Effect of anticoagulant and platelet inhibition on the risk of bacteremia among patients with acute pyelonephritis: a retrospective cohort study

Acute pyelonephritis is a common bacterial infection, often caused by Gram-negative bacteria, predominantly Escherichia coli. The infection can sometimes be associated with complications such as bacteremia and urosepsis [1], as well as acute kidney injury [2]. Considering the relatively high frequency of bacteremia, combined with high reported mortality rates [3], it is important to identify potential risk factors for severe outcomes.

During bacterial infection, there is an interplay between inflammation and coagulation, with thrombosis playing an important role in innate immunity [4‐6]. Many studies have investigated anticoagulants as potential adjunctive treatments of sepsis [7‐12]. Little is known, however, about the role of coagulation during localized bacterial infections, prior to systemic spread of bacteria. In rodents, vascular thrombus formation has been observed during experimental kidney infection [13‐17]. We previously visualized clot formation in peritubular capillaries following a localized kidney tubule infection [14‐16]. This clot formation appeared to be protective against urosepsis, as anticoagulant treatment delayed the initiation of clotting and resulted in systemic spread of bacteria [14]. While these results suggested a role of blood clots in preventing bacteremia in rodents, it implied that patients with antithrombotic treatment may be at higher risk of developing urosepsis during acute pyelonephritis.

The number of patients being prescribed different types of antithrombotic drugs (both anticoagulants and platelet inhibitors) is increasing worldwide. This is partially due to the introduction of routine screenings for atrial fibrillations along with an aging population [18]. Considering both the relatively high incidence of acute pyelonephritis, and the high numbers of patients on antithrombotic treatment, it is important to evaluate the possible impact of such treatment on the risk of developing bacteremia for patients with urinary tract infections. In this study, we investigated if antithrombotic treatment is associated with an increased risk of bacteremia in patients with acute pyelonephritis. While coagulation surrounding infected areas might potentially prevent bacteremia, it may also result in increased renal injury, which is important to investigate from a clinical perspective. Therefore, we also studied the association between antithrombotic treatment and risk of acute kidney injury among patients with acute pyelonephritis.

In this study we tested a hypothesis that following bacterial infection of renal tubules, coagulation in local capillaries form a physical barrier that limits the systemic spread of bacteria. Antithrombotic drugs may inhibit this apparently protective process and thereby promote bacteremia. This hypothesis was inspired by our experimental studies in rats as well as reports exploring the initiation of coagulation during localized acute pyelonephritis [14, 17, 20‐22]. In addition to hindering systemic bacterial spread, we speculated that this vascular disruption may also lead to more prominent kidney injury due to local ischemia. In contrast to our initial hypothesis, we did not find any convincing evidence of an increased risk of bacteremia in patients on antithrombotic treatment during acute pyelonephritis. Rather, we found a slightly lower risk of both bacteremia and acute kidney injury in patients undergoing treatment with LMWH at prophylactic doses, compared to patients without any antithrombotic treatment. As such, our results suggest that it is safe to continue ongoing antithrombotic treatment during acute pyelonephritis, with regards both to the risk of bacteremia and acute kidney injury.

To our knowledge, this is the first study on the association between antithrombotic treatment and bacteremia in patients with acute pyelonephritis. While there are several studies on anticoagulant therapy as adjunctive treatment of sepsis [7‐12], studies investigating associations between anticoagulants or platelet inhibitors and the risk of bacteremia are scarce. A small number of studies have investigated an association between anticoagulant treatment and risk of bacteremia, but did not take the site of infection origin into consideration [23, 24]. A lower risk of bacteremia has been reported among patients with atrial fibrillation treated with dabigatran, compared to patients treated with factor Xa-inhibitor [23]. However, this particular study did not compare risks of bacteremia in patients with and without anticoagulant treatment, which was the focus of our study. In contrast to a study showing increased risk of intravenous catheter-related bacteremia among patients with systemic anticoagulant treatment [24], we found a slightly reduced risk of bacteremia among patients in our cohort with prophylactic doses of LMWH. However, the causative microorganisms and their mode of infection are very different between these two studies, which could explain our contradictory findings.

The anticoagulant used in our original animal studies was unfractioned heparin [14], which is less frequently used in clinical practice and was not prescribed to any patients included in our current study. However, 309 patients were treated with LMWH, among whom we saw a reduced risk of bacteremia. Together with our observation that there was no difference in risk of bacteremia among patients with therapeutic doses of LMWH or other antithrombotics, this suggests that patients with antithrombotic treatment do not have higher risk of bacteremia during acute pyelonephritis. Still, we are cautious to suggest any strong protective effect of LMWH at prophylactic doses.

While it is clinically comforting that we did not find any evidence of increased risk of bacteremia among patients with antithrombotic treatment, we did observe that treatment with prophylactic doses of LMWH reduced the risk of acute kidney injury. This is in line with recent studies showing that both unfractioned heparin and LMWH treatment prevent acute kidney injury during acute pyelonephritis and sepsis [25‐28]. While our results partly support our hypothesis that activation of coagulation might contribute to acute kidney injury during acute pyelonephritis, the lack of convincing evidence of a protective effect of LMWH at therapeutic doses or non-LMWH anticoagulants, means we cannot draw any conclusions regarding the underlying mechanisms of these findings. The multifaceted biological effects of heparins, including both anticoagulatory [29] and immunomodulatory effects [30‐34], complicate the interpretation of both clinical and experimental studies using heparin or LMWH. However, we believe that our results highlight a potentially important association for further study.

The strengths of our study include a relatively large sample size and our focus on a group of patients who are at a potentially higher risk of bacteremia. We also included and adjusted for a range of clinically relevant covariates and potential confounders, with little or no missing data. Despite the strengths, there are of course limitations to consider. First, it is a single-center, observational study, and therefore generalization of our results should be interpreted cautiously. Being the first study of its kind, however, our work motivates further larger-scale prospective studies to validate these results. Second, there are restrictions in the available data. Due to the retrospective nature of the study, we did not have access to structured data for each hospital stay. For example, we do not know the exact duration of symptoms for each patient, and they were therefore likely included in the study at different stages of infection. Patients with antithrombotic treatment may also have different comorbidity burdens, and therefore have a different propensity to seek medical care. Thus, patients with and without antithrombotic treatment might have different baseline risks of bacteremia, as a longer duration of symptoms prior to diagnosis and initiation of antibiotic treatment, is related to higher risk of bacteremia and sepsis [35]. Further, due to the presence of certain comorbidities clinicians may be more inclined to admit patients with antithrombotic treatment to the hospital or to start antibiotic treatment earlier or with intravenous antibiotics. These effects are likely not fully removed by adjustment for comorbidity and other patient factors. Patients on anticoagulants may also have been kept in the hospital long enough to follow up with further serum creatinine measurements, allowing for detection of acute kidney injury. Therefore, missing data from patients without antithrombotic treatment may have resulted in the introduction of bias. Moreover, we did not have conclusive data on indications for antithrombotic treatment and could therefore not adjust for these as possible confounders. Thirdly, we only include patients treated in a university hospital setting, and only where blood cultures were obtained, which might limit generalizability. However, in this study we deliberately chose to observe a patient group with reported higher risk of bacteremia and where the occurrence of the outcome could be accurately ascertained. Further, our results show that bacteremia was present in approximately 20% of the cases, which is in line with earlier findings [1, 36, 37].

Patients with acute pyelonephritis and antithrombotic treatment do not appear to have a higher risk of developing bacteremia. In contrast to our initial hypothesis, we found a slightly lower risk of bacteremia among patients with LMWH treatment at prophylactic doses. For acute kidney injury, concordant with our hypothesis, we found that treatment with LMWH at prophylactic doses also seem to have protective effects. The observed decreases need to be confirmed in future studies. Collectively, our findings suggest that it is safe to continue antithrombotic treatments in patients with acute pyelonephritis if there are no other contraindications. While our results might indicate that coagulation has a role during acute pyelonephritis, future studies validating the potential protective effects, and investigating possible causative relationships are needed.