median, those with levels below the median had a four times greater odds of severe AKI, although this was not statistically significant (OR, 4.03; 95% CI, 0.87 to 18.70; P=0.08). We found no significant interaction between nature of surgery (P=0.87) or CKD status (P=0.50) and uromodulin-to-creatinine ratio with AKI.

View this table:
Table 2.

Association of urinary uromodulin-to-creatinine ratio and postoperative AKI

Lower levels of uromodulin-to-creatinine ratio were associated with a higher peak postoperative serum creatinine after multivariable adjustment (Figure 1). Each 1-SD lower uromodulin-to-creatinine ratio was associated with a 0.07-mg/dl (95% CI, 0.02 to 0.13; P=0.01) higher peak serum creatinine (Table 3).

Figure 1.
Figure 1.

Higher uromodulin-to-creatinine ratio is associated with lower peak serum creatinine in patients undergoing cardiac surgery. Restricted cubic spline depicting the relationship of preoperative uromodulin concentration and postoperative peak serum creatinine adjusted for age, sex, race, diabetes, heart failure, left ventricular ejection fraction, eGFR, type and elective nature of the cardiac surgery, and urine albumin-to-creatinine ratio. The solid line represents the estimated association of urinary uromodulin-to-creatinine ratio with peak serum creatinine, and the dashed lines represent the corresponding 95% confidence interval (95% CI). We used the default number and location of knots along the distribution of uromodulin quantiles 5%, 35%, 65%, and 95% with the following values of uromodulin-to-creatinine ratio: 2.11, 6.03, 17.32, and 44.77 μg/g, respectively. The global P tests for the overall association between uromodulin concentration and postoperative peak serum creatinine, with P<0.05 suggestive of a significant association; the linearity P tests for departure from linearity in this association, with P>0.05 suggestive of a significant linear relationship. Cr, creatinine.

View this table:
Table 3.

Association of urinary uromodulin-to-creatinine ratio with postoperative peak serum creatinine

The mean peak serum creatinine values at 24, 48, and 72 hours among patients who developed AKI were lowest among persons in the highest quartile of uromodulin-to-creatinine ratio (Figure 2). At 72 hours, the mean serum creatinine in the highest quartile was at least 0.31 mg/dl lower than the mean serum creatinine in any other quartile, although this did not reach statistical significance (Supplemental Table 3).

Figure 2.
Figure 2.

Higher uromodulin-to-creatinine ratio is associated with lesser rise of serum creatinine in patients with AKI. Figure shows the trend of mean (SD) serum creatinine values over 72 hours in patients with AKI. Each point represents the mean serum creatinine for patients in the respective uromodulin-to-creatinine ratio quartile (Q) preoperatively (0 hours) and 24, 48, and 72 hours postoperatively. The lines on either side of the point represent the SDs. The numbers at each time point indicate the numbers of patients with serum creatinine measures. uUMOD/cr, urinary uromodulin-to-creatinine ratio.

In a sensitivity analysis, the direction of the association of the raw nonindexed uromodulin was similar to the primary results in both the continuous models (OR, 1.13; 95% CI, 0.82 to 1.56; P=0.46) and the lowest versus highest quartile models (OR, 1.61; 95% CI, 0.67 to 3.90; P=0.30), but the strength of the association was weaker.

Discussion

In this study, we found that lower urinary concentrations of uromodulin are associated with higher odds for AKI in adults undergoing on–pump cardiac surgery. This association was of borderline statistical significance in multivariable models and consistent for more severe AKI, although there were too few events to make definitive conclusions. In addition, urinary uromodulin levels were inversely associated with the peak postoperative serum creatinine.

The incidence of AKI after cardiac surgery is as high as 30% (1–3). AKI is associated with increased hospital length of stay, in–hospital mortality, and risk of development of CKD (30). Even mild postoperative AKI may be associated with worse short– and long–term outcomes (31,32). A recent propensity–matched cohort of 833 patients undergoing cardiac surgery showed that persons who developed mild AKI had nearly eightfold greater risk of in-hospital mortality, longer intensive care and hospital stay, higher rate of neurologic complications, and greater sternal wound infection (33). Identifying persons at risk for AKI after cardiac surgery is an important step toward minimizing postoperative AKI and its complications. Assessing tubular function might help identify those at risk for AKI independent of eGFR.

Uromodulin forms a gel on the luminal surface of the thick ascending limb of the loop of Henle, preventing water permeability in this segment (6). In humans, uromodulin excretion is believed to increase gradually from birth, and concentrations remain relatively stable from the age of 4 years old to the seventh decade of life (5). Levels of uromodulin were significantly lower in our cohort than observed in healthy community–dwelling adults using the same assay (11) and also in other studies using a different ELISA (9,10) (25.7–26.0 μg/ml). Despite this, we showed better kidney outcomes among persons with higher uromodulin levels (11). Reasons for the lower uromodulin levels observed in our study are unclear, but possibilities include differences in assays and the patient characteristics. One study across diverse populations showed differences in uromodulin levels on the basis of a particular rs12917707genotype using a Luminex immunoassay (34). The patients in our study were undergoing cardiac surgery, some nonelectively, and we hypothesize that they were likely in poorer health with greater vascular disease and possibly, subclinical tubular damage, leading to lower uromodulin levels.

Umod gene knockout mice develop a greater rise in serum creatinine compared with wild-type mice (12) and display more histologic damage, with diffuse tubular necrosis affecting predominantly S3 segments of the outer medulla (12,35). Inflammation is an important contributor to the pathogenesis of AKI (36), and Umod gene knockout mice show a greater degree of neutrophil infiltration, especially around injured S3 segments, compared with wild-type mice after ischemic injury (35). During ischemia-reperfusion injury, interstitial uromodulin is associated with downregulation of inflammatory signaling in contiguous S3 proximal tubules, suggesting a role for uromodulin in a protective tubular crosstalk during AKI (35,37). Umod gene knockout mice also have impaired recovery from AKI up to 5 weeks after an ischemic injury, whereas wild-type mice experience renal recovery within 1 week of the injury (38). This suggests that the protein might be essential for the recovery from AKI.

Two small studies (n≤30) conducted in patients undergoing cardiac surgery and critically ill patients suggest that urinary uromodulin concentrations decrease after AKI (39,40). These studies did not evaluate whether lower uromodulin levels were associated with risk of AKI. To our knowledge, only two studies have assessed the relationship between uromodulin and risk of AKI. In one study of 36 liver transplant recipients, those who developed AKI had lower pretransplant urinary uromodulin concentrations compared with those who did not develop AKI (41). Concentrations of uromodulin in those who did not develop AKI were similar to those in patients not undergoing liver transplantation. In newborns admitted to an intensive care unit, low uromodulin levels were shown to be predictive of AKI (42). Our findings are consistent with the aforementioned experimental data and small observational studies in humans. We show that persons with lower preoperative urinary uromodulin concentrations have higher odds for developing AKI after cardiac surgery and higher peak serum creatinine. Studies of longer duration in patients with more severe AKI are needed to accurately assess if urinary uromodulin levels associate with faster recovery of kidney function.

Several limitations in our study should be noted. Most patients had AKI of mild severity, and therefore, our findings may not be generalizable to more severe forms of AKI. We measured uromodulin in urine specimens that were collected and stored for approximately 10 years. Storage for over 8 months, even at −80°C, may slightly decrease uromodulin levels (43). However, we do not expect a differential effect on AKI of long-term storage at this temperature. Because we did not include oligoanuria as one of the KDIGO criteria for diagnosing AKI, we may have missed some patients with AKI. However, it is unlikely that we missed any clinically important patients due to this limitation. Although urine output may have been maintained by diuretic use in our cohort, brief durations of oliguria may simply reflect insufficient volume resuscitation (44). Serum creatinine values were not systematically collected beyond 72 hours after cardiac surgery, thus limiting our ability to assess AKI later in the course of the hospitalization and also limiting the ability to assess whether uromodulin concentrations were associated with recovery from AKI. Finally, we are unable to comment on whether uromodulin concentrations change after AKI and whether serial measurement of uromodulin may be better at identifying persons at risk for nonrecovery from AKI.

Our study also has several strengths. To our knowledge, this is the first prospective study testing the hypothesis that higher urinary uromodulin, a marker of tubular health, is associated with lower postoperative risk of AKI in patients undergoing cardiac surgery. The stored urine samples in our study had never been thawed, thus minimizing the effect of freeze-thaw cycles on the measurement of uromodulin. We used a commercially available ELISA, which has been evaluated in prior studies (11,45–47). Despite relatively few events, we were able to detect an association that was of borderline significance between lower urinary uromodulin concentrations and higher odds for development of AKI. Importantly, the results were independent of baseline eGFR, which is a potential confounder (9). The higher risk of AKI with lower uromodulin concentrations is consistent with our previous work showing similar findings with progressive eGFR decline in a large cohort of community-dwelling adults (11). Our study evaluated whether uromodulin was associated with development of AKI in adults undergoing cardiac surgery with a goal of assessing kidney function through a novel axis of tubular function, but it was not to replace either eGFR or ACR. The proof of principle findings in this study are exploratory; they improve our understanding of how tubular health may be associated with AKI and highlight the need for further studies in this field.

In conclusion, among adults undergoing on–pump cardiac surgery, low uromodulin-to-creatinine ratio was associated with higher odds of AKI, although this was no longer significant in fully adjusted analyses. Large studies are needed to confirm these results and evaluate whether uromodulin can be used to identify high-risk patients and target therapies to prevent AKI.

Disclosures

None.

Acknowledgments

The parent study was supported by a grant from the Norman Coplon Research Program of Satellite Healthcare, Inc. (to B.L.J.) and grant 0535367N from the American Heart Association (to O.L.). P.S.G. was supported by National Institutes of Health (NIH) training grant 5T32DK007777 and the Tufts Medical Center Division of Nephrology Driscoll Fund. P.D. was supported by grant P50 DK096418 from the NIH.

Footnotes

  • Received March 7, 2016.
  • Accepted August 29, 2016.

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Association of Preoperative Urinary Uromodulin with AKI after Cardiac Surgery
Pranav S. Garimella, Bertrand L. Jaber, Hocine Tighiouart, Orfeas Liangos, Michael R. Bennett, Prasad Devarajan, Tarek M. El-Achkar, Mark J. Sarnak
CJASN Jan 2017, 12 (1) 10-18; DOI: 10.2215/CJN.02520316
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