Suppressed renoprotective purines in COVID-19 patients with acute kidney injury

Abstract

Acute kidney injury (AKI) is common in patients hospitalized for COVID-19, complicating their clinical course and contributing to worse outcomes. Animal studies show that adenosine, inosine and guanosine protect the kidney against some types of AKI. However, until now there was no evidence in patients supporting the possibility that abnormally low kidney levels of adenosine, inosine and guanosine contribute to AKI. Here, we addressed the question as to whether these renoprotective purines are altered in the urine of COVID-19 patients with AKI. Purines were measured by employing ultra-high-performance liquid chromatography-tandem mass spectrometry with stable-isotope-labeled internal standards for each purine of interest. Compared with COVID-19 patients without AKI (n = 23), COVID-19 patients with AKI (n = 20) had significantly lower urine levels of adenosine (P < 0.0001), inosine (P = 0.0008), and guanosine (P = 0.0008) (medians reduced by 85%, 48% and 61%, respectively) and lower levels (P = 0.0003; median reduced by 67%) of the 2nd messenger for A_2A and A_2B adenosine receptors, i.e., 3',5'-cAMP. Moreover, in COVID-19 patients with AKI, urine levels of 8-aminoguanine (endogenous inhibitor of inosine and guanosine metabolism) were nearly abolished (P < 0.0001). In contrast, the "upstream" precursors of renoprotective purines, namely 5'-AMP and 5'-GMP, were not significantly altered in COVID-19 patients with AKI, suggesting defective conversion of these precursors by CD73 (converts 5'-AMP to adenosine and 5'-GMP to guanosine). These findings imply that an imbalance in renoprotective purines may contribute to AKI in COVID-19 patients and that pharmacotherapy targeted to restore levels of renoprotective purines may attenuate the risk of AKI in susceptible patients with COVID-19.

Figure 1

Effects of acute kidney injury (AKI) on urine levels (ng/ml) of (A) 5’-AMP, (B) adenosine, (C) inosine, (D) hypoxanthine, (E) xanthine and (F) 3’,5’-cAMP. Dot plots show individual values. Also shown are medians with interquartile ranges and the percentage decreases (↓%) in both the median and mean values in AKI compared to patients without AKI (No AKI).

Figure 2

Effects of acute kidney injury (AKI) on urine levels (ng/ml) of (A) 5’-GMP, (B) guanosine, (C) guanine, (D) 3’,5’-cGMP and (E) 8-aminoguanine. Dot plots show individual values. Also shown are medians with interquartile ranges and the percentage decreases (↓%) in both the median and mean values in AKI compared to patients without AKI (No AKI).

Figure 3

Correlations between urinary excretion rates (ng/min) of adenosine (A), inosine (B), guanosine (C), adenosine + inosine (D), adenosine + guanosine (E) and adenosine + inosine + guanosine (F) versus creatinine clearance. The summation of the excretion rates of adenosine + inosine + guanosine (F) yielded the strongest positive correlation with renal function. Red symbols represent data from patients with acute kidney injury.