The prevalence of chronic kidney disease (CKD) is increasing1 2 3 , 4 5 , 6 7–10
Treatment strategies for HF range from lifestyle changes and medical management to heart transplant or ventricular assist device (VAD) depending on the severity of HF.11 , 12
Patients with VAD implants demonstrate an improvement in kidney function, as measured by any increase in glomerular filtration rate (GFR) after implantation.13 vs. <6014 , 15 vs. <4016 17 18
Herein, we include VAD patients across the kidney function spectrum, use baseline GFR to categorize patients into CKD stages as recommended by the Kidney Disease Outcomes Quality Initiative, and define improvement in kidney function as an increase in GFR that results in a CKD stage change to one of lesser severity. Using this framework, we assess improvement in kidney function post-VAD implantation, whether the improvement in kidney function is sustained for a period of 1 year, identify predictors of kidney function improvement, and examine whether kidney function improvement is associated with a decrease in risk of thromboembolic events, hemorrhagic events, and all-cause mortality.
Materials and Methods
Study Setting
The study enrolled patients who received a VAD from 2002 to 2012 at the University of Alabama at Birmingham under the approval of the Institutional Review Board.
Inclusion and Exclusion Criteria
Patients aged 19 years and older who had a VAD (continuous-flow or pulsatile flow) placed at UAB from 2002 to 2012 were included in this study. All patients received postimplant medical care at the implanting center. Most patients received inpatient care for 2–4 weeks postimplantation. After discharge, all patients received care as outpatients at monthly intervals.
Of the 241 VAD patients eligible, 13 patients were implanted at another institution and then received follow-up care at UAB. These people were excluded because their baseline kidney function assessment at time of implantation was not available. This resulted in 228 patients in our final study sample.
Data Collection
For all patients, information including demographic variables (age at implant, self-reported race, ethnicity, etc. ), medical history before VAD (comorbid conditions, HF etiology, etc. ), and laboratory assessments was collected at baseline (pre-VAD implantation). Clinical data, including medications and laboratory assessments, were collected from each post-VAD clinic visit or hospitalization period during the 1 year follow-up period. All patients were on standard antithrombotic therapy with warfarin (dose adjusted to maintain an international normalized ratio INR goal of 2–3) and aspirin (81 or 325 mg/day). Patients were followed for 1 year post-VAD implantation or until explantation of the device, transplant, or death before 1 year. All adverse events were defined using definitions from the Interagency Registry for Mechanically Assisted Circulatory Support Registry.19
Definition of Exposure
Kidney function was assessed based on estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration Formula20
We present CKD stages as recommended by the Kidney Disease Outcomes Quality Initiative guidelines: The groups were stage 1 (eGFR ≥ 90 ml/min/1.73 m2 ), stage 2 (eGFR 60–90 ml/min/1.73 m2 ), stage 3a (eGFR 45–59 ml/min/1.73 m2 ), stage 3b (eGFR 30–44 ml/min/1.73 m2 ), stage 4 (eGFR 15–30 ml/min/1.73 m2 ), and stage 5 (eGFR < 15 ml/min/1.73 m2 ).21
Improvement in kidney function was defined as an improvement in eGFR that resulted in a CKD stage change to one of lesser severity. For example, consider two patients with eGFR of 36 at baseline. One patient’s eGFR improves to 52 ml/min whereas the second patient’s eGFR improves to 39 ml/min. While eGFR improved in both patients, in the first patient the improvement would reclassify the CKD stage from stage 3b to stage 3a.
We also assessed if improvements in eGFR were sustained over the 1 year follow-up period postimplantation. Sustained improvement was defined as improvement in CKD stage over baseline and improvement in CKD stage that was sustained over the 1 year follow-up period. Patients with CKD stage 1 or 2 at baseline who maintained kidney function within the pre-VAD CKD stage were included in the sustained improvement category as they did not have a decrease in kidney function post-VAD.
Definition of Outcomes
Outcomes of interest included thromboembolic events, hemorrhagic events, and all-cause mortality. Outcomes were determined as a documented event through review of medical records. Thromboembolic events included ischemic stroke, transient ischemic attack, pulmonary embolus, deep vein thrombosis, pump thrombosis requiring hospitalization, and mediastinal clot requiring surgical removal. Hemorrhagic events included intracranial hemorrhage, pericardial bleeding, intra-articular bleeding, gastrointestinal bleed, greater than two units of packed red blood cells administered at one time, and mediastinal bleeding requiring surgical intervention. Mortality was defined as death from any cause.
Statistical Analysis
The χ2 test of independence was used to assess group differences for categorical variables and ANOVA/Student’s t-test or Kruskal-Wallis/Wilcoxon Rank Sum where appropriate for continuous variables. Logistic regression models were used to assess predictors of sustained improvement. Cox proportional hazards models were used to evaluate the association between kidney function and thromboembolism, hemorrhage, and death. Log survival plots were used to assess the proportional hazards assumption. For mortality analysis, follow-up time was censored at time of transplant, explant (removal of the VAD device), or death. For analysis of thromboembolic or hemorrhagic event, the follow-up time was censored at the time of first event; repeated events were not considered. For patients who did not experience a thromboembolic or hemorrhagic event, follow-up time was censored at the end of the study (1 year) or explantation (if earlier than 1 year). All tests were performed using SAS version 9.2 (SAS Institute, Cary, NC) at a nondirectional alpha level of 0.05.
Results
Overall Population
Of the 241 VAD patients who were treated at UAB between 2002 and 2012, 13 patients implanted at an outside hospital were excluded because baseline kidney function information was not available. Of the 228 patients (72% men, 71% White) included in the analysis, the mean age at implant was 52 years (14.6 SD), and the majority (57%) received VAD implants as a BTT (57%). At baseline, 35.5% participants had stage 1 or 2 CKD (eGFR ≥ 60 ml/min/1.73 m2 ), 23% had stage 3a CKD (eGFR 45–59 ml/min/1.73 m2 ), 23% had stage 3b CKD (eGFR 30–44 ml/min/1.73 m2 ), 13% had stage 4 CKD (eGFR 15–29 ml/min/1.73 m2 ), and 5% had stage 5 CKD (eGFR < 15 ml/min/1.73 m2 ). No patients were on dialysis before VAD implantation. Baseline characteristics of the cohort, stratified by kidney function, are presented in Table 1 p = 0.001), and those with history of diabetes (p = 0.02), and history of hypertension (p = 0.01) who had more baseline kidney dysfunction.
Table 1.: Demographic and Clinical Characteristics for the Entire Cohort Stratified by Kidney Function Before VAD Implantation
Change in Kidney Function over Time
Within the first 14 days, a majority (56.7%; n = 130) of VAD recipients demonstrated meaningful improvement in kidney function compared with baseline kidney function (Figure 1
Figure 1.: Change in kidney function over 1 year follow up from VAD implantation. Kidney function is presented as CKD stages as recommended by the Kidney Disease Outcomes Quality Initiative guidelines using eGFR from the CKD-EPI. The groups are stage 1 (eGFR ≥ 90 ml/min/1.73 m2 ), stage 2 (eGFR 60–90 ml/min/1.73 m2 ), stage 3a (eGRF 45–59 ml/min/1.73 m2 ), stage 3b (eGFR 30–44 ml/min/1.73 m2 ), stage 4 (eGFR 15–30 ml/min/1.73 m2 ), and stage 5 (eGFR<15 ml/min/1.73 m2 ). *At 14 days, 200 patients were included and 28 patients were excluded (two patients received transplants, one patient recovered and was explanted, and 25 patients died). **At 30 days, 188 patients were included and 12 patients were excluded (12 patients died). §At 3 months, 158 patients were included and 30 patients were excluded (four patient withdrawals, two patients recovered, 11 patients had a transplant and 13 patients died). †At 6 months, 136 patients were included and 22 patients were excluded (one withdrawal, 11 patients received transplants and 10 patients died). ‡At 9 months, 121 patients were included and 15 patients were excluded (10 patients received transplants and five patients died). ¥At 12 months, 104 patients were included and 17 patients were excluded (eight patients received transplants and nine patients died). eGFR, estimated glomerular filtration rate; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration Formula.
Increasing age at implantation was inversely associated with sustained improvement in kidney function. For each year increase in age at implant, the odds of having sustained improvement in kidney function decreased by 5% (OR 0.95, 95% CI: 0.92–0.97, p < 0.0001). This association remained after adjusting for baseline CKD stage, gender, race, history of diabetes, and history of hypertension (OR 0.93, 95% CI: 0.90–0.96, p < 0.0001). Patients who sustained kidney function improvement over time were more likely to receive a heart transplant than those who did not sustain kidney function over time (28% vs. 16%, p = 0.05).
Kidney Function and Thromboembolism
There were 39 thromboembolic events over a follow-up time of 101 person-years with an incidence rate of 3.9 per 10 person years (95% CI: 2.8–5.2). Neither baseline kidney function (Table 2 p = 0.95) were associated with the risk of thromboembolic events.
Table 2.: Influence of Baseline Kidney Function on Risk (Hazard Ratio [HR] and 95% Confidence Interval [CI]) of Thromboembolism and Hemorrhage
Kidney Function and Hemorrhage
There were 58 hemorrhagic events over a follow-up time of 101 person-years with an incidence rate of 5.7 per 10 person years (95% CI: 4.4–7.4). There was no statistically significant association with baseline kidney function and risk of hemorrhagic events (Table 2 p = 0.24).
Kidney Function and Death
A total of 74 deaths occurred over a follow-up time of 153.6 person-years with an incidence rate of 4.8 per 10 person-years (95% CI: 3.8–6.0). The primary etiology of death was multiorgan failure (85%; 63 of 74 deaths). The risk of death was higher amongst patients with compromised kidney function at baseline (Table 2 p = 0.039), CKD stage 4 (HR 3.94, 95% CI: 1.29–12.0, p = 0.02), and CKD stage 5 (HR 7.24, 95% CI: 2.18–24.1, p = 0.001) had a significantly higher risk of mortality compared to those with CKD stage 1. This association persisted, even after adjustment for device type, age at implant, history of diabetes, and history of hypertension (Figure 2 p = 0.03), and four times higher for CKD stage 4 (HR 4.07, 95% CI: 1.27–13.1, p = 0.02) and stage 5 (HR 4.01, 95% CI: 1.17–13.7, p = 0.03) compared to those with CKD stage 1. Improvement in kidney function that was sustained for 1 year was not associated with a lower risk of death (HR 1.03, 95% CI: 0.58–1.84, p = 0.91).
Figure 2.: Adjusted relative risk estimates for mortality stratified by baseline CKD stage. Kidney function is presented as CKD stages as recommended by the Kidney Disease Outcomes Quality Initiative guidelines using eGFR from the CKD-EPI. The groups are stage 1 (eGFR ≥ 90 ml/min/1.73 m2 ), stage 2 (eGFR 60–90 ml/min/1.73 m2 ), stage 3a (eGRF 45–59 ml/min/1.73 m2 ), stage 3b (eGFR 30–44 ml/min/1.73 m2 ), stage 4 (eGFR 15–30 ml/min/1.73 m2 ), and stage 5 (eGFR < 15 ml/min/1.73 m2 ). Cox proportional hazards models were used to assess the adjusted risk of death. The proportional hazards assumption was met. eGFR, estimated glomerular filtration rate; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration Formula.
Discussion
Our study demonstrates that VAD implantation is associated with clinically meaningful improvement in kidney function that is sustained over 1 year for most patients. However, improvement in kidney function did not influence the risk of thromboembolism, hemorrhage, or mortality. Although patients with stage 5 CKD (baseline GFR < 15) showed improvement in kidney function over the first 3 months, the improvement was not sustained. We found that kidney function at the time of implantation increased the risk of mortality, with patients in the more advanced stages of kidney dysfunction having the highest risk of death.
Kidney function has been shown to improve after VAD implantation, but clinically significant improvement and duration of improvement has not been well characterized. Our study fills this gap by investigating long-term kidney function with detailed information on the change in CKD stage and eGFR after VAD implantation. The limited follow up in prior reports has enabled demonstration of short-term kidney function improvement. Only two studies have explored kidney function over a longer time period (Table 3 et al. illustrated improvement in eGFR postimplant to 6 months in 83 VAD patients, and Kirklin et al. illustrated improvement in serum creatinine and blood urea nitrogen (BUN) up to 2 years postimplant in 4,917 VAD patients.15 , 20–23 Figure 1 provides another facet and timeline of changing kidney function post-VAD implantation. Our findings confirm previous observations that kidney function improves after VAD implantation and demonstrates that the improvements are clinically meaningful and sustained. However, among patients with stage 5 CKD at baseline, the improvements are only temporal and not as sustained as previously hypothesized.
Table 3.: Prior VAD Studies that Investigate Kidney Function post-VAD Implantation and the Relationship Between Kidney Function and Mortality
The greatest improvements in kidney function are realized early, in the first 14 days postimplant, as organ perfusion is increased. Although improvements in kidney function are sustained, early gains in eGFR are attenuated after 14 days. Therefore, gain in kidney function after 14 days may more closely represent the organ capacity that was previously masked due to poor kidney perfusion in these patients with poor cardiac function.
Decreased kidney function is the most common contraindication to heart transplantation.24 vs. inotrope support) have better kidney function at time of transplantation.25
In our study, neither baseline kidney function nor improvement in kidney function was associated with thromboembolism or hemorrhage. This is contrary to reports from VAD14 23 , 26–28
Decreased kidney function before VAD implant was associated with higher mortality consistent with recent reports.14 , 29
While previous studies have illustrated the influence of pre-VAD kidney function on post-VAD mortality, these studies have primarily assessed eGFR, creatinine and BUN as continuous measures, and their subsequent association with mortality. Consistent with previous studies, poor kidney function pre-VAD is associated with a higher mortality rate.14 , 22 , 29 et al. have demonstrated clinically meaningful differences in mortality among the two groups.30
The study has several strengths including a large (n = 228) sample size, a racially diverse population, uniformity of care at a single institution, detailed clinical documentation, and ascertainment of clinically relevant events. Moreover, only four patients transferred care out-of-state. Therefore, we could not ascertain their status for this analysis. Kidney function was assessed at multiple time points, and improvement in kidney function is defined using a clinically relevant rubric. However, we recognize its limitations such as lack of ascertainment of biomarkers. We also recognize our findings from this retrospective and single-center study may not be generalizable to larger VAD populations. Using CKD staging to characterize baseline kidney dysfunction may misclassify patients as having kidney disease when the kidney dysfunction could be due to acute kidney injury instead of CKD. We did not assess whether there is an association between right ventricular dysfunction or infections and kidney dysfunction. We recognize that this is a single-center study. Therefore, independent validation of our findings in larger datasets is needed to confirm our findings.
Regardless of baseline kidney function, most patients experience an improvement in kidney function after VAD implantation. Regardless of the improvement in kidney function post-VAD implant, risk of mortality is driven by baseline kidney function. Patients with CKD stage 3b, 4, or 5 before VAD are at an increased risk of mortality post-VAD implantation. This has important implications on patient selection during evaluation for VAD therapy. Further research is needed to establish whether patients with decreased kidney function due to advancing HF would benefit from earlier implantation of a VAD to reduce the mortality associated with advancing kidney dysfunction.
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