Outcomes of early and reversible renal impairment in patients with ST segment elevation myocardial infarction undergoing percutaneous coronary intervention

Objective:

Acute kidney injury (AKI) is a frequent complication in patients with ST segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). While AKI occurring post-PCI has been well studied, the incidence and clinical significance of early renal impairment evident on hospital admission prior to PCI and which resolves towards discharge has not been investigated.

Methods:

We retrospectively studied 2339 STEMI patients treated with primary PCI. The incidence of renal impairment and in-hospital complications as well as short and long-term mortality were compared between patients who did not develop renal impairment, patients who developed post-PCI AKI and those who presented with renal impairment on admission but improved their renal function during hospitalization (improved renal function). Improved renal function was defined as continuous and gradual decrease of ⩾ 0.3 mg/dL in serum creatinine levels obtained at hospital admission.

Results:

One hundred and nineteen patients (5%) had improved renal function and 230 patients (10%) developed post-PCI AKI. When compared with patients with no renal impairment, improved renal function and post-PCI AKI were associated with more complications and adverse events during hospitalization as well as higher 30-day mortality. Long-term mortality was significantly higher among those with post-PCI AKI (63/230, 27%) following STEMI than those without renal impairment (104/1990, 5%; p<0.001), but there was no significant difference in long term mortality between patients with no renal impairment and those with improved renal function (5% vs. 7.5%, p=0.17).

Conclusion:

In STEMI patients undergoing primary PCI, the presence of renal impairment prior to PCI which resolves towards discharge is not uncommon and is associated with adverse short-term outcomes but better long-term outcomes compared with post-PCI AKI.

Introduction

Deterioration of renal function resulting in acute kidney injury (AKI) is a frequent and deleterious complication among patients with acute ST elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).^1,,–4 The mechanism of AKI in these patients is complex and goes beyond contrast induced nephropathy (related mainly to the amount of contrast material and to pre-procedural renal function).^5,–7 Recent data have highlighted the central role of early hemodynamic deterioration in the pathogenesis of AKI, as sudden myocardial insult in STEMI often results in an acute reduction of cardiac output and reduced renal perfusion.^8,–10 All trials to date assessing AKI among STEMI patients defined this complication as a rise in serum creatinine (sCr) during hospitalization (following primary PCI) in comparison with sCr levels obtained on admission.^{1,,–4,8,,,–12} However, a subset of patients presenting with STEMI may demonstrate evidence of renal impairment on admission prior to PCI and contrast media application. This impairment, especially if reversible and improves towards discharge, may represent early renal response to hemodynamic alterations. This subset of STEMI patients who present with renal impairment at hospital admission and continuously improve their renal function during hospitalization (improved renal function) has been under-studied. In the present study, we investigated the incidence, characteristics and outcomes of patients with improved renal function and compared them with patients with no renal impairment and those with post-PCI AKI in a large cohort of STEMI patients undergoing primary PCI.

Methods

Study population

We performed a retrospective, single center observational study at the Tel-Aviv Sourasky Medical Center, a tertiary referral hospital with a 24/7 primary PCI service. We included all 2512 consecutive patients admitted between January 2008 and April 2017 to the Cardiac Intensive Care Unit with the diagnosis of acute STEMI. Excluded were 46 patients who were treated either conservatively or with thrombolysis, and 92 patients whose final diagnosis on discharge was other than STEMI (e.g. myocarditis or Takotusubo cardiomyopathy). Also excluded were patients who died within 24 h of admission (n=31), because they did not have sufficient time to develop post-PCI AKI, and patients requiring chronic peritoneal or hemodialysis (n=4) treatment. The final study population included 2339 patients whose baseline demographic, cardiovascular history, clinical risk factors, treatment characteristics and laboratory results were retrieved from their medical files.

Protocol

The diagnosis of STEMI was established by a typical history of chest pain, diagnostic electrocardiographic changes and serial elevation of serum cardiac biomarkers.¹³ Blood samples were withdrawn on admission from all patients. Primary PCI was performed in patients with symptoms ⩽12 h in duration as well as in patients with symptoms lasting 12–24 h in duration if the symptoms continued to persist at the time of admission. Following primary PCI, left ventricular ejection fraction was measured in all patients by bed-side echocardiography within the first 48 h of admission. High-sensitivity C-reactive protein (hs-CRP) was assessed using the Bayer wide-range assay as described previously.¹⁴ Patients’ records were evaluated for in-hospital mortality and complications occurring during hospitalization. These included cardiogenic shock or the need for intra-aortic balloon counter-pulsation treatment, need for emergent coronary artery bypass graft surgery, mechanical ventilation or heart failure episodes treated conservatively, clinically significant tachyarrhythmias (ventricular fibrillation, sustained ventricular tachycardia, and atrial fibrillation) and bradyarrhythmias requiring pacemaker, as well as major bleeding (requiring blood transfusion). Mortality was assessed over a median period of 1468 days (intra-quartile range 738–2406 days) up to 31 August 2017. Assessment of survival following hospital discharge was determined from computerized records of the population registry bureau. The study protocol was approved by the local institutional ethics committee.

Assessment of renal function

The sCr was determined upon hospital admission, prior to PCI, and at least once a day throughout hospitalization and was available for all analyzed patients. Conventional (post-PCI) AKI was defined using the recent KDIGO criteria.¹⁵ These criteria, which were modified from the earlier RIFLE criteria,¹⁵ suggested a lower threshold of sCr rise ⩾ 0.3 mg/dL within 48 h of admission to define AKI. As urinary output is not regularly assessed in STEMI patients (unless receiving diuretics or mechanically ventilated) we have only used the sCr criteria to define AKI, which was available for all patients. Improved renal function was defined as continuous and gradual decrease in sCr levels (i.e. sCr levels were lower each day compared with the previous result until discharge). For all of these patients sCr levels at hospital discharge were ⩾ 0.3 mg/dL lower compared with sCr levels obtained at hospital admission, thus patients with improved renal function were considered to have reversible renal impairment. The estimated glomerular filtration rate (eGFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.¹⁶ Chronic kidney disease (CKD) was defined as¹⁷ eGFR ⩽60 mL/min per 1.73 m² upon admission for patients with no renal impairment or post-PCI AKI. Since admission sCr in patients with improved renal function may not reflect their true baseline renal function, we used the sCr at discharge in these patients to determine the assumed baseline eGFR and renal insufficiency. We included only patients with CKD stage 1–4 in the analysis while four patients with stage 5 CKD were excluded, as stated above.

Statistical analysis

Normally distributed continuous variables are presented as mean ± standard deviation. Variables that deviated from normal distribution are presented as median and inter-quartile range (IQR). Categorical variables are reported as counts and percentages. Comparisons between groups were made using the Whitney–Mann test or t-test for continuous variables and chi-square analysis for categorical variables. The Kaplan–Meier and log-rank test were used to evaluate the unadjusted effect of kidney injury pattern on patient survival. Statistical significance was assumed at p value < 0.05. All analyses were performed with the SPSS 21 software (SPSS Inc., Chicago, IL, USA).

Results

A total of 2339 STEMI patients treated by primary PCI were included in the final analysis, 119 (5%) of whom had baseline renal insufficiency upon hospital admission and 230 (10%) developed post-PCI AKI. Only five patients (2%) of the latter group developed AKI requiring renal replacement therapy during hospitalization.

The baseline clinical characteristics of patients with improved AKI, no renal impairment and post-PCI AKI are listed in Table 1. With the exception of diabetes mellitus and admission hs-CRP levels, no significant differences were present between patients with no renal impairment and improved renal function. On the other hand, patients with post-PCI AKI were more likely to be older, of female gender, have more co-morbidities, longer symptom duration prior to emergency room admission, advanced coronary artery disease, higher hs-CRP, lower left ventricular ejection fraction and longer time until hospital discharge.

While both improved renal function and post-PCI AKI were associated with lower baseline eGFR and higher admission sCr (Table 1), sCr levels at discharge were significantly higher in patients who developed post-PCI AKI, compared with patients with improved renal function (1.64 ± 0.77 mg/dL vs. 1.19 ± 0.3 mg/dL; p <0.001).

Short- and long-term outcomes

When compared with no renal impairment, improved renal function was associated with more complications and adverse events during hospitalization (Table 2), as well as higher 30-day mortality (odds ratio 3.8, 95% confidence interval 1.6–8.8).

Over a median follow-up period of 1468 days (IQR 738–2406 days), 176 (7.5%) patients of the entire cohort died. Mortality was significantly higher among those with post-PCI AKI (63/230, 27%) following STEMI than those without renal impairment (104/1990, 5%; p<0.001), but there was no significant difference in long-term mortality between no renal impairment and improved renal function (5% vs. 7.5%, p=0.17) (Figure 1).

Discussion

We have demonstrated for the first time that among STEMI patients undergoing PCI, early and reversible renal impairment is not uncommon and is associated with adverse short-term outcomes but better long-term outcomes compared with post-PCI AKI.

Worsening of renal function throughout hospitalization in STEMI patients following primary PCI is multifactorial. While contrast nephropathy (related mainly to the amount of contrast volume and the presence of baseline CKD) was traditionally considered a major determinant for AKI occurrence, a growing amount of data now indicates that hemodynamic alterations have a central role in the development of AKI.^8,–10 This is further amplified by the demonstration of renal impairment prior to contrast injection.

Unlike patients with post-PCI AKI, patients with improved renal function had comparable baseline characteristics to those with no AKI, albeit worse hemodynamic profile. The sudden myocardial insult in STEMI often results in acute reduction of cardiac output and lower renal perfusion. In addition, concomitant arrhythmias (either bradycardia or tachycardia) in the acute STEMI setting, a finding which was more common among patients with early renal impairment, may have similar hemodynamic effects. Following the resumption of coronary flow and the improvement of left ventricular function as well as the resolution of arrhythmias, hemodynamic impairment often resolves. Short renal under-perfusion is often associated with a functional renal failure, defined as transient and reversible loss of renal activity without structural damage.¹⁸ More profound and prolonged under-perfusion, especially in the presence of CKD, anemia, hyperglycemia and/diabetes, primarily results in structural damage of tubular epithelial cells, which, in severe cases, is characterized by epithelial cell ischemia, necrosis and increased susceptibility to contrast nephropathy.¹⁹ In contrast to functional injury, these alterations can result in irreversible loss or delayed restoration of renal function, which in many cases results in irreversible renal damage.^20,21 It is therefore possible that some of the post-PCI AKI includes patients with early renal impairment who ultimately failed to improve because of a ‘second hit’ mechanism (i.e. contrast nephropathy).

Patients developing post-PCI AKI had longer symptom duration, possibly resulting in worse left ventricle (LV) function, with prolonged impairment of renal perfusion and possible conversion of early insult into tubular or glomerular injury. Indeed, a direct relation between time to reperfusion and post-PCI AKI was demonstrated among STEMI patients.¹⁸ In contrast, patients with improved renal function had comparable time to reperfusion and LV function to patients with no renal impairment.

Currently, there are only limited reports addressing the timing of renal insult and its relation to clinical outcomes. We have previously looked into the outcomes of improved renal function in 40 patients with STEMI undergoing PCI.²² We showed, for the first time, a trend towards higher 30-day mortality, but it did not reach statistical significance. The current study is the largest report on improved renal function in STEMI patients.

Tian et al. evaluated the clinical outcomes associated with an increase in sCr levels during hospitalization in a large cohort of unselected patients admitted to medical wards or community hospitals.²³ They demonstrated that an increase in sCr level ⩾ 0.3 mg/dL during the first 48 h of hospitalization predicted worse outcomes even if the sCr value returned to normal, whereas patients who presented to the hospital with an elevated sCr level that rapidly returned to normal had favorable outcomes approaching those with sCr levels found consistently in the normal range. A recent report by Kang et al.²⁴ showed that among patients admitted to a general intensive care unit (ICU), a decrease in sCr (⩾ 0.3 mg/dL) during the ICU stay when compared with admission levels was associated with higher 90-day mortality. In that report, however, patients who had a decrease in sCr levels had significantly different baseline characteristics compared with patients without renal impairment. Moreover, none of these patients underwent PCI and no information was present regarding administration of contrast material.

Our findings bear some important clinical implications. The fact that baseline sCr levels early after admission with STEMI may not reflect the true baseline sCr, especially if mild and no history of risk factors or prior renal failure is present, highlights the need for continuous sCr assessment throughout hospitalization. Indeed, some patients who are categorized upon admission as having CKD according to baseline sCr and eGFR calculation may demonstrate normal eGFR at discharge. This may also have possible implications on the doses of renin/angiotensin blockers administered. Moreover, once these patients survive the acute insult, their long-term outcomes are better than those who developed post-PCI AKI.

Several limitations need to be addressed. Data regarding the amount of fluids given to patients was absent in the majority of patients, thus their possible effect on renal function recovery could not be determined. It is possible that in some patients, fluid administration affected the volume of distribution so that the decrease in sCr was due to hemodilution rather than improved renal function. Similarly, concomitant therapy data with statins, renin/angiotensin blockers and diuretics throughout hospitalization was not present for many patients, and their effect on AKI development could not be assessed.

Patients who developed post-PCI AKI had different baseline characteristics from the other two groups, which were almost comparable. However, the link between post-PCI AKI and poor outcomes has been well established in numerous reports.^1,,–4

Although AKI definition using the KDIGO criteria¹⁵ refers to a sCr increase compared with the baseline value, the sCr at hospital admission, as we demonstrated, may not represent a true baseline value in STEMI patients. Moreover, as we had no access to patients’ baseline sCr values prior to hospital admission and following hospital discharge it is possible that discharge sCr did not truly reflect baseline sCr levels. Finally, the definition of KDIGO refers to sCr change within a timeframe of 48 h. As the change in sCr can lag beyond this time period due to delayed effects of contrast material and drugs, worsening of renal function might have occurred following hospital discharge in some patients, thus the true incidence of post- PCI AKI described in our study may have been underestimated.

We conclude that in STEMI patients undergoing PCI, early renal impairment evident on hospital admission (prior to PCI) and which resolves towards discharge is not uncommon. In contrast to the well described post-PCI AKI, this entity is often completely reversible and has better long-term outcomes.

All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

References